Pub Date : 2026-03-01Epub Date: 2025-12-20DOI: 10.1016/j.ejpb.2025.114970
Qiyao Zhai , Shuang Guo , Zhixiang Cui , Lu Qin , Jian Guan , Xin Zhang , Shirui Mao
The development of oral insulin delivery systems has advanced significantly, with polyelectrolyte nanocomplexes (PEC) showing promise due to their solvent-free synthesis. However, their efficacy is limited by poor mucus penetration and intestinal absorption. Inspired by the nature of mucin, chitosan (CS) modified with proline, threonine and serine to mimic the mucin’s PTS sequence were synthesized to enhance mucus permeability of the PEC. To further improve the mucus permeability and the trans-epithelial transport of the PEC, muco-penetrating nanocomplexes were fabricated by utilizing hyaluronic acid (HA), thus forming a surface with high-density positive and negative charges to mimic the surface charge properties of viruses. The nanocomplexes were self-assembled using modified CS and insulin, followed by HA coating. It was demonstrated that the nanocomplexes exhibited good physical stability, enhanced protection against enzymatic degradation, and increased penetration efficiency across the mucus layer and small intestine compared to unmodified counterparts. Furthermore, the in vivo hypoglycemic study further revealed a 2.16-fold increase in relative pharmacological availability for the nanocomplexes over the CS/Ins PEC Collectively, these findings reveal the potential of (PTS-CS/Ins)/HA, a dual-mimicking muco-penetrating nanocomplex based on the nature of mucin and virus, as a promising platform for oral insulin delivery.
{"title":"Exploration of a dual-mimetic mucus inert nanocomplex for enhanced oral insulin delivery","authors":"Qiyao Zhai , Shuang Guo , Zhixiang Cui , Lu Qin , Jian Guan , Xin Zhang , Shirui Mao","doi":"10.1016/j.ejpb.2025.114970","DOIUrl":"10.1016/j.ejpb.2025.114970","url":null,"abstract":"<div><div>The development of oral insulin delivery systems has advanced significantly, with polyelectrolyte nanocomplexes (PEC) showing promise due to their solvent-free synthesis. However, their efficacy is limited by poor mucus penetration and intestinal absorption. Inspired by the nature of mucin, chitosan (CS) modified with proline, threonine and serine to mimic the mucin’s PTS sequence were synthesized to enhance mucus permeability of the PEC. To further improve the mucus permeability and the <em>trans</em>-epithelial transport of the PEC, muco-penetrating nanocomplexes were fabricated by utilizing hyaluronic acid (HA), thus forming a surface with high-density positive and negative charges to mimic the surface charge properties of viruses. The nanocomplexes were self-assembled using modified CS and insulin, followed by HA coating. It was demonstrated that the nanocomplexes exhibited good physical stability, enhanced protection against enzymatic degradation, and increased penetration efficiency across the mucus layer and small intestine compared to unmodified counterparts. Furthermore, the <em>in vivo</em> hypoglycemic study further revealed a 2.16-fold increase in relative pharmacological availability for the nanocomplexes over the CS/Ins PEC Collectively, these findings reveal the potential of (PTS-CS/Ins)/HA, a dual-mimicking muco-penetrating nanocomplex based on the nature of mucin and virus, as a promising platform for oral insulin delivery.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114970"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801954","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}
5-fluorouracil (5-FU) is one of the most effective chemotherapeutic drugs for various solid tumors. However, its low water solubility and limited absorption rates in the stomach are crucial limitations that prevent it from being effectively applied in clinical practice. To address these issues, we first encapsulated 5-FU in β-cyclodextrin (5-FU–β-CD) to enhance its solubility, and the resulting 5-FU–β-CD was then loaded into a PLA film to prepare a novel gastro-retentive drug delivery system (GRDDS) based on shape-memory properties. The excipients, such as tributyl citrate (TBC), hydroxyethyl cellulose (HEC), citric acid (CA), and sodium bicarbonate (NaHCO3), were incorporated into the PLA matrix at an optimized ratio. This was done to enhance the performance of PLA as an ideal matrix material in GRDDS, including improvements in drug release, floating behavior, shape recovery, gastric retention, and in vivo anti-tumor activity. The results suggested that the solubility of the 5-FU–β-CD inclusion complex was significantly enhanced, which was 1.88-fold higher than that of pure 5-FU. The optimal shape-memory drug delivery formulation, 5-FU–β-CD–PLA/TBC (86/14), prepared in this study consists of PLA/TBC (86/14) incorporating 3 % HEC, 3 % NaHCO3, 1 % CA, and 3 % 5-FU. Its gastric retention time was notably prolonged to approximately 8 h following oral administration in mice, whereas the residual amount of 5-FU–β-CD at this time point was much lower than the initial loading. The oral bioavailability of the 5-FU–β-CD–PLA/TBC (86/14) was 269 % higher than that of pure 5-FU. Additionally, the mean tumor size and weight in the mouse model of gastric carcinoma administered with 5-FU–β-CD–PLA/TBC (86/14) were 215.3 mm3 and 241.4 mg respectively, significantly smaller than those in the 5-FU group. This indicates that the novel PLA-based drug delivery system has significantly enhanced anti-tumor effects. Its excellent therapeutic effects were further confirmed through HE, Ki67, and TUNEL staining. Taken together, 5-FU–β-CD–PLA/TBC (86/14) can be retained in the stomach to improve relative bioavailability. This system represents a promising carrier not only for 5-FU but also for other poorly soluble drugs that require prolonged retention in the stomach.
{"title":"Novel PLA-based shape-memory formulation: Design, preparation, and evaluation for gastro-retentive delivery of 5-fluorouracil to enhance oral bioavailability","authors":"Fengxue Liu , Xuefei Yu , Yanmei Wu , Ting Zhu , Ning Chen , Hao Chen , Wei Shen , Wei Zheng","doi":"10.1016/j.ejpb.2025.114968","DOIUrl":"10.1016/j.ejpb.2025.114968","url":null,"abstract":"<div><div>5-fluorouracil (5-FU) is one of the most effective chemotherapeutic drugs for various solid tumors. However, its low water solubility and limited absorption rates in the stomach are crucial limitations that prevent it from being effectively applied in clinical practice. To address these issues, we first encapsulated 5-FU in β-cyclodextrin (5-FU–β-CD) to enhance its solubility, and the resulting 5-FU–β-CD was then loaded into a PLA film to prepare a novel gastro-retentive drug delivery system (GRDDS) based on shape-memory properties. The excipients, such as tributyl citrate (TBC), hydroxyethyl cellulose (HEC), citric acid (CA), and sodium bicarbonate (NaHCO<sub>3</sub>), were incorporated into the PLA matrix at an optimized ratio. This was done to enhance the performance of PLA as an ideal matrix material in GRDDS, including improvements in drug release, floating behavior, shape recovery, gastric retention, and in vivo anti-tumor activity. The results suggested that the solubility of the 5-FU–β-CD inclusion complex was significantly enhanced, which was 1.88-fold higher than that of pure 5-FU. The optimal shape-memory drug delivery formulation, 5-FU–β-CD–PLA/TBC (86/14), prepared in this study consists of PLA/TBC (86/14) incorporating 3 % HEC, 3 % NaHCO<sub>3</sub>, 1 % CA, and 3 % 5-FU. Its gastric retention time was notably prolonged to approximately 8 h following oral administration in mice, whereas the residual amount of 5-FU–β-CD at this time point was much lower than the initial loading. The oral bioavailability of the 5-FU–β-CD–PLA/TBC (86/14) was 269 % higher than that of pure 5-FU. Additionally, the mean tumor size and weight in the mouse model of gastric carcinoma administered with 5-FU–β-CD–PLA/TBC (86/14) were 215.3 mm<sup>3</sup> and 241.4 mg respectively, significantly smaller than those in the 5-FU group. This indicates that the novel PLA-based drug delivery system has significantly enhanced anti-tumor effects. Its excellent therapeutic effects were further confirmed through HE, Ki67, and TUNEL staining. Taken together, 5-FU–β-CD–PLA/TBC (86/14) can be retained in the stomach to improve relative bioavailability. This system represents a promising carrier not only for 5-FU but also for other poorly soluble drugs that require prolonged retention in the stomach.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114968"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803457","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 : 2026-03-01Epub Date: 2026-01-03DOI: 10.1016/j.ejpb.2026.114981
O.V. Markov , D.N. Antropov , E.V. Shmendel , P.A. Puchkov , O.A. Yakovlev , M.D. Kerbitskaya , E.S. Zhuravlev , A.S. Dome , E.P. Goncharova , D.N. Shcherbakov , M.A. Zenkova , M.A. Maslov , G.A. Stepanov
The development of mRNA-based antiviral and antitumor therapeutics is progressing rapidly and shows considerable promise. Optimizing the composition of liposomal delivery vehicles is critical for enhancing mRNA vaccine efficacy. Among their components, PEG-lipids require careful optimization to improve the colloidal stability of mRNA-liposome complexes, prolong their in vivo circulation time, and enhance mRNA delivery efficiency, thereby eliciting a robust immune response. Here, we report a structure-functional analysis of PEG-lipids incorporated into cationic liposomes based on the cationic lipid 2X3 and the helper lipid DOPE. The following parameters of PEG-lipids were varied: PEG chain length (800–2000 Da), PEG-lipid architecture (classical head-to-tail vs. gemini-like structures), hydrophobic anchor chain length (C14 octadecyl and C18 tetradecyl residues) and molar amount of PEG-lipid in formulations (0.5–4 mol%). We demonstrated that optimized liposomes contained 4 mol% of a PEG-lipid composed of linear PEG2000 conjugated to a C14-dialkylglycerol anchor via a carbamate linker. This formulation enabled efficient in vivo expression of luciferase-encoding mRNA and, upon delivery of influenza A/California//07/09 (H1N1pdm09) hemagglutinin-encoding mRNA, induced robust antigen-specific humoral and cellular immunity. Our findings underscore the critical importance of PEG-lipid optimization for advancing potent mRNA delivery platforms for antiviral and antitumor vaccines.
{"title":"Tuning the in vivo transfection efficiency of mRNA-Loaded lipoplexes by PEG-Lipid structure and ratio","authors":"O.V. Markov , D.N. Antropov , E.V. Shmendel , P.A. Puchkov , O.A. Yakovlev , M.D. Kerbitskaya , E.S. Zhuravlev , A.S. Dome , E.P. Goncharova , D.N. Shcherbakov , M.A. Zenkova , M.A. Maslov , G.A. Stepanov","doi":"10.1016/j.ejpb.2026.114981","DOIUrl":"10.1016/j.ejpb.2026.114981","url":null,"abstract":"<div><div>The development of mRNA-based antiviral and antitumor therapeutics is progressing rapidly and shows considerable promise. Optimizing the composition of liposomal delivery vehicles is critical for enhancing mRNA vaccine efficacy. Among their components, PEG-lipids require careful optimization to improve the colloidal stability of mRNA-liposome complexes, prolong their <em>in vivo</em> circulation time, and enhance mRNA delivery efficiency, thereby eliciting a robust immune response. Here, we report a structure-functional analysis of PEG-lipids incorporated into cationic liposomes based on the cationic lipid 2X3 and the helper lipid DOPE. The following parameters of PEG-lipids were varied: PEG chain length (800–2000 Da), PEG-lipid architecture (classical head-to-tail vs. gemini-like structures), hydrophobic anchor chain length (C14 octadecyl and C18 tetradecyl residues) and molar amount of PEG-lipid in formulations (0.5–4 mol%). We demonstrated that optimized liposomes contained 4 mol% of a PEG-lipid composed of linear PEG2000 conjugated to a C14-dialkylglycerol anchor via a carbamate linker. This formulation enabled efficient <em>in vivo</em> expression of luciferase-encoding mRNA and, upon delivery of influenza A/California//07/09 (H1N1pdm09) hemagglutinin-encoding mRNA, induced robust antigen-specific humoral and cellular immunity. Our findings underscore the critical importance of PEG-lipid optimization for advancing potent mRNA delivery platforms for antiviral and antitumor vaccines.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114981"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905642","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 : 2026-03-01Epub Date: 2025-12-27DOI: 10.1016/j.ejpb.2025.114969
Samaa Abdullah , Samar Thiab , Abeer A. Altamimi , Alaa A. Al-Masud , Meshal Marzoog Al-Sharafa , Hatim S. AlKhatib , Imad Hamadneh
{"title":"Corrigendum to “Nanogel therapy for chronic and post-surgical wounds: a bioengineered Lactoferrin–Acacia–Alginate system enhancing tissue regeneration and inflammatory resolution” [Eur. J. Pharm. Biopharm. 219 (2026) 114952]","authors":"Samaa Abdullah , Samar Thiab , Abeer A. Altamimi , Alaa A. Al-Masud , Meshal Marzoog Al-Sharafa , Hatim S. AlKhatib , Imad Hamadneh","doi":"10.1016/j.ejpb.2025.114969","DOIUrl":"10.1016/j.ejpb.2025.114969","url":null,"abstract":"","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114969"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849568","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 : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.ejpb.2026.114988
Zhiling Chen , Huiling Zhou , Jie Song, Ben Xu, Can Wang, Fengchun He, Guisen Zhang, Tao Zhuang
Because the monotherapy of currently available pain killers often shows serious adverse effects or limited efficacy for treating neuropathic pain, multimodal analgesia has been highly recommended to gain improved antinociceptive effects and reduce dose-dependent side effects. Drug-drug co-amorphous systems emerge as a useful strategy for ameliorating the physicochemical properties of drug substances and achieving clinical benefits compared with individual components. New drug-drug co-amorphous products IMI-CEL at different ratios were prepared from imipramine hydrochloride (IMI) and a poorly water-soluble anti-inflammatory drug–celecoxib (CEL) by melt-quenching method, which were characterized by XRPD, DSC and IR. Co-amorphous product IMI-CEL (1:1) displayed notable improvement in the solubility (64.4 times) and dissolution rate (3.1 times) than crystalline CEL in pH 6.8 buffer, and IMI-CEL exhibited good physical stability under long-term storage conditions. Isobolographic analysis demonstrated that IMI-CEL (1:1) showed synergistic analgesic effects in paclitaxel-induced neuropathic pain in mice. Moreover, the oral bioavailability of 1:1 IMI-CEL was improved 1.396 times in rats when compared to the single drug. Above results suggested the potential of IMI-CEL to produce synergistic analgesic effects through developing drug-drug co-amorphous systems.
{"title":"A new drug-drug co-amorphous system of imipramine and celecoxib with improved solubility and synergistic antinociceptive effects","authors":"Zhiling Chen , Huiling Zhou , Jie Song, Ben Xu, Can Wang, Fengchun He, Guisen Zhang, Tao Zhuang","doi":"10.1016/j.ejpb.2026.114988","DOIUrl":"10.1016/j.ejpb.2026.114988","url":null,"abstract":"<div><div>Because the monotherapy of currently available pain killers often shows serious adverse effects or limited efficacy for treating neuropathic pain, multimodal analgesia has been highly recommended to gain improved antinociceptive effects and reduce dose-dependent side effects. Drug-drug co-amorphous systems emerge as a useful strategy for ameliorating the physicochemical properties of drug substances and achieving clinical benefits compared with individual components. New drug-drug co-amorphous products IMI-CEL at different ratios were prepared from imipramine hydrochloride (IMI) and a poorly water-soluble anti-inflammatory drug–celecoxib (CEL) by melt-quenching method, which were characterized by XRPD, DSC and IR. Co-amorphous product IMI-CEL (1:1) displayed notable improvement in the solubility (64.4 times) and dissolution rate (3.1 times) than crystalline CEL in pH 6.8 buffer, and IMI-CEL exhibited good physical stability under long-term storage conditions. Isobolographic analysis demonstrated that IMI-CEL (1:1) showed synergistic analgesic effects in paclitaxel-induced neuropathic pain in mice. Moreover, the oral bioavailability of 1:1 IMI-CEL was improved 1.396 times in rats when compared to the single drug. Above results suggested the potential of IMI-CEL to produce synergistic analgesic effects through developing drug-drug co-amorphous systems.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114988"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948423","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 : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.ejpb.2026.114980
Paula Gonzalez-Fernandez , Luca Morici , Luca Simula , Rajhi Takwa , Aya Benabdellah , Eric Allémann , Olivier Jordan
Osteoarthritis (OA) is the most common joint disease worldwide causing cartilage loss, inflammation and pain. Lorecivivint (LOR) is a new disease-modifying osteoarthritis drug (DMOAD) that targets the Wnt pathway to improve cartilage regeneration and reduce the pro-inflammatory cytokines production. However, its advancement in the clinical evaluation is facing certain challenges due to poor solubility and fast clearance from the joint. Our study is the first to improve LOR delivery using cationic liposomes for intra-articular injection.
DSPC-Chol-DOTAP-based liposomes were formulated using microfluidics with an encapsulation efficiency (EE) of 36 % of LOR and increasing the drug solubility over 120-fold in PBS and 100-fold in simulated synovial fluid. In a physiological environment, a prolonged release of 17 % of the LOR over 14 days was achieved, while faster release of 65 to 86 %, respectively, was observed in simulated synovial fluid. The surface charge of + 35 mV and the size of 145 nm were influential in increasing cartilage uptake in bovine explant of 1.4-fold and 3.6-fold compared to free LOR solution and suspension, respectively.
In vitro study by flow cytometry revealed there was no cytotoxicity at 10 nM in human chondrocytes (hCHs) and in human mesenchymal stem cells (MSCs). Nevertheless, some toxicity-related morphological changes in hCHs spheroids were observed at 300 nM, which corresponds to the IC80 of LOR. The safer liposomal concentration of 10 nM maintained the drug bioactivity and reduced by half TGF-β and IL-6 levels in two-dimensional hCHs and MSCs cell culture, which confirmed the anti-fibrotic and anti-inflammatory effects. An in vivo pilot study was conducted using a severe ACLT-hMnX rat model showing preliminary evidence of an alleviated osteophyte formation and reduced cartilage matrix loss in the medial tibial plateau. Overall, Lipo-LOR improved drug solubility, release and cartilage retention, which are critical requirements for implementing a localized intra-articular OA therapy.
{"title":"Cationic liposome-mediated intra-articular delivery of lorecivivint for osteoarthritis treatment","authors":"Paula Gonzalez-Fernandez , Luca Morici , Luca Simula , Rajhi Takwa , Aya Benabdellah , Eric Allémann , Olivier Jordan","doi":"10.1016/j.ejpb.2026.114980","DOIUrl":"10.1016/j.ejpb.2026.114980","url":null,"abstract":"<div><div>Osteoarthritis (OA) is the most common joint disease worldwide causing cartilage loss, inflammation and pain. Lorecivivint (LOR) is a new disease-modifying osteoarthritis drug (DMOAD) that targets the Wnt pathway to improve cartilage regeneration and reduce the pro-inflammatory cytokines production. However, its advancement in the clinical evaluation is facing certain challenges due to poor solubility and fast clearance from the joint. Our study is the first to improve LOR delivery using cationic liposomes for intra-articular injection.</div><div>DSPC-Chol-DOTAP-based liposomes were formulated using microfluidics with an encapsulation efficiency (EE) of 36 % of LOR and increasing the drug solubility over 120-fold in PBS and 100-fold in simulated synovial fluid. In a physiological environment, a prolonged release of 17 % of the LOR over 14 days was achieved, while faster release of 65 to 86 %, respectively, was observed in simulated synovial fluid. The surface charge of + 35 mV and the size of 145 nm were influential in increasing cartilage uptake in bovine explant of 1.4-fold and 3.6-fold compared to free LOR solution and suspension, respectively.</div><div><em>In vitro</em> study by flow cytometry revealed there was no cytotoxicity at 10 nM in human chondrocytes (hCHs) and in human mesenchymal stem cells (MSCs). Nevertheless, some toxicity-related morphological changes in hCHs spheroids were observed at 300 nM, which corresponds to the IC80 of LOR. The safer liposomal concentration of 10 nM maintained the drug bioactivity and reduced by half TGF-β and IL-6 levels in two-dimensional hCHs and MSCs cell culture, which confirmed the anti-fibrotic and anti-inflammatory effects. An <em>in vivo</em> pilot study was conducted using a severe ACLT-hMnX rat model showing preliminary evidence of an alleviated osteophyte formation and reduced cartilage matrix loss in the medial tibial plateau. Overall, Lipo-LOR improved drug solubility, release and cartilage retention, which are critical requirements for implementing a localized intra-articular OA therapy.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114980"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948398","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}
Volumetric muscle loss (VML) results in permanent functional deficits for which current therapeutic strategies are insufficient. We hypothesized that an injectable, thermoresponsive hydrogel enabling localized delivery of agmatine sulfate (AgS) and hyaluronic acid (HA) could synergistically promote robust neuromuscular regeneration. A poloxamer-based thermogel was systematically optimized using a 32 full factorial design. The lead formulation exhibited a physiologically advantageous gelation temperature (27 ± 1.03°C) and time (42 ± 1.4 s), with rapid bioactive release (85–90% within 18–24 h) matched to the critical satellite cell activation window. In vitro degradation studies confirmed complete gel erosion, providing burst delivery during the acute injury phase. In a rat tibialis anterior VML model, the AgS-HA combination therapy demonstrated profound synergistic effects, restoring grip strength and normalizing complex gait parameters to near-control levels. This functional recovery was corroborated by significantly reduced serum creatine kinase, indicating reduced muscle damage. Histopathological analysis revealed near-complete restitution of mature, organized myofiber architecture with minimal fibrosis, contrasting with extensive scar tissue in control groups. Notably, functional recovery occurred without significant modulation of systemic inflammatory markers (IL-6, IL-10, TNF-α), suggesting regeneration proceeds through direct pro-myogenic, anti-fibrotic, and neurovascular mechanisms rather than systemic anti-inflammatory effects. These findings demonstrate that a thermoresponsive hydrogel platform for rapid AgS and HA delivery effectively promotes comprehensive structural and functional recovery, representing a potent and clinically translatable strategy for VML.
{"title":"Injectable poloxamer-based thermogel as a delivery platform for agmatine and hyaluronic acid in muscle tissue engineering","authors":"Mohammad Qutub , Amol Tatode , Tanvi Premchandani , Jayshree Taksande , Milind Umekar","doi":"10.1016/j.ejpb.2026.114983","DOIUrl":"10.1016/j.ejpb.2026.114983","url":null,"abstract":"<div><div>Volumetric muscle loss (VML) results in permanent functional deficits for which current therapeutic strategies are insufficient. We hypothesized that an injectable, thermoresponsive hydrogel enabling localized delivery of agmatine sulfate (AgS) and hyaluronic acid (HA) could synergistically promote robust neuromuscular regeneration. A poloxamer-based thermogel was systematically optimized using a 3<sup>2</sup> full factorial design. The lead formulation exhibited a physiologically advantageous gelation temperature (27 ± 1.03°C) and time (42 ± 1.4 s), with rapid bioactive release (85–90% within 18–24 h) matched to the critical satellite cell activation window. In vitro degradation studies confirmed complete gel erosion, providing burst delivery during the acute injury phase. In a rat tibialis anterior VML model, the AgS-HA combination therapy demonstrated profound synergistic effects, restoring grip strength and normalizing complex gait parameters to near-control levels. This functional recovery was corroborated by significantly reduced serum creatine kinase, indicating reduced muscle damage. Histopathological analysis revealed near-complete restitution of mature, organized myofiber architecture with minimal fibrosis, contrasting with extensive scar tissue in control groups. Notably, functional recovery occurred without significant modulation of systemic inflammatory markers (IL-6, IL-10, TNF-α), suggesting regeneration proceeds through direct pro-myogenic, anti-fibrotic, and neurovascular mechanisms rather than systemic anti-inflammatory effects. These findings demonstrate that a thermoresponsive hydrogel platform for rapid AgS and HA delivery effectively promotes comprehensive structural and functional recovery, representing a potent and clinically translatable strategy for VML.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114983"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948442","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 : 2026-03-01Epub Date: 2025-12-23DOI: 10.1016/j.ejpb.2025.114979
Thomas Eason , Ellie Ponsonby-Thomas , Anna C. Pham , Shouyuan Huang , Simone Margaard Offersen , Thomas Thymann , Vanessa Zann , Malinda Salim , Ben J. Boyd
Milk-based formulations have been proposed as enabling formulations for the delivery of poorly water-soluble drugs to children due to their safety, dose versatility and ability to improve drug solubilisation through the digestion process. In this study the feasibility of using commercially available infant formula as an enabling formulation to enhance the solubilisation and oral bioavailability of clofazimine, a poorly soluble lipophilic drug, following oral administration was investigated. The solubilisation of crystalline clofazimine in digesting infant formula was assessed in vitro using synchrotron small-angle X-ray scattering. An in vivo pharmacokinetic study was then conducted to determine the oral bioavailability of a suspension of clofazimine in infant formula compared to a lipid-free aqueous suspension in both a rat and piglet animal model. Clofazimine administered in infant formula produced significantly higher plasma concentrations than the aqueous vehicle and resulted in comparable enhancements in relative oral bioavailability in both the piglet (235%) and rat animal models (256%). Results from this study demonstrated that infant formula was an effective enabling formulation, with a positive correlation between improved drug solubilisation during in vitro digestion of infant formula and enhanced in vivo drug exposure following oral administration. Infant formula therefore offers an inexpensive and scalable formulation approach for improving the bioavailability of paediatric drugs, like clofazimine, and enabling the treatment of infections in children.
{"title":"Co-administering clofazimine with infant formula enhances its oral bioavailability in rats and pigs","authors":"Thomas Eason , Ellie Ponsonby-Thomas , Anna C. Pham , Shouyuan Huang , Simone Margaard Offersen , Thomas Thymann , Vanessa Zann , Malinda Salim , Ben J. Boyd","doi":"10.1016/j.ejpb.2025.114979","DOIUrl":"10.1016/j.ejpb.2025.114979","url":null,"abstract":"<div><div>Milk-based formulations have been proposed as enabling formulations for the delivery of poorly water-soluble drugs to children due to their safety, dose versatility and ability to improve drug solubilisation through the digestion process. In this study the feasibility of using commercially available infant formula as an enabling formulation to enhance the solubilisation and oral bioavailability of clofazimine, a poorly soluble lipophilic drug, following oral administration was investigated. The solubilisation of crystalline clofazimine in digesting infant formula was assessed <em>in vitro</em> using synchrotron small-angle X-ray scattering. An <em>in vivo</em> pharmacokinetic study was then conducted to determine the oral bioavailability of a suspension of clofazimine in infant formula compared to a lipid-free aqueous suspension in both a rat and piglet animal model. Clofazimine administered in infant formula produced significantly higher plasma concentrations than the aqueous vehicle and resulted in comparable enhancements in relative oral bioavailability in both the piglet (235%) and rat animal models (256%). Results from this study demonstrated that infant formula was an effective enabling formulation, with a positive correlation between improved drug solubilisation during <em>in vitro</em> digestion of infant formula and enhanced <em>in vivo</em> drug exposure following oral administration. Infant formula therefore offers an inexpensive and scalable formulation approach for improving the bioavailability of paediatric drugs, like clofazimine, and enabling the treatment of infections in children.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114979"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833583","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}
This study investigated the development of poly(vinyl alcohol) (PVA)/sericin hydrogels incorporating humectant-plasticizers glycerin, propylene glycol, and mannitol for wound dressing applications. Although PVA/sericin hydrogels exhibit excellent cytocompatibility and promote fibroblast proliferation and collagen production, making them promising candidates for wound care, they suffer from rapid moisture loss and dimensional instability. To address these limitations, glycerin, propylene glycol, and/or mannitol were incorporated to enhance the properties of the hydrogels. The physicochemical and mechanical properties, together with the in vitro cytocompatibility of L929 fibroblasts, were evaluated. The results demonstrated that incorporating propylene glycol and/or mannitol improved dimensional stability, skin adhesion, moisture retention, exudate absorption, flexibility, and softness. Among all the formulations, the hydrogel containing 1 % v/v propylene glycol and 1 % w/v mannitol exhibited the most balanced performance, combining superior physicochemical and mechanical properties (time to initial upward bending: 2.83 h; time for complete upward bending of all four edges: 10.50 h; gel fraction: 60 %, highest absorption at 3 h: 34.41 %; tensile strength: 46.93 kPa, elastic modulus: 33.53 kPa, compressive strength: 19.94 kPa; compressive modulus: 15.58 kPa) with enhanced fibroblast viability (102 % cell viability) and sustained sericin release (∼90 % cumulative release at 168 h). In vitro assays confirmed the cytocompatibility of the optimized hydrogel. Taken together, these findings indicate its potential for effective management of moderately exudating wounds. This study introduces a simple and practical plasticization approach for PVA/sericin hydrogels, offering a promising candidate for wound dressing applications. Further clinical studies are warranted to evaluate its therapeutic efficacy and safety.
{"title":"Humectant-plasticized poly(vinyl alcohol)-sericin hydrogels with improved dimensional stability and moisture retention for wound dressing applications","authors":"Thunyaluk Meetam , Rungnapha Yamdech , Pithi Chanvorachote , Pornanong Aramwit","doi":"10.1016/j.ejpb.2026.114982","DOIUrl":"10.1016/j.ejpb.2026.114982","url":null,"abstract":"<div><div>This study investigated the development of poly(vinyl alcohol) (PVA)/sericin hydrogels incorporating humectant-plasticizers glycerin, propylene glycol, and mannitol for wound dressing applications. Although PVA/sericin hydrogels exhibit excellent cytocompatibility and promote fibroblast proliferation and collagen production, making them promising candidates for wound care, they suffer from rapid moisture loss and dimensional instability. To address these limitations, glycerin, propylene glycol, and/or mannitol were incorporated to enhance the properties of the hydrogels. The physicochemical and mechanical properties, together with the in vitro cytocompatibility of L929 fibroblasts, were evaluated. The results demonstrated that incorporating propylene glycol and/or mannitol improved dimensional stability, skin adhesion, moisture retention, exudate absorption, flexibility, and softness. Among all the formulations, the hydrogel containing 1 % v/v propylene glycol and 1 % w/v mannitol exhibited the most balanced performance, combining superior physicochemical and mechanical properties (time to initial upward bending: 2.83 h; time for complete upward bending of all four edges: 10.50 h; gel fraction: 60 %, highest absorption at 3 h: 34.41 %; tensile strength: 46.93 kPa, elastic modulus: 33.53 kPa, compressive strength: 19.94 kPa; compressive modulus: 15.58 kPa) with enhanced fibroblast viability (102 % cell viability) and sustained sericin release (∼90 % cumulative release at 168 h). In vitro assays confirmed the cytocompatibility of the optimized hydrogel. Taken together, these findings indicate its potential for effective management of moderately exudating wounds. This study introduces a simple and practical plasticization approach for PVA/sericin hydrogels, offering a promising candidate for wound dressing applications. Further clinical studies are warranted to evaluate its therapeutic efficacy and safety.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114982"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905599","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 : 2026-02-01Epub Date: 2025-12-02DOI: 10.1016/j.ejpb.2025.114943
Jingyu Wang, Xiaoqian Xie, Xuewei Cao, Le Sun
The physiologically-based characteristics, the convenience of species extrapolation, and the capacity to integrate diverse in vivo mechanisms have contributed to the increasing employment of the physiologically based pharmacokinetic (PBPK) model in the pharmacokinetic and pharmacodynamic investigations of nanoparticles. However, due to the significant differences in in vivo mechanisms between nanoparticles and small molecule drugs, there are variations in the establishment of PBPK models, such as distribution mechanisms, clearance pathways, drug release, in vivo circulation pathways and indication. This review highlights the distinctions in PBPK modeling strategies between nanoparticles and small molecule drugs. It conducts a comprehensive analysis of current progress in PBPK models for nanoparticles, including model structure design, such as the setup of compartments and sub-compartments, blood circulation and lymphatic circulation, mononuclear phagocyte system, and tumor compartment; the in vivo mechanisms of nanoparticles, such as the permeability-limited mechanism, protein coronas, and drug release from nanoparticles; as well as parameter setting, including the tissue-to-plasma partition coefficient, permeability coefficient, clearance rate, and parameters related to the mononuclear phagocyte system. Ultimately, this review analyzes the validation methods and accuracy of the 61 PBPK models developed over the past two decades. In addition, several existing issues within the PBPK models for nanoparticles, along with their potential solutions, are proposed. It is anticipated that this review will be beneficial to researchers engaged in establishing PBPK models for studying the in vivo behavior of nanoparticles.
{"title":"Prediction of in vivo behavior of nanoparticles using physiologically based pharmacokinetic model: The modeling approach and issues","authors":"Jingyu Wang, Xiaoqian Xie, Xuewei Cao, Le Sun","doi":"10.1016/j.ejpb.2025.114943","DOIUrl":"10.1016/j.ejpb.2025.114943","url":null,"abstract":"<div><div>The physiologically-based characteristics, the convenience of species extrapolation, and the capacity to integrate diverse <em>in vivo</em> mechanisms have contributed to the increasing employment of the physiologically based pharmacokinetic (PBPK) model in the pharmacokinetic and pharmacodynamic investigations of nanoparticles. However, due to the significant differences in <em>in vivo</em> mechanisms between nanoparticles and small molecule drugs, there are variations in the establishment of PBPK models, such as distribution mechanisms, clearance pathways, drug release, <em>in vivo</em> circulation pathways and indication. This review highlights the distinctions in PBPK modeling strategies between nanoparticles and small molecule drugs. It conducts a comprehensive analysis of current progress in PBPK models for nanoparticles, including model structure design, such as the setup of compartments and sub-compartments, blood circulation and lymphatic circulation, mononuclear phagocyte system, and tumor compartment; the <em>in vivo</em> mechanisms of nanoparticles, such as the permeability-limited mechanism, protein coronas, and drug release from nanoparticles; as well as parameter setting, including the tissue-to-plasma partition coefficient, permeability coefficient, clearance rate, and parameters related to the mononuclear phagocyte system. Ultimately, this review analyzes the validation methods and accuracy of the 61 PBPK models developed over the past two decades. In addition, several existing issues within the PBPK models for nanoparticles, along with their potential solutions, are proposed. It is anticipated that this review will be beneficial to researchers engaged in establishing PBPK models for studying the <em>in vivo</em> behavior of nanoparticles.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"219 ","pages":"Article 114943"},"PeriodicalIF":4.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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