AAPS PharmSciTech最新文献_第4页

A Novel Self-Assembled Paclitaxel Nanodispersion Facilitates Rapid In-Vitro/In-Vivo Dissociation and Protein Binding

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-12-05 DOI: 10.1208/s12249-024-02996-3

Ajay J. Khopade, Malay D. Shah, Bhushan Borole

The study aims to prepare and characterize a novel paclitaxel (PtX) preconcentrate formulation using polymer and lipid excipients that forms nanodispersion upon dilution. The goal was to understand the mechanism of nanodispersion formation and its properties. The water-insoluble PtX was dissolved in organic solvents containing ethanol, polyethylene glycol (PEG400), povidone (PVP), caprylic acid (CA), and sodium cholesterol sulfate (CS). This formulation was diluted in 5% w/v dextrose medium to form PtX nanodispersion, which was assessed for particle size, stability, in-vitro/in-vivo dissociation and protein binding. Transmission electron microscopy (TEM), Small Angle Neutron Scattering (SANS), and Molecular Dynamics (MD) simulations were used to analyse the structure of the nanoparticles. The formulation was a clear, slightly yellow solution. The PtX nanodispersion displays particle size of ~ 100 nm with a zeta potential of -25, and the pH of 4.0. It displayed nearly spherical coacervate nanoparticles with a sponge-like structure, lacking internal structure order as revealed by TEM and SANS. MD simulations confirmed self-assembly of PtX and excipients forming nanoparticles. In vitro dissociation studies in simulated plasma demonstrated rapid dissociation of nanodispersion, releasing free PtX that immediately binds to plasma proteins. In vivo studies in rabbits corroborated these findings, showing rapid dissolution. The results present a novel formulation design that forms sponge-like coacervate nanoparticle due to complimentary interactions of the excipients that otherwise are unable to self-assemble under similar conditions of dilution. This alternative formulation solves the limitations of currently marketed PtX products and can provide its effective delivery in clinical settings.

Graphical Abstract

{"title":"A Novel Self-Assembled Paclitaxel Nanodispersion Facilitates Rapid In-Vitro/In-Vivo Dissociation and Protein Binding","authors":"Ajay J. Khopade, Malay D. Shah, Bhushan Borole","doi":"10.1208/s12249-024-02996-3","DOIUrl":"10.1208/s12249-024-02996-3","url":null,"abstract":"<div><p>The study aims to prepare and characterize a novel paclitaxel (PtX) preconcentrate formulation using polymer and lipid excipients that forms nanodispersion upon dilution. The goal was to understand the mechanism of nanodispersion formation and its properties. The water-insoluble PtX was dissolved in organic solvents containing ethanol, polyethylene glycol (PEG400), povidone (PVP), caprylic acid (CA), and sodium cholesterol sulfate (CS). This formulation was diluted in 5% w/v dextrose medium to form PtX nanodispersion, which was assessed for particle size, stability, <i>in-vitro</i>/<i>in-vivo</i> dissociation and protein binding. Transmission electron microscopy (TEM), Small Angle Neutron Scattering (SANS), and Molecular Dynamics (MD) simulations were used to analyse the structure of the nanoparticles. The formulation was a clear, slightly yellow solution. The PtX nanodispersion displays particle size of ~ 100 nm with a zeta potential of -25, and the pH of 4.0. It displayed nearly spherical coacervate nanoparticles with a sponge-like structure, lacking internal structure order as revealed by TEM and SANS. MD simulations confirmed self-assembly of PtX and excipients forming nanoparticles. <i>In vitro</i> dissociation studies in simulated plasma demonstrated rapid dissociation of nanodispersion, releasing free PtX that immediately binds to plasma proteins. <i>In vivo</i> studies in rabbits corroborated these findings, showing rapid dissolution. The results present a novel formulation design that forms sponge-like coacervate nanoparticle due to complimentary interactions of the excipients that otherwise are unable to self-assemble under similar conditions of dilution. This alternative formulation solves the limitations of currently marketed PtX products and can provide its effective delivery in clinical settings.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Bifunctional Oxaliplatin (IV) Prodrug Based pH-Sensitive PEGylated Liposomes for Synergistic Anticancer Action Against Triple Negative Breast cancer

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-12-04 DOI: 10.1208/s12249-024-02988-3

Lavkesh Bhute, Sayali Dighe, Oly Katari, Vivek Yadav, Sanyog Jain

Triple negative breast cancer (TNBC) exhibits higher susceptibility towards oxaliplatin (OXA) due to a faulty DNA damage repair system. However, the unfavorable physicochemical properties and risk of toxicities limit the clinical utility of OXA. Therefore, to impart kinetic inertness, site-specific delivery, and multidrug action, an octahedral Pt(IV) prodrug was developed by using chlorambucil (CBL) as a choice of ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to maximize tumor-specific delivery, intracellular accumulation, and in-vivo performance, the developed prodrug (OXA-CBL) was encapsulated in pH-sensitive PEGylated liposomes into (OXA-CBL/PEG-Liposomes). The fabricated liposomes had smaller particle size < 200 nm and higher drug loading (~ 4.26 ± 0.18%). In-vitro release displayed pH-dependent sustained release for up to 48 h. Cellular internalization revealed maximal uptake via clathrin-mediated endocytosis. The cytotoxicity assay showed reduced IC₅₀ in the 4T1 (~ 1.559-fold) and MDA-MB-231 (~ 1.539-fold) cell lines than free OXA-CBL. In-vivo efficacy in 4T1-induced TNBC model revealed a marked increase in % tumor inhibition rate, while diminished % tumor burden in OXA-CBL/BSA-NPs treated animals. Toxicity assessment displayed no signs of systemic and hemolytic toxicity. Overall, delivery of Pt (IV) prodrug as a pH-sensitive PEGylated liposomes offers a safer and efficient system to manage TNBC.

Graphical Abstract

{"title":"Bifunctional Oxaliplatin (IV) Prodrug Based pH-Sensitive PEGylated Liposomes for Synergistic Anticancer Action Against Triple Negative Breast cancer","authors":"Lavkesh Bhute, Sayali Dighe, Oly Katari, Vivek Yadav, Sanyog Jain","doi":"10.1208/s12249-024-02988-3","DOIUrl":"10.1208/s12249-024-02988-3","url":null,"abstract":"<div><p>Triple negative breast cancer (TNBC) exhibits higher susceptibility towards oxaliplatin (OXA) due to a faulty DNA damage repair system. However, the unfavorable physicochemical properties and risk of toxicities limit the clinical utility of OXA. Therefore, to impart kinetic inertness, site-specific delivery, and multidrug action, an octahedral Pt(IV) prodrug was developed by using chlorambucil (CBL) as a choice of ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to maximize tumor-specific delivery, intracellular accumulation, and <i>in-vivo</i> performance, the developed prodrug (OXA-CBL) was encapsulated in pH-sensitive PEGylated liposomes into (OXA-CBL/PEG-Liposomes). The fabricated liposomes had smaller particle size < 200 nm and higher drug loading (~ 4.26 ± 0.18%). <i>In-vitro</i> release displayed pH-dependent sustained release for up to 48 h. Cellular internalization revealed maximal uptake via clathrin-mediated endocytosis. The cytotoxicity assay showed reduced IC<sub>50</sub> in the 4T1 (~ 1.559-fold) and MDA-MB-231 (~ 1.539-fold) cell lines than free OXA-CBL. <i>In-vivo</i> efficacy in 4T1-induced TNBC model revealed a marked increase in % tumor inhibition rate, while diminished % tumor burden in OXA-CBL/BSA-NPs treated animals. Toxicity assessment displayed no signs of systemic and hemolytic toxicity. Overall, delivery of Pt (IV) prodrug as a pH-sensitive PEGylated liposomes offers a safer and efficient system to manage TNBC.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Physiologically Based Biopharmaceutics Modeling Coupled with Biopredictive Dissolution in Development of Bioequivalent Formulation for Mesalamine Enteric Coated Tablet: A Tough Nut to Crack

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-12-02 DOI: 10.1208/s12249-024-02990-9

Sivacharan Kollipara, Pankaj Kumar Prabhat, Paramita Saha, Saurabh Gupta, Venkat Ramana Naidu, Tausif Ahmed

Mesalamine is a locally acting anti-inflammatory drug used to treat mild to moderate ulcerative colitis. Because of complex formulation principle and high in vivo variability, development of bioequivalent formulation for mesalamine is challenging. Further, fed state possess significant challenges for bioequivalence (BE) due to interplay of multiple factors. In the work, we have developed a novel biopredictive media for mesalamine enteric coated tablets and integrated into physiologically based biopharmaceutics model (PBBM) to predict in vivo fed behavior. USP III based gradient media was developed to mimic in vivo fed condition. The developed PBBM was initially validated with literature data and subsequently re-optimized with pilot BE study data. Further, virtual bioequivalence (VBE) was performed to evaluate model predictability for pilot BE data. Later, the model was applied for prospective BE predictions with increased subjects and parametric sensitivity analysis was performed to identify physiological factors that can impact in vivo performance. Further, the model was used to predict luminal and enterocyte concentrations in colon to demonstrate equivalent efficacy. Additionally, a novel dissolution/permeation tool (Dissoflux) was employed to compare permeability behavior of formulations. Overall, this work enabled BE prediction for complex mesalamine enteric coated tablets and helped to understand parameters that can impact in vivo performance.

Graphical Abstract

{"title":"Physiologically Based Biopharmaceutics Modeling Coupled with Biopredictive Dissolution in Development of Bioequivalent Formulation for Mesalamine Enteric Coated Tablet: A Tough Nut to Crack","authors":"Sivacharan Kollipara, Pankaj Kumar Prabhat, Paramita Saha, Saurabh Gupta, Venkat Ramana Naidu, Tausif Ahmed","doi":"10.1208/s12249-024-02990-9","DOIUrl":"10.1208/s12249-024-02990-9","url":null,"abstract":"<div><p>Mesalamine is a locally acting anti-inflammatory drug used to treat mild to moderate ulcerative colitis. Because of complex formulation principle and high <i>in vivo</i> variability, development of bioequivalent formulation for mesalamine is challenging. Further, fed state possess significant challenges for bioequivalence (BE) due to interplay of multiple factors. In the work, we have developed a novel biopredictive media for mesalamine enteric coated tablets and integrated into physiologically based biopharmaceutics model (PBBM) to predict <i>in vivo</i> fed behavior. USP III based gradient media was developed to mimic <i>in vivo</i> fed condition. The developed PBBM was initially validated with literature data and subsequently re-optimized with pilot BE study data. Further, virtual bioequivalence (VBE) was performed to evaluate model predictability for pilot BE data. Later, the model was applied for prospective BE predictions with increased subjects and parametric sensitivity analysis was performed to identify physiological factors that can impact <i>in vivo</i> performance. Further, the model was used to predict luminal and enterocyte concentrations in colon to demonstrate equivalent efficacy. Additionally, a novel dissolution/permeation tool (Dissoflux) was employed to compare permeability behavior of formulations. Overall, this work enabled BE prediction for complex mesalamine enteric coated tablets and helped to understand parameters that can impact <i>in vivo</i> performance.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142761957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Advancements in Exosome Proteins for Breast Cancer Diagnosis and Detection: With a Focus on Nanotechnology 用于乳腺癌诊断和检测的外泌体蛋白研究进展：聚焦纳米技术

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-11-27 DOI: 10.1208/s12249-024-02983-8

Mohamed J. Saadh, Afrah Majeed Ahmed Al-Rihaymee, Mandeep Kaur, Abhishek Kumar, Ahmed Faisal Mutee, Ghufran Lutfi Ismaeel, Shirin Shomurotova, Mahmood Hasen Shuhata Alubiady, Hamza Fadhel Hamzah, Zainab Abbas Abd Alhassan, Tuqa S. Alazzawi, Khursheed Muzammil, Merwa Alhadrawi

Breast cancer, a leading cause of mortality among women, has been recognized as requiring improved diagnostic methods. Exosome proteins, found in small extracellular vesicles, have emerged as a promising solution, reflecting the state of their cell of origin and playing key roles in cancer progression. This review examines their potential in breast cancer diagnosis, discussing advanced isolation and characterization techniques such as ultracentrifugation and microfluidic-based approaches. Various detection methods—including electrochemical, nano-based, optical, and machine learning platforms—were evaluated for their high sensitivity, specificity, and non-invasive capabilities. Electrochemical methods were used to identify unique protein signatures for rapid, cost-effective diagnosis, while machine learning enhanced the classification of exosome proteins. Nano-based techniques leveraged nanomaterials to detect low-abundance proteins, and optical methods offered real-time, label-free monitoring. Despite their promise, challenges in standardizing protocols and integrating these diagnostics into clinical practice remain. Future directions include technological advancements, personalized medicine, and exploring the therapeutic potential of exosome proteins.

Graphical Abstract

乳腺癌是妇女死亡的主要原因之一，已被认为需要改进诊断方法。外泌体蛋白存在于细小的细胞外囊泡中，是一种很有前景的解决方案，它能反映其起源细胞的状态，并在癌症进展中发挥关键作用。本综述探讨了它们在乳腺癌诊断中的潜力，讨论了先进的分离和表征技术，如超离心法和基于微流控的方法。对各种检测方法（包括电化学、纳米、光学和机器学习平台）的高灵敏度、特异性和无创能力进行了评估。电化学方法用于识别独特的蛋白质特征，以进行快速、经济有效的诊断，而机器学习则增强了外泌体蛋白质的分类能力。纳米技术利用纳米材料检测低丰度蛋白质，光学方法提供实时、无标记监测。尽管这些方法前景广阔，但在标准化方案和将这些诊断方法融入临床实践方面仍存在挑战。未来的发展方向包括技术进步、个性化医疗以及探索外泌体蛋白的治疗潜力。

{"title":"Advancements in Exosome Proteins for Breast Cancer Diagnosis and Detection: With a Focus on Nanotechnology","authors":"Mohamed J. Saadh, Afrah Majeed Ahmed Al-Rihaymee, Mandeep Kaur, Abhishek Kumar, Ahmed Faisal Mutee, Ghufran Lutfi Ismaeel, Shirin Shomurotova, Mahmood Hasen Shuhata Alubiady, Hamza Fadhel Hamzah, Zainab Abbas Abd Alhassan, Tuqa S. Alazzawi, Khursheed Muzammil, Merwa Alhadrawi","doi":"10.1208/s12249-024-02983-8","DOIUrl":"10.1208/s12249-024-02983-8","url":null,"abstract":"<div><p>Breast cancer, a leading cause of mortality among women, has been recognized as requiring improved diagnostic methods. Exosome proteins, found in small extracellular vesicles, have emerged as a promising solution, reflecting the state of their cell of origin and playing key roles in cancer progression. This review examines their potential in breast cancer diagnosis, discussing advanced isolation and characterization techniques such as ultracentrifugation and microfluidic-based approaches. Various detection methods—including electrochemical, nano-based, optical, and machine learning platforms—were evaluated for their high sensitivity, specificity, and non-invasive capabilities. Electrochemical methods were used to identify unique protein signatures for rapid, cost-effective diagnosis, while machine learning enhanced the classification of exosome proteins. Nano-based techniques leveraged nanomaterials to detect low-abundance proteins, and optical methods offered real-time, label-free monitoring. Despite their promise, challenges in standardizing protocols and integrating these diagnostics into clinical practice remain. Future directions include technological advancements, personalized medicine, and exploring the therapeutic potential of exosome proteins.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"25 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Unveiling Swelling and Erosion Dynamics: Early Development Screening of Mirabegron Extended Release Tablets 揭示膨胀和侵蚀动力学：米拉贝琼缓释片的早期开发筛选

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-11-27 DOI: 10.1208/s12249-024-02994-5

Ana S. Sousa, J. Serra, C. Estevens, R. Costa, António J. Ribeiro

Although the development of extended release (ER) matrices has been extensively investigated, understanding the most appropriate mechanism of drug release to achieve the desired release remains a cost- and time-consuming challenge in the early stages of formulation development. This study aimed to investigate the early stage of developing ER hydrophilic matrix tablets containing mirabegron as a model drug, focusing on the effects of polymer type, diluent type, and polymer amount on critical quality attributes (CQAs), namely, tablet swelling and erosion behavior. A full factorial design was employed to explore the interactions of control factors through multivariate regression analysis, emphasizing the application of quality by design (QbD) principles. The swelling and erosion performances of 72 formulations were evaluated. The swelling data were fitted to the Vergnaud model. Finally, in vitro drug release profiles were investigated for four of the formulations studied. The polymer type, diluent type, and polymer amount had distinct effects on the swelling and erosion behavior of the ER matrix tablets. Compared with those with isomalt (G720) or dextrate (DXT), formulations with polyethylene glycol 8000 (P8000) consistently exhibited greater swelling. Additionally, higher molecular weight was correlated with increased swelling within the same polymer type. Hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO)-based formulations showed higher swelling rates, while polyvinyl alcohol (PVA-80) displayed the highest erosion percentage. The findings highlight the significance of incorporating early-stage screening designs to maximize efficiency and optimize time and resource. This approach enables the development of a comprehensive understanding of drug release mechanisms from ER matrix tablets.

Graphical abstract

尽管对缓释（ER）基质的开发进行了广泛的研究，但在制剂开发的早期阶段，了解最合适的药物释放机制以实现理想的释放效果仍然是一项耗费成本和时间的挑战。本研究旨在调查以米拉贝琼为模型药物的ER亲水基质片剂开发的早期阶段，重点研究聚合物类型、稀释剂类型和聚合物用量对关键质量属性（CQA），即片剂溶胀和侵蚀行为的影响。研究采用了全因子设计，通过多元回归分析探讨了控制因素之间的相互作用，强调了质量源于设计（QbD）原则的应用。对 72 种制剂的溶胀和侵蚀性能进行了评估。膨胀数据与 Vergnaud 模型进行了拟合。最后，对四种配方的体外药物释放曲线进行了研究。聚合物类型、稀释剂类型和聚合物量对 ER 基质片剂的溶胀和侵蚀行为有明显的影响。与含有异麦芽酮（G720）或糊精（DXT）的制剂相比，含有聚乙二醇 8000（P8000）的制剂始终表现出更大的膨胀性。此外，在同一聚合物类型中，分子量越高，膨胀性越大。基于羟丙基甲基纤维素（HPMC）和聚环氧乙烷（PEO）的配方显示出更高的膨胀率，而聚乙烯醇（PVA-80）则显示出最高的侵蚀率。研究结果凸显了采用早期筛选设计以最大限度地提高效率并优化时间和资源的重要性。这种方法有助于全面了解 ER 基质片剂的药物释放机制。

{"title":"Unveiling Swelling and Erosion Dynamics: Early Development Screening of Mirabegron Extended Release Tablets","authors":"Ana S. Sousa, J. Serra, C. Estevens, R. Costa, António J. Ribeiro","doi":"10.1208/s12249-024-02994-5","DOIUrl":"10.1208/s12249-024-02994-5","url":null,"abstract":"<div><p>Although the development of extended release (ER) matrices has been extensively investigated, understanding the most appropriate mechanism of drug release to achieve the desired release remains a cost- and time-consuming challenge in the early stages of formulation development. This study aimed to investigate the early stage of developing ER hydrophilic matrix tablets containing mirabegron as a model drug, focusing on the effects of polymer type, diluent type, and polymer amount on critical quality attributes (CQAs), namely, tablet swelling and erosion behavior. A full factorial design was employed to explore the interactions of control factors through multivariate regression analysis, emphasizing the application of quality by design (QbD) principles. The swelling and erosion performances of 72 formulations were evaluated. The swelling data were fitted to the Vergnaud model. Finally, <i>in vitro</i> drug release profiles were investigated for four of the formulations studied. The polymer type, diluent type, and polymer amount had distinct effects on the swelling and erosion behavior of the ER matrix tablets. Compared with those with isomalt (G720) or dextrate (DXT), formulations with polyethylene glycol 8000 (P8000) consistently exhibited greater swelling. Additionally, higher molecular weight was correlated with increased swelling within the same polymer type. Hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO)-based formulations showed higher swelling rates, while polyvinyl alcohol (PVA-80) displayed the highest erosion percentage. The findings highlight the significance of incorporating early-stage screening designs to maximize efficiency and optimize time and resource. This approach enables the development of a comprehensive understanding of drug release mechanisms from ER matrix tablets.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"25 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-024-02994-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Comparison between Pilot-Grade Spray Dryer and Laboratory-Grade Spray Dryer: Structure, Powder Properties and Application for Direct Compaction 中试级喷雾干燥机与实验室级喷雾干燥机的比较：结构、粉末特性和直接压制应用

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-11-27 DOI: 10.1208/s12249-024-02991-8

Zhe Li, Wanghai Peng, Fucai Chen, Lin Zhu, Abid Naeem, Weifeng Zhu, Yongmei Guan, Yi Feng, Yanni Wu, Xiao Lin, Liangshan Ming

This study investigates the improvements in direct compaction powder properties achieved through particle design using laboratory and pilot-scale spray dryers. Hydroxypropyl methylcellulose and polyvinylpyrrolidone were used as modifying agent, which have low hygroscopicity and surface tension, good flowability, and excellent compactibility. Ammonium bicarbonate and sodium bicarbonate were used as pore-forming agents, and the composite particles were prepared using laboratory and pilot-scale spray dryers. The results showed that the structure of the composite particles and porous particles can effectively improve the flowability, tabletability, and disintegration behaviour; the composite particles prepared by laboratory-scale spray drying have better tabletability; the composite particles prepared by spray drying at pilot-scale had better flowability. In summary, there are significant differences in the properties of products prepared by different scales of spray drying. It will be beneficial to choose the appropriate equipment and the appropriate experimental design. Consequently, this study may contribute to the development of natural plant tablets.

Graphical Abstract

本研究通过使用实验室和中试规模的喷雾干燥机对颗粒进行设计，研究如何改善直接压制粉末的性能。羟丙基甲基纤维素和聚乙烯吡咯烷酮被用作改性剂，它们具有低吸湿性和表面张力、良好的流动性和优异的压实性。以碳酸氢铵和碳酸氢钠作为成孔剂，使用实验室和中试规模的喷雾干燥机制备了复合颗粒。结果表明，复合微粒和多孔微粒的结构能有效改善流动性、片剂性和崩解行为；实验室规模喷雾干燥制备的复合微粒具有更好的片剂性；中试规模喷雾干燥制备的复合微粒具有更好的流动性。总之，不同规模喷雾干燥制备的产品在性能上存在显著差异。选择合适的设备和适当的实验设计将大有裨益。因此，本研究可能有助于天然植物片剂的开发。

{"title":"The Comparison between Pilot-Grade Spray Dryer and Laboratory-Grade Spray Dryer: Structure, Powder Properties and Application for Direct Compaction","authors":"Zhe Li, Wanghai Peng, Fucai Chen, Lin Zhu, Abid Naeem, Weifeng Zhu, Yongmei Guan, Yi Feng, Yanni Wu, Xiao Lin, Liangshan Ming","doi":"10.1208/s12249-024-02991-8","DOIUrl":"10.1208/s12249-024-02991-8","url":null,"abstract":"<div><p>This study investigates the improvements in direct compaction powder properties achieved through particle design using laboratory and pilot-scale spray dryers. Hydroxypropyl methylcellulose and polyvinylpyrrolidone were used as modifying agent, which have low hygroscopicity and surface tension, good flowability, and excellent compactibility. Ammonium bicarbonate and sodium bicarbonate were used as pore-forming agents, and the composite particles were prepared using laboratory and pilot-scale spray dryers. The results showed that the structure of the composite particles and porous particles can effectively improve the flowability, tabletability, and disintegration behaviour; the composite particles prepared by laboratory-scale spray drying have better tabletability; the composite particles prepared by spray drying at pilot-scale had better flowability. In summary, there are significant differences in the properties of products prepared by different scales of spray drying. It will be beneficial to choose the appropriate equipment and the appropriate experimental design. Consequently, this study may contribute to the development of natural plant tablets.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"25 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

User-Friendliness Evaluation of Handling pMDI with Various Add-on Devices in Asthmatic Patients 对哮喘患者使用 pMDI 和各种附加设备的便利性进行评估。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-11-27 DOI: 10.1208/s12249-024-02998-1

Ahmed M. Abdelfattah, Rania M. Sarhan, Yasmin M. Madney, Ahmed F. Mady, Mohamed E. A. Abdelrahim, Hadeer S. Harb

The objective of this study was to assess the use of pMDI alone and pMDI with different spacers in asthmatic patients and to identify any associations between errors in handling the device for the first time and the sessions needed to reach the correct handling method, considering patient demographics and clinical characteristics. A total of 150 Asthmatic patients were crossed over to handle pMDI alone and with add-on inhalable devices (Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8) randomly, without receiving verbal or demonstrative instruction (baseline assessment). The assessment of the inhaler technique was performed using checklists that had been set beforehand. Subsequently, the proper utilization of the inhaler was exhibited, and the patient's inhaler usage was reassessed. The demonstration was repeated until an optimal technique was attained. The number of counselling attempts required to achieve successful management, together with patient demographics and clinical factors, were documented. The mean percentage of total errors at baseline shows that pMDI alone is significantly higher than pMDI attached to add-on devices (53.90 ± 9.71, 32.54 ± 13.93, 24.53 ± 14.93, 21.6 ± 14.48, 25.14 ± 10.99, 27.47 ± 10.28) for pMDI alone, Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8 respectively at p < 0.01. Able and Tips Haler spacers are significantly lower than other spacers with pMDI and pMDI alone in terms of total sessions needed to attain the complete optimal handling technique at p < 0.01. Weak and very weak correlations were observed between the percentage of total errors at baseline and the total sessions with education years, Montreal Cognitive Assessment, and age as well as some demographics and clinical variables. Handling pMDI can be challenging however the introduction of spacers simplifies this procedure. Different spacers cannot be treated as a homogeneous group due to variations in handling techniques and ease of use. the Able spacer requires the fewest handling steps of any spacer and has the highest percentage of patients who can use it without assistance.

Graphical Abstract

这项研究的目的是评估哮喘患者单独使用 pMDI 和使用带有不同间隔器的 pMDI 的情况，并在考虑患者人口统计学和临床特征的情况下，确定首次操作设备时出现的错误与达到正确操作方法所需的疗程之间是否存在关联。共对 150 名哮喘患者进行了交叉测试，在不接受口头或示范指导（基线评估）的情况下，让他们随机操作单独的 pMDI 和附加吸入器（Aerochamber plus、Tips Haler、Able、Dispozable 和 Aer-8）。对吸入器使用技巧的评估是通过事先设定的检查表进行的。随后，演示如何正确使用吸入器，并重新评估患者的吸入器使用情况。反复演示，直到达到最佳技术为止。成功管理所需的咨询次数以及患者的人口统计学和临床因素都被记录在案。基线总错误的平均百分比显示，单独使用 pMDI、Aerochamber plus、Tips Haler、Able、Dispozable 和 Aer-8 的错误率分别为（53.90 ± 9.71、32.54 ± 13.93、24.53 ± 14.93、21.6 ± 14.48、25.14 ± 10.99、27.47 ± 10.28）和（p），单独使用 pMDI 明显高于附加装置的错误率（53.90 ± 9.71、32.54 ± 13.93、24.53 ± 14.93、21.6 ± 14.48、25.14 ± 10.99、27.47 ± 10.28）。

{"title":"User-Friendliness Evaluation of Handling pMDI with Various Add-on Devices in Asthmatic Patients","authors":"Ahmed M. Abdelfattah, Rania M. Sarhan, Yasmin M. Madney, Ahmed F. Mady, Mohamed E. A. Abdelrahim, Hadeer S. Harb","doi":"10.1208/s12249-024-02998-1","DOIUrl":"10.1208/s12249-024-02998-1","url":null,"abstract":"<div><p>The objective of this study was to assess the use of pMDI alone and pMDI with different spacers in asthmatic patients and to identify any associations between errors in handling the device for the first time and the sessions needed to reach the correct handling method, considering patient demographics and clinical characteristics. A total of 150 Asthmatic patients were crossed over to handle pMDI alone and with add-on inhalable devices (Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8) randomly, without receiving verbal or demonstrative instruction (baseline assessment). The assessment of the inhaler technique was performed using checklists that had been set beforehand. Subsequently, the proper utilization of the inhaler was exhibited, and the patient's inhaler usage was reassessed. The demonstration was repeated until an optimal technique was attained. The number of counselling attempts required to achieve successful management, together with patient demographics and clinical factors, were documented. The mean percentage of total errors at baseline shows that pMDI alone is significantly higher than pMDI attached to add-on devices (53.90 ± 9.71, 32.54 ± 13.93, 24.53 ± 14.93, 21.6 ± 14.48, 25.14 ± 10.99, 27.47 ± 10.28) for pMDI alone, Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8 respectively at <i>p</i> < 0.01. Able and Tips Haler spacers are significantly lower than other spacers with pMDI and pMDI alone in terms of total sessions needed to attain the complete optimal handling technique at p < 0.01. Weak and very weak correlations were observed between the percentage of total errors at baseline and the total sessions with education years, Montreal Cognitive Assessment, and age as well as some demographics and clinical variables. Handling pMDI can be challenging however the introduction of spacers simplifies this procedure. Different spacers cannot be treated as a homogeneous group due to variations in handling techniques and ease of use. the Able spacer requires the fewest handling steps of any spacer and has the highest percentage of patients who can use it without assistance.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"25 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-024-02998-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-Circulating and Targeted Liposomes Co-loading Cisplatin and Mifamurtide: Formulation and Delivery in Osteosarcoma Cells 长循环和靶向脂质体共载顺铂和米伐肽：骨肉瘤细胞中的配制和递送

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-11-26 DOI: 10.1208/s12249-024-02992-7

Bo Li, Qianhui Zhao, Hanyu Yang, Xueyuying Wang, Zhijun Zhang, Yanling Gong, Xu Wan

Osteosarcoma (OS) is one of the most common primary bone sarcoma with high malignant degree and poor prognosis, for which there is an urgent need to develop novel therapeutic approaches. Recent research has revealed that mifamurtide significantly improved the outcome of OS patients when combined with adjuvant chemotherapy drugs including cisplatin (DDP). The present study aimed to construct a drug delivery system co-loading DDP and mifamurtide. Long-circulating targeted liposomes co-loading DDP and mifamurtide were constructed with Soy lecithin (SPC), cholesterol (Chol) and 1,2-distearoylglycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)] (DSPE-PEG), modified with MMP14 targeting peptide BCY-B in the surface of liposomes. In addition to characterization, the cellular uptake, endocytosis pathway and inhibition on cell viability, migration, invasion and cell apoptosis of MG-63 cells were explored. The constructed liposomal delivery possessed the basic characteristics of liposomes and showed high affinity to MG-63 cells, resulting in high uptake efficiency in MG-63 cells. The endocytosis might be involved in multiple pathways including caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis, dependently on energy. The constructed long-circulating targeted liposomes co-loading DDP and mifamurtide significantly inhibited the cell viability, migration, invasion and cell apoptosis of MG-63 cells, improving the antitumor effect of DDP and mifamurtide in vitro. The constructed liposomal delivery system is suitable for co-loading DDP and mifamurtide to achieve active tumor targeting, supplying a new strategy for the treatment of OS.

Graphical Abstract

骨肉瘤（Osteosarcoma，OS）是最常见的原发性骨肉瘤之一，恶性程度高、预后差，迫切需要开发新型治疗方法。最近的研究发现，米伐木肽与顺铂（DDP）等辅助化疗药物联合使用，能明显改善骨肉瘤患者的预后。本研究旨在构建一种共同负载 DDP 和米伐肽的给药系统。研究人员用大豆卵磷脂（SPC）、胆固醇（Chol）和1,2-二硬脂酰甘油-3-磷脂酰乙醇胺-n-[聚乙二醇]（DSPE-PEG）构建了长循环靶向脂质体，并在脂质体表面用MMP14靶向肽BCY-B修饰。除表征外，还探讨了细胞摄取、内吞途径以及对 MG-63 细胞活力、迁移、侵袭和细胞凋亡的抑制作用。所构建的脂质体递送具有脂质体的基本特征，对 MG-63 细胞具有高亲和力，因此在 MG-63 细胞中的摄取效率很高。内吞可能涉及多种途径，包括洞穴介导的内吞、凝胶酶介导的内吞和大蛋白细胞内吞，这与能量有关。构建的长循环靶向脂质体共载DDP和米伐肽，能显著抑制MG-63细胞的细胞活力、迁移、侵袭和细胞凋亡，提高了DDP和米伐肽的体外抗肿瘤效果。所构建的脂质体递送系统适用于联合负载DDP和米伐肽，实现肿瘤的主动靶向，为OS的治疗提供了一种新策略。

{"title":"Long-Circulating and Targeted Liposomes Co-loading Cisplatin and Mifamurtide: Formulation and Delivery in Osteosarcoma Cells","authors":"Bo Li, Qianhui Zhao, Hanyu Yang, Xueyuying Wang, Zhijun Zhang, Yanling Gong, Xu Wan","doi":"10.1208/s12249-024-02992-7","DOIUrl":"10.1208/s12249-024-02992-7","url":null,"abstract":"<div><p>Osteosarcoma (OS) is one of the most common primary bone sarcoma with high malignant degree and poor prognosis, for which there is an urgent need to develop novel therapeutic approaches. Recent research has revealed that mifamurtide significantly improved the outcome of OS patients when combined with adjuvant chemotherapy drugs including cisplatin (DDP). The present study aimed to construct a drug delivery system co-loading DDP and mifamurtide. Long-circulating targeted liposomes co-loading DDP and mifamurtide were constructed with Soy lecithin (SPC), cholesterol (Chol) and 1,2-distearoylglycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)] (DSPE-PEG), modified with MMP14 targeting peptide BCY-B in the surface of liposomes. In addition to characterization, the cellular uptake, endocytosis pathway and inhibition on cell viability, migration, invasion and cell apoptosis of MG-63 cells were explored. The constructed liposomal delivery possessed the basic characteristics of liposomes and showed high affinity to MG-63 cells, resulting in high uptake efficiency in MG-63 cells. The endocytosis might be involved in multiple pathways including caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis, dependently on energy. The constructed long-circulating targeted liposomes co-loading DDP and mifamurtide significantly inhibited the cell viability, migration, invasion and cell apoptosis of MG-63 cells, improving the antitumor effect of DDP and mifamurtide <i>in vitro</i>. The constructed liposomal delivery system is suitable for co-loading DDP and mifamurtide to achieve active tumor targeting, supplying a new strategy for the treatment of OS.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"25 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-024-02992-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Albumin and Polysorbate-80 Coated Sterile Nanosuspensions of Mebendazole for Glioblastoma Therapy 用于胶质母细胞瘤治疗的白蛋白和聚山梨醇酯-80 包裹的甲苯咪唑无菌纳米悬液

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-11-26 DOI: 10.1208/s12249-024-02978-5

Himaxi Patel, Akanksha Patel, Mukti Vats, Ketan Patel

The scarcity of existing and novel therapies for brain cancer has significantly affected the survival rate of glioblastoma patients. Mebendazole (MBZ), an antiparasitic agent demonstrated promising activity against brain cancer. However, poor solubility, multiple polymorphs, and insufficient permeability through blood–brain barrier (BBB) restricts its therapeutic efficacy through parenteral administration. The current study aimed to develop, optimize, and characterize sterile, injectable nanosuspension of mebendazole using parenterally acceptable stabilizers. Albumin and polysorbate 80 (PS-80) coated MBZ Nanosuspension (NS) was prepared using wet media milling technique. Design of experiment (DoE) approach was used to understand effect of drug loading versus stabilizer concentration. The optimized MBZ NS showed hydrodynamic diameter of 208.36 ± 0.24 nm with a poly dispersibility index (PDI) of 0.210 ± 0.03 and zeta potential of -20.41 ± 0.36 mV. The IC₅₀ value of MBZ NS in U-87 MG and LN-229 cell lines were found to be 0.49 ± 0.02 μM and 0.48 ± 0.05 μM, respectively. Additionally, MBZ NS demonstrated a 2.65-fold decrease in colony-forming efficiency and a 1.16-fold reduction in migration of the bridging area compared to MBZ. In 3D spheroids of the U-87 MG glioma cell line, MBZ NS exhibited a 50% reduction in tumor growth and increased cell apoptosis compared to the control. MBZ NS formulations were sterilized by gamma irradiation and tested as per the USP sterility test. Albumin-PS 80 coated NS is rendered to be useful parenteral delivery of mebendazole for the treatment of brain cancer.

Graphical Abstract

脑癌现有疗法和新型疗法的匮乏严重影响了胶质母细胞瘤患者的生存率。甲苯咪唑（MBZ）是一种抗寄生虫药物，对脑癌具有良好的活性。然而，由于其溶解性差、存在多种多态性以及通过血脑屏障（BBB）的渗透性不足，限制了其通过肠外给药的疗效。本研究旨在使用肠外可接受的稳定剂来开发、优化和表征甲苯咪唑的无菌注射用纳米悬浮液。采用湿介质研磨技术制备了白蛋白和聚山梨醇酯 80（PS-80）包被的甲苯咪唑纳米悬浮剂（NS）。实验设计（DoE）方法用于了解药物载量与稳定剂浓度的关系。优化后的 MBZ 纳米悬浮液的流体力学直径为 208.36 ± 0.24 nm，多分散指数（PDI）为 0.210 ± 0.03，Zeta 电位为 -20.41 ± 0.36 mV。在 U-87 MG 和 LN-229 细胞系中，MBZ NS 的 IC50 值分别为 0.49 ± 0.02 μM 和 0.48 ± 0.05 μM。此外，与 MBZ 相比，MBZ NS 的集落形成效率降低了 2.65 倍，桥接区的迁移率降低了 1.16 倍。在 U-87 MG 胶质瘤细胞系的三维球形体中，与对照组相比，MBZ NS 的肿瘤生长减少了 50%，细胞凋亡增加。MBZ NS 制剂经伽马射线辐照灭菌，并按照美国药典无菌测试进行了测试。白蛋白-PS 80包被的NS被认为是治疗脑癌的有用的甲苯咪唑肠外给药。

{"title":"Albumin and Polysorbate-80 Coated Sterile Nanosuspensions of Mebendazole for Glioblastoma Therapy","authors":"Himaxi Patel, Akanksha Patel, Mukti Vats, Ketan Patel","doi":"10.1208/s12249-024-02978-5","DOIUrl":"10.1208/s12249-024-02978-5","url":null,"abstract":"<div><p>The scarcity of existing and novel therapies for brain cancer has significantly affected the survival rate of glioblastoma patients. Mebendazole (MBZ), an antiparasitic agent demonstrated promising activity against brain cancer. However, poor solubility, multiple polymorphs, and insufficient permeability through blood–brain barrier (BBB) restricts its therapeutic efficacy through parenteral administration. The current study aimed to develop, optimize, and characterize sterile, injectable nanosuspension of mebendazole using parenterally acceptable stabilizers. Albumin and polysorbate 80 (PS-80) coated MBZ Nanosuspension (NS) was prepared using wet media milling technique. Design of experiment (DoE) approach was used to understand effect of drug loading versus stabilizer concentration. The optimized MBZ NS showed hydrodynamic diameter of 208.36 ± 0.24 nm with a poly dispersibility index (PDI) of 0.210 ± 0.03 and zeta potential of -20.41 ± 0.36 mV. The IC<sub>50</sub> value of MBZ NS in U-87 MG and LN-229 cell lines were found to be 0.49 ± 0.02 μM and 0.48 ± 0.05 μM, respectively. Additionally, MBZ NS demonstrated a 2.65-fold decrease in colony-forming efficiency and a 1.16-fold reduction in migration of the bridging area compared to MBZ. In 3D spheroids of the U-87 MG glioma cell line, MBZ NS exhibited a 50% reduction in tumor growth and increased cell apoptosis compared to the control. MBZ NS formulations were sterilized by gamma irradiation and tested as per the USP sterility test. Albumin-PS 80 coated NS is rendered to be useful parenteral delivery of mebendazole for the treatment of brain cancer.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"25 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Advancements in Antiviral Therapy: Favipiravir Sodium in Nasal Formulation 抗病毒疗法的进展：鼻用制剂法维拉韦钠

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-11-26 DOI: 10.1208/s12249-024-02986-5

Priti Darne, Shankar Vidhate, Somesh Shintre, Somnath Wagdare, Dhiraj Bhamare, Nisha Mehta, Vishal Rajagopalan, Sriram Padmanabhan

Favipiravir (FPV) is an Active Pharmaceutical Ingredient (API) known to have lower solubility in aqueous solvents. In the current study, efforts were made to generate a crystalline Favipiravir Sodium Salt (NaFPV) for enhanced solubility in aqueous media. The in-house generated NaFPV was characterized by NMR studies and its sodium content was determined by Flame Emission Spectroscopy (FES) as a confirmation of salt formation. Its solubility was determined where-in the solubility of NaFPV in water was about 100 times greater than FVP. FPV and NaFPV nasal spray formulations were prepared and its activity was determined against human coronavirus (hCoV) 229E strain. In the anti-hCoV assay as compared to FPV, NaFPV showed almost threefold higher anti-viral activity than its unmodified counterpart. Accelerated stability and spray pattern characteristics of both the formulations were studied. Interestingly, NaFPV showed higher physical stability during storage at conditions 40 ± 2 °C/ 75% ± 5% RH. The nasal spray formulations of both FPV and NaFPV showed ideal plume geometry and spray pattern of acceptable specifications. Due to its improvement in terms of solubility, NaFPV will have higher rate and extent of absorption, and faster onset of the therapeutic effect and may appear to be a feasible alternative to regular favipiravir for use in solid dosage forms.

Graphical Abstract

已知法维拉韦（Favipiravir，FPV）是一种活性药物成分（API），在水性溶剂中的溶解度较低。在本研究中，我们努力生成结晶的法维拉韦钠盐（NaFPV），以提高其在水介质中的溶解度。通过核磁共振研究对内部生成的 NaFPV 进行了表征，并通过火焰发射光谱（FES）测定其钠含量，以确认盐的形成。NaFPV 在水中的溶解度约为 FVP 的 100 倍。制备了 FPV 和 NaFPV 鼻腔喷雾制剂，并测定了它们对人类冠状病毒（hCoV）229E 株的活性。在抗 hCoV 试验中，与 FPV 相比，NaFPV 的抗病毒活性几乎是其未改性制剂的三倍。对两种制剂的加速稳定性和喷雾模式特性进行了研究。有趣的是，NaFPV 在 40±2 °C/75%±5% 相对湿度条件下储存时显示出更高的物理稳定性。FPV 和 NaFPV 的鼻腔喷雾配方都显示出理想的羽流几何形状和喷雾模式，达到了可接受的规格。由于 NaFPV 在溶解度方面的改进，它的吸收率和吸收范围会更高，治疗效果也会更快显现，因此可以作为常规法非拉韦的可行替代品，用于固体制剂中。

{"title":"Advancements in Antiviral Therapy: Favipiravir Sodium in Nasal Formulation","authors":"Priti Darne, Shankar Vidhate, Somesh Shintre, Somnath Wagdare, Dhiraj Bhamare, Nisha Mehta, Vishal Rajagopalan, Sriram Padmanabhan","doi":"10.1208/s12249-024-02986-5","DOIUrl":"10.1208/s12249-024-02986-5","url":null,"abstract":"<div><p>Favipiravir (FPV) is an Active Pharmaceutical Ingredient (API) known to have lower solubility in aqueous solvents. In the current study, efforts were made to generate a crystalline Favipiravir Sodium Salt (NaFPV) for enhanced solubility in aqueous media. The in-house generated NaFPV was characterized by NMR studies and its sodium content was determined by Flame Emission Spectroscopy (FES) as a confirmation of salt formation. Its solubility was determined where-in the solubility of NaFPV in water was about 100 times greater than FVP. FPV and NaFPV nasal spray formulations were prepared and its activity was determined against human coronavirus (hCoV) 229E strain. In the anti-hCoV assay as compared to FPV, NaFPV showed almost threefold higher anti-viral activity than its unmodified counterpart. Accelerated stability and spray pattern characteristics of both the formulations were studied. Interestingly, NaFPV showed higher physical stability during storage at conditions 40 ± 2 °C/ 75% ± 5% RH. The nasal spray formulations of both FPV and NaFPV showed ideal plume geometry and spray pattern of acceptable specifications. Due to its improvement in terms of solubility, NaFPV will have higher rate and extent of absorption, and faster onset of the therapeutic effect and may appear to be a feasible alternative to regular favipiravir for use in solid dosage forms.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"25 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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