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Factors affecting flash nanoprecipitation of Pharmaceuticals: Principles and applications. 影响药物闪蒸纳米沉淀的因素:原理和应用。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-07 DOI: 10.1016/j.ejpb.2026.114984
Wisdom Awuku, Bi-Botti Celestin Youan

Flash nanoprecipitation (FNP) has emerged as a transformative technique in the preparation of nanoparticles for targeted drug delivery. Traditional drug delivery systems often struggle with challenges such as poor solubility, limited bioavailability, and suboptimal targeting. FNP addresses these limitations through a one-step, scalable process that produces nanoparticles with tunable size, composition, morphology, and surface characteristics. This review explores the principles of FNP, focusing on its application in encapsulating bioactive agents, achieving controlled release, and enhancing bioavailability. Unlike conventional emulsification or antisolvent precipitation methods, FNP utilizes rapid mixing under kinetically controlled conditions to achieve high reproducibility and uniform particle distribution. The technique has been successfully employed for various pharmaceutical applications, including the delivery of small molecules, biologics, and nucleic acids. Beyond laboratory research, FNP has been adopted in industrial and clinical settings-for instance, in the scalable production of lipid nanoparticles (LNPs) for mRNA-based vaccines and other nucleic acid therapeutics-demonstrating its translational potential. Furthermore, its adaptability extends to theranostic and imaging applications. The review highlights critical formulation variables and process parameters, such as polymer type and its glass transition temperature, solvent selection, and Reynolds number, which influence key characteristics such as nanoparticle stability and performance. By synthesizing recent advances, this paper provides a comprehensive overview of how FNP is already transforming drug delivery, highlighting its current impact, and future research directions.

闪速纳米沉淀法(FNP)已成为一种变革性的技术,用于制备靶向药物递送的纳米颗粒。传统的给药系统经常面临溶解度差、生物利用度有限和靶向性不佳等挑战。FNP通过一步、可扩展的工艺解决了这些限制,生产出具有可调尺寸、组成、形态和表面特征的纳米颗粒。本文综述了FNP的原理,重点介绍了FNP在生物活性药物包封、控释和提高生物利用度等方面的应用。与传统的乳化或抗溶剂沉淀方法不同,FNP在动力学控制条件下快速混合,以实现高重现性和均匀的颗粒分布。该技术已成功应用于各种制药应用,包括小分子、生物制剂和核酸的输送。除实验室研究外,FNP已被应用于工业和临床环境中,例如用于mrna疫苗和其他核酸疗法的脂质纳米颗粒(LNPs)的规模化生产,证明了其转化潜力。此外,它的适应性扩展到治疗和成像应用。本文重点介绍了影响纳米颗粒稳定性和性能等关键特性的关键配方变量和工艺参数,如聚合物类型及其玻璃化转变温度、溶剂选择和雷诺数。通过综合近年来的研究进展,本文全面概述了FNP如何改变药物传递,突出了其目前的影响和未来的研究方向。
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引用次数: 0
Tuning the in vivo transfection efficiency of mRNA-Loaded lipoplexes by PEG-Lipid structure and ratio 通过peg -脂质结构和比例调节mrna负载脂质体的体内转染效率。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-03 DOI: 10.1016/j.ejpb.2026.114981
O.V. Markov , D.N. Antropov , E.V. Shmendel , P.A. Puchkov , O.A. Yakovlev , M.D. Kerbitskaya , E.S. Zhuravlev , A.S. Dome , E.P. Goncharova , D.N. Shcherbakov , M.A. Zenkova , M.A. Maslov , G.A. Stepanov
The development of mRNA-based antiviral and antitumor therapeutics is progressing rapidly and shows considerable promise. Optimizing the composition of liposomal delivery vehicles is critical for enhancing mRNA vaccine efficacy. Among their components, PEG-lipids require careful optimization to improve the colloidal stability of mRNA-liposome complexes, prolong their in vivo circulation time, and enhance mRNA delivery efficiency, thereby eliciting a robust immune response. Here, we report a structure-functional analysis of PEG-lipids incorporated into cationic liposomes based on the cationic lipid 2X3 and the helper lipid DOPE. The following parameters of PEG-lipids were varied: PEG chain length (800–2000 Da), PEG-lipid architecture (classical head-to-tail vs. gemini-like structures), hydrophobic anchor chain length (C14 octadecyl and C18 tetradecyl residues) and molar amount of PEG-lipid in formulations (0.5–4 mol%). We demonstrated that optimized liposomes contained 4 mol% of a PEG-lipid composed of linear PEG2000 conjugated to a C14-dialkylglycerol anchor via a carbamate linker. This formulation enabled efficient in vivo expression of luciferase-encoding mRNA and, upon delivery of influenza A/California//07/09 (H1N1pdm09) hemagglutinin-encoding mRNA, induced robust antigen-specific humoral and cellular immunity. Our findings underscore the critical importance of PEG-lipid optimization for advancing potent mRNA delivery platforms for antiviral and antitumor vaccines.
基于mrna的抗病毒和抗肿瘤治疗正在迅速发展,并显示出相当大的前景。优化脂质体递送载体的组成对提高mRNA疫苗的效力至关重要。在其成分中,peg -脂质需要精心优化,以提高mRNA-脂质体复合物的胶体稳定性,延长其体内循环时间,提高mRNA的传递效率,从而引发强大的免疫反应。在这里,我们报告了基于阳离子脂质2X3和辅助脂质DOPE的阳离子脂质体中peg -脂质的结构-功能分析。PEG-脂类的以下参数是不同的:PEG链长(800-2000 Da)、PEG-脂类结构(经典的头尾结构与双分子结构)、疏水锚链长度(C14十八烷基和C18十四烷基残基)和配方中PEG-脂类的摩尔量(0.5-4 摩尔%)。我们证明,优化的脂质体含有4 摩尔%的peg -脂质,由线性PEG2000通过氨基甲酸酯连接剂偶联到c14 -二烷基甘油锚定物。该制剂能够在体内高效表达荧光素酶编码mRNA,并在递送甲型流感/California//07/09 (H1N1pdm09)血凝素编码mRNA后,诱导强大的抗原特异性体液和细胞免疫。我们的研究结果强调了peg -脂质优化对于推进抗病毒和抗肿瘤疫苗的有效mRNA递送平台的重要性。
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引用次数: 0
Humectant-plasticized poly(vinyl alcohol)-sericin hydrogels with improved dimensional stability and moisture retention for wound dressing applications 湿润增塑型聚乙烯醇-丝胶水凝胶,具有更好的尺寸稳定性和保湿性,用于伤口敷料应用。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-03 DOI: 10.1016/j.ejpb.2026.114982
Thunyaluk Meetam , Rungnapha Yamdech , Pithi Chanvorachote , Pornanong Aramwit
This study investigated the development of poly(vinyl alcohol) (PVA)/sericin hydrogels incorporating humectant-plasticizers glycerin, propylene glycol, and mannitol for wound dressing applications. Although PVA/sericin hydrogels exhibit excellent cytocompatibility and promote fibroblast proliferation and collagen production, making them promising candidates for wound care, they suffer from rapid moisture loss and dimensional instability. To address these limitations, glycerin, propylene glycol, and/or mannitol were incorporated to enhance the properties of the hydrogels. The physicochemical and mechanical properties, together with the in vitro cytocompatibility of L929 fibroblasts, were evaluated. The results demonstrated that incorporating propylene glycol and/or mannitol improved dimensional stability, skin adhesion, moisture retention, exudate absorption, flexibility, and softness. Among all the formulations, the hydrogel containing 1 % v/v propylene glycol and 1 % w/v mannitol exhibited the most balanced performance, combining superior physicochemical and mechanical properties (time to initial upward bending: 2.83 h; time for complete upward bending of all four edges: 10.50 h; gel fraction: 60 %, highest absorption at 3 h: 34.41 %; tensile strength: 46.93 kPa, elastic modulus: 33.53 kPa, compressive strength: 19.94 kPa; compressive modulus: 15.58 kPa) with enhanced fibroblast viability (102 % cell viability) and sustained sericin release (∼90 % cumulative release at 168 h). In vitro assays confirmed the cytocompatibility of the optimized hydrogel. Taken together, these findings indicate its potential for effective management of moderately exudating wounds. This study introduces a simple and practical plasticization approach for PVA/sericin hydrogels, offering a promising candidate for wound dressing applications. Further clinical studies are warranted to evaluate its therapeutic efficacy and safety.
本研究探讨了含有湿润增塑剂甘油、丙二醇和甘露醇的聚乙烯醇/丝胶凝胶在伤口敷料中的应用。尽管PVA/丝胶水凝胶具有良好的细胞相容性,促进成纤维细胞增殖和胶原蛋白的产生,使其成为伤口护理的有希望的候选者,但它们具有快速的水分流失和尺寸不稳定性。为了解决这些限制,加入了甘油、丙二醇和/或甘露醇来增强水凝胶的性能。对L929成纤维细胞的理化、力学性能及体外细胞相容性进行了评价。结果表明,加入丙二醇和/或甘露醇可以改善尺寸稳定性、皮肤粘附性、保湿性、渗出物吸收性、柔韧性和柔软性。在所有的配方中,水凝胶含有1 % v / v丙二醇,1 % w /甘露醇展出最均衡的性能,结合优越的物理化学和力学性能(初始向上弯曲时间:2.83 h;时间完成向上弯曲的四个边:10.50 h;凝胶分数:60 %,最高吸收3 h: 34.41 %;抗拉强度:46.93 kPa,弹性模量:33.53 kPa,抗压强度:19.94 kPa;压缩模量:15.58 kPa),增强成纤维细胞活力(102 %细胞活力)和持续的丝胶蛋白释放(在168 h累积释放约90 %)。体外实验证实了优化后的水凝胶的细胞相容性。综上所述,这些发现表明其在中度渗出性伤口的有效管理潜力。本研究介绍了一种简单实用的PVA/丝胶水凝胶的塑化方法,为伤口敷料的应用提供了一个有前途的候选材料。需要进一步的临床研究来评价其治疗效果和安全性。
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引用次数: 0
Corrigendum to "Nanogel therapy for chronic and post-surgical wounds: a bioengineered Lactoferrin-Acacia-Alginate system enhancing tissue regeneration and inflammatory resolution" [Eur. J. Pharm. Biopharm. 219 (2026) 114952]. “纳米凝胶治疗慢性和术后伤口:生物工程乳铁蛋白-金银花-海藻酸盐系统增强组织再生和炎症消退”的更正[欧洲]。j .制药。生物医学工程学报,2009(5):349 - 349。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-27 DOI: 10.1016/j.ejpb.2025.114969
Samaa Abdullah, Samar Thiab, Abeer A Altamimi, Alaa A Al-Masud, Meshal Marzoog Al-Sharafa, Hatim S AlKhatib, Imad Hamadneh
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引用次数: 0
Co-administering clofazimine with infant formula enhances its oral bioavailability in rats and pigs 氯法齐明与婴儿配方奶粉联合使用可提高其在大鼠和猪体内的口服生物利用度。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-23 DOI: 10.1016/j.ejpb.2025.114979
Thomas Eason , Ellie Ponsonby-Thomas , Anna C. Pham , Shouyuan Huang , Simone Margaard Offersen , Thomas Thymann , Vanessa Zann , Malinda Salim , Ben J. Boyd
Milk-based formulations have been proposed as enabling formulations for the delivery of poorly water-soluble drugs to children due to their safety, dose versatility and ability to improve drug solubilisation through the digestion process. In this study the feasibility of using commercially available infant formula as an enabling formulation to enhance the solubilisation and oral bioavailability of clofazimine, a poorly soluble lipophilic drug, following oral administration was investigated. The solubilisation of crystalline clofazimine in digesting infant formula was assessed in vitro using synchrotron small-angle X-ray scattering. An in vivo pharmacokinetic study was then conducted to determine the oral bioavailability of a suspension of clofazimine in infant formula compared to a lipid-free aqueous suspension in both a rat and piglet animal model. Clofazimine administered in infant formula produced significantly higher plasma concentrations than the aqueous vehicle and resulted in comparable enhancements in relative oral bioavailability in both the piglet (235%) and rat animal models (256%). Results from this study demonstrated that infant formula was an effective enabling formulation, with a positive correlation between improved drug solubilisation during in vitro digestion of infant formula and enhanced in vivo drug exposure following oral administration. Infant formula therefore offers an inexpensive and scalable formulation approach for improving the bioavailability of paediatric drugs, like clofazimine, and enabling the treatment of infections in children.
由于其安全性、剂量控制的通用性和通过消化过程改善药物溶解的能力,牛奶基配方已被提议作为给儿童提供水溶性差药物的可行配方。在这项研究中,研究了在口服给药后,使用市售婴儿配方奶粉作为增强氯法齐明(一种难溶性亲脂药物)的增溶性和口服生物利用度的可行性。采用同步加速器小角x射线散射法研究了氯法齐明晶体在婴儿配方奶粉消化中的增溶作用。然后,在大鼠和仔猪动物模型中进行了体内药代动力学研究,以确定婴儿配方奶粉中氯法齐明悬浮液与无脂水悬浮液的口服生物利用度。氯法齐明在婴儿配方奶粉中的血浆浓度明显高于水溶液,在仔猪(235%)和大鼠动物模型(256%)中,氯法齐明的相对口服生物利用度都有相当的提高。本研究的结果表明,婴儿配方奶粉是一种有效的促进配方,在婴儿配方奶粉体外消化过程中改善药物增溶性与口服给药后增加体内药物暴露之间存在正相关关系。因此,婴儿配方奶粉为提高氯法齐明等儿科药物的生物利用度和治疗儿童感染提供了一种廉价和可扩展的配方方法。
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引用次数: 0
Sulfasalazine–quercetin co-amorphous systems: Sustained release behaviors and enhanced pharmacokinetics 柳氮磺胺吡啶-槲皮素共无定形体系:缓释行为和增强的药代动力学。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-22 DOI: 10.1016/j.ejpb.2025.114972
Jia Deng , Jiangying Li , Yangwen Peng , Qian Dai , Ningbo Pang , Zhe Wang , Hailu Zhang , Xin Chen
Sulfasalazine (SULF) is a well-established therapeutic agent for rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), but its oral absorption is limited by efflux transporters, particularly MRP2 and BCRP. Consequently, high daily doses (1–3 g) and frequent administration (three to four times daily) are required, increasing the risk of adverse effects during long-term therapy. To overcome these limitations, co-amorphous systems (CASs) of SULF with quercetin (QUE) were developed in this study. The CASs were systematically characterized using powder X-ray diffraction (PXRD), polarized light microscopy (PLM), scanning electron microscopy (SEM), and temperature-modulated differential scanning calorimetry (mDSC). The molecular-level formation mechanism was further elucidated via Fourier-transform infrared spectroscopy (FTIR) and molecular dynamics (MD) simulations. All SULF–QUE CASs exhibited glass transition temperatures around 113 °C and demonstrated sustained-release behavior, with markedly lower SULF dissolution (24.5–42.9 %) compared to the crystalline form (89.8 %) after 6 h. This reduction was attributed to the in situ formation of a dense “shell-like” recrystallized QUE surface structure resulting from its incongruent dissolution. Importantly, co-amorphous forms demonstrated enhanced oral bioavailability (1.52–2.80-fold) and prolonged Tmax (1.84–5.52-fold) compared to crystalline SULF, fulfilling the original goal of their development. Moreover, these systems exhibited satisfactory physical stability over time. Overall, the SULF–QUE CASs present a promising strategy to optimize the clinical dosage of SULF, reduce side effects, and offer a synergistic therapeutic approach for RA and IBD.
柳氮磺胺吡啶(SULF)是一种公认的治疗类风湿性关节炎(RA)和炎症性肠病(IBD)的药物,但其口服吸收受到外排转运蛋白,特别是MRP2和BCRP的限制。因此,需要每日高剂量(1-3 g)和频繁给药(每日三至四次),这增加了长期治疗期间不良反应的风险。为了克服这些限制,本研究开发了SULF与槲皮素(QUE)的共无定形体系(CASs)。采用粉末x射线衍射(PXRD)、偏振光显微镜(PLM)、扫描电镜(SEM)和温度调制差示扫描量热法(mDSC)对CASs进行了系统表征。通过傅里叶变换红外光谱(FTIR)和分子动力学(MD)模拟进一步阐明了分子水平的形成机理。所有的SULF- que CASs都表现出113 °C左右的玻璃化转变温度,并表现出缓释行为,在6 h后,SULF的溶解(24.5-42.9 %)明显低于结晶形式(89.8 %)。这种减少归因于原位形成致密的“贝壳状”再结晶QUE表面结构,这是由于其不均匀溶解造成的。重要的是,与结晶型磺胺砜相比,共无定形形式表现出更高的口服生物利用度(1.52-2.80倍)和延长的Tmax(1.84-5.52倍),实现了其开发的最初目标。此外,随着时间的推移,这些系统表现出令人满意的物理稳定性。总体而言,SULF- que CASs为优化SULF的临床剂量、减少副作用以及为RA和IBD提供协同治疗方法提供了一种有希望的策略。
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引用次数: 0
Reflection paper on the APV workshop on in vitro performance testing of topically applied and topically acting substances 外用和外用作用物质体外性能测试APV研讨会反思论文。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-21 DOI: 10.1016/j.ejpb.2025.114971
Dominique Lunter , Sascha Gorissen , Michael Herbig , Martin Hukauf , Adina Eichner
With great anticipation, the European Medicines Agency (EMA) guideline titled “Quality and Equivalence of Locally Applied, Locally Acting Cutaneous Products” officially came into effect on April 2, 2025. This regulatory document establishes the legal and scientific framework for the evaluation of generic topical medicinal products, particularly those for which systemic bioavailability is not a relevant endpoint. The guideline is designed to replace conventional clinical trials with scientifically justified alternative methodologies for demonstrating therapeutic equivalence to reference products in the context of generic marketing authorization. These methodologies include, most notably, in vitro release testing (IVRT), in vitro permeation testing (IVPT), stratum corneum sampling via tape stripping (TS), and the vasoconstriction assay for corticosteroids. Based on the draft guideline version released in 2018, preliminary experience has been gathered in recent years regarding the implementation and practical applicability of some testing parameters proposed. However, this early engagement also exposed several ambiguities and limitations in the draft guidance, prompting expectations that the finalized version would address these deficiencies and offer more comprehensive direction on the use of these methods. The present paper is intended to summarize these known limitations and critically examine selected aspects of the guideline. Thereby, it seeks to provide an informed perspective on the scope, robustness, and regulatory utility of the final guideline, and to facilitate a dialogue on its practical implementation in regulatory and industrial settings.
欧洲药品管理局(EMA)题为“局部应用、局部作用皮肤产品的质量和等效性”的指南于2025年4月2日正式生效。本规范性文件建立了非专利外用药品评价的法律和科学框架,特别是那些系统生物利用度不是相关终点的药品。该指南旨在用科学证明的替代方法取代传统临床试验,以证明仿制药上市许可背景下与参考产品的治疗等效性。这些方法包括,最值得注意的是,体外释放测试(IVRT),体外渗透测试(IVPT),角质层取样通过胶带剥离(TS),和皮质类固醇血管收缩试验。根据2018年发布的指南草案版本,近年来对所提出的一些测试参数的实施和实际适用性进行了初步的经验总结。然而,这种早期接触也暴露了指南草案中的一些含糊不清和限制,促使人们期望最终版本将解决这些缺陷,并就这些方法的使用提供更全面的指导。本文旨在总结这些已知的局限性,并严格检查指南的选定方面。因此,它试图就最终指南的范围、稳健性和监管效用提供一个知情的观点,并促进就其在监管和工业环境中的实际实施进行对话。
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引用次数: 0
Exploration of a dual-mimetic mucus inert nanocomplex for enhanced oral insulin delivery 双重模拟粘液惰性纳米复合物增强口服胰岛素递送的探索
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-20 DOI: 10.1016/j.ejpb.2025.114970
Qiyao Zhai , Shuang Guo , Zhixiang Cui , Lu Qin , Jian Guan , Xin Zhang , Shirui Mao
The development of oral insulin delivery systems has advanced significantly, with polyelectrolyte nanocomplexes (PEC) showing promise due to their solvent-free synthesis. However, their efficacy is limited by poor mucus penetration and intestinal absorption. Inspired by the nature of mucin, chitosan (CS) modified with proline, threonine and serine to mimic the mucin’s PTS sequence were synthesized to enhance mucus permeability of the PEC. To further improve the mucus permeability and the trans-epithelial transport of the PEC, muco-penetrating nanocomplexes were fabricated by utilizing hyaluronic acid (HA), thus forming a surface with high-density positive and negative charges to mimic the surface charge properties of viruses. The nanocomplexes were self-assembled using modified CS and insulin, followed by HA coating. It was demonstrated that the nanocomplexes exhibited good physical stability, enhanced protection against enzymatic degradation, and increased penetration efficiency across the mucus layer and small intestine compared to unmodified counterparts. Furthermore, the in vivo hypoglycemic study further revealed a 2.16-fold increase in relative pharmacological availability for the nanocomplexes over the CS/Ins PEC Collectively, these findings reveal the potential of (PTS-CS/Ins)/HA, a dual-mimicking muco-penetrating nanocomplex based on the nature of mucin and virus, as a promising platform for oral insulin delivery.
口服胰岛素递送系统的发展取得了显著进展,聚电解质纳米复合物(PEC)由于其无溶剂合成而显示出前景。然而,由于黏液渗透和肠道吸收较差,其疗效受到限制。受粘蛋白性质的启发,合成了脯氨酸、苏氨酸和丝氨酸修饰的壳聚糖(CS)来模拟粘蛋白的PTS序列,以提高PEC的粘液通透性。为了进一步提高PEC的粘液渗透性和跨上皮运输能力,我们利用透明质酸(HA)制备了粘膜穿透纳米复合物,从而形成具有高密度正负电荷的表面,以模拟病毒的表面电荷特性。采用改性CS和胰岛素自组装纳米复合物,然后包被透明质酸。结果表明,与未经修饰的纳米复合物相比,纳米复合物具有良好的物理稳定性,增强了对酶降解的保护作用,并提高了穿过黏液层和小肠的渗透效率。此外,体内降糖研究进一步显示,纳米复合物的相对药理学有效性比CS/Ins PEC增加了2.16倍。总之,这些发现揭示了(PTS-CS/Ins)/HA,一种基于粘蛋白和病毒性质的双重模拟粘膜穿透纳米复合物的潜力,作为口服胰岛素递送的有希望的平台。
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引用次数: 0
Novel PLA-based shape-memory formulation: Design, preparation, and evaluation for gastro-retentive delivery of 5-fluorouracil to enhance oral bioavailability 新型pla形状记忆制剂:5-氟尿嘧啶胃保留递送提高口服生物利用度的设计、制备和评估
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-19 DOI: 10.1016/j.ejpb.2025.114968
Fengxue Liu , Xuefei Yu , Yanmei Wu , Ting Zhu , Ning Chen , Hao Chen , Wei Shen , Wei Zheng
5-fluorouracil (5-FU) is one of the most effective chemotherapeutic drugs for various solid tumors. However, its low water solubility and limited absorption rates in the stomach are crucial limitations that prevent it from being effectively applied in clinical practice. To address these issues, we first encapsulated 5-FU in β-cyclodextrin (5-FU–β-CD) to enhance its solubility, and the resulting 5-FU–β-CD was then loaded into a PLA film to prepare a novel gastro-retentive drug delivery system (GRDDS) based on shape-memory properties. The excipients, such as tributyl citrate (TBC), hydroxyethyl cellulose (HEC), citric acid (CA), and sodium bicarbonate (NaHCO3), were incorporated into the PLA matrix at an optimized ratio. This was done to enhance the performance of PLA as an ideal matrix material in GRDDS, including improvements in drug release, floating behavior, shape recovery, gastric retention, and in vivo anti-tumor activity. The results suggested that the solubility of the 5-FU–β-CD inclusion complex was significantly enhanced, which was 1.88-fold higher than that of pure 5-FU. The optimal shape-memory drug delivery formulation, 5-FU–β-CD–PLA/TBC (86/14), prepared in this study consists of PLA/TBC (86/14) incorporating 3 % HEC, 3 % NaHCO3, 1 % CA, and 3 % 5-FU. Its gastric retention time was notably prolonged to approximately 8 h following oral administration in mice, whereas the residual amount of 5-FU–β-CD at this time point was much lower than the initial loading. The oral bioavailability of the 5-FU–β-CD–PLA/TBC (86/14) was 269 % higher than that of pure 5-FU. Additionally, the mean tumor size and weight in the mouse model of gastric carcinoma administered with 5-FU–β-CD–PLA/TBC (86/14) were 215.3 mm3 and 241.4 mg respectively, significantly smaller than those in the 5-FU group. This indicates that the novel PLA-based drug delivery system has significantly enhanced anti-tumor effects. Its excellent therapeutic effects were further confirmed through HE, Ki67, and TUNEL staining. Taken together, 5-FU–β-CD–PLA/TBC (86/14) can be retained in the stomach to improve relative bioavailability. This system represents a promising carrier not only for 5-FU but also for other poorly soluble drugs that require prolonged retention in the stomach.
5-氟尿嘧啶(5-FU)是治疗各种实体肿瘤最有效的化疗药物之一。然而,它的低水溶性和有限的胃吸收率是阻碍其有效应用于临床实践的关键限制。为了解决这些问题,我们首先将5-FU封装在β-环糊精(5-FU-β-CD)中以提高其溶解度,然后将得到的5-FU-β-CD装入PLA薄膜中,以制备一种基于形状记忆特性的新型胃保性给药系统(GRDDS)。将柠檬酸三丁酯(TBC)、羟乙基纤维素(HEC)、柠檬酸(CA)和碳酸氢钠(NaHCO3)等赋形剂以最佳配比掺入PLA基质中。这样做是为了提高PLA作为GRDDS理想基质材料的性能,包括改善药物释放、漂浮行为、形状恢复、胃潴留和体内抗肿瘤活性。结果表明,5-FU-β-CD包合物的溶解度显著提高,是纯5-FU的1.88倍。本研究制备的最佳形状记忆给药配方5-FU-β-CD-PLA/TBC(86/14)由PLA/TBC(86/14)组成,其中含有3 % HEC、3 % NaHCO3、1 % CA和3 % 5-FU。小鼠口服后,其胃潴留时间明显延长至约8 h,而5-FU-β-CD在此时间点的残留量远低于初始负荷。5-FU-β-CD-PLA/TBC的口服生物利用度(86/14)比纯5-FU高269 %。5-FU-β-CD-PLA/TBC组小鼠胃癌模型平均肿瘤大小和重量分别为215.3 mm3和241.4 mg(86/14),明显小于5-FU组。这表明基于pla的新型给药系统具有显著增强的抗肿瘤作用。HE、Ki67、TUNEL染色进一步证实其良好的治疗效果。综上所述,5-FU-β-CD-PLA/TBC(86/14)可保留在胃中,提高相对生物利用度。该系统不仅是5-FU的有前途的载体,也是其他需要在胃中长时间滞留的难溶性药物的载体。
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引用次数: 0
A biomimetic nano-suspension based on orthoester designed for the inhibition of postoperative tumor recurrence 一种基于矫形酯的仿生纳米悬浮液,用于抑制术后肿瘤复发。
IF 4.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-15 DOI: 10.1016/j.ejpb.2025.114967
Rongjian Hu , Xian Zhang , Weibin Shao , Na Li , Li Kang , Xin Wang
Tumor recurrence after surgery remains a major challenge. Herein, an orthoester (OE) compound was synthesized as a liquid pharmaceutical excipient. Next, an injectable suspension loaded with biomimetic nanoparticles and photothermal agents was constructed based on OE to inhibit tumor recurrence. The synthesized OE has the characteristics of simple structure, acid-sensitivity, clear degradation mechanism in vivo. More importantly, as a liquid excipient, OE can dissolve or disperse a variety of drugs, biomacromolecules or nanoparticles to form a stable suspension at extremely high concentrations. Thus, dasatinib (DAS) and sunitinib (SUN) were self-assembled to form nanoparticles, and cancer cell membrane vesicles were coated to obtain biomimetic nanoparticles (HCM@NPs). The self-assembly of DAS and SUN induces molecular aggregation, resulting in an aggregation-induced emission (AIE) effect, which facilitates the tracking of intracellular drug delivery. HCM@NPs and photothermal agent IR820 were co-dispersed in OE to obtain a synergistic therapeutic suspension (OE/IR/HCM@NPs). The suspension can be injected around the tumor or applied directly to the surgical bed to cover any suspicious areas. OE significantly improves the photothermal conversion efficiency of IR820 through its exceptionally low specific heat capacity (1.8 J/(g·℃)), which is markedly lower than that of water (4.2 J/(g·℃). In vitro and in vivo data demonstrated that the OE-based suspension directly inhibited tumor growth and prevented tumor recurrence. All mice receiving chemotherapy alone succumbed within 26 days due to tumor recurrence, whereas 66 % of those treated with the OE nano-suspension exhibited complete suppression of tumor recurrence over the observation period. This paper provides a new idea for the development of suspensions based on OE.
手术后肿瘤复发仍然是一个主要的挑战。本文合成了一种正畸酯(OE)化合物作为液体药物赋形剂。接下来,构建了一种基于OE的可注射悬液,负载仿生纳米颗粒和光热剂,以抑制肿瘤复发。合成的OE具有结构简单、酸敏感、体内降解机制明确等特点。更重要的是,OE作为一种液体赋形剂,可以溶解或分散多种药物、生物大分子或纳米颗粒,在极高的浓度下形成稳定的悬浮液。因此,达沙替尼(DAS)和舒尼替尼(SUN)自组装形成纳米颗粒,并包被癌细胞膜囊以获得仿生纳米颗粒(HCM@NPs)。DAS和SUN的自组装诱导分子聚集,产生聚集诱导发射(AIE)效应,有利于细胞内药物递送的跟踪。HCM@NPs和光热剂IR820共分散在OE中,获得协同治疗悬浮液(OE/IR/HCM@NPs)。悬浮液可以注射到肿瘤周围或直接应用到手术床上覆盖任何可疑区域。OE通过其极低的比热容(1.8 J/(g·℃))显著提高了IR820的光热转换效率,显著低于水(4.2 J/(g·℃))。体外和体内实验数据表明,基于o5的悬液能直接抑制肿瘤生长,防止肿瘤复发。所有单独接受化疗的小鼠都在26 天内因肿瘤复发而死亡,而66% %接受OE纳米悬浮液治疗的小鼠在观察期间完全抑制了肿瘤复发。本文为基于OE的悬架开发提供了新的思路。
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European Journal of Pharmaceutics and Biopharmaceutics
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