Pub Date : 2024-08-01Epub Date: 2024-07-13DOI: 10.1007/s11095-024-03729-8
M J Giménez, L Aguilar, L Alou, D Sevillano
{"title":"Comment on the article: In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model.","authors":"M J Giménez, L Aguilar, L Alou, D Sevillano","doi":"10.1007/s11095-024-03729-8","DOIUrl":"10.1007/s11095-024-03729-8","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601256","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}
Pub Date : 2024-08-01Epub Date: 2024-08-07DOI: 10.1007/s11095-024-03740-z
Mohammad A M Momin, Dale Farkas, Michael Hindle, Felicia Hall, Robert M DiBlasi, Worth Longest
Purpose: Improving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments.
Methods: A new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals.
Results: The best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7-17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min.
Conclusions: A high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS.
{"title":"Development of a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) - Part I: In Vitro Testing and Characterization.","authors":"Mohammad A M Momin, Dale Farkas, Michael Hindle, Felicia Hall, Robert M DiBlasi, Worth Longest","doi":"10.1007/s11095-024-03740-z","DOIUrl":"10.1007/s11095-024-03740-z","url":null,"abstract":"<p><strong>Purpose: </strong>Improving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments.</p><p><strong>Methods: </strong>A new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals.</p><p><strong>Results: </strong>The best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7-17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min.</p><p><strong>Conclusions: </strong>A high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902602","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}
Purpose: Predicting the quantitative fraction of glucuronidation (fgluc) by individual UDP-glucuronosyltransferase enzymes (UGTs) is challenging due to the lack of selective inhibitors and inconsistent activity of recombinant UGT systems (rUGTs). Our study compares the relative expression versus activity factors (REF versus RAF) to predict fgluc based on rUGT data to human liver and intestinal microsomes (HLM and HIM).
Methods: REF scalars were derived from a previous in-house proteomics study for eleven UGT enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17), whereas RAF was calculated by measuring activities in rUGTs to microsomes of selective UGT probe substrates. Protein-normalized activity factor (pnAF) values were generated after correcting activity of individual UGTs to their corresponding protein abundance. The utility of REF and RAF in predicting fgluc was assessed for three UGT substrates-diclofenac, vorinostat, and raltegravir.
Results: The REF values ranged from 0.02 to 1.75, RAF based on activity obtained in rUGTs to HLM/HIM were from 0.1 to 274. pnAF values were ~ 5 to 80-fold, except for UGT2B4 and UGT2B15, where pnAF was ~ 180 and > 1000, respectively. The results revealed confounding effect of differential specific activities (per pmol) of rUGTs in fgluc prediction.
Conclusion: The data suggest that the activity of UGT enzymes was significantly lower when compared to their activity in microsomes at the same absolute protein amount (pmol). Collectively, results of this study demonstrate poor and variable specific activity of different rUGTs (per pmol protein), as determined by pnAF values, which should be considered in fgluc scaling.
{"title":"Comparison of Relative Activity versus Relative Expression Factors (RAF versus REF) in Predicting Glucuronidation Mediated Drug Clearance Using Recombinant UGTs.","authors":"Sandhya Subash, Deepak Ahire, Mitesh Patel, Sahil Shaikh, Dilip Kumar Singh, Sujal Deshmukh, Bhagwat Prasad","doi":"10.1007/s11095-024-03750-x","DOIUrl":"10.1007/s11095-024-03750-x","url":null,"abstract":"<p><strong>Purpose: </strong>Predicting the quantitative fraction of glucuronidation (f<sub>gluc</sub>) by individual UDP-glucuronosyltransferase enzymes (UGTs) is challenging due to the lack of selective inhibitors and inconsistent activity of recombinant UGT systems (rUGTs). Our study compares the relative expression versus activity factors (REF versus RAF) to predict f<sub>gluc</sub> based on rUGT data to human liver and intestinal microsomes (HLM and HIM).</p><p><strong>Methods: </strong>REF scalars were derived from a previous in-house proteomics study for eleven UGT enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17), whereas RAF was calculated by measuring activities in rUGTs to microsomes of selective UGT probe substrates. Protein-normalized activity factor (pnAF) values were generated after correcting activity of individual UGTs to their corresponding protein abundance. The utility of REF and RAF in predicting f<sub>gluc</sub> was assessed for three UGT substrates-diclofenac, vorinostat, and raltegravir.</p><p><strong>Results: </strong>The REF values ranged from 0.02 to 1.75, RAF based on activity obtained in rUGTs to HLM/HIM were from 0.1 to 274. pnAF values were ~ 5 to 80-fold, except for UGT2B4 and UGT2B15, where pnAF was ~ 180 and > 1000, respectively. The results revealed confounding effect of differential specific activities (per pmol) of rUGTs in f<sub>gluc</sub> prediction.</p><p><strong>Conclusion: </strong>The data suggest that the activity of UGT enzymes was significantly lower when compared to their activity in microsomes at the same absolute protein amount (pmol). Collectively, results of this study demonstrate poor and variable specific activity of different rUGTs (per pmol protein), as determined by pnAF values, which should be considered in f<sub>gluc</sub> scaling.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898015","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}
Pub Date : 2024-08-01Epub Date: 2024-07-29DOI: 10.1007/s11095-024-03751-w
Shuai Bai Palmkron, Björn Bergenståhl, Stephen Hall, Sebastian Håkansson, Marie Wahlgren, Emanuel Larsson, Anna Millqvist Fureby
Objective: This paper investigates the critical role of material thickness in freeze-dried pellets for enhancing the storage stability of encapsulated bacteria. Freeze dried material of varying thicknesses obtained from different annealing durations is quantified using Scanning Electron Microscopy (SEM) and X-ray microtomography (μCT), the material thickness is then correlated to the storage stability of the encapsulated cells.
Methods: A formulation comprising of sucrose, maltodextrin, and probiotic cells is quenched in liquid nitrogen to form pellets. The pellets undergo different durations of annealing before undergoing freeze-drying. The material thickness is quantified using SEM and μCT. Storage stability in both oxygen-rich and oxygen-poor environments is evaluated by measuring CFU counts and correlated with the pellet structure.
Results: The varying annealing protocols produce a range of material thicknesses, with more extensive annealing resulting in thicker materials. Storage stability exhibits a positive correlation with material thickness, indicating improved stability with thicker materials. Non-annealed pellets exhibit structural irregularities and inconsistent storage stability, highlighting the impracticality of avoiding annealing in the freeze-drying process.
Conclusions: Extensive annealing not only enhances the storage stability of probiotic products but also provides greater control over the freeze-drying process, ensuring homogeneous and reproducible products. This study underscores the importance of material thickness in freeze-dried pellets for optimizing storage stability for probiotic formulations, and emphasize the necessity of annealing as a critical step in freeze-drying quenched pellets to achieve desired structural and stability outcomes.
目的:本文研究了冷冻干燥颗粒中材料厚度对提高封装细菌储存稳定性的关键作用。使用扫描电子显微镜(SEM)和 X 射线显微层析成像(μCT)对不同退火时间获得的不同厚度的冻干材料进行量化,然后将材料厚度与封装细胞的储存稳定性联系起来:方法:由蔗糖、麦芽糊精和益生菌细胞组成的配方在液氮中淬火形成颗粒。在进行冷冻干燥之前,颗粒要经过不同时间的退火处理。使用 SEM 和 μCT 对材料厚度进行量化。在富氧和缺氧环境中的储存稳定性通过测量 CFU 计数进行评估,并与颗粒结构相关联:结果:不同的退火方案会产生不同厚度的材料,退火范围越广,材料越厚。储存稳定性与材料厚度呈正相关,表明材料越厚稳定性越好。未经退火的颗粒结构不规则,储存稳定性也不稳定,这说明在冷冻干燥过程中避免退火是不切实际的:大面积退火不仅能提高益生菌产品的储存稳定性,还能更好地控制冻干过程,确保产品的均匀性和可重复性。这项研究强调了冷冻干燥颗粒中材料厚度对优化益生菌配方储存稳定性的重要性,并强调了退火作为冷冻干燥淬火颗粒的关键步骤对实现理想的结构和稳定性结果的必要性。
{"title":"The Impact of Annealing Methods on the Encapsulating Structure and Storage-Stability of Freeze-Dried Pellets of Probiotic Bacteria.","authors":"Shuai Bai Palmkron, Björn Bergenståhl, Stephen Hall, Sebastian Håkansson, Marie Wahlgren, Emanuel Larsson, Anna Millqvist Fureby","doi":"10.1007/s11095-024-03751-w","DOIUrl":"10.1007/s11095-024-03751-w","url":null,"abstract":"<p><strong>Objective: </strong>This paper investigates the critical role of material thickness in freeze-dried pellets for enhancing the storage stability of encapsulated bacteria. Freeze dried material of varying thicknesses obtained from different annealing durations is quantified using Scanning Electron Microscopy (SEM) and X-ray microtomography (μCT), the material thickness is then correlated to the storage stability of the encapsulated cells.</p><p><strong>Methods: </strong>A formulation comprising of sucrose, maltodextrin, and probiotic cells is quenched in liquid nitrogen to form pellets. The pellets undergo different durations of annealing before undergoing freeze-drying. The material thickness is quantified using SEM and μCT. Storage stability in both oxygen-rich and oxygen-poor environments is evaluated by measuring CFU counts and correlated with the pellet structure.</p><p><strong>Results: </strong>The varying annealing protocols produce a range of material thicknesses, with more extensive annealing resulting in thicker materials. Storage stability exhibits a positive correlation with material thickness, indicating improved stability with thicker materials. Non-annealed pellets exhibit structural irregularities and inconsistent storage stability, highlighting the impracticality of avoiding annealing in the freeze-drying process.</p><p><strong>Conclusions: </strong>Extensive annealing not only enhances the storage stability of probiotic products but also provides greater control over the freeze-drying process, ensuring homogeneous and reproducible products. This study underscores the importance of material thickness in freeze-dried pellets for optimizing storage stability for probiotic formulations, and emphasize the necessity of annealing as a critical step in freeze-drying quenched pellets to achieve desired structural and stability outcomes.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793052","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}
Pub Date : 2024-08-01Epub Date: 2024-07-24DOI: 10.1007/s11095-024-03741-y
Mohhammad Ramzan, Afzal Hussain, Tasneem Khan, Mohd Usman Mohd Siddique, Musarrat Husain Warsi
Objective: Tolterodine tartrate (TOTA) is a first-line therapy to treat overactive urinary bladder (OAB). Oral delivery causes high hepatic clearance, xerostomia, headache, constipation, and blurred vision. We addressed Hansen solubility parameter (HSP) and Design Expert oriented optimized cationic elastic liposomes for transdermal application.
Methods: The experimental solubility was conducted in HSPiP predicted excipients to tailor formulations using surfactants, stearylamine, ethanol, and phosphatidylcholine (PC). These were evaluated for formulation characteristics. The optimized OTEL1 and OTEL1-G (gel) were compared against the drug solution (DS) and liposomes. In vitro and ex vivo studies were accomplished to investigate the insights into the mechanistic understanding of TOTA release and permeation ability. Finally, confocal laser scanning microscopy (CLSM) supported ex vivo results.
Results: HSP values of TOTA were closely related to tween-80, stearylamine, and human's skin. The size (153 nm), %EE (87.6%), and PDI (0.25) values of OTEL1 were in good agreement to the predicted values (161 nm, 80.4%, and 0.31) with high desirability (0.963). Spherical and smooth OTEL1 (including OTEL1-G and liposomes) vesicles followed non-Fickian drug release as compared to DS (Fickian) as evidence with n > 0.5 (Korsmeyer and Peppas coefficient). OTEL1 (containing lipid and surfactant as 90 mg and 13.8 mg, respectively) exhibited 2.6 and 1.8-folds higher permeation flux than DS and liposomes, respectively. Biocompatible cationic OTEL1 was safe and non-hemolytic.
Conclusions: OTEL1 was promised as a lead vesicular approach and an alternative to conventional oral therapy to treat OAB in children and advanced age patients.
{"title":"Tolterodine Tartrate Loaded Cationic Elastic Liposomes for Transdermal Delivery: In Vitro, Ex Vivo, and In Vivo Evaluations.","authors":"Mohhammad Ramzan, Afzal Hussain, Tasneem Khan, Mohd Usman Mohd Siddique, Musarrat Husain Warsi","doi":"10.1007/s11095-024-03741-y","DOIUrl":"10.1007/s11095-024-03741-y","url":null,"abstract":"<p><strong>Objective: </strong>Tolterodine tartrate (TOTA) is a first-line therapy to treat overactive urinary bladder (OAB). Oral delivery causes high hepatic clearance, xerostomia, headache, constipation, and blurred vision. We addressed Hansen solubility parameter (HSP) and Design Expert oriented optimized cationic elastic liposomes for transdermal application.</p><p><strong>Methods: </strong>The experimental solubility was conducted in HSPiP predicted excipients to tailor formulations using surfactants, stearylamine, ethanol, and phosphatidylcholine (PC). These were evaluated for formulation characteristics. The optimized OTEL1 and OTEL1-G (gel) were compared against the drug solution (DS) and liposomes. In vitro and ex vivo studies were accomplished to investigate the insights into the mechanistic understanding of TOTA release and permeation ability. Finally, confocal laser scanning microscopy (CLSM) supported ex vivo results.</p><p><strong>Results: </strong>HSP values of TOTA were closely related to tween-80, stearylamine, and human's skin. The size (153 nm), %EE (87.6%), and PDI (0.25) values of OTEL1 were in good agreement to the predicted values (161 nm, 80.4%, and 0.31) with high desirability (0.963). Spherical and smooth OTEL1 (including OTEL1-G and liposomes) vesicles followed non-Fickian drug release as compared to DS (Fickian) as evidence with n > 0.5 (Korsmeyer and Peppas coefficient). OTEL1 (containing lipid and surfactant as 90 mg and 13.8 mg, respectively) exhibited 2.6 and 1.8-folds higher permeation flux than DS and liposomes, respectively. Biocompatible cationic OTEL1 was safe and non-hemolytic.</p><p><strong>Conclusions: </strong>OTEL1 was promised as a lead vesicular approach and an alternative to conventional oral therapy to treat OAB in children and advanced age patients.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760272","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}
Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare.
细胞外囊泡(EVs)是体内输送功能分子的内在系统,在各种生理现象和疾病中发挥着重要作用。无论是原生还是工程EVs,都是目前广泛研究的对象,因为它们具有靶向能力、生物相容性、低免疫原性和低致突变性等显著特性,是一种很有前景的治疗和给药系统。然而,由于多种限制,它们的临床应用仍然遥遥无期。在此背景下,日本药品和医疗器械管理局(PMDA)科学委员会进行了一次全面评估,以确定目前与基于 EV 的治疗产品的质量和安全性相关的问题。此外,我们还介绍了几个在 EV 生产中采用的最先进方法的实例,以及关键流程的指南,如 EV 治疗药物的生产、纯化、表征、质量评估和控制、安全评估以及临床开发和评估。这些努力旨在促进 EVs 的临床应用,并为其在医疗保健领域的变革性影响铺平道路。
{"title":"Quality and Safety Considerations for Therapeutic Products Based on Extracellular Vesicles.","authors":"Yoshinobu Takakura, Rikinari Hanayama, Kazunari Akiyoshi, Shiroh Futaki, Kyoko Hida, Takanori Ichiki, Akiko Ishii-Watabe, Masahiko Kuroda, Kazushige Maki, Yasuo Miura, Yoshiaki Okada, Naohiro Seo, Toshihide Takeuchi, Teruhide Yamaguchi, Yusuke Yoshioka","doi":"10.1007/s11095-024-03757-4","DOIUrl":"10.1007/s11095-024-03757-4","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902603","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}
Pub Date : 2024-08-01Epub Date: 2024-07-29DOI: 10.1007/s11095-024-03748-5
Wenxi Song, Na Wang, Ao Li, Xiongtao Ji, Xin Huang, Ting Wang, Hongxun Hao
Purpose: The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects.
Methods: In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques.
Results: The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.
目的:攀登唑(CLB)是一种广谱咪唑类抗真菌药物,其主要问题是水溶性低。为了提高其水溶性和抗真菌活性,本研究合成了三种新的多组分晶体,并对其分子间相互作用进行了系统研究。这项工作有助于优化 CLB 产品配方,拓展其应用前景:本研究成功合成了CLB-丙二酸(CLB-MA)盐、CLB-丁二酸(CLB-SA)共晶体和CLB-己二酸(CLB-AA)共晶体三种新型多组分晶体。并通过单晶 X 射线衍射(SCXRD)、热重分析(TGA)、差示扫描量热法(DSC)、动态水蒸气吸附(DVS)和粉末溶解试验等方法对三种多组分晶体的晶体结构、热力学性质、溶解性、溶出性、吸湿性和抗真菌活性进行了全面表征。采用希尔斯菲尔德表面(HS)、分子表面静电位(MEP)、相互作用区域指示(IRI)和原子与分子(AIM)技术研究了多组分晶体中的分子相互作用和分子堆积:结果表明,三种多组分晶体具有良好的防潮稳定性,其水溶性是纯 CLB 的 6-22 倍。同时,最低抑菌浓度(MIC)的测定证明,共晶体/盐的抗真菌活性强于攀唑。晶体结构的量子化学计算将多组分晶体中存在的相互作用可视化和量化,并探索了多组分晶体不同性能的微观机制。
{"title":"Multi-component Crystal Strategy for Improving Water Solubility and Antifungal Activity of Climbazole.","authors":"Wenxi Song, Na Wang, Ao Li, Xiongtao Ji, Xin Huang, Ting Wang, Hongxun Hao","doi":"10.1007/s11095-024-03748-5","DOIUrl":"10.1007/s11095-024-03748-5","url":null,"abstract":"<p><strong>Purpose: </strong>The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects.</p><p><strong>Methods: </strong>In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques.</p><p><strong>Results: </strong>The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793051","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}
Purpose: We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo.
Methods: Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point.
Results: The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma.
Conclusions: Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.
目的:我们研究了短期输注异丙酚是否会影响体内血脑屏障(BBB)的被动通透性:方法:给小鼠腹腔注射氯胺酮/恶嗪进行麻醉,然后通过尾静脉导管持续静脉注射丙泊酚脂质乳剂。对照组接受氯胺酮/恶嗪麻醉并输注 Intralipid,或仅接受氯胺酮/恶嗪麻醉。输注开始 15 分钟后,静脉注射[13C12]蔗糖作为渗透性标记物。蔗糖的脑吸收清除率 Kin 是根据 30 分钟时的脑浓度和血浆浓度时间曲线下的面积计算得出的。我们还测量了终点时间点丙泊酚的血浆和大脑浓度:结果:丙泊酚输注组和氯胺酮/恶嗪组的 Kin 值分别比 Intralipid 输注组和氯胺酮/恶嗪组高 1.55 倍和 1.87 倍,而对照组没有明显差异。各组脑内紧密连接蛋白的表达水平均无差异。输注结束时的丙泊酚血浆浓度(10.7 µM)符合人体血药浓度的临床相关范围,而大脑中的浓度是血浆浓度的2.5倍:结论:临床血浆浓度的丙泊酚会急性增加生物BB的通透性,这将我们之前对挥发性麻醉剂的研究结果扩展到了亲脂性注射剂。这促使我们进一步探索,从而有可能改进临床实践并确保安全,尤其是在延长异丙酚输注计划期间。
{"title":"The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.","authors":"Ehsan Nozohouri, Yeseul Ahn, Sumaih Zoubi, Dhavalkumar Patel, Sabrina Rahman Archie, Khondker Ayesha Akter, Muhammad Bilal Siddique, Juyang Huang, Thomas J Abbruscato, Ulrich Bickel","doi":"10.1007/s11095-024-03735-w","DOIUrl":"10.1007/s11095-024-03735-w","url":null,"abstract":"<p><strong>Purpose: </strong>We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABA<sub>A</sub> receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo.</p><p><strong>Methods: </strong>Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [<sup>13</sup>C<sub>12</sub>]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, K<sub>in</sub>, of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point.</p><p><strong>Results: </strong>The K<sub>in</sub> value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma.</p><p><strong>Conclusions: </strong>Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752375","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}
Pub Date : 2024-08-01Epub Date: 2024-07-24DOI: 10.1007/s11095-024-03749-4
Yu Yuan, Tony Wang, Jordan Sims, Kim Le, Cenk Undey, Erdal Oruklu
Purpose: In biotechnology, microscopic cell imaging is often used to identify and analyze cell morphology and cell state for a variety of applications. For example, microscopy can be used to detect the presence of cytopathic effects (CPE) in cell culture samples to determine virus contamination. Another application of microscopy is to verify clonality during cell line development. Conventionally, inspection of these microscopy images is performed manually by human analysts. This is both tedious and time consuming. In this paper, we propose using supervised deep learning algorithms to automate the cell detection processes mentioned above.
Methods: The proposed algorithms utilize image processing techniques and convolutional neural networks (CNN) to detect the presence of CPE and to verify the clonality in cell line development.
Results: We train and test the algorithms on image data which have been collected and labeled by domain experts. Our experiments have shown promising results in terms of both accuracy and speed.
Conclusion: Deep learning algorithms achieve high accuracy (more than 95%) on both CPE detection and clonal selection applications, resulting in a highly efficient and cost-effective automation process.
{"title":"Cytopathic Effect Detection and Clonal Selection using Deep Learning.","authors":"Yu Yuan, Tony Wang, Jordan Sims, Kim Le, Cenk Undey, Erdal Oruklu","doi":"10.1007/s11095-024-03749-4","DOIUrl":"10.1007/s11095-024-03749-4","url":null,"abstract":"<p><strong>Purpose: </strong>In biotechnology, microscopic cell imaging is often used to identify and analyze cell morphology and cell state for a variety of applications. For example, microscopy can be used to detect the presence of cytopathic effects (CPE) in cell culture samples to determine virus contamination. Another application of microscopy is to verify clonality during cell line development. Conventionally, inspection of these microscopy images is performed manually by human analysts. This is both tedious and time consuming. In this paper, we propose using supervised deep learning algorithms to automate the cell detection processes mentioned above.</p><p><strong>Methods: </strong>The proposed algorithms utilize image processing techniques and convolutional neural networks (CNN) to detect the presence of CPE and to verify the clonality in cell line development.</p><p><strong>Results: </strong>We train and test the algorithms on image data which have been collected and labeled by domain experts. Our experiments have shown promising results in terms of both accuracy and speed.</p><p><strong>Conclusion: </strong>Deep learning algorithms achieve high accuracy (more than 95%) on both CPE detection and clonal selection applications, resulting in a highly efficient and cost-effective automation process.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760270","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}
Pub Date : 2024-08-01DOI: 10.1007/s11095-024-03753-8
M J Giménez, L Aguilar, L Alou, D Sevillano
{"title":"Correction: Comment on the article: In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model.","authors":"M J Giménez, L Aguilar, L Alou, D Sevillano","doi":"10.1007/s11095-024-03753-8","DOIUrl":"10.1007/s11095-024-03753-8","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898016","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}