Pub Date : 2024-12-05DOI: 10.1208/s12249-024-03005-3
Subodh Mondal, Ritika Uppal, Satish CS
Pre-clinical studies in animals are an essential part of drug development for new chemical entities. Before clinical trials in humans, submission of safety data from one rodent and one non-rodent species is compulsory as per regulatory guidelines. Even though minipigs and monkeys are physiologically closer to humans, dogs are usually employed as the non-rodent pre-clinical species. In this study, the in vitro plasma protein binding of eleven marketed cardiovascular drugs was studied in dog, minipig, monkey and human to determine the preferred species. To conduct plasma protein binding studies, the most reliable equilibrium dialysis method was adopted. Ten out of eleven tested cardiovascular drugs showed statistically similar plasma protein binding in minipig and human plasma which was different from dog and monkey plasma. The results from the studies showed greater similarity between minipigs and humans suggesting that the minipig species maybe a better pre-clinical non-rodent model during drug development of cardiovascular drugs instead of the conventional dog species. Additionally, use of the more accessible minipig species may help in saving time, and resources during pre-clinical studies and may also be more predictive during the safety studies in humans during later stage clinical trials.
{"title":"Investigation of Minipigs as the Optimal Non-rodent Pre-clinical Species: Exploring Plasma Protein Binding of Marketed Cardiovascular Drugs Across Species","authors":"Subodh Mondal, Ritika Uppal, Satish CS","doi":"10.1208/s12249-024-03005-3","DOIUrl":"10.1208/s12249-024-03005-3","url":null,"abstract":"<div><p>Pre-clinical studies in animals are an essential part of drug development for new chemical entities. Before clinical trials in humans, submission of safety data from one rodent and one non-rodent species is compulsory as per regulatory guidelines. Even though minipigs and monkeys are physiologically closer to humans, dogs are usually employed as the non-rodent pre-clinical species. In this study, the <i>in vitro</i> plasma protein binding of eleven marketed cardiovascular drugs was studied in dog, minipig, monkey and human to determine the preferred species. To conduct plasma protein binding studies, the most reliable equilibrium dialysis method was adopted. Ten out of eleven tested cardiovascular drugs showed statistically similar plasma protein binding in minipig and human plasma which was different from dog and monkey plasma. The results from the studies showed greater similarity between minipigs and humans suggesting that the minipig species maybe a better pre-clinical non-rodent model during drug development of cardiovascular drugs instead of the conventional dog species. Additionally, use of the more accessible minipig species may help in saving time, and resources during pre-clinical studies and may also be more predictive during the safety studies in humans during later stage clinical trials.</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":"https://link.springer.com/content/pdf/10.1208/s12249-024-03005-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778576","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}
Cyclodextrin complexes have been widely used in pharmaceutical applications, but disadvantages such as the rapid clearance of cyclodextrins from the blood stream after in vivo administration or their replacement by other molecules in the biological medium with higher luminal affinity for cyclodextrins limit the application of cyclodextrins as drug carriers. Liposome-encapsulated hydrophobic drugs have low and unstable drug loading rates. Drug-in-CD-in-liposome (DCL), which encapsulate cyclodextrin inclusion complexes into liposomes, combine the advantages of both delivery systems, can effectively avoid the leakage and rapid release of lipophilic drugs in the lipid bilayer, and help to maintain the integrity of liposomes. This paper focuses on the preparation method, characterization and application of DCL, with a view to providing methods and references for the research and application of DCL technology.
Graphical Abstract
环糊精配合物已广泛应用于制药领域，但环糊精体内给药后迅速从血液中清除或在生物介质中被对环糊精具有更高腔内亲和力的其他分子所取代等缺点限制了环糊精作为药物载体的应用。脂质体包封的疏水药物载药率低且不稳定。药物- cd -in-脂质体（Drug-in-CD-in-liposome， DCL）将环糊精包合物包裹在脂质体中，结合了两种递送系统的优点，可有效避免亲脂药物在脂质双分子层中的泄漏和快速释放，有助于维持脂质体的完整性。本文重点介绍了DCL的制备方法、表征及应用，以期为DCL技术的研究和应用提供方法和参考。图形抽象
{"title":"Cyclodextrin Drugs in Liposomes: Preparation and Application of Anticancer Drug Carriers","authors":"Lanni Feng, Ruting Wei, Jiali Wu, Xinmei Chen, Yan Wen, Jianming Chen","doi":"10.1208/s12249-024-02999-0","DOIUrl":"10.1208/s12249-024-02999-0","url":null,"abstract":"<div><p>Cyclodextrin complexes have been widely used in pharmaceutical applications, but disadvantages such as the rapid clearance of cyclodextrins from the blood stream after <i>in vivo</i> administration or their replacement by other molecules in the biological medium with higher luminal affinity for cyclodextrins limit the application of cyclodextrins as drug carriers. Liposome-encapsulated hydrophobic drugs have low and unstable drug loading rates. Drug-in-CD-in-liposome (DCL), which encapsulate cyclodextrin inclusion complexes into liposomes, combine the advantages of both delivery systems, can effectively avoid the leakage and rapid release of lipophilic drugs in the lipid bilayer, and help to maintain the integrity of liposomes. This paper focuses on the preparation method, characterization and application of DCL, with a view to providing methods and references for the research and application of DCL technology.</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":"142778396","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}
Pub Date : 2024-12-05DOI: 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.
{"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}
Pub Date : 2024-12-04DOI: 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.
{"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}
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.
{"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}
Pub Date : 2024-11-27DOI: 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.
{"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}
Pub Date : 2024-11-27DOI: 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}
Pub Date : 2024-11-27DOI: 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.
{"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}
Pub Date : 2024-11-27DOI: 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.
{"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}
Pub Date : 2024-11-26DOI: 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.
{"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}
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