ADMET and DMPK最新文献

英文中文

Thickness of the aqueous boundary layer in stirred microtitre plate permeability assays (PAMPA and Caco-2), based on the Levich equation. 基于Levich方程的搅拌微滴板渗透性测定(PAMPA和Caco-2)中水边界层厚度

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2022-01-01 DOI: 10.5599/admet.1568

Alex Avdeef

The stirring frequency exponent of -1/2 in the theoretical Levich expression appears to apply to PAMPA and Caco-2 assays, where efficient individual-well magnetic stirring ( > 20 RPM) is used. If a single molecule is used as a stirring calibrant, then scaling suggested by Eq. (5) with microtitre plate data may be used. The error in calculating hABL based on unscaled hABLref can be as high as 30%. This is of practical importance in PAMPA, and perhaps cellular assays as well.

引用次数: 0

Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics 兽药物种胃肠道差异对口服药物溶解度、体内溶出度和兽药制剂的影响

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2022-01-01 DOI: 10.5599/admet.1140

Marilyn N. Martinez, M. Papich, R. Fahmy

Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid composition and the associated impact of food intake and dietary composition on in vivo drug solubilization. This information gap can lead to uncertainties with regard to how best to formulate pharmaceuticals for veterinary use or the in vitro test conditions that will be most predictive of species-specific in vivo oral product performance. To address these challenges, this overview explores species-specific factors that can influence oral drug solubility and the formulation approaches that can be employed to overcome solubility-associated bioavailability difficulties. These discussions are framed around some of the basic principles associated with drug solubilization, reported species differences in GI fluid composition, types of oral dosage forms typically given for the various animal species, and the effect of prandial state in dogs and cats. This basic information is integrated into a question-and-answer section that addresses some of the formulation issues that can arise in the development of veterinary medicinals.

我们对不同物种胃肠道(GI)液体组成的差异以及食物摄入和膳食组成对体内药物溶解的相关影响的理解存在许多空白。这种信息差距可能导致在如何最好地配制兽药或最能预测物种特异性体内口服产品性能的体外试验条件方面存在不确定性。为了应对这些挑战，本综述探讨了可能影响口服药物溶解度的物种特异性因素，以及可用于克服溶解度相关生物利用度困难的配方方法。这些讨论围绕着一些与药物增溶有关的基本原则，胃肠道液体组成的物种差异，各种动物通常给予的口服剂型类型，以及狗和猫的膳食状态的影响。这些基本信息被整合到一个问答部分，该部分解决了兽药开发中可能出现的一些配方问题。

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引用次数: 1

Food effect risk assessment in preformulation stage using material sparing μFLUX methodology. 采用省料μFLUX方法评价制剂预配制阶段的食品效应风险。

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2022-01-01 DOI: 10.5599/admet.1476

Corinne Jankovsky, Oksana Tsinman, Naveen K Thakral

The intake of food and meal type can strongly impact the bioavailability of orally administered drugs and can consequently impact drug efficacy and safety. During the early stages of drug development, only a small amount of drug substance is available, and the solubility difference between fasted state simulated intestinal fluid and fed state simulated intestinal fluid may provide an early indication about the probable food effect. But higher drug solubility in fed state simulated intestinal fluid may not always results in an increased oral absorption. In the present research, we demonstrated using 11 model compounds that in addition to the drug dissolution in biorelevant media, the evaluation of the diffusion flux of a drug in solution, across artificial lipid coated membrane, where only the unbound drug crosses the membrane, is a reliable way to predict the food effect. Although, the combination of dissolution and diffusion flux may not reliably predict the food effect in case of drugs undergoing intestinal metabolism or when transporters are involved in the drug absorption, the technique generally provides good information about the food effect at very early stages of drug development that may help in designing a clinical plan by adjusting the drug dose in the fed state.

食物的摄入和膳食类型对口服药物的生物利用度有很大影响，从而影响药物的有效性和安全性。在药物开发的早期，只有少量的原料药可用，禁食状态模拟肠液和进食状态模拟肠液的溶解度差异可以提供可能的食物效应的早期指示。但较高的药物溶解度在饲料状态模拟肠液可能并不总是导致增加口服吸收。在本研究中，我们使用11种模型化合物证明，除了药物在生物相关介质中的溶解，药物在溶液中的扩散通量评估，通过人工脂质包被膜，其中只有未结合的药物穿过膜，是预测食物效应的可靠方法。虽然溶出通量和扩散通量的结合可能不能可靠地预测药物在肠道代谢或转运体参与药物吸收时的食物效应，但该技术通常可以在药物开发的早期阶段提供有关食物效应的良好信息，这可能有助于通过调整进食状态下的药物剂量来设计临床计划。

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引用次数: 2

Numerical modeling of the dissolution of drug nanocrystals and its application to industrial product development. 药物纳米晶体溶解的数值模拟及其在工业产品开发中的应用。

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2022-01-01 DOI: 10.5599/admet.1437

Bastian Bonhoeffer, Andreas Kordikowski, Edgar John, Michael Juhnke

The apparent solubility of drug nanocrystals in equilibrium was experimentally determined for a drug-stabilizer system with different particle size distributions. True supersaturation was identified for ultrafine drug nanocrystals with an almost 2-fold increase compared to the thermodynamic solubility of related coarse drug crystals, highlighting their enabling potential to enhance bioavailability. The experimental results were applied to investigate in silico the associated dissolution behavior in a closed system by numerical modeling according to the Ostwald-Freundlich and Noyes-Whitney / Nernst-Brunner equations. Calculated results were found to be in agreement with the experimental results only when the entire particle size distribution of drug nanocrystals was considered. In silico dissolution, studies were conducted to simulate the complex interplay between drug nanocrystals, dissolution conditions and resulting temporal progression during dissolution up to the equilibrium state. Calculations were performed for selected in vivo and in vitro scenarios considering different drug nanocrystal particle size distributions, drug amount, dissolution media and volume. The achieved results demonstrated the importance of ultrafine drug nanocrystals for potential bioavailability improvement and the functional applicability of the modeling approach to investigate their dissolution behavior for configurable formulation variables in product development in terms of in vivo and in vitro relevant conditions.

实验测定了不同粒径分布的药物稳定剂体系中药物纳米晶在平衡状态下的表观溶解度。与相关的粗粒药物晶体相比，超细药物纳米晶体的热力学溶解度几乎增加了2倍，这表明它们具有提高生物利用度的潜力。根据Ostwald-Freundlich方程和noies - whitney / Nernst-Brunner方程，将实验结果应用于封闭体系中相关溶解行为的计算机模拟。只有在考虑药物纳米晶体的整个粒径分布时，计算结果才与实验结果一致。在硅溶出过程中，研究人员模拟了药物纳米晶体、溶出条件和溶出至平衡状态的时间进程之间复杂的相互作用。考虑不同的药物纳米晶粒径分布、药物用量、溶出介质和体积，计算了体内和体外的不同情况。所取得的结果证明了超细药物纳米晶体对潜在生物利用度提高的重要性，以及建模方法在体内和体外相关条件下研究其在产品开发中作为可配置配方变量的溶解行为的功能适用性。

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引用次数: 0

Ten years for PhysChem Forum-Japan (PCF-J). 物理计划论坛-日本(PCF-J)十年。

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2022-01-01 DOI: 10.5599/admet.1452

Takashi Mano

The ten years of PhysChem Forum-Japan and Konstantin Tsinman's great contributions to the forum are briefly described.

简要介绍了日本物理计划论坛的十年历程以及康斯坦丁·齐曼对论坛的重要贡献。

引用次数: 0

Development of fiber optic in vitro release testing method for dexamethasone release from the oil solutions. 地塞米松油溶液释放度的光纤体外释放测试方法的建立。

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2022-01-01 DOI: 10.5599/admet.1465

Filip Kozlina, Ivan Meštrović, Viktor Novak, Nikola Marjanović, Biserka Cetina-Čižmek

For many parenteral drugs, there is still no standardized method for in vitro release (IVR) testing available. This article presents the development of a new IVR method for oil solutions using a dialysis membrane and USP II apparatus coupled to a fiber optic UV-Vis spectrometer. Experiments were performed using dexamethasone formulations containing castor oil as a solvent with the addition of cosolvents, 20 % (v/v) of isopropanol or Capryol® 90. Based on solubility testing results, castor oil was chosen as the best solvent amongst other vegetable oils, while a significant increase in solubility was obtained by adding either of the two cosolvents. Partitioning experiments were performed to ensure these formulations could achieve prolonged drug release. IVR testing was performed with model formulations and critical test parameters were varied in order to examine the method’s sensitivity. The developed method was sensitive to temperature and stirring rate, while coupling the USP II apparatus with a fiber optic UV-Vis spectrometer enabled complete automation. Moreover, due to the interference of excipients on fiber optic detection of dexamethasone during the release testing, derivative spectroscopy was successfully introduced for the elimination of the interference. The developed IVR method described herein could be useful in preformulation investigations and the early development of novel formulations.

对于许多肠外药物，仍然没有标准化的体外释放(IVR)测试方法。本文介绍了一种使用透析膜和USP II装置耦合到光纤紫外-可见光谱仪的油溶液的新IVR方法的发展。实验使用含有蓖麻油的地塞米松配方作为溶剂，并添加20% (v/v)异丙醇或Capryol®90的助溶剂。根据溶解度测试结果，在其他植物油中选择蓖麻油作为最佳溶剂，而添加两种助溶剂中的任何一种都可以显著提高溶解度。通过配药实验，确保该制剂能达到较长的释药效果。使用模型配方进行IVR测试，并改变关键测试参数，以检查该方法的灵敏度。所开发的方法对温度和搅拌速度敏感，同时将USP II仪器与光纤UV-Vis光谱仪耦合，实现了完全自动化。此外，由于辅料对地塞米松释放试验中光纤检测的干扰，我们成功地引入了导数光谱来消除干扰。本文所述开发的IVR方法可用于预制剂研究和新制剂的早期开发。

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引用次数: 0

Synthesis of silymarin–selenium nanoparticle conjugate and examination of its biological activity in vitro 水飞蓟素-硒纳米颗粒缀合物的合成及其体外生物活性研究

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2021-11-14 DOI: 10.5599/admet.1023

S. Staroverov, S. Kozlov, A. Fomin, K. Gabalov, Vitaliy Khanadeev, D. Soldatov, I. Domnitsky, L. Dykman, S. Akchurin, O. Guliy

Silymarin (Sil) was conjugated to selenium nanoparticles (SeNPs) to increase Sil bioavailability. The conjugates were monodisperse; the average diameter of the native SeNPs was ~ 20-50 ± 1.5 nm, whereas that of the conjugates was 30-50 ± 0.5 nm. The use of SeNPs to increase the bioavailability of Sil was examined with the MH-22a, EPNT-5, HeLa, Hep-2, and SPEV-2 cell lines. The EPNT-5 (glioblastoma) cells were the most sensitive to the conjugates compared to the conjugate-free control. The conjugates increased the activity of cellular dehydrogenases and promoted the penetration of Sil into the intracellular space. Possibly, SeNPs play the main part in Sil penetration of cells and Sil penetration is not associated with phagocytosis. Thus, SeNPs are promising for use as a Sil carrier and as protective antigens.

将水飞蓟素(Sil)与硒纳米粒子(SeNPs)偶联以提高硒的生物利用度。共轭物是单分散的;天然SeNPs的平均直径为~ 20 ~ 50±1.5 nm，而共轭物的平均直径为30 ~ 50±0.5 nm。用MH-22a、EPNT-5、HeLa、Hep-2和SPEV-2细胞系研究了SeNPs提高Sil生物利用度的作用。EPNT-5(胶质母细胞瘤)细胞对偶联物最敏感，与无偶联物对照相比。这些偶联物增加了细胞脱氢酶的活性，促进了Sil渗透到细胞内空间。可能，SeNPs在Sil渗透细胞中起主要作用，而Sil渗透与吞噬作用无关。因此，SeNPs有望用作Sil载体和保护性抗原。

引用次数: 6

Bacteriocin-mediated inhibition of some common pathogens by wild and mutant Lactobacillus species and in vitro amplification of bacteriocin encoding genes 细菌素介导的野生和突变乳杆菌对一些常见病原体的抑制作用及细菌素编码基因的体外扩增

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2021-11-14 DOI: 10.5599/admet.1053

A. Ahsan, B. Mazhar, Muhammad Kamran Khan, Madiha Mustafa, M. Hammad, N. Ali

Lactobacilli are the most common probiotics used in food and other industries because of their capability of producing bacteriocins. Bacteriocins are compounds that are used to kill pathogenic microorganisms. As most bacteria have become resistant to synthetic antibacterial tools, the importance of using probiotics as antibacterial agents has increased. This work was done to check the bacteriocin effect on some common pathogens and the influence of mutation on the bacteriocin activity of Lactobacilli was also investigated. Four strains were isolated, identified from meat and pickles samples via culturing methods, staining, biochemical tests, and ribotyping. Preliminary tests, including Gram staining and catalase test, were done for the confirmation of Lactobacillus species. All strains were gram-positive and catalase-negative. Antibacterial activity was checked against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus thuringiensis, Escherichia coli, and Salmonella enteritis via agar well diffusion method. The mutations were done using ethidium bromide and the influence of wild and mutants were also checked. Interestingly, mutants developed more virulence than wild ones. It was also observed that they all were sensitive to pepsin. Protein estimation was done via Bradford method. Ribotyping of GCU-W-PS1 revealed 99 % homology with Lactobacillus plantarum and GCU-W-MS1 to Lactobacillus curvatus (99 % homology). Curvacin A, sakacin P, and plantaricin A genes were also amplified using specific primers. Gene sequence showed the presence of curvacin A gene in GCU-W-MS1. It was concluded that lactic acid bacteria could be used as antibacterial tools against common pathogens.

乳酸菌是食品和其他工业中最常用的益生菌，因为它们具有产生细菌素的能力。细菌素是用来杀死病原微生物的化合物。由于大多数细菌已经对合成抗菌工具产生耐药性，使用益生菌作为抗菌剂的重要性已经增加。本文研究了细菌素对几种常见病原菌的作用，并探讨了突变对乳酸菌细菌素活性的影响。通过培养、染色、生化试验和核分型等方法，从肉类和泡菜样品中分离得到4株菌株。初步试验包括革兰氏染色和过氧化氢酶试验，以确定乳酸菌的种类。所有菌株革兰氏阳性，过氧化氢酶阴性。采用琼脂孔扩散法检测对铜绿假单胞菌、金黄色葡萄球菌、苏云金芽孢杆菌、大肠杆菌和肠炎沙门氏菌的抑菌活性。使用溴化乙锭进行突变，并检查野生和突变体的影响。有趣的是，突变体比野生体的毒性更强。同时观察到它们都对胃蛋白酶敏感。用Bradford法测定蛋白质含量。GCU-W-PS1与植物乳杆菌同源性达99%，与弯曲乳杆菌同源性达99%。曲曲霉素A、sakacin P和plantaricin A基因也用特异性引物扩增。基因序列显示GCU-W-MS1中存在曲曲霉素A基因。结论:乳酸菌可作为常见病原菌的抗菌工具。

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引用次数: 2

Newly discovered Staphylococcus aureus serine hydrolase probe and drug targets 新发现的金黄色葡萄球菌丝氨酸水解酶探针及药物靶点

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2021-10-28 DOI: 10.5599/admet.1137

M. Fellner

There is an urgent need for new diagnosis and treatment options for the bacterial pathogen Staphylococcus aureus. This review will summarize data on ten recently discovered biofilm-associated serine hydrolases called fluorophosphonate-binding hydrolases (FphA-J). Based on the summarized findings, many of these proteins represent intriguing new targets for probe and drug development.

对于细菌病原体金黄色葡萄球菌，迫切需要新的诊断和治疗方案。本文综述了最近发现的10种与生物膜相关的丝氨酸水解酶，即氟膦酸结合水解酶(FphA-J)。根据总结的发现，许多这些蛋白质代表了探针和药物开发的有趣的新靶点。

引用次数: 2

Drug-like Properties and Fraction Lipophilicity Index as a combined metric 药物样性质和分数亲脂性指数作为联合度量

IF 2.5 Q2 CHEMISTRY, MEDICINAL

ADMET and DMPK

Pub Date : 2021-10-08 DOI: 10.5599/admet.1022

A. Tsantili-Kakoulidou, V. Demopoulos

Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log P and log D in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log P/log D assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medium absorption levels and class 2 including poorly absorbed drugs. The FLI and FLI-C (ClogP based FLI) drug-like range covers 92 % and 91 % of class 1 drugs, respectively. Using MlogP, a narrower drug-like FLI-M range 0-7 was established, covering 91 % of class 1 drugs. The dependence of the degree of ionization to intrinsic lipophilicity within the FLI (FLI-C, FLI-M) drug-like range as well as the inter-relation between the other Ro5 properties (Mw, HD, HA) was explored to define drug-like / non-drug-like combinations as a safer alternative to single properties for drug candidates’ prioritization. In this sense, we propose a combined metric of Mw and the number of polar atoms (Mw/NO) to account for both size and polarity. Setting the value 50 as cutoff, a distinct differentiation between class 1 and class 2 drugs was obtained with Mw/NO>50 for more than 70 % of class 1 drugs, while the opposite was observed for class 2 drugs.

分数脂性指数(FLI)是一种将对数P和对数D以加权方式结合起来的类似药物的复合指标。在本研究中，一个扩展的数据集证实了先前建立的药物样FLI范围为0-8，使用两种计算系统进行logP /log D评估，免费软件MedChem Designer和ClogP。根据吸收分数百分比(%FA)将数据集分为两类- 1类包括高至中等吸收水平的药物，2类包括吸收不良的药物。FLI和FLI- c(基于ClogP的FLI)类药物范围分别覆盖了92%和91%的1类药物。使用MlogP，建立了一个更窄的类似药物的FLI-M范围0-7，覆盖了91%的1类药物。研究了在FLI (FLI- c, FLI- m)类药物范围内电离程度对内在亲脂性的依赖，以及其他Ro5性质(Mw, HD, HA)之间的相互关系，以确定药物样/非药物样组合是候选药物优先考虑的单一性质的更安全选择。在这个意义上，我们提出了一个Mw和极性原子数量(Mw/NO)的组合度量来说明尺寸和极性。将50设为截止值，1类药物与2类药物的区别明显，超过70%的1类药物的Mw/NO>50，而2类药物的情况则相反。

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引用次数: 8

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