首页 > 最新文献

Journal of pharmaceutical sciences最新文献

英文 中文
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 : 2024-09-14 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。
{"title":"Contributions of multiple transport mechanisms to intestinal uptake of serotonin.","authors":"Suguru Asaji, Yuta Funai, Yuta Seki, Ikumi Tamai, Yoshiyuki Shirasaka","doi":"10.1016/j.xphs.2024.07.020","DOIUrl":"10.1016/j.xphs.2024.07.020","url":null,"abstract":"<p><p>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 K<sub>m</sub> 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.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289713","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
Improved Properties of Glass Vials for Primary Packaging with Atomic Layer Deposition. 利用原子层沉积技术改善初级包装用玻璃瓶的性能。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-13 DOI: 10.1016/j.xphs.2024.09.007
Ilkka Manninen, Riina Ritasalo, Samuli Hirsjärvi

Novel pharmaceuticals and drug delivery devices may require better performance from the packaging material e.g., in terms of extractables and leachables, and unwanted interactions. To address this, we applied atomic layer deposition (ALD) to build nanometer-range SiO2, ZrO2 and Al2O3-TiO2 films on primary packaging glass. Controlled modification of the surface also enabled creation of functionality without affecting visual appearance of the material. ALD-coated Type I borosilicate vials were compared to uncoated ones, and tailored functionality was presented by appropriate measurements. The tested ALD coatings formed a barrier on glass against extractables and leachables, from the vial and the coating alike. A good ALD coating prevents any leakage into the stored drug product. Hydrolytic resistance results improved by 85-92 %, and these results correlated well with straightforward water conductivity measurements. Opposite to uncoated borosilicate glass vials, no extracted elements could be detected from the extracts of the coated vials with stable ALD films. Improved surface integrity was observed with electron microscopy as well. ALD films increased hydrophilicity of the surface and tuning the ALD film thickness and composition allowed precise blocking of UV light wavelengths, without affecting transparency. As a conclusion, ALD is a versatile method to create barrier and functional films on primary packaging materials.

新型药品和给药装置可能需要包装材料具有更好的性能,例如在可萃取性、可浸出性和不需要的相互作用方面。为此,我们采用原子层沉积(ALD)技术,在初级包装玻璃上形成纳米范围的二氧化硅、二氧化锆和氧化铝-二氧化钛薄膜。在不影响材料视觉外观的前提下,通过对表面进行可控改性,还实现了功能性的创造。ALD 镀膜的 I 型硼硅玻璃瓶与未镀膜的玻璃瓶进行了比较,并通过适当的测量显示了量身定制的功能。测试的 ALD 涂层在玻璃上形成了一道屏障,防止玻璃瓶和涂层中的可萃取物和可浸出物。良好的 ALD 涂层可防止药物泄漏到储存的产品中。耐水解性结果提高了 85-92%,这些结果与直接的水传导性测量结果密切相关。与未镀膜的硼硅酸盐玻璃瓶相反,镀有稳定 ALD 膜的玻璃瓶提取物中检测不到任何萃取元素。电子显微镜也观察到了表面完整性的改善。ALD 膜增加了表面的亲水性,调整 ALD 膜的厚度和成分可精确阻挡紫外线波长,而不影响透明度。总之,ALD 是一种在初级包装材料上制造阻隔膜和功能膜的多功能方法。
{"title":"Improved Properties of Glass Vials for Primary Packaging with Atomic Layer Deposition.","authors":"Ilkka Manninen, Riina Ritasalo, Samuli Hirsjärvi","doi":"10.1016/j.xphs.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.09.007","url":null,"abstract":"<p><p>Novel pharmaceuticals and drug delivery devices may require better performance from the packaging material e.g., in terms of extractables and leachables, and unwanted interactions. To address this, we applied atomic layer deposition (ALD) to build nanometer-range SiO<sub>2</sub>, ZrO<sub>2</sub> and Al<sub>2</sub>O<sub>3</sub>-TiO<sub>2</sub> films on primary packaging glass. Controlled modification of the surface also enabled creation of functionality without affecting visual appearance of the material. ALD-coated Type I borosilicate vials were compared to uncoated ones, and tailored functionality was presented by appropriate measurements. The tested ALD coatings formed a barrier on glass against extractables and leachables, from the vial and the coating alike. A good ALD coating prevents any leakage into the stored drug product. Hydrolytic resistance results improved by 85-92 %, and these results correlated well with straightforward water conductivity measurements. Opposite to uncoated borosilicate glass vials, no extracted elements could be detected from the extracts of the coated vials with stable ALD films. Improved surface integrity was observed with electron microscopy as well. ALD films increased hydrophilicity of the surface and tuning the ALD film thickness and composition allowed precise blocking of UV light wavelengths, without affecting transparency. As a conclusion, ALD is a versatile method to create barrier and functional films on primary packaging materials.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289715","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
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 : 2024-09-13 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。
{"title":"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.","authors":"Patrick Poulin","doi":"10.1016/j.xphs.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.09.002","url":null,"abstract":"<p><p>Hypothetical and experimental models of unbound fraction have been proposed to facilitate predicting the hepatic clearance (CL<sub>H</sub>) of drugs from values of intrinsic clearance for the unbound drug (CL<sub>int-in vitro-unbound</sub>) and the well-stirred model (WSM). The hypothetical model (fu<sub>-adjusted</sub>) 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<sub>-adjusted</sub> is also adjusting the unbound fraction for a pH gradient effect across the membrane. Alternatively, the new experimental model (fu<sub>-dynamic</sub>) 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 CL<sub>H</sub> 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<sub>-adjusted</sub> 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<sub>-adjusted</sub>, again, generally provided the most accurate predictions of CL<sub>H</sub> because fu<sub>-dynamic</sub> has generated superior biases of underpredictions or overpredictions. For slowly metabolized drugs bound to ALB, fu<sub>-dynamic</sub> was definitively less accurate than fu<sub>-adjusted</sub>. For other drug properties, fu<sub>-dynamic</sub> fared better but it was still not generally more accurate than fu<sub>-adjusted</sub>. Furthermore, experimental values of fu<sub>-dynamic</sub> were sometimes incoherent. For example, drugs bound to alpha-acid glycoprotein (AGP) did not follow the principle of fu<sub>-dynamic</sub> (i.e., values of fu<sub>-dynamic</sub> did not correlate with values of CL<sub>int-in vitro-unbound</sub>) by contrast to those drugs bound to ALB. Therefore, the current experimental setting for fu<sub>-dynamic</sub> might be unsuitable in some circumstances. Overall, this study confirmed that calculated values of fu<sub>-adjusted</sub> were as accurate as experimental values of fu<sub>-dynamic</sub> and can even be more accurate. A guidance on which unbound fraction to use in the WSM is also provided.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289711","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
Current state of nanomedicine drug products: An industry perspective. 纳米药物产品的现状:行业视角。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-12 DOI: 10.1016/j.xphs.2024.09.005
Jeffrey D Clogston, Willard Foss, David Harris, Hardeep Oberoi, Jiayi Pan, Elaine Pu, Elisa A Torrico Guzmán, Katrin Walter, Scott Brown, Patrick Lim Soo

Nanomedicine drug products have reached an unprecedented high in terms of global commercial acceptance and media exposure with the approvals of the mRNA COVID-19 vaccines in 2021. In this paper, we examine the current state of the art for nanomedicine technologies as applied for pharmaceutical products and compare those trends with results from a recent IQ Consortium industry survey on nanomedicine drug products. We find that 1) industry companies continue to push the envelope in terms of new technologies for characterizing their specific drug products, 2) new analytical technologies continue to be utilized by industry to characterize the increasingly complex nanomedicine drug products and 3) alignment and communication are key between industry and regulatory authorities to better understand the regulatory filings that are being submitted. There are many CMC challenges that a company must overcome to successfully file a nanomedicine drug product. In 2022, the FDA Guidance on Drug Products containing Nanomaterials was published, and it provides a roadmap for submission of a nanomedicine drug product. We propose that our paper serves as a complimentary guide providing knowledge on specific CMC issues such as quality attributes, physicochemical characterization methods, excipients, and stability.

随着 2021 年 mRNA COVID-19 疫苗的批准,纳米药物产品在全球商业接受度和媒体曝光率方面达到了前所未有的高度。在本文中,我们研究了应用于医药产品的纳米医学技术的现状,并将这些趋势与 IQ Consortium 最近对纳米医学药物产品的行业调查结果进行了比较。我们发现:1)行业公司在表征其特定药物产品的新技术方面不断推陈出新;2)行业继续利用新的分析技术来表征日益复杂的纳米医药药物产品;3)行业与监管机构之间的协调和沟通是更好地理解所提交的监管文件的关键。要成功申报纳米药物产品,公司必须克服许多 CMC 挑战。2022 年,FDA 发布了《含纳米材料药物产品指南》,为纳米药物产品的申报提供了路线图。我们建议将我们的论文作为补充指南,提供有关质量属性、理化表征方法、辅料和稳定性等具体 CMC 问题的知识。
{"title":"Current state of nanomedicine drug products: An industry perspective.","authors":"Jeffrey D Clogston, Willard Foss, David Harris, Hardeep Oberoi, Jiayi Pan, Elaine Pu, Elisa A Torrico Guzmán, Katrin Walter, Scott Brown, Patrick Lim Soo","doi":"10.1016/j.xphs.2024.09.005","DOIUrl":"10.1016/j.xphs.2024.09.005","url":null,"abstract":"<p><p>Nanomedicine drug products have reached an unprecedented high in terms of global commercial acceptance and media exposure with the approvals of the mRNA COVID-19 vaccines in 2021. In this paper, we examine the current state of the art for nanomedicine technologies as applied for pharmaceutical products and compare those trends with results from a recent IQ Consortium industry survey on nanomedicine drug products. We find that 1) industry companies continue to push the envelope in terms of new technologies for characterizing their specific drug products, 2) new analytical technologies continue to be utilized by industry to characterize the increasingly complex nanomedicine drug products and 3) alignment and communication are key between industry and regulatory authorities to better understand the regulatory filings that are being submitted. There are many CMC challenges that a company must overcome to successfully file a nanomedicine drug product. In 2022, the FDA Guidance on Drug Products containing Nanomaterials was published, and it provides a roadmap for submission of a nanomedicine drug product. We propose that our paper serves as a complimentary guide providing knowledge on specific CMC issues such as quality attributes, physicochemical characterization methods, excipients, and stability.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289714","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
A Novel Encapsulation Approach to Enhance the Delivery and Antitumor Activity of Docetaxel in Breast Cancer Therapy. 在乳腺癌治疗中增强多西他赛给药和抗肿瘤活性的新型封装方法
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-12 DOI: 10.1016/j.xphs.2024.09.010
Shabnam Ghasedi, Vahab Jafarian, Yasaman Ghajari, Abbas Bahari, Mahsa Mekanik, Saeid Taghavi Fardood

Docetaxel (DTX) is one of the most potent anticancer drugs but its extensive side effects necessitate innovative formulations. In this study, we aimed to investigate the expression pattern of apoptotic proteins, cell cycle arrest, and apoptosis induction after treatment with encapsulated DTX in alginate-chitosan nanoparticles in both breast cancer cells (MCF-7) and peripheral blood mononuclear cells (PBMCs). The characterization of the nanoparticles revealed a spherical shape with a size <50 nm, a hydrodynamic diameter of 200 nm, a Polydispersity Index of 0.5, and an encapsulation efficiency of 98.75 %. The free drug was released completely within 11 h while encapsulated DTX was released only 34 % in 96 h. The encapsulated drug indicated higher cytotoxicity on MCF-7 cells and the half inhibitory concentration (IC50) value was 2 µg/ml after 72 h. Quantitative real-time PCR demonstrated a significant increase in cell death as the expression of apoptosis regulatory protein (Bcl-2) was downregulated with no impact on Bax in the MCF-7 cells. A notable decrease in the expression pattern of pro-inflammatory cytokine (IL-1β) in PBMCs indicated less inflammation induction. Flow cytometry analysis revealed that the newly formulated drug induced less opoptosis in PBMCs than the free DTX. Cell cycle arrest in the sub-G1 phase was observed for the free drug while the encapsulated drug exhibited no significant changes. Our results suggest the high toxicity of the formulated drug in contrast to the free DTX on the MCF-7 cell line, minimal blood cell side effects, and no inflammation positioning it as a promising alternative to free docetaxel.

多西他赛(DTX)是最有效的抗癌药物之一,但它的副作用很大,因此需要创新配方。在这项研究中,我们的目的是研究在乳腺癌细胞(MCF-7)和外周血单核细胞(PBMCs)中使用海藻酸盐-壳聚糖封装的 DTX 纳米颗粒后,凋亡蛋白的表达模式、细胞周期停滞和凋亡诱导。实时定量 PCR 显示,MCF-7 细胞中细胞凋亡调节蛋白(Bcl-2)的表达下调,而 Bax 的表达没有受到影响,因此细胞死亡明显增加。促炎细胞因子(IL-1β)在 PBMCs 中的表达模式明显下降,表明炎症诱导减少。流式细胞术分析表明,与游离 DTX 相比,新配制的药物在 PBMCs 中诱导的细胞凋亡更少。游离药物的细胞周期停滞在亚 G1 期,而封装药物则无明显变化。我们的研究结果表明,与游离 DTX 相比,新配制的药物对 MCF-7 细胞株的毒性较高,对血液细胞的副作用最小,而且不会引起炎症,因此有望成为游离多西他赛的替代品。
{"title":"A Novel Encapsulation Approach to Enhance the Delivery and Antitumor Activity of Docetaxel in Breast Cancer Therapy.","authors":"Shabnam Ghasedi, Vahab Jafarian, Yasaman Ghajari, Abbas Bahari, Mahsa Mekanik, Saeid Taghavi Fardood","doi":"10.1016/j.xphs.2024.09.010","DOIUrl":"10.1016/j.xphs.2024.09.010","url":null,"abstract":"<p><p>Docetaxel (DTX) is one of the most potent anticancer drugs but its extensive side effects necessitate innovative formulations. In this study, we aimed to investigate the expression pattern of apoptotic proteins, cell cycle arrest, and apoptosis induction after treatment with encapsulated DTX in alginate-chitosan nanoparticles in both breast cancer cells (MCF-7) and peripheral blood mononuclear cells (PBMCs). The characterization of the nanoparticles revealed a spherical shape with a size <50 nm, a hydrodynamic diameter of 200 nm, a Polydispersity Index of 0.5, and an encapsulation efficiency of 98.75 %. The free drug was released completely within 11 h while encapsulated DTX was released only 34 % in 96 h. The encapsulated drug indicated higher cytotoxicity on MCF-7 cells and the half inhibitory concentration (IC<sub>50</sub>) value was 2 µg/ml after 72 h. Quantitative real-time PCR demonstrated a significant increase in cell death as the expression of apoptosis regulatory protein (Bcl-2) was downregulated with no impact on Bax in the MCF-7 cells. A notable decrease in the expression pattern of pro-inflammatory cytokine (IL-1β) in PBMCs indicated less inflammation induction. Flow cytometry analysis revealed that the newly formulated drug induced less opoptosis in PBMCs than the free DTX. Cell cycle arrest in the sub-G<sub>1</sub> phase was observed for the free drug while the encapsulated drug exhibited no significant changes. Our results suggest the high toxicity of the formulated drug in contrast to the free DTX on the MCF-7 cell line, minimal blood cell side effects, and no inflammation positioning it as a promising alternative to free docetaxel.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289696","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
Is access to leadership roles contributing to the gender pay gap in the pharmaceutical sciences? 担任领导职务的机会是否导致了制药科学领域的性别薪酬差距?
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-10 DOI: 10.1016/j.xphs.2024.08.018
Adeola O Coker, Cynthia A Oksanen, Tina Morris, Kristen Kalmann

Gender disparity in the pharmaceutical sciences contributes to the overall gender pay gap. The gender pay inequity is worse at later career stages. Salary data for pharmaceutical scientists has been reviewed from both the American Association of Pharmaceutical Sciences (AAPS) Salary Survey and the American Association of Colleges of Pharmacy (AACP) Pharmacy Faculty Demographics and Salaries report. We share some potential causes of the pay inequity, including implicit bias, pipeline issues, family responsibilities, and others. We suggest how organizations can put processes in place to help narrow the gender pay gap. Additionally, we share suggestions for how women must take a proactive role to ensure they reach their full potential and pay equity.

制药科学领域的性别差异导致了整体的性别薪酬差距。在职业生涯的后期,性别薪酬不平等现象更为严重。我们审查了美国药学协会(AAPS)薪酬调查和美国药学院协会(AACP)药学教师人口统计和薪酬报告中有关药学科学家的薪酬数据。我们分享了薪酬不平等的一些潜在原因,包括隐性偏见、管道问题、家庭责任等。我们建议各组织如何制定相关流程,帮助缩小男女薪酬差距。此外,我们还就女性必须如何发挥积极主动的作用以确保她们充分发挥潜能和实现薪酬公平提出了建议。
{"title":"Is access to leadership roles contributing to the gender pay gap in the pharmaceutical sciences?","authors":"Adeola O Coker, Cynthia A Oksanen, Tina Morris, Kristen Kalmann","doi":"10.1016/j.xphs.2024.08.018","DOIUrl":"10.1016/j.xphs.2024.08.018","url":null,"abstract":"<p><p>Gender disparity in the pharmaceutical sciences contributes to the overall gender pay gap. The gender pay inequity is worse at later career stages. Salary data for pharmaceutical scientists has been reviewed from both the American Association of Pharmaceutical Sciences (AAPS) Salary Survey and the American Association of Colleges of Pharmacy (AACP) Pharmacy Faculty Demographics and Salaries report. We share some potential causes of the pay inequity, including implicit bias, pipeline issues, family responsibilities, and others. We suggest how organizations can put processes in place to help narrow the gender pay gap. Additionally, we share suggestions for how women must take a proactive role to ensure they reach their full potential and pay equity.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289716","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
Drug Delivery from A Ring Implant Attached to Intraocular Lens: An In-Silico Investigation. 眼内透镜环形植入物的药物输送:模拟研究
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-07 DOI: 10.1016/j.xphs.2024.09.001
Pawan Kumar Pandey, Manish Jain, Prateek K Jha

Multiple iterations required to design ocular implants, which will last for the desired operational period of months or even years, necessitate the use of in-silico models for ocular drug delivery. In this study, we developed an in-silico model to simulate the flow of Aqueous Humor (AH) and drug delivery from an implant to the Trabecular Meshwork (TM). The implant, attached to the side of the intraocular lens (IOL), and the TM are treated as porous media, with their effects on AH flow accounted for using the Darcy equation. This model accurately predicts the physiological values of Intraocular Pressure (IOP) for both healthy individuals and glaucoma patients, as reported in the literature. Results reveal that the effective diffusivity of the drug within the implant is the critical parameter that can alter the bioavailability time period (BTP) from a few days to months. Intuitively, BTP should increase as effective diffusivity decreases. However, we discovered that with lower levels of initial drug loading, BTP declines when effective diffusivity falls below a specific threshold. Our findings further reveal that, while AH flow has a minimal effect on the drug release profile at the implant site, it significantly impacts drug availability at the TM.

眼部植入物的设计需要多次反复,才能达到预期的几个月甚至几年的使用期限,因此有必要使用用于眼部给药的室内模型。在这项研究中,我们开发了一个硅内模型来模拟水液(AH)的流动以及药物从植入体到小梁网状结构(TM)的输送。植入体连接到眼内晶状体(IOL)的一侧,而小梁网被视为多孔介质,它们对 AH 流的影响通过达西方程来计算。根据文献报道,该模型能准确预测健康人和青光眼患者的眼压(IOP)生理值。结果显示,药物在植入体内的有效扩散率是关键参数,可改变生物利用度时间段(BTP),从几天到几个月不等。从直观上看,随着有效扩散率的降低,生物利用时间应该会延长。然而,我们发现,在初始药物负载水平较低的情况下,当有效扩散率低于特定阈值时,生物利用度时间段就会缩短。我们的研究结果进一步表明,虽然 AH 流量对植入部位的药物释放曲线影响甚微,但却对 TM 的药物可用性产生了重大影响。
{"title":"Drug Delivery from A Ring Implant Attached to Intraocular Lens: An In-Silico Investigation.","authors":"Pawan Kumar Pandey, Manish Jain, Prateek K Jha","doi":"10.1016/j.xphs.2024.09.001","DOIUrl":"10.1016/j.xphs.2024.09.001","url":null,"abstract":"<p><p>Multiple iterations required to design ocular implants, which will last for the desired operational period of months or even years, necessitate the use of in-silico models for ocular drug delivery. In this study, we developed an in-silico model to simulate the flow of Aqueous Humor (AH) and drug delivery from an implant to the Trabecular Meshwork (TM). The implant, attached to the side of the intraocular lens (IOL), and the TM are treated as porous media, with their effects on AH flow accounted for using the Darcy equation. This model accurately predicts the physiological values of Intraocular Pressure (IOP) for both healthy individuals and glaucoma patients, as reported in the literature. Results reveal that the effective diffusivity of the drug within the implant is the critical parameter that can alter the bioavailability time period (BTP) from a few days to months. Intuitively, BTP should increase as effective diffusivity decreases. However, we discovered that with lower levels of initial drug loading, BTP declines when effective diffusivity falls below a specific threshold. Our findings further reveal that, while AH flow has a minimal effect on the drug release profile at the implant site, it significantly impacts drug availability at the TM.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154452","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
Optimizing the dosing regimen of roxadustat in kidney transplant recipients with early post-transplant anemia. 优化肾移植受者移植后早期贫血的罗沙司他用药方案。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-07 DOI: 10.1016/j.xphs.2024.09.004
Zhuo-Wei Shen, Xiu-Yan Yang, Lu Han, Xi Yang, Jiao Xie, Xiao-Qin Liu, Jue-Hui Mao, Hao-Ran Dai, Wei-Wei Kong, Xiao-Ying Wu, Yun-Qing Qiu, Hong-Feng Huang, Yan Lou

Introduction: Roxadustat, an oral inhibitor of hypoxia-inducible factor prolyl hydroxylase domain enzymes, has been approved for the treatment of renal anemia. However, there is a lack of study on its pharmacokinetics in kidney transplant recipients (KTRs) with early posttransplant anemia (PTA). Therefore, the aim of this study is to elucidate the pharmacokinetic characteristics of roxadustat in KTRs with early PTA and optimize the dosing regimen.

Methods: A population pharmacokinetic (PopPK) analysis was performed based on 72-hour full concentration-time profiles collected from 52 Chinese KTRs. Covariates influencing exposure were assessed using stepwise covariate modelling. Monte Carlo simulations were conducted to recommend the dosing regimen for patients with different levels of covariates.

Results: PopPK analysis showed that the concentration-time data can be fully described by a two-compartment model. Body weight (BW) and direct bilirubin (DBIL) levels significant affected the apparent clearance of roxadustat. Based on the established model and the estimated exposures of roxadustat by Monte Carlo simulations, a recommended dosing regimen for KTRs with early PTA at varying BW and DBIL levels were developed. Roxadustat at 100 mg three times weekly were suitable for the majority of KTRs with a DBIL level around 3 μmol/L and BW between 50 and 75 kg. The required dose may need to be increased with higher BW and lower DBIL levels, while decreased with lower BW and higher DBIL levels.

Conclusions: It was the first PopPK analysis of roxadustat in KTRs with early PTA, which provide a research basis for optimizing the dosing regimen.

简介罗沙司他是缺氧诱导因子脯氨酰羟化酶域酶的口服抑制剂,已被批准用于治疗肾性贫血。然而,目前还缺乏对其在患有早期移植后贫血(PTA)的肾移植受者(KTR)中的药代动力学研究。因此,本研究旨在阐明罗沙度他在早期 PTA 肾移植受者中的药代动力学特征,并优化给药方案:方法:根据从 52 例中国 KTR 收集的 72 小时全浓度-时间曲线,进行了群体药代动力学(PopPK)分析。采用逐步协变量建模法评估了影响暴露的协变量。进行蒙特卡罗模拟,为不同协变量水平的患者推荐给药方案:结果:PopPK 分析表明,浓度-时间数据完全可以用两室模型来描述。体重(BW)和直接胆红素(DBIL)水平对罗沙度他的表观清除率有显著影响。根据已建立的模型和蒙特卡洛模拟对罗沙司他暴露量的估计,制定了在不同体重和DBIL水平下KTR早期PTA的推荐给药方案。罗沙司他的剂量为 100 毫克,每周三次,适用于 DBIL 水平在 3 μmol/L 左右、体重在 50 至 75 千克之间的大多数 KTR。体重越大、DBIL 水平越低,所需剂量可能需要增加,而体重越小、DBIL 水平越高,所需剂量可能需要减少:这是首次对患有早期 PTA 的 KTR 进行罗沙司他的 PopPK 分析,为优化给药方案提供了研究基础。
{"title":"Optimizing the dosing regimen of roxadustat in kidney transplant recipients with early post-transplant anemia.","authors":"Zhuo-Wei Shen, Xiu-Yan Yang, Lu Han, Xi Yang, Jiao Xie, Xiao-Qin Liu, Jue-Hui Mao, Hao-Ran Dai, Wei-Wei Kong, Xiao-Ying Wu, Yun-Qing Qiu, Hong-Feng Huang, Yan Lou","doi":"10.1016/j.xphs.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.09.004","url":null,"abstract":"<p><strong>Introduction: </strong>Roxadustat, an oral inhibitor of hypoxia-inducible factor prolyl hydroxylase domain enzymes, has been approved for the treatment of renal anemia. However, there is a lack of study on its pharmacokinetics in kidney transplant recipients (KTRs) with early posttransplant anemia (PTA). Therefore, the aim of this study is to elucidate the pharmacokinetic characteristics of roxadustat in KTRs with early PTA and optimize the dosing regimen.</p><p><strong>Methods: </strong>A population pharmacokinetic (PopPK) analysis was performed based on 72-hour full concentration-time profiles collected from 52 Chinese KTRs. Covariates influencing exposure were assessed using stepwise covariate modelling. Monte Carlo simulations were conducted to recommend the dosing regimen for patients with different levels of covariates.</p><p><strong>Results: </strong>PopPK analysis showed that the concentration-time data can be fully described by a two-compartment model. Body weight (BW) and direct bilirubin (DBIL) levels significant affected the apparent clearance of roxadustat. Based on the established model and the estimated exposures of roxadustat by Monte Carlo simulations, a recommended dosing regimen for KTRs with early PTA at varying BW and DBIL levels were developed. Roxadustat at 100 mg three times weekly were suitable for the majority of KTRs with a DBIL level around 3 μmol/L and BW between 50 and 75 kg. The required dose may need to be increased with higher BW and lower DBIL levels, while decreased with lower BW and higher DBIL levels.</p><p><strong>Conclusions: </strong>It was the first PopPK analysis of roxadustat in KTRs with early PTA, which provide a research basis for optimizing the dosing regimen.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289718","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
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 : 2024-09-06 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。
{"title":"Physiologically based pharmacokinetic model of brivaracetam to predict the exposure and dose exploration in hepatic impairment and elderly populations.","authors":"Yiming Li, Wenxin Shao, Xingwen Wang, Kuo Geng, Wenhui Wang, Zhiwei Liu, Youjun Chen, Chaozhuang Shen, Haitang Xie","doi":"10.1016/j.xphs.2024.08.022","DOIUrl":"10.1016/j.xphs.2024.08.022","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145858","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
Chemistry and Ionization of HPMCAS Influences the Dissolution and Solution-Mediated Crystallization of Posaconazole Amorphous Solid Dispersions. HPMCAS 的化学性质和电离作用影响泊沙康唑无定形固体分散体的溶解和溶液介导的结晶。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-05 DOI: 10.1016/j.xphs.2024.08.023
Dishan D Shah, Lynne S Taylor

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) is one of the polymers of choice in formulating amorphous solid dispersions (ASDs) and helps to sustain high levels of drug supersaturation by delaying drug crystallization. Herein, the impact of HPMCAS chemistry on the solution crystallization kinetics of a fast-crystallizing lipophilic drug, posaconazole (PCZ), from the aqueous bulk phase and the drug-rich phase generated by liquid-liquid phase separation (LLPS), was studied. Three grades of HPMCAS: L, M, and H, which differ in the degree of acetyl and succinoyl substitution (A/S ratio), were compared. The influence of the polymers on the nucleation induction time, and LLPS concentration of PCZ, as well as the size, ζ-potential and composition of the nano-sized drug-rich phase was determined. An increase in the nucleation induction time was observed with an increase in the polymer A/S ratio. A blue shift in the fluorescence emission spectrum of PCZ suggested a greater extent of interaction between PCZ and HPMCAS with an increase in the A/S ratio. More polymer partitioning into the drug-rich phase was also observed with an increase in the A/S ratio, resulting in smaller droplets. A greater extent of ionization of HPMCAS upon increasing the pH from 5.5 to 7.5 decreased the hydrophobicity of the polymer resulting in shorter nucleation induction times. The phase behavior of PCZ in ASD release studies was consistent with these observations, where the shortest duration of supersaturation was observed with the L grade. Although the H grade provided the best inhibition of crystallization, complete release was only observed at higher pH. HPMCAS grade thus influences the kinetics of PCZ crystallization following release from an ASD, as well as the extent of release at physiologically relevant pH conditions. This study provides insights into the role of HPMCAS chemistry and ionization as factors influencing its ability to act as a crystallization inhibitor.

羟丙基甲基纤维素醋酸琥珀酸酯(HPMCAS)是配制无定形固体分散体(ASD)的首选聚合物之一,它通过延迟药物结晶来帮助维持高水平的药物过饱和度。在此,我们研究了 HPMCAS 化学性质对亲脂性药物泊沙康唑(PCZ)快速结晶的溶液结晶动力学的影响。比较了三种等级的 HPMCAS:L、M 和 H,它们在乙酰基和琥珀酰取代程度(A/S 比)上有所不同。研究确定了聚合物对成核诱导时间、PCZ 的 LLPS 浓度以及纳米级富药相的尺寸、ζ电位和组成的影响。随着聚合物 A/S 比率的增加,成核诱导时间也随之增加。PCZ 荧光发射光谱的蓝移表明,随着 A/S 比的增加,PCZ 与 HPMCAS 之间的相互作用程度也会增加。随着 A/S 比的增加,还观察到更多的聚合物被分配到富含药物的相中,从而导致液滴变小。当 pH 值从 5.5 升至 7.5 时,HPMCAS 的电离程度增加,聚合物的疏水性降低,导致成核诱导时间缩短。PCZ 在 ASD 释放研究中的相行为与上述观察结果一致,其中 L 级产品的过饱和时间最短。虽然 H 级的结晶抑制效果最好,但只有在较高的 pH 值下才能观察到完全释放。因此,HPMCAS 牌号会影响 PCZ 从 ASD 释放后的结晶动力学,以及在生理相关 pH 条件下的释放程度。本研究深入探讨了 HPMCAS 化学性质和电离作用对其结晶抑制能力的影响因素。
{"title":"Chemistry and Ionization of HPMCAS Influences the Dissolution and Solution-Mediated Crystallization of Posaconazole Amorphous Solid Dispersions.","authors":"Dishan D Shah, Lynne S Taylor","doi":"10.1016/j.xphs.2024.08.023","DOIUrl":"10.1016/j.xphs.2024.08.023","url":null,"abstract":"<p><p>Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) is one of the polymers of choice in formulating amorphous solid dispersions (ASDs) and helps to sustain high levels of drug supersaturation by delaying drug crystallization. Herein, the impact of HPMCAS chemistry on the solution crystallization kinetics of a fast-crystallizing lipophilic drug, posaconazole (PCZ), from the aqueous bulk phase and the drug-rich phase generated by liquid-liquid phase separation (LLPS), was studied. Three grades of HPMCAS: L, M, and H, which differ in the degree of acetyl and succinoyl substitution (A/S ratio), were compared. The influence of the polymers on the nucleation induction time, and LLPS concentration of PCZ, as well as the size, ζ-potential and composition of the nano-sized drug-rich phase was determined. An increase in the nucleation induction time was observed with an increase in the polymer A/S ratio. A blue shift in the fluorescence emission spectrum of PCZ suggested a greater extent of interaction between PCZ and HPMCAS with an increase in the A/S ratio. More polymer partitioning into the drug-rich phase was also observed with an increase in the A/S ratio, resulting in smaller droplets. A greater extent of ionization of HPMCAS upon increasing the pH from 5.5 to 7.5 decreased the hydrophobicity of the polymer resulting in shorter nucleation induction times. The phase behavior of PCZ in ASD release studies was consistent with these observations, where the shortest duration of supersaturation was observed with the L grade. Although the H grade provided the best inhibition of crystallization, complete release was only observed at higher pH. HPMCAS grade thus influences the kinetics of PCZ crystallization following release from an ASD, as well as the extent of release at physiologically relevant pH conditions. This study provides insights into the role of HPMCAS chemistry and ionization as factors influencing its ability to act as a crystallization inhibitor.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145857","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
期刊
Journal of pharmaceutical sciences
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1