Pub Date : 2025-12-05DOI: 10.1016/j.ejpb.2025.114953
Nouf D. Alshammari , Prateek Uttreja , Rasha Elkanayati , Leela Raghava Jaidev Chakka , Sateesh Kumar Vemula , Michael A. Repka
Para-coumaric acid (P-CA), a plant-derived phenolic compound, exhibits potent antioxidant activity that counteracts oxidative stress, a key factor delaying wound repair. In this study, a novel biocompatible wound healing scaffold was developed by incorporating P-CA into a chitosan-based polymeric matrix using hot-melt extrusion (HME) combined with fused deposition modeling (FDM) 3D printing. Chitosan (CS), polyethylene oxide (PEO), and cryomilled polycaprolactone (PCL) were used to achieve optimal printability and mechanical strength. The physical mixtures were extruded (110 °C, 50 rpm, 2.5 mm die) and printed into scaffolds (20 × 20 × 1 mm, 80 % infill). The optimized formulation, PCL/CS/P-CA/PEO (35:20:10:35, %w/w), produced scaffolds with excellent dimensional accuracy and mechanical integrity. In-vitro drug release studies demonstrated a sustained release of P-CA over three days. Antibacterial testing against Escherichia coli (E.coli) showed no inhibition with PCL/PEO, while CS and P-CA provided moderate activity individually. Notably, their combination yielded the highest antibacterial effect, suggesting a synergistic effect. These results suggest that P-CA-loaded CS-based scaffolds can provide sustained drug delivery with enhanced antibacterial performance, offering promise for wound healing applications.
{"title":"Development of 3D-printed chitosan/p-coumaric acid scaffolds for wound healing: antibacterial properties and drug release kinetics","authors":"Nouf D. Alshammari , Prateek Uttreja , Rasha Elkanayati , Leela Raghava Jaidev Chakka , Sateesh Kumar Vemula , Michael A. Repka","doi":"10.1016/j.ejpb.2025.114953","DOIUrl":"10.1016/j.ejpb.2025.114953","url":null,"abstract":"<div><div>Para-coumaric acid (P-CA), a plant-derived phenolic compound, exhibits potent antioxidant activity that counteracts oxidative stress, a key factor delaying wound repair. In this study, a novel biocompatible wound healing scaffold was developed by incorporating P-CA into a chitosan-based polymeric matrix using hot-melt extrusion (HME) combined with fused deposition modeling (FDM) 3D printing. Chitosan (CS), polyethylene oxide (PEO), and cryomilled polycaprolactone (PCL) were used to achieve optimal printability and mechanical strength. The physical mixtures were extruded (110 °C, 50 rpm, 2.5 mm die) and printed into scaffolds (20 × 20 × 1 mm, 80 % infill). The optimized formulation, PCL/CS/P-CA/PEO (35:20:10:35, %w/w), produced scaffolds with excellent dimensional accuracy and mechanical integrity. In-vitro drug release studies demonstrated a sustained release of P-CA over three days. Antibacterial testing against <em>Escherichia coli</em> (<em>E.coli</em>) showed no inhibition with PCL/PEO, while CS and P-CA provided moderate activity individually. Notably, their combination yielded the highest antibacterial effect, suggesting a synergistic effect. These results suggest that P-CA-loaded CS-based scaffolds can provide sustained drug delivery with enhanced antibacterial performance, offering promise for wound healing applications.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"219 ","pages":"Article 114953"},"PeriodicalIF":4.3,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1016/j.ejpb.2025.114951
Oleksandr Zdoryk , Michael Lanz , Georgios Imanidis
An apparatus was designed and constructed to simulate the effect of large intestinal motility on drug release measurement in vitro, the purpose being to evaluate the influence of implementing gut motility on release rate from matrix tablets intended for controlled colonic delivery. The USP 1 dissolution apparatus was modified by replacing the basket with a bag holder and a mesh bag that contained the dosage form and adding polymer beads inside and outside of the bag in the dissolution vessel (Bag-Beads model). The motility index resulting from contractions of the gut wall was calculated from intraluminal pressure data measured in the large intestine of healthy volunteers with the SmartPill® ingestible telemetric capsule. It was possible to reproduce this motility index in the in vitro Bag-Beads model utilizing the SmartPill® by adjusting the number of beads of appropriate size and density and the rotation rate of the shaft holding the bag. Reproducibility of motility index and drug release measurement was established and a correlation between in vitro motility index and drug release rate was found for matrix tablets consisting of xyloglycan. This is a plant polysaccharide used as matrix former that was demonstrated previously to provide controlled colonic release by the action of bacterial enzymes. Drug release rate in the Bag-Beads model replicating the in vivo motility index was higher than release rate measured in the compendial USP 2 apparatus. This was true for different levels of bacterial xyloglucanase activity. It is concluded that this simulation of motility provides an indication of the effect of large intestinal dynamics on drug release. A comparison of the measured release rate with preclinical in vivo results is discussed, additional data is required, however, for an in vitro – in vivo correlation. The study highlights the potential to simulate the effect of contractile large intestinal activity for better in vitro prediction of drug release and the possibility to develop and optimize colonic targeting formulations under improved biorelevant testing conditions.
{"title":"Simulation of gut motility effect in the USP dissolution apparatus to study drug release in the large intestine","authors":"Oleksandr Zdoryk , Michael Lanz , Georgios Imanidis","doi":"10.1016/j.ejpb.2025.114951","DOIUrl":"10.1016/j.ejpb.2025.114951","url":null,"abstract":"<div><div>An apparatus was designed and constructed to simulate the effect of large intestinal motility on drug release measurement <em>in vitro</em>, the purpose being to evaluate the influence of implementing gut motility on release rate from matrix tablets intended for controlled colonic delivery. The USP 1 dissolution apparatus was modified by replacing the basket with a bag holder and a mesh bag that contained the dosage form and adding polymer beads inside and outside of the bag in the dissolution vessel (Bag-Beads model). The motility index resulting from contractions of the gut wall was calculated from intraluminal pressure data measured in the large intestine of healthy volunteers with the SmartPill® ingestible telemetric capsule. It was possible to reproduce this motility index in the <em>in vitro</em> Bag-Beads model utilizing the SmartPill® by adjusting the number of beads of appropriate size and density and the rotation rate of the shaft holding the bag. Reproducibility of motility index and drug release measurement was established and a correlation between <em>in vitro</em> motility index and drug release rate was found for matrix tablets consisting of xyloglycan. This is a plant polysaccharide used as matrix former that was demonstrated previously to provide controlled colonic release by the action of bacterial enzymes. Drug release rate in the Bag-Beads model replicating the <em>in vivo</em> motility index was higher than release rate measured in the compendial USP 2 apparatus. This was true for different levels of bacterial xyloglucanase activity. It is concluded that this simulation of motility provides an indication of the effect of large intestinal dynamics on drug release. A comparison of the measured release rate with preclinical <em>in vivo</em> results is discussed, additional data is required, however, for an <em>in vitro – in vivo</em> correlation. The study highlights the potential to simulate the effect of contractile large intestinal activity for better <em>in vitro</em> prediction of drug release and the possibility to develop and optimize colonic targeting formulations under improved biorelevant testing conditions.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"219 ","pages":"Article 114951"},"PeriodicalIF":4.3,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.ejpb.2025.114943
Jingyu Wang, Xiaoqian Xie, Xuewei Cao, Le Sun
The physiologically-based characteristics, the convenience of species extrapolation, and the capacity to integrate diverse in vivo mechanisms have contributed to the increasing employment of the physiologically based pharmacokinetic (PBPK) model in the pharmacokinetic and pharmacodynamic investigations of nanoparticles. However, due to the significant differences in in vivo mechanisms between nanoparticles and small molecule drugs, there are variations in the establishment of PBPK models, such as distribution mechanisms, clearance pathways, drug release, in vivo circulation pathways and indication. This review highlights the distinctions in PBPK modeling strategies between nanoparticles and small molecule drugs. It conducts a comprehensive analysis of current progress in PBPK models for nanoparticles, including model structure design, such as the setup of compartments and sub-compartments, blood circulation and lymphatic circulation, mononuclear phagocyte system, and tumor compartment; the in vivo mechanisms of nanoparticles, such as the permeability-limited mechanism, protein coronas, and drug release from nanoparticles; as well as parameter setting, including the tissue-to-plasma partition coefficient, permeability coefficient, clearance rate, and parameters related to the mononuclear phagocyte system. Ultimately, this review analyzes the validation methods and accuracy of the 61 PBPK models developed over the past two decades. In addition, several existing issues within the PBPK models for nanoparticles, along with their potential solutions, are proposed. It is anticipated that this review will be beneficial to researchers engaged in establishing PBPK models for studying the in vivo behavior of nanoparticles.
{"title":"Prediction of in vivo behavior of nanoparticles using physiologically based pharmacokinetic model: The modeling approach and issues","authors":"Jingyu Wang, Xiaoqian Xie, Xuewei Cao, Le Sun","doi":"10.1016/j.ejpb.2025.114943","DOIUrl":"10.1016/j.ejpb.2025.114943","url":null,"abstract":"<div><div>The physiologically-based characteristics, the convenience of species extrapolation, and the capacity to integrate diverse <em>in vivo</em> mechanisms have contributed to the increasing employment of the physiologically based pharmacokinetic (PBPK) model in the pharmacokinetic and pharmacodynamic investigations of nanoparticles. However, due to the significant differences in <em>in vivo</em> mechanisms between nanoparticles and small molecule drugs, there are variations in the establishment of PBPK models, such as distribution mechanisms, clearance pathways, drug release, <em>in vivo</em> circulation pathways and indication. This review highlights the distinctions in PBPK modeling strategies between nanoparticles and small molecule drugs. It conducts a comprehensive analysis of current progress in PBPK models for nanoparticles, including model structure design, such as the setup of compartments and sub-compartments, blood circulation and lymphatic circulation, mononuclear phagocyte system, and tumor compartment; the <em>in vivo</em> mechanisms of nanoparticles, such as the permeability-limited mechanism, protein coronas, and drug release from nanoparticles; as well as parameter setting, including the tissue-to-plasma partition coefficient, permeability coefficient, clearance rate, and parameters related to the mononuclear phagocyte system. Ultimately, this review analyzes the validation methods and accuracy of the 61 PBPK models developed over the past two decades. In addition, several existing issues within the PBPK models for nanoparticles, along with their potential solutions, are proposed. It is anticipated that this review will be beneficial to researchers engaged in establishing PBPK models for studying the <em>in vivo</em> behavior of nanoparticles.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"219 ","pages":"Article 114943"},"PeriodicalIF":4.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.ejpb.2025.114944
Elaf Mahmood Shihab , Rafif Raad , Saba Naseer Abbas , Maha Hameed Al-bahrani , Mastafa H. Al-Musawi , Hashim H. Al Zuaini , Farah E. Ismaeel , Sheida Mani , Fariborz Sharifianjazi , Ketevan Tavamaishvili , Marjan Mirhaj , Mohamadreza Tavakoli
Craniofacial fractures present intricate geometries that require defect-matched scaffolds for effective regeneration. Advanced 3D printing enables the fabrication of anatomically tailored structures, making it a powerful tool in bone tissue engineering. In this study, a novel 3D-printed scaffold integrating polyvinyl alcohol (PVA), hyaluronic acid (HA), fucoidan (Fc), and merwinite (Mr) nanoparticles with recombinant VEGF was developed as a multifunctional platform, with the aim of promoting both osteogenesis and angiogenesis in complex craniofacial defects. The HA.Fc.VEGF.Mr scaffold exhibited a compressive strength of 3.19 ± 0.11 MPa and an elastic modulus of 21.75 ± 3.32 MPa, making it suitable for craniofacial bone repair. After 28 days of immersion in PBS, the scaffold showed a degradation rate of 50.6 ± 4.6 %, while VEGF release reached 95.1 ± 5.1 % in a sustained, linear pattern by day 11. Bioactivity was validated through apatite-like deposition in SBF immersion for 28 days, alongside measurable release of Ca2+, Si4+, and Mg2+ ions. In vitro assessments demonstrated high cytocompatibility and enhanced osteogenic activity, confirmed by ALP levels, calcium deposition, and the upregulation of COL1, RUNX2, and osteocalcin. Angiogenic potential was further validated using the CAM assay, where the HA.Fc.VEGF.Mr scaffold exhibited superior neovascularization compared to other groups. These findings demonstrate the multifunctionality and regenerative potential of this scaffold for craniofacial bone repair.
{"title":"The effect of recombinant VEGF and merwinite nanoparticles within a 3D-printed scaffold containing hyaluronic acid–fucoidan on craniofacial osteoangiogenesis","authors":"Elaf Mahmood Shihab , Rafif Raad , Saba Naseer Abbas , Maha Hameed Al-bahrani , Mastafa H. Al-Musawi , Hashim H. Al Zuaini , Farah E. Ismaeel , Sheida Mani , Fariborz Sharifianjazi , Ketevan Tavamaishvili , Marjan Mirhaj , Mohamadreza Tavakoli","doi":"10.1016/j.ejpb.2025.114944","DOIUrl":"10.1016/j.ejpb.2025.114944","url":null,"abstract":"<div><div>Craniofacial fractures present intricate geometries that require defect-matched scaffolds for effective regeneration. Advanced 3D printing enables the fabrication of anatomically tailored structures, making it a powerful tool in bone tissue engineering. In this study, a novel 3D-printed scaffold integrating polyvinyl alcohol (PVA), hyaluronic acid (HA), fucoidan (Fc), and merwinite (Mr) nanoparticles with recombinant VEGF was developed as a multifunctional platform, with the aim of promoting both osteogenesis and angiogenesis in complex craniofacial defects. The HA.Fc.VEGF.Mr scaffold exhibited a compressive strength of 3.19 ± 0.11 MPa and an elastic modulus of 21.75 ± 3.32 MPa, making it suitable for craniofacial bone repair. After 28 days of immersion in PBS, the scaffold showed a degradation rate of 50.6 ± 4.6 %, while VEGF release reached 95.1 ± 5.1 % in a sustained, linear pattern by day 11. Bioactivity was validated through apatite-like deposition in SBF immersion for 28 days, alongside measurable release of Ca<sup>2+</sup>, Si<sup>4+</sup>, and Mg<sup>2+</sup> ions. <em>In vitro</em> assessments demonstrated high cytocompatibility and enhanced osteogenic activity, confirmed by ALP levels, calcium deposition, and the upregulation of COL1, RUNX2, and osteocalcin. Angiogenic potential was further validated using the CAM assay, where the HA.Fc.VEGF.Mr scaffold exhibited superior neovascularization compared to other groups. These findings demonstrate the multifunctionality and regenerative potential of this scaffold for craniofacial bone repair.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"219 ","pages":"Article 114944"},"PeriodicalIF":4.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1016/j.ejpb.2025.114942
Takuhiro Totoki , Koki Ogawa , Tetsuya Ozeki
Intranasal delivery offers a non-invasive route for transporting drugs to the brain by bypassing the blood–brain barrier. However, the limited fluid volume in the nasal cavity restricts the solubilization of poorly water-soluble drugs such as carbamazepine (CBZ). In this study, we developed an inclusion complex of CBZ with hydroxypropyl-β-cyclodextrin (HP-βCD) to enhance its solubility and facilitate nose-to-brain delivery. Phase solubility analysis and Job’s plot confirmed the formation of a 1:1 complex. Powder formulations were prepared via freeze-drying and spray freeze-drying. The powders completely dissolved within 5 min and maintained their amorphous state during long-term storage. Intranasal administration of the CBZ/HP-βCD complex powders in rats resulted in significantly improved brain uptake compared with that of the CBZ bulk drug or physical mixtures. Notably, the brain-to-plasma ratio was higher for powder formulations than for liquids, suggesting enhanced direct transport to the brain. Regional brain distribution analysis revealed predominant accumulation in the olfactory bulb, likely because of its anatomical proximity and neural connections with the nasal cavity. Although this pattern is commonly observed during nose-to-brain delivery, it may limit drug access to deeper brain regions. Therefore, further optimization using targeted strategies or delivery enhancers is required. Overall, HP-βCD inclusion complexation represents a promising approach to improve solubility, stability, and brain delivery efficiency of poorly soluble CNS-active drugs following intranasal administration.
{"title":"Inclusion complex of carbamazepine and hydroxypropyl-β-cyclodextrin enhances nose-to-brain delivery via improved solubility","authors":"Takuhiro Totoki , Koki Ogawa , Tetsuya Ozeki","doi":"10.1016/j.ejpb.2025.114942","DOIUrl":"10.1016/j.ejpb.2025.114942","url":null,"abstract":"<div><div>Intranasal delivery offers a non-invasive route for transporting drugs to the brain by bypassing the blood–brain barrier. However, the limited fluid volume in the nasal cavity restricts the solubilization of poorly water-soluble drugs such as carbamazepine (CBZ). In this study, we developed an inclusion complex of CBZ with hydroxypropyl-β-cyclodextrin (HP-βCD) to enhance its solubility and facilitate nose-to-brain delivery. Phase solubility analysis and Job’s plot confirmed the formation of a 1:1 complex. Powder formulations were prepared via freeze-drying and spray freeze-drying. The powders completely dissolved within 5 min and maintained their amorphous state during long-term storage. Intranasal administration of the CBZ/HP-βCD complex powders in rats resulted in significantly improved brain uptake compared with that of the CBZ bulk drug or physical mixtures. Notably, the brain-to-plasma ratio was higher for powder formulations than for liquids, suggesting enhanced direct transport to the brain. Regional brain distribution analysis revealed predominant accumulation in the olfactory bulb, likely because of its anatomical proximity and neural connections with the nasal cavity. Although this pattern is commonly observed during nose-to-brain delivery, it may limit drug access to deeper brain regions. Therefore, further optimization using targeted strategies or delivery enhancers is required. Overall, HP-βCD inclusion complexation represents a promising approach to improve solubility, stability, and brain delivery efficiency of poorly soluble CNS-active drugs following intranasal administration.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"218 ","pages":"Article 114942"},"PeriodicalIF":4.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.ejpb.2025.114941
Hongling Xu , Yangxue Su , Hailong Ma , Xin Zeng , Manlin Wang , Weijie Chen , Xingyu Chen , Qing Zhou , Yang Li , Yaxin Zheng
Macrophages can internalize liposomes and disrupt them to facilitate drug release in the body. However, the effect of targeting liposomes to macrophages on in vivo drug release remains unclear. In this study, we compared the in vivo drug release from macrophage-targeting liposomes (modified with 1,2-distearoyl phosphatidylserine, PS) and PEGylated liposomes in 4 T1 breast tumor-bearing mice. The macrophage-targeting capability of PS-modified liposomes was confirmed by their significantly enhanced cellular uptake in macrophages compared to that of PEGylated liposomes. In vivo drug release studies showed that PS-modified liposomes exhibited higher drug release in various tissues than that of PEGylated liposomes, suggesting that macrophages facilitate the release of the drug from liposomes in the body. Despite a higher percentage of drug release in the tumor, the PS-modified liposomes did not improve antitumor activity compared to PEGylated liposomes due to their rapid clearance. These results suggest that targeting liposomes to macrophages can enhance in vivo drug release but fail to increase antitumor activity due to low tumor selectivity. Therefore, selectively targeting liposomes to tumor-associated macrophages is essential for boosting antitumor effects.
{"title":"Probing in vivo drug release of macrophage-targeting liposomes","authors":"Hongling Xu , Yangxue Su , Hailong Ma , Xin Zeng , Manlin Wang , Weijie Chen , Xingyu Chen , Qing Zhou , Yang Li , Yaxin Zheng","doi":"10.1016/j.ejpb.2025.114941","DOIUrl":"10.1016/j.ejpb.2025.114941","url":null,"abstract":"<div><div>Macrophages can internalize liposomes and disrupt them to facilitate drug release in the body. However, the effect of targeting liposomes to macrophages on <em>in vivo</em> drug release remains unclear. In this study, we compared the <em>in vivo</em> drug release from macrophage-targeting liposomes (modified with 1,2-distearoyl phosphatidylserine, PS) and PEGylated liposomes in 4 T1 breast tumor-bearing mice. The macrophage-targeting capability of PS-modified liposomes was confirmed by their significantly enhanced cellular uptake in macrophages compared to that of PEGylated liposomes. <em>In vivo</em> drug release studies showed that PS-modified liposomes exhibited higher drug release in various tissues than that of PEGylated liposomes, suggesting that macrophages facilitate the release of the drug from liposomes in the body. Despite a higher percentage of drug release in the tumor, the PS-modified liposomes did not improve antitumor activity compared to PEGylated liposomes due to their rapid clearance. These results suggest that targeting liposomes to macrophages can enhance <em>in vivo</em> drug release but fail to increase antitumor activity due to low tumor selectivity. Therefore, selectively targeting liposomes to tumor-associated macrophages is essential for boosting antitumor effects.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"218 ","pages":"Article 114941"},"PeriodicalIF":4.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.ejpb.2025.114940
Jia-Yi Lv , Han Gao , Huan-Fang Xie , Meng-Jia Jin , Bin Di , Jin Xu , Wei-Jie Fang
Histidine (His)-hydrochloride (HCl) is widely used in freeze-dried monoclonal antibody (mAb) formulations, but alternative buffers are required when chloride ions are undesirable. This study evaluates His-acetate (Ac) as a substitute and its impact on the stability of two model mAbs with distinct physicochemical properties— infliximab (mAb-1) and a humanized anti-ricin mAb (mAb-2). pH shifts during freeze-drying were compared among His-Ac, His-HCl, and sodium Ac buffers, confirming strong buffering capacity of His-Ac within pH 5.5–6.5. Conformational and colloidal stability assessments revealed that both mAbs displayed higher melting temperatures or favorable diffusion interaction parameters in His-Ac formulations. Moreover, mAb-2 exhibited a higher collapse temperature in His-Ac compared to His-HCl, indicating improved structural integrity or drying efficiency during primary drying. No significant differences were observed in aggregation onset temperature and glass transition temperature. Aggregation and chemical stability under stress conditions were evaluated by micro-flow imaging, size exclusion chromatography, and ion exchange chromatography. No notable changes in subvisible particle counts or monomer content occurred after freeze-drying. Overall, His-Ac demonstrated stability comparable to or better than His-HCl, supporting its use in freeze-dried mAb formulations.
{"title":"A novel histidine-acetate buffer for freeze-dried monoclonal antibody formulations","authors":"Jia-Yi Lv , Han Gao , Huan-Fang Xie , Meng-Jia Jin , Bin Di , Jin Xu , Wei-Jie Fang","doi":"10.1016/j.ejpb.2025.114940","DOIUrl":"10.1016/j.ejpb.2025.114940","url":null,"abstract":"<div><div>Histidine (His)-hydrochloride (HCl) is widely used in freeze-dried monoclonal antibody (mAb) formulations, but alternative buffers are required when chloride ions are undesirable. This study evaluates His-acetate (Ac) as a substitute and its impact on the stability of two model mAbs with distinct physicochemical properties— infliximab (mAb-1) and a humanized anti-ricin mAb (mAb-2). pH shifts during freeze-drying were compared among His-Ac, His-HCl, and sodium Ac buffers, confirming strong buffering capacity of His-Ac within pH 5.5–6.5. Conformational and colloidal stability assessments revealed that both mAbs displayed higher melting temperatures or favorable diffusion interaction parameters in His-Ac formulations. Moreover, mAb-2 exhibited a higher collapse temperature in His-Ac compared to His-HCl, indicating improved structural integrity or drying efficiency during primary drying. No significant differences were observed in aggregation onset temperature and glass transition temperature. Aggregation and chemical stability under stress conditions were evaluated by micro-flow imaging, size exclusion chromatography, and ion exchange chromatography. No notable changes in subvisible particle counts or monomer content occurred after freeze-drying. Overall, His-Ac demonstrated stability comparable to or better than His-HCl, supporting its use in freeze-dried mAb formulations.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"218 ","pages":"Article 114940"},"PeriodicalIF":4.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-23DOI: 10.1016/j.ejpb.2025.114939
Nadine Lysyk Funk , Flávia Carvalho Tavaniello , Edilson Valmir Benvenutti , Cesar Liberato Petzhold , Karina Paese , Monique Deon , Ruy Carlos Beck
Off-label use of medicines administered via enteral feeding tubes (EFT) can lead to dose inaccuracies, adverse effects and tube obstruction, compromising therapeutic outcomes. Thus, new manufacturing processes are required to design medicines specifically for EFT administration. In this study, a 3D printing semi-solid extrusion (SSE) technique was employed to produce circular-shaped naproxen printlets (P-NPX) (18 × 18 × 2.6 mm, 30 % infill) for aqueous dispersion prior to EFT administration. Mesoporous silica nanoparticles (MSN) were used as NPX nanocarriers for development of printlets (P-NPX-MSN). Results show that MSN drug encapsulation enabled production of printlets with reproducible NPX content, without organic solvents; while providing better shape retention. Aqueous dispersion times were 806 ± 26 s for P-NPX and 813 ± 20 s for P-NPX-MSN. For both formulations, resulting dispersions were slightly acidic (pH ∼ 5), with viscosity of 1.3 cP and particle size distribution that ensured NPX administration without tube obstruction. Drug recovery was ∼ 100 % for both formulations after tube passage. Re-dispersed printlets had reduced vascular event compared to positive controls in Hen’s Egg Test − Chorioallantoic Membrane (HET-CAM) assay (in vitro alternative model) and were classified as slight irritants. This study provides an innovative route for drugs presenting gastric irritation, advancing SSE 3D printing for personalised EFT medicines.
{"title":"Naproxen printlets for extemporaneous dispersion: Designing new medicines for drug delivery through the enteral route","authors":"Nadine Lysyk Funk , Flávia Carvalho Tavaniello , Edilson Valmir Benvenutti , Cesar Liberato Petzhold , Karina Paese , Monique Deon , Ruy Carlos Beck","doi":"10.1016/j.ejpb.2025.114939","DOIUrl":"10.1016/j.ejpb.2025.114939","url":null,"abstract":"<div><div>Off-label use of medicines administered via enteral feeding tubes (EFT) can lead to dose inaccuracies, adverse effects and tube obstruction, compromising therapeutic outcomes. Thus, new manufacturing processes are required to design medicines specifically for EFT administration. In this study, a 3D printing semi-solid extrusion (SSE) technique was employed to produce circular-shaped naproxen printlets (P-NPX) (18 × 18 × 2.6 mm, 30 % infill) for aqueous dispersion prior to EFT administration. Mesoporous silica nanoparticles (MSN) were used as NPX nanocarriers for development of printlets (P-NPX-MSN). Results show that MSN drug encapsulation enabled production of printlets with reproducible NPX content, without organic solvents; while providing better shape retention. Aqueous dispersion times were 806 ± 26 s for P-NPX and 813 ± 20 s for P-NPX-MSN. For both formulations, resulting dispersions were slightly acidic (pH ∼ 5), with viscosity of 1.3 cP and particle size distribution that ensured NPX administration without tube obstruction. Drug recovery was ∼ 100 % for both formulations after tube passage. Re-dispersed printlets had reduced vascular event compared to positive controls in Hen’s Egg Test − Chorioallantoic Membrane (HET-CAM) assay (in vitro alternative model) and were classified as slight irritants. This study provides an innovative route for drugs presenting gastric irritation, advancing SSE 3D printing for personalised EFT medicines.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"218 ","pages":"Article 114939"},"PeriodicalIF":4.3,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145603263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.ejpb.2025.114937
Jack Wright , Keiran Logan , Thomas McKaig , Sukanta Kamila , Chloe McClenaghan , Heather Nesbitt , Mark A. Taylor , Mark Love , Eleanor Stride , Jia-Ling Ruan , Anthony P. McHale , John F. Callan
Despite significant advances in cancer treatment over the past five decades, survival outcomes for pancreatic cancer have remained largely unchanged. The effectiveness of chemotherapy as a treatment for pancreatic cancer is limited by the dense, protective tumour stroma, which impedes drug delivery. Ultrasound-targeted microbubble destruction (UTMD) has emerged as a promising strategy for enhancing the delivery of chemotherapy agents to solid tumours. In this study, we report the development and evaluation of a novel microbubble (MB) formulation, ST-001, which incorporates paclitaxel chemotherapy and a Rose Bengal sonosensitiser for targeted chemo-sonodynamic therapy of pancreatic cancer. The principle of UTMD using ST-001 was demonstrated in a murine model of pancreatic cancer, where B-mode ultrasound imaging was used to visualize MB accumulation within the tumour and its subsequent clearance following the application of therapeutic ultrasound. Preclinical efficacy studies demonstrated a significant survival advantage in ST-001 treated mice, which survived more than twice as long as those treated with standard Taxol, despite receiving only 14% of the paclitaxel dose. Additionally, a preclinical toxicology study in healthy mice demonstrated an excellent safety profile for ST-001, with no adverse effects observed in key hematological and blood biochemical markers, or in the histology of the spleen, liver, and kidneys.
{"title":"Paclitaxel and rose bengal loaded microbubbles for the ultrasound targeted chemo-sonodynamic therapy of pancreatic cancer","authors":"Jack Wright , Keiran Logan , Thomas McKaig , Sukanta Kamila , Chloe McClenaghan , Heather Nesbitt , Mark A. Taylor , Mark Love , Eleanor Stride , Jia-Ling Ruan , Anthony P. McHale , John F. Callan","doi":"10.1016/j.ejpb.2025.114937","DOIUrl":"10.1016/j.ejpb.2025.114937","url":null,"abstract":"<div><div>Despite significant advances in cancer treatment over the past five decades, survival outcomes for pancreatic cancer have remained largely unchanged. The effectiveness of chemotherapy as a treatment for pancreatic cancer is limited by the dense, protective tumour stroma, which impedes drug delivery. Ultrasound-targeted microbubble destruction (UTMD) has emerged as a promising strategy for enhancing the delivery of chemotherapy agents to solid tumours. In this study, we report the development and evaluation of a novel microbubble (MB) formulation, ST-001, which incorporates paclitaxel chemotherapy and a Rose Bengal sonosensitiser for targeted chemo-sonodynamic therapy of pancreatic cancer. The principle of UTMD using ST-001 was demonstrated in a murine model of pancreatic cancer, where B-mode ultrasound imaging was used to visualize MB accumulation within the tumour and its subsequent clearance following the application of therapeutic ultrasound. Preclinical efficacy studies demonstrated a significant survival advantage in ST-001 treated mice, which survived more than twice as long as those treated with standard Taxol, despite receiving only 14% of the paclitaxel dose. Additionally, a preclinical toxicology study in healthy mice demonstrated an excellent safety profile for ST-001, with no adverse effects observed in key hematological and blood biochemical markers, or in the histology of the spleen, liver, and kidneys.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"218 ","pages":"Article 114937"},"PeriodicalIF":4.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spinal cord injury (SCI) induces a cascade of secondary damage mechanisms, including oxidative stress, inflammation, and cell death, which severely impair neuronal recovery. In this study, N-acetylcysteine (NAC), a thiol-based antioxidant with limited CNS bioavailability, was encapsulated in polycaprolactone (PCL) nanofibers using emulsion electrospinning. This approach allows localized and sustained drug delivery. Span 80 and Poloxamer 407 were used as surfactants to stabilize the emulsion and increase the hydrophilicity of the fibers. The resulting core/shell nanofibers (NAC-CSN) exhibited uniform morphology, improved wettability, and favorable mechanical properties, while supporting cell viability and migration in vitro. Sustained NAC release over several days was achieved, indicating diffusion-controlled delivery. In a rat model of SCI, NAC-CSN treatment attenuated oxidative and ferroptotic damage and promoted early neuroregeneration, which enabled measurable locomotor recovery. These findings suggest that NAC-CSN scaffolds offer an effective neuroprotective strategy against secondary SCI damage and, by enabling localized antioxidant delivery at the lesion site, represent a clinically applicable platform for future tissue engineering and translational therapies.
{"title":"N-acetylcysteine loaded electrospun core/shell nanofibers: a promising system for ferroptosis in spinal cord injury","authors":"Meliha Gunes , Gizem Kaftan Öcal , Bünyamin Kılıclı , Anıl Murat Ozturk , Güliz Armagan , Sinem Yaprak Karavana","doi":"10.1016/j.ejpb.2025.114938","DOIUrl":"10.1016/j.ejpb.2025.114938","url":null,"abstract":"<div><div>Spinal cord injury (SCI) induces a cascade of secondary damage mechanisms, including oxidative stress, inflammation, and cell death, which severely impair neuronal recovery. In this study, N-acetylcysteine (NAC), a thiol-based antioxidant with limited CNS bioavailability, was encapsulated in polycaprolactone (PCL) nanofibers using emulsion electrospinning. This approach allows localized and sustained drug delivery. Span 80 and Poloxamer 407 were used as surfactants to stabilize the emulsion and increase the hydrophilicity of the fibers. The resulting core/shell nanofibers (NAC-CSN) exhibited uniform morphology, improved wettability, and favorable mechanical properties, while supporting cell viability and migration <em>in vitro</em>. Sustained NAC release over several days was achieved, indicating diffusion-controlled delivery. In a rat model of SCI, NAC-CSN treatment attenuated oxidative and ferroptotic damage and promoted early neuroregeneration, which enabled measurable locomotor recovery. These findings suggest that NAC-CSN scaffolds offer an effective neuroprotective strategy against secondary SCI damage and, by enabling localized antioxidant delivery at the lesion site, represent a clinically applicable platform for future tissue engineering and translational therapies.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"218 ","pages":"Article 114938"},"PeriodicalIF":4.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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