Pub Date : 2026-02-20Epub Date: 2026-01-14DOI: 10.1016/j.ijpharm.2026.126593
A. De Man , B. Van Snick , T. Verbeek , M. Otava , A. Kumar , C. Vervaet , V. Vanhoorne , T. De Beer
The current study investigated the differences in volumetric twin-screw feeding behaviour of 15 commonly known oral solid dosage powder materials between two loss-in-weight feeders, differing in scale. Principal Component Analysis (PCA) was applied to study the importance of material properties on various volumetric feeding output parameters. In addition, the developed PCA model was used to explore material properties that could explain observed differences in screw filling as a function of the screw speed per feeder. To study changes in the importance of material properties of various powder materials between two loss-in-weight feeding systems, multiple Partial Least Squares (PLS) regression models were developed. These PLS models focused on predicting screw filling, feeding capacity decay and short-term feeding variability. Overall, the difference in overhead pressure between both studied feeders appeared to affect the importance of material properties, mostly for the maximum screw filling. The developed models highlighted the importance of material properties on twin-screw feeding behaviour per loss-in-weight feeder and will support future research on developing a surrogate material identification and selection methodology.
{"title":"Exploring twin-screw feeding behaviour across different loss-in-weight feeders","authors":"A. De Man , B. Van Snick , T. Verbeek , M. Otava , A. Kumar , C. Vervaet , V. Vanhoorne , T. De Beer","doi":"10.1016/j.ijpharm.2026.126593","DOIUrl":"10.1016/j.ijpharm.2026.126593","url":null,"abstract":"<div><div>The current study investigated the differences in volumetric twin-screw feeding behaviour of 15 commonly known oral solid dosage powder materials between two loss-in-weight feeders, differing in scale. Principal Component Analysis (PCA) was applied to study the importance of material properties on various volumetric feeding output parameters. In addition, the developed PCA model was used to explore material properties that could explain observed differences in screw filling as a function of the screw speed per feeder. To study changes in the importance of material properties of various powder materials between two loss-in-weight feeding systems, multiple Partial Least Squares (PLS) regression models were developed. These PLS models focused on predicting screw filling, feeding capacity decay and short-term feeding variability. Overall, the difference in overhead pressure between both studied feeders appeared to affect the importance of material properties, mostly for the maximum screw filling. The developed models highlighted the importance of material properties on twin-screw feeding behaviour per loss-in-weight feeder and will support future research on developing a surrogate material identification and selection methodology.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126593"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989169","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 : 2026-02-20Epub Date: 2026-01-14DOI: 10.1016/j.ijpharm.2026.126592
Mona Mohammadkhani, Janusz Kozinski, Leila Pakzad
Optimizing pulmonary drug delivery requires a detailed understanding of aerosol–mucus interactions, particularly under pathological conditions such as chronic obstructive pulmonary disease (COPD), where mucus composition, rheology, and surface properties are markedly altered. This study investigated how modulating the drug–mucus contact angle—a surrogate for mucosal wettability—affects deposition outcomes in pressurized metered-dose inhalers (pMDIs). A realistic mouth–throat (MT) model was fabricated and coated with artificial pulmonary mucus, then experimentally characterized to establish a baseline contact angle of 22.5°. This baseline value was implemented in the numerical model, which was validated against in vitro Next Generation Impactor (NGI) data and subsequently extended to simulate contact angles of 40° and 60°, representing reduced wettability scenarios typical of severe COPD.
Our findings showed that disease-altered wettability conditions (θ = 60°) increased overall drug deposition by approximately 13.4 % compared with the healthy airway condition (θ = 22.5°), underscoring the adhesive contribution to droplet retention. Simulations further revealed that oropharyngeal deposition is highly sensitive to mucus wettability: lower interfacial tension promoted complete spreading and mucosal absorption, whereas higher interfacial tension led to droplet rebound, limited transfer, and downstream re-entrainment. Collectively, these findings provide mechanistic insight into how controlling drug–mucus interfacial characteristics can improve aerosol delivery in disease-compromised airways.
{"title":"Mucoadhesion-controlled deposition and impaction dynamics of inhaled drugs in artificial mucus-coated airways: a coupled experimental–computational study","authors":"Mona Mohammadkhani, Janusz Kozinski, Leila Pakzad","doi":"10.1016/j.ijpharm.2026.126592","DOIUrl":"10.1016/j.ijpharm.2026.126592","url":null,"abstract":"<div><div>Optimizing pulmonary drug delivery requires a detailed understanding of aerosol–mucus interactions, particularly under pathological conditions such as chronic obstructive pulmonary disease (COPD), where mucus composition, rheology, and surface properties are markedly altered. This study investigated how modulating the drug–mucus contact angle—a surrogate for mucosal wettability—affects deposition outcomes in pressurized metered-dose inhalers (pMDIs). A realistic mouth–throat (MT) model was fabricated and coated with artificial pulmonary mucus, then experimentally characterized to establish a baseline contact angle of 22.5°. This baseline value was implemented in the numerical model, which was validated against in vitro Next Generation Impactor (NGI) data and subsequently extended to simulate contact angles of 40° and 60°, representing reduced wettability scenarios typical of severe COPD.</div><div>Our findings showed that disease-altered wettability conditions (θ = 60°) increased overall drug deposition by approximately 13.4 % compared with the healthy airway condition (θ = 22.5°), underscoring the adhesive contribution to droplet retention. Simulations further revealed that oropharyngeal deposition is highly sensitive to mucus wettability: lower interfacial tension promoted complete spreading and mucosal absorption, whereas higher interfacial tension led to droplet rebound, limited transfer, and downstream re-entrainment. Collectively, these findings provide mechanistic insight into how controlling drug–mucus interfacial characteristics can improve aerosol delivery in disease-compromised airways.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126592"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989187","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 : 2026-02-20Epub Date: 2026-01-10DOI: 10.1016/j.ijpharm.2026.126586
Salvatore Zarrella , Elena Wanvig i Dot , J. Axel Zeitler , Timothy M. Korter
Terahertz time-domain spectroscopy (THz-TDS) is a non-destructive, high-resolution method that probes low-frequency vibrational modes and intermolecular interactions between the microwave and infrared regions inaccessible by other spectroscopic methods. The technique is established in the pharmaceutical sciences and is now spreading to other areas in need of an extensive understanding of material properties. Despite the growth in THz applications, measurements are still confined to specialized laboratories. This tutorial seeks to provide a practical standard operating procedure for taking transmission measurements of compacted powders and is designed for new users across disciplines. We describe sample preparation, spectrometer configuration, data acquisition, signal processing, quantitative analysis, and troubleshooting. Emphasis is placed on practical strategies such as selecting appropriate diluents, ensuring homogeneous sample mixing, optimizing pellet thickness, aligning the optical setup, and handling spectral artifacts like Fabry–Pérot etalons. Additionally, the tutorial guides users through data transformation using FFT and apodization techniques to extract accurate optical constants such as refractive index and absorption coefficients. By consolidating best practices and minimizing technical barriers, this resource aims to make THz spectroscopy more accessible and reproducible for researchers across disciplines.
{"title":"From powder to spectrum: A tutorial of terahertz transmission time-domain spectroscopy","authors":"Salvatore Zarrella , Elena Wanvig i Dot , J. Axel Zeitler , Timothy M. Korter","doi":"10.1016/j.ijpharm.2026.126586","DOIUrl":"10.1016/j.ijpharm.2026.126586","url":null,"abstract":"<div><div>Terahertz time-domain spectroscopy (THz-TDS) is a non-destructive, high-resolution method that probes low-frequency vibrational modes and intermolecular interactions between the microwave and infrared regions inaccessible by other spectroscopic methods. The technique is established in the pharmaceutical sciences and is now spreading to other areas in need of an extensive understanding of material properties. Despite the growth in THz applications, measurements are still confined to specialized laboratories. This tutorial seeks to provide a practical standard operating procedure for taking transmission measurements of compacted powders and is designed for new users across disciplines. We describe sample preparation, spectrometer configuration, data acquisition, signal processing, quantitative analysis, and troubleshooting. Emphasis is placed on practical strategies such as selecting appropriate diluents, ensuring homogeneous sample mixing, optimizing pellet thickness, aligning the optical setup, and handling spectral artifacts like Fabry–Pérot etalons. Additionally, the tutorial guides users through data transformation using FFT and apodization techniques to extract accurate optical constants such as refractive index and absorption coefficients. By consolidating best practices and minimizing technical barriers, this resource aims to make THz spectroscopy more accessible and reproducible for researchers across disciplines.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126586"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957679","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 : 2026-02-20Epub Date: 2026-01-12DOI: 10.1016/j.ijpharm.2026.126591
Ana Centeno Duarte , Nadia Toffoletto , Rita Martins Pais , Zélia Lumack do Monte , Madalena Salema-Oom , Sandra Tenreiro , Ana Paula Serro
Drug-eluting contact lenses (CLs) offer a promising approach to treat diabetic eye diseases. Compared to conventional treatments such as eye drops, CLs enhance drug bioavailability and residence time on the eye, while addressing patient compliance issues. Additionally, CLs are a safer alternative to ocular injections. In this study, CLs were designed for the sustained release of rosmarinic acid (RA), a natural polyphenol known for its antioxidant, anti-inflammatory, antibacterial and neuroprotective properties, which has been proposed as an alternative therapy for diabetic ocular complications. Acrylic and silicone-based hydrogels were produced and pre-treated with vitamin E. A sustained release of RA for up to 24 h was achieved under hydrodynamic conditions, which is compatible with the use of this hydrogel as daily CLs. Comprehensive characterization confirmed that the hydrogel’s physicochemical properties met commercial CLs standards, while no signs of ocular irritation nor cytotoxicity were observed in vitro. Ex vivo studies demonstrated that the drug could permeate through ocular tissues. The ocular RA distribution after the CL application was estimated in silico. Finally, the neuroprotective effect of RA was evaluated ex vivo in porcine retinal explants, confirming the therapeutic relevance of the designed hydrogels in the treatment of the diabetic eye.
{"title":"Rosmarinic acid-eluting contact lenses as a multifunctional therapeutic system for diabetic ocular complications","authors":"Ana Centeno Duarte , Nadia Toffoletto , Rita Martins Pais , Zélia Lumack do Monte , Madalena Salema-Oom , Sandra Tenreiro , Ana Paula Serro","doi":"10.1016/j.ijpharm.2026.126591","DOIUrl":"10.1016/j.ijpharm.2026.126591","url":null,"abstract":"<div><div>Drug-eluting contact lenses (CLs) offer a promising approach to treat diabetic eye diseases. Compared to conventional treatments such as eye drops, CLs enhance drug bioavailability and residence time on the eye, while addressing patient compliance issues. Additionally, CLs are a safer alternative to ocular injections. In this study, CLs were designed for the sustained release of rosmarinic acid (RA), a natural polyphenol known for its antioxidant, anti-inflammatory, antibacterial and neuroprotective properties, which has been proposed as an alternative therapy for diabetic ocular complications. Acrylic and silicone-based hydrogels were produced and pre-treated with vitamin E. A sustained release of RA for up to 24 h was achieved under hydrodynamic conditions, which is compatible with the use of this hydrogel as daily CLs. Comprehensive characterization confirmed that the hydrogel’s physicochemical properties met commercial CLs standards, while no signs of ocular irritation nor cytotoxicity were observed <em>in vitro</em>. <em>Ex vivo</em> studies demonstrated that the drug could permeate through ocular tissues. The ocular RA distribution after the CL application was estimated <em>in silico</em>. Finally, the neuroprotective effect of RA was evaluated <em>ex vivo</em> in porcine retinal explants, confirming the therapeutic relevance of the designed hydrogels in the treatment of the diabetic eye.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126591"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984754","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}
Bevacizumab was the first available anti-angiogenic therapy with a monoclonal antibody, initially approved against colorectal cancer. It is now used intravenously in the treatment of several other malignancies and in combination with chemotherapy. It binds to all circulating, soluble VEGF-A isoforms, inhibiting angiogenesis, and thereby reducing tumor vascularization. During storage, transport, dilution and administration, Bevacizumab is exposed to different stressors, including ambient light, which can compromise its efficacy and safety. Here, the chemico-physical instability induced by real-life doses of light on Bevacizumab-bvzr is reported in relation to the observed target recognition, anti-angiogenic activity and in vitro immunogenicity. By irradiating the diluted formulation with real-life light doses, mimicking the IV bag infusions, no conformational changes were found by UV and CD spectroscopy. However, light-exposed Bevacizumab-bvzr exhibited a marked reduction in VEGF-A binding, along with decreased anti-angiogenic efficacy in HUVEC-based assays. This loss of activity can be explained by the formation of a small amount of high molecular weight aggregates, detected by SEC, SDS-PAGE and TEM analyses, in all irradiated samples and in a concentration-dependent manner. The immunogenic properties of Bevacizumab aggregates were assessed on human monocytes-derived dendritic cells, which revealed no evidence of dendritic cell activation in vitro. At very high light doses, highlighting the amino acid modifications, mono/dioxidations and deamidation were detected by LC-MS fingerprinting analysis, involving Trp and Met, and Asn and Gln, respectively. Serine formylation and tyrosine oxidation mostly in 5 different peptides were also found. Notably, none of the identified modifications appeared within the complementarity-determining regions (CDRs). Although Bevacizumab is typically exposed to low levels of artificial and indoor light under clinical conditions, our findings indicate that it should be always protected from light. This is especially true during long IV administration periods, to avoid aggregate formation with potential reduction of the mAb therapeutic activity.
{"title":"Unveiling the effects of light exposure Bevacizumab stability in clinical settings","authors":"Elisabetta De Diana , Chiara Sottoriva , Giorgia Zorzetto , Giovanna Crivellaro , Nicoletta Rigamonti , Marina Coppola , Claudia Cecilia Vera , Claudio Darío Borsarelli , Benedetta Campara , Luca Menilli , Ilaria Battisti , Giulia Rocca , Giorgio Arrigoni , Giorgia Miolo","doi":"10.1016/j.ijpharm.2026.126578","DOIUrl":"10.1016/j.ijpharm.2026.126578","url":null,"abstract":"<div><div>Bevacizumab was the first available anti-angiogenic therapy with a monoclonal antibody, initially approved against colorectal cancer. It is now used intravenously in the treatment of several other malignancies and in combination with chemotherapy. It binds to all circulating, soluble VEGF-A isoforms, inhibiting angiogenesis, and thereby reducing tumor vascularization. During storage, transport, dilution and administration, Bevacizumab is exposed to different stressors, including ambient light, which can compromise its efficacy and safety. <em>Here</em>, the chemico-physical instability induced by real-life doses of light on Bevacizumab-bvzr is reported in relation to the observed target recognition, anti-angiogenic activity and <em>in vitro</em> immunogenicity. By irradiating the diluted formulation with real-life light doses, mimicking the IV bag infusions, no conformational changes were found by UV and CD spectroscopy. However, light-exposed Bevacizumab-bvzr exhibited a marked reduction in VEGF-A binding, along with decreased anti-angiogenic efficacy in HUVEC-based assays. This loss of activity can be explained by the formation of a small amount of high molecular weight aggregates, detected by SEC, SDS-PAGE and TEM analyses, in all irradiated samples and in a concentration-dependent manner. The immunogenic properties of Bevacizumab aggregates were assessed on human monocytes-derived dendritic cells, which revealed no evidence of dendritic cell activation <em>in vitro</em>. At very high light doses, highlighting the amino acid modifications, mono/dioxidations and deamidation were detected by LC-MS fingerprinting analysis, involving Trp and Met, and Asn and Gln, respectively. Serine formylation and tyrosine oxidation mostly in 5 different peptides were also found. Notably, none of the identified modifications appeared within the complementarity-determining regions (CDRs). Although Bevacizumab is typically exposed to low levels of artificial and indoor light under clinical conditions, our findings indicate that it should be always protected from light. This is especially true during long IV administration periods, to avoid aggregate formation with potential reduction of the mAb therapeutic activity.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126578"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145943767","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 : 2026-02-20Epub Date: 2026-01-12DOI: 10.1016/j.ijpharm.2026.126588
Chengfeng Yin , Chen Chen , Zihan Chen , Zhaohui Song , Fengyun Li
Cancer stem cells (CSCs) represent a distinct subpopulation within tumors, intricately linked to tumorigenesis, progression, drug resistance, recurrence, and metastasis. Therefore, targeting CSCs is essential for achieving a definitive cure for cancer. The concomitant administration of two drugs, aimed at both tumor cells and CSCs, presents a promising strategy for the comprehensive eradication of tumors. However, ensuring the synergistic efficacy and targeted delivery of these dual drugs at the tumor site remains a significant challenge. This review begins by elucidating the biological characteristics of CSCs, with a particular focus on their differentiation and self-renewal capabilities. It then provides a comprehensive overview of common therapeutic approaches targeting CSCs, highlighting the benefits of dual-drug combination therapy. The subsequent sections concentrate on the application of dual-drug delivery systems in CSC therapy, detailing various dual drug-loading strategies, including co-loading at the same site, loading at different sites, physical mixing, and self-assembly. Additionally, it also summarizes multimodal treatment strategies that integrate dual-drug delivery systems with other therapeutic modalities. Finally, the challenges associated with dual-drug delivery systems in CSC therapy are discussed, along with potential future developments in this field. This review aims to offer a theoretical foundation and methodological reference for the treatment of CSCs, ultimately contributing to the overarching goal of curing cancer.
{"title":"Targeting cancer stem cells: Dual-drug delivery systems and their role in cancer therapy","authors":"Chengfeng Yin , Chen Chen , Zihan Chen , Zhaohui Song , Fengyun Li","doi":"10.1016/j.ijpharm.2026.126588","DOIUrl":"10.1016/j.ijpharm.2026.126588","url":null,"abstract":"<div><div>Cancer stem cells (CSCs) represent a distinct subpopulation within tumors, intricately linked to tumorigenesis, progression, drug resistance, recurrence, and metastasis. Therefore, targeting CSCs is essential for achieving a definitive cure for cancer. The concomitant administration of two drugs, aimed at both tumor cells and CSCs, presents a promising strategy for the comprehensive eradication of tumors. However, ensuring the synergistic efficacy and targeted delivery of these dual drugs at the tumor site remains a significant challenge. This review begins by elucidating the biological characteristics of CSCs, with a particular focus on their differentiation and self-renewal capabilities. It then provides a comprehensive overview of common therapeutic approaches targeting CSCs, highlighting the benefits of dual-drug combination therapy. The subsequent sections concentrate on the application of dual-drug delivery systems in CSC therapy, detailing various dual drug-loading strategies, including co-loading at the same site, loading at different sites, physical mixing, and self-assembly. Additionally, it also summarizes multimodal treatment strategies that integrate dual-drug delivery systems with other therapeutic modalities. Finally, the challenges associated with dual-drug delivery systems in CSC therapy are discussed, along with potential future developments in this field. This review aims to offer a theoretical foundation and methodological reference for the treatment of CSCs, ultimately contributing to the overarching goal of curing cancer.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126588"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984820","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}
Osteoarthritis (OA) is a prevalent, debilitating disease marked by joint degeneration, pain, and reduced mobility. Among the factors that influence the pathogenesis and progression of OA, oxidative stress and inflammation are of major importance. As curcumin downregulates the expression of many inflammatory cytokines, scavenges free radicals, and upregulates the levels of collagen and aggrecan, it therefore reduces pain and helps with regeneration. On the other hand, oligonucleotides have emerged as next-generation therapeutics, capable of modulating specific gene expression. In this context, delivery of small interfering RNAs (siRNAs) through lipoplexes is a promising approach for repairing damaged cartilage tissues. Our study focused on developing lipoplexes for efficient co-delivery of curcumin and therapeutic siRNA in chondrocytes. In the first step, the Quality-by-design (QbD) principles guided the development of curcumin-loaded cationic liposomes (CLCL) and the selection of the optimum formulation. Further, optimum curcumin-loaded cationic liposomes (Opt-CLCL) were complexed with IL-6 and IL-8 siRNA to form co-loaded lipoplexes. The Opt-CLCL successfully reduced the oxidative stress levels in both patient-derived primary chondrocytes and a human chondrocyte cell line, while co-loaded lipoplexes transfected chondrocytes with no toxicity and efficiently reduced the inflammation markers. Thus, the developed co-loaded lipoplexes are promising for further testing in OA models. Moreover, the optimal vector designed within the study could serve as a platform for incorporating other lipophilic drugs and negatively charged oligonucleotides to address various ailments.
{"title":"A quality by design strategy to develop curcumin and siRNA co-loaded lipoplexes to target osteoarthritis-related inflammation and oxidative stress","authors":"Saketh Reddy Ranamalla , Lucia Tefas , Alina Porfire , Emilia Licarete , Rohith Pavan Parvathaneni , Oommen P. Varghese , Alina Sesarman , Monica Focsan , Ioan Tomuta , Manuela Banciu","doi":"10.1016/j.ijpharm.2025.126532","DOIUrl":"10.1016/j.ijpharm.2025.126532","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a prevalent, debilitating disease marked by joint degeneration, pain, and reduced mobility. Among the factors that influence the pathogenesis and progression of OA, oxidative stress and inflammation are of major importance. As curcumin downregulates the expression of many inflammatory cytokines, scavenges free radicals, and upregulates the levels of collagen and aggrecan, it therefore reduces pain and helps with regeneration. On the other hand, oligonucleotides have emerged as next-generation therapeutics, capable of modulating specific gene expression. In this context, delivery of small interfering RNAs (siRNAs) through lipoplexes is a promising approach for repairing damaged cartilage tissues. Our study focused on developing lipoplexes for efficient co-delivery of curcumin and therapeutic siRNA in chondrocytes. In the first step, the Quality-by-design (QbD) principles guided the development of curcumin-loaded cationic liposomes (CLCL) and the selection of the optimum formulation. Further, optimum curcumin-loaded cationic liposomes (Opt-CLCL) were complexed with IL-6 and IL-8 siRNA to form co-loaded lipoplexes. The Opt-CLCL successfully reduced the oxidative stress levels in both patient-derived primary chondrocytes and a human chondrocyte cell line, while co-loaded lipoplexes transfected chondrocytes with no toxicity and efficiently reduced the inflammation markers. Thus, the developed co-loaded lipoplexes are promising for further testing in OA models. Moreover, the optimal vector designed within the study could serve as a platform for incorporating other lipophilic drugs and negatively charged oligonucleotides to address various ailments.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126532"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843763","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 : 2026-02-20Epub Date: 2026-01-23DOI: 10.1016/j.ijpharm.2026.126613
Paula Gonzalez-Fernandez , Luca Simula , Sébastien Jenni , Domitille Schvartz , Florina Moldovan , Olivier Jordan , Eric Allémann
Mesenchymal stem cell (MSC) therapy shows potential in regenerative medicine, particularly in treating osteoarthritis (OA). MSCs injected into the joint can secrete growth factors and extracellular matrix molecules, contributing to paracrine communication and cartilage regeneration. However, in the non-vascularized joint environment, MSCs lacking nutrient supply, starve and die too quickly to efficiently deliver enough of these factors. We have recently synthesized a new hydrogel containing hyaluronic acid and glucose (HA-GLC). This hydrogel allows MSCs to survive and proliferate in an environment with otherwise low glucose levels. Furthermore, it releases glucose through enzymatic cleavage by ß-glucosidase, an enzyme which we have shown to be available and active in human bone marrow mesenchymal stem cells (BM-MSCs). In this study, we did incorporate MSCs to this HA-GLC hydrogel. Proteomic analysis of the MSC secretome revealed that glucose deprivation modified the profile of secreted factors, inducing changes in several key pathways, including extra-cellular matrix production. We then tested the effect of glucose deprivation in MSC secretome on human chondrocyte (hCH) proliferation and IL-6 secretion. Our results showed an increase in hCH proliferation and a significant decrease in IL-6 expression, when cells were exposed to the secretome of MSCs cultured in glucose-provided media rather than glucose-deprived conditions. These findings highlighted the ability of this new technology (HA-GLC hydrogel) to modulate the MSC secretome function, potentially enhancing cartilage regeneration in OA.
{"title":"Enzymatically-responsive hyaluronan–glucose hydrogel supports MSC survival and preserves paracrine function under glucose deprivation","authors":"Paula Gonzalez-Fernandez , Luca Simula , Sébastien Jenni , Domitille Schvartz , Florina Moldovan , Olivier Jordan , Eric Allémann","doi":"10.1016/j.ijpharm.2026.126613","DOIUrl":"10.1016/j.ijpharm.2026.126613","url":null,"abstract":"<div><div>Mesenchymal stem cell (MSC) therapy shows potential in regenerative medicine, particularly in treating osteoarthritis (OA). MSCs injected into the joint can secrete growth factors and extracellular matrix molecules, contributing to paracrine communication and cartilage regeneration. However, in the non-vascularized joint environment, MSCs lacking nutrient supply, starve and die too quickly to efficiently deliver enough of these factors. We have recently synthesized a new hydrogel containing hyaluronic acid and glucose (HA-GLC). This hydrogel allows MSCs to survive and proliferate in an environment with otherwise low glucose levels. Furthermore, it releases glucose through enzymatic cleavage by ß-glucosidase, an enzyme which we have shown to be available and active in human bone marrow mesenchymal stem cells (BM-MSCs). In this study, we did incorporate MSCs to this HA-GLC hydrogel. Proteomic analysis of the MSC secretome revealed that glucose deprivation modified the profile of secreted factors, inducing changes in several key pathways, including extra-cellular matrix production. We then tested the effect of glucose deprivation in MSC secretome on human chondrocyte (hCH) proliferation and IL-6 secretion. Our results showed an increase in hCH proliferation and a significant decrease in IL-6 expression, when cells were exposed to the secretome of MSCs cultured in glucose-provided media rather than glucose-deprived conditions. These findings highlighted the ability of this new technology (HA-GLC hydrogel) to modulate the MSC secretome function, potentially enhancing cartilage regeneration in OA.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126613"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046528","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 : 2026-02-20Epub Date: 2026-01-12DOI: 10.1016/j.ijpharm.2026.126589
I. Martínez-Camacho , L.F. Donis-Rabanales , S. Cortés-Lagunes , J.C. Durán-Álvarez , M.S. Córdova-Aguilar , A. Caballero-Ruiz , E.Brito-de la Fuente , M. Calderón-Santoyo , J.A. Ragazzo-Sánchez , G. Ascanio
A new device has been developed to examine how pharmaceutical tablets dissolve under conditions very similar to those in the human stomach. For that purpose, Prednisone USP compendial standard tablets were dissolved in two different apparatuses. On one side, a distal gastric simulator, known as the in vitro Distal Gastric Simulator (IV-DGS), was used. This simulator closely replicates the physiological conditions of the human stomach. It can mimic its operating environment, including peristaltic movement at 3 cycles per minute and an average maximum pressure of about 25 mm Hg. The results from the gastric simulator were compared with the dissolution rates measured using the United States Pharmacopeia-approved apparatus 2. The results show that after 12 min, the USP Apparatus 2 achieved 71.5% dissolution, while the IV-DGS reached 24.9%, indicating a slower dissolution rate but a more realistic gastric mixing. The dissolution data from both systems were modeled using a first-order and a Weibull model, with the latter providing a better fit. Although the results are not entirely comparable with USP 2, the gastric simulator offers a much more realistic alternative for in vitro drug dissolution studies.
{"title":"Dissolution tests of pharmaceutical tablets using a novel gastric simulator","authors":"I. Martínez-Camacho , L.F. Donis-Rabanales , S. Cortés-Lagunes , J.C. Durán-Álvarez , M.S. Córdova-Aguilar , A. Caballero-Ruiz , E.Brito-de la Fuente , M. Calderón-Santoyo , J.A. Ragazzo-Sánchez , G. Ascanio","doi":"10.1016/j.ijpharm.2026.126589","DOIUrl":"10.1016/j.ijpharm.2026.126589","url":null,"abstract":"<div><div>A new device has been developed to examine how pharmaceutical tablets dissolve under conditions very similar to those in the human stomach. For that purpose, Prednisone USP compendial standard tablets were dissolved in two different apparatuses. On one side, a distal gastric simulator, known as the <em>in vitro</em> Distal Gastric Simulator (IV-DGS), was used. This simulator closely replicates the physiological conditions of the human stomach. It can mimic its operating environment, including peristaltic movement at 3 cycles per minute and an average maximum pressure of about 25 mm Hg. The results from the gastric simulator were compared with the dissolution rates measured using the United States Pharmacopeia-approved apparatus 2. The results show that after 12 min, the USP Apparatus 2 achieved 71.5% dissolution, while the IV-DGS reached 24.9%, indicating a slower dissolution rate but a more realistic gastric mixing. The dissolution data from both systems were modeled using a first-order and a Weibull model, with the latter providing a better fit. Although the results are not entirely comparable with USP 2, the gastric simulator offers a much more realistic alternative for <em>in vitro</em> drug dissolution studies.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126589"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981499","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 : 2026-02-20Epub Date: 2026-01-10DOI: 10.1016/j.ijpharm.2026.126576
Yimei Sun , Cheng-Han Ye , Han Gao , Shang-Yin Wu , Wei-Jie Fang
With the rapid advancement of messenger RNA (mRNA) technologies, lipid nanoparticles (LNPs) have been widely adopted for vaccine and gene therapy applications. The stability of mRNA-LNP formulations is a critical determinant of their therapeutic efficacy; however, conventional stability prediction methods are often time-consuming and operationally complex. In this study, a label-free and real-time multi-parameter thermal profiling method was established to provide a rapid assessment of colloidal stability, simultaneously monitoring turbidity, cumulant radius (rh), and scattering. Six formulations sharing the same mRNA cargo and lipid composition but differing in buffer, preservative, and pH were evaluated to examine the discriminatory power of this assay. A redefined aggregation-onset temperature (Tagg) was introduced as the primary thermal stability readout and combined with Δrh to capture early structural perturbations under thermal stress, thereby enabling efficient parallel screening during early formulation development. Compared with conventional accelerated stability studies, this method markedly shortened the evaluation period while still capturing thermally induced colloidal-stability changes. Using Tagg and Δrh in a logistic regression model, thermal-profiling-based “Qualified/Not Qualified” calls demonstrated good concordance with 40 °C accelerated stability outcomes, supporting the use of this strategy as an early-stage screening tool within this mRNA-LNP platform. Nevertheless, its broader applicability across different cargos and lipid chemistries will require further validation.
{"title":"A label-free multi-parameter screening method for predicting the stability of mRNA-LNP formulations","authors":"Yimei Sun , Cheng-Han Ye , Han Gao , Shang-Yin Wu , Wei-Jie Fang","doi":"10.1016/j.ijpharm.2026.126576","DOIUrl":"10.1016/j.ijpharm.2026.126576","url":null,"abstract":"<div><div>With the rapid advancement of messenger RNA (mRNA) technologies, lipid nanoparticles (LNPs) have been widely adopted for vaccine and gene therapy applications. The stability of mRNA-LNP formulations is a critical determinant of their therapeutic efficacy; however, conventional stability prediction methods are often time-consuming and operationally complex. In this study, a label-free and real-time multi-parameter thermal profiling method was established to provide a rapid assessment of colloidal stability, simultaneously monitoring turbidity, cumulant radius (r<sub>h</sub>), and scattering. Six formulations sharing the same mRNA cargo and lipid composition but differing in buffer, preservative, and pH were evaluated to examine the discriminatory power of this assay. A redefined aggregation-onset temperature (<em>T</em><sub>agg</sub>) was introduced as the primary thermal stability readout and combined with <em>Δr</em><sub>h</sub> to capture early structural perturbations under thermal stress, thereby enabling efficient parallel screening during early formulation development. Compared with conventional accelerated stability studies, this method markedly shortened the evaluation period while still capturing thermally induced colloidal-stability changes. Using <em>T</em><sub>agg</sub> and <em>Δr</em><sub>h</sub> in a logistic regression model, thermal-profiling-based “Qualified/Not Qualified” calls demonstrated good concordance with 40 °C accelerated stability outcomes, supporting the use of this strategy as an early-stage screening tool within this mRNA-LNP platform. Nevertheless, its broader applicability across different cargos and lipid chemistries will require further validation.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"691 ","pages":"Article 126576"},"PeriodicalIF":5.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958904","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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