Pub Date : 2024-08-15DOI: 10.1016/j.ejpb.2024.114456
María Ximena Origoni , Anna Nardi-Ricart , Marc Suñé-Pou , Pilar Pérez-Lozano , Miquel Romero-Obón , Josep Maria Suñé- Negre , Ana Teresa Ochoa-Andrade , Encarna García- Montoya
Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM.
In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition.
水分活化干法制粒(MADG)是一种极具吸引力的制粒工艺。然而,只有少数几项研究探讨了通过 MADG 实现的改良药物释放,而且据作者所知,没有一项研究探讨了胃保留问题。本研究的目的是在 SeDeM 图的帮助下,探索 MADG 工艺在开发具有胃保留作用的安慰剂片剂中的适用性。漂浮能力和溶胀能力被确定为关键质量属性(CQA)。经过制剂筛选步骤,浮动基质形成剂和粘合剂的类型和浓度被确定为十种制剂中最相关的关键材料属性(CMA)。针对这些变化因素进行了多元线性回归分析(MLRA),以找到设计空间。根据主成分分析(PCA)结果和多元线性回归分析,制备了一种优化产品,并对其进行了表征。粒料还通过 SeDeM 进行了评估。总之,制粒可制成浮动片剂,浮动滞后时间短(4 小时),并显示出良好的溶胀特性。迄今为止所取得的结果很有希望,足以将 MADG 视为一种有利的制粒方法,用于获得胃复安片剂,甚至是其他需要在其成分中含有相对较多吸收材料的控制给药系统。
{"title":"Exploration of moisture activated dry granulation for the development of gastroretentive tablets aided by SeDeM diagram","authors":"María Ximena Origoni , Anna Nardi-Ricart , Marc Suñé-Pou , Pilar Pérez-Lozano , Miquel Romero-Obón , Josep Maria Suñé- Negre , Ana Teresa Ochoa-Andrade , Encarna García- Montoya","doi":"10.1016/j.ejpb.2024.114456","DOIUrl":"10.1016/j.ejpb.2024.114456","url":null,"abstract":"<div><p>Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM.</p><p>In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114456"},"PeriodicalIF":4.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002820/pdfft?md5=50a0ac915de9eaaca96fbbcfe51bc5be&pid=1-s2.0-S0939641124002820-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1016/j.ejpb.2024.114457
Tao Ju Cui , Max Beugeling , Wallace Kaserer , Anton J.P. van Heugten , Martinus A.H. Capelle
Through a synergistic collaboration of people with varying backgrounds and expertise, the root-cause of respiratory syncytial virus prefusion (preF) protein aggregation during freezing was identified to be supercooling. This issue was addressed through a comprehensive understanding of the product. Leveraging innovative and unconventional methods, apparatus, and approaches, it was effectively determined that key parameters influencing aggregation were the nucleation temperature and the duration of supercooling. Moreover, additional measurements revealed that a transition from the preF to the postfusion conformation occurs upon supercooling, which is likely caused by cold denaturation. The importance of considering freezing conditions is highlighted supporting analytical sampling and envisioning that better understanding of sample handling/freezing process can be applied to a wide range of protein-based products.
{"title":"Improved RSV preF protein vaccine quality and stability by elucidation of supercooling-induced aggregation phenomena","authors":"Tao Ju Cui , Max Beugeling , Wallace Kaserer , Anton J.P. van Heugten , Martinus A.H. Capelle","doi":"10.1016/j.ejpb.2024.114457","DOIUrl":"10.1016/j.ejpb.2024.114457","url":null,"abstract":"<div><p>Through a synergistic collaboration of people with varying backgrounds and expertise, the root-cause of respiratory syncytial virus prefusion (preF) protein aggregation during freezing was identified to be supercooling. This issue was addressed through a comprehensive understanding of the product. Leveraging innovative and unconventional methods, apparatus, and approaches, it was effectively determined that key parameters influencing aggregation were the nucleation temperature and the duration of supercooling. Moreover, additional measurements revealed that a transition from the preF to the postfusion conformation occurs upon supercooling, which is likely caused by cold denaturation. The importance of considering freezing conditions is highlighted supporting analytical sampling and envisioning that better understanding of sample handling/freezing process can be applied to a wide range of protein-based products.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114457"},"PeriodicalIF":4.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1016/j.ejpb.2024.114455
Seyed Masoud Vahedi, Jalel Azaiez
The transport of drug/magnetic particle (MP) conjugates in the presence of a Magnetic Field (MF) in Drug Eluting Stents (DESs) is modeled numerically using the Finite Volume Method (FVM). The effects of physiological conditions corresponding to different degrees of calcification, drug particles sizes and hematocrit level, were analyzed by investigating the roles of the tissue permeability, its anisotropy and the plasma viscosity. It was found that both in the absence and presence of the MF, as the tissue permeability decreases or the plasma viscosity increases, the free-phase drug and Extracellular Matrix (ECM)-bound phase contents increase. Stronger tissue anisotropy leads to a decrease of the free-phase drug content and an increase of the ECM-bound phase content. Within the explored ranges, the Specific Receptor (SR)-bound phase of the drug was found to be insensitive to the tissue permeability and plasma viscosity, and to be larger in anisotropic tissues. The activation of the MF leads systematically to larger free-phase drug contents, with the increases most prominent at smaller tissue permeability, anisotropy and plasma viscosity. On the other hand, the effects on the ECM-bound phase content are found to be stronger at larger permeability, smaller plasma viscosity and lower tissue anisotropy. For an isotropic tissue, the MF induces a decrease of the ECM-bound phase content at early times, followed by an increase at later times. For the considered ranges of permeability and viscosity, the MF does not seem to have any noticeable effects on the SR-bound phase. However, this phase of the drug tends to increase with the activation of the MF in isotropic tissues and is unchanged in anisotropic ones. These reported effects of the MF hold promise for alleviating two factors contributing to In-Stent Restenosis, namely the polymer coating width and thickness. The study reveals that a narrower or thinner polymer layer, in combination with the MF, can mimic the drug release dynamics of a wider or thicker polymer layer in the absence of the MF. The corresponding width and thickness of the magnetized stents, that we referred to as the equivalent polymer width (EPW) and equivalent polymer thickness (EPT) were determined and their dependence on the tissue permeability, isotropy and the plasma viscosity, was investigated. The study shows that it is possible to achieve the same drug delivery with polymer coating of half the width or half the thickness of the non-magnetized stent when an electric intensity of 3A is used.
{"title":"Optimization of polymer coating thickness and strut width in drug Eluting stents using Magnetic field","authors":"Seyed Masoud Vahedi, Jalel Azaiez","doi":"10.1016/j.ejpb.2024.114455","DOIUrl":"10.1016/j.ejpb.2024.114455","url":null,"abstract":"<div><p>The transport of drug/magnetic particle (MP) conjugates in the presence of a Magnetic Field (MF) in Drug Eluting Stents (DESs) is modeled numerically using the Finite Volume Method (FVM). The effects of physiological conditions corresponding to different degrees of calcification, drug particles sizes and hematocrit level, were analyzed by investigating the roles of the tissue permeability, its anisotropy and the plasma viscosity. It was found that both in the absence and presence of the MF, as the tissue permeability decreases or the plasma viscosity increases, the free-phase drug and Extracellular Matrix (ECM)-bound phase contents increase. Stronger tissue anisotropy leads to a decrease of the free-phase drug content and an increase of the ECM-bound phase content. Within the explored ranges, the Specific Receptor (SR)-bound phase of the drug was found to be insensitive to the tissue permeability and plasma viscosity, and to be larger in anisotropic tissues. The activation of the MF leads systematically to larger free-phase drug contents, with the increases most prominent at smaller tissue permeability, anisotropy and plasma viscosity. On the other hand, the effects on the ECM-bound phase content are found to be stronger at larger permeability, smaller plasma viscosity and lower tissue anisotropy. For an isotropic tissue, the MF induces a decrease of the ECM-bound phase content at early times, followed by an increase at later times. For the considered ranges of permeability and viscosity, the MF does not seem to have any noticeable effects on the SR-bound phase. However, this phase of the drug tends to increase with the activation of the MF in isotropic tissues and is unchanged in anisotropic ones. These reported effects of the MF hold promise for alleviating two factors contributing to In-Stent Restenosis, namely the polymer coating width and thickness. The study reveals that a narrower or thinner polymer layer, in combination with the MF, can mimic the drug release dynamics of a wider or thicker polymer layer in the absence of the MF. The corresponding width and thickness of the magnetized stents, that we referred to as the equivalent polymer width (EPW) and equivalent polymer thickness (EPT) were determined and their dependence on the tissue permeability, isotropy and the plasma viscosity, was investigated. The study shows that it is possible to achieve the same drug delivery with polymer coating of half the width or half the thickness of the non-magnetized stent when an electric intensity of 3A is used.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114455"},"PeriodicalIF":4.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In our previous studies, 3-O-β-D-galactosylated resveratrol (Gal-Res) was synthesized by structural modification and then 3-O-β-D-galactosylated resveratrol polydopamine nanoparticles (Gal-Res NPs) were successfully prepared to improve the bioavailability and liver distribution of Res. However, the pharmacodynamic efficacy and specific mechanism of Gal-Res NPs on hepatocellular carcinoma remain unclear. Herein, liver cancer model mice were successfully constructed by xenograft tumor modeling. Gal-Res NPs (34.2 mg/kg) significantly inhibited tumor growth of the liver cancer model mice with no significant effect on their body weight and no obvious toxic effect on major organs. Additionally, in vitro cellular uptake assay showed that Gal-Res NPs (37.5 μmol/L) increased the uptake of Gal-Res by Hepatocellular carcinoma (HepG2) cells, and significantly inhibited the cell migration and invasion. The experimental results of Hoechst 33342/propyl iodide (PI) double staining and flow cytometry both revealed that Gal-Res NPs could remarkably promote cell apoptosis. Moreover, the Western blot results revealed that Gal-Res NPs significantly regulated the Bcl-2/Bax and AKT/GSK3β/β-catenin signaling pathways. Taken together, the in vitro/in vivo results demonstrated that Gal-Res NPs significantly improved the antitumor efficiency of Gal-Res, which is a potential antitumor drug delivery system.
{"title":"Evaluation of 3-O-β-D-galactosylated resveratrol-loaded polydopamine nanoparticles for hepatocellular carcinoma treatment","authors":"Xiaoxiao Shan , Shujie Lv , Hongyan Cheng , Lele Zhou , Yu Gao , Chengjie Xing , Dawei Li , Wenwen Tao , Caiyun Zhang","doi":"10.1016/j.ejpb.2024.114454","DOIUrl":"10.1016/j.ejpb.2024.114454","url":null,"abstract":"<div><p>In our previous studies, 3-O-β-D-galactosylated resveratrol (Gal-Res) was synthesized by structural modification and then 3-O-β-D-galactosylated resveratrol polydopamine nanoparticles (Gal-Res NPs) were successfully prepared to improve the bioavailability and liver distribution of Res. However, the pharmacodynamic efficacy and specific mechanism of Gal-Res NPs on hepatocellular carcinoma remain unclear. Herein, liver cancer model mice were successfully constructed by xenograft tumor modeling. Gal-Res NPs (34.2 mg/kg) significantly inhibited tumor growth of the liver cancer model mice with no significant effect on their body weight and no obvious toxic effect on major organs. Additionally, <em>in vitro</em> cellular uptake assay showed that Gal-Res NPs (37.5 μmol/L) increased the uptake of Gal-Res by Hepatocellular carcinoma (HepG2) cells, and significantly inhibited the cell migration and invasion. The experimental results of Hoechst 33342/propyl iodide (PI) double staining and flow cytometry both revealed that Gal-Res NPs could remarkably promote cell apoptosis. Moreover, the Western blot results revealed that Gal-Res NPs significantly regulated the Bcl-2/Bax and AKT/GSK3β/β-catenin signaling pathways. Taken together, the <em>in vitro/in vivo</em> results demonstrated that Gal-Res NPs significantly improved the antitumor efficiency of Gal-Res, which is a potential antitumor drug delivery system.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114454"},"PeriodicalIF":4.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-10DOI: 10.1016/j.ejpb.2024.114453
Tahlia R. Meola , Srinivas Kamath , Aurelia S. Elz , Clive A. Prestidge , Anthony Wignall , Paul Joyce
Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable ∼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a ‘gut neutral’ effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota – an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.
{"title":"Contrasting the pharmacokinetic performance and gut microbiota effects of an amorphous solid dispersion and lipid nanoemulsion for a poorly water-soluble anti-psychotic","authors":"Tahlia R. Meola , Srinivas Kamath , Aurelia S. Elz , Clive A. Prestidge , Anthony Wignall , Paul Joyce","doi":"10.1016/j.ejpb.2024.114453","DOIUrl":"10.1016/j.ejpb.2024.114453","url":null,"abstract":"<div><p>Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within <em>in vitro</em> dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable ∼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a ‘gut neutral’ effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota – an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114453"},"PeriodicalIF":4.4,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002790/pdfft?md5=1d9d17ba068f3479e2e8fe68da2f19ef&pid=1-s2.0-S0939641124002790-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-10DOI: 10.1016/j.ejpb.2024.114448
Aili Wang , Xi Ruan , Xuejiao Wang , Yuyu Ren , Chunjiao Shen , Kaiyi Zhang , Zhenjie Song , Bai Xiang , Yinling Ma , Feng Zhao
Diabetic ulcers present a formidable obstacle in diabetes management, typically leading to high mortality and amputation rates. To overcome traditional monotherapy drawbacks, We developed a novel microneedle strategy for combined antimicrobial action: ingeniously integrating quercetin with Platelet-derived Growth Factor-BB(PDGF-BB) and Sucrose Octasulfate(SOS) into the microneedle system(QPS MN). This method allows to penetrate through biofilms, administering quercetin nanocrystals and PDGF-BB deep into the tissue to combat microbial infection, mitigate inflammation, and promote angiogenesis. The accompanying backing material contains SOS, which absorbs wound exudate and forms a dressing that provides a moist environment for wound healing In an in vitro wound-scratch assay demonstrated that co-cultivating Human Umbilical Vein Endothelial Cells(HUVEC) with QPS MN for 48 h (90.3 ± 2.51 %) significantly enhanced cell migration compared to the control group (20.2 ± 1.41 %). Moreover, treatment of streptozotocin-induced diabetic wounds in rats with QPS MN for 14 days resulted in a wound healing rate of 96.56 ± 3.44 %, far surpassing the healing rate of only 40.34 ± 7.26 % observed in the untreated control group. Furthermore, the QPS MN treated wounds exhibited a notable increase in skin appendages and neovascularisation, indicating promising potential for achieving complete wound healing. These results suggest that QPS MN may offer substantial therapeutic benefits for addressing diabetic wounds.
{"title":"A one-stop integrated natural antimicrobial microneedles with anti-inflammatory, pro-angiogenic and long-term moisturizing properties to accelerate diabetic wound healing","authors":"Aili Wang , Xi Ruan , Xuejiao Wang , Yuyu Ren , Chunjiao Shen , Kaiyi Zhang , Zhenjie Song , Bai Xiang , Yinling Ma , Feng Zhao","doi":"10.1016/j.ejpb.2024.114448","DOIUrl":"10.1016/j.ejpb.2024.114448","url":null,"abstract":"<div><p>Diabetic ulcers present a formidable obstacle in diabetes management, typically leading to high mortality and amputation <span><span>rates. To</span><svg><path></path></svg></span> overcome traditional monotherapy drawbacks, We developed a novel microneedle strategy for combined antimicrobial action: ingeniously integrating quercetin with Platelet-derived Growth Factor-BB(PDGF-BB) and Sucrose Octasulfate(SOS) into the microneedle system(QPS MN). This method allows to penetrate through biofilms, administering quercetin nanocrystals and PDGF-BB deep into the tissue to combat microbial infection, mitigate inflammation, and promote angiogenesis. The accompanying backing material contains SOS, which absorbs wound exudate and forms a dressing that provides a moist environment for wound healing In an in vitro wound-scratch assay demonstrated that co-cultivating Human Umbilical Vein Endothelial Cells(HUVEC) with QPS MN for 48 h (90.3 ± 2.51 %) significantly enhanced cell migration compared to the control group (20.2 ± 1.41 %). Moreover, treatment of streptozotocin-induced diabetic wounds in rats with QPS MN for 14 days resulted in a wound healing rate of 96.56 ± 3.44 %, far surpassing the healing rate of only 40.34 ± 7.26 % observed in the untreated control group. Furthermore, the QPS MN treated wounds exhibited a notable increase in skin appendages and neovascularisation, indicating promising potential for achieving complete wound healing. These results suggest that QPS MN may offer substantial therapeutic benefits for addressing diabetic wounds.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114448"},"PeriodicalIF":4.4,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1016/j.ejpb.2024.114447
Anjali Agrawal , Smita Salunke , Alfred Rumondor , Karen Thompson , Grazia Caivano , Jennifer Walsh , Brian Enright , Philip Sherratt , Kevin Hughes , David Clapham , Peter Kuehl , on behalf of the International Consortium (IQ) for Innovation and Quality in Pharmaceutical Development and European Paediatric Formulation Initiative (EuPFI)
It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The “Paediatric Excipient Risk Assessment (PERA)” framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products.
This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool’s usefulness.
{"title":"Paediatric excipient risk assessment (PERA) tool and application for selecting appropriate excipients for paediatric dosage forms – Part 2","authors":"Anjali Agrawal , Smita Salunke , Alfred Rumondor , Karen Thompson , Grazia Caivano , Jennifer Walsh , Brian Enright , Philip Sherratt , Kevin Hughes , David Clapham , Peter Kuehl , on behalf of the International Consortium (IQ) for Innovation and Quality in Pharmaceutical Development and European Paediatric Formulation Initiative (EuPFI)","doi":"10.1016/j.ejpb.2024.114447","DOIUrl":"10.1016/j.ejpb.2024.114447","url":null,"abstract":"<div><p>It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The “Paediatric Excipient Risk Assessment (PERA)” framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products.</p><p>This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool’s usefulness.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114447"},"PeriodicalIF":4.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S093964112400273X/pdfft?md5=edfa898d02ffe95b62ec366bfa2f0018&pid=1-s2.0-S093964112400273X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1016/j.ejpb.2024.114446
Andrea Bezze , Carlotta Mattioda , Gianluca Ciardelli, Clara Mattu
Efficient tumour treatment is hampered by the poor selectivity of anticancer drugs, resulting in scarce tumour accumulation and undesired off-target effects. Nano-sized drug-delivery systems in the form of nanoparticles (NPs) have been proposed to improve drug distribution to solid tumours, by virtue of their ability of passive and active tumour targeting. Despite these advantages, literature studies indicated that less than 1% of the administered NPs can successfully reach the tumour mass, highlighting the necessity for more efficient drug transporters in cancer treatment. Living cells, such as blood cells, circulating immune cells, platelets, and stem cells, are often found as an infiltrating component in most solid tumours, because of their ability to naturally circumvent immune recognition, bypass biological barriers, and reach inaccessible tissues through innate tropism and active motility. Therefore, the tumour-homing ability of these cells can be harnessed to design living cell carriers able to improve the transport of drugs and NPs to tumours. Albeit promising, this approach is still in its beginnings and suffers from difficult scalability, high cost, and poor reproducibility. In this review, we present an overview of the most common cell transporters of drugs and NPs, and we discuss how different cell types interact with biological barriers to deliver cargoes of various natures to tumours. Finally, we analyse the different techniques used to load drugs or NPs in living cells and discuss their advantages and disadvantages.
{"title":"Harnessing cells to improve transport of nanomedicines","authors":"Andrea Bezze , Carlotta Mattioda , Gianluca Ciardelli, Clara Mattu","doi":"10.1016/j.ejpb.2024.114446","DOIUrl":"10.1016/j.ejpb.2024.114446","url":null,"abstract":"<div><p>Efficient tumour treatment is hampered by the poor selectivity of anticancer drugs, resulting in scarce tumour accumulation and undesired off-target effects. Nano-sized drug-delivery systems in the form of nanoparticles (NPs) have been proposed to improve drug distribution to solid tumours, by virtue of their ability of passive and active tumour targeting. Despite these advantages, literature studies indicated that less than 1% of the administered NPs can successfully reach the tumour mass, highlighting the necessity for more efficient drug transporters in cancer treatment. Living cells, such as blood cells, circulating immune cells, platelets, and stem cells, are often found as an infiltrating component in most solid tumours, because of their ability to naturally circumvent immune recognition, bypass biological barriers, and reach inaccessible tissues through innate tropism and active motility. Therefore, the tumour-homing ability of these cells can be harnessed to design living cell carriers able to improve the transport of drugs and NPs to tumours. Albeit promising, this approach is still in its beginnings and suffers from difficult scalability, high cost, and poor reproducibility. In this review, we present an overview of the most common cell transporters of drugs and NPs, and we discuss how different cell types interact with biological barriers to deliver cargoes of various natures to tumours. Finally, we analyse the different techniques used to load drugs or NPs in living cells and discuss their advantages and disadvantages.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114446"},"PeriodicalIF":4.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002728/pdfft?md5=695bbf19575e46ad1ace60dd824d0b4e&pid=1-s2.0-S0939641124002728-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1016/j.ejpb.2024.114429
Evelina Maines , Giorgio Temporin , Michela Fedrizzi , Alessandra Pasqualini , Lorenzo Junior Masnata , Annalisa Campomori , Alessandro Iodice , Giovanni Piccoli , Massimo Soffiati , Roberto Franceschi , Silvana Anna Maria Urru
Background
sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients.
Materials and methods
we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD.
Results
we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance.
Conclusions
in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.
{"title":"Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency","authors":"Evelina Maines , Giorgio Temporin , Michela Fedrizzi , Alessandra Pasqualini , Lorenzo Junior Masnata , Annalisa Campomori , Alessandro Iodice , Giovanni Piccoli , Massimo Soffiati , Roberto Franceschi , Silvana Anna Maria Urru","doi":"10.1016/j.ejpb.2024.114429","DOIUrl":"10.1016/j.ejpb.2024.114429","url":null,"abstract":"<div><h3>Background</h3><p>sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients.</p></div><div><h3>Materials and methods</h3><p>we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD.</p></div><div><h3>Results</h3><p>we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance.</p></div><div><h3>Conclusions</h3><p>in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114429"},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1016/j.ejpb.2024.114437
M.M. Szachniewicz , S.J.F. van den Eeden , K.E. van Meijgaarden , K.L.M.C. Franken , S. van Veen , A. Geluk , J.A. Bouwstra , T.H.M. Ottenhoff
Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants – CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB.
In vitro in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. In vivo, the new vaccine administrated subcutaneously significantly reduced Mycobacterium tuberculosis (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine’s effectiveness in terms of its capacity to induce polyfunctional CD4+ and CD8+ T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69+ B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.
几个世纪以来,结核病(TB)一直是全球的紧急疾病,现在依然如此。通过接种疫苗预防疾病将对疾病的流行产生重大影响,但目前唯一可用的疫苗卡介苗效果不佳。本文利用 Ag85B-ESAT6-Rv2034 融合抗原、两种佐剂(CpG 和 MPLA)以及阳离子 pH 敏感脂质体作为递送系统,开发了一种新型结核病亚单位疫苗,这是一种以前从未报道过的结核病疫苗递送策略。在体外人树突状细胞(DCs)中,与不添加佐剂的脂质体相比,添加佐剂的配方诱导产生的(先天性)细胞因子和趋化因子显著增加。在体内,皮下注射新疫苗可显著减少小鼠肺部和脾脏中的结核分枝杆菌(Mtb)细菌量,明显优于接种抗原与佐剂混合但不含脂质体的小鼠。深入分析证实了疫苗在诱导多功能 CD4+ 和 CD8+ T 细胞反应方面的有效性,而这两种细胞反应都被认为是控制 Mtb 感染的关键。同样值得注意的是,各种 CD69+ B 细胞亚群的丰度不同,其中包括产生 IL17-A 的 B 细胞。疫苗激发了强大的抗原特异性抗体滴度,进一步扩大了其作为新型结核病保护剂的潜力。
{"title":"Cationic pH-sensitive liposome-based subunit tuberculosis vaccine induces protection in mice challenged with Mycobacterium tuberculosis","authors":"M.M. Szachniewicz , S.J.F. van den Eeden , K.E. van Meijgaarden , K.L.M.C. Franken , S. van Veen , A. Geluk , J.A. Bouwstra , T.H.M. Ottenhoff","doi":"10.1016/j.ejpb.2024.114437","DOIUrl":"10.1016/j.ejpb.2024.114437","url":null,"abstract":"<div><p>Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants – CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB.</p><p><em>In vitro</em> in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. <em>In vivo</em>, the new vaccine administrated subcutaneously significantly reduced <em>Mycobacterium tuberculosis</em> (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine’s effectiveness in terms of its capacity to induce polyfunctional CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69<sup>+</sup> B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114437"},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002637/pdfft?md5=1a1aa331630a54c5190dd72437be78fc&pid=1-s2.0-S0939641124002637-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}