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Pharmaceutics
Volume 17
Issue 2
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Pharmaceutics, Volume 17, Issue 2 (February 2025) – 50 articles

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18 pages, 648 KiB  
Review
AI-Driven Innovation in Skin Kinetics for Transdermal Drug Delivery: Overcoming Barriers and Enhancing Precision
by Nubul Albayati, Sesha Rajeswari Talluri, Nirali Dholaria and Bozena Michniak-Kohn
Pharmaceutics 2025, 17(2), 188; https://doi.org/10.3390/pharmaceutics17020188 - 2 Feb 2025
Viewed by 615
Abstract
Transdermal drug delivery systems (TDDS) offer an alternative to conventional oral and injectable drug administration by bypassing the gastrointestinal tract and liver metabolism, improving bioavailability, and minimizing systemic side effects. However, widespread adoption of TDDS is limited by challenges such as the skin’s [...] Read more.
Transdermal drug delivery systems (TDDS) offer an alternative to conventional oral and injectable drug administration by bypassing the gastrointestinal tract and liver metabolism, improving bioavailability, and minimizing systemic side effects. However, widespread adoption of TDDS is limited by challenges such as the skin’s permeability barrier, particularly the stratum corneum, and the need for optimized formulations. Factors like skin type, hydration levels, and age further complicate the development of universally effective solutions. Advances in artificial intelligence (AI) address these challenges through predictive modeling and personalized medicine approaches. Machine learning models trained on extensive molecular datasets predict skin permeability and accelerate the selection of suitable drug candidates. AI-driven algorithms optimize formulations, including penetration enhancers and advanced delivery technologies like microneedles and liposomes, while ensuring safety and efficacy. Personalized TDDS design tailors drug delivery to individual patient profiles, enhancing therapeutic precision. Innovative systems, such as sensor-integrated patches, dynamically adjust drug release based on real-time feedback, ensuring optimal outcomes. AI also streamlines the pharmaceutical process, from disease diagnosis to the prediction of drug distribution in skin layers, enabling efficient formulation development. This review highlights AI’s transformative role in TDDS, including applications of models such as Deep Neural Networks (DNN), Artificial Neural Networks (ANN), BioSIM, COMSOL, K-Nearest Neighbors (KNN), and Set Covering Machine (SVM). These technologies revolutionize TDDS for both skin and non-skin diseases, demonstrating AI’s potential to overcome existing barriers and improve patient care through innovative drug delivery solutions. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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13 pages, 1180 KiB  
Article
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
Viewed by 333
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  
Article
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
Viewed by 280
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  
Review
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
Viewed by 221
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  
Article
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
Viewed by 216
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  
Article
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
Viewed by 540
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  
Article
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
Viewed by 241
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  
Article
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
Viewed by 241
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  
Article
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
Viewed by 267
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  
Article
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
Viewed by 328
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  
Review
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
Viewed by 419
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  
Article
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
Viewed by 268
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  
Review
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
Viewed by 431
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  
Article
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
Viewed by 354
Abstract
Background: It is generally accepted that water as a plasticizer can decrease the glass transition temperatures (Tgs) 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 (Tgs) 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  
Review
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
Viewed by 425
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  
Article
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
Viewed by 599
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  
Article
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
Viewed by 879
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  
Article
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
Viewed by 411
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  
Article
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
Viewed by 464
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  
Article
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
Viewed by 540
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 AUC0–72h 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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25 pages, 5837 KiB  
Article
Emulgel Containing Metronidazole and Clindamycin for the Treatment of Rosacea
by Guillermo De Grau-Bassal, Ana Cristina Calpena-Campmany, Marcelle Silva-Abreu, Joaquim Suñer-Carbó, Mireia Mallandrich-Miret, Sergio Martínez-Ruiz, Cecilia Cordero, Alfonso Del Pozo and Núria Bozal-de Febrer
Pharmaceutics 2025, 17(2), 168; https://doi.org/10.3390/pharmaceutics17020168 - 27 Jan 2025
Viewed by 504
Abstract
Rosacea is a common skin condition with quite a relevance. It currently affects at least 10% of the European population at some point after the age of 30. It is a chronic disorder that mainly affects the skin on the face and is [...] Read more.
Rosacea is a common skin condition with quite a relevance. It currently affects at least 10% of the European population at some point after the age of 30. It is a chronic disorder that mainly affects the skin on the face and is characterized by outbreaks and remissions. Under normal circumstances, the skin face presents a wide range of commensal organisms, such as Staphylococcus epidermidis or Demodex folliculorum, but dysbiosis of the skin flora plays a relevant role in inflammatory processes and the development of the disease. Metronidazole (MD) is one of the main treatments indicated to reduce redness on the cheeks, nose, chin, or forehead and also to treat flushing, erythema, pimples, and other symptoms due in part to its anti-inflammatory action. On the other hand, clindamycin (CM) is another antibiotic used for rosacea, especially for its action against anaerobic and Gram-positive bacteria. Background/Objectives: This study aimed to develop an emulgel formulation that includes MD and CM, using excipients with non-comedogenic and non-irritating properties. Methods: The formulation was characterised physiochemically, rheological measurements were made, and short-term stability studies were carried out. In vitro release, permeation studies, toxicity an in vitro inflammation model were evaluated in a HaCaT cell model. To determine the interaction between the antibiotics, the minimum inhibitory concentration was determined separately and together using the broth microdilution method. To determine the formulation’s antimicrobial activity, an agar diffusion method was used. Results: The MD-CM-gel droplet size was measured by laser diffraction and the diameter obtained was less than 2.68 ± 0.18 µm in 50% of the particles. Suitable results was observed for the short-term stability. Release and permeation data revealed sustained drug release and adequate permeation through human skin. Non-toxicity was detected and the MD showed an anti-inflammatory effect with non-interference of CM. Also, there is no antagonism between the two antibiotics and the MD-CM-gel shows better results when compared to the formulations with the antibiotics separately and to commercial formulations. Conclusions: It is suggested that, following detailed preclinical and clinical studies, MD-CM-gel could be considered as an alternative for treating rosacea. Full article
(This article belongs to the Special Issue Drug Formulation Design and Pharmacokinetics for the Treatment of Skin Diseases)
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29 pages, 5553 KiB  
Article
Production of Prophylactic Nanoformulation for Dental Caries and Investigation of Its Effectiveness by In Vitro and In Silico Methods
by Yasemin Budama-Kilinc, Ozan Baris Kurtur, Bahar Gok, Serda Kecel-Gunduz, Sengul Alpay-Karaoglu, Pınar Yılmaz Atalı and Murat Kartal
Pharmaceutics 2025, 17(2), 167; https://doi.org/10.3390/pharmaceutics17020167 - 27 Jan 2025
Viewed by 518
Abstract
Background/Objectives: This study aimed to develop cinnamon bark essential oil (CEO), orange peel essential oil(OEO) and the combination of these two essential oils (OEO-CEO) loaded PLGA nanoparticles to prevent dental caries and to investigate their effectiveness in silico and in vitro methods. Methods: [...] Read more.
Background/Objectives: This study aimed to develop cinnamon bark essential oil (CEO), orange peel essential oil(OEO) and the combination of these two essential oils (OEO-CEO) loaded PLGA nanoparticles to prevent dental caries and to investigate their effectiveness in silico and in vitro methods. Methods: EO loaded PLGA nanoparticles were produced by single emulsion method. Detailed characterization studies were performed using different methods, and the controlled release profile was obtained. The antibacterial activity of the developed formulations was investigated on S. mutans and L. casei strains by in vitro and in silico methods. Additionally, the interaction mechanisms of EOs with DNA were evaluated. Results: Our findings showed that the average droplet size of EO-loaded PLGA nanoparticles varied between 243.1 ± 0.60 nm and 219 ± 4.49 nm, while PdI values varied between 0.069 ± 0.039 and 0.032 ± 0.01. In addition, the developed nanoparticles had high encapsulation efficiency (85.14% to 66.28%) and released the active ingredient in a continuous and controlled manner. Ames test showed that the genotoxicity of EOs was eliminated due to the encapsulation of EOs in PLGA nanoparticles and antibacterial tests showed that OEO-CEO-loaded PLGA nanoparticles were effective on L. casei and S. mutans. The antibacterial activity of EOs was also supported by in silico studies. Finally, it was revealed that EOs showed potential as antibacterial agents by interacting with DNA. Conclusions: The results showed that OEO-CEO-loaded PLGA nanoparticles have the potential to be a suitable nanoformulation for developing mouthwash or toothpaste for the prevention and treatment of dental caries. Full article
(This article belongs to the Special Issue Polymeric Nanoparticles for Pharmaceutical Applications)
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12 pages, 3701 KiB  
Article
IR813-Induced Photothermal Therapy: Leveraging Immunogenic Cell Death for Cancer Treatment
by Guangwei Jiang, Rong Huang, Min Qian, Wenjuan Hu and Rongqin Huang
Pharmaceutics 2025, 17(2), 166; https://doi.org/10.3390/pharmaceutics17020166 - 26 Jan 2025
Viewed by 335
Abstract
Background: Photothermal therapy has the potential to enhance the precision and safety of oncological treatments. However, applicable photothermal agents associated with its photothermal activated immunogenic cell death remain exploiting. Methods: This study evaluates the effectiveness of IR813, a photothermal agent, combined [...] Read more.
Background: Photothermal therapy has the potential to enhance the precision and safety of oncological treatments. However, applicable photothermal agents associated with its photothermal activated immunogenic cell death remain exploiting. Methods: This study evaluates the effectiveness of IR813, a photothermal agent, combined with near-infrared (NIR) light for cancer treatment. In vitro, 4T1 cancer cells were treated with IR813 (5 μg/mL) and exposed to NIR irradiation (1 W/cm2) for 5 min. In vivo, after the tumor-bearing mice administered with IR813 (1 mg/kg) and exposed to NIR irradiation (1 W/cm2) for 10 min, the tumor volume, survival and immune activation were evaluated. Results: IR813 significantly increased the cytotoxicity of 4T1 cancer cells following near-infrared irradiation, resulting in the release of damage-associated molecular patterns and immunogenic cell death. Specifically, the cell viability was reduced to 5% compared to the control group. In vivo, irradiating the accumulation of IR813 at the tumor site had the potential to mediate substantial photothermal tumor suppression, improved mouse survival, and reduced metastasis, with minimal adverse reactions. Furthermore, the immune responses stimulated by IR813-induced photothermal therapy were evidenced by increased mature dendritic cell and cytotoxic T lymphocyte counts and a decrease in regulatory T cells in the spleen, tumor, and lymph nodes. Conclusions: These findings suggest that IR813-induced photothermal therapy is a promising approach for enhancing immunotherapy, directly inhibiting tumors while boosting systemic anti-cancer immunity. Full article
(This article belongs to the Section Gene and Cell Therapy)
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27 pages, 5607 KiB  
Article
Experimental Investigation into the Design, Optimization, Toxicity, and Anti-Viral Efficacy of Proliposomes Loaded with Ivermectin Against Infectious Bronchitis Virus Using an Embryonated Chicken Egg Model
by Mohammad H. Alyami, Hamad S. Alyami, Asmaa M. Abdo, Shereen A. Sabry, Shimaa M. G. Mansour, Hanan M. El-Nahas and Margrit M. Ayoub
Pharmaceutics 2025, 17(2), 165; https://doi.org/10.3390/pharmaceutics17020165 - 25 Jan 2025
Viewed by 631
Abstract
Background: Infectious bronchitis virus (IBV) causes a significant illness in birds, making it a leading source of financial loss in the poultry business. The objective of this study was to assess the effectiveness of proliposomes (PLs) containing ivermectin (IVM) against IBV using [...] Read more.
Background: Infectious bronchitis virus (IBV) causes a significant illness in birds, making it a leading source of financial loss in the poultry business. The objective of this study was to assess the effectiveness of proliposomes (PLs) containing ivermectin (IVM) against IBV using embryonated chicken eggs (ECEs). Methods: A three-factor, two-level (23) full factorial design was employed; carrier/lipid phase ratio (A), stearyl glycyrrhetinate amount (B), and phospholipid type (C) were studied as independent variables, while product yield (PY), entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and cumulative percentage of drug released after 6 h (Q6h) were characterized. The selected formulations (PL2 and PL6) were subjected to further characterizations, including IVM toxicity and anti-viral activity. Results: The PY% ranged from 88.6 ± 2.19% to 98.8 ± 0.45%, EE% was from 71.8 ± 2.01% to 96.1 ± 0.51%, PS was from 330.1 ± 55.65 nm to 1801.6 ± 45.61 nm, PDI was from 0.205 ± 0.06 to 0.603 ± 0.03, ZP was from −18.2 ± 0.60 mV to −50.1 ± 1.80 mV, and Q6h was from 80.95 ± 1.36% to 88.79 ± 2.03%. IVM-loaded PLs had lower toxicity in ECEs than pure IVM; the mortality rate was substantially reduced in IBV-infected ECEs injected with PL2 rather than pure IVM. As further evidence of IVM’s anti-viral action against IBV, quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the PL2-treated group exhibited further reduction in IBV’s copies in comparison with the pure IVM-treated group. Conclusions: PLs loaded with IVM are an innovative and potentially effective way to inhibit IBV. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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16 pages, 1092 KiB  
Article
Development, Characterization, and Evaluation of Chi-Tn mAb-Functionalized DOTAP-PLGA Hybrid Nanoparticles Loaded with Docetaxel for Lung Cancer Therapy
by Analía Castro, Álvaro Pittini, Nora Berois, Ricardo Faccio, Pablo Miranda, Álvaro W. Mombrú, Eduardo Osinaga and Helena Pardo
Pharmaceutics 2025, 17(2), 164; https://doi.org/10.3390/pharmaceutics17020164 - 25 Jan 2025
Viewed by 454
Abstract
Background/Objectives: The focus of this study was to prepare and characterize docetaxel (DCX)-loaded lipid/polymer hybrid nanoparticles (LPHNps) functionalized with the monoclonal antibody (mAb) Chi-Tn for a potential active targeting approach in lung cancer treatment. Methods: We synthesized DOTAP-PLGA hybrid nanoparticles loaded with DCX [...] Read more.
Background/Objectives: The focus of this study was to prepare and characterize docetaxel (DCX)-loaded lipid/polymer hybrid nanoparticles (LPHNps) functionalized with the monoclonal antibody (mAb) Chi-Tn for a potential active targeting approach in lung cancer treatment. Methods: We synthesized DOTAP-PLGA hybrid nanoparticles loaded with DCX and functionalized them with Chi-Tn mAb through a biotin–avidin approach. The physicochemical characterization involved dynamic light scattering, transmission electron microscopy, Raman spectroscopy, and atomic force microscopy. The in vitro and in vivo evaluations encompassed uptake studies, cell viability tests, and the assessment of tumor growth control in a lung cancer model. Results: The nanoparticles featured a hydrophobic PLGA core with 99.9% DCX encapsulation efficiency, surrounded by a DOTAP lipid shell ensuring colloidal stability with a high positive surface charge. The incorporation of PEGylated lipids on their surface helps evade the immune system and facilitate Chi-Tn mAb attachment. The resulting nanoparticles exhibit a spherical shape with monodisperse particle sizes averaging 250 nm, and demonstrate sustained drug release. In vitro uptake studies and viability assays conducted in A549 cancer cells show that the Chi-Tn mAb enhances nanoparticle internalization and significantly reduces cell viability. In vivo studies demonstrate a notable reduction in tumor volume and an increased survival rate in the A549 tumor xenograft mice model when DCX was encapsulated in nanoparticles and targeted with Chi-Tn mAb in comparison to the free drug. Conclusions: Therefore, Chi-Tn-functionalized LPHNps hold promise as carriers for actively targeting DCX to Tn-expressing carcinomas. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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33 pages, 3922 KiB  
Article
Flavonoids as Potential Modulators of Pancreatic Lipase Catalytic Activity
by Sílvia Rocha, Carina Proença, Alberto N. Araújo, Marisa Freitas, Ismael Rufino, Natália Aniceto, Artur M. S. Silva, Félix Carvalho, Rita C. Guedes and Eduarda Fernandes
Pharmaceutics 2025, 17(2), 163; https://doi.org/10.3390/pharmaceutics17020163 - 25 Jan 2025
Viewed by 410
Abstract
Background/Objectives: Obesity has reached pandemic proportions, with predictions suggesting that, by 2030, over 1.5 billion people will be affected. Pancreatic lipase (PL), the enzyme primarily responsible for the absorption of dietary lipids, presents a potential target for obesity management. However, while porcine pancreatic [...] Read more.
Background/Objectives: Obesity has reached pandemic proportions, with predictions suggesting that, by 2030, over 1.5 billion people will be affected. Pancreatic lipase (PL), the enzyme primarily responsible for the absorption of dietary lipids, presents a potential target for obesity management. However, while porcine pancreatic lipase (PPL) is commonly used as the enzyme source for screening potential inhibitors, its effect on human pancreatic lipase (HPL) is rarely reported. This work aimed to screen the inhibitory effects of a library of flavonoids with different functional groups on the activity of PL from the human pancreas (triacylglycerol acyl hydrolase, EC 3.1.1.3) and compare it to the effects of the porcine pancreas (type II, EC 3.1.1.3), establishing, whenever possible, a structure–activity relationship. Methods: The inhibitory effects of a library of 48 flavonoids with different hydroxy, glycosyl, rutinosyl, galloyl, and extended alkyl groups were evaluated against PPL and HPL. The kinetic parameters and inhibitory mechanisms of the most active flavonoids were determined, and in silico docking studies of the more potent flavonoids were also performed, using the active site of HPL. Results/Conclusions: Variations in enzyme catalytic activity were observed depending on the source of the enzyme. The inhibitory effect was particularly influenced by the presence of extended alkyl groups at the C-3 of the C-ring and the C2=C3 double bond of the C-ring and the presence of a pyrogallol group at the C-2′, C-3′ and C-4′ of the B-ring. Docking results showed a strong correlation between docking scores and observed inhibitory activities, highlighting the critical role of specific substituents on the flavonoid backbone in enhancing detailed interaction dynamics with key amino acids. Compounds 28, 29, and 30, with alkyl groups, showed the highest docking scores, interacting with residues HIS151, PHE215, ARG256, and HIS263. Further analysis also revealed that specific substituents improved pocket occupancy and formed additional interactions with residues TYR114, PRO180, ILE209, and PHE215, which are crucial for inhibition. These binding characteristics closely mimic those observed with orlistat, reinforcing their mechanistic similarities in inhibiting HPL and validating their inhibitory activities. Full article
(This article belongs to the Section Drug Targeting and Design)
24 pages, 8551 KiB  
Article
Bioactive Hydrogel Supplemented with Stromal Cell-Derived Extracellular Vesicles Enhance Wound Healing
by Matteo Galbiati, Fabio Maiullari, Maria Grazia Ceraolo, Salma Bousselmi, Nicole Fratini, Klajdi Gega, Sandro Recchia, Anna Maria Ferretti, Giovanni Scala, Marco Costantini, Tommaso Sciarra, Roberto Rizzi and Claudia Bearzi
Pharmaceutics 2025, 17(2), 162; https://doi.org/10.3390/pharmaceutics17020162 - 25 Jan 2025
Viewed by 462
Abstract
Background/Objectives: Skin regeneration is a rapidly advancing field with significant implications for regenerative medicine, particularly in treating wounds and burns. This study explores the potential of hydrogels functionalized with fibroblast-derived extracellular vesicles (EVs) to enhance skin regeneration in vivo. Being immunoprivileged, EVs minimize [...] Read more.
Background/Objectives: Skin regeneration is a rapidly advancing field with significant implications for regenerative medicine, particularly in treating wounds and burns. This study explores the potential of hydrogels functionalized with fibroblast-derived extracellular vesicles (EVs) to enhance skin regeneration in vivo. Being immunoprivileged, EVs minimize immune rejection, offering an attractive alternative to whole-cell therapies by replicating fibroblasts’ key roles in tissue repair. Methods: To promote EVs’ versatility and effective application across different conditions, a lyophilization method with lyoprotectants was optimized. Then, EVs were used to functionalize a hydrogel to perform experiments on murine cutaneous wound models. Results: Gelatin methacrylate (GelMA) was selected as the polymeric hydrogel due to its biocompatibility, tunable mechanical properties, and ability to support wound healing. Mechanical tests confirmed GelMA’s strength and elasticity for this application. Fibroblast-derived EVs were characterized using Western blot, Transmission Electron Microscopy, and NanoSight analysis, proving their integrity, size distribution, and stability. miRNome profiling identified enriched biological pathways related to cell migration, differentiation, and angiogenesis, emphasizing the critical role of EV cargo in promoting wound repair. In a murine model, hydrogels loaded with fibroblast-derived EVs significantly accelerated wound healing compared to controls (mean wound area 0.62 mm2 and 4.4 mm2, respectively), with faster closure, enhanced epithelialization, increased vascularization, and reduced fibrosis. Notably, the lyoprotectants successfully preserved the EVs’ structure and bioactivity during freeze-drying, reducing EVs loss by 35% compared to the control group and underscoring the feasibility of this approach for long-term storage and clinical application. Conclusions: This study introduces a novel scalable and adaptable strategy for regenerative medicine by combining fibroblast-derived EVs with GelMA, optimizing EVs’ stability and functionality for enhanced wound healing in clinical settings, even in challenging contexts such as combat zones or large-scale natural disasters. Full article
(This article belongs to the Special Issue Engineering and Characterisation of Novel Nanomedicine Formulations, 2nd Edition)
12 pages, 1489 KiB  
Article
Acid-Neutralizing Omeprazole Formulation for Rapid Release and Absorption
by Sreela Ramesh, Vít Zvoníček, Daniel Pěček, Markéta Pišlová, Josef Beránek, Jiří Hofmann and Aleksandra Dumicic
Pharmaceutics 2025, 17(2), 161; https://doi.org/10.3390/pharmaceutics17020161 - 25 Jan 2025
Viewed by 372
Abstract
Background/Objectives: Omeprazole undergoes degradation in acidic conditions, which makes it unstable in low pHs found in the gastric environment. The vast majority of already marketed omeprazole formulations use enteric polymer coatings to protect the drug from exposure to acidic pH in the [...] Read more.
Background/Objectives: Omeprazole undergoes degradation in acidic conditions, which makes it unstable in low pHs found in the gastric environment. The vast majority of already marketed omeprazole formulations use enteric polymer coatings to protect the drug from exposure to acidic pH in the stomach, allowing for drug release in the small intestine where the pH is higher. This study aimed to explore the technical aspects of using stomach acid neutralizers as an alternative to polymeric coatings for omeprazole. Methods: After evaluating various neutralizers, magnesium oxide and sodium bicarbonate were chosen to be incorporated into capsules containing omeprazole, which then underwent in vitro dissolution testing to assess their ability to maintain optimal pH levels and ensure appropriate dissolution kinetics. Hygroscopicity and chemical stability of the selected formulation were tested to prove pharmaceutical quality of the product. An in vivo pharmacokinetic study was conducted to demonstrate the efficacy of the omeprazole–sodium bicarbonate formulation in providing faster absorption in humans. Results: Sodium bicarbonate was selected as the most suitable antacid for ensuring omeprazole stabilization. Its quantity was optimized to effectively neutralize stomach acid, facilitating the rapid release and absorption of omeprazole. In vitro studies demonstrated the ability of the formulation to neutralize gastric acid within five minutes. In vivo studies indicated that maximum concentrations of omeprazole were achieved within half an hour. The product met the requirements of pharmaceutical quality. Conclusions: An easily manufacturable, fast-absorbing oral formulation was developed as an alternative to enteric-coated omeprazole. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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17 pages, 2130 KiB  
Article
Accelerated Predictive Stability Testing: Accelerating Registration Phase and Application of Reduced Designs for Shelf-Life Determination of Parenteral Drug Product
by Lara Pavčnik, Mateja Prunk, Tina Trdan Lušin and Robert Roškar
Pharmaceutics 2025, 17(2), 160; https://doi.org/10.3390/pharmaceutics17020160 - 25 Jan 2025
Viewed by 385
Abstract
Objectives: This article explores the applicability of the accelerated stability assessment program (ASAP) in stability studies for parenteral medications. Conventional stability testing requires extensive evaluation over the entire shelf life of a product, which can be very time-consuming. In contrast, ASAP provides an [...] Read more.
Objectives: This article explores the applicability of the accelerated stability assessment program (ASAP) in stability studies for parenteral medications. Conventional stability testing requires extensive evaluation over the entire shelf life of a product, which can be very time-consuming. In contrast, ASAP provides an efficient approach to support drug product development and expedite regulatory procedures. Methods: The study involved subjecting the medication to different stress and long-term stability conditions and monitoring the formation of degradation products. A systematic methodology was employed to evaluate the stress stability data of the parenteral medication using various designs (full and reduced). ASAP models were then developed from these data and assessed using the statistical parameters R2 (coefficient of determination) and Q2 (predictive relevance). To validate the accuracy of the models, the predicted levels of degradation products from each of the 13 models were compared with the actual long-term stability results using the relative difference parameter. Results: The results confirmed the suitability of the evaluated full model and 11 reduced models for predicting degradation products, except for the two-temperature model, demonstrating the effectiveness of ASAP in stability studies and providing reliable predictions. However, the three-temperature model was identified as the most appropriate model for the parenteral medication under investigation. The statistical analyses showed high R2 and Q2 values, indicating robust model performance and predictive accuracy. Consequently, we applied the selected model on various formulations, demonstrating the suitability of the model and impurity levels below the ICH specification limit. Conclusions: This research enhances understanding of how ASAP designs can be applied to stability studies for parenteral medications and demonstrates the significance of the application of ASAP during drug product development to expedite the initiation of procedures and implement post-approval variations. Full article
(This article belongs to the Special Issue Stability of Medicines and Novel Approaches for Predicting Drug Stability)
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20 pages, 1183 KiB  
Article
Improving the Working Models for Drug–Drug Interactions: Impact on Preclinical and Clinical Drug Development
by James Nguyen, David Joseph, Xin Chen, Beshoy Armanios, Ashish Sharma, Peter Stopfer and Fenglei Huang
Pharmaceutics 2025, 17(2), 159; https://doi.org/10.3390/pharmaceutics17020159 - 24 Jan 2025
Viewed by 502
Abstract
Background: Pharmacokinetic drug–drug interactions (DDIs) can be caused by the effect of a pharmaceutical compound on the activity of one or more subtypes of the Cytochrome P450 (CYP) family, UDP-glucuronosyltransferases (UGTs), and/or transporters. As the number of therapeutic areas with polypharmacy has [...] Read more.
Background: Pharmacokinetic drug–drug interactions (DDIs) can be caused by the effect of a pharmaceutical compound on the activity of one or more subtypes of the Cytochrome P450 (CYP) family, UDP-glucuronosyltransferases (UGTs), and/or transporters. As the number of therapeutic areas with polypharmacy has increased, interest has grown in assessing the risk of DDIs during the early phases of drug development. Various lines of research have led to improved mathematical models to predict DDIs, culminating in the Food and Drug Administration’s (FDA) guidelines on evaluating pharmacokinetic DDI risks. However, the recommended static models are highly conservative and often result in false positive predictions. The current research aims to improve the workflow for assessing CYP-mediated DDI risk using Boehringer Ingelheim (BI) proprietary compounds. Methods: The Drug–drug Interaction Risk Calculator (PharmaPendium) was used to evaluate the mechanistic static model, and predictions were correlated with human pharmacokinetic studies from Phase I clinical trials. Results: The results demonstrated that the FDA formula performed well in predicting DDIs for BI proprietary compounds. Furthermore, the integration of either human renal excretion or preclinical species total excretion data into the mechanistic static model enhanced the predictive performance for candidate drugs as victims in DDIs. Conclusions: The basic static models (BSMs) for drug interactions should be used in early drug discovery to “rule out” DDI risks because of the minimal inputs required and the low rate of false negative predictions. Mechanistic static models (MSMs) can then be implemented for compounds that require additional evaluation. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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