Pharmaceutics

40 pages, 1380 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Donepezil Delivery Systems via the Nose-to-Brain Pathway

by Jiyoon Jon, Jieun Jeong, Joohee Jung, Hyosun Cho, Kyoung Song, Eun-Sook Kim, Sang Hyup Lee, Eunyoung Han, Woo-Hyun Chung, Aree Moon, Kyu-Tae Kang, Min-Soo Kim and Heejun Park

Pharmaceutics 2025, 17(8), 958; https://doi.org/10.3390/pharmaceutics17080958 - 24 Jul 2025

Cited by 6 | Viewed by 4600

Abstract

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, [...] Read more.

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, various dosage forms aimed at delivering DPZ have been explored. This discussion will focus on the nose-to-brain (N2B) delivery system, which represents the most promising approach for brain drug delivery. Intranasal (IN) drug delivery is a suitable system for directly delivering drugs to the brain, as it bypasses the BBB and avoids the first-pass effect, thereby targeting the central nervous system (CNS). Currently developed formulations include lipid-based, solid particle-based, solution-based, gel-based, and film-based types, and a systematic review of the N2B research related to these formulations has been conducted. According to the in vivo results, the brain drug concentration 15 min after IN administration was more than twice as high those from other routes of administration, and the direct delivery ratio of the N2B system improved to 80.32%. The research findings collectively suggest low toxicity and high therapeutic efficacy for AD. This review examines drug formulations and delivery methods optimized for the N2B delivery of DPZ, focusing on technologies that enhance mucosal residence time and bioavailability while discussing recent advancements in the field. Full article

(This article belongs to the Special Issue Nasal Nanotechnology: What Do We Know and What Is Yet to Come?)

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21 pages, 1905 KB

Open AccessEditor’s ChoiceArticle

Wax-Based Sustained-Release Felodipine Oral Dosage Forms Manufactured Using Hot-Melt Extrusion and Their Resistance to Alcohol-Induced Dose Dumping

by Gerard Sweeney, Dijia Liu, Taher Hatahet, David S. Jones, Shu Li and Gavin P. Andrews

Pharmaceutics 2025, 17(8), 955; https://doi.org/10.3390/pharmaceutics17080955 - 24 Jul 2025

Cited by 4 | Viewed by 2115

Abstract

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with [...] Read more.

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article

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

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21 pages, 3048 KB

Open AccessEditor’s ChoiceArticle

Transfersome-Based Delivery of Optimized Black Tea Extract for the Prevention of UVB-Induced Skin Damage

by Nadia Benedetto, Maria Ponticelli, Ludovica Lela, Emanuele Rosa, Flavia Carriero, Immacolata Faraone, Carla Caddeo, Luigi Milella and Antonio Vassallo

Pharmaceutics 2025, 17(8), 952; https://doi.org/10.3390/pharmaceutics17080952 - 23 Jul 2025

Cited by 4 | Viewed by 2263

Abstract

Background/Objectives: Ultraviolet B (UVB) radiation contributes significantly to skin aging and skin disorders by promoting oxidative stress, inflammation, and collagen degradation. Natural antioxidants such as theaflavins and thearubigins from Camellia sinensis L. (black tea) have shown photoprotective effects. This study aimed to optimize [...] Read more.

Background/Objectives: Ultraviolet B (UVB) radiation contributes significantly to skin aging and skin disorders by promoting oxidative stress, inflammation, and collagen degradation. Natural antioxidants such as theaflavins and thearubigins from Camellia sinensis L. (black tea) have shown photoprotective effects. This study aimed to optimize the extraction of theaflavins and thearubigins from black tea leaves and evaluate the efficacy of the extract against UVB-induced damage using a transfersome-based topical formulation. Methods: Extraction of theaflavins and thearubigins was optimized via response surface methodology (Box-Behnken Design), yielding an extract rich in active polyphenols. This extract was incorporated into transfersomes that were characterized for size, polydispersity, zeta potential, storage stability, and entrapment efficiency. Human dermal fibroblasts (NHDF) were used to assess cytotoxicity, protection against UVB-induced viability loss, collagen degradation, and expression of inflammatory (IL6, COX2, iNOS) and matrix-degrading (MMP1) markers. Cellular uptake of the extract’s bioactive marker compounds was measured via LC-MS/MS. Results: The transfersomes (~60 nm) showed a good stability and a high entrapment efficiency (>85%). The transfersomes significantly protected NHDF cells from UVB-induced cytotoxicity, restored collagen production, and reduced gene expression of MMP1, IL6, COX2, and iNOS. Cellular uptake of key extract’s polyphenols was markedly enhanced by the nanoformulation compared to the free extract. Conclusions: Black tea extract transfersomes effectively prevented UVB-induced oxidative and inflammatory damage in skin fibroblasts. This delivery system enhanced bioavailability of the extract and cellular protection, supporting the use of the optimized extract in cosmeceutical formulations targeting photoaging and UV-induced skin disorders. Full article

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

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21 pages, 1132 KB

Open AccessEditor’s ChoiceArticle

Ferroptosis Among the Antiproliferative Pathways Activated by a Lipophilic Ruthenium(III) Complex as a Candidate Drug for Triple-Negative Breast Cancer

by Maria Grazia Ferraro, Federica Iazzetti, Marco Bocchetti, Claudia Riccardi, Daniela Montesarchio, Rita Santamaria, Gabriella Misso, Marialuisa Piccolo and Carlo Irace

Pharmaceutics 2025, 17(7), 918; https://doi.org/10.3390/pharmaceutics17070918 - 16 Jul 2025

Cited by 3 | Viewed by 2290

Abstract

Background/Objectives: In the context of preclinical studies, we have hitherto showcased that a low-molecular-weight ruthenium(III) complex we named AziRu holds significant potential for further developments as an anticancer candidate drug. When appropriately converted into stable nanomaterials and delivered into tumor cells, AziRu [...] Read more.

Background/Objectives: In the context of preclinical studies, we have hitherto showcased that a low-molecular-weight ruthenium(III) complex we named AziRu holds significant potential for further developments as an anticancer candidate drug. When appropriately converted into stable nanomaterials and delivered into tumor cells, AziRu exhibits superior antiproliferative activity, benefiting from a multimodal mechanism of action. The activation of regulated cell death (RCD) pathways (i.e., apoptosis and autophagy) has been proved in metastatic phenotypes, including triple-negative breast cancer (TNBC) cells. This study focuses on a bioengineered lipophilic derivative of AziRu, named PalmiPyRu, that we are currently developing as a potential anticancer drug in preclinical studies. When delivered in this way, AziRu confirms a multimodal mechanism of action in effectively blocking the growth and proliferation of TNBC phenotypes. Special focus is reserved for the activation of the ferroptotic pathway as a consequence of redox imbalance and interference with iron homeostasis, as well as the glutathione biosynthetic pathway. Methods: Human preclinical models of specific TNBC phenotypes and healthy cell cultures of different histological origin were selected. After in vitro treatments, cellular responses were carefully analyzed, and targeted biochemical and molecular biology experiments coupled to confocal microscopy allowed us to explore the antiproliferative effects of PalmiPyRu. Results: In this study, we unveil that PalmiPyRu can enter TNBC cells and interfere with both the iron homeostasis and the cystine-glutamate antiporter system Xc-, causing significant oxidative stress and the accumulation of lipid oxidation products. The increase in intracellular reactive free iron and depletion of glutathione engender a lethal condition, driving cancer cells toward the activation of ferroptosis. Conclusions: Overall, these outcomes allow us, for the first time, to couple the antiproliferative effect of a ruthenium-based candidate drug with the inhibition of the Xc- antiporter system and Fenton chemistry, thereby branding PalmiPyRu as an effective multimodal inducer of ferroptosis. Molecular mechanisms of action deserve further investigations, and new studies are underway to uncover how interference with Xc- controls cell fate, allowing us to explore the connection between iron metabolism regulation, oxidative stress and RCD pathways activation. Full article

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

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34 pages, 4581 KB

Open AccessEditor’s ChoiceReview

Nanoradiopharmaceuticals: Design Principles, Radiolabeling Strategies, and Biomedicine Applications

by Andrés Núñez-Salinas, Cristian Parra-Garretón, Daniel Acuña, Sofía Peñaloza, Germán Günther, Soledad Bollo, Francisco Arriagada and Javier Morales

Pharmaceutics 2025, 17(7), 912; https://doi.org/10.3390/pharmaceutics17070912 - 14 Jul 2025

Cited by 14 | Viewed by 3862

Abstract

Nanoradiopharmaceuticals integrate nanotechnology with nuclear medicine to enhance the precision and effectiveness of radiopharmaceuticals used in diagnostic imaging and targeted therapies. Nanomaterials offer improved targeting capabilities and greater stability, helping to overcome several limitations. This review presents a comprehensive overview of the fundamental [...] Read more.

Nanoradiopharmaceuticals integrate nanotechnology with nuclear medicine to enhance the precision and effectiveness of radiopharmaceuticals used in diagnostic imaging and targeted therapies. Nanomaterials offer improved targeting capabilities and greater stability, helping to overcome several limitations. This review presents a comprehensive overview of the fundamental design principles, radiolabeling techniques, and biomedical applications of nanoradiopharmaceuticals, with a particular focus on their expanding role in precision oncology. It explores key areas, including single- and multi-modal imaging modalities (SPECT, PET), radionuclide therapies involving beta, alpha, and Auger emitters, and integrated theranostic systems. A diverse array of nanocarriers is examined, including liposomes, micelles, albumin nanoparticles, PLGA, dendrimers, and gold, iron oxide, and silica-based platforms, with an assessment of both preclinical and clinical research outcomes. Theranostic nanoplatforms, which integrate diagnostic and therapeutic functions within a single system, enable real-time monitoring and personalized dose optimization. Although some of these systems have progressed to clinical trials, several obstacles remain, including formulation stability, scalable manufacturing, regulatory compliance, and long-term safety considerations. In summary, nanoradiopharmaceuticals represent a promising frontier in personalized medicine, particularly in oncology. By combining diagnostic and therapeutic capabilities within a single nanosystem, they facilitate more individualized and adaptive treatment approaches. Continued innovation in formulation, radiochemistry, and regulatory harmonization will be crucial to their successful routine clinical use. Full article

(This article belongs to the Special Issue Nanosystems for Advanced Diagnostics and Therapy)

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24 pages, 8040 KB

Open AccessEditor’s ChoiceArticle

Development of Modified Drug Delivery Systems with Metformin Loaded in Mesoporous Silica Matrices: Experimental and Theoretical Designs

by Mousa Sha’at, Maria Ignat, Florica Doroftei, Vlad Ghizdovat, Maricel Agop, Alexandra Barsan (Bujor), Monica Stamate Cretan, Fawzia Sha’at, Ramona-Daniela Pavaloiu, Adrian Florin Spac, Lacramioara Ochiuz, Carmen Nicoleta Filip and Ovidiu Popa

Pharmaceutics 2025, 17(7), 882; https://doi.org/10.3390/pharmaceutics17070882 - 4 Jul 2025

Cited by 3 | Viewed by 2280

Abstract

Background/Objectives: Mesoporous silica materials, particularly KIT-6, offer promising features, such as large surface area, tunable pore structures, and biocompatibility, making them ideal candidates for advanced drug delivery systems. The aims of this study were to develop and evaluate an innovative modified-release platform for [...] Read more.

Background/Objectives: Mesoporous silica materials, particularly KIT-6, offer promising features, such as large surface area, tunable pore structures, and biocompatibility, making them ideal candidates for advanced drug delivery systems. The aims of this study were to develop and evaluate an innovative modified-release platform for metformin hydrochloride (MTF), using KIT-6 mesoporous silica as a matrix, to enhance oral antidiabetic therapy. Methods: KIT-6 was synthesized using an ultrasound-assisted sol-gel method and subsequently loaded with MTF via adsorption from alkaline aqueous solutions at two concentrations (1 and 3 mg/mL). The structural and morphological characteristics of the matrices—before and after drug loading—were assessed using SEM-EDX, TEM, and nitrogen adsorption–desorption isotherms (the BET method). In vitro drug release profiles were recorded in simulated gastric and intestinal fluids over 12 h. Kinetic modeling was performed using seven classical models, and a multifractal theoretical framework was used to further interpret the complex release behavior. Results: The loading efficiency increased with increasing drug concentration but nonlinearly, reaching 56.43 mg/g for 1 mg/mL and 131.69 mg/g for 3 mg/mL. BET analysis confirmed significant reductions in the surface area and pore volume upon MTF incorporation. In vitro dissolution showed a biphasic release: a fast initial phase in an acidic medium followed by sustained release at a neutral pH. The Korsmeyer–Peppas and Weibull models best described the release profiles, indicating a predominantly diffusion-controlled mechanism. The multifractal model supported the experimental findings, capturing nonlinear dynamics, memory effects, and soliton-like transport behavior across resolution scales. Conclusions: The study confirms the potential of KIT-6 as a reliable and efficient carrier for the modified oral delivery of metformin. The combination of experimental and multifractal modeling provides a deeper understanding of drug release mechanisms in mesoporous systems and offers a predictive tool for future drug delivery design. This integrated approach can be extended to other active pharmaceutical ingredients with complex release requirements. Full article

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

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23 pages, 1856 KB

Open AccessEditor’s ChoiceArticle

Comparative Evaluation of Gelatin and HPMC Inhalation Capsule Shells Exposed to Simulated Humidity Conditions

by Sabrina Magramane, Nikolett Kállai-Szabó, Dóra Farkas, Károly Süvegh, Romána Zelkó and István Antal

Pharmaceutics 2025, 17(7), 877; https://doi.org/10.3390/pharmaceutics17070877 - 3 Jul 2025

Cited by 6 | Viewed by 4916

Abstract

Background/Objectives: This study investigates the impact of high humidity (25 °C, 75% relative humidity) on gelatin and hydroxypropyl methylcellulose (HPMC) capsules used in dry powder inhalers (DPIs), focusing on moisture dynamics, structural responses, and mechanical performance, with an emphasis on understanding how [...] Read more.

Background/Objectives: This study investigates the impact of high humidity (25 °C, 75% relative humidity) on gelatin and hydroxypropyl methylcellulose (HPMC) capsules used in dry powder inhalers (DPIs), focusing on moisture dynamics, structural responses, and mechanical performance, with an emphasis on understanding how different capsule types respond to prolonged exposure to humid conditions. Methods: Capsules were exposed to controlled humidity conditions, and moisture uptake was measured via thermal analysis. Visual observations of silica bead color changes were performed to assess moisture absorption, while surface wettability was measured using the sessile drop method. Hardness testing, mechanical deformation, and puncture tests were performed to evaluate structural and mechanical changes. Positron annihilation lifetime spectroscopy (PALS) was used to analyze free volume expansion. Results: HPMC capsules exhibited rapid moisture uptake, attributed to their lower equilibrium moisture content and ability to rearrange dynamically, preventing brittleness. In contrast, gelatin capsules showed slower moisture absorption but reached higher equilibrium levels, resulting in plasticization and softening. Mechanical testing showed that HPMC capsules retained structural integrity with minimal deformation, while gelatin capsules became softer and exhibited reduced puncture resistance. Structural analysis revealed greater free volume expansion in HPMC capsules, consistent with their amorphous nature, compared with gelatin’s semi-crystalline matrix. Conclusions: HPMC capsules demonstrated superior humidity resilience, making them more suitable for protecting moisture-sensitive active pharmaceutical ingredients (APIs) in DPI formulations. These findings underline the importance of appropriate storage conditions, as outlined in the Summary of Product Characteristics, to ensure optimal capsule performance throughout patient use. Full article

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

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26 pages, 11210 KB

Open AccessEditor’s ChoiceArticle

Perspectives on the pH-Influenced Design of Chitosan–Genipin Nanogels for Cell-Targeted Delivery

by Julieta D. Glasman, Agustina Alaimo, Cecilia Samaniego López, María Edith Farías, Romina B. Currá, Diego G. Lamas and Oscar E. Pérez

Pharmaceutics 2025, 17(7), 876; https://doi.org/10.3390/pharmaceutics17070876 - 3 Jul 2025

Cited by 4 | Viewed by 2035

Abstract

Background: Chitosan (CS) crosslinked with genipin (GNP) provides a mild, non-toxic route to generate nanogels (NGs) with enhanced integrity and colloidal stability. Objectives: To develop and characterise CS-GNP NG as a novel platform for targeted cellular delivery, optimising design through physicochemical [...] Read more.

Background: Chitosan (CS) crosslinked with genipin (GNP) provides a mild, non-toxic route to generate nanogels (NGs) with enhanced integrity and colloidal stability. Objectives: To develop and characterise CS-GNP NG as a novel platform for targeted cellular delivery, optimising design through physicochemical characterisation and biocompatibility evaluation. Methods: NGs were synthesised under optimised conditions by adjusting the pH of the CS solution, followed by high-intensity ultrasound (HIUS) to achieve disaggregation. Physicochemical characterisation was carried out using UV-Vis spectroscopy, FTIR, dynamic light scattering (DLS), and scanning electron microscopy (SEM). Rheological studies and SAXS analysis assessed structural properties. Biocompatibility was evaluated via MTT assay, and internalisation was monitored by fluorescence microscopy on mammalian cell lines. Results: NG formation was highly pH-dependent, with optimal configuration at pH 4.5, yielding stable, uniformly sized particles (~200 nm, ζ-potential +29 mV). Kinetic modelling showed a sigmoidal formation pattern, suggesting nucleation, growth, and stabilisation. FTIR confirmed covalent bonding between CS and GNP via primary amide bonds and Schiff bases. Rheology indicated pseudoplastic behaviour, and SAXS revealed a compact network formation. Biocompatibility assays confirmed non-cytotoxicity below 100 µg/mL and efficient cellular uptake. Conclusions: This study presents a rapid, reproducible protocol for generating colloidally stable, biocompatible NGs suitable for drug delivery. Full article

(This article belongs to the Special Issue Biomaterial-Based Nanoencapsulation Systems for Drug Protection and Controlled Release)

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18 pages, 1061 KB

Open AccessEditor’s ChoiceArticle

Design of Clofazimine-Loaded Lipid Nanoparticles Using Smart Pharmaceutical Technology Approaches

by Helena Rouco, Nicola Filippo Virzì, Carolina Menéndez-Rodríguez, Carmen Potel, Patricia Diaz-Rodriguez and Mariana Landin

Pharmaceutics 2025, 17(7), 873; https://doi.org/10.3390/pharmaceutics17070873 - 2 Jul 2025

Cited by 1 | Viewed by 1693

Abstract

Background/Objectives: Clofazimine (CFZ) is a versatile antimicrobial active against several bacterial species, although its reduced aqueous solubility and the occurrence of side effects limit its use. Nanostructured lipid carriers (NLCs) constitute an interesting approach to increase drug bioavailability and safety. However, the [...] Read more.

Background/Objectives: Clofazimine (CFZ) is a versatile antimicrobial active against several bacterial species, although its reduced aqueous solubility and the occurrence of side effects limit its use. Nanostructured lipid carriers (NLCs) constitute an interesting approach to increase drug bioavailability and safety. However, the development of nanoparticle-based formulations is challenging. In the present work, a combination of smart pharmaceutical technology approaches was proposed to develop CFZ-loaded NLCs, taking advantage of previous knowledge on NLCs screening. Methods: A design space previously established using Artificial Intelligence (AI) tools was applied to develop CFZ-loaded NLC formulations. After formulation characterization, Neurofuzzy Logic (NFL) and in silico docking simulations were employed to enhance the understanding of lipid nanocarriers. Then, the performance of formulations designed following NFL guidelines was characterized in terms of biocompatibility, using murine fibroblasts, and antimicrobial activity against several strains of Staphylococcus aureus. Results: The followed approach enabled CFZ-loaded NLC formulations with optimal properties, including small size and high antimicrobial payload. NFL was useful to investigate the existing interactions between NLC components and homogenization conditions, that influence CFZ-loaded NLCs’ final properties. Also, in silico docking simulations were successfully applied to examine interactions and affinity between the drug and the lipid matrix components. Finally, the designed CFZ-loaded formulations demonstrated suitable biocompatibility, together with antimicrobial activity. Conclusions: The implementation of smart strategies during nanoparticle-based therapeutics development, such as those described in this manuscript, would enable the more efficient design of new systems for suitable antimicrobial delivery. Full article

(This article belongs to the Special Issue Smart Pharmaceutical Technologies for Drug Delivery and Tissue Engineering)

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16 pages, 1482 KB

Open AccessEditor’s ChoiceArticle

Nasal Residence Depending on the Administered Dosage Form: Impact of Formulation Type on the In Vivo Nasal Retention Time of Drugs in Rats

by Daisuke Inoue, Yoshihiro Seto and Hideto To

Pharmaceutics 2025, 17(7), 863; https://doi.org/10.3390/pharmaceutics17070863 - 30 Jun 2025

Cited by 3 | Viewed by 2368

Abstract

Background/Objectives: The precise control of drug absorption through the nasal mucosa following intranasal administration can be achieved through optimal formulation development that considers the nasal retention properties of the administered dosage form. This study aimed to quantitatively elucidate the effect of formulation [...] Read more.

Background/Objectives: The precise control of drug absorption through the nasal mucosa following intranasal administration can be achieved through optimal formulation development that considers the nasal retention properties of the administered dosage form. This study aimed to quantitatively elucidate the effect of formulation type on nasal residence time in vivo. Methods: The nasal residence behavior of various formulation types, including solutions, particulates, and powders, was estimated in rats. Furthermore, the effect of mucoadhesive polymers on the nasal residence time was investigated using gel and powder dosage forms of sodium alginate. Results: The nasal retention behavior of the formulation in the nasal cavity differed depending on the dosage form. The polystyrene microparticles and lactose powder, a non-adhesive powder, were quickly eliminated into the nasopharynx, whereas the solution remained in the nasal cavity longer than the other formulations. The clearance behavior of the solution was investigated, and it was found that the solution was quickly transported to the stomach without being retained in the esophagus. The disappearance of the gel and powder with the mucoadhesive polymer was different, with the powder clearing faster. This difference in clearance is thought to be due to the powder being cleared before dissolving and diffusing into the nasal mucus. Conclusions: It has been clearly shown that the nasal residence behavior differed depending on the dosage forms. The addition of mucoadhesive polymers was effective in improving the nasal residence of the drug, and more-effective formulations for nasal application can be developed by combining optimal dosage forms, such as powders and gels. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments, 2nd Edition)

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12 pages, 1213 KB

Open AccessEditor’s ChoiceArticle

Synthesis and In Vitro Evaluation of a Scandium-44 Radiolabeled Nanobody as a PD-L1 PET Imaging Probe

by Viktoria E. Krol, Aditya Bansal, Manasa Kethamreddy, Jason R. Ellinghuysen, Daniel J. Vail, Fabrice Lucien-Matteoni, Haidong Dong, Sean S. Park and Mukesh K. Pandey

Pharmaceutics 2025, 17(6), 796; https://doi.org/10.3390/pharmaceutics17060796 - 19 Jun 2025

Cited by 3 | Viewed by 1627

Abstract

Background/Objective: Noninvasive PET imaging-based assessment of PD-L1 expression is of high clinical value for better patient selection and treatment response rates to PD-L1 immunotherapies. Due to their shorter biological half-life and faster clearance from the blood pool, radiolabeled antibody fragments are an [...] Read more.

Background/Objective: Noninvasive PET imaging-based assessment of PD-L1 expression is of high clinical value for better patient selection and treatment response rates to PD-L1 immunotherapies. Due to their shorter biological half-life and faster clearance from the blood pool, radiolabeled antibody fragments are an attractive alternative for imaging than their full-length IgG counterpart. This work investigated the radiosynthesis and in vitro cell uptake of anti-PD-L1-B11-nanobody radiolabeled with ⁴⁴Sc (t_1/2 = 4.04 h) as an alternative to anti-PD-L1-B11-IgG, better suited for longer half-life radioisotopes such as ⁸⁹Zr (t_1/2 = 78.41 h). Methods: The proteins were conjugated with p-SCN-Bn-DTPA and radiolabeled at room temperature with ⁴⁴Sc, achieving a radiochemical yield of a RCY of 94.8 ± 3.1% (n = 3) for [⁴⁴Sc]Sc-B11-IgG and 73.6 ± 12.1% (n = 3) for [⁴⁴Sc]Sc-B11-nanobody, before purification. Results: Significantly higher uptake in the PD-L1₊ cells than PD-L1_KO cells was observed for both probes. However, high non-specific uptake, particularly of the radiolabeled B11-nanobody, was also observed which may negatively impact its potential as a molecular imaging probe. Conclusions: Due to the high non-specific uptake in vitro, the ⁴⁴Sc radiolabeled nanobody was not progressed to further in vivo evaluation. These results should, however, not discourage future evaluations of other nanobody based probes radiolabeled with ⁴⁴Sc, due to their well-matched biological and physical half-life. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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16 pages, 1258 KB

Open AccessEditor’s ChoiceArticle

NLC-Based Rifampicin Delivery System: Development and Characterization for Improved Drug Performance Against Staphylococcus aureus

by Javiera Carrasco-Rojas, Felipe I. Sandoval, Christina M. A. P. Schuh, Carlos F. Lagos, Javier O. Morales, Francisco Arriagada and Andrea C. Ortiz

Pharmaceutics 2025, 17(6), 799; https://doi.org/10.3390/pharmaceutics17060799 - 19 Jun 2025

Cited by 8 | Viewed by 2666

Abstract

Background/Objectives: Rifampicin is a typical antibiotic used for the treatment of Staphylococcus aureus (S. aureus) infections; however, its clinical utility is limited by poor aqueous solubility, chemical instability, and increasing bacterial resistance. Nanostructured lipid carriers (NLCs) offer a promising strategy [...] Read more.

Background/Objectives: Rifampicin is a typical antibiotic used for the treatment of Staphylococcus aureus (S. aureus) infections; however, its clinical utility is limited by poor aqueous solubility, chemical instability, and increasing bacterial resistance. Nanostructured lipid carriers (NLCs) offer a promising strategy to improve drug solubility, stability, and antimicrobial performance. Methods: In this study, rifampicin-loaded NLC (NLC-RIF) was developed using a hot homogenization with a low energy method and characterized in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, colloidal stability, and drug loading. Results: In vitro release studies under sink conditions demonstrated a biphasic release pattern, best described by the Korsmeyer–Peppas model, suggesting a combination of diffusion and matrix erosion mechanisms. Antimicrobial activity against S. aureus revealed a substantial increase in potency for NLC-RIF, with an IC₅₀ of 0.46 ng/mL, approximately threefold lower than that of free rifampicin. Cytotoxicity assays in HepG2 cells confirmed over 90% cell viability across all tested concentrations. Conclusions: These findings highlight the potential of NLC-RIF as a biocompatible and effective nanocarrier system for enhancing rifampicin delivery and antibacterial activity. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Targeted Drug Delivery Systems)

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21 pages, 3205 KB

Open AccessEditor’s ChoiceArticle

Click on Click: Click-Flavone Glycosides Encapsulated in Click-Functionalised Polymersomes for Glioblastoma Therapy

by Nuno M. Saraiva, Ana Alves, Ana Isabel Barbosa, Andreia Marinho, Salette Reis, Marta Correia-da-Silva and Paulo C. Costa

Pharmaceutics 2025, 17(6), 771; https://doi.org/10.3390/pharmaceutics17060771 - 12 Jun 2025

Viewed by 1753

Abstract

In this study, three new 3,7-dihydroxyflavone (1) derivatives with different sugars were designed and synthesised by click chemistry. Click chemistry requires the previously modification of building blocks with azide and alkyne groups and therefore, the 3,7-dihydroxyflavone (1) was first [...] Read more.

In this study, three new 3,7-dihydroxyflavone (1) derivatives with different sugars were designed and synthesised by click chemistry. Click chemistry requires the previously modification of building blocks with azide and alkyne groups and therefore, the 3,7-dihydroxyflavone (1) was first converted in 3,7-(prop-2-yn-yloxy)flavone (2) and acetobromo-α-D-glucose (3) was converted into 2,3,4,6-tetra-O-acetyl-β-glucopyranosyl azide (4). Subsequently, a click reaction was performed via copper-catalysed cycloaddition (CuAAC) between 2 and 4, as well as between 2 and 2-acetamido-3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl (AG931) and, 2 and commercial 2-azidoethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl (AG358), resulting in three distinct disubstituted flavone glycosides (5a–5c). Biological assays performed on L929 fibroblast cell lines and human glioblastoma astrocytoma U-251 cell lines indicated cytocompatibility with fibroblasts and reduced metabolic activity of GBM cells in the presence of compound 5b and 5c. To enhance therapeutic effect, improve local drug delivery, and overcome solubility issues of these high molecular weight compounds, the synthesised compounds were encapsulated in polymeric particles (polymersomes, PMs) composed of polylactic acid-polyethylene glycol (PEG-PLA) functionalized, once more by click chemistry, with 0.1 mol% transferrin mimetic (T7—HRPYIAH) peptide. The PMs were prepared by solvent displacement and exhibited stability over 100 days, encapsulation efficiency of 39–93%, and mean size diameters of 120–180 nm. The toxicity assays of the PMs on the U-251 cell line showed a significant decrease in metabolic activity, supporting the potential of this delivery system against GBM. Among the PMs tested, the flavone 5c-based PM demonstrated the highest efficacy. Full article

(This article belongs to the Special Issue Nano-Based Technology for Glioblastoma)

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18 pages, 2967 KB

Open AccessEditor’s ChoiceArticle

Adenoviruses Encapsulated in PEGylated DOTAP-Folate Liposomes Are Protected from the Pre-Existing Humoral Immune Response

by Abraham T. Phung, Jaimin R. Shah, Tao Dong, Omonigho Aisagbonhi, William C. Trogler, Andrew C. Kummel and Sarah L. Blair

Pharmaceutics 2025, 17(6), 769; https://doi.org/10.3390/pharmaceutics17060769 - 11 Jun 2025

Cited by 2 | Viewed by 1944

Abstract

Background/Objectives: While adenovirus (Ad) therapies have been proven to be effective in local administration, systemic Ad treatments have shown limited success due to pre-existing antibodies in the human blood that neutralize the virus. We developed a liposome coating procedure that protects the [...] Read more.

Background/Objectives: While adenovirus (Ad) therapies have been proven to be effective in local administration, systemic Ad treatments have shown limited success due to pre-existing antibodies in the human blood that neutralize the virus. We developed a liposome coating procedure that protects the Ad from pre-existing neutralizing antibodies in human blood. To assess the in vivo stability of the liposomes, the present study used a novel in vivo method to quantitatively assess the protective capabilities of liposome-encapsulated Ad (DfAd) from neutralizing antibodies. Methods: The assay systemically administers DfAd with a green fluorescent protein transgene (DfAd-GFP) into pre-immunized mice and allows it to circulate in the presence of neutralizing antibodies; the infected blood is extracted and used to transduce HEK293 cells, which emits fluorescence in the presence of protected, un-neutralized Ad. Results: The PEGylated liposome formulation provides 12× protection in vivo relative to unencapsulated Ads. In vitro optimization of the liposome coating reveals a strong correlation between the structural stability of liposomes and protection against anti-Ad neutralizing antibodies, where DSPE-PEG2000-carboxylic acid (DSPE-PEG2000-CA) is a critical component for liposome stability and increasing protection against antibody neutralization of the encapsulated Ad. Conclusions: The findings in the present study confirm that the DfAd liposome can protect against neutralizing antibodies in blood circulation. The novel in vivo assay for liposome protection against neutralizing antibodies and in vitro experiments in the present study provide new tools and insights toward designing liposome–Ad complexes for the systemic treatment of cancer. Full article

(This article belongs to the Special Issue Application of Nanostructured Lipid Carriers in Antibacterial and Anticancer)

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19 pages, 3044 KB

Open AccessEditor’s ChoiceArticle

Automated 3D Printing-Based Non-Sterile Compounding Technology for Pediatric Corticosteroid Dosage Forms in a Health System Pharmacy Setting

by M. Brooke Bernhardt, Farnaz Shokraneh, Ludmila Hrizanovska, Julius Lahtinen, Cynthia A. Brasher and Niklas Sandler

Pharmaceutics 2025, 17(6), 762; https://doi.org/10.3390/pharmaceutics17060762 - 9 Jun 2025

Cited by 8 | Viewed by 3089

Abstract

Background: Pharmaceutical compounding remains a predominantly manual process with limited innovation, particularly in non-sterile applications. This study explores the implementation of an automated compounding platform based on 3D printing to enhance precision, efficiency, and adaptability in pediatric corticosteroid formulations. Methods: Personalized hydrocortisone dosage [...] Read more.

Background: Pharmaceutical compounding remains a predominantly manual process with limited innovation, particularly in non-sterile applications. This study explores the implementation of an automated compounding platform based on 3D printing to enhance precision, efficiency, and adaptability in pediatric corticosteroid formulations. Methods: Personalized hydrocortisone dosage forms were prepared in a hospital pharmacy setting using a proprietary excipient base and standardized procedures, including automated dosing and syringe heating when required. Three dosage forms—3.2 mg gel tablets, 2.8 mg water-free troches, and 1.2 mg orodispersible films (ODFs)—were selected to demonstrate the platform’s versatility and to address pediatric needs for varying strengths and dosage types. All products were prepared using a reproducible semi-solid extrusion (SSE)-based workflow with the consistent API-excipient blending and automated deposition. Results: Analytical testing confirmed that all formulations met pharmacopeial criteria for mass and content uniformity. The ODF and troche forms achieved rapid drug release, exceeding 75% within 5 min, while the gel tablet showed a slower release profile, reaching 86% by 60 min. Additionally, in-process homogeneity testing across syringe printing cycles confirmed the consistent API distribution. Conclusions: The results support the feasibility of integrating automated compounding technologies into pharmacy workflows. Such systems can improve accuracy, minimize variability, and streamline the production of customized pediatric medications, particularly for drugs with poor palatability or narrow therapeutic windows. Overall, this study highlights the potential of automation to modernize non-sterile compounding, and to better support individualized therapy. Full article

(This article belongs to the Special Issue 3D Printing—Current Pharmaceutical Applications and Future Directions)

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22 pages, 3036 KB

Open AccessEditor’s ChoiceArticle

Synthesis and Characterization of Transferrin Receptor-Targeted Peptide Combination SN-38 and Rucaparib Conjugate for the Treatment of Glioblastoma

by Perpetue Bataille Backer and Simeon Kolawole Adesina

Pharmaceutics 2025, 17(6), 732; https://doi.org/10.3390/pharmaceutics17060732 - 2 Jun 2025

Cited by 2 | Viewed by 2779

Abstract

Background/Objectives: Glioblastoma represents a particularly aggressive and fatal type of brain tumor. Peptide-drug conjugates, which offer the promise of traversing the blood-brain barrier to selectively accumulate in tumor tissues and precisely target cancer cells, are an active area of research. We present the [...] Read more.

Background/Objectives: Glioblastoma represents a particularly aggressive and fatal type of brain tumor. Peptide-drug conjugates, which offer the promise of traversing the blood-brain barrier to selectively accumulate in tumor tissues and precisely target cancer cells, are an active area of research. We present the synthesis and characterization of the T7 peptide (HAIYPRH) as a targeting ligand for the transferrin receptor, which is highly expressed on both the blood-brain barrier and glioma cells. Methods: Using the T7 peptide, the synthesis, characterization, and biological evaluation of a transferrin receptor-targeted, combination SN-38 and rucaparib peptide drug conjugate (T7-SN-38-rucaparib) are described. Results: The T7 peptide drug conjugate readily cleaved in the presence of exogenous cathepsin B, releasing the active drug payloads. In vitro experiments demonstrated potent cytotoxic effects of the T7 peptide drug conjugate on glioblastoma cells (IC₅₀ = 22.27 nM), with reduced toxicity to non-cancerous HEK 293 cells (IC₅₀ = 115.78 nM), indicating selective toxicity toward cancer cells. Further investigations revealed that blocking transferrin receptors with drug-free T7 peptide significantly reduced the conjugate’s cytotoxicity, an effect that could be reversed by introducing exogenous cathepsin B to the cells. Conclusions: These findings highlight the potential of glioblastoma-targeted delivery of SN-38 and rucaparib based on specific recognition of the transferrin receptor for transport across the blood-brain barrier, offering the prospect of reduced toxicity and selective killing of cancer cells. Additionally, since rucaparib does not cross the blood-brain barrier, this work is significant to facilitate the use of rucaparib for the treatment of brain tumors. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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28 pages, 1508 KB

Open AccessEditor’s ChoiceReview

Tapinarof Nanogels as a Promising Therapeutic Approach

by Barbara Balogh, Ágota Pető, Pálma Fehér, Zoltán Ujhelyi and Ildikó Bácskay

Pharmaceutics 2025, 17(6), 731; https://doi.org/10.3390/pharmaceutics17060731 - 1 Jun 2025

Cited by 6 | Viewed by 3616

Abstract

Psoriasis is a chronic inflammatory skin disease characterised by increased oxidative stress, the overproliferation of keratinocytes, the accumulation of inflammatory mediators, and skin barrier damage. Although a number of therapeutic options are available, finding long-term treatments that are well-tolerated and patient-friendly treatments remains [...] Read more.

Psoriasis is a chronic inflammatory skin disease characterised by increased oxidative stress, the overproliferation of keratinocytes, the accumulation of inflammatory mediators, and skin barrier damage. Although a number of therapeutic options are available, finding long-term treatments that are well-tolerated and patient-friendly treatments remains a challenge. Tapinarof is a new type of aryl hydrocarbon receptor (AhR) modulator that has recently attracted attention as a promising non-steroidal alternative. However, its application may be limited by its poor water solubility and low degree of skin penetration. Nanotechnology-based drug carriers, specially nanogels, offer new opportunities to overcome these limitations by combining the advantages of targeted drug delivery and enhanced skin penetration. Furthermore, nanogel formulations can improve skin hydration and support the restoration of skin barrier function, which are important in the treatment of psoriasis. This review focuses on current and emerging therapeutic approaches, with particular emphasis on the potential of incorporating tapinarof into nanogel formulations as a novel alternative to topical psoriasis treatment. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Targeted Drug Delivery Systems)

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30 pages, 842 KB

Open AccessEditor’s ChoiceReview

Crossing the Blood–Brain Barrier: Innovations in Receptor- and Transporter-Mediated Transcytosis Strategies

by Ling Ding, Pratiksha Kshirsagar, Prachi Agrawal and Daryl J. Murry

Pharmaceutics 2025, 17(6), 706; https://doi.org/10.3390/pharmaceutics17060706 - 28 May 2025

Cited by 41 | Viewed by 14581

Abstract

The blood–brain barrier (BBB) is a highly selective and natural protective membrane that restricts the entry of therapeutic agents into the central nervous system (CNS). This restrictive nature poses a major challenge for pharmacological treatment of a wide range of CNS disorders, including [...] Read more.

The blood–brain barrier (BBB) is a highly selective and natural protective membrane that restricts the entry of therapeutic agents into the central nervous system (CNS). This restrictive nature poses a major challenge for pharmacological treatment of a wide range of CNS disorders, including neurodegenerative disorders, brain tumors, and psychiatric conditions. Many chemical drugs and biopharmaceuticals are unable to cross the BBB, and conventional drug delivery methods often fail to achieve sufficient brain concentrations, leading to reduced therapeutic efficacy and increased risk of systemic toxicity. In recent years, targeted drug delivery strategies have emerged as promising approaches to overcome the BBB and enhance the delivery of therapeutic agents to the brain. Among these, receptor-mediated transcytosis (RMT) and transporter-mediated transcytosis (TMT) are two of the most extensively studied mechanisms for transporting drugs across brain endothelial cells into the brain parenchyma. Advances in materials science and nanotechnology have facilitated the development of multifunctional carriers with optimized properties, improving drug targeting, stability, and release profiles within the brain. This review summarizes the physiological structure of the BBB and highlights recent innovations in RMT- and TMT-mediated brain drug delivery systems, emphasizing their potential not only to overcome current challenges in CNS drug development, but also to pave the way for next-generation therapies that enable more precise, effective, and personalized treatment of brain-related diseases. Full article

(This article belongs to the Special Issue Targeted Drug Delivery for Diagnostic and Therapeutic Applications)

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49 pages, 24112 KB

Open AccessEditor’s ChoiceReview

Synergistic Cancer Therapies Enhanced by Nanoparticles: Advancing Nanomedicine Through Multimodal Strategies

by Seyed Mohamad Sadegh Mousavi-Kiasary, Ahmood Senabreh, Ashkan Zandi, Rogelio Pena, Frances Cruz, Ali Adibi and Nasrin Hooshmand

Pharmaceutics 2025, 17(6), 682; https://doi.org/10.3390/pharmaceutics17060682 - 22 May 2025

Cited by 35 | Viewed by 5522

Abstract

Cancer remains a formidable global health challenge due to its complex pathophysiology and resistance to conventional treatments. In recent years, the convergence of nanotechnology and oncology has paved the way for innovative therapeutic platforms that address the limitations of traditional modalities. This review [...] Read more.

Cancer remains a formidable global health challenge due to its complex pathophysiology and resistance to conventional treatments. In recent years, the convergence of nanotechnology and oncology has paved the way for innovative therapeutic platforms that address the limitations of traditional modalities. This review examines how nanoparticle (NP)-based strategies enhance the efficacy of chemotherapy, radiotherapy, phototherapy, immunotherapy, and gene therapy by enabling targeted delivery, controlled drug release, and tumor-specific accumulation via the enhanced permeability and retention (EPR) effect. We discuss the design and functionalization of various organic, inorganic, and hybrid NPs, highlighting their roles in improving pharmacokinetics, overcoming multidrug resistance, and modulating the tumor microenvironment. Particular emphasis is placed on dual and multimodal therapies, such as chemo-phototherapy, chemo-immunotherapy, and gene-radiotherapy, that leverage nanoparticle carriers to amplify synergistic effects, minimize systemic toxicity, and improve clinical outcomes. We also explore cutting-edge advances in gene editing and personalized nanomedicine, as well as emerging strategies to address biological barriers and immunosuppressive mechanisms in the tumor niche. Despite the undeniable promise of nanoparticle-based cancer therapies, challenges related to toxicity, scalable manufacturing, regulatory oversight, and long-term biocompatibility must be overcome before they can fully enter clinical practice. By synthesizing recent findings and identifying key opportunities for innovation, this review provides insight into how nanoscale platforms are propelling the next generation of precision oncology. Full article

(This article belongs to the Special Issue Synergistic Nanomedicines: Integrating Chemotherapy and Phototherapy for Enhanced Cancer Treatment)

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19 pages, 7450 KB

Open AccessEditor’s ChoiceArticle

Curcumin-Induced Apoptotic Cell Death in Human Glioma Cells Is Enhanced by Clusterin Deficiency

by Pinky Sultana and Jiri Novotny

Pharmaceutics 2025, 17(6), 679; https://doi.org/10.3390/pharmaceutics17060679 - 22 May 2025

Cited by 2 | Viewed by 2049

Abstract

Background/Objectives: Glioblastoma is an aggressive brain tumor with limited treatment options and significant resistance to conventional therapies. Methods: In this study, we explored the effects of combining curcumin treatment with clusterin inhibition on cell death in glioma cells. Results: We observed that the [...] Read more.

Background/Objectives: Glioblastoma is an aggressive brain tumor with limited treatment options and significant resistance to conventional therapies. Methods: In this study, we explored the effects of combining curcumin treatment with clusterin inhibition on cell death in glioma cells. Results: We observed that the combination of clusterin silencing and curcumin treatment induces cell death. This combination therapy significantly elevated reactive oxygen species (ROS), triggering oxidative stress, which acted as a key upstream mediator of apoptosis. Elevated ROS levels were found to be associated with caspase activation, suggesting apoptosis as the primary mode of cell death. Furthermore, autophagy was induced as a complementary mechanism, with upregulation of LC3B contributing to the enhanced cytotoxic effects. Conclusions: The synergy between clusterin knockdown-induced senescence and curcumin’s pro-apoptotic and pro-autophagic effects highlights a potential novel therapeutic strategy for gliomas. These findings underscore the potential of this combination therapy in overcoming glioma resistance and improving treatment outcomes through the dual induction of oxidative stress and cell death pathways. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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23 pages, 14789 KB

Open AccessEditor’s ChoiceArticle

Feasibility of Hot Melt Extrusion in Converting Water-Based Nanosuspensions into Solid Dosage Forms

by Erasmo Ragucci, Marco Uboldi, Adam Sobczuk, Giorgio Facchetti, Alice Melocchi, Mauro Serratoni and Lucia Zema

Pharmaceutics 2025, 17(5), 662; https://doi.org/10.3390/pharmaceutics17050662 - 17 May 2025

Cited by 2 | Viewed by 2116

Abstract

Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in [...] Read more.

Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in transforming a cinnarizine-based NS, selected as a case study, into granules for oral intake. Methods: Thermoplastic polymers, in principle compatible with the thermal behavior of the selected drug and characterized by different interaction mechanisms with aqueous fluids, were used as carriers to absorb the NS and were processed by HME. Results: The extruded granules pointed out good physio-technological characteristics, a drug content > 85% with coefficient of variation (CV) < 5% and tunable in vitro performance coherent with the polymeric carriers they were composed of. Particle size as well as the solid state of cinnarizine was checked using several analytical techniques in combination (e.g., DSC, SEM, FT-IR, Raman). Depending on the composition of the granules, and specifically for formulations processed below 85 °C, the drug was found to remain crystalline and in the desired nanoscale. Conclusions: HME turned out to be a versatile process to transform, in a single-step, NSs into multi-particulate solid products for oral administration showing a variety of release profiles. Full article

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

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26 pages, 3061 KB

Open AccessEditor’s ChoiceArticle

Three-Dimensional-Printed Isoniazid Chewable Gels for On-Demand Latent Tuberculosis Treatment in Children

by Amanda de O. E. Moreira, Lêda Maria S. Azevedo Neta, Márcia Pietroluongo, Ana Paula dos S. Matos, Beatriz B. Correa, Beatriz H. Ortiz, André da S. Guimarães, Marcio Nele, Carollyne M. Santos, Ana Elizabeth C. Fai, Maria Helena Gonçalves, Flávio M. Shimizu, Monique S. Dos Santos, Rosemberg B. Moure, Diogo D. Nascimento, André Luis de A. Guimarães, Saint Clair dos S. G. Junior, Alessandra L. Vicosa and Lucio M. Cabral

Pharmaceutics 2025, 17(5), 658; https://doi.org/10.3390/pharmaceutics17050658 - 17 May 2025

Cited by 3 | Viewed by 2542

Abstract

Background/Objectives: Pediatric drug administration is hindered by difficulties in swallowing conventional medications and the unpalatable taste of many drugs. Among diseases highlighting the need for improved pediatric delivery, tuberculosis (TB) stands out. One form of the disease is latent TB infection (LTBI), [...] Read more.

Background/Objectives: Pediatric drug administration is hindered by difficulties in swallowing conventional medications and the unpalatable taste of many drugs. Among diseases highlighting the need for improved pediatric delivery, tuberculosis (TB) stands out. One form of the disease is latent TB infection (LTBI), which is concerning in children. Effective LTBI treatment is crucial for prevention, with isoniazid (INH) widely used for its proven efficacy and safety. This study aims to develop innovative 3D-printed chewable gels containing INH for LTBI treatment. Methods: The gels were formulated using gelatin and carrageenan gum, sugar-free sweeteners, and flavoring. Two batches were prepared, and using 3D printing (3DP) with a semi-solid extrusion (SSE) module, chewable gels were produced. Rheological properties were measured to assess the feasibility of 3DP-SSE, evaluating the structural integrity and adequate fluidity of the formulation. The 3D-printed chewable gels were evaluated by visual, mass, and dimensional characteristics. In addition, the water activity, texture profile, INH and degradation product content, in vitro release, and taste-masking were investigated. Results: The optimized formulation maintained suitable rheological properties for 3DP-SSE, demonstrating consistent weight, dimensions, and stability after the process. The texture achieved a balance between printing parameters and shape maintenance, and the INH presented an immediate-release profile (>85% within 30 min). The chewable gels showed an improvement in palatability compared to conventional INH tablets. Conclusions: This innovative approach offers a promising solution for pediatric LTBI treatment, as it improves efficacy, medication acceptability, and on-demand access. Full article

(This article belongs to the Special Issue 3D Printing in Personalized Drug Delivery)

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28 pages, 991 KB

Open AccessEditor’s ChoiceReview

Advancing Brain Targeting: Cost-Effective Surface-Modified Nanoparticles for Faster Market Entry

by Mariana Gomes, Maria João Ramalho, Joana A. Loureiro and Maria Carmo Pereira

Pharmaceutics 2025, 17(5), 661; https://doi.org/10.3390/pharmaceutics17050661 - 17 May 2025

Cited by 27 | Viewed by 3642

Abstract

Background/Objectives: The blood–brain barrier (BBB) poses a major obstacle to delivering therapeutic agents to the central nervous system (CNS), driving the need for innovative drug delivery strategies. Among these, nanoparticles (NPs) have gained attention due to their ability to enhance drug transport, [...] Read more.

Background/Objectives: The blood–brain barrier (BBB) poses a major obstacle to delivering therapeutic agents to the central nervous system (CNS), driving the need for innovative drug delivery strategies. Among these, nanoparticles (NPs) have gained attention due to their ability to enhance drug transport, improve bioavailability, and enable targeted delivery. Methods: This paper explores various surface modification strategies employed to optimize NP-mediated drug delivery across the BBB. Specifically, the functionalization of NPs with ligands such as transferrin (Tf), lactoferrin (Lf), protamine, and insulin is discussed, each demonstrating unique mechanisms for enhancing brain-targeting efficiency. In addition, this work provides a comprehensive overview of recent scientific advancements and market strategies aimed at accelerating the adoption of low-cost, surface-modified nanoparticles, ultimately improving patient access to effective CNS treatments. Conclusions: Preclinical and in vitro studies have demonstrated the effectiveness of these modifications in increasing drug retention and bioavailability in brain tissues. Additionally, while ligand-conjugated NPs hold significant promise for neuropharmacology, their clinical translation is often hindered by regulatory and economic constraints. Lengthy approval processes can slow market entry, but cost–benefit analyses indicate that surface-modified NPs remain financially viable, particularly as scalable manufacturing techniques and some ligands are cost-efficient. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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18 pages, 4166 KB

Open AccessEditor’s ChoiceArticle

GinExtraMed: Focus on Rosa canina L. Extract Encapsulated into Glycethosomes and Allanthosomes for Accelerating Skin Wound Healing

by Martina Rossi, Simone Rossello, Valentina Sallustio, Manuela Mandrone, Teresa Cerchiara, Ilaria Chiocchio, Giuseppe Chidichimo, Michele Protti, Laura Mercolini, Barbara Luppi, Federica Bigucci, Angela Abruzzo and Concettina Cappadone

Pharmaceutics 2025, 17(5), 632; https://doi.org/10.3390/pharmaceutics17050632 - 9 May 2025

Cited by 1 | Viewed by 1934

Abstract

Background/Objectives: Over the last decade, the development of innovative wound products has continued to be a focus of intense research to meet the huge demand of patients. The aim of this work was to develop novel medicated Spanish broom wound dressings capable of [...] Read more.

Background/Objectives: Over the last decade, the development of innovative wound products has continued to be a focus of intense research to meet the huge demand of patients. The aim of this work was to develop novel medicated Spanish broom wound dressings capable of releasing Rosa canina extract, recognized for its high antioxidant activity. Methods:Rosa canina extract was encapsulated in two different nanocarriers, namely glycethosomes and allanthosomes. The physico-chemical and functional characteristics of the obtained vesicles were described, including their size, particle size distribution, ζ potential, and encapsulation efficiency (EE). In addition, vesicles cytotoxicity and cell proliferation were evaluated on human fibroblasts. Furthermore, loaded vesicles were sunk into Spanish broom dressings, analyzed by confocal microscopy, and, finally, evaluated for their wound healing ability by scratch test. Results: Both carriers are nanometric in size, with a good EE (>70%), and a negative ζ potential. Additionally, vesicles are biosafe, non-cytotoxic, and lead to complete closure of the scratch in about 30 h. Conclusions: The findings showed that the developed Spanish broom dressings have the potential to be an efficient and innovative wound care product for accelerating skin wounds. Full article

(This article belongs to the Special Issue Innovations in Controlled Release Systems of Marine- and Plant/Herbal-Derived Bioactives for Pharmaceuticals and Nutraceuticals)

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28 pages, 6539 KB

Open AccessEditor’s ChoiceArticle

Hydrogel–Nanolipid Formulations for the Complex Anti-Inflammatory and Antimicrobial Therapy of Periodontitis

by Rabia Ashfaq, Nóra Tóth, Anita Kovács, Szilvia Berkó, Gábor Katona, Rita Ambrus, Tamás Ferenc Polgár, Mária Szécsényi, Katalin Burián and Mária Budai-Szűcs

Pharmaceutics 2025, 17(5), 620; https://doi.org/10.3390/pharmaceutics17050620 - 7 May 2025

Cited by 9 | Viewed by 3151

Abstract

Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation [...] Read more.

Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation was integrated into three hydrogels, hypromellose (HPMC), zinc hyaluronate (ZnHA), and sodium hyaluronate (NaHA), to conduct a comparative analysis focusing on enhanced localized drug delivery, improved mucoadhesion, prolonged retention, and significant therapeutic outcomes. Methods: NLC–Melox was prepared by homogenization and characterized by dynamic light scattering (DLS). Subsequently, NLC–Melox-loaded gels were subjected to transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Raman spectroscopy, and rheological analysis. In vitro drug release, anti-inflammatory activity (BSA denaturation assay), and antibacterial efficacy (MIC, MBC) were investigated to assess therapeutic potential. Results: DLS revealed a particle size of 183 nm with a polydispersity index of 0.26, indicating homogeneity. TEM confirmed consistent morphology and uniform nanoparticle distribution. DSC and XRD demonstrated the amorphous nature of Melox, enhancing solubility and stability. Spectroscopy confirmed no chemical interactions between components. Rheological studies identified ZnHA as the most mucoadhesive and structurally stable gel. In vitro release studies showed sustained drug release over 24 h. Melox and CO-loaded formulations demonstrated significant anti-inflammatory activity and notable antibacterial efficacy due to the antibacterial oil. Conclusions: The study highlighted the potential of NLC-based mucoadhesive hydrogels as an effective strategy for periodontitis treatment. The formulation offered improved drug solubility, therapeutic efficacy, mucoadhesivity, and prolonged delivery, making it a promising candidate for localized therapy. Full article

(This article belongs to the Special Issue Recent Insights Concerning the Use of Supramolecular Systems for Biomedical Applications)

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15 pages, 3492 KB

Open AccessEditor’s ChoiceArticle

Formulation Approaches for Optimizing Omeprazole Stability in Oral Liquid Dosage Forms

by Urszula Adamiak-Giera, Michał Gackowski, Damian Malinowski, Tomasz Osmałek, Marta Karaźniewicz-Łada, Anna Machoy-Mokrzyńska and Monika Białecka

Pharmaceutics 2025, 17(5), 594; https://doi.org/10.3390/pharmaceutics17050594 - 1 May 2025

Cited by 2 | Viewed by 3919

Abstract

Background/Objectives: This study aimed to evaluate the degradation of omeprazole suspension under various pH conditions and to propose recommendations for preparing compounded suspensions. Given the clinical need for alternative dosage forms for pediatric and geriatric patients and those with dysphagia, the research focused [...] Read more.

Background/Objectives: This study aimed to evaluate the degradation of omeprazole suspension under various pH conditions and to propose recommendations for preparing compounded suspensions. Given the clinical need for alternative dosage forms for pediatric and geriatric patients and those with dysphagia, the research focused on assessing whether modifications in formulation composition—specifically the inclusion of sodium bicarbonate—could improve omeprazole stability, thus enhancing its bioavailability. Methods: Three formulations were prepared: O1, based on crushed enteric-coated pellets from a commercial product; O2, with crushed pellets suspended in an 8% sodium bicarbonate solution with glycerin; and O3, with pure omeprazole suspended in an 8% sodium bicarbonate solution with glycerin. Release studies were conducted using basket or paddle apparatus under conditions simulating fasted (pH 1.2 and 6.8) and fed (pH 6, 4.5, and 3) gastric and intestinal juices at 37 °C over 120 min. At predetermined intervals, samples were withdrawn and analyzed by a validated HPLC method with UV detection to quantify the released omeprazole. Results: The commercial enteric-coated product showed no release at a low pH, confirming its protective coating. In contrast, formulation exhibited significant degradation in acidic environments. The O2 formulation, benefiting from the buffering effect of sodium bicarbonate, showed improved stability compared to O1. Notably, formulation O3 yielded the highest drug recovery, with approximately 74% released at pH 6 and 65% at pH 6.8, demonstrating significantly better performance, as confirmed by statistical analysis (p < 0.05). Conclusions: The composition of omeprazole suspensions substantially influences the drug stability and release profiles. The O3 formulation, based on pure omeprazole with sodium bicarbonate, is recommended for immediate-release suspensions to enhance bioavailability. Further studies are needed to optimize conditions for pediatric use. Full article

(This article belongs to the Section Biopharmaceutics)

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17 pages, 4960 KB

Open AccessEditor’s ChoiceArticle

PLA-Based Electrospun Nanofibrous Mats Towards Application as Antibiotic Carriers: Processing Parameters, Fabrication and Characterization

by Evi Christodoulou, Anastasia Chondromatidou, Nikolaos D. Bikiaris, Evangelia Balla, Marilena Vlachou, Panagiotis Barmpalexis and Dimitrios N. Bikiaris

Pharmaceutics 2025, 17(5), 589; https://doi.org/10.3390/pharmaceutics17050589 - 30 Apr 2025

Cited by 4 | Viewed by 1612

Abstract

Background/Objectives: Polymeric nanofibers are promising platforms for skin treatment applications due to their large surface area and high porosity, which promote enhanced drug delivery. This study aimed to develop and compare poly(lactic acid)-based (PLA) nanofibrous mats, using linear PLA and a star-like [...] Read more.

Background/Objectives: Polymeric nanofibers are promising platforms for skin treatment applications due to their large surface area and high porosity, which promote enhanced drug delivery. This study aimed to develop and compare poly(lactic acid)-based (PLA) nanofibrous mats, using linear PLA and a star-like PLA-pentaerythritol (PLA-PE) copolymer, as carriers for transdermal delivery of the antibacterial agent levofloxacin (LEV). Methods: Electrospinning was employed to fabricate nanofibers from PLA and PLA-PE solutions. Spinning parameters and polymer concentrations (10% w/v PLA and 20% w/v PLA-PE) were optimized to produce uniform fibers. LEV was loaded at 10% and 20% w/w. A sum of complementary characterization techniques, including scanning electron microscopy (SEM), infrared spectroscopy (FTIR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC), were applied to comparatively investigate the fibers’ morphology, structural properties, and crystallinity. Drug loading, porosity, degradation, and in vitro release profiles were evaluated. Results: PLA-PE nanofibers demonstrated smaller diameters and higher porosity (up to 90.1%) compared to PLA (82.4%), leading to enhanced drug loading (up to 34.78%) and faster degradation (55% vs. 43% mass loss over 60 days). Drug release exhibited a biphasic profile with an initial burst followed by sustained release. PLA-PE formulations released up to 60.2% LEV, compared to 38.1% for PLA counterparts. Conclusions: The star-like PLA-PE copolymer enhances nanofiber properties relevant to the desired application, including porosity, degradation rate, and drug release. These findings suggest that PLA-PE is a promising material for developing advanced transdermal antibiotic delivery systems. Full article

(This article belongs to the Special Issue Electrospinning in Drug Delivery Applications)

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14 pages, 2415 KB

Open AccessEditor’s ChoiceArticle

Influence of Ionization and the Addition of Cyclodextrins and Hydrophilic Excipients on the Solubility of Benzthiazide, Isoxicam, and Piroxicam

by Diego Lucero-Borja, Rebeca Ruiz, Elisabet Fuguet and Clara Ràfols

Pharmaceutics 2025, 17(5), 571; https://doi.org/10.3390/pharmaceutics17050571 - 25 Apr 2025

Cited by 4 | Viewed by 1432

Abstract

Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing [...] Read more.

Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing supersaturated solutions. Some of the most common excipients are cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins (captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdone S630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) is evaluated at biorelevant pH values, using two complementary techniques. Methods: The solubility enhancement was evaluated by the comparison of the solubility with and without the presence of excipients through the shake-flask and CheqSol methodology. Results: Captisol and cavasol slightly increase the concentration of the neutral species of the drugs in the solution before precipitation begins, although they do not enhance the supersaturation duration nor the thermodynamic solubility of the drugs. The increase in solubility in the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilic polymers not only improve thermodynamic solubility but also the extent and the duration of the supersaturation. Some metastable forms are observed for benzthiazide and isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flask method enabled the evaluation of thermodynamic solubility both in the absence and presence of excipients. Meanwhile, the CheqSol method provided insights into the presence of supersaturated solutions. Different behavior is observed depending on the nature of the excipient. Full article

(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)

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25 pages, 2761 KB

Open AccessEditor’s ChoiceReview

Transforming Pharmacogenomics and CRISPR Gene Editing with the Power of Artificial Intelligence for Precision Medicine

by Amit Kumar Srivastav, Manoj Kumar Mishra, James W. Lillard, Jr. and Rajesh Singh

Pharmaceutics 2025, 17(5), 555; https://doi.org/10.3390/pharmaceutics17050555 - 24 Apr 2025

Cited by 32 | Viewed by 8085

Abstract

Background: Advancements in pharmacogenomics, artificial intelligence (AI), and CRISPR gene-editing technology are revolutionizing precision medicine by enabling highly individualized therapeutic strategies. Artificial intelligence-driven computational techniques improve biomarker discovery and drug optimization while pharmacogenomics helps to identify genetic polymorphisms affecting medicine metabolism, efficacy, [...] Read more.

Background: Advancements in pharmacogenomics, artificial intelligence (AI), and CRISPR gene-editing technology are revolutionizing precision medicine by enabling highly individualized therapeutic strategies. Artificial intelligence-driven computational techniques improve biomarker discovery and drug optimization while pharmacogenomics helps to identify genetic polymorphisms affecting medicine metabolism, efficacy, and toxicity. Genetically editing based on CRISPR presents a precise method for changing gene expression and repairing damaging mutations. This review explores the convergence of these three fields to enhance improved precision medicine. Method: A methodical study of the current literature was performed on the effects of pharmacogenomics on drug response variability, artificial intelligence, and CRISPR in predictive modeling and gene-editing applications. Results: Driven by artificial intelligence, pharmacogenomics allows clinicians to classify patients and select the appropriate medications depending on their DNA profiles. This reduces the side effect risk and increases the therapeutic efficacy. Precision genetic modifications made feasible by CRISPR technology improve therapy outcomes in oncology, metabolic illnesses, neurological diseases, and other fields. The integration of artificial intelligence streamlines genome-editing applications, lowers off-target effects, and increases CRISPR specificity. Notwithstanding these advances, issues including computational biases, moral dilemmas, and legal constraints still arise. Conclusions: The synergy of artificial intelligence, pharmacogenomics, and CRISPR alters precision medicine by letting customized therapeutic interventions. Clinically translating, however, hinges on resolving data privacy concerns, assuring equitable access, and strengthening legal systems. Future research should focus on refining CRISPR gene-editing technologies, enhancing AI-driven pharmacogenomics, and developing moral guidelines for applying these tools in individualized medicine going forward. Full article

(This article belongs to the Section Gene and Cell Therapy)

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26 pages, 4052 KB

Open AccessEditor’s ChoiceReview

Use of Computational Intelligence in Customizing Drug Release from 3D-Printed Products: A Comprehensive Review

by Fantahun Molla Kassa, Souha H. Youssef, Yunmei Song and Sanjay Garg

Pharmaceutics 2025, 17(5), 551; https://doi.org/10.3390/pharmaceutics17050551 - 23 Apr 2025

Cited by 5 | Viewed by 2848

Abstract

Computational intelligence (CI) mimics human intelligence by expanding the capabilities of machines in data analysis, pattern recognition, and making informed decisions. CI has shown promising contributions to advancements in drug discovery, formulation, and manufacturing. Its ability to analyze vast amounts of patient data [...] Read more.

Computational intelligence (CI) mimics human intelligence by expanding the capabilities of machines in data analysis, pattern recognition, and making informed decisions. CI has shown promising contributions to advancements in drug discovery, formulation, and manufacturing. Its ability to analyze vast amounts of patient data and optimize drug formulations by predicting pharmacokinetic and pharmacodynamic responses makes it a very useful platform for personalized medicine. The integration of CI with 3D printing further strengthens this potential, as 3D printing enables the fabrication of personalized medicines with precise doses, controlled-release profiles, and complex formulations. Furthermore, the automated and digital capabilities of 3D printing make it suitable for integration with CI. CI has proven useful in predicting material printability, optimizing drug release rates, designing complex structures, ensuring quality control, and improving manufacturing processes in 3D printing. In the context of customizing drug release from 3D-printed products, CI techniques have been applied to predict drug release from input variables and to design geometries that achieve the desired release profile. This review explores the role of CI in customizing drug release from 3D-printed formulations. It provides overview of limitations of 3D printing; how CI can overcome these challenges, and its potential in customizing drug release; a comparison of CI with other methods of optimization; and real-world examples of CI integration in 3D printing. Full article

(This article belongs to the Special Issue 3D Printing of Drug Delivery Systems)

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24 pages, 6587 KB

Open AccessEditor’s ChoiceArticle

Salicylic Acid-Mediated Silver Nanoparticle Green Synthesis: Characterization, Enhanced Antimicrobial, and Antibiofilm Efficacy

by Jingqing Zhang, Yuxu Chen, Yuanyu Xu, Zhimin Zhao and Xinjun Xu

Pharmaceutics 2025, 17(4), 532; https://doi.org/10.3390/pharmaceutics17040532 - 18 Apr 2025

Cited by 8 | Viewed by 2803

Abstract

Objectives: Silver nanoparticles (AgNPs) were synthesized via an easy and rapid biogenic synthesis approach, utilizing the dual capabilities of salicylic acid as both a reducing and capping agent. Methods: The characterization of Salicylic Acid-Mediated Silver Nanoparticle (SA-AgNPs) was conducted using a variety of [...] Read more.

Objectives: Silver nanoparticles (AgNPs) were synthesized via an easy and rapid biogenic synthesis approach, utilizing the dual capabilities of salicylic acid as both a reducing and capping agent. Methods: The characterization of Salicylic Acid-Mediated Silver Nanoparticle (SA-AgNPs) was conducted using a variety of techniques, including ultraviolet-visible spectroscopy, dynamic light scattering, scanning electron microscopy combined with energy dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, as well as thermogravimetric analysis paired with differential scanning calorimetry. Results: SA-AgNPs demonstrated significant antibacterial properties against both Gram-positive (methicillin-resistant Staphylococcus epidermidis, Staphylococcus aureus, Cutibacterium acnes, methicillin-resistant Staphylococcus aureus) and Gram-negative (Escherichia coli), with minimum inhibitory concentrations (MICs) of 8, 9, 8, 4, and 6 μg/mL, respectively. At a concentration of 32 μg/mL, SA-AgNPs exhibited 99.9% killing efficiency against Escherichia coli (E. coli), Cutibacterium acnes (C. acnes), and methicillin-resistant Staphylococcus aureus (MRSA), within 4, 16, and 12 h, respectively. At the same concentration, SA-AgNPs effectively inhibited 95.61% of MRSA biofilm formation. SA-AgNPs induced the leakage of intracellular macromolecular substances by increasing the membrane permeability, which ultimately caused bacterial apoptosis. Conclusions: Overall, this study presents a fast and environmentally friendly approach for synthesizing SA-AgNPs, with potential applications as nano antibiotics antibacterial coatings for implantable medical devices and wound dressings. Full article

(This article belongs to the Special Issue Nanotechnology in Antibacterial Drug Delivery)

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18 pages, 4491 KB

Open AccessEditor’s ChoiceArticle

Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies

by Monica E. Susilo, Stephan Schaller, Luis David Jiménez-Franco, Alexander Kulesza, Wilhelmus E. A. de Witte, Shang-Chiung Chen, C. Andrew Boswell, Danielle Mandikian and Chi-Chung Li

Pharmaceutics 2025, 17(4), 500; https://doi.org/10.3390/pharmaceutics17040500 - 9 Apr 2025

Cited by 1 | Viewed by 3733

Abstract

Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy [...] Read more.

Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy in solid tumors. Optimizing biodistribution is key to overcoming these challenges. Methods: A physiologically based pharmacokinetic (PBPK) model was developed that incorporates T-cell transmigration, retention, receptor binding, receptor turnover, and cellular engagement. Preclinical biodistribution data were modeled using two TCB formats: one lacking tumor target binding and another with target arm binding, each with varying CD3 affinities in a transgenic tumor-bearing mouse model. Results: The PBPK model successfully described the distribution of activated T-cells and various TCB formats. It accurately predicted preclinical biodistribution patterns, demonstrating that higher CD3 affinity leads to faster clearance from the blood and increased accumulation in T-cell-rich organs, often reducing tumor exposure. Simulations of HER2-CD3 TCB doses (0.1 µg to 100 mg) revealed monotonic increases in synapse AUC within the tumor. A bell-shaped dose-Cmax relationship for synapse formation was observed, and Tmax was delayed at higher doses. Blood PK was a reasonable surrogate for tumor synapse at low doses but less predictive at higher doses. Conclusions: We developed a whole-body PBPK model to simulate the biodistribution of T-cells and TCB molecules. The insights from this model provide a comprehensive understanding of the factors affecting PK, synapse formation, and TCB activity, aiding in dose optimization and the design of effective therapeutic strategies. Full article

(This article belongs to the Special Issue Development of Physiologically Based Pharmacokinetic (PBPK) Modeling)

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13 pages, 2723 KB

Open AccessEditor’s ChoiceArticle

Carbon Dots as a Fluorescent Nanosystem for Crossing the Blood–Brain Barrier with Plausible Application in Neurological Diseases

by Catarina Araújo, Raquel O. Rodrigues, Manuel Bañobre-López, Adrián M. T. Silva and Rui S. Ribeiro

Pharmaceutics 2025, 17(4), 477; https://doi.org/10.3390/pharmaceutics17040477 - 6 Apr 2025

Cited by 11 | Viewed by 3415

Abstract

Background/Objectives: The development of effective therapies for brain disorders is highly correlated with the ability of drugs or nanosystems to cross the blood–brain barrier (BBB), which has been limited. Recently, carbon dots (CDs) have been receiving attention to be used as BBB-crossing [...] Read more.

Background/Objectives: The development of effective therapies for brain disorders is highly correlated with the ability of drugs or nanosystems to cross the blood–brain barrier (BBB), which has been limited. Recently, carbon dots (CDs) have been receiving attention to be used as BBB-crossing theranostic agents due to their inherent advantages, such as low size, excellent biocompatibility, high quantum yield (QY), tunable fluorescence, high drug loading, and relatively easy synthesis at low cost. The aim of this study was to design CDs with precisely controlled fluorescence properties for advanced bioimaging and an in-depth assessment of BBB permeability. Methods: CDs were synthesized using a microwave-assisted approach, optimized through microwaves’ irradiation time, and employing citric acid, urea, and sodium fluoride as precursors. The optimized sample was labeled as NF-CD. Results: A comprehensive physicochemical, photoluminescence, and biological characterization revealed the ability of NF-CD to diffuse across a neuromimetic-BBB model, mainly due to their small size (average diameter of 4.0 ± 1.1 nm), exhibiting excitation-dependent fluorescence in the blue and green wavelengths, high biocompatibility and QY, and exceptional photostability. Conclusions: Owing to the exceptional fluorescence characteristics and biological compatibility, NF-CD presents promising opportunities in theranostic applications, particularly in brain-targeted bioimaging, nanocarrier-based drug and immunotherapy delivery, early-stage diagnostics, and personalized medicine. NF-CD’s ability to cross the BBB further underscores the relevance of pioneering nanomaterial-based strategies for neurological disorder diagnostics and precision-targeted therapeutic interventions. Overall, this research contributes to the broader field of nanotechnology-driven biomedical advancements, fostering innovations in neurological diagnostics and therapeutic delivery systems. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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27 pages, 9025 KB

Open AccessEditor’s ChoiceArticle

Optimization, In Vitro, and In Silico Characterization of Theophylline Inhalable Powder Using Raffinose-Amino Acid Combination as Fine Co-Spray-Dried Carriers

by Petra Party, Lomass Soliman, Attila Nagy, Árpád Farkas and Rita Ambrus

Pharmaceutics 2025, 17(4), 466; https://doi.org/10.3390/pharmaceutics17040466 - 3 Apr 2025

Cited by 6 | Viewed by 3361

Abstract

Background/Objectives: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN’s physicochemical and aerodynamic properties to ensure [...] Read more.

Background/Objectives: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN’s physicochemical and aerodynamic properties to ensure efficient lung deposition. Methods: The process involves spray-drying each formulation’s solution using a mini spray drier. A rigorous assessment was conducted on particle size distribution, structural and thermal analysis, morphology study, in vitro and in silico aerodynamic investigation, and aerodynamic particle counter in addition to the solubility, in vitro dissolution, and diffusion of TN. Results: The carriers containing leucine and glycine revealed superior characteristics (mass median aerodynamic diameter (MMAD): 4.6–5 µm, fine particle fraction (FPF): 30.6–35.1%, and amorphous spherical structure) as candidates for further development of TN-DPIs, while arginine was excluded due to intensive aggregation and hygroscopicity, which led to poor aerodynamic performance. TN co-spray-dried samples demonstrated fine micronized particles (D [0.5]: 3.99–5.96 µm) with predominantly amorphous structure (crystallinity index: 24.1–45.2%) and significant solubility enhancement (~19-fold). Formulations containing leucine and leucine-glycine revealed the highest FPF (45.7–47.8%) and in silico lung deposition (39.3–40.1%), rapid in vitro drug release (~100% within 10 min), and improved in vitro diffusion (2.29–2.43-fold), respectively. Moreover, the aerodynamic counter confirmed the development of fine microparticles (mean number particle size = 2.3–2.02 µm). Conclusions: This innovative formulation possesses enhanced physicochemical, morphological, and aerodynamic characteristics of low-dose TN for local asthma treatment and could be applied as a promising carrier for dry powder inhaler development. Full article

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)

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16 pages, 1717 KB

Open AccessEditor’s ChoiceArticle

Anti-Candida Activity of Cysteine-Modified Amidated Decoralin in the Presence of Engineered Nanomaterials

by Vânia Rocha, Helena Almeida, Bruno Sarmento and José das Neves

Pharmaceutics 2025, 17(4), 460; https://doi.org/10.3390/pharmaceutics17040460 - 2 Apr 2025

Cited by 1 | Viewed by 1954

Abstract

Background: Candidiasis remains a chief concern in global healthcare. Drug safety issues and increasing resistance make it urgent to develop alternative antifungal agents, namely antimicrobial peptides. Amidated decoralin (Dec-CONH₂) possesses considerable anti-Candida activity, and its association with nanocarriers could help [...] Read more.

Background: Candidiasis remains a chief concern in global healthcare. Drug safety issues and increasing resistance make it urgent to develop alternative antifungal agents, namely antimicrobial peptides. Amidated decoralin (Dec-CONH₂) possesses considerable anti-Candida activity, and its association with nanocarriers could help in enhancing efficacy while reducing intrinsic toxicity to the host. Methods: We studied an N-terminal cysteine-modified version of the peptide (Cys-Dec-CONH₂) and screened the effects of different nanosystems (polymeric nanoparticles (NPs), liposomes and gold NPs) on its activity against azole-sensitive and azole-resistant Candida species using a clinically relevant in vitro assay. Results: The antifungal activity of Cys-Dec-CONH₂ was maintained (minimum inhibitory concentration (MIC) = 16–64 µg/mL), but the presence of poly(d,l-lactic-co-glycolic acid) (PLGA)- and polycaprolactone-based NPs impaired the antifungal effect of the peptide (MIC > 256 µg/mL). This effect was milder for polystyrene-based NPs, liposomes, and gold NPs (MIC ≤ 128 µg/mL). Additionally, the covalent surface functionalization of PLGA-based NPs with Cys-Dec-CONH₂ or the presence of relevant biomolecules (albumin and mucin) resulted in complete inhibition of antifungal activity. Conclusions: Our data suggest that Cys-Dec-CONH₂ is able to establish strong interfacial interactions with different nanomaterials, which need to be considered when developing nanomedicines based on this peptide for the management of candidiasis. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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44 pages, 7303 KB

Open AccessEditor’s ChoiceReview

Advances in Drug Delivery Integrated with Regenerative Medicine: Innovations, Challenges, and Future Frontiers

by Manoochehr Rasekh, Muhammad Sohail Arshad and Zeeshan Ahmad

Pharmaceutics 2025, 17(4), 456; https://doi.org/10.3390/pharmaceutics17040456 - 1 Apr 2025

Cited by 40 | Viewed by 5134

Abstract

Advances in drug delivery systems adapted with regenerative medicine have transformed healthcare by introducing innovative strategies to treat (and repair in many instances) disease-impacted regions of the human body. This review provides a comprehensive analysis of the latest developments and challenges in integrating [...] Read more.

Advances in drug delivery systems adapted with regenerative medicine have transformed healthcare by introducing innovative strategies to treat (and repair in many instances) disease-impacted regions of the human body. This review provides a comprehensive analysis of the latest developments and challenges in integrating drug delivery technologies with regenerative medicine. Recent advances in drug delivery technologies, including the design of biomaterials, localized delivery techniques, and controlled release systems guided by mathematical models, are explored to illustrate their role in enhancing therapeutic precision and efficacy. Additionally, regenerative medicine approaches are analyzed, with a focus on extracellular matrix components, stem cell-based therapies, and emerging strategies for organ regeneration in both soft and hard tissue and in vitro model engineering. In particular, the review also discusses the applications of cellular components, including stem cells, immune cells, endothelial cells, and specialized cells such as chondrocytes and osteoblasts, and highlights advancements in cell delivery methods and cell–cell interaction modulation. In addition, future directions and pivotal trends emphasizing the importance of interdisciplinary collaboration and cutting-edge innovations are provided to address successful therapeutic outcomes in regenerative medicine. Full article

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

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16 pages, 2909 KB

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 16 | Viewed by 3900

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

Cited by 4 | Viewed by 2642

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

Cited by 1 | Viewed by 2234

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 5 | Viewed by 3867

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 17 | Viewed by 5719

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

Cited by 4 | Viewed by 2076

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 16 | Viewed by 4648

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

Cited by 1 | Viewed by 2816

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 8 | Viewed by 5017

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 6 | Viewed by 4566

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 7 | Viewed by 3047

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 7 | Viewed by 2458

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 8 | Viewed by 4472

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 27 | Viewed by 7387

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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