Pub Date : 2026-01-23DOI: 10.1016/j.xphs.2026.104172
Hesham A Shamsel-Din, Ahmed B Ibrahim
Purine derivatives are valuable anticancer agents, but their limited stability and poor tumor selectivity restrict therapeutic efficacy. This study aimed to overcome these barriers by designing a multifunctional radiotheranostic system integrating a methoxy-substituted purine derivative with silver nanoparticles. The methoxy-purine compound was synthesized, structurally characterized, and radiolabeled with iodine-131 via electrophilic substitution, while also serving as a reducing and stabilizing agent for the green synthesis of silver nanoparticles. The resulting [¹³¹I]I-MeO-Purine-AgNPs were evaluated for radiochemical purity, stability, cytotoxicity, and biodistribution in tumor-bearing mice. Both the free and nanoparticle forms showed high radiochemical purity exceeding 95% and remained stable for 24 hours. The nanoformulation demonstrated significantly improved tumor uptake and retention, with a tumor-to-muscle ratio of 6.57 ± 0.52 compared with 5.20 ± 0.41 for the free compound. Enhanced cytotoxicity resulted from the synergistic actions of the purine pharmacophore, iodine-131 radiotherapeutic emissions, and silver nanoparticle-mediated tumor targeting. These findings demonstrate that the [¹³¹I]I-MeO-Purine-AgNP construct provides a promising, stable, and targeted nano-radiopharmaceutical platform for simultaneous cancer diagnosis and therapy.
{"title":"Promising purine-silver nanoparticles for tumor theranostic: Synthesis, radiolabeling, in vitro cytotoxicity, structure-activity relationship, and in vivo biodistribution studies.","authors":"Hesham A Shamsel-Din, Ahmed B Ibrahim","doi":"10.1016/j.xphs.2026.104172","DOIUrl":"https://doi.org/10.1016/j.xphs.2026.104172","url":null,"abstract":"<p><p>Purine derivatives are valuable anticancer agents, but their limited stability and poor tumor selectivity restrict therapeutic efficacy. This study aimed to overcome these barriers by designing a multifunctional radiotheranostic system integrating a methoxy-substituted purine derivative with silver nanoparticles. The methoxy-purine compound was synthesized, structurally characterized, and radiolabeled with iodine-131 via electrophilic substitution, while also serving as a reducing and stabilizing agent for the green synthesis of silver nanoparticles. The resulting [¹³¹I]I-MeO-Purine-AgNPs were evaluated for radiochemical purity, stability, cytotoxicity, and biodistribution in tumor-bearing mice. Both the free and nanoparticle forms showed high radiochemical purity exceeding 95% and remained stable for 24 hours. The nanoformulation demonstrated significantly improved tumor uptake and retention, with a tumor-to-muscle ratio of 6.57 ± 0.52 compared with 5.20 ± 0.41 for the free compound. Enhanced cytotoxicity resulted from the synergistic actions of the purine pharmacophore, iodine-131 radiotherapeutic emissions, and silver nanoparticle-mediated tumor targeting. These findings demonstrate that the [¹³¹I]I-MeO-Purine-AgNP construct provides a promising, stable, and targeted nano-radiopharmaceutical platform for simultaneous cancer diagnosis and therapy.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"104172"},"PeriodicalIF":3.8,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046636","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 : 2026-01-23DOI: 10.1016/j.xphs.2026.104171
Austin L. Daniels , Sushma Parab , Sigrid C. Kuebler , Soumen Das
Flow imaging microscopy (FIM) is a common imaging-based technique for measuring the subvisible particle content of protein therapies. FIM measurement accuracy strongly depends on particle segmentation, the process of detecting particles in digital images. Some FIM instruments like FlowCam allow users to adjust capture settings, parameters that influence segmentation algorithm performance. However, it has been challenging to identify settings that simultaneously yield accurate measurements of the various particle types found in protein formulations and common particle standards used for instrument qualification and validation. The present study describes generalized capture settings that allow FIM instruments to accurately measure the size and concentration of common particle types encountered in protein therapy development and manufacturing. The settings were developed using a mixture of qualitative and quantitative optimization strategies, as well as using both particle standards and representative samples. At these settings, FIM instruments yielded accurate measurements on opaque (e.g., polystyrene beads) and translucent (e.g., ethylene tetrafluoroethylene particles) particle standards. Protein formulations were also analyzed using these settings to investigate the impact of these settings on the measured subvisible particle content. These settings yield accurate measurements of typical particle types in protein formulations and aim to aid in standardizing FIM as an analytical technique.
{"title":"Generalized flow imaging microscopy instrument settings for measuring subvisible particle sizes and concentrations in protein therapies","authors":"Austin L. Daniels , Sushma Parab , Sigrid C. Kuebler , Soumen Das","doi":"10.1016/j.xphs.2026.104171","DOIUrl":"10.1016/j.xphs.2026.104171","url":null,"abstract":"<div><div>Flow imaging microscopy (FIM) is a common imaging-based technique for measuring the subvisible particle content of protein therapies. FIM measurement accuracy strongly depends on particle segmentation, the process of detecting particles in digital images. Some FIM instruments like FlowCam allow users to adjust capture settings, parameters that influence segmentation algorithm performance. However, it has been challenging to identify settings that simultaneously yield accurate measurements of the various particle types found in protein formulations and common particle standards used for instrument qualification and validation. The present study describes generalized capture settings that allow FIM instruments to accurately measure the size and concentration of common particle types encountered in protein therapy development and manufacturing. The settings were developed using a mixture of qualitative and quantitative optimization strategies, as well as using both particle standards and representative samples. At these settings, FIM instruments yielded accurate measurements on opaque (e.g., polystyrene beads) and translucent (e.g., ethylene tetrafluoroethylene particles) particle standards. Protein formulations were also analyzed using these settings to investigate the impact of these settings on the measured subvisible particle content. These settings yield accurate measurements of typical particle types in protein formulations and aim to aid in standardizing FIM as an analytical technique.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104171"},"PeriodicalIF":3.8,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046617","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 : 2026-01-17DOI: 10.1016/j.xphs.2026.104169
Klaus Wuchner, Felix Nikels, Patrick Garidel, Karoline Bechtold-Peters, Sanjay Gupta, Pierre Guibal, Linda Yi, Neil Steinmeyer, Cyrille Chery, Sebastian Peuker, Ryan E Mould, Shousong Jason Zhang, Charlie Bupp, Felix Wiggers, Yogita Krishnamachari, Indira Prajapati, Stefan Bleher
Polysorbates are commonly used in biotherapeutic drug formulations, but their stability over the course of the product's shelf life is a matter of concern. An industry-wide survey involving 15 biopharmaceutical companies found that 23 biotherapeutic drug products (DPs) in clinical development exhibited significant reductions in polysorbate (PS) content during long-term storage at 2-8 °C. In all cases, this decline did not impact critical quality attributes (CQAs), except for the formation of fatty acid (FA)-related sub-visible particles (SVP) in 7 DPs and FA-visible particles (VP) in 1 DP. Particle formation predominantly resulted from enzymatic or uncharacterized degradation mechanisms, not oxidative pathways. Corrective measures, such as optimization of downstream purification or reformulation, were undertaken only when SVP levels exceeded acceptable thresholds. For PS20 and PS80, the levels of FAs generated were estimated and translated into predicted SVP levels based on theoretical assumptions. Additionally, the current understanding of PS degradation in biopharmaceuticals, based on the latest literature, is summarized, with consideration of safety and immunogenicity aspects related to the primary PS degradation products. Overall, PS degradation is considered manageable and not problematic under practical conditions. Enzymatic hydrolysis of PS is generally deemed acceptable, provided that all CQAs are maintained within specified limits. If FA-related particles are formed it is recommended that the PS degradation pathway is well characterized, and an appropriate control strategy be implemented.
{"title":"Do we worry too much about polysorbate degradation? An industry-wide perspective with real-life case studies.","authors":"Klaus Wuchner, Felix Nikels, Patrick Garidel, Karoline Bechtold-Peters, Sanjay Gupta, Pierre Guibal, Linda Yi, Neil Steinmeyer, Cyrille Chery, Sebastian Peuker, Ryan E Mould, Shousong Jason Zhang, Charlie Bupp, Felix Wiggers, Yogita Krishnamachari, Indira Prajapati, Stefan Bleher","doi":"10.1016/j.xphs.2026.104169","DOIUrl":"10.1016/j.xphs.2026.104169","url":null,"abstract":"<p><p>Polysorbates are commonly used in biotherapeutic drug formulations, but their stability over the course of the product's shelf life is a matter of concern. An industry-wide survey involving 15 biopharmaceutical companies found that 23 biotherapeutic drug products (DPs) in clinical development exhibited significant reductions in polysorbate (PS) content during long-term storage at 2-8 °C. In all cases, this decline did not impact critical quality attributes (CQAs), except for the formation of fatty acid (FA)-related sub-visible particles (SVP) in 7 DPs and FA-visible particles (VP) in 1 DP. Particle formation predominantly resulted from enzymatic or uncharacterized degradation mechanisms, not oxidative pathways. Corrective measures, such as optimization of downstream purification or reformulation, were undertaken only when SVP levels exceeded acceptable thresholds. For PS20 and PS80, the levels of FAs generated were estimated and translated into predicted SVP levels based on theoretical assumptions. Additionally, the current understanding of PS degradation in biopharmaceuticals, based on the latest literature, is summarized, with consideration of safety and immunogenicity aspects related to the primary PS degradation products. Overall, PS degradation is considered manageable and not problematic under practical conditions. Enzymatic hydrolysis of PS is generally deemed acceptable, provided that all CQAs are maintained within specified limits. If FA-related particles are formed it is recommended that the PS degradation pathway is well characterized, and an appropriate control strategy be implemented.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"104169"},"PeriodicalIF":3.8,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003685","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 : 2026-01-16DOI: 10.1016/j.xphs.2026.104168
Bin Zhang , Katiria Flores , Nathyn Horvath , Nidia Gonzalez Lopez , Nishant Sawant , Eric Falcone , Stanley C. Kwok , Shalini Minocha , Vinay Radhakrishnan
Pre-filled syringes (PFSs) are a widely used container closure for therapeutic protein injections, enabling simplified preparation and at-home administration. PFSs are commonly lubricated with sprayed-on silicone oil (SiO), which may migrate into drug product as SiO particles during storage and transportation. Elevated subvisible particle (SVP) counts from SiO present challenges for meeting USP 〈788〉 specification and may raise potential immunogenicity and toxicity risks. Light Obscuration (LO), the primary compendial method for PFS product release and stability testing, cannot differentiate SiO SVPs from proteinaceous SVPs. This drives the need for more comprehensive SVP characterization approaches for PFS products. Microflow Imaging (MFI) measures SVP count, size distributions, morphology and could differentiate fibrillar and translucent proteinaceous SVPs from spherical SiO SVPs using a morphological Aspect Ratio (AR) < 0.85 filter. This manuscript proposes a SVP control strategy for PFS products using MFI, supported by data demonstrating sensitivity to particle detection and stability-indicating capability. Additional data from orthogonal FlowCam (for counts) and complementary Raman Microscopy (for SiO identification) are presented. For Protein X, MFI was tested on multiple lots and shown as effective characterization tool to develop a product-specific control strategy. The proposed SVP control strategy holds considerable promise to assess and control SVP for injectable drug products.
{"title":"Control strategy for subvisible particulates of therapeutic protein injections in pre-filled syringes using flow imaging","authors":"Bin Zhang , Katiria Flores , Nathyn Horvath , Nidia Gonzalez Lopez , Nishant Sawant , Eric Falcone , Stanley C. Kwok , Shalini Minocha , Vinay Radhakrishnan","doi":"10.1016/j.xphs.2026.104168","DOIUrl":"10.1016/j.xphs.2026.104168","url":null,"abstract":"<div><div>Pre-filled syringes (PFSs) are a widely used container closure for therapeutic protein injections, enabling simplified preparation and at-home administration. PFSs are commonly lubricated with sprayed-on silicone oil (SiO), which may migrate into drug product as SiO particles during storage and transportation. Elevated subvisible particle (SVP) counts from SiO present challenges for meeting USP 〈788〉 specification and may raise potential immunogenicity and toxicity risks. Light Obscuration (LO), the primary compendial method for PFS product release and stability testing, cannot differentiate SiO SVPs from proteinaceous SVPs. This drives the need for more comprehensive SVP characterization approaches for PFS products. Microflow Imaging (MFI) measures SVP count, size distributions, morphology and could differentiate fibrillar and translucent proteinaceous SVPs from spherical SiO SVPs using a morphological Aspect Ratio (AR) < 0.85 filter. This manuscript proposes a SVP control strategy for PFS products using MFI, supported by data demonstrating sensitivity to particle detection and stability-indicating capability. Additional data from orthogonal FlowCam (for counts) and complementary Raman Microscopy (for SiO identification) are presented. For Protein X, MFI was tested on multiple lots and shown as effective characterization tool to develop a product-specific control strategy. The proposed SVP control strategy holds considerable promise to assess and control SVP for injectable drug products.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104168"},"PeriodicalIF":3.8,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998423","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 : 2026-01-15DOI: 10.1016/j.xphs.2026.104165
Likhit Mandal , Dr. Praveen Kumar Vemuri
Antimicrobial resistance resulting from the widespread use of topical antibiotics has accelerated the need for non-antibiotic strategies in ocular therapy. Povidone-iodine (PVP-I) offers broad antimicrobial activity without inducing resistance, while dexamethasone provides potent anti-inflammatory effects, making their combination a promising ophthalmic suspension for infectious and inflammatory conditions. To ensure therapeutic consistency, in-vitro dissolution testing is critical for suspension of Dexamethasone, as it characterizes drug release, supports formulation optimization, and provides evidence for regulatory bio-waivers. This investigation was carried out to develop and validate a USP Type-IV flow-through cell method (closed-loop configuration) for assessing the in-vitro release behavior of dexamethasone (0.1%) from povidone-iodine (0.6%) and dexamethasone (0.1%) ophthalmic suspension. The current dissolution method employed phosphate buffer (pH 7.4) with 0.1% β-cyclodextrin as medium, chosen for solubility, stability, and sink condition. A 100 kDa cellulose ester membrane enabled controlled diffusion. Chromatographic separation was performed on an ACE Excel-5 C8 column (250 × 4.6 mm, 5 µm) using an isocratic mobile phase of 0.6% β-cyclodextrin in water and acetonitrile (1:1 v/v). Partial validation per ICH Q2(R2) confirmed excellent linearity (r² > 0.999), precision (%RSD < 2.0), accuracy (98.5–101.5%), and solution stability for 72 h. The method was discriminatory for formulation changes and suitable for routine and stability testing of ophthalmic suspensions.
{"title":"A comprehensive discussion on analytical method development and validation of a USP type-IV dissolution method for dexamethasone in a combination ophthalmic suspension with povidone-iodine","authors":"Likhit Mandal , Dr. Praveen Kumar Vemuri","doi":"10.1016/j.xphs.2026.104165","DOIUrl":"10.1016/j.xphs.2026.104165","url":null,"abstract":"<div><div>Antimicrobial resistance resulting from the widespread use of topical antibiotics has accelerated the need for non-antibiotic strategies in ocular therapy. Povidone-iodine (PVP-I) offers broad antimicrobial activity without inducing resistance, while dexamethasone provides potent anti-inflammatory effects, making their combination a promising ophthalmic suspension for infectious and inflammatory conditions. To ensure therapeutic consistency, in-vitro dissolution testing is critical for suspension of Dexamethasone, as it characterizes drug release, supports formulation optimization, and provides evidence for regulatory bio-waivers. This investigation was carried out to develop and validate a USP Type-IV flow-through cell method (closed-loop configuration) for assessing the in-vitro release behavior of dexamethasone (0.1%) from povidone-iodine (0.6%) and dexamethasone (0.1%) ophthalmic suspension. The current dissolution method employed phosphate buffer (pH 7.4) with 0.1% β-cyclodextrin as medium, chosen for solubility, stability, and sink condition. A 100 kDa cellulose ester membrane enabled controlled diffusion. Chromatographic separation was performed on an ACE Excel-5 C8 column (250 × 4.6 mm, 5 µm) using an isocratic mobile phase of 0.6% β-cyclodextrin in water and acetonitrile (1:1 v/v). Partial validation per ICH Q2(R2) confirmed excellent linearity (r² > 0.999), precision (%RSD < 2.0), accuracy (98.5–101.5%), and solution stability for 72 h. The method was discriminatory for formulation changes and suitable for routine and stability testing of ophthalmic suspensions.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104165"},"PeriodicalIF":3.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994529","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 : 2026-01-15DOI: 10.1016/j.xphs.2026.104167
Yu Tong Tam , Harsh Patel , Jeffrey C. Haley , Alexander Dimmling , Devin B. Tesar , Alavattam Sreedhara
Delivering large therapeutic monoclonal antibodies (mAbs) from solid polymer matrices via hot-melt extrusion (HME) is a promising approach to achieving a prolonged release profile. However, this approach presents significant challenges due to protein instability under high temperatures and high shear forces typically involved in the extrusion process and during extended-release duration in physiological conditions. Herein, we discuss the encapsulation of a large therapeutic mAb (MW ∼150 kDa) at a high loading (≥50%) via HME and vacuum compression molding (VCM) with ethylene vinyl acetate (EVA) and its stability analysis upon release from EVA rods. Protein stability of a model mAb (mAb1) with respect to protein aggregation, structural stability, and relative binding activity was evaluated. A solid spray-dried formulation of mAb1 can maintain its protein stability against elevated temperature and repeated heating cycles during the manufacturing process with EVA. In the present work, we show that applying a second thermal step via VCM can enable a homogeneous distribution of solid spray-dried particles of mAb1 embedded within the solid EVA matrix. Additionally, our results demonstrate that implementing a membrane coating on EVA rods can yield a slow release of mAb1 from EVA rods without significantly impacting protein stability, representing a viable approach for the long-acting delivery of mAbs using EVA as a non-biodegradable polymer implant.
{"title":"Long-acting delivery of a model monoclonal antibody from ethylene vinyl acetate implants at a high loading: Drug release and protein stability","authors":"Yu Tong Tam , Harsh Patel , Jeffrey C. Haley , Alexander Dimmling , Devin B. Tesar , Alavattam Sreedhara","doi":"10.1016/j.xphs.2026.104167","DOIUrl":"10.1016/j.xphs.2026.104167","url":null,"abstract":"<div><div>Delivering large therapeutic monoclonal antibodies (mAbs) from solid polymer matrices via hot-melt extrusion (HME) is a promising approach to achieving a prolonged release profile. However, this approach presents significant challenges due to protein instability under high temperatures and high shear forces typically involved in the extrusion process and during extended-release duration in physiological conditions. Herein, we discuss the encapsulation of a large therapeutic mAb (MW ∼150 kDa) at a high loading (≥50%) via HME and vacuum compression molding (VCM) with ethylene vinyl acetate (EVA) and its stability analysis upon release from EVA rods. Protein stability of a model mAb (mAb1) with respect to protein aggregation, structural stability, and relative binding activity was evaluated. A solid spray-dried formulation of mAb1 can maintain its protein stability against elevated temperature and repeated heating cycles during the manufacturing process with EVA. In the present work, we show that applying a second thermal step via VCM can enable a homogeneous distribution of solid spray-dried particles of mAb1 embedded within the solid EVA matrix. Additionally, our results demonstrate that implementing a membrane coating on EVA rods can yield a slow release of mAb1 from EVA rods without significantly impacting protein stability, representing a viable approach for the long-acting delivery of mAbs using EVA as a non-biodegradable polymer implant.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104167"},"PeriodicalIF":3.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994475","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 : 2026-01-14DOI: 10.1016/j.xphs.2026.104164
Charlotte Sikking , T.Ton Dinh , Mirjam Crul , Stefan G. Romeijn , Charlotte van Kesteren , Marieke M. Beex-Oosterhuis
For biological drugs, subvisible particle formation can cause loss of efficacy of the drug or trigger immune reactions. Transport of ready-to-administer infusion bags, to enable home treatment of cancer patients, might cause particle formation. The primary aim of this observational prospective pharmaceutical study is to investigate the effect of transport by car on the formation of subvisible particles in ready-to-administer infusion bags with trastuzumab. Hereto, trastuzumab was compounded (n = 19 infusion bags) in the hospital pharmacy and transported by car to patients’ homes and thereafter to the laboratory for analysis. The analysis comprised visual inspection and qualitative and quantitative analyses of particle formation. The key findings revealed no significant difference in amount of particles between transported and non-transported bags based on the FlowCam, nanoparticle and HP-SEC analyses. Light obscuration revealed a statistically significant lower amount of particles ≥10 μm in non-transported samples, although absolute numbers of these particles was low. Transporting reconstituted trastuzumab infusion bags by car does not lead to a significant increase in the amount of aggregates in the infusion bags. Therefore, with regards to particle formation, home treatment of patients with trastuzumab was safe.
{"title":"Analysis of the formation of (sub)visual particles in ready-to-administer trastuzumab infusion bags during transport from the hospital pharmacy to patients at home","authors":"Charlotte Sikking , T.Ton Dinh , Mirjam Crul , Stefan G. Romeijn , Charlotte van Kesteren , Marieke M. Beex-Oosterhuis","doi":"10.1016/j.xphs.2026.104164","DOIUrl":"10.1016/j.xphs.2026.104164","url":null,"abstract":"<div><div>For biological drugs, subvisible particle formation can cause loss of efficacy of the drug or trigger immune reactions. Transport of ready-to-administer infusion bags, to enable home treatment of cancer patients, might cause particle formation. The primary aim of this observational prospective pharmaceutical study is to investigate the effect of transport by car on the formation of subvisible particles in ready-to-administer infusion bags with trastuzumab. Hereto, trastuzumab was compounded (<em>n</em> = 19 infusion bags) in the hospital pharmacy and transported by car to patients’ homes and thereafter to the laboratory for analysis. The analysis comprised visual inspection and qualitative and quantitative analyses of particle formation. The key findings revealed no significant difference in amount of particles between transported and non-transported bags based on the FlowCam, nanoparticle and HP-SEC analyses. Light obscuration revealed a statistically significant lower amount of particles ≥10 μm in non-transported samples, although absolute numbers of these particles was low. Transporting reconstituted trastuzumab infusion bags by car does not lead to a significant increase in the amount of aggregates in the infusion bags. Therefore, with regards to particle formation, home treatment of patients with trastuzumab was safe.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104164"},"PeriodicalIF":3.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989762","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 : 2026-01-14DOI: 10.1016/j.xphs.2026.104166
Min-Jung Kim , Jaeeun Jung , Jieun Kang , Nohra Park , Sung Jun Lee , Geunhye Yeo , Sangho Lee
Hemopexin (Hx) is a plasma glycoprotein that scavenges free heme with sub-nanomolar affinity and under development as a therapeutic. Solvent/detergent treatment (S/D) is routinely applied to plasma-derived manufacturing for viral safety and generally considered non-disruptive. However, the histidine- and aromatic residue-rich heme pocket at the inter-domain interface may render Hx susceptible to S/D. We investigated whether S/D perturbs the tertiary structure of Hx and elevated ionic strength mitigates such effects. Changes in the apparent size and activity of Hx exposed to S/D were assessed by size-exclusion HPLC (SE-HPLC) and functional assays. S/D consistently reduced activity and shifted SE-HPLC profiles toward a larger hydrodynamic size. Small-angle X-ray scattering (SAXS) revealed expansion of the molecular envelope of Hx by S/D, suggesting that the heme pocket may initiate hinge relaxation between two β-propeller domains of Hx. To mitigate such expansion by S/D, we screened a formulation range of NaCl concentration. Increasing ionic strength compacted SAXS profiles toward the native state and restored activity, consistent with pocket stabilization by charge. These findings identify Hx as an exception to typical S/D tolerance and demonstrate that modulation of ionic strength represents an effective strategy to preserve structural integrity and function while fulfilling viral safety requirements.
{"title":"Ionic strength mitigates solvent/detergent–induced tertiary expansion of hemopexin","authors":"Min-Jung Kim , Jaeeun Jung , Jieun Kang , Nohra Park , Sung Jun Lee , Geunhye Yeo , Sangho Lee","doi":"10.1016/j.xphs.2026.104166","DOIUrl":"10.1016/j.xphs.2026.104166","url":null,"abstract":"<div><div>Hemopexin (Hx) is a plasma glycoprotein that scavenges free heme with sub-nanomolar affinity and under development as a therapeutic. Solvent/detergent treatment (S/D) is routinely applied to plasma-derived manufacturing for viral safety and generally considered non-disruptive. However, the histidine- and aromatic residue-rich heme pocket at the inter-domain interface may render Hx susceptible to S/D. We investigated whether S/D perturbs the tertiary structure of Hx and elevated ionic strength mitigates such effects. Changes in the apparent size and activity of Hx exposed to S/D were assessed by size-exclusion HPLC (SE-HPLC) and functional assays. S/D consistently reduced activity and shifted SE-HPLC profiles toward a larger hydrodynamic size. Small-angle X-ray scattering (SAXS) revealed expansion of the molecular envelope of Hx by S/D, suggesting that the heme pocket may initiate hinge relaxation between two β-propeller domains of Hx. To mitigate such expansion by S/D, we screened a formulation range of NaCl concentration. Increasing ionic strength compacted SAXS profiles toward the native state and restored activity, consistent with pocket stabilization by charge. These findings identify Hx as an exception to typical S/D tolerance and demonstrate that modulation of ionic strength represents an effective strategy to preserve structural integrity and function while fulfilling viral safety requirements.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104166"},"PeriodicalIF":3.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989735","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 : 2026-01-13DOI: 10.1016/j.xphs.2026.104160
Siyuan Zhao, Chang Chu, Cuiping Li, Qiaoli Zhai, Juan Liu, Huan Sun, Xin Wu, Kourong Shi, Wei Fan
This study aimed to develop a novel peptide-drug conjugate (PDC) by conjugating 3-fluoro-10-hydroxy-evodiamine (FOE) with a bicyclic peptide (BiP) targeting the EphA2 receptor. The goal was to enhance the solubility, tumor selectivity, and therapeutic efficacy of FOE against colorectal cancer (CRC). FOE and BiP were chemically synthesized and coupled through a valine-citrulline cleavable linker to generate BiP-FOE. The compound was structurally characterized, and its solubility, plasma stability, and in vitro cytotoxicity were evaluated in CRC cells. Its effects on cell migration, invasion, apoptosis, and the cell cycle were also assessed. The in vivo targeting ability, antitumor efficacy, and safety were evaluated in an HCT116 xenograft mouse model. BiP-FOE exhibited a greater than 200-fold improvement in aqueous solubility and good metabolic stability. In vitro, BiP-FOE showed selective and potent cytotoxicity toward EphA2-positive HCT116 cells, significantly inhibiting migration and invasion while inducing S-phase arrest and apoptosis. In vivo, BiP-FOE achieved significant accumulation at the tumor site and effectively suppressed tumor growth, with efficacy comparable to or exceeding that of 5-FU. It demonstrated a favorable safety profile, showing minimal body weight loss, negligible hemolysis, and no detectable organ toxicity. BiP-FOE successfully combines the cytotoxic potential of FOE with the tumor-targeting capacity of a bicyclic peptide, resulting in improved solubility, selectivity, efficacy, and safety. These findings highlight BiP-FOE as a promising candidate for targeted CRC therapy and warrant further preclinical development.
{"title":"A novel bicyclic peptide-drug conjugate of 3-fluoro-10-hydroxy-evodiamine for targeted colorectal cancer therapy.","authors":"Siyuan Zhao, Chang Chu, Cuiping Li, Qiaoli Zhai, Juan Liu, Huan Sun, Xin Wu, Kourong Shi, Wei Fan","doi":"10.1016/j.xphs.2026.104160","DOIUrl":"https://doi.org/10.1016/j.xphs.2026.104160","url":null,"abstract":"<p><p>This study aimed to develop a novel peptide-drug conjugate (PDC) by conjugating 3-fluoro-10-hydroxy-evodiamine (FOE) with a bicyclic peptide (BiP) targeting the EphA2 receptor. The goal was to enhance the solubility, tumor selectivity, and therapeutic efficacy of FOE against colorectal cancer (CRC). FOE and BiP were chemically synthesized and coupled through a valine-citrulline cleavable linker to generate BiP-FOE. The compound was structurally characterized, and its solubility, plasma stability, and in vitro cytotoxicity were evaluated in CRC cells. Its effects on cell migration, invasion, apoptosis, and the cell cycle were also assessed. The in vivo targeting ability, antitumor efficacy, and safety were evaluated in an HCT116 xenograft mouse model. BiP-FOE exhibited a greater than 200-fold improvement in aqueous solubility and good metabolic stability. In vitro, BiP-FOE showed selective and potent cytotoxicity toward EphA2-positive HCT116 cells, significantly inhibiting migration and invasion while inducing S-phase arrest and apoptosis. In vivo, BiP-FOE achieved significant accumulation at the tumor site and effectively suppressed tumor growth, with efficacy comparable to or exceeding that of 5-FU. It demonstrated a favorable safety profile, showing minimal body weight loss, negligible hemolysis, and no detectable organ toxicity. BiP-FOE successfully combines the cytotoxic potential of FOE with the tumor-targeting capacity of a bicyclic peptide, resulting in improved solubility, selectivity, efficacy, and safety. These findings highlight BiP-FOE as a promising candidate for targeted CRC therapy and warrant further preclinical development.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"104160"},"PeriodicalIF":3.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989746","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 : 2026-01-13DOI: 10.1016/j.xphs.2026.104163
Po-Chang Chiang , Jia Liu , Karthik Nagapudi , Jodie Pang , Emile Plise , Michael Dolton , Matthew R. Durk
The oral route of administration continues to be the preferred and most convenient method for drug delivery among both patients and healthcare professionals. This preference is based not only on its user-friendliness but also on the practicality it provides regarding formulation flexibility and dosage adjustability. Nevertheless, the effectiveness of oral drug delivery is significantly influenced by the ADME (Absorption, Distribution, Metabolism, and Excretion) characteristics of the drug. Among these characteristics, permeability is a key factor affecting oral bioavailability, making the exploration of permeability enhancers a vital research focus to boost oral absorption. Recent investigations have highlighted sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) as a promising permeability enhancer, demonstrating its potential to increase the absorption rates of various substances. Despite its proven effectiveness, the precise mechanisms by which SNAC promotes this enhancement are not yet fully understood. Furthermore, the specific dosage of SNAC required to improve drug absorption remains unclear. This study aims to examine the dose-dependent effects of SNAC on the model compound cyanocobalamin (Vitamin B12) in rats. The in vivo findings were integrated with modeling and simulation to determine the critical concentration of SNAC and the minimum molar ratio, and the overall enhancement effect at various SNAC concentrations for cyanocobalamin needed to achieve permeation enhancement. This knowledge could assist formulators in more effectively incorporating SNAC into formulations for enhanced therapeutic outcomes.
{"title":"Investigating the SNAC-to-drug ratio for the oral absorption of cyanocobalamin in rats","authors":"Po-Chang Chiang , Jia Liu , Karthik Nagapudi , Jodie Pang , Emile Plise , Michael Dolton , Matthew R. Durk","doi":"10.1016/j.xphs.2026.104163","DOIUrl":"10.1016/j.xphs.2026.104163","url":null,"abstract":"<div><div>The oral route of administration continues to be the preferred and most convenient method for drug delivery among both patients and healthcare professionals. This preference is based not only on its user-friendliness but also on the practicality it provides regarding formulation flexibility and dosage adjustability. Nevertheless, the effectiveness of oral drug delivery is significantly influenced by the ADME (Absorption, Distribution, Metabolism, and Excretion) characteristics of the drug. Among these characteristics, permeability is a key factor affecting oral bioavailability, making the exploration of permeability enhancers a vital research focus to boost oral absorption. Recent investigations have highlighted sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) as a promising permeability enhancer, demonstrating its potential to increase the absorption rates of various substances. Despite its proven effectiveness, the precise mechanisms by which SNAC promotes this enhancement are not yet fully understood. Furthermore, the specific dosage of SNAC required to improve drug absorption remains unclear. This study aims to examine the dose-dependent effects of SNAC on the model compound cyanocobalamin (Vitamin B12) in rats. The in vivo findings were integrated with modeling and simulation to determine the critical concentration of SNAC and the minimum molar ratio, and the overall enhancement effect at various SNAC concentrations for cyanocobalamin needed to achieve permeation enhancement. This knowledge could assist formulators in more effectively incorporating SNAC into formulations for enhanced therapeutic outcomes.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104163"},"PeriodicalIF":3.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989798","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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