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Evaluation of the impact of mucin on supersaturation and permeation of BCS class 2 basic drugs 评估粘蛋白对 BCS 2 类基本药物过饱和度和渗透性的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.016
Tania Ng, Dawen Kou
This study evaluated the impact of mucin on supersaturation and permeation of BCS Class 2 basic drugs in a pH-shift, 2-stage model using three model compounds, dipyridamole, ricobendazole, and Compound A. The three compounds showed various degrees of supersaturation (DoS) in Stage 2 and modest to no increases in flux with the presence of mucin in the dissolution media. Mucin's impact on DoS and flux, if any, appeared to be compound specific and possibly related to its pKa and ionization state. Overall, the increases in supersaturation and permeation due to mucin ranged from modest to minimal for the three model compounds under the conditions tested. The pH-shift model using MacroFLUX was able to monitor gastric and intestinal dissolution and simultaneously assess the effect of intestinal mucin on supersaturation and flux.
本研究评估了在 pH 值偏移的 2 阶段模型中,粘蛋白对 BCS 第 2 类碱性药物的过饱和及渗透的影响。粘蛋白对 DoS 和通量的影响(如果有的话)似乎是针对特定化合物的,可能与其 pKa 和电离状态有关。总体而言,在测试条件下,粘蛋白对三种模型化合物的过饱和度和渗透性的影响从适度到极小不等。使用 MacroFLUX 的 pH 值偏移模型能够监测胃和肠道溶解情况,并同时评估肠道粘蛋白对过饱和度和通量的影响。
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引用次数: 0
Brain targeting of venlafaxine via intranasal transbilosomes thermogel for improved management of depressive disorder 通过鼻内透纤体热凝胶实现文拉法辛的脑靶向治疗,从而改善抑郁症的治疗。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.026
Omar A. Alsaidan , Mohammed H. Elkomy , Randa Mohammed Zaki , Alaa S. Tulbah , Rehab Mohammad Yusif , Hussein M. Eid
The current research aimed to design and optimize hyaluronic acid-coated transbilosomes containing venlafaxine (VLF-HA-TBLs) for nose-to-brain delivery for improved management of depressive disorder. Venlafaxine-loaded transbilosomes (VLF-TBLs) were developed according to the film hydration procedure, optimized for maximum efficiency using the quality by design-based Box-Behnken design (BBD), and then coated with hyaluronic acid (HA). The optimized VLF-HA-TBLs were subjected to in vitro characterization, integrated into a thermolabile gel, and then exposed to in vivo evaluation studies. The results revealed that the VLF-HA-TBLs formulation exhibited acceptable size (185.6 ± 4.9 nm), surface charge (-39.8 ± 1.7 mV), and entrapment efficiency (69.6 ± 2.6 %). The morphological study revealed that nanovesicles were spherical and displayed a consistent size distribution without particle aggregation. It also showed improved ex vivo nasal diffusion and a prolonged release profile. In addition, the formulated VLF-HA-TBLs were stable under the studied conditions and tolerable when applied intranasally. Compared to the intranasal administration of VLF solution (VLF-SOL), the biodistribution analysis showed that VLF-HA-TBLs delivered intranasally had a relative bioavailability of 441 % in the brain and 288 % in plasma. Moreover, the intranasal delivery of VLF-HA-TBLs demonstrated much higher bioavailability (512 %) in the brain compared to VLF-SOL administered intravenously. Collectively, it could be possible to infer that HA-TBLs might be an effective nanocarrier to administer VLF to the brain via the nasal route.
目前的研究旨在设计和优化含有文拉法辛的透明质酸涂层经纤体(VLF-HA-TBLs),用于鼻脑给药,改善抑郁症的治疗。根据薄膜水合过程开发出了文拉法辛负载型反式螺旋体(VLF-TBLs),并利用基于设计的盒-贝肯设计(BBD)方法对其进行了优化,以实现最高效率,然后在其表面涂上透明质酸(HA)。对优化后的 VLF-HA-TBLs 进行了体外表征,将其整合到热稳定凝胶中,然后进行了体内评估研究。结果表明,VLF-HA-TBLs 制剂具有可接受的尺寸(185.6±4.9 nm)、表面电荷(-39.8±1.7 mV)和夹持效率(69.6±2.6%)。形态学研究显示,纳米微粒呈球形,大小分布一致,无颗粒聚集。它还显示出较好的体内鼻腔扩散性和较长的释放曲线。此外,配制的 VLF-HA-TBLs 在研究条件下是稳定的,鼻内使用时也是可耐受的。与VLF溶液(VLF-SOL)鼻内给药相比,生物分布分析表明,VLF-HA-TBLs鼻内给药在大脑中的相对生物利用率为441%,在血浆中的生物利用率为288%。此外,与静脉注射 VLF-SOL 相比,鼻内给药的 VLF-HA-TBLs 在大脑中的生物利用率要高得多(512%)。综上所述,可以推断HA-TBLs可能是一种有效的纳米载体,可通过鼻腔途径将VLF注入大脑。
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引用次数: 0
Engineering of layer-by-layer acetate-coated paclitaxel loaded poly(lactide-co-glycolide) acid nanoparticles for prostate cancer therapy- in vitro 用于前列腺癌治疗的逐层醋酸纤维包覆紫杉醇聚乳酸-共聚甘醇酸纳米粒子的体外工程学研究
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.09.014
Albert Nguessan Ngo , Kierston K. Chatman , Dezirae Douglas , Keb M. Mosley-Kellum , Ke Wu , Jaydutt Vadgama
It is hypothesized that layer-by-layer acetate-coated Paclitaxel-loaded PLGA nanoparticles (F2) can be engineered to potentiate the effectiveness of Paclitaxel (PTX) on LNCaP, a human prostate cancer cell line. The core of the layer-by-layer NPs is formed by nanoprecipitation, and the shell of the NPs is engineered using the sodium acetate's unique coating mechanism and surface-active properties. The resulting nanoformulation physicochemical properties are characterized by Fourier Transform Infra-Red (FTIR), Differential Scanning Calorimetry (DSC) Transmission Electron Microscopy (TEM), NanoSight NS300, spectrophotometry, Korsmeyer-Peppas model, respectively. The NP's cytotoxicity on LNCaP is assessed by MTS assay. The DSC and the FTIR confirm SA's coating of the NPs. The particle's mean diameters (PMD) are 89.4±2.3- to 114.4±7.6 nm. The TEM shows a unique multilayer and spherical nanoparticle. The encapsulation efficiency of commonly PTX-loaded PLGA NPs (F1) and F2 are 84.37±2.71% and 86.74±2.22, respectively. The drug transport mechanism of F1 and F2 is anomalous transport and case II, respectively. F2 follows a zero-order release mechanism. The cell viability is 45.08±2.18% and 60.17±4.72% when LNCaP is treated with 10 µg/mL of F2 and F1, respectively, after 48 hours of exposure. F2 and F1 cell growth inhibition are dose-dependent. This unique process of engineering the layer-by-layer NPs will provide new horizons for developing future innovative nanoparticles for targeted prostate cancer therapy.
该研究假设,逐层醋酸钠包覆的紫杉醇负载PLGA纳米粒子(F2)可增强紫杉醇(PTX)对人类前列腺癌细胞系LNCaP的疗效。逐层 NPs 的核心是通过纳米沉淀形成的,而 NPs 的外壳则是利用醋酸钠独特的涂层机制和表面活性特性设计的。傅立叶变换红外光谱法(FTIR)、差示扫描量热法(DSC)、透射电子显微镜(TEM)、NanoSight NS300、分光光度法、Korsmeyer-Peppas 模型分别对所制备的纳米制剂的理化性质进行了表征。NP 对 LNCaP 的细胞毒性通过 MTS 试验进行评估。DSC 和傅立叶变换红外光谱证实了 NPs 上的 SA 涂层。颗粒的平均直径(PMD)为 89.4±2.3- 至 114.4±7.6 nm。TEM 显示了独特的多层球形纳米粒子。常见的PTX负载PLGA NPs(F1)和F2的包封效率分别为84.37±2.71%和86.74±2.22。F1和F2的药物转运机制分别为反常转运和情况II。F2 遵循零阶释放机制。用 10 µg/mL 的 F2 和 F1 处理 LNCaP 细胞 48 小时后,细胞存活率分别为 45.08±2.18% 和 60.17±4.72%。F2 和 F1 对细胞生长的抑制具有剂量依赖性。这种独特的逐层 NPs 工程工艺将为开发未来用于前列腺癌靶向治疗的创新纳米粒子提供新的前景。
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引用次数: 0
Contributions of multiple transport mechanisms to intestinal uptake of serotonin 多种转运机制对羟色胺肠道吸收的贡献
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.07.020
Suguru Asaji, Yuta Funai, Yuta Seki, Ikumi Tamai, Yoshiyuki Shirasaka
This study aimed to analyze the contributions of multiple transport mechanisms to the intestinal uptake of serotonin (5-HT) by employing a variety of in vitro experimental techniques, focusing on organic cation transporters expressed in the gastrointestinal (GI) tract, such as SERT, PMAT, THTR2, OCT3, and OCTN2. Analysis of the concentration dependence of 5-HT uptake by Caco-2 cells revealed multi-affinity kinetics with high-affinity and low-affinity components, suggesting that multiple transporters are involved in the intestinal 5-HT uptake. Comparative analysis of transporters using Km values obtained in Xenopus oocyte expression systems suggested that SERT is responsible for the high-affinity transport, while PMAT, THTR2, and OCT3 contribute to the low-affinity transport. Further analysis indicated that the relative contributions of SERT and PMAT to the intestinal 5-HT uptake (0.01 µM) are approximately 94.9% and 1.1%, respectively. Interestingly, at the concentration of 10 µM, the reported steady-state concentration of 5-HT in the human colon, the contributions of SERT, PMAT, THTR2, and OCT3 were estimated to be approximately 37.0%, 1.0%, 18.2%, and 20.5%, respectively. In conclusion, the present study indicated that the contributions of multiple transporters to 5-HT uptake in the GI tract are dependent upon the colon luminal concentration of 5-HT.
本研究旨在采用多种体外实验技术,分析多种转运机制对5-羟色胺(5-HT)肠道摄取的贡献,重点研究胃肠道(GI)中表达的有机阳离子转运体,如SERT、PMAT、THTR2、OCT3和OCTN2。对 Caco-2 细胞摄取 5-HT 的浓度依赖性进行的分析表明,5-HT 的摄取具有高亲和力和低亲和力的多亲和力动力学,这表明有多个转运体参与了肠道 5-HT 的摄取。利用在爪蟾卵母细胞表达系统中获得的 Km 值对转运体进行的比较分析表明,SERT 负责高亲和力转运,而 PMAT、THTR2 和 OCT3 对低亲和力转运做出了贡献。进一步分析表明,SERT 和 PMAT 对肠道 5-HT 摄取(0.01 µM)的相对贡献率分别约为 94.9% 和 1.1%。有趣的是,当浓度为 10 µM(据报道 5-HT 在人体结肠中的稳态浓度)时,SERT、PMAT、THTR2 和 OCT3 的贡献率估计分别约为 37.0%、1.0%、18.2% 和 20.5%。总之,本研究表明,多种转运体对消化道 5-HT 摄取的贡献取决于结肠腔内 5-HT 的浓度。
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引用次数: 0
Formulation of three tailed bacteriophages by spray-drying and atomic layer deposition for thermal stability and controlled release 利用喷雾干燥和原子层沉积技术配制三尾噬菌体,实现热稳定性和控释。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.005
Holly J. Coleman , Qin Yang , Amanda Robert , Hannah Padgette , Hans H. Funke , Carlos E. Catalano , Theodore W. Randolph
Deep infection is the second most common complication of arthroplasty following loosening of the implant. Antibiotic-loaded bone cements (ALBCs) and high concentrations of systemic broad-spectrum antibiotics are commonly used to prevent infections following injury and surgery. However, clinical data fails to show that ALBCs are effective against deep infection, and negative side effects can result following prolonged administration of antibiotics. Additionally, the rise of multidrug resistant (MDR) bacteria provides an urgent need for alternatives to broad-spectrum antibiotics. Phage therapy, or the use of bacteriophages (viruses that infect bacteria) to target pathogenic bacteria, might offer a safe alternative to combat MDR bacteria. Application of phage therapy in the setting of deep infections requires formulation strategies that would stabilize bacteriophage against chemical and thermal stress during bone-cement polymerization, that maintain bacteriophage activity for weeks or months at physiological temperatures, and that allow for sustained release of phage to combat slow-growing, persistent bacteria. Here, we demonstrate the formulation of three phages that target diverse bacterial pathogens, which includes spray-drying of the particles for enhanced thermal stability at 37 °C and above. Additionally, we use atomic layer deposition (ALD) to coat spray-dried powders with alumina to allow for delayed release of phage from the dry formulations, and potentially protect phage against chemical damage during bone cement polymerization. Together, these findings present a strategy to formulate phages that possess thermal stability and sustained release properties for use in deep infections.
深部感染是继假体松动之后关节置换术的第二大常见并发症。1 通常使用抗生素骨水泥(ALBC)和高浓度的全身广谱抗生素来预防损伤和手术后的感染。4 噬菌体疗法或使用噬菌体(感染细菌的病毒)来针对病原菌,可能会为抗击 MDR 细菌提供一种安全的替代方法。在深度感染中应用噬菌体疗法需要采取配方策略,在骨水泥聚合过程中稳定噬菌体以抵御化学和热应力,在生理温度下保持噬菌体活性数周或数月,并允许持续释放噬菌体以对抗生长缓慢的顽固细菌。在这里,我们展示了针对不同细菌病原体的三种噬菌体的配方,其中包括喷雾干燥颗粒,以增强在 37°C 及以上温度下的热稳定性。此外,我们还使用原子层沉积(ALD)技术在喷雾干燥的粉末上涂覆氧化铝,以延迟噬菌体从干燥配方中的释放,并在骨水泥聚合过程中保护噬菌体免受化学损伤。总之,这些发现为配制具有热稳定性和持续释放特性的噬菌体以用于深度感染提供了一种策略。
{"title":"Formulation of three tailed bacteriophages by spray-drying and atomic layer deposition for thermal stability and controlled release","authors":"Holly J. Coleman ,&nbsp;Qin Yang ,&nbsp;Amanda Robert ,&nbsp;Hannah Padgette ,&nbsp;Hans H. Funke ,&nbsp;Carlos E. Catalano ,&nbsp;Theodore W. Randolph","doi":"10.1016/j.xphs.2024.08.005","DOIUrl":"10.1016/j.xphs.2024.08.005","url":null,"abstract":"<div><div>Deep infection is the second most common complication of arthroplasty following loosening of the implant. Antibiotic-loaded bone cements (ALBCs) and high concentrations of systemic broad-spectrum antibiotics are commonly used to prevent infections following injury and surgery. However, clinical data fails to show that ALBCs are effective against deep infection, and negative side effects can result following prolonged administration of antibiotics. Additionally, the rise of multidrug resistant (MDR) bacteria provides an urgent need for alternatives to broad-spectrum antibiotics. Phage therapy, or the use of bacteriophages (viruses that infect bacteria) to target pathogenic bacteria, might offer a safe alternative to combat MDR bacteria. Application of phage therapy in the setting of deep infections requires formulation strategies that would stabilize bacteriophage against chemical and thermal stress during bone-cement polymerization, that maintain bacteriophage activity for weeks or months at physiological temperatures, and that allow for sustained release of phage to combat slow-growing, persistent bacteria. Here, we demonstrate the formulation of three phages that target diverse bacterial pathogens, which includes spray-drying of the particles for enhanced thermal stability at 37 °C and above. Additionally, we use atomic layer deposition (ALD) to coat spray-dried powders with alumina to allow for delayed release of phage from the dry formulations, and potentially protect phage against chemical damage during bone cement polymerization. Together, these findings present a strategy to formulate phages that possess thermal stability and sustained release properties for use in deep infections.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"113 11","pages":"Pages 3238-3245"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Industry's perspective on challenges assessing the in vivo impact of removing titanium dioxide (TiO2) from drug products 从行业角度看评估从药物产品中去除二氧化钛 (TiO2) 的体内影响所面临的挑战。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.002
Andreas Abend , Diana Sperger , Dorys Argelia Diaz , Ruiqiong Guo , Regina Reul , Sy-Juen Wu
The European Commission (EC) has tasked the European Medicines Agency (EMA) to provide a recommendation towards the acceptability of titanium dioxide (TiO2) in pharmaceutical products by early 2024 to inform on final decision in early 2025[1]. Unlike the already implemented ban of TiO2 in foods, removing this excipient from pharmaceutical products will likely have significant impact on the pharmaceutical industry, regulatory agencies, and patients. This commentary explores the challenges facing the pharmaceutical industry tasked with supporting the development and registration of TiO2 free (TF) drug products. Specifically, justification of formulation changes and potential impact to in vitro and in vivo performance, as well as differences in global regulatory comparative dissolution requirements to justify changing to TF drug product are discussed. Particularly, the uncertainties around how a formulation change such as removal of TiO2 from immediate release solid oral dosage forms will be viewed in Europe compared to other regions is discussed. To respond to these challenges and avoid disruption to the medicines supply chain in case in vitro data such as dissolution is either too challenging or insufficient to justify changing to TF product, pharmaceutical companies may have to decide if the level of risk is worth the effort needed to reformulate, develop, and register a new TF product.
欧盟委员会(EC)已责成欧洲药品管理局(EMA)在 2024 年初就药品中二氧化钛(TiO2)的可接受性提出建议,以便在 2025 年初做出最终决定[1]。与已在食品中实施的二氧化钛禁令不同,从药品中去除这种辅料可能会对制药行业、监管机构和患者产生重大影响。本评论探讨了制药行业在支持开发和注册不含二氧化钛(TF)的药品时所面临的挑战。具体而言,讨论了改变配方的理由、对体外和体内性能的潜在影响,以及全球监管机构对溶出度比较要求的差异,以证明改用TF药物产品的合理性。特别是,讨论了欧洲与其他地区相比如何看待制剂变更的不确定性,如在速释口服固体制剂中去除二氧化钛。为了应对这些挑战,避免在溶出度等体外数据太难或不足以证明有理由改用 TF 产品的情况下中断药品供应链,制药公司可能必须决定风险程度是否值得为重新配制、开发和注册新的 TF 产品而付出努力。
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引用次数: 0
Physiologically based pharmacokinetic model of brivaracetam to predict the exposure and dose exploration in hepatic impairment and elderly populations 基于生理学的 brivaracetam 药代动力学模型,用于预测肝功能损伤和老年人群的暴露量和剂量探索。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.022
Yiming Li , Wenxin Shao , Xingwen Wang , Kuo Geng , Wenhui Wang , Zhiwei Liu , Youjun Chen , Chaozhuang Shen , Haitang Xie
Brivaracetam (BRV) is a new third-generation antiseizure medication for the treatment of focal epileptic seizures. Its use has been increasing among epileptic populations in recent years, but pharmacokinetic (PK) behavior may change in hepatic impairment and the elderly populations. Due to ethical constraints, clinical trials are difficult to conduct and data are limited. This study used PK-Sim® to develop a physiologically based pharmacokinetic (PBPK) model for adults and extrapolate it to hepatic impairment and the elderly populations. The model was evaluated with clinical PK data, and dosage explorations were conducted. For the adult population with mild hepatic impairment, the dose is recommended to be adjusted to 70 % of the recommended dose, and to 60 % for moderate and severe hepatic impairment. For the elderly population with mild hepatic impairment under 80 years old, it is recommended that the dose be adjusted to 60 % of the recommended dose and to 50 % for moderate and severe conditions. The elderly population with hepatic impairment over 80 years old is adjusted to 50 % of the recommended dose for all stages. Healthy elderly do not need to adjust. The BRV PBPK model was successfully developed, studying exposure in hepatic impairment and elderly populations and optimizing dosing regimens.
布里瓦西坦(Brivaracetam,BRV)是一种新型第三代抗癫痫药物,用于治疗局灶性癫痫发作。近年来,该药在癫痫患者中的使用量不断增加,但在肝功能受损和老年人群中,药代动力学(PK)行为可能会发生变化。由于伦理方面的限制,临床试验很难进行,数据也很有限。本研究使用 PK-Sim® 建立了一个基于生理的成人药代动力学(PBPK)模型,并将其推断到肝功能受损和老年人群。该模型通过临床 PK 数据进行了评估,并进行了剂量探索。对于有轻度肝功能损害的成人,建议将剂量调整为推荐剂量的 70%,对于中度和重度肝功能损害,建议将剂量调整为推荐剂量的 60%。对于 80 岁以下患有轻度肝功能损害的老年人群,建议将剂量调整为建议剂量的 60%,中度和重度肝功能损害的老年人群建议将剂量调整为建议剂量的 50%。80岁以上肝功能受损的老年人群,所有阶段的剂量调整为推荐剂量的50%。健康老人无需调整。BRV PBPK 模型的成功开发,研究了肝功能损害和老年人群的暴露情况,并优化了给药方案。
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引用次数: 0
An overview of interpretability of two models of unbound fraction that are used in combination with the well-stirred model for predicting hepatic clearance of drugs 综述两种非结合部分模型的可解释性,这两种模型与搅匀模型结合使用,用于预测药物的肝清除率。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.09.002
Patrick Poulin
Hypothetical and experimental models of unbound fraction have been proposed to facilitate predicting the hepatic clearance (CLH) of drugs from values of intrinsic clearance for the unbound drug (CLint-in vitro-unbound) and the well-stirred model (WSM). The hypothetical model (fu-adjusted) is adjusting the unbound fractions determined in plasma in vitro to estimate the maximum unbound fractions at the hepatocytes if each drug-protein complex in plasma becomes fully dissociated at the membrane by any albumin (ALB)-facilitated hepatic uptake mechanism. The model of fu-adjusted is also adjusting the unbound fraction for a pH gradient effect across the membrane. Alternatively, the new experimental model (fu-dynamic) measures the unbound fractions resulting to the dynamic dissociation kinetics from proteins in the presence of plasma and a liver enzyme in an in vitro assay. The objective of this study was to conduct an in-depth analysis of previous CLH predictions made with these unbound fractions in a companion manuscript. Furthermore, a new dataset on transporter substrates was also included in this study. Finally, the physiological basis of fu-adjusted has been redefined to extend its applicability with more drugs. In this case, there are lower concentrations of binding proteins in liver versus plasma that could also explain the higher unbound fractions for that organ. The outcomes associated to additional analyses pointed out that fu-adjusted, again, generally provided the most accurate predictions of CLH because fu-dynamic has generated superior biases of underpredictions or overpredictions. For slowly metabolized drugs bound to ALB, fu-dynamic was definitively less accurate than fu-adjusted. For other drug properties, fu-dynamic fared better but it was still not generally more accurate than fu-adjusted. Furthermore, experimental values of fu-dynamic were sometimes incoherent. For example, drugs bound to alpha-acid glycoprotein (AGP) did not follow the principle of fu-dynamic (i.e., values of fu-dynamic did not correlate with values of CLint-in vitro-unbound) by contrast to those drugs bound to ALB. Therefore, the current experimental setting for fu-dynamic might be unsuitable in some circumstances. Overall, this study confirmed that calculated values of fu-adjusted were as accurate as experimental values of fu-dynamic and can even be more accurate. A guidance on which unbound fraction to use in the WSM is also provided.
有人提出了非结合组分的假设模型和实验模型,以便根据非结合药物的固有清除率值(体外非结合清除率)和良好搅拌模型(WSM)预测药物的肝清除率(CLH)。假设模型(fu-adjusted)是对体外血浆中测定的未结合部分进行调整,以估计如果血浆中的每种药物蛋白复合物通过任何白蛋白(ALB)促进的肝摄取机制在膜上完全解离,则肝细胞中的最大未结合部分。fu-adjusted 模型还根据膜上的 pH 梯度效应对非结合部分进行了调整。另外,新的实验模型(fu-dynamic)在体外试验中测量了在有血浆和肝酶存在的情况下与蛋白质动态解离动力学所产生的非结合部分。本研究的目的是深入分析之前在相关手稿中利用这些非结合馏分进行的 CLH 预测。此外,本研究还包括一个关于转运体底物的新数据集。最后,重新定义了傅调整的生理基础,以扩大其对更多药物的适用性。在这种情况下,与血浆相比,肝脏中结合蛋白的浓度较低,这也可以解释为什么该器官的未结合组分较高。与其他分析相关的结果表明,一般来说,fu-调整也能提供最准确的CLH预测,因为fu-动态会产生预测不足或预测过高的偏差。对于与 ALB 结合的慢代谢药物,动态赋值的准确性明显低于赋值调整的准确性。在其他药物特性方面,fu-dynamic 的表现要好一些,但总体上仍不比 fu-adjusted 更准确。此外,动态赋形剂的实验值有时并不一致。例如,与α-酸性糖蛋白(AGP)结合的药物与与 ALB 结合的药物相比,并不遵循 fu-动态的原则(即 fu-动态值与体外-非结合 CLint 值不相关)。因此,目前的 fu-dynamic 实验设置在某些情况下可能并不合适。总之,本研究证实,fu-调整值的计算值与 fu-动态值的实验值一样准确,甚至可能更准确。研究还为在 WSM 中使用哪种非结合分数提供了指导。
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引用次数: 0
Developing analytical ion exchange chromatography methods for antibody drug conjugates containing the hydrolysis-prone succinimide-thioether conjugation chemistry 为含有易水解琥珀酰亚胺-硫醚共轭化学成分的抗体药物共轭物开发离子交换色谱分析方法。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.021
Jessica Webb, Chendi Niu, Benjamin Ritter, Methal Albarghouthi, Xiaoyu Chen, Chunlei Wang
Charge variants are one of the most important quality attributes for protein therapeutics, including antibody drug conjugates (ADCs). ADCs are conjugation products between monoclonal antibodies (mAbs) and highly potent payloads. After attaching a payload, the charge profile of a mAb can be modified due to the change in net charge or surface charge. In this study, we present a unique challenge of charge assay development that arises from a desirable engineering of ADCs that incorporates the hydrolysis-prone succinimide-thioether conjugation chemistry. This engineered hydrolysis at conjugation sites is usually not complete during conjugation process and continuously progressing during mild stress. This hydrolysis also creates a carboxylic functional group, which manifests as acidic peaks in the ADC charge profiles. As a result, ion exchange chromatograms become sensitive measurements of this hydrolysis, which often masks the charge profile change due to other important post-translational modifications. In this study, two approaches were explored to address this unique challenge: to remove the hydrolysis heterogeneity by incubating ADCs under high pH conditions to drive complete hydrolysis; and to analyze charge variants at the subunit level after IdeS digestion. Acceptable charge profiles and quantitative integration results were successfully obtained by both approaches.
电荷变异是蛋白质疗法(包括抗体药物共轭物 (ADC))最重要的质量属性之一。ADC 是单克隆抗体 (mAbs) 与高效有效载荷之间的共轭产物。在连接有效载荷后,由于净电荷或表面电荷的变化,mAb 的电荷分布会发生改变。在本研究中,我们提出了电荷检测开发中的一个独特挑战,该挑战源于结合了易水解琥珀酰亚胺-硫醚共轭化学的 ADC 的理想工程设计。共轭位点的这种工程水解通常在共轭过程中并不完全,在轻微应力作用下会持续进行。这种水解也会产生羧基官能团,在 ADC 电荷谱中表现为酸性峰。因此,离子交换色谱可灵敏地测量这种水解,而这种水解往往会掩盖其他重要的翻译后修饰引起的电荷谱变化。本研究探索了两种方法来应对这一独特的挑战:通过在高 pH 条件下培养 ADC 来驱动完全水解,从而消除水解异质性;以及在 IdeS 消化后分析亚基水平的电荷变异。这两种方法都成功地获得了可接受的电荷曲线和定量整合结果。
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引用次数: 0
Characterization of oral drug absorption from jelly formulations: Effects of membrane permeability and intestinal fluid volume 果冻制剂口服药物吸收的特征:膜渗透性和肠液容量的影响。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.07.016
Junko Nakamura , Yukari Kakino , Makoto Kataoka , Shinji Yamashita , Yoshihiro Hishikawa , Keiko Minami
This study aims to clarify the process of oral drug absorption from jelly formulations. Agar and pectin-based jellies containing drugs with different membrane permeability (high: antipyrine [ANT], medium: metoprolol [MET], low: atenolol [ATE]) were prepared and tested for in vitro drug release and in vivo drug absorption in rats. All drugs showed similar release profiles in vitro from both jelly formulations, except for the faster release from pectin jelly at neutral pH. In contrast, in vivo absorption of ATE but not of ANT from jelly formulations was significantly lower than from solution. Absorption of ATE and MET was low from agar jelly after oral administration, whereas additional water intake significantly increased the absorption. The process of drug absorption was described by the compartmental model consisting of jelly, intestinal fluid, and blood compartments. Drugs in the jelly diffuse into the intestinal fluid and then permeate the intestinal membrane. By considering the rate-limiting process, membrane permeability-dependent drug absorption from agar jelly and the effects of water intake were identified. In conclusion, jelly formulations may potentially decrease and delay drug oral absorption, especially of poorly permeable drugs. Intestinal fluid volume is one of the important factors to control the drug absorption.
本研究旨在阐明果冻制剂的口服药物吸收过程。研究人员制备了含有不同膜渗透性药物(高:安替比林[ANT];中:美托洛尔[MET];低:阿替洛尔[ATE])的琼脂果冻和果胶果冻,并在大鼠体内进行了体外药物释放和体内药物吸收试验。除了果胶果冻在中性 pH 值下释放较快外,所有药物在两种果冻配方中的体外释放曲线相似。相比之下,大鼠体内对果冻制剂中 ATE 的吸收率明显低于对溶液中 ANT 的吸收率。口服后,琼脂胶冻对 ATE 和 MET 的吸收率较低,而额外摄入的水分可显著增加吸收率。药物吸收过程由果冻、肠液和血液组成的区室模型来描述。果冻中的药物扩散到肠液中,然后渗透到肠膜上。通过考虑限速过程,确定了琼脂果冻的药物吸收依赖于膜渗透性以及水摄入量的影响。总之,果冻制剂可能会减少和延迟药物的口服吸收,尤其是渗透性差的药物。肠液容量是控制药物吸收的重要因素之一。
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Journal of pharmaceutical sciences
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