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Exploration of moisture activated dry granulation for the development of gastroretentive tablets aided by SeDeM diagram 在 SeDeM 图的帮助下,探索湿气活化干法制粒技术,以开发胃复安片剂。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-15 DOI: 10.1016/j.ejpb.2024.114456
María Ximena Origoni , Anna Nardi-Ricart , Marc Suñé-Pou , Pilar Pérez-Lozano , Miquel Romero-Obón , Josep Maria Suñé- Negre , Ana Teresa Ochoa-Andrade , Encarna García- Montoya

Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM.

In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition.

水分活化干法制粒(MADG)是一种极具吸引力的制粒工艺。然而,只有少数几项研究探讨了通过 MADG 实现的改良药物释放,而且据作者所知,没有一项研究探讨了胃保留问题。本研究的目的是在 SeDeM 图的帮助下,探索 MADG 工艺在开发具有胃保留作用的安慰剂片剂中的适用性。漂浮能力和溶胀能力被确定为关键质量属性(CQA)。经过制剂筛选步骤,浮动基质形成剂和粘合剂的类型和浓度被确定为十种制剂中最相关的关键材料属性(CMA)。针对这些变化因素进行了多元线性回归分析(MLRA),以找到设计空间。根据主成分分析(PCA)结果和多元线性回归分析,制备了一种优化产品,并对其进行了表征。粒料还通过 SeDeM 进行了评估。总之,制粒可制成浮动片剂,浮动滞后时间短(4 小时),并显示出良好的溶胀特性。迄今为止所取得的结果很有希望,足以将 MADG 视为一种有利的制粒方法,用于获得胃复安片剂,甚至是其他需要在其成分中含有相对较多吸收材料的控制给药系统。
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引用次数: 0
Improved RSV preF protein vaccine quality and stability by elucidation of supercooling-induced aggregation phenomena 通过阐明过冷引起的聚集现象提高 RSV PreF 蛋白疫苗的质量和稳定性。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-14 DOI: 10.1016/j.ejpb.2024.114457
Tao Ju Cui , Max Beugeling , Wallace Kaserer , Anton J.P. van Heugten , Martinus A.H. Capelle

Through a synergistic collaboration of people with varying backgrounds and expertise, the root-cause of respiratory syncytial virus prefusion (preF) protein aggregation during freezing was identified to be supercooling. This issue was addressed through a comprehensive understanding of the product. Leveraging innovative and unconventional methods, apparatus, and approaches, it was effectively determined that key parameters influencing aggregation were the nucleation temperature and the duration of supercooling. Moreover, additional measurements revealed that a transition from the preF to the postfusion conformation occurs upon supercooling, which is likely caused by cold denaturation. The importance of considering freezing conditions is highlighted supporting analytical sampling and envisioning that better understanding of sample handling/freezing process can be applied to a wide range of protein-based products.

通过具有不同背景和专业知识的人员的协同合作,确定了呼吸道合胞病毒预融合(preF)蛋白在冷冻过程中聚集的根本原因是过冷。通过对产品的全面了解,这一问题得以解决。利用创新和非常规的方法、设备和途径,有效确定了影响聚集的关键参数是成核温度和过冷持续时间。此外,额外的测量结果表明,过冷时会发生前F构象向后融合构象的转变,这很可能是由冷变性引起的。考虑冷冻条件的重要性得到了强调,这有助于分析取样,并设想更好地了解样品处理/冷冻过程可应用于各种蛋白质产品。
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引用次数: 0
Optimization of polymer coating thickness and strut width in drug Eluting stents using Magnetic field 利用磁场优化药物洗脱支架的聚合物涂层厚度和支架宽度。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-13 DOI: 10.1016/j.ejpb.2024.114455
Seyed Masoud Vahedi, Jalel Azaiez

The transport of drug/magnetic particle (MP) conjugates in the presence of a Magnetic Field (MF) in Drug Eluting Stents (DESs) is modeled numerically using the Finite Volume Method (FVM). The effects of physiological conditions corresponding to different degrees of calcification, drug particles sizes and hematocrit level, were analyzed by investigating the roles of the tissue permeability, its anisotropy and the plasma viscosity. It was found that both in the absence and presence of the MF, as the tissue permeability decreases or the plasma viscosity increases, the free-phase drug and Extracellular Matrix (ECM)-bound phase contents increase. Stronger tissue anisotropy leads to a decrease of the free-phase drug content and an increase of the ECM-bound phase content. Within the explored ranges, the Specific Receptor (SR)-bound phase of the drug was found to be insensitive to the tissue permeability and plasma viscosity, and to be larger in anisotropic tissues. The activation of the MF leads systematically to larger free-phase drug contents, with the increases most prominent at smaller tissue permeability, anisotropy and plasma viscosity. On the other hand, the effects on the ECM-bound phase content are found to be stronger at larger permeability, smaller plasma viscosity and lower tissue anisotropy. For an isotropic tissue, the MF induces a decrease of the ECM-bound phase content at early times, followed by an increase at later times. For the considered ranges of permeability and viscosity, the MF does not seem to have any noticeable effects on the SR-bound phase. However, this phase of the drug tends to increase with the activation of the MF in isotropic tissues and is unchanged in anisotropic ones. These reported effects of the MF hold promise for alleviating two factors contributing to In-Stent Restenosis, namely the polymer coating width and thickness. The study reveals that a narrower or thinner polymer layer, in combination with the MF, can mimic the drug release dynamics of a wider or thicker polymer layer in the absence of the MF. The corresponding width and thickness of the magnetized stents, that we referred to as the equivalent polymer width (EPW) and equivalent polymer thickness (EPT) were determined and their dependence on the tissue permeability, isotropy and the plasma viscosity, was investigated. The study shows that it is possible to achieve the same drug delivery with polymer coating of half the width or half the thickness of the non-magnetized stent when an electric intensity of 3A is used.

利用有限体积法(FVM)对药物洗脱支架(DES)中存在磁场(MF)时药物/磁性颗粒(MP)共轭物的传输进行了数值模拟。通过研究组织渗透性、其各向异性和血浆粘度的作用,分析了不同钙化程度、药物颗粒大小和血细胞比容水平等生理条件的影响。研究发现,在没有 MF 和有 MF 的情况下,随着组织渗透性的降低或血浆粘度的增加,游离相药物和细胞外基质(ECM)结合相的含量都会增加。组织各向异性越强,自由相药物含量就越低,而与细胞外基质(ECM)结合相的含量就越高。在探讨的范围内,发现药物的特异性受体(SR)结合相对组织渗透性和血浆粘度不敏感,而且在各向异性组织中更大。激活 MF 会系统性地导致自由相药物含量增加,在组织渗透性、各向异性和血浆粘度较小的情况下,药物含量的增加最为显著。另一方面,在渗透性较大、血浆粘度较小和组织各向异性较低时,对 ECM 结合相含量的影响更大。对于各向同性组织,MF 在早期会导致 ECM 结合相含量减少,随后会增加。在考虑的渗透性和粘度范围内,MF 似乎不会对 SR 结合相产生任何明显影响。不过,在各向同性的组织中,药物的这一阶段往往会随着 MF 的激活而增加,而在各向异性的组织中则保持不变。据报道,MF 的这些作用有望缓解导致支架内再狭窄的两个因素,即聚合物涂层的宽度和厚度。研究表明,较窄或较薄的聚合物层与磁场纤维相结合,可以模拟较宽或较厚的聚合物层在没有磁场纤维的情况下的药物释放动态。我们确定了磁化支架的相应宽度和厚度(我们称之为等效聚合物宽度(EPW)和等效聚合物厚度(EPT)),并研究了它们与组织渗透性、各向同性和等离子体粘度的关系。研究结果表明,当使用 3A 的电流强度时,宽度或厚度只有非磁化支架一半的聚合物涂层可以达到相同的药物输送效果。
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引用次数: 0
Evaluation of 3-O-β-D-galactosylated resveratrol-loaded polydopamine nanoparticles for hepatocellular carcinoma treatment 评估 3-O-β-D-Galactosylated resveratrol-loaded polydopamine 纳米粒子治疗肝细胞癌的效果。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-13 DOI: 10.1016/j.ejpb.2024.114454
Xiaoxiao Shan , Shujie Lv , Hongyan Cheng , Lele Zhou , Yu Gao , Chengjie Xing , Dawei Li , Wenwen Tao , Caiyun Zhang

In our previous studies, 3-O-β-D-galactosylated resveratrol (Gal-Res) was synthesized by structural modification and then 3-O-β-D-galactosylated resveratrol polydopamine nanoparticles (Gal-Res NPs) were successfully prepared to improve the bioavailability and liver distribution of Res. However, the pharmacodynamic efficacy and specific mechanism of Gal-Res NPs on hepatocellular carcinoma remain unclear. Herein, liver cancer model mice were successfully constructed by xenograft tumor modeling. Gal-Res NPs (34.2 mg/kg) significantly inhibited tumor growth of the liver cancer model mice with no significant effect on their body weight and no obvious toxic effect on major organs. Additionally, in vitro cellular uptake assay showed that Gal-Res NPs (37.5 μmol/L) increased the uptake of Gal-Res by Hepatocellular carcinoma (HepG2) cells, and significantly inhibited the cell migration and invasion. The experimental results of Hoechst 33342/propyl iodide (PI) double staining and flow cytometry both revealed that Gal-Res NPs could remarkably promote cell apoptosis. Moreover, the Western blot results revealed that Gal-Res NPs significantly regulated the Bcl-2/Bax and AKT/GSK3β/β-catenin signaling pathways. Taken together, the in vitro/in vivo results demonstrated that Gal-Res NPs significantly improved the antitumor efficiency of Gal-Res, which is a potential antitumor drug delivery system.

在以往的研究中,我们通过结构修饰合成了3-O-β-D-半乳糖基化白藜芦醇(Gal-Res),并成功制备了3-O-β-D-半乳糖基化白藜芦醇多巴胺纳米颗粒(Gal-Res NPs),提高了Res的生物利用度和肝脏分布。在此,我们通过异种移植肿瘤模型成功构建了肝癌模型小鼠。Gal-Res NPs(34.2 mg/kg)能显著抑制肝癌模型小鼠的肿瘤生长,且对其体重无明显影响,对主要器官无明显毒性作用。此外,体外细胞摄取实验表明,Gal-Res NPs(37.5 μmol/L)能增加肝癌(HepG2)细胞对 Gal-Res 的摄取,并能明显抑制细胞的迁移和侵袭。Hoechst 33342/propyl iodide (PI) 双染色和流式细胞术的实验结果均显示,Gal-Res NPs 能显著促进细胞凋亡。此外,Western blot 结果显示,Gal-Res NPs 能显著调控 Bcl-2/Bax 和 AKT/GSK3β/β-catenin 信号通路。综上所述,体外/体内研究结果表明,Gal-Res NPs能明显提高Gal-Res的抗肿瘤效率,是一种潜在的抗肿瘤药物递送系统。
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引用次数: 0
Contrasting the pharmacokinetic performance and gut microbiota effects of an amorphous solid dispersion and lipid nanoemulsion for a poorly water-soluble anti-psychotic 对比无定形固体分散剂和脂质纳米乳剂对一种水溶性较差的抗精神病药物的药代动力学性能和肠道微生物群的影响。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-10 DOI: 10.1016/j.ejpb.2024.114453
Tahlia R. Meola , Srinivas Kamath , Aurelia S. Elz , Clive A. Prestidge , Anthony Wignall , Paul Joyce

Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable ∼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a ‘gut neutral’ effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota – an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.

人们越来越重视了解口服药物与肠道微生物群之间存在的双向关系。然而,药用辅料对肠道微生物群的影响往往被忽视。因此,在本研究中,我们对比了两种常用的难溶性化合物制剂的药代动力学表现和肠道微生物群的相互作用,这两种制剂分别是:1)由聚乙烯吡咯烷酮 K-30 稳定的无定形固体分散体(ASD);2)由中链甘油酯和卵磷脂组成的脂质纳米乳液(LNE)。由于抗精神病药物鲁拉西酮溶解度低、口服生物利用度差、食物效应明显,因此将其与 ASD 和 LNE 一起配制。在模拟胃肠道环境的体外溶解研究中,ASD 和 LNE 均被证明可促进鲁拉西酮的过饱和。与纯药相比,ASD 和 LNE 可将鲁拉西酮的生物利用度提高 2.5 倍。这两种口服制剂对肠道微生物群的影响截然不同,LNE会降低微生物生态系统的丰富度和丰度,α多样性(Chao1指数)和操作分类单位(OTUs)的减少就证明了这一点。与此相反,ASD 产生了 "肠道中性 "效应,观察到阿尔法多样性和 OTUs 有轻度富集。重要的是,这表明 ASD 是一种有效的增溶制剂,在使用时不会影响肠道微生物群的完整性--由于肠道微生物群在调节情绪和认知方面的作用,这是治疗精神疾病(如精神分裂症)不可或缺的考虑因素。
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引用次数: 0
A one-stop integrated natural antimicrobial microneedles with anti-inflammatory, pro-angiogenic and long-term moisturizing properties to accelerate diabetic wound healing 一站式集成天然抗菌微针,具有消炎、促进血管生成和长期保湿的特性,可加速糖尿病伤口愈合。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-10 DOI: 10.1016/j.ejpb.2024.114448
Aili Wang , Xi Ruan , Xuejiao Wang , Yuyu Ren , Chunjiao Shen , Kaiyi Zhang , Zhenjie Song , Bai Xiang , Yinling Ma , Feng Zhao

Diabetic ulcers present a formidable obstacle in diabetes management, typically leading to high mortality and amputation rates. To overcome traditional monotherapy drawbacks, We developed a novel microneedle strategy for combined antimicrobial action: ingeniously integrating quercetin with Platelet-derived Growth Factor-BB(PDGF-BB) and Sucrose Octasulfate(SOS) into the microneedle system(QPS MN). This method allows to penetrate through biofilms, administering quercetin nanocrystals and PDGF-BB deep into the tissue to combat microbial infection, mitigate inflammation, and promote angiogenesis. The accompanying backing material contains SOS, which absorbs wound exudate and forms a dressing that provides a moist environment for wound healing In an in vitro wound-scratch assay demonstrated that co-cultivating Human Umbilical Vein Endothelial Cells(HUVEC) with QPS MN for 48 h (90.3 ± 2.51 %) significantly enhanced cell migration compared to the control group (20.2 ± 1.41 %). Moreover, treatment of streptozotocin-induced diabetic wounds in rats with QPS MN for 14 days resulted in a wound healing rate of 96.56 ± 3.44 %, far surpassing the healing rate of only 40.34 ± 7.26 % observed in the untreated control group. Furthermore, the QPS MN treated wounds exhibited a notable increase in skin appendages and neovascularisation, indicating promising potential for achieving complete wound healing. These results suggest that QPS MN may offer substantial therapeutic benefits for addressing diabetic wounds.

糖尿病溃疡是糖尿病治疗中的一个巨大障碍,通常会导致很高的死亡率和截肢率。为了克服传统单一疗法的弊端,我们开发了一种新型微针联合抗菌策略:将槲皮素、血小板衍生生长因子-BB(PDGF-BB)和八硫酸蔗糖(SOS)巧妙地整合到微针系统(QPS MN)中。这种方法可以穿透生物膜,将槲皮素纳米晶体和 PDGF-BB 深入组织,以抗击微生物感染、缓解炎症和促进血管生成。体外伤口划痕试验表明,与对照组(20.2 ± 1.41 %)相比,将人脐静脉内皮细胞(HUVEC)与 QPS MN 共同培养 48 小时(90.3 ± 2.51 %)可显著提高细胞迁移率。此外,用 QPS MN 治疗链脲佐菌素诱导的糖尿病大鼠伤口 14 天后,伤口愈合率为 96.56 ± 3.44 %,远远超过了未经治疗的对照组仅为 40.34 ± 7.26 % 的愈合率。此外,QPS MN 处理过的伤口显示出皮肤附属物和新生血管明显增多,表明其具有实现伤口完全愈合的潜力。这些结果表明,QPS MN 可为糖尿病伤口的治疗带来巨大的益处。
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引用次数: 0
Paediatric excipient risk assessment (PERA) tool and application for selecting appropriate excipients for paediatric dosage forms – Part 2 儿科辅料风险评估(PERA)工具及应用,用于选择合适的儿科剂型辅料--第 2 部分。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-08 DOI: 10.1016/j.ejpb.2024.114447
Anjali Agrawal , Smita Salunke , Alfred Rumondor , Karen Thompson , Grazia Caivano , Jennifer Walsh , Brian Enright , Philip Sherratt , Kevin Hughes , David Clapham , Peter Kuehl , on behalf of the International Consortium (IQ) for Innovation and Quality in Pharmaceutical Development and European Paediatric Formulation Initiative (EuPFI)

It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The “Paediatric Excipient Risk Assessment (PERA)” framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products.

This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool’s usefulness.

有必要采用科学合理的辅料风险评估、选择和管理程序,以开发既安全又有效的儿科医药产品。儿科辅料风险评估(PERA)"框架通过考虑与患者、剂型和辅料属性有关的所有相关因素,提出了一种全面的方法。本文是该系列的第 2 部分,介绍了 PERA 工具,该工具可方便地采用 PERA 框架。PERA 工具采用直接的热图评分法(红色、黄色和绿色类别)进行风险评估,可用于比较和选择辅料。PERA 工具将帮助用户识别辅料信息中的潜在差距,从而有助于制定基于风险的缓解规划。几项案例研究涵盖了口服常用辅料和新型辅料,以及新生儿肠外给药产品辅料的选择,这些案例说明了 PERA 工具的实用性。
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引用次数: 0
Harnessing cells to improve transport of nanomedicines 利用细胞改善纳米药物的运输。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-08 DOI: 10.1016/j.ejpb.2024.114446
Andrea Bezze , Carlotta Mattioda , Gianluca Ciardelli, Clara Mattu

Efficient tumour treatment is hampered by the poor selectivity of anticancer drugs, resulting in scarce tumour accumulation and undesired off-target effects. Nano-sized drug-delivery systems in the form of nanoparticles (NPs) have been proposed to improve drug distribution to solid tumours, by virtue of their ability of passive and active tumour targeting. Despite these advantages, literature studies indicated that less than 1% of the administered NPs can successfully reach the tumour mass, highlighting the necessity for more efficient drug transporters in cancer treatment. Living cells, such as blood cells, circulating immune cells, platelets, and stem cells, are often found as an infiltrating component in most solid tumours, because of their ability to naturally circumvent immune recognition, bypass biological barriers, and reach inaccessible tissues through innate tropism and active motility. Therefore, the tumour-homing ability of these cells can be harnessed to design living cell carriers able to improve the transport of drugs and NPs to tumours. Albeit promising, this approach is still in its beginnings and suffers from difficult scalability, high cost, and poor reproducibility. In this review, we present an overview of the most common cell transporters of drugs and NPs, and we discuss how different cell types interact with biological barriers to deliver cargoes of various natures to tumours. Finally, we analyse the different techniques used to load drugs or NPs in living cells and discuss their advantages and disadvantages.

由于抗癌药物的选择性较差,导致肿瘤积聚较少,并产生不希望出现的脱靶效应,从而阻碍了肿瘤的有效治疗。纳米颗粒(NPs)形式的纳米尺寸给药系统凭借其被动和主动靶向肿瘤的能力,被提出来改善药物在实体瘤中的分布。尽管有这些优点,但文献研究表明,只有不到 1%的给药 NPs 能成功到达肿瘤组织,这突出表明在癌症治疗中需要更高效的药物运输工具。活细胞,如血细胞、循环免疫细胞、血小板和干细胞,通常是大多数实体瘤的浸润成分,因为它们能够自然地绕过免疫识别、绕过生物屏障,并通过先天性趋向性和主动运动性到达无法进入的组织。因此,可以利用这些细胞的肿瘤 "归宿 "能力来设计活细胞载体,从而改善药物和 NPs 向肿瘤的运输。尽管前景广阔,但这种方法仍处于起步阶段,存在难以扩展、成本高昂和可重复性差等问题。在这篇综述中,我们概述了药物和 NPs 最常见的细胞转运体,并讨论了不同类型的细胞如何与生物屏障相互作用,将不同性质的货物运送到肿瘤中。最后,我们分析了用于在活细胞中装载药物或 NPs 的不同技术,并讨论了它们的优缺点。
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引用次数: 0
Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency 用于治疗sepiapterin还原酶缺乏症的卡比多巴/左旋多巴口服溶液的配方和临床评估。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-07 DOI: 10.1016/j.ejpb.2024.114429
Evelina Maines , Giorgio Temporin , Michela Fedrizzi , Alessandra Pasqualini , Lorenzo Junior Masnata , Annalisa Campomori , Alessandro Iodice , Giovanni Piccoli , Massimo Soffiati , Roberto Franceschi , Silvana Anna Maria Urru

Background

sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients.

Materials and methods

we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD.

Results

we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance.

Conclusions

in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.

背景:sepiapterine还原酶缺乏症(SRD)是一种罕见的左旋多巴(L-多巴)反应性疾病,可通过控释左旋多巴和卡比多巴联合疗法进行治疗。目前可用的卡比多巴/左旋多巴控释制剂并不完全符合儿童患者长期治疗的要求。事实上,如果按成人剂量服用已制成的药片,就必须根据儿童的需要进行调整,如将药片分成小份或用水稀释。必须强调的是,药片不能压碎,否则会破坏控释机制,影响药效。目前还没有商业液体制剂。材料和方法:我们介绍了 1:10 比例的卡比多巴/多巴风味(薄荷、覆盆子、可可、浆果)和无味口服制剂(未添加甜味剂)的样品制备、物理和微生物分析、口味测试和耐受性。我们还报告了对两名患有SRD的儿童患者的长期随访结果:我们记录了液体溶液在25°C下28天的稳定性。所有制剂的耐受性都很好,在评估口感和耐受性期间或之后均未发现不良反应。对两名患者的长期随访显示,他们的症状得到了有效控制,治疗的依从性和顺应性也达到了最佳水平。鉴于口感对服药依从性的重要影响,在开发左旋多巴/卡比多巴液体制剂时使用调味剂是一项非常有用的策略,可使儿科患者获得最佳的服药依从性。
{"title":"Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency","authors":"Evelina Maines ,&nbsp;Giorgio Temporin ,&nbsp;Michela Fedrizzi ,&nbsp;Alessandra Pasqualini ,&nbsp;Lorenzo Junior Masnata ,&nbsp;Annalisa Campomori ,&nbsp;Alessandro Iodice ,&nbsp;Giovanni Piccoli ,&nbsp;Massimo Soffiati ,&nbsp;Roberto Franceschi ,&nbsp;Silvana Anna Maria Urru","doi":"10.1016/j.ejpb.2024.114429","DOIUrl":"10.1016/j.ejpb.2024.114429","url":null,"abstract":"<div><h3>Background</h3><p>sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients.</p></div><div><h3>Materials and methods</h3><p>we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD.</p></div><div><h3>Results</h3><p>we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance.</p></div><div><h3>Conclusions</h3><p>in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114429"},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Cationic pH-sensitive liposome-based subunit tuberculosis vaccine induces protection in mice challenged with Mycobacterium tuberculosis 对 pH 值敏感的阳离子脂质体结核亚单位疫苗能在受到结核分枝杆菌挑战的小鼠体内产生保护作用。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-07 DOI: 10.1016/j.ejpb.2024.114437
M.M. Szachniewicz , S.J.F. van den Eeden , K.E. van Meijgaarden , K.L.M.C. Franken , S. van Veen , A. Geluk , J.A. Bouwstra , T.H.M. Ottenhoff

Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants – CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB.

In vitro in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. In vivo, the new vaccine administrated subcutaneously significantly reduced Mycobacterium tuberculosis (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine’s effectiveness in terms of its capacity to induce polyfunctional CD4+ and CD8+ T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69+ B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.

几个世纪以来,结核病(TB)一直是全球的紧急疾病,现在依然如此。通过接种疫苗预防疾病将对疾病的流行产生重大影响,但目前唯一可用的疫苗卡介苗效果不佳。本文利用 Ag85B-ESAT6-Rv2034 融合抗原、两种佐剂(CpG 和 MPLA)以及阳离子 pH 敏感脂质体作为递送系统,开发了一种新型结核病亚单位疫苗,这是一种以前从未报道过的结核病疫苗递送策略。在体外人树突状细胞(DCs)中,与不添加佐剂的脂质体相比,添加佐剂的配方诱导产生的(先天性)细胞因子和趋化因子显著增加。在体内,皮下注射新疫苗可显著减少小鼠肺部和脾脏中的结核分枝杆菌(Mtb)细菌量,明显优于接种抗原与佐剂混合但不含脂质体的小鼠。深入分析证实了疫苗在诱导多功能 CD4+ 和 CD8+ T 细胞反应方面的有效性,而这两种细胞反应都被认为是控制 Mtb 感染的关键。同样值得注意的是,各种 CD69+ B 细胞亚群的丰度不同,其中包括产生 IL17-A 的 B 细胞。疫苗激发了强大的抗原特异性抗体滴度,进一步扩大了其作为新型结核病保护剂的潜力。
{"title":"Cationic pH-sensitive liposome-based subunit tuberculosis vaccine induces protection in mice challenged with Mycobacterium tuberculosis","authors":"M.M. Szachniewicz ,&nbsp;S.J.F. van den Eeden ,&nbsp;K.E. van Meijgaarden ,&nbsp;K.L.M.C. Franken ,&nbsp;S. van Veen ,&nbsp;A. Geluk ,&nbsp;J.A. Bouwstra ,&nbsp;T.H.M. Ottenhoff","doi":"10.1016/j.ejpb.2024.114437","DOIUrl":"10.1016/j.ejpb.2024.114437","url":null,"abstract":"<div><p>Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants – CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB.</p><p><em>In vitro</em> in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. <em>In vivo</em>, the new vaccine administrated subcutaneously significantly reduced <em>Mycobacterium tuberculosis</em> (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine’s effectiveness in terms of its capacity to induce polyfunctional CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69<sup>+</sup> B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114437"},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002637/pdfft?md5=1a1aa331630a54c5190dd72437be78fc&pid=1-s2.0-S0939641124002637-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
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European Journal of Pharmaceutics and Biopharmaceutics
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