Pub Date : 2024-10-28DOI: 10.1016/j.ejpb.2024.114552
María de la Cabeza Fernández , Marta Sánchez , Laura Lozano-Chamizo , Ana Cristina Abreu , Ana Anguís-Morillas , Padreep K Divakar , Marzia Marciello , Marco Filice , Victor Gonzalez-Rumayor , Ignacio Fernández , Rafael Contreras-Cáceres , Pilar Gómez-Serranillos
This research is based on the incorporation of the methanolic extract of the Usnea ghattensis into poly (caprolactone) (PCL) nanofibers (NFs) to investigate the capacity in reducing reactive oxygen species (ROS). PCL-NFs were fabricated by the electrospinning technique and are investigated as potential dressing material focused on the release of usnic acid (PCL-USNIC NFs), and its encapsulation efficiency and kinetic release were analyzed by high performance liquid chromatography (HPLC). This investigation was performed by analyzing the usnic acid concentration as a function of the distance from the mat center point. The kinetic release analysis is also developed with the usnea ghattensis extract (PCL-USNEA NFs), performing a metabolomic analysis of the released molecules as a function of time by nuclear magnetic resonance (NMR). Usnic acid was revealed as the most relevant compound together with other molecules, such as sucrose, mannitol, arabitol or glycerol that generate a positive matrix effect on the release of usnic acid. Finally, we analize the cytotoxicity and the neuroprotective effect of PCL-USNEA and PCL-USNIC NFs using a human neuroblastoma cell line model. Negligible toxicity was appreciated for both polymeric systems, showing high protective effects in presence of highly oxidative environment (e.g. in presence of H2O2).
{"title":"Electrospun nanofibers for localized drug release of a neuroprotective natural extract of Usnea ghattensis","authors":"María de la Cabeza Fernández , Marta Sánchez , Laura Lozano-Chamizo , Ana Cristina Abreu , Ana Anguís-Morillas , Padreep K Divakar , Marzia Marciello , Marco Filice , Victor Gonzalez-Rumayor , Ignacio Fernández , Rafael Contreras-Cáceres , Pilar Gómez-Serranillos","doi":"10.1016/j.ejpb.2024.114552","DOIUrl":"10.1016/j.ejpb.2024.114552","url":null,"abstract":"<div><div>This research is based on the incorporation of the methanolic extract of the <em>Usnea ghattensis</em> into poly (caprolactone) (PCL) nanofibers (NFs) to investigate the capacity in reducing reactive oxygen species (ROS). PCL-NFs were fabricated by the electrospinning technique and are investigated as potential dressing material focused on the release of usnic acid (PCL-USNIC NFs), and its encapsulation efficiency and kinetic release were analyzed by high performance liquid chromatography (HPLC). This investigation was performed by analyzing the usnic acid concentration as a function of the distance from the mat center point. The kinetic release analysis is also developed with the <em>usnea ghattensis</em> extract (PCL-USNEA NFs), performing a metabolomic analysis of the released molecules as a function of time by nuclear magnetic resonance (NMR). Usnic acid was revealed as the most relevant compound together with other molecules, such as sucrose, mannitol, arabitol or glycerol that generate a positive matrix effect on the release of usnic acid. Finally, we analize the cytotoxicity and the neuroprotective effect of PCL-USNEA and PCL-USNIC NFs using a human neuroblastoma cell line model. Negligible toxicity was appreciated for both polymeric systems, showing high protective effects in presence of highly oxidative environment (e.g. in presence of H<sub>2</sub>O<sub>2</sub>).</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114552"},"PeriodicalIF":4.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544581","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 : 2024-10-28DOI: 10.1016/j.ejpb.2024.114571
David Schultz , Rasmus D. Münter , Alex M. Cantín , Paul J. Kempen , Nadin Jahnke , Thomas L. Andresen , Jens B. Simonsen , Andrew J. Urquhart
To quantify concentration and encapsulation efficiency (EE) of mRNA in lipid nanoparticles (LNPs) the RiboGreen assay is extensively used. As part of this assay, a surfactant is used to release mRNA from LNPs for detection with the RiboGreen dye. So far, the surfactant of choice has been Triton X-100, which is harmful to human health and the environment. Alternatives to Triton X-100 are therefore needed, but surprisingly no such effort has yet been described in the literature. Here we show how three, less harmful, surfactants (Brij 93, Zwittergent 3–14 and Tween 20) compare to Triton X-100 for releasing mRNA from LNPs for detection with the RiboGreen assay. We found that Zwittergent 3–14 and Tween 20 at high concentrations (0.5 %) are at the minimum as effective as Triton X-100 at high concentration (0.5 %) across three different mRNA-LNP formulations. Interestingly, Tween 20 was the most effective at releasing mRNA from LNPs, across all concentration ranges explored (0.0025 %, 0.01 %, 0.1 % and to 0.5 % (v/v)) highlighting its potency at solubilizing the three different LNP formulations. Our results show that Tween 20 can be used as an alternative to Triton X-100 in the RiboGreen assay, resulting in more accurate quantification of the total mRNA concentration and EE%, as well as making the assay more environmentally friendly. Such improvement could potentially increase the likelihood of identifying therapeutically attractive hard-to-solubilize LNP-mRNA formulations that would be discharged when using Triton X-100 due to their apparent low EE values, as well as ensure more accurate mRNA dosing in both in vitro and in vivo studies.
{"title":"Enhancing RNA encapsulation quantification in lipid nanoparticles: Sustainable alternatives to Triton X-100 in the RiboGreen assay","authors":"David Schultz , Rasmus D. Münter , Alex M. Cantín , Paul J. Kempen , Nadin Jahnke , Thomas L. Andresen , Jens B. Simonsen , Andrew J. Urquhart","doi":"10.1016/j.ejpb.2024.114571","DOIUrl":"10.1016/j.ejpb.2024.114571","url":null,"abstract":"<div><div>To quantify concentration and encapsulation efficiency (EE) of mRNA in lipid nanoparticles (LNPs) the RiboGreen assay is extensively used. As part of this assay, a surfactant is used to release mRNA from LNPs for detection with the RiboGreen dye. So far, the surfactant of choice has been Triton X-100, which is harmful to human health and the environment. Alternatives to Triton X-100 are therefore needed, but surprisingly no such effort has yet been described in the literature. Here we show how three, less harmful, surfactants (Brij 93, Zwittergent 3–14 and Tween 20) compare to Triton X-100 for releasing mRNA from LNPs for detection with the RiboGreen assay. We found that Zwittergent 3–14 and Tween 20 at high concentrations (0.5 %) are at the minimum as effective as Triton X-100 at high concentration (0.5 %) across three different mRNA-LNP formulations. Interestingly, Tween 20 was the most effective at releasing mRNA from LNPs, across all concentration ranges explored (0.0025 %, 0.01 %, 0.1 % and to 0.5 % (v/v)) highlighting its potency at solubilizing the three different LNP formulations. Our results show that Tween 20 can be used as an alternative to Triton X-100 in the RiboGreen assay, resulting in more accurate quantification of the total mRNA concentration and EE%, as well as making the assay more environmentally friendly. Such improvement could potentially increase the likelihood of identifying therapeutically attractive hard-to-solubilize LNP-mRNA formulations that would be discharged when using Triton X-100 due to their apparent low EE values, as well as ensure more accurate mRNA dosing in both in vitro and in vivo studies.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114571"},"PeriodicalIF":4.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568161","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 : 2024-10-28DOI: 10.1016/j.ejpb.2024.114566
Binbin Shi , Qiaohua Yang , Zenghui Liang , Runjie Yu , Hui Li , Qilong Wu , Mingling Fang , Lili Lin , Huafang Chen , Yingzheng Zhao , Bin Chen
Arterial thrombotic disease is a common and serious clinical medical problem. Nitric oxide (NO), as a therapeutic gas, can delay the progression of thrombosis and reduce tissue ischemia and hypoxia damage. However, systemic delivery of NO causes complications, and NO in the body is easily cleared by hemoglobin in the blood. In this study, we designed a lipid microbubble carrying NO (NO-MBs) combined with ultrasound-targeted microbubble destruction (UTMD) technology to achieve targeted delivery of NO under real-time contrast-enhanced ultrasound monitoring. The good stability of the NO-MBs was demonstrated by examining the changes in diameter, concentration and contrast-enhanced ultrasound intensity with time. Moreover, in vivo and in vitro thrombolysis experiments, it was confirmed that the combination of NO-MBs and UTMD could accelerate arterial thrombolysis. Meanwhile, the levels of inflammatory factors, superoxide dismutase (SOD) and malondialdehyde (MDA) in vascular tissue after treatment were detected, which showed that NO-MBs could significantly reduce the inflammatory response and oxidative stress induced by thromboembolism. In addition, so as to evaluate the safety of the NO-MBs UTMD treatment strategy, MTT assay, hemolysis test, detection of serum biochemical indicators, and H&E staining of major organs were performed. The results showed that this treatment strategy had excellent biosafety. In conclusion, the NO-MBs UTMD treatment strategy has great potential in the treatment of arterial thrombotic diseases.
动脉血栓性疾病是一种常见而严重的临床医学问题。一氧化氮（NO）作为一种治疗气体，可以延缓血栓形成的进展，减轻组织缺血缺氧损伤。然而，NO 的全身给药会引起并发症，而且体内的 NO 很容易被血液中的血红蛋白清除。在这项研究中，我们设计了一种携带 NO 的脂质微泡（NO-MBs），并结合超声靶向微泡破坏（UTMD）技术，在实时造影剂增强超声监测下实现 NO 的靶向输送。通过检测NO-MB的直径、浓度和造影剂增强超声强度随时间的变化，证明了其良好的稳定性。此外，体内和体外溶栓实验证实，NO-MB 和 UTMD 的结合可加速动脉溶栓。同时，检测了治疗后血管组织中炎症因子、超氧化物歧化酶（SOD）和丙二醛（MDA）的水平，结果表明 NO-MBs 能显著减轻血栓栓塞引起的炎症反应和氧化应激。此外，为了评估 NO-MBs UTMD 治疗策略的安全性，研究人员还进行了 MTT 试验、溶血试验、血清生化指标检测和主要器官的 H&E 染色。结果表明，这种治疗策略具有良好的生物安全性。总之，NO-MBs UTMD 治疗策略在治疗动脉血栓性疾病方面具有巨大潜力。
{"title":"Accelerating thrombolysis of arterial thrombus with NO-MBs UTMD therapy","authors":"Binbin Shi , Qiaohua Yang , Zenghui Liang , Runjie Yu , Hui Li , Qilong Wu , Mingling Fang , Lili Lin , Huafang Chen , Yingzheng Zhao , Bin Chen","doi":"10.1016/j.ejpb.2024.114566","DOIUrl":"10.1016/j.ejpb.2024.114566","url":null,"abstract":"<div><div>Arterial thrombotic disease is a common and serious clinical medical problem. Nitric oxide (NO), as a therapeutic gas, can delay the progression of thrombosis and reduce tissue ischemia and hypoxia damage. However, systemic delivery of NO causes complications, and NO in the body is easily cleared by hemoglobin in the blood. In this study, we designed a lipid microbubble carrying NO (NO-MBs) combined with ultrasound-targeted microbubble destruction (UTMD) technology to achieve targeted delivery of NO under real-time contrast-enhanced ultrasound monitoring. The good stability of the NO-MBs was demonstrated by examining the changes in diameter, concentration and contrast-enhanced ultrasound intensity with time. Moreover, in vivo and in vitro thrombolysis experiments, it was confirmed that the combination of NO-MBs and UTMD could accelerate arterial thrombolysis. Meanwhile, the levels of inflammatory factors, superoxide dismutase (SOD) and malondialdehyde (MDA) in vascular tissue after treatment were detected, which showed that NO-MBs could significantly reduce the inflammatory response and oxidative stress induced by thromboembolism. In addition, so as to evaluate the safety of the NO-MBs UTMD treatment strategy, MTT assay, hemolysis test, detection of serum biochemical indicators, and H&E staining of major organs were performed. The results showed that this treatment strategy had excellent biosafety. In conclusion, the NO-MBs UTMD treatment strategy has great potential in the treatment of arterial thrombotic diseases.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114566"},"PeriodicalIF":4.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544579","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}
Tandospirone(Tan) is a commonly used drug for anxiety treatment. However, it has a significant first-pass effect and needs to be taken three times a day. To increase the bioavailability of the drug and reduce the number of administrations, this work amid to prepare a Tan patch that can be administered once a day by using the strategy of therapeutic deep eutectic solvent(THEDES) in cooperation with chemical permeation enhancer(CPE). In this study, four organic acids and five permeation enhancers were selected, and the optimized formulation was obtained by single-factor investigation and Box-Behnken design. The optimized formulation could significantly enhance drug loading by 2.5-fold and skin permeation up to 586.6 ± 17 μg/cm2 in rats. Based on pharmacokinetic results, compared to oral administration, the drug exhibited a substantially elevated bioavailability, registering a 17-fold increase(from 3.01 % to 52.17 %), alongside a 10-fold rise in the mean residence time(MRT). Meanwhile, the patch was not irritating. The results of the mechanistic study showed that levulinic acid(LeA) acted as a bridge to increase the interaction between the Tan and the matrix and inhibited the crystallization of the drug in the patch, and THEDES together with CPE improved the matrix fluidity and skin permeability. This study provides a reference for the joint application of THEDES and CPEs in patch development.
{"title":"Deep eutectic solvent combined with permeation enhancer strategy to convert tandospirone from oral to transdermal formulations improving drug bioavailability","authors":"Peng Sun, Hui Li, Kaihua Gong, Yang Zhang, Yu Cai, Chao Liu, Liang Fang","doi":"10.1016/j.ejpb.2024.114570","DOIUrl":"10.1016/j.ejpb.2024.114570","url":null,"abstract":"<div><div>Tandospirone(Tan) is a commonly used drug for anxiety treatment. However, it has a significant first-pass effect and needs to be taken three times a day. To increase the bioavailability of the drug and reduce the number of administrations, this work amid to prepare a Tan patch that can be administered once a day by using the strategy of therapeutic deep eutectic solvent(THEDES) in cooperation with chemical permeation enhancer(CPE). In this study, four organic acids and five permeation enhancers were selected, and the optimized formulation was obtained by single-factor investigation and Box-Behnken design. The optimized formulation could significantly enhance drug loading by 2.5-fold and skin permeation up to 586.6 ± 17 μg/cm<sup>2</sup> in rats. Based on pharmacokinetic results, compared to oral administration, the drug exhibited a substantially elevated bioavailability, registering a 17-fold increase(from 3.01 % to 52.17 %), alongside a 10-fold rise in the mean residence time(MRT). Meanwhile, the patch was not irritating. The results of the mechanistic study showed that levulinic acid(LeA) acted as a bridge to increase the interaction between the Tan and the matrix and inhibited the crystallization of the drug in the patch, and THEDES together with CPE improved the matrix fluidity and skin permeability. This study provides a reference for the joint application of THEDES and CPEs in patch development.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114570"},"PeriodicalIF":4.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554301","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}
{"title":"Corrigendum \"The chemotherapeutic potential of doxorubicin-loaded PEG-b-PLGA nanopolymersomes in mouse breast cancer model\" [Eur. J. Pharm. Biopharm. 94 (2015) 521-531].","authors":"Mona Alibolandi, Fatemeh Sadeghi, Khalil Abnous, Fatemeh Atyabi, Mohammad Ramezani, Farzin Hadizadeh","doi":"10.1016/j.ejpb.2024.114568","DOIUrl":"https://doi.org/10.1016/j.ejpb.2024.114568","url":null,"abstract":"","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":" ","pages":"114568"},"PeriodicalIF":4.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544580","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 : 2024-10-26DOI: 10.1016/j.ejpb.2024.114553
Dejan Krajcar , Dejan Velušček , Iztok Grabnar
Background
Bioequivalence risk assessment as an extension of quality risk management lacks examples of quantitative approaches to risk assessment at an early stage of generic drug development. The aim of our study was to develop a model-based approach for bioequivalence risk assessment that uses pharmacokinetic and physicochemical characteristics of drugs as predictors and would standardize the first step of risk assessment.
Methods
The Sandoz in-house bioequivalence database of 128 bioequivalence studies with poorly soluble drugs (23.5% non-bioequivalent) was used to train and validate the model. Four different modeling approaches, random forest, XGBoost, logistic regression and naïve Bayes, were compared.
Results
Among the best performing machine learning models, random forest was selected and optimized for the number of features, resulting in an accuracy of 84% on the test data set. The most important features for prediction were those related to solubility (dose number, acid dissociation constant), absorption and elimination rate, effective permeability, variability of pharmacokinetic endpoints, and absolute bioavailability. All features had a conceivable influence on the model predictions.
Conclusion
The model was used to develop a bioequivalence risk assessment approach to categorize drugs in early development into high, medium or low risk classes.
{"title":"Machine learning driven bioequivalence risk assessment at an early stage of generic drug development","authors":"Dejan Krajcar , Dejan Velušček , Iztok Grabnar","doi":"10.1016/j.ejpb.2024.114553","DOIUrl":"10.1016/j.ejpb.2024.114553","url":null,"abstract":"<div><h3>Background</h3><div>Bioequivalence risk assessment as an extension of quality risk management lacks examples of quantitative approaches to risk assessment at an early stage of generic drug development. The aim of our study was to develop a model-based approach for bioequivalence risk assessment that uses pharmacokinetic and physicochemical characteristics of drugs as predictors and would standardize the first step of risk assessment.</div></div><div><h3>Methods</h3><div>The Sandoz in-house bioequivalence database of 128 bioequivalence studies with poorly soluble drugs (23.5% non-bioequivalent) was used to train and validate the model. Four different modeling approaches, random forest, XGBoost, logistic regression and naïve Bayes, were compared.</div></div><div><h3>Results</h3><div>Among the best performing machine learning models, random forest was selected and optimized for the number of features, resulting in an accuracy of 84% on the test data set. The most important features for prediction were those related to solubility (dose number, acid dissociation constant), absorption and elimination rate, effective permeability, variability of pharmacokinetic endpoints, and absolute bioavailability. All features had a conceivable influence on the model predictions.</div></div><div><h3>Conclusion</h3><div>The model was used to develop a bioequivalence risk assessment approach to categorize drugs in early development into high, medium or low risk classes.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114553"},"PeriodicalIF":4.4,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560962","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 : 2024-10-24DOI: 10.1016/j.ejpb.2024.114567
M.O.F. Muñoz-Correa , Diego A. Bravo-Alfaro , L.G. Mendoza-Sánchez , Gabriel Luna-Barcenas , Hugo S. Garcia , Rebeca Garcia-Varela
This study investigated the potential of self-nanoemulsifying drug delivery systems (SNEDDS) to optimize the oral bioavailability of insulin. Insulin complexes with phospholipids and enzymatically-modified phospholipids were developed and incorporated into the SNEDDS using Lauroglycol FCC as the oily phase and Cremophor EL and Labrafil M1944CS as the surfactant and co-surfactant, respectively. Additionally, mucoadhesive polysaccharides (sodium alginate and guar gum) were added further to enhance the bioavailability of insulin in these systems. The objective was to increase the bioavailability and bioactivity of an insulin-modified phosphatidylcholine complex by incorporating mucoadhesives into the SNEDDS. After polymer inclusion, the resulting nanoemulsions exhibited droplet diameters ranging from 57 to 83 nm. Cytotoxicity and apparent permeability tests were conducted on Caco-2 and NIH 3 T3 cell lines, revealing that toxicity was related to the concentrations of insulin and surfactant in the nanosystems—formulations containing guar gum as a mucoadhesive showed better tolerance to cell death in the Caco-2 line. In a murine diabetes model, the SNEDDS were observed to reduce glucose levels by up to 61.63 %, with a relative bioavailability of 2.25 % compared to subcutaneously administered insulin. These results suggest that SNEDDS incorporating mucoadhesives could represent a promising strategy for improving oral insulin delivery.
{"title":"Evaluation of a mucoadhesive auto-nanoemulsifying drug delivery system (SNEDDS) for oral insulin administration","authors":"M.O.F. Muñoz-Correa , Diego A. Bravo-Alfaro , L.G. Mendoza-Sánchez , Gabriel Luna-Barcenas , Hugo S. Garcia , Rebeca Garcia-Varela","doi":"10.1016/j.ejpb.2024.114567","DOIUrl":"10.1016/j.ejpb.2024.114567","url":null,"abstract":"<div><div>This study investigated the potential of self-nanoemulsifying drug delivery systems (SNEDDS) to optimize the oral bioavailability of insulin. Insulin complexes with phospholipids and enzymatically-modified phospholipids were developed and incorporated into the SNEDDS using Lauroglycol FCC as the oily phase and Cremophor EL and Labrafil M1944CS as the surfactant and co-surfactant, respectively. Additionally, mucoadhesive polysaccharides (sodium alginate and guar gum) were added further to enhance the bioavailability of insulin in these systems. The objective was to increase the bioavailability and bioactivity of an insulin-modified phosphatidylcholine complex by incorporating mucoadhesives into the SNEDDS. After polymer inclusion, the resulting nanoemulsions exhibited droplet diameters ranging from 57 to 83 nm. Cytotoxicity and apparent permeability tests were conducted on Caco-2 and NIH 3 T3 cell lines, revealing that toxicity was related to the concentrations of insulin and surfactant in the nanosystems—formulations containing guar gum as a mucoadhesive showed better tolerance to cell death in the Caco-2 line. In a murine diabetes model, the SNEDDS were observed to reduce glucose levels by up to 61.63 %, with a relative bioavailability of 2.25 % compared to subcutaneously administered insulin. These results suggest that SNEDDS incorporating mucoadhesives could represent a promising strategy for improving oral insulin delivery.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114567"},"PeriodicalIF":4.4,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497547","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 : 2024-10-24DOI: 10.1016/j.ejpb.2024.114538
João Azevedo-Silva , Manuela Amorim , Diana Tavares-Valente , Pedro Sousa , Raodoh Mohamath , Emily A. Voigt , Jeffrey A. Guderian , Robert Kinsey , Sofia Viana , Flávio Reis , Manuela E. Pintado , Christopher J. Paddon , Christopher B. Fox , João C. Fernandes
Vaccine adjuvants are important for enhancing vaccine efficacy, and although aluminium salts (Alum) are the most used, their limited ability to induce specific immune responses has spurred the search for new adjuvants. However, many adjuvants fail during product development due to manufacturability, supply, stability, or safety concerns. This work hypothesizes that protein-free yeast glucans can be used as vaccine adjuvants due to their known immunostimulatory activity and high abundancy. Thus, high molecular weight glucans with over 99% purity, comprising 64–70% β-glucans and 29–35% α-glucans, were extracted from a wild-type yeast and an engineered yeast to produce a steviol glycoside. These glucans underwent carboxymethylation to enhance solubility. Both water-dispersible and particulate glucans were evaluated as adjuvants, either alone or in combination with Alum or squalene stable emulsion (SE), for a SARS-CoV-2 vaccine. The study demonstrated that glucans triggered a robust immune response and enhanced the effects of Alum and SE when used in combination, both in vitro and in vivo. Water-dispersible glucans combined with Alum, and particulate glucans combined with SE, increased the production of specific antibodies against SARS-CoV-2 spike protein and enhanced serum neutralization titers against SARS-CoV-2 pseudovirus. Furthermore, the results indicated that larger molecular weight glucans from engineered yeast exhibited stronger immunogenic activity in comparison to wild-type yeast glucans. In conclusion, appropriately formulated glucans have the potential to be scalable, low-cost vaccine adjuvants, potentially overcoming the limitations of current adjuvants.
{"title":"Exploring yeast glucans for vaccine enhancement: Sustainable strategies for overcoming adjuvant challenges in a SARS-CoV-2 model","authors":"João Azevedo-Silva , Manuela Amorim , Diana Tavares-Valente , Pedro Sousa , Raodoh Mohamath , Emily A. Voigt , Jeffrey A. Guderian , Robert Kinsey , Sofia Viana , Flávio Reis , Manuela E. Pintado , Christopher J. Paddon , Christopher B. Fox , João C. Fernandes","doi":"10.1016/j.ejpb.2024.114538","DOIUrl":"10.1016/j.ejpb.2024.114538","url":null,"abstract":"<div><div>Vaccine adjuvants are important for enhancing vaccine efficacy, and although aluminium salts (Alum) are the most used, their limited ability to induce specific immune responses has spurred the search for new adjuvants. However, many adjuvants fail during product development due to manufacturability, supply, stability, or safety concerns. This work hypothesizes that protein-free yeast glucans can be used as vaccine adjuvants due to their known immunostimulatory activity and high abundancy. Thus, high molecular weight glucans with over 99% purity, comprising 64–70% β-glucans and 29–35% α-glucans, were extracted from a wild-type yeast and an engineered yeast to produce a steviol glycoside. These glucans underwent carboxymethylation to enhance solubility. Both water-dispersible and particulate glucans were evaluated as adjuvants, either alone or in combination with Alum or squalene stable emulsion (SE), for a SARS-CoV-2 vaccine. The study demonstrated that glucans triggered a robust immune response and enhanced the effects of Alum and SE when used in combination, both <em>in vitro</em> and <em>in vivo</em>. Water-dispersible glucans combined with Alum, and particulate glucans combined with SE, increased the production of specific antibodies against SARS-CoV-2 spike protein and enhanced serum neutralization titers against SARS-CoV-2 pseudovirus. Furthermore, the results indicated that larger molecular weight glucans from engineered yeast exhibited stronger immunogenic activity in comparison to wild-type yeast glucans. In conclusion, appropriately formulated glucans have the potential to be scalable, low-cost vaccine adjuvants, potentially overcoming the limitations of current adjuvants.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114538"},"PeriodicalIF":4.4,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497548","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 : 2024-10-23DOI: 10.1016/j.ejpb.2024.114565
Xueyan Zhang , Jicong Chen , Yaxin Cui , Yiying Cui , Guodong Yan , Haifeng Tang , Yuhong Man , Jie Yang , Ye Bi , Lesheng Teng
Osteoporosis is a disease with an increased incidence of fractures due to decreased bone mass and destruction of the microstructure of bone tissue. Salmon calcitonin (sCT), as a peptide, possesses the ability to inhibit osteoclast activity and thus regulate bone metabolism in clinical. However, short half-life and unstable physicochemical properties leading to rapid degradation of sCT have severely limited its clinical application. In this study, a size-switchable microsphere was developed to solve the problem of frequent administration and poor stability of sCT. sCT was encapsulated into Egg PC to form anhydrous reverse micelles (ARM) and then ARM was encapsulated into microspheres (MS@ARM). The degradable composite microspheres were utilized to provide a drug reservoir for sustained release of ARM encapsulated with sCT to reduce the frequency of drug administration, while the released ARM encapsulated with sCT entered the blood circulation to further protect sCT. In vitro release experiments demonstrated that the microspheres could sustain the release of sCT for at least 16 days. The microspheres MS@ARM showed the advanced therapeutic effect on the mouse model of glucocorticoid-induced osteoporosis (GIOP) at a low dosing frequency. The size-switchable microsphere is expected to be a new strategy for delivering sCT for osteoporosis treatment.
骨质疏松症是一种由于骨量减少和骨组织微结构破坏而导致骨折发生率增加的疾病。鲑鱼降钙素（sCT）作为一种多肽，具有抑制破骨细胞活性的能力，从而在临床上调节骨代谢。然而，sCT 的半衰期短、理化性质不稳定导致其快速降解，严重限制了其临床应用。本研究开发了一种尺寸可调的微球，以解决 sCT 频繁给药和稳定性差的问题。将 sCT 包囊到蛋 PC 中形成无水反向胶束（ARM），然后将 ARM 包囊到微球（MS@ARM）中。这种可降解的复合微球可作为药物储库，用于持续释放包裹有sCT的ARM，以减少给药次数，同时释放的包裹有sCT的ARM进入血液循环，进一步保护sCT。体外释放实验表明，微球可持续释放 sCT 至少 16 天。微球MS@ARM在糖皮质激素诱导的骨质疏松症（GIOP）小鼠模型上显示出了低剂量的先进治疗效果。这种尺寸可调的微球有望成为一种将 sCT 用于骨质疏松症治疗的新策略。
{"title":"A size-switchable microsphere loaded with salmon calcitonin as two-weekly dosing for osteoporosis therapy","authors":"Xueyan Zhang , Jicong Chen , Yaxin Cui , Yiying Cui , Guodong Yan , Haifeng Tang , Yuhong Man , Jie Yang , Ye Bi , Lesheng Teng","doi":"10.1016/j.ejpb.2024.114565","DOIUrl":"10.1016/j.ejpb.2024.114565","url":null,"abstract":"<div><div>Osteoporosis is a disease with an increased incidence of fractures due to decreased bone mass and destruction of the microstructure of bone tissue. Salmon calcitonin (sCT), as a peptide, possesses the ability to inhibit osteoclast activity and thus regulate bone metabolism in clinical. However, short half-life and unstable physicochemical properties leading to rapid degradation of sCT have severely limited its clinical application. In this study, a size-switchable microsphere was developed to solve the problem of frequent administration and poor stability of sCT. sCT was encapsulated into Egg PC to form anhydrous reverse micelles (ARM) and then ARM was encapsulated into microspheres (MS@ARM). The degradable composite microspheres were utilized to provide a drug reservoir for sustained release of ARM encapsulated with sCT to reduce the frequency of drug administration, while the released ARM encapsulated with sCT entered the blood circulation to further protect sCT. <em>In vitro</em> release experiments demonstrated that the microspheres could sustain the release of sCT for at least 16 days. The microspheres MS@ARM showed the advanced therapeutic effect on the mouse model of glucocorticoid-induced osteoporosis (GIOP) at a low dosing frequency. The size-switchable microsphere is expected to be a new strategy for delivering sCT for osteoporosis treatment.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114565"},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497536","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 : 2024-10-22DOI: 10.1016/j.ejpb.2024.114560
Wenjing Yang , Ke Yan , Yecheng Feng , Xubo Zhao
Improving the efficiency of drug delivery is one of the most important goals in the field of drug delivery. One strategy for drug delivery efficiency is to make the drug delivery system capable of charge reversal. In this study, we used hyaluronic acid (HA) as the skeleton to anchor dimethylmaleic anhydride-modified polylysine (PLL-DMMA) and N-(3-Aminopropyl)-imidazole (IMI) to construct a pH-sensitive (IMI/Zn2+)-HA-PLL-DMMA system via Zn coordination. The (IMI/Zn2+)-HA-PLL-DMMA system can detach DMMA moieties and expose PLL with a positive charge in the acidic tumor microenvironment (TME), which enhances cellular uptake in cancer cells through charge reversal. Once the drug-loaded (IMI/Zn2+)-HA-PLL-DMMA enters cancer cells, it specifically responds and disassembles in the acidic TME, resulting in drug release and inhibition of cancer cell viability. The (IMI/Zn2+)-HA-PLL-DMMA system is designed to regulate drug release behavior with Zn2+ and IMI groups as control units. The HA-based system shows synergistic selective drug delivery in suppressing tumor cells and has potential in cancer therapy.
{"title":"Charge reversible hyaluronic acid-based drug delivery system with pH-responsive dissociation for enhanced drug delivery","authors":"Wenjing Yang , Ke Yan , Yecheng Feng , Xubo Zhao","doi":"10.1016/j.ejpb.2024.114560","DOIUrl":"10.1016/j.ejpb.2024.114560","url":null,"abstract":"<div><div>Improving the efficiency of drug delivery is one of the most important goals in the field of drug delivery. One strategy for drug delivery efficiency is to make the drug delivery system capable of charge reversal. In this study, we used hyaluronic acid (HA) as the skeleton to anchor dimethylmaleic anhydride-modified polylysine (PLL-DMMA) and N-(3-Aminopropyl)-imidazole (IMI) to construct a pH-sensitive (IMI/Zn<sup>2+</sup>)-HA-PLL-DMMA system via Zn coordination. The (IMI/Zn<sup>2+</sup>)-HA-PLL-DMMA system can detach DMMA moieties and expose PLL with a positive charge in the acidic tumor microenvironment (TME), which enhances cellular uptake in cancer cells through charge reversal. Once the drug-loaded (IMI/Zn<sup>2+</sup>)-HA-PLL-DMMA enters cancer cells, it specifically responds and disassembles in the acidic TME, resulting in drug release and inhibition of cancer cell viability. The (IMI/Zn<sup>2+</sup>)-HA-PLL-DMMA system is designed to regulate drug release behavior with Zn<sup>2+</sup> and IMI groups as control units. The HA-based system shows synergistic selective drug delivery in suppressing tumor cells and has potential in cancer therapy.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114560"},"PeriodicalIF":4.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497537","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}
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