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Pharmaceutics
Volume 17
Issue 12
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Pharmaceutics, Volume 17, Issue 12 (December 2025) – 125 articles

Cover Story (view full-size image): Ophthalmic drug delivery faces major anatomical and physiological barriers, necessitating the development of novel drug delivery systems. This review highlights nanoemulsions, microemulsions, self-emulsifying drug delivery systems including self-nano emulsifying drug delivery systems and self-micro emulsifying drug delivery systems, emulgels, and in situ-forming emulgels as emerging platforms that improve ocular retention, stability, permeability, bioavailability, and ultimately therapeutic activity. It covers ocular diseases, limitations of conventional formulations, mechanisms of enhanced permeation by emulsion systems, formulation and optimization strategies, characterization, recent patents, clinical trials, marketed products, and future prospects of these systems for ocular diseases. View this paper
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30 pages, 2306 KB  
Review
Silymarin and Silybin: Rejuvenating Traditional Remedies with Modern Delivery Strategies
by Xiuyan Li, Han Zhu, Yanhong Wang, Xiwu Zhang, Zhixin Yang, Xueying Yan and Qin Yu
Pharmaceutics 2025, 17(12), 1628; https://doi.org/10.3390/pharmaceutics17121628 - 18 Dec 2025
Viewed by 461
Abstract
Silymarin, a polyphenolic flavonolignan complex extracted from Silybum marianum (milk thistle), has long been recognized for its hepatoprotective, antioxidant, anti-inflammatory, and anticancer properties. Among its constituents, silybin is the most pharmacologically active and has been extensively studied in both preclinical and clinical settings. [...] Read more.
Silymarin, a polyphenolic flavonolignan complex extracted from Silybum marianum (milk thistle), has long been recognized for its hepatoprotective, antioxidant, anti-inflammatory, and anticancer properties. Among its constituents, silybin is the most pharmacologically active and has been extensively studied in both preclinical and clinical settings. However, the clinical application of silymarin-based therapies remains limited by poor aqueous solubility, low oral bioavailability, rapid metabolism, and physicochemical instability. This review systematically outlines the pharmacokinetic challenges of silymarin and highlights recent advancements in formulation strategies designed to overcome these barriers. Key innovations include nanotechnology-enabled delivery systems, lipid-based carriers, water-soluble derivatives, bioavailability enhancers, parenteral and transdermal formulations, as well as controlled and synchronous release technologies. These approaches significantly improve tissue targeting, intracellular uptake, and pharmacological efficacy. Additionally, this review evaluates currently marketed silymarin formulations and recent clinical/preclinical evidence, revealing a persistent gap between laboratory advances and commercially available products. By synthesizing the mechanistic, regulatory, and manufacturability barriers that hinder translation, we delineate the key challenges that must be addressed to enable clinically deployable next-generation silymarin products. Collectively, these insights illustrate a paradigm shift in the modernization of phytomedicine, positioning silymarin as a model compound for the transformation of traditional herbal remedies into precision therapeutics through interdisciplinary drug delivery innovations. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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18 pages, 1520 KB  
Article
Selection of Solubility Enhancement Technologies for S-892216, a Novel COVID-19 Drug Candidate
by Ryo Ohashi, Shuichi Otake, Tatsuhiko Murata, Ryosuke Watari, Shinpei Yoshida, Mikiko Kitade, Daisuke Kondo and Go Kimura
Pharmaceutics 2025, 17(12), 1627; https://doi.org/10.3390/pharmaceutics17121627 - 18 Dec 2025
Viewed by 390
Abstract
Background/Objectives: S-892216 is a poorly water-soluble drug developed as a novel oral treatment for COVID-19, although its oral absorption is low. For Phase 1 (Ph1) studies and commercial use, both oral solution and solid dispersion technologies are evaluated to enhance drug solubility. [...] Read more.
Background/Objectives: S-892216 is a poorly water-soluble drug developed as a novel oral treatment for COVID-19, although its oral absorption is low. For Phase 1 (Ph1) studies and commercial use, both oral solution and solid dispersion technologies are evaluated to enhance drug solubility. Methods: The solubility enhancement technology was selected by considering physicochemical factors such as stability and oral absorption, along with patient and customer acceptability. Results: Pharmacokinetics study in rats revealed that both the polyethylene glycol 400 oral solution and polyvinylpyrrolidone-vinyl acetate (PVPVA) amorphous solid dispersion powder suspension showed almost 100% oral bioavailability. Therefore, they can be proposed as clinical formulations for Ph1 studies. PVPVA solid dispersion tablets were developed as a to-be-marketed formulation showed higher bioavailability in dogs than the anhydrous crystal formulation. Additionally, the stability of the developed solid dispersion tablet was acceptable. Conclusions: This study demonstrates that multiple solubility enhancement technologies can be adopted for S-892216 development, and amorphous solid dispersion technology was selected for commercialization. Full article
(This article belongs to the Special Issue Technology and Preparation of Solid Dispersion for the Enhancement of Oral Bioavailability)
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22 pages, 4131 KB  
Article
Transcriptome-Guided Drug Repurposing Identifies Homoharringtonine (HHT) as a Candidate for Radiation-Induced Pulmonary Fibrosis
by Mohamed El-Agamy Farh, Sang Yeon Kim, Sunjoo Park, Cui Ronglan, InSuk Sohn and Jaeho Cho
Pharmaceutics 2025, 17(12), 1626; https://doi.org/10.3390/pharmaceutics17121626 - 18 Dec 2025
Viewed by 395
Abstract
Background: Radiation-induced pulmonary fibrosis (RPF) remains a major burden of successful lung cancer radiotherapy. Clinically validated drugs targeting RPF remains scarce. Methods: We employed a transcriptome-based drug repurposing approach using REMEDY, a computational platform built on the Library of Integrated Network-Based Cellular Signatures [...] Read more.
Background: Radiation-induced pulmonary fibrosis (RPF) remains a major burden of successful lung cancer radiotherapy. Clinically validated drugs targeting RPF remains scarce. Methods: We employed a transcriptome-based drug repurposing approach using REMEDY, a computational platform built on the Library of Integrated Network-Based Cellular Signatures (LINCS). Differentially expressed genes (DEGs) derived from radiation-induced lung injury (RILI) models were used as a query to identify compounds capable of reversing pro-fibrotic expression profile. Among top-ranked candidates, homoharringtonine (HHT), an FDA-approved protein synthesis inhibitor, was selected for experimental validation. Anti-fibrotic effects of HHT were assessed using an optimized in vitro fibrotic model based on activation of MRC-5 human lung fibroblasts. Complementary in silico molecular docking analyses were also conducted to explore the mechanistic basis of HHT’s actions. This represents the first transcriptome-guided, LINCS-based drug repurposing study applied specifically to radiation-induced pulmonary fibrosis, utilizing RPF-derived molecular signatures rather than general fibrosis-related datasets. Results: HHT significantly attenuated key fibrotic phenotypes, including fibroblast proliferation, myofibroblast differentiation, and extracellular matrix (ECM) production. Notably, HHT suppressed expression of cyclin D1 and α-smooth muscle actin (α-SMA), and reduced collagen deposition. Mechanistic investigations revealed that HHT modulates two pro-fibrotic pathways: RhoA/ROCK and Wnt/β-catenin signaling. Molecular docking further suggested that HHT may directly interact with fibrosis-related receptors such as integrins and Frizzled, providing structural insight into its anti-fibrotic potential. These findings underscore the novelty of reassigning HHT to a radiation-specific fibrotic context using a signature-reversal strategy uniquely tailored to RPF biology. Conclusions: Our findings identify HHT as a promising treatment of RPF, offering a dual mechanism of action—interruption of protein synthesis and targeted inhibition of fibrotic signaling pathways. This study highlights the value of computational drug repurposing platforms for accelerating therapeutic discovery. Further preclinical investigations are warranted to evaluate HHT’s in vivo efficacy and clinical applicability in RPF. Full article
(This article belongs to the Section Drug Targeting and Design)
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2 pages, 133 KB  
Correction
Correction: Ortiz-Islas et al. Evolution of Alzheimer’s Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy. Pharmaceutics 2025, 17, 128
by Emma Ortiz-Islas, Pedro Montes, Citlali Ekaterina Rodríguez-Pérez, Elizabeth Ruiz-Sánchez, Talía Sánchez-Barbosa, Diego Pichardo-Rojas, Cecilia Zavala-Tecuapetla, Karla Carvajal-Aguilera and Victoria Campos-Peña
Pharmaceutics 2025, 17(12), 1625; https://doi.org/10.3390/pharmaceutics17121625 - 18 Dec 2025
Viewed by 234
Abstract
References [...] Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
2 pages, 137 KB  
Retraction
RETRACTED: Khan et al. Norfloxacin Loaded Lipid Polymer Hybrid Nanoparticles for Oral Administration: Fabrication, Characterization, In Silico Modelling and Toxicity Evaluation. Pharmaceutics 2021, 13, 1632
by Muhammad Asghar Khan, Shahzeb Khan, Mohsin Kazi, Sultan M. Alshehri, Muhammad Shahid, Shafi Ullah Khan, Zahid Hussain, Muhammad Sohail, Muhammad Shafique, Hajra Afeera Hamid, Mahwish Kamran, Abdelbary Elhissi, Muhammad Wasim and Hnin Ei Thu
Pharmaceutics 2025, 17(12), 1624; https://doi.org/10.3390/pharmaceutics17121624 - 18 Dec 2025
Viewed by 302
Abstract
The journal retracts the article “Norfloxacin Loaded Lipid Polymer Hybrid Nanoparticles for Oral Administration: Fabrication, Characterization, In Silico Modelling and Toxicity Evaluation” [...] Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
19 pages, 4311 KB  
Article
Nitric Oxide-Releasing S-Nitrosoglutathione-Conjugated TEMPO-Oxidized Nanocellulose Hydrogel for the Treatment of MRSA-Infected Wounds
by Dongmin Kwak, Chavi Dagar, Jihyun Kim, Juho Lee, Hyunwoo Kim, Muneeb Ullah, Md. Lukman Hakim, Minjeong Kim, Mst. Sanzida Yeasmin, Ng’wisho Nyalali and Jin-Wook Yoo
Pharmaceutics 2025, 17(12), 1623; https://doi.org/10.3390/pharmaceutics17121623 - 17 Dec 2025
Viewed by 373
Abstract
Background: Cutaneous wound infections caused by methicillin-resistant Staphylococcus aureus (MRSA) pose serious threats to public health. Nitric oxide (NO), an endogenous gaseous molecule with antibacterial and wound-healing properties, is a promising next-generation antimicrobial agent with a minimal risk of resistance. However, conventional [...] Read more.
Background: Cutaneous wound infections caused by methicillin-resistant Staphylococcus aureus (MRSA) pose serious threats to public health. Nitric oxide (NO), an endogenous gaseous molecule with antibacterial and wound-healing properties, is a promising next-generation antimicrobial agent with a minimal risk of resistance. However, conventional S-nitrosoglutathione (GSNO)-loaded formulations suffer from GSNO leakage, which could compromise the treatment effect or induce systemic side effects. Although conjugation strategies have been introduced to mitigate this issue, there is still a lack of GSNO-conjugated systems that simultaneously achieve high NO loading and sustained NO release while avoiding harsh external stimuli and complex multistep synthetic processes. Objectives: This research aims to develop a high NO-loading system produced through a simple synthetic process that provides sustained NO release without harsh external stimuli while preventing GSNO leakage for effective treatment of MRSA-infected wounds. Methods: We developed cellulose-based GSNO conjugates via a simple EDC/NHS-mediated covalent coupling to TEMPO-oxidized nanocellulose (NC-GSNO). Results: The NC-GSNO hydrogel achieved high NO loading, minimal leakage, and sustained NO release for more than three days. This controlled NO delivery promoted enhanced wound healing in MRSA-infected models. Conclusions: These findings demonstrate that the NC-GSNO hydrogel is a promising platform for controlled NO delivery and the effective treatment of MRSA-infected wounds. Full article
(This article belongs to the Special Issue Hydrogels-Based Drug Delivery System for Wound Healing)
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28 pages, 2932 KB  
Review
Chitosan Sponges as Next-Generation Biomaterials for Dental Tissue Engineering and Periodontal Regeneration
by Magdalena Paczkowska-Walendowska, Maciej Kulawik, Jakub Kwiatek, Dimitrios Bikiaris and Judyta Cielecka-Piontek
Pharmaceutics 2025, 17(12), 1622; https://doi.org/10.3390/pharmaceutics17121622 - 17 Dec 2025
Viewed by 413
Abstract
Chitosan, a naturally derived polysaccharide obtained by chitin deacetylation, has attracted considerable attention in dentistry as a multifunctional biomaterial owing to its excellent biocompatibility, biodegradability, and tunable physicochemical properties. This narrative review provides an up-to-date overview of the use of chitosan-based sponges in [...] Read more.
Chitosan, a naturally derived polysaccharide obtained by chitin deacetylation, has attracted considerable attention in dentistry as a multifunctional biomaterial owing to its excellent biocompatibility, biodegradability, and tunable physicochemical properties. This narrative review provides an up-to-date overview of the use of chitosan-based sponges in dental tissue engineering, bone regeneration, post-extraction wound management, and periodontal therapy. Chitosan sponges, characterized by high porosity, flexibility, and superior absorbency, serve as effective wound dressings, drug delivery carriers, and scaffolds that promote cell proliferation and tissue regeneration. Their intrinsic antibacterial, antifungal, hemostatic, and immunomodulatory properties further enhance their therapeutic value in managing complex oral conditions. In periodontal treatment, they enable localized drug delivery and support soft and hard tissue healing, while in post-extraction care, they aid hemostasis and reduce complications such as alveolar osteitis. Moreover, their osteoconductive and osteoinductive potential positions them as promising materials for alveolar bone repair and implantology. Chemical modification of chitosan and the incorporation of bioactive compounds allow customization of sponge formulations to meet specific clinical needs. Despite encouraging preclinical findings, challenges remain due to variability in chitosan sources, differences in the degree of deacetylation, and limited clinical validation. This review highlights the potential of chitosan sponges as innovative tools in regenerative dentistry and underscores the need for further standardization, mechanistic studies, and long-term clinical trials to ensure their safe and effective translation into dental practice. Moreover, the broad clinical applications of chitosan sponges beyond dentistry confirm their potential as a universal biomaterial platform in regenerative medicine. Full article
(This article belongs to the Special Issue Biomaterials for Oral and Dental Drug Delivery)
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20 pages, 4255 KB  
Article
Hydroxypropyl Methylcellulose Capsules Enhance Aerodynamic Performance of Carrier-Based Dry Powder Inhaler Formulations: A Comprehensive Evaluation of Capsule Material Effects
by Camille Dumont, Sandrine Picco, Beatriz Noriega-Fernandes, Pierre Verlhac, Andrea Elena Cortez, Camille Boulet, Molly Gallagher, Christopher Bock and Vincent Jannin
Pharmaceutics 2025, 17(12), 1621; https://doi.org/10.3390/pharmaceutics17121621 - 17 Dec 2025
Viewed by 505
Abstract
Background/Objectives: This study aims to investigate the underexplored impact of capsule type on the performances of capsule-based dry powder inhalers (cDPIs). It compares specific properties of hard gelatin-based capsules (Hard Gelatin Capsules (HGC), HGC including polyethylene glycol (HGC + PEG)) and hypromellose-based [...] Read more.
Background/Objectives: This study aims to investigate the underexplored impact of capsule type on the performances of capsule-based dry powder inhalers (cDPIs). It compares specific properties of hard gelatin-based capsules (Hard Gelatin Capsules (HGC), HGC including polyethylene glycol (HGC + PEG)) and hypromellose-based capsules, (Zephyr® Vcaps® (VC), Zephyr® Vcaps® Plus (VCP) and Vcaps® Plus Zephyr Inhance™ (VCP-I)) with aerosolization performances of model carrier-based formulation, providing insights into their impact on pulmonary drug delivery efficacy. Methods: Aerosolization properties of a model phenytoin/lactose blend formulation filled in the different capsules was evaluated using a Next Generation Impactor (NGI) with RS01 device. Capsule shell characteristics were evaluated in terms of water activity, static charges, and inner surface aspect and roughness. Results: Hypromellose-based capsules, especially VC and VCP-I, exhibited significantly higher drug delivery performances compared to gelatin-based capsules. In particular, VCP-I demonstrated good results with excellent batch-to-batch reproducibility and 51% of the nominal dose available for lung absorption. Although capsule inner surface showed clear differences between both polymer families, no clear correlation could be found between cDPI performances and capsule roughness and density of charge. All capsules presented good mechanical properties in the conditions of the tests. Conclusions: Capsule type exerts a significant impact on cDPI performances. These findings highlight the importance of capsule selection as a critical material attribute in the design and optimization of inhalation products. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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5 pages, 1628 KB  
Editorial
Nanotechnology-Enabled Combination Therapies and Diagnostic Innovation: An Integrative Overview of Recent Advances
by Renato Sonchini Gonçalves
Pharmaceutics 2025, 17(12), 1620; https://doi.org/10.3390/pharmaceutics17121620 - 17 Dec 2025
Viewed by 320
Abstract
Noncommunicable diseases (NCDs) and other high-impact health challenges continue to impose a substantial and persistent burden on global public health [...] Full article
(This article belongs to the Special Issue Advanced Nanotechnology for Combination Therapy and Diagnosis)
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23 pages, 2256 KB  
Systematic Review
Systematic Review and Meta-Analysis of Treatments on Melasma Area Severity Index and Quality of Life
by Milena Mariano Ribeiro, Ana Cleia Cardoso da Silva, Heloise Dalagrana, Maria Eduarda A. Galiciolli, Ana Carolina Irioda, Quelen Iane Garlet and Cláudia Sirlene Oliveira
Pharmaceutics 2025, 17(12), 1619; https://doi.org/10.3390/pharmaceutics17121619 - 16 Dec 2025
Viewed by 542
Abstract
Background: Melasma is a chronic skin condition resulting from increased melanogenic activity, which induces a significant emotional impact on the patient’s quality of life. The efficacy of melasma treatments depends on individual response and on the chosen therapeutic approach, which may include topical [...] Read more.
Background: Melasma is a chronic skin condition resulting from increased melanogenic activity, which induces a significant emotional impact on the patient’s quality of life. The efficacy of melasma treatments depends on individual response and on the chosen therapeutic approach, which may include topical skin-lightening agents, oral drugs, and chemical peels. Objectives: We aimed to evaluate the reported efficacy of treatment techniques on melasma control and patients’ quality of life through a systematic review and meta-analysis, as well as to investigate a putative relationship between melasma severity and quality of life. Methods: Following PRISMA guidelines, we collected data from PubMed, Scopus, and Embase databases. The eligibility criteria included studies that analyzed the quality of life through the Melasma Quality of Life (MELASQoL) scale from populations of patients suffering from melasma, scored by the Melasma Area Severity Index (MASI). Results: We retrieved 1296 records; those that did not meet the eligibility criteria and duplicates were excluded, resulting in 41 papers that underwent qualitative analysis (information synthesis), from which 23 papers containing 34 studies were included in the meta-analysis. The meta-analysis revealed a decrease in both MASI and MELASQoL scores following oral or topical treatment, as well as the chemical peeling procedure. Spearman correlation test showed a mild positive relationship between MASI and MELASQoL scores. Conclusions: This study provides evidence supporting oral and topical pharmacological treatments, as well as chemical peels, as effective interventions for melasma management. Despite high heterogeneity among studies and methodological limitations, all treatment modalities analyzed improved patients’ quality of life. Full article
(This article belongs to the Special Issue Skin Care Products for Healthy and Diseased Skin)
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23 pages, 9113 KB  
Article
A Biomimetic Macrophage-Membrane-Fused Liposomal System Loaded with GVs-HV Recombinant Plasmid for Targeted Anti-Atherosclerosis Therapy
by Yuelin Zhang, Wenting Gu, Kailing Yu, Qihong Chen, Hong Wang, Yinghui Wei, Hangsheng Zheng, Hongyue Zheng, Lin Liu and Fanzhu Li
Pharmaceutics 2025, 17(12), 1618; https://doi.org/10.3390/pharmaceutics17121618 - 16 Dec 2025
Viewed by 393
Abstract
Background: Cardiovascular disease is one of the leading causes of death worldwide. The presence of atherosclerotic plaques in the arteries leads to continuous growth and obstruction of blood vessels, which ultimately leads to acute myocardial infarction and sudden cardiac death. Ultrasound-triggered GVs cavitation [...] Read more.
Background: Cardiovascular disease is one of the leading causes of death worldwide. The presence of atherosclerotic plaques in the arteries leads to continuous growth and obstruction of blood vessels, which ultimately leads to acute myocardial infarction and sudden cardiac death. Ultrasound-triggered GVs cavitation has great potential in plaque treatment due to its noninvasive nature and safety. Methods: In this work, we constructed a Hirudin–Gas Vesicle Recombinant Plasmid to achieve gene delivery using macrophage membrane/lipid membrane fusion bio-vesicles. Results: The bio-fusion vesicles retained the macrophage membrane protein integrin α4β1 to combine with vascular adhesion molecules highly expressed by inflammatory cells to achieve delivery; the Hirudin–Gas Vesicle Recombinant Plasmid could escape lysosomes and enter the nucleus to achieve highly efficient transfection; Hirudin and Gas Vesicles are exocytosed through cleavage peptide and exocytosis peptide, respectively; their pharmacological effects are linked and complementary. Gas vesicles can break up lesion plates with the assistance of in vitro ultrasound, and Hirudin achieves fragment ablation and anti-inflammatory and lipid regulation. Conclusions: GVs-HV@MM-Lipo exerts potent anti-atherosclerotic and anti-inflammatory effects with favorable safety. GVs-HV@Lipo reduces mice aortic arch plaque area by 17%, while GVs-HV@MM-Lipo+US achieves further plaque regression and improved hemodynamics. Our work opens up a new paradigm in the treatment of atherosclerosis with Chinese medicine. Full article
(This article belongs to the Special Issue Biocompatible Liposomes for Drug Delivery: Materials and Applications)
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40 pages, 2651 KB  
Review
Redefining the Limits of Nanodevices-Based Drug Delivery Systems: Extracellular Vesicles
by Marina Lucia Díaz, Victoria Simón, Luciano Alejandro Benedini and Paula Verónica Messina
Pharmaceutics 2025, 17(12), 1617; https://doi.org/10.3390/pharmaceutics17121617 - 16 Dec 2025
Viewed by 454
Abstract
Extracellular vesicles (EVs) are naturally occurring cell-derived vesicles that contain the same nucleic acids, proteins, and lipids as their source cells. These nano-sized systems, which are derived from a wide range of cell types within an organism and are present in all body [...] Read more.
Extracellular vesicles (EVs) are naturally occurring cell-derived vesicles that contain the same nucleic acids, proteins, and lipids as their source cells. These nano-sized systems, which are derived from a wide range of cell types within an organism and are present in all body fluids. EVs play a crucial role both in health and disease, particularly in cancer and neurodegenerative disorders. Due to their particular structure, they can function as natural carriers for therapeutic agents and drugs, akin to synthetic liposomes. EVs exhibit numerous advantages over conventional synthetic nanocarriers and other lipid-based delivery systems, including their favorable biocompatibility, natural blood–brain barrier penetration, and capacity for gene delivery. However, EVs’ complex characterization and standardization, as well as being more expensive than other vesicular systems, are major drawbacks that need to be addressed before drug loading. The present review introduces the classification of EVs and their physiological roles, currently popular methods for isolating and purifying EVs, the main therapeutic approaches of EV-mediated drug delivery, and the functionalization of EVs as carriers. Consequently, it establishes novel pathways for advancing EV-based therapeutic methodologies across diverse medical disciplines. The study concludes with a discussion of the new challenges and future perspectives related to the clinical application of EVs. Full article
(This article belongs to the Special Issue Biomimetic Nanoparticles for Disease Treatment and Diagnosis)
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19 pages, 2932 KB  
Article
PEGylated Terpesome-Loaded 3D-Printed Aripiprazole Ocuserts for the Treatment of Ocular Candidiasis
by Rofida Albash, Mariam Hassan, Ahmed M. Agiba, Wessam H. Abd-Elsalam, Diana Aziz, Youssef R. Hassan, Amira B. Kassem, Asmaa Saleh and Moaz A. Eltabeeb
Pharmaceutics 2025, 17(12), 1616; https://doi.org/10.3390/pharmaceutics17121616 - 16 Dec 2025
Viewed by 415
Abstract
Background/Objectives: This study aimed to repurpose aripiprazole (AR), an antipsychotic clinically approved by the FDA, as a novel antifungal drug and to potentiate its therapeutic efficacy through PEGylated terpesomes (PEG-TERs). Methods: PEG-TERs were prepared by thin-film hydration and optimized using a central composite [...] Read more.
Background/Objectives: This study aimed to repurpose aripiprazole (AR), an antipsychotic clinically approved by the FDA, as a novel antifungal drug and to potentiate its therapeutic efficacy through PEGylated terpesomes (PEG-TERs). Methods: PEG-TERs were prepared by thin-film hydration and optimized using a central composite design. The optimum PEG-TER formulation was characterized for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP), and subsequently integrated into polylactic acid (PLA)-based 3D-printed ocuserts. Results: The optimized formulation exhibited spherical vesicles with high EE%, nanoscale PS, narrow PDI, and favorable ZP, alongside excellent stability and mucoadhesive properties. Ex vivo permeation demonstrated a sustained release profile of AR from PEG-TERs compared with an AR suspension, while confocal microscopy confirmed efficient corneal deposition of fluorescein-labeled PEG-TERs. In vivo, the optimum AR-loaded PEG-TERs ocusert exhibited a substantial therapeutic effect in a rabbit model of Candida albicans keratitis, while histopathological assessment confirmed its ocular safety and biocompatibility. Conclusions: In conclusion, AR-loaded PEG-TERs embedded in PLA-based 3D-printed ocuserts represent a promising, safe, and innovative therapeutic platform for the management of Candida albicans-induced corneal infections, offering both drug repurposing and emerging opportunities in advanced ocular drug delivery. Full article
(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation, 2nd Edition)
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3 pages, 8763 KB  
Correction
Correction: Chen et al. Neutrophil-Camouflaged Stealth Liposomes for Photothermal-Induced Tumor Immunotherapy Through Intratumoral Bacterial Activation. Pharmaceutics 2025, 17, 614
by Xinxin Chen, Jiang Sun, Tingxian Ye and Fanzhu Li
Pharmaceutics 2025, 17(12), 1615; https://doi.org/10.3390/pharmaceutics17121615 - 16 Dec 2025
Viewed by 234
Abstract
Error in Figure [...] Full article
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41 pages, 2242 KB  
Article
Synthesis and Characterization of Triphenyl Phosphonium-Modified Triterpenoids with Never Reported Antibacterial Effects Against Clinically Relevant Gram-Positive Superbugs
by Dafni Graikioti, Constantinos M. Athanassopoulos, Anna Maria Schito and Silvana Alfei
Pharmaceutics 2025, 17(12), 1614; https://doi.org/10.3390/pharmaceutics17121614 - 16 Dec 2025
Viewed by 359
Abstract
Background: To meet the urgent need for novel antibacterial agents that are active also against worrying superbugs, natural pentacyclic triterpenoids, including totally inactive betulin (BET) and betulinic acid (BA), as well as ursolic acid (UA), active on Gram-positive bacteria, have been chemically [...] Read more.
Background: To meet the urgent need for novel antibacterial agents that are active also against worrying superbugs, natural pentacyclic triterpenoids, including totally inactive betulin (BET) and betulinic acid (BA), as well as ursolic acid (UA), active on Gram-positive bacteria, have been chemically modified, achieving compounds 1–7. Methods: Triterpenoid derivatives 1–7 and all synthetic intermediates were characterized by chemometric-assisted FTIR and NMR spectroscopy, as well as by other analytical techniques, which confirmed their structure and high purity. Minimum inhibitory concentration values (MICs) of 1–7, BET, BA and UA were determined by the broth dilution method, using a selection of Gram-positive and Gram-negative clinically isolated superbugs. Results: Performed experiments evidenced that compounds 4–7 had potent antibacterial effects against Gram-positive methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE), as well as against vancomycin-resistant Enterococcus faecalis and E. faecium (VRE). The antibacterial effects of 4–7 were due to the insertion of a triphenyl phosphonium (TPP) group and were higher than those reported so far for other BET, BA and UA derivatives, especially considering the complex pattern of resistance of the isolates used here and their clinical source. Conclusions: For the first time, by inserting TPP, a real activity (MICs 2–16 µg/mL) was conferred to inactive BET and BA (MICs > 1024 and 256 µg/mL). Moreover, the antibacterial effects of UA were improved 16- and 32-fold against MRSE and MRSA (MICs = 2 vs. 32 and 64 μg/mL). Future Perspectives: Based on these very promising microbiologic results, new experiments are currently underway with the best-performing compounds 5 and 7 (MICs = 2 μg/mL) on an enlarged number of Gram-positive isolates, to confirm their MICs. Moreover, investigations about their possible antibiofilm activity, time-killing curves and cytotoxicity on eukaryotic cells will be carried out to define their pharmacological behavior and clinical potential. Full article
(This article belongs to the Special Issue Natural Products with Antimicrobial Activity and Their Pharmaceutical Delivery Systems)
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33 pages, 1373 KB  
Review
PLGA-Based Co-Delivery Nanoformulations: Overview, Strategies, and Recent Advances
by Magdalena M. Stevanović, Kun Qian, Lin Huang and Marija Vukomanović
Pharmaceutics 2025, 17(12), 1613; https://doi.org/10.3390/pharmaceutics17121613 - 15 Dec 2025
Viewed by 558
Abstract
Poly (lactic-co-glycolic acid) (PLGA) is a widely used copolymer with applications across medical, pharmaceutical, and other industrial fields. Its biodegradability and biocompatibility make it one of the most versatile polymers for nanoscale drug delivery. The present review addresses current knowledge and recent advances [...] Read more.
Poly (lactic-co-glycolic acid) (PLGA) is a widely used copolymer with applications across medical, pharmaceutical, and other industrial fields. Its biodegradability and biocompatibility make it one of the most versatile polymers for nanoscale drug delivery. The present review addresses current knowledge and recent advances in PLGA-based co-delivery nanoformulations with a special reference to design strategies, functional mechanisms, and translational potential. Conventional and advanced fabrication methods, the structural design of PLGA-based nanocarriers, approaches to scale-up and reproducibility, classification of co-delivery types, mechanisms governing drug release, surface modification and functionalization are all discussed. Special attention is given to PLGA-based co-delivery systems, encompassing drug–drug, drug–gene, gene–gene and multi-modal combinations, supported by recent studies demonstrating synergistic therapeutic outcomes. The review also examines clinical translation efforts and the regulatory landscape for PLGA-based nanocarriers. Unlike most existing reviews that typically focus either on PLGA fundamentals or on co-delivery approaches in isolation, this article bridges these domains by providing an integrated, comparative analysis of PLGA-based co-delivery systems and elucidating a critical gap in linking design strategies with translational requirements. In addition, by emphasising the relevance of PLGA-based co-delivery for combination therapies, particularly in cancer and other complex diseases, the review highlights the strong clinical and translational potential of these platforms. Key challenges, such as reproducibility, large-scale manufacturing, and complex regulatory pathways, are discussed alongside emerging trends and future perspectives. Taken together, this review positions PLGA-based co-delivery strategies as a critical driver for advancing precision therapeutics and shaping the future landscape of nanomedicine. Full article
(This article belongs to the Special Issue Biocompatible Polymers: Fascinating Materials for Drug Delivery Applications)
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28 pages, 5006 KB  
Article
Gold-Doped Hybrid Nanoparticles: A Versatile Tool for Multimodal Imaging of Cell Trafficking
by Andrea Bezze, Jessica Ponti, Deborah Stanco, Carlotta Mattioda and Clara Mattu
Pharmaceutics 2025, 17(12), 1612; https://doi.org/10.3390/pharmaceutics17121612 - 15 Dec 2025
Viewed by 604
Abstract
Background: Nanomedicine has demonstrated great potential to improve drug delivery across various diseases. However, accurately monitoring the real-time trafficking of organic nanoparticles (NPs) within biological systems remains a significant challenge. Current detection methods rely heavily on fluorescence, while high-resolution, label-free imaging is often [...] Read more.
Background: Nanomedicine has demonstrated great potential to improve drug delivery across various diseases. However, accurately monitoring the real-time trafficking of organic nanoparticles (NPs) within biological systems remains a significant challenge. Current detection methods rely heavily on fluorescence, while high-resolution, label-free imaging is often precluded by the limited optical contrast of organic materials, limiting a comprehensive understanding of NP fate. Metallic doping allows simultaneous detection of carriers using multiple imaging and analysis techniques. This study presents a novel approach to prepare gold-doped hybrid NPs compatible with multimodal imaging, thus facilitating multimodal tracking. Methods: Gold-doped NPs were successfully synthesized via nanoprecipitation, yielding stable, monodisperse carriers with optimal size, confirmed by Dynamic Light Scattering and Nanoparticle Tracking Analysis. UV/Vis spectroscopy confirmed effective gold-doping, with doping efficiency of approximately 50%. Transmission Electron Microscopy (TEM) showed gold NP accumulation throughout the polymer core and near the lipid shell. Results: Although gold doping resulted in a slight increase in NP size and zeta potential, no effects on cytocompatibility or cellular uptake by glioblastoma and microglia cells were observed. Furthermore, the optical properties (i.e., the refractive index and the UV spectrum) of the NPs were successfully modified to enable tracking across complementary imaging modalities. Real-time, label-free visualization of NP accumulation in the cytoplasm of U87 cells was achieved via holotomography by exploiting the enhanced refractive index after gold-doping. This observation was confirmed through correlation with fluorescence confocal microscopy, using fluorescently labelled gold-doped NPs. Furthermore, the high electron density of the gold tracer facilitated the precise localization of NPs within intracellular compartments via TEM, bypassing the inherently low contrast of organic NPs. Conclusions: These findings validated the gold-doped NPs as versatile nanoplatforms for multimodal imaging, showcasing their potential for non-invasive, high-resolution tracking and more accurate quantification of intracellular accumulation using diverse analytical techniques. Full article
(This article belongs to the Special Issue Selected Papers from the European Society of Biomaterials 2025 Congress (ESB 2025))
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29 pages, 25356 KB  
Article
Improving the Culture of Human Skin Explants for Use in Preclinical Testing of Wound Healing Treatments
by Xiao Guo, Martina Hüging, Ursula Mirastschijski, Ulrike Blume-Peytavi, Annika Vogt, Christoph Schaudinn and Fiorenza Rancan
Pharmaceutics 2025, 17(12), 1611; https://doi.org/10.3390/pharmaceutics17121611 - 15 Dec 2025
Viewed by 360
Abstract
Background: Cultured human skin explants provide preclinical models to investigate drug delivery and the efficacy of topical treatments for wound healing. However, different culture conditions may affect cell viability, proliferation, and even wound healing. Since animal-derived supplements can influence the investigation of human [...] Read more.
Background: Cultured human skin explants provide preclinical models to investigate drug delivery and the efficacy of topical treatments for wound healing. However, different culture conditions may affect cell viability, proliferation, and even wound healing. Since animal-derived supplements can influence the investigation of human physiological responses, this study evaluated the effects of non-animal supplements on the ex vivo wound healing process to improve the use of this model for preclinical drug efficacy tests. Methods: In in vitro scratch assays using HaCaT cells and fibroblasts, for media supplemented with normal human serum (NHS), oxygen carriers (OCs) had a positive impact on cell migration, supporting the further evaluation in ex vivo skin culture models. Human skin explants with standardized superficial wounds were cultured in four supplemented media: (i) Dulbecco’s Modified Eagle Medium High Glucose (DMEM) with fetal calf serum (FCS), (ii) DMEM with NHS and OC, (iii) CnT-PrimeTM with NHS and OC, and (iv) EpiLife™ with NHS and an OC. Results: During the 12-day culture, we observed re-epithelialization in all groups with the exception of EpiLife + NHS + OC (with no Ca++ supplement). For these samples, starting from day 6, we noticed a loosening of the dermal–epidermal junction and disruption of the upper epidermal layer. Furthermore, an immunohistochemical analysis of extracellular matrix components and remodeling factors, including type I and III collagen, transforming growth factor-β2, and matrix metalloproteinase-9, provided insights into tissue repair dynamics. Conclusions: NHS plus OC is comparable to FCS supplementation and represents a more physiological and ethical alternative. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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15 pages, 7552 KB  
Article
Augmented Wound-Healing Effect of Sodium Thiosulfate-Infused Cosmetic Creams in Frostbite
by George J. Dugbartey, Liam McFarlane, Tamara S. Ortas, Sally Major, Aaron Haig and Alp Sener
Pharmaceutics 2025, 17(12), 1610; https://doi.org/10.3390/pharmaceutics17121610 - 15 Dec 2025
Viewed by 409
Abstract
Background: Frostbite injury is a thermal injury where ice crystals form in skin tissues and subsequently lead to damage due to prolonged exposure to cold temperatures below 0 °C. The extremities are mostly affected, leading to potential amputation. As there is no pharmacological [...] Read more.
Background: Frostbite injury is a thermal injury where ice crystals form in skin tissues and subsequently lead to damage due to prolonged exposure to cold temperatures below 0 °C. The extremities are mostly affected, leading to potential amputation. As there is no pharmacological treatment of frostbite injury, we recently reported that non-clinically viable hydrogen sulfide (H2S) donors promote frostbite wound healing in mice. In this study, we investigated whether commonly used cosmetic creams supplemented with sodium thiosulfate (STS), a clinically viable H2S donor drug, also promote healing of frostbite wounds. Methods: Frozen magnets (−80 °C) were placed on the dorsal skin of 40 C57BL/6 mice for 3 min to induce frostbite injury. Next, commercially available cosmetic creams (Aveeno, Dove, Neutrogena, and Nivea) were topically applied on frostbite wounds daily for 14 days with or without 150 µM of STS supplementation. The mice were sacrificed on day 15 after induction of frostbite injury, and samples of the injured dorsal skin tissue were collected for analysis. Results: Addition of STS enhanced frostbite wound healing, as evidenced by progressive and significantly reduced wound area by about 50% and inflammation (p < 0.05), and markedly increased granulation tissue formation by >45%, fibroblast maturation by >28%, and re-epithelialization by >63% compared to control groups (p < 0.05), with Nivea producing a superior wound-healing effect. Also, STS supplementation significantly upregulated the expression of CD31 (by >25%), KI-67 (by >25%), CD163 (by >20%), fibronectin (by >14%), and cytokeratin (by >50%) in frostbite wounds compared to control groups, with Aveeno and Nivea producing a better wound-healing effect than Dove and Neutrogena creams. Conclusions: In conclusion, STS accelerated healing of frostbite wounds. Therefore, it could be considered as a novel pharmacological treatment of clinical frostbite. Full article
(This article belongs to the Section Drug Targeting and Design)
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16 pages, 1227 KB  
Systematic Review
Effects of Turmeric and Turmeric Plus Piperine Supplementation on Lipid Profiles in Adults with Cardiometabolic Risk Conditions: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Following PRISMA Guidelines
by Francisco Epelde
Pharmaceutics 2025, 17(12), 1609; https://doi.org/10.3390/pharmaceutics17121609 - 15 Dec 2025
Viewed by 1001
Abstract
Background: Turmeric (Curcuma longa) and its main bioactive compound curcumin are widely promoted for cardiometabolic health, yet their efficacy on lipid parameters remains uncertain. Piperine, an alkaloid from black pepper, enhances curcumin bioavailability and may potentiate its effects. This systematic [...] Read more.
Background: Turmeric (Curcuma longa) and its main bioactive compound curcumin are widely promoted for cardiometabolic health, yet their efficacy on lipid parameters remains uncertain. Piperine, an alkaloid from black pepper, enhances curcumin bioavailability and may potentiate its effects. This systematic review and meta-analysis aimed to assess the impact of turmeric, alone or combined with piperine, on lipid profiles in adults with metabolic disorders. Methods: A systematic search was conducted (2010–2025) in PubMed, Scopus, and Cochrane CENTRAL. Randomized controlled trials (RCTs) evaluating turmeric supplementation (with or without piperine) on lipid outcomes were included. Methodological quality was assessed with Cochrane RoB 2; certainty of evidence was rated using GRADE. Meta-analyses were performed with random-effects models. The protocol followed PRISMA 2020 guidelines. Results: Ten records were identified; six full texts were assessed; three RCTs (n ≈ 250) were included in quantitative synthesis, and three additional RCTs narratively. Pooled analysis demonstrated significant reductions in triglycerides (WMD −25.5 mg/dL, 95% CI −32.5 to −18.4), total cholesterol (−14.1 mg/dL, 95% CI −22.9 to −5.3), and LDL-C (−17.0 mg/dL, 95% CI −25.2 to −8.8), with an increase in HDL-C (+5.7 mg/dL, 95% CI +2.0 to +9.4). Subgroup analysis suggested greater LDL-C reduction with turmeric+piperine (−29.6 mg/dL) compared to turmeric alone (−16.2 mg/dL). Certainty of evidence was moderate for TG, TC, LDL-C, and low for HDL-C. Conclusions: Turmeric supplementation, particularly when combined with piperine, improves lipid profiles in adults with metabolic disorders. These effects are clinically relevant and comparable to other nutraceuticals, although evidence remains limited by short trial duration and small sample sizes. Larger, long-term RCTs are warranted before turmeric can be recommended in evidence-based dyslipidemia guidelines. Full article
(This article belongs to the Section Clinical Pharmaceutics)
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38 pages, 2034 KB  
Review
The Application of Nanomaterials in Breast Cancer
by Kexin Guo, Yue Sun and Huihua Xiong
Pharmaceutics 2025, 17(12), 1608; https://doi.org/10.3390/pharmaceutics17121608 - 14 Dec 2025
Viewed by 400
Abstract
Breast cancer is one of the most prevalent malignant tumors worldwide, with the highest incidence and mortality among women. Early precise diagnosis and the development of efficient treatment regimens remain major clinical challenges. Harnessing the programmable size, surface chemistry, and tumor microenvironment (TME) [...] Read more.
Breast cancer is one of the most prevalent malignant tumors worldwide, with the highest incidence and mortality among women. Early precise diagnosis and the development of efficient treatment regimens remain major clinical challenges. Harnessing the programmable size, surface chemistry, and tumor microenvironment (TME) responsiveness of nanomaterials, there is tremendous potential for their applications in breast cancer diagnosis and therapy. In the diagnostic arena, nanomaterials serve as core components of novel contrast agents (e.g., gold nanorods, quantum dots, superparamagnetic iron oxide nanoparticles) and biosensing platforms, substantially enhancing the sensitivity and specificity of molecular imaging modalities—such as magnetic resonance imaging (MRI), computed tomography (CT), and fluorescence imaging (FLI)—and enabling high-sensitivity detection of circulating tumor cells and tumor-derived exosomes, among various liquid biopsy biomarkers. In therapy, nanoscale carriers (e.g., liposomes, polymeric micelles) improve tumor targeting and accumulation efficiency through passive and active targeting strategies, thereby augmenting anticancer efficacy while effectively reducing systemic toxicity. Furthermore, nanotechnology has spurred the rapid advancement of emerging modalities, including photothermal therapy (PTT), photodynamic therapy (PDT), and immunotherapy. Notably, the construction of theranostic platforms that integrate diagnostic and therapeutic units within a single nanosystem enables in vivo, real-time visualization of drug delivery, treatment monitoring, and therapeutic response feedback, providing a powerful toolkit for advancing breast cancer toward personalized, precision medicine. Despite challenges that remain before clinical translation—such as biocompatibility, scalable manufacturing, and standardized evaluation—nanomaterials are undoubtedly reshaping the paradigm of breast cancer diagnosis and treatment. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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29 pages, 13985 KB  
Article
Thermosensitive Sprayable Lidocaine–Allantoin Hydrogel: Optimization and In Vitro Evaluation for Wound Healing
by Muhammet Davut Arpa and Sevde Nur Biltekin Kaleli
Pharmaceutics 2025, 17(12), 1607; https://doi.org/10.3390/pharmaceutics17121607 - 14 Dec 2025
Viewed by 441
Abstract
Background/Objectives: Wound healing requires simultaneous pain control, inflammation management, infection prevention, and tissue regeneration. This study aimed to develop and evaluate in vitro a non-contact thermosensitive spray hydrogel combining lidocaine for rapid analgesia and allantoin for tissue repair. Methods: The effects of [...] Read more.
Background/Objectives: Wound healing requires simultaneous pain control, inflammation management, infection prevention, and tissue regeneration. This study aimed to develop and evaluate in vitro a non-contact thermosensitive spray hydrogel combining lidocaine for rapid analgesia and allantoin for tissue repair. Methods: The effects of chitosan and Poloxamer 407 on viscosity, spray diameter, and bioadhesion ability of hydrogels were optimized using response surface methodology. Lead formulations (S1 and S2) were selected via a desirability function within the software. The pH, gelation temperature (TG), rheological behavior, sprayability, bioadhesion, and lidocaine release using the dialysis bag method were assessed. The in vitro cytotoxicity, anti-inflammatory activity (TNF-α), and cell migration (scratch assay) of the formulations were investigated. Results: The viscosity values (42.7–58.7 mPa·s) indicated suitability for spraying at room temperature. TG was 28.7 ± 0.6 °C (S1) and 29.3 ± 0.3 °C (S2), enabling rapid sol–gel transition at skin temperature. The lidocaine release reached 95–100% within 120 min. S2 exhibited lower viscosity and wider spray diameter, improving applicability on larger wound areas. In vitro cytotoxicity, scratch assay, and inflammatory marker analyses demonstrated that the optimized sprayable hydrogels exhibited a biocompatible and cell-healing profile. Conclusions: The developed thermosensitive spray hydrogel enables the combined delivery of lidocaine and allantoin, rapid gelation at body temperature, and touch-free administration. Its suitable viscosity and sprayability, and fast lidocaine release profile indicate high patient compliance and a significant advantage over conventional cream/ointment formulations, particularly regarding painless application, reduced contamination risk, enhanced therapeutic potential, and confirmed in vitro biocompatibility with supportive effects on keratinocyte behavior. Full article
(This article belongs to the Special Issue Application of Stimuli-Sensitive Hydrogel for the Treatment of Human and Animal Diseases)
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19 pages, 3873 KB  
Article
Investigating the Mechanical Behaviour of Viscoelastic and Brittle Pharmaceutical Excipients During Tabletting: Revealing the Unobvious Potential of Advanced Compaction Simulation
by Daniel Zakowiecki, Kirils Kukuls, Krzysztof Cal, Adrien Pelloux and Valentyn Mohylyuk
Pharmaceutics 2025, 17(12), 1606; https://doi.org/10.3390/pharmaceutics17121606 - 13 Dec 2025
Viewed by 487
Abstract
Background: The compaction of formulation blends is a critical stage in pharmaceutical tablet manufacturing, particularly when drug substances or functional excipients exhibit limited flowability and tabletability. Objectives: This study systematically examined the mechanical behaviour of viscoelastic microcrystalline cellulose (MCC) and brittle [...] Read more.
Background: The compaction of formulation blends is a critical stage in pharmaceutical tablet manufacturing, particularly when drug substances or functional excipients exhibit limited flowability and tabletability. Objectives: This study systematically examined the mechanical behaviour of viscoelastic microcrystalline cellulose (MCC) and brittle anhydrous dibasic calcium phosphate (DCPA), as well as their mixtures, to check how deformation mechanisms influence powder handling and tablet performance. Methods: A compaction simulator, mimicking a small rotary tablet press, was used to evaluate tablet weight variability, densification profiles, die-filling height, force–displacement behaviour, and in-die Heckel analysis. Additional assessments included compression times, breaking force, tensile strength, elastic recovery, as well as in-die and out-of-die tablet thickness across various compositions and compaction pressures. Results/Conclusions: Bulk density values from the simulator showed strong correlation with pharmacopeial measurements (R2 ≥ 0.997). Measurable differences in true density and cohesiveness led to poor flowability for MCC and good flow for DCPA, with mixtures containing higher DCPA concentration displaying markedly improved flow characteristic. Compaction analyses confirmed extensive plastic deformation for MCC and fragmentation for DCPA. Increasing MCC content elevated die-fill height, compaction energy, and tablet weight variability, whereas higher DCPA fractions decreased apparent density of tablets and reduced energy demand. Tabletability and compressibility profiles reflected that MCC generated hard tablets but exhibited higher elastic recovery, while DCPA formed softer tablets with closer to linear strength–pressure relationships. Energy profiling demonstrated that MCC stored more elastic energy and required higher overall compression work, whereas DCPA reduced elastic accumulation. Overall, blending viscoelastic and brittle excipients offers a robust strategy for optimizing manufacturability, mechanical strength, and energy efficiency in tablet production. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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48 pages, 5616 KB  
Review
Recent Developments in Pharmaceutical Spray Drying: Modeling, Process Optimization, and Emerging Trends with Machine Learning
by Waasif Wahab, Raya Alshamsi, Bouta Alharsousi, Manar Alnuaimi, Zaina Alhammadi and Belal Al-Zaitone
Pharmaceutics 2025, 17(12), 1605; https://doi.org/10.3390/pharmaceutics17121605 - 13 Dec 2025
Viewed by 944
Abstract
Spray drying techniques are widely used in the pharmaceutical industry to produce fine drug powders with different properties depending on the route of administration. Process parameters play a vital role in the critical quality attributes of the final product. This review highlights the [...] Read more.
Spray drying techniques are widely used in the pharmaceutical industry to produce fine drug powders with different properties depending on the route of administration. Process parameters play a vital role in the critical quality attributes of the final product. This review highlights the progress and challenges in modeling the spray-drying process, with a focus on pharmaceutical applications. Computational fluid dynamics (CFD) is a well-known method used for the modeling and numerical simulation of spray drying processes. However, owing to their limitations, including high computational costs, experimental validation, and limited accuracy under complex spray drying conditions. Machine learning (ML) models have recently emerged as integral tools for modeling/optimizing the spray drying process. Despite promising accuracy, ML models depend on high-quality data and may fail to predict the influence of new formulation or process parameters on the properties of the dried powder. This review outlines the shortcomings of CFD modeling in the spray drying process. A hybrid model combining ML and CFD models, emerging techniques such as the digital twin approach, transfer learning, and explainable AI (XAI) are also discussed. A hybrid model combining ML and CFD models is also discussed. ML is considered an emerging technique that could assist the spray drying process, and most importantly, the utilization of this method in pharmaceutical spray drying. Full article
(This article belongs to the Special Issue Advancements in Industrial Pharmaceutics: Innovations and Future Directions)
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33 pages, 1418 KB  
Review
Pharmacokinetic Landscape and Interaction Potential of SGLT2 Inhibitors: Bridging In Vitro Findings and Clinical Implications
by Nahyun Koo, Eun Ji Lee, Ji-Eun Chang, Kyeong-Ryoon Lee and Yoon-Jee Chae
Pharmaceutics 2025, 17(12), 1604; https://doi.org/10.3390/pharmaceutics17121604 - 12 Dec 2025
Viewed by 650
Abstract
Sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes and cardiometabolic diseases, and their pharmacokinetic characteristics generally confer a low risk of clinically relevant drug–drug interactions (DDIs). Most clinical studies demonstrate that these agents can be co-administered safely with commonly [...] Read more.
Sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes and cardiometabolic diseases, and their pharmacokinetic characteristics generally confer a low risk of clinically relevant drug–drug interactions (DDIs). Most clinical studies demonstrate that these agents can be co-administered safely with commonly prescribed medications without dose adjustment, although strong enzyme inducers such as rifampin can reduce systemic exposure, and pharmacodynamic interactions may still arise. However, existing evidence is largely derived from short-term studies in healthy volunteers, with limited data in special populations and minimal evaluation of metabolite- or transporter-mediated interactions. This review summarizes the available in vitro and in vivo pharmacokinetic and DDI data for SGLT2 inhibitors, identifies key knowledge gaps related to polypharmacy, metabolite effects, and vulnerable patient groups, and outlines future research priorities to ensure their safe and effective use in real-world clinical practice. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Drug Interactions)
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30 pages, 16113 KB  
Article
Flavonifractor plautii as a Next-Generation Probiotic Enhancing the NGP F/P Index in a Simulated Human Gut Microbiome Ecosystem
by Md Sarower Hossen Shuvo, Sukyung Kim, Sujin Jo, Md Abdur Rahim, Indrajeet Barman, Mohammed Solayman Hossain, Youjin Yoon, Hanieh Tajdozian, Izaz Ahmed, Ali Atashi, GangWon Jeong, Ho-Seong Suh, JiMin You, Chaemin Sung, Mijung Kim, Hoonhee Seo and Ho-Yeon Song
Pharmaceutics 2025, 17(12), 1603; https://doi.org/10.3390/pharmaceutics17121603 - 12 Dec 2025
Viewed by 543
Abstract
Background/Objectives: Traditionally consumed fermented foods and lactic acid bacteria (LAB)-based products have primarily been investigated for their nutritional and health-promoting benefits as dietary supplements. More recently, research has advanced toward exploring their therapeutic potential in pharmaceutical development. However, reliance on conventional LAB [...] Read more.
Background/Objectives: Traditionally consumed fermented foods and lactic acid bacteria (LAB)-based products have primarily been investigated for their nutritional and health-promoting benefits as dietary supplements. More recently, research has advanced toward exploring their therapeutic potential in pharmaceutical development. However, reliance on conventional LAB strains despite their established safety and efficacy has led to saturation at the strain level, underscoring the need for next-generation probiotics (NGPs) with novel therapeutic potential. In this context, we identified Flavonifractor plautii from human feces as a candidate NGP and investigated its effects on the human gut microbiota. Methods: Whole-genome sequencing revealed distinct genetic features that supported its uniqueness, and the strain was designated PMC93. A human gut microbial ecosystem simulator was used to administer F. plautii daily for one week, after which microbial community changes were evaluated using 16S rRNA gene-based metagenomic sequencing. Results: The administration did not induce significant changes in alpha or beta diversity, suggesting that F. plautii does not disrupt overall bacterial community structure, thereby supporting its microbial community safety. Taxonomic analysis demonstrated a significant increase in the Firmicutes-to-Proteobacteria ratio (NGP F/P index). The improvement surpassed that of conventional LAB treatments and was consistently maintained under supplementation with commonly encountered pharmaceutical compounds and nutrients. The shift was associated with an increase in short-chain fatty acid (SCFA)-producing beneficial taxa and a decrease in pro-inflammatory and potentially pathogenic groups. Functional outcomes, including elevated SCFA levels and downregulation of inflammation-related gene expression, further corroborated these compositional changes. The strain also demonstrated safety in in vivo models. Conclusions: Collectively, these findings suggest that strain PMC93 is a promising NGP candidate with substantial therapeutic potential for microbiota-associated health and disease modulation, particularly due to its ability to enhance the NGP F/P index. Full article
(This article belongs to the Section Drug Targeting and Design)
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40 pages, 2992 KB  
Review
Advances in Mesoporous Silica and Hybrid Nanoparticles for Drug Delivery: Synthesis, Functionalization, and Biomedical Applications
by Ahmad Almatroudi
Pharmaceutics 2025, 17(12), 1602; https://doi.org/10.3390/pharmaceutics17121602 - 12 Dec 2025
Cited by 1 | Viewed by 590
Abstract
Mesoporous silica nanoparticles (MSNs) are among the most adaptable nanocarriers in modern pharmaceutics, characterized by a high surface area, tunable pore size, controllable morphology, and excellent biocompatibility. These qualities enable effective encapsulation, protection, and the delivery of drugs in a specific area and, [...] Read more.
Mesoporous silica nanoparticles (MSNs) are among the most adaptable nanocarriers in modern pharmaceutics, characterized by a high surface area, tunable pore size, controllable morphology, and excellent biocompatibility. These qualities enable effective encapsulation, protection, and the delivery of drugs in a specific area and, therefore, MSNs are powerful platforms for the targeted and controlled delivery of drugs and theragnostic agents. Over the past ten years and within the 2021–2025 period, the advancement of MSN design has led to the creation of hybrid nanostructures into polymers, lipids, metals, and biomolecules that have yielded multifunctional carriers with enhanced stability, responsiveness, and biological activities. The current review provides a review of the synthesis methods, surface functionalization techniques, and physicochemical characterization techniques that define the next-generation MSN-based delivery systems. The particular focus is put on stimuli-responsive systems, such as redox, pH, enzyme-activated, and light-activated systems, that enable delivering drugs in a controlled and localized manner. We further provide a summary of the biomedical use of MSNs and their hybrids such as in cancer chemotherapy, gene and nucleic acid delivery, antimicrobial and vaccine delivery, and central nervous system targeting, supported by recent in vivo and in vitro studies. Important evaluations of biocompatibility, immunogenicity, degradation, and biodistribution in vivo are also provided with a focus on safety in addition to the regulatory impediments to clinical translation. The review concludes by saying that there are still limitations such as large-scale reproducibility, long-term toxicity, and standardization by the regulators, and that directions are being taken in the future in the fields of smart programmable nanocarriers, green synthesis, and sustainable manufacture. Overall, mesoporous silica and hybrid nanoparticles represent a breakthrough technology in the nanomedicine sector with potentials that are unrivaled in relation to targeted, controlled, and personalized therapeutic interventions. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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2 pages, 152 KB  
Correction
Correction: Sennato et al. Optimization of Lipoplexes Functionalized with a Sialic Acid Mimetic (F9-PEG) to Target the C1858T PTPN22 Variant for Preclinical Assessment of a Novel Immunotherapy in Endocrine Autoimmunity. Pharmaceutics 2025, 17, 710
by Simona Sennato, Giorgia Paldino, Cecilia Bombelli, Irene Mezzani, Stefania Petrini, Eugenia Belcastro, Domenico Vittorio Delfino, Francesco Fiorentino, Carlotta Marianecci, Alessia Ciogli, Dante Rotili, Francesca Ceccacci and Alessandra Fierabracci
Pharmaceutics 2025, 17(12), 1601; https://doi.org/10.3390/pharmaceutics17121601 - 12 Dec 2025
Viewed by 253
Abstract
Eugenia Belcastro was not included as an author in the original publication [...] Full article
17 pages, 1233 KB  
Review
Sulfated Hyaluronan in Dermatology: What’s New? Overview of Evidence in Specific Dermatological Diseases
by Giovanni Pellacani, Simone Michelini, Federica Trovato, Alessandra Rallo, Giuseppe Gemma, Camilla Chello, Mauro Pavan, Cristian Guarise and Alberto Giuseppe Passi
Pharmaceutics 2025, 17(12), 1600; https://doi.org/10.3390/pharmaceutics17121600 - 12 Dec 2025
Viewed by 440
Abstract
Background/Objectives: Sulfated hyaluronic acid (sHA) is a chemically modified derivative of native hyaluronic acid (HA), characterized by enhanced physicochemical stability and increased biological activity. Glycosaminoglycans (GAGs), including HA, are key regulators of skin structure, hydration, and immune homeostasis. This review aims to critically [...] Read more.
Background/Objectives: Sulfated hyaluronic acid (sHA) is a chemically modified derivative of native hyaluronic acid (HA), characterized by enhanced physicochemical stability and increased biological activity. Glycosaminoglycans (GAGs), including HA, are key regulators of skin structure, hydration, and immune homeostasis. This review aims to critically summarize current knowledge on the structural and functional properties of GAGs—particularly HA and its sulfated forms—and to explore their potential dermatological applications in skin aging and inflammatory diseases such as atopic dermatitis, psoriasis, and acne. Methods: A narrative literature review was conducted using PubMed and Scopus databases up to June 2025, including experimental, preclinical, and clinical studies investigating the biological effects, mechanisms of action, and dermatological uses of sHA compared with native HA and other HA derivatives. Results: Compared with HA, sHA demonstrates increased enzymatic resistance, higher charge density, and improved water-binding and antioxidant capacity. These properties contribute to the restoration of skin barrier function, modulation of oxidative stress and inflammation, and promotion of extracellular matrix remodeling. Preclinical evidence supports the efficacy of sHA in reducing dryness, irritation, and inflammatory responses in atopic dermatitis, psoriasis, and acne. Preliminary findings also suggest potential benefits in wound healing and skin barrier repair. Conclusions: sHA represents a promising multifunctional molecule in dermatology and cosmetology, capable of reducing inflammation and supporting tissue regeneration. However, current evidence remains limited to preliminary studies. Future controlled clinical trials are required to confirm efficacy, optimize formulations, and establish standardized treatment protocols. Full article
(This article belongs to the Special Issue Hyaluronic Acid-Based Drug Delivery Systems)
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19 pages, 4487 KB  
Article
Therapeutic Delivery of Phloretin by Mixed Emulsifier-Stabilized Nanoemulsion Alleviated Cerebral Ischemia/Reperfusion Injury
by Tingting Huang, Changjing Wu, Wenchai Lu, Houbo Lv, Ronghui Jin, Jingyao Gan and Yuandong Zhang
Pharmaceutics 2025, 17(12), 1599; https://doi.org/10.3390/pharmaceutics17121599 - 11 Dec 2025
Viewed by 388
Abstract
Background: Cerebral ischemia/reperfusion injury (CIRI) is a major challenge in ischemic stroke treatment. Phloretin (PHL), despite its potent antioxidant and anti-inflammatory properties, has limited clinical application due to poor oral bioavailability. This study aimed to develop an orally administered phloretin-loaded nanoemulsion (NE-PHL) to [...] Read more.
Background: Cerebral ischemia/reperfusion injury (CIRI) is a major challenge in ischemic stroke treatment. Phloretin (PHL), despite its potent antioxidant and anti-inflammatory properties, has limited clinical application due to poor oral bioavailability. This study aimed to develop an orally administered phloretin-loaded nanoemulsion (NE-PHL) to enhance brain delivery and neuroprotective efficacy against CIRI. Methods: NE-PHL was optimized via an orthogonal experimental design combined with ultrasonication. The optimized formulation was characterized for physicochemical properties and evaluated for pharmacokinetics and brain bioavailability. Its therapeutic efficacy was assessed in middle cerebral artery occlusion (MCAO) rats by measuring infarct volume, neurological scores, oxidative stress markers, and inflammatory cytokines. RNA sequencing analysis was performed to elucidate the underlying mechanisms. Results: The optimized NE-PHL exhibited a small droplet size (96.26 ± 0.86 nm), high encapsulation efficiency (84.58 ± 3.03%), and good storage stability over a period of 120 days. Pharmacokinetic studies showed a 2.72-fold increase in AUC 0–12h for NE-PHL compared to free PHL. In MCAO rats, NE-PHL treatment significantly improved neurological function, reduced cerebral infarct volume, attenuated oxidative stress, and modulated inflammatory responses by suppressing pro-inflammatory cytokines and enhancing anti-inflammatory activity. RNA sequencing analysis further confirmed coordinated downregulation of key pathways related to oxidative stress and inflammation. Conclusions: NE-PHL represents a promising oral nanotherapeutic strategy for the effective management of CIRI, offering enhanced bioavailability and significant neuroprotection. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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