首页 > 最新文献

AAPS Journal最新文献

英文 中文
Therapeutic Fusion Proteins. 治疗性融合蛋白。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-30 DOI: 10.1208/s12248-023-00873-8
Morgan C Marsh, Shawn C Owen

Therapeutic fusion proteins are a class of hybrid constructs that combine distinct biomolecules into a single platform with the additive effects of the components. The ability to fuse two unrelated proteins provides a means to localize mechanisms to better treat a range of diseases. Fusion proteins can be designed to impart diverse functions, including increasing half-life, providing targeting, and enabling sustained signaling. Of these, half-life extenders, which are fused to a therapeutic protein to increase exposure, are the most established group of fusion proteins, with many clinical successes. Rapid advances in antibody and antibody-derivative technology have enabled the fusion of targeting domains with therapeutic proteins. An emerging group of therapeutic fusion proteins has two separate active functions. Although most research for therapeutic fusion proteins focuses on cancer, prior successes provide a foundation for studies into other diseases as well. The exponential emergence of biopharmaceuticals gives precedence for increased research into therapeutic fusion proteins for a multitude of diseases.

治疗性融合蛋白是一类混合结构,它将不同的生物分子结合到一个具有组分加性效应的单一平台中。融合两种不相关蛋白质的能力提供了一种定位机制以更好地治疗一系列疾病的手段。融合蛋白可以被设计成具有多种功能,包括延长半衰期、提供靶向性和实现持续的信号传导。其中,与治疗蛋白融合以增加暴露的半衰期延长剂是最成熟的融合蛋白组,在临床上取得了许多成功。抗体和抗体衍生物技术的快速发展使得靶向结构域与治疗蛋白的融合成为可能。一组新兴的治疗性融合蛋白具有两种不同的活性功能。虽然大多数治疗性融合蛋白的研究都集中在癌症上,但先前的成功也为其他疾病的研究提供了基础。生物制药的指数级出现,优先增加了对多种疾病的治疗性融合蛋白的研究。
{"title":"Therapeutic Fusion Proteins.","authors":"Morgan C Marsh, Shawn C Owen","doi":"10.1208/s12248-023-00873-8","DOIUrl":"10.1208/s12248-023-00873-8","url":null,"abstract":"<p><p>Therapeutic fusion proteins are a class of hybrid constructs that combine distinct biomolecules into a single platform with the additive effects of the components. The ability to fuse two unrelated proteins provides a means to localize mechanisms to better treat a range of diseases. Fusion proteins can be designed to impart diverse functions, including increasing half-life, providing targeting, and enabling sustained signaling. Of these, half-life extenders, which are fused to a therapeutic protein to increase exposure, are the most established group of fusion proteins, with many clinical successes. Rapid advances in antibody and antibody-derivative technology have enabled the fusion of targeting domains with therapeutic proteins. An emerging group of therapeutic fusion proteins has two separate active functions. Although most research for therapeutic fusion proteins focuses on cancer, prior successes provide a foundation for studies into other diseases as well. The exponential emergence of biopharmaceuticals gives precedence for increased research into therapeutic fusion proteins for a multitude of diseases.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"3"},"PeriodicalIF":4.5,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138464118","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}
引用次数: 0
Correction: A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications. 更正:一种用于预测药代动力学应用的连续再循环的新型微流体肝组织芯片。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-20 DOI: 10.1208/s12248-023-00872-9
Shiny Amala Priya Rajan, Jason Sherfey, Shivam Ohri, Lauren Nichols, J Tyler Smith, Paarth Parekh, Eugene P Kadar, Frances Clark, Billy T George, Lauren Gregory, David Tess, James R Gosset, Jennifer Liras, Emily Geishecker, R Scott Obach, Murat Cirit
{"title":"Correction: A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications.","authors":"Shiny Amala Priya Rajan, Jason Sherfey, Shivam Ohri, Lauren Nichols, J Tyler Smith, Paarth Parekh, Eugene P Kadar, Frances Clark, Billy T George, Lauren Gregory, David Tess, James R Gosset, Jennifer Liras, Emily Geishecker, R Scott Obach, Murat Cirit","doi":"10.1208/s12248-023-00872-9","DOIUrl":"10.1208/s12248-023-00872-9","url":null,"abstract":"","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"2"},"PeriodicalIF":4.5,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177929","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}
引用次数: 0
Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development. 临床桥接研究和建模方法,以实现以患者为中心的抽样技术在帕德维尼临床开发。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-16 DOI: 10.1208/s12248-023-00866-7
Hester Kramer, Ceyhun Bicer, Christian Otoul, Chiara Rospo, Merran Macpherson, Mark Watling, Massimo Bani, David Sciberras, Hugues Chanteux

Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra®) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra®) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).

近年来,体积吸收微采样(VAMS)技术作为临床试验中血液药代动力学(PK)样本采集的创新工具而广受欢迎,因为它比干血点和传统静脉血采样具有许多优点。Mitra®是一种基于体积吸收微采样(VAMS)技术的血液采集设备,在抗癫痫药物(ASM)候选药物padsevonil (PSL)的临床开发过程中实施。本研究描述了用于连接血浆(从传统静脉血取样获得)和血液暴露(使用Mitra®获得)的方法,以支持在临床试验中使用Mitra作为唯一的血液PK取样方法。在健康志愿者和癫痫患者中采集配对血液(使用Mitra®)和血浆样本(使用常规静脉血取样)。采用不同的方法分析血浆和血液中的PSL浓度,包括血浆比(B/P)随时间的变化,线性回归,Bland-Altman分析以及基于临床药理学研究的线性混合效应模型。结果表明,两种采集方法的体内B/P观测值和测量偏差与体外B/P测量值一致。图形分析表明,时间对B/P有明显的影响,这在抽样时间为显著协变量的线性混合效应模型中得到了证实。最后,使用独立数据集对内置模型进行了验证,并证明该模型能够充分预测基于血药浓度的血药浓度,平均偏差小于9%(预测血药浓度与观察血药浓度)。
{"title":"Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development.","authors":"Hester Kramer, Ceyhun Bicer, Christian Otoul, Chiara Rospo, Merran Macpherson, Mark Watling, Massimo Bani, David Sciberras, Hugues Chanteux","doi":"10.1208/s12248-023-00866-7","DOIUrl":"10.1208/s12248-023-00866-7","url":null,"abstract":"<p><p>Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra<sup>®</sup>, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra<sup>®</sup>) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra<sup>®</sup>) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"1"},"PeriodicalIF":4.5,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136400138","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}
引用次数: 0
The AAPS Journal Theme Issue: "Perspectives on Clinical Drug Development of Long-Acting Injectables". AAPS杂志主题议题:“长效注射剂临床药物开发展望”。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-14 DOI: 10.1208/s12248-023-00871-w
Huybrecht T'jollyn, Oliver Ackaert
The development of long-acting injectable (LAI) drugs has gained increased interest during the last decades because of their favorable properties towards compliance, safety, and efficacy by maintaining stable drug concentrations throughout an extended period following a single intramuscular (IM) or subcutaneous (SC) injection. Historically, several LAIs have been successfully marketed, mainly as lifecycle product extensions of oral formulations (1). More recently, several therapeutics are also being developed for LAI use only with limited or no information available from oral administration to be leveraged (2). There is therefore a need for more quantitative understanding of (i) the physicochemical properties, (ii) the influence of the formulations
{"title":"The AAPS Journal Theme Issue: \"Perspectives on Clinical Drug Development of Long-Acting Injectables\".","authors":"Huybrecht T'jollyn, Oliver Ackaert","doi":"10.1208/s12248-023-00871-w","DOIUrl":"10.1208/s12248-023-00871-w","url":null,"abstract":"The development of long-acting injectable (LAI) drugs has gained increased interest during the last decades because of their favorable properties towards compliance, safety, and efficacy by maintaining stable drug concentrations throughout an extended period following a single intramuscular (IM) or subcutaneous (SC) injection. Historically, several LAIs have been successfully marketed, mainly as lifecycle product extensions of oral formulations (1). More recently, several therapeutics are also being developed for LAI use only with limited or no information available from oral administration to be leveraged (2). There is therefore a need for more quantitative understanding of (i) the physicochemical properties, (ii) the influence of the formulations","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"104"},"PeriodicalIF":4.5,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107592710","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}
引用次数: 0
Drug Dissolution in Oral Drug Absorption: Workshop Report. 口服药物吸收中的药物溶出度:研讨会报告。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-07 DOI: 10.1208/s12248-023-00865-8
Kimberly Raines, Payal Agarwal, Patrick Augustijns, Alaadin Alayoubi, Lucas Attia, Annette Bauer-Brandl, Martin Brandl, Parnali Chatterjee, Hansong Chen, Yuly Chiang Yu, Carrie Coutant, Ana Luisa Coutinho, David Curran, Jennifer Dressman, Bryan Ericksen, Leah Falade, Yi Gao, Zongming Gao, Debasis Ghosh, Tapash Ghosh, Anitha Govada, Elizabeth Gray, Ruiqiong Guo, Dana Hammell, Andre Hermans, Rohit Jaini, Hanlin Li, Haritha Mandula, Shuaiqian Men, Johanna Milsmann, Huong Moldthan, Rebecca Moody, Dana E Moseson, Anette Müllertz, Roshni Patel, Kalpana Paudel, Christos Reppas, Rajesh Savkur, Kerstin Schaefer, Abu Serajuddin, Lynne S Taylor, Rutu Valapil, Kevin Wei, Werner Weitschies, Shinji Yamashita, James E Polli

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of "dissolved drug," particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.

“口服药物吸收中的药物溶解”面对面研讨会于2023年5月23日至24日在美国马里兰州巴尔的摩举行。研讨会分为讲座和分组会议。不同讲师再次访问的三个共同主题是无定形固体分散体(ASD)、溶解/渗透相互作用以及预测体内生物制药性能和风险的体外方法。在分组会议中反复出现的主题如下:(1)“溶解药物”的含义和评估,特别是胶体环境中水溶性差的药物(如喂养条件、ASD);(2) 对水溶性差的药物采用下沉条件的测试的潜在局限性;(3) 非药典方法(例如,两阶段或多阶段方法、溶解/渗透方法);(4) 非药典条件(例如,顶端血管、非汇点条件);以及(5)同时具有用于分批释放的质量控制方法和用于生物豁免或桥接场景的生物预测/生物相关方法的潜在益处。非药典方法的一个公认障碍是全球监管机构对此类方法接受程度的不确定性。
{"title":"Drug Dissolution in Oral Drug Absorption: Workshop Report.","authors":"Kimberly Raines, Payal Agarwal, Patrick Augustijns, Alaadin Alayoubi, Lucas Attia, Annette Bauer-Brandl, Martin Brandl, Parnali Chatterjee, Hansong Chen, Yuly Chiang Yu, Carrie Coutant, Ana Luisa Coutinho, David Curran, Jennifer Dressman, Bryan Ericksen, Leah Falade, Yi Gao, Zongming Gao, Debasis Ghosh, Tapash Ghosh, Anitha Govada, Elizabeth Gray, Ruiqiong Guo, Dana Hammell, Andre Hermans, Rohit Jaini, Hanlin Li, Haritha Mandula, Shuaiqian Men, Johanna Milsmann, Huong Moldthan, Rebecca Moody, Dana E Moseson, Anette Müllertz, Roshni Patel, Kalpana Paudel, Christos Reppas, Rajesh Savkur, Kerstin Schaefer, Abu Serajuddin, Lynne S Taylor, Rutu Valapil, Kevin Wei, Werner Weitschies, Shinji Yamashita, James E Polli","doi":"10.1208/s12248-023-00865-8","DOIUrl":"10.1208/s12248-023-00865-8","url":null,"abstract":"<p><p>The in-person workshop \"Drug Dissolution in Oral Drug Absorption\" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of \"dissolved drug,\" particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"103"},"PeriodicalIF":4.5,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71488498","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}
引用次数: 0
A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications. 一种用于预测药代动力学应用的新型连续再循环微流体肝组织芯片。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00870-x
Shiny Amala Priya Rajan, Jason Sherfey, Shivam Ohri, Lauren Nichols, J Tyler Smith, Paarth Parekh, Eugene P Kadar, Frances Clark, Billy T George, Lauren Gregory, David Tess, James R Gosset, Jennifer Liras, Emily Geishecker, R Scott Obach, Murat Cirit

A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance using in vitro methods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during long-term incubation. To address these technological needs, we developed a novel milli-fluidic human liver tissue chip (LTC) that was designed with continuous media recirculation and optimized for hepatic cultures using human primary hepatocytes. Here, we characterized the LTC using a series of physiologically relevant metrics and test compounds to demonstrate that we could accurately predict the PK of both low- and high-clearance compounds. The non-biological characterization indicated that the cyclic olefin copolymer (COC)-based LTC exhibited negligible evaporation and minimal non-specific binding of drugs of varying ionic states and lipophilicity. Biologically, the LTC exhibited functional and polarized hepatic culture with sustained metabolic CYP activity for at least 15 days. This long-term culture was then used for drug clearance studies for low- and high-clearance compounds for at least 12 days, and clearance was estimated for a range of compounds with high in vitro-in vivo correlation (IVIVC). We also demonstrated that LTC can be induced by rifampicin, and the culture age had insignificant effect on depletion kinetic and predicted clearance value. Thus, we used advances in bioengineering to develop a novel purpose-built platform with high reproducibility and minimal variability to address unmet needs for PK applications.

药物开发过程中铅选择的一个关键步骤是使用体外方法准确估计和优化肝脏清除率。然而,目前的方法受到缺乏生理相关性、培养/孵育时间短(与患者的药物暴露模式不一致)、药物吸收材料的使用以及长期孵育过程中的蒸发等因素的限制。为了满足这些技术需求,我们开发了一种新型的微流体人类肝组织芯片(LTC),该芯片设计具有连续介质再循环,并针对使用人类原代肝细胞的肝培养进行了优化。在这里,我们使用一系列生理相关指标和测试化合物来表征LTC,以证明我们可以准确预测低清除率和高清除率化合物的PK。非生物学特性表明,基于环烯烃共聚物(COC)的LTC对不同离子状态和亲脂性的药物表现出可忽略的蒸发和最小的非特异性结合。在生物学上,LTC表现出功能性和极化的肝脏培养,具有至少15天的持续代谢CYP活性。然后将这种长期培养用于低清除率和高清除率化合物的药物清除研究至少12天,并对一系列具有高体外-体内相关性(IVIVC)的化合物进行清除率估计。我们还证明,LTC可以由利福平诱导,培养年龄对耗竭动力学和预测清除值的影响不大。因此,我们利用生物工程的进展开发了一种具有高再现性和最小可变性的新型专门构建的平台,以满足PK应用未满足的需求。
{"title":"A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications.","authors":"Shiny Amala Priya Rajan, Jason Sherfey, Shivam Ohri, Lauren Nichols, J Tyler Smith, Paarth Parekh, Eugene P Kadar, Frances Clark, Billy T George, Lauren Gregory, David Tess, James R Gosset, Jennifer Liras, Emily Geishecker, R Scott Obach, Murat Cirit","doi":"10.1208/s12248-023-00870-x","DOIUrl":"10.1208/s12248-023-00870-x","url":null,"abstract":"<p><p>A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance using in vitro methods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during long-term incubation. To address these technological needs, we developed a novel milli-fluidic human liver tissue chip (LTC) that was designed with continuous media recirculation and optimized for hepatic cultures using human primary hepatocytes. Here, we characterized the LTC using a series of physiologically relevant metrics and test compounds to demonstrate that we could accurately predict the PK of both low- and high-clearance compounds. The non-biological characterization indicated that the cyclic olefin copolymer (COC)-based LTC exhibited negligible evaporation and minimal non-specific binding of drugs of varying ionic states and lipophilicity. Biologically, the LTC exhibited functional and polarized hepatic culture with sustained metabolic CYP activity for at least 15 days. This long-term culture was then used for drug clearance studies for low- and high-clearance compounds for at least 12 days, and clearance was estimated for a range of compounds with high in vitro-in vivo correlation (IVIVC). We also demonstrated that LTC can be induced by rifampicin, and the culture age had insignificant effect on depletion kinetic and predicted clearance value. Thus, we used advances in bioengineering to develop a novel purpose-built platform with high reproducibility and minimal variability to address unmet needs for PK applications.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"102"},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566036","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}
引用次数: 0
Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications. 调节乳液性质会影响用于药物递送应用的聚(己内酯)颗粒的尺寸。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00869-4
Ashbey N Manning, Claire E Rowlands, Hope Saindon, Brittany E Givens

Advances in drug delivery have been accelerated with the addition of polymeric drug carriers. Direct delivery to a target site is a promising step in developing effective drug and gene therapies to treat disease. The efficacy of these drug carriers heavily relies on cell uptake without compromising critical cellular processes that promote cell viability. Drug release from biodegradable polymers is mediated largely by polymer degradation, and therefore the rate of polymer degradation dictates the feasibility of drug delivery applications. Traditionally, poly(caprolactone) (PCL) has only been used in long-term biomedical applications because the degradation time is much slower than other polymers. However, the biocompatibility of this polymer and the potential for longer delivery windows renders it a promising polymer candidate for drug delivery. In this work, we outline sixteen emulsion solvent evaporation preparation methods for PCL nanoparticles and microparticles to develop particles between 300 nm and 1.7 μm and with zeta potentials of -1.8 mV. We further investigated particles in a size range suitable for systemic tumor delivery and inhaled aerosol delivery to determine cell biocompatibility with the polymer in lung adenocarcinoma, endometrial adenocarcinoma, and human embryonic kidney cells. We determined these particles aren't detrimental to cell viability below particle monolayer coverage atop cells and therefore these formulations hold promise for the next stage of development as sustained-release drug delivery carriers.

聚合物药物载体的加入加速了药物递送的进展。直接递送到靶位点是开发治疗疾病的有效药物和基因疗法的一个有希望的步骤。这些药物载体的疗效在很大程度上依赖于细胞摄取,而不会损害促进细胞活力的关键细胞过程。可生物降解聚合物的药物释放主要由聚合物降解介导,因此聚合物降解速率决定了药物递送应用的可行性。传统上,聚己内酯(PCL)仅用于长期的生物医学应用,因为其降解时间比其他聚合物慢得多。然而,这种聚合物的生物相容性和更长递送窗口的潜力使其成为药物递送的一种有前途的候选聚合物。在该工作中,我们概述了16种乳液溶剂蒸发制备PCL纳米颗粒和微粒的方法,使其形成300nm至1.7μm的颗粒,ζ电位为-1.8mV。我们进一步研究了适合全身肿瘤递送和吸入气溶胶递送的尺寸范围内的颗粒,以确定肺腺癌中聚合物的细胞生物相容性,子宫内膜腺癌和人胚胎肾细胞。我们确定,在细胞上颗粒单层覆盖率以下,这些颗粒对细胞活力没有损害,因此这些制剂有望作为缓释药物递送载体进入下一阶段。
{"title":"Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications.","authors":"Ashbey N Manning, Claire E Rowlands, Hope Saindon, Brittany E Givens","doi":"10.1208/s12248-023-00869-4","DOIUrl":"10.1208/s12248-023-00869-4","url":null,"abstract":"<p><p>Advances in drug delivery have been accelerated with the addition of polymeric drug carriers. Direct delivery to a target site is a promising step in developing effective drug and gene therapies to treat disease. The efficacy of these drug carriers heavily relies on cell uptake without compromising critical cellular processes that promote cell viability. Drug release from biodegradable polymers is mediated largely by polymer degradation, and therefore the rate of polymer degradation dictates the feasibility of drug delivery applications. Traditionally, poly(caprolactone) (PCL) has only been used in long-term biomedical applications because the degradation time is much slower than other polymers. However, the biocompatibility of this polymer and the potential for longer delivery windows renders it a promising polymer candidate for drug delivery. In this work, we outline sixteen emulsion solvent evaporation preparation methods for PCL nanoparticles and microparticles to develop particles between 300 nm and 1.7 μm and with zeta potentials of -1.8 mV. We further investigated particles in a size range suitable for systemic tumor delivery and inhaled aerosol delivery to determine cell biocompatibility with the polymer in lung adenocarcinoma, endometrial adenocarcinoma, and human embryonic kidney cells. We determined these particles aren't detrimental to cell viability below particle monolayer coverage atop cells and therefore these formulations hold promise for the next stage of development as sustained-release drug delivery carriers.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"100"},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566038","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}
引用次数: 0
Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors. 用于病毒载体基因治疗的转基因产物的种间标度:使用来自11种病毒载体的数据的方法评估。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00867-6
Tao Zhang, Peng Zou

The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose-response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose-response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight^-0.25 (AS by W^-0.25) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors.

转基因产物在人中表达的预测对于指导基于病毒载体的基因替代疗法的首次人内(FIH)剂量选择是重要的。最近,来自临床前数据的异速计量标度和种间剂量反应标准化(D-R)关系已被用于预测腺相关病毒(AAV)载体的人类转基因产物表达。在这项研究中,我们评估了两种种种间异速缩放方法和两种剂量反应方法,以预测九种静脉注射的AAV载体、一种肌肉注射的AA病毒载体和一种膀胱内注射的腺病毒载体的人类转基因产物表达。在这四种方法中,归一化D-R方法产生了最高的预测精度,几何平均倍数误差(GMFE)为2.9倍,75%的预测在观察到的人类转基因产品水平的五倍偏差内。基于vg/kg的D-R方法对局部递送的载体有效,但显著高估了一些血友病A和B载体的人类转基因产物水平。对于静脉注射和局部给药载体,使用体重^-0.25(AS乘以W^-0.25)的异速标度的预测准确性优于使用log(体重)(AS乘以logW)的异速度标度。本研究成功地将异速缩放和种间D-R标准化方法用于人类转基因产物预测的用途从静脉内病毒载体扩展到局部递送的病毒载体。
{"title":"Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors.","authors":"Tao Zhang, Peng Zou","doi":"10.1208/s12248-023-00867-6","DOIUrl":"10.1208/s12248-023-00867-6","url":null,"abstract":"<p><p>The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose-response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose-response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight<sup>^-0.25</sup> (AS by W<sup>^-0.25</sup>) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"101"},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566037","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}
引用次数: 0
Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development. 建模和模拟在临床前和临床长效注射药物开发中的作用。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-17 DOI: 10.1208/s12248-023-00864-9
Maxime Siemons, Bram Schroyen, Nicolas Darville, Navin Goyal

Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our understanding of the injection space and aid in describing the long-acting injectable (LAI) drug's behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of employing a model-based framework in the LAI preclinical and clinical space. This review provides a brief overview of the LAI development process before delving deeper into the current status of modeling and simulation approaches in characterizing the preclinical and clinical LAI pharmacokinetics, focused on aqueous crystalline suspensions. A closer look is provided on in vitro release methods, available biopharmaceutical models and reported in vitro/in vivo correlations (IVIVCs) that may advance LAI drug development. The overview allows identifying the opportunities for use of model-informed drug development approaches and potential gaps where further research may be most warranted. Continued investment in improving our understanding of LAI PK across species through translational approaches may facilitate the future development of LAI drug products.

长效注射药物开发领域的创新报道越来越多。更先进的体外和体内表征可以提高我们对注射空间的理解,并有助于更机械地描述长效注射(LAI)药物在注射部位的行为。这些创新可能能够释放在LAI临床前和临床空间中使用基于模型的框架的潜力。这篇综述简要概述了LAI的开发过程,然后深入研究了表征临床前和临床LAI药代动力学的建模和模拟方法的现状,重点是结晶悬浮液。对可能促进LAI药物开发的体外释放方法、可用的生物制药模型和已报道的体外/体内相关性(IVIVCs)进行了更深入的研究。概述允许确定使用基于模型的药物开发方法的机会,以及最有必要进行进一步研究的潜在差距。通过翻译方法继续投资于提高我们对跨物种LAI PK的理解,可能有助于LAI药物产品的未来开发。
{"title":"Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development.","authors":"Maxime Siemons, Bram Schroyen, Nicolas Darville, Navin Goyal","doi":"10.1208/s12248-023-00864-9","DOIUrl":"10.1208/s12248-023-00864-9","url":null,"abstract":"<p><p>Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our understanding of the injection space and aid in describing the long-acting injectable (LAI) drug's behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of employing a model-based framework in the LAI preclinical and clinical space. This review provides a brief overview of the LAI development process before delving deeper into the current status of modeling and simulation approaches in characterizing the preclinical and clinical LAI pharmacokinetics, focused on aqueous crystalline suspensions. A closer look is provided on in vitro release methods, available biopharmaceutical models and reported in vitro/in vivo correlations (IVIVCs) that may advance LAI drug development. The overview allows identifying the opportunities for use of model-informed drug development approaches and potential gaps where further research may be most warranted. Continued investment in improving our understanding of LAI PK across species through translational approaches may facilitate the future development of LAI drug products.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"99"},"PeriodicalIF":4.5,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240633","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}
引用次数: 1
Quantitative Translation of Substrate Intrinsic Clearance from Recombinant CYP1A1 to Humans. 从重组CYP1A1到人的底物内在清除的定量翻译。
IF 4.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-05 DOI: 10.1208/s12248-023-00863-w
Li Di

CYP1A1 is a cytochrome P450 family 1 enzyme that is mostly expressed in the extrahepatic tissues. To understand the CYP1A1 contribution to drug clearance in humans, we examined the in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance (CLint) for a set of drugs that are in vitro CYP1A1 substrates. Despite being strong in vitro CYP1A1 substrates, 82% of drugs gave good IVIVE with predicted CLint within 2-3-fold of the observed values using human liver microsomes and hepatocytes, suggesting they were not in vivo CYP1A1 substrates due to the lack of extrahepatic contribution to CLint. Only three drugs (riluzole, melatonin and ramelteon) that are CYP1A2 substrates yielded significant underprediction of in vivo CLint up to 11-fold. The fold of CLint underprediction was linearly proportional to human recombinant CYP1A1 (rCYP1A1) CLint, indicating they were likely to be in vivo CYP1A1 substrates. Using these three substrates, a calibration curve can be developed to enable direct translation from in vitro rCYP1A1 CLint to in vivo extrahepatic contributions in humans. In vivo CYP1A1 substrates are planar and small, which is consistent with the structure of the active site. This is in contrast to the in vitro substrates, which include large and nonplanar molecules, suggesting rCYP1A1 is more accessible than what is in vivo. The impact of CYP1A1 on first-pass intestinal metabolism was also evaluated and shown to be minimal. This is the first study providing new insights on in vivo translation of CYP1A1 contributions to human clearance using in vitro rCYP1A1 data.

CYP1A1是一种细胞色素P450家族1酶,主要在肝外组织中表达。为了了解CYP1A1对人类药物清除的贡献,我们检查了一组体外CYP1A1底物药物的内在清除(CLint)的体外-体内外推法(IVIVE)。尽管是强大的体外CYP1A1底物,但82%的药物提供了良好的IVIVE,其预测的CLint在使用人类肝微粒体和肝细胞观察值的2-3倍内,这表明它们不是体内CYP1A1基质,因为缺乏对CLint的肝外贡献。只有三种作为CYP1A2底物的药物(利鲁唑、褪黑素和拉美顿)对体内CLint的预测显著不足,达11倍。CLint预测不足的倍数与人重组CYP1A1(rCYP1A1)CLint成线性比例,表明它们可能是体内CYP1A1底物。使用这三种底物,可以开发校准曲线,以使人类能够从体外rCYP1A1-CLint直接转化为体内肝外贡献。体内CYP1A1底物是平面的和小的,这与活性位点的结构一致。这与体外基质形成对比,体外基质包括大分子和非平面分子,表明rCYP1A1比体内更容易获得。CYP1A1对首次肠道代谢的影响也进行了评估,并显示为最小。这是第一项使用体外rCYP1A1数据对CYP1A1对人体清除的贡献的体内翻译提供新见解的研究。
{"title":"Quantitative Translation of Substrate Intrinsic Clearance from Recombinant CYP1A1 to Humans.","authors":"Li Di","doi":"10.1208/s12248-023-00863-w","DOIUrl":"10.1208/s12248-023-00863-w","url":null,"abstract":"<p><p>CYP1A1 is a cytochrome P450 family 1 enzyme that is mostly expressed in the extrahepatic tissues. To understand the CYP1A1 contribution to drug clearance in humans, we examined the in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance (CL<sub>int</sub>) for a set of drugs that are in vitro CYP1A1 substrates. Despite being strong in vitro CYP1A1 substrates, 82% of drugs gave good IVIVE with predicted CL<sub>int</sub> within 2-3-fold of the observed values using human liver microsomes and hepatocytes, suggesting they were not in vivo CYP1A1 substrates due to the lack of extrahepatic contribution to CL<sub>int</sub>. Only three drugs (riluzole, melatonin and ramelteon) that are CYP1A2 substrates yielded significant underprediction of in vivo CL<sub>int</sub> up to 11-fold. The fold of CL<sub>int</sub> underprediction was linearly proportional to human recombinant CYP1A1 (rCYP1A1) CL<sub>int</sub>, indicating they were likely to be in vivo CYP1A1 substrates. Using these three substrates, a calibration curve can be developed to enable direct translation from in vitro rCYP1A1 CL<sub>int</sub> to in vivo extrahepatic contributions in humans. In vivo CYP1A1 substrates are planar and small, which is consistent with the structure of the active site. This is in contrast to the in vitro substrates, which include large and nonplanar molecules, suggesting rCYP1A1 is more accessible than what is in vivo. The impact of CYP1A1 on first-pass intestinal metabolism was also evaluated and shown to be minimal. This is the first study providing new insights on in vivo translation of CYP1A1 contributions to human clearance using in vitro rCYP1A1 data.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"98"},"PeriodicalIF":4.5,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41164815","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}
引用次数: 0
期刊
AAPS Journal
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1