Pharmaceutical Research最新文献

{"title":"Alternative Techniques for Porous Microparticle Production: Electrospraying, Microfluidics, and Supercritical CO₂.","authors":"Simon Pöttgen, Christian Wischke","doi":"10.1007/s11095-025-03923-2","DOIUrl":"10.1007/s11095-025-03923-2","url":null,"abstract":"<p><p>Microparticles have been established as injectable drug carriers designed to enable a long-term release of the encapsulated active pharmaceutical ingredients (API). To regulate this release, the diffusion barrier provided by the matrix material - typically hydrolytically degradable polyesters - must be controlled through precise levels of matrix porosity. This mini-review presents processing methods that are alternatives to the most common batch emulsification techniques for the manufacturing of porous polymer particles. A focus is placed on mechanistically describing the particle and pore formation in droplet-based microfluidics, electrospraying, and by supercritical fluids, critically discussing their opportunities and challenges. Ultimately, this review assesses the potential of these techniques in advancing the engineering of porous polymeric carrier systems in the light of scale-up and continuous production.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1461-1480"},"PeriodicalIF":4.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041063","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":"Physiological Considerations and Delivery Strategies for Targeting Tumors Through Intraperitoneal Delivery.","authors":"Md Jobair Hossen Jony, Sheyda Ranjbar, Rama Prajapati, Seyyed Majid Eslami, Zixuan Zhen, Mittal Darji, Xueli Zhu, Xiuling Lu","doi":"10.1007/s11095-025-03917-0","DOIUrl":"https://doi.org/10.1007/s11095-025-03917-0","url":null,"abstract":"<p><p>The peritoneal cavity presents both unique challenges and promising opportunities for targeted therapy in malignancies like ovarian, gastric, pancreatic, and colorectal cancers. Intraperitoneal drug delivery offers significant pharmacokinetic advantages over intravenous administration by achieving high local drug concentrations and tumor-specific delivery potential while minimizing systemic toxicity. Despite these theoretical advantages, the clinical implementation of intraperitoneal therapy is limited by several barriers, including restricted tissue penetration, incomplete peritoneal coverage, rapid drug clearance, catheter-related complications, posttreatment peritoneal adhesions, and ascites-induced permeability dysregulation. This review highlights three advanced strategies developed to overcome these obstacles: (1) particulate-based delivery systems, such as nanoparticles to enhance tumor specificity through passive accumulation, active targeting and on-demand drug release in response to internal or external stimuli; (2) Sustained drug release hydrogels and (3) pressurized intraperitoneal aerosol chemotherapy. Despite promising preclinical and clinical advancements, successful translation requires systematic optimization of multiple parameters, such as ascites dynamics, tumor heterogeneity, and multidrug resistance. The integration of advanced delivery technologies with a comprehensive understanding of peritoneal physiology remains crucial for achieving safe and effective clinical applications.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144964779","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":"Fragment-Based Screening Identifies Novel Non-Amino Acid Inhibitors of the Sodium-Coupled Neutral Amino Acid Transporter SNAT2.","authors":"Sebastian Jakobsen, Carsten Uhd Nielsen","doi":"10.1007/s11095-025-03902-7","DOIUrl":"10.1007/s11095-025-03902-7","url":null,"abstract":"<p><strong>Introduction: </strong>Amino acid transporters like the sodium-coupled neutral amino acid transporter 2 (SNAT2, SLC38A2) have gained interest for their roles in, e.g., the central nervous system and in cancer. Efforts in discovering inhibitors against these transporters often result in amino acid-based inhibitors that lack selectivity and are likely to compete with amino acid substrates to bind their targets. To circumvent this, we aimed to discover novel non-amino acid inhibitors of SNAT2 by screening a library of fragment-sized compounds.</p><p><strong>Methods: </strong>320 fragment compounds were screened for their inhibition of ³H-Gly uptake in hyperosmotically upregulated SNAT2-expressing PC-3 cells. The top five hits were studied further for their inhibitory potency and structure-activity relationship (SAR). Their ability to be translocated by SNAT2 was studied using the FLIPR membrane potential (FMP) assay, as well as their mechanism of inhibition.</p><p><strong>Results: </strong>The screen revealed two similar scaffolds that showed SNAT2 inhibition, namely 1,3-benzothiazole-2-amine and 1,3-benzoxazole-2-amine. The SAR revealed how hydrophobic substituents at specific positions were needed for the structures to show SNAT2 inhibition. The best inhibitors inhibited SNAT2 with IC₅₀s in the range of 0.64-1.08 mM. Many of the fragment compounds showed an apparent hyperpolarization in the FMP assay, making it difficult to determine their ability to be translocated by SNAT2. An allosteric mechanism of inhibition was implied for the thiazole and oxazole scaffolds, as these resulted in inhibition patterns that resembled non- or un-competitive inhibitors.</p><p><strong>Conclusion: </strong>In conclusion, we discovered multiple novel non-amino acid compounds that inhibited SNAT2 and can serve as starting points for the further development of SNAT2 inhibitors.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1285-1297"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799914","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":"Cancer-specific Regulation of Metabolic and Epigenetic Pathways by Dietary Phytochemicals.","authors":"Yuxin Pan, Rebecca Mary Peter, Pochung Chou, Parv Dushyant Dave, Jiawei Xu, Ahmad Shanner, Md Shahid Sarwar, Ah-Ng Kong","doi":"10.1007/s11095-025-03898-0","DOIUrl":"10.1007/s11095-025-03898-0","url":null,"abstract":"<p><strong>Background: </strong>Cancer is a complex disease triggered by a combination of genetic mutations, metabolic reprogramming, epigenetic modifications, and environmental factors, and is one of the leading health burdens worldwide. Dietary phytochemical are effective in reducing the incidence of cancer by regulating epigenetic and metabolic pathways and possess great potential in cancer prevention and treatment.</p><p><strong>Objectives: </strong>This review aims to summarize the relevant metabolic and epigenetic changes in cancer, recent research progress in the mechanism study of dietary phytochemicals by regulating key pathways and provides new insights for further research.</p><p><strong>Methods: </strong>We searched the relevant literature by searching through common databases, such as PubMed, Medline, ScienceDirect, Google Scholar and Web of Science, and summarized the anticancer effects of potential dietary phytochemicals regulating epigenetic and metabolic pathways in common cancers, such as colorectal cancer, prostate cancer, lung cancer, skin cancer, and breast cancer.</p><p><strong>Results: </strong>Natural phytochemicals not only regulate key pathways, such as DNA methylation, histone modifications, oxidative stress, inflammation, and metabolic reprogramming, but also demonstrate multi-targeted intervention in tumor therapy by inducing apoptosis, inhibiting cell proliferation, angiogenesis, and metastasis. Additionally, the potential of dietary phytochemicals to reverse metabolic and epigenetic changes makes them promising as adjunctive or alternative therapies.</p><p><strong>Conclusion: </strong>Phytochemicals exhibit significant effects in cancer prevention and treatment by targeting metabolic and epigenetic regulatory networks. Future research should further explore their mechanisms, clinical translational value, and synergistic effects with traditional therapies to provide theoretical foundations and practical guidance for developing new cancer intervention strategies.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1443-1457"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785006","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":"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":"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":"1331-1345"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","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":"Assessment of Minipigs as a Non-clinical Model for Screening and Derisking Injection Site Reactions in Clinical Trials.","authors":"Kaoutar Abbou Oucherif, Shiven Kapur, Ronghua Bei, Shawn Berens, Patricia L Brown-Augsburger","doi":"10.1007/s11095-025-03907-2","DOIUrl":"10.1007/s11095-025-03907-2","url":null,"abstract":"<p><strong>Purpose: </strong>Injection site reactions (ISRs), including edema, erythema, pruritus, and pain, impact patient experience and drug tolerability. ISRs are commonly observed and pose challenges in therapeutic development, yet no non-clinical model exists for screening and derisking them before human trials. To fill in this gap, we sought to evaluate the minipig as a non-clinical model for ISRs.</p><p><strong>Methods: </strong>The minipig model was assessed using six ISR-inducing molecules (positive controls) and two placebos with matching formulations (negative controls). Additionally, to evaluate the physiological similarity between minipigs and humans, we tested whether antihistamine pre-treatment, which is known to reduce ISRs in humans, had a similar effect in minipigs.</p><p><strong>Results: </strong>The minipig model consistently responded to all six positive control molecules, though at higher doses than in humans. Minor ISRs occurred in a quarter of the negative controls but their frequency and/or severity was easily distinguishable from positive controls. Antihistamine pre-treatment effectively reduced ISR severity.</p><p><strong>Conclusion: </strong>Our results suggest that the minipig model shows promise for non-clinical screening of high-risk molecules. If a molecule consistently triggers ISRs in the minipig model, phase-appropriate derisking and/or mitigation strategies are warranted. We note that the minipig model is often used for other purposes during pre-clinical subcutaneous drug development; therefore, adding ISR readouts to existing studies would incur minimal operational burden and cost. In summary, our results indicate the potential value of the minipig model in pre-clinical ISR risk assessment.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1307-1314"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822264","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":"10.1007/s11095-025-03895-3","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1459"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","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":"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":"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":"1385-1396"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405019/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Numerical Investigation to Improve Pulmonary Drug Delivery via Dry Powder Inhalers: A Review of In-Silico Modeling.","authors":"Salar Salmanipour, Sasan Salmani Pour Avval, Kiao Inthavong, Hamed Hamishehkar","doi":"10.1007/s11095-025-03906-3","DOIUrl":"10.1007/s11095-025-03906-3","url":null,"abstract":"<p><p>This review focuses on the application of computational fluid dynamics (CFD) in pulmonary drug delivery, particularly for treating asthma and COPD with pharmaceutical aerosols via dry powder inhalers (DPIs). Aerosol drug delivery effectiveness relies on accurate assessment and prediction of particle deposition in the respiratory system. This method is crucial due to the high number of pulmonary disease cases, efficient lung absorption capabilities, lower dosage required, and reduced systemic side effects compared to oral medications. Given the limits of in vivo and in vitro methods, CFD modeling has advanced rapidly over 20 years, especially when combined with discrete phase model (DPM) and discrete element method (DEM) approaches. CFD simulations can correctly account for a wide range of realistic or idealized parameters using numerical solutions of particle and airflow transport equations. Achieving accurate simulations requires avoiding simplifications and approximating real-world conditions, which will soon be more possible with advancing computing tools. The research aims to review numerical modeling of pulmonary drug delivery along the mouth-to-lung pathway, encompassing governing equations, forces, boundary conditions, the influence of lung geometry on CFD modeling, the effects of powder characteristics on aerosolization and pulmonary deposition, validation of computational results with in vitro/in vivo data, and a discussion of current challenges and future prospects.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1251-1283"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855972","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":"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":"1347-1362"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","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}