Pharmaceutics

16 pages, 2909 KB

Open AccessEditor’s ChoiceArticle

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 6 | Viewed by 1882

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

Open AccessEditor’s ChoiceArticle

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

Viewed by 1391

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

Open AccessEditor’s ChoiceArticle

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 1285

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

Open AccessEditor’s ChoiceReview

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 1843

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

Open AccessEditor’s ChoiceReview

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 5 | Viewed by 3548

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

Open AccessEditor’s ChoiceArticle

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

Viewed by 1264

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

Open AccessEditor’s ChoiceReview

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 5 | Viewed by 2846

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

Open AccessEditor’s ChoiceArticle

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

Viewed by 1495

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

Open AccessEditor’s ChoiceArticle

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 2809

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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25 pages, 9259 KB

Open AccessEditor’s ChoiceArticle

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 3 | Viewed by 2984

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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15 pages, 2556 KB

Open AccessEditor’s ChoiceArticle

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 4 | Viewed by 1761

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, 6641 KB

Open AccessEditor’s ChoiceArticle

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 3 | Viewed by 1560

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

Open AccessEditor’s ChoiceReview

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 2 | Viewed by 2587

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

Open AccessEditor’s ChoiceReview

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 8 | Viewed by 4632

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

Open AccessEditor’s ChoiceArticle

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 2 | Viewed by 2830

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

Open AccessEditor’s ChoiceReview

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 63 | Viewed by 7216

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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23 pages, 4253 KB

Open AccessEditor’s ChoiceReview

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 4 | Viewed by 3193

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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19 pages, 3013 KB

Open AccessEditor’s ChoiceArticle

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 1952

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 [L_{DPPC/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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18 pages, 648 KB

Open AccessEditor’s ChoiceReview

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 19 | Viewed by 7432

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

Open AccessEditor’s ChoiceArticle

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 5995

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

Open AccessEditor’s ChoiceArticle

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 1579

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

Open AccessEditor’s ChoiceArticle

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 7 | Viewed by 2448

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

Open AccessEditor’s ChoiceArticle

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 5 | Viewed by 2286

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

Open AccessEditor’s ChoiceArticle

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 4 | Viewed by 2845

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

Open AccessEditor’s ChoiceArticle

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 3 | Viewed by 2158

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

Open AccessEditor’s ChoiceReview

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 31 | Viewed by 17611

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

Open AccessEditor’s ChoiceArticle

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 4384

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

Open AccessEditor’s ChoiceArticle

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 1 | Viewed by 2368

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

Open AccessEditor’s ChoiceArticle

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 2676

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

Open AccessEditor’s ChoiceArticle

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 3 | Viewed by 2248

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

Open AccessEditor’s ChoiceReview

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 4 | Viewed by 5016

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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15 pages, 5690 KB

Open AccessEditor’s ChoiceArticle

L-Threonine-Derived Biodegradable Polyurethane Nanoparticles for Sustained Carboplatin Release

by Seoeun Oh, Soo-Yong Park, Hyung Il Seo and Ildoo Chung

Pharmaceutics 2025, 17(1), 28; https://doi.org/10.3390/pharmaceutics17010028 - 27 Dec 2024

Cited by 1 | Viewed by 1462

Abstract

Background and objectives: The use of polymeric nanoparticles (NPs) in drug delivery systems offers the advantages of enhancing drug efficacy and minimizing side effects; Methods: In this study, L-threonine polyurethane (LTPU) NPs have been fabricated by water-in-oil-in-water emulsion and solvent evaporation using biodegradable [...] Read more.

Background and objectives: The use of polymeric nanoparticles (NPs) in drug delivery systems offers the advantages of enhancing drug efficacy and minimizing side effects; Methods: In this study, L-threonine polyurethane (LTPU) NPs have been fabricated by water-in-oil-in-water emulsion and solvent evaporation using biodegradable and biocompatible LTPU. This polymer was pre-synthesized through the use of an amino acid-based chain extender, desaminotyrosyl L-threonine hexyl ester (DLTHE), where urethane bonds are formed by poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) triblock copolymer and 1,6-hexamethylene diisocyanate (HDI). LTPU is designed to be degraded by hydrolysis and enzymatic activity due to the presence of ester bonds and peptide bonds within the polymer backbone. LTPU NPs were fabricated by water-in-oil-in-water double emulsion solvent evaporation methods; Results: The polymerization of LTPU was confirmed by ¹H-NMR, ¹³C-NMR, and FT-IR spectroscopies. The molecular weights and polydispersity, determined with GPC, were 28,800 g/mol and 1.46, respectively. The morphology and size of NPs, characterized by DLS, FE-SEM, TEM, and confocal microscopy, showed smooth and spherical particles with diameters less than 200 nm; Conclusions: In addition, the drug loading, encapsulation efficiency, and drug release profiles, using UV-Vis spectroscopy, showed the highest encapsulation efficiency with 2.5% carboplatin and sustained release profile. Full article

(This article belongs to the Special Issue Advances in Polymeric Drug Delivery Systems, 2nd Edition)

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27 pages, 12316 KB

Open AccessEditor’s ChoiceArticle

Application of the Box–Behnken Design in the Development of Amorphous PVP K30–Phosphatidylcholine Dispersions for the Co-Delivery of Curcumin and Hesperetin Prepared by Hot-Melt Extrusion

by Kamil Wdowiak, Lidia Tajber, Andrzej Miklaszewski and Judyta Cielecka-Piontek

Pharmaceutics 2025, 17(1), 26; https://doi.org/10.3390/pharmaceutics17010026 - 27 Dec 2024

Cited by 1 | Viewed by 2117

Abstract

Background: Curcumin and hesperetin are plant polyphenols known for their poor solubility. To address this limitation, we prepared amorphous PVP K30–phosphatidylcholine dispersions via hot-melt extrusion. Methods: This study aimed to evaluate the effects of the amounts of active ingredients and phosphatidylcholine, as well [...] Read more.

Background: Curcumin and hesperetin are plant polyphenols known for their poor solubility. To address this limitation, we prepared amorphous PVP K30–phosphatidylcholine dispersions via hot-melt extrusion. Methods: This study aimed to evaluate the effects of the amounts of active ingredients and phosphatidylcholine, as well as the process temperature, on the performance of the dispersions. A Box–Behnken design was employed to assess these factors. Solid-state characterization and biopharmaceutical studies were then conducted. X-ray powder diffraction (XRPD) was used to confirm the amorphous nature of the dispersions, while differential scanning calorimetry (DSC) provided insight into the miscibility of the systems. Fourier-transform infrared spectroscopy (FTIR) was employed to assess the intermolecular interactions. The apparent solubility and dissolution profiles of the systems were studied in phosphate buffer at pH 6.8. In vitro permeability across the gastrointestinal tract and blood–brain barrier was evaluated using the parallel artificial membrane permeability assay. Results: The quantities of polyphenols and phospholipids were identified as significant factors influencing the biopharmaceutical performance of the systems. Solid-state analysis confirmed the formation of amorphous dispersions and the development of interactions among components. Notably, a significant improvement in solubility was observed, with formulations exhibiting distinct release patterns for the active compounds. Furthermore, the in vitro permeability through the gastrointestinal tract and blood–brain barrier was enhanced. Conclusions: The findings suggest that amorphous PVP K30–phosphatidylcholine dispersions have the potential to improve the biopharmaceutical properties of curcumin and hesperetin. Full article

(This article belongs to the Special Issue Preparation and Development of Amorphous Solid Dispersions)

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15 pages, 2482 KB

Open AccessEditor’s ChoiceArticle

Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs

by Arina Ranjit, Chae Bin Lee, Lukáš Tenora, Vijaya Saradhi Mettu, Arindom Pal, Jesse Alt, Barbara S. Slusher and Rana Rais

Pharmaceutics 2025, 17(1), 20; https://doi.org/10.3390/pharmaceutics17010020 - 26 Dec 2024

Viewed by 2147

Abstract

Background: Extracellular vesicles (EVs) can carry pathological cargo, contributing to disease progression. The enzyme neutral sphingomyelinase 2 (nSMase2) plays a critical role in EV biogenesis, making it a promising therapeutic target. Our lab previously identified a potent and selective inhibitor of nSMase2, [...] Read more.

Background: Extracellular vesicles (EVs) can carry pathological cargo, contributing to disease progression. The enzyme neutral sphingomyelinase 2 (nSMase2) plays a critical role in EV biogenesis, making it a promising therapeutic target. Our lab previously identified a potent and selective inhibitor of nSMase2, named DPTIP (IC₅₀ = 30 nM). Although promising, DPTIP exhibits poor pharmacokinetics (PKs) with a low oral bioavailability (%F < 5), and a short half-life (t_1/2 ≤ 0.5 h). To address these limitations, we previously developed DPTIP prodrugs by masking its phenolic hydroxyl group, demonstrating improved plasma exposure in mice. Recognizing that species-specific metabolic differences can influence prodrug PK, we expanded our studies to evaluate selected prodrugs in both mice and dogs. Methods: The scaleup of selected prodrugs was completed and two additional valine- ester based prodrugs were synthesized. Mice were dosed prodrugs via peroral route (10 mg/kg equivalent). For dog studies DPTIP was dosed via intravenous (1 mg/kg) or peroral route (2 mg/kg) and prodrugs were given peroral at a dose 2 mg/kg DPTIP equivalent. Plasma samples were collected at predetermined points and analyzed using developed LC/MS-MS methods. Results: In mice, several of the tested prodrugs showed similar or improved plasma exposures compared to DPTIP. However, in dog studies, the double valine ester prodrug 9, showed significant improvement with an almost two-fold increase in DPTIP plasma exposure (AUC_0–t = 1352 vs. 701 pmol·h/mL), enhancing oral bioavailability from 8.9% to 17.3%. Conclusions: These findings identify prodrug 9 as a promising candidate for further evaluation and underscore the critical role of species-specific differences in prodrug PKs. Full article

(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)

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18 pages, 4357 KB

Open AccessEditor’s ChoiceArticle

Enteric Coated Pellets with Lactoferrin for Oral Delivery: Improved Shelf Life of the Product

by Nika Kržišnik, Blaž Grilc and Robert Roškar

Pharmaceutics 2025, 17(1), 23; https://doi.org/10.3390/pharmaceutics17010023 - 26 Dec 2024

Viewed by 3289

Abstract

Background/Objectives: Lactoferrin (Lf), a multifunctional iron-binding protein, has considerable potential for use as an active ingredient in food supplements due to its numerous positive effects on health. As Lf is prone to degradation, we aimed to develop a formulation that would ensure sufficient [...] Read more.

Background/Objectives: Lactoferrin (Lf), a multifunctional iron-binding protein, has considerable potential for use as an active ingredient in food supplements due to its numerous positive effects on health. As Lf is prone to degradation, we aimed to develop a formulation that would ensure sufficient stability of Lf in the gastrointestinal tract and during product storage. Methods: A simple, efficient, and well-established technology that has potential for industrial production was used for the double-coating of neutral pellet cores with an Lf layer and a protective enteric coating. Results: The encapsulation efficiency was 85%, which is among the highest compared to other reported Lf formulations. The results of the dissolution tests performed indicated effective protection of Lf from gastric digestion. A comprehensive stability study showed that the stability was similar regardless of the neutral pellet core used, while a significant influence of temperature, moisture, product composition, and packaging on the stability of Lf were observed, and were therefore considered in the development of the final product. The experimentally determined shelf life is extended from 15 to almost 30 months if the product is stored in a refrigerator instead of at room temperature, which ensures the commercial applicability of the product. Conclusion: We successfully transferred a technology commonly used for small molecules to a protein-containing product, effectively protected it from the destructive effects of gastric juice, and achieved an acceptable shelf life. Full article

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

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14 pages, 3619 KB

Open AccessEditor’s ChoiceArticle

Bioadhesive Chitosan Films Loading Curcumin for Safe and Effective Skin Cancer Topical Treatment

by Seila Tolentino, Mylene M. Monteiro, Felipe Saldanha-Araújo, Marcilio Cunha-Filho, Tais Gratieri, Eliete N. Silva Guerra and Guilherme M. Gelfuso

Pharmaceutics 2025, 17(1), 18; https://doi.org/10.3390/pharmaceutics17010018 - 26 Dec 2024

Cited by 5 | Viewed by 2011

Abstract

Background/Objectives: This study aimed to evaluate the safety and efficacy of chitosan-based bioadhesive films for facilitating the topical delivery of curcumin in skin cancer treatment, addressing the pharmacokinetic limitations associated with oral administration. Methods: The films, which incorporated curcumin, were formulated [...] Read more.

Background/Objectives: This study aimed to evaluate the safety and efficacy of chitosan-based bioadhesive films for facilitating the topical delivery of curcumin in skin cancer treatment, addressing the pharmacokinetic limitations associated with oral administration. Methods: The films, which incorporated curcumin, were formulated using varying proportions of chitosan, polyvinyl alcohol, Poloxamer^® 407, and propylene glycol. These films were assessed for stability, drug release, in vitro skin permeation, cell viability (with and without radiotherapy), and skin irritation. Results: The films demonstrated physical stability and preserved curcumin content at room temperature for 90 days. Drug release was effectively controlled during the first 8 h, with release rates ranging from 51.6 ± 4.8% to 65.6 ± 13.0%. The films also enhanced drug penetration into the skin compared to a curcumin solution used as a control (stratum corneum: 1.3 ± 0.1 to 1.9 ± 0.8 µg/cm²; deeper skin layers: 1.7 ± 0.1 to 2.7 ± 0.2 µg/cm²). A cytotoxicity test on metastatic melanoma cells showed that curcumin at topical doses exerted activity similar to that delivered via the skin. Furthermore, curcumin alone was more effective in inhibiting tumor cells than radiotherapy alone (p < 0.01), with no additional benefit observed when curcumin was combined with radiotherapy. Finally, irritation tests confirmed that the films were safe for topical application. Conclusion: The developed chitosan-based bioadhesive films represent a promising alternative for the topical treatment of skin tumors using curcumin. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition)

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26 pages, 2866 KB

Open AccessEditor’s ChoiceReview

Enhancing Patient-Centric Drug Development: Coupling Hot Melt Extrusion with Fused Deposition Modeling and Pressure-Assisted Microsyringe Additive Manufacturing Platforms with Quality by Design

by Dinesh Nyavanandi, Preethi Mandati, Nithin Vidiyala, Prashanth Parupathi, Praveen Kolimi and Hemanth Kumar Mamidi

Pharmaceutics 2025, 17(1), 14; https://doi.org/10.3390/pharmaceutics17010014 - 25 Dec 2024

Cited by 6 | Viewed by 2158

Abstract

In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is [...] Read more.

In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is well known that “one size fits all” is not true for pharmaceutical medicines. Depending on the age, sex, and disease state, each patient might need a different dose, combination of medicines, and drug release pattern from the medications. By employing traditional practices, developing patient-centric medications remains challenging and unaddressed. Over the last few years, much research has been conducted exploring various additive manufacturing techniques for developing on-demand, complex, and patient-centric medications. Among all the techniques, nozzle-based additive manufacturing platforms such as pressure-assisted microsyringe (PAM) and fused deposition modeling (FDM) have been investigated thoroughly to develop various medications. Both nozzle-based techniques involve the application of thermal energy. However, PAM can also be operated under ambient conditions to process semi-solid materials. Nozzle-based techniques can also be paired with the hot melt extrusion (HME) process for establishing a continuous manufacturing platform by employing various in-line process analytical technology (PAT) tools for monitoring critical process parameters (CPPs) and critical material attributes (CMAs) for delivering safe, efficacious, and quality medications to the patient population without compromising critical quality attributes (CQAs). This review covers an in-depth discussion of various critical parameters and their influence on product quality, along with a note on the continuous manufacturing process, quality by design, and future perspectives. Full article

(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)

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32 pages, 6632 KB

Open AccessEditor’s ChoiceArticle

Evaluation of Biologics ACE2/Ang(1–7) Encapsulated in Plant Cells for FDA Approval: Safety and Toxicology Studies

by Henry Daniell, Geetanjali Wakade, Smruti K. Nair, Rahul Singh, Steven A. Emanuel, Barry Brock and Kenneth B. Margulies

Pharmaceutics 2025, 17(1), 12; https://doi.org/10.3390/pharmaceutics17010012 - 25 Dec 2024

Cited by 2 | Viewed by 3283

Abstract

Background/Objectives: For several decades, protein drugs (biologics) made in cell cultures have been delivered as sterile injections, decreasing their affordability and patient preference. Angiotensin Converting Enzyme 2 (ACE2) gum is the first engineered human blood protein expressed in plant cells approved by the [...] Read more.

Background/Objectives: For several decades, protein drugs (biologics) made in cell cultures have been delivered as sterile injections, decreasing their affordability and patient preference. Angiotensin Converting Enzyme 2 (ACE2) gum is the first engineered human blood protein expressed in plant cells approved by the FDA without the need for purification and is a cold-chain and noninvasive drug delivery. This biologic is currently being evaluated in human clinical studies to debulk SARS-CoV-2 in the oral cavity to reduce coronavirus infection/transmission (NCT 0543318). Methods: Chemistry, manufacturing, and control (CMC) studies for the ACE2/Ang(1–7) drug substances (DSs) and ACE2 gum drug product (DP) were conducted following USP guidelines. GLP-compliant toxicology studies were conducted on Sprague Dawley rats (n = 120; 15/sex/group) in four groups—placebo, low (1.6/1.0 mg), medium (3.2/2.0 mg), and high (8.3/5.0 mg) doses IP/kg/day. Oral gavage was performed twice daily for 14 days (the dosing phase) followed by the recovery phase (35 days). Plasma samples (n = 216) were analyzed for the product Ang(1–7) by ELISA. Results: The ACE2 protein was stable in the gum for at least up to 78 weeks. The toxicology study revealed the dose-related drug delivery to the plasma and increases in the AUC (56.6%) and Cmax (52.9%) after 28 high-dose gavages (95% C.I.), although this quantitation excludes exogenously delivered membrane-associated ACE2/Ang(1–7). Vital biomarkers and organs were not adversely affected despite the 10-fold higher absorption in the tissues, demonstrating the safety for the first in-human clinical trials of ACE2/Ang(1–7). The NOAEL observed in the rats was 2.5–7.5-fold higher than that of the anticipated efficacious therapeutic dose in humans for the treatment of cardiopulmonary disorders, and it was 314-fold higher than the NOAEL for topical delivery via chewing gum. Conclusions: This report lays the foundation for the regulatory process approval for noninvasive and affordable human biologic drugs bioencapsulated in plant cells. Full article

(This article belongs to the Special Issue Peptide–Drug Conjugates for Targeted Delivery)

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24 pages, 5118 KB

Open AccessEditor’s ChoiceArticle

Development of a Novel Co-Amorphous Curcumin and L-Arginine (1:2): Structural Characterization, Biological Activity and Pharmacokinetics

by Jose Antonio Mancillas-Quiroz, Miriam del Carmen Carrasco-Portugal, Karina Mondragón-Vásquez, Juan Carlos Huerta-Cruz, Juan Rodríguez-Silverio, Leyanis Rodríguez-Vera, Juan Gerardo Reyes-García, Francisco Javier Flores-Murrieta, Jorge Guillermo Domínguez-Chávez and Héctor Isaac Rocha-González

Pharmaceutics 2025, 17(1), 11; https://doi.org/10.3390/pharmaceutics17010011 - 25 Dec 2024

Cited by 4 | Viewed by 3322

Abstract

Background: Curcumin appears to be well tolerated and effective for managing chronic inflammatory pain, but its poor oral bioavailability has been a hurdle in its use as a therapeutic agent. The current study was performed to characterize a novel co-amorphous compound based on [...] Read more.

Background: Curcumin appears to be well tolerated and effective for managing chronic inflammatory pain, but its poor oral bioavailability has been a hurdle in its use as a therapeutic agent. The current study was performed to characterize a novel co-amorphous compound based on curcumin/L-arginine 1:2 (CAC12). Methods: Stability, solubility and structural characterization of the CAC12 were carried out by spectrometry techniques and in vitro assays, whereas the antinociceptive and anti-inflammatory effects were evaluated by CFA or carrageenan models. The mechanism of action was determined by cytokine quantification, and pharmacokinetic parameters were obtained through UPLC-MS/MS. The co-amorphous compound was prepared by fast solvent evaporation. Powder XRD, ¹³C-NMR, ATR-FTIR and TGA/DSC thermal analysis showed a 1:2 stoichiometry for the CAC12. Results: CAC12 was 1000 times more soluble than curcumin, and it was stable for 1 month at 40 °C and 75% relative humidity or for 60 min in physiological medium at pH 4.5–6.8. Co-amorphous curcumin/L-arginine, but not curcumin + L-arginine, decreased carrageenan- or CFA-induced inflammation and nociception by decreasing IL-1α, IL-1β, IL-6, TNF-α, MCP-1 and CXCL1 cytokines. The bioavailability of free plasmatic curcumin increased about 22.4 times when it was given as CAC12 relative to a phytosome formulation at the equivalent dose. Conclusions: Results suggest the possible use of CAC12 to treat inflammatory pain disorders in human beings. Full article

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

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17 pages, 5873 KB

Open AccessEditor’s ChoiceArticle

Injectable Tumoricidal Neural Stem Cell-Laden Hydrogel for Treatment of Glioblastoma Multiforme—An In Vivo Safety, Persistence, and Efficacy Study

by Jasmine L. King, Alain Valdivia, Shawn D. Hingtgen and S. Rahima Benhabbour

Pharmaceutics 2025, 17(1), 3; https://doi.org/10.3390/pharmaceutics17010003 - 24 Dec 2024

Cited by 3 | Viewed by 2513

Abstract

Background/Objectives: Glioblastoma multiforme (GBM) is the most common high-grade primary brain cancer in adults. Despite efforts to advance treatment, GBM remains treatment resistant and inevitably progresses after first-line therapy. Induced neural stem cell (iNSC) therapy is a promising, personalized cell therapy approach that [...] Read more.

Background/Objectives: Glioblastoma multiforme (GBM) is the most common high-grade primary brain cancer in adults. Despite efforts to advance treatment, GBM remains treatment resistant and inevitably progresses after first-line therapy. Induced neural stem cell (iNSC) therapy is a promising, personalized cell therapy approach that has been explored to circumvent challenges associated with the current GBM treatment. Methods: Herein, we developed a chitosan-based (CS) injectable, biodegradable, in situ forming thermo-responsive hydrogel as a cell delivery vehicle for the treatment of GBM. Tumoricidal neural stem cells were encapsulated in the injectable CS hydrogel as stem cell therapy for treatment of post-surgical GBM. In this report, we investigated the safety of the injectable CS hydrogel in an immune-competent mouse model. Furthermore, we evaluated the persistence and efficacy of iNSC-laden CS hydrogels in a post-surgical GBM mouse model. Results: The injectable CS hydrogel was well tolerated in mice with no signs of chronic local inflammation. Induced neural stem cells (iNSCs) persisted in the CS hydrogels for over 196 days in comparison to 21 days for iNSCs (cell injection) only. GBM recurrence was significantly slower in mice treated with iNSC-laden CS hydrogels with a 50% increase in overall median survival in comparison to iNSCs (cell injection) only. Conclusions: Collectively, we demonstrated the ability to encapsulate, retain, and deliver iNSCs in an injectable CS hydrogel that is well tolerated with better survival rates than iNSCs alone. Full article

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

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13 pages, 3856 KB

Open AccessEditor’s ChoiceArticle

Inhibition of Aβ Aggregation by Cholesterol-End-Modified PEG Vesicles and Micelles

by Shota Watanabe, Motoki Ueda and Shoichiro Asayama

Pharmaceutics 2025, 17(1), 1; https://doi.org/10.3390/pharmaceutics17010001 - 24 Dec 2024

Cited by 3 | Viewed by 1796

Abstract

Background/Objectives: This study aimed to design and evaluate Chol-PEG₂₀₀₀ micelles and Chol-PEG₅₀₀ vesicles as drug delivery system (DDS) carriers and inhibitors of amyloid-β (Aβ) aggregation, a key factor in Alzheimer’s disease (AD). Methods: The physical properties of Chol-PEG assemblies [...] Read more.

Background/Objectives: This study aimed to design and evaluate Chol-PEG₂₀₀₀ micelles and Chol-PEG₅₀₀ vesicles as drug delivery system (DDS) carriers and inhibitors of amyloid-β (Aβ) aggregation, a key factor in Alzheimer’s disease (AD). Methods: The physical properties of Chol-PEG assemblies were characterized using dynamic light scattering (DLS), electrophoretic light scattering (ELS), and transmission electron microscopy (TEM). Inhibitory effects on Aβ aggregation were assessed via thioflavin T (ThT) assay, circular dichroism (CD) spectroscopy, and native polyacrylamide gel electrophoresis (native-PAGE). Results: Chol-PEG₂₀₀₀ micelles and Chol-PEG₅₀₀ vesicles were found to exhibit diameters of 20–30 nm and 70–80 nm, respectively, with neutral surface charges and those physical properties indicated the high affinity for Aβ. At a 10-fold molar ratio, thioflavin T (ThT) assay revealed that Chol-PEG₂₀₀₀ delayed Aβ fibril elongation by 20 hours, while Chol-PEG₅₀₀ delayed it by 40 hours against Aβ peptide. At a 50-fold molar ratio, both Chol-PEG₂₀₀₀ and Chol-PEG₅₀₀ significantly inhibited Aβ aggregation, as indicated by minimal fluorescence intensity increases over 48 hours. CD spectroscopy indicated that Aβ maintained its random coil structure in the presence of Chol-PEG assemblies at a 50-fold molar ratio. Native-PAGE analysis demonstrated a retardation in Aβ migration immediately after mixing with Chol-PEG assemblies, suggesting complex formation. However, this retardation disappeared within 5 min, implying rapid dissociation of the complexes. Conclusions: This study demonstrated that Chol-PEG₅₀₀ vesicles more effectively inhibit Aβ aggregation than Chol-PEG₂₀₀₀ micelles. Chol-PEG assemblies perform as DDS carriers to be capable of inhibiting Aβ aggregation. Chol-PEG assemblies can deliver additional therapeutics targeting other aspects of AD pathology. This dual-function platform shows promise as both a DDS carrier and a therapeutic agent, potentially contributing to a fundamental cure for AD. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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16 pages, 3140 KB

Open AccessEditor’s ChoiceArticle

Cationic Hydroxyethyl Cellulose Nanocomplexes and RANK siRNA/Zoledronate Co-Delivery Systems for Osteoclast Inhibition

by Sohyun Lee, Seoyeon Park and Tae-il Kim

Pharmaceutics 2024, 16(12), 1623; https://doi.org/10.3390/pharmaceutics16121623 - 22 Dec 2024

Viewed by 1369

Abstract

Background/Objectives: In this study, HECP2k polymer, polyethylenimine2k (PEI2k)-modified hydroxyethyl cellulose (HEC) was utilized to form the nanocomplexes with receptor activator of nuclear factor k-B (RANK) siRNA and zoledronate (Zol) for osteoclast inhibition. HECP2k/(RANK siRNA + Zol) nanocomplexes prepared by simple mixing were anticipated [...] Read more.

Background/Objectives: In this study, HECP2k polymer, polyethylenimine2k (PEI2k)-modified hydroxyethyl cellulose (HEC) was utilized to form the nanocomplexes with receptor activator of nuclear factor k-B (RANK) siRNA and zoledronate (Zol) for osteoclast inhibition. HECP2k/(RANK siRNA + Zol) nanocomplexes prepared by simple mixing were anticipated to overcome the low transfection efficiency of siRNA and the low bioavailability of Zol. Methods: The characterization of both HECP2k/(pDNA + Zol) nanocomplexes and HECP2k/(RANK siRNA + Zol) nanocomplexes was performed. Results: The nanocomplexes were successfully formed even in the presence of Zol, showing about 200 nm sizes and about 20 mV of positive zeta potential values suitable for efficient cellular uptake. They also possessed high endosome buffering ability by PEI and Zol, suggesting the potential for efficient endosomal escape. It was found that the low cytotoxic nanocomplexes (>90% cell viability) displayed greater transfection efficiency than PEI25k and even HECP2k polyplexes. Finally, it was found by tartrate-resistant acid phosphatase (TRAP) assay and qPCR analysis that HECP2k/(RANK siRNA + Zol) nanocomplexes could inhibit the TRAP to about 50% value and another characteristic osteoclastic gene expression, increasing FAS gene expression to about 16 times higher than control and more efficiently (about 3 times and 5 times higher, respectively) than HECP2k/siRNA polyplexes and Zol only. Conclusions: HECP2k/(RANK siRNA + Zol) nanocomplexes formed by simple mixing showed great potential for inhibiting osteoclast differentiation and osteoclast activity, inducing the apoptosis via combinatorial effects of RANK siRNA and Zol. Full article

(This article belongs to the Special Issue Drug Nanocarriers for Pharmaceutical Applications)

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13 pages, 1531 KB

Open AccessEditor’s ChoiceArticle

Sustained-Release Solid Dispersions of Fenofibrate for Simultaneous Enhancement of the Extent and Duration of Drug Exposure

by Seong-Jin Park, Gyu Lin Kim and Hyo-Kyung Han

Pharmaceutics 2024, 16(12), 1617; https://doi.org/10.3390/pharmaceutics16121617 - 20 Dec 2024

Viewed by 2177

Abstract

Background/Objectives: A sustained-release formulation of fenofibrate while enhancing drug dissolution with minimal food effect is critical for maximizing the therapeutic benefits of fenofibrate. Therefore, this study aimed to develop an effective solid dispersion formulation of fenofibrate for simultaneous enhancement in the extent and [...] Read more.

Background/Objectives: A sustained-release formulation of fenofibrate while enhancing drug dissolution with minimal food effect is critical for maximizing the therapeutic benefits of fenofibrate. Therefore, this study aimed to develop an effective solid dispersion formulation of fenofibrate for simultaneous enhancement in the extent and duration of drug exposure. Methods: Fenofibrate-loaded solid dispersions (FNSDs) were prepared using poloxamer 407 and Eudragit^® RSPO at varied ratios via solvent evaporation. In vitro/in vivo characteristics of FNSDs were examined in comparison with untreated drugs. Results: Based on dissolution profiles of FNSDs in aqueous media, the weight ratio of fenofibrate: poloxamer 407: Eudragit^® RSPO at 1:1:4 (FNSD2) was selected as the optimal composition for achieving sustained drug release while maximizing the drug dissolution. The enhanced and sustained drug release of FNSD2 was also confirmed in a buffer transition system mimicking the pH change in the gastrointestinal tract. FNSD2 achieved approximately 66% drug release over 12 h, while pure drug exhibited only 12%. Furthermore, FNSD2 maintained similar release rates under fed and fasted conditions, while the entire drug dissolution slightly increased in the fed state. Structural analysis by x-ray diffraction showed that fenofibrate remained crystalline in FNSD2. Pharmacokinetic studies in rats revealed that orally administered FNSD2 significantly improved the extent and duration of systemic drug exposure. Compared to pure drugs, the FNSD2 formulation increased the oral bioavailability of fenofibrate by 22 folds with the delayed T_max of 4 h in rats. Conclusion: FNSD2 formulation is effective in improving the extent and duration of drug exposure simultaneously. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology in Korea)

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22 pages, 3006 KB

Open AccessEditor’s ChoiceReview

How to Fabricate Hyaluronic Acid for Ocular Drug Delivery

by Martha Kim, Mi-Young Jung, Do-Yeon Lee, So Min Ahn, Gyeong Min Lee and Choul Yong Park

Pharmaceutics 2024, 16(12), 1604; https://doi.org/10.3390/pharmaceutics16121604 - 16 Dec 2024

Cited by 4 | Viewed by 3730

Abstract

This review aims to examine existing research on the development of ocular drug delivery devices utilizing hyaluronic acid (HA). Renowned for its exceptional biocompatibility, viscoelastic properties, and ability to enhance drug bioavailability, HA is a naturally occurring biopolymer. The review discussed specific mechanisms [...] Read more.

This review aims to examine existing research on the development of ocular drug delivery devices utilizing hyaluronic acid (HA). Renowned for its exceptional biocompatibility, viscoelastic properties, and ability to enhance drug bioavailability, HA is a naturally occurring biopolymer. The review discussed specific mechanisms by which HA enhances drug delivery, including prolonging drug residence time on ocular surfaces, facilitating controlled drug release, and improving drug penetration through ocular tissues. By focusing on these unique functionalities, this review highlights the potential of HA-based systems to revolutionize ocular treatment. Various fabrication techniques for HA-based ocular drug delivery systems, including hydrogels, nanoparticles, and microneedles, are discussed, highlighting their respective advantages and limitations. Additionally, this review explores the clinical applications of HA-based devices in treating a range of ocular diseases, such as dry eye syndrome, glaucoma, retinal disorders, and ocular infections. By comparing the efficacy and safety profiles of these devices with traditional ocular drug delivery methods, this review aims to provide a comprehensive understanding of the potential benefits and challenges associated with HA-based systems. Moreover, this review discusses current limitations and future directions in the field, such as the need for standardized fabrication protocols, long-term biocompatibility studies, and large-scale clinical trials. The insights and advancements presented in this review aim to guide future research and development efforts, ultimately enhancing the effectiveness of ocular drug delivery and improving patient outcomes. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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14 pages, 3511 KB

Open AccessEditor’s ChoiceArticle

Drug–Phospholipid Co-Amorphous Formulations: The Role of Preparation Methods and Phospholipid Selection

by Keyoomars Khorami, Sam Darestani Farahani, Anette Müllertz and Thomas Rades

Pharmaceutics 2024, 16(12), 1602; https://doi.org/10.3390/pharmaceutics16121602 - 16 Dec 2024

Cited by 1 | Viewed by 1610

Abstract

Background/Objectives: This study aims to broaden the knowledge on co-amorphous phospholipid systems (CAPSs) by exploring the formation of CAPSs with a broader range of poorly water-soluble drugs, celecoxib (CCX), furosemide (FUR), nilotinib (NIL), and ritonavir (RIT), combined with amphiphilic phospholipids (PLs), including [...] Read more.

Background/Objectives: This study aims to broaden the knowledge on co-amorphous phospholipid systems (CAPSs) by exploring the formation of CAPSs with a broader range of poorly water-soluble drugs, celecoxib (CCX), furosemide (FUR), nilotinib (NIL), and ritonavir (RIT), combined with amphiphilic phospholipids (PLs), including soybean phosphatidylcholine (SPC), hydrogenated phosphatidylcholine (HPC), and mono-acyl phosphatidylcholine (MAPC). Methods: The CAPSs were initially prepared at equimolar drug-to-phospholipid (PL) ratios by mechano-chemical activation-based, melt-based, and solvent-based preparation methods, i.e., ball milling (BM), quench cooling (QC), and solvent evaporation (SE), respectively. The solid state of the product was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), and differential scanning calorimetry (DSC). The long-term physical stability of the CAPSs was investigated at room temperature under dry conditions (0% RH) and at 75% RH. The dissolution behavior of the CCX CAPS and RIT CAPS was studied. Results: Our findings indicate that SE consistently prepared CAPSs for CCX-PLs, FUR-PLs, and RIT-PLs, whereas the QC method could only form CAPSs for RIT-PLs, CCX-SPC, and CCX-MAPC. In contrast, the BM method failed to produce CAPSs, but all drugs alone could be fully amorphized. While the stability of each drug varied depending on the PLs used, the SE CAPS consistently demonstrated the highest stability by a significant margin. Initially, a 1:1 molar ratio was used for screening all systems, though the optimal molar ratio for drug stability remained uncertain. To address this, various molar ratios were investigated to determine the ratio yielding the highest amorphous drug stability. Our results indicate that all systems remained physically stable at a 1.5:1 ratio and with excess of PL. Furthermore, the CAPS formed by the SE significantly improves the dissolution behavior of CCX and RIT, whereas the PLs provide a slight precipitation inhibition for supersaturated CCX and RIT. Conclusions: These findings support the use of a 1:1 molar ratio in screening processes and suggest that CAPSs can be effectively prepared with relatively high drug loads compared to traditional drug–polymer systems. Furthermore, the study highlights the critical role of drug selection, the preparation method, and the PL type in developing stable and effective CAPSs. Full article

(This article belongs to the Special Issue Advances in the Preparation and Technology of Pharmaceutical Solid Dosage Forms)

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17 pages, 1668 KB

Open AccessEditor’s ChoiceArticle

Zein Nanoparticles-Loaded Flavonoids-Rich Fraction from Fridericia platyphylla: Potential Antileishmanial Applications

by Monica Araujo das Neves, Caroline Martins de Jesus, Jhones Luiz de Oliveira, Samuel dos Santos Soares Buna, Lucilene Amorim Silva, Leonardo Fernandes Fraceto and Cláudia Quintino da Rocha

Pharmaceutics 2024, 16(12), 1603; https://doi.org/10.3390/pharmaceutics16121603 - 16 Dec 2024

Cited by 1 | Viewed by 1877

Abstract

Background/Objectives: Leishmaniasis, caused by protozoa of the genus Leishmania, is a major global health issue due to the limitations of current treatments, which include low efficacy, high costs, and severe side effects. This study aimed to develop a more effective and less [...] Read more.

Background/Objectives: Leishmaniasis, caused by protozoa of the genus Leishmania, is a major global health issue due to the limitations of current treatments, which include low efficacy, high costs, and severe side effects. This study aimed to develop a more effective and less toxic therapy by utilizing zein nanoparticles (ZNPs) in combination with a nonpolar fraction (DCMF) from Fridericia platyphylla (Syn. Arrabidaea brachypoda), a plant rich in dimeric flavonoids called brachydins. Methods: Zein nanoparticles were used as carriers to encapsulate DCMF. The system was characterized by measuring particle diameter, polydispersity index, zeta potential, and encapsulation efficiency. Analytical techniques such as FTIR, DSC, and AFM were employed to confirm the encapsulation and stability of DCMF. Antileishmanial activity was assessed against Leishmania amazonensis promastigotes and amastigotes, while cytotoxicity was tested on RAW264.7 macrophages. Results: The ZNP-DCMF system exhibited favorable properties, including a particle diameter of 141 nm, a polydispersity index below 0.2, and a zeta potential of 11.3 mV. DCMF was encapsulated with an efficiency of 94.6% and remained stable for 49 days. In antileishmanial assays, ZNP-DCMF inhibited the viability of promastigotes with an IC50 of 36.33 μg/mL and amastigotes with an IC50 of 0.72 μg/mL, demonstrating higher selectivity (SI = 694.44) compared to DCMF alone (SI = 43.11). ZNP-DCMF was non-cytotoxic to RAW264.7 macrophages, with a CC50 > 500 μg/mL. Conclusions: Combining F. platyphylla DCMF with zein nanoparticles as a carrier presents a promising approach for leishmaniasis treatment, offering improved efficacy, reduced toxicity, and protection of bioactive compounds from degradation. Full article

(This article belongs to the Special Issue Anti-parasitic Applications of Nanoparticles)

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15 pages, 4876 KB

Open AccessEditor’s ChoiceArticle

Exploring Micelles and Nanospheres as Delivery Systems for Phenothiazine Derivatives in Cancer Therapy

by Katarzyna Jelonek, Monika Musiał-Kulik, Małgorzata Pastusiak, Aleksander Foryś, Andrzej Zięba and Janusz Kasperczyk

Pharmaceutics 2024, 16(12), 1597; https://doi.org/10.3390/pharmaceutics16121597 - 16 Dec 2024

Cited by 1 | Viewed by 1353

Abstract

Objectives: Cancer remains one of the leading causes of death worldwide, and thus, there is a need for the development of innovative and more effective treatment strategies. The aim of the study was to evaluate two types of nanoparticles—nanospheres and micelles—obtained from [...] Read more.

Objectives: Cancer remains one of the leading causes of death worldwide, and thus, there is a need for the development of innovative and more effective treatment strategies. The aim of the study was to evaluate two types of nanoparticles—nanospheres and micelles—obtained from PLA-based polymers to discover their potential for delivering four types of phenothiazine derivatives. Methods: The morphology, drug-loading properties, cytocompatibility, hemolytic properties and anticancer activity were analyzed. Results: The micelles exhibited significantly higher drug-loading properties, release process and cytotoxic activity against cancer cells compared to the nanospheres. The micelles containing 5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride with an OH group as a substituent in the 10-position of the quinobenzothiazine ring showed the highest drug-loading content, the most efficient drug release, the lowest hemolytic activity and the most significant cytotoxic effect against HeLa cells. Conclusions: The conducted study enabled the development of a delivery system for the new anticancer compound and showed that the choice of drug carrier has a crucial effect on its cytotoxic potential against cancer cells. Full article

(This article belongs to the Special Issue Design of Novel Polymeric Systems for Controlled Drug Delivery, 2nd Edition)

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14 pages, 2279 KB

Open AccessEditor’s ChoiceArticle

Evaluation of the Drug–Drug Interaction Potential of Cannabidiol Against UGT2B7-Mediated Morphine Metabolism Using Physiologically Based Pharmacokinetic Modeling

by Shelby Coates, Keti Bardhi, Bhagwat Prasad and Philip Lazarus

Pharmaceutics 2024, 16(12), 1599; https://doi.org/10.3390/pharmaceutics16121599 - 16 Dec 2024

Cited by 2 | Viewed by 3216

Abstract

Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown [...] Read more.

Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown that chronic pain patients have increasingly used other supplements to treat their chronic pain, including cannabidiol (CBD). Up to 50% of chronic pain patients report that they co-use cannabis with their prescribed opioid for pain management, including morphine. Previous work has shown that cannabidiol is a potent inhibitor of UGT2B7, including morphine-mediated metabolism. Co-use of morphine and CBD may result in unwanted drug–drug interactions (DDIs). Methods: Using available physiochemical and clinical parameters, morphine and CBD physiologically based pharmacokinetic (PBPK) models were developed and validated in both healthy and cirrhotic populations. Models for the two populations were then combined to predict the severity and clinical relevance of the potential DDIs during coadministration of both morphine and CBD in both healthy and hepatic-impaired virtual populations. Results: The predictive DDI model suggests that a ~5% increase in morphine exposure is to be expected in healthy populations. A similar increase in exposure of morphine is predicted in severe hepatic-impaired populations with an increase of ~10. Conclusions: While these predicted increases in morphine exposure are below the Food and Drug Administration’s cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5–10% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)

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11 pages, 716 KB

Open AccessEditor’s ChoiceArticle

Experimental and Theoretical Design on the Development of Matrix Tablets with Multiple Drug Loadings Aimed at Optimizing Antidiabetic Medication

by Mousa Sha’at, Lacramioara Ochiuz, Cristina Marcela Rusu, Maricel Agop, Alexandra Barsan (Bujor), Monica Stamate Cretan, Mihaela Hartan and Adrian Florin Spac

Pharmaceutics 2024, 16(12), 1595; https://doi.org/10.3390/pharmaceutics16121595 - 14 Dec 2024

Viewed by 2151

Abstract

Background: Diabetes is a growing global health crisis that requires effective therapeutic strategies to optimize treatment outcomes. This study aims to address this challenge by developing and characterizing extended-release polymeric matrix tablets containing metformin hydrochloride (M-HCl), a first-line treatment for type 2 diabetes, [...] Read more.

Background: Diabetes is a growing global health crisis that requires effective therapeutic strategies to optimize treatment outcomes. This study aims to address this challenge by developing and characterizing extended-release polymeric matrix tablets containing metformin hydrochloride (M-HCl), a first-line treatment for type 2 diabetes, and honokiol (HNK), a bioactive compound with potential therapeutic benefits. The objective is to enhance glycemic control and overall therapeutic outcomes through an innovative dual-drug delivery system. Methods: The tablets were formulated using hydrophilic polymers, such as Carbopol^® 71G NF and Noveon^® AA-1. The release kinetics of M-HCl and HNK were investigated through advanced mathematical models, including fractal and multifractal dynamics, to capture the non-linear and time-dependent release processes. Traditional kinetic models (zero-order, first-order, Higuchi equations) were also evaluated for comparison. In vitro dissolution studies were conducted to determine the release profiles of the active ingredients under varying polymer concentrations. Results: The study revealed distinct release profiles for the two active ingredients. M-HCl exhibited a rapid release phase, with 80% of the drug released within 4–7 h depending on polymer concentration. In contrast, HNK demonstrated a slower release profile, achieving 80% release after 9–10 h, indicating a greater sensitivity to polymer concentration. At shorter intervals, drug release followed classical kinetic models, while multifractal dynamics dominated at longer intervals. Higher polymer concentrations resulted in slower drug release rates due to the formation of a gel-like structure upon hydration, which hindered drug diffusion. The mechanical properties and stability of the matrix tablets confirmed their suitability for extended-release applications. Mathematical modeling validated the experimental findings and provided insights into the structural and time-dependent factors influencing drug release. Conclusions: This study successfully developed dual-drug extended-release matrix tablets containing metformin hydrochloride and honokiol, highlighting the potential of hydrophilic polymers to regulate drug release. The findings emphasize the utility of advanced mathematical models for predicting release kinetics and underscore the potential of these formulations to improve patient compliance and therapeutic outcomes in diabetes management. Full article

(This article belongs to the Special Issue Mathematical Modeling of Polymer-Based Drug Delivery Systems: Mechanisms and Applications)

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12 pages, 2663 KB

Open AccessEditor’s ChoiceArticle

A QbD Approach for the Formulation and Control of Triclabendazole in Uncoated Tablets: From Polymorphs to Drug Formulation

by Lucas P. Muzi, Marina Antonio and Rubén M. Maggio

Pharmaceutics 2024, 16(12), 1594; https://doi.org/10.3390/pharmaceutics16121594 - 13 Dec 2024

Viewed by 1656

Abstract

Triclabendazole (TCB) is a well-established anthelmintic effective in treating fascioliasis, a neglected tropical disease. This study employs quality by design (QbD) to investigate the impact of TCB polymorphism and pharmacotechnical variables, from the development of immediate-release tablets to process optimization and green analysis. [...] Read more.

Triclabendazole (TCB) is a well-established anthelmintic effective in treating fascioliasis, a neglected tropical disease. This study employs quality by design (QbD) to investigate the impact of TCB polymorphism and pharmacotechnical variables, from the development of immediate-release tablets to process optimization and green analysis. Critical process parameters (CPPs) and critical material attributes (CMAs), characterized by type of polymorph, composition of excipients (talc, lactose, cornstarch, and magnesium stearate), and compression force, were screened using a Plackett–Burman design (n = 24), identifying polymorphic purity and cornstarch as a CPP. To establish a mathematical model linking CPP to dissolution behaviour, a multiple linear regression (MLR) was applied to the training design (central composite design, n = 18). Simultaneously, a near-infrared spectroscopy coupled to partial least squares (NIR-PLSs) method was developed to analyze CPPs. An independent set of samples was prepared and analyzed using the NIR-PLSs model, and their dissolution profiles were also obtained. The PLSs model successfully predicted the CPPs in the new samples, yielding almost quantitative results (100 ± 3%), and MLR dissolution predictions mirrored the actual dissolution profiles (f2 = 85). In conclusion, the developed model could serve as a comprehensive tool for the development and control of pharmaceutical formulations, starting from the polymorphic composition and extending to achieve targeted dissolution outcomes. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design, 2nd Edition)

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