Pharmaceutics

37 pages, 2537 KB

Open AccessArticle

Bioactive PLA Filament with Antibacterial and Ion-Releasing Properties for Additive Manufacturing of Bone Scaffolds: QbD-Guided Development

by Anastassiya Khrustaleva, Azamat Yedrissov, Dmitriy Khrustalev, Ivan Chernykh, Aleksandr Samorodov, Saule Akhmetova, Artyom Savelyev, Marlen Kiikbayev, Polina Rusyaeva, Vladimir Kazantsev, Kristina Perepelitsyna and Sofiya Shapovalenko

Pharmaceutics 2026, 18(9), 1055; https://doi.org/10.3390/pharmaceutics18091055 - 25 Aug 2026

Abstract

Background/Objectives: The development of multifunctional biomaterials for bone regeneration remains a key challenge in additive manufacturing. Although polylactic acid (PLA) is widely used in fused deposition modeling (FDM), its limited bioactivity and lack of intrinsic antibacterial functionality restrict its application in implantable constructs. [...] Read more.

Background/Objectives: The development of multifunctional biomaterials for bone regeneration remains a key challenge in additive manufacturing. Although polylactic acid (PLA) is widely used in fused deposition modeling (FDM), its limited bioactivity and lack of intrinsic antibacterial functionality restrict its application in implantable constructs. This study aimed to develop a PLA-based composite filament combining ion-mediated bioactive potential and local antibacterial functionality using a Quality by Design (QbD) approach. Methods: PLA-based composite filaments incorporating a mollusk shell-derived biogenic calcium-containing filler (20 wt.%) and gentamicin (5 wt.%) were fabricated by solvent-free melt extrusion. A QbD framework was applied to define the Quality Target Product Profile (QTPP), identify critical quality attributes (CQAs), and assess critical material attributes (CMAs) and critical process parameters (CPPs). The material was characterized by SEM–EDS combined with ImageJ-based quantitative image analysis, TGA/DSC, mechanical testing, ICP-AES analysis of aqueous extracts, agar diffusion antibacterial assays, FDM printability assessment, and in vivo biocompatibility testing in a rat subcutaneous implantation model. Results: The developed PLA–Gen–MS material was obtained as a continuous filament with a diameter of 1.75 ± 0.05 mm and was successfully used for FDM printing of model scaffold structures. SEM–EDS confirmed matrix continuity and distribution of the calcium-containing mineral phase. ICP-AES revealed a calcium-dominant multicomponent ion release profile, with Ca as the predominant element and measurable levels of Sr, Mg, P, Mn, and Fe. TGA/DSC confirmed thermal compatibility of the components under melt-processing conditions. PLA–Gen–MS demonstrated antibacterial activity against all tested strains, with inhibition zones of approximately 20–21 mm. In vivo, the material showed a favorable preliminary tissue response compared with TiLOOP^®, including faster reduction of inflammatory infiltration and absence of foreign body giant cells by day 14. Conclusions: The QbD-guided strategy enabled the development of a multifunctional PLA-based filament integrating melt processability, structural integrity, ion-mediated bioactive potential, antibacterial functionality, printability, and favorable preliminary biocompatibility. PLA–Gen–MS can be considered a promising platform for further development of personalized bioactive and antibacterial scaffold constructs for bone regeneration. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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60 pages, 7133 KB

Open AccessReview

Wound Healing Potential of Multifunctional Nanomaterials: Mechanism, Future Prospects, and Challenges

by Akshay Kumar, Devesh Kumar, Mohit Agrawal, Jaspreet Kaur, Mohit Kumar, Dinesh Kumar, Neeraj Choudhary, Thakur Gurjeet Singh, Ankit Awasthi and Emad M. Abdallah

Pharmaceutics 2026, 18(9), 1054; https://doi.org/10.3390/pharmaceutics18091054 - 25 Aug 2026

Abstract

Wound healing is a dynamic and highly coordinated process that involves inflammation, cell proliferation, angiogenesis, re-epithelialization, extracellular matrix remodeling, and tissue maturation. The altered expression of important signaling pathways, such as transforming growth factor-β (TGF-β)/Smad, nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), [...] Read more.

Wound healing is a dynamic and highly coordinated process that involves inflammation, cell proliferation, angiogenesis, re-epithelialization, extracellular matrix remodeling, and tissue maturation. The altered expression of important signaling pathways, such as transforming growth factor-β (TGF-β)/Smad, nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin, may be responsible for slower wound healing, chronic inflammation, excessive fibrosis, and impaired tissue regeneration. Multifunctional nanomaterials are a promising strategy for tuning these highly coordinated processes due to their tunable physicochemical properties, high surface area, and the ability to deliver cargo, as well as the integration of antimicrobial, antioxidant, anti-inflammatory, and pro-angiogenic properties. The aim of current review is to summarize the potential of multifunctional nanomaterials to promote wound healing, with a focus on mechanisms of action and modulation of key cellular signaling pathways. A systematic review of the literature was conducted using PubMed, Scopus, Web of Science, and Google Scholar, searching for publications from 1996 to June 2026, and representative experimental, mechanistic, preclinical, and translational studies were critically evaluated. In this review, the authors discuss the role of nanomaterial properties, therapeutic payload, molecular targets, modulation of cellular signaling pathways, and regenerative effects. These platforms have been shown in in vitro and animal studies to influence inflammatory signaling, oxidative stress, angiogenesis, collagen remodeling, re-epithelialization, cellular proliferation, and migration. However, the modulation of these pathways are dose-responsive, time-dependent, and cell- and wound-stage-specific. Despite the promising therapeutic potential of nanomaterial-based wound care strategies, the available evidence remains predominantly preclinical, with relatively limited clinical data supporting their use in humans. Concerns regarding long-term toxicity, biodistribution, batch-to-batch reproducibility, sterilization, scalable manufacturing, regulatory approval, and commercial feasibility further challenge translation into clinical practice. Multifunctional nanomaterials may offer a promising approach for pathway-specific and multimodal wound management; however, comprehensive mechanistic studies, long-term safety and biodistribution assessments, and well-designed clinically relevant investigations are required to establish their efficacy, safety, and true translational potential. Full article

(This article belongs to the Special Issue Advances in Nanomaterials for Wound Healing)

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31 pages, 13323 KB

Open AccessArticle

Probing the Capsid: pH-Driven Gating at the AAV 5-Fold Pore and Its Role in Peptide Ligand Binding

by Arianna Minzoni, Benjamin Bobay, Shriarjun Shastry, Eduardo Barbieri, Brandon Brino, Crystal Collazo, Shizuo Kamita, Danni Wang, Ciera Khuu, Alexander Polgar, Joseph Siino, Sushmita Koley, Peyton Russelburg, Mark Snyder, Christopher Belisle, Michael Daniele and Stefano Menegatti

Pharmaceutics 2026, 18(9), 1053; https://doi.org/10.3390/pharmaceutics18091053 - 25 Aug 2026

Abstract

Background/Objectives: Adeno-associated virus (AAV) capsids undergo pH-dependent conformational gating at the 5-fold symmetry pore, but how these structural dynamics shape serotype-specific behavior and affinity-ligand recognition remains unclear, particularly for the clinically important serotypes AAV8 and AAV9. This study aimed to establish a pH-resolved [...] Read more.

Background/Objectives: Adeno-associated virus (AAV) capsids undergo pH-dependent conformational gating at the 5-fold symmetry pore, but how these structural dynamics shape serotype-specific behavior and affinity-ligand recognition remains unclear, particularly for the clinically important serotypes AAV8 and AAV9. This study aimed to establish a pH-resolved structural framework linking 5-fold pore dynamics to peptide-ligand recognition and to translate this framework into sequence-based design principles for affinity capture of gene therapy vectors. Methods: AAV8 and AAV9 5-fold capsid assemblies were subjected to 500 ns molecular dynamics simulations under acidic (pH 5), neutral (pH 7), and basic (pH 9) conditions, with analysis of pore volume, inter-residue contact networks, electrostatic potential, and solvent-accessible surface area. In parallel, affinity chromatography using three mixed-mode peptide ligands (RVVAVYRI, TTFRAHHI, and TYHHHHII) was performed on clarified HEK293 lysates containing AAV8 or AAV9, with capsid yield, host-cell-protein clearance, and transduction activity assessed by ELISA, SEC-HPLC, and flow-cytometry-based transduction assays. Results: AAV8 displayed a heterogeneous, bimodal pore conformational landscape at pH 7, whereas AAV9 exhibited a discrete gate-like transition with maximal pore constriction at physiological pH; both serotypes showed pore-proximal contact remodeling with distinct network topologies. Experimentally, TYHHHHII achieved the highest selectivity for genome-containing capsids at pH 7, with transduction activity enrichment factors of 2.82 (AAV8) and 5.61 (AAV9), while TTFRAHHI provided the broadest operational pH range for bulk capsid recovery. Conclusions: These findings establish a structural framework linking pH-dependent pore dynamics to affinity ligand recognition and suggest practical sequence-design rules for ligand engineering: clustered histidines for neutral-pH selectivity, Arg-containing motifs for broad-pH robustness, and aromatic or hydrophobic residues for reinforcement of capsid binding. Full article

(This article belongs to the Special Issue From Bench to Bedside: AAV, Lentivirus, Adenovirus, and Retrovirus in Gene Therapy)

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21 pages, 3956 KB

Open AccessArticle

Pharmacokinetics of Ceftriaxone Encapsulated in Carrier Erythrocytes in Experimental Study

by Kulzhan Berikkhanova, Alexandr Gulyayev, Yernur Zakirov, Askhat Zhilkaidarov, Azhar Zhaisanova, Nurgul Daniyeva, Ardak Omarbekov, Gulsara Berikkhanova, Yessenkhan Sultan, Zhannat Zhakiyanova and Gulyash Tanysheva

Pharmaceutics 2026, 18(9), 1052; https://doi.org/10.3390/pharmaceutics18091052 - 25 Aug 2026

Abstract

Background/Objectives: Ceftriaxone (Ctx) is a third-generation cephalosporin widely used to treat infections caused by Gram-positive and Gram-negative bacteria. However, its clinical efficacy may be limited by rapid systemic elimination and suboptimal tissue distribution. Erythrocyte-based targeted drug delivery systems (TDDSs) have emerged as [...] Read more.

Background/Objectives: Ceftriaxone (Ctx) is a third-generation cephalosporin widely used to treat infections caused by Gram-positive and Gram-negative bacteria. However, its clinical efficacy may be limited by rapid systemic elimination and suboptimal tissue distribution. Erythrocyte-based targeted drug delivery systems (TDDSs) have emerged as a promising approach to prolong drug circulation and enhance site-specific accumulation. This study investigated the pharmacokinetic profile and tissue distribution of ceftriaxone encapsulated in autologous erythrocytes (RBC-Ctx) compared with free ceftriaxone (Free-Ctx) following intravenous administration in rats. Methods: Ceftriaxone was encapsulated into autologous rat erythrocytes using a hypoosmotic hemolysis loading technique. Drug-loaded erythrocytes are called pharmacocytes. Adult male Wistar rats received a single intravenous injection of Free-Ctx or RBC-Ctx at an equivalent ceftriaxone dose of 340 mg/kg. Plasma samples were collected over 24 h for pharmacokinetic analysis, while the liver, spleen, lungs, kidneys, heart, pancreas, and skeletal muscle were harvested at 1 and 12 h for tissue distribution studies. Ceftriaxone concentrations were quantified by high-performance liquid chromatography with UV detection. Results: Erythrocyte encapsulation significantly modified the pharmacokinetic behavior of ceftriaxone. Compared with Free-Ctx, RBC-Ctx prolonged the elimination half-life (4.4 ± 0.6 vs. 1.8 ± 0.1 h), increased systemic exposure (AUC₀–last, 1.6 ± 0.1 vs. 1.2 ± 0.2 mg·h/mL), reduced total body clearance (218.2 ± 11.0 vs. 294.0 ± 48.8 mL/h/kg), and increased the apparent volume of distribution at steady state (688.3 ± 61.0 vs. 435.0 ± 23.1 mL/kg). In addition, RBC-Ctx was associated with a distinct relative tissue-distribution pattern of ceftriaxone, particularly in reticuloendothelial system-rich organs such as the liver and spleen, while ceftriaxone remained detectable in several tissues at 12 h after administration. In contrast, ceftriaxone concentrations following Free-Ctx declined markedly or became undetectable over the same period. Conclusions: Encapsulation of ceftriaxone into autologous erythrocytes substantially prolonged systemic circulation, enhanced drug exposure, reduced clearance, and altered the relative tissue distribution of ceftriaxone. These findings demonstrate that erythrocyte-based carriers effectively modulate ceftriaxone pharmacokinetics and tissue distribution, supporting their potential as a targeted antibiotic delivery platform for improving antimicrobial therapy, particularly for infections involving reticuloendothelial system-associated tissues. Further studies in experimental models of infection and inflammation are warranted to evaluate therapeutic efficacy under pathological conditions and to optimize this delivery strategy. Full article

(This article belongs to the Special Issue Optimizing Pharmacokinetics Through Formulation Science and Technology)

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10 pages, 805 KB

Open AccessArticle

Intra-Subject Variability in Pharmacokinetics and Pharmacodynamics of Basal Insulin at Two Single-Dose Levels: Findings from Euglycemic Glucose Clamp Bioequivalence Studies of Insulin Degludec

by Hui Liu, Ting Li, Xinlei Chen, Hongling Yu, Yuchun Men, Huiwen Tan, Jiaqi Li and Yerong Yu

Pharmaceutics 2026, 18(9), 1051; https://doi.org/10.3390/pharmaceutics18091051 - 25 Aug 2026

Abstract

Background/Objectives: Standard protocols for euglycemic clamp studies involving long-acting insulin formulations typically recommend a dosage range of 0.4~0.6 U/kg for a single dose. This investigation aimed to evaluate the bioequivalence of an insulin degludec (IDeg) biosimilar versus its reference product, while simultaneously [...] Read more.

Background/Objectives: Standard protocols for euglycemic clamp studies involving long-acting insulin formulations typically recommend a dosage range of 0.4~0.6 U/kg for a single dose. This investigation aimed to evaluate the bioequivalence of an insulin degludec (IDeg) biosimilar versus its reference product, while simultaneously analyzing intra-subject variability in pharmacokinetic (PK) and pharmacodynamic (PD) metrics at doses of 0.4 U/kg and 0.5 U/kg in healthy Chinese adults. Methods: This randomized, single-dose, crossover euglycemic clamp study involved 52 participants who received either 0.4 U/kg (Group A, n = 26) or 0.5 U/kg (Group B, n = 26) of both formulations. Key outcomes measured included AUC_IDeg,0–24h, C_max,IDeg, and AUC_GIR,0–24h. Secondary endpoints encompassed AUC of IDeg or GIR at specified intervals and time-related metrics. Intra-subject variability (intra-CV) was assessed for PK/PD parameters. Results: All subjects completed the study without dropping out. Baseline demographics showed no significant disparities between groups. Bioequivalence criteria were satisfied for all PK/PD endpoints, with 90% confidence intervals (CIs) falling within the 0.80~1.25 range, with the exception of AUC_GIR,0–12h at the 0.4 U/kg dose (90% CI: 0.944~1.333). Notably, the 0.4 U/kg dose exhibited significantly higher intra-CV for AUC_GIR,0–24h (24.9% vs. 20.2%, p = 0.049) and AUC_GIR,0–12h (37.6% vs. 27.6%, p = 0.005) compared to the 0.5 U/kg dose. Conclusions: Applying a 0.5 U/kg dose reduced intra-subject PD variability and improved equivalence likelihood for secondary endpoints, indicating that a higher single dose might be optimal in bioequivalence study design. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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31 pages, 9092 KB

Open AccessArticle

Exploring the Anti-Inflammatory Potential of Saudi Propolis Through Phytochemical Characterization, Molecular Docking, and Dynamic Simulation

by Hanan Aati, Jawaher H. Alqahtani, Areej Al-Taweel and Sultan Y. Aati

Pharmaceutics 2026, 18(9), 1050; https://doi.org/10.3390/pharmaceutics18091050 - 24 Aug 2026

Abstract

Background/Objectives: Propolis is a resinous natural product rich in phenolic acids and flavonoids, recognized in ethnopharmacology for its antioxidant and anti-inflammatory properties. This study aimed to identify the most bioactive Saudi propolis extract using a bioassay-guided strategy and investigate its chemical profile [...] Read more.

Background/Objectives: Propolis is a resinous natural product rich in phenolic acids and flavonoids, recognized in ethnopharmacology for its antioxidant and anti-inflammatory properties. This study aimed to identify the most bioactive Saudi propolis extract using a bioassay-guided strategy and investigate its chemical profile and mechanistic anti-inflammatory potential. Methods: Four propolis extracts (P1–P4) collected from different regions of Saudi Arabia were evaluated for their antioxidant (DPPH and ABTS) and anti-inflammatory (COX-1 and COX-2) activities. The most active extract was profiled using liquid chromatography–mass spectrometry (LC–MS), followed by molecular docking and molecular dynamics simulations. Results: Among all samples, P3 demonstrated the strongest antioxidant activity, with IC₅₀ values of 25.84 ± 0.96 µg/mL (DPPH) and 32.30 ± 1.20 µg/mL (ABTS), comparable to ascorbic acid (27.45 ± 1.42 and 21.22 ± 0.79, respectively). P3 also exhibited potent and selective COX-2 inhibition with an IC₅₀ of 6.19 ± 0.21 µg/mL (relative to celecoxib, IC₅₀ 0.681 ± 0.02 as positive control). LC–MS analysis identified 26 secondary metabolites. Computational studies ranked kaempferol as forming the most conformationally stable COX-2 complex among the ligands examined, including the reference inhibitor, on the basis of molecular dynamics descriptors of pose persistence and conformational confinement. Conclusions: Saudi propolis P3 is a potent source of bioactive compounds with strong antioxidant and selective COX-2 inhibitory activity. These findings highlight its anti-inflammatory potential and suggest its value as a natural lead for developing safer therapeutics targeting inflammation-related chronic diseases. Full article

(This article belongs to the Section Drug Targeting and Design)

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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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