European Journal of Pharmaceutical Sciences最新文献

英文中文

Protective effects of SA-31 in a psychostimulant-induced neurotoxicity model using SH-SY5Y cells SA-31在精神兴奋剂诱导的SH-SY5Y细胞神经毒性模型中的保护作用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-07 DOI: 10.1016/j.ejps.2025.107399

Charles E. Amankwa , Biddut DebNath , Arlene Abraham , Olivia Young , Sudershan R Gondi , Michael J Forster , Ritu A. Shetty , Suchismita Acharya

Background

Cocaine- and methamphetamine (METH)-induced mitochondrial dysfunction and oxidative stress are key contributors to the neuropathology of psychostimulant addiction. These effects are often accompanied by epigenetic alterations, mitochondrial damage, and the accumulation of reactive oxygen species (ROS). Methionine synthase (MS) plays a critical role in epigenetic regulation and neuronal survival and may offer neuroprotection against psychostimulant-induced toxicity. We hypothesize that SA-31, a novel thiourea-based analog of TEMPOL, will attenuate cocaine or METH induced decrease in antioxidant, anti-inflammatory, and MS activities in neuronal cells.

Methods

SA-31 was synthesized and characterized via ¹H NMR and mass spectrometry. Human SH-SY5Y dopaminergic neural cells were exposed to tert‑butyl hydrogen peroxide (TBHP), cocaine hydrochloride, or methamphetamine (METH), with or without co-treatment with SA-31 for 24 h. Cell viability was measured using MTT assays. MS activity, IL-1β, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase levels were assessed via ELISA. Mitochondrial function was evaluated using Seahorse-based oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays.

Results

SA-31 (10–100 µM) significantly protected cells from TBHP-, cocaine-, and METH-induced cytotoxicity. TBHP and METH reduced MS activity, which was significantly restored by SA-31. The compound also reversed cocaine-induced reductions in SOD, GPx, and catalase and lowered pro-inflammatory IL-1β levels. Additionally, SA-31 (1–100 µM) enhanced mitochondrial respiration and glycolytic activity.

Conclusion

These findings suggest that SA-31 confers neuroprotection by enhancing MS activity, upregulating antioxidant defenses, and improving mitochondrial function. Further studies in rodent models of addiction are planned to evaluate its therapeutic potential for psychostimulant use disorders and related neurodegenerative conditions.

背景：可卡因和甲基苯丙胺（冰毒）诱导的线粒体功能障碍和氧化应激是精神兴奋剂成瘾神经病理的关键因素。这些影响通常伴随着表观遗传改变、线粒体损伤和活性氧（ROS）的积累。蛋氨酸合成酶（Methionine synthase， MS）在表观遗传调控和神经元存活中起关键作用，并可能对精神兴奋剂引起的毒性提供神经保护。我们假设SA-31，一种新的基于硫脲的TEMPOL类似物，将减弱可卡因或冰毒引起的神经细胞抗氧化、抗炎和MS活性的下降。方法：合成SA-31，采用1H NMR和质谱法对其进行表征。将人SH-SY5Y多巴胺能神经细胞暴露于过氧化叔丁基氢（thbhp）、盐酸可卡因或甲基苯丙胺（METH）中，与SA-31或不与SA-31共同处理24小时。采用MTT法测定细胞活力。ELISA法检测MS活性、IL-1β、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）、过氧化氢酶（过氧化氢酶）水平。采用海马耗氧率（OCR）和细胞外酸化率（ECAR）检测评估线粒体功能。结果：SA-31（10-100µM）对thbhp、可卡因和meth诱导的细胞毒性有显著的保护作用。TBHP和甲基安非他明降低MS活性，SA-31显著恢复MS活性。该化合物还逆转了可卡因诱导的SOD、GPx和过氧化氢酶的减少，并降低了促炎IL-1β水平。此外，SA-31（1-100µM）可增强线粒体呼吸和糖酵解活性。结论：这些发现提示SA-31通过增强MS活性、上调抗氧化防御和改善线粒体功能来发挥神经保护作用。研究人员计划在啮齿动物成瘾模型中进一步研究，以评估其治疗精神兴奋剂使用障碍和相关神经退行性疾病的潜力。

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引用次数: 0

Recent developments of novel nanotechnology-based drug delivery systems for dermal and transdermal applications 基于纳米技术的皮肤和透皮给药系统的最新进展。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-11 DOI: 10.1016/j.ejps.2025.107413

Nazlı Erdoğar , Betül Gür , Dilara Örgül

Topical and transdermal drug delivery faces continuous challenges, primarily due to the formidable barrier function of the stratum corneum (SC), which limits the bioavailability of therapeutics. Nanotechnology-based drug delivery systems (NDDS) have emerged as powerful strategies to overcome these limitations, offering improved drug permeation, sustained release, and enhanced solubility for hydrophobic compounds. This review provides a critical and concise analysis of the latest advancements in NDDS, specifically those employed for both dermal (localized) and transdermal (systemic) delivery. Key nanosystems, including lipid-based, polymeric nanoparticles, vesicular structures, nanoemulsions, nanofibers, dendrimers and micelles are explored, highlighting how their unique physicochemical properties facilitate optimized drug performance. Crucially, the design strategies that selectively target the dermis versus those engineered for transdermal penetration are compared and contrasted. Furthermore, the often-overlooked clinical aspects, including the current understanding of the in vivo fate, biocompatibility, and safety profile of these nanocarriers within the skin layers, are addressed. This comprehensive evaluation provides a foundation for future development of safer and more effective nanomedicines for cutaneous applications.

局部和透皮给药面临着持续的挑战，主要是由于角质层强大的屏障功能，这限制了治疗药物的生物利用度。基于纳米技术的药物传递系统（NDDS）已经成为克服这些限制的有力策略，提供了改善的药物渗透、缓释和增强的疏水性化合物的溶解度。本文综述了NDDS的最新进展，特别是用于真皮（局部）和透皮（全身）给药的进展。关键的纳米系统，包括基于脂质，聚合物纳米粒子，囊泡结构，纳米乳液，纳米纤维，树状大分子和胶束的探索，突出其独特的物理化学性质如何促进优化药物性能。至关重要的是，对选择性靶向真皮层的设计策略与为透皮渗透而设计的设计策略进行了比较和对比。此外，还讨论了经常被忽视的临床方面，包括目前对这些纳米载体在皮肤层内的体内命运、生物相容性和安全性的理解。这一综合评价为今后开发更安全、更有效的皮肤纳米药物奠定了基础。

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引用次数: 0

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

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-11-22 DOI: 10.1016/j.ejps.2025.107387

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

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

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

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引用次数: 0

Diphenyl carbonate crosslinked β-cyclodextrin nanosponge-based topically applied gel for co-delivery of baricitinib and tenoxicam in rheumatoid arthritis 碳酸二苯交联β-环糊精纳米海绵凝胶局部应用于类风湿性关节炎的巴西替尼和替诺昔康的共递送。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-17 DOI: 10.1016/j.ejps.2025.107418

Manxiang Wang , Umara Arif , Tayyaba Kaleem , Humaira Majeed Khan , Abid Mehmood Yousaf , Nadeem Ahmad , Imran Nazir , Yasser Shahzad

The present study is aimed at developing baricitinib (BAR) and tenoxicam (TNX) loaded nanosponge (NS) gel for potential topical treatment of rheumatoid arthritis (RA). DPC crosslinked β-CD NS were synthesized at various molar ratios (1:2–1:20), with the 1:8 ratio showing the highest drug loading efficiency (67.0 ± 6.9% for BAR; 82.1 ± 6.8% for TNX). XRD and DSC analysis confirmed amorphization of drugs, SEM revealed porous morphology, DLS revealed particle sizes of 545.5 ± 16.4 nm (BAR-NS) and 585.2 ± 57.7 nm (TNX-NS) with zeta potentials of −11.1 ± 4.4 and −14.6 ± 3.9 mV, respectively. The optimized NS were formulated into topical gels, demonstrating sustained release (BAR: 77–90%; TNX: 96% within 12 h). In vivo evaluation using a CFA-induced RA rat model revealed that combined BAR-NS and TNX-NS gel (0.05/0.25% w/w) inhibited paw edema by >90% at day 25, significantly downregulated pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), restored IL-10, and normalized liver enzymes (ALT, AST, ALP). Histopathological analysis confirmed preservation of cartilage and bone with minimal synovial infiltration. In conclusion, combination of BAR-NS and TNX-NS gel showed synergistic anti-arthritic and anti-inflammatory effects, thus offering a potential topical alternative to conventional therapies for the management of RA.

本研究旨在开发baricitinib （BAR）和tenoxicam （TNX）负载纳米海绵（NS）凝胶，用于潜在的局部治疗类风湿性关节炎（RA）。以不同的摩尔比（1:2-1:20）合成DPC交联β-CD NS，其中1:8的载药效率最高（BAR为67.0±6.9%，TNX为82.1±6.8%）。XRD和DSC分析证实了药物的非晶化，SEM显示出多孔形态，DLS显示药物粒径为545.5±16.4 nm （BAR-NS）和585.2±57.7 nm (TNX-NS)， zeta电位分别为-11.1±4.4和-14.6±3.9 mV。优化后的NS配制成外用凝胶，12 h内BAR: 77-90%， TNX: 96%。用cfa诱导的RA大鼠模型进行体内评估显示，BAR-NS和TNX-NS凝胶（0.05/0.25% w/w）在第25天抑制足跖水肿达90%，显著下调促炎细胞因子（IL-6、IL-1β、TNF-α），恢复IL-10，并使肝酶（ALT、AST、ALP）正常化。组织病理学分析证实软骨和骨保留，滑膜浸润最小。总之，BAR-NS和TNX-NS凝胶联合使用具有协同抗关节炎和抗炎作用，因此为治疗RA提供了一种潜在的局部替代疗法。

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引用次数: 0

The relationship between PDE4 and AQP5 in lung tissue under inflammatory conditions: An experimental study 炎症条件下肺组织PDE4与AQP5关系的实验研究

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-08 DOI: 10.1016/j.ejps.2025.107400

Ayse Bozkurt , Zafer Bayraktutan , Erdem Toktay , Adem Kara , Zekai Halici , Elif Cadirci

Objective

This study aimed to examine the relationship between Phosphodiesterase 4 (PDE4) and Aquaporin-5 (AQP5) under Lipopolysaccharide (LPS) induced-inflammatory condition.

Methods

Inflammatory Acute lung injury (ALI) was induced by intratracheal LPS (5 mg/kg) administration. Rolipram (intraperitoneal) was used as PDE4 inhibiting agent at three different doses (1, 3 and 5 mg/kg) in rat groups. 24 h after LPS administration lung tissues obtained and following analyses performed. AQP5, Phosphodiesterase 4D (PDE4D), Cyclic adenosine monophosphate (cAMP) levels were evaluated for determination of the relationship between these parameters. Also Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), Nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPK) levels were evaluated as ALI markers.

Results

LPS-induced ALI resulted in increased PDE4 enzyme and inflammatory marker levels (IL-6, TNF-α, NF-κB and MAPK) and decreased AQP5 and cAMP levels. Inhibition of PDE4 enzyme to increase cAMP levels by Rolipram resulted in increased AQP5 expression and decreased inflammatory condition and in lung tissues. These results were supported by histopathological and immunhistochemical results.

Conclusion

The fact that this study observed a decreases PDE4 expression and increases in AQP5 expression upon Rolipram administration might indicate a close relationship of these two parameters in inflammatory lung disease.

目的：探讨脂多糖（LPS）诱导炎症状态下磷酸二酯酶4 （PDE4）与水通道蛋白5 （AQP5）的关系。方法：气管内注射LPS （5 mg/kg）诱导炎性急性肺损伤（ALI）。大鼠组采用罗利普兰（Rolipram，腹腔注射）作为PDE4抑制剂，剂量分别为1、3、5 mg/kg。LPS给药24小时后获得肺组织并进行以下分析。评估AQP5、磷酸二酯酶4D （PDE4D）、环磷酸腺苷（cAMP）水平，以确定这些参数之间的关系。白细胞介素-6 （IL-6）、肿瘤坏死因子-α (TNF-α)、核因子κB （NF-κB）、丝裂原活化蛋白激酶（MAPK）水平作为ALI的标志物。结果：脂多糖诱导的ALI导致PDE4酶和炎症标志物（IL-6、TNF-α、NF-κB和MAPK）水平升高，AQP5和cAMP水平降低。罗利普兰抑制PDE4酶增加cAMP水平，导致AQP5表达增加，炎症状况和肺组织减轻。这些结果得到了组织病理学和免疫组织化学结果的支持。结论：本研究观察到罗利普兰给药后PDE4表达降低，AQP5表达升高，可能提示这两个参数在炎症性肺病中的关系密切。

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引用次数: 0

High-throughput screening of amorphous solid dispersions: a systematic approach to enhance bioaccessibility of a poorly soluble drug 非晶固体分散体的高通量筛选：一种提高难溶性药物生物可及性的系统方法。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-06 DOI: 10.1016/j.ejps.2025.107401

Malte Bøgh Senniksen , Justus Johann Lange , Wiebke Saal , Patrick O’Dwyer , Martin Kuentz , Brendan T. Griffin , Susanne Page , Jennifer Dressman , Nicole Wyttenbach

Poor aqueous solubility and thereby poor and/or variable bioavailability of drug candidates is frequently overcome by developing enabling formulations such as amorphous solid dispersions (ASDs). This study proposes a systematic, miniaturized approach to evaluate the ASD developability of an active pharmaceutical ingredient (API) based on i) assessment of glass forming ability ii) assessment of the supersaturation potential of the neat API by supersaturation/permeation testing, iii) selection of an appropriate ASD carrier system using high-throughput dissolution screening of ASD films and iv) performing high-throughput dissolution/permeation testing of ASD films. The model drug candidate, RO6897779, exhibited good glass forming ability. Eight pharmaceutical polymers (CAP, Eudragit® E, Eudragit® L100, HPMC 100LV, HPMCAS-M, PVP K25, PVP VA64, and Soluplus®) were screened as ASD carriers by high-throughput dissolution testing at drug loads of 20, 30 and 40 % [w/w]. Due to poor performance of the binary systems, ternary ASDs containing Soluplus® were prepared at surfactant loads of 4, 6 and 8 % [w/w] and subsequently, high-throughput dissolution/permeation studies were conducted on selected compositions. The composition containing RO6897779 at a drug load of 20 % in Soluplus®[w/w] with the addition of 6 % [w/w] SDS yielded the best performance, but was inferior to the permeation of supersaturated neat RO6897779. Further studies should be conducted to assess the ability of this four-step, miniaturized approach to predict optimal ASD formulations over a broad range of API physicochemical properties.

通过开发诸如无定形固体分散体（asd）之类的使能配方，经常可以克服候选药物的水溶性差和因此较差和/或可变的生物利用度。本研究提出了一种系统的、小型化的方法来评估活性药物成分（API）的ASD显影性，该方法基于i)评估玻璃形成能力ii)通过过饱和/渗透测试评估纯API的过饱和电位，iii)使用高通量ASD膜溶出筛选选择合适的ASD载体系统，iv)进行ASD膜的高通量溶出/渗透测试。模型候选药物RO6897779具有良好的玻璃化能力。通过高通量溶出试验筛选8种药物聚合物（CAP、Eudragit®E、Eudragit®L100、HPMC 100LV、HPMCAS-M、PVP K25、PVP VA64和Soluplus®）作为ASD载体，载药量分别为20%、30%和40% [w/w]。由于二元体系的性能较差，在表面活性剂负载为4,6和8% [w/w]的情况下，制备了含有Soluplus®的三元asd，随后对选定的组合物进行了高通量溶解/渗透研究。在Soluplus®[w/w]中添加6% [w/w] SDS时，含RO6897779的组合物在载药量为20%时的渗透性最好，但其渗透性不如过饱和纯RO6897779。进一步的研究应该评估这种四步、小型化的方法在广泛的原料药物理化学性质下预测最佳ASD配方的能力。

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引用次数: 0

Corrigendum to “Physiologically-based pharmacokinetic modeling of natalizumab for multiple sclerosis patients to predict the withdrawal time in pregnancy and vaccine time in infants” [European Journal of Pharmaceutical Sciences, 215 (2025), 107301] “基于生理的纳塔珠单抗用于多发性硬化症患者的药代动力学建模，以预测妊娠期停药时间和婴儿疫苗接种时间”的勘误表[European Journal of Pharmaceutical Sciences， 215 (2025), 107301]

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2026-01-07 DOI: 10.1016/j.ejps.2025.107420

Peilin Zhou , Chenming Zhong , Wanhong Wu , Meng Ke , Jianwen Xu , Rongfang Lin , Pinfang Huang , Cuihong Lin

引用次数: 0

Enhanced nuclear enrichment of chemotherapeutics by a biomimetic ZIF-8 nanosystem for multidrug-resistant cancer treatment 利用仿生ZIF-8纳米系统增强化疗药物的核富集，用于多药耐药癌症治疗。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-03 DOI: 10.1016/j.ejps.2025.107396

Jingyan Hu , Jieting Wang , Junyang Zhuang , Heng Zhu , Ao Zhou , Jingyan Jia , Xueyang Ji , Yan Zhao , Luying Yu , Yu Deng , Ning Li , Fang Wang

The exclusion of chemo-drugs from their target sites, e.g. the nucleus, is a critical factor contributing to the failure of chemotherapy. Nanoparticle-based technology holds promise for specific delivery of chemo-drugs to nucleus. However, limited lysosomal escape, small size of nuclear pores and incapability of direct regulation of drug efflux-related transporters made great challenges for nanoparticles. Here, a zeolitic imidazolate framework-8 (ZIF-8)-based nanosystem was found able to disrupt lysosomes by the pH-responsiveness of ZIF-8 and mediate the nuclear entry of chemotherapeutics through promotion of their passive diffusion, resulting in the decrease of half maximal inhibitory concentration (IC50) by 3.4-fold compared to free drugs. The additional encapsulation of small interfering RNA (siRNA) to specifically silence multidrug resistance gene 1 (MDR1) for reduction of drug efflux further enhanced the chemotherapy of cancer with multidrug resistance (MDR) (IC50 reduced by 5.2-fold compared to free drugs). With a macrophage membrane biosurface coating onto the nanoparticles, targeted and potent synergistic chemo-gene therapy was achieved in mice bearing cancer with MDR. The unique function of promoting chemotherapeutic nuclear accumulation by ZIF-8-based nanoparticles to fight against MDR may deepen our understanding of the nano/bio-interactions and give novel insights into the design of smart bioresponsive nanosystems for advanced therapy.

化疗药物从靶部位（如细胞核）排除是导致化疗失败的一个关键因素。基于纳米粒子的技术有望将化学药物特异性地输送到细胞核。然而，溶酶体逃逸受限、核孔体积小以及不能直接调节药物外排相关转运体等因素给纳米颗粒带来了巨大挑战。本研究发现，基于沸石咪唑酸框架-8 （ZIF-8）的纳米系统能够通过ZIF-8的ph响应性破坏溶酶体，并通过促进化疗药物的被动扩散介导化疗药物的核进入，导致一半最大抑制浓度（IC50）比游离药物降低3.4倍。额外包封小干扰RNA （siRNA）特异性沉默多药耐药基因1 （MDR1）以减少药物外排，进一步增强了多药耐药（MDR）癌症的化疗（IC50比游离药物降低5.2倍）。将巨噬细胞膜生物表面包覆在纳米颗粒上，实现了耐多药耐药小鼠的靶向和有效的协同化学-基因治疗。基于zif -8的纳米颗粒促进化疗核积累以对抗MDR的独特功能可能加深我们对纳米/生物相互作用的理解，并为设计用于高级治疗的智能生物反应纳米系统提供新的见解。

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引用次数: 0

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

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-11-27 DOI: 10.1016/j.ejps.2025.107389

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

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

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

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引用次数: 0

Design of an in situ forming methylcellulose hydrogel as universal vehicle for preclinical intravitreal injection of particulate formulations 一种原位形成甲基纤维素水凝胶的设计，作为临床前玻璃体内注射颗粒制剂的通用载体。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 Epub Date: 2025-10-22 DOI: 10.1016/j.ejps.2025.107346

Marco Block , Grazia Giorgio , Christoph Saal , Remko A. Bakker , Achim Goepferich , Achim Grube , Roman Simon

Preclinical development of novel intravitreal pharmaceuticals is reliant on the use of animal pharmacokinetic (PK) and pharmacodynamic (PD) models, incipiently performed in small rodents. As most novel molecular entities exhibit fast intravitreal clearance, tailored preclinical extended-release (XR) formulations like microparticle suspensions are required to ensure sufficient exposure in the eye for 1 – 4 weeks which are required for PD experiments. Still, their use is very limited due to three major drawbacks: (i) Limited injectability of high particle concentrations, (ii) high intravitreal mobility, and (iii) attachment to vitreoretinal tissues and the lens. (ii) and (iii) complicate or prohibit PK and PD readouts.

We developed a universal hydrogel vehicle to specifically enable microparticulate XR formulations for preclinical intravitreal injection. By optimizing the interplay of methylcellulose and kosmotropic additives, namely Na-citrate and Na-tartrate, rapid thermal gelation at vitreous temperature of 34 °C was ensured. The hydrogel vehicle enabled injection of microparticulate XR formulations (Poly-lactide-co-glycolide and silica matrix particles) even when using non-siliconized syringes with small 34 gauge needles. Reduced intravitreal mobility and facilitated separation of formulation from retinal tissues was demonstrated ex vivo in porcine eyes. Rheological examination validated almost complete obstruction of embedded particulate XR formulations. In vitro XR of drugs (small molecules up to full length antibodies) was not altered. Experiments on ARPE-19 cells in vitro showed good tolerability and low toxicity. Furthermore, the hydrogel vehicle masked the cytotoxicity of embedded silica microparticles in high concentration. Our results suggest the hydrogel vehicle as a highly promising universal vehicle for preclinical intravitreal injection.

新型玻璃体内药物的临床前开发依赖于动物药代动力学（PK）和药效学（PD）模型的使用，最初是在小型啮齿动物中进行的。由于大多数新型分子实体在玻璃体内表现出快速清除，因此需要定制临床前缓释（XR）配方，如微粒悬浮液，以确保PD实验所需的1 - 4周内在眼睛中充分暴露。然而，由于三个主要缺点，它们的使用非常有限：(i)高颗粒浓度的可注射性有限，（ii）玻璃体内流动性高，（iii）附着在玻璃体视网膜组织和晶状体上。（ii）和（iii）使PK和PD读数复杂化或禁止。我们开发了一种通用的水凝胶载体，专门用于临床前玻璃体内注射的微颗粒XR配方。通过优化甲基纤维素与嗜氧性添加剂（柠檬酸钠和酒石酸钠）的相互作用，保证了在玻璃体温度34℃下的快速热凝胶化。即使使用34号针头的非硅化注射器，水凝胶载体也可以注射微颗粒XR制剂（聚乳酸-共聚物和二氧化硅基质颗粒）。体外实验证明，在猪眼中，降低了玻璃体内的流动性，促进了配方与视网膜组织的分离。流变学检查证实几乎完全阻断了包埋颗粒XR配方。药物（小分子到全长抗体）的体外XR没有改变。体外ARPE-19细胞耐受性好，毒性低。此外，水凝胶载体掩盖了高浓度二氧化硅微粒的细胞毒性。我们的结果表明水凝胶载体是一种非常有前途的临床前玻璃体内注射的通用载体。

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