Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.10.055
Kristian Beran , Bertil Abrahamsson , Naseem Charoo , Rodrigo Cristofoletti , René Holm , Atsushi Kambayashi , Peter Langguth , Alan Parr , James E. Polli , Vinod P. Shah , Jennifer Dressman
According to the ICH M9 Guideline, the triazole antifungal voriconazole is a Biopharmaceutics Classification System (BCS) class II drug, being highly soluble at the highest dose strength but not at the highest single dose. Although the ICH M9 allows for consideration of BCS-based biowaivers in such cases, voriconazole does not meet the additional requirement of dose proportional pharmacokinetics (PK) over the therapeutic dose range. By contrast, if the classification were based on the FDA solubility criteria that were in place prior to ICH M9 (based on the highest dose strength), voriconazole would belong to BCS class I and thus qualify for the BCS-based biowaiver. Since the highest oral dose strength of voriconazole dissolves very rapidly under all BCS conditions, and comparative in vitro dissolution of different tablet formulations aligns with the demonstration of BE in clinical studies, it seems that the ICH Guideline may be unnecessarily restrictive in the case of voriconazole. Therefore, this review discusses potential revisions of eligibility criteria and the extension of biowaiver approvals to encompass a wider range of appropriate drugs. Specifically, a classification system that is more relevant to in vivo conditions, the refined Developability Classification System (rDCS), coupled with biorelevant dissolution testing, may be more applicable to compounds like voriconazole.
根据 ICH M9 准则，三唑类抗真菌药物伏立康唑属于生物制药分类系统（BCS）II 类药物，在最高剂量强度下具有高溶解性，但在最高单剂量下不具有高溶解性。虽然 ICH M9 允许在这种情况下考虑基于 BCS 的生物豁免，但伏立康唑不符合在治疗剂量范围内剂量与药代动力学（PK）成比例的额外要求。相比之下，如果根据 ICH M9 之前的 FDA 溶解度标准（基于最高剂量强度）进行分类，伏立康唑将属于 BCS I 类，从而符合基于 BCS 的生物豁免条件。由于伏立康唑的最高口服剂量强度在所有 BCS 条件下都能快速溶解，且不同片剂的体外溶解度比较与临床研究中的 BE 证明一致，因此 ICH 指南似乎对伏立康唑有不必要的限制。因此，本综述讨论了资格标准的可能修订以及生物豁免批准范围的扩大，以涵盖更广泛的适当药物。具体来说，一个与体内条件更相关的分类系统，即改良的可发展性分类系统（rDCS），再加上与生物相关的溶出度测试，可能更适用于伏立康唑等化合物。
{"title":"Biowaiver monographs for immediate-release solid oral dosage forms: Voriconazole","authors":"Kristian Beran , Bertil Abrahamsson , Naseem Charoo , Rodrigo Cristofoletti , René Holm , Atsushi Kambayashi , Peter Langguth , Alan Parr , James E. Polli , Vinod P. Shah , Jennifer Dressman","doi":"10.1016/j.xphs.2024.10.055","DOIUrl":"10.1016/j.xphs.2024.10.055","url":null,"abstract":"<div><div>According to the ICH M9 Guideline, the triazole antifungal voriconazole is a Biopharmaceutics Classification System (BCS) class II drug, being highly soluble at the highest dose strength but not at the highest single dose. Although the ICH M9 allows for consideration of BCS-based biowaivers in such cases, voriconazole does not meet the additional requirement of dose proportional pharmacokinetics (PK) over the therapeutic dose range. By contrast, if the classification were based on the FDA solubility criteria that were in place prior to ICH M9 (based on the highest dose strength), voriconazole would belong to BCS class I and thus qualify for the BCS-based biowaiver. Since the highest oral dose strength of voriconazole dissolves very rapidly under all BCS conditions, and comparative <em>in vitro</em> dissolution of different tablet formulations aligns with the demonstration of BE in clinical studies, it seems that the ICH Guideline may be unnecessarily restrictive in the case of voriconazole. Therefore, this review discusses potential revisions of eligibility criteria and the extension of biowaiver approvals to encompass a wider range of appropriate drugs. Specifically, a classification system that is more relevant to <em>in vivo</em> conditions, the refined Developability Classification System (rDCS), coupled with biorelevant dissolution testing, may be more applicable to compounds like voriconazole.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 660-680"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.11.006
Ranga Dissanayake , Nauman Nazeer , Zeyaealdin Zarei , Adnan Murad Bhayo , Marya Ahmed
Self-assembled peptide nanoparticles are unique stimuli responsive biodegradable materials with applications in biomedicines as delivery carriers and imaging agents. This study investigates the controlled self-assembly of chicken Angiogenin 4 derived immunomodulatory macrocyclic peptide (mCA4-5) in the presence of an inert amphipathic stabilizing peptide and as a function of pH, temperature and presence of ions to yield optically active, physiologically stable and biodegradable peptide nanoparticles. The photoluminescent peptide nanoparticles (PLPNs) produced were characterized for the size, surface charge, optical properties and crystallinity. The carvacrol loaded nanoparticles prepared by facile encapsulation of the drug during the self-assembly process were evaluated for the drug release efficacies, as a function of pH and in the presence of reducing agent. Carvacrol loaded, physiologically stable PLPNs obtained with high conversion efficacy were highly effective against planktonic bacteria and bacterial biofilms and efficiently eradicated intracellular bacteria in infected macrophages and fibroblast. Furthermore, the drug-loaded nanoparticles exhibited significant antioxidant activities and immunomodulatory effects, highlighting their multifunctional therapeutic potential.
{"title":"Controlled self-assembly of macrocyclic peptide into multifunctional photoluminescent nanoparticles","authors":"Ranga Dissanayake , Nauman Nazeer , Zeyaealdin Zarei , Adnan Murad Bhayo , Marya Ahmed","doi":"10.1016/j.xphs.2024.11.006","DOIUrl":"10.1016/j.xphs.2024.11.006","url":null,"abstract":"<div><div>Self-assembled peptide nanoparticles are unique stimuli responsive biodegradable materials with applications in biomedicines as delivery carriers and imaging agents. This study investigates the controlled self-assembly of chicken Angiogenin 4 derived immunomodulatory macrocyclic peptide (mCA4-5) in the presence of an inert amphipathic stabilizing peptide and as a function of pH, temperature and presence of ions to yield optically active, physiologically stable and biodegradable peptide nanoparticles. The photoluminescent peptide nanoparticles (PLPNs) produced were characterized for the size, surface charge, optical properties and crystallinity. The carvacrol loaded nanoparticles prepared by facile encapsulation of the drug during the self-assembly process were evaluated for the drug release efficacies, as a function of pH and in the presence of reducing agent. Carvacrol loaded, physiologically stable PLPNs obtained with high conversion efficacy were highly effective against planktonic bacteria and bacterial biofilms and efficiently eradicated intracellular bacteria in infected macrophages and fibroblast. Furthermore, the drug-loaded nanoparticles exhibited significant antioxidant activities and immunomodulatory effects, highlighting their multifunctional therapeutic potential.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 990-1001"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.11.009
Yanshan Dai, Adithi Adusumilli, Faiza Adeel, Alexander Kozhich, Vibha Jawa
This study evaluated the effectiveness of the Reverse Transcription-droplet digital PCR (RT-ddPCR) method in measuring T-cell-mediated immunity by quantifying IFN-γ mRNA expression. The results demonstrated that peak IFN-γ expression occurred approximately 4 h after stimulation of whole blood and peripheral blood mononuclear cells (PBMCs) by stimulants. The fold activation of IFN-γ mRNA expression in 100 µL of blood challenged with CEF peptides was lower than that observed in PBMCs.
Our findings highlighted the effectiveness of the RT-ddPCR assay in detecting IFN-γ mRNA expression with the least number of cells and at the lowest stimulant concentration for varying numbers of PBMCs. Additionally, there was a strong and significant positive correlation between the number of SARS-CoV-2-specific spot-forming units (SFUs) and the fold activation of IFN-γ gene expression (r = 0.78, p < 0.02) in PBMC from 10 donors vaccinated with SARS-CoV-2, further supporting the usefulness of the RT-ddPCR method.
Importantly, even with just 10,000 PBMCs, we detected SARS-CoV-2-specific IFN-γ mRNA induction. The RT-ddPCR and ELISpot assays demonstrated similar sensitivities and measured IFN-γ activation by low concentrations of stimulants. This study suggests that the RT-ddPCR method effectively assesses T-cell mediated immunity through IFN-γ expression, offering a feasible alternative to the ELISpot assay.
{"title":"Monitoring antigen-specific cellular immune response using an RT-ddPCR-based assay for IFN-γ gene expression","authors":"Yanshan Dai, Adithi Adusumilli, Faiza Adeel, Alexander Kozhich, Vibha Jawa","doi":"10.1016/j.xphs.2024.11.009","DOIUrl":"10.1016/j.xphs.2024.11.009","url":null,"abstract":"<div><div>This study evaluated the effectiveness of the Reverse Transcription-droplet digital PCR (RT-ddPCR) method in measuring T-cell-mediated immunity by quantifying IFN-γ mRNA expression. The results demonstrated that peak IFN-γ expression occurred approximately 4 h after stimulation of whole blood and peripheral blood mononuclear cells (PBMCs) by stimulants. The fold activation of IFN-γ mRNA expression in 100 µL of blood challenged with CEF peptides was lower than that observed in PBMCs.</div><div>Our findings highlighted the effectiveness of the RT-ddPCR assay in detecting IFN-γ mRNA expression with the least number of cells and at the lowest stimulant concentration for varying numbers of PBMCs. Additionally, there was a strong and significant positive correlation between the number of SARS-CoV-2-specific spot-forming units (SFUs) and the fold activation of IFN-γ gene expression (<em>r</em> = 0.78, <em>p</em> < 0.02) in PBMC from 10 donors vaccinated with SARS-CoV-2, further supporting the usefulness of the RT-ddPCR method.</div><div>Importantly, even with just 10,000 PBMCs, we detected SARS-CoV-2-specific IFN-γ mRNA induction. The RT-ddPCR and ELISpot assays demonstrated similar sensitivities and measured IFN-γ activation by low concentrations of stimulants. This study suggests that the RT-ddPCR method effectively assesses T-cell mediated immunity through IFN-γ expression, offering a feasible alternative to the ELISpot assay.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1017-1023"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.11.015
John F. Seeler, Yongting Ma, Vish Swami, Sophie Sun, Brian Yurasko, Bruce D. Mason, Nazila Salamat-Miller
Although Closed System Transfer Devices (CSTDs) are used in oncology for dose preparation and administration, the impact of CSTDs on biologics and other non-small molecular modalities are not fully understood. We investigated particle formation when preparing and mock administering three experimental biologics (mAb, ADC, and fusion protein) using seven models of CSTDs. A wide range of visible and subvisible particle formation was observed among CSTD models. Particles were found to consist of silicone oil and protein. X-ray micro-computed tomographic images of the fluid paths of the CSTDs showed that most have highly tortuous fluid paths. Computational fluid dynamics analysis of dose preparation using the CSTDs that produced the highest and lowest amounts of particles demonstrated a 154-fold difference in maximum shear stress as well as a significant difference in solution residence time. Control experiments with silicone oil spiking showed that exposing the proteins to silicone oil does not account for the majority of visible and subvisible particle formation. These results demonstrate that the geometry of the fluid paths of CSTDs can have a detrimental effect on protein stability.
{"title":"A systematic study of CSTD-generated stress on different biomolecular modalities","authors":"John F. Seeler, Yongting Ma, Vish Swami, Sophie Sun, Brian Yurasko, Bruce D. Mason, Nazila Salamat-Miller","doi":"10.1016/j.xphs.2024.11.015","DOIUrl":"10.1016/j.xphs.2024.11.015","url":null,"abstract":"<div><div>Although Closed System Transfer Devices (CSTDs) are used in oncology for dose preparation and administration, the impact of CSTDs on biologics and other non-small molecular modalities are not fully understood. We investigated particle formation when preparing and mock administering three experimental biologics (mAb, ADC, and fusion protein) using seven models of CSTDs. A wide range of visible and subvisible particle formation was observed among CSTD models. Particles were found to consist of silicone oil and protein. X-ray micro-computed tomographic images of the fluid paths of the CSTDs showed that most have highly tortuous fluid paths. Computational fluid dynamics analysis of dose preparation using the CSTDs that produced the highest and lowest amounts of particles demonstrated a 154-fold difference in maximum shear stress as well as a significant difference in solution residence time. Control experiments with silicone oil spiking showed that exposing the proteins to silicone oil does not account for the majority of visible and subvisible particle formation. These results demonstrate that the geometry of the fluid paths of CSTDs can have a detrimental effect on protein stability.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1051-1060"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.11.024
Jieqiang Zhong, Ming Huang, Haibo Qiu, Haeri Seol, Yuetian Yan, Shunhai Wang, Ning Li
N-linked glycosylation, an extensively studied protein post-translational modification, was conventionally understood to occur at asparagine (Asn or N) sites with the consensus motif NXS/T, where X can be any amino acid residue except for proline, followed by serine or threonine. However, with advancements in characterization techniques and bioinformatic tools, increasing evidence indicates that Asn residues that are not located in the NXS/T consensus motif can also undergo N-glycosylation, which is also known as non-consensus or noncanonical N-glycosylation. Characterizing non-consensus N-glycosylation remains challenging because of the unpredictable sequon and its relatively low abundance. Here, we report an endoglycosidase-assisted peptide mapping workflow for mass spectrometry (MS) characterization of non-consensus N-glycosylation in monoclonal antibodies (mAbs). The feasibility of the workflow was demonstrated by a challenging case study, in which an atypical glycosite located within an NPNNXN sequence in a 25-residue tryptic peptide was identified in the fragment antigen-binding (Fab) region of a mAb. With the aids of endoglycosidase treatment, the resulting truncated glycan structures improved peptide ionization efficiency in MS and hence facilitated reliable quantitation of glycosite occupancy. Meanwhile, the remaining mono-/di-saccharides served as a large mass tag enabling differentiation between the glycopeptide and deamidated peptide, thus allowing for database searching for glycosite localization and semi-automation of the data processing workflow. This workflow offers a simple solution for characterizing non-consensus N-glycosylation for the development of therapeutic mAbs.
{"title":"Simple endoglycosidase-assisted peptide mapping workflow for characterizing non-consensus n-glycosylation in therapeutic monoclonal antibodies","authors":"Jieqiang Zhong, Ming Huang, Haibo Qiu, Haeri Seol, Yuetian Yan, Shunhai Wang, Ning Li","doi":"10.1016/j.xphs.2024.11.024","DOIUrl":"10.1016/j.xphs.2024.11.024","url":null,"abstract":"<div><div>N-linked glycosylation, an extensively studied protein post-translational modification, was conventionally understood to occur at asparagine (Asn or N) sites with the consensus motif NXS/T, where X can be any amino acid residue except for proline, followed by serine or threonine. However, with advancements in characterization techniques and bioinformatic tools, increasing evidence indicates that Asn residues that are not located in the NXS/T consensus motif can also undergo N-glycosylation, which is also known as non-consensus or noncanonical N-glycosylation. Characterizing non-consensus N-glycosylation remains challenging because of the unpredictable sequon and its relatively low abundance. Here, we report an endoglycosidase-assisted peptide mapping workflow for mass spectrometry (MS) characterization of non-consensus N-glycosylation in monoclonal antibodies (mAbs). The feasibility of the workflow was demonstrated by a challenging case study, in which an atypical glycosite located within an NPNNXN sequence in a 25-residue tryptic peptide was identified in the fragment antigen-binding (Fab) region of a mAb. With the aids of endoglycosidase treatment, the resulting truncated glycan structures improved peptide ionization efficiency in MS and hence facilitated reliable quantitation of glycosite occupancy. Meanwhile, the remaining mono-/di-saccharides served as a large mass tag enabling differentiation between the glycopeptide and deamidated peptide, thus allowing for database searching for glycosite localization and semi-automation of the data processing workflow. This workflow offers a simple solution for characterizing non-consensus N-glycosylation for the development of therapeutic mAbs.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1125-1132"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A diabetic wound is one of the most devastating difficulties associated with diabetes and leads to significant death and morbidity. Hence, the aim was to make Doxycycline-loaded chitosan nanoparticles (DOX-CNPs) using ionic gelation with a cross-linking technique. In the Box-Behnken design, the DOX-CNPs were optimized by considering the effects of the following 3 variables independently, namely chitosan, sodium tripolyphosphate in volume ratio, strength of chitosan and sodium tripolyphosphate, among several response variables related to nanoparticle properties. The Fourier transform infrared, transmission electron microscopy, differential scanning calorimeter, X-ray diffraction, particle size, entrapment efficiency, and drug release in-vitro were used to characterized the nanoparticles. Additionally, DPPH scavenging activity and activity against Escherichia coli and Staphylococcus aureus bacteria and in vivo characterization were carried out to optimize DOX-CNPs. Then effective delivery of DOX-CNPs is incorporated in chitosan hydrogel for diabetic wounds. The findings of this study indicate that DOX-CNPs exhibit free radical scavenging properties, demonstrate significant antibacterial activity, and enhance cell viability and migration in an in vitro wound healing assay using the L929 fibroblast cell line, and in vivo demonstrate increased blood vessels, collagen deposition epithelization. Chitosan could be used as a drug carrier in a DOX-chitosan-NP system to help develop procedures that can be used in the lab and to treat diabetic wounds.
{"title":"Optimization and preparation of doxycycline-loaded chitosan nanoparticles using Box-Behnken design for better diabetic wound healing","authors":"Harish Bhardwaj , Ram Kumar Sahu , Rajendra Kumar Jangde","doi":"10.1016/j.xphs.2024.11.014","DOIUrl":"10.1016/j.xphs.2024.11.014","url":null,"abstract":"<div><div>A diabetic wound is one of the most devastating difficulties associated with diabetes and leads to significant death and morbidity. Hence, the aim was to make Doxycycline-loaded chitosan nanoparticles (DOX-CNPs) using ionic gelation with a cross-linking technique. In the Box-Behnken design, the DOX-CNPs were optimized by considering the effects of the following 3 variables independently, namely chitosan, sodium tripolyphosphate in volume ratio, strength of chitosan and sodium tripolyphosphate, among several response variables related to nanoparticle properties. The Fourier transform infrared, transmission electron microscopy, differential scanning calorimeter, X-ray diffraction, particle size, entrapment efficiency, and drug release in-<em>vitro</em> were used to characterized the nanoparticles. Additionally, DPPH scavenging activity and activity against <em>Escherichia coli</em> and <em>Staphylococcus aureus</em> bacteria and in <em>vivo</em> characterization were carried out to optimize DOX-CNPs. Then effective delivery of DOX-CNPs is incorporated in chitosan hydrogel for diabetic wounds. The findings of this study indicate that DOX-CNPs exhibit free radical scavenging properties, demonstrate significant antibacterial activity, and enhance cell viability and migration in an in <em>vitro</em> wound healing assay using the L929 fibroblast cell line, and in <em>vivo</em> demonstrate increased blood vessels, collagen deposition epithelization. Chitosan could be used as a drug carrier in a DOX-chitosan-NP system to help develop procedures that can be used in the lab and to treat diabetic wounds.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1035-1050"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.11.026
Qi Liu , Lijun Luo , Xiaofeng Gao , Di Zhang , Xinqian Feng , Peng Yang , Hui Li , Shengjun Mao
{"title":"Corrigendum to “Co-Delivery of Daunorubicin and Homoharringtonine in Folic Acid Modified-Liposomes for Enhancing Therapeutic Effect on Acute Myeloid Leukemia” [Journal of Pharmaceutical Sciences Volume 112 (2023) 123-131]","authors":"Qi Liu , Lijun Luo , Xiaofeng Gao , Di Zhang , Xinqian Feng , Peng Yang , Hui Li , Shengjun Mao","doi":"10.1016/j.xphs.2024.11.026","DOIUrl":"10.1016/j.xphs.2024.11.026","url":null,"abstract":"","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1529-1531"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.11.008
Clara Hartmanshenn , Alexander Bechtold , Thomas Kwok , Jeff Mora , Nathan Contrella , Alex Confer , Rachel Bade , Teresa Andreani , Jonathan M.E. Hughes , Billy Chen , Eric Sirota , Lorenzo Codan , David J. Lamberto , Yingju Xu , Nastaran Salehi , Stephen Crowley
To make investigational drug candidates available to patients sooner, timelines for drug development are becoming shorter. Synthesis route scouting for active pharmaceutical ingredients (API) and drug product development often must occur simultaneously, requiring formulators to make decisions regarding drug product process selection before commercial API route finalization. Alternatively, the formulation strategy may be locked, thereby constraining drug substance processes with strict API attribute requirements. Critical quality attributes of the drug product can depend heavily on the API, yet final physical attributes may not be known early on in development. Furthermore, the desire to reduce pill burden means higher drug loading in formulations, leaving little room for excipients to compensate for suboptimal API performance. The opposing challenges of API synthetic route and drug product formulation development typically lead to elongated development timelines requiring an iterative approach. In this work, a coordinated strategy was designed and implemented to deliberately range API attributes via crystallization and milling techniques to enable robust assessment of downstream manufacturing and significantly reduce the time for final process selection. The study presented was conducted on a protease inhibitor targeted for treatment of Covid-19. Given the emergent need for treatment options, this dramatically accelerated approach was crucial for potential emergency use authorization (EUA).
{"title":"Attribute ranging as a coordinated strategy between drug substance and drug product to accelerate commercial process nomination","authors":"Clara Hartmanshenn , Alexander Bechtold , Thomas Kwok , Jeff Mora , Nathan Contrella , Alex Confer , Rachel Bade , Teresa Andreani , Jonathan M.E. Hughes , Billy Chen , Eric Sirota , Lorenzo Codan , David J. Lamberto , Yingju Xu , Nastaran Salehi , Stephen Crowley","doi":"10.1016/j.xphs.2024.11.008","DOIUrl":"10.1016/j.xphs.2024.11.008","url":null,"abstract":"<div><div>To make investigational drug candidates available to patients sooner, timelines for drug development are becoming shorter. Synthesis route scouting for active pharmaceutical ingredients (API) and drug product development often must occur simultaneously, requiring formulators to make decisions regarding drug product process selection before commercial API route finalization. Alternatively, the formulation strategy may be locked, thereby constraining drug substance processes with strict API attribute requirements. Critical quality attributes of the drug product can depend heavily on the API, yet final physical attributes may not be known early on in development. Furthermore, the desire to reduce pill burden means higher drug loading in formulations, leaving little room for excipients to compensate for suboptimal API performance. The opposing challenges of API synthetic route and drug product formulation development typically lead to elongated development timelines requiring an iterative approach. In this work, a coordinated strategy was designed and implemented to deliberately range API attributes via crystallization and milling techniques to enable robust assessment of downstream manufacturing and significantly reduce the time for final process selection. The study presented was conducted on a protease inhibitor targeted for treatment of Covid-19. Given the emergent need for treatment options, this dramatically accelerated approach was crucial for potential emergency use authorization (EUA).</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1010-1016"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.xphs.2024.10.012
Robbe Van Pottelberge , Roman Matthessen , Shauna Salem , Ben Goffin , Nancee Oien , Pratima Bharti , David Ripley
Ribonucleases (RNases) are ubiquitous in nature, being able to cleave a wide range of polyribonucleotides. While the presence of microbial and viral contamination in sterile manufacturing is highly studied and controlled, there are no standardized practices for evaluating RNase in the production facility. Since the COVID-19 pandemic, mRNA-LNP based vaccines have become part of routine large-scale manufacturing. The unstable nature of mRNA poses new challenges to safeguard the working efficacy of mRNA – Lipid nanoparticle (LNP) based vaccines or therapeutics, where the presence of RNase in the formulation process could have a profound impact on the mRNA integrity. In this article, lessons learned are presented with respect to the evaluation of RNase contamination during LNP drug product formulation and analysis. Using sensitive detection methods, the potential presence of RNase in the manufacturing of mRNA-LNPs was investigated. Additionally, capillary gel electrophoresis (CGE) data, used to measure mRNA integrity, demonstrate the quality of the active mRNA substance and importance of suitable RNase control strategies. The results and cases presented in this paper should pave the way forward for evaluation and control strategies dedicated to mRNA-LNP based vaccines and therapeutics.
{"title":"Importance of RNase monitoring during large-scale manufacturing and analysis of mRNA-LNP based vaccines","authors":"Robbe Van Pottelberge , Roman Matthessen , Shauna Salem , Ben Goffin , Nancee Oien , Pratima Bharti , David Ripley","doi":"10.1016/j.xphs.2024.10.012","DOIUrl":"10.1016/j.xphs.2024.10.012","url":null,"abstract":"<div><div>Ribonucleases (RNases) are ubiquitous in nature, being able to cleave a wide range of polyribonucleotides. While the presence of microbial and viral contamination in sterile manufacturing is highly studied and controlled, there are no standardized practices for evaluating RNase in the production facility. Since the COVID-19 pandemic, mRNA-LNP based vaccines have become part of routine large-scale manufacturing. The unstable nature of mRNA poses new challenges to safeguard the working efficacy of mRNA – Lipid nanoparticle (LNP) based vaccines or therapeutics, where the presence of RNase in the formulation process could have a profound impact on the mRNA integrity. In this article, lessons learned are presented with respect to the evaluation of RNase contamination during LNP drug product formulation and analysis. Using sensitive detection methods, the potential presence of RNase in the manufacturing of mRNA-LNPs was investigated. Additionally, capillary gel electrophoresis (CGE) data, used to measure mRNA integrity, demonstrate the quality of the active mRNA substance and importance of suitable RNase control strategies. The results and cases presented in this paper should pave the way forward for evaluation and control strategies dedicated to mRNA-LNP based vaccines and therapeutics.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1520-1528"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acyl glucuronide (AG) is a reactive metabolite that causes idiosyncratic drug toxicity (IDT). Although the instability of AG is used to predict the IDT risk of novel drug candidates, it sometimes overestimates the IDT risk. We investigated whether the rate of enzymatic AG hydrolysis in human liver microsomes (HLM) can predict the risk of IDT. We used 16 drugs classified into three categories in terms of IDT risk: drugs withdrawn from the market owing to severe IDT (withdrawn, WDN) and drugs still being on the market, regardless of IDT risk (warning, WA) or not (safe, SA). AG was incubated with HLM, and the resulting parent drugs for AG hydrolysis were quantified using HPLC. The rate of enzymatic AG hydrolysis in the HLM of WDN was higher than that in WA and SA, and no difference was observed between WA and SA. We categorized WA and SA as commercially available (CA) drugs and performed a logistic regression analysis. The rate of enzymatic AG hydrolysis in HLM significantly distinguished WDN drugs from CA drugs, with an estimated classification value of 0.189 nmol/min/mg protein. In conclusion, the rate of enzymatic AG hydrolysis in HLM may be useful for predicting the risk in drug development.
{"title":"Enzymatic hydrolysis of acyl glucuronide metabolites in human liver microsomes correlates to the risk of idiosyncratic drug toxicity","authors":"Hiroaki Shimada, Hiroyuki Ikuta, Yu Hashimoto, Yusuke Yabuuchi, Atsushi Kawase, Sumio Matzno, Masahiro Iwaki","doi":"10.1016/j.xphs.2025.01.014","DOIUrl":"10.1016/j.xphs.2025.01.014","url":null,"abstract":"<div><div>Acyl glucuronide (AG) is a reactive metabolite that causes idiosyncratic drug toxicity (IDT). Although the instability of AG is used to predict the IDT risk of novel drug candidates, it sometimes overestimates the IDT risk. We investigated whether the rate of enzymatic AG hydrolysis in human liver microsomes (HLM) can predict the risk of IDT. We used 16 drugs classified into three categories in terms of IDT risk: drugs withdrawn from the market owing to severe IDT (withdrawn, WDN) and drugs still being on the market, regardless of IDT risk (warning, WA) or not (safe, SA). AG was incubated with HLM, and the resulting parent drugs for AG hydrolysis were quantified using HPLC. The rate of enzymatic AG hydrolysis in the HLM of WDN was higher than that in WA and SA, and no difference was observed between WA and SA. We categorized WA and SA as commercially available (CA) drugs and performed a logistic regression analysis. The rate of enzymatic AG hydrolysis in HLM significantly distinguished WDN drugs from CA drugs, with an estimated classification value of 0.189 nmol/min/mg protein. In conclusion, the rate of enzymatic AG hydrolysis in HLM may be useful for predicting the risk in drug development.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 2","pages":"Pages 1307-1314"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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