European Journal of Pharmaceutical Sciences最新文献

{"title":"The state-of-the-art machine learning model for plasma protein binding prediction: Computational modeling with OCHEM and experimental validation","authors":"Zunsheng Han ,&nbsp;Zhonghua Xia ,&nbsp;Jie Xia ,&nbsp;Igor V. Tetko ,&nbsp;Song Wu","doi":"10.1016/j.ejps.2024.106946","DOIUrl":"10.1016/j.ejps.2024.106946","url":null,"abstract":"<div><div>Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Existing models for predicting PPB often suffer from low prediction accuracy and poor interpretability, especially for high PPB compounds, and are most often not experimentally validated. Here, we carried out a strict data curation protocol, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model (available on the OCHEM platform <span><span>https://ochem.eu/article/29</span><svg><path></path></svg></span>) was further retrospectively validated for a set of 63 poly-fluorinated molecules and prospectively validated for a set of 25 highly diverse compounds, and its performance for both these sets was superior to that of the other previously reported models. Furthermore, we identified the physicochemical and structural characteristics of high and low PPB molecules for further structural optimization. Finally, we provide practical and detailed recommendations for structural optimization to decrease PPB binding of lead compounds.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106946"},"PeriodicalIF":4.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring pharmaceutical powder behavior in commercial-scale bin blending: A DEM simulation study","authors":"F. Mostafaei ,&nbsp;B. Benque ,&nbsp;P. Doshi ,&nbsp;M.T. Santangelo ,&nbsp;H.G. Lee ,&nbsp;D. Gomes Lopes ,&nbsp;M. Schaefer ,&nbsp;J.G. Khinast ,&nbsp;D. Jajcevic","doi":"10.1016/j.ejps.2024.106950","DOIUrl":"10.1016/j.ejps.2024.106950","url":null,"abstract":"<div><div>Bin blending is one of the main steps in pharmaceutical production processes. Commercial-scale production of expensive products typically does not allow to perform a large number of experiments in order to optimize the process. Alternatively, Discrete Element Method (DEM) simulations can be used to evaluate the powder behavior (flow and blending pattern) during blending, identify the risks (e.g., segregation), and provide solutions to mitigate them. In this work, DEM simulations are used to investigate the blending of two granulated powders in commercial-scale cone and cylindrical (hoop) blenders. The DEM contact model parameters were calibrated based on the experimental compression and ring shear tests for both granulated powders to mimic the bulk powder behavior in the simulations. The model's output was compared to the experiments in one of the blending cases. The blending efficiency in the cone blenders was evaluated considering the fill levels, the presence of baffles, the rotating directions, the filling order, and the bin sizes. Furthermore, for the hoop blenders, the effects of blender's angle, rotation speed, and filling order were addressed. The main findings of the work were that, in cone blenders, the blending can be improved by introducing baffles and changing in the rotational direction frequently. In hoop blenders, blending can be improved by increasing the inclination angle from the horizontal plane and the rotational speed.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106950"},"PeriodicalIF":4.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards a switchable nanoparticle behavior using inverse electron-demand Diels-Alder chemistry and ectoenzyme-based ligand activation","authors":"Johannes Lang,&nbsp;Kathrin Schorr,&nbsp;Achim Goepferich","doi":"10.1016/j.ejps.2024.106944","DOIUrl":"10.1016/j.ejps.2024.106944","url":null,"abstract":"<div><div>Nanoparticles (NPs) as drug delivery platforms encounter numerous obstacles on their journey from administration to the target site. Often, diametrically opposing particle properties are desirable to overcome biological and physical barriers. Therefore, stimuli-responsive NPs have been developed to allow for specific particle adaptation. In this work, it was demonstrated that NPs can be rendered switchable with respect to their interaction with a receptor through an external chemical stimulus. A combination of the inverse electron-demand Diels-Alder (iEDDA) reaction for subsequent NP functionalization and ectoenzyme-based ligand activation allowed for specific particle tailoring. Building on this, a two-step process for target cell recognition was developed. First, NPs were functionalized with Angiotensin-I (Ang-I) as inactive ligand using iEDDA chemistry. At the target site, the ligand was enzymatically processed to Angiotensin-ll (Ang-II) by cellular ectoenzymes. Ang-ll binds as active ligand to the angiotensin ll type 1 (AT1) receptor on the target cell surface. This enzymatic activation aims to minimize the biological effect of the ligand prior to particle binding, while the NP target cell specificity is increased by a two-step recognition with enzymatic processing and receptor binding.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106944"},"PeriodicalIF":4.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards the understanding of the IVPT results variability—Development, verification and validation of the PBPK model of caffeine in vitro human skin permeation","authors":"Laura Krumpholz ,&nbsp;Sebastian Polak ,&nbsp;Barbara Wiśniowska","doi":"10.1016/j.ejps.2024.106943","DOIUrl":"10.1016/j.ejps.2024.106943","url":null,"abstract":"<div><div>In the context of evaluating the safety and efficacy of dermal products, pharmacokinetic (PK) studies face considerable challenges, particularly concerning topically applied formulations. This underscores the necessity for alternative methods, such as in vitro permeation tests (IVPT) and physiologically based pharmacokinetic (PBPK) modelling, to better understand the dermal pharmacokinetics of a product. The purpose of this study was to modify, verify, and validate the PBPK model of caffeine permeation through human skin previously developed by Patel et al. (2022), and compare simulation results with experimental data from IVPT studies. Moreover, the study aimed to analyse the IVPT data variability and explore the potential of using the PBPK model to understand the influence of biological and drug-related factors on the IVPT results. In total, eight manuscripts describing nine experiments were included. The overall shapes of the permeation curves were considered acceptable based on visual checks for all analysed experiments. Five out of nine experiments met the predefined standard 2-fold difference criterion for comparison of the cumulative amount of caffeine in the receptor solution.. Our investigation highlights challenges in validating PBPK models for IVPT experiments, as the quality and consistency of experimental results pose significant hurdles. Despite access to data on caffeine permeation in scientific literature, reliable model validation is currently infeasible. Inter-laboratory variation suggests that alternative validation methods may be needed. Further studies should focus on issues with other compounds, especially lipophilic ones.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106943"},"PeriodicalIF":4.3,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper-coordinated nanomedicine for the concurrent treatment of lung cancer through the induction of cuproptosis and apoptosis","authors":"Pei Huang ,&nbsp;Gongfa Wu ,&nbsp;Min Huang ,&nbsp;Yating Deng ,&nbsp;Xuming Chen ,&nbsp;Guodong Ye ,&nbsp;Xiyong Yu ,&nbsp;He Wang ,&nbsp;Huaying Wen ,&nbsp;Yi Zhou","doi":"10.1016/j.ejps.2024.106942","DOIUrl":"10.1016/j.ejps.2024.106942","url":null,"abstract":"<div><div>The resistance of tumor cells to apoptosis often leads to chemoresistance and treatment failure in clinic. In this study, we have developed a Cu²⁺-coordinated lignosulfonate (CLS) /doxorubicin (DOX) biological complex (referred to as LCD) with the aim of overcoming cellular resistance to apoptosis for combined lung cancer therapy. The copper complexes modified by CLS exhibit significant water solubility and excellent in vivo biocompatibility. The proportion of copper in the composite is simultaneously increased. Due to the coordination and π-π stacking effects, the self-assembled LCD exhibits nanometer-scale particle size, a narrow and homogeneous grain distribution, as well as excellent dispersion stability. Furthermore, LCD has the potential to disassemble in the presence of high levels of glutathione (GSH) and low pH, leading to effective drug release. Cu²⁺-mediated cuproptosis can lead to the down-regulation of FDX1 and DLAT protein expression by reducing mitochondrial membrane potential, resulting in non-apoptotic programmed cell death (PCD) regardless of cellular resistance to apoptosis. Moreover, the released DOX not only exhibits a preference for localizing in the cell nucleus to induce apoptosis for combined chemotherapy, but also generates a substantial amount of H₂O₂. This H₂O₂ further produces ROS to induce apoptosis through Fenton reaction with Cu²⁺. LCD demonstrates significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity through the combined action of cuproptosis and apoptosis. This study may provide a potential avenue for the advancement of self-delivery nanomedicine to overcome resistance to apoptosis in tumor therapy.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106942"},"PeriodicalIF":4.3,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the influence of the initial high molecular weight level on monoclonal antibody particle formation kinetics using a short-term chemical stress study","authors":"Michael Strebl ,&nbsp;Anis Arache ,&nbsp;Michaela Blech ,&nbsp;Udo Bakowsky ,&nbsp;Patrick Garidel","doi":"10.1016/j.ejps.2024.106924","DOIUrl":"10.1016/j.ejps.2024.106924","url":null,"abstract":"<div><div>Protein formulations may form proteinaceous particles that vary in size from nanometers to millimeters. Monitoring the kinetics of protein particle formation, e.g., through accelerated degradation studies, is an attempt to understand and assess the rate and progression of particle populations. Little is known about whether the initial level of high molecular weight (HMW) species, or initial HMW level (IHL), of a protein solution influences the propagation of protein particle formation, and thus affects the storage stability of proteins.</div><div>In this study, we have established a method to generate protein solutions of different IHLs by thermal stress. We have evaluated a 16-week thermal stability study at 40 °C of two monoclonal antibodies (mAb-A and mAb-B) at different IHLs using size exclusion chromatography (SEC) and sub-visible particle analysis. We have performed an isothermal stress study with guanidinium hydrochloride (GuaHCl) at room temperature for 300-min to evaluate the formation of HMWs analysed by SEC. The application of the Finke-Watzky (F-W) two-step nucleation model allowed us to mathematically describe the kinetics of HMW formation and to extract kinetic parameters of this process.</div><div>For mAb-A, the IHLs had a marginal influence on the loss of monomer rate; instead, mAb-A exhibited fragmentation at 40 °C, which was independent of the IHL. Nevertheless, above a threshold of ≥ 7 % IHL, existing trimers/tetramers undergo conversion into higher-order oligomers at 40 °C, which is not observed at lower IHLs. In contrast, mAb-B exhibited an increased HMW formation rate above a threshold of ≥ 4 % IHL, which was reflected in the monomer decay rates at 40 °C and the F-W kinetic parameters of the chemical stress study.</div><div>This case study shows that the initial level of HMWs exerts a differential influence on the progression of HMW formation. In one instance, there is a discernible acceleration in the formation of HMWs with rising IHLs. Conversely, in another example, the IHL exerts only a slight influence on HMW formation. Moreover, the results of our short-term chemical stress study are in accordance with those of a classical storage stability study conducted at 40 °C, which evaluated different IHLs. The analysis of HMW formation kinetics will enhance our understanding of the protein particle formation process and facilitate the formulation development of biotherapeutics.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"203 ","pages":"Article 106924"},"PeriodicalIF":4.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Pharmacometrics and systems pharmacology: Principles and applications","authors":"Francine Johansson Azeredo,&nbsp;Stephan Schmidt","doi":"10.1016/j.ejps.2024.106941","DOIUrl":"10.1016/j.ejps.2024.106941","url":null,"abstract":"","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"203 ","pages":"Article 106941"},"PeriodicalIF":4.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies","authors":"Elsayed A. Elmorsy ,&nbsp;Sameh Saber ,&nbsp;Rabab S. Hamad ,&nbsp;Mustafa Ahmed Abdel-Reheim ,&nbsp;Attalla F. El-kott ,&nbsp;Mohammed A. AlShehri ,&nbsp;Kareem Morsy ,&nbsp;Salama A. Salama ,&nbsp;Mahmoud E. Youssef","doi":"10.1016/j.ejps.2024.106939","DOIUrl":"10.1016/j.ejps.2024.106939","url":null,"abstract":"<div><div>Cisplatin, a widely used chemotherapeutic agent, has proven efficacy against various malignancies. However, its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. This review aims to provide a comprehensive overview of cisplatin toxicity, encompassing its underlying mechanisms, risk factors, and emerging therapeutic strategies. The mechanisms of cisplatin toxicity are multifactorial and involve oxidative stress, inflammation, DNA damage, and cellular apoptosis. Various risk factors contribute to the interindividual variability in susceptibility to cisplatin toxicity. The risk of developing cisplatin-induced toxicity could be related to pre-existing conditions, including kidney disease, hearing impairment, neuropathy, impaired liver function, and other comorbidities. Additionally, this review highlights the emerging therapeutic strategies that could be applied to minimize cisplatin-induced toxicities and aid in optimizing cisplatin treatment regimens, improving patient outcomes, and enhancing the overall quality of cancer care.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"203 ","pages":"Article 106939"},"PeriodicalIF":4.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence-driven pharmaceutical industry: A paradigm shift in drug discovery, formulation development, manufacturing, quality control, and post-market surveillance","authors":"Kampanart Huanbutta ,&nbsp;Kanokporn Burapapadh ,&nbsp;Pakorn Kraisit ,&nbsp;Pornsak Sriamornsak ,&nbsp;Thittaporn Ganokratanaa ,&nbsp;Kittipat Suwanpitak ,&nbsp;Tanikan Sangnim","doi":"10.1016/j.ejps.2024.106938","DOIUrl":"10.1016/j.ejps.2024.106938","url":null,"abstract":"<div><div>The advent of artificial intelligence (AI) has catalyzed a profound transformation in the pharmaceutical industry, ushering in a paradigm shift across various domains, including drug discovery, formulation development, manufacturing, quality control, and post-market surveillance. This comprehensive review examines the multifaceted impact of AI-driven technologies on all stages of the pharmaceutical life cycle. It discusses the application of machine learning algorithms, data analytics, and predictive modeling to accelerate drug discovery processes, optimize formulation development, enhance manufacturing efficiency, ensure stringent quality control measures, and revolutionize post-market surveillance methodologies. By describing the advancements, challenges, and future prospects of harnessing AI in the pharmaceutical landscape, this review offers valuable insights into the evolving dynamics of drug development and regulatory practices in the era of AI-driven innovation.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"203 ","pages":"Article 106938"},"PeriodicalIF":4.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The L-type amino acid transporter 1 enhances drug delivery to the mouse pancreatic beta cell line (MIN6)","authors":"Janne Tampio ,&nbsp;Ahmed B. Montaser ,&nbsp;Juulia Järvinen ,&nbsp;Marko Lehtonen ,&nbsp;Aaro J. Jalkanen ,&nbsp;Mika Reinisalo ,&nbsp;Tarja Kokkola ,&nbsp;Tetsuya Terasaki ,&nbsp;Markku Laakso ,&nbsp;Jaana Rysä ,&nbsp;Anu Kauppinen ,&nbsp;Kristiina M. Huttunen","doi":"10.1016/j.ejps.2024.106937","DOIUrl":"10.1016/j.ejps.2024.106937","url":null,"abstract":"<div><div><span>l</span>-type amino acid transporter 1 (LAT1) is a membrane transporter responsible for carrying large, neutral <span>l</span>-configured amino acids as well as appropriate (pro)drugs into a cell. It has shown a great potential to improve drug delivery across the blood-brain barrier and to increase cell uptake into several brain and cancer cell types. However, besides the brain, the LAT1-utilizing compounds are also delivered more efficiently into the pancreas <em>in vivo</em>. In this study, we quantified the expression of LAT1 along several other membrane transporters in mouse pancreatic β-cell line (MIN6). Furthermore, we studied the function of LAT1 in MIN6 cells, and its ability to deliver non-steroidal anti-inflammatory drug (NSAID)-derived prodrugs there. The results showed that LAT1 was highly abundant in MIN6 cells, with an even expression on cell pseudoislets. The <span>l</span>-leucine uptake as a probe substrate was efficient, with comparable affinity and capacity to previously studied immortalized mouse microglia (BV2). The NSAID-derived prodrugs utilized LAT1 for their delivery and were uptaken into MIN6 cells 2–300 times more efficiently when compared to their parent drugs. A similar increase in pancreatic delivery was observed also <em>in vivo</em>, where the pancreatic exposure was 2–10 times higher with selected prodrugs, indicating an excellent correlation between <em>in vitro</em> uptake and <em>in vivo</em> pancreatic delivery. Finally, the LAT1-utilizing prodrugs were able to reverse the effects of cytokines on insulin secretion in MIN6 cells, showing that improved delivery via LAT1 can enhance drug effects in the mouse pancreatic β-cell line.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"203 ","pages":"Article 106937"},"PeriodicalIF":4.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}