Journal of pharmaceutical sciences最新文献_第7页

Interaction of isoniazid derivatives active against drug-resistant tuberculosis with models of the lung surfactant and of the Mycobacterium tuberculosis cell wall 抗耐药结核的异烟肼衍生物与肺表面活性剂和结核分枝杆菌细胞壁模型的相互作用。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-30 DOI: 10.1016/j.xphs.2025.104151

Weronika Śliżewska , Filomena Martins , Rodrigo F.M. de Almeida , Joaquim T. Marquês

Tuberculosis is one of the most important causes of death in the world. The emergence and increased prominence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), non-susceptible to currently available therapies, has toughened the fight to eradicate this disease. This study focuses on further investigating the therapeutic potential of promising antitubercular compounds, namely, isoniazid (INH), and three INH derivatives, N'-decanoylisonicotinohydrazide (INH-C10), N'-(E)-(4-phenoxybenzylidene)isonicotinohydrazide (N34) and N’-(4-phenoxybenzyl)isonicotinohydrazide (N34red). INH-C10 and N34 have been selected due to their high selectivity index against the Mtb mutant bearing the primary mutation responsible for INH drug resistance. In opposition, N34red, which differs from N34 only in the saturation of the N′ = C bond, exhibits a poor selectivity index. Moreover, INH-C10 and N34 interact with human serum albumin and model lipid membranes mimicking the plasma membrane of human cells, showing their promising potential. In the current study, the interaction of these compounds with models of the lung surfactant (LS) and of the mycolic acid (MA)-enriched Mtb cell wall was assessed, in order to further explore their ability to interact with and cross the various biological barriers to be encountered on their way to the molecular target inside Mtb. We show that all the INH derivatives were able to interact with both the LS and the mycolic acid-enriched cell wall models. INH-C10 and N34 had a smaller impact than N34red on the pulmonary surfactant model. On the other hand, INH-C10 promoted the most extensive perturbation of the MA-enriched cell wall model, which correlates well with the previously shown ability of this compound to incorporate into and disturb gel-phase lipid bilayers. This indicates that INH-C10 may penetrate a MA rich barrier more easily, reaching higher intracellular levels, and increase its permeability. These traits contribute to explain the high antimicrobial activity of this derivative against the most common drug-resistant Mtb mutant.

结核病是世界上最重要的死亡原因之一。对现有疗法不敏感的耐多药结核分枝杆菌（Mtb）菌株的出现和日益突出，加强了根除这一疾病的斗争。本研究的重点是进一步研究有前景的抗结核化合物，即异烟肼（INH）及其三个INH衍生物N'-癸烷基异烟碱肼（INH- c10）， N'-(E)-（4-苯氧苄基）异烟碱肼（N34）和N'-（4-苯氧苄基）异烟碱肼（N34red）的治疗潜力。选择INH- c10和N34是因为它们对携带INH耐药主要突变的Mtb突变体具有高选择性指数。相反，N34red与N34的区别仅在于N' = C键的饱和度，其选择性指数较差。此外，INH-C10和N34与人血清白蛋白和模拟人细胞膜的模型脂质膜相互作用，显示出其良好的潜力。在本研究中，我们评估了这些化合物与肺表面活性物质（LS）和富含霉菌酸（MA）的结核分枝杆菌细胞壁模型的相互作用，以进一步探索它们与结核分枝杆菌内部分子靶点到达过程中遇到的各种生物屏障相互作用和跨越的能力。我们发现所有的INH衍生物都能与LS和富含霉菌酸的细胞壁模型相互作用。INH-C10和N34对肺表面活性物质模型的影响小于N34red。另一方面，INH-C10促进了对富含ma的细胞壁模型的最广泛的扰动，这与先前显示的该化合物融入并干扰凝胶相脂质双分子层的能力密切相关。这表明INH-C10可能更容易穿透富含MA的屏障，达到更高的细胞内水平，并增加其通透性。这些特征有助于解释该衍生物对最常见的耐药结核分枝杆菌突变体具有较高的抗菌活性。

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引用次数: 0

Experimental determination of extinction coefficients by sedimentation velocity analytical ultracentrifugation for accurate quantification of recombinant adeno-associated virus 用沉降速度分析超离心法测定重组腺相关病毒消光系数的精确定量。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-30 DOI: 10.1016/j.xphs.2025.104150

Yuki Yamaguchi , Takahiro Maruno , Takaaki Kurinomaru , Risa Shibuya , Mitsuko Fukuhara , Yasuo Tsunaka , Susumu Uchiyama

Recombinant adeno-associated virus (rAAV) is widely used as a gene delivery vector. Sedimentation velocity analytical ultracentrifugation (SV–AUC) is the gold standard for quantifying the ratio of full particles (FPs) to the sum of empty particles (EPs) and FPs (F/E ratio) of rAAVs. Here, we experimentally determined the molar extinction coefficients (ε) and mass extinction coefficients of highly purified FPs and EPs of AAV serotypes 2, 5, 6, 8, and 9 using SV–AUC with interference and multi-wavelength absorbance detection. At 230 nm, the difference in ε between EPs and FPs was the smallest, although the ε of FPs remained 1.2-fold higher than that of EPs. Expectedly, the differences in ε between FPs and EPs were almost identical across serotypes with the same genome length and increased linearly in a genome length-dependent manner, although both sets of ε differed across serotypes. Consequently, accurate quantification of F/E ratio requires the use of distinct ε values for EPs and FPs. The ε per base of single-stranded DNA was independent of serotype and genome length, allowing estimation of the ε of FPs from that of EPs. Coupling these ε values with SV–AUC enables the determination of absolute rAAV concentrations. This study provides practical guidance for accurate absorbance-based rAAV quantification.

重组腺相关病毒（rAAV）作为一种基因传递载体被广泛应用。沉降速度分析超离心（SV-AUC）是定量测定raav中满颗粒（FPs）与空颗粒（EPs）和FPs （F/E比）之比的金标准。本研究采用干涉和多波长吸光度检测的SV-AUC技术，测定了AAV血清型2、5、6、8和9的高纯度FPs和EPs的摩尔消光系数（ε）和质量消光系数。在230 nm处，EPs和FPs的ε值差异最小，但FPs的ε值仍然是EPs的1.2倍。出乎意料的是，在相同基因组长度的血清型中，FPs和EPs之间的ε差异几乎相同，并且以基因组长度依赖的方式线性增加，尽管两组ε在血清型中存在差异。因此，准确量化F/E比率需要对EPs和FPs使用不同的ε值。单链DNA的每碱基ε与血清型和基因组长度无关，可以通过EPs的ε来估计FPs的ε。将这些ε值与SV-AUC耦合，可以确定rAAV的绝对浓度。本研究为基于吸光度的rAAV准确定量提供了实用指导。

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引用次数: 0

Design and evaluation of diacerein-loaded oleoliposome dry-powder inhalation nano-formulation for targeted anti-inflammatory therapy in COPD 载二肾上腺素油脂质体干粉吸入纳米制剂靶向抗炎治疗COPD的设计与评价。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-11-10 DOI: 10.1016/j.xphs.2025.104057

Khaled Almansour , Amira A. Boseila , Ahmed A. Katamesh , Shimaa M. Hassoun , Ossama M Sayed

Background & objective

Chronic obstructive pulmonary disease (COPD) is accompanied by chronic bronchitis and emphysema; current inhaled therapies suffer from short half-life, poor lung deposition, and corticosteroid resistance. Diacerein (DIA) is an IL-1β/TNF-α inhibitor with demonstrated anti-inflammatory activity in lung fibrosis models, yet it has never been explored for pulmonary delivery. We aimed to develop an inhalable DIA-loaded oleoliposomes (DIA-OL) nano-formulation that overcomes the limitations of conventional dosage forms and to evaluate its suitability for treating inflammatory lung diseases.

Methods

An I-optimal design (Design-Expert® 13) was employed to optimize DIA-OL prepared by thin-film hydration. Independent variables were phospholipid amount (100–250 mg) and oleic acid: DDAB ratio (0–100 % w/w); responses were vesicle size (R1), entrapment efficiency (EE %) (R2), and zeta potential (R3). Optimized formula was lyophilized with mannitol/lactose ± glycine, characterized for morphology (TEM), in-vitro release, micromeritics (Carr’s index), and aerodynamic performance (Andersen cascade impactor, 60 L min⁻¹). Biological activity was assessed in LPS-stimulated A549 cells: cytotoxicity (MTT), TNF-α/IL-6 secretion (ELISA), and NF-κB pathway proteins (Western blot).

Key results

Optimized DIA-OL (phospholipid 145 mg, oleic acid: DDAB 78:22) exhibited 138 ± 3 nm, EE 82.4 ± 1.9 %, and ζ-potential −31.6 ± 0.8 mV, all within predicted ranges (< 5 % deviation). Release profile followed Higuchi kinetics (R² = 0.987), releasing 78 % of DIA in 24 h versus 95 % burst release from free powder (which formula with glycine or without glycine). Lyophilized powders showed excellent flow (Carr’s index 12.8 % with glycine) and emitted doses > 90 %. Aerodynamic performance was markedly superior: MMAD 2.25 ± 0.15 µm, FPF 38.75 ± 1.9 % versus 4.04 ± 0.11 µm and 21.17 ± 1.36 % for raw DIA (p < 0.05). In A549 cells, DIA-OL (10⁻² mg mL⁻¹) reduced LPS-induced TNF-α and IL-6 by 68 % and 55 %, respectively (p < 0.01), without cytotoxicity; this was accompanied by down-regulation of p-NF-κB p65 and p-IκBα.

Conclusions

The developed DIA-OL nano-dry powder inhaler (DIA-OL) combines small aerodynamic diameter, high lung deposition, sustained release, and potent anti-inflammatory action, positioning it as a promising non-steroidal, biologic-free inhalation therapy for COPD and related inflammatory lung disorders.

背景与目的：慢性阻塞性肺疾病（COPD）伴发慢性支气管炎和肺气肿；目前的吸入疗法存在半衰期短、肺沉积不良和皮质类固醇抵抗等问题。Diacerein （DIA）是一种IL-1β/TNF-α抑制剂，在肺纤维化模型中具有抗炎活性，但从未被用于肺输送。我们的目标是开发一种可吸入的负载dia的油脂质体（DIA-OL）纳米制剂，克服传统剂型的局限性，并评估其治疗炎症性肺部疾病的适用性。方法：采用i -优化设计（design - expert®13）对薄膜水化制备的DIA-OL进行优化。自变量为磷脂含量（100-250 mg）和油酸：DDAB比（0- 100% w/w）；反应是囊泡大小（R1）、包裹效率（EE %）（R2）和zeta电位（R3）。优化后的配方用甘露醇/乳糖±甘氨酸冻干，进行形貌（TEM）、体外释放、微量指标（Carr’s指数）和空气动力学（Andersen级联器，60 L min⁻¹）的表征。在lps刺激的A549细胞中评估生物活性：细胞毒性（MTT）、TNF-α/IL-6分泌（ELISA）和NF-κB通路蛋白（Western blot）。关键结果：优化后的DIA-OL（磷脂145 mg，油酸：DDAB 78:22）表现为138±3 nm， EE为82.4±1.9%，ζ-电位为-31.6±0.8 mV，均在预测范围内（偏差< 5%）。释放曲线符合Higuchi动力学（R² = 0.987），在24 h内释放78%的DIA，而自由粉末（含甘氨酸或不含甘氨酸的配方）的释放率为95%。冻干粉末表现出良好的流动性（甘氨酸的卡尔指数为12.8%）和释放剂量bbb90 %。气动性能明显优于原DIA: MMAD为2.25±0.15µm， FPF为38.75±1.9%，而原DIA为4.04±0.11µm, 21.17±1.36% （p < 0.05）。在A549细胞中，DIA-OL（10⁻²mg mL⁻¹）分别使lps诱导的TNF-α和IL-6减少68%和55% (p < 0.01)，无细胞毒性；p-NF-κB p65和p -κB α表达下调。结论：所研制的DIA-OL纳米干粉吸入器（DIA-OL）具有气动直径小、肺沉积高、缓释、抗炎作用强等特点，是治疗COPD及相关炎性肺疾病的一种有前景的非甾体、无生物吸入疗法。

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引用次数: 0

Development of HRP-based 3D intercellular exchange assay for high throughput screening 基于酶解蛋白的三维细胞间交换高通量筛选试验的开发。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-03 DOI: 10.1016/j.xphs.2025.104115

Xian Wu , Xiangxiang Hu , Yiqin Li , Hong-Bo Pang

Extracellular vesicles (EVs) play a vital role in mediating intercellular communication and regulatory processes. Using a three-dimensional (3D) intercellular exchange assay, we previously demonstrated that EVs facilitate the intercellular transfer of nanoparticles (NPs) among cells in vitro and are essential for the efficient delivery of NPs in vivo. This assay was further employed to identify small molecules capable of regulating the intercellular exchange process. However, the original assay relied on fluorescence labeling and flow cytometry for detection, which posed limitations for adaptation to high-throughput screening (HTS) platforms. In this study, we developed an enhanced intercellular exchange assay based on horseradish peroxidase (HRP) labeling. Specifically, cell-penetrating peptide-conjugated silver nanoparticles (CPP-AgNPs) were labeled with HRP, allowing signal amplification through the enzymatic reaction between HRP and its substrate. This modification significantly improved the signal-to-noise ratio (S/N) to approximately 6:1. Additionally, we optimized the gel composition within the assay system to ensure compatibility with HTS workflows. Using this HRP-based assay, we validated that LDN-214117, a previously identified agonist of intercellular exchange, significantly promoted the transfer of CPP-AgNPs between various cell pairs. Collectively, our work presents a novel, rapid, and versatile platform for identifying modulators of intercellular exchange in a high-throughput format.

细胞外囊泡（EVs）在细胞间通讯和调节过程中起着至关重要的作用。利用三维（3D）细胞间交换实验，我们先前证明了体外ev促进纳米颗粒（NPs）在细胞间的细胞间转移，并且对于体内NPs的有效递送至关重要。该试验进一步用于鉴定能够调节细胞间交换过程的小分子。然而，最初的检测依赖于荧光标记和流式细胞术进行检测，这对适应高通量筛选（HTS）平台构成了限制。在这项研究中，我们开发了一种基于辣根过氧化物酶（HRP）标记的增强细胞间交换试验。具体来说，用HRP标记细胞穿透肽共轭银纳米粒子（cppp - agnps），通过HRP与其底物之间的酶促反应放大信号。这种改进显著地提高了信噪比（S/N）到大约6:1。此外，我们优化了分析系统内的凝胶组成，以确保与HTS工作流程的兼容性。通过这种基于酶解酶的实验，我们证实了LDN-214117，一种先前鉴定的细胞间交换激动剂，可以显著促进pcp - agnps在不同细胞对之间的转移。总的来说，我们的工作提出了一个新的、快速的、通用的平台，用于以高通量格式识别细胞间交换的调节剂。

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引用次数: 0

Characterization of peristaltic pumps and application to fill & finish operations: Part I 蠕动泵的特性及其在灌装和精加工中的应用：第1部分。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2026-01-10 DOI: 10.1016/j.xphs.2026.104162

Mostafa Nakach , Lionel Bardet , Fabian Voll , Doriane Calvet , Jean-René Authelin

Peristaltic pumps are widely used in fill and finish operations for parenteral drugs, especially biologics. These pumps are believed to work as volumetric pumps and to deliver a constant flow rate. However, this is only true within a limited range of backpressure. In this article, we show that if the backpressure exceeds a certain threshold, which depends on the pump tuning, the flow decreases progressively until it completely vanishes at a certain backpressure. We demonstrate that this behavior may have practical consequences on the various operations, including the filtration of biologic solutions and the filling accuracy especially for viscous solutions.

蠕动泵广泛应用于肠外药物，特别是生物制剂的灌装和收尾操作。这些泵被认为是作为容积泵工作，并提供恒定的流量。然而，这只适用于有限的反压范围。在本文中，我们表明，如果背压超过一定的阈值，这取决于泵的调整，流量逐渐减少，直到在一定的背压下完全消失。我们证明，这种行为可能对各种操作产生实际影响，包括生物溶液的过滤和灌装精度，特别是粘性溶液。

引用次数: 0

Chemical instability of cefaclor in simple suspensions alkalinized with magnesium oxide and the structural elucidation of the degradation products 氧化镁碱化头孢克洛简单混悬液的化学不稳定性及降解产物的结构分析。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-11-12 DOI: 10.1016/j.xphs.2025.104063

Ginjiro Kato , Hidemichi Mitome , Mitsuki Yamanaka , Noriaki Hidaka , Mamoru Tanaka , Kazuki Akira

A simple suspension method, where solid formulations are soaked in water (55 °C) and suspended followed by tube administration, has been widely used in Japan for patients with dysphagia. However, information on the chemical stability of drugs concomitantly suspended with acidic or basic ones is insufficient. Cefaclor, a β-lactam antibiotic, is commonly used to treat various infectious diseases. This drug has been reported to be unstable depending on pH and temperature. Also, magnesium oxide (MgO) is a typical alkaline drug frequently prescribed as a laxative. These drugs are occasionally taken together, particularly by older patients. In this study, we have investigated the chemical stability of cefaclor in a concomitant simple suspension with MgO. A cefaclor capsule with or without an MgO tablet was subjected to the simple suspension method, and the suspensions were analyzed by high-performance liquid chromatography. No degradation was observed for the suspension of cefaclor alone, whereas when concomitantly suspended with MgO, the peak intensity of cefaclor considerably decreased, and two degradation peaks appeared. The results showed that co-suspensions with MgO should be avoided. The degradation products were isolated and spectroscopically identified to be piperazine derivatives including a novel one. Their plausible formation mechanisms have also been proposed.

一种简单的悬浮方法，将固体制剂浸泡在水中（55°C）并悬浮，然后管给药，已在日本广泛用于吞咽困难患者。然而，关于与酸性或碱性悬浮剂混悬的药物的化学稳定性的资料还不够。头孢克洛是一种β-内酰胺类抗生素，通常用于治疗各种传染病。据报道，这种药物不稳定取决于pH值和温度。此外，氧化镁（MgO）是一种典型的碱性药物，经常作为泻药处方。这些药物偶尔会同时服用，尤其是老年患者。在这项研究中，我们研究了头孢克洛在与氧化镁共混的简单混悬液中的化学稳定性。采用简单悬浮法对头孢克洛胶囊进行混悬，并采用高效液相色谱法对混悬液进行分析。头孢克洛单独悬浮液未见降解现象，而与氧化镁同时悬浮液时，头孢克洛的峰值强度明显降低，出现两个降解峰。结果表明，应避免与MgO共混悬液。分离得到的降解产物经光谱鉴定为哌嗪衍生物，其中包括一种新的哌嗪衍生物。还提出了它们的形成机制。

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引用次数: 0

Ensuring pharmaceutical safety: Highthroughput LC-MS/MS method for plastic additive detection 确保药品安全：高通量LC-MS/MS方法检测塑料添加剂。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-16 DOI: 10.1016/j.xphs.2025.104135

İbrahim Hakkı Demircioğlu , Oğuzhan Dalkılıç , Saffet Çelik , Tugrul Cagri Akman , Hamdullah Kılıç , Levent Kandemir , Alptuğ Atila

Extractables and Leachables studies require highly reliable and sensitive analytical methods to ensure pharmaceutical product safety. Plastic additives are widely used during production to improve the physicochemical properties of polymeric products. However, these additives may constitute a potential toxicological risk by contaminating active pharmaceutical ingredients and pharmaceutical preparations. In this study, a short-term, sensitive, accurate, and reliable LC-MS/MS method was developed for the analysis of 15 plastic additives defined in the European Pharmacopoeia and validated in accordance with the ICH Q2(R2) guideline. An electrospray ionization source was used for the analyses in both negative and positive modes. Chromatographic separation was carried out using a reverse-phase phenyl C18 column and a mixture of methanol and ultrapure water containing 5 mM ammonium acetate as the mobile phase by the gradient elution method. As a result of method optimization, the flow rate and total analysis time were determined to be 0.7 mL/min and 15 min, respectively. Diphenyl phthalate was chosen as the internal standard. The LLOQ values of plastic additives were generally determined as 50 ng/mL (150 ng/mL for oleamide). The reliability of the method was verified by intraday/interday precision and accuracy analyses. Both extractable and leachable studies were performed using the developed method. It was effectively used to detect plastic additive contamination in pharmaceutical products such as bromobutyl stoppers, LDPE containers, disposable eye drop packaging, and polypropylene bags. The developed LC-MS/MS method was successfully applied to the analysis of pharmaceutical formulations containing 1.4% polyvinyl alcohol and 0.6% povidone, sodium hyaluronate, salbutamol sulfate, and 0.9% isotonic sodium chloride.

可萃取物和可浸出物的研究需要高度可靠和敏感的分析方法，以确保药品安全。塑料助剂在生产过程中被广泛使用，以改善聚合物产品的物理化学性能。然而，这些添加剂可能通过污染活性药物成分和药物制剂而构成潜在的毒理学风险。本研究建立了一种短期、灵敏、准确、可靠的LC-MS/MS方法，用于分析欧洲药典中定义的15种塑料添加剂，并根据ICH Q2（R2）指南进行了验证。采用电喷雾电离源进行了正负两种模式的分析。色谱分离采用苯基C18反相色谱柱，流动相为甲醇与含5 mM乙酸铵的超纯水混合物，采用梯度洗脱法。通过方法优化，确定流速为0.7 mL/min，总分析时间为15 min。内标选用邻苯二甲酸二苯酯。塑料助剂的定量限一般为50 ng/mL（油酰胺为150 ng/mL）。通过日内/日精密度和准确度分析，验证了该方法的可靠性。使用开发的方法进行了可提取和可浸出的研究。该方法可有效检测溴丁基瓶塞、LDPE容器、一次性眼药水包装、聚丙烯包装袋等药品中塑料添加剂的污染情况。所建立的LC-MS/MS方法成功地应用于含有1.4%聚乙烯醇和0.6%聚维酮、透明质酸钠、硫酸沙丁胺醇和0.9%等渗氯化钠的药品配方的分析。

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引用次数: 0

Response to comments on "diacerein-loaded oleoliposome dry-powder inhalation nano-formulation for COPD" 对“慢性阻塞性肺病（COPD）载二黄芩素油脂质体干粉吸入纳米制剂”评价的回应。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-16 DOI: 10.1016/j.xphs.2025.104129

Ossama M Sayed, Khaled Almansour, Amira A. Boseila, Ahmed A. Katamesh, Shimaa M. Hassoun

引用次数: 0

Large language models in drug delivery: A review of the current landscape and future perspectives 药物传递中的大型语言模型：现状和未来展望的回顾。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-24 DOI: 10.1016/j.xphs.2025.104147

Molham Sakkal , Abdallah Abou Hajal

The development of effective drug delivery systems (DDS) faces persistent challenges, including biological barriers, formulation stability, low bioavailability, and complex regulatory demands. While artificial intelligence (AI) and machine learning (ML) have gained traction in pharmaceutical research, the role of large language models (LLMs) in DDS design and development remains an emerging and underexplored area. This review provides a structured overview of the intersection between LLMs and pharmaceutical formulation. It introduces the foundational principles of LLMs, frames key formulation challenges within drug delivery, and critically examines how existing LLM-powered tools are being applied to literature mining, protocol generation, molecular property prediction, and preformulation guidance. Practical examples from recent studies are discussed to illustrate potential use cases.

We further identify key limitations in current LLM integration, including the lack of domain-specific models, limited data accessibility, risks of hallucinated outputs, and usability challenges for non-specialists. Finally, we propose essential future research directions to bridge these gaps and enhance real-world applicability. This review equips pharmaceutical scientists, formulation researchers, and interdisciplinary R&D teams with critical insights to support the responsible adoption of LLMs, ultimately accelerating the development of personalized and efficient drug delivery solutions.

开发有效的给药系统（DDS）面临着持续的挑战，包括生物屏障、配方稳定性、低生物利用度和复杂的监管要求。虽然人工智能（AI）和机器学习（ML）在制药研究中获得了牵引力，但大型语言模型（llm）在DDS设计和开发中的作用仍然是一个新兴且未充分开发的领域。这篇综述提供了法学硕士和药物制剂之间交叉的结构化概述。它介绍了法学硕士的基本原理，框架药物输送中的关键配方挑战，并批判性地检查了现有的法学硕士支持的工具如何应用于文献挖掘，协议生成，分子性质预测和配方预指导。本文讨论了来自最近研究的实际示例，以说明潜在的用例。我们进一步确定了当前LLM集成的关键限制，包括缺乏特定领域的模型，有限的数据可访问性，幻觉输出的风险以及非专业人员的可用性挑战。最后，我们提出了未来重要的研究方向，以弥合这些差距并增强现实世界的适用性。这篇综述为制药科学家、配方研究人员和跨学科研发团队提供了重要的见解，以支持负责任地采用法学硕士，最终加速个性化和高效给药解决方案的开发。

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引用次数: 0

Augmenting the cytotoxicity and apoptosis induction of green synthesized copper oxide nanoparticles from Artemisia sieberi by combining with tamoxifen: Mechanism involving Bax/Bcl-2 modulation 他莫昔芬联合青蒿绿色合成氧化铜纳米颗粒增强细胞毒性和诱导凋亡：Bax/Bcl-2调节机制

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2026-02-01 Epub Date: 2025-12-23 DOI: 10.1016/j.xphs.2025.104143

Saeed Seghatoleslami , Mohammadreza Pourmohammad , Homa Mahmoudzadeh , Jina Khayatzadeh

Treatment of breast cancer is severely hindered by dose-limiting toxicity and acquired Tamoxifen (Tam) resistance. This study investigated the synergistic anti-cancer effect and molecular mechanism of green-synthesized Copper Oxide Nanoparticles (CuO NPs) when combined with Tam against the MCF−7 human breast cancer cell line. CuO NPs were successfully produced using an aqueous extract of Artemisia sieberi as a dual reducing/capping agent. Characterization confirmed the formation of stable nanoparticles, evidenced by a Surface Plasmon Resonance (SPR) peak at 552 nm, an average size of ∼36 nm (TEM), and excellent colloidal stability with a highly negative Zeta Potential (-33.5 mV). The MTT assay demonstrated that the combination regimen exhibited a strong synergistic cytotoxic effect (CI<1) toward MCF−7 cells. Synergy was achieved even at low concentrations, such as 15.0 μg/mL CuO NPs:1.0 μM Tam (CI=0.99), with the most potent synergy (CI=0.69) observed at the maximum dose. Quantitative analysis via Annexin V/PI flow cytometry confirmed this enhancement, showing the combination reduced the viable cell population to a minimal 4.87 %. Mechanistically, RT−qPCR analysis revealed a maximal perturbation of the mitochondrial apoptotic pathway. The combined treatment simultaneously maximized the up-regulation of the pro-apoptotic gene BAX and the down-regulation of the anti-apoptotic gene BCL−2. This synergistic action resulted in a 16.74-fold increase in the critical BAX/BCL−2 ratio, approximately two times greater than either monotherapy. These findings validate CuO NPs co-administration with Tamoxifen as a promising strategy for overcoming acquired Tamoxifen resistance.

剂量限制性毒性和获得性他莫昔芬（Tam）耐药性严重阻碍了乳腺癌的治疗。本研究探讨了绿色合成的氧化铜纳米颗粒（CuO NPs）与Tam联合对MCF-7人乳腺癌细胞系的协同抗癌作用及其分子机制。采用青蒿水提物作为双还原/封盖剂，成功制备了CuO NPs。表征证实形成了稳定的纳米颗粒，表面等离子体共振（SPR）峰位于552 nm，平均尺寸为~ 36 nm (TEM)，具有优异的胶体稳定性，具有高度负的Zeta电位（-33.5 mV）。MTT试验表明，联合用药方案具有较强的协同细胞毒作用（CI）

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