Journal of pharmaceutical sciences最新文献

英文中文

Richard H. Guy-He has skin in the game. 理查德·h·盖伊——他有自己的利益。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-12 DOI: 10.1016/j.xphs.2025.104130

Russell O Potts

A review of the Potts-Guy equation and its impact on drug delivery.

Potts-Guy方程的回顾及其对药物输送的影响。

引用次数: 0

When heat strikes: Investigating unexpected particles in sodium bicarbonate injections 当热来袭：研究碳酸氢钠注射剂中意想不到的颗粒。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-11 DOI: 10.1016/j.xphs.2025.104127

Narasimha Swamy Kollu, Ravikiran Allada

The presence of particles in injectable formulations presents significant risks, such as embolism, phlebitis, and thrombophlebitis. Moreover, visible particles violate pharmacopeial standards and may lead to regulatory actions. Therefore, it is crucial to identify the underlying cause and eliminate visible particles to ensure both patient safety and regulatory compliance. Sodium Bicarbonate Injection, a straightforward formulation containing only the active pharmaceutical ingredient and water for injection, is commonly packaged in glass vials for commercial use. This study reports an unexpected observation that, when subjected to sterilization at 121 °C, Sodium Bicarbonate Injection can develop particulate matter. Through thorough analysis, we discovered that the particles as crystals of sodium dawsonite; surprisingly, this forms at high temperatures due to the interaction between the drug product and aluminium leached from the glass vial. This important finding highlights the risks associated with exposing the drug product to elevated sterilization temperatures, emphasizing the need for alternative sterilization methods or careful optimization of heat-based conditions. It also underscores the importance of particle identification through the use of a combination of techniques that help identify the root cause and prevent formation, thereby ensuring safety and efficacy.

注射制剂中颗粒的存在带来重大风险，如栓塞、静脉炎和血栓性静脉炎。此外，可见颗粒违反药典标准，可能导致监管行动。因此，确定根本原因并消除可见颗粒以确保患者安全和法规遵从性至关重要。碳酸氢钠注射液是一种简单的配方，只含有活性药物成分和注射用水，通常包装在玻璃小瓶中用于商业用途。本研究报告了一个意想不到的观察结果，即当在121 °C下进行灭菌时，碳酸氢钠注射液可以产生颗粒物质。通过深入的分析，我们发现这些颗粒为钠盐晶体；令人惊讶的是，由于药品和从玻璃小瓶中浸出的铝之间的相互作用，这种物质在高温下形成。这一重要发现强调了将药品暴露在较高灭菌温度下的风险，强调了替代灭菌方法或仔细优化热基条件的必要性。它还强调了通过使用多种技术来识别颗粒的重要性，这些技术有助于确定根本原因并防止形成，从而确保安全性和有效性。

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引用次数: 0

Clinical translation considerations for diacerein-loaded oleoliposome dry-powder inhalation in COPD 慢性阻塞性肺病患者吸入含二肾上腺素油脂质体干粉的临床翻译考虑。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-11 DOI: 10.1016/j.xphs.2025.104128

Devendra Kumar Singh , Thakur Rohit Singh , Varshini Vadhithala , Sachin Kumar , Jeffrin Reneus Paul

引用次数: 0

Specific polysorbate fingerprints of CHO hydrolases and implications for indirect assays CHO水解酶的聚山梨酸酯指纹图谱及其间接测定的意义。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-10 DOI: 10.1016/j.xphs.2025.104126

Melanie Maier , Viktor Gross , Linus Weiss , Simon Kluters , Joey Studts , Matthias Franzreb , Patrick Garidel

Polysorbate degradation in biopharmaceutical formulations can impact the stability and efficacy of therapeutic proteins. This degradation is predominantly caused by specific residual host cell hydrolases present at sub-ppm concentrations. Their low abundance, combined with the lack of sensitive, enzyme specific detection methods, is a major analytical challenge. This study presents a novel approach using reverse-phase ultra-performance liquid chromatography coupled with mass spectrometry (RP-UPLC-MS) to systematically analyse the specific polysorbate degradation patterns of hydrolases expressed by Chinese hamster ovary (CHO) cells. Our findings reveal distinct degradation fingerprints of five CHO-derived hydrolases, highlighting their unique preferences for different polysorbate species based on ester linkages (e.g. monoester or multiester), hydrophilic head groups and FA chain length. This study is the first of its kind to provide such detailed insights into the enzymatic cleavage patterns of polysorbates using enzymes directly derived from CHO cells.

Our results underscore the limitations of indirect polysorbate quantification assays, such as the fluorescence micelle assay (FMA) and 4-methylumbelliferone (MU4)-based hydrolytic activity assays, in accurately reflecting the activity of specific hydrolases. For instance, the FMA tends to overestimate the contribution of certain polysorbate species due to its reliance on micelle formation, while the MU4 assay's predictive reliability is limited by its use of surrogate substrates. In contrast, RP-UPLC-MS enables the precise identification of individual polysorbate species and their degradation products, providing a direct measure of hydrolase activity. The detailed enzymatic fingerprints obtained in this study pave the way for future advancements in enzyme classification and the potential application of computational tools for automated hydrolase identification.

生物制剂中聚山梨酸酯的降解会影响治疗性蛋白的稳定性和功效。这种降解主要是由亚ppm浓度下存在的特定残留宿主细胞水解酶引起的。它们的丰度低，加上缺乏敏感的酶特异性检测方法，提出了一个主要的分析挑战。本研究采用反相超高效液相色谱-质谱联用技术（PR-UPLC-MS）系统分析了中国仓鼠卵巢（CHO）细胞中水解酶的聚山梨酸酯特异性降解模式。我们的研究结果揭示了五种cho衍生水解酶的不同降解指纹，突出了它们基于酯键（如单酯或多酯）、亲水性头基和FA链长度对不同聚山梨酯种类的独特偏好。这项研究首次使用直接来源于CHO细胞的酶对聚山梨酯的酶裂解模式提供了如此详细的见解。我们的结果强调了间接聚山梨酸定量分析的局限性，如荧光胶束测定（FMA）和基于4-甲基伞花酮（MU4）的水解活性测定，在准确反映特定水解酶的活性方面。例如，由于依赖胶束形成，FMA倾向于高估某些聚山梨酸酯物种的贡献，而MU4测定的预测可靠性受到其使用替代底物的限制。相反，RP-UPLC-MS能够精确鉴定单个聚山梨酸酯物种及其降解产物，提供水解酶活性的直接测量。本研究中获得的详细的酶指纹图谱为酶分类的未来发展和自动水解酶鉴定的计算工具的潜在应用铺平了道路。

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引用次数: 0

Paper-based reaction devices as accelerated platforms in forced degradation studies 纸基反应装置在强制降解研究中的加速平台。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-04 DOI: 10.1016/j.xphs.2025.104111

Airton G. Salles Jr. , Willian R. de Araujo , Manoel T. Rodrigues Jr. , Bruno B. Guidotti

The stability of pharmaceutical compounds is a central concern in drug development, as degradation can compromise both efficacy and safety. Conventional forced degradation studies, while effective, are often time-consuming and resource-intensive, highlighting the need for accessible and high-throughput alternatives. In this study, we introduce paper-based reaction devices (PRDs) as an innovative platform for accelerating drug degradation experiments. Strips of cellulose paper were employed as reactive microenvironments to investigate the degradation of two model drugs, cyclobenzaprine (CBP) and deflazacort (DFL), under oxidative, acidic, basic, and metal-ion stress conditions. Chromatographic analysis using HPLC-PDA and high-resolution mass spectrometry (HRMS) revealed that the paper interface preserved mechanistic relevance, yielding degradation profiles consistent with solution-based studies while markedly enhancing degradation rates. Mechanistic trends were consistent with the hypothesis that hydroxyl-rich cellulose surfaces promote kinetic amplification through hydrogen-bond-mediated microconfinement. Mass-balance assessments demonstrated reproducibility and validated the reliability of the approach across stress conditions. The PRD approach is proposed as an investigational and preformulation-level tool for early-phase stability assessment, complementing rather than replacing conventional stress testing methods. Its simple, robust, and high-throughput format offers a valuable alternative for rapid stability evaluation during the early stages of drug development and formulation design.

药物化合物的稳定性是药物开发中的一个中心问题，因为降解会损害疗效和安全性。传统的强制降解研究虽然有效，但往往耗时且资源密集，因此需要可获得的高通量替代品。在这项研究中，我们介绍了纸基反应装置（PRDs）作为加速药物降解实验的创新平台。以纤维素纸条为反应微环境，研究了两种模型药物环苯扎林（cyclobenzapprine， CBP）和地氮唑特（deflazacort， DFL）在氧化、酸性、碱性和金属离子胁迫条件下的降解。使用HPLC-PDA和高分辨率质谱（HRMS）的色谱分析显示，纸界面保持了机制相关性，产生的降解谱与基于溶液的研究一致，同时显著提高了降解率。机理趋势与假设一致，即富含羟基的纤维素表面通过氢键介导的微约束促进动力学放大。质量平衡评估证明了再现性，并验证了该方法在各种应力条件下的可靠性。PRD方法被建议作为早期稳定性评估的研究和预制定水平的工具，补充而不是取代传统的压力测试方法。其简单、稳健和高通量的格式为药物开发和配方设计早期阶段的快速稳定性评估提供了有价值的替代方案。

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引用次数: 0

Development and evaluation of high-flowability spherical crystals of tofacitinib citrate Form A for direct powder compression 用于直接粉末压缩的A型柠檬酸托法替尼高流动性球形晶体的研制与评价。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-04 DOI: 10.1016/j.xphs.2025.104114

Xueyao Zeng, Xiao Ke, Xinnuo Xiong, Xiaoyan Zhao, Lirong Yan, Fubo Cai, Jun Yan

A novel method for preparing spherical crystals of tofacitinib citrate Form A is presented in this study, alongside the determination of its single-crystal structure. Tofacitinib citrate was dissolved in a ternary solvent system of two alcohols and water at elevated temperatures, followed by cooling and the addition of a bridging agent to induce crystallization under stirring, resulting in spherical crystals of tofacitinib citrate Form A. Conventional methods for preparing tofacitinib citrate often yield uneven particle size distribution, typically necessitating a pulverization step. Subsequent wet granulation and other processing techniques into oral solid dosage forms inevitably lead to raw material loss, active dust pollution, and increased costs and processing times. This study leveraged the characteristics of spherical aggregates observed in previously reported crystallization systems and, based on experimental design, hypothesized a mechanism for sphere formation. By employing supersaturation control coupled with a spherical agglomeration method, the morphology of the crystalline product was successfully modified, yielding tofacitinib citrate spherical crystals with excellent flow properties and high bulk density. These crystals exhibit a uniform particle size distribution and good dissolution performance, meeting the requirements for direct compression into oral solid dosage forms without the need for milling. The preparation method is straightforward, facilitating the industrial production of both the active pharmaceutical ingredients and oral formulations.

本研究提出了一种制备柠檬酸托法替尼A型球形晶体的新方法，并测定了其单晶结构。将托法替尼柠檬酸盐在高温下溶解于由两种醇和水组成的三溶剂体系中，然后冷却并加入桥接剂在搅拌下诱导结晶，得到形式为a的托法替尼柠檬酸盐球形晶体。制备托法替尼柠檬酸盐的常规方法通常会产生不均匀的粒度分布，通常需要粉碎步骤。随后的湿造粒和其他加工技术不可避免地导致原料损失、活性粉尘污染以及成本和加工时间的增加。本研究利用了在先前报道的结晶系统中观察到的球形聚集体的特征，并基于实验设计，假设了球形形成的机制。通过过饱和调控和球形团聚法制备柠檬酸托法替尼，成功地对结晶产物的形貌进行了修饰，得到了具有优良流动性能和高堆积密度的柠檬酸托法替尼球形结晶。这些晶体具有均匀的粒度分布和良好的溶解性能，满足直接压缩成口服固体剂型的要求，无需研磨。该制备方法简单，便于活性药物成分和口服制剂的工业化生产。

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引用次数: 0

An alternative nonclinical approach to support the first-in-human clinical trial of a T-cell bispecific targeting EGFRvIII 一种替代的非临床方法来支持针对EGFRvIII的t细胞双特异性的首次人体临床试验。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-04 DOI: 10.1016/j.xphs.2025.104112

Elisabeth Husar , Silke Simon , Afsaneh Abdolzade-Bavil , Angelique Augustin , Miro J. Eigenmann , Anne Freimoser-Grundschober , Alina Gavrilov , Reto Gianotti , Nikolche Gjorevski , Patricio Godoy , Andreas Hollenstein , Martin Lechmann , Valeria G. Nicolini , Liudmila Polonchuk , Nadine Stokar-Regenscheit , Roberto Villaseñor , Cornelia Wagner , Inja Waldhauer , Antje-Christine Walz

As a tumor specific protein, EGFRvIII represents an ideal target for targeted cancer immunotherapies. Here we report the nonclinical evaluation of EGFRvIII-TCB, a novel EGFRvIII-targeted T-cell bispecific antibody designed for glioblastoma treatment. The antibody exhibited high specificity for EGFRvIII, with no effects on EGFR wild-type cells. In the absence of a relevant species, the nonclinical safety assessment to support its first-in-human clinical trial, was conducted applying an alternative in vitro strategy to predict potential off-target toxicity. A 3D blood-brain barrier-glioblastoma model was used to optimize the starting dose. Our translational strategy addressed regulatory feedback received from the Danish Health and Medicines Agency (DKMA) and the FDA to further increase confidence in the applied in vitro approach and ultimately led to the regulatory approval of our Ph1 study protocol across multiple countries.

作为一种肿瘤特异性蛋白，EGFRvIII是靶向癌症免疫治疗的理想靶点。在这里，我们报告了EGFRvIII-TCB的非临床评估，EGFRvIII-TCB是一种新型的egfrviii靶向t细胞双特异性抗体，旨在治疗胶质母细胞瘤。该抗体对EGFRvIII具有高特异性，对EGFR野生型细胞无影响。在缺乏相关物种的情况下，非临床安全性评估支持其首次人体临床试验，采用另一种体外策略来预测潜在的脱靶毒性。采用三维血脑屏障-胶质母细胞瘤模型优化起始剂量。我们的转化策略解决了从丹麦卫生和药品管理局（DKMA）和FDA收到的监管反馈，以进一步增加对体外应用方法的信心，并最终导致我们的Ph1研究方案在多个国家获得监管批准。

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引用次数: 0

Modeling Filtration Flow Rate in Peristaltic Pump Systems for High-Viscosity Bovine Serum Albumin: A Multivariate Nonlinear Approach. 高粘度牛血清白蛋白蠕动泵系统中过滤流速的建模：一种多元非线性方法。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-04 DOI: 10.1016/j.xphs.2025.104113

Jianwei Chang, Yu Zhang, Fang Zhang, Yu Wang, Wei Qin, Tingting Wang, Qizhou Chen, Jeremy Guo

Filtration of highly viscous pharmaceutical solutions exhibits a non-linear relationship between pump speed and flow rate. To systematically investigate this phenomenon, experiments were conducted across a wide range of solution viscosities (1.0-25.7 cP) and pump speeds (10-120 rpm). In 1.0 and 2.5 cP solutions, flow rate increases linearly with pump speed. However, for solutions with viscosity ≥ 5 cP, the relationship exhibits a linear region followed by a nonlinear decline beyond a critical inflection point. Notably, this inflection point shifts to lower pump speeds as viscosity increases. Four different models were fitted and compared, a segmented kinetic model was developed to describe the relationship between flow rate, pump speed, and viscosity, capturing both linear and nonlinear regimes. By identifying a consistent inflection point at approximately 19 psi and applying a power-law function to characterize viscosity-dependent pump speed, Darcy's law and theoretical flow limits were integrated to enable direct calculation of key process parameters. This model achieved an excellent fit (R²: 0.998), reduced prediction error (MAPE: 3.2%, MAE: 0.229, RMSE: 0.303), and revealed consistent kinetic behavior. These findings provide a predictive method for optimizing filtration performance, improving technology transfer, and enhancing scale-up reliability in biopharmaceutical manufacturing.

高粘性药物溶液的过滤在泵速和流量之间表现出非线性关系。为了系统地研究这一现象，在广泛的溶液粘度（1.0-25.7 cP）和泵速（10-120 rpm）范围内进行了实验。在1.0和2.5 cP溶液中，流量随泵速线性增加。然而，对于粘度≥5cp的溶液，关系表现为线性区域，然后在临界拐点之后非线性下降。值得注意的是，随着粘度的增加，这个拐点转向较低的泵速。通过对四种不同的模型进行拟合和比较，建立了一个分段动力学模型来描述流量、泵转速和粘度之间的关系，同时捕捉了线性和非线性状态。通过在大约19 psi处确定一致的拐点，并应用幂律函数来表征粘度相关的泵速，达西定律和理论流量限制相结合，可以直接计算关键工艺参数。该模型拟合良好（R²：0.998），降低了预测误差（MAPE: 3.2%, MAE: 0.229, RMSE: 0.303），并显示了一致的动力学行为。这些发现为优化过滤性能、改善技术转移和提高生物制药生产的规模可靠性提供了预测方法。

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引用次数: 0

Development of HRP-based 3D intercellular exchange assay for high throughput screening 基于酶解蛋白的三维细胞间交换高通量筛选试验的开发。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-03 DOI: 10.1016/j.xphs.2025.104115

Xian Wu , Xiangxiang Hu , Yiqin Li , Hong-Bo Pang

Extracellular vesicles (EVs) play a vital role in mediating intercellular communication and regulatory processes. Using a three-dimensional (3D) intercellular exchange assay, we previously demonstrated that EVs facilitate the intercellular transfer of nanoparticles (NPs) among cells in vitro and are essential for the efficient delivery of NPs in vivo. This assay was further employed to identify small molecules capable of regulating the intercellular exchange process. However, the original assay relied on fluorescence labeling and flow cytometry for detection, which posed limitations for adaptation to high-throughput screening (HTS) platforms. In this study, we developed an enhanced intercellular exchange assay based on horseradish peroxidase (HRP) labeling. Specifically, cell-penetrating peptide-conjugated silver nanoparticles (CPP-AgNPs) were labeled with HRP, allowing signal amplification through the enzymatic reaction between HRP and its substrate. This modification significantly improved the signal-to-noise ratio (S/N) to approximately 6:1. Additionally, we optimized the gel composition within the assay system to ensure compatibility with HTS workflows. Using this HRP-based assay, we validated that LDN-214117, a previously identified agonist of intercellular exchange, significantly promoted the transfer of CPP-AgNPs between various cell pairs. Collectively, our work presents a novel, rapid, and versatile platform for identifying modulators of intercellular exchange in a high-throughput format.

细胞外囊泡（EVs）在细胞间通讯和调节过程中起着至关重要的作用。利用三维（3D）细胞间交换实验，我们先前证明了体外ev促进纳米颗粒（NPs）在细胞间的细胞间转移，并且对于体内NPs的有效递送至关重要。该试验进一步用于鉴定能够调节细胞间交换过程的小分子。然而，最初的检测依赖于荧光标记和流式细胞术进行检测，这对适应高通量筛选（HTS）平台构成了限制。在这项研究中，我们开发了一种基于辣根过氧化物酶（HRP）标记的增强细胞间交换试验。具体来说，用HRP标记细胞穿透肽共轭银纳米粒子（cppp - agnps），通过HRP与其底物之间的酶促反应放大信号。这种改进显著地提高了信噪比（S/N）到大约6:1。此外，我们优化了分析系统内的凝胶组成，以确保与HTS工作流程的兼容性。通过这种基于酶解酶的实验，我们证实了LDN-214117，一种先前鉴定的细胞间交换激动剂，可以显著促进pcp - agnps在不同细胞对之间的转移。总的来说，我们的工作提出了一个新的、快速的、通用的平台，用于以高通量格式识别细胞间交换的调节剂。

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引用次数: 0

Thermodynamic analysis of synergistic effect of cyclodextrins and electrolytes on the solubility of aromatic amino acids 环糊精与电解质协同作用对芳香氨基酸溶解度的热力学分析。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103762

Maame Esi Baidoo, Jonghoon Kang

引用次数: 0

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