Pub Date : 2024-11-05DOI: 10.1016/j.ejps.2024.106940
Juan Aparicio-Blanco , Irene I. López-Torres , María Alonso-Berenguel , Ana I. Torres-Suárez , Cristina Martín-Sabroso
Infections associated with implants are the most serious complications in joint replacement surgeries and can jeopardize the functionality of orthopedic implants. Local antimicrobial delivery could enable antibiotics to attain concentrations above the minimum inhibitory concentration (MIC) threshold at the joint replacement site while preventing systemic side effects.
Therefore, there is a dire need for the development of improved biomaterial-based delivery systems for local antibiotic administration in prosthetic infections. In this context, this review highlights the latest breakthroughs in the design of biomaterial-based formulations intended for the prophylaxis and treatment of prosthetic infections. Delivery systems for distinct forms of administration (i.e., direct intra-articular administration, loading into bone cements, coating of implant surfaces, or loading into hydrogels) are here comprehensively compiled with a focus on the design of microparticles and nanosystems for local antimicrobial administration and their impact on distinct in vitro and in vivo models of implant infections.
{"title":"Local antimicrobial delivery systems for prophylaxis and treatment of periprosthetic traumatological infections","authors":"Juan Aparicio-Blanco , Irene I. López-Torres , María Alonso-Berenguel , Ana I. Torres-Suárez , Cristina Martín-Sabroso","doi":"10.1016/j.ejps.2024.106940","DOIUrl":"10.1016/j.ejps.2024.106940","url":null,"abstract":"<div><div>Infections associated with implants are the most serious complications in joint replacement surgeries and can jeopardize the functionality of orthopedic implants. Local antimicrobial delivery could enable antibiotics to attain concentrations above the minimum inhibitory concentration (MIC) threshold at the joint replacement site while preventing systemic side effects.</div><div>Therefore, there is a dire need for the development of improved biomaterial-based delivery systems for local antibiotic administration in prosthetic infections. In this context, this review highlights the latest breakthroughs in the design of biomaterial-based formulations intended for the prophylaxis and treatment of prosthetic infections. Delivery systems for distinct forms of administration (<em>i.e.</em>, direct intra-articular administration, loading into bone cements, coating of implant surfaces, or loading into hydrogels) are here comprehensively compiled with a focus on the design of microparticles and nanosystems for local antimicrobial administration and their impact on distinct <em>in vitro</em> and <em>in vivo</em> models of implant infections.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106940"},"PeriodicalIF":4.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142586453","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 : 2024-11-05DOI: 10.1016/j.ejps.2024.106956
Paula Översti , Bing Han , Jari Kavakka , Staffan Torssell , Esko Tirronen , Marjatta Louhi-Kultanen , Pekka Oinas
Phytosterols (C29H50O), also known as plant sterols and stanols, are valuable biomolecules with a variety of applications in the pharma, food, and cosmetics industries. Phytosterols are typically manufactured from vegetable oil and tall oil feedstocks through a cooling crystallization process. Depending on the feedstock used, the composition regarding individual phytosterols and phytostanols (saturated analogs of phytosterols), also varies to a large extent. In the current research it was observed that by adding a small amount of water to the organic solvent [i.e., n(water)/n(acetone) of 0.17, n(water)/n(ethanol) of 0.13, and n(water)/n(ethyl acetate) of 0.10], the final phytosterol profile regarding phytosterol and phytostanol concentrations can be modified. This can be explained by the different solubility behavior of phytosterols and phytostanols in the studied solvent systems, based on experimental results obtained from transmissivity measurements. Phytostanols have surprisingly low solubility when compared to phytosterols in all the studied solvent systems. However, in the presence of water, phytosterol solubility decreased more compared to phytostanols. To the best of our knowledge, this is the first time that phytostanol solubility has been systematically studied. Moreover, phytosterol and phytostanol concentrations in a crystallized product with varying binary solvent systems containing water has not previously been reported. The measured experimental solubility data correlated well with the studied solubility models (van't Hoff, modified Apelblat, Buchowski-Ksiazaczak (λh), and polynomial equations). Understanding the solubility behavior of phytosterols and phytostanols allows to optimize the crystallization process itself toward a broader raw material selection, and better yield and quality in the production of phytosterols from plant-based raw materials. In addition, these findings can potentially be further utilized in phytosterol formulations for various applications.
{"title":"The effect of water on the crystallization of phytosterols and phytostanols in organic solutions","authors":"Paula Översti , Bing Han , Jari Kavakka , Staffan Torssell , Esko Tirronen , Marjatta Louhi-Kultanen , Pekka Oinas","doi":"10.1016/j.ejps.2024.106956","DOIUrl":"10.1016/j.ejps.2024.106956","url":null,"abstract":"<div><div>Phytosterols (C<sub>29</sub>H<sub>50</sub>O), also known as plant sterols and stanols, are valuable biomolecules with a variety of applications in the pharma, food, and cosmetics industries. Phytosterols are typically manufactured from vegetable oil and tall oil feedstocks through a cooling crystallization process. Depending on the feedstock used, the composition regarding individual phytosterols and phytostanols (saturated analogs of phytosterols), also varies to a large extent. In the current research it was observed that by adding a small amount of water to the organic solvent [i.e., n(water)/n(acetone) of 0.17, n(water)/n(ethanol) of 0.13, and n(water)/n(ethyl acetate) of 0.10], the final phytosterol profile regarding phytosterol and phytostanol concentrations can be modified. This can be explained by the different solubility behavior of phytosterols and phytostanols in the studied solvent systems, based on experimental results obtained from transmissivity measurements. Phytostanols have surprisingly low solubility when compared to phytosterols in all the studied solvent systems. However, in the presence of water, phytosterol solubility decreased more compared to phytostanols. To the best of our knowledge, this is the first time that phytostanol solubility has been systematically studied. Moreover, phytosterol and phytostanol concentrations in a crystallized product with varying binary solvent systems containing water has not previously been reported. The measured experimental solubility data correlated well with the studied solubility models (van't Hoff, modified Apelblat, Buchowski-Ksiazaczak (λh), and polynomial equations). Understanding the solubility behavior of phytosterols and phytostanols allows to optimize the crystallization process itself toward a broader raw material selection, and better yield and quality in the production of phytosterols from plant-based raw materials. In addition, these findings can potentially be further utilized in phytosterol formulations for various applications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106956"},"PeriodicalIF":4.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603735","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 : 2024-11-04DOI: 10.1016/j.ejps.2024.106955
Menghan Wang , Ying Yang , Dongdong Li , Yanmei Wang , Tailin Ji , Qingqing Li , Jiye Zhang , Peipei Zhang , Jin Su
As one of the most common and serious infections caused by Candida albicans (C. albicans), periprosthetic joint infection (PJI) increasingly concerns surgeons and scientists. Generally, biofilms shield C. albicans from antifungal agents and immune clearance and induce drug-resistant strains. Developing novel strategies for PJI to get rid of current drug-resistant problems is highly needed. In our study, splitomicin (SP) can inhibit the mycelium formation of C. albicans and enhance the drug sensitivity of C. albicans to miconazole nitrate (MCZ). The combination of SP and MCZ significantly inhibited the viability, proliferation and adhesion of C. albicans, reduced the yeast to hyphae transition and biofilm formation. When SP and MCZ were coloaded in the β-glucan hydrogel, a viscoelastic solid with porous 3D network, sustained release and erosion properties was obtained. In the in vivo PJI mice model, SP-MCZ-β-glucan hydrogel effectively reduced the colonization and aggregation of C. albicans around the implant, reduced the pathological changes caused by C. albicans in the femur tissue. Therefore, SP-MCZ-β-glucan hydrogel holds a great promise for the management of C. albicans infection around joint prosthesis.
{"title":"Miconazole-splitomicin combined β-glucan hydrogel for effective prevention of Candida albicans periprosthetic joint infection","authors":"Menghan Wang , Ying Yang , Dongdong Li , Yanmei Wang , Tailin Ji , Qingqing Li , Jiye Zhang , Peipei Zhang , Jin Su","doi":"10.1016/j.ejps.2024.106955","DOIUrl":"10.1016/j.ejps.2024.106955","url":null,"abstract":"<div><div>As one of the most common and serious infections caused by <em>Candida albicans</em> (<em>C. albicans</em>), periprosthetic joint infection (PJI) increasingly concerns surgeons and scientists. Generally, biofilms shield <em>C. albicans</em> from antifungal agents and immune clearance and induce drug-resistant strains. Developing novel strategies for PJI to get rid of current drug-resistant problems is highly needed. In our study, splitomicin (SP) can inhibit the mycelium formation of <em>C. albicans</em> and enhance the drug sensitivity of <em>C. albicans</em> to miconazole nitrate (MCZ). The combination of SP and MCZ significantly inhibited the viability, proliferation and adhesion of <em>C. albicans</em>, reduced the yeast to hyphae transition and biofilm formation. When SP and MCZ were coloaded in the β-glucan hydrogel, a viscoelastic solid with porous 3D network, sustained release and erosion properties was obtained. In the <em>in vivo</em> PJI mice model, SP-MCZ-β-glucan hydrogel effectively reduced the colonization and aggregation of <em>C. albicans</em> around the implant, reduced the pathological changes caused by <em>C. albicans</em> in the femur tissue. Therefore, SP-MCZ-β-glucan hydrogel holds a great promise for the management of <em>C. albicans</em> infection around joint prosthesis.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106955"},"PeriodicalIF":4.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590361","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}
Preterm birth (PTB) remains a leading cause of infant mortality and morbidity, significantly affecting the long-term health, welfare, and development of newborns. Tocolytics, such as ritodrine, a β2-adrenergic receptor agonist, are widely used in developing countries due to their affordability for preventing PTB by inhibiting uterine contractions. However, ritodrine's short half-life necessitates frequent administration, and prolonged high-dose usage often leads to serious maternal side effects, prompting discontinuation. The uterine first-pass effect, where vaginally administered drugs preferentially target the uterus, can enhance drug concentration in uterine tissue while minimizing systemic absorption and side effects. This study designed a kind of ritodrine-loaded thermosensitive gel (Gel@Rit) to intervene in PTB by exploiting the uterine first-pass effect and investigate its underlying mechanisms. The gel, formulated with poloxamer, demonstrated excellent temperature sensitivity and viscosity, ensuring sustained ritodrine release in vitro. Plasma pharmacokinetic and tissue distribution studies in pregnant mice confirmed the uterine first-pass effect, showing significantly higher drug concentrations in the uterus and markedly lower plasma levels following Gel@Rit administration. The distinctive drug-time curve in Gel@Rit-treated mice, along with uterine tissue fluorescence profiles, elucidated four mechanisms of uterine localization: diffusion through reproductive tract cavities, penetration via vaginal and uterine structures, diffusion through systemic circulation, and retrograde transvaginal veno-uterine artery exchange. This study provides valuable insights into vaginal drug delivery research methodologies, advancing therapeutic strategies for uterine-related conditions and benefiting clinical outcomes in PTB prevention.
{"title":"Uterine first-pass effect: Unlocking the potential of vaginally administered ritodrine-loaded thermosensitive gel for uterine drug delivery","authors":"Yu Xin , Weidong Fei , Meng Zhang , Yue Chen , Yujie Peng , Dongli Sun , Xiaoling Zheng , Xiaojun Zhu , Yunchun Zhao , Caihong Zheng","doi":"10.1016/j.ejps.2024.106945","DOIUrl":"10.1016/j.ejps.2024.106945","url":null,"abstract":"<div><div>Preterm birth (PTB) remains a leading cause of infant mortality and morbidity, significantly affecting the long-term health, welfare, and development of newborns. Tocolytics, such as ritodrine, a β<sub>2</sub>-adrenergic receptor agonist, are widely used in developing countries due to their affordability for preventing PTB by inhibiting uterine contractions. However, ritodrine's short half-life necessitates frequent administration, and prolonged high-dose usage often leads to serious maternal side effects, prompting discontinuation. The uterine first-pass effect, where vaginally administered drugs preferentially target the uterus, can enhance drug concentration in uterine tissue while minimizing systemic absorption and side effects. This study designed a kind of ritodrine-loaded thermosensitive gel (Gel@Rit) to intervene in PTB by exploiting the uterine first-pass effect and investigate its underlying mechanisms. The gel, formulated with poloxamer, demonstrated excellent temperature sensitivity and viscosity, ensuring sustained ritodrine release <em>in vitro</em>. Plasma pharmacokinetic and tissue distribution studies in pregnant mice confirmed the uterine first-pass effect, showing significantly higher drug concentrations in the uterus and markedly lower plasma levels following Gel@Rit administration. The distinctive drug-time curve in Gel@Rit-treated mice, along with uterine tissue fluorescence profiles, elucidated four mechanisms of uterine localization: diffusion through reproductive tract cavities, penetration via vaginal and uterine structures, diffusion through systemic circulation, and retrograde transvaginal veno-uterine artery exchange. This study provides valuable insights into vaginal drug delivery research methodologies, advancing therapeutic strategies for uterine-related conditions and benefiting clinical outcomes in PTB prevention.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106945"},"PeriodicalIF":4.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568138","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 : 2024-11-01DOI: 10.1016/j.ejps.2024.106953
Sa Wang, Pengyu Wang, Xiaotong Song, Xinyuan Ma, Long Wei, Yongxiang Zheng, Rong Yu, Chun Zhang
Interleukin-11 (IL-11) has recently been identified as a critical profibrotic cytokine, and IL-11 signaling pathway via IL-11Rα and GP130 receptors has been shown to be a promising therapeutic target for the treatment of fibrotic diseases. Herein, we devised two kinds of IL-11 dimer with receptor-biased binding ability through site-specific crosslinking at the interface involving GP130 binding and signaling, aiming to explore their therapeutic potentials for bleomycin-induced pulmonary fibrosis in mice. A single cysteine mutation at site W147 of human IL-11 (IL-11 W147C) was conducted for site-specific crosslinking. The ability of GP130 to bind to IL-11 W147C dimer was substantially weakened by cysteine-based dimerization, while the ability of IL-11 W147C dimer to bind to IL-11Rα was almost entirely preserved or even enhanced. The IL-11 W147C dimer potently inhibited TF-1 cell proliferation and TGF-β1-induced human lung fibroblast differentiation into myofibroblasts. We also showed that dimerization substantially extended the circulation time of IL-11 W147C dimer in healthy rats. Subcutaneous administration of IL-11 W147C dimer significantly reduced extracellular matrix deposition, preserved alveolar architecture and alleviated pulmonary fibrosis development in mice. The findings of this study may provide a general strategy for the design of cytokine-based receptor-biased antagonists and agonists targeting these multifaceted signaling pathways.
{"title":"Site-specific dimerization of interleukin-11 alleviates bleomycin-induced pulmonary fibrosis in mice","authors":"Sa Wang, Pengyu Wang, Xiaotong Song, Xinyuan Ma, Long Wei, Yongxiang Zheng, Rong Yu, Chun Zhang","doi":"10.1016/j.ejps.2024.106953","DOIUrl":"10.1016/j.ejps.2024.106953","url":null,"abstract":"<div><div>Interleukin-11 (IL-11) has recently been identified as a critical profibrotic cytokine, and IL-11 signaling pathway via IL-11Rα and GP130 receptors has been shown to be a promising therapeutic target for the treatment of fibrotic diseases. Herein, we devised two kinds of IL-11 dimer with receptor-biased binding ability through site-specific crosslinking at the interface involving GP130 binding and signaling, aiming to explore their therapeutic potentials for bleomycin-induced pulmonary fibrosis in mice. A single cysteine mutation at site W147 of human IL-11 (IL-11 W147C) was conducted for site-specific crosslinking. The ability of GP130 to bind to IL-11 W147C dimer was substantially weakened by cysteine-based dimerization, while the ability of IL-11 W147C dimer to bind to IL-11Rα was almost entirely preserved or even enhanced. The IL-11 W147C dimer potently inhibited TF-1 cell proliferation and TGF-β1-induced human lung fibroblast differentiation into myofibroblasts. We also showed that dimerization substantially extended the circulation time of IL-11 W147C dimer in healthy rats. Subcutaneous administration of IL-11 W147C dimer significantly reduced extracellular matrix deposition, preserved alveolar architecture and alleviated pulmonary fibrosis development in mice. The findings of this study may provide a general strategy for the design of cytokine-based receptor-biased antagonists and agonists targeting these multifaceted signaling pathways.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106953"},"PeriodicalIF":4.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568133","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 : 2024-11-01DOI: 10.1016/j.ejps.2024.106954
Maximilian Zäh , Christoph Brandenbusch , Fiora Artusio , Gabriele Sadowski , Roberto Pisano
Pharmaceutical peptides are susceptible to aggregation in solution, making stabilization by addition of suitable excipients essential. To investigate this stabilization, lengthy and cost-intensive experiments are often necessary. In this work, a differential scanning calorimetry (DSC) based method was developed that allows a rapid assessment of the stabilization properties of excipients regarding the aggregation of pharmaceutical peptides. The stabilization properties of investigated excipients are derived from the thermal behavior around Tg', the glass-transition temperature of the excipient-rich phase after freezing, as a function of repeated freeze-thaw cycles.
The pharmaceutical peptide glucagon was investigated in combination with the excipients trehalose and lactose. In addition to the type of excipient, the concentration ratio of peptide/excipient was also varied. Lactose proved to better stabilize glucagon solutions compared to trehalose. On the one hand, the onset of aggregation could be delayed and after aggregation started the aggregation kinetics were slowed down. In addition, it was shown that a high excipient to peptide ratio, regardless of the type of excipient tested, reduces the aggregation tendency of glucagon.
{"title":"DSC reveals the excipient impact on aggregation propensity of pharmaceutical peptides during freezing","authors":"Maximilian Zäh , Christoph Brandenbusch , Fiora Artusio , Gabriele Sadowski , Roberto Pisano","doi":"10.1016/j.ejps.2024.106954","DOIUrl":"10.1016/j.ejps.2024.106954","url":null,"abstract":"<div><div>Pharmaceutical peptides are susceptible to aggregation in solution, making stabilization by addition of suitable excipients essential. To investigate this stabilization, lengthy and cost-intensive experiments are often necessary. In this work, a differential scanning calorimetry (DSC) based method was developed that allows a rapid assessment of the stabilization properties of excipients regarding the aggregation of pharmaceutical peptides. The stabilization properties of investigated excipients are derived from the thermal behavior around T<sub>g</sub>', the glass-transition temperature of the excipient-rich phase after freezing, as a function of repeated freeze-thaw cycles.</div><div>The pharmaceutical peptide glucagon was investigated in combination with the excipients trehalose and lactose. In addition to the type of excipient, the concentration ratio of peptide/excipient was also varied. Lactose proved to better stabilize glucagon solutions compared to trehalose. On the one hand, the onset of aggregation could be delayed and after aggregation started the aggregation kinetics were slowed down. In addition, it was shown that a high excipient to peptide ratio, regardless of the type of excipient tested, reduces the aggregation tendency of glucagon.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106954"},"PeriodicalIF":4.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568056","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}
Solid lipid nanoparticles (SLNs) are becoming increasingly favored for their robust biocompatibility and their capacity to enhance drug solubility, particularly for drugs with limited water solubility. This study delves into the effectiveness of the hot melt sonication technique in fabricating SLNs with high drug loading capabilities and sustained release characteristics. Griseofulvin (GF), chosen as a representative drug due to its poor water solubility, was encapsulated into SLNs composed of stearic acid. Optimization of chitosan-coated GF-loaded SLNs (CS-GF-SLN) was conducted using a Box-Behnken design. Utilizing the desirability approach, optimal parameters were determined, including a lipid quantity of 450.593 mg, chitosan content of 268.67 mg, and sonication duration of 2.14 h. These parameters resulted in a zeta potential of -34.8 mV and a particle size (PS) of 56.87 nm. Following optimization, the refined formulation underwent comprehensive assessment across various parameters. Notably, the drug encapsulated within SLNs exhibited sustained release over three days, as illustrated by the in-vitro drug release profile. The optimized formulation demonstrated a bioavailability enhancement by approximately 1.7 to 2.0 times compared to the conventional formulation. Furthermore, administration of drug-loaded SLNs to a macrophage cell line demonstrated no cytotoxicity, affirming their suitability as conventional drug delivery platforms for GF.
{"title":"Formulation optimization of chitosan surface coated solid lipid nanoparticles of griseofulvin: A Box-Behnken design and in vivo pharmacokinetic study","authors":"Nagaraja Sreeharsha , Samathoti Prasanthi , Gudhanti Siva Naga Koteswara Rao , Lakshmi Radhika Gajula , Nikita Biradar , Prakash Goudanavar , Nimbagal Raghavendra Naveen , Predeepkumar Narayanappa Shiroorkar , Girish Meravanige , Mallikarjun Telsang , Afzal Haq Asif , Pavan Kumar Pavagada Sreenivasalu","doi":"10.1016/j.ejps.2024.106951","DOIUrl":"10.1016/j.ejps.2024.106951","url":null,"abstract":"<div><div>Solid lipid nanoparticles (SLNs) are becoming increasingly favored for their robust biocompatibility and their capacity to enhance drug solubility, particularly for drugs with limited water solubility. This study delves into the effectiveness of the hot melt sonication technique in fabricating SLNs with high drug loading capabilities and sustained release characteristics. Griseofulvin (GF), chosen as a representative drug due to its poor water solubility, was encapsulated into SLNs composed of stearic acid. Optimization of chitosan-coated GF-loaded SLNs (CS-GF-SLN) was conducted using a Box-Behnken design. Utilizing the desirability approach, optimal parameters were determined, including a lipid quantity of 450.593 mg, chitosan content of 268.67 mg, and sonication duration of 2.14 h. These parameters resulted in a zeta potential of -34.8 mV and a particle size (PS) of 56.87 nm. Following optimization, the refined formulation underwent comprehensive assessment across various parameters. Notably, the drug encapsulated within SLNs exhibited sustained release over three days, as illustrated by the in-vitro drug release profile. The optimized formulation demonstrated a bioavailability enhancement by approximately 1.7 to 2.0 times compared to the conventional formulation. Furthermore, administration of drug-loaded SLNs to a macrophage cell line demonstrated no cytotoxicity, affirming their suitability as conventional drug delivery platforms for GF.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106951"},"PeriodicalIF":4.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564127","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 : 2024-10-29DOI: 10.1016/j.ejps.2024.106952
Michaela Cohrs , Nele Clottens , Pieter Ramaut , Kevin Braeckmans , Stefaan De Smedt , Tiene Bauters , Hristo L. Svilenov
Postproduction handling and in-hospital transportation of antibody drugs cause mechanical stress, including interfacial and shear stress, that can induce antibody unfolding and aggregation. The handling practices differ significantly between hospitals and the impact on protein stability is unknown. For example, the mechanical stress caused by transport via pneumatic tube systems (PTS) on therapeutic antibody aggregation is a potential safety and quality gap.
The aim of this study was to investigate whether mechanical stress and PTS transportation in a hospital cause aggregation of five commonly used antibody drugs diluted in infusion bags.
Orthogonal analytical methods showed that the handling and PTS transportation in this hospital did not cause aggregation of the investigated mAbs. The absence of aggregation could be explained by the reduction of interfacial stress due to headspace removal from the infusion bags and a mechanical sensor indicated that there was also only a moderate amount of mechanical stress caused by transportation with this particular PTS.
Although this case study focuses on five antibody drugs and the practices in one hospital, the work demonstrates how to evaluate whether other handling and transportation practices cause significant mechanical stress that could compromise the quality and safety of antibody drugs.
{"title":"Impact of pneumatic tube transportation on the aggregation of monoclonal antibodies in clinical practice","authors":"Michaela Cohrs , Nele Clottens , Pieter Ramaut , Kevin Braeckmans , Stefaan De Smedt , Tiene Bauters , Hristo L. Svilenov","doi":"10.1016/j.ejps.2024.106952","DOIUrl":"10.1016/j.ejps.2024.106952","url":null,"abstract":"<div><div>Postproduction handling and in-hospital transportation of antibody drugs cause mechanical stress, including interfacial and shear stress, that can induce antibody unfolding and aggregation. The handling practices differ significantly between hospitals and the impact on protein stability is unknown. For example, the mechanical stress caused by transport via pneumatic tube systems (PTS) on therapeutic antibody aggregation is a potential safety and quality gap.</div><div>The aim of this study was to investigate whether mechanical stress and PTS transportation in a hospital cause aggregation of five commonly used antibody drugs diluted in infusion bags.</div><div>Orthogonal analytical methods showed that the handling and PTS transportation in this hospital did not cause aggregation of the investigated mAbs. The absence of aggregation could be explained by the reduction of interfacial stress due to headspace removal from the infusion bags and a mechanical sensor indicated that there was also only a moderate amount of mechanical stress caused by transportation with this particular PTS.</div><div>Although this case study focuses on five antibody drugs and the practices in one hospital, the work demonstrates how to evaluate whether other handling and transportation practices cause significant mechanical stress that could compromise the quality and safety of antibody drugs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106952"},"PeriodicalIF":4.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557407","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 : 2024-10-28DOI: 10.1016/j.ejps.2024.106946
Zunsheng Han , Zhonghua Xia , Jie Xia , Igor V. Tetko , Song Wu
Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Existing models for predicting PPB often suffer from low prediction accuracy and poor interpretability, especially for high PPB compounds, and are most often not experimentally validated. Here, we carried out a strict data curation protocol, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model (available on the OCHEM platform https://ochem.eu/article/29) was further retrospectively validated for a set of 63 poly-fluorinated molecules and prospectively validated for a set of 25 highly diverse compounds, and its performance for both these sets was superior to that of the other previously reported models. Furthermore, we identified the physicochemical and structural characteristics of high and low PPB molecules for further structural optimization. Finally, we provide practical and detailed recommendations for structural optimization to decrease PPB binding of lead compounds.
{"title":"The state-of-the-art machine learning model for plasma protein binding prediction: Computational modeling with OCHEM and experimental validation","authors":"Zunsheng Han , Zhonghua Xia , Jie Xia , Igor V. Tetko , Song Wu","doi":"10.1016/j.ejps.2024.106946","DOIUrl":"10.1016/j.ejps.2024.106946","url":null,"abstract":"<div><div>Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Existing models for predicting PPB often suffer from low prediction accuracy and poor interpretability, especially for high PPB compounds, and are most often not experimentally validated. Here, we carried out a strict data curation protocol, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model (available on the OCHEM platform <span><span>https://ochem.eu/article/29</span><svg><path></path></svg></span>) was further retrospectively validated for a set of 63 poly-fluorinated molecules and prospectively validated for a set of 25 highly diverse compounds, and its performance for both these sets was superior to that of the other previously reported models. Furthermore, we identified the physicochemical and structural characteristics of high and low PPB molecules for further structural optimization. Finally, we provide practical and detailed recommendations for structural optimization to decrease PPB binding of lead compounds.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106946"},"PeriodicalIF":4.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561379","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 : 2024-10-26DOI: 10.1016/j.ejps.2024.106950
F. Mostafaei , B. Benque , P. Doshi , M.T. Santangelo , H.G. Lee , D. Gomes Lopes , M. Schaefer , J.G. Khinast , D. Jajcevic
Bin blending is one of the main steps in pharmaceutical production processes. Commercial-scale production of expensive products typically does not allow to perform a large number of experiments in order to optimize the process. Alternatively, Discrete Element Method (DEM) simulations can be used to evaluate the powder behavior (flow and blending pattern) during blending, identify the risks (e.g., segregation), and provide solutions to mitigate them. In this work, DEM simulations are used to investigate the blending of two granulated powders in commercial-scale cone and cylindrical (hoop) blenders. The DEM contact model parameters were calibrated based on the experimental compression and ring shear tests for both granulated powders to mimic the bulk powder behavior in the simulations. The model's output was compared to the experiments in one of the blending cases. The blending efficiency in the cone blenders was evaluated considering the fill levels, the presence of baffles, the rotating directions, the filling order, and the bin sizes. Furthermore, for the hoop blenders, the effects of blender's angle, rotation speed, and filling order were addressed. The main findings of the work were that, in cone blenders, the blending can be improved by introducing baffles and changing in the rotational direction frequently. In hoop blenders, blending can be improved by increasing the inclination angle from the horizontal plane and the rotational speed.
{"title":"Exploring pharmaceutical powder behavior in commercial-scale bin blending: A DEM simulation study","authors":"F. Mostafaei , B. Benque , P. Doshi , M.T. Santangelo , H.G. Lee , D. Gomes Lopes , M. Schaefer , J.G. Khinast , D. Jajcevic","doi":"10.1016/j.ejps.2024.106950","DOIUrl":"10.1016/j.ejps.2024.106950","url":null,"abstract":"<div><div>Bin blending is one of the main steps in pharmaceutical production processes. Commercial-scale production of expensive products typically does not allow to perform a large number of experiments in order to optimize the process. Alternatively, Discrete Element Method (DEM) simulations can be used to evaluate the powder behavior (flow and blending pattern) during blending, identify the risks (e.g., segregation), and provide solutions to mitigate them. In this work, DEM simulations are used to investigate the blending of two granulated powders in commercial-scale cone and cylindrical (hoop) blenders. The DEM contact model parameters were calibrated based on the experimental compression and ring shear tests for both granulated powders to mimic the bulk powder behavior in the simulations. The model's output was compared to the experiments in one of the blending cases. The blending efficiency in the cone blenders was evaluated considering the fill levels, the presence of baffles, the rotating directions, the filling order, and the bin sizes. Furthermore, for the hoop blenders, the effects of blender's angle, rotation speed, and filling order were addressed. The main findings of the work were that, in cone blenders, the blending can be improved by introducing baffles and changing in the rotational direction frequently. In hoop blenders, blending can be improved by increasing the inclination angle from the horizontal plane and the rotational speed.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106950"},"PeriodicalIF":4.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568065","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}
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