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Elucidating the uptake and trafficking of nanostructured lipid carriers as delivery systems for miRNA 阐明作为 miRNA 运送系统的纳米结构脂质载体的吸收和迁移。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-25 DOI: 10.1016/j.ejps.2024.106973
Ivana Ruseska , Amina Tucak-Smajić , Andreas Zimmer
Cationic nanostructured lipid carriers (cNLCs) represent promising non-viral carriers for nucleic acids, such as miRNAs, forming stable self-assembled miRNA complexes due to electrostatic interactions. Prepared by high-pressure homogenization, cNLC formulations, both with and without Nile Red dye demonstrated stable particle sizes in the range of 100–120 nm and positive surface charges (>30 mV), which are necessary for effective cellular uptake. The miRNA complexes formed at mass ratios of 1:2.5 and 1:5 showed similar stability and size, with positive zeta potentials, as well as high cell viability (> 80 %) in 3T3-L1 and MCF-7 cell lines. The cellular uptake studies of miRNA:cNLC complexes in both cell lines revealed that uptake was time- and concentration-dependent, with rapid initial uptake in 30 min and a zig-zag pattern over 24 h. To elucidate the endocytosis mechanism of miRNA:cNLC complexes, 3T3-L1 and MCF-7 cells were incubated with different inhibitors (chlorpromazine, 5-[N-ethyl-N-isopropyl] amiloride, dynasore, nystatin, or sodium azide with 2-deoxy-d-glucose). Results showed significant inhibition of uptake at low temperatures and with ATP depletion, suggesting endocytosis, particularly macropinocytosis, as the main uptake mechanism in 3T3-L1 cells. In MCF-7 cells, the uptake was less inhibited by the substances, indicating the need for more specific methods to fully decipher the endocytic mechanisms involved. Confocal laser scanning microscopy images revealed that the complexes are internalized in vesicles, and are primarily localized in the juxtanuclear region, suggesting trafficking through the endolysosomal system. Colocalization study with LysoTracker™ Green DND-26 showed significant colocalization of miRNA:cNLC complexes with lysosomes in 3T3-L1 cells, indicating trafficking through the endolysosomal system. In MCF-7 cells, colocalization was lower, suggesting macropinocytosis as the primary uptake mechanism. Additional studies showed partial colocalization between labeled NLCs and miRNA, indicating that about 50 % of miRNA is released from NLCs within 30 min post-transfection.
阳离子纳米结构脂质载体(cNLCs)是很有前途的核酸(如 miRNAs)非病毒载体,可通过静电相互作用形成稳定的自组装 miRNA 复合物。通过高压均质法制备的 cNLC 配方,无论是否含有尼罗河红染料,都显示出稳定的粒度(100-120 nm)和正表面电荷(大于 30 mV),而这正是细胞有效吸收所必需的。以 1:2.5 和 1:5 的质量比形成的 miRNA 复合物显示出相似的稳定性和大小,zeta 电位为正,在 3T3-L1 和 MCF-7 细胞系中的细胞存活率较高(> 80%)。miRNA:cNLC 复合物在这两种细胞系中的细胞摄取研究表明,细胞摄取与时间和浓度有关,30 分钟内开始快速摄取,24 小时内呈 "之 "字形摄取。为了阐明 miRNA:cNLC 复合物的内吞机制,3T3-L1 和 MCF-7 细胞与不同的抑制剂(氯丙嗪、5-[N-乙基-N-异丙基]阿米洛利、达那索、硝司他丁或叠氮化钠加 2-脱氧-D-葡萄糖)进行了孵育。结果表明,在低温和 ATP 耗尽的情况下,摄取会受到明显抑制,这表明内吞作用,尤其是大蛋白内吞作用,是 3T3-L1 细胞的主要摄取机制。在 MCF-7 细胞中,这些物质对摄取的抑制作用较小,这表明需要采用更具体的方法来全面解密其中的内吞机制。共聚焦激光扫描显微镜图像显示,复合物以囊泡形式内化,主要定位于并核区,这表明它们是通过内溶酶体系统运输的。用 LysoTracker™ Green DND-26 进行的共定位研究显示,在 3T3-L1 细胞中,miRNA:cNLC 复合物与溶酶体有明显的共定位,表明它们是通过溶酶体内系统转运的。在 MCF-7 细胞中,共定位程度较低,这表明大蛋白细胞是主要的摄取机制。其他研究显示,标记的 NLC 与 miRNA 之间存在部分共定位,表明转染后 30 分钟内约有 50% 的 miRNA 从 NLC 中释放出来。
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引用次数: 0
Scaling up controlled nucleation in freeze drying: Translating vacuum-induced surface freezing from laboratory to GMP 扩大冷冻干燥中的受控成核:将真空诱导表面冷冻从实验室应用到 GMP。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-22 DOI: 10.1016/j.ejps.2024.106968
Stefan C. Schneid, Michaela Cohrs , Julian H. Lenger
The freezing step often causes batch inhomogeneity and issues during freeze drying process transfer. The nucleation temperature at which the first ice is formed during freezing differs from vial to vial, and significantly between scales. To solve this issue, Controlled Ice Nucleation techniques can be applied to induce ice nucleation at a defined product temperature across the whole batch. This study describes the application of vacuum-induced surface freezing (VISF) for a therapeutic antibody formulation, including the process transfer from laboratory scale through pilot scale to a GMP line. The VISF method could be successfully implemented on all scales of freeze dryers without equipment adaptation. Some scale-dependent changes in pressure control and degassing were necessary to achieve nucleation in all vials and avoid defects. The resulting lyophilized products were characterized and further analyzed in a stability study. While most critical quality attributes were comparable for product manufactured with and without Controlled Nucleation, the appearance of cakes processed using VISF was much better, which could be linked to different product morphology due to freeze-concentration. The results of this study allow direct comparison of the application of controlled nucleation for an antibody formulation at different scales and confirm the applicability of the technology.
在冷冻干燥工艺转移过程中,冷冻步骤往往会造成批次不均匀和问题。冷冻过程中形成第一块冰的成核温度因瓶而异,在不同规模之间也有很大差异。为解决这一问题,可采用受控冰成核技术,在整个批次中以确定的产品温度诱导冰成核。本研究介绍了真空诱导表面冷冻(VISF)在治疗性抗体制剂中的应用,包括从实验室规模到中试规模再到 GMP 生产线的工艺转移。VISF 方法可在所有规模的冷冻干燥机上成功实施,无需对设备进行调整。为了在所有小瓶中实现成核并避免缺陷,有必要根据规模改变压力控制和脱气方式。在一项稳定性研究中,对所得冻干产品进行了表征和进一步分析。虽然使用和不使用可控成核技术生产的产品在大多数关键质量属性上具有可比性,但使用 VISF 加工的蛋糕外观要好得多,这可能与冷冻浓缩造成的不同产品形态有关。这项研究的结果可以直接比较在不同规模的抗体配方中应用可控成核的情况,并证实了该技术的适用性。
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引用次数: 0
In vitro and in silico study of the synergistic anticancer effect of alpinumisoflavone with gemcitabine on pancreatic ductal adenocarcinoma through suppression of ribonucleotide reductase subunit-M1 通过抑制核糖核苷酸还原酶亚基-M1对胰腺导管腺癌的协同抗癌作用的体外和硅学研究。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-21 DOI: 10.1016/j.ejps.2024.106969
Woonghee Lee , Gwonhwa Song , Hyocheol Bae
A highly aggressive neoplastic disease, pancreatic ductal adenocarcinoma (PDAC) is documented as the third chief cause of cancer-associated mortality in both sexes combined in the United States. For decades, gemcitabine-based chemotherapy has been embraced as a cornerstone drug for the treatment of PDAC. However, there have been several unsolved problems, including cytotoxicity, and chemoresistance. Gemcitabine efficacy was attributed to the attenuation of ribonucleotide reductase subunit-M1 (RRM1). Overexpression of RRM1 in PDAC is highly correlated with gemcitabine resistance and reduced gemcitabine sensitivity, resulting in a poor survival rate even after gemcitabine treatment. Moreover, the status of TP53, a tumor suppressor gene, assumes a decisive role in the response of PDAC to gemcitabine. Therefore, targeting RRM1 and P53 might be a therapeutic strategy for strengthening gemcitabine efficacy and cytotoxicity against PDAC. Alpinumisoflavone (AIF) is a prenylated isoflavone originated in Cudrania tricuspidate with versatile bioactive properties, including anticancer activity. However, there was no report whether AIF can exert anticancer effect and exhibit synergistic effect with gemcitabine against PDAC. Therefore, the anticancer properties of AIF were assessed with PANC-1 and MIA PaCa-2. In addition, synergism between AIF and gemcitabine were analyzed. Moreover, the contribution of P53 and RRM1 expression to gemcitabine resistance was assessed by comparing their protein levels in PDAC cells and normal pancreatic cells. The interactions of AIF with RRM1 protein were confirmed by molecular docking and dynamics simulation. Therefore, AIF enhances gemcitabine efficacy against PDAC through the regulation of P53 and RRM1.
胰腺导管腺癌(PDAC)是一种侵袭性极强的肿瘤性疾病,在美国,它是导致男女癌症相关死亡率的第三大主要原因。几十年来,以吉西他滨为基础的化疗一直是治疗 PDAC 的基石药物。然而,吉西他滨也存在一些尚未解决的问题,包括细胞毒性和化疗耐药性。吉西他滨的疗效归因于核糖核苷酸还原酶亚基-M1(RRM1)的衰减。RRM1 在 PDAC 中的过表达与吉西他滨耐药和吉西他滨敏感性降低高度相关,导致吉西他滨治疗后的存活率仍很低。此外,抑癌基因 TP53 的状态在 PDAC 对吉西他滨的反应中起着决定性作用。因此,靶向 RRM1 和 P53 可能是加强吉西他滨对 PDAC 的疗效和细胞毒性的一种治疗策略。Alpinumisoflavone(AIF)是一种源于三尖杉的前烯化异黄酮,具有多种生物活性,包括抗癌活性。然而,AIF 能否发挥抗癌作用,并与吉西他滨对 PDAC 产生协同效应,目前尚无报道。因此,我们用 PANC-1 和 MIA PaCa-2 评估了 AIF 的抗癌特性。此外,还分析了 AIF 与吉西他滨之间的协同作用。此外,通过比较 P53 和 RRM1 在 PDAC 细胞和正常胰腺细胞中的蛋白水平,评估了 P53 和 RRM1 的表达对吉西他滨耐药性的贡献。分子对接和动力学模拟证实了AIF与RRM1蛋白的相互作用。因此,AIF通过调控P53和RRM1增强了吉西他滨对PDAC的疗效。
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引用次数: 0
Population pharmacokinetic analysis in children with different diseases treated with mycophenolate mofetil—Integrated analysis of clinical trials and real-world clinical data 使用霉酚酸酯治疗不同疾病儿童的群体药代动力学分析--临床试验和实际临床数据的综合分析。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-21 DOI: 10.1016/j.ejps.2024.106970
Jumpei Saito , Akimasa Yamatani , Miki Akabane , Mayumi Sako , Kandai Nozu , Kazumoto Iijima , Hidefumi Nakamura

Objectives

This study aims to develop a population pharmacokinetic (PK) model of mycophenolic acid (MPA) in pediatric patients with different diseases.

Methods

To develop the PK model, electronic medical records (EMR) of pediatric patients with different diseases who received mycophenolic acid mofetil (MMF) at the National Center for Child Health and Development from February 2013 to May 2022 and the results of the MMF pharmacokinetic study of pediatric complicated frequently relapsing steroid-dependent nephrotic syndrome under the Advanced Medical Care B protocol (JSKDC09 study) from October 2015 to June 2019 were integrated and analyzed. Non-linear mixed-effects modeling was used to 1) develop a cross-disease population PK model and 2) estimate PK parameters (apparent clearance CL/F and Q/F; apparent volume of distribution Vc/F and Vp/F; absorption rate constant Ka) by post-hoc Bayesian methods. Patient backgrounds, concomitant medications, and laboratory data were included in the covariate analysis. Visual predictive checks with bootstrap and predictive correction were performed to evaluate the final model.

Results

A total of 249 patients with 1495 measurements were used in the analysis, including 68 with post-liver transplant, 65 with nephrotic syndrome, 28 with post-renal transplant, 31 with autoimmune diseases (17 with lupus nephritis and 14 with other collagen diseases), 13 with hematopoietic stem cell transplantation, and 5 with others from EMR and 39 with nephrotic syndrome from the JSKDC09 study. A two-compartment model with a first-order rate absorption process best explained the PK of MPA. A nonlinear relationship between dose and MPA exposure was observed and described by the power function of the model. The final population mean PK parameter estimates (95 % confidence interval) for non-renal transplant patients and average albumin levels were CL/F 15.2 (13.3, 18.0) L/h/70 kg, Vc/F 15.4 (14.4, 17.2) L, Vp/F 246.8 (159.1, 332.1) L, Q/F 7.0 (5.0, 9.0) L/h, and Ka (without proton pump inhibitor [PPI]) 4.4 (2.4, 4.9) h–1. Weight, disease (post-renal transplant), and serum albumin level were significant covariates for CL/F, and serum albumin level for Vc/F. The use of PPIs also affected Ka.

Conclusions

An integrated population PK model of MPA was developed in children with the following conditions: post-solid organ transplantation, post-HSCTx, autoimmune disease, and nephrotic syndrome. Estimated parameters and parameter covariates were similar to those previously reported. This model is expected to provide useful information for using MPA in various diseases in the Japanese population.
研究目的本研究旨在建立霉酚酸(MPA)在不同疾病儿科患者中的群体药代动力学(PK)模型:为了建立PK模型,我们整合并分析了2013年2月至2022年5月在国家儿童健康与发展中心接受霉酚酸莫非替酯(MMF)治疗的不同疾病儿科患者的电子病历(EMR),以及2015年10月至2019年6月根据高级医疗护理B方案(JSKDC09研究)进行的儿科复杂性频繁复发类固醇依赖性肾病综合征MMF药代动力学研究的结果。非线性混合效应模型用于:1)建立跨疾病人群PK模型;2)通过事后贝叶斯方法估计PK参数(表观清除率CL/F和Q/F;表观分布容积Vc/F和Vp/F;吸收率常数Ka)。协变量分析包括患者背景、伴随药物和实验室数据。通过引导和预测校正进行视觉预测检查,以评估最终模型:共有249名患者的1495次测量数据被用于分析,其中包括68名肝移植后患者、65名肾病综合征患者、28名肾移植后患者、31名自身免疫性疾病患者(17名狼疮肾炎患者和14名其他胶原性疾病患者)、13名造血干细胞移植患者、5名来自EMR的其他患者以及39名来自JSKDC09研究的肾病综合征患者。具有一阶吸收率过程的二室模型最能解释 MPA 的 PK。观察到剂量与MPA暴露量之间存在非线性关系,并用模型的幂函数进行了描述。非肾移植患者和平均白蛋白水平的最终人群平均 PK 参数估计值(95% 置信区间)为:CL/F 15.2 (13.3, 18.0) L/h/70 kg、Vc/F 15.4 (14.4, 17.2) L、Vp/F 246.8 (159.1, 332.1) L、Q/F 7.0 (5.0, 9.0) L/h、Ka(不含质子泵抑制剂 [PPI])4.4 (2.4, 4.9) h-1。体重、疾病(肾移植后)和血清白蛋白水平是影响CL/F的重要协变量,血清白蛋白水平是影响Vc/F的重要协变量。PPIs的使用也会影响Ka:结论:针对以下情况的儿童建立了MPA的综合人群PK模型:实体器官移植后、HSCTx后、自身免疫性疾病和肾病综合征。估计参数和参数协变量与之前报道的相似。该模型有望为日本人在各种疾病中使用 MPA 提供有用的信息。
{"title":"Population pharmacokinetic analysis in children with different diseases treated with mycophenolate mofetil—Integrated analysis of clinical trials and real-world clinical data","authors":"Jumpei Saito ,&nbsp;Akimasa Yamatani ,&nbsp;Miki Akabane ,&nbsp;Mayumi Sako ,&nbsp;Kandai Nozu ,&nbsp;Kazumoto Iijima ,&nbsp;Hidefumi Nakamura","doi":"10.1016/j.ejps.2024.106970","DOIUrl":"10.1016/j.ejps.2024.106970","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aims to develop a population pharmacokinetic (PK) model of mycophenolic acid (MPA) in pediatric patients with different diseases.</div></div><div><h3>Methods</h3><div>To develop the PK model, electronic medical records (EMR) of pediatric patients with different diseases who received mycophenolic acid mofetil (MMF) at the National Center for Child Health and Development from February 2013 to May 2022 and the results of the MMF pharmacokinetic study of pediatric complicated frequently relapsing steroid-dependent nephrotic syndrome under the Advanced Medical Care B protocol (JSKDC09 study) from October 2015 to June 2019 were integrated and analyzed. Non-linear mixed-effects modeling was used to 1) develop a cross-disease population PK model and 2) estimate PK parameters (apparent clearance CL/F and Q/F; apparent volume of distribution Vc/F and Vp/F; absorption rate constant Ka) by post-hoc Bayesian methods. Patient backgrounds, concomitant medications, and laboratory data were included in the covariate analysis. Visual predictive checks with bootstrap and predictive correction were performed to evaluate the final model.</div></div><div><h3>Results</h3><div>A total of 249 patients with 1495 measurements were used in the analysis, including 68 with post-liver transplant, 65 with nephrotic syndrome, 28 with post-renal transplant, 31 with autoimmune diseases (17 with lupus nephritis and 14 with other collagen diseases), 13 with hematopoietic stem cell transplantation, and 5 with others from EMR and 39 with nephrotic syndrome from the JSKDC09 study. A two-compartment model with a first-order rate absorption process best explained the PK of MPA. A nonlinear relationship between dose and MPA exposure was observed and described by the power function of the model. The final population mean PK parameter estimates (95 % confidence interval) for non-renal transplant patients and average albumin levels were CL/F 15.2 (13.3, 18.0) L/h/70 kg, Vc/F 15.4 (14.4, 17.2) L, Vp/F 246.8 (159.1, 332.1) L, Q/F 7.0 (5.0, 9.0) L/h, and Ka (without proton pump inhibitor [PPI]) 4.4 (2.4, 4.9) h<sup>–1</sup>. Weight, disease (post-renal transplant), and serum albumin level were significant covariates for CL/F, and serum albumin level for Vc/F. The use of PPIs also affected Ka.</div></div><div><h3>Conclusions</h3><div>An integrated population PK model of MPA was developed in children with the following conditions: post-solid organ transplantation, post-HSCTx, autoimmune disease, and nephrotic syndrome. Estimated parameters and parameter covariates were similar to those previously reported. This model is expected to provide useful information for using MPA in various diseases in the Japanese population.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106970"},"PeriodicalIF":4.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695219","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}
引用次数: 0
Multiphysics simulation of liposome release from hydrogels for cavity filling following patient-specific breast tumor surgery 针对患者乳腺肿瘤手术后腔隙填充从水凝胶中释放脂质体的多物理场模拟
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-19 DOI: 10.1016/j.ejps.2024.106966
Álvaro González-Garcinuño , Antonio Tabernero , Celia Nieto , Eva Martín del Valle , Sasa Kenjeres
Several studies have recommended the use of hydrogels for localized targeted delivery of chemotherapeutic drugs following tumor removal surgery. This approach aims to both fill the cavity and prevent cancer recurrence. The use of Multiphysics-based simulation emerges as a valuable strategy for minimizing experimental work, providing detailed insights into how drug release occurs in the tissue, and enabling the optimization of the design.
In this study, we introduced a mathematical model, utilizing experimental data, to investigate the transport of liposomes carrying MZ1 from a thermosensitive hydrogel and their impact on the viability of breast cancer cells. The proposed comprehensive model considers not just the transport within the interstitial tissue, represented as a porous medium, but also the uptake by cells and its influence on cell viability, along with the potential lymphatic drainage.
The six real patient-specific tumor shapes extracted from MRI scans were used to investigate how the size and form of the tumor can modify the transport pattern. The computational results revealed that the concentration of liposomes in the tissue is significantly influenced by their release from the hydrogel, which proved to be the limiting step. Liposome concentrations of approximately 0.1 % weight were found to be sufficient in ensuring minimal cell survival in the vicinity of the tumor.
一些研究建议在肿瘤切除手术后使用水凝胶局部靶向输送化疗药物。这种方法既能填充空腔,又能防止癌症复发。使用基于多物理场的模拟是一种有价值的策略,可最大限度地减少实验工作,详细了解药物在组织中的释放过程,并优化设计。在本研究中,我们利用实验数据引入了一个数学模型,研究携带 MZ1 的脂质体从热敏水凝胶中的传输及其对乳腺癌细胞活力的影响。所提出的综合模型不仅考虑了作为多孔介质的间质组织内的传输,还考虑了细胞的吸收及其对细胞活力的影响,以及潜在的淋巴引流。我们利用从核磁共振扫描中提取的六种真实的特定患者肿瘤形状来研究肿瘤的大小和形态如何改变传输模式。计算结果显示,脂质体在组织中的浓度受其从水凝胶中释放的影响很大,这被证明是限制性步骤。研究发现,脂质体的浓度约为 0.1%,足以确保肿瘤附近的细胞存活率最低。
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引用次数: 0
Automated extrusion-based dispensing: Personalized dosing and quality control of clopidogrel tablets for pediatric care 基于挤压的自动配药:用于儿科护理的氯吡格雷片剂的个性化剂量和质量控制。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-19 DOI: 10.1016/j.ejps.2024.106967
Farnaz Shokraneh , Anne M. Filppula , Aleksi Tornio , Jaan Aruväli , Urve Paaver , Niklas Sandler Topelius
The exploration of three-dimensional (3D) printing inspired technologies in pharmaceutical compounding reveals a promising frontier in personalized medicine manufacture. This study focuses on the development of clopidogrel bisulphate tablets, with doses ranging from 2 mg to 20 mg per tablet, suitable for pediatric use. The study explored a semi-solid extrusion-based deposition technology already being used in compounding pharmacies across several European locations. The investigation explored various properties of two formulations of 1 % and 2 % clopidogrel gel tablets, with a specific focus on mass variation, drug content uniformity, in vitro drug release profiles, disintegration time, and stability.
The mean weights of the smallest printed 200 mg tablets with 1 % and 2 % clopidogrel concentrations were 199.1 ± 4.6 mg and 201.0 ± 3.2 mg, respectively. For the largest printed 500 mg tablets with 1 % and 2 % concentrations, the mean weights were 499.3 ± 7.7 mg and 501.7 ± 6.5 mg, respectively. The mean clopidogrel content uniformity for 1 % clopidogrel 200 mg and 500 mg tablets were 102.0 ± 1.8 %and 96.6 ± 2.6 %, respectively, and for 2 % clopidogrel 200 mg and 500 mg were 102.6 ± 3.9 % and 101.2 ± 1.6 %, respectively, well within the acceptable acceptance value (AV) range of 3 to 12. Both 1 % and 2 % formulations of clopidogrel tablets exhibited rapid drug release, meeting the USP pharmacopeial target of 85 % release in 15 min. All tablet sizes formulated at 1 % and 2 % concentrations met specified disintegration specifications. The stability assessment over three months revealed consistent pH values and assay results within target specifications for both clopidogrel formulations (93.5 % for 1 % formulation and 93.6 % for 2 % formulation). At three months, X-ray Diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) results demonstrated stability in clopidogrel tablets.
In conclusion, a comprehensive evaluation of our developed clopidogrel tablets demonstrate their suitability for clinical use in an extemporaneous setting using the presented semi-solid extrusion-based automation technology.
三维(3D)打印技术在药物复方制剂中的应用揭示了个性化药物生产的一个前景广阔的前沿领域。这项研究的重点是开发适合儿科使用的硫酸氢氯吡格雷片剂,每片剂量从2毫克到20毫克不等。研究探索了一种基于半固体挤压的沉积技术,该技术已在欧洲多个地区的配制药房中使用。该研究探讨了 1%和 2%氯吡格雷凝胶片剂的各种特性,重点关注质量变化、药物含量均匀性、体外药物释放曲线、崩解时间和稳定性。浓度分别为 1%和 2%的氯吡格雷最小 200 毫克印刷片的平均重量分别为 199.1 ± 4.6 毫克和 201.0 ± 3.2 毫克。最大的 500 毫克印刷片(氯吡格雷浓度分别为 1%和 2%)的平均重量分别为 499.3 ± 7.7 毫克和 501.7 ± 6.5 毫克。1% 氯吡格雷 200 毫克和 500 毫克片剂的平均氯吡格雷含量均匀度分别为 102.0 ± 1.8% 和 96.6 ± 2.6%,2% 氯吡格雷 200 毫克和 500 毫克片剂的平均氯吡格雷含量均匀度分别为 102.6 ± 3.9% 和 101.2 ± 1.6%,均在 3 至 12 的可接受值(AV)范围内。氯吡格雷片剂的 1%和 2%配方都能快速释放药物,达到了美国药典规定的 15 分钟内释放 85% 的目标。浓度为 1%和 2% 的所有规格片剂均符合规定的崩解规格。三个月的稳定性评估显示,两种氯吡格雷制剂的 pH 值和检测结果均符合目标规格(1% 浓度制剂为 93.5%,2% 浓度制剂为 93.6%)。三个月后,X 射线衍射(XRD)和傅立叶变换红外光谱(FTIR)结果表明氯吡格雷片剂具有稳定性。总之,对我们开发的氯吡格雷片剂进行的全面评估表明,采用所介绍的基于半固体挤压的自动化技术,该片剂适用于临时临床使用。
{"title":"Automated extrusion-based dispensing: Personalized dosing and quality control of clopidogrel tablets for pediatric care","authors":"Farnaz Shokraneh ,&nbsp;Anne M. Filppula ,&nbsp;Aleksi Tornio ,&nbsp;Jaan Aruväli ,&nbsp;Urve Paaver ,&nbsp;Niklas Sandler Topelius","doi":"10.1016/j.ejps.2024.106967","DOIUrl":"10.1016/j.ejps.2024.106967","url":null,"abstract":"<div><div>The exploration of three-dimensional (3D) printing inspired technologies in pharmaceutical compounding reveals a promising frontier in personalized medicine manufacture. This study focuses on the development of clopidogrel bisulphate tablets, with doses ranging from 2 mg to 20 mg per tablet, suitable for pediatric use. The study explored a semi-solid extrusion-based deposition technology already being used in compounding pharmacies across several European locations. The investigation explored various properties of two formulations of 1 % and 2 % clopidogrel gel tablets, with a specific focus on mass variation, drug content uniformity, <em>in vitro</em> drug release profiles, disintegration time, and stability.</div><div>The mean weights of the smallest printed 200 mg tablets with 1 % and 2 % clopidogrel concentrations were 199.1 ± 4.6 mg and 201.0 ± 3.2 mg, respectively. For the largest printed 500 mg tablets with 1 % and 2 % concentrations, the mean weights were 499.3 ± 7.7 mg and 501.7 ± 6.5 mg, respectively. The mean clopidogrel content uniformity for 1 % clopidogrel 200 mg and 500 mg tablets were 102.0 ± 1.8 %and 96.6 ± 2.6 %, respectively, and for 2 % clopidogrel 200 mg and 500 mg were 102.6 ± 3.9 % and 101.2 ± 1.6 %, respectively, well within the acceptable acceptance value (AV) range of 3 to 12. Both 1 % and 2 % formulations of clopidogrel tablets exhibited rapid drug release, meeting the USP pharmacopeial target of 85 % release in 15 min. All tablet sizes formulated at 1 % and 2 % concentrations met specified disintegration specifications. The stability assessment over three months revealed consistent pH values and assay results within target specifications for both clopidogrel formulations (93.5 % for 1 % formulation and 93.6 % for 2 % formulation). At three months, X-ray Diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) results demonstrated stability in clopidogrel tablets.</div><div>In conclusion, a comprehensive evaluation of our developed clopidogrel tablets demonstrate their suitability for clinical use in an extemporaneous setting using the presented semi-solid extrusion-based automation technology.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106967"},"PeriodicalIF":4.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686337","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}
引用次数: 0
Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: A population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite 优化小儿急性淋巴细胞白血病维持阶段的地塞米松疗法:地塞米松和代谢物的群体药代动力学和药效学研究。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-17 DOI: 10.1016/j.ejps.2024.106964
Letao Li , Annelienke M. van Hulst , Emma J. Verwaaijen , M.(Marry) van den Heuvel-Eibrink , E.L.T.(Erica) van den Akker , W (Wim) J R Rietdijk , B.C.P.(Birgit) Koch , S.D.T.(Sebastiaan) Sassen
Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining their association with dexamethasone-induced toxicity. Peak and trough concentrations were collected during the maintenance phase from pediatric ALL patients who received oral dexamethasone (6mg/m2/day). NONMEM was used to study the population pharmacokinetics including covariates. Pharmacokinetic (PK) and pharmacodynamic (PD) correlations between drug and its active metabolite exposure and adverse effects were examined. 382 samples (dexamethasone: n = 191; 6β-hydroxydexamethasone: n = 191) from 104 children (age range 3.0 -18.8 years) were collected. A one-compartment model described the data best. The estimated apparent dexamethasone total clearance was 26 L/h/70 kg with 18 % inter-individual variability, and an apparent volume of distribution of 123 L/70 kg, yielding a half-life of 3.3 h. Covariate analysis demonstrated that when asparaginase was co-administered, there was a 50 % reduction in both the clearance of dexamethasone and the extent to which dexamethasone was metabolized to 6β-hydroxydexamethasone. A statistically significant but weak positive correlation was observed between dexamethasone drug exposure and fasting hunger scores. Dexamethasone exposure significantly increased with asparaginase co-administration by inhibition of the CYP3A4 pathway. Our study found a statistically significant but weak positive correlation between dexamethasone exposure and increased hunger. These results support the need for more studies on how to personalize dexamethasone dosing in pediatric ALL treatment and adjust doses to limit side effects, especially in case of co-medication.
地塞米松对小儿急性淋巴细胞白血病(ALL)的治疗至关重要,但有关地塞米松及其代谢物药代动力学的研究却很少。我们的研究对地塞米松及其代谢物进行了全面的药代动力学-药效学分析,考察了它们与地塞米松引起的毒性之间的关系。研究收集了口服地塞米松(6 毫克/平方米/天)的小儿 ALL 患者在维持治疗阶段的峰值和谷值浓度。使用 NONMEM 研究了包括协变量在内的群体药代动力学。研究了药物及其活性代谢物暴露与不良反应之间的药代动力学(PK)和药效学(PD)相关性。研究收集了 104 名儿童(年龄在 3.0 -18.8 岁之间)的 382 份样本(地塞米松:191 份;6β-羟基地塞米松:191 份)。单室模型对数据进行了最佳描述。估计地塞米松的表观总清除率为 26 升/小时/70 千克,个体间变异率为 18%,表观分布容积为 123 升/70 千克,半衰期为 3.3 小时。协变量分析表明,同时服用天冬酰胺酶时,地塞米松的清除率和地塞米松代谢为 6β-hydroxydexamethasone 的程度均降低 50%。地塞米松药物暴露量与空腹饥饿评分之间存在统计学意义上的微弱正相关。通过抑制 CYP3A4 途径,地塞米松的暴露量在同时服用天冬酰胺酶时显著增加。我们的研究发现,地塞米松暴露量与饥饿感增加之间存在统计学意义上的显著但微弱的正相关。这些结果支持我们有必要开展更多研究,探讨如何在儿童 ALL 治疗中个性化地调整地塞米松剂量,并调整剂量以限制副作用,尤其是在联合用药的情况下。
{"title":"Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: A population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite","authors":"Letao Li ,&nbsp;Annelienke M. van Hulst ,&nbsp;Emma J. Verwaaijen ,&nbsp;M.(Marry) van den Heuvel-Eibrink ,&nbsp;E.L.T.(Erica) van den Akker ,&nbsp;W (Wim) J R Rietdijk ,&nbsp;B.C.P.(Birgit) Koch ,&nbsp;S.D.T.(Sebastiaan) Sassen","doi":"10.1016/j.ejps.2024.106964","DOIUrl":"10.1016/j.ejps.2024.106964","url":null,"abstract":"<div><div>Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining their association with dexamethasone-induced toxicity. Peak and trough concentrations were collected during the maintenance phase from pediatric ALL patients who received oral dexamethasone (6mg/m2/day). NONMEM was used to study the population pharmacokinetics including covariates. Pharmacokinetic (PK) and pharmacodynamic (PD) correlations between drug and its active metabolite exposure and adverse effects were examined. 382 samples (dexamethasone: <em>n</em> = 191; 6β-hydroxydexamethasone: <em>n</em> = 191) from 104 children (age range 3.0 -18.8 years) were collected. A one-compartment model described the data best. The estimated apparent dexamethasone total clearance was 26 L/h/70 kg with 18 % inter-individual variability, and an apparent volume of distribution of 123 L/70 kg, yielding a half-life of 3.3 h. Covariate analysis demonstrated that when asparaginase was co-administered, there was a 50 % reduction in both the clearance of dexamethasone and the extent to which dexamethasone was metabolized to 6β-hydroxydexamethasone. A statistically significant but weak positive correlation was observed between dexamethasone drug exposure and fasting hunger scores. Dexamethasone exposure significantly increased with asparaginase co-administration by inhibition of the CYP3A4 pathway. Our study found a statistically significant but weak positive correlation between dexamethasone exposure and increased hunger. These results support the need for more studies on how to personalize dexamethasone dosing in pediatric ALL treatment and adjust doses to limit side effects, especially in case of co-medication.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106964"},"PeriodicalIF":4.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675517","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}
引用次数: 0
Disassembly and in vitro cell compatibility of α-lactalbumin particulates under physiologically relevant conditions α-乳白蛋白颗粒在生理相关条件下的分解和体外细胞相容性。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-16 DOI: 10.1016/j.ejps.2024.106962
Mai Bay Stie , Dirk Fennema Galparsoro , Xin Zhou , Vito Foderà
Protein self-assemblies in the form of ordered supramolecular structures such as particulates hold great potential as new biomaterials. However, research in this field is rarely conducted under physiologically relevant conditions but such studies are crucially needed to unravel the potential use of particulates and other amyloid structures in health sciences. In this study, particulates of α-lactalbumin (ALA) were prepared at different stages of maturation by thermal incubation. Disassembly of particulates in isotonic buffer, neutral pH and at 37 °C was investigated by simultaneously measuring Thioflavin T fluorescence intensity and light scattering. Freshly formed particulates quickly disassembled and displayed complete release of soluble ALA within 1 h. Mature particulates displayed slower disassembly kinetics with incomplete release of ALA within 1 h. The biocompatibility of particulates at different maturation stages to epithelial lung and fibroblast cells was assessed in vitro. Good cell compatibility was observed in the presence of the particulates and their released species. Our findings display protein particulates as biodegradable and highly tunable particles, promoting them as good candidates for drug delivery purposes.
有序超分子结构形式的蛋白质自组装(如微粒)具有作为新型生物材料的巨大潜力。然而,该领域的研究很少在生理相关条件下进行,但要揭示微粒和其他淀粉样结构在健康科学中的潜在用途,此类研究是非常必要的。本研究通过热孵育法制备了处于不同成熟阶段的α-乳白蛋白(ALA)微粒。通过同时测量硫黄素 T 荧光强度和光散射,研究了微粒在等渗缓冲液、中性 pH 和 37 °C条件下的分解情况。在体外评估了不同成熟阶段的微粒对肺上皮细胞和成纤维细胞的生物相容性。在微粒及其释放物存在的情况下,观察到了良好的细胞相容性。我们的研究结果表明,蛋白质微粒具有生物可降解性和高度可调性,是药物输送的理想候选材料。
{"title":"Disassembly and in vitro cell compatibility of α-lactalbumin particulates under physiologically relevant conditions","authors":"Mai Bay Stie ,&nbsp;Dirk Fennema Galparsoro ,&nbsp;Xin Zhou ,&nbsp;Vito Foderà","doi":"10.1016/j.ejps.2024.106962","DOIUrl":"10.1016/j.ejps.2024.106962","url":null,"abstract":"<div><div>Protein self-assemblies in the form of ordered supramolecular structures such as particulates hold great potential as new biomaterials. However, research in this field is rarely conducted under physiologically relevant conditions but such studies are crucially needed to unravel the potential use of particulates and other amyloid structures in health sciences. In this study, particulates of α-lactalbumin (ALA) were prepared at different stages of maturation by thermal incubation. Disassembly of particulates in isotonic buffer, neutral pH and at 37 °C was investigated by simultaneously measuring Thioflavin T fluorescence intensity and light scattering. Freshly formed particulates quickly disassembled and displayed complete release of soluble ALA within 1 h. Mature particulates displayed slower disassembly kinetics with incomplete release of ALA within 1 h. The biocompatibility of particulates at different maturation stages to epithelial lung and fibroblast cells was assessed <em>in vitro</em>. Good cell compatibility was observed in the presence of the particulates and their released species. Our findings display protein particulates as biodegradable and highly tunable particles, promoting them as good candidates for drug delivery purposes.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106962"},"PeriodicalIF":4.3,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647192","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}
引用次数: 0
Optimization of continuous spin-freeze-drying: The role of spin-freezing on quality attributes and drying efficiency of a model peptide formulation 连续旋转冷冻干燥的优化:旋转冷冻对肽制剂模型的质量属性和干燥效率的影响
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-15 DOI: 10.1016/j.ejps.2024.106963
Zarah Schaal , Pieter-Jan Van Bockstal , Joris Lammens , Julian H. Lenger , Adrian P. Funke , Stefan C. Schneid , Hristo L. Svilenov , Thomas De Beer
Continuous spin-freeze-drying is an innovative pharmaceutical manufacturing approach offering real-time monitoring and control at the individual vial level, unlike conventional batch lyophilization. A central feature of this technology is spin-freezing, which involves rapidly spinning liquid-filled vials under a precisely controlled cold gas flow, resulting in a thin, uniform frozen product layer. Using a model peptide formulation, we investigated the impact of different cooling and crystallization rates on quality attributes (QA) and primary drying duration. Key QAs included monomer content, peptide assay, moisture content, and pore structure. The monomer content, peptide content, and primary drying duration remained consistent across all spin-freezing conditions. However, scanning electron microscopy (SEM) and Karl Fischer titration revealed that freezing parameters significantly influenced pore structure and residual moisture content. Samples with smaller pores displayed lower residual moisture, as larger surface areas facilitate moisture desorption. Variations in freezing parameters also significantly impacted desorption kinetics during secondary drying. Slower crystallization rates led to more cracks and less shrinkage in the cake structure, while faster rates resulted in more uniform, stable cakes. Although specific to the product under study, these findings highlight the crucial role of spin-freezing in enhancing freeze-drying efficiency and product quality of biopharmaceuticals.
连续旋转冷冻干燥是一种创新的制药方法,与传统的批量冻干不同,它能在单个小瓶层面进行实时监测和控制。该技术的核心特点是旋转冷冻,即在精确控制的冷气流下快速旋转装满液体的小瓶,从而形成薄而均匀的冷冻产品层。我们使用一个肽配方模型,研究了不同冷却和结晶速率对质量属性(QA)和一次干燥持续时间的影响。关键的质量属性包括单体含量、肽检测、水分含量和孔隙结构。在所有旋转冷冻条件下,单体含量、肽含量和初干持续时间都保持一致。不过,扫描电子显微镜(SEM)和卡尔费休滴定法显示,冷冻参数对孔隙结构和残余水分含量有显著影响。孔隙较小的样品残留水分较低,因为较大的表面积有利于水分的解吸。冷冻参数的变化对二次干燥过程中的解吸动力学也有很大影响。较慢的结晶速度会导致更多的裂缝和更小的饼结构收缩,而较快的结晶速度则会产生更均匀、更稳定的饼。尽管这些研究结果是针对所研究的产品而言的,但它们突出了旋转冷冻在提高生物制药的冷冻干燥效率和产品质量方面的关键作用。
{"title":"Optimization of continuous spin-freeze-drying: The role of spin-freezing on quality attributes and drying efficiency of a model peptide formulation","authors":"Zarah Schaal ,&nbsp;Pieter-Jan Van Bockstal ,&nbsp;Joris Lammens ,&nbsp;Julian H. Lenger ,&nbsp;Adrian P. Funke ,&nbsp;Stefan C. Schneid ,&nbsp;Hristo L. Svilenov ,&nbsp;Thomas De Beer","doi":"10.1016/j.ejps.2024.106963","DOIUrl":"10.1016/j.ejps.2024.106963","url":null,"abstract":"<div><div>Continuous spin-freeze-drying is an innovative pharmaceutical manufacturing approach offering real-time monitoring and control at the individual vial level, unlike conventional batch lyophilization. A central feature of this technology is spin-freezing, which involves rapidly spinning liquid-filled vials under a precisely controlled cold gas flow, resulting in a thin, uniform frozen product layer. Using a model peptide formulation, we investigated the impact of different cooling and crystallization rates on quality attributes (QA) and primary drying duration. Key QAs included monomer content, peptide assay, moisture content, and pore structure. The monomer content, peptide content, and primary drying duration remained consistent across all spin-freezing conditions. However, scanning electron microscopy (SEM) and Karl Fischer titration revealed that freezing parameters significantly influenced pore structure and residual moisture content. Samples with smaller pores displayed lower residual moisture, as larger surface areas facilitate moisture desorption. Variations in freezing parameters also significantly impacted desorption kinetics during secondary drying. Slower crystallization rates led to more cracks and less shrinkage in the cake structure, while faster rates resulted in more uniform, stable cakes. Although specific to the product under study, these findings highlight the crucial role of spin-freezing in enhancing freeze-drying efficiency and product quality of biopharmaceuticals.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106963"},"PeriodicalIF":4.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647191","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}
引用次数: 0
Biophysical insight into the interaction mechanism of 4-bromo-N-(thiazol-2-yl)benzenesulfonamide and human serum albumin using multi-spectroscopic and computational studies 利用多光谱和计算研究对 4-溴-N-(噻唑-2-基)苯磺酰胺与人血清白蛋白相互作用机制的生物物理洞察。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-09 DOI: 10.1016/j.ejps.2024.106961
Francis Ayimbila , Kamonrat Phopin , Waralee Ruankham , Ratchanok Pingaew , Supaluk Prachayasittikul , Virapong Prachayasittikul , Tanawut Tantimongcolwat
4-Bromo-N-(thiazol-2-yl)benzenesulfonamide (1) is enriched with bioactive components and is highlighted for its pharmacological properties. However, its pharmacokinetic characteristics are yet to be reported. The interaction of compound 1 with carrier proteins in the bloodstream is an important factor that affects its potential therapeutic efficacy. This study aimed to elucidate the pharmacokinetic mechanisms of compound 1 in relation to human serum albumin (HSA) using multi-spectroscopic and computational techniques. Its predicted drug-like properties revealed no mutagenicity, although potential hepatotoxicity and interactions with certain cytochrome P450 enzymes were observed. Spectroscopic analyses extensively provided the interaction between HSA and 1 through a static fluorescence quenching mechanism with spontaneous hydrophobic interactions and hydrogen bonding. The binding constant of the HSA‒1 complex was relatively moderate to strong at a level of 106 M−1. Various spectroscopic techniques including ultraviolet-visible, Fourier transform infrared, and circular dichroism spectroscopies indicated that its binding induced alteration in the α-helix content of HSA. Competitive binding and molecular docking studies designated the preferential binding of 1 to sub-structural domain IIA binding site I of HSA. Molecular dynamic simulations further illustrated the formation of a stable complex between 1 and HSA, accompanied by conformational changes in the protein. Importantly, esterase capacity of the HSA‒1 complex increased compared to the free HSA. Therefore, elucidation of the HSA‒1 binding mechanism provides valuable insights into the pharmacokinetics, suggesting potential benefits for the further development of 1 as a therapeutic agent.
4-溴-N-(噻唑-2-基)苯磺酰胺(1)富含生物活性成分,药理特性突出。然而,其药代动力学特征尚未见报道。化合物 1 与血液中载体蛋白的相互作用是影响其潜在疗效的一个重要因素。本研究旨在利用多光谱和计算技术阐明化合物 1 与人血清白蛋白(HSA)的药动学机制。尽管观察到了潜在的肝毒性和与某些细胞色素 P450 酶的相互作用,但其预测的类药物特性显示没有诱变性。光谱分析广泛提供了 HSA 与 1 之间通过自发疏水相互作用和氢键的静态荧光淬灭机制进行的相互作用。HSA-1 复合物的结合常数在 106 M-1 的水平上属于中等偏强。紫外-可见光谱、傅立叶变换红外光谱和圆二色光谱等多种光谱技术表明,它的结合引起了 HSA α-螺旋含量的改变。竞争性结合和分子对接研究表明,1 优先与 HSA 的亚结构域 IIA 结合位点 I 结合。分子动态模拟进一步表明,1 与 HSA 之间形成了稳定的复合物,并伴随着蛋白质构象的变化。重要的是,与游离的 HSA 相比,HSA-1 复合物的酯酶能力有所提高。因此,阐明 HSA-1 的结合机制为药代动力学提供了有价值的见解,为进一步开发 1 作为治疗药物提供了潜在的益处。
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引用次数: 0
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European Journal of Pharmaceutical Sciences
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