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Novel Anti-Trop2 Nanobodies Disrupt Receptor Dimerization and Inhibit Tumor Cell Growth. 新型抗 Trop2 纳米抗体破坏受体二聚化并抑制肿瘤细胞生长
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-27 DOI: 10.3390/pharmaceutics16101255
Junwen Deng, Zhongmin Geng, Linli Luan, Dingwen Jiang, Jian Lu, Hanzhong Zhang, Bingguan Chen, Xinlin Liu, Dongming Xing

Background: Trop2 (trophoblast cell-surface antigen 2) is overexpressed in multiple malignancies and is closely associated with poor prognosis, thus positioning it as a promising target for pan-cancer therapies. Despite the approval of Trop2-targeted antibody-drug conjugates (ADCs), challenges such as side effects, drug resistance, and limited efficacy persist. Recent studies have shown that the dimeric forms of Trop2 are crucial for its oncogenic functions, and the binding epitopes of existing Trop2-targeted drugs lie distant from the dimerization interface, potentially limiting their antitumor efficacy. Method: A well-established synthetic nanobody library was screened against Trop2-ECD. The identified nanobodies were extensively characterized, including their binding specificity and affinity, as well as their bioactivities in antigen-antibody endocytosis, cell proliferation, and the inhibition of Trop2 dimer assembly. Finally, ELISA based epitope analysis and AlphaFold 3 were employed to elucidate the binding modes of the nanobodies. Results: We identified two nanobodies, N14 and N152, which demonstrated high affinity and specificity for Trop2. Cell-based assays confirmed that N14 and N152 can facilitate receptor internalization and inhibit growth in Trop2-positive tumor cells. Epitope analysis uncovered that N14 and N152 are capable of binding with all three subdomains of Trop2-ECD and effectively disrupt Trop2 dimerization. Predictive modeling suggests that N14 and N152 likely target the epitopes at the interface of Trop2 cis-dimerization. The binding modality and mechanism of action demonstrated by N14 and N152 are unique among Trop2-targeted antibodies. Conclusions: we identified two novel nanobodies, N14 and N152, that specifically bind to Trop2. Importantly, these nanobodies exhibit significant anti-tumor efficacy and distinctive binding patterns, underscoring their potential as innovative Trop2-targeted therapeutics.

背景:Trop2(滋养层细胞表面抗原 2)在多种恶性肿瘤中过度表达,并与预后不良密切相关,因此是一种很有前景的泛癌疗法靶点。尽管 Trop2 靶向抗体-药物共轭物(ADC)已获批准,但副作用、耐药性和疗效有限等挑战依然存在。最近的研究表明,Trop2的二聚体形式对其致癌功能至关重要,而现有的Trop2靶向药物的结合表位远离二聚体界面,可能会限制其抗肿瘤疗效。方法是针对Trop2-ECD筛选了一个成熟的合成纳米抗体库。对鉴定出的纳米抗体进行了广泛的表征,包括它们的结合特异性和亲和性,以及它们在抗原-抗体内吞、细胞增殖和抑制 Trop2 二聚体组装方面的生物活性。最后,利用基于酶联免疫吸附的表位分析和 AlphaFold 3 来阐明纳米抗体的结合模式。结果我们发现了两种纳米抗体N14和N152,它们对Trop2具有高亲和力和特异性。基于细胞的实验证实,N14和N152能促进受体内化并抑制Trop2阳性肿瘤细胞的生长。表位分析发现,N14 和 N152 能够与 Trop2-ECD 的所有三个亚域结合,并有效地破坏 Trop2 的二聚化。预测模型表明,N14和N152可能以Trop2顺式二聚化界面上的表位为靶点。N14 和 N152 的结合方式和作用机制在 Trop2 靶向抗体中是独一无二的。结论:我们发现了两种新型纳米抗体N14和N152,它们能特异性地与Trop2结合。重要的是,这些纳米抗体具有显著的抗肿瘤疗效和独特的结合模式,凸显了它们作为创新性Trop2靶向疗法的潜力。
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引用次数: 0
Pulmonary Pharmacokinetics of Antibody and Antibody Fragments Following Systemic and Local Administration in Mice. 小鼠全身和局部给药后抗体和抗体片段的肺部药代动力学
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-27 DOI: 10.3390/pharmaceutics16101259
Prabhas Jagdale, Ashwni Verma, Dhaval K Shah

Objective: This study aimed to investigate the effect of molecular size on the pulmonary pharmacokinetics (PK) of proteins following systemic and local administration in wild-type mice. Methods: A non-cross-reactive antibody trastuzumab, and F(ab')2, Fab, and scFv fragments of this antibody were used for the investigation. Proteins were injected intravenously or via intratracheal instillation, and PK was measured in plasma, lungs, trachea, bronchi, and bronchoalveolar lavage (BAL) using ELISA. Concentrations in BAL were urea normalized. Results: Following systemic administration, the biodistribution coefficient (BC) for lungs, trachea, bronchi, and BAL was 11%, 11%, 15%, and 2% for the antibody; 15%, 7%, 13%, and 8% for F(ab')2; 25%, 17%, 28%, and 46% for Fab; and 14%, 1%, 2%, and 50% for scFv. The antibody exposure in BAL was ~50-fold lower than plasma and ~5-7-fold lower than lung tissues. A tissue-dependent BC vs. molecular size relationship was observed, where distribution in tissues was the highest for Fab (50 kDa), and scFv demonstrated the highest distribution in the BAL. PK data generated following local administration were quite variable; however, local dosing resulted in BAL exposures that were 10-100-fold higher than those achieved after systemic dosing for all proteins. The BAL antibody concentrations were 100-1000-fold higher than plasma concentrations initially, which normalized by day 14. For most proteins, local dosing resulted in higher lung concentrations than trachea and bronchi, opposite to what was observed after systemic dosing. Conclusions: The PK data presented here provide an unprecedented quantitative insight into the effect of molecular size on the pulmonary disposition of proteins following systemic and local administration.

研究目的本研究旨在探讨野生型小鼠全身和局部给药后,分子大小对蛋白质肺药代动力学(PK)的影响。研究方法研究使用了一种无交叉反应的抗体曲妥珠单抗以及该抗体的 F(ab')2、Fab 和 scFv 片段。蛋白质经静脉注射或气管内灌注,用酶联免疫吸附法测定血浆、肺、气管、支气管和支气管肺泡灌洗液(BAL)中的 PK 值。对 BAL 中的浓度进行了尿素归一化处理。结果:全身给药后,肺、气管、支气管和 BAL 的生物分布系数(BC)分别为:抗体 11%、11%、15% 和 2%;F(ab')2 15%、7%、13% 和 8% ;Fab 25%、17%、28% 和 46% ;scFv 14%、1%、2% 和 50% 。BAL 中的抗体暴露量比血浆低约 50 倍,比肺部组织低约 5-7 倍。观察到一种组织依赖性 BC 与分子大小的关系,其中 Fab(50 kDa)在组织中的分布最高,而 scFv 在 BAL 中的分布最高。局部用药后产生的 PK 数据变化很大;但是,对于所有蛋白,局部用药导致的 BAL 暴露量比全身用药后的暴露量高 10-100 倍。最初,BAL 中的抗体浓度是血浆浓度的 100-1000 倍,到第 14 天时浓度趋于正常。对于大多数蛋白质,局部用药导致肺部浓度高于气管和支气管,这与全身用药后观察到的情况相反。结论本文介绍的 PK 数据提供了前所未有的定量洞察力,让我们了解了分子大小对全身和局部给药后蛋白质肺部处置的影响。
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引用次数: 0
High-Throughput Drug Stability Assessment via Biomimetic Metalloporphyrin-Catalyzed Reactions Using Laser-Assisted Rapid Evaporative Ionization Mass Spectrometry (LA-REIMS). 利用激光辅助快速蒸发电离质谱法 (LA-REIMS) 通过仿生金属卟啉催化反应进行高通量药物稳定性评估
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-27 DOI: 10.3390/pharmaceutics16101266
András Marton, Zsombor Mohácsi, Balázs Decsi, Balázs Csillag, Júlia Balog, Richard Schäffer, Tamás Karancsi, György Tibor Balogh

Background: Building extensive drug candidate libraries as early in the development pipeline as possible, with high-throughput in vitro absorption, distribution, metabolism, and excretion (ADME) profiling, is crucial for the selection of lead compounds to guide subsequent research and production phases. Traditionally, the analysis of metabolic stability assays heavily relies on high-throughput LC-MS/MS (liquid chromatography tandem mass spectrometry) techniques to meet with the lead profiling demands. Laser-assisted rapid evaporative ionization mass spectrometry (LA-REIMS) is a quick and efficient technique for characterizing complex biological samples without laborious sample preparation. Objective: In this study, using an automated LA-REIMS well plate reader, achieving an 8 s per sample measurement time, the oxidative metabolic stability of active drug agents was assessed using biomimetic metalloporphyrin-based oxidative model reactions. Results: The results obtained using the novel LA-REIMS-based protocol were compared to and corroborated by those obtained using conventional HPLC-UV-MS (high performance liquid chromatography with ultra-violet detection coupled with mass spectrometry) measurements. Conclusions: LA-REIMS emerges as a promising technique, demonstrating potential suitability for semi-quantitative high-throughput metabolic stability in an optimized solvent environment.

背景:通过高通量体外吸收、分布、代谢和排泄(ADME)分析,在研发初期建立广泛的候选药物库,对于选择先导化合物以指导后续研究和生产阶段至关重要。传统上,代谢稳定性分析主要依靠高通量 LC-MS/MS(液相色谱串联质谱)技术来满足先导化合物分析的需求。激光辅助快速蒸发离子化质谱(LA-REIMS)是一种快速、高效的技术,可用于表征复杂的生物样品,而无需费力地制备样品。研究目的本研究使用自动 LA-REIMS 孔板阅读器,在每个样品 8 秒的测量时间内,利用基于仿金属卟啉的生物氧化模型反应评估了活性药物的氧化代谢稳定性。结果:使用基于 LA-REIMS 的新方案得出的结果与使用传统 HPLC-UV-MS(高效液相色谱-紫外检测-质谱联用)测量得出的结果进行了比较和印证。结论LA-REIMS 是一种很有前途的技术,它证明了在优化的溶剂环境中半定量高通量代谢稳定性的潜在适用性。
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引用次数: 0
Investigation of the Impact of Manufacturing Methods on Protein-Based Long-Acting Injectable Formulations: A Comparative Assessment for Microfluidics vs. Conventional Methods. 生产方法对蛋白质长效注射剂配方影响的调查:微流控与传统方法的比较评估。
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-27 DOI: 10.3390/pharmaceutics16101264
Nihan Yonet-Tanyeri, Robert S Parker, Louis D Falo, Steven R Little

Background/Objectives: Microparticle-based drug delivery systems offer several advantages for protein-based drug formulations, enhancing patient compliance and therapeutic efficiency through the sustained delivery of the active pharmaceutical ingredient. Over the past few decades, the microfluidics method has emerged as a continuous manufacturing process for preparing drug-encapsulating microparticles, mainly for small molecule drugs. However, comparative assessments for the conventional batch method vs. the microfluidics method for protein-based drug formulations have been lacking. The main objective of this study was to generate immunomodulatory protein drug-loaded injectable formulations using both conventional batch and microfluidics methods.

Methods: Therefore, rhCCL22-loaded poly(lactic-co-glycolic) acid (PLGA) microparticles were prepared by conventional homogenization and microfluidics methods.

Results: The resulting microparticles were analyzed comparatively, focusing on critical quality attributes such as microparticle size, size distribution, morphology, drug encapsulation efficiency, release kinetics, and batch-to-batch variations in relation to the manufacturing method. Our results demonstrated that the conventional method resulted in microparticles with denser surface porosity and wider size distribution as opposed to microparticles prepared by the microfluidics method, which could contribute to a significant difference in the drug-release kinetics. Additionally, our findings indicated minimal variation within batches for the microparticles prepared by the microfluidics method.

Conclusion: Overall, this study highlights the comparative assessment of several critical quality attributes and batch variations associated with the manufacturing methods of protein-loaded microparticles which is crucial for ensuring consistency in efficacy, regulatory compliance, and quality control in the drug formulation manufacturing process.

背景/目标:基于微粒的给药系统为基于蛋白质的药物制剂提供了多种优势,通过持续给药活性药物成分,提高了患者的依从性和治疗效率。在过去几十年中,微流控方法已成为制备药物封装微粒(主要用于小分子药物)的一种连续生产工艺。然而,对于基于蛋白质的药物制剂,一直缺乏传统批量法与微流控方法的比较评估。本研究的主要目的是利用传统批次法和微流体法生成免疫调节蛋白质药物负载注射制剂:因此,采用传统的均质化和微流控方法制备了负载rhCCL22的聚乳酸(PLGA)微颗粒:结果:我们对制备的微颗粒进行了比较分析,重点是微颗粒尺寸、尺寸分布、形态、药物包封效率、释放动力学等关键质量属性,以及与制备方法有关的批次间差异。我们的研究结果表明,与微流控方法制备的微粒相比,传统方法制备的微粒表面孔隙率更大,粒度分布更广,这可能会导致药物释放动力学的显著差异。此外,我们的研究结果表明,微流控方法制备的微颗粒在批次内的差异极小:总之,本研究突出强调了与蛋白质负载微颗粒生产方法相关的几个关键质量属性和批次差异的比较评估,这对于确保药物制剂生产过程中的疗效一致性、合规性和质量控制至关重要。
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引用次数: 0
Development of Novel ROCK Inhibitors via 3D-QSAR and Molecular Docking Studies: A Framework for Multi-Target Drug Design. 通过 3D-QSAR 和分子对接研究开发新型 ROCK 抑制剂:多靶点药物设计框架。
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-26 DOI: 10.3390/pharmaceutics16101250
Milan Beljkas, Milos Petkovic, Ana Vuletic, Ana Djuric, Juan Francisco Santibanez, Tatjana Srdic-Rajic, Katarina Nikolic, Slavica Oljacic

Background/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics-ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies.

背景/目的:肌动蛋白细胞骨架的改变与肿瘤进展相关,并影响粘附、迁移和侵袭等关键细胞过程。Rho相关含线圈蛋白激酶(ROCK1和ROCK2)是肌动蛋白细胞骨架的重要调节因子,在各种恶性肿瘤中经常过度表达。因此,本研究旨在利用计算机辅助药物设计(CADD)方法确定 ROCK1/ROCK2 抑制剂的关键结构特征。此外,新开发的 ROCK 抑制剂为开发多靶点疗法-ROCK/HDAC(组蛋白去乙酰化酶)多靶点抑制剂提供了重要框架。方法:采用三维-QSAR(定量结构-活性关系研究)和分子对接研究来确定与 ROCK 抑制作用正相关的关键结构特征。采用 MDA-MB-231、HCC1937、Panc-1 和 Mia PaCa-2 细胞评估合成化合物的抗癌特性。结果C-19 显示出了强大的抗癌特性,尤其是在胰腺癌细胞系中增强了细胞凋亡和细胞周期调控。此外,C-19 和 C-22 还显示出与著名的 ROCK 抑制剂法舒地尔相当的强效抗迁移和抗侵袭作用。结论:根据这项研究的结果,我们提出了一种新的多靶点方法,重点是根据 C-19 和 C-22 的结构开发 HDAC/ROCK 双抑制剂,利用这两种信号通路的协同潜力来提高对转移性肿瘤的疗效。我们的研究结果强调了多靶点 ROCK 抑制剂作为未来癌症疗法基础的潜力。
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引用次数: 0
Topical Application of Centella asiatica in Wound Healing: Recent Insights into Mechanisms and Clinical Efficacy. 积雪草在伤口愈合中的局部应用:对机制和临床疗效的最新见解。
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-26 DOI: 10.3390/pharmaceutics16101252
Katarzyna Witkowska, Magdalena Paczkowska-Walendowska, Ewa Garbiec, Judyta Cielecka-Piontek

Centella asiatica, widely known as Gotu kola, is a traditional herb celebrated for its benefits in skin health and wound healing. Recent research has provided new insights into its efficacy, particularly through topical applications. This review highlights the plant's mechanisms, focusing on its active compounds such as asiaticoside, madecassoside, asiatic acid, and madecassic acid, which enhance collagen synthesis, modulate inflammation, and offer antioxidant protection. Clinical trials have been collected and summarized that innovative delivery systems, such as hydrogels, nanostructures or microneedles, can accelerate wound healing, reduce wound size, and improve recovery times in various wound types, including diabetic ulcers and burns. Future research will likely refine these technologies and explore new applications, reinforcing the role of C. asiatica in contemporary wound care. Advances in formulation and delivery will continue to enhance the plant's therapeutic potential, offering promising solutions for effective wound management.

积雪草被广泛称为哥度柯拉,是一种传统草药,因其在皮肤健康和伤口愈合方面的功效而备受赞誉。最近的研究对其功效有了新的认识,特别是通过局部应用。这篇综述重点介绍了该植物的作用机制,重点是其活性化合物,如积雪草苷、积雪草甙、积雪草酸和积雪草酸,它们能促进胶原蛋白合成、调节炎症反应并提供抗氧化保护。收集和总结的临床试验表明,水凝胶、纳米结构或微针等创新给药系统可以加速伤口愈合,缩小伤口面积,并改善各种伤口(包括糖尿病溃疡和烧伤)的恢复时间。未来的研究很可能会完善这些技术并探索新的应用,从而加强积雪草在现代伤口护理中的作用。制剂和给药方面的进步将继续增强该植物的治疗潜力,为有效的伤口管理提供前景广阔的解决方案。
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引用次数: 0
Use of Natural Polymers for the Encapsulation of Eugenol by Spray Drying. 利用天然聚合物通过喷雾干燥法封装丁香酚。
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-26 DOI: 10.3390/pharmaceutics16101251
Aitor Caballero-Román, Anna Nardi-Ricart, Roser Vila, Salvador Cañigueral, Josep R Ticó, Montserrat Miñarro

Background: Eugenol is a colourless or yellowish compound whose presence in clove essential oil surpasses the 75% of its composition. This phenylpropanoid, widely used as an antiseptic, anaesthetic and antioxidant, can be extracted by steam distillation from the dried flower buds of Syzygium aromaticum (L.). Due to its chemical instability in presence of light and air, it should be protected when developing a formulation to avoid or minimise its degradation. Methods: A promising approach would be encapsulation by spray drying, using natural coating products such as maltodextrin, gum arabic, and soy lecithin. To do so, a factorial design was carried out to evaluate the effect of five variables at two levels (inlet temperature, aspirator and flow rate, method of homogenisation of the emulsion and its eugenol:polymers ratio). Studied outcomes were yield and outlet temperature of the spray drying process, eugenol encapsulation efficiency, and particle size expressed as d(0.9). Results: The best three formulations were prepared by using a lower amount of eugenol than polymers (1:2 ratio), homogenised by Ultra-Turrax®, and pumped to the spray dryer at 35 m3/h. Inlet temperature and flow rate varied in the top three formulations, but their values in the best formulation (DF22) were 130 °C and 4.5 mL/min. These microcapsules encapsulated between 47.37% and 65.69% of eugenol and were spray-dried achieving more than a 57.20% of product recovery. Their size, ranged from 22.40 μm to 55.60 μm. Conclusions: Overall, the whole spray drying process was optimised, and biodegradable stable polymeric microcapsules containing eugenol were successfully prepared.

背景介绍丁香酚是一种无色或淡黄色化合物,在丁香精油中的含量超过其成分的 75%。丁香酚是一种无色或黄色的化合物,在丁香精油中的含量超过其成分的 75%。这种苯丙酮类化合物可通过蒸汽蒸馏从丁香(Syzygium aromaticum (L.))的干花蕾中提取,被广泛用作防腐剂、麻醉剂和抗氧化剂。由于它在光照和空气中的化学性质不稳定,因此在开发配方时应加以保护,以避免或尽量减少其降解。方法:一种可行的方法是使用麦芽糊精、阿拉伯树胶和大豆卵磷脂等天然包衣产品,通过喷雾干燥进行封装。为此,采用了一个因子设计来评估五个变量在两个层面上的影响(入口温度、吸气器和流速、乳液均化方法以及丁香酚与聚合物的比例)。研究结果包括喷雾干燥过程的产量和出口温度、丁香酚封装效率以及以 d(0.9)表示的粒度。研究结果丁香酚的用量低于聚合物的用量(比例为 1:2),用 Ultra-Turrax® 进行均质,并以 35 m3/h 的速度泵入喷雾干燥器,制备出三种最佳配方。前三种配方的入口温度和流速各不相同,但最佳配方(DF22)的入口温度和流速分别为 130 °C 和 4.5 mL/min。这些微胶囊封装了 47.37% 至 65.69% 的丁香酚,经喷雾干燥后,产品回收率超过 57.20%。它们的尺寸从 22.40 μm 到 55.60 μm。结论总之,整个喷雾干燥过程得到了优化,并成功制备出了含有丁香酚的可生物降解的稳定聚合物微胶囊。
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引用次数: 0
Buprenorphine Transdermal Delivery System: Bioequivalence Assessment and Adhesion Performance of Two Patch Formulations. 丁丙诺啡透皮给药系统:两种贴片配方的生物等效性评估和粘附性能。
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-26 DOI: 10.3390/pharmaceutics16101249
Marcelo Gomes Davanço, Miguel Fortuny, Alejandro Scasso, Jessica Meulman, Fernando Costa, Thalita Martins da Silva, Débora Renz Barreto Vianna, Leonardo de Souza Teixeira, Karini Bruno Bellorio, Ana Carolina Costa Sampaio, Celso Francisco Pimentel Vespasiano

Background and Objective: Buprenorphine is an opioid drug indicated for the management of severe and persistent pain. The buprenorphine transdermal patch provides a non-invasive method of rate-controlled drug release, ensuring constant and predictable drug plasma levels over an extended period. This study aimed to assess the bioequivalence, skin adhesion non-inferiority, and tolerability of two buprenorphine transdermal patches to meet the regulatory requirements for the registration of a generic product in Brazil. Methods: A randomized, single-dose, two-period, two-sequence crossover trial was performed involving healthy subjects of both genders. The subjects received a single dose of either the test formulation or the reference formulation (Restiva®), separated by a 29-day washout period. For pharmacokinetic analysis, blood samples were collected up to 12 days post-dose and quantified using a validated bioanalytical method. Skin adhesion was assessed over a 7-day period (dosing interval) following patch application. Seventy-six subjects were enrolled and fifty-two completed the study. Results and Conclusion: The 90% confidence intervals for Cmax, AUC0-t, and partial AUCs were within the acceptable bioequivalence limits of 80 to 125%. Adhesion comparison showed the non-inferiority of the test formulation. Based on ANVISA's regulatory requirements, the test and reference formulations were considered bioequivalent and could be interchangeable in clinical practice.

背景和目的:丁丙诺啡是一种阿片类药物,适用于治疗严重和持续性疼痛。丁丙诺啡透皮贴片提供了一种非侵入性的药物释放速率控制方法,可确保在较长时间内保持稳定和可预测的药物血浆水平。本研究旨在评估两种丁丙诺啡透皮贴剂的生物等效性、皮肤粘附性和耐受性,以满足巴西仿制药注册的监管要求。研究方法对健康的男女受试者进行了随机、单剂量、两阶段、两序列交叉试验。受试者单剂量服用试验制剂或参比制剂(Restiva®),中间有 29 天的冲洗期。为了进行药代动力学分析,在用药后 12 天内采集了血液样本,并采用经过验证的生物分析方法进行了定量。在贴敷后的 7 天内(用药间隔)对皮肤粘附性进行评估。研究共招募了 76 名受试者,其中 52 人完成了研究。结果与结论Cmax、AUC0-t 和部分 AUC 的 90% 置信区间在 80% 至 125% 的可接受生物等效性范围内。粘附性比较显示试验制剂无劣效。根据 ANVISA 的监管要求,试验制剂和参比制剂被认为具有生物等效性,在临床实践中可以互换。
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引用次数: 0
An Efficient Fabrication Approach for Multi-Cancer Responsive Chemoimmuno Co-Delivery Nanoparticles. 多种癌症响应性化学免疫共给药纳米颗粒的高效制造方法
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-25 DOI: 10.3390/pharmaceutics16101246
Jianxi Huang, Yu-Ting Chien, Qingxin Mu, Miqin Zhang

Background/Objectives: Cancer remains one of the leading causes of death, with breast, liver, and pancreatic cancers significantly contributing to this burden. Traditional treatments face issues including dose-limiting toxicity, drug resistance, and limited efficacy. Combining therapeutic agents can enhance effectiveness and reduce toxicity, but separate administration often leads to inefficiencies due to differing pharmacokinetics and biodistribution. Co-formulating hydrophobic chemotherapeutics such as paclitaxel (PTX) and hydrophilic immunologic agents such as polyinosinic-polycytidylic acid (Poly IC) is particularly challenging due to their distinct physicochemical properties. This study presents a novel and efficient approach for the co-delivery of PTX and Poly IC using chitosan-based nanoparticles. Method: Chitosan-PEG (CP) nanoparticles were developed to encapsulate both PTX and Poly IC, overcoming their differing physicochemical properties and enhancing therapeutic efficacy. Results: With an average size of ~100 nm, these nanoparticles facilitate efficient cellular uptake and stability. In vitro results showed that CP-PTX-Poly IC nanoparticles significantly reduced cancer cell viability in breast (4T1), liver (HepG2), and pancreatic (Pan02) cancer types, while also enhancing dendritic cell (DC) maturation. Conclusions: This dual-modal delivery system effectively combines chemotherapy and immunotherapy, offering a promising solution for more effective cancer treatment and improved outcomes.

背景/目标:癌症仍然是导致死亡的主要原因之一,其中乳腺癌、肝癌和胰腺癌是造成这一负担的主要原因。传统治疗方法面临着剂量限制毒性、耐药性和疗效有限等问题。联合使用治疗药物可以提高疗效、减少毒性,但由于药代动力学和生物分布不同,单独给药往往导致效率低下。由于紫杉醇(PTX)等疏水性化疗药物和聚肌苷酸-聚胞苷酸(Poly IC)等亲水性免疫药物的理化性质各不相同,两者的联合配伍尤其具有挑战性。本研究提出了一种利用壳聚糖基纳米颗粒联合递送 PTX 和 Poly IC 的新型高效方法。研究方法开发了壳聚糖-聚乙二醇(CP)纳米颗粒,用于包裹 PTX 和聚 IC,克服了它们不同的理化性质,提高了疗效。结果这些纳米粒子的平均粒径约为 100 纳米,有助于细胞的有效吸收和稳定性。体外实验结果表明,CP-PTX-Poly IC 纳米粒子能显著降低乳腺癌(4T1)、肝癌(HepG2)和胰腺癌(Pan02)的癌细胞存活率,同时还能促进树突状细胞(DC)成熟。结论这种双模式给药系统有效地结合了化疗和免疫疗法,为更有效地治疗癌症和改善预后提供了一种前景广阔的解决方案。
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引用次数: 0
Comparative Pharmacokinetics of Sustained-Release versus Immediate-Release Melatonin Capsules in Fasting Healthy Adults: A Randomized, Open-Label, Cross-Over Study. 空腹健康成人服用缓释和速释褪黑素胶囊的药代动力学比较:一项随机、开放标签、交叉研究。
IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-25 DOI: 10.3390/pharmaceutics16101248
Shefali Thanawala, R Abiraamasundari, Rajat Shah

Background: Exogenous melatonin, a nutraceutical for maintaining a healthy sleep-wake cycle and managing sleep disorders, requires large, repeated doses due to its low bioavailability and short half-life. This necessitates the development of a sustained-release formulation with a longer half-life and sustained plasma concentration. Therefore, exogenous novel 5 mg sustained-release melatonin capsules (Melatonin-SR, test product) were formulated. Methods: This open-label cross-over study compared the pharmacokinetics (maximum concentration [Cmax], time to reach Cmax [Tmax], area under the curve [AUC], and elimination half-life [t1/2]) and the safety of Melatonin-SR with 5 mg immediate-release melatonin capsules (Melatonin-IR, reference product) after single-dose oral administration in healthy fasting adults. Results: Sixteen participants (aged 18-45 years) were randomized (1:1) to receive either Melatonin-SR or Melatonin-IR in two periods with a 7-day washout period. Melatonin-SR reported a lower Cmax (11,446.87 pg/mL) compared to Melatonin-IR (22,786.30 pg/mL). The mean Tmax of Melatonin-SR and Melatonin-IR was 1.26 h and 0.87 h, respectively. The mean t1/2 of Melatonin-SR (5.10 h) was prolonged by five-fold compared to Melatonin-IR (1.01 h). One adverse event (vomiting) was reported following the administration of the Melatonin-IR. Conclusions: Melatonin-SR resulted in higher and sustained plasma melatonin concentrations for an extended period and was well-tolerated. Hence, Melatonin-SR may be a promising nutraceutical for maintaining healthy sleep.

背景:外源性褪黑素是一种营养保健品,可用于维持健康的睡眠-觉醒周期和控制睡眠障碍,但由于其生物利用度低、半衰期短,因此需要重复服用大剂量褪黑素。这就需要开发一种半衰期更长、血浆浓度更持久的缓释制剂。因此,我们配制了外源性新型 5 毫克褪黑素缓释胶囊(Melatonin-SR,试验产品)。研究方法这项开放标签交叉研究比较了褪黑素-SR与5毫克速释褪黑素胶囊(褪黑素-IR,参比产品)在健康空腹成年人中单次口服后的药代动力学(最大浓度[Cmax]、达到Cmax的时间[Tmax]、曲线下面积[AUC]和消除半衰期[t1/2])和安全性。结果:16名参与者(18-45岁)被随机(1:1)分两次服用褪黑素-SR或褪黑素-IR,并有7天的冲洗期。与褪黑素-IR(22786.30 pg/mL)相比,褪黑素-SR的Cmax较低(11446.87 pg/mL)。褪黑素-SR和褪黑素-IR的平均Tmax分别为1.26小时和0.87小时。褪黑素-SR的平均t1/2(5.10小时)比褪黑素-IR(1.01小时)延长了5倍。服用褪黑素-IR后出现了一次不良反应(呕吐)。结论褪黑素-SR可使血浆中的褪黑素浓度更高且持续时间更长,并且耐受性良好。因此,Melatonin-SR 可能是一种很有前途的维持健康睡眠的营养保健品。
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引用次数: 0
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Pharmaceutics
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