ADMET and DMPK最新文献_第10页

Do you know your r2? 你知道r2吗?

IF 2.5

ADMET and DMPK Pub Date : 2020-08-30 DOI: 10.5599/admet.888

A. Avdeef

引用次数: 7

The effect of drug ionization on lipid-based formulations for the oral delivery of anti-psychotics 药物电离对口服抗精神病药物脂基制剂的影响

IF 2.5

ADMET and DMPK Pub Date : 2020-07-17 DOI: 10.5599/admet.830

Tahlia R. Meola, K. Paxton, P. Joyce, H. B. Schultz, C. Prestidge

{"title":"The effect of drug ionization on lipid-based formulations for the oral delivery of anti-psychotics","authors":"Tahlia R. Meola, K. Paxton, P. Joyce, H. B. Schultz, C. Prestidge","doi":"10.5599/admet.830","DOIUrl":"https://doi.org/10.5599/admet.830","url":null,"abstract":"Lipid-based formulations (LBFs) are well-known to improve the oral bioavailability of poorly water-soluble drugs (PWSDs) by presenting the drug to the gastrointestinal environment in a molecularly dispersed state, thus avoiding the rate-limiting dissolution step. Risperidone and lurasidone are antipsychotics drugs which experience erratic and variable absorption, leading to a low oral bioavailability. The aim of this research was to develop and investigate the performance of risperidone and lurasidone when formulated as an emulsion and silica-lipid hybrid (SLH). Lurasidone and risperidone were dissolved in Capmul® MCM at 100% and 80% their equilibrium solubility, respectively, prior to forming a sub-micron emulsion. SLH microparticles were fabricated by spray-drying a silica stabilised sub-micron emulsion to form a solid powder. The performances of the formulations were evaluated in simulated intestinal media under digesting conditions, where the emulsion and SLH provided a 17-fold and 23-fold increase in LUR solubilisation, respectively. However, the performance of RIS was reduced by 2.2-fold when encapsulated within SLH compared to pure drug. Owing to its pKa, RIS adsorbed to the silica and thus, dissolution was significantly hindered. The results reveal that LBFs may not overcome the challenges of all PWSDs and physiochemical properties must be carefully considered when predicting drug performance.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"43 1","pages":"437 - 451"},"PeriodicalIF":2.5,"publicationDate":"2020-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85906440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Image-based dissolution analysis for tracking the surface stability of amorphous powders 基于图像的溶解分析用于跟踪非晶粉末的表面稳定性

IF 2.5

ADMET and DMPK Pub Date : 2020-07-13 DOI: 10.5599/admet.839

Jernej Štukelj, M. Agopov, J. Yliruusi, C. Strachan, Sami Svanbäck

{"title":"Image-based dissolution analysis for tracking the surface stability of amorphous powders","authors":"Jernej Štukelj, M. Agopov, J. Yliruusi, C. Strachan, Sami Svanbäck","doi":"10.5599/admet.839","DOIUrl":"https://doi.org/10.5599/admet.839","url":null,"abstract":"Poor solubility of crystalline drugs can be overcome by amorphization – the production of high-energy disordered solid with improved solubility. However, the improved solubility comes at a cost of reduced stability; amorphous drugs are prone to recrystallization. Because of recrystallization, the initial solubility enhancement is eventually lost. Therefore, it is important to understand the recrystallization process during storage of amorphous materials and its impact on dissolution/solubility. Here, we demonstrate the use of image-based single-particle analysis (SPA) to consistently monitor the solubility of an amorphous indomethacin sample over time. The results are compared to the XRPD signal of the same sample. For the sample stored at 22 °C/23% relative humidity (RH), full crystallinity as indicated by XRPD was reached around day 40, whereas a solubility corresponding to that of the γ crystalline form was measured with SPA at day 25. For the sample stored at 22 °C/75% RH, the XRPD signal indicated a rapid initial phase of crystallization. However, the sample failed to fully crystallize in 80 days. With SPA, solubility slightly above that of the crystalline γ form was measured already on the second day. To conclude, the solubility measured with SPA directly reflects the solid-state changes occurring on the particle surface. Therefore, it can provide vital information – in a straightforward manner while requiring only minuscule sample amounts – for understanding the effect of storage conditions on the dissolution/solubility of amorphous materials, especially important in pharmaceutical science.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"136 1","pages":"401 - 409"},"PeriodicalIF":2.5,"publicationDate":"2020-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77467674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

In vitro release studies of furosemide reference tablets: influence of agitation rate, USP apparatus, and dissolution media 速尿参比片体外释放研究:搅拌速率、USP仪器和溶出介质的影响

IF 2.5

ADMET and DMPK Pub Date : 2020-06-29 DOI: 10.5599/admet.801

R. Medina-López, Sergio Guillén-Moedano, Marcela Hurtado

{"title":"In vitro release studies of furosemide reference tablets: influence of agitation rate, USP apparatus, and dissolution media","authors":"R. Medina-López, Sergio Guillén-Moedano, Marcela Hurtado","doi":"10.5599/admet.801","DOIUrl":"https://doi.org/10.5599/admet.801","url":null,"abstract":"Furosemide is a diuretic drug widely used in chronic renal failure. The drug has low solubility and permeability, which cause clinical problems. Studying the in vitro release performance elucidates the rate and extent of drug dissolved from dosage forms under different conditions. Furosemide reference tablets were tested using USP Apparatuses 1 and 2 as well as the flow-through cell method (USP Apparatus 4), a dissolution apparatus that simulates the human gastrointestinal tract better than the other methods. Dissolution profiles were created with USP Apparatuses 1 and 2 at 25, 50, and 75 rpm and 900 mL of 0.1 M hydrochloric acid, acetate buffer (pH 4.5), and phosphate buffer (pH 6.8). USP Apparatus 4 with a laminar flow of 16 mL/min and 22.6 mm cells was used. Drug dissolution was quantified at 274 nm for 60 min. Mean dissolution time, dissolution efficiency, time to 50% dissolution, and time to 80% dissolution data were used to compare dissolution profiles. Additionally, zero-order, first-order, Higuchi, Hixson-Crowell, Makoid-Banakar, and Weibull models were used to adjust furosemide dissolution data. Between USP Apparatus 1 and 2, significant differences were observed in almost all parameters at 50 and 75 rpm (p < 0.05). A similar dissolution profile (f2 > 50) with a pharmacopoeial dissolution method (USP Apparatus 2 at 50 rpm and 900 mL of phosphate buffer pH 5.8) and USP Apparatus 4 (laminar flow of 16 mL/min, 22.6 mm cells, and pH 6.8) was observed. The Weibull function was the best mathematical model to describe the in vitro release performance of furosemide in the three USP dissolution apparatuses. These results could be used to manufacture better furosemide dosage forms and decrease the negative clinical impact of current furosemide formulations.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"4 1","pages":"411 - 423"},"PeriodicalIF":2.5,"publicationDate":"2020-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79029226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Supercritical fluid technology for solubilization of poorly water soluble drugs via micro- and naonosized particle generation 超临界流体技术通过微颗粒和纳米颗粒的产生来增溶难水溶性药物

IF 2.5

ADMET and DMPK Pub Date : 2020-06-29 DOI: 10.5599/admet.811

S. Misra, K. Pathak

{"title":"Supercritical fluid technology for solubilization of poorly water soluble drugs via micro- and naonosized particle generation","authors":"S. Misra, K. Pathak","doi":"10.5599/admet.811","DOIUrl":"https://doi.org/10.5599/admet.811","url":null,"abstract":"Approximately two-third of the compounds in the pharmaceutical industry were developed through combinatorial chemistry and high throughput screening of particulate solids. Poor solubility and bioavailability of these pharmaceuticals are challenging attributes confronted by a formulator during product development. Hence, substantial efforts have been directed into the research on particle generation techniques. Although the conventional methods, such as crushing or milling and crystallization or precipitation, are still used; supercritical fluid technology introduced in the mid-1980s presents a new method of particle generation. Supercritical fluid processes not only produce micro- and nanoparticles with a narrow size distribution, they are also employed for the microencapsulation, cocrystallization, and surface coating with polymer. Recognized as a green technology, it has emerged as successful variants chiefly as Rapid Expansion of supercritical solutions (RESS), Supercritical anti-solvent (SAS) and Particles from Gas Saturated Solution (PGSS) depending upon type of solvent, solute, antisolvent and nebulization techniques. Being economical and eco-friendly, supercritical fluid technolgy has garnered considerable interest both in academia and industry for modification of physicochemical properties such as particle size, shape, density and ultimately solubility. The current manuscript is a comprehensive update on different supercritical fluid processes used for particle generation with the purpose of solubility enhancement of drugs and hence bioavailability.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":" 34","pages":"355 - 374"},"PeriodicalIF":2.5,"publicationDate":"2020-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.5599/admet.811","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72380863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 12

GAFF/IPolQ-Mod+LJ-Fit: Optimized force field parameters for solvation free energy predictions GAFF/IPolQ-Mod+LJ-Fit:溶剂化自由能预测的优化力场参数

IF 2.5

ADMET and DMPK Pub Date : 2020-06-28 DOI: 10.5599/admet.837

A. Mecklenfeld, G. Raabe

{"title":"GAFF/IPolQ-Mod+LJ-Fit: Optimized force field parameters for solvation free energy predictions","authors":"A. Mecklenfeld, G. Raabe","doi":"10.5599/admet.837","DOIUrl":"https://doi.org/10.5599/admet.837","url":null,"abstract":"Rational drug design featuring explicit solubility considerations can greatly benefit from molecular dynamics simulations, as they allow for the prediction of the Gibbs free energy of solvation and thus relative solubilities. In our previous work (A. Mecklenfeld, G. Raabe. J. Chem. Theory Comput. 13 no. 12 (2017) 6266–6274), we have compared solvation free energy results obtained with the General Amber Force Field (GAFF) and its default restrained electrostatic potential (RESP) partial charges to those obtained by modified implicitly polarized charges (IPolQ-Mod) for an implicit representation of impactful polarization effects. In this work, we have adapted Lennard-Jones parameters for GAFF atom types in combination with IPolQ-Mod to further improve the accuracies of solvation free energy and liquid density predictions. We thereby focus on prominent atom types in common drugs. For the refitting, 357 respectively 384 systems were considered for free energies and densities and validation was performed for 142 free energies and 100 densities of binary mixtures. By the in-depth comparison of simulation results for default GAFF, GAFF with IPolQ-Mod and our new set of parameters, which we label GAFF/IPolQ-Mod+LJ-Fit, we can clearly highlight the improvements of our new model for the description of both relative solubilities and fluid phase behaviour.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"226 1","pages":"274 - 296"},"PeriodicalIF":2.5,"publicationDate":"2020-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73254570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Solubility of proteins 蛋白质的溶解度

IF 2.5

ADMET and DMPK Pub Date : 2020-06-28 DOI: 10.5599/admet.831

M. Vihinen

{"title":"Solubility of proteins","authors":"M. Vihinen","doi":"10.5599/admet.831","DOIUrl":"https://doi.org/10.5599/admet.831","url":null,"abstract":"Solubility is a fundamental protein property that has important connotations for therapeutics and use in diagnosis. Solubility of many proteins is low and affect heterologous overexpression of proteins, formulation of products and their stability. Two processes are related to soluble and solid phase relations. Solubility refers to the process where proteins have correctly folded structure, whereas aggregation is related to the formation of fibrils, oligomers or amorphous particles. Both processes are related to some diseases. Amyloid fibril formation is one of the characteristic features in several neurodegenerative diseases, but it is related to many other diseases, including cancers. Severe complex V deficiency and cataract are examples of diseases due to reduced protein solubility. Methods and approaches are described for prediction of protein solubility and aggregation, as well as predictions of consequences of amino acid substitutions. Finally, protein engineering solutions are discussed. Protein solubility can be increased, although such alterations are relatively rare and can lead to trade-off with some other properties. The aggregation prediction methods mainly aim to detect aggregation-prone sequence patches and then making them more soluble. The solubility predictors utilize a wide spectrum of features.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"195 1","pages":"391 - 399"},"PeriodicalIF":2.5,"publicationDate":"2020-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79851366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Exploring the impact of Crohn’s disease on the intragastric environment of fasted adults 探讨克罗恩病对禁食成人胃内环境的影响

IF 2.5

ADMET and DMPK Pub Date : 2020-06-15 DOI: 10.5599/admet.846

M. Vertzoni, Christina Koulouri, A. Poulou, K. Goumas, C. Reppas

{"title":"Exploring the impact of Crohn’s disease on the intragastric environment of fasted adults","authors":"M. Vertzoni, Christina Koulouri, A. Poulou, K. Goumas, C. Reppas","doi":"10.5599/admet.846","DOIUrl":"https://doi.org/10.5599/admet.846","url":null,"abstract":"We explored the potential impact of Crohn’s disease on the intragastric environment of fasted adults with a view to potential effects on intragastric performance of orally administered drugs in the fasted state. Data were collected from 15 healthy individuals and 15 patients with Crohn’s disease. All subjects remained fasted for at least 12h prior to gastroscopy. Intragastric resting volume and pH were measured upon aspiration. Osmolality, surface tension, pepsin activity, and content of six bile acids were measured within 4 months upon sample collection. Unlike intragastric volumes, intragastric osmolality was significantly increased by Crohn’s disease. However, mean osmolality value in patients was only slightly higher than in healthy individuals (293 vs. 257 mOsmol/kg, respectively), therefore, unlikely to affect intragastric drug product performance. Primarily due to the high variability of data in healthy individuals, the potential effects on intragastric pH and surface activity could not be evaluated on a statistical basis. However, based on average (mean and median) values, even if they are statistically significant, it seems unlikely to be of clinical significance. Inter-subject variability of pepsin activity, and total bile acids content was high in both the healthy and the patients’ groups. Statistical investigation of the potential impact of Crohn’s disease on these parameters requires prior designation of the minimum differences to be detected; such differences will determine the minimum sample size required of relevant investigations.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"79 1","pages":"122 - 128"},"PeriodicalIF":2.5,"publicationDate":"2020-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74811284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Molecular docking investigation of the amantadine binding to the enzymes upregulated or downregulated in Parkinson’s disease 金刚烷胺与帕金森病上调或下调酶结合的分子对接研究

IF 2.5

ADMET and DMPK Pub Date : 2020-06-15 DOI: 10.5599/admet.854

M. Ionescu

{"title":"Molecular docking investigation of the amantadine binding to the enzymes upregulated or downregulated in Parkinson’s disease","authors":"M. Ionescu","doi":"10.5599/admet.854","DOIUrl":"https://doi.org/10.5599/admet.854","url":null,"abstract":"Parkinson’s disease (PD) is a progressive neurodegenerative disease. Levodopa in combination with amantadine has a demonstrated efficacy in motility impairment. An extensive investigation of some enzymes described to be upregulated or downregulated in PD was made – adenylate kinase (AK), adenine phosphoribosyltransferase (APRT), ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), nucleoside-diphosphate kinase 3 (NDK3), purine nucleoside phosphorylase 1 (PNP1), and ecto-5’-nucleotidase (NT5E). Also, creatine kinase (CK) was included in the study because it is one of the main enzymes involved in the regulation of the nucleotide ratio in energy metabolism. To date, there is no proven link between amantadine treatment of PD and these enzymes. Because there are many AKs isoforms modified in PD, the AK was the first investigated. The molecular docking experiments allow the analysis of the selective binding of amantadine – unionized (with –NH2 group) and ionized form (with –NH3+ group) – to the AKs’ isoforms implicated in PD. Using available X-ray 3D structures of human AKs in closed-conformation, it was demonstrated that there are notable differences between the interactions of the two forms of amantadine for the zebrafish AK1 (5XZ2), human AK2 (2C9Y), human AK5 (2BWJ), and AK from B.stearothermophilus. The cytosolic human AK1 and human AK2 mostly interact with ionized amantadine by AMP binding residues. The human AK5 interaction with ionized amantadine does not involve the residues from the catalytic site. Among other enzymes tested in the present study, APRT revealed the best results in respect of binding amantadine ionized form. The results offer a new perspective for further investigation of the connections between amantadine treatment of PD and some enzymes involved in purine metabolism.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"6 1","pages":"149 - 175"},"PeriodicalIF":2.5,"publicationDate":"2020-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74209810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Mechanistic modeling of gastrointestinal motility with integrated dissolution for simulating drug absorption 利用综合溶出模拟药物吸收的胃肠运动机制模型

IF 2.5

ADMET and DMPK Pub Date : 2020-06-09 DOI: 10.5599/admet.829

Kevin C. Johnson

{"title":"Mechanistic modeling of gastrointestinal motility with integrated dissolution for simulating drug absorption","authors":"Kevin C. Johnson","doi":"10.5599/admet.829","DOIUrl":"https://doi.org/10.5599/admet.829","url":null,"abstract":"A new computational method – the multiple moving plug (MMP) model – is described to simulate the effect of gastrointestinal motility and dissolution on the pharmacokinetic profile of any given drug. The method is physiologically more consistent with the experimental evidence that fluid exists in discrete plugs in the gastrointestinal tract, and therefore is more realistic than modeling the gastrointestinal tract as a series of compartments with first-order transfer. The number of plugs used in simulations, their gastric emptying times and volumes, and their residence times in the small intestine can be matched with experimental data on motility. In sample simulations, drug absorption from a series of fluid plugs emptied from the stomach at evenly spaced time intervals showed lower Cmax and higher Tmax than an equivalent dose emptied immediately as a single plug. To the extent that new techniques can establish typical ranges for the volumes of fluid emptied from the stomach and their respective timing, the MMP model may be able to predict the effect of gastric emptying on the variability seen in pharmacokinetic profiles. This could lead to an expanded safe space for the regulatory acceptance of formulations based on dissolution data.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 1","pages":"314 - 324"},"PeriodicalIF":2.5,"publicationDate":"2020-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79488859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3