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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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30 pages, 842 KB  
Review
Crossing the Blood–Brain Barrier: Innovations in Receptor- and Transporter-Mediated Transcytosis Strategies
by Ling Ding, Pratiksha Kshirsagar, Prachi Agrawal and Daryl J. Murry
Pharmaceutics 2025, 17(6), 706; https://doi.org/10.3390/pharmaceutics17060706 - 28 May 2025
Cited by 18 | Viewed by 10456
Abstract
The blood–brain barrier (BBB) is a highly selective and natural protective membrane that restricts the entry of therapeutic agents into the central nervous system (CNS). This restrictive nature poses a major challenge for pharmacological treatment of a wide range of CNS disorders, including [...] Read more.
The blood–brain barrier (BBB) is a highly selective and natural protective membrane that restricts the entry of therapeutic agents into the central nervous system (CNS). This restrictive nature poses a major challenge for pharmacological treatment of a wide range of CNS disorders, including neurodegenerative disorders, brain tumors, and psychiatric conditions. Many chemical drugs and biopharmaceuticals are unable to cross the BBB, and conventional drug delivery methods often fail to achieve sufficient brain concentrations, leading to reduced therapeutic efficacy and increased risk of systemic toxicity. In recent years, targeted drug delivery strategies have emerged as promising approaches to overcome the BBB and enhance the delivery of therapeutic agents to the brain. Among these, receptor-mediated transcytosis (RMT) and transporter-mediated transcytosis (TMT) are two of the most extensively studied mechanisms for transporting drugs across brain endothelial cells into the brain parenchyma. Advances in materials science and nanotechnology have facilitated the development of multifunctional carriers with optimized properties, improving drug targeting, stability, and release profiles within the brain. This review summarizes the physiological structure of the BBB and highlights recent innovations in RMT- and TMT-mediated brain drug delivery systems, emphasizing their potential not only to overcome current challenges in CNS drug development, but also to pave the way for next-generation therapies that enable more precise, effective, and personalized treatment of brain-related diseases. Full article
(This article belongs to the Special Issue Targeted Drug Delivery for Diagnostic and Therapeutic Applications)
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19 pages, 7450 KB  
Article
Curcumin-Induced Apoptotic Cell Death in Human Glioma Cells Is Enhanced by Clusterin Deficiency
by Pinky Sultana and Jiri Novotny
Pharmaceutics 2025, 17(6), 679; https://doi.org/10.3390/pharmaceutics17060679 - 22 May 2025
Cited by 1 | Viewed by 1493
Abstract
Background/Objectives: Glioblastoma is an aggressive brain tumor with limited treatment options and significant resistance to conventional therapies. Methods: In this study, we explored the effects of combining curcumin treatment with clusterin inhibition on cell death in glioma cells. Results: We observed that the [...] Read more.
Background/Objectives: Glioblastoma is an aggressive brain tumor with limited treatment options and significant resistance to conventional therapies. Methods: In this study, we explored the effects of combining curcumin treatment with clusterin inhibition on cell death in glioma cells. Results: We observed that the combination of clusterin silencing and curcumin treatment induces cell death. This combination therapy significantly elevated reactive oxygen species (ROS), triggering oxidative stress, which acted as a key upstream mediator of apoptosis. Elevated ROS levels were found to be associated with caspase activation, suggesting apoptosis as the primary mode of cell death. Furthermore, autophagy was induced as a complementary mechanism, with upregulation of LC3B contributing to the enhanced cytotoxic effects. Conclusions: The synergy between clusterin knockdown-induced senescence and curcumin’s pro-apoptotic and pro-autophagic effects highlights a potential novel therapeutic strategy for gliomas. These findings underscore the potential of this combination therapy in overcoming glioma resistance and improving treatment outcomes through the dual induction of oxidative stress and cell death pathways. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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49 pages, 24112 KB  
Review
Synergistic Cancer Therapies Enhanced by Nanoparticles: Advancing Nanomedicine Through Multimodal Strategies
by Seyed Mohamad Sadegh Mousavi-Kiasary, Ahmood Senabreh, Ashkan Zandi, Rogelio Pena, Frances Cruz, Ali Adibi and Nasrin Hooshmand
Pharmaceutics 2025, 17(6), 682; https://doi.org/10.3390/pharmaceutics17060682 - 22 May 2025
Cited by 14 | Viewed by 3888
Abstract
Cancer remains a formidable global health challenge due to its complex pathophysiology and resistance to conventional treatments. In recent years, the convergence of nanotechnology and oncology has paved the way for innovative therapeutic platforms that address the limitations of traditional modalities. This review [...] Read more.
Cancer remains a formidable global health challenge due to its complex pathophysiology and resistance to conventional treatments. In recent years, the convergence of nanotechnology and oncology has paved the way for innovative therapeutic platforms that address the limitations of traditional modalities. This review examines how nanoparticle (NP)-based strategies enhance the efficacy of chemotherapy, radiotherapy, phototherapy, immunotherapy, and gene therapy by enabling targeted delivery, controlled drug release, and tumor-specific accumulation via the enhanced permeability and retention (EPR) effect. We discuss the design and functionalization of various organic, inorganic, and hybrid NPs, highlighting their roles in improving pharmacokinetics, overcoming multidrug resistance, and modulating the tumor microenvironment. Particular emphasis is placed on dual and multimodal therapies, such as chemo-phototherapy, chemo-immunotherapy, and gene-radiotherapy, that leverage nanoparticle carriers to amplify synergistic effects, minimize systemic toxicity, and improve clinical outcomes. We also explore cutting-edge advances in gene editing and personalized nanomedicine, as well as emerging strategies to address biological barriers and immunosuppressive mechanisms in the tumor niche. Despite the undeniable promise of nanoparticle-based cancer therapies, challenges related to toxicity, scalable manufacturing, regulatory oversight, and long-term biocompatibility must be overcome before they can fully enter clinical practice. By synthesizing recent findings and identifying key opportunities for innovation, this review provides insight into how nanoscale platforms are propelling the next generation of precision oncology. Full article
(This article belongs to the Special Issue Synergistic Nanomedicines: Integrating Chemotherapy and Phototherapy for Enhanced Cancer Treatment)
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28 pages, 991 KB  
Review
Advancing Brain Targeting: Cost-Effective Surface-Modified Nanoparticles for Faster Market Entry
by Mariana Gomes, Maria João Ramalho, Joana A. Loureiro and Maria Carmo Pereira
Pharmaceutics 2025, 17(5), 661; https://doi.org/10.3390/pharmaceutics17050661 - 17 May 2025
Cited by 14 | Viewed by 2481
Abstract
Background/Objectives: The blood–brain barrier (BBB) poses a major obstacle to delivering therapeutic agents to the central nervous system (CNS), driving the need for innovative drug delivery strategies. Among these, nanoparticles (NPs) have gained attention due to their ability to enhance drug transport, [...] Read more.
Background/Objectives: The blood–brain barrier (BBB) poses a major obstacle to delivering therapeutic agents to the central nervous system (CNS), driving the need for innovative drug delivery strategies. Among these, nanoparticles (NPs) have gained attention due to their ability to enhance drug transport, improve bioavailability, and enable targeted delivery. Methods: This paper explores various surface modification strategies employed to optimize NP-mediated drug delivery across the BBB. Specifically, the functionalization of NPs with ligands such as transferrin (Tf), lactoferrin (Lf), protamine, and insulin is discussed, each demonstrating unique mechanisms for enhancing brain-targeting efficiency. In addition, this work provides a comprehensive overview of recent scientific advancements and market strategies aimed at accelerating the adoption of low-cost, surface-modified nanoparticles, ultimately improving patient access to effective CNS treatments. Conclusions: Preclinical and in vitro studies have demonstrated the effectiveness of these modifications in increasing drug retention and bioavailability in brain tissues. Additionally, while ligand-conjugated NPs hold significant promise for neuropharmacology, their clinical translation is often hindered by regulatory and economic constraints. Lengthy approval processes can slow market entry, but cost–benefit analyses indicate that surface-modified NPs remain financially viable, particularly as scalable manufacturing techniques and some ligands are cost-efficient. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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26 pages, 3061 KB  
Article
Three-Dimensional-Printed Isoniazid Chewable Gels for On-Demand Latent Tuberculosis Treatment in Children
by Amanda de O. E. Moreira, Lêda Maria S. Azevedo Neta, Márcia Pietroluongo, Ana Paula dos S. Matos, Beatriz B. Correa, Beatriz H. Ortiz, André da S. Guimarães, Marcio Nele, Carollyne M. Santos, Ana Elizabeth C. Fai, Maria Helena Gonçalves, Flávio M. Shimizu, Monique S. Dos Santos, Rosemberg B. Moure, Diogo D. Nascimento, André Luis de A. Guimarães, Saint Clair dos S. G. Junior, Alessandra L. Vicosa and Lucio M. Cabral
Pharmaceutics 2025, 17(5), 658; https://doi.org/10.3390/pharmaceutics17050658 - 17 May 2025
Cited by 2 | Viewed by 1703
Abstract
Background/Objectives: Pediatric drug administration is hindered by difficulties in swallowing conventional medications and the unpalatable taste of many drugs. Among diseases highlighting the need for improved pediatric delivery, tuberculosis (TB) stands out. One form of the disease is latent TB infection (LTBI), [...] Read more.
Background/Objectives: Pediatric drug administration is hindered by difficulties in swallowing conventional medications and the unpalatable taste of many drugs. Among diseases highlighting the need for improved pediatric delivery, tuberculosis (TB) stands out. One form of the disease is latent TB infection (LTBI), which is concerning in children. Effective LTBI treatment is crucial for prevention, with isoniazid (INH) widely used for its proven efficacy and safety. This study aims to develop innovative 3D-printed chewable gels containing INH for LTBI treatment. Methods: The gels were formulated using gelatin and carrageenan gum, sugar-free sweeteners, and flavoring. Two batches were prepared, and using 3D printing (3DP) with a semi-solid extrusion (SSE) module, chewable gels were produced. Rheological properties were measured to assess the feasibility of 3DP-SSE, evaluating the structural integrity and adequate fluidity of the formulation. The 3D-printed chewable gels were evaluated by visual, mass, and dimensional characteristics. In addition, the water activity, texture profile, INH and degradation product content, in vitro release, and taste-masking were investigated. Results: The optimized formulation maintained suitable rheological properties for 3DP-SSE, demonstrating consistent weight, dimensions, and stability after the process. The texture achieved a balance between printing parameters and shape maintenance, and the INH presented an immediate-release profile (>85% within 30 min). The chewable gels showed an improvement in palatability compared to conventional INH tablets. Conclusions: This innovative approach offers a promising solution for pediatric LTBI treatment, as it improves efficacy, medication acceptability, and on-demand access. Full article
(This article belongs to the Special Issue 3D Printing in Personalized Drug Delivery)
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23 pages, 14789 KB  
Article
Feasibility of Hot Melt Extrusion in Converting Water-Based Nanosuspensions into Solid Dosage Forms
by Erasmo Ragucci, Marco Uboldi, Adam Sobczuk, Giorgio Facchetti, Alice Melocchi, Mauro Serratoni and Lucia Zema
Pharmaceutics 2025, 17(5), 662; https://doi.org/10.3390/pharmaceutics17050662 - 17 May 2025
Viewed by 1549
Abstract
Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in [...] Read more.
Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in transforming a cinnarizine-based NS, selected as a case study, into granules for oral intake. Methods: Thermoplastic polymers, in principle compatible with the thermal behavior of the selected drug and characterized by different interaction mechanisms with aqueous fluids, were used as carriers to absorb the NS and were processed by HME. Results: The extruded granules pointed out good physio-technological characteristics, a drug content > 85% with coefficient of variation (CV) < 5% and tunable in vitro performance coherent with the polymeric carriers they were composed of. Particle size as well as the solid state of cinnarizine was checked using several analytical techniques in combination (e.g., DSC, SEM, FT-IR, Raman). Depending on the composition of the granules, and specifically for formulations processed below 85 °C, the drug was found to remain crystalline and in the desired nanoscale. Conclusions: HME turned out to be a versatile process to transform, in a single-step, NSs into multi-particulate solid products for oral administration showing a variety of release profiles. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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18 pages, 4166 KB  
Article
GinExtraMed: Focus on Rosa canina L. Extract Encapsulated into Glycethosomes and Allanthosomes for Accelerating Skin Wound Healing
by Martina Rossi, Simone Rossello, Valentina Sallustio, Manuela Mandrone, Teresa Cerchiara, Ilaria Chiocchio, Giuseppe Chidichimo, Michele Protti, Laura Mercolini, Barbara Luppi, Federica Bigucci, Angela Abruzzo and Concettina Cappadone
Pharmaceutics 2025, 17(5), 632; https://doi.org/10.3390/pharmaceutics17050632 - 9 May 2025
Cited by 1 | Viewed by 1273
Abstract
Background/Objectives: Over the last decade, the development of innovative wound products has continued to be a focus of intense research to meet the huge demand of patients. The aim of this work was to develop novel medicated Spanish broom wound dressings capable of [...] Read more.
Background/Objectives: Over the last decade, the development of innovative wound products has continued to be a focus of intense research to meet the huge demand of patients. The aim of this work was to develop novel medicated Spanish broom wound dressings capable of releasing Rosa canina extract, recognized for its high antioxidant activity. Methods:Rosa canina extract was encapsulated in two different nanocarriers, namely glycethosomes and allanthosomes. The physico-chemical and functional characteristics of the obtained vesicles were described, including their size, particle size distribution, ζ potential, and encapsulation efficiency (EE). In addition, vesicles cytotoxicity and cell proliferation were evaluated on human fibroblasts. Furthermore, loaded vesicles were sunk into Spanish broom dressings, analyzed by confocal microscopy, and, finally, evaluated for their wound healing ability by scratch test. Results: Both carriers are nanometric in size, with a good EE (>70%), and a negative ζ potential. Additionally, vesicles are biosafe, non-cytotoxic, and lead to complete closure of the scratch in about 30 h. Conclusions: The findings showed that the developed Spanish broom dressings have the potential to be an efficient and innovative wound care product for accelerating skin wounds. Full article
(This article belongs to the Special Issue Innovations in Controlled Release Systems of Marine- and Plant/Herbal-Derived Bioactives for Pharmaceuticals and Nutraceuticals)
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28 pages, 6539 KB  
Article
Hydrogel–Nanolipid Formulations for the Complex Anti-Inflammatory and Antimicrobial Therapy of Periodontitis
by Rabia Ashfaq, Nóra Tóth, Anita Kovács, Szilvia Berkó, Gábor Katona, Rita Ambrus, Tamás Ferenc Polgár, Mária Szécsényi, Katalin Burián and Mária Budai-Szűcs
Pharmaceutics 2025, 17(5), 620; https://doi.org/10.3390/pharmaceutics17050620 - 7 May 2025
Cited by 6 | Viewed by 2107
Abstract
Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation [...] Read more.
Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation was integrated into three hydrogels, hypromellose (HPMC), zinc hyaluronate (ZnHA), and sodium hyaluronate (NaHA), to conduct a comparative analysis focusing on enhanced localized drug delivery, improved mucoadhesion, prolonged retention, and significant therapeutic outcomes. Methods: NLC–Melox was prepared by homogenization and characterized by dynamic light scattering (DLS). Subsequently, NLC–Melox-loaded gels were subjected to transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Raman spectroscopy, and rheological analysis. In vitro drug release, anti-inflammatory activity (BSA denaturation assay), and antibacterial efficacy (MIC, MBC) were investigated to assess therapeutic potential. Results: DLS revealed a particle size of 183 nm with a polydispersity index of 0.26, indicating homogeneity. TEM confirmed consistent morphology and uniform nanoparticle distribution. DSC and XRD demonstrated the amorphous nature of Melox, enhancing solubility and stability. Spectroscopy confirmed no chemical interactions between components. Rheological studies identified ZnHA as the most mucoadhesive and structurally stable gel. In vitro release studies showed sustained drug release over 24 h. Melox and CO-loaded formulations demonstrated significant anti-inflammatory activity and notable antibacterial efficacy due to the antibacterial oil. Conclusions: The study highlighted the potential of NLC-based mucoadhesive hydrogels as an effective strategy for periodontitis treatment. The formulation offered improved drug solubility, therapeutic efficacy, mucoadhesivity, and prolonged delivery, making it a promising candidate for localized therapy. Full article
(This article belongs to the Special Issue Recent Insights Concerning the Use of Supramolecular Systems for Biomedical Applications)
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15 pages, 3492 KB  
Article
Formulation Approaches for Optimizing Omeprazole Stability in Oral Liquid Dosage Forms
by Urszula Adamiak-Giera, Michał Gackowski, Damian Malinowski, Tomasz Osmałek, Marta Karaźniewicz-Łada, Anna Machoy-Mokrzyńska and Monika Białecka
Pharmaceutics 2025, 17(5), 594; https://doi.org/10.3390/pharmaceutics17050594 - 1 May 2025
Viewed by 3001
Abstract
Background/Objectives: This study aimed to evaluate the degradation of omeprazole suspension under various pH conditions and to propose recommendations for preparing compounded suspensions. Given the clinical need for alternative dosage forms for pediatric and geriatric patients and those with dysphagia, the research focused [...] Read more.
Background/Objectives: This study aimed to evaluate the degradation of omeprazole suspension under various pH conditions and to propose recommendations for preparing compounded suspensions. Given the clinical need for alternative dosage forms for pediatric and geriatric patients and those with dysphagia, the research focused on assessing whether modifications in formulation composition—specifically the inclusion of sodium bicarbonate—could improve omeprazole stability, thus enhancing its bioavailability. Methods: Three formulations were prepared: O1, based on crushed enteric-coated pellets from a commercial product; O2, with crushed pellets suspended in an 8% sodium bicarbonate solution with glycerin; and O3, with pure omeprazole suspended in an 8% sodium bicarbonate solution with glycerin. Release studies were conducted using basket or paddle apparatus under conditions simulating fasted (pH 1.2 and 6.8) and fed (pH 6, 4.5, and 3) gastric and intestinal juices at 37 °C over 120 min. At predetermined intervals, samples were withdrawn and analyzed by a validated HPLC method with UV detection to quantify the released omeprazole. Results: The commercial enteric-coated product showed no release at a low pH, confirming its protective coating. In contrast, formulation exhibited significant degradation in acidic environments. The O2 formulation, benefiting from the buffering effect of sodium bicarbonate, showed improved stability compared to O1. Notably, formulation O3 yielded the highest drug recovery, with approximately 74% released at pH 6 and 65% at pH 6.8, demonstrating significantly better performance, as confirmed by statistical analysis (p < 0.05). Conclusions: The composition of omeprazole suspensions substantially influences the drug stability and release profiles. The O3 formulation, based on pure omeprazole with sodium bicarbonate, is recommended for immediate-release suspensions to enhance bioavailability. Further studies are needed to optimize conditions for pediatric use. Full article
(This article belongs to the Section Biopharmaceutics)
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17 pages, 4960 KB  
Article
PLA-Based Electrospun Nanofibrous Mats Towards Application as Antibiotic Carriers: Processing Parameters, Fabrication and Characterization
by Evi Christodoulou, Anastasia Chondromatidou, Nikolaos D. Bikiaris, Evangelia Balla, Marilena Vlachou, Panagiotis Barmpalexis and Dimitrios N. Bikiaris
Pharmaceutics 2025, 17(5), 589; https://doi.org/10.3390/pharmaceutics17050589 - 30 Apr 2025
Cited by 2 | Viewed by 1209
Abstract
Background/Objectives: Polymeric nanofibers are promising platforms for skin treatment applications due to their large surface area and high porosity, which promote enhanced drug delivery. This study aimed to develop and compare poly(lactic acid)-based (PLA) nanofibrous mats, using linear PLA and a star-like [...] Read more.
Background/Objectives: Polymeric nanofibers are promising platforms for skin treatment applications due to their large surface area and high porosity, which promote enhanced drug delivery. This study aimed to develop and compare poly(lactic acid)-based (PLA) nanofibrous mats, using linear PLA and a star-like PLA-pentaerythritol (PLA-PE) copolymer, as carriers for transdermal delivery of the antibacterial agent levofloxacin (LEV). Methods: Electrospinning was employed to fabricate nanofibers from PLA and PLA-PE solutions. Spinning parameters and polymer concentrations (10% w/v PLA and 20% w/v PLA-PE) were optimized to produce uniform fibers. LEV was loaded at 10% and 20% w/w. A sum of complementary characterization techniques, including scanning electron microscopy (SEM), infrared spectroscopy (FTIR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC), were applied to comparatively investigate the fibers’ morphology, structural properties, and crystallinity. Drug loading, porosity, degradation, and in vitro release profiles were evaluated. Results: PLA-PE nanofibers demonstrated smaller diameters and higher porosity (up to 90.1%) compared to PLA (82.4%), leading to enhanced drug loading (up to 34.78%) and faster degradation (55% vs. 43% mass loss over 60 days). Drug release exhibited a biphasic profile with an initial burst followed by sustained release. PLA-PE formulations released up to 60.2% LEV, compared to 38.1% for PLA counterparts. Conclusions: The star-like PLA-PE copolymer enhances nanofiber properties relevant to the desired application, including porosity, degradation rate, and drug release. These findings suggest that PLA-PE is a promising material for developing advanced transdermal antibiotic delivery systems. Full article
(This article belongs to the Special Issue Electrospinning in Drug Delivery Applications)
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14 pages, 2415 KB  
Article
Influence of Ionization and the Addition of Cyclodextrins and Hydrophilic Excipients on the Solubility of Benzthiazide, Isoxicam, and Piroxicam
by Diego Lucero-Borja, Rebeca Ruiz, Elisabet Fuguet and Clara Ràfols
Pharmaceutics 2025, 17(5), 571; https://doi.org/10.3390/pharmaceutics17050571 - 25 Apr 2025
Cited by 1 | Viewed by 1101
Abstract
Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing [...] Read more.
Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing supersaturated solutions. Some of the most common excipients are cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins (captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdone S630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) is evaluated at biorelevant pH values, using two complementary techniques. Methods: The solubility enhancement was evaluated by the comparison of the solubility with and without the presence of excipients through the shake-flask and CheqSol methodology. Results: Captisol and cavasol slightly increase the concentration of the neutral species of the drugs in the solution before precipitation begins, although they do not enhance the supersaturation duration nor the thermodynamic solubility of the drugs. The increase in solubility in the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilic polymers not only improve thermodynamic solubility but also the extent and the duration of the supersaturation. Some metastable forms are observed for benzthiazide and isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flask method enabled the evaluation of thermodynamic solubility both in the absence and presence of excipients. Meanwhile, the CheqSol method provided insights into the presence of supersaturated solutions. Different behavior is observed depending on the nature of the excipient. Full article
(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)
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25 pages, 2761 KB  
Review
Transforming Pharmacogenomics and CRISPR Gene Editing with the Power of Artificial Intelligence for Precision Medicine
by Amit Kumar Srivastav, Manoj Kumar Mishra, James W. Lillard, Jr. and Rajesh Singh
Pharmaceutics 2025, 17(5), 555; https://doi.org/10.3390/pharmaceutics17050555 - 24 Apr 2025
Cited by 19 | Viewed by 6239
Abstract
Background: Advancements in pharmacogenomics, artificial intelligence (AI), and CRISPR gene-editing technology are revolutionizing precision medicine by enabling highly individualized therapeutic strategies. Artificial intelligence-driven computational techniques improve biomarker discovery and drug optimization while pharmacogenomics helps to identify genetic polymorphisms affecting medicine metabolism, efficacy, [...] Read more.
Background: Advancements in pharmacogenomics, artificial intelligence (AI), and CRISPR gene-editing technology are revolutionizing precision medicine by enabling highly individualized therapeutic strategies. Artificial intelligence-driven computational techniques improve biomarker discovery and drug optimization while pharmacogenomics helps to identify genetic polymorphisms affecting medicine metabolism, efficacy, and toxicity. Genetically editing based on CRISPR presents a precise method for changing gene expression and repairing damaging mutations. This review explores the convergence of these three fields to enhance improved precision medicine. Method: A methodical study of the current literature was performed on the effects of pharmacogenomics on drug response variability, artificial intelligence, and CRISPR in predictive modeling and gene-editing applications. Results: Driven by artificial intelligence, pharmacogenomics allows clinicians to classify patients and select the appropriate medications depending on their DNA profiles. This reduces the side effect risk and increases the therapeutic efficacy. Precision genetic modifications made feasible by CRISPR technology improve therapy outcomes in oncology, metabolic illnesses, neurological diseases, and other fields. The integration of artificial intelligence streamlines genome-editing applications, lowers off-target effects, and increases CRISPR specificity. Notwithstanding these advances, issues including computational biases, moral dilemmas, and legal constraints still arise. Conclusions: The synergy of artificial intelligence, pharmacogenomics, and CRISPR alters precision medicine by letting customized therapeutic interventions. Clinically translating, however, hinges on resolving data privacy concerns, assuring equitable access, and strengthening legal systems. Future research should focus on refining CRISPR gene-editing technologies, enhancing AI-driven pharmacogenomics, and developing moral guidelines for applying these tools in individualized medicine going forward. Full article
(This article belongs to the Section Gene and Cell Therapy)
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26 pages, 4052 KB  
Review
Use of Computational Intelligence in Customizing Drug Release from 3D-Printed Products: A Comprehensive Review
by Fantahun Molla Kassa, Souha H. Youssef, Yunmei Song and Sanjay Garg
Pharmaceutics 2025, 17(5), 551; https://doi.org/10.3390/pharmaceutics17050551 - 23 Apr 2025
Viewed by 2160
Abstract
Computational intelligence (CI) mimics human intelligence by expanding the capabilities of machines in data analysis, pattern recognition, and making informed decisions. CI has shown promising contributions to advancements in drug discovery, formulation, and manufacturing. Its ability to analyze vast amounts of patient data [...] Read more.
Computational intelligence (CI) mimics human intelligence by expanding the capabilities of machines in data analysis, pattern recognition, and making informed decisions. CI has shown promising contributions to advancements in drug discovery, formulation, and manufacturing. Its ability to analyze vast amounts of patient data and optimize drug formulations by predicting pharmacokinetic and pharmacodynamic responses makes it a very useful platform for personalized medicine. The integration of CI with 3D printing further strengthens this potential, as 3D printing enables the fabrication of personalized medicines with precise doses, controlled-release profiles, and complex formulations. Furthermore, the automated and digital capabilities of 3D printing make it suitable for integration with CI. CI has proven useful in predicting material printability, optimizing drug release rates, designing complex structures, ensuring quality control, and improving manufacturing processes in 3D printing. In the context of customizing drug release from 3D-printed products, CI techniques have been applied to predict drug release from input variables and to design geometries that achieve the desired release profile. This review explores the role of CI in customizing drug release from 3D-printed formulations. It provides overview of limitations of 3D printing; how CI can overcome these challenges, and its potential in customizing drug release; a comparison of CI with other methods of optimization; and real-world examples of CI integration in 3D printing. Full article
(This article belongs to the Special Issue 3D Printing of Drug Delivery Systems)
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24 pages, 6587 KB  
Article
Salicylic Acid-Mediated Silver Nanoparticle Green Synthesis: Characterization, Enhanced Antimicrobial, and Antibiofilm Efficacy
by Jingqing Zhang, Yuxu Chen, Yuanyu Xu, Zhimin Zhao and Xinjun Xu
Pharmaceutics 2025, 17(4), 532; https://doi.org/10.3390/pharmaceutics17040532 - 18 Apr 2025
Cited by 4 | Viewed by 1933
Abstract
Objectives: Silver nanoparticles (AgNPs) were synthesized via an easy and rapid biogenic synthesis approach, utilizing the dual capabilities of salicylic acid as both a reducing and capping agent. Methods: The characterization of Salicylic Acid-Mediated Silver Nanoparticle (SA-AgNPs) was conducted using a variety of [...] Read more.
Objectives: Silver nanoparticles (AgNPs) were synthesized via an easy and rapid biogenic synthesis approach, utilizing the dual capabilities of salicylic acid as both a reducing and capping agent. Methods: The characterization of Salicylic Acid-Mediated Silver Nanoparticle (SA-AgNPs) was conducted using a variety of techniques, including ultraviolet-visible spectroscopy, dynamic light scattering, scanning electron microscopy combined with energy dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, as well as thermogravimetric analysis paired with differential scanning calorimetry. Results: SA-AgNPs demonstrated significant antibacterial properties against both Gram-positive (methicillin-resistant Staphylococcus epidermidis, Staphylococcus aureus, Cutibacterium acnes, methicillin-resistant Staphylococcus aureus) and Gram-negative (Escherichia coli), with minimum inhibitory concentrations (MICs) of 8, 9, 8, 4, and 6 μg/mL, respectively. At a concentration of 32 μg/mL, SA-AgNPs exhibited 99.9% killing efficiency against Escherichia coli (E. coli), Cutibacterium acnes (C. acnes), and methicillin-resistant Staphylococcus aureus (MRSA), within 4, 16, and 12 h, respectively. At the same concentration, SA-AgNPs effectively inhibited 95.61% of MRSA biofilm formation. SA-AgNPs induced the leakage of intracellular macromolecular substances by increasing the membrane permeability, which ultimately caused bacterial apoptosis. Conclusions: Overall, this study presents a fast and environmentally friendly approach for synthesizing SA-AgNPs, with potential applications as nano antibiotics antibacterial coatings for implantable medical devices and wound dressings. Full article
(This article belongs to the Special Issue Nanotechnology in Antibacterial Drug Delivery)
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18 pages, 4491 KB  
Article
Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies
by Monica E. Susilo, Stephan Schaller, Luis David Jiménez-Franco, Alexander Kulesza, Wilhelmus E. A. de Witte, Shang-Chiung Chen, C. Andrew Boswell, Danielle Mandikian and Chi-Chung Li
Pharmaceutics 2025, 17(4), 500; https://doi.org/10.3390/pharmaceutics17040500 - 9 Apr 2025
Cited by 1 | Viewed by 2717
Abstract
Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy [...] Read more.
Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy in solid tumors. Optimizing biodistribution is key to overcoming these challenges. Methods: A physiologically based pharmacokinetic (PBPK) model was developed that incorporates T-cell transmigration, retention, receptor binding, receptor turnover, and cellular engagement. Preclinical biodistribution data were modeled using two TCB formats: one lacking tumor target binding and another with target arm binding, each with varying CD3 affinities in a transgenic tumor-bearing mouse model. Results: The PBPK model successfully described the distribution of activated T-cells and various TCB formats. It accurately predicted preclinical biodistribution patterns, demonstrating that higher CD3 affinity leads to faster clearance from the blood and increased accumulation in T-cell-rich organs, often reducing tumor exposure. Simulations of HER2-CD3 TCB doses (0.1 µg to 100 mg) revealed monotonic increases in synapse AUC within the tumor. A bell-shaped dose-Cmax relationship for synapse formation was observed, and Tmax was delayed at higher doses. Blood PK was a reasonable surrogate for tumor synapse at low doses but less predictive at higher doses. Conclusions: We developed a whole-body PBPK model to simulate the biodistribution of T-cells and TCB molecules. The insights from this model provide a comprehensive understanding of the factors affecting PK, synapse formation, and TCB activity, aiding in dose optimization and the design of effective therapeutic strategies. Full article
(This article belongs to the Special Issue Development of Physiologically Based Pharmacokinetic (PBPK) Modeling)
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13 pages, 2723 KB  
Article
Carbon Dots as a Fluorescent Nanosystem for Crossing the Blood–Brain Barrier with Plausible Application in Neurological Diseases
by Catarina Araújo, Raquel O. Rodrigues, Manuel Bañobre-López, Adrián M. T. Silva and Rui S. Ribeiro
Pharmaceutics 2025, 17(4), 477; https://doi.org/10.3390/pharmaceutics17040477 - 6 Apr 2025
Cited by 4 | Viewed by 2566
Abstract
Background/Objectives: The development of effective therapies for brain disorders is highly correlated with the ability of drugs or nanosystems to cross the blood–brain barrier (BBB), which has been limited. Recently, carbon dots (CDs) have been receiving attention to be used as BBB-crossing [...] Read more.
Background/Objectives: The development of effective therapies for brain disorders is highly correlated with the ability of drugs or nanosystems to cross the blood–brain barrier (BBB), which has been limited. Recently, carbon dots (CDs) have been receiving attention to be used as BBB-crossing theranostic agents due to their inherent advantages, such as low size, excellent biocompatibility, high quantum yield (QY), tunable fluorescence, high drug loading, and relatively easy synthesis at low cost. The aim of this study was to design CDs with precisely controlled fluorescence properties for advanced bioimaging and an in-depth assessment of BBB permeability. Methods: CDs were synthesized using a microwave-assisted approach, optimized through microwaves’ irradiation time, and employing citric acid, urea, and sodium fluoride as precursors. The optimized sample was labeled as NF-CD. Results: A comprehensive physicochemical, photoluminescence, and biological characterization revealed the ability of NF-CD to diffuse across a neuromimetic-BBB model, mainly due to their small size (average diameter of 4.0 ± 1.1 nm), exhibiting excitation-dependent fluorescence in the blue and green wavelengths, high biocompatibility and QY, and exceptional photostability. Conclusions: Owing to the exceptional fluorescence characteristics and biological compatibility, NF-CD presents promising opportunities in theranostic applications, particularly in brain-targeted bioimaging, nanocarrier-based drug and immunotherapy delivery, early-stage diagnostics, and personalized medicine. NF-CD’s ability to cross the BBB further underscores the relevance of pioneering nanomaterial-based strategies for neurological disorder diagnostics and precision-targeted therapeutic interventions. Overall, this research contributes to the broader field of nanotechnology-driven biomedical advancements, fostering innovations in neurological diagnostics and therapeutic delivery systems. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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27 pages, 9025 KB  
Article
Optimization, In Vitro, and In Silico Characterization of Theophylline Inhalable Powder Using Raffinose-Amino Acid Combination as Fine Co-Spray-Dried Carriers
by Petra Party, Lomass Soliman, Attila Nagy, Árpád Farkas and Rita Ambrus
Pharmaceutics 2025, 17(4), 466; https://doi.org/10.3390/pharmaceutics17040466 - 3 Apr 2025
Cited by 4 | Viewed by 2313
Abstract
Background/Objectives: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN’s physicochemical and aerodynamic properties to ensure [...] Read more.
Background/Objectives: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN’s physicochemical and aerodynamic properties to ensure efficient lung deposition. Methods: The process involves spray-drying each formulation’s solution using a mini spray drier. A rigorous assessment was conducted on particle size distribution, structural and thermal analysis, morphology study, in vitro and in silico aerodynamic investigation, and aerodynamic particle counter in addition to the solubility, in vitro dissolution, and diffusion of TN. Results: The carriers containing leucine and glycine revealed superior characteristics (mass median aerodynamic diameter (MMAD): 4.6–5 µm, fine particle fraction (FPF): 30.6–35.1%, and amorphous spherical structure) as candidates for further development of TN-DPIs, while arginine was excluded due to intensive aggregation and hygroscopicity, which led to poor aerodynamic performance. TN co-spray-dried samples demonstrated fine micronized particles (D [0.5]: 3.99–5.96 µm) with predominantly amorphous structure (crystallinity index: 24.1–45.2%) and significant solubility enhancement (~19-fold). Formulations containing leucine and leucine-glycine revealed the highest FPF (45.7–47.8%) and in silico lung deposition (39.3–40.1%), rapid in vitro drug release (~100% within 10 min), and improved in vitro diffusion (2.29–2.43-fold), respectively. Moreover, the aerodynamic counter confirmed the development of fine microparticles (mean number particle size = 2.3–2.02 µm). Conclusions: This innovative formulation possesses enhanced physicochemical, morphological, and aerodynamic characteristics of low-dose TN for local asthma treatment and could be applied as a promising carrier for dry powder inhaler development. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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16 pages, 1717 KB  
Article
Anti-Candida Activity of Cysteine-Modified Amidated Decoralin in the Presence of Engineered Nanomaterials
by Vânia Rocha, Helena Almeida, Bruno Sarmento and José das Neves
Pharmaceutics 2025, 17(4), 460; https://doi.org/10.3390/pharmaceutics17040460 - 2 Apr 2025
Cited by 1 | Viewed by 1352
Abstract
Background: Candidiasis remains a chief concern in global healthcare. Drug safety issues and increasing resistance make it urgent to develop alternative antifungal agents, namely antimicrobial peptides. Amidated decoralin (Dec-CONH2) possesses considerable anti-Candida activity, and its association with nanocarriers could help [...] Read more.
Background: Candidiasis remains a chief concern in global healthcare. Drug safety issues and increasing resistance make it urgent to develop alternative antifungal agents, namely antimicrobial peptides. Amidated decoralin (Dec-CONH2) possesses considerable anti-Candida activity, and its association with nanocarriers could help in enhancing efficacy while reducing intrinsic toxicity to the host. Methods: We studied an N-terminal cysteine-modified version of the peptide (Cys-Dec-CONH2) and screened the effects of different nanosystems (polymeric nanoparticles (NPs), liposomes and gold NPs) on its activity against azole-sensitive and azole-resistant Candida species using a clinically relevant in vitro assay. Results: The antifungal activity of Cys-Dec-CONH2 was maintained (minimum inhibitory concentration (MIC) = 16–64 µg/mL), but the presence of poly(d,l-lactic-co-glycolic acid) (PLGA)- and polycaprolactone-based NPs impaired the antifungal effect of the peptide (MIC > 256 µg/mL). This effect was milder for polystyrene-based NPs, liposomes, and gold NPs (MIC ≤ 128 µg/mL). Additionally, the covalent surface functionalization of PLGA-based NPs with Cys-Dec-CONH2 or the presence of relevant biomolecules (albumin and mucin) resulted in complete inhibition of antifungal activity. Conclusions: Our data suggest that Cys-Dec-CONH2 is able to establish strong interfacial interactions with different nanomaterials, which need to be considered when developing nanomedicines based on this peptide for the management of candidiasis. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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44 pages, 7303 KB  
Review
Advances in Drug Delivery Integrated with Regenerative Medicine: Innovations, Challenges, and Future Frontiers
by Manoochehr Rasekh, Muhammad Sohail Arshad and Zeeshan Ahmad
Pharmaceutics 2025, 17(4), 456; https://doi.org/10.3390/pharmaceutics17040456 - 1 Apr 2025
Cited by 21 | Viewed by 3513
Abstract
Advances in drug delivery systems adapted with regenerative medicine have transformed healthcare by introducing innovative strategies to treat (and repair in many instances) disease-impacted regions of the human body. This review provides a comprehensive analysis of the latest developments and challenges in integrating [...] Read more.
Advances in drug delivery systems adapted with regenerative medicine have transformed healthcare by introducing innovative strategies to treat (and repair in many instances) disease-impacted regions of the human body. This review provides a comprehensive analysis of the latest developments and challenges in integrating drug delivery technologies with regenerative medicine. Recent advances in drug delivery technologies, including the design of biomaterials, localized delivery techniques, and controlled release systems guided by mathematical models, are explored to illustrate their role in enhancing therapeutic precision and efficacy. Additionally, regenerative medicine approaches are analyzed, with a focus on extracellular matrix components, stem cell-based therapies, and emerging strategies for organ regeneration in both soft and hard tissue and in vitro model engineering. In particular, the review also discusses the applications of cellular components, including stem cells, immune cells, endothelial cells, and specialized cells such as chondrocytes and osteoblasts, and highlights advancements in cell delivery methods and cell–cell interaction modulation. In addition, future directions and pivotal trends emphasizing the importance of interdisciplinary collaboration and cutting-edge innovations are provided to address successful therapeutic outcomes in regenerative medicine. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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16 pages, 2909 KB  
Article
Development of Inhalable Bacteriophage Liposomes Against Pseudomonas aeruginosa
by Shruti S. Sawant, Maizbha Uddin Ahmed, Nathan-Gautham Gantala, Caitlin Chiu, Li Qu and Qi Zhou
Pharmaceutics 2025, 17(4), 405; https://doi.org/10.3390/pharmaceutics17040405 - 24 Mar 2025
Cited by 9 | Viewed by 2463
Abstract
Background: Pseudomonas aeruginosa is one of the major pathogens that cause respiratory infections. The rise of antimicrobial resistance has prompted a need for alternatives to conventional antibiotics. Bacteriophages (phages), natural predators of bacteria, are gaining interest as an alternative therapeutic option against [...] Read more.
Background: Pseudomonas aeruginosa is one of the major pathogens that cause respiratory infections. The rise of antimicrobial resistance has prompted a need for alternatives to conventional antibiotics. Bacteriophages (phages), natural predators of bacteria, are gaining interest as an alternative therapeutic option against drug-resistant infections. However, phage viability can be lost during manufacturing and delivery. Recent studies show that phages can be taken up by lung epithelial cells, which makes fewer phages available for antibacterial action against extracellular bacteria P. aeruginosa in the airways. Methods: In this study, we encapsulated phages in liposomes using thin film hydration. The effect of processing conditions and phage loading titer on the phage encapsulation and viability was studied. The impact of nebulization on phage viability was tested using an air-jet nebulizer (PARI-LC Plus). Phage cellular uptake was evaluated using an in vitro H441 lung epithelial cell model, grown at the air–liquid interface. Results: Our results demonstrate favorable encapsulation (58 ± 6.02%) can be achieved with minimum loss in phage titer (0.64 ± 0.21 log) by using a low phage titer for hydration. The liposomal formulations exhibited controlled release of phages over 10 h. The formulation also reduced the loss of phage viability during nebulization from 1.55 ± 0.04 log (for phage suspension) to 1.08 ± 0.05 log (for phage liposomes). Encapsulation of phages in liposomes enabled a two-fold reduction in phage cellular uptake and longer extracellular phage retention in the human lung epithelial cell monolayer. Conclusions: Our results indicate that liposomal encapsulation favors phage protection and improves phage availability for antibacterial activity. These findings highlight the potential of liposomes for inhaled phage delivery. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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17 pages, 6660 KB  
Article
Development and Optimization of Chitosan-Ascorbate-Based Mucoadhesive Films for Buccal Delivery of Captopril
by Krisztián Pamlényi, Hala Rayya, Alharith A. A. Hassan, Orsolya Jójárt-Laczkovich, Tamás Sovány, Klára Pintye-Hódi, Géza Regdon, Jr. and Katalin Kristó
Pharmaceutics 2025, 17(4), 401; https://doi.org/10.3390/pharmaceutics17040401 - 22 Mar 2025
Cited by 1 | Viewed by 1806
Abstract
Background: Captopril (CAP), an angiotensin-converting enzyme inhibitor (ACEI), is widely prescribed for managing hypertension, heart failure, and related conditions. When administered orally, CAP undergoes hepatic metabolism, resulting in a bioavailability of 60–75%. However, to bypass the first-pass metabolism and other limitations of the [...] Read more.
Background: Captopril (CAP), an angiotensin-converting enzyme inhibitor (ACEI), is widely prescribed for managing hypertension, heart failure, and related conditions. When administered orally, CAP undergoes hepatic metabolism, resulting in a bioavailability of 60–75%. However, to bypass the first-pass metabolism and other limitations of the oral route, mucoadhesive buccal films have gained attention as a promising alternative with several advantages. The aim of this work was the formulation and optimization of chitosan-ascorbate mucoadhesive films for buccal delivery of CAP for the management of a hypertension crisis (10 mg and 20 mg) by employing quality by design (QbD) principles and the design of experiment (DoE) approach. Materials and methods: In the present work, chitosan (CHI) was selected as a film-forming agent due to its permeability-enhancing properties, which could be further improved through salification with ascorbic acid (AA). The polymer films were prepared by the solvent casting method. Results: The optimized CAP-loaded formula showed appropriate in vitro mucoadhesion force (>15 N) and breaking hardness (>14 N). The different CAP-containing films had a high drug content (>95%) with homogeneous drug distribution, thus complying with the requirements of Pharmacopeia. FT-IR and RAMAN spectroscopy analyses demonstrated successful incorporation of the drug, and interaction was observed between the excipients of the films, especially in the form of hydrogen bonds. The dissolution test showed immediate release of the API with a similar release pattern from both concentrations of CAP-loaded films. Conclusions: The properties of the prepared films met the predetermined critical quality attribute requirements. The optimized formula of CHI 1.4%, AA 2.5%, and glycerol 0.3% appears to be a promising buccal drug delivery system for CAP. Full article
(This article belongs to the Special Issue Development and Optimization of Buccal Films Formulations)
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16 pages, 6558 KB  
Article
Simvastatin-Loaded Chitosan-Functionalized PLGA Nanoparticles: Characterization and Use in Intimal Hyperplasia Therapy
by Ashley A. Peters, Chanpreet Kaur, Maleen Cabe, Kelly A. Langert, Kristopher Maier and Vivian Gahtan
Pharmaceutics 2025, 17(3), 391; https://doi.org/10.3390/pharmaceutics17030391 - 20 Mar 2025
Viewed by 1609
Abstract
Background: Statins have beneficial pleiotropic effects, including reducing intimal hyperplasia (IH), but off-target effects remain a concern. Here, we tested the hypothesis that chitosan-functionalized polymeric nanoparticles (NPs) loaded with simvastatin (SL-cNPs) would (1) readily associate with endothelial cells (ECs) and vascular smooth [...] Read more.
Background: Statins have beneficial pleiotropic effects, including reducing intimal hyperplasia (IH), but off-target effects remain a concern. Here, we tested the hypothesis that chitosan-functionalized polymeric nanoparticles (NPs) loaded with simvastatin (SL-cNPs) would (1) readily associate with endothelial cells (ECs) and vascular smooth muscle cells (VSMCs); (2) affect EC and VSMC function; and (3) reduce IH compared to systemic simvastatin. Methods: Human aortic ECs and VSMCs were cultured with fluorescently labeled SL-cNPs. The association of SL-cNPs was assessed by immunostaining and flow cytometry. The effect of SL-cNPs, empty cNPs (E-cNPs), and free simvastatin on cells was determined using qRT-PCR for RhoA and RhoB. Carotid artery balloon-injured rats were treated intraoperatively with intraluminal saline, E-cNPs, low- or high-dose SL-cNPs, periadventitial high-dose SL-cNPs, or with pre- and post-operative oral simvastatin plus intraoperative intraluminal saline or low-dose SL-cNPs. Rats were euthanized (day 14) and IH was quantified. Results: SL-cNPs readily associated with ECs and VSMCs. Low- and high-dose SL-cNPs induced significant increases in EC and VSMC RhoA gene expression. High-dose SL-cNPs induced a significant increase in EC RhoB expression, while free simvastatin and low- and high-dose SL-cNPs significantly increased RhoB expression in VSMCs. In vivo, oral simvastatin plus intraluminal SL-cNPs significantly reduced IH compared to controls. Conclusions: cNPs can be used as a vehicle to locally deliver statins to vascular cells. However, other NP formulations may be preferential for IH reduction given only the combination of oral simvastatin and SL-cNPs effectively reduced IH. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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19 pages, 1651 KB  
Review
Nanotechnology-Based Therapies for Preventing Post-Surgical Adhesions
by Zi Yi Teo, Samyuktha Dhanalakshmi Senthilkumar and Dinesh Kumar Srinivasan
Pharmaceutics 2025, 17(3), 389; https://doi.org/10.3390/pharmaceutics17030389 - 19 Mar 2025
Cited by 2 | Viewed by 2514
Abstract
Adhesions are the body’s natural response to various inflammatory causes, with surgery being the most common cause. However, the formation of postoperative adhesions can lead to significant complications, including intestinal obstruction and chronic pain. To prevent such postoperative complications associated with adhesions, developing [...] Read more.
Adhesions are the body’s natural response to various inflammatory causes, with surgery being the most common cause. However, the formation of postoperative adhesions can lead to significant complications, including intestinal obstruction and chronic pain. To prevent such postoperative complications associated with adhesions, developing effective strategies for adhesion prevention has been a major focus of research. Currently, several therapeutic models have been developed to achieve this objective. These include pharmaceuticals, inert polymers, functional biomaterials, and nanotherapeutics. Among the various strategies developed, nanotherapeutics, though still in its early stages, has shown promise as a potential approach. Other therapeutic models are associated with adverse side effects and complications related to their application. On the other hand, nanotherapeutic models are able to overcome the limitations of the other strategies and provide their own set of unique advantages. Hence, nanotherapeutics represents a promising area for further research. Further efforts should be made to refine existing nanotherapeutics for clinical application while also addressing associated safety and ethical concerns related to their use in medical practice. Therefore, this article aims to review the various nanotherapeutic approaches developed for the prevention of postoperative adhesions, explore their regulatory pathways, and discuss associated safety and ethical concerns. Full article
(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)
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31 pages, 4979 KB  
Review
Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles
by Yuan Zou, Jing Zhang, Longmin Chen, Qianqian Xu, Sheng Yao and Hong Chen
Pharmaceutics 2025, 17(3), 388; https://doi.org/10.3390/pharmaceutics17030388 - 18 Mar 2025
Cited by 8 | Viewed by 4411
Abstract
Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently [...] Read more.
Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood–brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases. Full article
(This article belongs to the Special Issue Advances in Oral Delivery of Lipid Nanoparticles for Treating Inflammatory Diseases)
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26 pages, 3935 KB  
Article
Nasal Administration of a Nanoemulsion Based on Methyl Ferulate and Eugenol Encapsulated in Chitosan Oleate: Uptake Studies in the Central Nervous System
by Giada Botti, Laura Catenacci, Alessandro Dalpiaz, Luca Randi, Maria Cristina Bonferoni, Sara Perteghella, Sarah Beggiato, Luca Ferraro, Barbara Pavan and Milena Sorrenti
Pharmaceutics 2025, 17(3), 367; https://doi.org/10.3390/pharmaceutics17030367 - 13 Mar 2025
Cited by 2 | Viewed by 1614
Abstract
Background/Objectives: The phytochemicals ferulic acid (Fer) and eugenol display neuroprotective effects for their anti-oxidative properties; moreover, eugenol can induce dopamine (DA) release from dopaminergic neuronal cells. However, poor bioavailability and/or fast elimination rate limit their clinical benefits. We therefore propose a new [...] Read more.
Background/Objectives: The phytochemicals ferulic acid (Fer) and eugenol display neuroprotective effects for their anti-oxidative properties; moreover, eugenol can induce dopamine (DA) release from dopaminergic neuronal cells. However, poor bioavailability and/or fast elimination rate limit their clinical benefits. We therefore propose a new nasal formulation based on a nanoemulsion (NE) for the jointed brain-targeting of eugenol and methyl ferulate (Fer-Me, i.e., a Fer-lipidized derivative maintaining the parent compound anti-oxidative properties). NE was obtained using chitosan oleate, a surfactant combining mucoadhesive and absorption-enhancing properties with stabilizing effects on the dispersion of eugenol, used as a Fer-Me vehicle. Methods: The nasal formulation was obtained by spontaneous emulsification processes; cell viability and uptake studies were performed on an in vitro model of respiratory mucosa (RPMI 2650 cells). After intravenous and nasal administrations, the pharmacokinetic profiles of eugenol and Fer-Me in rats’ bloodstreams and cerebrospinal fluid (CSF) were analyzed via HPLC-UV analysis. Results: The NE dispersed-phase mean diameter was 249.22 ± 32.78 nm; Fer-Me and eugenol loading in NE was about 1 and 2 mg/mL, respectively. NE increased the uptake of loaded compounds by mucosal cells. Following intravenous administration, the Fer-Me plasma half-life was 10.08 ± 0.37 min, and a negligible ability of the compound to permeate in the CSF, compared to eugenol, was observed. NE nasal administration allowed us to sensibly increase the Fer-Me brain-targeting and prolong the eugenol permanence in the CSF. Conclusions: This nasal formulation appears promising to overcome Fer and eugenol pharmacokinetic issues. The possible translational relevance of the present findings is discussed. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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31 pages, 1762 KB  
Review
Pharmaceutical 3D Printing Technology Integrating Nanomaterials and Nanodevices for Precision Neurological Therapies
by Jurga Bernatoniene, Mindaugas Plieskis and Kestutis Petrikonis
Pharmaceutics 2025, 17(3), 352; https://doi.org/10.3390/pharmaceutics17030352 - 9 Mar 2025
Cited by 6 | Viewed by 3534
Abstract
Pharmaceutical 3D printing, combined with nanomaterials and nanodevices, presents a transformative approach to precision medicine for treating neurological diseases. This technology enables the creation of tailored dosage forms with controlled release profiles, enhancing drug delivery across the blood−brain barrier (BBB). The integration of [...] Read more.
Pharmaceutical 3D printing, combined with nanomaterials and nanodevices, presents a transformative approach to precision medicine for treating neurological diseases. This technology enables the creation of tailored dosage forms with controlled release profiles, enhancing drug delivery across the blood−brain barrier (BBB). The integration of nanoparticles, such as poly lactic-co-glycolic acid (PLGA), chitosan, and metallic nanomaterials, into 3D-printed scaffolds improves treatment efficacy by providing targeted and prolonged drug release. Recent advances have demonstrated the potential of these systems in treating conditions like Parkinson’s disease, epilepsy, and brain tumors. Moreover, 3D printing allows for multi-drug combinations and personalized formulations that adapt to individual patient needs. Novel drug delivery approaches, including stimuli-responsive systems, on-demand dosing, and theragnostics, provide new possibilities for the real-time monitoring and treatment of neurological disorders. Despite these innovations, challenges remain in terms of scalability, regulatory approval, and long-term safety. The future perspectives of this technology suggest its potential to revolutionize neurological treatments by offering patient-specific therapies, improved drug penetration, and enhanced treatment outcomes. This review discusses the current state, applications, and transformative potential of 3D printing and nanotechnology in neurological treatment, highlighting the need for further research to overcome the existing challenges. Full article
(This article belongs to the Special Issue Applications of Nanomaterials in Drug Delivery and Drug Release)
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22 pages, 2396 KB  
Article
Analysis of Polymer/siRNA Nanoparticle Efficacy and Biocompatibility in 3D Air–Liquid Interface Culture Compared to 2D Cell Culture
by Sandra Noske, Martin Krueger, Alexander Ewe and Achim Aigner
Pharmaceutics 2025, 17(3), 339; https://doi.org/10.3390/pharmaceutics17030339 - 6 Mar 2025
Cited by 1 | Viewed by 1894
Abstract
Background: Polymeric nanoparticles have been explored as efficient tools for siRNA delivery to induce RNAi-mediated gene knockdown. Chemical modifications of polyethylenimines (PEI) enhance nanoparticle efficacy and biocompatibility. Their in vivo use, however, benefits from prior analyses in relevant in vitro 3D conditions. Methods: [...] Read more.
Background: Polymeric nanoparticles have been explored as efficient tools for siRNA delivery to induce RNAi-mediated gene knockdown. Chemical modifications of polyethylenimines (PEI) enhance nanoparticle efficacy and biocompatibility. Their in vivo use, however, benefits from prior analyses in relevant in vitro 3D conditions. Methods: We utilize a 3D ALI cell culture model for testing the biological activities and toxicities of a set of different PEI-based nanoparticles with different chemical modifications. This also includes a novel, fluoroalkyl-modified PEI. Reporter gene knockdown is directly compared to 2D cell culture. In parallel, biocompatibility is assessed by measuring cell viability and lactate dehydrogenase (LDH) release. Results: Knockdown efficacies in the 3D ALI model are dependent on the chemical modification and complex preparation conditions. Results only correlate in part with gene knockdown in 2D cell culture, identifying nanoparticle penetration and cellular internalization under 3D conditions as important parameters. The 3D ALI cell culture is also suitable for the quantitative determination of nanoparticle effects on cell viability and acute toxicity, with biocompatibility benefitting from PEI modifications. Conclusions: The 3D ALI cell model allows for a more realistic assessment of biological nanoparticle effects. A novel fluoroalkyl-modified PEI is described. Optimal preparations of PEI-based nanoparticles for siRNA delivery and gene knockdown are identified. Full article
(This article belongs to the Special Issue Current Research on Polymeric Nanoparticles for Drug Delivery Applications)
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24 pages, 4800 KB  
Article
The Role of Natural Deep Eutectic Solvents in a Hydrogel Formulation Containing Lidocaine
by Feria Hasanpour, Mária Budai-Szűcs, Anita Kovács, Rita Ambrus, Orsolya Jójárt-Laczkovich, Boglárka Szalai, Branimir Pavlić, Péter Simon, Levente Törteli and Szilvia Berkó
Pharmaceutics 2025, 17(3), 324; https://doi.org/10.3390/pharmaceutics17030324 - 2 Mar 2025
Cited by 4 | Viewed by 3503
Abstract
Background/Objectives: This study investigates the use of natural deep eutectic solvents (NADESs) in enhancing the solubility and skin permeation of a lidocaine base, a lipophilic form, in hydrogel systems. The aim was to develop an environmentally sustainable and biocompatible alternative to conventional [...] Read more.
Background/Objectives: This study investigates the use of natural deep eutectic solvents (NADESs) in enhancing the solubility and skin permeation of a lidocaine base, a lipophilic form, in hydrogel systems. The aim was to develop an environmentally sustainable and biocompatible alternative to conventional lidocaine formulations, improving the dermal permeation and therapeutic efficacy. Methods: The lidocaine base was dissolved in a hydrophilic NADES system composed of choline chloride and citric acid, facilitating enhanced solubility, likely through new molecular interactions. Then, pH-adjusted hydrogels were formulated and optimized by employing a 32 full factorial design. Raman and nuclear magnetic resonance (NMR) spectroscopy were applied to evaluate the stability of lidocaine in the optimal formulation. The biopharmaceutical properties were investigated using in vitro drug release and skin permeation studies. In vivo tests assessed physiological skin parameters such as the hydration and transepidermal water loss. Results: The developed NADES-containing hydrogel significantly improved the solubility and stability of lidocaine. Skin permeation studies demonstrated enhanced dermal permeation compared with conventional hydrogel and ointment. These improvements, namely the enhanced solubility of lidocaine in the formulation and its increased permeation, were attributed to the dual effect of the NADES. Conclusions: NADES-containing hydrogels represent a promising green technology for formulating lidocaine-containing dermal preparations. This approach offers a biocompatible, natural-based alternative that can enhance the bioavailability and efficacy of topical anesthetics. Full article
(This article belongs to the Special Issue Transdermal Delivery: Challenges and Opportunities)
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15 pages, 2556 KB  
Article
A Step Towards Real-Time Release Testing of Pharmaceutical Tablets: Utilization of CIELAB Color Space
by René Brands, Trieu Nam Le, Jens Bartsch and Markus Thommes
Pharmaceutics 2025, 17(3), 311; https://doi.org/10.3390/pharmaceutics17030311 - 28 Feb 2025
Cited by 5 | Viewed by 2190
Abstract
Background: The pharmaceutical industry is shifting from end-product testing towards real-time release testing. This approach is based on the continuous collection of process data and product information, which is finally utilized for the release decision. For continuous direct compression, spectroscopic technologies are preferred [...] Read more.
Background: The pharmaceutical industry is shifting from end-product testing towards real-time release testing. This approach is based on the continuous collection of process data and product information, which is finally utilized for the release decision. For continuous direct compression, spectroscopic technologies are preferred due to their short acquisition time and non-destructive nature. Methods: Here, the feasibility of the CIELAB color space was demonstrated for porosity and tensile strength. Five different formulations were processed, varying in particle size and deformation behavior. The compression forces were varied from 3 to 18 kN and the CIELAB color space was measured in-line using a UV/Vis probe implemented in the ejection position of the tablet machine. Results: Increasing the main compression force during tableting decreases the tablet surface roughness and porosity. In addition, the tablet tensile strength increases. These changes affected the reflection behavior of radiation on the tablet surface, resulting in a change in the chroma value C*. These dependencies were utilized for the in-line monitoring of porosity and tensile strength. Linear relations were observed for all formulations as exemplary, indicated by sufficient coefficients of determination and verification runs. Conclusions: Finally, UV/Vis diffuse reflectance spectroscopy in combination with a CIELAB color space transformation was demonstrated to be a suitable real-time release tool. Full article
(This article belongs to the Special Issue Pharmaceutical Solids: Advanced Manufacturing and Characterization)
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25 pages, 9259 KB  
Article
Formulation of W/O/W Emulsion-Based Chitosan-Alginate Microcapsules for Encapsulation of Cannabidiol and A. annua L. Extract Containing Luteolin and Apigenin: A Response Surface Optimization Approach
by Emilija Nemickaite, Ugne Zlabiene, Agne Mazurkeviciute, Mindaugas Marksa and Jurga Bernatoniene
Pharmaceutics 2025, 17(3), 309; https://doi.org/10.3390/pharmaceutics17030309 - 28 Feb 2025
Cited by 4 | Viewed by 3473
Abstract
Background/Objectives: Chitosan–alginate microcapsules were produced to encapsulate bioactive compounds from Artemisia annua L. extract (apigenin, luteolin) and cannabidiol (CBD). The study aimed to optimize emulsion composition and encapsulation parameters for potential applications in food supplements and pharmaceuticals. Methods: A water-in-oil-in-water (W/O/W) emulsion and [...] Read more.
Background/Objectives: Chitosan–alginate microcapsules were produced to encapsulate bioactive compounds from Artemisia annua L. extract (apigenin, luteolin) and cannabidiol (CBD). The study aimed to optimize emulsion composition and encapsulation parameters for potential applications in food supplements and pharmaceuticals. Methods: A water-in-oil-in-water (W/O/W) emulsion and a modified coacervation extrusion technique were employed. The study was conducted in two phases using response surface methodology. Key metrics included encapsulation efficiency (EE), yield (EY), cumulative release in vitro, and physicochemical and morphological properties, analyzed via scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), high-performance liquid chromatography with a diode array detector (HPLC-DAD), and gas chromatography with flame ionization detection (GC-FID). Results: The optimal conditions were identified as 0.1% Tween 20, 3.8% Span 80, 3.8% CBD, 19.9% A. annua L. extract, 1.5% outer-phase Tween 20, 48.5% sodium alginate, 200 rpm stirring for 30 min, and a 0.05 mL/min flow rate. The EE values were 80.32 ± 4.11% for CBD, 88.13 ± 3.13% for apigenin, and 88.41 ± 4.17% for luteolin, with respective cumulative releases of 77.18 ± 4.4%, 75.12 ± 4.81%, and 75.32 ± 4.53%. Conclusions: The developed microcapsules demonstrated high encapsulation efficiency and controlled release, highlighting their potential for further development in food supplements and pharmaceuticals. Future studies should focus on refining the formulation for improved bioavailability and stability. Full article
(This article belongs to the Special Issue Natural Pharmaceuticals Focused on Anti-inflammatory Activities)
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25 pages, 6641 KB  
Article
Development of an Innovative Dual Construct for Targeted Drug Delivery in the Oral Cavity
by Elena Mazzinelli, Ilaria Favuzzi, Marianna Messina, Giorgia Fratocchi, Federica Vincenzoni, Eleonora Santo Stefano, Francesco Cecconi, Carlo Lajolo, Alessia Basco, Raffaella Castagnola, Massimo Cordaro, Francesco Scilla, Valerio Papa, Alessandro Arcovito, Ilaria Cacciotti and Giuseppina Nocca
Pharmaceutics 2025, 17(2), 272; https://doi.org/10.3390/pharmaceutics17020272 - 18 Feb 2025
Cited by 6 | Viewed by 1789
Abstract
Background: Oral lichen planus (OLP) is a chronic autoimmune disease of the oral mucosa, classified among potentially malignant oral disorders (OPMDs). It is characterized by keratinocyte apoptosis and persistent inflammation. Standard treatments involve topical corticosteroids administered via mouthwashes, gels, or ointments, but these [...] Read more.
Background: Oral lichen planus (OLP) is a chronic autoimmune disease of the oral mucosa, classified among potentially malignant oral disorders (OPMDs). It is characterized by keratinocyte apoptosis and persistent inflammation. Standard treatments involve topical corticosteroids administered via mouthwashes, gels, or ointments, but these require frequent application, have limited retention, and may cause side effects. To address these limitations, this study aimed to develop an innovative dexamethasone delivery system targeting the oral cavity, based on poly(lactic acid) (PLA) fibers coated with chitosan (CS) and poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Methods: CS-coated PLA fibers were characterized for their mucoadhesive and cytocompatibility properties, while PLGA nanoparticles were analyzed for size, shape, encapsulation efficiency, cellular uptake, drug release efficiency, and cytocompatibility. Results: Both polymers demonstrated cytocompatibility, and chitosan-coated PLA fibers exhibited mucoadhesive properties. PLGA nanoparticles were effectively internalized by the cells and successfully released the drug into the cytoplasm. The combination of CS-coated PLA fibers and PLGA nanoparticles provided dual benefits: mucoadhesion and efficient cellular uptake, even under conditions simulating salivation. Conclusions: These findings highlight the potential of the proposed system to improve mucoadhesive drug delivery. Further optimization is needed to enhance patient compliance and therapeutic efficacy. Full article
(This article belongs to the Special Issue Next-Generation Biomaterials for Oral Healthcare: Focus on Regenerative and Delivery Functions)
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17 pages, 3780 KB  
Review
Roles of Supersaturation and Liquid–Liquid Phase Separation for Enhanced Oral Absorption of Poorly Soluble Drugs from Amorphous Solid Dispersions
by Kohsaku Kawakami
Pharmaceutics 2025, 17(2), 262; https://doi.org/10.3390/pharmaceutics17020262 - 16 Feb 2025
Cited by 3 | Viewed by 3240
Abstract
Amorphous solid dispersion (ASD) is one of the most important enabling formulation technologies for the development of poorly soluble drugs. Because of its thermodynamically unstable nature in both solid and wet states, the evaluation and optimization of the formulation performance involves some difficulties. [...] Read more.
Amorphous solid dispersion (ASD) is one of the most important enabling formulation technologies for the development of poorly soluble drugs. Because of its thermodynamically unstable nature in both solid and wet states, the evaluation and optimization of the formulation performance involves some difficulties. The dissolution process is sensitively influenced by various factors, including the applied dose, medium composition, and pH. Supersaturated solutions can cause liquid–liquid phase separation (LLPS) and/or crystallization, which complicates the comprehension of the dissolution process. However, LLPS should be evaluated carefully because it is closely related to oral absorption. As LLPS concentration is analogous to amorphous solubility, it can be a key factor in predicting oral absorption from ASDs, if absorption is limited by solubility. Moreover, LLPS droplets are expected to increase transmembrane flux by increasing the drug concentration near the epithelial cell membrane. In this review, recently updated knowledge on the dissolution, membrane permeation, and oral absorption behaviors of ASDs is discussed with an emphasis on LLPS behavior. Full article
(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology, 3rd Edition)
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36 pages, 3932 KB  
Review
Innovations in Cancer Therapy: Endogenous Stimuli-Responsive Liposomes as Advanced Nanocarriers
by Jazmín Torres, Johanna Karina Valenzuela Oses, Antonio María Rabasco-Álvarez, María Luisa González-Rodríguez and Mónica Cristina García
Pharmaceutics 2025, 17(2), 245; https://doi.org/10.3390/pharmaceutics17020245 - 13 Feb 2025
Cited by 14 | Viewed by 5632
Abstract
Recent advancements in nanotechnology have revolutionized cancer therapy—one of the most pressing global health challenges and a leading cause of death—through the development of liposomes (L), lipid-based nanovesicles known for their biocompatibility and ability to encapsulate both hydrophilic and lipophilic drugs. More recent [...] Read more.
Recent advancements in nanotechnology have revolutionized cancer therapy—one of the most pressing global health challenges and a leading cause of death—through the development of liposomes (L), lipid-based nanovesicles known for their biocompatibility and ability to encapsulate both hydrophilic and lipophilic drugs. More recent innovations have led to the creation of stimuli-responsive L that release their payloads in response to specific endogenous or exogenous triggers. Dual- and multi-responsive L, which react to multiple stimuli, offer even greater precision, improving therapeutic outcomes while reducing systemic toxicity. Additionally, these smart L can adjust their physicochemical properties and morphology to enable site-specific targeting and controlled drug release, enhancing treatment efficacy while minimizing adverse effects. This review explores the latest advancements in endogenous stimuli-responsive liposomal nanocarriers, as well as dual- and multi-responsive L that integrate internal and external triggers, with a focus on their design strategies, mechanisms, and applications in cancer therapy. Full article
(This article belongs to the Special Issue Lipid Nanostructures as Drug Carriers for Cancer Therapy)
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13 pages, 3020 KB  
Article
C24 Ceramide Lipid Nanoparticles for Skin Wound Healing
by Ji-Hye Lee, Jin-Hyun Kim, Tong-Il Hyeon, Khee-Tae Min, Se-Young Lee, Han-Chul Ko, Hong-Seok Choi, Kuk-Youn Ju, Young-Seok Cho and Tae-Jong Yoon
Pharmaceutics 2025, 17(2), 242; https://doi.org/10.3390/pharmaceutics17020242 - 12 Feb 2025
Cited by 6 | Viewed by 3453
Abstract
Background/Objectives: C24 ceramide plays a crucial role in skin regeneration and wound healing; however, its hydrophobic nature limits its application in therapeutic formulations. This study aims to enhance the bioavailability and efficacy of C24 ceramide by developing ceramide-based lipid nanoparticles (C24-LNP) and [...] Read more.
Background/Objectives: C24 ceramide plays a crucial role in skin regeneration and wound healing; however, its hydrophobic nature limits its application in therapeutic formulations. This study aims to enhance the bioavailability and efficacy of C24 ceramide by developing ceramide-based lipid nanoparticles (C24-LNP) and evaluate their impact on skin regeneration and wound healing. Methods: C24-LNP was synthesized and characterized for aqueous stability and bioavailability. In vitro experiments were conducted to assess its effects on keratinocyte proliferation and migration. Molecular biological analysis examined key signaling pathways, including AKT and ERK1/2 phosphorylation. Additionally, an in vivo mouse wound model was utilized to evaluate wound healing efficacy, with histological analysis performed to assess epidermal and dermal regeneration. Results: C24-LNP exhibited improved aqueous stability and bioavailability compared to free C24 ceramide. In vitro studies demonstrated that C24-LNP significantly promoted keratinocyte proliferation and migration. Molecular analysis revealed activation of the AKT and ERK1/2 signaling pathways, which are critical for cell growth and skin regeneration. In vivo wound healing experiments showed that C24-LNP accelerated wound closure compared to the control group. Histological analysis confirmed enhanced epidermal and dermal regeneration, leading to improved structural and functional skin repair. Conclusion: The lipid nanoparticle formulation of C24 ceramide effectively increases its bioavailability and enhances its therapeutic efficacy in skin regeneration and wound healing. C24-LNP presents a scalable and cost-effective alternative to traditional growth factor-based therapies, offering significant potential for clinical applications in wound care and dermatological treatments. Full article
(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)
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47 pages, 3462 KB  
Review
Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems
by Ernesto J. Delgado-Pujol, Guillermo Martínez, David Casado-Jurado, Juan Vázquez, Jesús León-Barberena, David Rodríguez-Lucena, Yadir Torres, Ana Alcudia and Belén Begines
Pharmaceutics 2025, 17(2), 215; https://doi.org/10.3390/pharmaceutics17020215 - 7 Feb 2025
Cited by 98 | Viewed by 8709
Abstract
Conventional drug delivery approaches, including tablets and capsules, often suffer from reduced therapeutic effectiveness, largely attributed to inadequate bioavailability and difficulties in ensuring patient adherence. These challenges have driven the development of advanced drug delivery systems (DDS), with hydrogels and especially nanogels emerging [...] Read more.
Conventional drug delivery approaches, including tablets and capsules, often suffer from reduced therapeutic effectiveness, largely attributed to inadequate bioavailability and difficulties in ensuring patient adherence. These challenges have driven the development of advanced drug delivery systems (DDS), with hydrogels and especially nanogels emerging as promising materials to overcome these limitations. Hydrogels, with their biocompatibility, high water content, and stimuli-responsive properties, provide controlled and targeted drug release. This review explores the evolution, properties, and classifications of hydrogels versus nanogels and their applications in drug delivery, detailing synthesis methods, including chemical crosslinking, physical self-assembly, and advanced techniques such as microfluidics and 3D printing. It also examines drug-loading mechanisms (e.g., physical encapsulation and electrostatic interactions) and release strategies (e.g., diffusion, stimuli-responsive, and enzyme-triggered). These gels demonstrate significant advantages in addressing the limitations of traditional DDS, offering improved drug stability, sustained release, and high specificity. Their adaptability extends to various routes of administration, including topical, oral, and injectable forms, while emerging nanogels further enhance therapeutic targeting through nanoscale precision and stimuli responsiveness. Although hydrogels and nanogels have transformative potential in personalized medicine, challenges remain in scalable manufacturing, regulatory approval, and targeted delivery. Future strategies include integrating biosensors for real-time monitoring, developing dual-stimuli-responsive systems, and optimizing surface functionalization for specificity. These advancements aim to establish hydrogels and nanogels as cornerstones of next-generation therapeutic solutions, revolutionizing drug delivery, and paving the way for innovative, patient-centered treatments. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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19 pages, 3013 KB  
Article
Preparing a Liposome-Aided Drug Delivery System: The Entrapment and Release Profiles of Doxorubicin and 9-(N-Piperazinyl)-5-methyl-12(H)-quino [3,4-b][1,4]benzothiazinium Chloride with Human Serum Albumin
by Danuta Pentak, Violetta Kozik, Andrzej Zieba, Marlena Paździor-Heiske, Aleksandra Szymczyk, Josef Jampilek and Andrzej Bak
Pharmaceutics 2025, 17(2), 202; https://doi.org/10.3390/pharmaceutics17020202 - 6 Feb 2025
Cited by 2 | Viewed by 2364
Abstract
Background/Objectives: The principal aim of this work was to prepare a liposomal drug delivery system based on the commercial drug doxorubicin (DOX) and a budding agent with promising anticancer activity, 9-(N-piperazinyl)-5-methyl-12(H)-quino [3,4-b][1,4]benzothiazinium chloride (9-PBThACl). Methods: A spectrophotometric methodology [...] Read more.
Background/Objectives: The principal aim of this work was to prepare a liposomal drug delivery system based on the commercial drug doxorubicin (DOX) and a budding agent with promising anticancer activity, 9-(N-piperazinyl)-5-methyl-12(H)-quino [3,4-b][1,4]benzothiazinium chloride (9-PBThACl). Methods: A spectrophotometric methodology was used to meticulously investigate the drug entrapment and release characteristics of the new liposomal complexes (L) based on dipalmitoylphosphatidylcholine (DPPC) with human serum albumin (HSA) and its defeated analog (dHSA). Results: The impact of the operational parameters (temperature and pH) on the liposome/drug(s)/(d)HSA, namely [LDPPC/9-PBThACl/DOX ]:(d)HSA] systems, as well as the polarity of the phospholipid bilayer, was examined. In order to compare the experimental findings, mathematical models were employed to specify the analytical factors controlling the process of drug release/potential drug release from liposomes. The observed variations in the drug encapsulation and release profiles were due to the combination of liposomal conjugates with human plasma protein. Conclusions: It was proven that changes in the environmental pH directly affect the percentage of drug entrapment in liposomes and the medicine release efficiency. Moreover, the grouping tendency of the liposomal combinations was investigated using a principal component analysis (PCA) and a hierarchical clustering analysis (HCA). Finally, an analysis of variance (ANOVA) confirmed the statistical impact of pH buffering and changing temperature factors on the drug release characteristics of liposomal conjugates. Full article
(This article belongs to the Special Issue Advanced Nanopharmaceuticals for Anticancer Therapy)
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23 pages, 4253 KB  
Review
Emerging Trends in Snake Venom-Loaded Nanobiosystems for Advanced Medical Applications: A Comprehensive Overview
by Álisson E. F. Alves, Anne B. C. Barros, Lindomara C. F. Silva, Lucas M. M. Carvalho, Graziela M. A. Pereira, Ana F. C. Uchôa, José M. Barbosa-Filho, Marcelo S. Silva, Karla P. O. Luna, Karla S. R. Soares and Francisco H. Xavier-Júnior
Pharmaceutics 2025, 17(2), 204; https://doi.org/10.3390/pharmaceutics17020204 - 6 Feb 2025
Cited by 5 | Viewed by 3768
Abstract
Advances in medical nanobiotechnology have notably enhanced the application of snake venom toxins, facilitating the development of new therapies with animal-derived toxins. The vast diversity of snake species and their venom complexities underline the need for ongoing research. This review is dedicated to [...] Read more.
Advances in medical nanobiotechnology have notably enhanced the application of snake venom toxins, facilitating the development of new therapies with animal-derived toxins. The vast diversity of snake species and their venom complexities underline the need for ongoing research. This review is dedicated to exploring the integration of snake venom with nanoparticles to enable their use in human therapies aiming to develop treatments. The complex mixture of snake venom not only inflicts significant pathological effects but also offers valuable insights for the creation of innovative therapies, particularly in the realm of nanobiotechnology. Nanoscale encapsulation not only mitigates the inherent toxicity of snake venom but also amplifies their antitumoral, antimicrobial, and immunomodulatory properties. The synergy between venom-derived macromolecules and nanotechnology offers a novel pathway for augmenting the efficacy and safety of conventional antivenom therapies, extending their applicability beyond treating bites to potentially addressing a myriad of health issues. In conclusion, nanotechnology presents a compelling therapeutic frontier that promises to improve current treatment modalities and ameliorate the adverse effects associated with venomous snakebites. Full article
(This article belongs to the Special Issue Nanoparticle-Mediated Targeted Drug Delivery Systems)
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18 pages, 648 KB  
Review
AI-Driven Innovation in Skin Kinetics for Transdermal Drug Delivery: Overcoming Barriers and Enhancing Precision
by Nubul Albayati, Sesha Rajeswari Talluri, Nirali Dholaria and Bozena Michniak-Kohn
Pharmaceutics 2025, 17(2), 188; https://doi.org/10.3390/pharmaceutics17020188 - 2 Feb 2025
Cited by 30 | Viewed by 8352
Abstract
Transdermal drug delivery systems (TDDS) offer an alternative to conventional oral and injectable drug administration by bypassing the gastrointestinal tract and liver metabolism, improving bioavailability, and minimizing systemic side effects. However, widespread adoption of TDDS is limited by challenges such as the skin’s [...] Read more.
Transdermal drug delivery systems (TDDS) offer an alternative to conventional oral and injectable drug administration by bypassing the gastrointestinal tract and liver metabolism, improving bioavailability, and minimizing systemic side effects. However, widespread adoption of TDDS is limited by challenges such as the skin’s permeability barrier, particularly the stratum corneum, and the need for optimized formulations. Factors like skin type, hydration levels, and age further complicate the development of universally effective solutions. Advances in artificial intelligence (AI) address these challenges through predictive modeling and personalized medicine approaches. Machine learning models trained on extensive molecular datasets predict skin permeability and accelerate the selection of suitable drug candidates. AI-driven algorithms optimize formulations, including penetration enhancers and advanced delivery technologies like microneedles and liposomes, while ensuring safety and efficacy. Personalized TDDS design tailors drug delivery to individual patient profiles, enhancing therapeutic precision. Innovative systems, such as sensor-integrated patches, dynamically adjust drug release based on real-time feedback, ensuring optimal outcomes. AI also streamlines the pharmaceutical process, from disease diagnosis to the prediction of drug distribution in skin layers, enabling efficient formulation development. This review highlights AI’s transformative role in TDDS, including applications of models such as Deep Neural Networks (DNN), Artificial Neural Networks (ANN), BioSIM, COMSOL, K-Nearest Neighbors (KNN), and Set Covering Machine (SVM). These technologies revolutionize TDDS for both skin and non-skin diseases, demonstrating AI’s potential to overcome existing barriers and improve patient care through innovative drug delivery solutions. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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20 pages, 8895 KB  
Article
Novel Solid Forms of Cardarine/GW501516 and Their Characterization by X-Ray Diffraction, Thermal, Computational, FTIR, and UV Analysis
by Alexandru Turza, Maria Bosca, Marieta Muresan-Pop, Liviu Mare, Gheorghe Borodi and Violeta Popescu
Pharmaceutics 2025, 17(2), 152; https://doi.org/10.3390/pharmaceutics17020152 - 23 Jan 2025
Viewed by 7252
Abstract
Cardarine (C21H18F3NO3S2), better known by the popular name of GW501516, is a peroxisome proliferator-activated receptor delta (PPR-δ) agonist that presents potential use in the approach of cardiovascular diseases and metabolic disorders, dyslipidemia, and [...] Read more.
Cardarine (C21H18F3NO3S2), better known by the popular name of GW501516, is a peroxisome proliferator-activated receptor delta (PPR-δ) agonist that presents potential use in the approach of cardiovascular diseases and metabolic disorders, dyslipidemia, and insulin resistance. The capability of cardarine to exhibit new solid forms by recrystallization from a broad class of solvents was explored. A total of four new solid forms were obtained: a new polymorph of cardarine (C21H18F3NO3S2), the cardarine: 4,4′-bipyridine cocrystal (C21H18F3NO3S2·0.5C10H8N2), the cardarine methanol solvate (C21H18F3NO3S2·CH3OH), and the cardarine dimethylformamide solvate (C21H18F3NO3S2·C3H7NO). Moreover, two derivatives of cardarine were obtained, in the form of the mono-oxidized cardarine structure (C21H18F3NO4S2) and the dioxidized cardarine structure (C21H18F3NO5S2). The formation process was proven by the determination of their crystal structures using single crystal X-ray diffraction and followed by their lattice energies evaluation. Further investigations have been conducted by powder X-ray diffraction, DTA/TGA thermal analysis, and FTIR spectroscopy. The stability and solubility were analyzed as well. Full article
(This article belongs to the Special Issue Pharmaceutical Polymorphs and Cocrystals and Their In Vitro and In Vivo Evaluation)
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19 pages, 6908 KB  
Article
Three-Dimensional-Printed Osteochondral Scaffold with Biomimetic Surface Curvature for Osteochondral Regeneration
by Yan Yang, Qu Lin, Zhenhai Hou, Gensheng Yang and Lian Shen
Pharmaceutics 2025, 17(2), 153; https://doi.org/10.3390/pharmaceutics17020153 - 23 Jan 2025
Cited by 2 | Viewed by 1800
Abstract
Objectives: Treatment of osteochondral defects is hindered by several challenges, including the failure of traditional scaffolds with a predefined cylindrical or cuboid shape to comprehensively match the natural osteochondral tissue. Herein, we employed reverse modeling and three-dimensional (3D) printing technologies to prepare subchondral [...] Read more.
Objectives: Treatment of osteochondral defects is hindered by several challenges, including the failure of traditional scaffolds with a predefined cylindrical or cuboid shape to comprehensively match the natural osteochondral tissue. Herein, we employed reverse modeling and three-dimensional (3D) printing technologies to prepare subchondral bone and cartilage. Methods: The osteochondral scaffold was prepared by bonding the subchondral bone and cartilage layers, and the curvature distribution and biomechanical behavior were compared with those of the native tissue. Biocompatibility and osteochondral regeneration performance were further evaluated using cell adhesion and proliferation assays, as well as animal osteochondral defect repair tests. Results: We found that increasing the printing temperature or decreasing the layer height improved the dimensional accuracy of printed subchondral bones, whereas increasing the exposure time or decreasing the layer height enhanced the dimensional accuracy of the printed cartilage. Biomimetic scaffolds exhibited curvature distribution and biomechanical behavior more similar to native tissues than traditional cylindrical scaffolds. Incorporating gelatin methacryloyl into poly (ethylene glycol) diacrylate markedly improved the biocompatibility, and correspondingly prepared osteochondral scaffolds had better osteochondral regeneration ability than the traditional scaffolds. Conclusions: Osteochondral scaffolds exhibiting biomimetic morphology and an internal structure could be prepared based on reverse modeling and 3D printing, facilitating personalized osteochondral injury treatment. Full article
(This article belongs to the Special Issue Advancements in Industrial Pharmaceutics: Innovations and Future Directions)
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26 pages, 11321 KB  
Article
Curcumin-Loaded Lipid Nanocarriers: A Targeted Approach for Combating Oxidative Stress in Skin Applications
by Aggeliki Liakopoulou, Sophia Letsiou, Konstantinos Avgoustakis, George P. Patrinos, Fotini N. Lamari and Sophia Hatziantoniou
Pharmaceutics 2025, 17(2), 144; https://doi.org/10.3390/pharmaceutics17020144 - 21 Jan 2025
Cited by 8 | Viewed by 2940
Abstract
Background/Objectives: Oxidative stress significantly impacts skin health, contributing to conditions like aging, pigmentation, and inflammatory disorders. Curcumin, with its potent antioxidant properties, faces challenges of low solubility, stability, and bioavailability. This study aimed to encapsulate curcumin in three lipid nanocarriers—solid lipid nanoparticles (SLNs), [...] Read more.
Background/Objectives: Oxidative stress significantly impacts skin health, contributing to conditions like aging, pigmentation, and inflammatory disorders. Curcumin, with its potent antioxidant properties, faces challenges of low solubility, stability, and bioavailability. This study aimed to encapsulate curcumin in three lipid nanocarriers—solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and nanoemulsions (NEs)—to enhance its stability, bioavailability, and antioxidant efficacy for potential therapeutic applications in oxidative-stress-related skin disorders. Methods: The lipid nanocarriers were characterized for size, polydispersity index, ζ-potential, and encapsulation efficiency. Stability tests under various conditions and antioxidant activity assays (DPPH and FRAP methods) were conducted. Cytotoxicity in human dermal fibroblasts was assessed using MTT assays, while the expression of key antioxidant genes was evaluated in human dermal fibroblasts under oxidative stress. Skin penetration studies were performed to analyze curcumin’s distribution across the stratum corneum layers. Results: All nanocarriers demonstrated high encapsulation efficiency and stability over 90 days. NLCs exhibited superior long-term stability and enhanced skin penetration, while NE formulations facilitated rapid antioxidant effects. Antioxidant assays confirmed that curcumin encapsulation preserved and enhanced its bioactivity, particularly in NLCs. Gene expression analysis revealed upregulation of key antioxidant markers (GPX1, GPX4, SOD1, KEAP1, and NRF2) with curcumin-loaded nanocarriers under oxidative and non-oxidative conditions. Cytotoxicity studies confirmed biocompatibility across all formulations. Conclusions: Lipid nanocarriers effectively enhance curcumin’s stability, antioxidant activity, and skin penetration, presenting a targeted strategy for managing oxidative stress in skin applications. Their versatility offers opportunities for tailored therapeutic formulations addressing specific skin conditions, from chronic disorders like psoriasis to acute stress responses such as sunburn. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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21 pages, 2408 KB  
Article
Chitosan Nanoparticles for Enhanced Immune Response and Delivery of Multi-Epitope Helicobacter pylori Vaccines in a BALB/c Mouse Model
by Rita Amaral, Tomás Concha, Jorge Vítor, António J. Almeida, Cecília Calado and Lídia M. Gonçalves
Pharmaceutics 2025, 17(1), 132; https://doi.org/10.3390/pharmaceutics17010132 - 18 Jan 2025
Cited by 6 | Viewed by 2619
Abstract
Background/Objectives: Helicobacter pylori is the leading cause of chronic gastritis, peptic ulcer, gastric adenocarcinoma, and mucosal-associated lymphoma. Due to the emerging problems with antibiotic treatment against H. pylori in clinical practice, H. pylori vaccination has gained more interest. Oral immunization is considered [...] Read more.
Background/Objectives: Helicobacter pylori is the leading cause of chronic gastritis, peptic ulcer, gastric adenocarcinoma, and mucosal-associated lymphoma. Due to the emerging problems with antibiotic treatment against H. pylori in clinical practice, H. pylori vaccination has gained more interest. Oral immunization is considered a promising approach for preventing initial colonization of this bacterium in the gastrointestinal tract, establishing a first line of defense at gastric mucosal surfaces. Chitosan nanoparticles can be exploited effectively for oral vaccine delivery due to their stability, simplicity of target accessibility, and beneficial mucoadhesive and immunogenic properties. Methods: In this study, new multi-epitope pDNA- and recombinant protein-based vaccines incorporating multiple H. pylori antigens were produced and encapsulated in chitosan nanoparticles for oral and intramuscular administration. The induced immune response was assessed through the levels of antigen-specific IgGs, secreted mucosal SIgA, and cytokines (IL-2, IL-10, and IFN-γ) in immunized BALB/C mice. Results: Intramuscular administration of both pDNA and recombinant protein-based vaccines efficiently stimulated the production of specific IgG2a and IgG1, which was supported by cytokines levels. Oral immunizations with either pDNA or recombinant protein vaccines revealed high SIgA levels, suggesting effective gastric mucosal immunization, contrasting with intramuscular immunizations, which did not induce SIgA. Conclusions: These findings indicate that both pDNA and recombinant protein vaccines encapsulated into chitosan nanoparticles are promising candidates for eradicating H. pylori and mitigating associated gastric diseases in humans. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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16 pages, 6706 KB  
Article
Scalable Manufacturing Method for Model Protein-Loaded PLGA Nanoparticles: Biocompatibility, Trafficking and Release Properties
by Selin Akpinar Adscheid, Marta Rojas-Rodríguez, Salma M. Abdel-Hafez, Francesco S. Pavone, Marc Schneider, Akif E. Türeli, Martino Calamai and Nazende Günday-Türeli
Pharmaceutics 2025, 17(1), 87; https://doi.org/10.3390/pharmaceutics17010087 - 10 Jan 2025
Cited by 6 | Viewed by 3320
Abstract
Background and Objectives: Drug delivery systems (DDSs) offer efficient treatment solutions to challenging diseases such as central nervous system (CNS) diseases by bypassing biological barriers such as the blood–brain barrier (BBB). Among DDSs, polymeric nanoparticles (NPs), particularly poly(lactic-co-glycolic acid) (PLGA) NPs, hold [...] Read more.
Background and Objectives: Drug delivery systems (DDSs) offer efficient treatment solutions to challenging diseases such as central nervous system (CNS) diseases by bypassing biological barriers such as the blood–brain barrier (BBB). Among DDSs, polymeric nanoparticles (NPs), particularly poly(lactic-co-glycolic acid) (PLGA) NPs, hold an outstanding position due to their biocompatible and biodegradable qualities. Despite their potential, the translation of PLGA NPs from laboratory-scale production to clinical applications remains a significant challenge. This study aims to address these limitations by developing scalable PLGA NPs and evaluating their potential biological applications. Methods: We prepared blank and model-protein-loaded (albumin–FITC and wheat germ agglutinin-488 (WGA-488)) fluorescent PLGA NPs using the traditional double-emulsion method combined with the micro-spray-reactor system, a novel approach that enables fine particle production enabling scale-up applications. We tested the biocompatibility of the NPs in living RPMI 2650 and neuroblastoma cell lines, as well as their trafficking and uptake. Release kinetics of the encapsulated proteins were investigated through confocal microscopy and in vitro release studies, providing insights into the stability and functionality of the released proteins. Results: The formulation demonstrated sustained and prolonged protein release profiles. Importantly, cellular uptake studies revealed that the NPs were not internalized. Furthermore, encapsulated WGA-488 protein retained its functional activity after release, validating the integrity of the encapsulation and release processes. Conclusions: The proof-of-concept study on NP manufacturing and an innovative drug trafficking and release approach can bring new perspectives on scalable preparations of PLGA NPs and their biological applications. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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14 pages, 1694 KB  
Article
Formulation Design of Orally Disintegrating Film Using Two Cellulose Derivatives as a Blend Polymer
by Yoshiko Takeuchi, Fumika Hayakawa and Hirofumi Takeuchi
Pharmaceutics 2025, 17(1), 84; https://doi.org/10.3390/pharmaceutics17010084 - 10 Jan 2025
Cited by 4 | Viewed by 2606
Abstract
Background/Objectives: Orally disintegrating film (ODF) is prepared using water-soluble polymers as film-forming agents. To improve mechanical and disintegration properties, some polymers need to be blended with others. This study aimed to investigate the utility of hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose [...] Read more.
Background/Objectives: Orally disintegrating film (ODF) is prepared using water-soluble polymers as film-forming agents. To improve mechanical and disintegration properties, some polymers need to be blended with others. This study aimed to investigate the utility of hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC) as blend film-forming components for ODFs. Methods: Placebo ODFs were prepared using polymer mixtures with blend ratios ranging from 20% to 80% HPC with HPMC. Mechanical properties, including tensile strength, elastic modulus, elongation at break, and folding endurance, as well as disintegration times, were evaluated. Additionally, blend films incorporating donepezil hydrochloride (DH) as a model active pharmaceutical ingredient (API) were prepared and assessed to determine their mechanical properties and disintegration behavior. Results: Blend films were successfully formed using HPMC/HPC solutions. The 40/60 and 20/80 HPMC/HPC blends exhibited the lowest mechanical strength and elongation, whereas blends containing more than 40% HPC demonstrated shorter disintegration times. Films with DH were successfully formed, though the addition of DH reduced tensile strength and elongation. The decline in mechanical properties was mitigated in HPMC/HPC blend films. Our results, including DSC and FTIR results, led us to conclude that the HPMC/HPC blend films were micro-immiscible, but they were macro-miscible when the amount of the minor component was sufficiently small. Conclusions: HPMC/HPC blends in appropriate ratios are effective as film-forming polymers for ODFs. The addition of DH impacts the mechanical properties, but the decline is less pronounced when using HPMC/HPC blends. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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33 pages, 2920 KB  
Review
Self-Emulsifying Drug Delivery Systems (SEDDS): Transition from Liquid to Solid—A Comprehensive Review of Formulation, Characterization, Applications, and Future Trends
by Prateek Uttreja, Indrajeet Karnik, Ahmed Adel Ali Youssef, Nagarjuna Narala, Rasha M. Elkanayati, Srikanth Baisa, Nouf D. Alshammari, Srikanth Banda, Sateesh Kumar Vemula and Michael A. Repka
Pharmaceutics 2025, 17(1), 63; https://doi.org/10.3390/pharmaceutics17010063 - 5 Jan 2025
Cited by 50 | Viewed by 21072
Abstract
Self-emulsifying drug delivery systems (SEDDS) represent an innovative approach to improving the solubility and bioavailability of poorly water-soluble drugs, addressing significant challenges associated with oral drug delivery. This review highlights the advancements and applications of SEDDS, including their transition from liquid to solid [...] Read more.
Self-emulsifying drug delivery systems (SEDDS) represent an innovative approach to improving the solubility and bioavailability of poorly water-soluble drugs, addressing significant challenges associated with oral drug delivery. This review highlights the advancements and applications of SEDDS, including their transition from liquid to solid forms, while addressing the formulation strategies, characterization techniques, and future prospects in pharmaceutical sciences. The review systematically analyzes existing studies on SEDDS, focusing on their classification into liquid and solid forms and their preparation methods, including spray drying, hot-melt extrusion, and adsorption onto carriers. Characterization techniques such as droplet size analysis, dissolution studies, and solid-state evaluations are detailed. Additionally, emerging trends, including 3D printing, hybrid systems, and supersaturable SEDDS (Su-SEDDS), are explored. Liquid SEDDS (L-SEDDS) enhance drug solubility and absorption by forming emulsions upon contact with gastrointestinal fluids. However, they suffer from stability and leakage issues. Transitioning to solid SEDDS (S-SEDDS) has resolved these limitations, offering enhanced stability, scalability, and patient compliance. Innovations such as personalized 3D-printed SEDDS, biologics delivery, and targeted systems demonstrate their potential for diverse therapeutic applications. Computational modeling and in silico approaches further accelerate formulation optimization. SEDDS have revolutionized drug delivery by improving bioavailability and enabling precise, patient-centric therapies. While challenges such as scalability and excipient toxicity persist, emerging technologies and multidisciplinary collaborations are paving the way for next-generation SEDDS. Their adaptability and potential for personalized medicine solidify their role as a cornerstone in modern pharmaceutical development. Full article
(This article belongs to the Special Issue Microemulsion Utility in Pharmaceuticals)
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17 pages, 2865 KB  
Article
Inhibition of Endothelial Cell Tube Formation by Anti-Vascular Endothelial Growth Factor/Anti-Angiopoietin-2 RNA Nanoparticles
by Cheng Zhong, Zhanquan Shi, Chia-Yang Liu, Daniel W. Binzel, Kai Jin, Xin Li, Peixuan Guo and S. Kevin Li
Pharmaceutics 2025, 17(1), 55; https://doi.org/10.3390/pharmaceutics17010055 - 3 Jan 2025
Viewed by 4823
Abstract
RNA nanoparticles, derived from the packaging RNA three-way junction motif (pRNA-3WJ) of the bacteriophage phi29 DNA packaging motor, have been demonstrated to be thermodynamically and chemically stable, with promise as a nanodelivery system. Background/Objectives: A previous study showed that RNA nanoparticles with [...] Read more.
RNA nanoparticles, derived from the packaging RNA three-way junction motif (pRNA-3WJ) of the bacteriophage phi29 DNA packaging motor, have been demonstrated to be thermodynamically and chemically stable, with promise as a nanodelivery system. Background/Objectives: A previous study showed that RNA nanoparticles with antiangiogenic aptamers (anti-vascular endothelial growth factor (VEGF) and anti-angiopoietin-2 (Ang2) aptamers) inhibited cell proliferation via WST-1 assay. To further investigate the antiangiogenic potential of these RNA nanoparticles, a modified three-dimensional (3D) spheroid sprouting assay model of human umbilical vein endothelial cells was utilized in the present study. Methods: Three groups of RNA nanoparticles were evaluated, namely, pRNA-3WJ series, RNA square series (polygon-type RNA nanoparticles), and 8WJ series (multiple-way junction RNA nanoparticles), which were conjugated with a single anti-VEGF, the combination of one anti-VEGF and one anti-Ang2, or multiple anti-VEGF aptamers. The core scaffold RNA nanoparticles (without aptamers) were used as the references, and bevacizumab was used as the positive control. Results: The results demonstrated the inhibition effects of the RNA nanoparticles on endothelial cell tube formation at 67 nM in a 3D spheroid sprouting model. The results in the 3D spheroid sprouting assay are consistent with those of the WST-1 proliferation assays. Conclusions: Among the RNA nanoparticles evaluated, 3WJ-3VEGF and SQR-VEGF-Ang2 had inhibition effects equivalent to bevacizumab and were promising for anti-angiogenesis treatment. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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16 pages, 2656 KB  
Article
Innovative Lipid Nanoparticles Co-Delivering Hydroxychloroquine and siRNA for Enhanced Rheumatoid Arthritis Therapy
by Yanru Feng, Xintong Pan, Ziqian Li, Yue Li, Ya’nan Sun, Shaokun Yang, Chaoxing He, Yunjie Dang, Lu Huang and Bai Xiang
Pharmaceutics 2025, 17(1), 45; https://doi.org/10.3390/pharmaceutics17010045 - 1 Jan 2025
Cited by 2 | Viewed by 2850
Abstract
Background: Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by chronic inflammation and joint damage. Despite advancements in treatment, complete remission remains elusive. Methods: In this study, we introduce a novel lipid nanoparticle formulation co-delivering hydroxychloroquine (HCQ) and siRNA targeting TNF-α (si [...] Read more.
Background: Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by chronic inflammation and joint damage. Despite advancements in treatment, complete remission remains elusive. Methods: In this study, we introduce a novel lipid nanoparticle formulation co-delivering hydroxychloroquine (HCQ) and siRNA targeting TNF-α (siTNF-α) using microfluidic technology, marking the first use of such a combination for RA therapy. Results: In LPS-stimulated RAW 264.7 cells, the nanoparticles effectively reduced inflammatory markers. When administered via an intra-articular injection in a rat model, they significantly decreased joint inflammation and demonstrated good biological safety. Conclusions: This pioneering approach highlights the potential of lipid nanoparticles as a dual-delivery platform for enhanced RA treatment through targeted intra-articular administration. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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16 pages, 3190 KB  
Article
Therapeutic Efficacy of Intranasal N-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice
by Hiroshi Nango, Ai Takahashi, Naoto Suzuki, Takumi Kurano, Saia Sakamoto, Taiki Nagatomo, Toyofumi Suzuki, Takanori Kanazawa, Yasuhiro Kosuge and Hiroko Miyagishi
Pharmaceutics 2025, 17(1), 44; https://doi.org/10.3390/pharmaceutics17010044 - 1 Jan 2025
Cited by 5 | Viewed by 3202
Abstract
Background/Objectives: We previously demonstrated that the intranasal administration of cell-penetrating Tat peptide-modified carrier, PEG-PCL-Tat, improves drug delivery to the central nervous system. This study aimed to evaluate the potential of the post-onset intranasal administration of N-acetyl-L-cysteine (NAC) combined with PEG-PCL-Tat (NAC/PPT) [...] Read more.
Background/Objectives: We previously demonstrated that the intranasal administration of cell-penetrating Tat peptide-modified carrier, PEG-PCL-Tat, improves drug delivery to the central nervous system. This study aimed to evaluate the potential of the post-onset intranasal administration of N-acetyl-L-cysteine (NAC) combined with PEG-PCL-Tat (NAC/PPT) for neuropathic pain. Methods: Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Mechanical allodynia was assessed using the von Frey test on days 11–14 post-ligation. NAC or NAC/PPT was intranasally administered after pain onset. Western blotting and immunohistochemistry were conducted to evaluate ionized calcium-binding adapter molecule 1 (Iba-1) expression and microglial activation in the spinal cord. Results: Mechanical allodynia was exacerbated 11 days after the ligation in PSNL mice. The intranasal administration of NAC alone prevented allodynia exacerbation but failed to provide a therapeutic effect against allodynia in PSNL mice. In contrast, NAC/PPT administration ameliorated PSNL-induced tactile allodynia, with maximum efficacy seen 13 and 14 days after ligation. Western blotting demonstrated that Iba-1 levels tended to increase in PSNL mice compared to controls. This trend of increased Iba-1 levels in PSNL mice was attenuated by the administration of NAC/PPT, but not by NAC alone. Immunohistochemistry revealed an increased number of Iba-1-stained microglia in the ipsilateral spinal cord of PSNL mice, which were significantly suppressed by the administration of NAC/PPT. Conclusions: These results suggest that the post-onset intranasal administration of NAC/PPT ameliorates mechanical allodynia by suppressing microglia induction and that intranasal delivery with PEG-PCL-Tat might be a useful tool for the pharmacological management of neuropathic pain. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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12 pages, 1677 KB  
Article
Enhanced Drug Skin Permeation by Azone-Mimicking Ionic Liquids: Effects of Fatty Acids Forming Ionic Liquids
by Takeshi Oshizaka, Shunsuke Kodera, Rika Kawakubo, Issei Takeuchi, Kenji Mori and Kenji Sugibayashi
Pharmaceutics 2025, 17(1), 41; https://doi.org/10.3390/pharmaceutics17010041 - 30 Dec 2024
Cited by 4 | Viewed by 2627
Abstract
Background/Objectives: Laurocapram (Azone) attracted attention 40 years ago as a compound with the highest skin-penetration-enhancing effect at that time; however, its development was shelved due to strong skin irritation. We had already prepared and tested an ante-enhancer (IL-Azone), an ionic liquid (IL) [...] Read more.
Background/Objectives: Laurocapram (Azone) attracted attention 40 years ago as a compound with the highest skin-penetration-enhancing effect at that time; however, its development was shelved due to strong skin irritation. We had already prepared and tested an ante-enhancer (IL-Azone), an ionic liquid (IL) with a similar structure to Azone, consisting of ε-caprolactam and myristic acid, as an enhancer candidate that maintains the high skin-penetration-enhancing effect of Azone with low skin irritation. In the present study, fatty acids with different carbon numbers (caprylic acid: C8, capric acid: C10, lauric acid: C12, myristic acid: C14, and oleic acid: C18:1) were selected and used with ε-caprolactam to prepare various IL-Azones in the search for a more effective IL-Azone. Methods: Excised porcine skin was pretreated with each IL-Azone to assess the in vitro skin permeability of antipyrine (ANP) as a model penetrant. In addition, 1,3-butanediol was selected for the skin permeation test to confirm whether the effect of IL-Azone was due to fatty acids and if this effect differed depending on the concentration of IL-Azone applied. Results: The results obtained showed that C12 IL-Azone exerted the highest skin-penetration-enhancing effect, which was higher than Azone. On the other hand, many of the IL-Azones tested had a lower skin-penetration-enhancing effect. Conclusions: These results suggest the potential of C12 IL-Azone as a strong and useful penetration enhancer. Full article
(This article belongs to the Special Issue Transdermal Delivery of Low-Molecular-Weight Drugs and New Modality of Drugs: Recent Innovation to Penetration Enhancement Techniques)
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46 pages, 1601 KB  
Review
Drug-Drug Interactions Between HIV Antivirals and Concomitant Drugs in HIV Patients: What We Know and What We Need to Know
by Emanuela De Bellis, Danilo Donnarumma, Adele Zarrella, Salvatore Maria Mazzeo, Annarita Pagano, Valentina Manzo, Ines Mazza, Francesco Sabbatino, Graziamaria Corbi, Pasquale Pagliano, Amelia Filippelli and Valeria Conti
Pharmaceutics 2025, 17(1), 31; https://doi.org/10.3390/pharmaceutics17010031 - 28 Dec 2024
Cited by 6 | Viewed by 6561
Abstract
Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance [...] Read more.
Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance of which has often not been determined during registration trials of the drugs involved. Therefore, it is important to identify potential clinically relevant DDIs in order to establish the most appropriate therapeutic approaches. This review aims to summarize and analyze data from studies published over the last two decades on DDI-related adverse clinical outcomes involving anti-HIV drugs and those used to treat comorbidities. Several studies have examined the pharmacokinetics and tolerability of different drug combinations. Protease inhibitors, followed by nonnucleoside reverse transcriptase inhibitors and integrase inhibitors have been recognized as the main players in DDIs with antivirals used to control co-infection, such as Hepatitis C virus, or with drugs commonly used to treat HIV comorbidities, such as lipid-lowering agents, proton pump inhibitors and anticancer drugs. However, the studies do not seem to be consistent with regard to sample size and follow-up, the drugs involved, or the results obtained. It should be noted that most of the available studies were conducted in healthy volunteers without being replicated in patients. This hampered the assessment of the clinical burden of DDIs and, consequently, the optimal pharmacological management of people living with HIV. Full article
(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)
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