Journal of pharmaceutical sciences最新文献

{"title":"Microfluidic blood-milk barrier and physiologically based pharmacokinetic model to predict lofexidine secretion into breast milk","authors":"Sanat Kumar Dash ,&nbsp;Mohammad Asikur Rahman ,&nbsp;Bofang Yi ,&nbsp;Brianna Williams ,&nbsp;Gi S. Lim ,&nbsp;Sindi Zhou ,&nbsp;Peng Zou ,&nbsp;Yanyan Li ,&nbsp;Gretchen J. Mahler ,&nbsp;Tao Zhang","doi":"10.1016/j.xphs.2025.103767","DOIUrl":"10.1016/j.xphs.2025.103767","url":null,"abstract":"<div><h3>Introduction</h3><div>Lofexidine (LUCEMYRA®) is the only FDA-approved, non-opioid, non-addictive treatment for opioid withdrawal symptoms, crucial for postpartum and pregnant women affected by the opioid crisis. Despite its clinical importance, data on its secretion into breast milk is limited. This study aims to develop a novel, microfluidic-based blood-milk-barrier on a chip model, a static human mammary cell transwell model, and a physiologically based pharmacokinetic (PBPK) lactation model to estimate the breast milk secretion of lofexidine, thereby ensuring maternal and infant safety and improving withdrawal management.</div></div><div><h3>Methods</h3><div>A novel microfluidic device was developed to build a mammary epithelium-on-a-chip model, and a transwell plate was used to develop a static mammary epithelium using a human noncarcinogenic mammary epithelial cell (MEC) population that can form an integrated barrier with tight junctions. Both models were used to evaluate the transfer of lofexidine through the in vitro mammary cell barrier. The fraction of unbound lofexidine in the breast milk was determined by a Rapid Equilibrium Dialysis (RED) assay. Eleven approaches, including a novel, previously published in vitro to in vivo extrapolation (IVIVE) approach and various other approaches, were used to estimate milk-to-plasma (M/P) ratios of lofexidine. A whole-body lactation PBPK model was built using Simcyp® simulator v22 and used to predict the concentration-time profiles of lofexidine in both human plasma and breast milk.</div></div><div><h3>Results</h3><div>A subpopulation of human normal mammary epithelial MCF10A cells (named MCF10A-TJ) was identified to form an integrated barrier that reaches trans-epithelial electrical resistance (TEER) values of over 1000 Ω·cm² by culturing with in-house designed maintenance and boosting medium. The microfluidic device-based mammary epithelium-on-a-chip model generated slightly higher lofexidine permeability values than the static transwell mammary epithelial cell model. The predicted milk-to-plasma (M/P) ratio of lofexidine ranged from 0.40 to 15.88. Four approaches estimated an M/P ratio below 1, while seven predicted values above 1, mostly between 1.35 and 5.48. The whole-body lactation PBPK model predicted the concentration-time profile of lofexidine in breast milk, with an estimated M/P ratio of approximately 2.0. This value falls within the mid-range of the predictions obtained from all eleven methods.</div></div><div><h3>Conclusion</h3><div>This study introduces comprehensive and novel approaches to predict lofexidine secretion into breast milk. Most predictions suggest higher lofexidine concentration in milk than in plasma, raising potential safety concerns for opioid withdrawal management. Further pharmacokinetic clinical lactation studies are needed to validate these predictions.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103767"},"PeriodicalIF":3.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670182","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":"Procedural modifications proposed for the screening of substances extracted from pharmaceutical packaging systems and medical devices with the goal of improving inter-laboratory consistency of the data generated","authors":"Steven A. Zdravkovic ,&nbsp;Samuel Kikandi ,&nbsp;Qiang Fu ,&nbsp;Bhargava Jana ,&nbsp;Jason Creasey ,&nbsp;Aaron Flick ,&nbsp;Lee Nagao ,&nbsp;Mary Kate Bielinski","doi":"10.1016/j.xphs.2025.103764","DOIUrl":"10.1016/j.xphs.2025.103764","url":null,"abstract":"<div><div>Substances that migrate (<em>leachables</em>) into a pharmaceutical product from the materials that comprise its manufacturing, packaging, and/or delivery system(s) have the potential to negatively impact its safety and/or quality. Mitigating the impact of this interaction typically includes the screening of substances that can be extracted (<em>extractables</em>) from these materials using appropriate solvents and exposure conditions. Despite the importance of such extractable screening studies in assuring product quality and patient safety, it has become apparent that inconsistencies in their execution between laboratories have resulted in the potential for differences in the qualitative and/or quantitative aspects of the extractable profiles obtained. Since this issue was discovered primarily through anecdotal accounts, a working group within ELSIE conducted two industry surveys that inquired into impactful variables of extractable screening study design and execution. After completion of these surveys, it was concluded that there were numerous variables where labs were not well aligned, which may be impacting the consistency of the data generated to some extent. To that end, this commentary summarizes recommendations proposed by the ELSIE working group to address the discrepancies in extractable study design and ultimately produce more consistent and reliable extractable profiles between laboratories.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 5","pages":"Article 103764"},"PeriodicalIF":3.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674094","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":"Thermodynamic analysis of synergistic effect of cyclodextrins and electrolytes on the solubility of aromatic amino acids.","authors":"Maame Esi Baidoo, Jonghoon Kang","doi":"10.1016/j.xphs.2025.103762","DOIUrl":"10.1016/j.xphs.2025.103762","url":null,"abstract":"","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103762"},"PeriodicalIF":3.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670184","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":"Response with statistical assessment to \"Thermodynamic analysis of synergistic effect of cyclodextrins and electrolytes on the solubility of aromatic amino acids\".","authors":"Masakazu Fukuda, Kanako Takahashi, Toru Takarada, Shunsuke Saito, Masafumi Tanaka","doi":"10.1016/j.xphs.2025.103763","DOIUrl":"10.1016/j.xphs.2025.103763","url":null,"abstract":"","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103763"},"PeriodicalIF":3.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670183","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":"Editorial Advisory Board","authors":"","doi":"10.1016/S0022-3549(25)00215-1","DOIUrl":"10.1016/S0022-3549(25)00215-1","url":null,"abstract":"","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 4","pages":"Article 103757"},"PeriodicalIF":3.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642522","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":"Ternary Lipids-based Novel Thermoresponsive Lipid Nanoparticles for Targeting Doxorubicin to Breast Cancer Cells.","authors":"Maryam Anwar, Mubashar Rehman, Tofeeq Ur-Rehman, Muhammad Imran Khan, Naveed Ahmed, Asadullah Madni, Muhammad Tayyab","doi":"10.1016/j.xphs.2025.103723","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103723","url":null,"abstract":"<p><p>Conventional thermoresponsive liposomes have failed to meet cancer targeting potential due to poor safety profile, unpredictable fate, and low therapeutic response in clinical studies. Recently, we reported phase-change nanostructured lipid carriers, termed thermoresponsive lipid nanoparticles (TLNs), for targeting cancer cells under hyperthermia. Herein, we have prepared ternary eutectic mixtures of myristic, stearic, and palmitic acid at a ratio of 2.5:1:1.5 yielded a melting point or solid-liquid phase transition temperature of 41°C. Doxorubicin (DOX)-loaded TLNs were fabricated and optimized using Box-Behnken Design Expert® software and exhibited desirable particle size (191.7±2.88 nm), polydispersity index (0.213±0.025), zeta-potential (-21.2±2.29 mV), spherical shape, high entrapment efficiency (92.24±1.05), and desirable physicochemical stability. In-vitro drug release studies showed hyperthermia-aided abrupt DOX release within 2 hours at 41°C and 43°C while sustained drug release pattern for 12 hours at 37°C. In-vitro cytotoxicity studies of TLN also exhibited the highest breast cancer (MCF-7) cells killing at hyperthermia (41°C), more than 3-fold compared to 37°C and free DOX solution. A 23-fold higher cell uptake in breast cancer cells further confirmed that ternary eutectic mixture-based DOX-loaded TLNs are an excellent candidate for breast cancer targeting and may be preferred over other nano-carriers due to the feasible preparation and superior stability.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103723"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663718","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":"Predictive dissolution modeling across USP apparatuses I, II, and III.","authors":"Alexander M Kubinski, Ricardo D Sosa, Gayathri Shivkumar, Reuben Georgi, Susan George, Eric J Murphy, Tzuchi R Ju","doi":"10.1016/j.xphs.2025.103765","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103765","url":null,"abstract":"<p><p>Dissolution testing provides in vitro drug release characterization and serves a critical role in the development of solid oral dosage forms. The most common dissolution apparatuses are the USP apparatuses I and II, for which in silico tools have been previously developed for predictive dissolution modeling (PDM). While apparatuses I and II serve the greater volume of projects, apparatus III offers higher agitation levels and multivessel capabilities, which is critical for certain projects, and the physics of which have not been previously characterized. To mitigate that knowledge gap, the present work characterizes the transport physics and thermodynamics of dissolution apparatus III, such that a 1-D model is established and validated which scales release kinetics with agitation level across apparatuses I, II, and III. The resulting PDM is calibrated with at least two dissolution experiments at different agitation levels, for a particular formulation-medium combination, after which release kinetics are predicted within the design spaces of the three apparatuses. Calibration data can come from experiments using a single apparatus or different apparatuses, while still predicting across all three apparatuses. Erosion-based formulations are used for validation. Additionally, apparatus III vessel residence time analysis is demonstrated.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103765"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663712","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":"Streamlining Viral Safety in AAV Manufacturing: Simultaneous Cell Lysis and Viral Inactivation Using Biodegradable Detergents.","authors":"Tuhidul Islam, Jungmin Oh, Lori Fortin, Courtney Connors, Nandkumar Deorkar","doi":"10.1016/j.xphs.2025.103761","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103761","url":null,"abstract":"<p><p>Ensuring viral safety in biopharmaceutical production is vital for global regulatory standards adherence and safeguarding patients. This study evaluates the efficacy of newly developed biodegradable detergent formulations, designed to comply with regulatory requirements, for inactivating enveloped viruses during the cell lysis step of adeno-associated virus (AAV) production. Virus clearance (VC) studies showed robust inactivation kinetics against Xenotropic Murine Leukemia Virus (XMuLV), achieving a log reduction value (LRV) of ≥5.34 within 30 to 120 minutes. Comparative testing in crude cell lysate and PBS buffer showed consistent viral inactivation across different matrices, highlighting the versatility of the detergent formulations. Importantly, the detergent composition preserved AAV capsid integrity, and subsequent purification steps, including affinity and ion-exchange chromatography, effectively removed residual detergent. Overall, this study demonstrates the potential of biodegradable detergents to simultaneously facilitate cell lysis and viral inactivation in AAV manufacturing, offering a sustainable alternative that aligns with industry standards.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103761"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663715","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":"Rational cyclodextrin formulation design through insights into drug release mechanism in the gastrointestinal tract via molecular dynamics simulations","authors":"Hao Zhong ,&nbsp;Wei Wang ,&nbsp;Ruifeng Wang ,&nbsp;Aixin Han ,&nbsp;Xianfeng Chen ,&nbsp;Defang Ouyang","doi":"10.1016/j.xphs.2025.103760","DOIUrl":"10.1016/j.xphs.2025.103760","url":null,"abstract":"<div><div>Cyclodextrin formulations are crucial for enhancing the solubility of drugs. Bile salts are recognized as potential agents for displacing drugs from cyclodextrin formulations in intestinal fluids. However, the mechanism underlying this displacement remains unclear. This study aims to investigate the mechanism of competitive displacement using molecular dynamics simulations and to develop guidelines for effective cyclodextrin formulation design. The umbrella sampling method is employed to investigate the binding free energy between bile salts and cyclodextrin molecules, while metadynamics is utilized to simulate the dynamic replacement process. The results indicate that the optimal binding free energy interval between cyclodextrins and drugs ranges from -30 kJ/mol to -8 kJ/mol. Additionally, the optimal concentration ratio between drugs and cyclodextrins can be calculated based on the binding free energy. Displacement simulations showed that free single bile salt molecules are more likely to complete the displacement compared to clusters of bile salts. This suggests that the bioavailability of cyclodextrins may be higher in fasting conditions than in the fed state. This study will not only enhance our understanding of the relationships between cyclodextrin formulations and bile salts but also facilitate the rational design of more effective pharmaceutical formulations.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 5","pages":"Article 103760"},"PeriodicalIF":3.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639575","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":"Liposomal formulation co-encapsulating α-tocopheryl succinate and α-tocopherol ameliorates high-fat diet-induced obesity","authors":"Yuika Seto ,&nbsp;S. M. Tafsirul Alam Tapu ,&nbsp;Natsuho Kugisaki ,&nbsp;Shintaro Yoneda ,&nbsp;Naoshi Yamazaki ,&nbsp;Kentaro Kogure","doi":"10.1016/j.xphs.2025.103724","DOIUrl":"10.1016/j.xphs.2025.103724","url":null,"abstract":"<div><div>Lipid accumulation inhibition is a pivotal focus for anti-obesity drugs. α-Tocopheryl succinate (TS) is a derivative of α-tocopherol (T) that inhibits lipid accumulation, making it a propitious candidate for an anti-obesity agent. However, cytotoxicity of TS limits its application. Reactive oxygen species produced by TS are responsible for the cytotoxicity, which can be mitigated by T. Herein, we evaluated the effect of a liposomal formulation co-encapsulating TS and T (TS/T-lipo) on obesity. We prepared TS/T-lipo and evaluated the resultant cytotoxicity and lipid accumulation inhibition effect in vitro. TS/T-lipo showed a significant inhibitory effect on lipid accumulation without cytotoxicity. The inhibitory effect on lipid accumulation is likely due to upregulation of Uncoupling Protein 1, which causes lipid consumption. Moreover, we evaluated the effect of TS/T-lipo on a high-fat diet-induced obese mouse model and found that body weight significantly decreased in the TS/T-lipo group without elevation of liver toxicity or blood glucose levels. Additionally, increased glycerol serum levels are suggestive of increased lipolysis upon treatment with TS/T-lipo. Histological analysis supports inhibition of lipid accumulation by treatment with TS/T-lipo. Taken together, this evidence demonstrates that co-administration of TS/T can reduce cytotoxicity and may be a promising candidate for an anti-obesity drug.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 5","pages":"Article 103724"},"PeriodicalIF":3.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634062","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}