Pharmaceutics

14 pages, 548 KB

Open AccessArticle

Pharmacokinetics of Isavuconazole in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO) Support: A Prospective Exploratory Observational Study

by Alba Escolà-Rodríguez, Elena Sandoval, Jorge Moisés, Adrián Téllez Santoyo, Albert Carramiñana, Jaime I. Sainz de Medrano, Cristina Espinosa, Carlos Roca, Marta Hernández Meneses, Sabina Herrera, Mercè Brunet Serra, Pedro Castro, Dolors Soy Muner and Carla Bastida

Pharmaceutics 2026, 18(9), 1049; https://doi.org/10.3390/pharmaceutics18091049 - 24 Aug 2026

Abstract

Background: Isavuconazole, a broad-spectrum triazole antifungal, exhibits high lipophilicity and extensive plasma protein binding, properties that may predispose it to sequestration within extracorporeal membrane oxygenation (ECMO) circuits. This study aimed to characterize the pharmacokinetics (PK) of isavuconazole and to evaluate drug sequestration within [...] Read more.

Background: Isavuconazole, a broad-spectrum triazole antifungal, exhibits high lipophilicity and extensive plasma protein binding, properties that may predispose it to sequestration within extracorporeal membrane oxygenation (ECMO) circuits. This study aimed to characterize the pharmacokinetics (PK) of isavuconazole and to evaluate drug sequestration within the ECMO circuit in critically ill patients receiving ECMO support. Methods: We conducted a prospective, exploratory, single-center observational study including critically ill patients receiving ECMO (veno-venous (VV) or veno-arterial (VA)) and treated with intravenous isavuconazole. Serial blood samples were collected simultaneously from the patient’s arterial line and from pre- and post-membrane oxygenator sampling sites. Non-compartmental analysis was performed on arterial line samples to estimate PK measures, and concentration differences across sampling sites were analyzed to estimate circuit-related drug loss. PK/pharmacodynamic (PD) target attainment was assessed using established efficacy thresholds (AUC_0–24/MIC ≥ 25 and Cmin > 2 mg/L). Results: A total of 41 plasma samples from 3 critically ill patients (2 VV-ECMO, 1 VA-ECMO) were included in the analysis. Limited, component-specific isavuconazole loss was observed in tubing and connectors (6.62% ± 20.8%, p = 0.294) and across the entire ECMO circuit (7.74% ± 20.2%, p = 0.211). Likewise, no relevant concentration difference was detected across the membrane oxygenator (0.849% ± 6.15%, p = 0.642). Interindividual variability was observed across PK parameters, particularly in measures of elimination and distribution. All patients achieved predefined PK/PD efficacy targets, with mean Cmin and AUC_0–24/MIC of 3.07 ± 0.261 mg/L and 85.3 ± 4.03, respectively, and none exceeded the established toxicity threshold. Conclusions: Preliminary results showed variable concentration differences across ECMO sampling sites, with no consistent pattern of isavuconazole loss across the ECMO circuit under the conditions evaluated. All patients achieved predefined PK/PD efficacy targets using currently recommended dosing regimens; however, interindividual PK variability was observed, supporting the potential value of therapeutic drug monitoring (TDM) to guide individualized dosing decisions in this population. Larger population PK studies are warranted to further characterize determinants of isavuconazole exposure during ECMO support and refine evidence-based dosing strategies. Full article

(This article belongs to the Special Issue Clinical Pharmacokinetics and Pharmacodynamics of Antimicrobial Therapy)

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23 pages, 3066 KB

Open AccessReview

Targeted Delivery of Specialized Pro-Resolving Mediators (SPMs) for Improved Treatments of Inflammatory Diseases and Cancer

by Adeola Aminu and Zhenjia Wang

Pharmaceutics 2026, 18(9), 1048; https://doi.org/10.3390/pharmaceutics18091048 - 23 Aug 2026

Abstract

Acute and chronic inflammation underlies the pathogenesis of numerous diseases, including autoimmune disorders, atherosclerosis, infections, and cancer. Although non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are widely used to control inflammation, their clinical utility is limited by adverse effects such as gastrointestinal toxicity and [...] Read more.

Acute and chronic inflammation underlies the pathogenesis of numerous diseases, including autoimmune disorders, atherosclerosis, infections, and cancer. Although non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are widely used to control inflammation, their clinical utility is limited by adverse effects such as gastrointestinal toxicity and immunosuppression. Specialized pro-resolving mediators (SPMs), a family of endogenous lipid mediators derived from omega-3 fatty acids, have emerged as promising therapeutics because they actively promote the resolution of inflammation without suppressing host immunity. However, their clinical translation is hindered by poor chemical stability, rapid metabolic degradation, and short circulation half-lives. To overcome these limitations, a variety of delivery platforms—including liposomes, extracellular vesicles, PLGA nanoparticles, and hydrogels—have been developed to improve SPM stability, pharmacokinetics, and therapeutic efficacy. This review summarizes the cellular targets of SPMs, current delivery challenges, and emerging strategies for cell- and tissue-specific SPM delivery. We also discuss future opportunities for targeted SPM therapies in the treatment of inflammatory diseases and cancer. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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33 pages, 1319 KB

Open AccessSystematic Review

A Systematic Review of Recent Developments in Wound Healing and Skin Regeneration Properties of Plant-Extract-Based Hydrogels for Skin Delivery: A Focus on Asteraceae and Lamiaceae Families

by Monika Michalak

Pharmaceutics 2026, 18(9), 1047; https://doi.org/10.3390/pharmaceutics18091047 - 23 Aug 2026

Abstract

Background: Plants have been traditionally used for centuries to treat wounds and, over time, have been tested for their healing properties. There is a constant search for new natural resources that could be used to develop various topical wound care products. Methods: A [...] Read more.

Background: Plants have been traditionally used for centuries to treat wounds and, over time, have been tested for their healing properties. There is a constant search for new natural resources that could be used to develop various topical wound care products. Methods: A comprehensive search of the literature was conducted in PubMed/MEDLINE, Scopus, and Web of Science databases (2022–2026) in accordance with the PRISMA 2020 guidelines. Included studies focused on current in vitro and in vivo research on hydrogels containing plant extracts from the Asteraceae and Lamiaceae families and their potential application in wound healing and skin regeneration. Results: An analysis of 24 included studies confirms that both families include interesting and valuable plants with antioxidant, antimicrobial and anti-inflammatory properties; these plants also influence collagen deposition, fibroblast proliferation, and epithelialization, and reduce the risk of infection, thereby contributing to faster wound healing. The most frequently tested phytoextract in this respect was Calendula officinalis (Asteraceae) incorporated into a hydrogel. A variety of materials, including natural, semi-synthetic, and synthetic polymers, as well as hybrid matrix, but also diverse formulation strategies, from simple solutions to more advanced and modern methods, have been used to produce hydrogels. Conclusions: This systematic review summarizes the current evidence, highlights directions and possibilities for the use of phytoextract-based hydrogels, and discusses limitations and future perspectives in the development of effective externally applied formulations to support wound healing. Full article

(This article belongs to the Special Issue Natural Product-Based Pharmaceutical Formulations for Skin Drug Delivery)

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21 pages, 4744 KB

Open AccessArticle

Influence of Core and Membrane Composition on Drug Release from MCC/Isomalt-Based Matrix Pellets in Biorelevant Osmolarity Media

by Christian Fleck, Isameddin Aghrbi, Kristina Vlahovic, Franciska Erdő, András József Laki, Nikolett Kállai-Szabó, István Antal and Miléna Lengyel

Pharmaceutics 2026, 18(9), 1046; https://doi.org/10.3390/pharmaceutics18091046 - 23 Aug 2026

Abstract

Background/Objectives: Matrix pellet formulations enable homogeneous incorporation of the active ingredient and advanced control of release depending on the excipients added. The aim of this study was to develop, characterize, and assess the drug release profiles of microcrystalline cellulose (MCC) and isomalt-based [...] Read more.

Background/Objectives: Matrix pellet formulations enable homogeneous incorporation of the active ingredient and advanced control of release depending on the excipients added. The aim of this study was to develop, characterize, and assess the drug release profiles of microcrystalline cellulose (MCC) and isomalt-based matrix pellets with direct drug incorporation, advancing beyond the earlier concept of isomalt as a mere inert core with layered drug application, under simulated physiological conditions in vitro. Methods: Matrix pellets with varying MCC–isomalt ratios (90:10, 70:30, and 50:50) were produced by extrusion/spheronization and subsequently coated with film-forming polymers. Dissolution experiments were performed under varying osmolarity to characterize release profiles. The experimental design data were statistically evaluated. Results: The extrusion/spheronization technique yielded uniform, robust matrix pellets with acceptable sphericity and mechanical integrity, even at high isomalt levels. Release from coated pellets was significantly influenced by the polymer coating and osmolarity of the dissolution medium. However, with increasing isomalt content in the matrix, the dependence of drug release kinetics on medium osmolarity was substantially reduced. Conclusions: The production of MCC–isomalt matrix pellets in which isomalt acts as a functional matrix component reduced the effect of osmolarity of dissolution medium on the release of ibuprofen sodium salt in in vitro experiments. Full article

(This article belongs to the Special Issue Advances in Solid and Semi-Solid Dosage Form Design for Enhanced Biopharmaceutical Performance)

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42 pages, 3921 KB

Open AccessReview

Lipid-Based Delivery Systems for Therapeutic Glycoproteins: Current Advances, Challenges, and Future Perspectives

by Hamad Alrbyawi

Pharmaceutics 2026, 18(9), 1045; https://doi.org/10.3390/pharmaceutics18091045 - 22 Aug 2026

Abstract

Therapeutic glycoproteins, a pivotal class of biopharmaceuticals, have transformed modern medicine through their broad applications in oncology, immunotherapy, and infectious disease management. Their structural complexity and biological specificity make them highly effective in targeting disease pathways; however, challenges related to stability, bioavailability, and [...] Read more.

Therapeutic glycoproteins, a pivotal class of biopharmaceuticals, have transformed modern medicine through their broad applications in oncology, immunotherapy, and infectious disease management. Their structural complexity and biological specificity make them highly effective in targeting disease pathways; however, challenges related to stability, bioavailability, and delivery efficacy limit their full potential. Recent advancements in delivery technologies have sought to address these challenges through innovative approaches such as nanotechnology-based carriers, controlled-release systems, and molecular engineering. These strategies have demonstrated the ability to enhance glycoprotein stability, optimize pharmacokinetics, and achieve targeted delivery with minimal off-target effects. This review provides a comprehensive overview of state-of-the-art lipid-based delivery systems specifically designed to overcome the unique pharmaceutical challenges associated with therapeutic glycoproteins, highlighting their design principles, formulation strategies, mechanisms of encapsulation and release, and therapeutic advantages in improving glycoprotein stability, bioavailability, targeted delivery, and treatment efficacy. In addition to surveying the current landscape, this review delves into the key challenges impeding the widespread adoption of advanced delivery systems, including immunogenicity, manufacturing scalability, and clinical translation. The review concludes with insights into emerging trends in the development of lipid-based delivery systems, positioning glycoprotein therapeutics at the forefront of innovation in biopharmaceuticals. This overview of advancements and challenges aims to provide a roadmap for future progress in the field of glycoprotein delivery and therapeutic applications. Full article

(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation, 2nd Edition)

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52 pages, 7768 KB

Open AccessReview

Smart Mesoporous Silica Nanoparticle-Based Drug Delivery Systems: Recent Advances in Biomedical Applications, Wound Healing and Therapeutic Perspectives

by Manickam Rajkumar, Nadarajan Prathap, Vivekanand Ankush Kashid, Bhupendra G. Prajapati, Kokila Palani, Parappurath Narayanan Sudha, Prabhakaran Rajkumar and Biswajit Basu

Pharmaceutics 2026, 18(8), 1044; https://doi.org/10.3390/pharmaceutics18081044 - 21 Aug 2026

Abstract

Mesoporous silica nanoparticles (MSNs) have emerged as versatile nanocarriers for biomedical applications because of their unique physicochemical properties, including high surface area, large pore volume, excellent drug-loading capacity, controllable biodegradation, and facile surface functionalization. These characteristics have enabled the development of advanced drug [...] Read more.

Mesoporous silica nanoparticles (MSNs) have emerged as versatile nanocarriers for biomedical applications because of their unique physicochemical properties, including high surface area, large pore volume, excellent drug-loading capacity, controllable biodegradation, and facile surface functionalization. These characteristics have enabled the development of advanced drug delivery systems with enhanced therapeutic efficacy, targeted delivery, improved bioavailability, and reduced systemic toxicity. Recent advances in MSN synthesis, physicochemical properties, surface engineering, and functionalization strategies have significantly improved their biological performance and therapeutic potential. In particular, integrating polymers, lipids, and liposomes with MSN platforms has enhanced colloidal stability, circulation time, cellular uptake, and target specificity, thereby facilitating efficient, stimuli-responsive drug delivery. This review highlights MSN-based drug delivery systems in cancer therapy, where multifunctional nanocarriers enable site-specific delivery, controlled drug release, enhanced tumor accumulation, and reduced off-target effects. The review discusses the expanding roles of MSNs in antimicrobial therapy, wound healing, tissue engineering, and regenerative medicine, emphasizing their ability to promote localized therapeutic delivery, immunomodulation, angiogenesis, and tissue regeneration. The review discusses the diagnostic and theragnostic capabilities of MSNs for disease imaging and monitoring. It also critically evaluates current challenges related to biocompatibility, biodegradation, toxicity, biological barriers, large-scale manufacturing, clinical translation, and regulatory considerations. This review provides a comprehensive overview of recent progress, current limitations, and future opportunities for MSN-based platforms in targeted drug delivery and advanced biomedical applications, supporting their continued advancement toward clinical translation and precision medicine. Full article

(This article belongs to the Special Issue Research on Drug Delivery System Based on Mesoporous Silica Nanoparticles)

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32 pages, 2551 KB

Open AccessArticle

Aqueous Incubation Reveals Transformation of Rosmarinic Acid in Medicinally Important Nepetoideae Species and Leads to Novel Bioactive Compounds

by Adila Nazli, Bernadett Szögi-Tatár, Szilvia Bősze, Gergő Tóth, Katalin Solymosi, Szabolcs Béni and Imre Boldizsár

Pharmaceutics 2026, 18(8), 1043; https://doi.org/10.3390/pharmaceutics18081043 - 21 Aug 2026

Abstract

Background: Rosmarinic acid (RA) is a major phenylpropanoid constituent of many medicinal plants belonging to the Nepetoideae subfamily of the Lamiaceae family and contributes significantly to their biological activities. Traditionally, RA-containing extracts have been prepared using organic solvents or hot-water extraction. Methods: In [...] Read more.

Background: Rosmarinic acid (RA) is a major phenylpropanoid constituent of many medicinal plants belonging to the Nepetoideae subfamily of the Lamiaceae family and contributes significantly to their biological activities. Traditionally, RA-containing extracts have been prepared using organic solvents or hot-water extraction. Methods: In addition to conventional extraction techniques, the phenylpropanoid composition of medicinally important tissues from 13 Nepetoideae species was investigated following incubation in an aqueous medium at room temperature. Phenylpropanoids in the differently prepared extracts were identified by extensive HPLC-UV-HR-MS/MS and NMR analyses. The antioxidant and cytostatic activities of isolated phenylpropanoids were evaluated using DPPH and Alamar Blue assays, respectively. Results: In tissues of all investigated species, RA underwent rapid enzyme-catalyzed conversion during aqueous incubation through oxidative decarboxylation, accompanied by the transient accumulation of nepetoidins A and B. The RA-related phenylpropanoid salvianolic acid K was identified in the roots of three Salvia species, while a previously undescribed isomer, designated salvianolic acid O, was discovered in the roots of Salvia verticillata. Both compounds underwent enzymatic transformations analogous to those of RA in aqueous medium, yielding two previously undescribed phenylpropanoids, salvianolic acids P and Q. Optimized aqueous incubation conditions enabled the high-yield accumulation of these conversion products. Together with their parent compounds, seven phenylpropanoids were isolated from selected plant tissues and were found to exhibit structure-dependent antioxidant and metabolic inhibitory activities in vitro. Conclusions: Aqueous incubation of Nepetoideae plant tissues markedly alters their phytochemical composition and provides access to previously unavailable bioactive phenylpropanoids. Full article

(This article belongs to the Section Biopharmaceutics)

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24 pages, 1958 KB

Open AccessArticle

DDI-HierPred: An Artificial Intelligence-Based Hierarchical PK/PD Platform for Drug–Drug Interaction Prediction

by Mebarka Ouassaf and Bader Y. Alhatlani

Pharmaceutics 2026, 18(8), 1042; https://doi.org/10.3390/pharmaceutics18081042 - 21 Aug 2026

Abstract

Background/Objectives: Pharmacokinetic and pharmacodynamic drug–drug interactions are major determinants of drug safety in polypharmacy, with potential consequences including reduced therapeutic efficacy, altered drug exposure, and increased adverse effects. This study presents DDI-HierPred, an artificial intelligence-based hierarchical framework for drug–drug interaction prediction using Morgan [...] Read more.

Background/Objectives: Pharmacokinetic and pharmacodynamic drug–drug interactions are major determinants of drug safety in polypharmacy, with potential consequences including reduced therapeutic efficacy, altered drug exposure, and increased adverse effects. This study presents DDI-HierPred, an artificial intelligence-based hierarchical framework for drug–drug interaction prediction using Morgan fingerprint-based drug-pair representations. Methods: At Level 1, Logistic Regression, Random Forest, Linear SVM, and XGBoost were compared for pharmacokinetic/pharmacodynamic (PK/PD) classification. At Level 2, an XGBoost multiclass classifier was used to predict 61 interaction subtype classes. End-to-end performance was evaluated using predicted Level 1 routing, and additional drug-identity-disjoint evaluations were conducted to assess generalization when one or both drugs were unseen during training. Y-randomization analyses were performed for both classification levels. Results: Linear SVM achieved the best Level 1 performance, yielding an accuracy of 0.8661, a ROC-AUC of 0.9380, and an MCC of 0.7303 on the independent test set. At Level 2, the XGBoost classifier achieved an accuracy of 0.8712, a balanced accuracy of 0.9087, a macro F1-score of 0.9115, and a Top-3 accuracy of 0.9868. Because the Level 2 test partition was also used for algorithm comparison and model selection, these results should be regarded as exploratory and potentially optimistic rather than as an independent final evaluation. When evaluated end-to-end using predicted Level 1 routing, performance decreased to an accuracy of 0.5767, balanced accuracy of 0.3573, and macro F1-score of 0.4379. Additional drug-identity-disjoint evaluations showed further performance reductions when one or both drugs were unseen during training, highlighting the greater difficulty of generalization to previously unseen drug identities. Y-randomization analyses supported the robustness of both classification levels. Conclusions: The framework was deployed as a publicly accessible web platform integrating documented interaction lookup, hierarchical PK/PD classification, Level 1-constrained subtype prediction, confidence scoring, single-pair and batch analysis, ranked Top-3 predictions, and downloadable reports. These findings indicate that upstream routing and unseen-drug generalization remain important limitations of the current framework. DDI-HierPred therefore provides a computational platform for research-oriented screening, interpretation, and prioritization of potential drug–drug interactions. Full article

(This article belongs to the Special Issue In Silico Pharmacokinetic and Pharmacodynamic (PK-PD) Modeling)

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20 pages, 1649 KB

Open AccessArticle

The Impact of Sugar Moieties on the Solubility of Naringin-Neohesperidin Co-Amorphous Solid Dispersions

by Hua Jiang, Zhong-Kang Yang, Jun Li and Yu-Pin Wang

Pharmaceutics 2026, 18(8), 1041; https://doi.org/10.3390/pharmaceutics18081041 - 21 Aug 2026

Abstract

Background/Objectives: Co-amorphous solid dispersions (c-ASD) are a promising strategy for enhancing the dissolution of poorly water-soluble drugs. Naringin (NA) and neohesperidin (NE) are dihydroflavonoid components and are poorly soluble. They can form a c-ASD. Concerning the c-ASD formation mechanism, the intermolecular forces [...] Read more.

Background/Objectives: Co-amorphous solid dispersions (c-ASD) are a promising strategy for enhancing the dissolution of poorly water-soluble drugs. Naringin (NA) and neohesperidin (NE) are dihydroflavonoid components and are poorly soluble. They can form a c-ASD. Concerning the c-ASD formation mechanism, the intermolecular forces between the non-sugar aglycones of NA and NE have been determined; however, the roles of the sugar chains, which account for nearly 50% of the overall molecular weight of both compounds, are unclear. Therefore, the impact of the sugar moiety on the solubility of NA-NE c-ASD needs to be investigated. Methods: The sugar removal products of NA and NE are naringenin-7-O-glucoside, naringenin, hesperetin-7-O-glucoside, and hesperetin. Therefore, in this study, the solubility profiles of NA with hesperetin-7-O-glucoside and hesperetin, and of NE with naringenin-7-O-glucoside and naringenin were assessed by dissolution determination and analyzed by PXRD. Results: These results indicated that the rhamnose and glucose moieties on the NE sugar chain and the glucose moiety on the NA sugar chain are vital to the stability and solubility of NE-NA c-ASD. The rhamnose moiety on the sugar chain of NA is removable, without which a stable soluble aggregator may also be constructed, but the soluble aggregator formation ability is weakened. Conclusions: The results of this study not only inform the rational selection of co-formers for structurally similar flavanone glycosides but can also help chemists modify the c-ASD structure based on the sugar moiety. Full article

(This article belongs to the Special Issue Molecular Strategies to Enhance Drug Solubility)

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31 pages, 3214 KB

Open AccessReview

Combining Gene Therapy with Current Modulator Treatments for Cystic Fibrosis: A Promising Area of Research

by Xavier Buin, Rosy Ghanem, Ines Pankonien, Frédéric Becq, Margarida Amaral and Tristan Montier

Pharmaceutics 2026, 18(8), 1040; https://doi.org/10.3390/pharmaceutics18081040 - 21 Aug 2026

Abstract

Since the development of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator in 2012, these therapies have revolutionized patients’ health. They are now the most effective treatment for people with cystic fibrosis (pwCF). In fact, elexacaftor/tezacaftor/ivacaftor and vanzacaftor/tezacaftor/deutivacaftor, the latest combination therapies [...] Read more.

Since the development of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator in 2012, these therapies have revolutionized patients’ health. They are now the most effective treatment for people with cystic fibrosis (pwCF). In fact, elexacaftor/tezacaftor/ivacaftor and vanzacaftor/tezacaftor/deutivacaftor, the latest combination therapies consisting of a CFTR potentiator and two CFTR correctors, improved lung function by 14% in pwCF. Other modulator therapies targeting CFTR mRNA and/or protein are currently under preclinical/clinical investigation. However, due to the variant-specific nature of these therapies, about 10% of pwCF in Europe remains without effective treatment, and many treated pwCF experience various adverse events such as headaches, infections, hepatotoxicity, hypertension, and depression. Therefore, mutation-agnostic strategies such as gene therapy are needed. They could expand treatment eligibility for all pwCF and improve outcomes. In fact, nucleic acid delivery (e.g., pDNA, mRNA, oligonucleotides, genome editing) or targeting non-CFTR channels to restore ion transport represent promising future additional directions for CF therapy. This review aims to discuss a potential combination between gene therapy approaches and existing modulators to improve treatment eligibility, safety, and efficacy. Full article

(This article belongs to the Special Issue Translating Gene Therapies from Bench to Bedside)

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25 pages, 4557 KB

Open AccessArticle

Amniotic Mesenchymal Stromal Cell Administration Prevents and Stops Lung Fibrosis and Is Associated with Distinct Macrophage Signatures

by Anna Cargnoni, Serafina Farigu, Pietro Romele, Andrea Papait, Marta Magatti, Antonietta Silini and Ornella Parolini

Pharmaceutics 2026, 18(8), 1039; https://doi.org/10.3390/pharmaceutics18081039 - 20 Aug 2026

Abstract

Background/Objectives: Mesenchymal stromal cells from the amniotic membrane (hAMSCs) counteract fibrosis progression, primarily via anti-inflammatory effects like promoting macrophage polarization toward an anti-inflammatory, pro-regenerative phenotype. Methods: We investigated hAMSCs’ ability to prevent and halt lung fibrosis in a bleomycin-induced fibrosis murine [...] Read more.

Background/Objectives: Mesenchymal stromal cells from the amniotic membrane (hAMSCs) counteract fibrosis progression, primarily via anti-inflammatory effects like promoting macrophage polarization toward an anti-inflammatory, pro-regenerative phenotype. Methods: We investigated hAMSCs’ ability to prevent and halt lung fibrosis in a bleomycin-induced fibrosis murine model. We focused on their impact on recruitment and polarization of different macrophage populations, including SPARC- and CD169-expressing macrophages, implicated in resolving pulmonary inflammation and fibrosis. Results: hAMSCs, administered early (concomitant with bleomycin, during acute inflammation), or late (at day 7 post-bleomycin, during established fibrosis), showed anti-fibrotic activity, preserving alveolar area, reducing the extent of lung fibrosis, and decreasing α-SMA levels. These preventive and late anti-fibrotic effects of hAMSCs are associated with a context-dependent presence of distinct macrophage signatures. Early treatment reduced macrophage recruitment and increased levels of Arg1⁺/iNOS⁻ macrophages, curbing injury-induced inflammation. Late treatment uniquely increased the lung levels of CD169⁺ macrophages, suggesting their contribution to hAMSCs’ anti-fibrotic effect. We hypothesized a potential involvement of lung CD169⁺ macrophages in promoting recruitment of regulatory T cells (Tregs) to the lungs. Although these macrophages can establish a CCL22-CCR4 axis with Tregs, and treatment effectively boosted Treg lung levels, the Treg increase is not directly attributable to higher CD169⁺ macrophage numbers, implying other potentially IL-10-driven mechanisms. Conclusions: hAMSC treatment effectively prevents and blocks lung fibrosis. These effects are associated with distinct lung macrophage marker profiles, suggesting a potential involvement of different macrophage populations in a time-dependent manner; thus highlighting administration timing’s role in optimizing therapeutic synergy. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed? (2nd Edition))

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18 pages, 8018 KB

Open AccessArticle

Targeting TTLL1 Alleviates Aβ-Induced Microtubule Disruption and TAU Pathology in Human iPSC-Derived Cortical Neurons

by Mohamed Aghyad Al Kabbani, Laura Köhler, Tamara Wied, Daniel Adam, Jennifer Klimek and Hans Zempel

Pharmaceutics 2026, 18(8), 1038; https://doi.org/10.3390/pharmaceutics18081038 - 20 Aug 2026

Abstract

Background: Microtubules play a crucial role in neuronal structure and function, with their stability and dynamics regulated by posttranslational modifications (PTMs) such as polyglutamylation. In Alzheimer’s disease (AD), the microtubule-associated protein TAU becomes mislocalized into the somatodendritic compartment (‘TAU missorting’), dissociates from microtubules, [...] Read more.

Background: Microtubules play a crucial role in neuronal structure and function, with their stability and dynamics regulated by posttranslational modifications (PTMs) such as polyglutamylation. In Alzheimer’s disease (AD), the microtubule-associated protein TAU becomes mislocalized into the somatodendritic compartment (‘TAU missorting’), dissociates from microtubules, aggregates into neurofibrillary tangles, and contributes to microtubule destabilization and neuronal death. Objectives and Methods: Here, we investigated the role of tubulin tyrosine ligase-like proteins (TTLLs) in TAU missorting and microtubule dysregulation using human-induced pluripotent stem cell (hiPSC)-derived cortical neurons treated with oligomeric amyloid-beta (oAβ) to replicate AD-like conditions. TTLL1, TTLL4, and TTLL6 were selectively knocked down (KD) to assess their impact on TAU missorting and microtubule stability. Fluorescence resonance energy transfer (FRET) microscopy was used to examine proximities between TAU and TTLL proteins. Results: We observed TAU missorting, increased tubulin polyglutamylation, decreased tubulin acetylation associated with microtubule destabilization, and synaptic declustering in oAβ-treated neurons. TTLL1 KD significantly reduced TAU missorting, tubulin polyglutamylation, and synaptic disintegration, while TTLL4 KD showed moderate effects, and TTLL6 KD restored microtubule acetylation. Importantly, TTLL KD did not impair neuritic networks, dendritic complexity, or neuronal activity. FRET microscopy in HEK293T cells revealed a close molecular proximity between TAU and TTLL1 consistent with a potential direct or complex-mediated association, but not with other TTLLs, suggesting a direct role of TTLL1 in TAU-mediated toxicity. Conclusions: Our findings identify TTLL1 as a promising therapeutic target for limiting TAU-associated cytoskeletal pathology in AD. These results support further development of pharmacological or genetic strategies targeting TTLL1 as a disease-modifying approach for AD and related tauopathies. Full article

(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)

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26 pages, 2154 KB

Open AccessArticle

Cycloastragenol Provides Pharmacokinetic Advantages over Astragaloside IV with Enhanced Cochlear Exposure and Protection Against Age-Associated Hearing Dysfunction

by Yaqian Gao, Yiheng Liang, Haiyan Chen, Zigui Wang, Yanchang Huang, Wei Zhou and Zhiyun Du

Pharmaceutics 2026, 18(8), 1037; https://doi.org/10.3390/pharmaceutics18081037 - 20 Aug 2026

Abstract

Background: Adequate inner-ear exposure is a key challenge in treating age-related hearing loss (ARHL). Astragaloside IV (AS-IV), the principal saponin of Astragalus membranaceus, has anti-aging activity but poor oral bioavailability; its aglycone cycloastragenol (CAG) may represent a pharmacokinetically optimized active moiety. Methods: [...] Read more.

Background: Adequate inner-ear exposure is a key challenge in treating age-related hearing loss (ARHL). Astragaloside IV (AS-IV), the principal saponin of Astragalus membranaceus, has anti-aging activity but poor oral bioavailability; its aglycone cycloastragenol (CAG) may represent a pharmacokinetically optimized active moiety. Methods: We compared the pharmacokinetics, cochlear exposure, and biotransformation of CAG and AS-IV after oral dosing in mice by LC-MS/MS, and evaluated CAG in a D-galactose-induced accelerated-aging rat model (ABR, hair-cell morphology, redox and cytokine assays) and in D-galactose-stressed HEI-OC1 cells. Results: CAG achieved markedly higher plasma and perfused whole-cochlea exposure than intact AS-IV after equivalent dosing, even after molar-dose normalization. AS-IV was biotransformed to CAG in vivo and in liver microsomes, supporting CAG as a quantitatively important active metabolite. In rats, oral CAG reduced ABR threshold elevation and preserved hair-cell architecture, improved cochlear redox status (higher SOD/GSH; lower ROS/MDA), and lowered serum TNF-α/IL-6. In HEI-OC1 cells, CAG attenuated mitochondrial membrane-potential loss and apoptosis. Conclusions: At equimolar concentrations, CAG and AS-IV showed comparable protective activity in vitro, indicating that the advantage of CAG resides mainly in its pharmacokinetic profile. CAG thus attenuates auditory dysfunction in an accelerated-aging model with superior exposure, supporting its further development for age-associated hearing disorders. Full article

(This article belongs to the Special Issue Prodrug Strategies for Enhancing Drug Stability and Pharmacokinetics)

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26 pages, 5322 KB

Open AccessArticle

N-Acetylcysteine-Functionalized Mixed Micelles Overcome Multiple Intestinal Barriers to Improve Oral Bioavailability and Antioxidant Protection of Imperatorin

by Yu Zhang, Jian Guo, Haonan Qiu, Jiale Liu, Chi Zhang, Lutan Zhou, Chunfei Wang, Lihua Li and Xuefeng Hou

Pharmaceutics 2026, 18(8), 1036; https://doi.org/10.3390/pharmaceutics18081036 - 20 Aug 2026

Abstract

Background: Imperatorin (IPT) is a natural furanocoumarin featuring robust anti-inflammatory, antifibrotic and antioxidant activities. However, poor aqueous solubility and insufficient oral bioavailability restrict its clinical application. Multiple gastrointestinal barriers, including the mucus barrier, limited epithelial penetration and P-glycoprotein-triggered drug efflux, are major [...] Read more.

Background: Imperatorin (IPT) is a natural furanocoumarin featuring robust anti-inflammatory, antifibrotic and antioxidant activities. However, poor aqueous solubility and insufficient oral bioavailability restrict its clinical application. Multiple gastrointestinal barriers, including the mucus barrier, limited epithelial penetration and P-glycoprotein-triggered drug efflux, are major obstacles hindering IPT oral absorption. Methods: N-acetylcysteine (NAC)-functionalized TPGS conjugates were synthesized first. Using Pluronic^® F108 and Lipoid^® S-100 as a matrix, imperatorin@N-acetylcysteine-TPGS/Pluronic^® F108/Lipoid^® S-100 (IPT@NAC-TFS) micelles were fabricated. We characterized their physicochemical features and in vitro release behavior. The Caco-2/HT29-MTX-E12 co-culture cell model was adopted to explore mucus permeation, cellular uptake and transepithelial transport mechanisms. In vivo intestinal distribution and pharmacokinetic tests in rats were carried out to confirm the oral absorption-enhancing effect of micelles. Results: Optimized micelles displayed a uniform shape and favorable encapsulation efficiency. Low CMC maintained structural stability upon gastrointestinal dilution. NAC modification conferred mucus-penetrating capacity on micelles. TPGS simultaneously improved epithelial barrier permeability and inhibited drug efflux, switching IPT transport mode. The micelles effectively cleared intracellular ROS, recovered SOD activity and lowered MDA levels in BLM-impaired MLg fibroblasts. In vivo results revealed enhanced intestinal drug accumulation, with the relative oral bioavailability of IPT increased by 6.07-fold. Conclusions: IPT@NAC-TFS micelles overcome multiple gastrointestinal barriers for oral IPT delivery. Combining mucus penetration, efflux suppression and antioxidative capacity, this system offers a promising strategy to develop oral formulations of poorly soluble antifibrotic natural products. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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33 pages, 38128 KB

Open AccessArticle

Mechanistic Comparison of Semi-Solid Extrusion 3D-Printed Printlets and Hot-Moulded Tablets: Linking Polymer–API Interactions, Microstructure, and Dissolution of Plant-Based Formulations

by Emilija Nemickaite, Pooja Todke, Vaidotas Cicenas, Elena Jasiūnienė, Mindaugas Marksa and Jurga Bernatoniene

Pharmaceutics 2026, 18(8), 1035; https://doi.org/10.3390/pharmaceutics18081035 - 20 Aug 2026

Abstract

Background: Three-dimensional printing (3DP) is rapidly advancing personalised medicine, yet systematic performance comparison with conventional manufacturing remains limited, particularly for plant-based formulations. Methods: This study compared tablets containing plant-based APIs (cannabidiol, apigenin, and luteolin) produced via conventional hot moulding and semi-solid [...] Read more.

Background: Three-dimensional printing (3DP) is rapidly advancing personalised medicine, yet systematic performance comparison with conventional manufacturing remains limited, particularly for plant-based formulations. Methods: This study compared tablets containing plant-based APIs (cannabidiol, apigenin, and luteolin) produced via conventional hot moulding and semi-solid extrusion (SSE) 3DP. The formulations were evaluated for physicochemical, mechanical, rheological, structural, and drug-release properties. Results: Both manufacturing methods produced tablets with comparable dimensions and mass; however, pronounced formulation-dependent differences were observed in mechanical strength, rheology, and microstructure. The molecular modelling predictions were consistent with the experimental findings. Agar–pectin exhibited the strongest predicted polymer–polymer and polymer–API interactions, including multiple hydrogen bonds, and formed a comparatively dense and cohesive matrix associated with slower API release. In contrast, the weaker interactions predicted for gelatine–pectin were associated with a less cohesive and more porous matrix that facilitated medium penetration, API diffusion, and drug release. SSE printlets generally exhibited greater porosity and more heterogeneous internal architectures than moulded tablets, resulting in enhanced drug release of approximately 95%. Micro-CT analysis provided important structural confirmation; API incorporation increased the void volume of gelatine–pectin printlets from 1.15% to 8.77%, demonstrating that disruption of polymer interactions contributed to pore formation and enhanced molecular diffusion. The observed release behaviour correlated with predicted molecular interactions and experimentally observed microstructural features, where increased porosity and weaker polymer–API interactions facilitated enhanced drug diffusion. Conclusions: Overall, SSE-3DP outperformed conventional moulding, demonstrating superior tunability and performance. This work provides a mechanistically informed strategy for designing plant-based, personalised natural products using 3DP technologies. Full article

(This article belongs to the Special Issue 3D Printing Technologies in Pharmaceutical Formulation)

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23 pages, 2593 KB

Open AccessArticle

Comparative Investigation of Red Wine Concentrates as Multifunctional Skin-Protective Agents

by Gorana Ilić, Ivana Beara, Ljiljana Milovanović, Aleksandra Jovanović, Dragana Dekanski and Andrea Pirković

Pharmaceutics 2026, 18(8), 1034; https://doi.org/10.3390/pharmaceutics18081034 - 20 Aug 2026

Abstract

Background/Objectives: Vitis vinifera is a rich source of polyphenolic compounds that are known for their benefits on skin health, including antioxidant, anti-inflammatory, and photoprotective effects. Red wines have shown a positive impact on cardiovascular disease, diabetes, and cancer prevention; however, evidence regarding [...] Read more.

Background/Objectives: Vitis vinifera is a rich source of polyphenolic compounds that are known for their benefits on skin health, including antioxidant, anti-inflammatory, and photoprotective effects. Red wines have shown a positive impact on cardiovascular disease, diabetes, and cancer prevention; however, evidence regarding their effects on skin biology remains scarce. This study evaluated red wine concentrates obtained from Cabernet Sauvignon and Merlot varieties, selected based on their previously demonstrated biological activities, to identify the samples with the highest potential for skin health applications by assessing their inhibitory activity against skin-related enzymes (tyrosinase, elastase, and collagenase), along with their effects on HaCaT cells, including cytotoxic, antioxidant, anti-inflammatory, and wound healing activities. Methods: Enzyme inhibition studies were based on spectrophotometric methods; the MTT and CV assays were carried out to test the cytotoxicity, and the DCFH-DA assay was employed to evaluate the antioxidant activity of the wine concentrates; wound healing potential was examined by the cell scratch assay, and anti-inflammatory activity was investigated using ELISA and qPCR analyses. PCA of the samples and their biological activity was performed as well. Results: Examined red wine concentrates exhibited significant enzyme inhibitory activity and showed no cytotoxicity on HaCaT cells up to the concentration of 50 μg/mL; the samples stimulated cell migration, inhibited intracellular ROS production in AAPH-stressed keratinocytes, and selectively modulated TNF-α-induced inflammatory responses, reducing IL-8 secretion while enhancing certain cytokine transcripts, underscoring the complexity of their bioactive effects. Conclusions: Red wine concentrates showed significant potential as skin-beneficial agents, demonstrating strong antiaging, marked cellular antioxidant effects and wound healing activity when applied at non-cytotoxic concentrations. Multivariate analysis revealed distinct bioactivity profiles among the wine concentrates. Full article

(This article belongs to the Special Issue New Therapeutic Approaches for the Application of Natural Products in Skin Diseases)

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21 pages, 2552 KB

Open AccessArticle

Plasmid-DNA Encoded gata3 and eomes Increase Antibody Response and Performance of an Inactivated Salmonid Alphavirus Subtype 3 Vaccine

by Filipe Figueiredo, Kristian Gillebo Sørmo, Aleksander Pettersen, Heng Chi, Jaya Kumari Swain, Toni Erkinharju, Trilochan Swain, Shripathi Bhat, Kim Præbel, Stefano Peruzzi, Jacques Godfroid, Øystein Evensen, Hetron Mweemba Munang’andu and Roy Ambli Dalmo

Pharmaceutics 2026, 18(8), 1033; https://doi.org/10.3390/pharmaceutics18081033 - 20 Aug 2026

Abstract

Background: Pancreas disease, caused by salmonid alphavirus subtype 3 (SAV3), remains a significant threat to Atlantic salmon (Salmo salar L.) aquaculture in Norway despite the widespread use of inactivated vaccines. Molecular adjuvants represent a promising strategy to improve vaccine efficacy by [...] Read more.

Background: Pancreas disease, caused by salmonid alphavirus subtype 3 (SAV3), remains a significant threat to Atlantic salmon (Salmo salar L.) aquaculture in Norway despite the widespread use of inactivated vaccines. Molecular adjuvants represent a promising strategy to improve vaccine efficacy by enhancing immune responses. Methods: In this study, we evaluated the immunological and protective effects of two transcription factors, gata3 and eomes encoded by plasmid DNA adjuvants in combination with a low-dose inactivated SAV3 vaccine. Atlantic salmon were immunized with inactivated virus alone or in combination with either gata3- or eomes-encoding plasmids, followed by SAV3 challenge. Vaccine performance was assessed by growth, antibody response (ELISA and virus neutralization assay), and histopathological scoring of heart and pancreas. Results: The effects of gata3 and eomes were context-dependent: eomes reduced pancreas lesions at 4 weeks post-challenge, while both plasmid-adjuvant groups showed improved growth at 10 weeks post-challenge compared to the plasmid control. Although antibody responses were increased in all vaccinated groups at 6 weeks post-immunization, the plasmid control performed comparably to the GATA3 or EOMES groups, and no significant differences were detected in the virus neutralization test. Interestingly, the empty plasmids given to control fish exhibited immunostimulatory activity, warranting further investigation. In vitro and in vivo fluorescence microscopy confirmed expression of the transcription factors in transfected cells and at the injection site. Conclusions: Our results suggest that transcription factor-encoding plasmids can provide selective adjuvant effects, while also highlighting the potential that plasmid DNA can have as adjuvants in fish vaccine development. Full article

(This article belongs to the Special Issue Advances in Vaccine Delivery and Vaccine Administration)

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48 pages, 24461 KB

Open AccessArticle

Engineering Allogeneic FE002-Cart Chondroprogenitor Spheroids for Large Knee Chondral Defects: Investigating Microenvironmental Cues for Functional Control, GMP Formulation, and Logistical Viability

by Lee Ann Applegate, Farid Hadjab, Sandra Jaccoud, Alexandre Porcello, Virginie Philippe, Nathalie Hirt-Burri, Corinne Scaletta, Brigitte M. Jolles, Dominique P. Pioletti, Robin Martin and Alexis E. Laurent

Pharmaceutics 2026, 18(8), 1032; https://doi.org/10.3390/pharmaceutics18081032 - 20 Aug 2026

Abstract

Background: The clinical translation of cell-based therapies for knee articular cartilage repair is fundamentally restricted by the severe biological unpredictability of autologous cell sources, inherent manufacturing bottlenecks, and the rapid phenotypic dedifferentiation of cells expanded in conventional 2D monolayers. To overcome these translational [...] Read more.

Background: The clinical translation of cell-based therapies for knee articular cartilage repair is fundamentally restricted by the severe biological unpredictability of autologous cell sources, inherent manufacturing bottlenecks, and the rapid phenotypic dedifferentiation of cells expanded in conventional 2D monolayers. To overcome these translational hurdles, this study engineered a scaffold-free, 3D formulation of highly characterized allogeneic FE002-Cart chondroprogenitor spheroids. Methods: We systematically investigated the specific microenvironmental cues and Good Manufacturing Practice (GMP) formulation parameters required to direct functional chondrogenesis. The structural and biochemical performance of this allogeneic formulation was benchmarked against multiple primary adult autologous chondrocyte types. Finally, we evaluated the phenotypic resilience of the microtissues in simulated osteoarthritic (OA) environments and investigated both short-term liquid storage and advanced terminal preservation strategies to establish off-the-shelf logistical viability. Results: Precise microenvironmental regulation proved to be a critical biological prerequisite. The synergistic combination of physiological hypoxia (2% O₂) and stringent glucocorticoid limitation (10 nM dexamethasone) induced robust glycosaminoglycan (GAG) deposition and a > 200-fold upregulation of ACAN and COL2, while suppressing the terminal hypertrophic drift observed in adult chondrocytes. Benchmarking revealed that the allogeneic FE002-Cart formulation substantially mitigates the profound morphological and biochemical unpredictability inherent to adult autologous cell sources. Furthermore, the scaffold-free spheroid geometry yielded a 10-fold increase in GAG production per cell compared to traditional matrix-seeded (MACI) platforms. Transitioning to a GMP-compatible manufacturing process revealed extreme cellular sensitivities; excipients within standard pharmaceutical-grade dexamethasone severely aborted chondrogenic differentiation, emphasizing the necessity of rigorous raw-material qualification. Functionally, the 3D architecture acted as a protective physical shield, sustaining high cellular viability when subjected to severe inflammatory stress and 100% OA patient synovial fluid. Logistically, the viable spheroids maintained matrix integrity and inter-spheroid fusion potential for up to 7 days at ambient temperature in transport medium. Finally, advanced spheroid preservation via lyophilization and high-dose gamma irradiation eliminated biological viability but successfully transitioned the microtissues into highly organized, terminally irradiated matrices capable of heterologous in vitro structural merging. Conclusions: These findings define the critical biological thresholds for manufacturing, demonstrate the enhanced in vitro biosynthetic efficiency of 3D allogeneic microtissues compared to specific autologous and matrix-dependent baselines, and establish a highly practical, off-the-shelf logistical framework for the regenerative treatment of large knee chondral defects. Full article

(This article belongs to the Section Gene and Cell Therapy)

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15 pages, 3603 KB

Open AccessArticle

Moxifloxacin-Mediated Downregulation of Intestinal P-Glycoprotein Alters the Pharmacokinetics of Dabigatran Etexilate: Mechanistic Insights in Rats and PBPK Model-Informed Dose Optimization

by Yuchen Qu, Zhuan Yang, Wen Ma, Peng Xiao, Yani Gu, Jie Pan, Xinyun Zhang, Chen Zhao and Yunli Yu

Pharmaceutics 2026, 18(8), 1031; https://doi.org/10.3390/pharmaceutics18081031 - 20 Aug 2026

Abstract

Background: In patients with atrial fibrillation receiving long-term anticoagulation therapy with dabigatran etexilate (DABE), moxifloxacin (MFLX) is frequently coadministered to treat concurrent infections; however, the potential drug–drug interaction (DDI) between these agents remains unclear. Herein, we examined the underlying mechanism by which [...] Read more.

Background: In patients with atrial fibrillation receiving long-term anticoagulation therapy with dabigatran etexilate (DABE), moxifloxacin (MFLX) is frequently coadministered to treat concurrent infections; however, the potential drug–drug interaction (DDI) between these agents remains unclear. Herein, we examined the underlying mechanism by which MFLX attenuates DABE pharmacokinetics in rats; subsequently, we elucidated the DDI in humans by establishing a physiologically based pharmacokinetic (PBPK) model based on these animal data. Methods: The 3- and 14-day effects of 40 mg/kg MFLX once daily and secondary bile acid (SBA)-containing dietary intervention on the pharmacokinetic profile of DABE and its active form, dabigatran (DAB), were examined in a rat model. Ileum tissues were harvested to measure the expression of P-glycoprotein (P-gp), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPARα). In addition, we examined the effects of secondary bile acids (SBAs) on P-gp expression and quantified P-gp-mediated DABE efflux transport activity in Caco-2 cells. A PBPK model was used to predict the risk of DAB exposure under this DDI scenario and under combined high-risk conditions, including renal impairment and advanced age. Results: Treatment with MFLX for 3 and 14 days inhibited SBA-producing gut microbiota, thereby suppressing the conversion of primary bile acids to SBAs. Concurrently, a marked reduction in intestinal P-gp expression was observed, along with a significant enhancement of the oral bioavailability of DABE. These effects were reversed by SBA-containing diets. In vitro experiments using Caco-2 cells revealed that physiologically relevant concentrations of SBA significantly upregulated P-gp expression and function, whereas MFLX incubation alone showed no direct modulatory effect on these transporters or regulators. PBPK simulation results showed that in vivo exposure of DAB would increase by 41.7%, 104%, 251%, and 115% when coadministered with MFLX alone, with coexisting mild renal impairment, moderate renal impairment, and aging, respectively. Conclusions: MFLX increases DAB exposure by reducing SBA-regulated intestinal P-gp function. PBPK simulations suggest a low risk of DDI from MFLX coadministration alone; however, caution is warranted in patients with aging or renal impairment. Full article

(This article belongs to the Special Issue Model-Informed Precision Dosing in Drug Development and Clinical Practice)

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