Pharmaceutics

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

Viewed by 629

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

Viewed by 467

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

Viewed by 386

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

Viewed by 388

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

Viewed by 594

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

Viewed by 525

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

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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

Viewed by 437

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

Viewed by 378

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

Viewed by 362

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

Viewed by 370

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

Viewed by 434

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

Viewed by 407

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

Viewed by 370

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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20 pages, 2428 KB

Open AccessArticle

Physiologically Based Pharmacokinetic (PBPK) Modeling of FIX in Pediatric Hemophilia B: Extravascular Distribution and Dosing Optimization

by Mengmeng Liu, Guoqing Liu, Qixian Ling, Yongbo Chen, Haojie Xu, Runhui Wu, Zhenping Chen and Libo Zhao

Pharmaceutics 2026, 18(8), 1030; https://doi.org/10.3390/pharmaceutics18081030 - 20 Aug 2026

Viewed by 386

Abstract

Background: Prophylaxis in children with hemophilia B (HB) lacks quantitative approaches that integrate both plasma exposure and tissue distribution. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model of factor IX (FIX) for pediatric HB. The model incorporated [...] Read more.

Background: Prophylaxis in children with hemophilia B (HB) lacks quantitative approaches that integrate both plasma exposure and tissue distribution. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model of factor IX (FIX) for pediatric HB. The model incorporated the binding of FIX to type IV collagen (Col4) to characterize its distribution in both plasma and extravascular tissues. Methods: A total of 20 children with severe HB were included, contributing 219 plasma samples. The base PBPK model was first established and verified using adult and plasma-derived FIX (pdFIX) data. It was subsequently extrapolated to children by integrating FIX-CTBB parameters and pediatric observations for model calibration. The validated model was used to characterize plasma pharmacokinetics, predict tissue distribution and target attainment, and simulate alternative prophylactic dosing regimens. Results: The model adequately described the plasma pharmacokinetics of FIX in children and predicted substantial extravascular distribution. Total extravascular exposure was approximately sixfold higher than plasma exposure. Marked heterogeneity in target attainment was identified across tissues. Lower target attainment was observed in the colon, pancreas, and brain, whereas delayed attainment occurred in bone and muscle. Simulations of prophylactic dosing regimens suggested that 75 IU/kg twice weekly may provide a favorable balance among sustained FIX exposure, tissue-level target attainment, and treatment burden. Conclusions: This PBPK model provides a mechanistic and quantitative framework for characterizing plasma and tissue exposure to FIX in children with HB and may support individualized optimization of FIX prophylactic dosing. Full article

(This article belongs to the Special Issue Novel Research on Physiologically-Based Pharmacokinetic Modeling)

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39 pages, 14046 KB

Open AccessArticle

Telmisartan Repurposing Targets Novel Biomarkers for Precision Colorectal Cancer Therapy

by Sarah Hunachagi, Hoor Hashim Alqudihi, Sayed AbdulAzeez, J. Francis Borgio and Dana Almohazey

Pharmaceutics 2026, 18(8), 1029; https://doi.org/10.3390/pharmaceutics18081029 - 20 Aug 2026

Viewed by 503

Abstract

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-associated mortality worldwide. The current therapeutic interventions are heavily constrained by the development of resistance and severe systemic toxicity. To address these challenges, this study integrated a multi-disciplinary framework involving high-throughput in silico [...] Read more.

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-associated mortality worldwide. The current therapeutic interventions are heavily constrained by the development of resistance and severe systemic toxicity. To address these challenges, this study integrated a multi-disciplinary framework involving high-throughput in silico screening followed by in vitro experimental validation to identify novel genetic targets of CRC and evaluate the efficacy of FDA-approved drugs. The primary objective was to identify safe and selective therapeutic agents capable of modulating their effect. Methods: The methodology employed a systematic screening of recent large-scale Genome-Wide Association Studies (GWASs) to pinpoint novel targets, followed by in silico pathogenicity prediction, homology modelling and high-throughput virtual screening of over 1615 FDA-approved drugs. The prioritized candidates were validated in vitro using MTT cytotoxicity assays and differential gene expression analysis across CRC cell lines (HCT116 and HT29) and a non-tumorigenic control, Human embryonic kidney cell line HEK293. Results: In silico analysis identified CLUH, CLSTN3 and SLC11A2 as novel potential targets. Based on in silico predicted deleterious mutations and subsequent molecular docking-based virtual screening, Telmisartan, Dutasteride and Venetoclax were prioritized. This prioritization was supported by their high binding affinity and dose-dependent cytotoxicity in MTT assays; thus, suggesting their repurposing potential for CRC treatment. Telmisartan exhibited a superior therapeutic profile not only in terms of the statistically significant cytotoxicity (p < 0.01), but also its selective effect on HCT116 and HT29 when compared to high safety profile in HEK293. This was further validated when Telmisartan selectively downregulated CLUH and SLC11A2 in CRC cell lines, HCT116 and HT29 while maintaining expression levels in the non-cancerous HEK293 cell line remained significantly unaffected. Furthermore, a 100 ns molecular dynamics simulation confirmed the stable binding conformation and structural reliability of the SLC11A2 (Trp179Ser)–Telmisartan complex. Conclucions: Our findings conclude that Telmisartan is a promising candidate for drug repurposing for CRC treatment and capable of modulating selected novel biomarkers CLUH and SLC11A2. However, further multi-omics-based confirmatory studies and pre-clinical validation studies are needed in the future to confirm the long-term efficacy of this repositioning strategy. Full article

(This article belongs to the Special Issue Advances in Drug Delivery, Diagnostics, and Therapeutics for Cancer: Toward Personalized Oncology)

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20 pages, 10945 KB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Novel SN38 Based Albumin-Binding Peptide–Drug Conjugates in Pancreatic Ductal Adenocarcinoma

by Yi Su, Yingxin Lu, Jiahui Yu, Chen Jin, Yi Chen, Wei Lu and Jian Ding

Pharmaceutics 2026, 18(8), 1028; https://doi.org/10.3390/pharmaceutics18081028 - 19 Aug 2026

Viewed by 389

Abstract

Background and Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense extracellular matrix (ECM) with overexpression of extra domain B fibronectin (EDB-FN). Methods: Herein, we investigated novel albumin-binding peptide–drug conjugates, Mc-ZD2-SN38 and SSC-ZD2-SN38, which integrate the prolonged circulation properties of albumin with [...] Read more.

Background and Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense extracellular matrix (ECM) with overexpression of extra domain B fibronectin (EDB-FN). Methods: Herein, we investigated novel albumin-binding peptide–drug conjugates, Mc-ZD2-SN38 and SSC-ZD2-SN38, which integrate the prolonged circulation properties of albumin with the active targeting capability of the ZD2 peptide toward EDB-FN. Covalent and noncovalent albumin-binding strategies extended the half-life by approximately 100-fold and 15-fold, respectively, compared with the non-albumin-binding peptide–drug conjugate (PDC) (ZD2-SN38). Results: Notably, ZD2-mediated targeting markedly reduced payload accumulation in major organs, resulting in an improved safety profile. In a BxPC-3 xenograft model, Mc-ZD2-SN38 and SSC-ZD2-SN38 demonstrated potent and sustained antitumor efficacy. Conclusions: These findings establish a long circulation and active targeting drug delivery strategy, providing an ideal framework for the development of PDCs with enhanced therapeutic indices. Full article

(This article belongs to the Special Issue Advanced Drug Carrier Systems for Enhanced Controlled and Targeted Drug Release)

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21 pages, 10402 KB

Open AccessArticle

Comprehensive Evaluation of Storage Stability and Cytotoxicity of Co-Spray-Dried Theophylline Dry Powders for Inhalation: Follow-Up Study

by Lomass Soliman, Dóra Paróczai, Katalin Burián and Rita Ambrus

Pharmaceutics 2026, 18(8), 1027; https://doi.org/10.3390/pharmaceutics18081027 - 19 Aug 2026

Viewed by 431

Abstract

Background/Objectives: The stability and biological safety of newly developed formulations must be established to support their therapeutic efficacy and clinical translation in pulmonary drug delivery. Therefore, this follow-up study comprehensively evaluated the short- and long-term stability and the in vitro cytotoxicity of [...] Read more.

Background/Objectives: The stability and biological safety of newly developed formulations must be established to support their therapeutic efficacy and clinical translation in pulmonary drug delivery. Therefore, this follow-up study comprehensively evaluated the short- and long-term stability and the in vitro cytotoxicity of optimized, co-spray-dried theophylline (THN) dry powders for inhalation against A549 lung epithelial cells. Methods: Two established formulations were selected: THN-RAF (raffinose–leucine–glycine based) and THN-TRE (trehalose–leucine based). Stability was assessed under accelerated conditions (40 °C/75% RH, 3 months) and long-term desiccator storage (25 °C, 1 year) using laser diffraction, SEM, XRPD, FTIR, DSC, TGA, and Andersen Cascade Impaction. As THN-TRE had been previously confirmed to be cytocompatible, only THN-RAF and its components were evaluated against A549 human alveolar epithelial cells using the MTT assay. Results: Under accelerated conditions, both formulations exhibited pronounced recrystallization (Xc up to 89.9%), agglomeration (D [0.9] up to 217.08 µm for THN-TRE), and deterioration in aerodynamic performance (FPF as low as 11.55%, MMAD up to 6.68 µm). By contrast, long-term desiccator storage induced substantial recrystallization (Xc up to 80.7%) while preserving thermal, chemical, and aerodynamic performance (FPF ≈ 40%; MMAD 4.99–5.21 µm). THN-RAF was more resistant to stress-induced agglomeration than THN-TRE. Cytotoxicity assessment confirmed cytocompatibility of THN-RAF, with cell viability exceeding 70.99% at all tested concentrations (up to 500 µg/mL). Conclusions: These findings reveal a marked discrepancy between the outcomes of ICH accelerated testing and long-term desiccator storage. They underscore the importance of considering moisture-protective packaging configurations when designing stability protocols for amorphous inhalable formulations. Full article

(This article belongs to the Special Issue Optimizing Aerosol Therapy: Strategies for Pulmonary Drug Delivery)

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19 pages, 1012 KB

Open AccessReview

Artificial Intelligence-Based Optimization of Pulmonary Drug Delivery Performance in Smart Inhaler Drug–Device Combination Systems

by Harshada B. Pawar, Pawan Ganesh Nayak, Amatha Sreedevi, Ramya Ravi and Pradeep M. Muragundi

Pharmaceutics 2026, 18(8), 1026; https://doi.org/10.3390/pharmaceutics18081026 - 19 Aug 2026

Viewed by 528

Abstract

Advancements in pulmonary drug delivery have enabled effective treatment approaches for more severe disease conditions, such as chronic obstructive pulmonary diseases, asthma, cystic fibrosis, and other pulmonary disorders, via targeted, sustained, and immediate drug delivery routes with minimal systemic side effects. However, conventional [...] Read more.

Advancements in pulmonary drug delivery have enabled effective treatment approaches for more severe disease conditions, such as chronic obstructive pulmonary diseases, asthma, cystic fibrosis, and other pulmonary disorders, via targeted, sustained, and immediate drug delivery routes with minimal systemic side effects. However, conventional delivery systems have many limitations, such as poor drug targeting, adherence, and deposition, which ultimately cause variations in drug profiles and therapeutic efficacy. Recent advances in artificial intelligence (AI) and machine learning (ML) have enabled the development of smart inhaler drug–device combination systems for personalized therapy using predictive formulation parameters, design variables, device performance, and inhalation pattern monitoring. Advanced AI techniques, such as artificial neural networks, deep learning, random forests, support vector machines, deep learning algorithms, and computational modeling, predict the mass median aerodynamic diameter (MMAD), fine-particle fraction (FPF), emitted dose, and regional lung deposition. Smart inhalation devices coupled with digital sensors and computing systems enable the real-time monitoring of inhalation profiles and adherence. Moreover, AI- and ML-enabled Quality by Design (QbD) and digital twin framework technologies enhance the optimization of manufacturing process parameters, consistency, robustness, and scale-up performance. Although several developments have been reported, there is still room for improvement in terms of data heterogeneity, algorithm transparency, interpretability, cybersecurity, regulations, and long-term clinical standardization. This review emphasizes the use of AI to improve the performance of pulmonary drug delivery through smart inhaler drug–device combination therapies, focusing on technological advancements, formulation optimizations, smart inhalers, regulatory issues, current limitations, and future perspectives of AI-based pulmonary drug delivery. Full article

(This article belongs to the Special Issue Advances in AI-Driven Drug Delivery Systems)

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27 pages, 16823 KB

Open AccessArticle

Multifunctional VEGF/CeO₂-Loaded Methacrylated Chitosan Hydrogel Promotes Renal Repair Through Immune-Metabolic Reprogramming and Structural Preservation Following Ischemia–Reperfusion Injury

by Qing Sun, Yang Fu, Tianwei Wang, Zongyuan Xu, Zeping Gui, Kun Liu and Xuzhong Liu

Pharmaceutics 2026, 18(8), 1025; https://doi.org/10.3390/pharmaceutics18081025 - 18 Aug 2026

Viewed by 387

Abstract

Background/Objectives: Renal ischemia–reperfusion injury (IRI) and infection-associated renal damage are characterized by persistent inflammation, oxidative stress, microvascular dysfunction, and impaired tissue regeneration, creating a hostile microenvironment that limits effective repair. We developed an injectable, photocrosslinkable methacrylated chitosan (CSMA) hydrogel for the localized [...] Read more.

Background/Objectives: Renal ischemia–reperfusion injury (IRI) and infection-associated renal damage are characterized by persistent inflammation, oxidative stress, microvascular dysfunction, and impaired tissue regeneration, creating a hostile microenvironment that limits effective repair. We developed an injectable, photocrosslinkable methacrylated chitosan (CSMA) hydrogel for the localized co-delivery of cerium oxide nanoparticles (CeO₂NPs) and vascular endothelial growth factor (VEGF), aiming to integrate redox modulation, antibacterial activity, and regenerative support. Methods: Gelation, microstructure, rheology, degradation, and CeO2NP/VEGF were characterized. Tubular epithelial and fibroblast migration and endothelial network formation, angiogenic gene expression, and antibacterial activity against Staphylococcus aureus and Escherichia coli were evaluated in vitro. Theraputic performance was assessed by renal surface application in a rat renal IRI model and catheter-mediated interavsical administration in an ascending urinary tract infection model. Systematic biocompatibility was evaluated separately in a 14-day subcutaneous implantation study. Renal response were further investigated using transcriptomic and targeted molecular analyses. Results: The CSMA/VEGF/CeO₂NPs hydrogel exhibited rapid in situ gelation, interconnected porous architecture, stable viscoelasticity, gradual degradation, and sustained release of both CeO₂NPs and VEGF. The formulation enhanced tubular epithelial and fibroblast migration, promoted endothelial network formation and angiogenic gene expression and effectively inhibited both S. aureus and E. coli. In a surgically controlled rat renal IRI model, direct renal-surface application of the hydrogel reduced tubular injury, inflammatory infiltration, and fibrotic remodeling. In a separate ascending urinary tract infection model, catheter-based intravesical administration reduced the ascending renal bacterial burden and infection-associated inflammatory injury. No detectable adverse systemic effects observed under the tested conditions over the 14-day observation period in the subcutaneous implantation. Transcriptomic analyses further revealed that CSMA/VEGF/CeO₂NPs treatment was associated with marked remodeling of the renal injury microenvironment, characterized by suppression of antigen presentation and immune activation pathways, alongside restoration of metabolic programs associated with amino acid, lipid, and purine metabolism. These molecular changes were accompanied by downregulation of CIITA/CD74/MHC-II signaling, recovery of metabolic regulators AGXT and ACOX1, modulation of Hippo/YAP- and ECM-associated pathways, and preservation of renal structural markers including nephrin and WT1. Conclusions: The localized CSMA-mediated co-delivery of CSMA/VEGF/CeO₂NPs hydrogel promotes renal repair through resolution of maladaptive immune activation, metabolic reprogramming, angiogenic enhancement, and preservation of renal structural integrity, providing a promising biomaterial strategy for the treatment of ischemic and infection-associated renal injuries. Full article

(This article belongs to the Special Issue Nanomaterials for Cell Biological and Biomedical Applications)

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18 pages, 2605 KB

Open AccessArticle

Influence of Lipid Matrix Composition on the Intestinal Permeation of Curcumin-Loaded Lipid Nanoparticles

by Anam Sajjad Khan, Daniela Müller and Cornelia M. Keck

Pharmaceutics 2026, 18(8), 1024; https://doi.org/10.3390/pharmaceutics18081024 - 18 Aug 2026

Viewed by 409

Abstract

Background: Lipid nanoparticles are widely investigated as oral drug delivery systems, but their intestinal performance remains difficult to predict based only on physicochemical properties. This study aimed to elucidate how the lipid matrix composition influences the intestinal permeation of curcumin from lipid nanoparticles. [...] Read more.

Background: Lipid nanoparticles are widely investigated as oral drug delivery systems, but their intestinal performance remains difficult to predict based only on physicochemical properties. This study aimed to elucidate how the lipid matrix composition influences the intestinal permeation of curcumin from lipid nanoparticles. Methods: Curcumin-loaded nanoemulsions, nanostructured lipid carriers with defined solid-to-liquid lipid ratios, and solid lipid nanoparticles were prepared by high-pressure homogenization. All formulations were characterized with respect to particle size, polydispersity index, and zeta potential before and after simulated intestinal pre-incubation in a simplified SDS-containing intestinal fluid. Intestinal permeation was evaluated ex vivo using porcine gut tissue by analysis of semi-quantitative fluorescence-based permeation readouts (ART) and mean permeation depth (MPD) after 30 and 60 min. Results: All formulations maintained stable physicochemical properties with particle sizes around 200 nm and negative zeta potentials; pre-incubation increased the negativity of the zeta potential but left particle size unchanged. Despite similar attributes, the formulations differed in intestinal curcumin permeation based on time and composition. At 30 min, nanoemulsions and mixed nanostructured lipid carriers achieved the highest performance. By 60 min, lipid carriers with more liquid lipid significantly increased both the fluorescence intensity and the depth of curcumin permeation, while other systems showed little further improvement. Conclusions: The intestinal permeation of drug from lipid nanoparticles is governed by the lipid matrix architecture and its interaction with the hydrated intestinal environment, which together affect drug-release kinetics and the ability to sustain a trans-epithelial concentration gradient over time. Thus, optimizing oral lipid nanoparticles requires time-resolved, biologically relevant models rather than physicochemical characterization alone, consistent with observed similar matrix-driven effects in dermal delivery systems. Full article

(This article belongs to the Special Issue Novel Formulation Strategies to Overcome Biological Barrier Permeability Challenges)

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24 pages, 17192 KB

Open AccessArticle

Mannitol as a Critical Excipient in Spray-Dried Chitosan Microspheres for Nasal Donepezil Delivery: Insights from Integrated Biomimetic Models

by Mirna Perkušić, Laura Nižić Nodilo, Mario Jug, Cvijeta Jakobušić Brala, Regina Scherließ and Anita Hafner

Pharmaceutics 2026, 18(8), 1023; https://doi.org/10.3390/pharmaceutics18081023 - 18 Aug 2026

Viewed by 436

Abstract

Background/Objectives: The aim of this study was to develop and apply a novel integrated approach for predicting local mucosal tolerability of spray-dried chitosan/mannitol microspheres previously developed for nose-to-brain donepezil delivery. Methods: Microspheres were prepared by ultrasonic spray-drying, and process reproducibility was evaluated based [...] Read more.

Background/Objectives: The aim of this study was to develop and apply a novel integrated approach for predicting local mucosal tolerability of spray-dried chitosan/mannitol microspheres previously developed for nose-to-brain donepezil delivery. Methods: Microspheres were prepared by ultrasonic spray-drying, and process reproducibility was evaluated based on particle size distribution, entrapment efficiency, and process yield across independent batches. A lactose-based formulation served as a comparative control. A novel biomimetic model was developed to investigate water evaporation under simulated nasal conditions, enabling prediction of formulation dehydration and crust-like layer formation on the nasal mucosa during nasal residence time. Donepezil-loaded chitosan microspheres and their physical mixture with mannitol were used as controls. Analyses were complemented by solid-state and rheological characterization to elucidate the effects of formulation composition and processing on the observed behavior. Irritation potential was further assessed using the established slug mucosal irritation (SMI) assay. Results: Reproducible microsphere size distribution (Dv10 11.5 ± 1.1 µm, RSD 9.6%; Dv50 28.4 ± 3.9 µm, RSD 13.7; Dv90 61.3 ± 8.4 µm, RSD 8.4%), entrapment efficiency (99.6 ± 1.8%, RSD 1.8%) and process yield (40.9 ± 5.5%, RSD 13.3%) confirmed the robustness of the ultrasonic spray-drying. Replacing mannitol with lactose failed to achieve the desired particle size distribution, highlighting the key role of mannitol under the investigated processing conditions. The biomimetic model coupled with rheological studies demonstrated that chitosan-based gels formed by microsphere swelling in simulated nasal fluid, maintain viscosity, resist dehydration, and undergo rehydration. Additionally, mannitol enhanced water retention and reduced evaporation without increasing occlusivity or the risk of mucosal dehydration. Furthermore, powders containing mannitol exhibited a lower irritation potential in the SMI assay compared to chitosan microspheres alone. Conclusions: Mannitol is a critical determinant of the performance of donepezil-loaded chitosan-based microspheres, contributing to the desired particle size distribution, process reproducibility, favorable hydration and improved mucosal tolerability, thereby supporting the suitability of this platform for nasal donepezil delivery. Full article

(This article belongs to the Special Issue The Latest Strategies, Technologies and Innovations in Nasal Drug Delivery)

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49 pages, 2888 KB

Open AccessReview

Microneedles for Vaccination: Mechanistic Foundations, Materials Innovation, Clinical Translation, and Global Health Implementation

by Hiep X. Nguyen and Mai Phuong Ho

Pharmaceutics 2026, 18(8), 1022; https://doi.org/10.3390/pharmaceutics18081022 - 17 Aug 2026

Viewed by 623

Abstract

Vaccination ranks among the most consequential interventions in medicine, yet cold-chain dependence, sharps hazards, needle phobia, and reliance on trained vaccinators limit coverage where vaccine-preventable mortality is highest. Microneedle patches deposit antigen into the antigen-presenting-cell-rich epidermis and upper dermis through projections that penetrate [...] Read more.

Vaccination ranks among the most consequential interventions in medicine, yet cold-chain dependence, sharps hazards, needle phobia, and reliance on trained vaccinators limit coverage where vaccine-preventable mortality is highest. Microneedle patches deposit antigen into the antigen-presenting-cell-rich epidermis and upper dermis through projections that penetrate the stratum corneum without reaching dermal nociceptors. Such targeting yields immunogenicity matching or exceeding intramuscular injection at a fraction of the antigen mass, with dose-sparing up to six-fold recorded for influenza, polio, and SARS-CoV-2 antigens. Solid-state formulation converts that immunological advantage into a logistical one, since polymeric matrices preserve potency for as long as two years at ambient temperature, removing the refrigeration infrastructure that consumes significant delivery cost. Six microneedle types have reached preclinical or clinical maturity, with dissolving microneedle patches the most advanced. Two trials provide the clinical evidence: a Phase I influenza study showing non-inferior antibody responses and successful self-application, and a Phase I/II measles–rubella trial in The Gambia reaching 93% measles and 100% rubella seroconversion in infants without related serious adverse events. Engineering advances currently include an automated printer producing thermostable mRNA–lipid nanoparticle patches that retain bioactivity for six months at ambient temperature, the first intradermal self-amplifying RNA patch, and quantum-dot on-body immunization records. Sterility assurance, dose uniformity, nucleic acid integrity within solid matrices, and fragmented regulatory guidance remain the challenging obstacles, alongside a clinical pipeline concentrated on few antigens. This review integrates the mechanistic, materials, manufacturing, clinical, regulatory, and global health dimensions of the field to guide translation and equitable deployment. Full article

(This article belongs to the Special Issue Microneedles for Drug and Vaccine Delivery)

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26 pages, 7639 KB

Open AccessArticle

Magnetic Hyperthermia via Zn_0.2Mn_0.8Fe₂O₄ Oleic Acid Nanoparticles Enhances Chemotherapy Efficacy in a Lewis Lung Carcinoma Model

by Denis E. Yakobson, Mikhail N. Zharkov, Oleg A. Kulikov, Vasilisa I. Kulikova, Vladislav S. Bobrov, Aleksey O. Makarov, Ekaterina P. Brodovskaya, Larisa A. Balykova, Ran Yan and Nikolay A. Pyataev

Pharmaceutics 2026, 18(8), 1021; https://doi.org/10.3390/pharmaceutics18081021 - 17 Aug 2026

Viewed by 413

Abstract

Background/Objectives: Combining chemotherapy with local magnetic hyperthermia (MHT) is promising because heating tumor tissue can increase cell damage, sensitize cells to cytostatic drugs, impair DNA repair, and change tumor microenvironment permeability. This creates conditions for enhancing the antitumor efficacy of chemotherapy while [...] Read more.

Background/Objectives: Combining chemotherapy with local magnetic hyperthermia (MHT) is promising because heating tumor tissue can increase cell damage, sensitize cells to cytostatic drugs, impair DNA repair, and change tumor microenvironment permeability. This creates conditions for enhancing the antitumor efficacy of chemotherapy while potentially reducing systemic toxicity. The aim of this study was to evaluate the efficacy of MHT with Zn_0.2Mn_0.8Fe₂O₄@OA nanoparticles alone and in combination with cisplatin in a Lewis lung carcinoma model. Methods: Four types of magnetic nanoparticles were synthesized and characterized: Fe₃O₄ and Zn_0.2Mn_0.8Fe₂O₄ coated with oleic acid (OA) or SiO₂-NH₂. Their physicochemical and magnetothermal properties, cytotoxicity, reactive oxygen species generation, and biodegradation in vivo were evaluated. Antitumor efficacy was studied in C57Bl/6 mice with LLC tumors after intratumoral administration of nanoparticles and two MHT sessions (100 kHz, 8 kA/m, 30 min). In combination therapy, ZnMn@OA and cisplatin at doses of 9 or 18 mg/kg were used. Results/Conclusions: Zn_0.2Mn_0.8Fe₂O₄@OA combined efficient heating, biodegradation, and the most pronounced effect among the MHT-alone groups, although MHT without chemotherapy did not provide sustained inhibition of tumor growth or a significant increase in survival. The combination of Zn_0.2Mn_0.8Fe₂O₄@OA-MHT with cisplatin 9 mg/kg produced the best therapeutic outcome: median survival increased significantly by two fold compared with the control group and by 1.8-fold compared with the chemotherapy-alone group at the comparable cisplatin dose. This regimen also stabilized body weight, reduced systemic toxicity, and restored RBC, HGB, and HCT parameters to the level of healthy animals by day 7 of the experiment. These data confirm the potential of MHT as a chemosensitizing approach that improves the efficacy and tolerability of cisplatin therapy. Full article

(This article belongs to the Special Issue Functionalized Metal Nanoparticles in Cancer Therapy)

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11 pages, 3126 KB

Open AccessArticle

Short-Term Pharmacokinetics of Ropivacaine in Arterial Plasma During Erector Spinae Plane Block in Thoracic and Cardiac Surgery

by Amedeo De Nicolò, Alessandra Manca, Edoardo Ceraolo, Giulio Luca Rosboch, Antonio Toscano, Luca Neitzert, Eleonora Balzani, Jessica Cusato, Alice Palermiti, Giorgia Giuseppina Montrucchio and Antonio D’Avolio

Pharmaceutics 2026, 18(8), 1020; https://doi.org/10.3390/pharmaceutics18081020 - 17 Aug 2026

Viewed by 348

Abstract

Background/Objectives: Local anesthetics (LAs) are used in a variety of different contexts, from loco-regional anesthesia to analgesia. In cardiothoracic surgery, fascial plane blocks are deserving of attention, including erector spinae plane block (ESPB). In this context, ropivacaine is convenient, due to its [...] Read more.

Background/Objectives: Local anesthetics (LAs) are used in a variety of different contexts, from loco-regional anesthesia to analgesia. In cardiothoracic surgery, fascial plane blocks are deserving of attention, including erector spinae plane block (ESPB). In this context, ropivacaine is convenient, due to its peculiar pharmacokinetic/pharmacodynamic properties. Nevertheless, LAs can still cause systemic toxicity (LAST), due to erroneous injection and/or variable systemic adsorption/distribution. This interindividual pharmacokinetic variability can be intensified by the tendency to use a fixed ropivacaine dose in ESPB. The aims of this work were investigating systemic exposure to ropivacaine during ESPB in the context of cardiac and thoracic surgery, comparing it to the literature-reported maximum tolerated concentrations, and identifying potential predictors of exposure. Methods: Patients receiving ultrasound-guided injection of 40 mL of ropivacaine 0.375% solution for ESPB were enrolled. Arterial blood was sampled at 5, 15, 30, 45, 60, 120, and 180 min after the injection, and total and free concentrations of ropivacaine were determined by means of LC-MS/MS analysis of arterial plasma. Results: Concentrations showed wide variability, particularly during the first hour post-dose. Significant differences were observed between patients undergoing cardiac and thoracic surgery, with the latter showing higher concentrations, potentially above the cutoff values predictive of LAST. Pharmacokinetic differences were mainly explained by anthropometric (body weight and BSA) and clinical/hemodynamic (NYHA score) characteristics. Conclusions: This study shows that about 5% of patients could reach arterial plasma concentrations of ropivacaine above the cutoff level for LAST after ESPB with a 150 mg dose. Considering patients’ weight could be beneficial to maintain exposure below the toxicity cutoff. Full article

(This article belongs to the Special Issue Personalized Drug Therapy: The Role of Pharmacokinetics and Therapeutic Drug Monitoring, 2nd Edition)

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36 pages, 1381 KB

Open AccessReview

Nanoparticle Platforms in Cancer Immunotherapy: A Critical Comparative Review of PLGA, Mesoporous Silica, Magnetic Nanoparticles, and Covalent Organic Frameworks

by Sarfaraz K. Niazi

Pharmaceutics 2026, 18(8), 1019; https://doi.org/10.3390/pharmaceutics18081019 - 17 Aug 2026

Viewed by 480

Abstract

Background/Objectives: Nanoparticle carriers can enhance cancer immunotherapy by improving tumor delivery, activating innate immune responses, and remodeling tumor microenvironments. This review evaluates four categories of formulations: poly(lactic-co-glycolic acid) (PLGA) nanoparticles, mesoporous silica nanoparticles (MSNs), magnetic or iron oxide nanoparticles (MNPs), and covalent [...] Read more.

Background/Objectives: Nanoparticle carriers can enhance cancer immunotherapy by improving tumor delivery, activating innate immune responses, and remodeling tumor microenvironments. This review evaluates four categories of formulations: poly(lactic-co-glycolic acid) (PLGA) nanoparticles, mesoporous silica nanoparticles (MSNs), magnetic or iron oxide nanoparticles (MNPs), and covalent organic frameworks (COFs). Methods: A reproducible PubMed audit identified 568 records. A rule-assisted title-and-abstract screen, followed by verification, removed 320 reviews, non-primary publications, and reports lacking qualifying in vivo formulation evidence. Of 248 potentially relevant reports, 15 primary studies were selected as representative examples; the remaining 233 were not classified as ineligible but were not selected as representative examples. These reports yielded 16 formulation-level records. One author conducted screening and extraction without protocol registration, duplicate review, or formal risk-of-bias scoring. Results: PLGA demonstrates the most robust polymer-level regulatory and manufacturing precedent; however, it remains limited by cargo instability, burst release, and challenges associated with process transfer. Biodegradable mesoporous silica nanoparticles (MSNs) facilitate pore-based protection and cytosolic delivery of cyclic dinucleotides, although their degradation and clearance are dependent on formulation specifics. Magnetic nanoparticles (MNPs) integrate magnetic targeting, imaging, and hyperthermia capabilities but necessitate formulation-specific magnetic characterization, field dosimetry, and repeated-dose safety assessments. Covalent organic frameworks (COFs) provide extensive stimulus-responsive and catalytic functionalities but exhibit the least mature evidence concerning biodegradation, scalable manufacturing, and independent reproducibility. Efficacy data across different studies were not pooled due to heterogeneity in models, schedules, comparators, and tumor-growth-inhibition formulas. Conclusions: The evidence does not endorse a universal platform ranking. Translation depends on standardized immune endpoints, explicit efficacy formulas, quantitative biodistribution assessments, mechanism-confirming experiments, repeat-dose toxicology studies, scalable manufacturing processes, and independent replication. The resulting evidence map serves as a descriptive and hypothesis-generating tool rather than a meta-analysis or clinical-priority scoring system. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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14 pages, 4366 KB

Open AccessArticle

Evaluating the Incremental Value of Three-Dimensional Conformer Descriptors for Blood–Brain Barrier Permeability Prediction Using the B3DB Benchmark Dataset

by Saurabh Tiwari, Katarzyna Mądra-Gackowska, Marcin Gackowski and Łukasz Szeleszczuk

Pharmaceutics 2026, 18(8), 1018; https://doi.org/10.3390/pharmaceutics18081018 - 17 Aug 2026

Viewed by 409

Abstract

Background/Objectives: Predicting blood–brain barrier (BBB) permeability remains a major challenge in central nervous system (CNS) drug discovery. Three-dimensional (3D) conformer-derived molecular descriptors are often proposed as improvements over conventional two-dimensional (2D) topological representations; however, their incremental predictive value remains unclear. Methods: Here, we [...] Read more.

Background/Objectives: Predicting blood–brain barrier (BBB) permeability remains a major challenge in central nervous system (CNS) drug discovery. Three-dimensional (3D) conformer-derived molecular descriptors are often proposed as improvements over conventional two-dimensional (2D) topological representations; however, their incremental predictive value remains unclear. Methods: Here, we systematically evaluated six molecular feature sets comprising curated 2D Mordred descriptors, Morgan/ECFP4 fingerprints, 3D conformer-derived descriptors, and their combinations, using LightGBM regression on the B3DB benchmark dataset (1054 compounds with experimental logBB values). The model performance was assessed using 30 independent random splits and 30 Murcko scaffold-based splits. Results: The 2D descriptor model achieved mean test R² values of 0.567 ± 0.060 and 0.418 ± 0.085 under random and scaffold splitting, respectively, whereas the 3D descriptor model performed substantially worse (0.430 ± 0.066 and 0.298 ± 0.097, respectively). Incorporating 3D descriptors into the 2D feature set yielded only a marginal improvement under random splitting (+0.008 R²; p = 0.039), which disappeared during scaffold-based validation (p = 0.599). Similarly, adding 3D descriptors to the combined 2D + fingerprint representation did not yield any significant benefits. Fingerprints alone exhibited pronounced scaffold fragility, with the mean R² decreasing from 0.441 to 0.312 between the random and scaffold evaluations. SHAP analysis identified TopoPSA (NO) as the dominant predictor (mean |SHAP| = 0.332), highlighting the central role of desolvation in BBB permeation. Applicability domain analysis showed that 94.8% of the test compounds fell within the structural coverage of the training set. Conclusions: Overall, on the B3DB benchmark and under the descriptor implementation evaluated here, 3D conformer descriptors provided limited incremental value and no scaffold-robust advantage over well-curated 2D molecular representations for BBB permeability predictions. Full article

(This article belongs to the Special Issue Artificial Intelligence in Drug Discovery, Pharmaceutical Processes, and Drug Delivery)

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29 pages, 3396 KB

Open AccessArticle

Exploitation of Nanoparticle–Essential Oil Combinations to Enhance the Efficacy of Antimicrobial Agents Against Staphylococcus equorum

by Simona Hisirová, Patrícia Hudecová, Vanda Hajdučková, Stanislav Lauko, Nikola Dančová, Lívia Mačák, Oksana Velgosova, Peter Paľove-Balang and Ján Király

Pharmaceutics 2026, 18(8), 1017; https://doi.org/10.3390/pharmaceutics18081017 - 17 Aug 2026

Viewed by 457

Abstract

Background: This study evaluated the antibacterial, antibiofilm, and biofilm eradication activities of biogenically synthesized silver nanoparticles (AgNPs-L, AgNPs-R) mediated by extracts of Lavandula angustifolia and Salvia rosmarinus, individually and in combination with their respective essential oils (EOs) and ampicillin (AMP), against a [...] Read more.

Background: This study evaluated the antibacterial, antibiofilm, and biofilm eradication activities of biogenically synthesized silver nanoparticles (AgNPs-L, AgNPs-R) mediated by extracts of Lavandula angustifolia and Salvia rosmarinus, individually and in combination with their respective essential oils (EOs) and ampicillin (AMP), against a multidrug-resistant biofilm-forming Staphylococcus equorum strain. Physicochemical characterization confirmed the successful biosynthesis of spherical AgNPs-L (10–25 nm) and AgNPs-R (5–15 nm). Individual treatments exhibited distinct antibacterial activity, with MIC values of 25 µg/mL for AgNPs-L, 12.5 µg/mL for AgNPs-R, and 0.1% (v/v) for both EOs; however, they showed no ability to eradicate preformed biofilms. Dual AgNPs/EO combinations at subinhibitory concentrations demonstrated borderline additive effects (FICI = 0.501) and significantly potentiated antibacterial and antibiofilm activity compared with individual treatments. Triple AgNPs/EO/AMP combinations exhibited the most pronounced biological effects, with predominantly additive interactions depending on AMP concentration. Lavender-based triple combinations achieved up to 63.9% inhibition of planktonic growth, 78.1% prevention of biofilm formation, and 37.3% eradication of mature biofilms, whereas rosemary-based combinations resulted in 57.1%, 69.4%, and 42.7% inhibition, respectively. These findings highlight the potential of multi-component systems integrating biogenic nanomaterials, phytochemicals, and conventional antibiotics as a promising strategy to enhance antimicrobial efficacy against persistent biofilm-forming non-aureus staphylococci. Full article

(This article belongs to the Special Issue Novel Antimicrobial Drug and Formulation Design: Overcoming Antimicrobial Resistance and Exploring Combination Therapies)

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23 pages, 1780 KB

Open AccessArticle

Applying Raman Spectroscopy for Real-Time Monitoring of Ultra- and Diafiltration Steps in Viral Vector Purification

by Cláudia S. Paiva, Hadi El Radi, Diogo Chagas, Kévin Grollier, Johan Cailletaud, Sébastien Delacroix, Paolo Gabaldi, Tiago Q. Faria and Cristina Peixoto

Pharmaceutics 2026, 18(8), 1016; https://doi.org/10.3390/pharmaceutics18081016 - 17 Aug 2026

Viewed by 692

Abstract

Background: Process analytical technology (PAT) enhances product quality by monitoring and controlling critical quality attributes (CQAs), offering better insights into process performance. Raman spectroscopy is a promising PAT tool to support the development of control systems for continuous and automated processes. In this [...] Read more.

Background: Process analytical technology (PAT) enhances product quality by monitoring and controlling critical quality attributes (CQAs), offering better insights into process performance. Raman spectroscopy is a promising PAT tool to support the development of control systems for continuous and automated processes. In this study, Raman spectroscopy was used to monitor in real-time ultra- and diafiltration (UF/DF) of adeno-associated virus (AAV) and lentiviral vector (LV). Method: The incorporation of a Raman probe in a tangential flow filtration (TFF) system, when operated in open loop, enabled spectral acquisition during a five-fold concentration of clarified bulk followed by a buffer exchange to PBS with five diafiltration volumes. Results: Principal Component Analysis reduced the dimensionality of the training set, and a Partial Least Squares model was developed for each parameter in each phase. After validation, Raman monitoring platforms showed good performance in predicting CQA of both viral vectors. Batch-to-batch variability was identified as the principal source of spectral variation, and its impact on UF/DF operation was observed. Discussion: This study emphasises the potential of Raman spectroscopy as a PAT for monitoring and control strategies in the downstream processing of viral vectors. Conclusions: These monitoring platforms enhance understanding of TFF’s operation and enable timely decision making by providing real-time information on multiple parameters. Full article

(This article belongs to the Special Issue Quality by Design in Pharmaceutical Manufacturing)

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20 pages, 2438 KB

Open AccessArticle

Formulation and Characterization of Captopril-Loaded Chitosan Mucoadhesive Buccal Films with Different Permeation-Enhancing Components

by Hala Rayya, Raghad Alsheikh, Dániel Nemes, Lajos Nagy, Géza Regdon, Jr., Ildikó Bácskay, Krisztián Pamlényi and Katalin Kristó

Pharmaceutics 2026, 18(8), 1015; https://doi.org/10.3390/pharmaceutics18081015 - 16 Aug 2026

Viewed by 451

Abstract

Background/Objectives: The buccal mucosa offers a promising non-invasive route for systemic drug delivery, particularly for hydrophilic compounds like captopril (CAP), which exhibit low permeability and are subject to gastrointestinal instability and first-pass metabolism. This study aimed to develop and characterize captopril-loaded, chitosan-based mucoadhesive [...] Read more.

Background/Objectives: The buccal mucosa offers a promising non-invasive route for systemic drug delivery, particularly for hydrophilic compounds like captopril (CAP), which exhibit low permeability and are subject to gastrointestinal instability and first-pass metabolism. This study aimed to develop and characterize captopril-loaded, chitosan-based mucoadhesive buccal films with different permeation enhancers and to evaluate their physicochemical properties, drug release, cytocompatibility, and in vitro transport across a TR146 buccal epithelial cell model. Methods: Films were prepared by the solvent-casting method using chitosan as the film-forming polymer. Different enhancers were investigated, including organic acid salts of chitosan (ascorbate, citrate, and lactate) and chemical permeation enhancers (sodium lauryl sulfate, polyethylene glycol 400, Span 20, and EDTA). Results: The resulting films exhibited acceptable thickness, moisture content, appropriate mechanical properties, and good mucoadhesive strength. In vitro dissolution studies demonstrated rapid CAP release, with >50% released within 15 min and near-complete release by 180 min across all formulations. Cytotoxicity assessment via a Neutral Red uptake assay in TR146 cells confirmed high cell viability (>81%) after 4 h of exposure, indicating good biocompatibility. In vitro permeation experiments revealed that films prepared with chitosan ascorbate and chitosan lactate enhanced CAP transport compared to other formulations, achieving the highest flux and apparent permeability coefficients. Conclusions: These findings demonstrate that chitosan ascorbate and lactate salts effectively improve the buccal permeability of captopril while maintaining good film properties and biocompatibility. This work highlights the potential of chitosan ascorbate- and lactate-based mucoadhesive films as an efficient platform for the buccal delivery of CAP. Full article

(This article belongs to the Special Issue Next-Generation Biomaterials for Oral Healthcare: Focus on Regenerative and Delivery Functions)

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Pharmaceutics, Volume 18, Issue 8 (August 2026) – 141 articles

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