Pharmaceutics

27 pages, 1354 KiB

Open AccessReview

Biomedical Applications of Functionalized Composites Based on Metal–Organic Frameworks in Bone Diseases

by Chenxi Yun, Zhe Yuan, Rim El Haddaoui-Drissi, Ruitong Ni, Yunyun Xiao, Zhenhui Qi, Jie Shang and Xiao Lin

Pharmaceutics 2025, 17(6), 757; https://doi.org/10.3390/pharmaceutics17060757 (registering DOI) - 8 Jun 2025

Abstract

Every year, millions of people worldwide suffer from bone tissue damage caused by bone trauma and surgical operations, as well as diseases such as osteoporosis, osteoarthritis, osteomyelitis, and periodontitis. Bone defect repair is one of the major challenges in the field of regenerative [...] Read more.

Every year, millions of people worldwide suffer from bone tissue damage caused by bone trauma and surgical operations, as well as diseases such as osteoporosis, osteoarthritis, osteomyelitis, and periodontitis. Bone defect repair is one of the major challenges in the field of regenerative medicine. Although bone grafts are the gold standard for treating bone defects, factors such as donor sources and immune responses limit their application. Functionalized nanomaterials have become an effective means of treating bone diseases due to their good biocompatibility and osteoinductivity, anti-inflammatory, and antibacterial properties. Metal–organic frameworks (MOFs) are porous coordination polymers composed of metal ions and organic ligands, featuring unique physical properties, including a high surface area–volume ratio and porosity. In regenerative medicine, MOFs function as the functions of drug carriers, metal ion donors, nanozymes, and photosensitizers. When combined with other functional materials, they regulate cellular reactive oxygen species, macrophage phenotypic transformation, bone resorption, osteogenesis, and mineralization, providing a new paradigm for bone tissue engineering. This study reviews the classification of functionalized MOF composites in biomedicine and the application of their synthesis techniques in bone diseases. The unique in vivo and in vitro applications of MOFs in bone diseases, including osteoarthritis, osteoporosis, bone tumors, osteomyelitis, and periodontitis, are explored. Their properties include excellent drug loading and sustained release abilities, high antibacterial activity, and bone induction abilities. This review enables readers to better understand the cutting-edge progress of MOFs in bone regeneration applications, which is crucial for the design of and functional research on MOF-related nanomaterials. Full article

(This article belongs to the Special Issue Challenges and Future Trends of Nano-Based Drug Delivery System in the Treatment of Bone Diseases)

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19 pages, 2738 KiB

Open AccessArticle

Formulation and Bioequivalence Evaluation of a Miniaturized Fexofenadine Hydrochloride Tablet

by Woo-Yul Song, Chang-Soo Han, Won-Sang Yu, Jae-Won Jang, Gyoung-Won Kim, Yoo-Shin Jeon, Young-Jin Kim, So-Jeong Jeong, Ji-Hyun Kang, Dong-Wook Kim, Yun-Sang Park and Chun-Woong Park

Pharmaceutics 2025, 17(6), 756; https://doi.org/10.3390/pharmaceutics17060756 (registering DOI) - 8 Jun 2025

Abstract

Background: Fexofenadine hydrochloride (FEX) is widely used to treat allergic rhinitis. However, poor solubility, high cohesiveness, and risk of polymorphic transformation present significant formulation challenges. Conventional FEX tablet formulations are large and may pose swallowing difficulties for patients with dysphagia. Therefore, a miniaturized [...] Read more.

Background: Fexofenadine hydrochloride (FEX) is widely used to treat allergic rhinitis. However, poor solubility, high cohesiveness, and risk of polymorphic transformation present significant formulation challenges. Conventional FEX tablet formulations are large and may pose swallowing difficulties for patients with dysphagia. Therefore, a miniaturized FEX tablet that maintained bioequivalence with the marketed product was developed. Methods: An organic solvent-based binder and porous carrier enhanced solubility, flowability, and process efficiency. The formulation was optimized using a design of experiments approach to assess the effects of tablet size and porous carrier incorporation on dissolution and residual solvent content. Scale-up feasibility was evaluated using Froude number-based process optimization, and stability studies were conducted under accelerated conditions (40 °C and 75% relative humidity) to ensure long-term formulation robustness. Results: The miniaturized tablet exhibited dissolution at pH 4.0 and pH 6.8 equivalent to that of the reference product, whereas a faster dissolution rate was observed at pH 1.2. No significant changes were observed in the dissolution rate, crystalline structure, or impurity levels over six months. An in vivo bioequivalence study demonstrated that the test formulation met the bioequivalence criteria, with 90% confidence intervals for the area under the curve and the C_max falling within the regulatory acceptance range. Conclusions: A miniaturized and commercially viable fexofenadine hydrochloride tablet was developed (44% weight reduction and 50% volume reduction compared to the marketed product). The organic solvent-based binder and porous carrier system improved manufacturing efficiency, stability, and solubility, thereby ensuring compliance with regulatory standards. These findings provide valuable insights into size reduction, solubility enhancement, and large-scale production strategies for the development of future pharmaceutical formulations. Full article

(This article belongs to the Special Issue Pharmaceutical Solid Dosage Forms: Manufacturing, Design, Development, and Biomedical Applications)

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13 pages, 2021 KiB

Open AccessArticle

Nanoemulsion of Gomortega keule Essential Oil: Characterization, Chemical Composition, and Anti-Yeast Activity Against Candida spp.

by Iván Montenegro, Bastián Fuentes, Valentina Silva, Francisca Valdés, Enrique Werner, Rocío Santander, Daniel Moraga-Espinoza and Alejandro Madrid

Pharmaceutics 2025, 17(6), 755; https://doi.org/10.3390/pharmaceutics17060755 (registering DOI) - 8 Jun 2025

Abstract

Background/Objectives: Candidiasis, an opportunistic fungal infection caused by Candida species, is a major health problem, particularly in immunocompromised individuals. Increasing resistance of yeasts such as Candida spp. to pharmacological antifungal agents makes it necessary to explore alternative treatments. The aim of this study [...] Read more.

Background/Objectives: Candidiasis, an opportunistic fungal infection caused by Candida species, is a major health problem, particularly in immunocompromised individuals. Increasing resistance of yeasts such as Candida spp. to pharmacological antifungal agents makes it necessary to explore alternative treatments. The aim of this study was to evaluate the antifungal potential of Gomortega keule essential oil (GKEO) against Candida spp. by assessing growth and development at 24 and 48 h. Encapsulation and characterization of a stable nanoemulsion were carried out to enhance efficacy. Methods: The anti-yeast activity of both free GKEO and the nanoemulsion against Candida albicans, C. glabrata, and C. guilliermondii was evaluated using a microdilution method to determine the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) at 24 and 48 h. Results: GC-MS/MS analysis identified forty-one components in GKEO, the main ones being eucalyptol (21.41%), 4-terpineol (19.62%), and α-terpinyl acetate (13.89%). Antifungal assays revealed that both free and nanoemulsion-formulated GKEO inhibited the growth of all tested Candida strains. At 48 h, the nanoformulated GKEO achieved a MIC value of 32 µg/mL and an MFC of 64 µg/mL for C. albicans and C. glabrata and showed higher antifungal activity compared to the free oil, in particular against C. albicans, exhibiting a four-fold lower MFC value. The activity of the nanoformulation was comparable to or better than fluconazole against C. glabrata and C. guilliermondii. Conclusions: The GKEO nanoemulsion potentiated anti-yeast activity against Candida spp. The formulation improved the efficacy of GKEO, suggesting its potential as an alternative or adjunctive treatment for candidiasis. Full article

(This article belongs to the Special Issue Antibacterial Nanoformulations Based on Natural Products)

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42 pages, 1728 KiB

Open AccessReview

Unraveling Nature’s Pharmacy: Transforming Medicinal Plants into Modern Therapeutic Agents

by Natalia Vaou, Chrysoula (Chrysa) Voidarou, Georgios Rozos, Chrysa Saldari, Elisavet Stavropoulou, Georgia Vrioni and Athanasios Tsakris

Pharmaceutics 2025, 17(6), 754; https://doi.org/10.3390/pharmaceutics17060754 (registering DOI) - 7 Jun 2025

Abstract

Natural products (NPs) serve as a crucial source for leading bioactive compounds in drug discovery research. Numerous drugs currently utilized as therapeutic agents have been derived from natural origins, with medicinal plant (MP) sources being particularly significant. Despite the advancement of synthetic chemistry, [...] Read more.

Natural products (NPs) serve as a crucial source for leading bioactive compounds in drug discovery research. Numerous drugs currently utilized as therapeutic agents have been derived from natural origins, with medicinal plant (MP) sources being particularly significant. Despite the advancement of synthetic chemistry, the importance of NPs persists due to their distinct chemical structures and varied biological activities. Moreover, recent advancements in technology have significantly aided in overcoming challenges, primarily due to inherent complexity. This review explores the potential of NPs in the process of drug discovery and development, placing emphasis on the blend of traditional knowledge with modern drug discovery techniques. A brief history of the development of NP drug discovery and examples of significant NPs developed in recent decades are also provided. The focus is on the various methods employed in authentication, selection, extraction/isolation, and bioactivity screening through the application of modern drug-development principles for NPs. Several cutting-edge techniques, such as genetic engineering, metabolic engineering, plant cell culture and synthetic biology utilizing “omics” technologies and computational methodologies enhancing research in NP drug discovery, are also highlighted. There are several problems and inherent challenges regarding NP drug discovery that need to be overcome. Despite the challenges that exist, NPs will be crucial for the future development of new therapeutic drugs, and it is expected that continuous research and the effective utilization of new approaches will further enhance drug discovery efforts. Full article

(This article belongs to the Special Issue Natural Products for Antimicrobial and Drug Delivery: A Look into the Future)

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20 pages, 624 KiB

Open AccessReview

Current and Emerging Therapies for Eosinophilic Esophagitis (EoE): A Comprehensive Review

by Brooke G. Musburger, Maria Gonzalez Echeandia, Elias L. Suskind, David L. Suskind, Hengqi Betty Zheng and Dominique Mark

Pharmaceutics 2025, 17(6), 753; https://doi.org/10.3390/pharmaceutics17060753 (registering DOI) - 7 Jun 2025

Abstract

Eosinophilic Esophagitis (EoE) is a chronic, immune-mediated disorder that is characterized by symptoms of esophageal dysfunction and the presence of increased eosinophils in the esophageal mucosa. It is becoming increasingly prevalent among children and adults and its pathogenesis arises from the complex interaction [...] Read more.

Eosinophilic Esophagitis (EoE) is a chronic, immune-mediated disorder that is characterized by symptoms of esophageal dysfunction and the presence of increased eosinophils in the esophageal mucosa. It is becoming increasingly prevalent among children and adults and its pathogenesis arises from the complex interaction of genetic predisposition and environmental triggers, both which contribute to esophageal inflammation. Current societal guidelines recommend the use of proton pump inhibitors, topical steroids, and dietary interventions such as elimination diets as first-line treatments, however, the recent approval of Dupliumab has provided an additional therapeutic avenue. There are a number of investigational biologic agents targeting other immune pathways which are making their way through the pipeline of pharmacologic options in treating this chronic disorder. Full article

(This article belongs to the Special Issue Therapeutic Drugs and Delivery Strategies for Gastrointestinal Diseases)

21 pages, 1593 KiB

Open AccessReview

Cyclodextrins as Modulators of Gut Microbiota: Pharmaceutical Applications and Impact on Intestinal Health

by Renata Maria Varut, Mircea Sorin Ciolofan, Maria Elena Veronica, Kristina Radivojević, Diana Maria Trasca, Cristina Popescu, Oana Diaconu and Cristina Elena Singer

Pharmaceutics 2025, 17(6), 752; https://doi.org/10.3390/pharmaceutics17060752 (registering DOI) - 7 Jun 2025

Abstract

Background/Objectives: Cyclodextrins (CDs) have garnered increasing attention in pharmaceutical research due to their ability to enhance drug solubility, bioavailability, and therapeutic efficacy. Meanwhile, the gut microbiota, a key regulator of human health, has emerged as an important target in evaluating the safety and [...] Read more.

Background/Objectives: Cyclodextrins (CDs) have garnered increasing attention in pharmaceutical research due to their ability to enhance drug solubility, bioavailability, and therapeutic efficacy. Meanwhile, the gut microbiota, a key regulator of human health, has emerged as an important target in evaluating the safety and broader implications of pharmaceutical excipients. This review aims to synthesize current knowledge regarding the effects of CDs on the composition and function of the gut microbiota. Methods: A literature search following PRISMA guidelines was conducted in PubMed, ScienceDirect, and Google Scholar to identify studies on cyclodextrins and their interactions with gut microbiota. Results: Cyclodextrins, particularly α-, β-, and γ-CDs, demonstrated the capacity to modulate gut microbiota composition, promoting the growth of beneficial bacteria such as Bifidobacterium and Akkermansia. Supplementation with CDs was also associated with an increased production of short-chain fatty acids (SCFAs), which are essential for maintaining intestinal homeostasis and metabolic health. Moreover, CDs exhibited potential in lowering lipid levels and improving postprandial glycemic control without enhancing insulin secretion. Although generally recognized as safe, the toxicological profile of CDs varies depending on their type, dosage, and route of administration. Conclusions: Cyclodextrins hold considerable promise not only as pharmaceutical excipients but also as modulators of gut microbial communities, suggesting a dual therapeutic and prebiotic role. Future studies integrating metagenomic and metabolomic approaches are necessary to further elucidate the molecular mechanisms underlying CD–microbiota interactions and to optimize their application in enhancing drug delivery efficiency and promoting intestinal health. Full article

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

47 pages, 12171 KiB

Open AccessArticle

Design and Evaluation of a Zingiber officinale–Kaolinite–Maltodextrin Delivery System: Antioxidant, Antimicrobial, and Cytotoxic Activity Assessment

by Adina-Elena Segneanu, Ionela Amalia Bradu, Gabriela Vlase, Titus Vlase, Cornelia Bejenaru, Ludovic Everard Bejenaru, George Dan Mogoşanu, Maria Viorica Ciocîlteu, Dumitru-Daniel Herea and Eugen Radu Boia

Pharmaceutics 2025, 17(6), 751; https://doi.org/10.3390/pharmaceutics17060751 - 6 Jun 2025

Abstract

Background/Objectives: Zingiber officinale Roscoe (Zingiberaceae) is widely recognized for its diverse biological activities; however, the stability and bioavailability of its bioactive compounds remain significant challenges. This study aimed to investigate an innovative approach to enhance the stability and efficacy of [...] Read more.

Background/Objectives: Zingiber officinale Roscoe (Zingiberaceae) is widely recognized for its diverse biological activities; however, the stability and bioavailability of its bioactive compounds remain significant challenges. This study aimed to investigate an innovative approach to enhance the stability and efficacy of Z. officinale phytoconstituents through advanced encapsulation techniques. Methods: Two novel carrier systems were developed: (i) direct micro-spray encapsulation of Z. officinale in maltodextrin (MZO) and (ii) a two-step process involving the creation of a kaolinite-based phytocarrier system (ZO–kaolinite), followed by micro-spray encapsulation in maltodextrin to form the MZO–kaolinite system. Results: Comprehensive chemical profiling using GC–MS and ESI–QTOF–MS identified 105 phytochemicals, including terpenoids, gingerols, shogaols, flavonoids, and phenolic acids. Morphostructural analyses (XRD, FTIR, Raman, SEM) confirmed the successful development of the newly engineered kaolinite carrier systems (ZO–kaolinite and MZO–kaolinite systems). Both the ZO–kaolinite and MZO–kaolinite systems exhibited superior antioxidant activity, potent antimicrobial efficacy against major bacterial pathogens (Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli), and enhanced cytotoxicity against MCF-7, HCT-116, and HeLa cancer cell lines. Conclusions: This study underscores the synergistic action of kaolinite and maltodextrin in developing multifunctional therapeutic systems, emphasizing the importance of phytoconstituent stabilization and nanotechnology in addressing antimicrobial resistance and advancing innovative medical applications. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds in Micro- and Nanocarriers)

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43 pages, 2715 KiB

Open AccessReview

Phase-Inversion In Situ Systems: Problems and Prospects of Biomedical Application

by Elena O. Bakhrushina, Svetlana A. Titova, Polina S. Sakharova, Olga N. Plakhotnaya, Viktoriya V. Grikh, Alla R. Patalova, Anna V. Gorbacheva, Ivan I. Krasnyuk, Jr. and Ivan I. Krasnyuk

Pharmaceutics 2025, 17(6), 750; https://doi.org/10.3390/pharmaceutics17060750 - 6 Jun 2025

Abstract

Stimuli-sensitive (in situ) drug delivery systems are a dynamically developing area of pharmaceutical research. Over the past decade, the number of studies on such systems has doubled. Among these, phase-inversion (or phase-sensitive) formulations, which were among the earliest proposed, offer significant advantages, including [...] Read more.

Stimuli-sensitive (in situ) drug delivery systems are a dynamically developing area of pharmaceutical research. Over the past decade, the number of studies on such systems has doubled. Among these, phase-inversion (or phase-sensitive) formulations, which were among the earliest proposed, offer significant advantages, including enhanced stability and stimuli-responsiveness. However, phase-inversion systems have remained relatively understudied. Despite the existence of three patented technologies (Atrigel^®, BEPO^®, FluidCrystal^®) for delivery systems utilizing phase inversion for various routes of administration, the absence of unified approaches to development and standardization has significantly impeded the introduction of novel, effective drugs into clinical practice. This review examined the main polymers and solvents used to create phase-inversion compositions and discussed the feasibility of introducing other excipients to modify the systems’ physicochemical properties. The most commonly used polymers included polylactide-co-glycolide, shellac, and polylactic acid. The most frequently used solvents were N-methylpyrrolidone and dimethyl sulfoxide. Following an analysis of clinical studies of phase-sensitive drugs conducted over the past 25 years, as well as original research indexed in PubMed, ScienceDirect, and Google Scholar, the main problems hindering the broader adoption of phase-inversion systems in clinical practice were identified, and recommendations for further development in this promising area were provided. Full article

(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)

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Graphical abstract

24 pages, 2093 KiB

Open AccessArticle

Development of 3D-Printed Hydrogel Disks as Standardized Platform for Evaluating Excipient Impact on Metronidazole’s Antimicrobial Activity

by Tomasz Gnatowski, Joanna Kwiecińska-Piróg and Tomasz Bogiel

Pharmaceutics 2025, 17(6), 749; https://doi.org/10.3390/pharmaceutics17060749 - 6 Jun 2025

Abstract

Background/Objectives: Effective drug delivery systems require precise formulation and understanding of excipient impact on active pharmaceutical ingredient (API) stability and efficacy, as uncontrolled interactions can compromise outcomes. This study developed and validated a semi-solid extrusion (SSE) 3D printing method for polyvinyl alcohol (PVA)-based [...] Read more.

Background/Objectives: Effective drug delivery systems require precise formulation and understanding of excipient impact on active pharmaceutical ingredient (API) stability and efficacy, as uncontrolled interactions can compromise outcomes. This study developed and validated a semi-solid extrusion (SSE) 3D printing method for polyvinyl alcohol (PVA)-based hydrogel disks with metronidazole (MET). These disks served as a standardized platform to assess excipient influence on MET’s antimicrobial activity, focusing on plasticizers (polyethylene glycol 400, glycerol, propylene glycol, and diethylene glycol monoethyl ether)—excipients that modify hydrogel properties for their application in printing dressing matrices—with the platform’s capabilities demonstrated using in vitro antimicrobial susceptibility testing against Bacteroides fragilis. Methods: Hydrogel inks based on PVA with added plasticizers and MET were prepared. These inks were used to 3D-print standardized disks. The MET content in the disks was precisely determined. The antimicrobial activity of all formulation variants was evaluated using the disk diffusion method against B. fragilis. Results: The incorporated plasticizers did not negatively affect the antimicrobial efficacy of MET against B. fragilis. All printed hydrogel matrices exhibited clear antimicrobial activity. The 3D-printed disks showed high repeatability and precision regarding MET content. Conclusions: SSE 3D printing is viable for manufacturing precise, reproducible MET-loaded PVA hydrogel disks. It provides a standardized platform to evaluate diverse excipient impacts, like plasticizers, on API antimicrobial performance. The tested plasticizers were compatible with MET. This platform aids rational formulation design and screening for optimal excipients in designed formulations and for various pharmaceutical applications. Full article

(This article belongs to the Special Issue Nanocomposite Hydrogels and Their Application in Drug Delivery and Tissue Engineering)

20 pages, 7892 KiB

Open AccessArticle

Tissue Distribution and Pharmacokinetic Characteristics of Aztreonam Based on Multi-Species PBPK Model

by Xiao Ye, Xiaolong Sun, Jianing Zhang, Min Yu, Nie Wen, Xingchao Geng and Ying Liu

Pharmaceutics 2025, 17(6), 748; https://doi.org/10.3390/pharmaceutics17060748 - 6 Jun 2025

Abstract

Background/Objectives: As a monocyclic β-lactam antibiotic, aztreonam has regained attention recently because combining it with β-lactamase inhibitors helps fight drug-resistant bacteria. This study aimed to systematically characterize the plasma and tissue concentration-time profiles of aztreonam in rats, mice, dogs, monkeys, and humans [...] Read more.

Background/Objectives: As a monocyclic β-lactam antibiotic, aztreonam has regained attention recently because combining it with β-lactamase inhibitors helps fight drug-resistant bacteria. This study aimed to systematically characterize the plasma and tissue concentration-time profiles of aztreonam in rats, mice, dogs, monkeys, and humans by developing a multi-species, physiologically based pharmacokinetic (PBPK) model. Methods: A rat PBPK model was optimized and validated using plasma concentration-time curves determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS) following intravenous administration, with reliability confirmed through another dose experiment. The rat model characteristics, modeling experience, ADMET Predictor (11.0) software prediction results, and allometric scaling were used to extrapolate to mouse, human, dog, and monkey models. The tissue-to-plasma partition coefficients (K_p values) were predicted using GastroPlus (9.0) software, and the sensitivity analyses of key parameters were evaluated. Finally, the cross-species validation was performed using the average fold error (AFE) and absolute relative error (ARE). Results: The cross-species validation showed that the model predictions were highly consistent with the experimental data (AFE < 2, ARE < 30%), but the deviation of the volume of distribution (V_ss) in dogs and monkeys suggested the need to supplement the species-specific parameters to optimize the prediction accuracy. The K_p values revealed a high distribution of aztreonam in the kidneys (K_p = 2.0–3.0), which was consistent with its clearance mechanism dominated by renal excretion. Conclusions: The PBPK model developed in this study can be used to predict aztreonam pharmacokinetics across species, elucidating its renal-targeted distribution and providing key theoretical support for the clinical dose optimization of aztreonam, the assessment of target tissue exposure in drug-resistant bacterial infections, and the development of combination therapy strategies. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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37 pages, 1088 KiB

Open AccessReview

A Review on New Frontiers in Drug-Drug Interaction Predictions and Safety Evaluations with In Vitro Cellular Models

by Lara Marques and Nuno Vale

Pharmaceutics 2025, 17(6), 747; https://doi.org/10.3390/pharmaceutics17060747 - 6 Jun 2025

Abstract

The characterization of a drug’s ADME (absorption, distribution, metabolism, and excretion) profile is crucial for accurately determining its safety and efficacy. The rising prevalence of polypharmacy has significantly increased the risk of drug-drug interactions (DDIs). These interactions can lead to altered drug exposure, [...] Read more.

The characterization of a drug’s ADME (absorption, distribution, metabolism, and excretion) profile is crucial for accurately determining its safety and efficacy. The rising prevalence of polypharmacy has significantly increased the risk of drug-drug interactions (DDIs). These interactions can lead to altered drug exposure, potentially compromising efficacy or increasing the risk of adverse drug reactions (ADRs), thereby posing significant clinical and regulatory concerns. Traditional methods for assessing potential DDIs rely heavily on in vitro models, including enzymatic assays and transporter studies. While indispensable, these approaches have inherent limitations in scalability, cost, and ability to predict complex interactions. Recent advancements in analytical technologies, particularly the development of more sophisticated cellular models and computational modeling, have paved the way for more accurate and efficient DDI assessments. Emerging methodologies, such as organoids, physiologically based pharmacokinetic (PBPK) modeling, and artificial intelligence (AI), demonstrate significant potential in this field. A powerful and increasingly adopted approach is the integration of in vitro data with in silico modeling, which can lead to better in vitro-in vivo extrapolation (IVIVE). This review provides a comprehensive overview of both conventional and novel strategies for DDI predictions, highlighting their strengths and limitations. Equipping researchers with a structured framework for selecting optimal methodologies improves safety and efficacy evaluation and regulatory decision-making and deepens the understanding of DDIs. Full article

(This article belongs to the Topic Pharmacokinetic and Pharmacodynamic Modelling in Drug Discovery and Development)

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28 pages, 963 KiB

Open AccessReview

Advances in Transdermal Drug Delivery Systems and Clinical Applications in Inflammatory Skin Diseases

by Sizhuo Liu, Tinghan Deng, Hongbin Cheng, Jun Lu and Jingping Wu

Pharmaceutics 2025, 17(6), 746; https://doi.org/10.3390/pharmaceutics17060746 - 6 Jun 2025

Abstract

Inflammatory skin diseases are highly prevalent conditions characterized by complex immune responses that result in skin tissue damage and pain, significantly impacting patients’ physical health. Traditional therapeutic approaches, including oral administration and injections, continue to exhibit inherent limitations. Consequently, there is growing interest [...] Read more.

Inflammatory skin diseases are highly prevalent conditions characterized by complex immune responses that result in skin tissue damage and pain, significantly impacting patients’ physical health. Traditional therapeutic approaches, including oral administration and injections, continue to exhibit inherent limitations. Consequently, there is growing interest in exploring alternative drug delivery systems that offer more effective, targeted, and patient-friendly therapeutic options. Transdermal administration emerges as a promising solution for managing inflammatory skin diseases, facilitating sustained drug release, and reducing the frequency of dosing. This review provides a comprehensive overview of the skin barrier and critically summarizes clinically adopted transdermal drug delivery systems (TDDSs), including sonophoresis, iontophoresis, chemical penetration enhancers, and electroporation. Particular emphasis is placed on emerging advances in microneedle- and nanocarrier-facilitated transdermal delivery strategies. Moreover, the article synthesizes recent fundamental evidence regarding the application of TDDSs in the treatment of atopic dermatitis, psoriasis, and acne. This review examines fundamental research evaluating various transdermal drug delivery systems for the treatment of major inflammatory skin diseases, with an emphasis on their mechanisms of action, advantages, challenges, and future directions. Transdermal drug delivery systems hold the potential to deliver more efficient and safer treatment and management strategies for patients afflicted with inflammatory skin diseases. Full article

(This article belongs to the Special Issue Emerging Trends in Skin Delivery Systems)

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23 pages, 2680 KiB

Open AccessArticle

Novel Polymorphic Patterns for Elacestrant Dihydrochloride

by Zia Uddin Masum, P. Grant Spoors, Matt D. Burke and Vivek Gupta

Pharmaceutics 2025, 17(6), 745; https://doi.org/10.3390/pharmaceutics17060745 - 5 Jun 2025

Abstract

Objective: This study expands on the polymorphic characterization of elacestrant dihydrochloride, developed by Stemline Therapeutics and approved by the FDA in 2023. The article focuses on more extensive polymorphism screening using various methods and solvents to discover the new polymorphism forms of this [...] Read more.

Objective: This study expands on the polymorphic characterization of elacestrant dihydrochloride, developed by Stemline Therapeutics and approved by the FDA in 2023. The article focuses on more extensive polymorphism screening using various methods and solvents to discover the new polymorphism forms of this molecule, besides identifying three polymorphic forms in the previously published studies. Methods: The crystalline and amorphous elacestrant hydrochloride solubility was assessed, and crystals were formed, followed by polymorph screening using 40 non-conventional solvents via different techniques to obtain the new polymorphic forms. XRPD, NMR, DSC, TGA, IC, and HPLC were used for solid-state characterization. Results: Patterns A, B, C, D, E, F, and G, and previously published forms 1,3, were identified in multiple studies during the extensive polymorphism screening using various methods and numerous solvent systems. Solid state characterization and purity analysis were completed using different relevant instruments. After the characterization, it was found that Pattern A was the most stable, like the desired/most stable Form 1, but it had fewer crystals; Pattern B is like Form 3 but a unique XRPD pattern; Pattern D is degradant; Pattern C, E, F, and G are considered as the new pattern of elacestrant along with patterns A and B. Conclusions: With XRPD, six new patterns (A, B, C, E, F, G) were identified. Patterns A, C, and E are promising crystalline candidates for further analysis and scale-up. Full article

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

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15 pages, 715 KiB

Open AccessReview

Molecular Design of Novel Protein-Degrading Therapeutics Agents Currently in Clinical Trial

by Ela Kacin and Raj Nayan Sewduth

Pharmaceutics 2025, 17(6), 744; https://doi.org/10.3390/pharmaceutics17060744 - 5 Jun 2025

Abstract

The landscape of clinical trials aimed at targeting specific proteins has experienced significant advancements, presenting promising opportunities for the development of effective therapeutics across a range of diseases. These trials focus on the investigation of modulation of protein functions, utilizing innovative technologies such [...] Read more.

The landscape of clinical trials aimed at targeting specific proteins has experienced significant advancements, presenting promising opportunities for the development of effective therapeutics across a range of diseases. These trials focus on the investigation of modulation of protein functions, utilizing innovative technologies such as PROTACs (Proteolysis-Targeting Chimeras) and other protein degraders. These innovative approaches aim to address previously undruggable targets, enhancing the specificity and efficacy of treatments. The current landscape of clinical trials encompasses a diverse array of therapeutic areas, including oncology, autoimmune diseases, and neurological disorders. For instance, drugs like ARV-471 and ARV-110 are in advanced phases for treating metastatic breast cancer and prostate cancer, respectively, by targeting estrogen and androgen receptors. Early-phase trials explored the potential of targeting proteins like IKZF1/3 in multiple myeloma and IRAK4 in autoimmune diseases. The conducted trials not only emphasize the therapeutic potential of protein degradation but also highlight the challenges associated with bioavailability, stability, and delivery mechanisms. As these clinical trials advance, they possess the potential to transform treatment paradigms, providing renewed hope for patients facing complex and refractory conditions. Full article

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

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18 pages, 2973 KiB

Open AccessArticle

A TAT Peptide-Functionalized Liposome Delivery Phage System (TAT-Lip@PHM) for an Enhanced Eradication of Intracellular MRSA

by Kaixin Liu, Xin Lu, Xudong Guo, Yi Yang, Wanying Liu, Hongbin Song and Rongtao Zhao

Pharmaceutics 2025, 17(6), 743; https://doi.org/10.3390/pharmaceutics17060743 - 5 Jun 2025

Abstract

Background: Intracellular bacteria frequently result in chronic and recurrent infections. MRSA is one of the most prevalent facultative intracellular bacteria in clinical infections. The drug resistance of MRSA and the difficulty of most antibiotics in entering cells result in a suboptimal clinical efficacy [...] Read more.

Background: Intracellular bacteria frequently result in chronic and recurrent infections. MRSA is one of the most prevalent facultative intracellular bacteria in clinical infections. The drug resistance of MRSA and the difficulty of most antibiotics in entering cells result in a suboptimal clinical efficacy of antibiotics in the treatment of intracellular MRSA. Bacteriophages represent a promising alternative therapy in the context of the current antimicrobial resistance crisis. Nevertheless, the low efficiency of phage entry into cells and their rapid inactivation remain challenges in the treatment of intracellular MRSA using phages. The utilization of functionalized carriers for the delivery of phages into cells and their protection represents a feasible strategy. Methods: In this study, a new MRSA bacteriophage (vB_SauS_PHM) was isolated from hospital sewage, exhibiting the characteristics of short incubation period, large lytic amount, and good environmental tolerance. Subsequently, vB_SauS_PHM was encapsulated by TAT peptide-functionalized liposomes through microfluidic technology and size-exclusion chromatography (SEC), forming a phage delivery system, designated TAT-Lip@PHM. Results: The encapsulation rate of the phage by TAT-Lip@PHM was 20.3%, and the cell entry efficiency was ≥90% after 8 h. The 24 h eradication rate of 300 μg/mL TAT-Lip@PHM against intracellular MRSA was 94.05% (superior to the 21.24% and 44.90% of vB_SauS_PHM and Lip@PHM, respectively), while the mammalian cell activity was >85% after 24 h incubation. Conclusions: The TAT-Lip@PHM effectively delivered the phage into the cell and showed an excellent killing effect on intracellular MRSA with low cytotoxicity. This work provides a technical reference for the application of phages in the treatment of intracellular bacterial infection. Full article

(This article belongs to the Special Issue Advanced Nanomaterials and Drug Delivery Systems for Wound Healing and Antimicrobial Therapy)

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4 pages, 144 KiB

Open AccessEditorial

Expanding the Toolbox of Biomedical HIV Prevention Options Through Innovative Design

by J. Gerardo García-Lerma

Pharmaceutics 2025, 17(6), 742; https://doi.org/10.3390/pharmaceutics17060742 - 5 Jun 2025

Abstract

Research on biomedical HIV prevention has shown that no single product can meet the needs and preferences of all individuals [...] Full article

19 pages, 3200 KiB

Open AccessArticle

Linking TLR-7 Signaling to Downregulation of Placental P-Glycoprotein: Implications for Fetal Drug Exposure

by Mario Riera-Romo, Eliza R McColl and Micheline Piquette-Miller

Pharmaceutics 2025, 17(6), 741; https://doi.org/10.3390/pharmaceutics17060741 - 5 Jun 2025

Abstract

Background/Objectives: Activation of the Toll-like receptor 7 (TLR-7) plays an important role in the pathogenesis of many autoimmune diseases and viral infections. Although we have previously observed inflammation-mediated dysregulation of placental transporters, the role of TLR-7 has not been examined. Using the TLR-7 [...] Read more.

Background/Objectives: Activation of the Toll-like receptor 7 (TLR-7) plays an important role in the pathogenesis of many autoimmune diseases and viral infections. Although we have previously observed inflammation-mediated dysregulation of placental transporters, the role of TLR-7 has not been examined. Using the TLR-7 agonist, imiquimod (IMQ), we evaluated transporter expression in IMQ-treated pregnant rats and ex vivo in cultured rat placental explants. Methods: We administered 5 mg/kg (IP) of IMQ to pregnant Sprague Dawley rats on gestational day (GD) 14. The expression levels of inflammatory biomarkers and transporters were measured in maternal and fetal tissues by qRT-PCR and immunodetection methods, and effects on the placental proteome were assessed using LC/MS/MS. The involvement of TLR-7 was confirmed in rat placental explants. Results: IMQ administration resulted in Irf7 induction and increased levels of IL-6, Tnf-α, and type-I/II interferon pathways in maternal liver and placenta, which is consistent with TLR-7 activation. Proteomic profiling revealed IMQ-mediated activation of pathways involved in immune response, vesicle trafficking, and oxidative stress. Significantly decreased placental, hepatic, and renal protein expression of P-glycoprotein (PGP) was seen in the IMQ group. Likewise, TLR-7 activation using single-stranded RNA resulted in an induction of inflammatory biomarkers and downregulation of PGP in rat placental explants. Conclusions: We demonstrated that the activation of TLR-7 signaling during pregnancy reduces the expression of PGP in placenta and maternal tissues. Further studies are warranted, as decreased protein expression could result in decreased activity and altered fetal exposure to its substrates. Full article

(This article belongs to the Section Biopharmaceutics)

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3 pages, 143 KiB

Open AccessEditorial

Fiber-Based Scaffolds as Drug Carriers: Recent Advances

by Helena P. Felgueiras

Pharmaceutics 2025, 17(6), 740; https://doi.org/10.3390/pharmaceutics17060740 - 5 Jun 2025

Abstract

In recent years, fiber-based materials have been widely explored for their use in biomedical applications, ranging from wound dressings and bone tissue engineering to drug-controlled release and delivery platforms [...] Full article

(This article belongs to the Special Issue Fiber-Based Scaffolds as Drug Carriers: Recent Advances)

20 pages, 4435 KiB

Open AccessArticle

⁸⁹Zr-Radiolabelling of p-NCS-Bz-DFO-Anti-HER2 Affibody Immunoconjugate: Characterization and Assessment of In Vitro Potential in HER2-Positive Breast Cancer Imaging

by Maria-Roxana Tudoroiu-Cornoiu, Radu Marian Șerban, Diana Cocioabă, Dragoș Andrei Niculae, Doina Drăgănescu, Radu Leonte, Alina Catrinel Ion and Dana Niculae

Pharmaceutics 2025, 17(6), 739; https://doi.org/10.3390/pharmaceutics17060739 - 4 Jun 2025

Abstract

Background: The ⁸⁹Zr radioisotope is increasingly vital in positron emission tomography (PET), especially immuno-PET, due to its long half-life of 78.4 h, allowing extended tracking of biological processes. This makes it particularly suitable for researching medicines with slow pharmacokinetics and enhances the [...] Read more.

Background: The ⁸⁹Zr radioisotope is increasingly vital in positron emission tomography (PET), especially immuno-PET, due to its long half-life of 78.4 h, allowing extended tracking of biological processes. This makes it particularly suitable for researching medicines with slow pharmacokinetics and enhances the precision of molecular imaging, especially in oncology. Despite zirconium’s potential for skeletal accumulation, effective chelation with agents like deferoxamine (DFO) enables high-resolution imaging of antigen-specific tumours, such as HER2-positive breast cancer, offering insights into tumour biology and treatment response. Methods: ⁸⁹Zr was produced at the ACSI TR-19 cyclotron via ⁸⁹Y(p,n)⁸⁹Zr reaction. Natural yttrium foils (250 μm) were irradiated with 12.9 MeV protons on target, with 100 μA·h. An HER2-targeting affibody was synthesized and conjugated with p-NCS-Bz-DFO (1:4 mass ratio) at 37 °C for 60 min (pH 9.2 ± 0.2), then purified on a PD-10 column. Radiolabelling was performed with [⁸⁹Zr]Zr-oxalate at pH ranging from 7.0 to 9.0, with concentrations from 110 to 460 MBq/mL. Results: Final activity reached 2.95 ± 0.31 GBq/batch (EOB corrected), with ≥ 99.9% radionuclide and ≥95% radiochemical purities. The anti-HER2 affibody was successfully radiolabelled with ⁸⁹Zr, resulting in a radiochemical purity of over 85% with molar activity of 26.5 ± 4.4 and 11.45 MBq/nmol at pH 7.0–7.5. In vitro tests on BT-474 and MCF-7 cell lines confirmed high uptake in HER2-positive cells, validating specificity and stability. Conclusions: The successful synthesis and labelling of the [⁸⁹Zr]Zr-p-NCS-Bz-DFO-anti-HER2 affibody are promising achievements for its further application in targeted immuno-PET imaging for HER2-positive malignancies. Further in vivo studies are needed to support its clinical translation. Full article

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

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