European Journal of Pharmaceutical Sciences最新文献

{"title":"Microfluidic post-insertion of polyethylene glycol lipids and KK or RGD high functionality and quality lipids in milk-derived extracellular vesicles","authors":"","doi":"10.1016/j.ejps.2024.106929","DOIUrl":"10.1016/j.ejps.2024.106929","url":null,"abstract":"<div><div>To achieve the desired delivery effect, extracellular vesicles (EVs) must bypass rapid clearance from circulation and exhibit affinity for target cells; however, it is difficult to simultaneously incorporate two materials into EVs. Post-insertion is a general modification method that can be performed by simply mixing different solutions. Previously, we have developed a microfluidic post-insertion method that supported fast and upscaled modification of EVs using KK-modified high-functionality and -quality (HFQ) lipids. Here, we used microfluidic post-insertion to achieve simultaneous incorporation of polyethylene glycol (PEG) lipids and KK or RGD-modified HFQ lipids into milk-derived EVs to avoid uptake from the reticuloendothelial system and increase the uptake into target cells. PEG lipid and HFQ lipids were formulated to produce micelles and subsequently mixed with EV solution using a microfluidic device. Compared to bulk mixing, microfluidic post-insertion showed higher cellular association. Altered cellular association capacities and endocytic pathways indicated simultaneous incorporation. The cellular association of modified EVs can be adjusted by altering the ratio of (EK)₄-KK in micelles with slight changes in physicochemical properties. Furthermore, microfluidic post-insertion is also suitable for (SG)₅-RGD, which is insoluble in phosphate-buffered saline (PBS). Our results may be valuable for the development and manufacture of functional EVs as drug delivery systems for clinical applications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399821","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":"Esophageal transit of solid oral dosage forms – impact of different surface materials characterized in vitro and in vivo by MRI in healthy volunteers","authors":"","doi":"10.1016/j.ejps.2024.106926","DOIUrl":"10.1016/j.ejps.2024.106926","url":null,"abstract":"<div><div>Acceptable swallowability and complete esophageal transit are decisive for the safe and effective administration of solid oral dosage forms. This applies in particular to the main user group of medicines, older adults, who often suffer from swallowing difficulties. It is well known that surface properties play an important role in this respect. In the past, this has led to the development of numerous coating formulations for tablets with improved swallowability. However, <em>in vitro</em> and especially <em>in vivo</em> data investigating a positive effect of different coating materials is limited. Therefore, we investigated coating materials being based on polyvinyl alcohol, hydroxypropyl methylcellulose, and a copolymer of methacrylate in respect to their influence on swallowability and esophageal transit of a tablet formulation. They were compared to uncoated tablets as well as to hard gelatin capsules. Three <em>in vitro</em> assays suitable for routine use in pharmaceutical development were performed: i.) Wettability test in artificial saliva; ii.) Swelling measurement in artificial saliva; iii.) Measurement of the adhesion between surface materials and a simulated mucosa surface. All three assays resulted in a differentiation of the surface materials. The coated tablets showed favorable behavior compared to uncoated tablets and hard gelatin capsules. To test the effect of the different materials <em>in vivo</em>, an intervention study was conducted. 36 adults were included and the likeliness of prolonged esophageal transit of (un-)coated tablets as well as a hard gelatin capsule of the same weight was objectively evaluated by means of magnetic resonance imaging. While hard gelatin capsules showed highest rates for prolonged esophageal transit, the tendency for adhesion was reduced for uncoated tablets, and least for coated tablets, i.e., prolonged esophageal transit in 22.2 %, 11.1 %, and ≤5.6 % of the cases, respectively. Further differentiation of the coating materials was not possible. Subjective evaluations of each participant with respect to subjective swallowability and esophageal transit did not correlate well with the objective measurements by means of magnetic resonance imaging. The use of coatings in general has a positive influence on esophageal transit. However, the selection of coating type seems to be of greater importance in respect to patients' oral perception of the dosage forms compared to their influence on the probability for prolonged esophageal transit.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389107","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":"Ligand binding to proteins – when flawed fluorescence quenching methodology and interpretation become the new norm","authors":"","doi":"10.1016/j.ejps.2024.106930","DOIUrl":"10.1016/j.ejps.2024.106930","url":null,"abstract":"<div><div>Intrinsic protein fluorescence quenching measurements have become a widespread methodology to determine ligand-binding properties of in particular serum albumin. Particularly common is the use of double log equations to extract parameters like binding constant and stoichiometry and/or number of binding sites. In this article we discuss that the methodology has several significant and often unrecognized pitfalls, and the double log equations are improperly derived for their purported use. Using simulations, it is shown that the binding stoichiometry and binding constants obtained using these equations may differ substantially from their true values. In addition, it is illustrated how this methodology, via the use of site markers, is unsuited to determine the binding site of ligands on serum albumin. We thus call for a reassessment of the literature in which this methodology plays a central role in characterizing ligand binding to proteins.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389109","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 experimental, knowledge-based and computational cocrystal screening methods to advance drug-drug cocrystal fixed-dose combination development","authors":"","doi":"10.1016/j.ejps.2024.106931","DOIUrl":"10.1016/j.ejps.2024.106931","url":null,"abstract":"<div><div>Fixed-dose combinations (FDCs) offer significant advantages to patients and the pharmaceutical industry alike through improved dissolution profiles, synergistic effects and extended patent lifetimes. Identifying whether two active pharmaceutical ingredients have the potential to form a drug-drug cocrystal (DDC) or interact is an essential step in determining the most suitable type of FDC to formulate. The lack of coherent strategies to determine if two active pharmaceutical ingredients that can be co-administered can form a cocrystal, has significantly impacted DDC commercialisation. This review aims to accelerate the development of FDCs and DDCs by evaluating existing experimental, knowledge-based and computational cocrystal screening methods; the background of their development, their application in screening for cocrystals and DDCs, and their limitations are discussed. The evaluation provided in this review will act as a guide for selecting suitable screening methods to accelerate FDC development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399820","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":"Data-driven insights into the properties of liquisolid systems based on machine learning algorithms","authors":"","doi":"10.1016/j.ejps.2024.106927","DOIUrl":"10.1016/j.ejps.2024.106927","url":null,"abstract":"<div><div>Liquisolid systems (LS) represent a formulation approach where liquid drug or its dispersion is transformed into a powder with good flowability and compactibility, leading to enhanced drug dissolution and bioavailability. Many research groups have focused on the preparation and investigation of LS, leading to a higher need for comprehensive evaluation of factors impacting LS characteristics. The aim of this work was to investigate the applicability of machine learning algorithms in the LS evaluation, using data mined from published literature, and provide an insight into critical factors governing the liquisolid system performance.</div><div>The dataset was prepared using publication search engines and relevant keywords, with a total of 425 formulations included in the database. The database focused on preparation methods, formulation parameters, and liquisolid system characteristics. Subsequently, critical properties of the liquisolid system, i.e. flowability, compact hardness, and drug dissolution, were analyzed using machine learning algorithms, including Gradient Boosting, Adaptive Boosting and Random Forest.</div><div>In addition to conventional preparation methods and excipients, novel technologies (fluid bed preparation, extrusion/spheronization) and materials (Neusilin®, Fujicalin®, and Syloid®) enhanced the properties of liquisolid systems. The analysis revealed that formulation factors, such as carrier and coating agent type and content, liquid phase load, model drug type and content, as well as preparation method, significantly influenced liquisolid system characteristics. The models developed exhibited high prediction accuracy when applied on test data (higher than 80 %). This indicates that the machine learning models may provide an insight into the critical attributes affecting the LS performance and may be used as a valuable tool in the development and optimization of these samples.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389105","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":"Establishment of a semi-continuous nano-production line using the Microfluidizer® technology for the fabrication of lipid-based nanoparticles part 1: Screening of critical parameters and design of experiment optimization studies","authors":"","doi":"10.1016/j.ejps.2024.106928","DOIUrl":"10.1016/j.ejps.2024.106928","url":null,"abstract":"<div><div>A variety of strategies for producing high-quality nanoparticles have been reported in recent years. Batch-based bottom-up and top-down technologies are generally the most efficient methods, but present a number of challenges, particularly in terms of variability, safety, sustainability and large-scale production. In this study, a scalable, semi-continuous production line was built by connecting individual processing units, including a high shear mixing device, the Microfluidizer® technology and a cooling system. Each unit was equipped with an adequate temperature control to allow solvent-free production of solid lipid nanoparticles (consisting of Precirol® ATO 5 or Gelucire® 43/01) and nanostructured lipid carriers (additionally comprising Labrafac™ lipophile WL 1349). Subsequently, critical formulation parameters and critical process parameters (CPPs) of the individual processing units and their effects on particle size (i.e., critical quality attribute (CQA)) were investigated to identify appropriate input parameters for the subsequent Design of Experiment (DoE) studies conducted after linking the process units to a semi-continuous production line. For particle size monitoring, spatially resolved dynamic light scattering (SR-DLS) measurements were conducted and compared to standard DLS measurements to evaluate the applicability of SR-DLS as an inline monitoring tool. It was found that matrix composition, emulsifier concentration, pressure and number of cycles when processing through Microfluidizer® processor were the most influencing parameters. By optimizing these parameters, five-times higher throughputs could be achieved by the semi-continuous manufacturing line. In addition, the particle size measurements with SR-DLS confirmed the feasibility of implementing this technology for real-time particle size monitoring as an important safety factor in quality control.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389108","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":"Development and evaluation of nanostructured systems for cutaneous delivery of H₂S-releasing corticosteroids for skin inflammatory diseases.","authors":"Daniel A G Miranda, Anderson R A Cerqueira, Marcelo N Muscará, Beatrice Severino, Giuseppe Caliendo, Angela Corvino, Giorgia Andreozzi, Antonia Scognamiglio, Marlus Chorilli, Francesco Frecentese, Soraia K P Costa, Luciana B Lopes","doi":"10.1016/j.ejps.2024.106925","DOIUrl":"10.1016/j.ejps.2024.106925","url":null,"abstract":"<p><p>Psoriasis is an immune-mediated chronic inflammatory disease that causes major psychosocial impact. Topical corticosteroids represent the standard pharmacological treatment for mild-to-moderate disease, but their local and systemic adverse effects reinforce the need for treatment innovations. Here we developed lamellar phase-based formulations for topical delivery of a hybrid dexamethasone and hydrogen sulfide (H₂S) donor molecule (Dexa-TBZ), aiming to potentiate the effects of the glucocorticoid with H₂S. They offer the possibility to obtain precursor formulations free of water that originate lamellar phases upon water addition, preventing drug hydrolysis during storage. Two groups of formulations were developed varying the surfactants and oil phase types and content. Systems containing 20 and 70 % of water formed, respectively, bulk lamellar phase and a more fluid formulation consisting of dispersed droplets (< 1000 nm) stabilized by lamellar phase. Both presented pseudoplastic behavior. Dexa-TBZ was incorporated at 1 %, remaining stable for 8 h. Drug content decreased to ∼80 % after 1 week in precursor formulations free of water, but remained stable after that. Without causing changes to the cutaneous barrier function ex vivo or to the histological structure of the skin in vivo, the formulation containing phosphatidylcholine as surfactant and 70 % of water promoted 1.8- and 2.7-fold increases in Dexa-TBZ penetration in the stratum corneum and epidermis+dermis, respectively, compared to a control solution, demonstrating their potential applicability as topical delivery systems.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389106","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}

{"title":"Characterising and preventing the gut microbiota's inactivation of trifluridine, a colorectal cancer drug","authors":"","doi":"10.1016/j.ejps.2024.106922","DOIUrl":"10.1016/j.ejps.2024.106922","url":null,"abstract":"<div><div>The gut microbiome can metabolise hundreds of drugs, potentially affecting their bioavailability and pharmacological effect. As most gut bacteria reside in the colon, drugs that reach the colon in significant proportions may be most impacted by microbiome metabolism. In this study the anti-colorectal cancer drug trifluridine was used as a model drug for characterising metabolism by the colonic microbiota, identifying correlations between bacterial species and individuals’ rates of microbiome drug inactivation, and developing strategies to prevent drug inactivation following targeted colonic delivery. High performance liquid chromatography and ultra-high performance liquid chromatography coupled with high resolution tandem mass spectrometry demonstrated trifluridine's variable and multi-route metabolism by the faecal microbiota sourced from six healthy humans. Here, four drug metabolites were linked to the microbiome for the first time. Metagenomic sequencing of the human microbiota samples revealed their composition, which facilitated prediction of individual donors’ microbial trifluridine inactivation. Notably, the abundance of <em>Clostridium perfringens</em> strongly correlated with the extent of trifluridine inactivation by microbiota samples after 2 hours (R² = 0.8966). Finally, several strategies were trialled for the prevention of microbial trifluridine metabolism. It was shown that uridine, a safe and well-tolerated molecule, significantly reduced the microbiota's metabolism of trifluridine by acting as a competitive enzyme inhibitor. Further, uridine was found to provide prebiotic effects. The findings in this study greatly expand knowledge on trifluridine's interactions with the gut microbiome and provide valuable insights for investigating the microbiome metabolism of other drugs. The results demonstrate how protection strategies could enhance the colonic stability of microbiome-sensitive drugs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377820","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":"Pharmacodynamic insights into maresin 1: Enhancing flap viability via the keap1/Nrf2 axis to control ROS-driven apoptosis and ferroptosis","authors":"","doi":"10.1016/j.ejps.2024.106923","DOIUrl":"10.1016/j.ejps.2024.106923","url":null,"abstract":"<div><div>Random flaps are widely used in tissue reconstruction, but the high incidence of flap necrosis after operation remains a significant challenge. Maresin 1 (MaR1), a mediator derived from docosahexaenoic acid, has been shown to have significant effects in resolving inflammation and promoting tissue regeneration. This study investigated the role of MaR1 in the survival of random flaps. Histological analysis, laser Doppler blood flow imaging, Masson trichrome staining, and survival area analysis were used to assess the viability of the flaps. Apoptosis, ferroptosis, oxidative stress, angiogenesis, and the underlying mechanisms were explored by examining the expression of specific molecules using immunofluorescence, western blotting, and other immunological and molecular biology techniques. The findings demonstrated that MaR1 could improve flap lifespan by significantly reducing oxidative stress, apoptosis, and ferroptosis, as well as by enhancing angiogenesis. The Keap1-Nrf2 pathway was upregulated by MaR1, which inhibited ROS-mediated apoptosis and ferroptosis. The protective effect of MaR1 on flap survival was abolished by ML385. Our findings indicate that MaR1 could be a novel therapeutic agent for enhancing flap treatment outcomes.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377821","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":"Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity","authors":"","doi":"10.1016/j.ejps.2024.106921","DOIUrl":"10.1016/j.ejps.2024.106921","url":null,"abstract":"<div><div>Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (<em>Z</em>)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (<strong>15c</strong>), exhibited antiproliferative activity, with a GI₅₀ of 2 µM, against neuroblastoma cell lines. <strong>15c</strong> also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364877","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}