Pharmaceutics

18 pages, 4198 KB

Open AccessArticle

X-Ray Structures, Intermolecular Interactions, and Structural Transformations of Dihydroquercetin Solvates and Polymorphs

by Xin Meng, Yao Zou, Shiying Yang, Cheng Xing, Ningbo Gong, Guanhua Du and Yang Lu

Pharmaceutics 2025, 17(12), 1512; https://doi.org/10.3390/pharmaceutics17121512 (registering DOI) - 23 Nov 2025

Abstract

Background/Objectives: Dihydroquercetin, known for its broad biological activities, is a key component in dietary supplements and functional foods. This study aims to identify its novel pure solid forms, advancing understanding of its physicochemical properties and polymorphism. Methods: Systematic screening, preparation, and [...] Read more.

Background/Objectives: Dihydroquercetin, known for its broad biological activities, is a key component in dietary supplements and functional foods. This study aims to identify its novel pure solid forms, advancing understanding of its physicochemical properties and polymorphism. Methods: Systematic screening, preparation, and characterization efforts identified five solvates: dihydroquercetin monohydrate (1:1, S1 and S2), sesquihydrate (1:1.5, S3), dihydrate (1:2, S4), and ACN solvate (1:1, S5), along with one solvent-free phase (S6). Results: The crystal structures of the five solvates were successfully elucidated for the first time. A comprehensive suite of techniques, including single-crystal and powder X-ray diffraction, DSC, TG, and FT-IR, were employed to characterize the solvates and polymorphs. Hirshfeld surface analysis, void map analysis, intermolecular energy calculations, and energy framework methods were utilized to investigate the characteristics of the solvates. The crystal transformation relationships among these forms were also explored. Conclusions: Results demonstrate that O···H interactions dominate the intermolecular forces, accounting for over 35% of the total interactions. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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17 pages, 2323 KB

Open AccessArticle

Curcumin and Resveratrol vs. Ferrocene-Modified Polyphenols: Role in Enhancing Protective Properties in Human Keratinocytes

by Marina Miletić, Veronika Kovač, Lidija Barišić, Alen Supičić, Bruno Doskočil, Irena Landeka Jurčević, Jelka Pleadin, Branimir Šimić, Ivana Kmetič and Teuta Murati

Pharmaceutics 2025, 17(12), 1511; https://doi.org/10.3390/pharmaceutics17121511 (registering DOI) - 22 Nov 2025

Abstract

Background/Objectives: Resveratrol (RSV) and curcumin (CRC) have antioxidant, anti-inflammatory, photoprotective, and cell-repairing properties. We selected them to investigate the potential role involved in human keratinocyte protection. Additionally, we tried to overcome the limitations of their application due to poor pharmacokinetics by introducing [...] Read more.

Background/Objectives: Resveratrol (RSV) and curcumin (CRC) have antioxidant, anti-inflammatory, photoprotective, and cell-repairing properties. We selected them to investigate the potential role involved in human keratinocyte protection. Additionally, we tried to overcome the limitations of their application due to poor pharmacokinetics by introducing ferrocene into their structure. Methods: The multiple cellular endpoints—viability (determined by MTT and Trypan Blue method), ROS (reactive oxygen species) formation (evaluated by fluorescence intensity measurement), apoptosis and autophagy (assessed using flow cytometry) of trans-3,5,4′-tri(4-ferrocenylbutanoyloxy)-stilbene (RF) and (E)-5-(4-hydroxy-3-methoxyphenyl)-1-ferrocenylpent-4-ene-1,3-dione (CF), as well as of RSV and CRC, were evaluated in the HaCaT cell line. Results: RF and CF showed significantly lower antiproliferative activity, and cell survival was markedly pronounced compared to RSV or CRC-treated cells. CRC exerted the highest cytotoxicity, and cell viability was almost completely impaired at >50 µM. All compounds showed a beneficial effect on the reduction of ROS induced by tBHP (tert-butyl hydroperoxide), while in UV (ultraviolet) experiments, results were inconclusive (variable depending on dose). CRC and CF had the most prominent antioxidant capacity. Cytofluorimetry showed that CRC has a diverse range of targets in HaCaT cells, including cell proliferation arrest, apoptosis, and autophagy induction. RF at the lowest dose (5 µM) slightly induced autophagy, while treatment with CF even led to a decrease in the autophagy induction ratio. Conclusions: Based on the results, introducing ferrocene into natural compounds is an appropriate approach to protect skin cells, considering the low cytotoxicity of ferrocene-modified polyphenols and their retained antioxidant ability. However, caution should be exercised with CRC at ≥20 µM as it significantly impairs cell viability and induces cell death. Full article

(This article belongs to the Special Issue From Nature to Pharmacy: Advances in Bio-Based Pharmaceutical Formulations)

17 pages, 1940 KB

Open AccessArticle

Adaptive Closed-Loop Control System for the Optimization of Tablet Manufacturing Processes

by Xiaorong Luo, Zhijian Zhong, Pan Deng, Yicheng Fei, Pengdi Cui, Weifeng Zhu, Zhiqiang Xiao, Ting Wang and Liying Li

Pharmaceutics 2025, 17(12), 1510; https://doi.org/10.3390/pharmaceutics17121510 (registering DOI) - 22 Nov 2025

Abstract

Background: Tablet manufacturing is challenged by strong dynamic coupling of process parameters, significant material property fluctuations, and delayed quality control, with tablet weight stability being particularly critical in high-speed production. Traditional static optimization methods relying on empirical judgment struggle to manage these [...] Read more.

Background: Tablet manufacturing is challenged by strong dynamic coupling of process parameters, significant material property fluctuations, and delayed quality control, with tablet weight stability being particularly critical in high-speed production. Traditional static optimization methods relying on empirical judgment struggle to manage these dynamics, leading to substantial variations in tablet weight and hardness that severely compromise production efficiency. Methods: This study proposes a data-driven closed-loop control system centered on a novel Iterative Learning Model Predictive Control (IL-MPC) architecture. The core innovation lies in directly integrating iterative learning constraints within the MPC optimization framework. This constraint-embedding mechanism enables systematic utilization of historical batch data while preserving real-time optimization capabilities. The IL-MPC approach achieves enhanced batch-to-batch performance consistency with reduced computational burden, effectively combining the dual advantages of learning and optimization. Results: Simulation experiments and industrial production data validate the practical feasibility of the IL-MPC algorithm. Implementation results demonstrate that the proposed system effectively manages dynamic process variations, significantly improving control precision for both tablet weight and hardness, outperforming conventional control methods. Conclusions: This research breaks through the technical bottleneck of dynamic regulation in tablet manufacturing. The developed IL-MPC framework provides a reproducible closed-loop control paradigm for intelligent pharmaceutical manufacturing, promoting the industry’s transformation toward data-driven models and advancing intelligent drug production. Full article

(This article belongs to the Special Issue Advancements in Industrial Pharmaceutics: Innovations and Future Directions)

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21 pages, 1567 KB

Open AccessArticle

Carbutamide, an Obsolete Anti-Diabetic Drug, Has Potential as a Potent Anticolitic Agent via Azo-Conjugation with Mesalazine

by Sanghyun Ju, Suji Kim, Taeyoung Kim, Jin-Wook Yoo, In-Soo Yoon, Eunsoo Kim and Yunjin Jung

Pharmaceutics 2025, 17(12), 1509; https://doi.org/10.3390/pharmaceutics17121509 (registering DOI) - 22 Nov 2025

Abstract

Background: To repurpose carbutamide (CBT), a discontinued sulfonylurea-class anti-diabetic drug, as an anti-inflammatory bowel disease (IBD) drug, CBT azo-linked with salicylic acid (CAA) was designed and synthesized as a colon-specific prodrug to co-release CBT and mesalazine (5-ASA) selectively in the large intestine. Methods: [...] Read more.

Background: To repurpose carbutamide (CBT), a discontinued sulfonylurea-class anti-diabetic drug, as an anti-inflammatory bowel disease (IBD) drug, CBT azo-linked with salicylic acid (CAA) was designed and synthesized as a colon-specific prodrug to co-release CBT and mesalazine (5-ASA) selectively in the large intestine. Methods: CAA exhibited reduced lipophilicity and decreased transintestinal transport compared to CBT, as shown in an ex vivo experiment using isolated rat jejunal segments. It also underwent cleavage into CBT and 5-ASA when incubated with cecal contents of rats. Additionally, oral administration of CAA and Sulfasalazine (SSZ), a colon-specific prodrug of 5-ASA currently used for IBD treatment, resulted in similar levels of 5-ASA accumulation in the rat cecal region. Results: In a dinitrobenzene sulfonic acid-triggered colitis model in rats, CAA produced a more pronounced improvement in colon injury and inflammation than SSZ. Furthermore, rectal co-administration of CBT and 5-ASA conferred enhanced protective outcomes compared to monotherapy with either agent alone, suggesting a combined anticolitic action. The two drugs also jointly suppressed valacyclovir uptake via peptide transporter 1 (PepT1) in the distal colon, supporting PepT1 as a target contributing to their combined anticolitic effect. Unlike CBT, which significantly reduced blood glucose following oral administration, equimolar administration of CAA did not alter glycemic levels, consistent with reduced systemic exposure to CBT. Conclusions: In conclusion, CAA functions as a colon-specific mutual prodrug that surpasses SSZ in anticolitic performance while minimizing hypoglycemia risk, thus facilitating the repurposing of CBT as a treatment for IBD. Full article

(This article belongs to the Special Issue Controlled-Release Drug Delivery Systems for Anti-Inflammatory and Wound Healing Action)

10 pages, 1385 KB

Open AccessReview

A Cursory Gaze at Solitary Radiopharmaceutical Chelators Incorporating Macrocyclic and Acyclic Moieties

by Stephen Ahenkorah and Danni Ramdhani

Pharmaceutics 2025, 17(12), 1508; https://doi.org/10.3390/pharmaceutics17121508 (registering DOI) - 22 Nov 2025

Abstract

Radiopharmaceutical development usually requires chelators to route radiometals to specific cancer targets. However, there is no universal chelator. To reduce off-target side effects, new chelators are needed as the radiometal toolset grows. DOTA is the most often used chelator for radiometals in radiopharmaceutical [...] Read more.

Radiopharmaceutical development usually requires chelators to route radiometals to specific cancer targets. However, there is no universal chelator. To reduce off-target side effects, new chelators are needed as the radiometal toolset grows. DOTA is the most often used chelator for radiometals in radiopharmaceutical development, however DOTA’s extreme conditions make it unsuitable for labeling heat sensitive biological vectors. The ideal chelator should be thermodynamically and kinetically stable, allowing labeling under mild conditions (~37 °C). In recent years, new hybrid chelators with enhanced characteristics have emerged, warranting further investigation for medical applications. This paper aims to discuss some of these promising chelators. Full article

(This article belongs to the Special Issue Recent Advances in Metal-Based Drug Delivery Systems for Cancer Therapy)

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17 pages, 1744 KB

Open AccessArticle

Three-Dimensional Screen Printing Technology Enables Sequential Release of Carbidopa and Levodopa—A New Approach Improving Levodopa Delivery for Treating Parkinson’s Disease

by Marcel Enke, Moritz Bünger, Emily Aedtner, Stephan Kastner, Franka Gruschwitz, Klaus Kühne, Dominika Czernik-Schulz, David R. Greeley, Dieter Volc, Andrea Buzachnich-Ladinig and Achim Schneeberger

Pharmaceutics 2025, 17(12), 1507; https://doi.org/10.3390/pharmaceutics17121507 (registering DOI) - 22 Nov 2025

Abstract

Introduction: Levodopa (LD) is the most efficacious antiparkinsonian drug. However, long-term conventional LD treatment of Parkinson’s disease (PD) is frequently associated with motor complications. This can be attributed to pulsatile dopaminergic stimulation given the short LD half-life of conventional dosage forms. Tablets capable [...] Read more.

Introduction: Levodopa (LD) is the most efficacious antiparkinsonian drug. However, long-term conventional LD treatment of Parkinson’s disease (PD) is frequently associated with motor complications. This can be attributed to pulsatile dopaminergic stimulation given the short LD half-life of conventional dosage forms. Tablets capable of delivering more stable and sustained dopaminergic stimulation would better mimic the brain’s natural dopamine activity. Methods: In this study, 3D screen printing technology was used to manufacture oral dosage forms characterized by the sequential release of Carbidopa and Levodopa. This was achieved by separating the two compounds into different compartments within the same dosage form, which were arranged (LXM.5-1) or formulated (LXM.5-2) in a specific way. Both novel dosage forms were compared to conventional immediate release forms such as Sinemet^®. The physicochemical properties of the resulting tablets, LXM.5-1 and LXM.5-2, were assessed in accordance with the USP. Their pharmacokinetic profiles were defined in pigs. Results: The physicochemical properties of LXM.5-1 and LXM.5-2 complied with regulatory requirements. Dissolution studies revealed sequential CD and LD release for both novel dosage forms. They differed regarding the interval between CD and LD release which was shorter for LXM.5-1. PK studies demonstrated that both novel dosage forms exhibited higher LD bioavailability in comparison to Sinemet^®, which was 211.36% and 383.64% for LXM.5-1 and LXM.5-2, respectively. Furthermore, blood levels were more stable and sustained, particularly for LXM.5-2. Conclusions: We conclude that 3D screen-printed LXM.5-1 and LXM.5-2 and variations thereof have the potential to transform the pharmacotherapy of Parkinson’s disease. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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23 pages, 2166 KB

Open AccessReview

Dimethyl Fumarate vs. Monomethyl Fumarate: Unresolved Pharmacologic Issues

by Jana Kopincova and Iveta Bernatova

Pharmaceutics 2025, 17(12), 1506; https://doi.org/10.3390/pharmaceutics17121506 (registering DOI) - 22 Nov 2025

Abstract

Dimethyl fumarate (DMF) has established a significant position among therapies for multiple sclerosis and psoriasis and is now being investigated for repurposing to many other non-malignant diseases. Despite decades of preclinical research, some issues about its pharmacology remain unresolved, with ongoing debate over [...] Read more.

Dimethyl fumarate (DMF) has established a significant position among therapies for multiple sclerosis and psoriasis and is now being investigated for repurposing to many other non-malignant diseases. Despite decades of preclinical research, some issues about its pharmacology remain unresolved, with ongoing debate over which of the methyl esters of fumarate, whether DMF or monomethyl fumarate (MMF), is the active ingredient. It is generally accepted that DMF undergoes enzymatic hydrolysis to MMF and methanol. However, there is disagreement regarding its exact site, its extent, and the responsible enzyme(s). The enzymatic mechanisms, particularly the roles of carboxylesterases-1 and 2, vary across tissues and species, complicating the translation of in vitro and in vivo preclinical findings into clinical practice. In addition, the impact of DMF and MMF is often not clearly distinguishable and sometimes overlaps, making the true molecular mediators of therapeutic and side effects unclear. Thus, the interpretation of some results obtained in studies is inconsistent because of interchanging of in vitro and in vivo observed features of fumarate esters: while DMF demonstrates rapid and strong effects in cell culture studies, including nuclear factor erythroid 2-related factor 2 (NRF2) function activation and glutathione depletion, these observations may not exactly reflect systemic pharmacology and physiology dominated by MMF. Moreover, methanol, the co-product of DMF metabolism, may contribute to the observed DMF effects through increased production of reactive oxygen species, which could result in activation of NRF2-dependent mechanisms. This review highlights specific unresolved issues in DMF metabolism, which are sometimes overlooked. Full article

(This article belongs to the Special Issue Therapeutic Advances in Chronic Diseases: Innovation and Drug Repurposing)

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17 pages, 4214 KB

Open AccessArticle

Enhanced Antiproliferative Activity of Docetaxel by Extremely Low Frequency Electromagnetic Fields in MCF-7 Breast Cancer Cells

by Maryam Vesal, Yasaman Moazen Safaei, Shahin Ramazi, Abdollah Allahverdi, Parviz Abdolmaleki and Hossein Naderi-Manesh

Pharmaceutics 2025, 17(12), 1505; https://doi.org/10.3390/pharmaceutics17121505 - 21 Nov 2025

Abstract

Background/Objectives: Breast cancer remains one of the leading causes of cancer-related mortality in women. While ongoing efforts seek new treatment options, improving the efficacy of existing therapies is equally crucial. Despite advancements in chemotherapy, severe side effects continue to limit treatment success. [...] Read more.

Background/Objectives: Breast cancer remains one of the leading causes of cancer-related mortality in women. While ongoing efforts seek new treatment options, improving the efficacy of existing therapies is equally crucial. Despite advancements in chemotherapy, severe side effects continue to limit treatment success. Combining therapies to enhance efficacy is a promising strategy. Emerging evidence suggests that electromagnetic fields (EMF) can act as chemotherapy enhancers, potentially allowing for lower drug doses. One proposed mechanism is the elevation of reactive oxygen species (ROS), which contributes to cell death. This study explores whether such enhancement exists for chemotherapeutics like docetaxel, where ROS is not the primary, but a contributing, mechanism of action. Methods: We investigated the effects of 50 Hz, 20 mT extremely low-frequency EMF (ELF-EMF) exposure to MCF-7 breast cancer cells in the presence of docetaxel. Cytotoxicity was assessed using the MTT assay, while apoptosis, ROS generation, and cell cycle distribution were analyzed via flow cytometry. Morphological changes associated with apoptosis were examined using acridine orange/propidium iodide dual staining and fluorescence microscopy. Results: Results showed that 50 μM docetaxel reduced cell viability by 50%, while the combination of ELF-EMF and docetaxel achieved the same effect at a significantly lower docetaxel concentration (14 μM). Flow cytometry revealed similar G2/M phase arrest and apoptotic cell death in the combined treatment group, along with elevated ROS levels. Conclusions: These findings suggest that ELF-EMF can potentiate the effects of docetaxel, even when ROS is not the dominant mechanism, supporting its potential as a complementary therapy in breast cancer treatment. Full article

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

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81 pages, 3044 KB

Open AccessReview

Emulsion and Emulgel-Based Ophthalmic Drug Delivery Systems

by Debadatta Mohapatra, Eleen Yang and Timothy W. Corson

Pharmaceutics 2025, 17(12), 1504; https://doi.org/10.3390/pharmaceutics17121504 - 21 Nov 2025

Abstract

Ophthalmic drug delivery encounters unique challenges due to the anatomical and physiological ocular barriers, necessitating the development of novel drug delivery systems (NDDSs). This review focuses on emerging therapeutic platforms, including nanoemulsions (NEs), microemulsions (MEs), self-emulsifying drug delivery systems (SEDDSs) such as self-nano [...] Read more.

Ophthalmic drug delivery encounters unique challenges due to the anatomical and physiological ocular barriers, necessitating the development of novel drug delivery systems (NDDSs). This review focuses on emerging therapeutic platforms, including nanoemulsions (NEs), microemulsions (MEs), self-emulsifying drug delivery systems (SEDDSs) such as self-nano emulsifying drug delivery systems (SNEDDSs) and self-micro emulsifying drug delivery systems (SMEDDSs), emulgels, and in situ-forming emulgels, as novel strategies for enhancing ocular drug delivery. NEs and MEs, due to their small globule size, excellent drug solubility, stability, and bioavailability, offer promising solutions for effective ocular therapy. SEDDSs further enhance the stability and bioavailability of hydrophobic drugs through self-emulsification in aqueous environments. Emulgels, combining the benefits of emulsions and gels, provide sustained and controlled release of therapeutic agents, improving the ocular retention time and therapeutic efficacy. Additionally, in situ-forming emulgels offer the advantage of liquid-to-gel transition upon contact with ocular surfaces, optimizing drug delivery. The review discusses various ocular diseases, challenges for ocular delivery of conventional formulations, updates on emulsion-based novel drug delivery systems for ophthalmic drug delivery, mechanisms of enhanced ocular permeation, formulation strategies, advantages, and challenges, design-of-experiment considerations for optimization, characterizations, and recent advancements in these systems including patents and clinical trials, highlighting their potential for improving the treatment of various ocular diseases. Furthermore, this review explores marketed ophthalmic emulsions and future prospects for integrating these NDDSs into clinical ophthalmology, emphasizing their ability to overcome ocular barriers and enhance therapeutic efficacy. Full article

(This article belongs to the Special Issue Drug Delivery Systems for Ocular Diseases)

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28 pages, 7715 KB

Open AccessArticle

Functional pH-Responsive Nanoparticles for Immune Reprogramming in MSS Colorectal Cancer via ER Stress-Induced Proteostasis Disruption, PD-L1-Targeting miRNA, and TLR7 Activation

by Yu-Li Lo, Hua-Ching Lin, Ching-Yao Li, Bryant Huang, Ching-Ping Yang, Hui-Yen Chuang and Tsui-Fen Chou

Pharmaceutics 2025, 17(11), 1503; https://doi.org/10.3390/pharmaceutics17111503 - 20 Nov 2025

Abstract

Background: Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid [...] Read more.

Background: Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 inhibitor), miR-142 (a PD-L1-targeting microRNA), and imiquimod (R, a TLR7 agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Methods: The SLNs were coated with PEG–PGA for pH-triggered de-shielding and functionalized with PD-L1- and EGFR-binding peptides plus an ER-homing peptide, enabling tumor-selective and subcellular targeting. Results: The nanoplatform displayed acid-triggered PEG–PGA detachment, selective CRC/TAM uptake, and ER localization. CB-mediated VCP inhibition activated IRE1α/XBP1s/LC3II, PERK/eIF2α/ATF4/CHOP, and JNK/Beclin signaling, driving apoptosis and autophagy, while miR-142 suppressed PD-L1 expression and epithelial–mesenchymal transition markers. R facilitated dendritic cell maturation and M1 polarization. Combined CB + miR + R/SLN-CSW suppressed IL-17, G-CSF, and CXCL1, increased infiltration of CD4⁺ and CD8⁺ T cells, reduced Tregs and M2-TAMs, and inhibited tumor growth in CT-26 bearing mice. The treatment induced immunogenic cell death, reprogramming the TME into a T cell-permissive state and conferring resistance to tumor rechallenge. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. Conclusions: This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology-Based Approaches for Pharmaceutical Applications, 2nd Edition)

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29 pages, 941 KB

Open AccessReview

Nanoparticles Used for the Delivery of RNAi-Based Therapeutics

by Tianrui Ren, Liang Ma, Ping Fu and Chuyue Zhang

Pharmaceutics 2025, 17(11), 1502; https://doi.org/10.3390/pharmaceutics17111502 - 20 Nov 2025

Abstract

RNA interference (RNAi) offers programmable, sequence-specific silencing via small interfering RNA (siRNA) and microRNA (miRNA), but clinical translation hinges on overcoming instability, immunogenicity, and inefficient endosomal escape. This review synthesizes advances in non-viral nanocarriers—liposomes, polymeric nanoparticles, and extracellular vesicles (EVs)—that stabilize nucleic acids, [...] Read more.

RNA interference (RNAi) offers programmable, sequence-specific silencing via small interfering RNA (siRNA) and microRNA (miRNA), but clinical translation hinges on overcoming instability, immunogenicity, and inefficient endosomal escape. This review synthesizes advances in non-viral nanocarriers—liposomes, polymeric nanoparticles, and extracellular vesicles (EVs)—that stabilize nucleic acids, tune biodistribution, and enable organ- and cell-selective delivery. We highlight design levers that now define the field: ligand-guided targeting, stimuli-responsive release, biomimicry and endogenous carriers, and rational co-delivery with small molecules. Across major disease areas—cancer and cardiovascular, respiratory, and urological disorders—these platforms achieve tissue-selective uptake (e.g., macrophages, endothelium, and myocardium), traverse physiological barriers (including the blood–brain barrier and fibrotic stroma), and remodel hostile microenvironments or immune programs to enhance efficacy while maintaining favorable safety profiles. Early clinical studies reflect this diversity, spanning targeted nanoparticles, local drug depots, exosome and cellular carriers, and inhaled formulations, e.g., and converge on core phase-I endpoints (safety, maximum tolerated dose, pharmacokinetics/pharmacodynamics, and early activity). Looking ahead, priorities include good manufacturing practice scale, consistent manufacture—especially for EVs; more efficient loading and cargo control; improved endosomal escape and biodistribution; and rigorous, long-term safety evaluation with standardized, head-to-head benchmarking. Emerging directions such as in vivo EVs biogenesis, theragnostic integration, and data-driven formulation discovery are poised to accelerate translation. Collectively, nanoparticle-enabled RNAi has matured into a versatile, clinically relevant toolkit for precise gene silencing, positioning the field to deliver next-generation therapies across diverse indications. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of Vesicle and Nanocarrier Delivery Strategies)

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40 pages, 5705 KB

Open AccessReview

Polymer- and Lipid-Based Nanostructures for Wound Healing with Barrier-Resolved Design

by Eunsoo Cho, Soyeon Yun, Subin Lee, Minse Kim, Jaewon Choi, Sun Eun Choi, Kwang Suk Lim, Suk-Jin Ha, Jang-Hyuk Yun and Hyun-Ouk Kim

Pharmaceutics 2025, 17(11), 1501; https://doi.org/10.3390/pharmaceutics17111501 - 20 Nov 2025

Abstract

Chronic and hard-to-heal wounds remain burdensome because microbial contamination, dysregulated inflammation, and fragile tissue regeneration slow closure, while passive dressings often injure new tissue during removal. This review synthesizes polymer- and lipid-based nanostructures through a barrier-resolved lens that links composition, architecture, and processing [...] Read more.

Chronic and hard-to-heal wounds remain burdensome because microbial contamination, dysregulated inflammation, and fragile tissue regeneration slow closure, while passive dressings often injure new tissue during removal. This review synthesizes polymer- and lipid-based nanostructures through a barrier-resolved lens that links composition, architecture, and processing to performance in protease- and salt-rich exudate across topical and transdermal routes. Quantitative trends include effective diameters of approximately 50–300 nm, practical constraints of sterile filtration at 0.2 μm, and therapeutic windows that prioritize contamination control on the first day, support proliferation around day three, and sustain remodeling beyond one week. Mechanistic evidence indicates that interfacial charge and the protein corona govern residence and uptake, lipid bilayers enable dual loading, degradable polymer matrices provide depot-like behavior, and hybrid constructs temper the early burst while improving storage stability. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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23 pages, 3339 KB

Open AccessArticle

Serendipitous Hinge Modulation Hypothetically Reprograms Caerin 1.1-LC Antibacterial Mechanism and Gram-Negative Selectivity

by Zhengze Sun, Ruixin Zhao, Yueao Zhang, Xiaonan Ma, Yangyang Jiang, Tao Wang, Xiaoling Chen, Chengbang Ma, Tianbao Chen, Chris Shaw, Mei Zhou and Lei Wang

Pharmaceutics 2025, 17(11), 1500; https://doi.org/10.3390/pharmaceutics17111500 - 20 Nov 2025

Abstract

Background: The golden era of antibiotics has long passed, and the clinical failures caused by emerging drug-resistant bacteria have intensified the demand for novel antimicrobial agents. Antimicrobial peptides have attracted significant attention as promising candidates for next-generation antibiotics. Methods: In this study, we [...] Read more.

Background: The golden era of antibiotics has long passed, and the clinical failures caused by emerging drug-resistant bacteria have intensified the demand for novel antimicrobial agents. Antimicrobial peptides have attracted significant attention as promising candidates for next-generation antibiotics. Methods: In this study, we identified a novel antimicrobial peptide, Caerin 1.1-LC, from the skin secretion of the Australian green tree frog, Litoria caerulea. Subsequent structure–activity relationship studies led us to design a series of analogues and revealed the critical role of the peptide’s intrinsic hinge structure in shaping its biological activity. Results: Incorporation of D-isomers at the valine residues within the hinge preserved overall helical content but altered the hinge conformation, resulting in an 8-fold increase in antibacterial activity against Gram-negative bacteria. Simultaneously, haemolytic activity was markedly reduced, leading to a 56-fold improvement in therapeutic index (from 0.47 to 26.6). Structural modulation of the hinge also switched the mechanism of action from classical membrane disruption with associated permeability changes to a non-membrane-permeabilising, ‘cell-penetrating-like’ behaviour, inducing membrane potential depolarisation and ATP disruption to trigger bacterial death. In vivo studies using infected larval models, along with in vitro LPS neutralisation assays, further demonstrated the therapeutic potential of the D-analogue as a novel antibacterial agent. Conclusions: This work highlights the pivotal role of hinge structures in Caerin-family/hinge-containing AMPs, offering a strategic avenue for optimising antibacterial efficacy. Full article

(This article belongs to the Special Issue Antimicrobial Peptides as Promising Therapeutic Agents)

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12 pages, 298 KB

Open AccessArticle

The Association Between Genetic Polymorphisms of UGT1A1, ABCG2, and NR1I2 and Dolutegravir Pharmacokinetic Parameters in Thai People Living with HIV

by Anan Chanruang, Angela K. Birnbaum, Sasithorn Sirilun, Suthunya Chupradit, Sasiwimol Ubolyam, Napon Hiranburana, Yong Soon Cho, Jae Gook Shin, Anchalee Avihingsanon and Baralee Punyawudho

Pharmaceutics 2025, 17(11), 1499; https://doi.org/10.3390/pharmaceutics17111499 - 20 Nov 2025

Abstract

Background/Objectives: Dolutegravir (DTG) is recommended as first-line treatment for Thai people living with HIV (PLWH). Real-world studies show high plasma concentration variability, which may increase neuropsychiatric adverse effects. This variability can be influenced by both genetic and nongenetic factors, but data for [...] Read more.

Background/Objectives: Dolutegravir (DTG) is recommended as first-line treatment for Thai people living with HIV (PLWH). Real-world studies show high plasma concentration variability, which may increase neuropsychiatric adverse effects. This variability can be influenced by both genetic and nongenetic factors, but data for the Thai population are insufficient. We investigated factors associated with DTG pharmacokinetics in Thai PLWH. Methods: A cross-sectional analysis was conducted in Thai PLWH receiving a 50 mg DTG-based regimen. Intensive blood sampling was performed to determine DTG pharmacokinetic parameters using a non-compartmental analysis. Genotyping for UGT1A1, ABCG2, and NR1I2 was performed. Univariable and multivariable linear regression analyses were used to identify factors associated with DTG pharmacokinetics. Results: A total of 104 Thai PLWH were included. Multivariable analysis demonstrated that both the UGT1A1 poor metabolizer phenotype and body weight were independently associated with DTG exposure. After adjusting for body weight, the UGT1A1 poor metabolizer phenotype was associated with increases of 5.18% in AUC_0–24 and 20.59% in C_trough. No significant association was found between the ABCG2 421 C>A polymorphism and DTG pharmacokinetic parameters. Conclusions: Body weight and the UGT1A1 poor metabolizer phenotype significantly impacted DTG exposure in Thai PLWH. Those with the UGT1A1 poor metabolizer, particularly with lower body weight, had significantly increased DTG exposures. These findings highlight that dose optimization may be worth exploring in selected individuals in this population. Full article

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

27 pages, 4957 KB

Open AccessArticle

Mould-Free Microneedles in a Single Step: 3D Printing with Photopolymer Resins for Transdermal Delivery

by Rutuja N. Meshram and Dimitrios A. Lamprou

Pharmaceutics 2025, 17(11), 1498; https://doi.org/10.3390/pharmaceutics17111498 - 19 Nov 2025

Abstract

Background: Digital light processing (DLP) 3D printing has emerged as a rapid alternative to labour-intensive micro-moulding for producing microneedle (MN) arrays, yet its use in biodegradable, dissolving MNs has been limited by proprietary, non-degradable resins. Methods: The current study proposed an innovative, biocompatible [...] Read more.

Background: Digital light processing (DLP) 3D printing has emerged as a rapid alternative to labour-intensive micro-moulding for producing microneedle (MN) arrays, yet its use in biodegradable, dissolving MNs has been limited by proprietary, non-degradable resins. Methods: The current study proposed an innovative, biocompatible PEGDA–vinyl-pyrrolidone photo-resin with lithium phenyl(2,4,6-trimethylbenzoyl) phosphinate initiator, which systematically optimises its rheology and photo-reactivity for DLP printing. Resin formulations were evaluated through viscosity profiling, cure kinetics, FTIR, and ¹H NMR, and MN arrays were printed using a desktop DLP platform and characterised by optical microscopy, mechanical testing, thermal analysis, and dissolution studies. Results: A 40% PEGDA up-to 100% VP blend with 0.4% initiator was identified as providing rapid photopolymerisation, low shrinkage and complete vinyl conversion. Using a desktop DLP platform, 6 × 6 MN patches were printed in a single step without moulds and analysed by optical and scanning electron microscopy. The printed MNs reproduced CAD dimensions with <3% deviation, achieving a height of 1.40 ± 0.02 mm and a base thickness of 1.00 ± 0.01 mm, and showed a tip radius consistent with sharp penetration. Compression testing measured an array force of 32 N, corresponding to ~0.9 N per needle, exceeding the 0.2 N threshold for skin insertion. FTIR and ¹H NMR confirmed near-quantitative crosslinking, thermogravimetric and differential scanning calorimetry indicated stability at ambient conditions, and dissolution studies showed complete needle dissolution. Conclusions: An optimised PEGDA/VP resin yields geometrically precise, mechanically robust dissolving MNs in a single step, addressing the limitations of micro-moulding and paving the way for customisable, on-demand transdermal delivery of active molecules and biologics. Full article

(This article belongs to the Special Issue Recent Advances in 3D Printing of Pharmaceutical Dosage Forms)

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18 pages, 3402 KB

Open AccessArticle

Targeted Biocatalyst Design for Asymmetric Citalopram Conversion in a Membrane Reactor

by Oliwia Degórska, Natalia Zasada, Weronika Badzińska, Qiang Fu, Teofil Jesionowski and Jakub Zdarta

Pharmaceutics 2025, 17(11), 1497; https://doi.org/10.3390/pharmaceutics17111497 - 19 Nov 2025

Abstract

Objective: This study aimed to develop a stable and active biocatalytic system for enzyme immobilization, utilizing an electrospun support doped with a metal–organic framework (MOF) and supplemented with an ionic liquid as a lipase stabilizer and activity enhancer. Methodology: The system was applied [...] Read more.

Objective: This study aimed to develop a stable and active biocatalytic system for enzyme immobilization, utilizing an electrospun support doped with a metal–organic framework (MOF) and supplemented with an ionic liquid as a lipase stabilizer and activity enhancer. Methodology: The system was applied for an efficient and enantioselective resolution of racemic citalopram. Key parameters, including MOF concentration, electrospinning and immobilization conditions, ionic liquid selection, and reaction time, were optimized to enhance biocatalyst performance. Results: The optimal immobilization time was determined to be 24 h, achieving 52% immobilization efficiency and 100% activity recovery. The resulting biocatalytic system HIGH PVC-MOF-lip-CA exhibited superior storage stability, retaining 80% of its initial activity, a 75% improvement over the free enzyme. In the resolution of citalopram, the system achieved 96% conversion of S-citalopram within 24 h, with the enantiomeric excess of 93% in favor of the S-ester over the R-ester. These findings demonstrate the system’s potential for efficient and stereoselective biocatalytic applications. Full article

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

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37 pages, 7790 KB

Open AccessReview

Cyclodextrin: Dual Functions as a Therapeutic Agent and Nanocarrier for Regulating Cholesterol Homeostasis in Atherosclerosis

by Hao Cui, Yaqi Xu, Shulin Pu, Xue Guo, Danyu Zhao, Yuan Liu, Ye Yang and Chengxiao Wang

Pharmaceutics 2025, 17(11), 1496; https://doi.org/10.3390/pharmaceutics17111496 - 19 Nov 2025

Abstract

The progression of atherosclerosis (AS) is strongly linked to lipid crystals accumulation caused by cholesterol metabolism disorders and the worsening of the inflammatory microenvironment. Cyclodextrin (CD), characterized by their unique hydrophobic cavity structure, effectively solubilize cholesterol crystals (CCs) through host–guest recognition and act [...] Read more.

The progression of atherosclerosis (AS) is strongly linked to lipid crystals accumulation caused by cholesterol metabolism disorders and the worsening of the inflammatory microenvironment. Cyclodextrin (CD), characterized by their unique hydrophobic cavity structure, effectively solubilize cholesterol crystals (CCs) through host–guest recognition and act as a multifunctional nanocarrier core, facilitating synergistic therapy that combines pharmaceutical and adjuvant properties. CD-based nano drug delivery systems (CD-NDDS) enable precise targeting of atherosclerotic plaques. By employing synergistic functions (e.g., CCs solubilization, cholesterol efflux promotion via ABCA1/ABCG1 pathways, inflammasome inhibition, and inflammatory microenvironment alleviation), this system provides an effective strategy for AS therapy. Furthermore, CD-NDDS bestows additional pharmaceutical attributes, including enhanced solubility, controlled release, and responsive stimulation. This review begins by elucidating the intrinsic relationship between cholesterol and AS, followed by an examination of the structure-activity relationship governing CD’s cholesterol adsorption. It then explores the construction strategies, structural characteristics, and targeting mechanisms of CD nanodelivery systems in detail. The work systematically assesses CD’s formulation and pharmacological properties in targeted nanodelivery systems for combating AS, integrating drugs and adjuvants. Finally, future research directions are outlined, addressing biocompatibility optimization, targeting efficiency enhancement, and clinical translation challenges to provide a theoretical foundation and technical guidance for precise AS treatment. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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31 pages, 10581 KB

Open AccessArticle

Advancing Personalized Medicine Through FDM 3D Printing: Ketoprofen Tablets with Customizable Drug Release Profiles and In Silico Simulation

by Haya Khader Ahmad Yasin, Moawia M. Al-Tabakha and Siok Yee Chan

Pharmaceutics 2025, 17(11), 1495; https://doi.org/10.3390/pharmaceutics17111495 - 19 Nov 2025

Abstract

Background/Objectives: Fused deposition modeling (FDM) three-dimensional (3D) printing represents an emerging manufacturing platform for personalized oral dosage forms. Its success relies on developing robust drug-loaded filaments with consistent mechanical, thermal, and dissolution properties. This work aims to (i) develop and characterize ketoprofen-loaded [...] Read more.

Background/Objectives: Fused deposition modeling (FDM) three-dimensional (3D) printing represents an emerging manufacturing platform for personalized oral dosage forms. Its success relies on developing robust drug-loaded filaments with consistent mechanical, thermal, and dissolution properties. This work aims to (i) develop and characterize ketoprofen-loaded filaments using hot-melt extrusion (HME) and (ii) utilize them to fabricate both immediate-release (IR) and sustained-release (SR) tablets via FDM 3D printing. Methods: Filaments were prepared using Kollicoat^® IR and hydroxypropyl methylcellulose (HPMC, 2600–5600 cP) as functional polymers. Sorbitol and sodium lauryl sulfate (SLS) were incorporated as plasticizer and surfactant, respectively. Filaments were evaluated for quality attributes, drug content, tensile strength, and physicochemical and surface characteristics using Scanning Electron Microscopy (SEM), Attenuated Total Reflection Fourier-transform infrared (ATR-FTIR), X-ray Diffraction (XRD), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Optimized filaments were fed into an FDM 3D printer to fabricate ketoprofen tablets with varied geometries, shell numbers, and infill densities. Tablets were subjected to USP tests (weight variation, friability, hardness, disintegration, assay, content uniformity), dissolution profiling, and release kinetics modeling. Comparative dissolution studies with market Profenid^® and Bi-Profenid^® tablets were conducted. GastroPlus^® simulations were used for in vitro–in silico correlation. Results: Among the tested formulations, Kollicoat^® IR-based filaments with sorbitol and SLS (F6) demonstrated superior printability, characterized by consistent feeding, stable extrusion, and reliable formation of uniform structures for immediate-release applications. In contrast, HPMC-based filaments with sorbitol (F13) offered the most robust performance for SR formulations. Both exhibited uniform diameter, drug loading, and mechanical strength. IR tablets achieved >80% release within 30 min, while SR tablets prolonged release up to 12 h, following Higuchi and Korsmeyer–Peppas kinetics. All quality attributes complied with USP limits. Market products showed comparable dissolution, validating the approach. GastroPlus^® simulations predicted pharmacokinetic profiles consistent with reported data, supporting IVIVC. Conclusions: This integrated workflow establishes a robust strategy for producing IR and SR ketoprofen tablets from a single FDM platform. The results highlight the feasibility of point-of-care, personalized medicine using 3D printing technologies. Full article

(This article belongs to the Special Issue Advancements in Industrial Pharmaceutics: Innovations and Future Directions)

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16 pages, 3941 KB

Open AccessArticle

Bis-Oxadiazole Assemblies as NO-Releasing Anticancer Agents

by Egor M. Matnurov, Irina A. Stebletsova, Alexander A. Larin, Jemma Arakelyan, Ivan V. Ananyev, Artem L. Gushchin, Leonid L. Fershtat and Maria V. Babak

Pharmaceutics 2025, 17(11), 1494; https://doi.org/10.3390/pharmaceutics17111494 - 19 Nov 2025

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-associated cancer characterized by dysregulated nitric oxide (NO) signaling and increased NO levels that facilitate tumor progression. Paradoxically, this aberrant NO environment creates a therapeutic vulnerability that can be exploited by NO-donor prodrugs, which [...] Read more.

Background: Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-associated cancer characterized by dysregulated nitric oxide (NO) signaling and increased NO levels that facilitate tumor progression. Paradoxically, this aberrant NO environment creates a therapeutic vulnerability that can be exploited by NO-donor prodrugs, which overwhelm cellular defenses with cytotoxic concentrations of NO, inducing nitrosative stress and apoptosis. Within this framework, oxadiazole-based scaffolds have emerged as a promising platform for prodrug development owing to their versatile chemistry and potential as novel NO donors or synergistic agents. In our previous studies, we developed several series of hybrid architectures incorporating 1,2,5-oxadiazole 2-oxide (furoxan) and 1,2,4-oxadiazole scaffolds, producing compounds with diverse and tunable NO-donor activities. We further observed that the cytotoxicity of these hybrids was significantly influenced by the substituents introduced at position 3 of the furoxan ring. Methods: We designed and synthesized a series of bis(1,2,4-oxadiazolyl)furoxans to systematically investigate their NO-donating capacity, cytotoxicity against MPM cell lines, selectivity over healthy lung fibroblasts, and underlying anticancer mechanisms. Results: The bis(1,2,4-oxadiazolyl)furoxans exhibited lower overall cytotoxicity but significantly higher selectivity compared with previously studied 3-cyano-4-(1,2,4-oxadiazolyl)furoxans. Their NO-releasing properties showed a strong correlation with their ability to induce mitochondrial damage, as evidenced by membrane depolarization. Moreover, the incorporation of specific substituents, such as a furan ring, on the 1,2,4-oxadiazole moiety introduced an additional mechanism of action through the induction of reactive oxygen species. Conclusions: Analysis of cancer cell death confirmed that these compounds acted through a multimodal mechanism dependent on both NO release and the specific substituents on the 1,2,4-oxadiazole moiety. Full article

(This article belongs to the Special Issue Prodrug Applications for Targeted Cancer Therapy)

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