3D-printed polypills have considerably changed the way oral medications can be delivered. They offer a way to create a single dosage form that can be customized to meet the needs of individual patients, while also allowing multiple drugs to be stored in distinct compartments, layers, or designs. Using 3D printing techniques such as fused deposition modeling (FDM), inkjet printing, stereolithography (SLA), selective laser sintering (SLS), and Arburg Plastic Freeforming (APF), it is possible to create tablet structures that provide control over various aspects of dissolution and drug release through engineered porosity and density of the material used during fabrication. Several technologies have been developed to enable the fabrication of polypills, along with methods for selecting the correct excipients, controlling drug release through various mechanisms, and considering the principles of quality-by-design when creating a polypill. In recent years, new material innovations have significantly enhanced the ability of polypills to deliver drugs with improved mechanical strength, stability, and accuracy upon printing. The ability to provide personalized medication regimens for patients with chronic diseases requiring precise titration or a complex regimen is expected to have a great impact on the management of patients taking 3D-printed polypills. 3D-printed polypills have significant translational challenges due to inconsistent production, difficulty obtaining regulatory approval, the inability to scale up batch manufacture, and inadequate long-term stability of the final product.
{"title":"3D-printed polypills for personalized medicine and precision oral drug delivery in pharmaceutical practice: A review","authors":"Mahesha Keerikkadu, Sathvik Chennamsetty, Akshay Shetty, Vamshi Krishna Tippavajhala, Mahalaxmi Rathnanand","doi":"10.1016/j.ijpx.2025.100474","DOIUrl":"10.1016/j.ijpx.2025.100474","url":null,"abstract":"<div><div>3D-printed polypills have considerably changed the way oral medications can be delivered. They offer a way to create a single dosage form that can be customized to meet the needs of individual patients, while also allowing multiple drugs to be stored in distinct compartments, layers, or designs. Using 3D printing techniques such as fused deposition modeling (FDM), inkjet printing, stereolithography (SLA), selective laser sintering (SLS), and Arburg Plastic Freeforming (APF), it is possible to create tablet structures that provide control over various aspects of dissolution and drug release through engineered porosity and density of the material used during fabrication. Several technologies have been developed to enable the fabrication of polypills, along with methods for selecting the correct excipients, controlling drug release through various mechanisms, and considering the principles of quality-by-design when creating a polypill. In recent years, new material innovations have significantly enhanced the ability of polypills to deliver drugs with improved mechanical strength, stability, and accuracy upon printing. The ability to provide personalized medication regimens for patients with chronic diseases requiring precise titration or a complex regimen is expected to have a great impact on the management of patients taking 3D-printed polypills. 3D-printed polypills have significant translational challenges due to inconsistent production, difficulty obtaining regulatory approval, the inability to scale up batch manufacture, and inadequate long-term stability of the final product.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100474"},"PeriodicalIF":6.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.ijpx.2025.100472
Verena Santer , Adyl-Michaёl El Guamra , Tohru Kawaguchi , Mouad Lamrani , Yogeshvar N. Kalia
Reduction of the use of animal models in research is encouraged for the sake of animal wellbeing. However, available in vitro models in the specific case of topical ocular delivery/penetration studies are often oversimplified by the use of excised corneal or scleral tissue and the frequent lack of dynamic barriers such as the lacrimal outwash. This is why we have developed our novel ex vivo porcine eye globe 3D printed laboratory setup with simulated tear flow, using enucleated porcine eyes. This setup was employed to investigate the penetration of a common topical formulation excipient Dexpanthenol (Dxp). First, Dxp deposition in soft contact lenses following usage of SOLOCARE AQUA® care solution was quantified by UHPLC-MS/MS. The subsequent penetration into corneal tissue and aqueous humour of Dxp from SOLOCARE AQUA® care solution treated contact lenses was compared to that following application of eye drop solutions Bepanthen® and Siccaprotect®, containing equivalent Dxp concentrations. The results showed that the Dxp concentration in the anterior segment was three-fold higher after application of the Dxp-containing eye drops as compared to contact lens application. Given that Dxp uptake was greater following the application of the marketed eye drops, this confirmed the safety of the Dxp-containing contact lens care solution. This research demonstrates how topical delivery studies on the ocular surface can be simulated in our novel ex vivo porcine eye globe model without the need to sacrifice laboratory animals.
{"title":"3D printed system using ex vivo porcine eye globes to investigate intracorneal absorption of dexpanthenol from contact lens care solution and eye drops","authors":"Verena Santer , Adyl-Michaёl El Guamra , Tohru Kawaguchi , Mouad Lamrani , Yogeshvar N. Kalia","doi":"10.1016/j.ijpx.2025.100472","DOIUrl":"10.1016/j.ijpx.2025.100472","url":null,"abstract":"<div><div>Reduction of the use of animal models in research is encouraged for the sake of animal wellbeing. However, available <em>in vitro</em> models in the specific case of topical ocular delivery/penetration studies are often oversimplified by the use of excised corneal or scleral tissue and the frequent lack of dynamic barriers such as the lacrimal outwash. This is why we have developed our novel <em>ex vivo</em> porcine eye globe 3D printed laboratory setup with simulated tear flow, using enucleated porcine eyes. This setup was employed to investigate the penetration of a common topical formulation excipient Dexpanthenol (Dxp). First, Dxp deposition in soft contact lenses following usage of SOLOCARE AQUA® care solution was quantified by UHPLC-MS/MS. The subsequent penetration into corneal tissue and aqueous humour of Dxp from SOLOCARE AQUA® care solution treated contact lenses was compared to that following application of eye drop solutions Bepanthen® and Siccaprotect®, containing equivalent Dxp concentrations. The results showed that the Dxp concentration in the anterior segment was three-fold higher after application of the Dxp-containing eye drops as compared to contact lens application. Given that Dxp uptake was greater following the application of the marketed eye drops, this confirmed the safety of the Dxp-containing contact lens care solution. This research demonstrates how topical delivery studies on the ocular surface can be simulated in our novel <em>ex vivo</em> porcine eye globe model without the need to sacrifice laboratory animals<strong>.</strong></div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100472"},"PeriodicalIF":6.4,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799374","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}
Clotrimazole is a synthetic imidazole with broad-spectrum antimycotic effect that has been widely used for the topical treatment for athlete's foot (tinea pedis), oropharyngeal and vulvovaginal candidiasis. The objective of the study was to develop a nano-delivery system containing to improve the penetration capacity of Clotrimazole. Microemulsions were formulated and the chemophysical properties, permeability through rat skin and irritancy examined by HET-CAM test of drug-loaded formulations and stability were evaluated. The average droplet size and viscosity of all clotrimazole-loaded microemulsion formulations were respectively between 126.7–228.13 nm with PDI value less than 0.31 and 24.53–155.16 mPa·s. The penetration capacity of clotrimazole was markedly improved by using microemulsion formulations as delivery carriers: the 24-h cumulative permeated amount from the optimized microemulsion was approximately three-fold higher than that from the clotrimazole solution (drug dissolved in 30 % ethanol) and about 6.5-fold higher than that from the commercial product. The HET-CAM test showed the irritancy on skin of designed clotrimazole-loaded formulation was acceptable compared to the positive control of 0.8 % paraformaldehyde aqueous solution. The stability studies showed that the physicochemical characteristics and residual drug percentage (about 95.3 %) of F2 clotrimazole-loaded formulation were fairly stable after thermodynamic and storage tests, indicating designed microemulsions as a delivery carrier could be considered as a potential strategy for clotrimazole topical dosage form deployment.
{"title":"Development and evaluation of clotrimazole microemulsions for topical application: Effects of HLB value of surfactant mixture and cosurfactant type on formulation design","authors":"Chih-Wun Fang , Yu-Wen Lin , I-Hui Chiu , Pao-Chu Wu","doi":"10.1016/j.ijpx.2025.100469","DOIUrl":"10.1016/j.ijpx.2025.100469","url":null,"abstract":"<div><div>Clotrimazole is a synthetic imidazole with broad-spectrum antimycotic effect that has been widely used for the topical treatment for athlete's foot (tinea pedis), oropharyngeal and vulvovaginal candidiasis. The objective of the study was to develop a nano-delivery system containing to improve the penetration capacity of Clotrimazole. Microemulsions were formulated and the chemophysical properties, permeability through rat skin and irritancy examined by HET-CAM test of drug-loaded formulations and stability were evaluated. The average droplet size and viscosity of all clotrimazole-loaded microemulsion formulations were respectively between 126.7–228.13 nm with PDI value less than 0.31 and 24.53–155.16 mPa·s. The penetration capacity of clotrimazole was markedly improved by using microemulsion formulations as delivery carriers: the 24-h cumulative permeated amount from the optimized microemulsion was approximately three-fold higher than that from the clotrimazole solution (drug dissolved in 30 % ethanol) and about 6.5-fold higher than that from the commercial product. The HET-CAM test showed the irritancy on skin of designed clotrimazole-loaded formulation was acceptable compared to the positive control of 0.8 % paraformaldehyde aqueous solution. The stability studies showed that the physicochemical characteristics and residual drug percentage (about 95.3 %) of F2 clotrimazole-loaded formulation were fairly stable after thermodynamic and storage tests, indicating designed microemulsions as a delivery carrier could be considered as a potential strategy for clotrimazole topical dosage form deployment.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100469"},"PeriodicalIF":6.4,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.ijpx.2025.100467
Benediktus Yohan Arman , Andrea Magri , Matteo N. Barbaglia , Lawrence Petherbridge , Jennifer Brook , Tehmina Bharucha , Isabelle Legge , John Walsby-Tickle , Michael Deats , Sneha Banerjee , Sara Mosca , Rajender Jena , Dnyanesh S. Ranade , Shrikrishna R. Chunekar , Kundan D. Patil , Sunil Gairola , Hamid A. Merchant , Robert Stokes , Rutendo Kuwana , Alexandrine Maes , Bevin Gangadharan
Maintaining cold-chain integrity is vital for vaccines to ensure that they remain within the recommended temperature limits during routine storage and transportation. This ensures vaccine stability, efficacy, and avoids degradation. Here, we propose rapid and low-cost tests based on simple glucose assays to detect heat-exposed degraded sucrose-containing vaccines through sucrose's inherent gradual conversion to glucose when exposed to elevated temperatures. Bioluminescent and colorimetric assays and a clinical biochemical analyser for urine samples could successfully determine effects of heat exposure on vaccines by detecting a significant increase in glucose levels. We show that this increase in glucose also correlates with the loss of vaccine potency. When vaccines were incubated at 37 and 45 °C, the bioluminescent assay was able to detect an increase in glucose levels from 12 h of heat exposure. The biochemical analyser could successfully detect increased glucose levels in a COVID-19 vaccine which had been exposed to 37 and 45 °C. Most importantly, the colorimetric assay has the advantage of producing a colour change visually upon simply mixing the vaccine with a reagent without the need for a plate reader or any other sophisticated devices. To our knowledge, this is the first simple, rapid and device-free test of its kind to detect heat-exposed substandard vaccines, making it a potential test for deploying at key points in the supply chain in warm and hot countries to check the integrity of vaccine cold-chain. Although this test does not replace the more definitive lot release assays such as potency assays, it could initially be used as a rapid and low-cost test to identify substandard sucrose-containing vaccines within supply chains, in support of WHO's Prevent, Detect, and Respond strategy.
{"title":"Ensuring vaccine cold chain integrity: A rapid and low-cost test for identifying heat-exposed sucrose-containing vaccines","authors":"Benediktus Yohan Arman , Andrea Magri , Matteo N. Barbaglia , Lawrence Petherbridge , Jennifer Brook , Tehmina Bharucha , Isabelle Legge , John Walsby-Tickle , Michael Deats , Sneha Banerjee , Sara Mosca , Rajender Jena , Dnyanesh S. Ranade , Shrikrishna R. Chunekar , Kundan D. Patil , Sunil Gairola , Hamid A. Merchant , Robert Stokes , Rutendo Kuwana , Alexandrine Maes , Bevin Gangadharan","doi":"10.1016/j.ijpx.2025.100467","DOIUrl":"10.1016/j.ijpx.2025.100467","url":null,"abstract":"<div><div>Maintaining cold-chain integrity is vital for vaccines to ensure that they remain within the recommended temperature limits during routine storage and transportation. This ensures vaccine stability, efficacy, and avoids degradation. Here, we propose rapid and low-cost tests based on simple glucose assays to detect heat-exposed degraded sucrose-containing vaccines through sucrose's inherent gradual conversion to glucose when exposed to elevated temperatures. Bioluminescent and colorimetric assays and a clinical biochemical analyser for urine samples could successfully determine effects of heat exposure on vaccines by detecting a significant increase in glucose levels. We show that this increase in glucose also correlates with the loss of vaccine potency. When vaccines were incubated at 37 and 45 °C, the bioluminescent assay was able to detect an increase in glucose levels from 12 h of heat exposure. The biochemical analyser could successfully detect increased glucose levels in a COVID-19 vaccine which had been exposed to 37 and 45 °C. Most importantly, the colorimetric assay has the advantage of producing a colour change visually upon simply mixing the vaccine with a reagent without the need for a plate reader or any other sophisticated devices. To our knowledge, this is the first simple, rapid and device-free test of its kind to detect heat-exposed substandard vaccines, making it a potential test for deploying at key points in the supply chain in warm and hot countries to check the integrity of vaccine cold-chain. Although this test does not replace the more definitive lot release assays such as potency assays, it could initially be used as a rapid and low-cost test to identify substandard sucrose-containing vaccines within supply chains, in support of WHO's Prevent, Detect, and Respond strategy.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100467"},"PeriodicalIF":6.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-06eCollection Date: 2025-12-01DOI: 10.1016/j.ijpx.2025.100465
Antonella Barone, Luigi Ciriolo, Salvatore Panza, Nicola d'Avanzo, Giuliana Faggio, Giacomo Messina, Tanzeel U Rehman, Caterina M Tone, Maria P De Santo, Rosario Mare, Anna M Tolomeo, Massimo Fresta, Donatella Paolino
The development of biocompatible nanotherapeutics for skin regeneration remains a major goal in regenerative medicine. Here, we report the isolation and characterization of rose petal-derived extracellular vesicle-like nanovesicles (RPDNVs) obtained by differential ultracentrifugation and size exclusion chromatography. Comprehensive physicochemical analyses confirmed their vesicular morphology, nanoscale size distribution, and antioxidant-enriched molecular cargo, including lipids, phenols, and proteins. RPDNVs demonstrated mechanical stability compatible with tissue interfacing. Functionally, they enhanced fibroblast migration and modulated extracellular matrix gene expression without inducing fibrotic responses. Their biocompatibility was confirmed by in vitro and in vivo studies on human volunteers, thus supporting their translational relevance. Notably, RPDNVs retained structural and functional stability following freeze-drying in the absence of cryoprotectants, enabling long-term storage. These results establish RPDNVs as a promising class of plant-derived nanocarriers for therapeutic skin repair.
{"title":"Self-assembling rose-derived nanovesicles: A multifunctional tool for tissue regeneration.","authors":"Antonella Barone, Luigi Ciriolo, Salvatore Panza, Nicola d'Avanzo, Giuliana Faggio, Giacomo Messina, Tanzeel U Rehman, Caterina M Tone, Maria P De Santo, Rosario Mare, Anna M Tolomeo, Massimo Fresta, Donatella Paolino","doi":"10.1016/j.ijpx.2025.100465","DOIUrl":"10.1016/j.ijpx.2025.100465","url":null,"abstract":"<p><p>The development of biocompatible nanotherapeutics for skin regeneration remains a major goal in regenerative medicine. Here, we report the isolation and characterization of rose petal-derived extracellular vesicle-like nanovesicles (RPDNVs) obtained by differential ultracentrifugation and size exclusion chromatography. Comprehensive physicochemical analyses confirmed their vesicular morphology, nanoscale size distribution, and antioxidant-enriched molecular cargo, including lipids, phenols, and proteins. RPDNVs demonstrated mechanical stability compatible with tissue interfacing. Functionally, they enhanced fibroblast migration and modulated extracellular matrix gene expression without inducing fibrotic responses. Their biocompatibility was confirmed by in vitro and in vivo studies on human volunteers, thus supporting their translational relevance. Notably, RPDNVs retained structural and functional stability following freeze-drying in the absence of cryoprotectants, enabling long-term storage. These results establish RPDNVs as a promising class of plant-derived nanocarriers for therapeutic skin repair.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100465"},"PeriodicalIF":6.4,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12741408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.ijpx.2025.100464
Rong Huang , Wenjia Yang , Tao Wang , Xianbin Cao , Shiyu Sun , Jiaxin Jiang , Hongsheng Liu , Jianzhong Peng
Bacterial-infected diabetic wounds, characterized by a persistent hyperglycemic environment, susceptibility to secondary bacterial infections, and chronic inflammatory responses, often exhibit impaired healing processes, posing a significant challenge in clinical management. To address this issue, this study designed and constructed a near-infrared (NIR) light-activated intelligent hydrogel drug delivery system—LSZBP@CMO. This system integrates highly efficient photothermal conversion components with a pH-responsive CMO hydrogel based on Schiff base reactions, achieving a dual-stimuli responsive drug release mechanism governed by exogenous NIR light and endogenous microenvironmental acidity. Under NIR irradiation, localized mild hyperthermia is generated, leading to the disruption of thermosensitive structures within the system and exposure of nanoparticles. This process, synergizing with the mildly acidic environment, further triggers rapid drug release, significantly enhancing antibacterial efficacy. Both in vitro and in vivo experimental results demonstrated that LSZBP@CMO not only efficiently eliminates bacteria but also effectively alleviates oxidative stress, modulates the inflammatory microenvironment, and markedly promotes angiogenesis, collagen deposition, and epithelial regeneration. In a diabetic rat model with infected wounds, the treatment group exhibited outstanding repair performance, achieving a wound healing ratio of 97.39 ± 1.60 % by day 7. This study provides an actively controllable strategy with promising clinical application prospects for on-demand therapy of refractory bacterial-infected diabetic wounds.
{"title":"Photothermally-activated nano-delivery system for on-demand treatment of diabetic wound infections","authors":"Rong Huang , Wenjia Yang , Tao Wang , Xianbin Cao , Shiyu Sun , Jiaxin Jiang , Hongsheng Liu , Jianzhong Peng","doi":"10.1016/j.ijpx.2025.100464","DOIUrl":"10.1016/j.ijpx.2025.100464","url":null,"abstract":"<div><div>Bacterial-infected diabetic wounds, characterized by a persistent hyperglycemic environment, susceptibility to secondary bacterial infections, and chronic inflammatory responses, often exhibit impaired healing processes, posing a significant challenge in clinical management. To address this issue, this study designed and constructed a near-infrared (NIR) light-activated intelligent hydrogel drug delivery system—LSZBP@CMO. This system integrates highly efficient photothermal conversion components with a pH-responsive CMO hydrogel based on Schiff base reactions, achieving a dual-stimuli responsive drug release mechanism governed by exogenous NIR light and endogenous microenvironmental acidity. Under NIR irradiation, localized mild hyperthermia is generated, leading to the disruption of thermosensitive structures within the system and exposure of nanoparticles. This process, synergizing with the mildly acidic environment, further triggers rapid drug release, significantly enhancing antibacterial efficacy. Both in vitro and in vivo experimental results demonstrated that LSZBP@CMO not only efficiently eliminates bacteria but also effectively alleviates oxidative stress, modulates the inflammatory microenvironment, and markedly promotes angiogenesis, collagen deposition, and epithelial regeneration. In a diabetic rat model with infected wounds, the treatment group exhibited outstanding repair performance, achieving a wound healing ratio of 97.39 ± 1.60 % by day 7. This study provides an actively controllable strategy with promising clinical application prospects for on-demand therapy of refractory bacterial-infected diabetic wounds.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100464"},"PeriodicalIF":6.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1016/j.ijpx.2025.100458
Najeeb Abdelrahman, Stefan Klinken-Uth
The development of robust oral tablet formulations remains time-consuming, often limited by scarce data and the difficulty of incorporating categorical formulation variables into predictive models. Traditional regression methods are interpretable but struggle with nonlinear interactions, whereas modern machine learning approaches offer higher predictive power at the expense of transparency. In this study, we present a neural network framework that employs word embedding layers to represent categorical formulation factors, such as active pharmaceutical ingredients (APIs), as trainable semantic vectors. These embeddings are integrated with empirically-guided output functions and a deep ensemble strategy to predict tablet quality attributes, including tensile strength and density as well as ejection force, and dosing height, based solely on formulation composition, compression pressure, and tablet weight. The model achieved predictive accuracy comparable to or exceeding classical regression while reliably avoiding physically implausible outputs. Analysis of the learned embedding vectors revealed meaningful clustering of APIs, enabling transfer learning across materials and robust predictions even for APIs with few or no training data. Furthermore, information gain analysis demonstrated that low-concentration formulations can substantially enhance predictive accuracy, supporting more material-efficient experimental designs. These results highlight embedding-based, empirically-guided neural networks as explainable and practical tools that could accelerate pharmaceutical formulation development in the future.
{"title":"Data-efficient prediction in tableting using word embeddings and empirically-guided neural networks","authors":"Najeeb Abdelrahman, Stefan Klinken-Uth","doi":"10.1016/j.ijpx.2025.100458","DOIUrl":"10.1016/j.ijpx.2025.100458","url":null,"abstract":"<div><div>The development of robust oral tablet formulations remains time-consuming, often limited by scarce data and the difficulty of incorporating categorical formulation variables into predictive models. Traditional regression methods are interpretable but struggle with nonlinear interactions, whereas modern machine learning approaches offer higher predictive power at the expense of transparency. In this study, we present a neural network framework that employs word embedding layers to represent categorical formulation factors, such as active pharmaceutical ingredients (APIs), as trainable semantic vectors. These embeddings are integrated with empirically-guided output functions and a deep ensemble strategy to predict tablet quality attributes, including tensile strength and density as well as ejection force, and dosing height, based solely on formulation composition, compression pressure, and tablet weight. The model achieved predictive accuracy comparable to or exceeding classical regression while reliably avoiding physically implausible outputs. Analysis of the learned embedding vectors revealed meaningful clustering of APIs, enabling transfer learning across materials and robust predictions even for APIs with few or no training data. Furthermore, information gain analysis demonstrated that low-concentration formulations can substantially enhance predictive accuracy, supporting more material-efficient experimental designs. These results highlight embedding-based, empirically-guided neural networks as explainable and practical tools that could accelerate pharmaceutical formulation development in the future.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100458"},"PeriodicalIF":6.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02eCollection Date: 2025-12-01DOI: 10.1016/j.ijpx.2025.100463
Yating Chen, Yan Yu, Bingzheng Shen
Wound management is significantly challenged by drug-resistant bacterial infections. In this study, a novel fungal defensin peptide derived from Blastomyces dermatitis was identified. The full-length peptide named bladesin was composed of 116 amino acids containing three regions: signal peptide, pro-peptide, and mature peptide. Sequence and structural analysis revealed that the linear mature peptide (reduced type) was consisted of 38 amino acids. The mature bladesin contains three intramolecular disulfide bonds (Cys4-Cys29, Cys14-Cys35 and Cys18-Cys37) and can form a characteristic cysteine-stabilized alpha-beta motif in the native state. In vitro studies demonstrated it exhibited potent antibacterial activity against Gram-positive pathogens with minimum inhibitory concentrations (MICs) ranging from 4 to 32 μM. Furthermore, bladesin was found to promote the proliferation of NIH/3 T3 fibroblasts cells. Using the Poloxamer 407 as the thermosensitive matrix, a bladesin-loaded sustained-release hydrogel was successfully prepared. In vivo experiments showed bladesin hydrogels can accelerate cutaneous wound healing. The mechanism exploration revealed that it can promote pathogen clearance, enhance collagen deposition and regulate inflammatory responses. These findings suggested that this bladesin-based dressings represented a promising therapeutic strategy for the treatment of infected wounds.
{"title":"A multifunctional fungal defensin bladesin loaded-hydrogel for accelerated infectious wound healing.","authors":"Yating Chen, Yan Yu, Bingzheng Shen","doi":"10.1016/j.ijpx.2025.100463","DOIUrl":"10.1016/j.ijpx.2025.100463","url":null,"abstract":"<p><p>Wound management is significantly challenged by drug-resistant bacterial infections. In this study, a novel fungal defensin peptide derived from <i>Blastomyces dermatitis</i> was identified. The full-length peptide named bladesin was composed of 116 amino acids containing three regions: signal peptide, pro-peptide, and mature peptide. Sequence and structural analysis revealed that the linear mature peptide (reduced type) was consisted of 38 amino acids. The mature bladesin contains three intramolecular disulfide bonds (Cys4-Cys29, Cys14-Cys35 and Cys18-Cys37) and can form a characteristic cysteine-stabilized alpha-beta motif in the native state. <i>In vitro</i> studies demonstrated it exhibited potent antibacterial activity against Gram-positive pathogens with minimum inhibitory concentrations (MICs) ranging from 4 to 32 μM. Furthermore, bladesin was found to promote the proliferation of NIH/3 T3 fibroblasts cells. Using the Poloxamer 407 as the thermosensitive matrix, a bladesin-loaded sustained-release hydrogel was successfully prepared. <i>In vivo</i> experiments showed bladesin hydrogels can accelerate cutaneous wound healing. The mechanism exploration revealed that it can promote pathogen clearance, enhance collagen deposition and regulate inflammatory responses. These findings suggested that this bladesin-based dressings represented a promising therapeutic strategy for the treatment of infected wounds.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100463"},"PeriodicalIF":6.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Psoriasis is a chronic, multifactorial, proliferative inflammatory skin disease characterized by immune-mediated relapsing and remitting phases. Topical treatments for mild to moderate psoriasis, as well as systemic treatments for severe cases, can be insufficiently effective and are often associated with significant side effects. The primary objective of this study was to develop a dissolvable microneedle patch containing the flavonoid hesperidin within a polymeric matrix composed of dextran modified polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) aiming to achieve effective control of psoriasis symptoms. The innovative laser ablation technique used in master mold fabrication resulted in well-structured pyramidal arrays, as evidenced by SEM images of the microneedle patches (MNPs). Various formulations were developed in which almost complete dissolving of the needle occured only 30 s. MNP containing PVP 150 mg, PVA 75 mg and Dextran 50 mg, with the highest compressive failure force, was able to sink into the skin well. Over 70 % of hesperidin was released within approximately 15 h from the dissolved MNs into skin. Animal studies were conducted using an imiquimod-induced psoriasis mouse model. PASI score or cumulative amount of three parameters; desquamation or scaling, erythema, and induration or thickness for each group on experimental days 1 to 7 were studied. Significant clinical improvement on PASI scores, was observed in the group treated with hesperidin-loaded optimal MNP (1.67 ± 0.47) compared to the positive control (11.67 ± 0.47) and the oral hesperidin groups (6.00 ± 0.82). The results of this study indicate that dextran modified MNPs of hesperidin can reduce epidermal hyperplasia and inflammatory cell infiltration, demonstrating an effective method for transdermal drug delivery.
{"title":"Dextran-modified dissolving microneedle patches for effective amelioration of psoriasis through transdermal delivery of hesperidin.","authors":"Nooshin Etemadi, Jaleh Varshosaz, Nahal Shamaeizadeh, Amir Mohamadsharifi Renani, Mohsen Minaiyan","doi":"10.1016/j.ijpx.2025.100462","DOIUrl":"10.1016/j.ijpx.2025.100462","url":null,"abstract":"<p><p>Psoriasis is a chronic, multifactorial, proliferative inflammatory skin disease characterized by immune-mediated relapsing and remitting phases. Topical treatments for mild to moderate psoriasis, as well as systemic treatments for severe cases, can be insufficiently effective and are often associated with significant side effects. The primary objective of this study was to develop a dissolvable microneedle patch containing the flavonoid hesperidin within a polymeric matrix composed of dextran modified polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) aiming to achieve effective control of psoriasis symptoms. The innovative laser ablation technique used in master mold fabrication resulted in well-structured pyramidal arrays, as evidenced by SEM images of the microneedle patches (MNPs). Various formulations were developed in which almost complete dissolving of the needle occured only 30 s. MNP containing PVP 150 mg, PVA 75 mg and Dextran 50 mg, with the highest compressive failure force, was able to sink into the skin well. Over 70 % of hesperidin was released within approximately 15 h from the dissolved MNs into skin. Animal studies were conducted using an imiquimod-induced psoriasis mouse model. PASI score or cumulative amount of three parameters; desquamation or scaling, erythema, and induration or thickness for each group on experimental days 1 to 7 were studied. Significant clinical improvement on PASI scores, was observed in the group treated with hesperidin-loaded optimal MNP (1.67 ± 0.47) compared to the positive control (11.67 ± 0.47) and the oral hesperidin groups (6.00 ± 0.82). The results of this study indicate that dextran modified MNPs of hesperidin can reduce epidermal hyperplasia and inflammatory cell infiltration, demonstrating an effective method for transdermal drug delivery.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100462"},"PeriodicalIF":6.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12720357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145819226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02eCollection Date: 2025-12-01DOI: 10.1016/j.ijpx.2025.100457
Mehrnaz Salahi, Jaleh Varshosaz, Mahboubeh Rostami, Salar Nasr Esfahani, Arsham Hekmat, Ali Jahanian-Najafaabadi, Mohsen Minayian
Triple-negative breast cancer (TNBC) remains one of the most aggressive subtypes with limited therapeutic options. To address this unmet need, this study aimed to enhance the cellular uptake and cytotoxicity of mitomycin C (MMC) using surface-modified nanoliposomes functionalized with poly-L-arginine (PLA), a cell-penetrating peptide, and chondroitin sulfate (CS), a CD44-targeting ligand. Another object was to investigate how the conjugation manner of the targeting agent-chondroitin sulfate (CS), a CD44-targeting ligand, and a tandem cell-penetrating peptide (CPP) made of poly-L-arginine (PLA)-affects the enhancement of cellular uptake and anti-tumor effects of Mitomycin C (MMC) nanoliposomes in triple-negative breast cancer (TNBC). We synthesized and characterized four liposomal formulations; CS-liposomes, PLA-liposomes, PLA-CS-liposomes, and CS-PLA-liposomes and their particle size, polydispersity index, zeta potential, encapsulation efficiency, and drug release were evaluated. In vitro studies on 4 T1 TNBC cells included cytotoxicity (MTT), cellular uptake, apoptosis, cell cycle arrest, and caspase-3/8 expression (qRT-PCR). In vivo efficacy was tested in BALB/c mice bearing orthotopic 4 T1 tumors by monitoring tumor growth, body weight, and histopathology (H&E and Ki-67). Optimized PLA-CS liposomes had a mean particle size of 144.0 ± 2.4 nm, a PDI of 0.31 ± 0.02, and 73 % encapsulation efficiency, with sustained MMC release over 24 h. PLA-functionalized liposomes showed significantly greater cytotoxicity and uptake than free MMC and non-targeted controls. They induced G1 cell cycle arrest and strongly upregulated caspase-3 (+64-fold in CS-PLA, +13-fold in PLA-CS), consistent with activation of the intrinsic apoptosis pathway. Animal studies revealed PLA-CS liposomes produced the strongest tumor suppression (Ki-67 index 6 %), reduced tumor grade to 1, and showed no liver or kidney metastasis. All liposomal formulations performed better than free MMC in tumor control and safety. PLA-CS-liposomes provide a potent and well-tolerated delivery platform for MMC in TNBC, combining improved tumor targeting, enhanced apoptotic response, and favorable organ safety.
{"title":"The impact of the conjugation manner of targeting agent and tandem cell-penetrating peptide on the efficacy of mitomycin C liposomes in treating triple-negative breast tumors.","authors":"Mehrnaz Salahi, Jaleh Varshosaz, Mahboubeh Rostami, Salar Nasr Esfahani, Arsham Hekmat, Ali Jahanian-Najafaabadi, Mohsen Minayian","doi":"10.1016/j.ijpx.2025.100457","DOIUrl":"10.1016/j.ijpx.2025.100457","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains one of the most aggressive subtypes with limited therapeutic options. To address this unmet need, this study aimed to enhance the cellular uptake and cytotoxicity of mitomycin C (MMC) using surface-modified nanoliposomes functionalized with poly-L-arginine (PLA), a cell-penetrating peptide, and chondroitin sulfate (CS), a CD44-targeting ligand. Another object was to investigate how the conjugation manner of the targeting agent-chondroitin sulfate (CS), a CD44-targeting ligand, and a tandem cell-penetrating peptide (CPP) made of poly-L-arginine (PLA)-affects the enhancement of cellular uptake and anti-tumor effects of Mitomycin C (MMC) nanoliposomes in triple-negative breast cancer (TNBC). We synthesized and characterized four liposomal formulations; CS-liposomes, PLA-liposomes, PLA-CS-liposomes, and CS-PLA-liposomes and their particle size, polydispersity index, zeta potential, encapsulation efficiency, and drug release were evaluated. In vitro studies on 4 T1 TNBC cells included cytotoxicity (MTT), cellular uptake, apoptosis, cell cycle arrest, and caspase-3/8 expression (qRT-PCR). In vivo efficacy was tested in BALB/c mice bearing orthotopic 4 T1 tumors by monitoring tumor growth, body weight, and histopathology (H&E and Ki-67). Optimized PLA-CS liposomes had a mean particle size of 144.0 ± 2.4 nm, a PDI of 0.31 ± 0.02, and 73 % encapsulation efficiency, with sustained MMC release over 24 h. PLA-functionalized liposomes showed significantly greater cytotoxicity and uptake than free MMC and non-targeted controls. They induced G1 cell cycle arrest and strongly upregulated caspase-3 (+64-fold in CS-PLA, +13-fold in PLA-CS), consistent with activation of the intrinsic apoptosis pathway. Animal studies revealed PLA-CS liposomes produced the strongest tumor suppression (Ki-67 index 6 %), reduced tumor grade to 1, and showed no liver or kidney metastasis. All liposomal formulations performed better than free MMC in tumor control and safety. PLA-CS-liposomes provide a potent and well-tolerated delivery platform for MMC in TNBC, combining improved tumor targeting, enhanced apoptotic response, and favorable organ safety.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100457"},"PeriodicalIF":6.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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