Pharmaceutics

13 pages, 1180 KiB

Open AccessArticle

Ustekinumab Drug Clearance Is Better Associated with Disease Control than Serum Trough Concentrations in a Prospective Cohort of Inflammatory Bowel Disease

by Andres J. Yarur, Thierry Dervieux, Ryan Ungaro, Elizabeth A. Spencer, Alexandra Bruss, Lizbeth Nunez, Brandon Berens, Séverine Vermeire, Zhigang Wang, John C. Panetta, Erwin Dreesen and Marla C. Dubinsky

Pharmaceutics 2025, 17(2), 187; https://doi.org/10.3390/pharmaceutics17020187 - 2 Feb 2025

Abstract

Background/Objectives: This study aimed to compare the association of ustekinumab (UST) drug clearance (CL) and trough drug concentrations with disease activity in patients with inflammatory bowel diseases (IBDs). Methods: A prospective cohort of 83 patients with IBD receiving maintenance therapy with [...] Read more.

Background/Objectives: This study aimed to compare the association of ustekinumab (UST) drug clearance (CL) and trough drug concentrations with disease activity in patients with inflammatory bowel diseases (IBDs). Methods: A prospective cohort of 83 patients with IBD receiving maintenance therapy with 90 mg subcutaneous UST was analyzed using Bayesian PK modeling. UST concentrations and antibodies to UST (ATU) were collected at the trough and measured using a drug-tolerant homogenous mobility shift assay (HMSA). CL was estimated using Bayesian estimation methods with priors from a previous population pharmacokinetic study specifically reparametrized using HMSA. Outcomes were combined clinical and biochemical remission and endoscopic healing index (EHI) score, a validated marker of endoscopic active disease in IBD. Statistical analysis consisted of linear and nonlinear mixed effect models for repeated time-to-event analysis. Results: A total of 83 patients with IBD were enrolled (median age 42 years, 52% female) and evaluated across 312 dose cycles (median follow-up: 279 days, median of 3 cycles/patient). Median concentrations and CL were 5.0 µg/mL and 0.157 L/day, respectively. Most patients (89%) were exposed to other biologics before starting UST, which was associated with lower rates of clinical and biochemical remission (p = 0.01). Longitudinal changes in concentrations were not associated with remission (p = 0.53). Conversely, higher CL was associated with a lower likelihood of remission (p < 0.01). EHI > 50 points (endoscopic active disease, n = 303 cycles) was associated with higher UST CL (p < 0.01). Conclusions: UST CL was more strongly associated with clinical and biochemical outcomes than trough concentrations, highlighting its potential role in therapy optimization. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)

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17 pages, 2919 KiB

Open AccessArticle

Antimicrobial and Antibiofilm Activity of Chitosan Nanoparticles Against Staphylococcus aureus Strains Isolated from Bovine Mastitis Milk

by Carlos Alarcón Godoy, Iván Balic, Adrián A. Moreno, Oscar Diaz, Carla Arenas Colarte, Tamara Bruna Larenas, Alexander Gamboa and Nelson Caro Fuentes

Pharmaceutics 2025, 17(2), 186; https://doi.org/10.3390/pharmaceutics17020186 - 2 Feb 2025

Abstract

Background/Objectives: Bovine mastitis (BM), a prevalent and economically burdensome bacterial infection affecting dairy cattle, poses a significant challenge to the dairy industry. The traditional approach to combating BM, relying heavily on antibiotics, faces growing concerns due to the increasing antibiotic resistance exhibited by [...] Read more.

Background/Objectives: Bovine mastitis (BM), a prevalent and economically burdensome bacterial infection affecting dairy cattle, poses a significant challenge to the dairy industry. The traditional approach to combating BM, relying heavily on antibiotics, faces growing concerns due to the increasing antibiotic resistance exhibited by pathogens. The objective of this study was to evaluate and determine the antimicrobial and anti-biofilm potential of chitosan nanoparticles (NQo) on S. aureus strains isolated from milk samples obtained from dairy areas in southern Chile from cows diagnosed with BM. Methods: NQo were synthesized using the ionotropic gelation method and thoroughly characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Results: The NQo exhibit a robust positive charge (Z-potential of +55.4 ± 2.5 mV) and an exceptionally small size (20.3 ± 3.2 nm). This unique combination of properties makes NQo particularly well-suited for targeting and interacting with bacterial pathogens. To assess the effectiveness of NQo against BM, we conducted a series of experiments using a Staphylococcus aureus strain isolated from milk samples of cows diagnosed with BM in southern Chile. NQo demonstrated a remarkable ability to inhibit bacterial proliferation and effectively modulate biofilm formation in the S. aureus strains. Furthermore, the performance of NQo in comparison to established antibiotics like ampicillin and gentamicin strongly suggests that these nanoparticles hold immense potential as an attractive alternative for the control, prevention, and/or treatment of BM. Conclusions: NQo exhibit both antimicrobial and antibiofilm activity against a clinically relevant BM pathogen. Further investigations are necessary to develop a hydrogel formulation optimized for effective delivery to the target diseased tissue. Full article

(This article belongs to the Special Issue Chitosan-Based Nanoparticles as Carriers for Drug Delivery and Biomedical Applications)

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40 pages, 5796 KiB

Open AccessReview

Microencapsulation of Probiotics for Enhanced Stability and Health Benefits in Dairy Functional Foods: A Focus on Pasta Filata Cheese

by Vita D’Amico, Mariasimona Cavaliere, Marianna Ivone, Chiara Lacassia, Giuseppe Celano, Mirco Vacca, Flavia Maria la Forgia, Sergio Fontana, Maria De Angelis, Nunzio Denora and Angela Assunta Lopedota

Pharmaceutics 2025, 17(2), 185; https://doi.org/10.3390/pharmaceutics17020185 - 2 Feb 2025

Abstract

Probiotics provide significant health benefits, but their viability is often compromised during production, storage, and passage through the gastrointestinal tract. These challenges hinder their effective incorporation into functional applications, particularly in dairy functional foods, in which factors such as acidity, oxygen exposure, and [...] Read more.

Probiotics provide significant health benefits, but their viability is often compromised during production, storage, and passage through the gastrointestinal tract. These challenges hinder their effective incorporation into functional applications, particularly in dairy functional foods, in which factors such as acidity, oxygen exposure, and storage conditions negatively impact cell survival. The focus was on functional dairy foods, particularly on pasta filata cheeses. Indeed, the use of probiotics in pasta filata cheeses presents significant challenges due to the specific manufacturing processes, which encompass the application of high temperatures and other harsh conditions. These factors can adversely affect the viability and availability of probiotic microorganisms. However, microencapsulation has emerged as a promising solution, offering a protective barrier that enhances probiotic stability, improves survival rates, and facilitates targeted release in the gastrointestinal environment. This review examines the pivotal role of microencapsulation in stabilising probiotics for functional applications, emphasising its relevance in high-value food systems. Functional applications, including foods designed to offer essential nutritional benefits and promote host health, play a crucial role in disease prevention and immune system support, reducing the risk of infections and other physiological impairments. Key microencapsulation technologies are analysed, focusing on their benefits, limitations, and challenges related to scalability and industrial implementation. Additionally, this review discusses strategies to optimise formulations, ensure the sensory quality of final products, and explore future opportunities for expanding innovative applications that align with growing consumer demand for health-promoting solutions. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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14 pages, 5458 KiB

Open AccessArticle

Docetaxel Micelles: A New Formulation to Diminish Hypersensitivity Reactions

by Lanlan Xiang, Hao Wang, Jiajie Liu, Yuchen Shen, Yanfen Hu, Wenchen Che, Ran Li, Sisi Yang and Xin Teng

Pharmaceutics 2025, 17(2), 184; https://doi.org/10.3390/pharmaceutics17020184 - 2 Feb 2025

Abstract

Background/Objectives: Docetaxel is a potent anti-cancer agent capable of treating various types of cancer. However, it often induces a range of adverse reactions when used with its standard solubilizer, Tween-80, necessitating allergy prophylaxis with dexamethasone prior to administration. To mitigate the risk [...] Read more.

Background/Objectives: Docetaxel is a potent anti-cancer agent capable of treating various types of cancer. However, it often induces a range of adverse reactions when used with its standard solubilizer, Tween-80, necessitating allergy prophylaxis with dexamethasone prior to administration. To mitigate the risk of allergic reactions, with nanomicelles garnering significant interest due to their enhanced solubility and thermodynamic stability. Methods: In this research, a mPEG-PLA-Lys(Fmoc) micellar carrier with m = 45 and n = 10 was engineered to encapsulate docetaxel, and its self-assembly into micelles was investigated. Additionally, allergic reaction studies were conducted on animals. Results: The findings indicated that the formulation did not cause hemolysis, vascular, or muscle irritation in rabbits, nor did it elicit an allergic response in guinea pigs. Conclusions: These results suggest that nanomicelle-encapsulated docetaxel can diminish the allergic reactions associated with docetaxel injections, offering a novel approach to enhance the therapeutic utility of this outstanding anti-cancer drug. Full article

(This article belongs to the Special Issue Advances in Nanocarriers for Drug Delivery and Targeting, 2nd Edition)

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19 pages, 4933 KiB

Open AccessArticle

Evaluating Swellable Cross-Linked Biopolymer Impact on Ink Rheology and Mechanical Properties of Drug-Contained 3D-Printed Thin Film

by Farzana Khan Rony, Jonathan Appiah, Asmaa Alawbali, Distinee Clay, Shamsuddin Ilias and Mohammad A. Azad

Pharmaceutics 2025, 17(2), 183; https://doi.org/10.3390/pharmaceutics17020183 - 1 Feb 2025

Abstract

Background/Objectives: Interest in 3D printing oral thin films (OTFs) has increased substantially. The challenge of 3D printing is film printability, which is strongly affected by the rheological properties of the ink and having suitable mechanical properties. This research assesses the suitability of sodium [...] Read more.

Background/Objectives: Interest in 3D printing oral thin films (OTFs) has increased substantially. The challenge of 3D printing is film printability, which is strongly affected by the rheological properties of the ink and having suitable mechanical properties. This research assesses the suitability of sodium starch glycolate (SSG), a swellable cross-linked biopolymer, on ink rheology and the film’s mechanical properties. Methods: A water-based ink comprising sodium alginate (SA), the drug fenofibrate (FNB), SSG, glycerin, and polyvinylpyrrolidone (PVP) was formulated, and its rheology was assessed through flow, amplitude sweeps, and thixotropy tests. Films (10 mm × 15 mm × 0.35 mm) were 3D-printed using a 410 µm nozzle, 50% infill density, 60 kPa pressure, and 10 mm/s speed, with mechanical properties (Young’s modulus, tensile strength, and elongation at break) analyzed using a TA-XT Plus C texture analyzer. Results: The rheology showed SSG-based ink has suitable properties (shear-thinning behavior, high viscosity, higher modulus, and quick recovery) for 3D printing. SSG enhanced the rheology (viscosity and modulus) of ink but not the mechanical properties of film. XRD and DSC confirmed preserved FNB crystallinity without polymorphic changes. SEM images showed surface morphology and particle distribution across the film. The film demonstrated a drug loading of 44.28% (RSD 5.62%) and a dissolution rate of ~77% within 30 min. Conclusions: SSG improves ink rheology, makes it compatible with 3D printing, and enhances drug dissolution (formulation F-5). Plasticizer glycerin is essential with SSG to achieve the film’s required mechanical properties. The study confirms SSG’s suitability for 3D printing of OTFs. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of 3D Printing)

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24 pages, 9926 KiB

Open AccessArticle

Development, Characterization, and Antimicrobial Evaluation of Hybrid Nanoparticles (HNPs) Based on Phospholipids, Cholesterol, Colistin, and Chitosan Against Multidrug-Resistant Gram-Negative Bacteria

by Isabella Perdomo, Carolina Mora, Juan Pinillos, José Oñate-Garzón and Constain H. Salamanca

Pharmaceutics 2025, 17(2), 182; https://doi.org/10.3390/pharmaceutics17020182 - 1 Feb 2025

Abstract

Background: Colistin, a lipopeptide antibiotic usually used as a last resort against multidrug-resistant bacterial strains, has also begun to address the challenge of antimicrobial resistance. Objective: this study evaluates whether hybrid nanoparticles (HNPs) composed of Phospholipon^® 90G, cholesterol, and colistin can [...] Read more.

Background: Colistin, a lipopeptide antibiotic usually used as a last resort against multidrug-resistant bacterial strains, has also begun to address the challenge of antimicrobial resistance. Objective: this study evaluates whether hybrid nanoparticles (HNPs) composed of Phospholipon^® 90G, cholesterol, and colistin can enhance its effectiveness against resistant clinical isolates of Klebsiella pneumoniae, a clinically significant Gram-negative bacterium. Methods: HNPs were developed using the ethanol injection method and coated with chitosan through a layer-by-layer technique. HNP characterization included measurements of particle size, polydispersity index (PDI), and zeta potential, along with thermal (DSC) and spectrophotometric (FT-IR) analyses. Ultrafiltration and ATR-FTIR were employed to assess colistin’s association and release efficiencies. The biological evaluation followed CLSI guidelines. Results: uncoated hybrid nanoparticles (U-HNP) and chitosan-coated hybrid nanoparticles (Ch-HNP) described monodisperse populations, with respective PDI values of ~0.124 and ~0.150, Z-averages of ~249 nm and ~250 nm, and zeta potential values of +17 mV and +20 mV. Colistin’s association and release efficiencies were approximately 79% and 10%, respectively. Regarding antimicrobial activity, results showed that colistin as part of HNPs is poorly effective against this microorganism. However, in the most resistant strain, colistin activity increased slightly when the HNP was coated with chitosan. Conclusions: HNPs described high stability against disaggregation, limiting the colistin release and, therefore, affecting antimicrobial performance. Full article

(This article belongs to the Special Issue Delivery System for Biomacromolecule Drugs: Design and Application)

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22 pages, 12170 KiB

Open AccessArticle

Evaluation of Preclinical Efficacy of Curcumin-Loaded Bicosome Systems in Amelioration of Oral Mucositis

by Daniela Vergara, Claudia Sanhueza, Susana Méndez, Mariela Bustamante, Benjamín Vega, Francisca Acevedo and Olga López

Pharmaceutics 2025, 17(2), 181; https://doi.org/10.3390/pharmaceutics17020181 - 1 Feb 2025

Abstract

Background/Objectives: Oral mucositis (OM) is a common and debilitating side effect of cancer therapy, characterized by ulceration or inflammation of the oral mucosa. This study evaluates the preclinical efficacy of curcumin-loaded bicosome systems (cur-BS) in mitigating chemotherapy-induced OM in mice. Methods: BS were [...] Read more.

Background/Objectives: Oral mucositis (OM) is a common and debilitating side effect of cancer therapy, characterized by ulceration or inflammation of the oral mucosa. This study evaluates the preclinical efficacy of curcumin-loaded bicosome systems (cur-BS) in mitigating chemotherapy-induced OM in mice. Methods: BS were prepared using a combination of 1,2-di-palmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC), α-tocopherol, and curcumin, encapsulated within liposomal vesicles. Three formulations with different curcumin concentrations (180, 540, and 900 μM) were characterized by particle size, polydispersity index (PDI), encapsulation efficiency (EE), appearance, and morphology. The formulation with the highest concentration (cur-BS 5×) was selected for ex vivo permeability studies, release profile analysis, and in vitro anti-inflammatory efficacy. OM was induced in mice using 5-fluorouracil (5-FU) and acetic acid. Cur-BS 5× was compared to the commercial product Dentoxol^®. Results: The results showed that cur-BS 5× provided sustained release through a mechanism involving both diffusion and matrix relaxation, enhancing curcumin retention in deeper skin layers. Treatment with cur-BS 5× downregulated the expression of inflammatory markers (IL-1β and TNF-α). Macroscopic assessments demonstrated that both cur-BS 5× and Dentoxol^® reduced OM severity, with the greatest improvement observed between days 6 and 9. By day 24, OM scores were 1.25 ± 0.5 for cur-BS 5× and 1.0 ± 0.0 for Dentoxol^®, indicating effectiveness in both treatments. However, histological analysis revealed superior tissue recovery with cur-BS 5×, showing better epithelial structure and reduced inflammation. Cur-BS 5×-treated mice also exhibited greater weight recovery and higher survival rates compared to the Dentoxol^® group. Conclusions: These findings suggest that cur-BS 5× may enhance OM treatment, offering outcomes comparable to or better than those of Dentoxol^®. Full article

(This article belongs to the Special Issue Advanced Liposomes for Drug Delivery, 2nd Edition)

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18 pages, 7624 KiB

Open AccessArticle

Assessment of the In Vitro Biological Activities of Schiff Base-Synthesized Copper Oxide Nanoparticles as an Anti-Diabetic, Anti-Alzheimer, and Anti-Cancer Agent

by Abdulrahman A. Almehizia, Ahmed M. Naglah, Sadeem S. Aljafen, Ashraf S. Hassan and Wael M. Aboulthana

Pharmaceutics 2025, 17(2), 180; https://doi.org/10.3390/pharmaceutics17020180 - 1 Feb 2025

Abstract

Background/Objectives: Numerous diseases such as diabetes, Alzheimer’s disease, and cancer have spread in the whole world, especially in the Arab world. Also, various applications of Schiff-base functionalized nanoparticles and copper oxide nanoparticles (CuO-NPs) such as therapeutic applications have been discovered. Thus, the current [...] Read more.

Background/Objectives: Numerous diseases such as diabetes, Alzheimer’s disease, and cancer have spread in the whole world, especially in the Arab world. Also, various applications of Schiff-base functionalized nanoparticles and copper oxide nanoparticles (CuO-NPs) such as therapeutic applications have been discovered. Thus, the current research highlights (i) the synthesis of copper oxide nanoparticles (CuO-NPs) produced with a Schiff base (SB) serving as a capping agent during their synthesis and (ii) assessment of the in vitro biological activities of Schiff base-synthesized copper oxide nanoparticles (SB-CuO-NPs) and a Schiff base (SB). Methods: SB-CuO-NPs were characterized using ultraviolet-visible (UV-Vis) spectroscopy, zeta potential, DLS analysis, and transmission electron microscope (TEM). It also focuses on assessing the in vitro biological applications and activities, including antioxidant, scavenging, anti-diabetic, anti-Alzheimer, anti-arthritic, anti-inflammatory, cytotoxic activities, and enzymes inhibitory potential, of Schiff base-synthesized copper oxide nanoparticles (SB-CuO-NPs) and a Schiff base (SB) using methods described in the literature. Results: The results of the biological activities of the SB-CuO-NPs were compared with those of the SB. The SB-CuO-NPs demonstrated superior in vitro biological activities when compared to the SB from which they were produced. Conclusions: The results of this investigation concluded that the CuO-NPs, synthesized with the SB serving as an alternative capping agent, exhibited enhanced biological efficacy relative to the original SB. In the future, the biological efficiency of SB-CuO-NPs against diabetes, Alzheimer’s, and cancer diseases will be assessed in experimental animals (in vivo). Full article

(This article belongs to the Special Issue Metal Nanoparticles for Biomedical Applications)

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24 pages, 1595 KiB

Open AccessArticle

Physiologically Based Pharmacokinetic Model of CYP2D6 Associated Interaction Between Venlafaxine and Strong Inhibitor Bupropion—The Influence of Age-Relevant Changes and Inhibitory Dose to Classify Therapeutical Success and Harm

by Ulrich Ruben Luecht, Wolfgang Scholz, Ann-Kathrin Geiben, Ekkehard Haen and Georg Hempel

Pharmaceutics 2025, 17(2), 179; https://doi.org/10.3390/pharmaceutics17020179 - 31 Jan 2025

Abstract

Background/Objectives: Venlafaxine (VEN) is commonly used in young and elderly patients. Bupropion (BUP) is occasionally added to depression treatments with VEN. BUP’s inhibitory potential toward CYP2D6, VEN’s main metabolic pathway, may provoke a higher risk for toxic or adverse drug effects. Therefore, the [...] Read more.

Background/Objectives: Venlafaxine (VEN) is commonly used in young and elderly patients. Bupropion (BUP) is occasionally added to depression treatments with VEN. BUP’s inhibitory potential toward CYP2D6, VEN’s main metabolic pathway, may provoke a higher risk for toxic or adverse drug effects. Therefore, the question arises if a dose reduction in VEN or BUP is needed to avoid clinically relevant changes in exposure to VEN and its metabolite O-desmethylvenlafaxine (ODV). Methods: The literature-based PBPK models of VEN, BUP and their active metabolites under single-dose and steady-state conditions were created by using PK-Sim^®. To evaluate the DDI model‘s predictive performance, trough plasma concentrations (<65 years, n = 54 and ≥65 years, n = 13) of VEN/ODV were extracted from the TDM database KONBEST. DDI’s clinical extent was assessed by AUC changes in VEN, ODV and active moiety (AM). The prediction was compared to the results of SCHOLZ Databank’s MDDI calculator (MDDIcalc). Results: Models accurately describe VEN’s and BUP’s pharmacokinetics and BUP’s effect on VEN’s metabolism in the age strata. The model predicts higher exposure to VEN (+110% to 132%), lower exposure to ODV (−50.0% to −61.5%) and a negligible change in AM (−1.02% to −2.40%). The AUC changes increase with higher BUP doses but is independent of patients’ age. Because of the missing AUC change in the AM, the DDI is considered clinically irrelevant. The MDDIcalc predicts no relevant effect on the AUC of AM with BUP. Conclusions: Both PBPK and MDDIcalc provide, in their own way, valuable tools to predict the DDI’s extent. Further research is needed regarding elderly patients, renal or hepatic impairment and polymorphisms, especially CYP2D6, CYP2C9, CYP2C19 and UGT. Full article

(This article belongs to the Special Issue Pathophysiological Influences on Pharmacokinetics and Pharmacodynamics)

24 pages, 342 KiB

Open AccessReview

Lipid Nanoparticles Carrying Essential Oils for Multiple Applications as Antimicrobials

by Elenice Francisco da Silva, Fernanda Aparecida Longato dos Santos, Henrique Machado Pires, Luciana Machado Bastos and Lígia Nunes de Morais Ribeiro

Pharmaceutics 2025, 17(2), 178; https://doi.org/10.3390/pharmaceutics17020178 - 31 Jan 2025

Abstract

Lipid nanoparticles (LNPs) are versatile delivery systems with high interest because they allow the release of hydrophobic and hydrophilic molecules, such as essential oils (EOs) and plant extracts. This review covers published works between 2019 and 2024 that have reported the use of [...] Read more.

Lipid nanoparticles (LNPs) are versatile delivery systems with high interest because they allow the release of hydrophobic and hydrophilic molecules, such as essential oils (EOs) and plant extracts. This review covers published works between 2019 and 2024 that have reported the use of essential EO-based LNPs with antimicrobial properties and applications in human and animal health, as well as biopesticides. In the human healthcare field, reports have addressed the effect of encapsulating EOs in lipid nanosystems with antiviral, antibacterial, antiprotozoal and antifungal activities. In animal care, this still needs to be more deeply explored while looking for more sustainable alternatives against different types of parasites that affect animal health. Overall, the antibacterial activities of LNPs carrying EOs are described as alternatives to the use of synthetic antibiotics. In the field of agriculture, studies showed that these approaches in the control of phytopathogens and other pests that affect food production. There is a growing demand for innovative and more sustainable technologies. However, there are still some challenges to be overcome in order to allow these innovations to reach the market. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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22 pages, 5524 KiB

Open AccessArticle

Advanced Nanopharmaceutical Intervention for the Reduction of Inflammatory Responses and the Enhancement of Behavioral Outcomes in APP/PS1 Transgenic Mouse Models

by Jun Li, Dongqing Huang, Wanchen Liao, Yulin Wang, Yibiao Liu and Ping Luan

Pharmaceutics 2025, 17(2), 177; https://doi.org/10.3390/pharmaceutics17020177 - 31 Jan 2025

Abstract

Background: The excessive accumulation of Aβ plays a critical role in the development of Alzheimer’s disease. However, the therapeutic potential of drugs like curcumin is often limited by low biocompatibility and BBB permeability. In this study, we developed a nanomaterial, BP-PEG-Tar@Cur, which [...] Read more.

Background: The excessive accumulation of Aβ plays a critical role in the development of Alzheimer’s disease. However, the therapeutic potential of drugs like curcumin is often limited by low biocompatibility and BBB permeability. In this study, we developed a nanomaterial, BP-PEG-Tar@Cur, which was designed to enhance the biocompatibility of (curcumin) Cur, target Aβ, and augment BBB permeability through near-infrared (NIR) photothermal effects. Methods: Soluble Aβ, ThT fluorescence, and Aβ depolymerization fluorescence experiments were conducted to evaluate the ability of BP-PEG-Tar@Cur to inhibit Aβ aggregation and dissociate Aβ fibrils. Cell uptake assays were performed to confirm the targeting ability of BP-PEG-Tar@Cur towards Aβ. In vitro mitochondrial ROS clearance and in vivo detection of inflammatory factors were used to assess the anti-inflammatory and antioxidant properties of the nanodrug. Water maze behavioral experiments were conducted to evaluate the effect of BP-PEG-Tar@Cur on spatial memory, learning ability, and behavioral disorders in AD mice. Results: The nanodrug effectively inhibited Aβ aggregation and dissociated Aβ fibrils in vitro. BP-PEG-Tar@Cur demonstrated efficiency in curbing ROS overproduction in mitochondria and dampening the activation of microglia and astrocytes triggered by Aβ aggregation. Water maze behavioral experiments revealed that BP-PEG-Tar@Cur enhanced spatial memory, learning ability, and alleviated behavioral disorders in AD mice. Conclusions: Collectively, these findings demonstrate that BP-PEG-Tar@Cur has the potential to be an effective targeted drug for inhibiting Aβ aggregation and improving cognitive impairment in AD mice. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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33 pages, 4150 KiB

Open AccessReview

Exploring the Potential of Gold Nanoparticles in Proton Therapy: Mechanisms, Advances, and Clinical Horizons

by Giorgio Giuseppe Carbone, Stefania Mariano, Alessandra Gabriele, Sabrina Cennamo, Vitantonio Primiceri, Muhammad Rizwan Aziz, Elisa Panzarini and Lucio Calcagnile

Pharmaceutics 2025, 17(2), 176; https://doi.org/10.3390/pharmaceutics17020176 - 30 Jan 2025

Abstract

Proton therapy represents a groundbreaking advancement in cancer radiotherapy, leveraging the unique spatial energy distribution of protons to deliver precise, high-dose radiation to tumors while sparing surrounding healthy tissues. Despite its clinical success, proton therapy faces challenges in optimizing its therapeutic precision and [...] Read more.

Proton therapy represents a groundbreaking advancement in cancer radiotherapy, leveraging the unique spatial energy distribution of protons to deliver precise, high-dose radiation to tumors while sparing surrounding healthy tissues. Despite its clinical success, proton therapy faces challenges in optimizing its therapeutic precision and efficacy. Recent research has highlighted the potential of gold nanoparticles to enhance proton therapy outcomes. Due to their high atomic number and favorable biological properties, gold nanoparticles act as radiosensitizers by amplifying the generation of secondary electrons and reactive oxygen species upon proton irradiation. This enhances DNA damage in tumor cells while preserving healthy tissues. Additionally, functionalization of gold nanoparticles with tumor-targeting ligands offers improved precision, making proton therapy more effective against a broader range of cancers. This review synthesizes current knowledge on the mechanisms of gold nanoparticle radiosensitization, preclinical evidence, and the technological hurdles that must be addressed to integrate this promising approach into clinical practice, aiming to advance the efficacy and accessibility of proton therapy in cancer therapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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18 pages, 1754 KiB

Open AccessArticle

Mechanistic Investigation into Crystallization of Hydrated Co-Amorphous Systems of Flurbiprofen and Lidocaine

by Xiaoyue Xu, Holger Grohganz, Justyna Knapik-Kowalczuk, Marian Paluch and Thomas Rades

Pharmaceutics 2025, 17(2), 175; https://doi.org/10.3390/pharmaceutics17020175 - 30 Jan 2025

Abstract

Background: It is generally accepted that water as a plasticizer can decrease the glass transition temperatures (T_gs) of amorphous drugs and drug delivery systems, resulting in physical instabilities. However, a recent study has reported an anti-plasticizing effect of water on amorphous [...] Read more.

Background: It is generally accepted that water as a plasticizer can decrease the glass transition temperatures (T_gs) of amorphous drugs and drug delivery systems, resulting in physical instabilities. However, a recent study has reported an anti-plasticizing effect of water on amorphous lidocaine (LID). In co-amorphous systems, LID might be used as a co-former to impair the plasticizing effect of water. Method: Flurbiprofen (FLB) was used to form a co-amorphous system with a mole fraction of LID of 0.8. The effect of water on the stability of co-amorphous FLB-LID upon hydration was investigated. The crystallization behaviors of anhydrous and hydrated co-amorphous FLB-LID systems were measured by an isothermal modulated differential scanning calorimetric (iMDSC) method. The relaxation times of the co-amorphous FLB-LID system upon hydration were measured by a broadband dielectric spectroscopy (BDS), and the differences in Gibbs free energy (ΔG) and entropy (ΔS) between the amorphous and crystalline phases were determined by differential scanning calorimetry (DSC). Results: It was found that the crystallization tendency of co-amorphous FLB-LID decreased with the addition of water. Molecular mobility and thermodynamic factors were both investigated to explain the difference in crystallization tendencies of co-amorphous FLB-LID upon hydration. Conclusions: The results of the study showed that LID could be used as an effective co-former to decrease the crystallization tendency of co-amorphous FLB-LID upon hydration by enhancing the entropic (ΔS) and thermodynamic activation barriers (TΔS)³/ΔG²) to crystallization. Full article

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

11 pages, 506 KiB

Open AccessReview

The Effects of Slow-Release Dexamethasone in the Treatment of Diabetic Macular Edema

by Enzo Maria Vingolo, Simona Mascolo, Lorenzo Casillo and Mattia Calabro

Pharmaceutics 2025, 17(2), 174; https://doi.org/10.3390/pharmaceutics17020174 - 30 Jan 2025

Abstract

Objectives: to evaluate the efficacy of 0.7 mg dexamethasone intravitreal implant in the treatment of patients with diabetic macular edema through mean retinal sensitivity (MRS), best corrected visual acuity (BCVA), central retinal thickness (CRT) and fixation stability. Methods: patients (n = 50) with [...] Read more.

Objectives: to evaluate the efficacy of 0.7 mg dexamethasone intravitreal implant in the treatment of patients with diabetic macular edema through mean retinal sensitivity (MRS), best corrected visual acuity (BCVA), central retinal thickness (CRT) and fixation stability. Methods: patients (n = 50) with DME, best corrected visual acuity (BCVA) of 0.1 logMAR, and central retinal thickness (CRT) of ≥300 μm determined by optical coherence tomography were treated with 0.7 mg slow-release dexamethasone, and endpoints were evaluated one and three months after the injection. Results: The best corrected visual acuity, BCVA, whose mean values at baseline were 0.42 logMAR, improved significantly post dexamethasone injection, with mean values of 0.20 logMAR at one month and 0.24 logMAR at three months. The mean central retinal thickness, CRT, was 463 µm at baseline increasing to 297 µm at one month, and 315 µm at three months. Mean retinal sensitivity (MRS) was 12.31 dB at baseline. In line with other parameters, MRS also showed significant improvement at one month after slow-release dexamethasone treatment, with a mean value of 15.35 Db and the improvement was sustained at three months after injection, with a mean value of 14.71 dB. Fixation stability was assessed using the area of the third BCEA ellipse. At baseline, patients had an ellipse area of 53.68 degrees. At one month after injection, patients showed an improvement, with a mean ellipse area of 5.23 degrees, which was maintained at three months, with a mean ellipse area of 4.13 degrees. Conclusions: The dexamethasone implant of 0.7 mg met the efficacy endpoint for improvement in MRS, BCVA, CRT and fixation stability. Full article

(This article belongs to the Special Issue Drugs and Drug Delivery for Diabetes Mellitus Treatment, 2nd Edition)

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13 pages, 1860 KiB

Open AccessArticle

Targeted Elimination of Influenza Virus and Infected Cells with Near-Infrared Antiviral Photoimmunotherapy (NIR-AVPIT)

by Terumi Mizukoshi, Koichiro Tateishi, Mizuki Tokusanai, Yoshiyuki Yoshinaka, Aisaku Yamamoto, Naoki Yamamoto and Norio Yamamoto

Pharmaceutics 2025, 17(2), 173; https://doi.org/10.3390/pharmaceutics17020173 - 28 Jan 2025

Abstract

Background: Seasonal influenza causes significant morbidity and mortality each year. Since viruses can easily acquire drug-resistant mutations, it is necessary to develop new antiviral strategies with different targets. Near-infrared photoimmunotherapy (NIR-PIT) is a type of anti-cancer therapy that has recently attracted considerable [...] Read more.

Background: Seasonal influenza causes significant morbidity and mortality each year. Since viruses can easily acquire drug-resistant mutations, it is necessary to develop new antiviral strategies with different targets. Near-infrared photoimmunotherapy (NIR-PIT) is a type of anti-cancer therapy that has recently attracted considerable attention, with favorable outcomes reported for several cancers. In this study, we investigated whether this approach could be used as a novel anti-influenza therapy to destroy influenza virus and infected cells. Methods: To evaluate the efficacy of near-infrared antiviral photoimmunotherapy (NIR-AVPIT), we prepared an anti-hemagglutinin (HA) monoclonal antibody without neutralizing activity against influenza A virus (FluV) labeled with IR-700 and reacted it with FluV and infected cells, as well as HA-expressing HEK293 cells. Results: NIR-AVPIT strongly inactivated FluV virions, suppressed cytopathic effects, and achieved more than a 4-log reduction in viral RNA amplification. Treatment of FluV-infected cells with the antibody-IR700 complex and NIR in the early stages of infection significantly inhibited viral propagation, and double treatment with time apart exerted a greater inhibitory effect. NIR-AVPIT rapidly induced morphological changes in HA-expressing HEK293 cells and inhibited the proliferation of these cells. Conclusions: These results suggest that NIR-AVPIT targeting HA antigens could inactivate FluV and eliminate infected cells in vitro. This strategy is a promising approach to treat various viral infections, including influenza. Full article

(This article belongs to the Special Issue Antiviral and Antibacterial: Focus on Novel Therapeutic Agents and Drug Delivery Systems)

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25 pages, 6701 KiB

Open AccessArticle

Therapeutic Effects of Nanocoating of Apitoxin (Bee Venom) and Polyvinyl Alcohol Supplemented with Zinc Oxide Nanoparticles

by Husam Qanash, Abdulrahman S. Bazaid, Shahad F. Alharbi, Naif K. Binsaleh, Heba Barnawi, Bandar Alharbi, Ahmed Alsolami and Majed N. Almashjary

Pharmaceutics 2025, 17(2), 172; https://doi.org/10.3390/pharmaceutics17020172 - 28 Jan 2025

Abstract

Background/Objectives: Bee venom (BV), as a natural product, is one of the foundations of the pharmaceutical industry, through which many diseases, including serious ones, can be effectively treated. The BV nanofilm is an effective antidote delivered into the human body to target the [...] Read more.

Background/Objectives: Bee venom (BV), as a natural product, is one of the foundations of the pharmaceutical industry, through which many diseases, including serious ones, can be effectively treated. The BV nanofilm is an effective antidote delivered into the human body to target the affected area and address the issue without major side effects. In this study, we investigated the intriguing therapeutic effects of apitoxin (bee venom) used in isolation, combined with the powerful properties of zinc oxide nanoparticles. Methods and Results: BV nanofilm was evaluated using Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD). The BV extract was analyzed using mass spectrometry (MS), which identified 84 active components present at varying concentrations. BV was treated with both polyvinyl alcohol (PVA) and zinc oxide nanoparticles (ZNPs) to increase the intensity of OH and CH₂ groups and to enhance the dispersion of C=O. BV has demonstrated anti-type 2 diabetes activity by inhibiting α-amylase and α-glucosidase, which are starch-degrading enzymes. The nanofilm is an active mixture of BV, PVA, and ZNPs, which exhibited the highest antidiabetic activity with IC₅₀ values of 30.33 μg/mL and 5.55 μg/mL for the inhibition of α-amylase and α-glucosidase, compared to IC₅₀ of 51.69 µg/mL and IC₅₀ of 7.30 µg/mL for BV, respectively. The nanofilm also showed higher anti-inflammatory activity by inhibiting red blood cell (RBC) hemolysis, with an IC₅₀ of 16.99 μg/mL in comparison to IC₅₀ of 72.99 µg/mL for BV alone. The nanofilm demonstrated broad-spectrum antimicrobial activity, effectively targeting both Gram-positive (Staphylococcus aureus ATCC 6538 and Bacillus subtilis ATCC 6633) and Gram-negative bacteria (Salmonella typhi ATCC 6539, Escherichia coli ATCC 8739). Furthermore, increased antioxidant activity was recorded by inhibiting the 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging effect with an IC₅₀ of 4.26 μg/mL and 19.43 μg/mL for nanofilm and BV, respectively. BV was found to be more toxic to liver tissue (HepG2 cell line) than nanofilm, with IC₅₀ values of 18.5 ± 0.08 μg/mL and 52.27 ± 0.7 μg/mL, respectively. The BV extract displayed higher toxicity to liver tissue (2.3%) with 97.7% viability at 250 μg/mL, compared to nanofilm, which showed 0.09% toxicity and 99.9% viability at the same concentration. Conclusions: the BV nanofilm emerges as a promising alternative medicine, offering an innovative solution for treating various diseases through its high concentration of therapeutically active compounds and effortless targeting delivery. Full article

(This article belongs to the Special Issue Plant Extracts and Their Biomedical Applications)

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13 pages, 1410 KiB

Open AccessArticle

Anti-Inflammatory and Pain-Relieving Effects of Arnica Extract Hydrogel Patch in Carrageenan-Induced Inflammation and Hot Plate Pain Models

by Sang Gil Lee, Eun Byul Lee, Tack Soo Nam, Sunho You, Dahye Im, Kyusun Kim, Bonseung Gu, Ga-young Nam, Hyerim Lee, Soon Jae Kwon, Yun Seok Kim and Sang Geon Kim

Pharmaceutics 2025, 17(2), 171; https://doi.org/10.3390/pharmaceutics17020171 - 28 Jan 2025

Abstract

Arnica montana (AM), which belongs to the daisy family Asteraceae, has a longstanding traditional use in Europe and North America for pain and inflammation treatment. This study investigates the inhibitory effects of ‘Arnica montana extract hydrogel patch (AHP)’ on Carrageenan-induced paw edema [...] Read more.

Arnica montana (AM), which belongs to the daisy family Asteraceae, has a longstanding traditional use in Europe and North America for pain and inflammation treatment. This study investigates the inhibitory effects of ‘Arnica montana extract hydrogel patch (AHP)’ on Carrageenan-induced paw edema and hot plate-induced pain models. AHP exhibited transdermal permeability without the occurrence of issues like crystal precipitation. This study employed two animal model assessments using AHP, in comparison with Arnicare Gel (AG), to evaluate anti-inflammatory and pain relief effects. AHP treatment for 2 days showed a decrease in paw edema thickness in mice as compared to vehicle or AG groups; Carrageenan-induced swelling increased maximally at 1 h with the AHP group demonstrating a higher reduction. Thus, the AHP group exhibited a lower ratio of right/left paw thickness and a superior reduction in swelling, supportive of its ability to diminish edema. A histological analysis showed that AHP treatment reduced inflammatory cell infiltration. Consistently, the mRNA levels of inflammatory markers (tnfa, il1b, and il6) were decreased to a greater extent than the AG group. Particularly, tnfa inhibition was better in the AHP group, and the levels of il1b and il6 transcripts showed ~80% and 40% lower. Likewise, AHP reduced pain scores in a hot plate-induced rat model, although AG failed to do so. Together, these results demonstrate that AHP has long-lasting inhibitory effects on fluid effusion and edema formation, the production of inflammatory mediators, and pain-sensation, supporting its anti-inflammatory and pain-relieving pharmacological effects. Full article

(This article belongs to the Special Issue Transdermal Delivery of Low-Molecular-Weight Drugs and New Modality of Drugs: Recent Innovation to Penetration Enhancement Techniques)

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23 pages, 1248 KiB

Open AccessArticle

Formulation and Evaluation of Polymeric Spherical Agglomerates-Based Porous Orodispersible Tablets of Cilnidipine

by Yahya Alhamhoom, Sanjana S. Prakash, Avichal Kumar, Shivakumar Hagalavadi Nanjappa, Mohamed Rahamathulla, Megha S. Kamath, Syeda Ayesha Farhana, Mohammed Muqtader Ahmed and Thippeswamy Boreddy-Shivanandappa

Pharmaceutics 2025, 17(2), 170; https://doi.org/10.3390/pharmaceutics17020170 - 28 Jan 2025

Abstract

Background/Objectives: Cilnidipine (CIL) is a calcium channel blocker that exhibits low bioavailability (~13%) due to poor aqueous solubility and extensive pre-systemic gut wall metabolism. The current study aimed to enhance the oral bioavailability of CIL by formulation of polymeric spherical agglomerates (CILSAs)-based orodispersible [...] Read more.

Background/Objectives: Cilnidipine (CIL) is a calcium channel blocker that exhibits low bioavailability (~13%) due to poor aqueous solubility and extensive pre-systemic gut wall metabolism. The current study aimed to enhance the oral bioavailability of CIL by formulation of polymeric spherical agglomerates (CILSAs)-based orodispersible tablets (ODTs). Methods: Eight different batches of CILSAs were prepared by a crystallo-co-agglomeration technique using different proportions of hydrophilic polymers like hydroxy propyl methyl cellulose E50, polyvinyl pyrrolidone K30, or polyethylene glycol (PEG) 6000 as carriers. Fourier transform infrared spectroscopy (FTIR) of CILSAs proved the chemical integrity of CIL in SAs, while scanning electron microscopy revealed the spherical shape of CILSAs. Results: Differential scanning calorimetry and powder X-ray diffraction studies confirmed that CIL was rendered more amorphous in CILSAs. CILSAs displayed good flow behavior, high percentage yield, and high drug loads. The batch F4 composed of PEG 6000 emerged as the optimized batch as it displayed high percentage dissolution efficiency (57.01 ± 0.01%), which was significantly greater (p < 0.001) compared to CIL (26.27 ± 0.06%). The optimized formulation of CILSAs was directly compressed into ODTs that were rendered porous by vacuum drying. The optimized formulation of porous ODTs (T3) displayed low friability (0.28 ± 0.03%), short disintegration time (6.26 ± 0.29 s), and quicker dissolution (94.16 ± 1.41% in 60 min) as compared to marketed tablet Cildipin^®10 mg (85 ± 2.3%). Conclusions: Thus, porous ODTs of CILSAs can rapidly release the drug, bypass gut metabolism, enhance oral bioavailability, and improve CIL's therapeutic effectiveness for angina and hypertension. Full article

(This article belongs to the Special Issue Improving the Bioavailability and Solubility of Pharmaceutical Formulations)

13 pages, 4128 KiB

Open AccessArticle

Pharmacokinetic and Pharmacodynamic Study of Folic Acid-Modified Chitosan–Stearic Acid Nanomicelles Loaded with Tetrandrine for Rheumatoid Arthritis

by Shuai Ma, Fei Xue, Lan Yang, Long Chen, Pei Liu, Jinhua Chang and Ruxing Wang

Pharmaceutics 2025, 17(2), 169; https://doi.org/10.3390/pharmaceutics17020169 - 27 Jan 2025

Abstract

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease, and it is currently incurable. Tetrandrine (TET) has an obvious curative effect with therapeutic efficacy on RA, but its use is limited due to its poor water-solubility and bioavailability. Therefore, TET-loaded nanomicelles modified with [...] Read more.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease, and it is currently incurable. Tetrandrine (TET) has an obvious curative effect with therapeutic efficacy on RA, but its use is limited due to its poor water-solubility and bioavailability. Therefore, TET-loaded nanomicelles modified with chitosan, stearic acid, and folic acid (FCST) was prepared in the study, and the pharmacokinetics and pharmacodynamics were studied. Methods: The plasma concentrations of FCST and TET were measured by the PLC-MS/MS method at different times, and the pharmacokinetic parameters were calculated. A collagen-induced arthritis (CIA) model was established with rats. On the 16th day after the first immunization, 50 rats were randomized into five groups with 10 rats in each group according to the arthritis score. The drugs were administered by intraperitoneal injection for 30 days. The swelling degree and joint score of the rats were tested during each administration. In addition, the pro-inflammatory factors IL-1β, IL-6, IL-17, and TNF-α in the serum of the rats were tested by an ELISA kit, and their joints were examined by histopathology. Results: Pharmacokinetic studies showed that the AUC_0–72h of FCST was 1.93 times that of TET. FCST demonstrated higher bioavailability compared to TET (p < 0.05). Pharmacodynamic studies demonstrated that FCST had significant anti-inflammatory effects, and its anti-inflammatory activity was stronger compared to the same dose of TET, as evidenced by measuring toe thickness and observing toe appearance. It significantly reduced the expression of IL-1, IL-6, IL-17, and TNF-α in rats with rheumatoid arthritis (p < 0.05). Conclusions: FCST can significantly improve bioavailability and has a significant therapeutic effect on rheumatoid arthritis. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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