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Pharmaceutics, Volume 17, Issue 7 (July 2025) – 102 articles

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15 pages, 3148 KiB  
Article
Development of an Antimicrobial Coating Film for Denture Lining Materials
by Kumiko Yoshihara, Takeru Kameyama, Noriyuki Nagaoka, Yukinori Maruo, Yasuhiro Yoshida, Bart Van Meerbeek and Takumi Okihara
Pharmaceutics 2025, 17(7), 902; https://doi.org/10.3390/pharmaceutics17070902 (registering DOI) - 11 Jul 2025
Abstract
Background/Objectives: Denture hygiene is essential for the prevention of oral candidiasis, a condition frequently associated with Candida albicans colonization on denture surfaces. Cetylpyridinium chloride (CPC)-loaded montmorillonite (CPC-Mont) has demonstrated antimicrobial efficacy in tissue conditioners and demonstrates potential for use in antimicrobial coatings. In [...] Read more.
Background/Objectives: Denture hygiene is essential for the prevention of oral candidiasis, a condition frequently associated with Candida albicans colonization on denture surfaces. Cetylpyridinium chloride (CPC)-loaded montmorillonite (CPC-Mont) has demonstrated antimicrobial efficacy in tissue conditioners and demonstrates potential for use in antimicrobial coatings. In this study, we aimed to develop and characterize CPC-Mont-containing coating films for dentures, focusing on their physicochemical behaviors and antifungal efficacies. Methods: CPC was intercalated into sodium-type montmorillonite to prepare CPC-Mont; thereafter, films containing CPC-Mont were fabricated using emulsions of different polymer types (nonionic, cationic, and anionic). CPC loading, release, and recharging behaviors were assessed at various temperatures, and activation energies were calculated using Arrhenius plots. Antimicrobial efficacy against Candida albicans was evaluated for each film using standard microbial assays. Results: X-ray diffraction analysis confirmed the expansion of montmorillonite interlayer spacing by approximately 3 nm upon CPC loading. CPC-Mont showed temperature-dependent release and recharging behavior, with higher temperatures enhancing its performance. The activation energy for CPC release was 38 kJ/mol, while that for recharging was 26 kJ/mol. Nonionic emulsions supported uniform CPC-Mont dispersion and successful film formation, while cationic and anionic emulsions did not. CPC-Mont-containing coatings maintained antimicrobial activity against Candida albicans on dentures. Conclusions: CPC-Mont can be effectively incorporated into nonionic emulsion-based films to create antimicrobial coatings for denture applications. The films exhibited temperature-responsive, reversible CPC release and recharging behaviors, while maintaining antifungal efficacy, findings which suggest the potential utility of CPC-Mont-containing films as a practical strategy to prevent denture-related candidiasis. Full article
(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)
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16 pages, 999 KiB  
Article
Insulin-Enhanced Biological Visual Rehabilitation in Neuroretinal Degeneration Patients Treated with Mesenchymal Cell-Derived Secretome
by Paolo Giuseppe Limoli, Celeste Limoli and Marcella Nebbioso
Pharmaceutics 2025, 17(7), 901; https://doi.org/10.3390/pharmaceutics17070901 - 11 Jul 2025
Abstract
Objectives: Insulin plays a crucial role in neuronal survival and oxidative stress modulation, making it a potential therapeutic target. This study investigates the effects of insulin in combination with a mesenchymal cell-derived secretome in patients with degenerative neuroretinal diseases. Methods: Sixty-four patients with [...] Read more.
Objectives: Insulin plays a crucial role in neuronal survival and oxidative stress modulation, making it a potential therapeutic target. This study investigates the effects of insulin in combination with a mesenchymal cell-derived secretome in patients with degenerative neuroretinal diseases. Methods: Sixty-four patients with severe neuroretinal diseases who had previously undergone the Limoli Retinal Restoration Technique (LRRT) were included in this longitudinal study and divided into groups: group 1 received a single injection of 5 units of insulin lispro into the suprachoroidal space of the worse-seeing eye; group 2 received insulin injection in the better-seeing eye. Retinal function was assessed using microperimetry (MY) before and after treatment (approximately 1 year for eye drops). Group 3 consisted of patients who demonstrated improvement in MY after insulin injection. These patients continued treatment with daily insulin eye drops. Results: In group 1, insulin-treated eyes showed a significant increase in retinal sensitivity from 10.09 dB to 10.75 dB (p = 0.0067), while untreated eyes declined from 12.35 dB to 11.92 dB (p = 0.0448). In group 2, insulin-treated eyes improved from 10.8 dB to 11.63 dB (p = 0.05), whereas untreated eyes exhibited a decline from 8.68 dB to 8.50 dB (p = 0.6771). In group 3, patients using insulin eye drops showed a stabilization or mild increase in retinal sensitivity, from 11.39 dB to 11.73 dB (p = 0.231). Conclusions: The addition of insulin in patients previously treated with the LRRT was associated with improved sensitivity and a stabilizing effect on neuroretinal function. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Ocular Diseases)
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22 pages, 13140 KiB  
Article
Development and Characterization of Optimized Drug-Loaded Niosomes for Delivery of 5-FU and Irinotecan
by Kafilat O. Agbaje, Simeon K. Adesina and Amusa S. Adebayo
Pharmaceutics 2025, 17(7), 900; https://doi.org/10.3390/pharmaceutics17070900 - 11 Jul 2025
Abstract
Background/Objectives: 5-Fluorouracil (5-FU) and Irinotecan (IRT) are two of the most used chemotherapeutic agents in CRC treatment. However, achieving treatment goals has been hampered by poor drug delivery to tumor sites and associated toxicity from off-target binding to healthy cells. Though the [...] Read more.
Background/Objectives: 5-Fluorouracil (5-FU) and Irinotecan (IRT) are two of the most used chemotherapeutic agents in CRC treatment. However, achieving treatment goals has been hampered by poor drug delivery to tumor sites and associated toxicity from off-target binding to healthy cells. Though the synergism of 5-FU-IRT has provided incremental improvements in clinical outcomes, the short elimination half-life and off-target binding to healthy cells remain significant challenges. We postulated that nanoencapsulation of a combination of 5-FU and IRT in niosomes would prolong the drugs’ half-lives, while over-encapsulation lyophilized powder in Targit® oral capsules would passively the CRC microenvironment and avoid extensive systemic distribution. Methods: Ranges of formulation and process variables were input into design of experiment (DOE Fusion One) software, to generate screening experiments. Niosomes were prepared using the thin-film hydration method and characterized by size, the polydispersity index (PDI), morphology and intrastructure, and drug loading. Blank niosomes ranged in size from 215 nm to 257 nm. Results: After loading with the 5-FU-IRT combination, the niosomes averaged 251 ± 2.20 nm with a mean PDI of 0.293 ± 0.01. The surfactant-to-cholesterol ratio significantly influenced the niosome size and the PDI. The hydrophilic 5-FU exhibited superior loading compared to the lipophilic IRT molecules, which probably competed with other lipophilic niosome components in niosomes’ palisade layers. In vitro dissolution in biorelevant media showed delayed release until lower intestinal region (IRT) or colonic region (5-FU). Conclusions: Thus, co-nanoencapsulation of 5-FU/IRT in niosomes, lyophilization, and over-encapsulation of powder in colon-specific capsules could passively target the CRC cells in the colonic microenvironment. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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40 pages, 1203 KiB  
Review
Overview of Preclinical and Clinical Trials of Nanoparticles for the Treatment of Brain Metastases
by Muhammad Izhar, Mohamed Al Gharyani, Ahed H. Kattaa, Juan J. Cardona, Ruchit P. Jain, Elaheh Shaghaghian, Yusuke S. Hori, Fred C. Lam, Deyaaldeen Abu Reesh, Sara C. Emrich, Louisa Ustrzynski, Armine Tayag, Maciej S. Lesniak, Steven D. Chang and David J. Park
Pharmaceutics 2025, 17(7), 899; https://doi.org/10.3390/pharmaceutics17070899 - 11 Jul 2025
Abstract
Brain metastases (BM), which most commonly originate from lung, breast, or skin cancers, remain a major clinical challenge, with standard treatments such as stereotactic radiosurgery (SRS), surgical resection, and whole-brain radiation therapy (WBRT). The prognosis for patients with BM remains poor, with a [...] Read more.
Brain metastases (BM), which most commonly originate from lung, breast, or skin cancers, remain a major clinical challenge, with standard treatments such as stereotactic radiosurgery (SRS), surgical resection, and whole-brain radiation therapy (WBRT). The prognosis for patients with BM remains poor, with a median overall survival (OS) of just 10–16 months. Although recent advances in systemic therapies, including small molecule inhibitors, monoclonal antibodies, chemotherapeutics, and gene therapies, have demonstrated success in other malignancies, their effectiveness in central nervous system (CNS) cancers is significantly limited by poor blood–brain barrier (BBB) permeability and subtherapeutic drug concentrations in the brain. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome these limitations by enhancing CNS drug penetration and selectively targeting metastatic brain tumor cells while minimizing off-target effects. This review summarizes recent preclinical and clinical developments in nanoparticle-based therapies for BM. It is evident from these studies that NPs can carry with them a range of therapeutics, including chemotherapy, immunotherapy, small molecule inhibitors, gene therapies, radiosensitizers, and modulators of tumor microenvironment to the BM. Moreover, preclinical studies have shown encouraging efficacy in murine models, highlighting the potential of these platforms to improve therapeutic outcomes. However, clinical translation remains limited, with few ongoing trials. To close this translational gap, future work must address clinical challenges such as trial design, regulatory hurdles, and variability in BBB permeability while developing personalized nanoparticle-based therapies tailored to individual tumor characteristics. Full article
(This article belongs to the Special Issue Development of Novel Tumor-Targeting Nanoparticles, 2nd Edition)
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17 pages, 593 KiB  
Review
Patent-Based Technological Overview of Propolis–Cyclodextrin Inclusion Complexes with Pharmaceutical Potential
by Salvana Costa, Ighor Costa Barreto, Nataly Gama, Kathylen Santos, Cleomárcio Miguel de Oliveira, Isabela Silva Costa, Monique Vila Nova, Ruane Santos, Arthur Borges, José Marcos Teixeira de Alencar Filho and Ticiano Gomes do Nascimento
Pharmaceutics 2025, 17(7), 898; https://doi.org/10.3390/pharmaceutics17070898 - 11 Jul 2025
Abstract
Background/objectives: Propolis, known for its medicinal properties, faces challenges in pharmaceutical applications due to its low aqueous solubility, attributed to its resinous and hydrophobic nature. This limits oral administration, reducing its bioavailability and pharmacological activities. To overcome these barriers, cyclodextrins (CDs), cyclic oligosaccharides, [...] Read more.
Background/objectives: Propolis, known for its medicinal properties, faces challenges in pharmaceutical applications due to its low aqueous solubility, attributed to its resinous and hydrophobic nature. This limits oral administration, reducing its bioavailability and pharmacological activities. To overcome these barriers, cyclodextrins (CDs), cyclic oligosaccharides, are widely studied as carrier systems that enhance the solubility and bioavailability of propolis and other nonpolar compounds. This study aimed to review patents that developed innovative therapeutic approaches to improve the physicochemical and biological properties of propolis through complexation with CDs. Methods: Active and application patents registered over the last 17 years were searched across multiple databases, resulting in the selection of eight inventions for detailed analysis. Results: These patents highlight therapeutic applications of propolis–CD systems for conditions such as diabetes and skin and gastrointestinal cancers, as well as antimicrobial, immunostimulant, and antioxidant effects. Additionally, novel extraction processes free of organic solvents, including nanometric-scale powder extracts, are described. Conclusions: Findings from scientific articles support the patent data, demonstrating that CD complexation significantly enhances the solubility and therapeutic efficacy of propolis. Thus, these patents present an innovative and promising strategy for developing propolis-based pharmaceutical products. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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22 pages, 1305 KiB  
Review
Hydrogel Conjugation: Engineering of Hydrogels for Drug Delivery
by Linh Dinh, Sung-Joo Hwang and Bingfang Yan
Pharmaceutics 2025, 17(7), 897; https://doi.org/10.3390/pharmaceutics17070897 - 10 Jul 2025
Abstract
Background: Hydrogels are 3D networks of hydrophilic polymers with various biomedical applications, including tissue regeneration, wound healing, and localized drug delivery. Hydrogel conjugation links therapeutic agents to a hydrogel network, creating a delivery system with adjustable and flexible hydrogel properties and drug [...] Read more.
Background: Hydrogels are 3D networks of hydrophilic polymers with various biomedical applications, including tissue regeneration, wound healing, and localized drug delivery. Hydrogel conjugation links therapeutic agents to a hydrogel network, creating a delivery system with adjustable and flexible hydrogel properties and drug activity, allowing for controlled release and enhanced drug stability. Conjugating therapeutic agents to hydrogels provides innovative delivery formats, including injectable and sprayable dosage forms, which facilitate localized and long-lasting delivery. This approach enables non-viral therapeutic methods, such as insertional mutagenesis, and minimally invasive drug administration. Scope and Objectives: While numerous reviews have analyzed advancements in hydrogel synthesis, characterization, properties, and hydrogels as a drug delivery vehicle, this review focuses on hydrogel conjugation, which enables the precise functionalization of hydrogels with small molecules and macromolecules. Subsequently, a description and discussion of several bio-conjugated hydrogel systems, as well as binding motifs (e.g., “click” chemistry, functional group coupling, enzymatic ligation, etc.) and their potential for clinical translation, are provided. In addition, the integration of therapeutic agents with nucleic acid-based hydrogels can be leveraged for sequence-specific binding, representing a leap forward in biomaterials. Key findings: Special attention was given to the latest conjugation approaches and binding motifs that are useful for designing hydrogel-based drug delivery systems. The review systematically categorizes hydrogel conjugates for drug delivery, focusing on conjugating hydrogels with major classes of therapeutic agents, including small-molecule drugs, nucleic acids, proteins, etc., each with distinct conjugation challenges. The design principles were discussed along with their properties and drug release profiles. Finally, future opportunities and current limitations of conjugated hydrogel systems are addressed. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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18 pages, 4976 KiB  
Article
Mechanistic Insights into Cytokine Antagonist-Drug Interactions: A Physiologically Based Pharmacokinetic Modelling Approach with Tocilizumab as a Case Study
by Xian Pan, Cong Liu, Felix Stader, Abdallah Derbalah, Masoud Jamei and Iain Gardner
Pharmaceutics 2025, 17(7), 896; https://doi.org/10.3390/pharmaceutics17070896 - 10 Jul 2025
Abstract
Background: Understanding interactions between cytokine antagonists and drugs is essential for effective medication management in inflammatory conditions. Recent regulatory authority guidelines emphasise a systematic, risk-based approach to evaluating these interactions, underscoring the need for mechanistic insight. Proinflammatory cytokines, such as interleukin-6 (IL-6), modulate [...] Read more.
Background: Understanding interactions between cytokine antagonists and drugs is essential for effective medication management in inflammatory conditions. Recent regulatory authority guidelines emphasise a systematic, risk-based approach to evaluating these interactions, underscoring the need for mechanistic insight. Proinflammatory cytokines, such as interleukin-6 (IL-6), modulate cytochrome P450 (CYP) enzymes, reducing the metabolism of CYP substrates. Cytokine antagonists (such as IL-6 receptor antagonists) can counteract this effect, restoring CYP activity and increasing drug clearance. However, quantitative prediction of cytokine-mediated drug interactions remains challenging, as existing models often lack the mechanistic detail needed to capture the dynamic relationship between cytokine signalling, receptor engagement, and downstream modulation of drug metabolism. Methods: A physiologically based pharmacokinetic (PBPK) framework incorporating cytokine–receptor binding, subsequent downregulation of CYP expression, and blockade of the cytokine signalling by a therapeutic protein antagonist was developed to simulate and investigate cytokine antagonist-drug interactions. Tocilizumab, a humanised IL-6 receptor antagonist used to treat several inflammatory conditions associated with elevated IL-6 levels, was selected as a model drug to demonstrate the utility of the framework. Results: The developed PBPK model accurately predicted the pharmacokinetics profiles of tocilizumab and captured clinically observed dynamic changes in simvastatin exposure before and after tocilizumab treatment in rheumatoid arthritis (RA) patients. Simulated IL-6 dynamics aligned with observed clinical profiles, showing transient elevation following receptor blockade and associated restoration of CYP3A4 activity. Prospective simulations with commonly co-administered CYP substrates (celecoxib, chloroquine, cyclosporine, ibuprofen, prednisone, simvastatin, and theophylline) in RA patients revealed dose regimen- and drug-dependent differences in interaction magnitude. Conclusions: This study demonstrated the utility of PBPK models in providing a mechanistic understanding of cytokine antagonist-drug interactions, supporting enhanced therapeutic decision-making and optimising patient care in inflammatory conditions. Full article
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22 pages, 4797 KiB  
Article
Silver Nanoparticles Synthesized from Enicostemma littorale Exhibit Gut Tight Junction Restoration and Hepatoprotective Activity via Regulation of the Inflammatory Pathway
by Hiral Aghara, Simran Samanta, Manali Patel, Prashsti Chadha, Divyesh Patel, Anamika Jha and Palash Mandal
Pharmaceutics 2025, 17(7), 895; https://doi.org/10.3390/pharmaceutics17070895 - 9 Jul 2025
Abstract
Background: Alcohol-associated liver disease (ALD) is a primary global health concern, exacerbated by oxidative stress, inflammation, and gut barrier dysfunction. Conventional phytocompounds exhibit hepatoprotective potential but are hindered by low bioavailability. This study aimed to evaluate the hepatoprotective and gut-barrier-restorative effects of green-synthesized [...] Read more.
Background: Alcohol-associated liver disease (ALD) is a primary global health concern, exacerbated by oxidative stress, inflammation, and gut barrier dysfunction. Conventional phytocompounds exhibit hepatoprotective potential but are hindered by low bioavailability. This study aimed to evaluate the hepatoprotective and gut-barrier-restorative effects of green-synthesized silver nanoparticles (AgNPs) derived from Enicostemma littorale, a medicinal plant known for its antioxidant and anti-inflammatory properties. Methods: AgNPs were synthesized using aqueous leaf extract of E. littorale and characterized using UV-Vis, XRD, FTIR, DLS, and SEM. HepG2 (liver) and Caco-2 (colon) cells were exposed to 0.2 M ethanol, AgNPs (1–100 µg/mL), or both, to simulate ethanol-induced toxicity. A range of in vitro assays was performed to assess cell viability, oxidative stress (H2DCFDA), nuclear and morphological integrity (DAPI and AO/EtBr staining), lipid accumulation (Oil Red O), and gene expression of pro- and anti-inflammatory, antioxidant, and tight-junction markers using RT-qPCR. Results: Ethanol exposure significantly increased ROS, lipid accumulation, and the expression of inflammatory genes, while decreasing antioxidant enzymes and tight-junction proteins. Green AgNPs at lower concentrations (1 and 10 µg/mL) restored cell viability, reduced ROS levels, preserved nuclear morphology, and downregulated CYP2E1 and SREBP expression. Notably, AgNPs improved the expression of Nrf2, HO-1, ZO-1, and IL-10, and reduced TNF-α and IL-6 expression in both cell lines, indicating protective effects on both liver and intestinal cells. Conclusions: Green-synthesized AgNPs from E. littorale exhibit potent hepatoprotective and gut-barrier-restoring effects through antioxidant, anti-inflammatory, and antilipidemic mechanisms. These findings support the therapeutic potential of plant-based nanoparticles in mitigating ethanol-induced gut–liver axis dysfunction. Full article
(This article belongs to the Special Issue Nanoparticles for Liver Diseases Therapy)
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4 pages, 166 KiB  
Editorial
An Editorial on the Special Issue “Where Are We Now and Where Is Cell Therapy Headed?”
by Andrea Papait and Paola Chiodelli
Pharmaceutics 2025, 17(7), 894; https://doi.org/10.3390/pharmaceutics17070894 - 9 Jul 2025
Abstract
Cell-based therapies have swiftly transitioned from experimental modalities to core components of modern translational medicine [...] Full article
(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)
41 pages, 4547 KiB  
Review
Inhalable Nanotechnology-Based Drug Delivery Systems for the Treatment of Inflammatory Lung Diseases
by Doaa Elsayed Mahmoud, Seyedeh Hanieh Hosseini, Hassaan Anwer Rathore, Alaaldin M. Alkilany, Andreas Heise and Abdelbary Elhissi
Pharmaceutics 2025, 17(7), 893; https://doi.org/10.3390/pharmaceutics17070893 - 9 Jul 2025
Abstract
This review explores recent advancements in inhaled nanoparticle formulations and inhalation devices, with a focus on various types of nanoparticles used for inhalation to treat inflammatory lung diseases and the types of devices used in their delivery. Medical nebulizers have been found to [...] Read more.
This review explores recent advancements in inhaled nanoparticle formulations and inhalation devices, with a focus on various types of nanoparticles used for inhalation to treat inflammatory lung diseases and the types of devices used in their delivery. Medical nebulizers have been found to be the most appropriate type of inhalation devices for the pulmonary delivery of nanoparticles, since formulations can be prepared using straightforward techniques, with no need for liquefied propellants as in the case of pressurized metered dose inhalers (pMDIs), or complicated preparation procedures as in the case of dry powder inhalers (DPIs). We demonstrated examples of how formulations should be designed considering the operation mechanism of nebulizers, and how an interplay of factors can affect the aerosol characteristics of nanoparticle formulations. Overall, nanoparticle-based formulations offer promising potential for the treatment of inflammatory lung diseases due to their unique physicochemical properties and ability to provide localized drug delivery in the lung following inhalation. Full article
(This article belongs to the Special Issue Recent Advances in Pulmonary Inhalation of Nanoformulations)
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27 pages, 3554 KiB  
Article
Impact of Poly(Lactic Acid) and Graphene Oxide Nanocomposite on Cellular Viability and Proliferation
by Karina Torres Pomini, Júlia Carolina Ferreira, Laira Mireli Dias da Silva, Paulo Gabriel Friedrich Totti, Monique Gonçalves Alves, Eliana de Souza Bastos Mazuqueli Pereira, Marcelo Melo Soares, Durvanei Augusto Maria and Rose Eli Grassi Rici
Pharmaceutics 2025, 17(7), 892; https://doi.org/10.3390/pharmaceutics17070892 - 9 Jul 2025
Abstract
Background/Objectives: Although the nanocomposite of poly(L-lactic acid) with graphene oxide (PLLA-GO) shows promise for tissue engineering, its specific bioactive interactions with diverse cell lineages during early tissue regeneration remain unclear. This study comprehensively investigated the in vitro multifaceted biocompatibility of PLLA-GO using human [...] Read more.
Background/Objectives: Although the nanocomposite of poly(L-lactic acid) with graphene oxide (PLLA-GO) shows promise for tissue engineering, its specific bioactive interactions with diverse cell lineages during early tissue regeneration remain unclear. This study comprehensively investigated the in vitro multifaceted biocompatibility of PLLA-GO using human fibroblasts (FN1 cells), murine mesenchymal stem cells (mBMSCs), and human umbilical vein endothelial cells (HUVECs). Methods: Morphological analyses were performed using optical and scanning electron microscopy, while proliferation dynamics were assessed via CFSE staining. Cell cycle progression was evaluated using flow cytometry, mitochondrial activity was examined through TMRE staining, and inflammatory cytokine profiling was performed via Cytometric Bead Array (CBA). Results: PLLA-GO exhibited primary biocompatibility across all evaluated cell lines, characterized by efficient adhesion and proliferation. However, significant cell-type-dependent modulations were observed. The FN1 cells exhibited proliferative adaptation but induced accelerated scaffold degradation, as evidenced by a substantial increase in cellular debris (5.93% control vs. 34.38% PLLA-GO; p = 0.03). mBMSCs showed a transient initial proliferative response and a significant 21.66% increase in TNF-α production (179.67 pg/mL vs. 147.68 pg/mL in control; p = 0.03). HUVECs demonstrated heightened mitochondrial sensitivity, exhibiting a 32.19% reduction in mitochondrial electrical potential (97.07% control vs. 65.82% PLLA-GO; p ≤ 0.05), alongside reductions in pro-inflammatory cytokines TNF-α (8.73%) and IL-6 (12.47%). Conclusions: The PLLA-GO processing method is crucial for its properties and subsequent cellular interactions. Therefore, rigorous and specific preclinical evaluations—considering both cellular contexts and fabrication—are indispensable to ensure the safety and therapeutic potential of PLLA-GO in tissue engineering and regenerative medicine. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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2 pages, 610 KiB  
Correction
Correction: Balas et al. Photodynamic Activity of TMPyP4/TiO2 Complex under Blue Light in Human Melanoma Cells: Potential for Cancer-Selective Therapy. Pharmaceutics 2023, 15, 1194
by Mihaela Balas, Simona Nistorescu, Madalina Andreea Badea, Anca Dinischiotu, Mihai Boni, Andra Dinache, Adriana Smarandache, Ana-Maria Udrea, Petronela Prepelita and Angela Staicu
Pharmaceutics 2025, 17(7), 891; https://doi.org/10.3390/pharmaceutics17070891 - 9 Jul 2025
Abstract
In the original publication [...] Full article
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13 pages, 2107 KiB  
Article
Unlocking the Bioactivity of Sweet Wormwood (Artemisia annua L., Asteraceae) Ethanolic Extract: Phenolics, Antioxidants, and Cytotoxic Effects
by Neda Gavarić, Milica Aćimović, Nebojša Kladar, Maja Hitl, Jovana Drljača Lero, Nataša Milić and Katarina Radovanović
Pharmaceutics 2025, 17(7), 890; https://doi.org/10.3390/pharmaceutics17070890 - 9 Jul 2025
Abstract
Objectives: The aim of this work was to determine the phenolic composition of sweet wormwood (Artemisia annua L., Asteraceae) from controlled cultivation in Serbia and to assess the potential antioxidant effects and cytotoxicity. Methods: High-performance liquid chromatography was used to [...] Read more.
Objectives: The aim of this work was to determine the phenolic composition of sweet wormwood (Artemisia annua L., Asteraceae) from controlled cultivation in Serbia and to assess the potential antioxidant effects and cytotoxicity. Methods: High-performance liquid chromatography was used to determine the phenolic composition of Artemisia annua ethanolic extract. The antioxidant activity was studied using in vitro tests of inhibition of the neutralization of 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), and nitroso (NO) radicals, as well as the process of inhibiting lipid peroxidation and the ferric reducing antioxidant power (FRAP). The cytotoxicity was evaluated by the effect on three cell lines (the rat pancreatic insulinoma cell line (Rin-5F), the rat hepatoma cell line (H4IIE), and human hepatocellular carcinoma (Hep G2)) using the MTT test of viability. Results: Ethanol extract showed the highest potency in inhibiting the DPPH radical, and the half maximal inhibitory concentration (IC50) was 5.17 μg/mL. Chlorogenic acid was the dominant phenolic compound with an amount of 651 μg/g of dry extract. The results of the MTT viability test showed that the extract has the potential to inhibit the growth of the Rin-5F and Hep G2 cell lines, while no growth inhibition was observed on the H4IIE cell line. Conclusions: Undoubtedly, Artemisia annua is a powerful plant and a rich source of phenolic compounds. Inhibitory activity on causes of oxidative stress shows that the plant has a good antioxidant effect. Also, the anticancer activity shown through the inhibition of cell growth is not negligible. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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21 pages, 1170 KiB  
Review
Innovative Controlled-Release Systems for Fucoxanthin: Research Progress and Applications
by Shiyan Wang, Mengran Guo and Zhaohui Jin
Pharmaceutics 2025, 17(7), 889; https://doi.org/10.3390/pharmaceutics17070889 - 8 Jul 2025
Abstract
Fucoxanthin, a marine-derived carotenoid primarily sourced from algae and microalgae, holds significant potential for pharmaceutical and nutraceutical applications. However, its highly unsaturated structure presents critical challenges, including structural instability, poor aqueous solubility, and limited bioavailability. These restrict its application despite its abundant natural [...] Read more.
Fucoxanthin, a marine-derived carotenoid primarily sourced from algae and microalgae, holds significant potential for pharmaceutical and nutraceutical applications. However, its highly unsaturated structure presents critical challenges, including structural instability, poor aqueous solubility, and limited bioavailability. These restrict its application despite its abundant natural availability. Recently, various controlled-release nanotechnologies have been applied to improve the properties of fucoxanthin formulations. In this review, we systematically summarized the bioactivities of fucoxanthin and highlighted recent advancements in controlled-release systems designed to address the limitations. These controlled-release systems mainly use natural or synthetic organic materials and are employed to develop various formulations, including emulsions, nanoparticles, nanofibers, and nanostructured lipid carriers. In addition, the emerging bioinspired drug delivery systems, particularly extracellular vesicles and cell-membrane-derived biomimetic systems, have gained prominence for their immunocompatibility and ability to penetrate physiological barriers, which is regarded as superior encapsulation vesicles for fucoxanthin. Focusing on innovations, we discussed the state-of-the-art delivery systems for fucoxanthin encapsulation and emphasized their roles in improving biosafety, enhancing bioavailability, preserving bioactivity, and optimizing therapeutic performance across various disease models. These insights will provide promising guidance for engineering controlled-release platforms and will aim to unlock fucoxanthin’s full potential in drug development and dietary supplement formulations. Full article
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12 pages, 926 KiB  
Review
Nanotechnology Approaches for Mitigating Biologic Immunogenicity: A Literature Review
by Jouri Alanazi, Fadilah Sfouq Aleanizy and Fulwah Yahya Alqahtani
Pharmaceutics 2025, 17(7), 888; https://doi.org/10.3390/pharmaceutics17070888 - 7 Jul 2025
Viewed by 168
Abstract
Biologic therapeutics, particularly monoclonal antibodies (mAbs), have revolutionized disease treatment paradigms; however, their clinical success is often hindered by immunogenicity. Host immune recognition of these biologics can induce anti-drug antibody (ADA) formation, leading to reduced therapeutic efficacy, altered pharmacokinetics and serious adverse events, [...] Read more.
Biologic therapeutics, particularly monoclonal antibodies (mAbs), have revolutionized disease treatment paradigms; however, their clinical success is often hindered by immunogenicity. Host immune recognition of these biologics can induce anti-drug antibody (ADA) formation, leading to reduced therapeutic efficacy, altered pharmacokinetics and serious adverse events, such as infusion reactions and loss of response. Overcoming these immunogenicity challenges is essential to maximize the clinical effect of biologics and ensure patient safety. This paper offers an overview of the mechanisms underlying the formation of anti-drug antibodies and explores potential nanotechnology-based strategies to reduce or eliminate these responses. Specifically, the review examines how the immune system recognizes biologics and develops ADAs, which can impact drug efficacy and safety. The review then investigates various nanotechnology approaches aimed at mitigating ADA formation, potentially improving the therapeutic outcomes of biologic drugs. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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17 pages, 2146 KiB  
Article
Synthesis and Antiviral Activity of Nanowire Polymers Activated with Ag, Zn, and Cu Nanoclusters
by Thomas Thomberg, Hanna Bulgarin, Andres Lust, Jaak Nerut, Tavo Romann and Enn Lust
Pharmaceutics 2025, 17(7), 887; https://doi.org/10.3390/pharmaceutics17070887 - 6 Jul 2025
Viewed by 220
Abstract
Background/Objectives: Airborne viral diseases pose a health risk, due to which there is a growing interest in developing filter materials capable of capturing fine particles containing virions from the air and that also have a virucidal effect. Nanofiber membranes made of poly(vinylidene fluoride) [...] Read more.
Background/Objectives: Airborne viral diseases pose a health risk, due to which there is a growing interest in developing filter materials capable of capturing fine particles containing virions from the air and that also have a virucidal effect. Nanofiber membranes made of poly(vinylidene fluoride) dissolved in N,N-dimethylacetamide and functionalized with copper, silver, and zinc nanoclusters were fabricated via electrospinning. This study aims to evaluate and compare the virucidal effects of nanofibers functionalized with metal nanoclusters against the human influenza A virus A/WSN/1933 (H1N1) and SARS-CoV-2. Methods: A comprehensive characterization of materials, including X-ray diffraction, scanning electron microscopy, microwave plasma atomic emission spectroscopy, thermogravimetric analysis, contact angle measurements, nitrogen sorption analysis, mercury intrusion porosimetry, filtration efficiency, and virucidal tests, was used to understand the interdependence of the materials’ physical characteristics and biological effects, as well as to determine their suitability for application as antiviral materials in air filtration systems. Results: All the filter materials tested demonstrated very high particle filtration efficiency (≥98.0%). The material embedded with copper nanoclusters showed strong virucidal efficacy against the SARS-CoV-2 alpha variant, achieving an approximately 1000-fold reduction in infectious virions within 12 h. The fibrous nanowire polymer functionalized with zinc nanoclusters was the most effective material against the human influenza A virus strain A/WSN/1933 (H1N1). Conclusions: The materials with Cu nanoclusters can be used with high efficiency to passivate and kill the SARS-CoV-2 alpha variant virions, and Zn nanoclusters modified activated porous membranes for killing human influenza A virus A7WSN/1933 (H1N1) virions. Full article
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26 pages, 3269 KiB  
Review
ROS-Responsive Nanoplatforms for Targeted Tumor Immunomodulation: A Paradigm Shift in Precision Cancer Immunotherapy
by Yuan-Yuan Fan, Hong Wu and Chuan Xu
Pharmaceutics 2025, 17(7), 886; https://doi.org/10.3390/pharmaceutics17070886 - 5 Jul 2025
Viewed by 175
Abstract
Despite remarkable advancements in cancer immunotherapy, its clinical efficacy remains constrained in solid tumors due to the immunosuppressive tumor microenvironment (TME). Reactive oxygen species (ROS), which exhibit dual regulatory roles in the TME by regulating immunogenic cell death (ICD) and reprogramming immune cell [...] Read more.
Despite remarkable advancements in cancer immunotherapy, its clinical efficacy remains constrained in solid tumors due to the immunosuppressive tumor microenvironment (TME). Reactive oxygen species (ROS), which exhibit dual regulatory roles in the TME by regulating immunogenic cell death (ICD) and reprogramming immune cell functionality, have emerged as a pivotal therapeutic target. Nano-enabled drug delivery systems present distinct advantages for TME modulation due to their structural versatility, tumor-specific targeting precision, and spatiotemporally controlled drug release. In particular, ROS-responsive nanoplatforms demonstrate multifaceted immunomodulatory potential by synergistically restoring ICD and remodeling immunosuppressive immune cell phenotypes within the TME. These platforms further amplify the therapeutic outcomes of conventional modalities including chemotherapy, radiotherapy, and photodynamic therapy (PDT) through ROS-mediated sensitization mechanisms. This review comprehensively examines recent breakthroughs in ROS-responsive nanosystems for antitumor immunotherapy, emphasizing their mechanistic interplay with TME components and clinical translation potential. Herein, we provide a framework for developing integrated therapeutic strategies to overcome the current limitations in cancer immunotherapy. Full article
(This article belongs to the Special Issue ROS-Mediated Nano Drug Delivery for Antitumor Therapy)
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17 pages, 3316 KiB  
Review
Advances in Liposomal Drug Delivery: Multidirectional Perspectives on Overcoming Biological Barriers
by Żaneta Sobol, Rafał Chiczewski and Dorota Wątróbska-Świetlikowska
Pharmaceutics 2025, 17(7), 885; https://doi.org/10.3390/pharmaceutics17070885 - 5 Jul 2025
Viewed by 212
Abstract
Liposomes represent a cornerstone of modern drug delivery systems due to their unique structural and physicochemical characteristics. Extensive research has refined their formulation, stability, and targeting capabilities, leading to numerous clinical applications, particularly in oncology. A key clinical feature is their ability to [...] Read more.
Liposomes represent a cornerstone of modern drug delivery systems due to their unique structural and physicochemical characteristics. Extensive research has refined their formulation, stability, and targeting capabilities, leading to numerous clinical applications, particularly in oncology. A key clinical feature is their ability to accumulate in malignant tissues via the enhanced permeability and retention effect, offering improved pharmacokinetics and reduced systemic toxicity. Advances in liposomal engineering, including PEGylation and ligand-based targeting, have significantly enhanced pharmacokinetic profiles and tissue specificity, minimizing off-target toxicity. The modern approach to nanocarrier-based drugs offers multidirectional perspectives on targeted therapy. Liposomes can bypass drug resistance mechanisms and provide controlled or stimuli-responsive drug release. Current trends in liposome research focus on hybrid nanocarriers, personalized medicine applications, and combination therapies. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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15 pages, 1142 KiB  
Article
Prediction of Monoclonal Antibody Pharmacokinetics in Pediatric Populations Using PBPK Modeling and Simulation
by Chiara Zunino, Virginie Gualano, Haiying Zhou, Viera Lukacova and Maxime Le Merdy
Pharmaceutics 2025, 17(7), 884; https://doi.org/10.3390/pharmaceutics17070884 - 5 Jul 2025
Viewed by 242
Abstract
Background: Accurately determining pediatric dosing is essential prior to initiating clinical trials or administering medications in routine clinical settings. In children, ethical considerations demand careful evaluation of both safety and effectiveness. Typically, dosing recommendations for therapeutic proteins, such as monoclonal antibodies (mAbs), [...] Read more.
Background: Accurately determining pediatric dosing is essential prior to initiating clinical trials or administering medications in routine clinical settings. In children, ethical considerations demand careful evaluation of both safety and effectiveness. Typically, dosing recommendations for therapeutic proteins, such as monoclonal antibodies (mAbs), are derived from adult dosages using body weight as a scaling factor. However, this method overlooks key physiological and biochemical distinctions between pediatric and adult patients. Therefore, this could lead to the underexposure of mAbs, limiting their efficacy in this population. Additional methods are necessary to predict pediatric doses mechanistically. For small molecules, physiologically based pharmacokinetic (PBPK) models have been extensively used to predict pediatric doses based on physiological age-related changes and enzymes/transporters ontogeny. This study aims to evaluate the ability of PBPK models to predict mAbs’ pediatric exposure. Methods: Three mAbs were used for model development and validation: bevacizumab, infliximab, and atezolizumab. The PBPK models were built using GastroPlus© Biologics module. For each mAb, the PBPK model was developed based on observed data in healthy and/or patient adults. Then, the physiological parameters were scaled to describe the pediatric physiology to predict exposure to the pediatric populations. Predicted plasma concentration–time courses were overlaid with reported observed data to assess the ability of the PBPK model to predict pediatric exposure. Results: Results showed that PBPK models accurately predicted pediatric pharmacokinetics for mAbs. Conclusions: This research marks a significant step in validating mechanistic extrapolation methods for biologics exposure prediction in children using PBPK models. Full article
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28 pages, 9146 KiB  
Review
Nanoscale Porphyrin-Based Metal–Organic Frameworks for Enhanced Radiotherapy–Radiodynamic Therapy: A Comprehensive Review
by Bin Gong, Qiuyun Zhang, Yijie Qu, Xiaohua Zheng and Weiqi Wang
Pharmaceutics 2025, 17(7), 883; https://doi.org/10.3390/pharmaceutics17070883 - 4 Jul 2025
Viewed by 278
Abstract
The phototherapeutic applications of porphyrin-based nanoscale metal–organic frameworks (nMOFs) are limited by the poor penetration of conventional excitation light sources into biological tissues. Radiodynamic therapy (RDT), which directly excites photosensitizers using X-rays, can overcome the issue of tissue penetration. However, RDT faces the [...] Read more.
The phototherapeutic applications of porphyrin-based nanoscale metal–organic frameworks (nMOFs) are limited by the poor penetration of conventional excitation light sources into biological tissues. Radiodynamic therapy (RDT), which directly excites photosensitizers using X-rays, can overcome the issue of tissue penetration. However, RDT faces the problems of low energy conversion efficiency, requiring a relatively high radiation dose, and the potential to cause damage to normal tissues. Researchers have found that by using some metals with high atomic numbers (high Z) as X-ray scintillators and coordinating them with porphyrin photosensitizers to form MOF materials, the excellent antitumor effect of radiotherapy (RT) and RDT can be achieved under low-dose X-ray irradiation, which can not only effectively avoid the penetration limitations of light excitation methods but also eliminate the defect issues associated with directly using X-rays to excite photosensitizers. This review summarizes the relevant research work in recent years, in which researchers have used metal ions with high Z, such as Hf4+, Th4+, Ta5+, and Bi3+, in coordination with carboxyl porphyrins to form MOF materials for combined RT and RDT toward various cancer cells. This review compares the therapeutic effects and advantages of using different high-Z metals and introduces the application of the heavy atom effect. Furthermore, it explores the introduction of a chemodynamic therapy (CDT) mechanism through iron coordination at the porphyrin center, along with optimization strategies such as oxygen delivery using hemoglobin to enhance the efficacy of these MOFs as radiosensitizers. This review also summarizes the potential of these materials in preclinical applications and highlights the current challenges they face. It is expected that the summary and prospects outlined in this review can further promote preclinical biomedical research into and the development of porphyrin-based nMOFs. Full article
(This article belongs to the Special Issue Advanced Nanotechnology for Combination Therapy and Diagnosis)
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24 pages, 8040 KiB  
Article
Development of Modified Drug Delivery Systems with Metformin Loaded in Mesoporous Silica Matrices: Experimental and Theoretical Designs
by Mousa Sha’at, Maria Ignat, Florica Doroftei, Vlad Ghizdovat, Maricel Agop, Alexandra Barsan (Bujor), Monica Stamate Cretan, Fawzia Sha’at, Ramona-Daniela Pavaloiu, Adrian Florin Spac, Lacramioara Ochiuz, Carmen Nicoleta Filip and Ovidiu Popa
Pharmaceutics 2025, 17(7), 882; https://doi.org/10.3390/pharmaceutics17070882 - 4 Jul 2025
Viewed by 385
Abstract
Background/Objectives: Mesoporous silica materials, particularly KIT-6, offer promising features, such as large surface area, tunable pore structures, and biocompatibility, making them ideal candidates for advanced drug delivery systems. The aims of this study were to develop and evaluate an innovative modified-release platform for [...] Read more.
Background/Objectives: Mesoporous silica materials, particularly KIT-6, offer promising features, such as large surface area, tunable pore structures, and biocompatibility, making them ideal candidates for advanced drug delivery systems. The aims of this study were to develop and evaluate an innovative modified-release platform for metformin hydrochloride (MTF), using KIT-6 mesoporous silica as a matrix, to enhance oral antidiabetic therapy. Methods: KIT-6 was synthesized using an ultrasound-assisted sol-gel method and subsequently loaded with MTF via adsorption from alkaline aqueous solutions at two concentrations (1 and 3 mg/mL). The structural and morphological characteristics of the matrices—before and after drug loading—were assessed using SEM-EDX, TEM, and nitrogen adsorption–desorption isotherms (the BET method). In vitro drug release profiles were recorded in simulated gastric and intestinal fluids over 12 h. Kinetic modeling was performed using seven classical models, and a multifractal theoretical framework was used to further interpret the complex release behavior. Results: The loading efficiency increased with increasing drug concentration but nonlinearly, reaching 56.43 mg/g for 1 mg/mL and 131.69 mg/g for 3 mg/mL. BET analysis confirmed significant reductions in the surface area and pore volume upon MTF incorporation. In vitro dissolution showed a biphasic release: a fast initial phase in an acidic medium followed by sustained release at a neutral pH. The Korsmeyer–Peppas and Weibull models best described the release profiles, indicating a predominantly diffusion-controlled mechanism. The multifractal model supported the experimental findings, capturing nonlinear dynamics, memory effects, and soliton-like transport behavior across resolution scales. Conclusions: The study confirms the potential of KIT-6 as a reliable and efficient carrier for the modified oral delivery of metformin. The combination of experimental and multifractal modeling provides a deeper understanding of drug release mechanisms in mesoporous systems and offers a predictive tool for future drug delivery design. This integrated approach can be extended to other active pharmaceutical ingredients with complex release requirements. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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16 pages, 3597 KiB  
Article
Towards a Customized Oral Drug Therapy for Pediatric Applications: Chewable Propranolol Gel Tablets Printed by an Automated Extrusion-Based Material Deposition Method
by Kristiine Roostar, Andres Meos, Ivo Laidmäe, Jaan Aruväli, Heikki Räikkönen, Leena Peltonen, Sari Airaksinen, Niklas Sandler Topelius, Jyrki Heinämäki and Urve Paaver
Pharmaceutics 2025, 17(7), 881; https://doi.org/10.3390/pharmaceutics17070881 - 4 Jul 2025
Viewed by 213
Abstract
Background: Automated semi-solid extrusion (SSE) material deposition is a promising new technology for preparing personalized medicines for different patient groups and veterinary applications. The technology enables the preparation of custom-made oral elastic gel tablets of active pharmaceutical ingredient (API) by using a semi-solid [...] Read more.
Background: Automated semi-solid extrusion (SSE) material deposition is a promising new technology for preparing personalized medicines for different patient groups and veterinary applications. The technology enables the preparation of custom-made oral elastic gel tablets of active pharmaceutical ingredient (API) by using a semi-solid polymeric printing ink. Methods: An automated SSE material deposition method was used for generating chewable gel tablets loaded with propranolol hydrochloride (-HCl) at three different API content levels (3.0 mg, 4.0 mg, 5.0 mg). The physical appearance, surface morphology, dimensions, mass and mass variation, process-derived solid-state changes, mechanical properties, and in-vitro drug release of the gel tablets were studied. Results: The inclusion of API (1% w/w) in the semi-solid CuraBlendTM printing mixture decreased viscosity and increased fluidity, thus promoting the spreading of the mixture on the printed (material deposition) bed and the printing performance of the gel tablets. The printed gel tablets were elastic, soft, jelly-like, chewable preparations. The mechanical properties of the gel tablets were dependent on the printing ink composition (i.e., with or without propranolol HCl). The maximum load for the final deformation of the CuraBlend™-API (3.0 mg) gel tablets was very uniform, ranging from 73 N to 80 N. The in-vitro dissolution test showed that more than 85% of the drug load was released within 15–20 min, thus verifying the immediate-release behavior of these drug preparations. Conclusions: Automated SSE material deposition as a modified 3D printing method is a feasible technology for preparing customized oral chewable gel tablets of propranolol HCl. Full article
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20 pages, 4947 KiB  
Article
Novel Micellar Formulation of Silymarin (Milk Thistle) with Enhanced Bioavailability in a Double-Blind, Randomized, Crossover Human Trial
by Chuck Chang, Yiming Zhang, Yun Chai Kuo, Min Du, Kyle Roh, Roland Gahler, Afoke Ibi and Julia Solnier
Pharmaceutics 2025, 17(7), 880; https://doi.org/10.3390/pharmaceutics17070880 - 4 Jul 2025
Viewed by 271
Abstract
Background: Silymarin, a flavonoid complex, and the main bioactive component of milk thistle (Silybum marianum), is known for its hepatoprotective properties but suffers from poor bioavailability due to its low solubility and extensive first-pass metabolism. Method: This study aimed to evaluate [...] Read more.
Background: Silymarin, a flavonoid complex, and the main bioactive component of milk thistle (Silybum marianum), is known for its hepatoprotective properties but suffers from poor bioavailability due to its low solubility and extensive first-pass metabolism. Method: This study aimed to evaluate the pharmacokinetics and tolerability of a novel micellar milk thistle formulation designed to enhance silymarin absorption, compared to an unformulated/standard milk thistle product, in a small-scale human bioavailability trial. In a randomized, double-blinded, crossover study, 16 healthy participants received a single dose of either the micellar formulation (LipoMicel Milk Thistle; LMM) or the standard formulation (STD) at a total daily dose of 130 mg silymarin. Blood concentrations were measured over 24 h, and key pharmacokinetic parameters—maximum plasma concentration (Cmax), time to reach maximum concentration (Tmax), and area under the curve (AUC)—were calculated. Tolerability and safety were assessed through adverse event monitoring during the study period. Results: Results demonstrated a significant increase in bioavailability with the micellar formulation, with 18.9-fold higher Cmax (95% CI: 1.9–30.7 ng/mL vs. 74.4–288.3 ng/mL; p = 0.007) and 11.4-fold higher AUC0–24 (95% CI: 7.40–113.5 ng·h/mL vs. 178–612.5 ng·h/mL; p = 0.015). Tmax was 0.5 (95% CI: 0.5–4.0) hours for the micellar formulation versus 2.5 (95% CI: 0.5–8.0) hours for the standard product (p = 0.015) indicating faster absorption of LMM. The standard formulation exhibited a significantly longer mean residence time compared to the LMM formulation (95% CI: 4.4–7.5 h vs. 2.8–4.2 h; p = 0.015). Conclusions: No adverse events or significant safety concerns were observed in either group. Compared to the standard, the micellar formulation showed superior pharmacokinetic outcomes, suggesting it may enhance silymarin’s clinical efficacy in liver health. Full article
(This article belongs to the Collection Pharmaceutical Sciences in Canada)
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15 pages, 4132 KiB  
Article
Crotoxin-Loaded Silica Nanoparticles: A Nanovenom Approach
by Florencia Silvina Conti, Exequiel Giorgi, Laura Montaldo, Juan Pablo Rodríguez, Mauricio Cesar De Marzi and Federico Gastón Baudou
Pharmaceutics 2025, 17(7), 879; https://doi.org/10.3390/pharmaceutics17070879 - 4 Jul 2025
Viewed by 225
Abstract
Background: Ophidism is a globally neglected health problem. In Argentina, Crotalus durissus terrificus (C.d.t., South American rattlesnake) is one of the species of greatest medical importance since its venom contains mainly crotoxin (CTX), a potent enzyme–toxin with PLA2 activity, [...] Read more.
Background: Ophidism is a globally neglected health problem. In Argentina, Crotalus durissus terrificus (C.d.t., South American rattlesnake) is one of the species of greatest medical importance since its venom contains mainly crotoxin (CTX), a potent enzyme–toxin with PLA2 activity, which is responsible for its high lethality. Objective: In this work, we aimed to generate nanovenoms (NVs), complexes formed by CTX adsorbed onto 150 nm silica nanoparticles (SiNPs), and to study their physicochemical, biological, and immunomodulatory activities for potential use as adjuvants (ADJs) in antivenom (AV) production. Methods: CTX was isolated and corroborated by SDS-PAGE. Then, CTX was adsorbed on the synthetized Stöber SiNPs’ surfaces, forming a monolayer and retaining its biological activity (as observed by the MTT cell proliferation assay using the THP-1 cell line). Results: Immunomodulatory activity revealed a high pro-inflammatory (IL-1β) response induced by SiNPs followed by NVs. In the case of the anti-inflammatory response, NVs presented significant differences for TGF-β only after cell activation with LPS. No significant differences were observed in IL-10 levels. Conclusions: Thus, these results suggest that NVs together with SiNPs could increase immunogenicity and enhance immune response, turning them into potential tools for the generation of new antivenoms. Full article
(This article belongs to the Special Issue Delivery System for Biomacromolecule Drugs: Design and Application)
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16 pages, 2915 KiB  
Article
Extrusion-Based 3D Printing of Rutin Using Aqueous Polyethylene Oxide Gel Inks
by Oleh Koshovyi, Jyrki Heinämäki, Alina Shpychak, Andres Meos, Niklas Sandler Topelius and Ain Raal
Pharmaceutics 2025, 17(7), 878; https://doi.org/10.3390/pharmaceutics17070878 - 3 Jul 2025
Viewed by 278
Abstract
Background/Objectives. Flavonoids are a vast class of phenolic substances. To date, approximately 6000 plant-origin flavonoids have been discovered, with many of them being used in drug therapy. Therapeutic flavonoids are commonly formulated to conventional “one-size-fits-all” dosage forms, such as conventional tablets or hard [...] Read more.
Background/Objectives. Flavonoids are a vast class of phenolic substances. To date, approximately 6000 plant-origin flavonoids have been discovered, with many of them being used in drug therapy. Therapeutic flavonoids are commonly formulated to conventional “one-size-fits-all” dosage forms, such as conventional tablets or hard capsules. However, the current trends in pharmacy and medicine are centred on personalised drug therapy and drug delivery systems (DDSs). Therefore, 3D printing is an interesting technique for designing and preparing novel personalised pharmaceuticals for flavonoids. The aim of the present study was to develop aqueous polyethylene oxide (PEO) gel inks loaded with rutin for semisolid extrusion (SSE) 3D printing. Methods. Rutin (a model substance for therapeutic flavonoids), Tween 80, PEO (MW approx. 900,000), ethanol, and purified water were used in PEO gels at different proportions. The viscosity and homogeneity of the gels were determined. The rutin–PEO gels were printed with a bench-top Hyrel 3D printer into lattices and discs, and their weight and effective surface area were investigated. Results. The key SSE 3D-printing process parameters were established and verified. The results showed the compatibility of rutin as a model flavonoid and PEO as a carrier polymer. The rutin content (%) and content uniformity of the 3D-printed preparations were assayed by UV spectrophotometry and high-performance liquid chromatography (HPLC). Conclusions. The most feasible aqueous PEO gel ink formulation for SSE 3D printing contained rutin 100 mg/mL and Tween 80 50 mg/mL in a 12% aqueous PEO gel. The 3D-printed dosage forms are intended for the oral administration of flavonoids. Full article
(This article belongs to the Special Issue 3D Printing of Drug Delivery Systems)
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23 pages, 1856 KiB  
Article
Comparative Evaluation of Gelatin and HPMC Inhalation Capsule Shells Exposed to Simulated Humidity Conditions
by Sabrina Magramane, Nikolett Kállai-Szabó, Dóra Farkas, Károly Süvegh, Romána Zelkó and István Antal
Pharmaceutics 2025, 17(7), 877; https://doi.org/10.3390/pharmaceutics17070877 - 3 Jul 2025
Viewed by 274
Abstract
Background/Objectives: This study investigates the impact of high humidity (25 °C, 75% relative humidity) on gelatin and hydroxypropyl methylcellulose (HPMC) capsules used in dry powder inhalers (DPIs), focusing on moisture dynamics, structural responses, and mechanical performance, with an emphasis on understanding how [...] Read more.
Background/Objectives: This study investigates the impact of high humidity (25 °C, 75% relative humidity) on gelatin and hydroxypropyl methylcellulose (HPMC) capsules used in dry powder inhalers (DPIs), focusing on moisture dynamics, structural responses, and mechanical performance, with an emphasis on understanding how different capsule types respond to prolonged exposure to humid conditions. Methods: Capsules were exposed to controlled humidity conditions, and moisture uptake was measured via thermal analysis. Visual observations of silica bead color changes were performed to assess moisture absorption, while surface wettability was measured using the sessile drop method. Hardness testing, mechanical deformation, and puncture tests were performed to evaluate structural and mechanical changes. Positron annihilation lifetime spectroscopy (PALS) was used to analyze free volume expansion. Results: HPMC capsules exhibited rapid moisture uptake, attributed to their lower equilibrium moisture content and ability to rearrange dynamically, preventing brittleness. In contrast, gelatin capsules showed slower moisture absorption but reached higher equilibrium levels, resulting in plasticization and softening. Mechanical testing showed that HPMC capsules retained structural integrity with minimal deformation, while gelatin capsules became softer and exhibited reduced puncture resistance. Structural analysis revealed greater free volume expansion in HPMC capsules, consistent with their amorphous nature, compared with gelatin’s semi-crystalline matrix. Conclusions: HPMC capsules demonstrated superior humidity resilience, making them more suitable for protecting moisture-sensitive active pharmaceutical ingredients (APIs) in DPI formulations. These findings underline the importance of appropriate storage conditions, as outlined in the Summary of Product Characteristics, to ensure optimal capsule performance throughout patient use. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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26 pages, 11210 KiB  
Article
Perspectives on the pH-Influenced Design of Chitosan–Genipin Nanogels for Cell-Targeted Delivery
by Julieta D. Glasman, Agustina Alaimo, Cecilia Samaniego López, María Edith Farías, Romina B. Currá, Diego G. Lamas and Oscar E. Pérez
Pharmaceutics 2025, 17(7), 876; https://doi.org/10.3390/pharmaceutics17070876 - 3 Jul 2025
Viewed by 275
Abstract
Background: Chitosan (CS) crosslinked with genipin (GNP) provides a mild, non-toxic route to generate nanogels (NGs) with enhanced integrity and colloidal stability. Objectives: To develop and characterise CS-GNP NG as a novel platform for targeted cellular delivery, optimising design through physicochemical [...] Read more.
Background: Chitosan (CS) crosslinked with genipin (GNP) provides a mild, non-toxic route to generate nanogels (NGs) with enhanced integrity and colloidal stability. Objectives: To develop and characterise CS-GNP NG as a novel platform for targeted cellular delivery, optimising design through physicochemical characterisation and biocompatibility evaluation. Methods: NGs were synthesised under optimised conditions by adjusting the pH of the CS solution, followed by high-intensity ultrasound (HIUS) to achieve disaggregation. Physicochemical characterisation was carried out using UV-Vis spectroscopy, FTIR, dynamic light scattering (DLS), and scanning electron microscopy (SEM). Rheological studies and SAXS analysis assessed structural properties. Biocompatibility was evaluated via MTT assay, and internalisation was monitored by fluorescence microscopy on mammalian cell lines. Results: NG formation was highly pH-dependent, with optimal configuration at pH 4.5, yielding stable, uniformly sized particles (~200 nm, ζ-potential +29 mV). Kinetic modelling showed a sigmoidal formation pattern, suggesting nucleation, growth, and stabilisation. FTIR confirmed covalent bonding between CS and GNP via primary amide bonds and Schiff bases. Rheology indicated pseudoplastic behaviour, and SAXS revealed a compact network formation. Biocompatibility assays confirmed non-cytotoxicity below 100 µg/mL and efficient cellular uptake. Conclusions: This study presents a rapid, reproducible protocol for generating colloidally stable, biocompatible NGs suitable for drug delivery. Full article
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23 pages, 4426 KiB  
Article
Laser Microinterferometry for API Solubility and Phase Equilibria: Darunavir as a Case Example
by Veronika Makarova, Mark Mandrik and Sergey Antonov
Pharmaceutics 2025, 17(7), 875; https://doi.org/10.3390/pharmaceutics17070875 - 3 Jul 2025
Viewed by 270
Abstract
Background: The solubility and phase behavior of APIs are crucial for the development of medicines and ensuring their stability. However, conventional experimental approaches often do not allow for the precise determination of phase transitions and solubility limits, especially for poorly soluble compounds. Purpose: [...] Read more.
Background: The solubility and phase behavior of APIs are crucial for the development of medicines and ensuring their stability. However, conventional experimental approaches often do not allow for the precise determination of phase transitions and solubility limits, especially for poorly soluble compounds. Purpose: The aim of this study was to demonstrate the possibility of using the laser microinterferometry method, traditionally used to define the phase equilibria of polymer systems, to determine the thermodynamic solubility of the APIs. Methods: Using laser microinterferometry, the thermodynamic solubility and phase behavior of amorphous darunavir were determined in various pharmaceutical solvents, including vaseline and olive oils, water, glycerol, alcohols (methanol, ethanol, isopropanol), glycols (propylene glycol, polyethylene glycol 400, polypropylene glycol 425, polyethylene glycol 4000), and ethoxylated polyethylene glycol ether obtained from castor oil in the temperature range of 25–130 °C. Dissolution kinetics was estimated at 25 °C. Hansen solubility parameter calculations were also performed for comparison. Results: Darunavir is practically insoluble in olive and vaseline oils. In water and glycerol, an amorphous equilibrium with an upper critical solution temperature was observed, and phase diagrams were constructed for the first time. In alcohols, glycols, and ethoxylated polyethylene glycol ether obtained from castor oil, darunavir showed high solubility, accompanied by the formation of crystalline solvates. Kinetic evaluation showed that the dissolution rate of darunavir in methanol is four times faster than in ethanol and thirty times faster than in isopropanol. Comparison of the obtained data with previously published and calculated values of solubility parameters demonstrates a good correlation. Conclusions: Laser microinterferometry has been demonstrated as a potential tool for determining the thermodynamic solubility of APIs. This method allows for directly observing the dissolution process, determining the solubility limits, and detecting phase transitions. These studies are necessary for selecting appropriate excipients, preventing the formation of undesirable solvates and predicting formulation stability, which are all critical factors in early-stage drug development and pharmaceutical formulation design. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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11 pages, 1018 KiB  
Article
The Influence of Moisturizer Co-Application Protocols on In Vitro Penetration of Betamethasone in Porcine Skin
by Daiane L. Rost, Geisa N. Barbalho, Jayanaraian F. M. Andrade, Marcilio Cunha-Filho, Guilherme M. Gelfuso and Tais Gratieri
Pharmaceutics 2025, 17(7), 874; https://doi.org/10.3390/pharmaceutics17070874 - 3 Jul 2025
Viewed by 244
Abstract
Background/Objectives: The treatment of atopic dermatitis frequently involves using a topical corticosteroid and a moisturizer. While the sequential application of these products is a common dermatological practice, their influence on drug penetration remains poorly understood. There is no clear evidence on how hydration, [...] Read more.
Background/Objectives: The treatment of atopic dermatitis frequently involves using a topical corticosteroid and a moisturizer. While the sequential application of these products is a common dermatological practice, their influence on drug penetration remains poorly understood. There is no clear evidence on how hydration, application sequence, and massage affect cutaneous drug delivery. Hence, this study aimed to evaluate the effects of formulation type, moisturizer composition, application sequence, and mechanical stimulation on betamethasone dipropionate (BET) cutaneous penetration. Methods: Two commercial formulations (cream and ointment) of BET were evaluated in different experimental conditions, including drug application combined with moisturizers (Cetaphil®, as an emollient; Nivea®, as an occlusive) pre- or post-application, with or without a 30 s massage. In vitro skin penetration assays were conducted for 12 h using porcine skin mounted in modified Franz diffusion cells. BET levels were extracted from the skin layers and quantified by HPLC. Results: The cutaneous BET penetration was strongly influenced by the application sequence, type of moisturizer, and mechanical stimuli. Pre-application of an occlusive or emollient moisturizer, followed by 30 s physical stimuli, significantly enhanced drug retention in the stratum corneum. For the cream, pre-application of moisturizers followed by massage notably increased BET levels in both the stratum corneum and viable skin. Conversely, post-application of moisturizers hindered BET absorption. The ointment showed limited penetration across all conditions, with no drug detected in the viable skin. Conclusions: The results showed pre-hydrating the skin, combined with a 30 s massage, was the best strategy for BET diffusion into the skin following cream administration. The formulation type and the order of application directly influence the effectiveness of drug therapy and the topical absorption of BET. Full article
(This article belongs to the Special Issue Skin Care Products for Healthy and Diseased Skin)
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18 pages, 1061 KiB  
Article
Design of Clofazimine-Loaded Lipid Nanoparticles Using Smart Pharmaceutical Technology Approaches
by Helena Rouco, Nicola Filippo Virzì, Carolina Menéndez-Rodríguez, Carmen Potel, Patricia Diaz-Rodriguez and Mariana Landin
Pharmaceutics 2025, 17(7), 873; https://doi.org/10.3390/pharmaceutics17070873 - 2 Jul 2025
Viewed by 261
Abstract
Background/Objectives: Clofazimine (CFZ) is a versatile antimicrobial active against several bacterial species, although its reduced aqueous solubility and the occurrence of side effects limit its use. Nanostructured lipid carriers (NLCs) constitute an interesting approach to increase drug bioavailability and safety. However, the [...] Read more.
Background/Objectives: Clofazimine (CFZ) is a versatile antimicrobial active against several bacterial species, although its reduced aqueous solubility and the occurrence of side effects limit its use. Nanostructured lipid carriers (NLCs) constitute an interesting approach to increase drug bioavailability and safety. However, the development of nanoparticle-based formulations is challenging. In the present work, a combination of smart pharmaceutical technology approaches was proposed to develop CFZ-loaded NLCs, taking advantage of previous knowledge on NLCs screening. Methods: A design space previously established using Artificial Intelligence (AI) tools was applied to develop CFZ-loaded NLC formulations. After formulation characterization, Neurofuzzy Logic (NFL) and in silico docking simulations were employed to enhance the understanding of lipid nanocarriers. Then, the performance of formulations designed following NFL guidelines was characterized in terms of biocompatibility, using murine fibroblasts, and antimicrobial activity against several strains of Staphylococcus aureus. Results: The followed approach enabled CFZ-loaded NLC formulations with optimal properties, including small size and high antimicrobial payload. NFL was useful to investigate the existing interactions between NLC components and homogenization conditions, that influence CFZ-loaded NLCs’ final properties. Also, in silico docking simulations were successfully applied to examine interactions and affinity between the drug and the lipid matrix components. Finally, the designed CFZ-loaded formulations demonstrated suitable biocompatibility, together with antimicrobial activity. Conclusions: The implementation of smart strategies during nanoparticle-based therapeutics development, such as those described in this manuscript, would enable the more efficient design of new systems for suitable antimicrobial delivery. Full article
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