European Journal of Pharmaceutics and Biopharmaceutics最新文献_第6页

Comparing effects of terpene-based deep eutectic solvent and solid microneedles on skin permeation of drugs with varying lipophilicity 比较萜烯基深共晶溶剂和固体微针对不同亲脂性药物皮肤渗透的影响

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-11-09 DOI: 10.1016/j.ejpb.2024.114576

Grzegorz S. Czyrski, Mikkel K. Frese Hjort, Thomas Rades, Andrea Heinz

Transdermal delivery of therapeutic molecules is often hindered by the properties of the skin, with the stratum corneum serving as the primary permeation barrier. To overcome this barrier, the integrity of the stratum corneum can be modified by chemical permeation enhancers, such as deep eutectic solvents (DESs), or by mechanically impairing the skin with microneedles (MNs). However, a systematic comparison between these strategies is currently lacking. Hence, this study examined the potential of DESs and MNs to promote the permeation and retention of drugs with varying lipophilicities – specifically, the hydrophilic drug metronidazole (logP ∼ 0), the moderately lipophilic drug lidocaine (logP ∼ 2.3), and the highly lipophilic drug clotrimazole (logP ∼ 5). A mixture of menthol and thymol was selected as a model terpene-based DES and delivery vehicle, while a DermaPen equipped with solid MNs was used to mechanically impair the skin. Permeation rates of model drugs applied to the skin with either DES, MNs, or both were compared to the rates determined for the drugs applied in control vehicles. Both strategies were found to compromise the skin barrier function, but their permeation-enhancing effect was dependent on the lipophilicity of tested model drug. The DES was most effective for the hydrophilic drug metronidazole, while the MNs were more effective in increasing the permeation of the highly lipophilic drug clotrimazole. For the moderately lipophilic drug lidocaine, neither the DES nor MNs increased its permeation rate, as the drug permeated through the skin well on its own. Notably, the combination of both enhancement strategies did not result in significantly better permeation rates of the drugs compared to the individual approaches. In conclusion, both the terpene-based DES and solid MNs are effective strategies to enhance drug permeation through the skin, but our results suggest that the choice of strategy should be dictated by the drug’s lipophilicity. Moreover, from a permeation-enhancing perspective, there is no benefit in combining these two strategies.

治疗分子的透皮给药通常受到皮肤特性的阻碍，而角质层是主要的渗透屏障。为了克服这一障碍，可以通过化学渗透促进剂（如深共晶溶剂（DES））或微针（MN）机械损伤皮肤来改变角质层的完整性。然而，目前还缺乏对这些策略的系统比较。因此，本研究考察了 DESs 和 MNs 促进不同亲脂性药物渗透和保留的潜力，特别是亲水性药物甲硝唑（logP ∼ 0）、中等亲脂性药物利多卡因（logP ∼ 2.3）和高亲脂性药物克霉唑（logP ∼ 5）。薄荷醇和百里酚的混合物被选为基于萜烯的 DES 和输送载体模型，而装有固体 MNs 的 DermaPen 则用于机械损伤皮肤。将使用 DES、MNs 或两者的皮肤模型药物渗透率与使用对照载体的药物渗透率进行了比较。结果发现，这两种方法都会损害皮肤屏障功能，但它们的渗透增强效果取决于被测模型药物的亲脂性。DES 对亲水性药物甲硝唑最有效，而 MN 对增加高亲脂性药物克霉唑的渗透更有效。对于中等亲脂性药物利多卡因，DES 和微针都不能提高其渗透率，因为这种药物本身就能很好地透过皮肤。值得注意的是，与单独使用两种方法相比，两种增强策略的结合并没有明显提高药物的渗透率。总之，基于萜烯的 DES 和固体 MNs 都是增强药物在皮肤中渗透的有效策略，但我们的研究结果表明，策略的选择应取决于药物的亲脂性。此外，从促进渗透的角度来看，将这两种策略结合使用并无益处。

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引用次数: 0

Unveiling the potential of pulmonary surfactant-based nanocarriers for protein inhalation therapy 揭示基于肺表面活性物质的纳米载体在蛋白质吸入疗法中的潜力。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-11-07 DOI: 10.1016/j.ejpb.2024.114574

Kiramat Ali Shah , Anam Razzaq , Bengang You , Amos Dormocara , Haroon Iqbal , Jing-Hao Cui

The study investigates the effect of pulmonary surfactant (PS) coating on the performance of lysozyme-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs). The NPs were fabricated using a double emulsification technique and optimized using the Box-Behnken experimental design (BBED). The NPs were assessed for size, polydispersity index (PDI), zeta potential, drug loading (DL%), and encapsulation efficiency (EE%). In addition, the optimized PLGA NPs were modified with either a neutral dipalmitoylphosphatidylcholine DPPC or an anionic dipalmitoyl phosphatidylglycerol (DPPG) with different molar ratios of PS to PLGA (PS: PLGA = 1:2, 1:1 and 2:1). These NPs were assessed for biological activity, drug release, mucus adhesion, mucus penetration, cellular uptake, toxicity, and in vivo destiny after intratracheal (IT) instillation to mice. Results showed a bi-phasic drug release, with no significant effect of PS on the release and biological activities of PLGA NPs. The PS@PLGA NPs improved mucus adhesion, decreased mucus penetration, and increased cellular internalization of PLGA NPs. In addition, ex vivo experiments demonstrated that DPPC@PLGA NPs and DPPG@PLGA NPs could adhere to mucus. These NPs created a thicker layer at the interface of the airway compared to unmodified PLGA NPs. Moreover, interaction of PS@PLGA NPs with BALF suggested improved mucoadhesive characteristics. Finally, the in vivo studies confirmed the precise distribution of all NPs in the lungs after IT administration. The study presents empirical evidence and scientific guidance for developing a lung surfactant-modified nanocarrier system for lung drug delivery.

本研究探讨了肺表面活性物质（PS）涂层对溶菌酶负载的聚（乳酸-共聚乙醇）酸（PLGA）纳米粒子（NPs）性能的影响。NPs 采用双乳化技术制备，并通过盒式-贝肯实验设计（BBED）进行了优化。对 NPs 的尺寸、多分散指数（PDI）、ZETA 电位、载药量（DL%）和封装效率（EE%）进行了评估。此外，还用中性二棕榈酰基磷脂酰胆碱 DPPC 或阴离子二棕榈酰基磷脂酰甘油 (DPPG) 对优化的 PLGA NPs 进行了修饰，PS 与 PLGA 的摩尔比各不相同（PS: PLGA = 1:2、1:1 和 2:1）。对这些 NPs 进行了生物活性、药物释放、粘液粘附、粘液渗透、细胞摄取、毒性和小鼠气管内（IT）灌注后的体内去向评估。结果表明，PS 对 PLGA NPs 的释放和生物活性无明显影响，药物释放呈双相进行。PS@PLGA NPs 改善了粘液粘附性，降低了粘液穿透性，增加了 PLGA NPs 的细胞内化。此外，体内外实验表明，DPPC@PLGA NPs 和 DPPG@PLGA NPs 可以粘附在粘液上。与未改性的 PLGA NPs 相比，这些 NPs 在气道界面上形成了更厚的一层。此外，PS@PLGA NPs 与 BALF 的相互作用表明它们具有更好的粘液粘附特性。最后，体内研究证实了所有 NPs 在 IT 给药后在肺部的精确分布。该研究为开发用于肺部给药的肺表面活性剂修饰纳米载体系统提供了经验证据和科学指导。

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引用次数: 0

Functionalisation of chitosan with methacryloyl and crotonoyl groups as a strategy to enhance its mucoadhesive properties 用甲基丙烯酰基和巴豆酰基对壳聚糖进行官能化处理，以增强其粘附性。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-11-06 DOI: 10.1016/j.ejpb.2024.114575

Shiva Vanukuru , Fraser Steele , Natalia N. Porfiryeva , Alejandro Sosnik , Vitaliy V. Khutoryanskiy

Mucoadhesive polymers are crucial for prolonging drug retention on mucosal surfaces. This study focuses on synthesising and characterising novel derivatives by reacting chitosan with crotonic and methacrylic anhydrides. The structure of the resulting derivatives was confirmed using proton-nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy. It was established that the degree of substitution plays a crucial role in the pH-dependent solubility profiles and electrophoretic mobility of the chitosan derivatives. Spray-drying chitosan solutions enabled preparation of microparticles, whose mucoadhesive properties were evaluated using fluorescence flow-through studies and tensile test, demonstrating improved retention on sheep nasal mucosa for modified derivatives. Acute toxicity studies conducted in vivo using planaria and in vitro using MTT assay with the Caco-2 cell line, a model of the mucosal epithelium in vitro, showed that the novel derivatives are not cytotoxic. These findings emphasise the potential of tailored chitosan chemical modifications for enhancing transmucosal drug delivery.

粘液黏性聚合物对于延长药物在粘膜表面的滞留时间至关重要。本研究的重点是通过壳聚糖与巴豆酸酐和甲基丙烯酸酐的反应合成新型衍生物并确定其特性。利用质子-核磁共振波谱和傅立叶变换红外光谱确认了所得衍生物的结构。结果表明，取代度对壳聚糖衍生物随 pH 值变化的溶解度曲线和电泳迁移率起着至关重要的作用。通过对壳聚糖溶液进行喷雾干燥，制备出了微颗粒，并利用荧光流动研究和拉伸试验对其粘附性进行了评估，结果表明改性衍生物在绵羊鼻粘膜上的粘附性有所改善。利用疟原虫进行的体内急性毒性研究和利用体外粘膜上皮细胞模型 Caco-2 细胞系进行的 MTT 试验表明，新型衍生物没有细胞毒性。这些发现强调了壳聚糖定制化学修饰在加强经粘膜给药方面的潜力。

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引用次数: 0

Transitioning from Pickering emulsions to Pickering emulsion hydrogels: A potential advancement in cosmeceuticals 从皮克林乳液过渡到皮克林乳液水凝胶：药用化妆品的潜在进步。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-30 DOI: 10.1016/j.ejpb.2024.114572

Akashni Rajoo , Sangeetaprivya P. Siva , Chin Siew Sia , Eng-Seng Chan , Beng Ti Tey , Liang Ee Low

Cosmeceuticals, focusing on enhancing skin health and appearance, heavily rely on emulsions as one of the common mediums. These emulsions pose a challenge due to their dependence on surfactants which are essential for stability but are causing concerns about environmental impact as well as evolving consumer preferences. This has led to research focused on Pickering emulsions (PEs), which are colloidal particle-based emulsion alternatives. Compared to conventional emulsions, PEs offer enhanced stability and functionality in addition to serving as a sustainable alternative but still pose challenges such as rheological control and requiring further improvement in long-term stability, whereby the limitations could be addressed through the introduction of a hydrogel network. In this review, we first highlight the strategies and considerations to optimize active ingredient (AI) absorption and penetration in a PE-based formulation. We then delve into a comprehensive overview of the potential of Pickering-based cosmeceutical emulsions including their attractive features, the various Pickering particles that can be employed, past studies and their limitations. Further, PE hydrogels (PEHs), which combines the features between PE and hydrogel as an innovative solution to address challenges posed by both conventional emulsions and PEs in the cosmeceutical industry is explored. Moreover, concerns related to toxicity and biocompatibility are critically examined, alongside considerations of scalability and commercial viability, providing a forward-looking perspective on potential future research directions centered on the application of PEHs in the cosmeceutical field.

注重增强皮肤健康和外观的药妆产品在很大程度上依赖乳液作为常用介质之一。这些乳液对表面活性剂的依赖是一个挑战，表面活性剂对稳定性至关重要，但却引起了人们对环境影响和消费者偏好不断变化的担忧。因此，研究重点转向皮克林乳液（PE），这是一种基于胶体颗粒的乳液替代品。与传统乳液相比，皮克林乳液除了作为一种可持续的替代品外，还具有更高的稳定性和功能性，但仍面临流变控制等挑战，需要进一步提高长期稳定性，而这些限制可通过引入水凝胶网络来解决。在本综述中，我们首先强调了在聚乙烯制剂中优化活性成分（AI）吸收和渗透的策略和注意事项。然后，我们全面概述了基于皮克林的药用化妆品乳剂的潜力，包括其诱人的特点、可采用的各种皮克林颗粒、以往的研究及其局限性。此外，还探讨了聚乙烯水凝胶（PEHs），它结合了聚乙烯和水凝胶的特点，是解决传统乳剂和聚乙烯在药用化妆品行业所面临挑战的创新解决方案。此外，还批判性地研究了与毒性和生物相容性有关的问题，以及可扩展性和商业可行性方面的考虑因素，为以聚乙烯水凝胶在药妆领域的应用为中心的潜在未来研究方向提供了前瞻性视角。

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引用次数: 0

Computational and experimental analysis of Luteolin-β-cyclodextrin supramolecular complexes: Insights into conformational dynamics and phase solubility 木犀草素-β-环糊精超分子复合物的计算和实验分析：对构象动力学和相溶解性的见解。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-29 DOI: 10.1016/j.ejpb.2024.114569

Pramod Kumar , Vijay Kumar Bhardwaj , Pravin Shende , Rituraj Purohit

Investigating the structural stability of poorly-soluble luteolin (LuT) after encapsulation within cyclodextrins (CDs) is crucial for unlocking the therapeutic potential of LuT bioactive molecule. Herein, native and modified β-CD were employed to investigate LuT inclusion complex formation. Molecular mechanics (MM) and quantum mechanics (QM) were utilized for structural dynamics analysis. Microsecond timescale MD simulations yielded insights into LuT-CD interactions. The binding affinity between LuT and selected β-CDs was assessed by calculating the binding free energy using MM-PBSA and umbrella sampling simulations. The MM-PBSA results indicated that Heptakis-O-(2-hydroxypropyl)-β-CD (HP-β-CD) (−82.59+/-11.67 kJ/mol) and Di-O-methyl-β-CD (DM-β-CD) (−54.01+/-11.07 kJ/mol) exhibited good binding affinity for LuT. Subsequently, derivative screening of HP-β-CD revealed that only 2-HP-β-CD (HP-β-CD-1)/LuT (−21.38 kJ/mol) displayed a superior binding free energy (obtained from umbrella sampling) than HP-β-CD/LuT (−16.55 kJ/mol) inclusion complex. We conducted QM calculations on the top three inclusion complexes namelly HP-β-CD, DM-β-CD, and HP-β-CD-1 employing wB97X-D/6–311 + G(d,p) model chemistry to strengthen the MM results. The computational analysis aligns with experimental findings (phase solubility analysis), validating HP-β-CD-1 as most effective cavitand molecule for improving the solubility of LuT. This study offers critical structural insights for developing novel HP-β-CD derivatives with enhanced host capacity to encapsulate guest molecules efficiently.

研究溶解性差的木犀草素（LuT）被环糊精（CD）包裹后的结构稳定性，对于挖掘 LuT 生物活性分子的治疗潜力至关重要。本文采用原生和改性β-CD来研究LuT包合物的形成。分子力学（MM）和量子力学（QM）被用于结构动力学分析。微秒级的 MD 模拟揭示了 LuT 与 CD 之间的相互作用。通过使用 MM-PBSA 和伞状采样模拟计算结合自由能，评估了 LuT 与所选 β-CD 之间的结合亲和力。MM-PBSA 结果表明，Heptakis-O-（2-羟基丙基）-β-CD（HP-β-CD）（-82.59+/-11.67 kJ/mol）和 Di-O-methyl-β-CD （DM-β-CD）（-54.01+/-11.07 kJ/mol）与 LuT 具有良好的结合亲和力。随后，对 HP-β-CD 进行衍生筛选后发现，只有 2-HP-β-CD (HP-β-CD-1)/LuT (-21.38 kJ/mol) 的结合自由能（通过伞状取样获得）高于 HP-β-CD/LuT (-19.15 kJ/mol) 包合物。我们采用 wB97X-D/6-311 + G(d,p) 化学模型对排名前三的复合物命名为 HP-β-CD、DM-β-CD 和 HP-β-CD-1 进行了 QM 计算，以加强 MM 结果。计算分析结果与实验结果（相溶解度分析）一致，验证了 HP-β-CD-1 是提高 LuT 溶解度最有效的空穴剂分子。这项研究为开发新型 HP-β-CD 衍生物提供了重要的结构见解，这些衍生物具有更强的宿主能力，能有效地包裹客体分子。

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引用次数: 0

Electrospun nanofibers for localized drug release of a neuroprotective natural extract of Usnea ghattensis 用于局部释放具有神经保护作用的 USNEA ghattensis 天然提取物的电纺纳米纤维。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-28 DOI: 10.1016/j.ejpb.2024.114552

María de la Cabeza Fernández , Marta Sánchez , Laura Lozano-Chamizo , Ana Cristina Abreu , Ana Anguís-Morillas , Padreep K Divakar , Marzia Marciello , Marco Filice , Victor Gonzalez-Rumayor , Ignacio Fernández , Rafael Contreras-Cáceres , Pilar Gómez-Serranillos

This research is based on the incorporation of the methanolic extract of the Usnea ghattensis into poly (caprolactone) (PCL) nanofibers (NFs) to investigate the capacity in reducing reactive oxygen species (ROS). PCL-NFs were fabricated by the electrospinning technique and are investigated as potential dressing material focused on the release of usnic acid (PCL-USNIC NFs), and its encapsulation efficiency and kinetic release were analyzed by high performance liquid chromatography (HPLC). This investigation was performed by analyzing the usnic acid concentration as a function of the distance from the mat center point. The kinetic release analysis is also developed with the usnea ghattensis extract (PCL-USNEA NFs), performing a metabolomic analysis of the released molecules as a function of time by nuclear magnetic resonance (NMR). Usnic acid was revealed as the most relevant compound together with other molecules, such as sucrose, mannitol, arabitol or glycerol that generate a positive matrix effect on the release of usnic acid. Finally, we analize the cytotoxicity and the neuroprotective effect of PCL-USNEA and PCL-USNIC NFs using a human neuroblastoma cell line model. Negligible toxicity was appreciated for both polymeric systems, showing high protective effects in presence of highly oxidative environment (e.g. in presence of H₂O₂).

本研究的基础是将乌蛇床子的甲醇提取物加入聚己内酯（PCL）纳米纤维（NFs）中，研究其减少活性氧（ROS）的能力。研究人员采用电纺丝技术制备了 PCL-NFs 并将其作为一种潜在的敷料材料进行了研究，该材料主要用于释放鼠李酸（PCL-USNIC NFs），并通过高效液相色谱法（HPLC）分析了其封装效率和释放动力学。这项研究是通过分析烟酸浓度与垫中心点距离的函数关系来进行的。此外，还对麝香草提取物（PCL-USNEA NFs）进行了动力学释放分析，通过核磁共振（NMR）对释放分子随时间变化的代谢组学分析。结果表明，鸟苷酸是最相关的化合物，其他分子如蔗糖、甘露醇、阿拉伯糖醇或甘油也对鸟苷酸的释放产生积极的基质效应。最后，我们利用人类神经母细胞瘤细胞系模型分析了 PCL-USNEA 和 PCL-USNIC NFs 的细胞毒性和神经保护作用。结果表明，这两种聚合物系统的毒性都很低，在高氧化环境（如 H2O2）下具有很强的保护作用。

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引用次数: 0

Enhancing RNA encapsulation quantification in lipid nanoparticles: Sustainable alternatives to Triton X-100 in the RiboGreen assay 增强脂质纳米颗粒中的 RNA 封装定量：RiboGreen 试验中 Triton X-100 的可持续替代品。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-28 DOI: 10.1016/j.ejpb.2024.114571

David Schultz , Rasmus D. Münter , Alex M. Cantín , Paul J. Kempen , Nadin Jahnke , Thomas L. Andresen , Jens B. Simonsen , Andrew J. Urquhart

To quantify concentration and encapsulation efficiency (EE) of mRNA in lipid nanoparticles (LNPs) the RiboGreen assay is extensively used. As part of this assay, a surfactant is used to release mRNA from LNPs for detection with the RiboGreen dye. So far, the surfactant of choice has been Triton X-100, which is harmful to human health and the environment. Alternatives to Triton X-100 are therefore needed, but surprisingly no such effort has yet been described in the literature. Here we show how three, less harmful, surfactants (Brij 93, Zwittergent 3–14 and Tween 20) compare to Triton X-100 for releasing mRNA from LNPs for detection with the RiboGreen assay. We found that Zwittergent 3–14 and Tween 20 at high concentrations (0.5 %) are at the minimum as effective as Triton X-100 at high concentration (0.5 %) across three different mRNA-LNP formulations. Interestingly, Tween 20 was the most effective at releasing mRNA from LNPs, across all concentration ranges explored (0.0025 %, 0.01 %, 0.1 % and to 0.5 % (v/v)) highlighting its potency at solubilizing the three different LNP formulations. Our results show that Tween 20 can be used as an alternative to Triton X-100 in the RiboGreen assay, resulting in more accurate quantification of the total mRNA concentration and EE%, as well as making the assay more environmentally friendly. Such improvement could potentially increase the likelihood of identifying therapeutically attractive hard-to-solubilize LNP-mRNA formulations that would be discharged when using Triton X-100 due to their apparent low EE values, as well as ensure more accurate mRNA dosing in both in vitro and in vivo studies.

为了量化脂质纳米粒子（LNPs）中 mRNA 的浓度和封装效率（EE），RiboGreen 分析法被广泛使用。作为该检测方法的一部分，表面活性剂被用来从 LNPs 中释放 mRNA，以便用 RiboGreen 染料进行检测。迄今为止，首选的表面活性剂是 Triton X-100，它对人体健康和环境有害。因此，我们需要 Triton X-100 的替代品，但令人惊讶的是，文献中还没有这方面的描述。在这里，我们展示了三种危害较小的表面活性剂（Brij 93、Zwittergent 3-14 和 Tween 20）与 Triton X-100 相比，如何从 LNPs 中释放 mRNA，以便用 RiboGreen 检测法进行检测。我们发现，在三种不同的 mRNA-LNP 配方中，高浓度（0.5%）的 Zwittergent 3-14 和 Tween 20 与高浓度（0.5%）的 Triton X-100 的效果相当。有趣的是，在所探讨的所有浓度范围（0.0025%、0.01%、0.1% 至 0.5%（v/v））内，吐温 20 从 LNPs 中释放 mRNA 的效果最好，这凸显了它对三种不同 LNP 配方的增溶作用。我们的研究结果表明，在 RiboGreen 检测中，吐温 20 可替代 Triton X-100，从而更准确地量化总 mRNA 浓度和 EE%，并使检测更环保。这种改进有可能提高识别具有治疗吸引力的难以溶解的 LNP-mRNA 制剂的可能性，这些制剂在使用 Triton X-100 时会因其明显的低 EE 值而被排出，同时还能确保在体外和体内研究中的 mRNA 剂量更准确。

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引用次数: 0

Accelerating thrombolysis of arterial thrombus with NO-MBs UTMD therapy 利用 NO-MBs UTMD 疗法加速动脉血栓溶解。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-28 DOI: 10.1016/j.ejpb.2024.114566

Binbin Shi , Qiaohua Yang , Zenghui Liang , Runjie Yu , Hui Li , Qilong Wu , Mingling Fang , Lili Lin , Huafang Chen , Yingzheng Zhao , Bin Chen

Arterial thrombotic disease is a common and serious clinical medical problem. Nitric oxide (NO), as a therapeutic gas, can delay the progression of thrombosis and reduce tissue ischemia and hypoxia damage. However, systemic delivery of NO causes complications, and NO in the body is easily cleared by hemoglobin in the blood. In this study, we designed a lipid microbubble carrying NO (NO-MBs) combined with ultrasound-targeted microbubble destruction (UTMD) technology to achieve targeted delivery of NO under real-time contrast-enhanced ultrasound monitoring. The good stability of the NO-MBs was demonstrated by examining the changes in diameter, concentration and contrast-enhanced ultrasound intensity with time. Moreover, in vivo and in vitro thrombolysis experiments, it was confirmed that the combination of NO-MBs and UTMD could accelerate arterial thrombolysis. Meanwhile, the levels of inflammatory factors, superoxide dismutase (SOD) and malondialdehyde (MDA) in vascular tissue after treatment were detected, which showed that NO-MBs could significantly reduce the inflammatory response and oxidative stress induced by thromboembolism. In addition, so as to‌ evaluate the safety of the NO-MBs UTMD treatment strategy, MTT assay, hemolysis test, detection of serum biochemical indicators, and H&E staining of major organs were performed. The results showed that this treatment strategy had excellent biosafety. In conclusion, the NO-MBs UTMD treatment strategy has great potential in the treatment of arterial thrombotic diseases.

动脉血栓性疾病是一种常见而严重的临床医学问题。一氧化氮（NO）作为一种治疗气体，可以延缓血栓形成的进展，减轻组织缺血缺氧损伤。然而，NO 的全身给药会引起并发症，而且体内的 NO 很容易被血液中的血红蛋白清除。在这项研究中，我们设计了一种携带 NO 的脂质微泡（NO-MBs），并结合超声靶向微泡破坏（UTMD）技术，在实时造影剂增强超声监测下实现 NO 的靶向输送。通过检测NO-MB的直径、浓度和造影剂增强超声强度随时间的变化，证明了其良好的稳定性。此外，体内和体外溶栓实验证实，NO-MB 和 UTMD 的结合可加速动脉溶栓。同时，检测了治疗后血管组织中炎症因子、超氧化物歧化酶（SOD）和丙二醛（MDA）的水平，结果表明 NO-MBs 能显著减轻血栓栓塞引起的炎症反应和氧化应激。此外，为了评估 NO-MBs UTMD 治疗策略的安全性，研究人员还进行了 MTT 试验、溶血试验、血清生化指标检测和主要器官的 H&E 染色。结果表明，这种治疗策略具有良好的生物安全性。总之，NO-MBs UTMD 治疗策略在治疗动脉血栓性疾病方面具有巨大潜力。

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引用次数: 0

Deep eutectic solvent combined with permeation enhancer strategy to convert tandospirone from oral to transdermal formulations improving drug bioavailability 深层共晶溶剂与渗透促进剂相结合的策略可将坦度螺酮从口服制剂转化为透皮制剂，从而提高药物的生物利用度

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-28 DOI: 10.1016/j.ejpb.2024.114570

Peng Sun, Hui Li, Kaihua Gong, Yang Zhang, Yu Cai, Chao Liu, Liang Fang

Tandospirone(Tan) is a commonly used drug for anxiety treatment. However, it has a significant first-pass effect and needs to be taken three times a day. To increase the bioavailability of the drug and reduce the number of administrations, this work amid to prepare a Tan patch that can be administered once a day by using the strategy of therapeutic deep eutectic solvent(THEDES) in cooperation with chemical permeation enhancer(CPE). In this study, four organic acids and five permeation enhancers were selected, and the optimized formulation was obtained by single-factor investigation and Box-Behnken design. The optimized formulation could significantly enhance drug loading by 2.5-fold and skin permeation up to 586.6 ± 17 μg/cm² in rats. Based on pharmacokinetic results, compared to oral administration, the drug exhibited a substantially elevated bioavailability, registering a 17-fold increase(from 3.01 % to 52.17 %), alongside a 10-fold rise in the mean residence time(MRT). Meanwhile, the patch was not irritating. The results of the mechanistic study showed that levulinic acid(LeA) acted as a bridge to increase the interaction between the Tan and the matrix and inhibited the crystallization of the drug in the patch, and THEDES together with CPE improved the matrix fluidity and skin permeability. This study provides a reference for the joint application of THEDES and CPEs in patch development.

坦度螺酮（Tan）是治疗焦虑症的常用药物。然而，它有明显的首过效应，每天需要服用三次。为了提高该药物的生物利用度并减少给药次数，本研究采用治疗性深共晶溶剂（THEDES）与化学渗透促进剂（CPE）相结合的策略，制备了一种每天给药一次的坦度螺酮贴片。本研究选择了四种有机酸和五种渗透促进剂，并通过单因素考察和盒-贝肯设计获得了优化配方。优化后的制剂可使大鼠的载药量提高 2.5 倍，皮肤渗透率达到 586.6 ± 17 μg/cm2。药代动力学结果显示，与口服给药相比，该药物的生物利用度大幅提高，提高了 17 倍（从 3.01% 提高到 52.17%），平均滞留时间（MRT）也提高了 10 倍。同时，该贴片没有刺激性。机理研究结果表明，乙酰丙酸（LeA）作为桥梁增加了鞣剂与基质之间的相互作用，抑制了药物在贴片中的结晶，而 THEDES 与 CPE 一起提高了基质的流动性和皮肤的渗透性。这项研究为在贴片开发中联合应用 THEDES 和 CPE 提供了参考。

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引用次数: 0

Machine learning driven bioequivalence risk assessment at an early stage of generic drug development 仿制药开发早期阶段的机器学习驱动生物等效性风险评估

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-26 DOI: 10.1016/j.ejpb.2024.114553

Dejan Krajcar , Dejan Velušček , Iztok Grabnar

Background

Bioequivalence risk assessment as an extension of quality risk management lacks examples of quantitative approaches to risk assessment at an early stage of generic drug development. The aim of our study was to develop a model-based approach for bioequivalence risk assessment that uses pharmacokinetic and physicochemical characteristics of drugs as predictors and would standardize the first step of risk assessment.

Methods

The Sandoz in-house bioequivalence database of 128 bioequivalence studies with poorly soluble drugs (23.5% non-bioequivalent) was used to train and validate the model. Four different modeling approaches, random forest, XGBoost, logistic regression and naïve Bayes, were compared.

Results

Among the best performing machine learning models, random forest was selected and optimized for the number of features, resulting in an accuracy of 84% on the test data set. The most important features for prediction were those related to solubility (dose number, acid dissociation constant), absorption and elimination rate, effective permeability, variability of pharmacokinetic endpoints, and absolute bioavailability. All features had a conceivable influence on the model predictions.

Conclusion

The model was used to develop a bioequivalence risk assessment approach to categorize drugs in early development into high, medium or low risk classes.

背景生物等效性风险评估作为质量风险管理的延伸，在仿制药开发的早期阶段缺乏定量风险评估方法的实例。我们的研究旨在开发一种基于模型的生物等效性风险评估方法，该方法将药物的药代动力学和物理化学特征作为预测因素，并将风险评估的第一步标准化。方法使用山德士公司内部的生物等效性数据库来训练和验证模型，该数据库包含 128 项生物等效性研究，其中有溶解性较差的药物（23.5% 为非生物等效性）。结果在性能最好的机器学习模型中，随机森林被选中并对特征数量进行了优化，结果在测试数据集上的准确率达到 84%。预测中最重要的特征与溶解度（剂量数、酸解离常数）、吸收和消除率、有效渗透性、药动学终点的可变性和绝对生物利用度有关。结论该模型用于开发生物等效性风险评估方法，将早期开发药物分为高、中或低风险等级。

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引用次数: 0