Journal of pharmaceutical sciences最新文献

{"title":"Revealing the pore structure variance of lyophilized cakes from microcollapse, controlled ice nucleation, and protein concentration changes","authors":"Lisa Ma ,&nbsp;Lokesh Kumar ,&nbsp;Fredric Lim ,&nbsp;Shawn Zhang ,&nbsp;Jeffrey Wong ,&nbsp;Phillip D. Yawman ,&nbsp;Debby Chang","doi":"10.1016/j.xphs.2025.103775","DOIUrl":"10.1016/j.xphs.2025.103775","url":null,"abstract":"<div><div>This study investigates the application of X-ray microscopy (XRM) as an advanced characterization tool for optimizing lyophilization cycles in pharmaceutical formulations. Utilizing non-invasive, high-resolution imaging, XRM provided comprehensive insights into the macro- and microstructural features of lyophilized cakes, revealing distinct differences attributable to lyophilization processing. High primary drying temperatures and aggressive conditions led to microstructural alterations, including fractures and microcollapse, while conservative drying methods resulted in more uniform and homogeneous structure. The controlled ice nucleation (CIN) process notably enhanced sublimation rates by forming extensive macroporous zones. Calibrated intensity analysis via XRM detected variations in solid content, and high-resolution imaging highlighted subtle microstructural differences among samples, contributing to a deeper understanding of cake properties. Surface area measurements obtained from XRM showed a strong correlation with conventional BET analysis, validating its quantitative accuracy. Additionally, simulated diffusivity derived from XRM data correlated well with dry layer resistance values from thermocouple measurements, underscoring its utility in evaluating mass transport behaviors. XRM's non-destructive nature and detailed imaging capabilities make it a valuable complementary tool to existing characterization techniques, enabling more efficient cycle development and optimization.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103775"},"PeriodicalIF":3.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753217","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":"Bioorthogonal catalytic microvesicle-mediated prodrug activation against liver cancer","authors":"Xiaotian Wan ,&nbsp;Xiyu Liu ,&nbsp;Pan Wu ,&nbsp;Yongmei Li,&nbsp;Yuanyuan Shi,&nbsp;Yueli Nie,&nbsp;Keyong Zhang,&nbsp;Ze Jin,&nbsp;Ruiyun Song,&nbsp;Zhikun Zhang,&nbsp;Lu Gan,&nbsp;Jian He","doi":"10.1016/j.xphs.2025.103774","DOIUrl":"10.1016/j.xphs.2025.103774","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;Exploring the role and mechanism of a novel bioorthogonal system using transition metals as catalysts in the treatment of hepatocellular carcinoma (HCC).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Initially, a catalytic ruthenium (Ru) complex and the substrate alloc-RH 110 were synthesized, followed by the identification of their structures utilizing mass spectrometry and nuclear magnetic resonance (NMR) techniques. The catalytic efficacy of the Ru complex was then assessed using a fluorescence spectrophotometer. Subsequently, employing HepG2 cells as the cellular source, cell-derived vesicles encapsulating the Ru complexes, designated as EVs@Ru, were prepared. The EVs@Ru were characterized by measuring their particle size and Zeta potential, observing morphological features under transmission electron microscopy (TEM), and detecting specific protein expressions via Western blot analysis. Drug loading within the EVs@Ru was quantified using inductively coupled plasma mass spectrometry (ICP-MS), and their catalytic efficiency was evaluated. In vitro, the low-activity prodrug alloc-DOX was synthesized and its toxicity, along with the drug concentration in EVs@Ru, was determined. Further, the catalytic cytotoxicity of alloc-DOX against HepG2 cells encapsulated in EVs@Ru was analyzed through microscopic observation, CCK-8 assays, and apoptosis experiments. For in vivo studies, a tumor-bearing mouse model was established using human liver cancer HepG2 cells to observe the antitumor effects. Finally, the primary organs of each group of tumor-bearing mice were assessed for in vivo safety.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;ESI-MS and 1H NMR confirmed the accurate structure of Ru complexes and alloc-RH 110. The Ru complexes achieved full catalytic conversion of alloc-RH 110 within 24 hours. EVs and EVs@Ru exhibited particle sizes of ∼116.85 nm and ∼281.88 nm, respectively, with Zeta potentials of ∼-20.86 mV and ∼-25.89 mV, both appearing quasi-circular under TEM. WB analysis verified the presence of vesicle-specific marker proteins in both, confirming their cell-derived nature. ICP-MS determined a drug loading of 21.90 μg/mL for EVs@Ru, with an encapsulation efficiency of ∼24.86%. Fluorescence spectrophotometry demonstrated 100% catalytic efficiency for EVs@Ru. Synthetic alloc-DOX validated by 1H NMR and ESI-MS matched literature data. MTT and CCK-8 assays confirmed low toxicity for alloc-DOX and Ru complexes, setting the experimental drug concentration at 4μM. In vitro, the EVs@Ru+alloc-DOX group exhibited potent HepG2 cell killing and apoptosis. In vivo, this group significantly inhibited tumor growth in tumor-bearing mice, with no observed toxicity to vital organs, indicating good biosafety.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;The integration of bio-derived microvesicles (MVs) with transition metal catalysts has resulted in a biologically orthogonal system for efficient Ru complex delivery to tumor sites. This system facilit","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103774"},"PeriodicalIF":3.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753214","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":"Navigating ICH Q2(R2) compliance in analytical method validation: A gap analysis toolkit to streamline risk assessment and change management","authors":"Brianna Cassidy ,&nbsp;Timothy Bloomingdale ,&nbsp;Judy Carmody","doi":"10.1016/j.xphs.2025.103749","DOIUrl":"10.1016/j.xphs.2025.103749","url":null,"abstract":"<div><div>The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) officially adopted Q2(R2) and Q14 as harmonized guidelines on November 1, 2023. Updated guidance for validating analytical methods is provided in Q2(R2), while Q14 introduces, for the first time, comprehensive guidance on the development of analytical methods. Multiple regulatory authorities have officially incorporated Q2(R2) and Q14, and many others are in the process. However, a detailed list of differences between Q2(R1) and Q2(R2) has yet to be made available. The toolkit presented here is designed to streamline risk assessment and change management efforts for updating systems based on long-established Q2(R1) guidance; 56 specific omissions, expansions, and additions are identified, and a process for navigating these changes is proposed. Suggestions for improving Q2(R2) and related chapters (including Q7, <em>Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Guidance for Industry</em>) are also discussed. Given the close relationship between analytical method development and validation, many aspects of Q14 are included in Q2(R2) and are therefore described here.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103749"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro characterization of SLCO2B1 genetic variants","authors":"Alli Sinokki ,&nbsp;Annika Miinalainen ,&nbsp;Saara Kivioja ,&nbsp;Wilma Kiander ,&nbsp;Kati-Sisko Vellonen ,&nbsp;Madhushree Bhattacharya ,&nbsp;Mikko Gynther ,&nbsp;Kristiina M. Huttunen ,&nbsp;Seppo Auriola ,&nbsp;Mikko Niemi ,&nbsp;Heidi Kidron","doi":"10.1016/j.xphs.2025.103772","DOIUrl":"10.1016/j.xphs.2025.103772","url":null,"abstract":"<div><div>OATP2B1, encoded by <em>SLCO2B1</em>, is a drug transporter expressed widely throughout the body in tissues such as the intestine and liver. Genetic variation of this transporter may lead to altered disposition of OATP2B1 substrate drugs, but especially the effects of rare variants are poorly understood. The aim of this study was to characterize the effects of naturally occurring missense single nucleotide variants of <em>SLCO2B1</em> (c.601G&gt;A, c.935G&gt;A, c.953C&gt;T, c.1175C&gt;, c.1457C&gt;T, c.1559G&gt;C, c.1596C&gt;A, and the c.601G&gt;A + c.935G&gt;A haplotype) on the <em>in vitro</em> functionality of OATP2B1. To characterize transport activity, cellular uptake of dibromofluorescein, 5-carboxyfluorescein, estrone sulfate, and rosuvastatin was compared in OATP2B1 reference- and variant-expressing HEK293 cells. The abundance of OATP2B1 variants in HEK293 crude membrane preparations was quantified with LC-MS/MS-based quantitative targeted absolute proteomics analysis. Variant c.1559G&gt;C impaired OATP2B1-mediated uptake of all tested substrates almost completely, but protein abundance was not reduced to the same extent. Other studied variants had comparable or only modestly reduced protein abundance and transport function compared to reference OATP2B1. These results can be utilized to understand findings from clinical pharmacogenetic studies. More importantly, the results can aid in predicting the consequences of rare variants, such as the loss-of-function variant c.1559G&gt;C, which can be difficult to detect in clinical studies.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103772"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742134","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":"Enhancing the solubility and bioavailability of itraconazole through pharmaceutical cocrystallization: A promising strategy for drug formulation","authors":"Meet Chhatbar ,&nbsp;Chetan Borkhataria ,&nbsp;Om Patel ,&nbsp;Komal Raichura ,&nbsp;Trupesh Pethani ,&nbsp;Ghanshyam Parmar ,&nbsp;Dhaval Mori ,&nbsp;Ravi Manek","doi":"10.1016/j.xphs.2025.103770","DOIUrl":"10.1016/j.xphs.2025.103770","url":null,"abstract":"<div><div>Itraconazole, a potent antifungal agent, is classified as a Biopharmaceutics Classification System (BCS) Class II drug, exhibiting high permeability but poor aqueous solubility, which significantly limits its bioavailability and therapeutic efficacy. Conventional solubility enhancement techniques such as salt formation, particle size reduction, and encapsulation have shown limited success due to the drug's non-ionizable nature and pH-dependent solubility. Cocrystallization has emerged as a promising pharmaceutical strategy to address these limitations by modifying the crystal lattice structure through non-covalent interactions with pharmaceutically acceptable co-formers. This study explores the formulation of Itraconazole cocrystals with various co-formers to enhance its solubility, dissolution rate, and micromeritic properties, thereby improving its processability in solid dosage forms. The optimized cocrystal formulation (B16) demonstrated a 2.4-fold increase in solubility in 0.1 N HCl (60.47 ± 2.7 µg/mL) and a 25.77-fold increase in phosphate buffer (pH 6.8, 60.57 ± 5.64 µg/mL) compared to pure Itraconazole. The dissolution rate was also significantly improved, with 40.12% drug release in 120 minutes in acidic medium, compared to 32.65% for pure Itraconazole. Furthermore, pharmacokinetic studies in rats revealed a 2.8-fold increase in AUC (3717.58 ng·h/mL) and a C_max of 206.86 ng/mL, compared to 88.06 ng/mL for the pure drug. The study further examines the industrial feasibility of cocrystallization as an innovative approach for optimizing poorly soluble drugs in commercial formulations. The results highlight the potential of cocrystal technology in overcoming formulation challenges and advancing the development of more effective and patient-friendly antifungal therapies.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103770"},"PeriodicalIF":3.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730556","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":"Highly variable aggregation and glycosylation profiles and their roles in immunogenicity to protein-based therapeutics","authors":"Sina Sarsarshahi ,&nbsp;Sanghati Bhattacharya ,&nbsp;Zeb R. Zacharias ,&nbsp;Eman S. Kamel ,&nbsp;Jon C.D. Houtman ,&nbsp;Reza Nejadnik","doi":"10.1016/j.xphs.2025.103771","DOIUrl":"10.1016/j.xphs.2025.103771","url":null,"abstract":"<div><div>Production of antibodies against protein-based therapeutics (e.g., monoclonal antibodies (mAbs)) by a recipient's immune system can vary from benign symptoms to chronic neutralization of the compound, and in rare cases, a lethal cytokine storm. One critical factor that can induce or contribute to an anti-drug antibody (ADA) response is believed to be the presence of aggregated proteins in protein-based therapeutics. There is a high level of variability in the aggregation of different proteins, which adds to the complexity in understanding the immune response to these drugs. Furthermore, the level of glycosylation of proteins, which increases drug stability, functionality, and serum half-life, is highly variable and may influence their immunogenicity. Considering the abundance of literature on the effect of aggregation and glycosylation on the immunogenicity of protein-based therapeutics, this review aims to summarize the current knowledge and clarify the immunogenic effects of different protein-based therapeutics such as mAbs. This review focuses on the properties of aggregated proteins and elucidates their relationship with immunogenicity. The contribution of different immune cell subsets and the mechanisms in aggregation-induced immunogenicity are also reviewed. Finally, the potential effects of each glycan, such as sialic acid, mannose, and fucose, on protein-based therapeutics’ immunogenicity and stability is discussed.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103771"},"PeriodicalIF":3.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730558","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":"PLGA/TPGS nanoparticles for docetaxel delivery: The pegylation effect on nanoparticle physicochemical properties and uptake and cytotoxicity in prostate cancer cells","authors":"Lívia de Queiróz Carvalho Silva ,&nbsp;Giovanni Loureiro Raspantini ,&nbsp;Juliana Palma Abriata ,&nbsp;Marcela Tavares Luiz ,&nbsp;Ana Carolina Cruz de Sousa ,&nbsp;Thais da Silva Moreira ,&nbsp;Emanuel Paula Magalhães ,&nbsp;Ramon Róseo Paula Pessoa Bezerra de Menezes ,&nbsp;Raquel Petrilli ,&nbsp;Juliana Maldonado Marchetti ,&nbsp;Josimar O. Eloy","doi":"10.1016/j.xphs.2025.103766","DOIUrl":"10.1016/j.xphs.2025.103766","url":null,"abstract":"<div><div>Prostate cancer is the most common malignancy in men worldwide and docetaxel (DTX) is the treatment of choice. However, both the drug and formulation excipients for drug solubilization can cause side effects. In this context, the development of polymeric nanoparticles offers advantages to improve drug delivery and reduce toxicity. In the present work, factorial design was used to evaluate the effect of the amount of poly(L-lactide-co-glycolide) (PLGA) or poly(L-lactide-co-glycolide acid-polyethylene glycol) (PLGA-PEG), D-Alpha-Tocopheryl Polyethylene Glycol Succinate (TPGS) and ratio between aqueous and oily phases on the nanoparticle characteristics. The nanocarriers were characterized regarding particle size, polydispersity, zeta potential, DTX encapsulation efficiency, morphology by transmission electron microscopy, DSC, TGA and FTIR. It was evaluated in <em>vitro</em> for cytotoxicity and cellular uptake in prostate cancer cells. Pegylated nanoparticles, which have a different composition (TPGS%, AP:OP ratio), reduced the nanoparticle size to 105.97 ± 5.16 nm, in PDI 0.13 ± 0.03, zeta potential of -34.73 ± 1.19 mV and increased the encapsulation efficiency to 96.78 ± 1.20%. Characterization by DSC, TGA and FTIR confirmed drug encapsulation and showed colloidal stability. Pegylated nanoparticles were more stable upon serum incubation and adsorbed less proteins. In conclusion, the pegylation of the nanoparticles affected the physicochemical parameters. Also, the pegylation of nanoparticles decreased uptake by macrophages. Finally, cellular uptake and cell cytotoxicity were higher in tumor cells when compared to non-tumor cells, although they were not affected by pegylation.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103766"},"PeriodicalIF":3.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692552","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":"Effectiveness of manufacturing annealing temperature on sterilization and depyrogenation of closed ampoules compared with other techniques.","authors":"Ahmed M Rashed, Ahmed M A Hetta, Zeinab S Hashem, Mo'men H El-Katatny","doi":"10.1016/j.xphs.2025.103769","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103769","url":null,"abstract":"<p><p>The presence of endotoxin in the bloodstream can lead to unexpected fever and, in severe cases, endotoxemia and bacteremia that can lead to death. The reduction of bacterial endotoxin, known as depyrogenation, is crucial for preparing primary packaging components like ampoules for use in injectable drug products. The durability of glass ampoules depends on the proper annealing process. If glass is not annealed correctly, it is prone to cracking or shattering from even small changes in temperature or from mechanical shock or stress. To evaluate the effectiveness of sterilization and depyrogenation, a dry heat oven at 250°C was used for 30 minutes. The Limulus Amebocyte Lysate (LAL) assay was utilized to detect endotoxin, and efficient sterilization and depyrogenation were observed at this temperature. The impact of heating glass ampoules to various temperatures on the process of sterilization and depyrogenation was studied. This investigation covered a range of temperatures (250°C - 550°C), and included holding stage times (105, 120, and 200 seconds) corresponding to the belt speed. The removal of endotoxins was achieved by exposing to temperatures from 350°C to 550°C for specific time intervals and at 300°C with an exposure time of 200 seconds. The absence of endotoxin was observed when annealing glass ampoules at 500°C for 105 seconds, regardless of the ampoules' size. Alternative methods for testing depyrogenation of sealed ampoules, such as ethylene oxide (EtO), sodium hydroxide (NaOH), and hydrochloric acid (HCl), were also demonstrated to have a clear comparison against temperature which considered the best effective economic method . This research indicates that annealing sealed glass ampoules at specific temperatures can serve as a replacement for sterilization and depyrogenation processes prior to filling, leading to savings in time, labor, machine work, energy, and cost.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103769"},"PeriodicalIF":3.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692551","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":"Sequence optimization of lipid-modified amphiphilic tetrapeptides as anticancer drug carriers","authors":"Asuka Inada,&nbsp;Ayane Sawao,&nbsp;Mizuki Shinoda,&nbsp;Tatsuya Oshima","doi":"10.1016/j.xphs.2025.103768","DOIUrl":"10.1016/j.xphs.2025.103768","url":null,"abstract":"<div><div>In this study, 19 tetrapeptides, each consisting of four amino acid residues, were designed and modified with oleic acid to serve as amphiphilic dispersants for anticancer drug delivery. The lipid-modified peptides (Ole-pep) were evaluated for their ability to disperse paclitaxel (Ptx), a poorly water-soluble anticancer drug. The water dispersibility of Ptx was significantly increased when peptides with two or more positively or negatively charged functional groups were used as dispersants. One specific Ole-pep demonstrated a critical micelle concentration of 0.0682 × 10⁻³ mol/dm³, confirming its excellent amphiphilic properties and capacity to encapsulate Ptx. Cytotoxicity studies in HeLa cells, a cell line derived from human cervical cancer cells, confirmed that the complexes with Ptx were highly cytotoxic regardless of the peptide used. Additionally, the results suggested that certain peptides, particularly those with a high number of Lys residues, exhibited cytotoxicity on their own.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 6","pages":"Article 103768"},"PeriodicalIF":3.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692554","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":"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}