European Journal of Pharmaceutical Sciences最新文献_第9页

Vancomycin release kinetics for treatment of bone tissue infection: design of a loaded scaffold and evaluation of a dynamic model 万古霉素治疗骨组织感染的释放动力学：负载支架的设计和动态模型的评估。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-29 DOI: 10.1016/j.ejps.2025.107391

Antoine Recorda , Cynthia Abane , Emeline Renaudie , Patricia Pascaud-Mathieu , Arnaud Beaumont , Karine Giry , Sylvie Delebassée , Amandine Magnaudeix , Betty Laverdet , Chantal Damia

The development of local drug delivery systems (DDS) has emerged as a promising strategy for targeted therapeutic applications, enabling high drug concentrations at specific sites while minimizing systemic toxicity. However, the evaluation of drug release kinetics remains challenging due to the limitations of current in vitro models, which often fail to replicate physiological conditions. To address this issue, dynamic models, such as flow perfusion bioreactors, offer a more realistic approach to studying DDS, particularly in cases where prolonged drug release is required, such as the prevention of surgical site infections (SSI) in bone grafts. In this study, a macroporous hydroxyapatite (HA) scaffold was designed through robocasting, an additive manufacturing technique, to obtain a bone substitute with a controlled macroporous architecture. HA was chosen for its chemical similarity to the mineral phase of bone, its non-biodegradability, and its ability to support antibiotic loading and release. Vancomycin, a broad-spectrum antibiotic commonly used against Staphylococcus aureus, was incorporated into a thermosensitive chitosan hydrogel to regulate its release kinetics. The loaded scaffolds were evaluated using a perfusion bioreactor to model the bone microenvironment. The antibiotic release profile was determined using high-performance liquid chromatography (HPLC) and an iterative algorithm. The objective is to establish a proof of concept and demonstrate the relevance of a dynamic, animal-free model for studying the kinetics of local antibiotic release. The results showed that the combination of a macroporous HA scaffold and a chitosan hydrogel enabled sustained antibiotic release over time. Furthermore, in vitro antibacterial assays confirmed the efficacy of the released vancomycin against Staphylococcus aureus. This study highlights the potential of using perfusion bioreactors and additive manufacturing techniques to develop physiologically relevant DDS models, ultimately contributing to the refinement of antibiotic delivery strategies.

局部给药系统（DDS）的发展已经成为靶向治疗应用的一种有前途的策略，可以在特定部位实现高药物浓度，同时最大限度地减少全身毒性。然而，由于目前体外模型的局限性，药物释放动力学的评估仍然具有挑战性，这些模型往往无法复制生理条件。为了解决这一问题，动态模型，如流动灌注生物反应器，提供了一种更现实的方法来研究DDS，特别是在需要延长药物释放的情况下，如骨移植手术部位感染（SSI）的预防。在本研究中，通过增材制造技术robocasting设计了一种大孔羟基磷灰石（HA）支架，以获得具有可控大孔结构的骨替代品。选择透明质酸是因为它的化学成分与骨的矿物相相似，它的不可生物降解性，以及它支持抗生素加载和释放的能力。万古霉素是一种广谱抗生素，通常用于治疗金黄色葡萄球菌，我们将万古霉素加入到热敏壳聚糖水凝胶中，以调节其释放动力学。使用灌注生物反应器模拟骨微环境，对负载支架进行评估。采用高效液相色谱法和迭代算法测定抗生素的释放谱。目的是建立一个概念的证明，并证明一个动态的，无动物模型的相关性，以研究局部抗生素释放的动力学。结果表明，大孔透明质酸支架和壳聚糖水凝胶的组合可以随着时间的推移持续释放抗生素。此外，体外抗菌实验证实了释放的万古霉素对金黄色葡萄球菌的抑制作用。这项研究强调了使用灌注生物反应器和增材制造技术开发生理学相关DDS模型的潜力，最终有助于改进抗生素的给药策略。

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引用次数: 0

Application of a forward design-based multi-attribute decision-making method in quality assessment in pharmaceutical tablet manufacturing 基于正向设计的多属性决策方法在片剂生产质量评价中的应用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-29 DOI: 10.1016/j.ejps.2025.107392

Xinhao Wan , Ming Yang , Zhijian Zhong , Xiaoqing Zhou , Xuecheng Wang , Qing Tao , Zhenfeng Wu

With the modernization of the pharmaceutical industry and increasingly stringent regulatory requirements, ensuring the quality and process stability of pharmaceutical tablets has become a critical challenge. In particular, chewable tablets, as a unique type of oral solid dosage form designed to be chewed before swallowing, require special attention to mechanical properties and sensory attributes such as texture, mouthfeel, and taste acceptability. This study aims to implement a forward design-based multi-attribute decision-making (MADM) framework for systematic and accurate multi-criteria quality assessment and prediction of pharmaceutical chewable tablets. Tablets were produced using batch-based tableting technology, and critical quality attributes—including weight variation, friability, porosity, and hardness—were systematically evaluated under varying process conditions. Tensile strength was employed as an external validation index. To overcome the limitations of traditional evaluation methods, the proposed MADM framework incorporates a game theory (GT)-based combinatorial weighting strategy, effectively integrating subjective experience-based judgment with objective data-driven metrics. In addition, a backpropagation neural network (BPNN) model was developed to capture the nonlinear relationships between process parameters and the comprehensive quality index. Compared to conventional weighting approaches such as the analytic hierarchy process (AHP), entropy method (EM), and mean-based weighting, the GT-based strategy demonstrated superior performance in terms of evaluation robustness and accuracy. The MADM results showed strong agreement with the tensile strength data, confirming the reliability and consistency of the evaluation framework. Furthermore, the BPNN model achieved high prediction accuracy, providing solid quantitative support for process optimization. Overall, the proposed method offers a robust and generalizable solution for multi-criteria quality assessment and prediction of pharmaceutical chewable tablets. When integrated with industrial information systems, it enables data-driven optimization, intelligent quality control, and automation, thereby contributing to the advancement of smart pharmaceutical manufacturing.

随着医药工业的现代化和监管要求的日益严格，保证片剂的质量和工艺稳定性已成为一项严峻的挑战。特别是咀嚼片，作为一种独特的口服固体剂型，在吞咽前需要咀嚼，需要特别注意机械性能和感官属性，如质地、口感和口味可接受性。本研究旨在建立基于正向设计的多属性决策（MADM）框架，对药用咀嚼片进行系统、准确的多准则质量评价与预测。片剂采用基于批量的压片技术生产，并在不同的工艺条件下系统地评估了关键的质量属性，包括重量变化、脆性、孔隙度和硬度。拉伸强度作为外部验证指标。为了克服传统评价方法的局限性，本文提出的MADM框架引入了基于博弈论（GT）的组合加权策略，有效地将基于主观经验的判断与客观数据驱动的指标相结合。此外，建立了反向传播神经网络（BPNN）模型来捕捉工艺参数与综合质量指标之间的非线性关系。与传统的加权方法如层次分析法（AHP）、熵值法（EM）和均值加权相比，基于遗传算法的策略在评估稳健性和准确性方面表现出更强的性能。MADM结果与拉伸强度数据非常吻合，证实了评估框架的可靠性和一致性。此外，BPNN模型具有较高的预测精度，为过程优化提供了坚实的定量支持。总体而言，该方法为药用咀嚼片的多标准质量评价和预测提供了一种鲁棒性和可推广的解决方案。当与工业信息系统集成时，它可以实现数据驱动的优化，智能质量控制和自动化，从而促进智能制药制造的发展。

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引用次数: 0

Nortriptyline-targeted siRNA-loaded liposomes: Design, affinity, biodistribution, and bioactivity in a murine Herpes Simplex Virus 1 corneal infection model 去甲替林靶向sirna负载脂质体：小鼠单纯疱疹病毒1型角膜感染模型的设计、亲和力、生物分布和生物活性

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-27 DOI: 10.1016/j.ejps.2025.107388

Doaa Jbara-Agbaria , Neethi C Thathapudi , Marc Groleau , Majd Agbaria , Marie-Claude Robert , Natalia Callai Da Silva , Sebastien Talbot , Janet Laganiere , May Griffith , Gershon Golomb

Herpes simplex virus type 1 (HSV1) establishes latency in the trigeminal ganglia and reactivates to cause recurrent infections and severe complications, including herpes simplex keratitis (HSK), the leading cause of infectious corneal blindness in developed countries. We developed and characterized a targeted siRNA delivery system designed to suppress HSV1 by silencing the immediate-early gene ICP0, which encodes a protein essential for lytic infection and viral reactivation. To enhance neuronal accumulation, siRNA-loaded liposomes were decorated with nortriptyline (NTP), a ligand with high affinity for neuronal cells, including those in the trigeminal ganglia. The liposomes were optimized to exhibit nanoscale size, low polydispersity, neutral surface charge, high siRNA loading, spherical morphology, and long-term shelf stability. Studies in cell lines confirmed efficient internalization with good tolerability, and targeted liposomes showed enhanced binding to differentiated PC‑12 neuronal cells, competitively inhibited by free NTP, supporting their targeting specificity. Following retro-orbital administration in mice, NTP-targeted siHSV1 liposomes preferentially accumulated in the trigeminal ganglia. Antiviral efficacy was further assessed by topical application of siHSV1‑loaded liposomes within a biocompatible hydrogel in a murine HSV1 corneal perforation model of HSK. In the corneal limbus, targeted liposomes produced a significant reduction in viral load, whereas in the contralateral trigeminal ganglia, they significantly reduced viral load with a pronounced trend toward decreased ICP0 expression. These results demonstrate the feasibility of using NTP-mediated targeting ligand and support the potential of this delivery platform for treating latent HSV1, warranting further optimization for improved therapeutic efficacy.

1型单纯疱疹病毒（HSV1）在三叉神经节中潜伏，并重新激活，引起复发性感染和严重并发症，包括单纯疱疹角膜炎（HSK），这是发达国家感染性角膜失明的主要原因。我们开发并表征了一种靶向siRNA递送系统，该系统通过沉默直接早期基因ICP0来抑制HSV1， ICP0编码一种裂解感染和病毒再激活所必需的蛋白质。为了促进神经元的积累，用去甲替林（NTP）修饰装载sirna的脂质体，去甲替林是一种对神经细胞（包括三叉神经节细胞）具有高亲和力的配体。优化后的脂质体具有纳米级尺寸、低多分散性、中性表面电荷、高siRNA负载、球形形态和长期货架稳定性。细胞系研究证实了有效的内化和良好的耐受性，靶向脂质体与分化的PC‑12神经元细胞的结合增强，被游离NTP竞争性抑制，支持其靶向特异性。在小鼠眼眶后给药后，ntp靶向siHSV1脂质体优先积聚在三叉神经节。通过在生物相容性水凝胶中局部应用负载siHSV1的脂质体，在HSK小鼠HSV1角膜穿孔模型中进一步评估抗病毒效果。在角膜边缘，靶向脂质体显著降低了病毒载量，而在对侧三叉神经节，它们显著降低了病毒载量，并显著降低了ICP0的表达。这些结果证明了使用ntp介导的靶向配体的可行性，并支持该递送平台治疗潜伏性HSV1的潜力，需要进一步优化以提高治疗效果。

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引用次数: 0

Development of a controlled-release tofacitinib formulation using acid-sensitive pore-forming components for an osmotic drug delivery system 一种控释托法替尼配方的开发，使用酸敏感的成孔成分用于渗透给药系统。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-27 DOI: 10.1016/j.ejps.2025.107389

Jin Ah Lee , Yun Jung Lee , Jeong A Seong , Myung Kwan Chun , Kwon Yeon Weon

Acid-sensitive ingredient porosity osmotic drug delivery systems (AID) are a simplified and scalable alternative to conventional ODDS. In the current study, the tofacitinib-loaded AID formulation was optimized using an I-optimal mixture design. The three coating excipients examined as independent variables were cellulose acetate (X₁; 25.8–43.8 %), sodium bicarbonate (X₂; 20.0–30.0 %), and hydroxypropyl cellulose (X₃; 26.3–46.3 %). Response variables included cumulative drug release at 2 h (Y₁), 4 h (Y₂), and 8 h (Y₃), as well as the percentage of residual drug after 8 h (Y₄), which were analyzed using a quadratic model within the I-optimal framework. The coefficient of determination (R²) values for Y₁, Y₂, Y₃, and Y₄ were 0.79, 0.74, 0.55, and 0.48, respectively. The optimized AID exhibited zero-order drug release kinetics (R² = 0.9931), with a release rate constant (K₀) of 0.20 h⁻¹, indicating a consistent and controlled release profile throughout the evaluation period. Pharmacokinetic studies indicated no significant lag time for the AID, while Xeljanz® XR 11 mg exhibited an initial lag time of approximately 0.64 h, consistent with the characteristics of conventional ODDS technologies. Maximum plasma concentrations (C_max) were 75.7 ± 40.8 ng/mL for Xeljanz® XR 11 mg and 79.4 ± 37.1 ng/mL for AID. The areas under the plasma concentration-time curve were 610.0 ± 187.5 ng/mL for Xeljanz® XR 11 mg and 586.1 ± 210.5 ng/mL for AID. Times to maximum plasma concentration were 5 h for Xeljanz® XR 11 mg and 2 h for AID. Collectively, this modified approach reduces the initial lag time and allows for faster drug action.

酸敏感成分孔隙渗透给药系统（AID）是传统ODDS的一种简化和可扩展的替代方案。在本研究中，采用i -最优混合设计优化了托法替尼负载的AID配方。作为自变量检查的三种涂层辅料是醋酸纤维素（X₁；25.8-43.8%）、碳酸氢钠（X₂；20.0-30.0%）和羟丙基纤维素（X₃；26.3-46.3%）。响应变量包括2 h （Y₁）、4 h （Y₂）和8 h （Y₃）的累积药物释放，以及8 h （Y₄）后残留药物的百分比，这些变量使用i -最优框架内的二次模型进行了分析。Y₁、Y₂、Y₃和Y₄的决定系数（R²）值分别为0.79、0.74、0.55和0.48。优化后的AID具有零级药物释放动力学（R² = 0.9931），其释放速率常数（K 0）为0.20 h⁻¹，表明其在整个评价期内具有一致性和可控的释放特性。药代动力学研究表明，AID没有明显的滞后时间，而Xeljanz®XR 11 mg的初始滞后时间约为0.64 h，与传统ODDS技术的特征一致。Xeljanz®XR 11 mg的最大血药浓度（Cmax）为75.7 ± 40.8 ng/mL， AID为79.4 ± 37.1 ng/mL。Xeljanz®XR 11 mg的血药浓度-时间曲线下面积为610.0 ± 187.5 ng/mL， AID为586.1 ± 210.5 ng/mL。Xeljanz®XR 11 mg达到最大血药浓度的时间为5小时，AID为2小时。总的来说，这种改进的方法减少了初始滞后时间，并允许更快的药物作用。

{"title":"Development of a controlled-release tofacitinib formulation using acid-sensitive pore-forming components for an osmotic drug delivery system","authors":"Jin Ah Lee , Yun Jung Lee , Jeong A Seong , Myung Kwan Chun , Kwon Yeon Weon","doi":"10.1016/j.ejps.2025.107389","DOIUrl":"10.1016/j.ejps.2025.107389","url":null,"abstract":"<div><div>Acid-sensitive ingredient porosity osmotic drug delivery systems (AID) are a simplified and scalable alternative to conventional ODDS. In the current study, the tofacitinib-loaded AID formulation was optimized using an I-optimal mixture design. The three coating excipients examined as independent variables were cellulose acetate (X₁; 25.8–43.8 %), sodium bicarbonate (X₂; 20.0–30.0 %), and hydroxypropyl cellulose (X₃; 26.3–46.3 %). Response variables included cumulative drug release at 2 h (Y₁), 4 h (Y₂), and 8 h (Y₃), as well as the percentage of residual drug after 8 h (Y₄), which were analyzed using a quadratic model within the I-optimal framework. The coefficient of determination (R²) values for Y₁, Y₂, Y₃, and Y₄ were 0.79, 0.74, 0.55, and 0.48, respectively. The optimized AID exhibited zero-order drug release kinetics (R² = 0.9931), with a release rate constant (K₀) of 0.20 h⁻¹, indicating a consistent and controlled release profile throughout the evaluation period. Pharmacokinetic studies indicated no significant lag time for the AID, while Xeljanz® XR 11 mg exhibited an initial lag time of approximately 0.64 h, consistent with the characteristics of conventional ODDS technologies. Maximum plasma concentrations (C<sub>max</sub>) were 75.7 ± 40.8 ng/mL for Xeljanz® XR 11 mg and 79.4 ± 37.1 ng/mL for AID. The areas under the plasma concentration-time curve were 610.0 ± 187.5 ng/mL for Xeljanz® XR 11 mg and 586.1 ± 210.5 ng/mL for AID. Times to maximum plasma concentration were 5 h for Xeljanz® XR 11 mg and 2 h for AID. Collectively, this modified approach reduces the initial lag time and allows for faster drug action.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107389"},"PeriodicalIF":4.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631391","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}

引用次数: 0

Corrigendum to “Effects of nonsense genetic variants on OATP1B1 expression and transport activity in vitro” [European Journal of Pharmaceutical Sciences 215 (2025) 107322] “无义基因变异对OATP1B1表达和体外转运活性的影响”的更正[欧洲药物科学杂志215(2025)107322]。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-22 DOI: 10.1016/j.ejps.2025.107381

Wilma Kiander , Hatam Rashidpour , Mikko Gynther , Kati-Sisko Vellonen , Mikko Neuvonen , Laura Vesalainen , Kristiina M. Huttunen , Mikko Niemi , Heidi Kidron

引用次数: 0

Uncertainties in drug dissolution tests - identification and CFD evaluation of factors limiting the accuracy of the USP2 test 药物溶出度试验的不确定度。限制USP2试验准确性因素的鉴定和CFD评估

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-22 DOI: 10.1016/j.ejps.2025.107387

Normunds Jekabsons , Sabīne Upnere , Artūrs Lācis , Ance Bārzdiņa , Daniela Paula Prudņikova , Una Lote Vītoliņa , Baiba Mauriņa , Agnese Brangule

Accurate USP2 paddle dissolution testing is crucial for the quality characterisation, development, and research of solid‑dosage forms, but measurement uncertainties, particularly during the initial flow‑build‑up phase, can mask batch‑to‑batch differences. This work focuses on Computational Fluid Dynamics (CFD) using high-resolution simulations to identify and quantify the main factors contributing to uncertainty in the dissolution of single-component paracetamol tablets. CFD simulations were performed using the OpenFOAM toolkit using a custom solver that simultaneously resolves Navier–Stokes flow and the convective‑diffusive transport of paracetamol. The dissolution process was modelled using the Direct Numerical Simulation and the Smagorinsky-Lilly LES formulation with Van Driest wall damping. Targeted dissolution experiments were used to validate the numerical predictions. Laboratory-prepared tablets (500 ± 1.6 mg) were tested under three configurations: (i) free floating, (ii) magnetically fixed, and (iii) fixed with the tablet bottom coated to suppress rear‑face dissolution. Tests were conducted in a USP2 apparatus at paddle speeds of 25, 50, and 75 RPM, with sampling from 0.5 min to 40 min to capture the time dynamics. The simulated concentration and integral mass fluxes matched experimental dissolution rates.

准确的USP2桨溶出度测试对于固体剂型的质量表征、开发和研究至关重要，但测量的不确定性，特别是在初始流动建立阶段，可以掩盖批次之间的差异。本研究的重点是计算流体动力学（CFD），利用高分辨率模拟来识别和量化导致单组分扑热息痛片溶出不确定性的主要因素。使用OpenFOAM工具包进行CFD模拟，使用自定义求解器同时求解Navier-Stokes流和扑热息痛的对流扩散传输。采用直接数值模拟和考虑Van Driest壁阻尼的Smagorinsky-Lilly LES公式对溶解过程进行了模拟。利用目标溶出实验对数值预测进行了验证。实验室制备的片剂（500±1.6 mg）在三种配置下进行测试：(i)自由漂浮，（ii）磁性固定，（iii）片底包衣固定以抑制背面溶出。测试在USP2设备中进行，桨速分别为25、50和75 RPM，采样时间从0.5分钟到40分钟，以捕捉时间动态。模拟的浓度和整体质量通量与实验溶解速率相匹配。

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引用次数: 0

Pulmonary delivery of siRNA lipoplexes and lipid nanoparticles using a vibrating mesh nebuliser 使用振动网状喷雾器的siRNA脂质体和脂质纳米颗粒的肺输送。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-20 DOI: 10.1016/j.ejps.2025.107386

Michael T. Neary , Lianne M. Mulder , Ciaran O. Leime , Ronan MacLoughlin , Brunella Grassiri , Łukasz Baranowski , Piotr S. Kowalski , Abina M. Crean , Katie B. Ryan

Inhalation via nebulisation is a promising method to deliver high concentrations of siRNA to the lung epithelium in a direct and non-invasive manner for the treatment of numerous respiratory-related illnesses. However, nebulisation can be destructive towards siRNA nanocarriers leading to loss of siRNA and a diminished therapeutic outcome. Herein, we sought to explore how the nebulisation process, including adjustments in aerosol droplet size impacts the physicochemical properties of several lipid-based siRNA nanocarrier formulations. These included PEGylated and non-PEGylated cationic DOTAP-based lipoplexes (LPXs) and C12–200 based lipid nanoparticles (LNPs). Two Aerogen® Pro vibrating mesh nebuliser devices with capacities to generate aerosols of differing volumetric mean diameters (VMD) were utilised. The aerosol droplet sizes for the different siRNA formulations were 4.80 to 4.89 µm (High VMD device) and 3.56 to 3.59 µm (Low VMD device) demonstrating that the emitted droplet size distribution was consistent across multiple siRNA nanocarrier types. Further, the formulations exhibited mass median aerodynamic diameters (MMAD) of 4.03 – 4.84 µm (High VMD device) indicating their potential for targeting siRNA lung deposition. Aggregation in both lipoplex formulations and a significant reduction in LNPs’ siRNA encapsulation efficiency were observed. In vitro studies in Firefly luciferase (Fluc) expressing alveolar A549 cells demonstrated that cell viability and Fluc knockdown were generally unaffected by nebulisation. However, Fluc knockdown varied depending on formulation type and was highest for LNPs (93 %) and lowest for the PEGylated LPXs (max 30 %). Overall, this study shows that aerosols with consistent droplet size can be generated but the choice of nanocarrier impacts the stability and delivery efficacy and requires careful consideration for efficient nebulised siRNA delivery.

雾化吸入是一种很有前途的方法，可以直接和无创地将高浓度siRNA输送到肺上皮，用于治疗许多呼吸相关疾病。然而，雾化可能对siRNA纳米载体具有破坏性，导致siRNA的丢失和治疗效果降低。在此，我们试图探索雾化过程，包括气溶胶液滴大小的调整如何影响几种脂基siRNA纳米载体配方的物理化学性质。这些包括聚乙二醇化和非聚乙二醇化的阳离子dotap基脂质复合物（LPXs）和基于C12-200的脂质纳米颗粒（LNPs）。使用了两个Aerogen Pro®振动网状喷雾器装置，具有产生不同体积平均直径（VMD）的气溶胶的能力。不同siRNA配方的气溶胶液滴尺寸分别为4.80 ~ 4.89µm（高VMD装置）和3.56 ~ 3.59µm（低VMD装置），表明不同siRNA纳米载体类型的气溶胶液滴尺寸分布一致。此外，该配方的质量中位数气动直径（MMAD）为4.03 - 4.84µm（高VMD装置），表明它们具有靶向siRNA肺沉积的潜力。观察到两种脂质体制剂中的聚集和LNPs的siRNA包封效率的显着降低。对表达肺泡A549荧光素酶（Fluc）的萤火虫细胞的体外研究表明，细胞活力和Fluc敲除通常不受雾化影响。然而，Fluc敲除因制剂类型而异，LNPs最高（93%），PEGylated LPXs最低（最大30%）。总体而言，本研究表明，可以生成具有一致液滴大小的气溶胶，但纳米载体的选择会影响其稳定性和递送效率，需要仔细考虑雾化siRNA的有效递送。

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引用次数: 0

Impact of yeast cell wall incorporation on the mucoadhesion, stability, oral permeability and release profile of alginate/whey protein beads loaded with insulin 酵母细胞壁掺入对装载胰岛素的海藻酸盐/乳清蛋白珠黏附、稳定性、口服渗透性和释放特性的影响。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-19 DOI: 10.1016/j.ejps.2025.107385

Emmanuelle Lainé , Valerie Hoffart , Imen Dhifallah , Ghislain Garrait , Eric Beyssac

This study aimed to evaluate the impact of incorporating yeast cell wall (YCW) into alginate/whey protein (ALG/WP) particles as a strategy to improve oral insulin delivery. Insulin-loaded particles were produced by an extrusion–gelation process with or without YCW, and their physicochemical, mucoadhesive, and permeability properties were assessed in vitro, ex vivo, and in vivo. The inclusion of YCW increased the viscosity of the polymeric solution, resulting in more cohesive particles and a significant reduction in insulin loss during coating. Encapsulation efficiencies ranged from 65 to 99%. However, YCW did not significantly affect particle size or the release mechanism, which remained diffusion-controlled. Although YCW-containing beads exhibited enzyme inhibitory and mucoadhesive properties, insulin protection against enzymatic degradation was similar to that of control beads. YCW moderately enhanced insulin permeability in Caco-2 cell monolayers without cytotoxicity, consistent with a reversible reduction of transepithelial electrical resistance. This effect did not translate into a measurable increase in insulin absorption in ex vivo duodenum or in vivo duodenal administration, indicating that its contribution as an absorption enhancer is limited under physiologically complex conditions.

本研究旨在评估将酵母细胞壁（YCW）掺入海藻酸盐/乳清蛋白（ALG/WP）颗粒中作为改善口服胰岛素递送的策略的影响。通过添加或不添加YCW的挤出-凝胶工艺生产胰岛素负载颗粒，并在体外、离体和体内评估其物理化学、黏附性和渗透性。YCW的加入增加了聚合物溶液的粘度，使颗粒更有凝聚力，并显著减少了包覆过程中的胰岛素损失。封装效率从65%到99%不等。然而，YCW对颗粒大小和释放机制没有显著影响，仍然是扩散控制的。虽然含有ycw的微球表现出酶抑制和粘接特性，但胰岛素对酶降解的保护作用与对照微球相似。YCW适度增强Caco-2细胞单层的胰岛素通透性，无细胞毒性，与经上皮电阻可逆降低一致。这种作用并没有转化为体外十二指肠或体内十二指肠吸收的可测量的增加，表明其作为吸收促进剂的贡献在生理复杂的条件下是有限的。

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引用次数: 0

Impact of formulation and process parameters on the stability and bioactivity of RNA-loaded lipid nanoparticles during nebulization 配方和工艺参数对雾化过程中负载rna的脂质纳米颗粒稳定性和生物活性的影响。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-19 DOI: 10.1016/j.ejps.2025.107383

Katrin F. Wiebe , Stefan C. Schneid , Werner Hoheisel , Wolfgang Frieß , Olivia M. Merkel

During the pandemic, lipid nanoparticles (LNPs) became widely established as RNA nanocarriers, and hold the promise of future targeting of a broad variety of previously untreatable diseases. LNPs are mostly administered invasively via intramuscular or intravenous injections. Given the lung’s large surface, high vascularization and low nuclease abundance, inhalation offers a promising alternative for both local and systemic delivery of LNPs. Vibrating mesh nebulizers present a patient-friendly, high-dose delivery platform. However, the nebulization process imposes thermal and mechanical stress on the LNP formulation. This study contributes to a better understanding of how nebulization affects the physicochemical properties and biological activity of LNPs, depending on formulation and process parameters. We investigated the impact of formulation and process variables such as temperature, concentration, buffer type, and RNA modality on LNP properties including particle size distribution, zeta potential, in vitro activity, and RNA integrity. While aggregating, siRNA LNPs protected the encapsulated RNA from degradation, and preserved biological function. In contrast, after the nebulization of mRNA LNPs the cargo was degraded and the biological function diminished. This observation can possibly be attributed both to the higher sensitivity of mRNA toward physical and chemical degradation, and the cargo-dependent morphology of LNPs. While demonstrating that siRNA LNPs preserved their most important characteristics, namely RNA integrity and biological function, our findings emphasize the need for route-specific optimization of LNPs, which need to meet different critical quality criteria when used for inhalation rather than injection.

在大流行期间，脂质纳米颗粒（LNPs）被广泛确立为RNA纳米载体，并有望在未来靶向多种以前无法治愈的疾病。LNPs大多通过肌内或静脉注射侵入性给药。考虑到肺的大表面，高血管化和低核酸酶丰度，吸入为局部和全身输送LNPs提供了一个有希望的选择。振动网状雾化器提供了一个对患者友好的高剂量输送平台。然而，雾化过程对LNP配方施加了热应力和机械应力。这项研究有助于更好地了解雾化如何影响LNPs的物理化学性质和生物活性，这取决于配方和工艺参数。我们研究了配方和工艺变量（如温度、浓度、缓冲液类型和RNA模式）对LNP性质的影响，包括粒径分布、zeta电位、体外活性和RNA完整性。在聚合过程中，siRNA LNPs保护被封装的RNA不被降解，并保留了生物功能。相比之下，雾化mRNA LNPs后，货物被降解，生物功能下降。这一观察结果可能归因于mRNA对物理和化学降解的更高敏感性，以及LNPs的货物依赖性形态。虽然证明siRNA LNPs保留了其最重要的特征，即RNA完整性和生物学功能，但我们的研究结果强调了LNPs需要进行路线特异性优化，当用于吸入而不是注射时，LNPs需要满足不同的关键质量标准。

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引用次数: 0

The influence of dapagliflozin on diabetic ocular complications: An observational cohort study 达格列净对糖尿病眼部并发症的影响：一项观察性队列研究。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-11-17 DOI: 10.1016/j.ejps.2025.107382

Jo-Hsin Chen , Fei-Hung Hung , Yu-Ting Wang , Jin-Hua Chen , Shu-Fen Liao , Chun-Mei Hsueh , Jong-Shiuan Yeh , Gregory Y.H. Lip

Background

This study aimed to evaluate the risk of developing ocular outcomes, including diabetic retinopathy (DR), open-angle glaucoma (OAG), and visual loss, in patients with type 2 diabetes mellitus (T2DM) treated with dapagliflozin, a sodium glucose cotransporter 2 inhibitor (SGLT2i), compared to those receiving other hypoglycemic agents.

Methods

This was an observational, retrospective, multi-center cohort study using data from the Taipei Medical University Clinical Research Database (2016–2020). Participants included 18,854 newly diagnosed T2DM patients with an estimated glomerular filtration rate above 45 ml/min/m². After excluding those with a history of DR, OAG, or visual loss, 1400 dapagliflozin users and 1400 non-SGLT2i users were matched using 1:1 propensity score matching. The primary outcome was the composite incidence of DR, OAG, or visual loss.

Results

After 1-year follow-up, dapagliflozin users had a significantly lower incidence of DR, OAG, or visual loss (2.78 % vs. 5.35 %; adjusted hazard ratio [aHR], 0.53; 95 % CI, 0.36–0.79, p = 0.002). At the 2-year follow-up, the incidence was 3.85 % in dapagliflozin users compared to 6.35 % in non-SGLT2i users (aHR, 0.63; 95 % CI, 0.44–0.88, p = 0.007).

Conclusions

Dapagliflozin was associated with a significantly lower incidence of DR, OAG, or visual loss in newly diagnosed T2DM patients within five years, suggesting its potential benefit in preventing ocular complications.

背景：本研究旨在评估2型糖尿病（T2DM）患者接受钠葡萄糖共转运蛋白2抑制剂（SGLT2i）达格列净治疗与接受其他降糖药治疗相比，发生眼部结局的风险，包括糖尿病视网膜病变（DR）、开角型青光眼（OAG）和视力丧失。方法：本研究是一项观察性、回顾性、多中心队列研究，数据来自台北医科大学临床研究数据库（2016-2020）。参与者包括18,854名新诊断的T2DM患者，估计肾小球滤过率高于45 ml/min/m²。在排除有DR、OAG或视力丧失史的患者后，1400名dapag列净使用者和1400名非sglt2i使用者使用1:1倾向评分匹配进行匹配。主要结局是DR、OAG或视力丧失的综合发生率。结果：经过1年的随访，达格列净使用者DR、OAG或视力丧失的发生率显著降低（2.78% vs. 5.35%；校正风险比[aHR]， 0.53; 95% CI, 0.36-0.79, p=0.002）。在2年随访中，达格列净服用者的发病率为3.85%，而非sglt2i服用者的发病率为6.35% （aHR, 0.63; 95% CI, 0.44-0.88, p=0.007）。结论：达格列净与新诊断T2DM患者5年内DR、OAG或视力丧失的发生率显著降低相关，提示其在预防眼部并发症方面的潜在益处。

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