Pharmaceutics

18 pages, 2967 KiB

Open AccessArticle

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

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

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

Abstract

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

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

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

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14 pages, 1586 KiB

Open AccessArticle

Stability-Guided Formulation of a Light-Sensitive D-LSD Capsule for Clinical Investigation

by Bernard Do, Luc Mallet, Maxime Annereau, Danielle Libong, Audrey Solgadi, Florence Vorspan, Muriel Paul and Philippe-Henri Secretan

Pharmaceutics 2025, 17(6), 767; https://doi.org/10.3390/pharmaceutics17060767 - 11 Jun 2025

Abstract

Background/Objectives: D-lysergic acid diethylamide (D-LSD) is under investigation as a potential therapeutic strategy for alcohol use disorder (AUD). However, the extreme light sensitivity of D-LSD presents a significant challenge in developing suitable pharmaceutical forms, particularly for clinical trial settings. This study proposes a [...] Read more.

Background/Objectives: D-lysergic acid diethylamide (D-LSD) is under investigation as a potential therapeutic strategy for alcohol use disorder (AUD). However, the extreme light sensitivity of D-LSD presents a significant challenge in developing suitable pharmaceutical forms, particularly for clinical trial settings. This study proposes a liquid-filled capsule formulation designed to provide accurate dosing while protecting D-LSD from photodegradation. Methods: To support formulation development and ensure its suitability as an investigational medicinal product, a multi-tiered analytical strategy was employed. This included liquid chromatography coupled with ion mobility spectrometry and mass spectrometry (LC-IM-MS), along with quantum chemical calculations (density functional theory (DFT) and time dependent-DFT (TD-DFT)), to ensure robust and orthogonal structural characterization of degradation products. Results: Photostress studies demonstrated that while D-LSD in solution rapidly degrades into photoisomers and photooxidative byproducts, the capsule formulation markedly mitigates these transformations under ICH-compliant conditions. Conclusions: These findings highlight the essential role of orthogonal stability profiling in guiding formulation development and demonstrate that this approach may offer a viable, photostable platform for future clinical investigation of D-LSD in the treatment of AUD. Full article

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

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17 pages, 5473 KiB

Open AccessArticle

Sivelestat-Loaded Neutrophil-Membrane-Coated Antioxidative Nanoparticles for Targeted Endothelial Protection in Sepsis

by Juexian Wei, Aijia Zhong, Yuting Zhang, Ehua Deng, Hengzong Mo, Hongyu Zhao, Jiayu Huang, Huaidong Peng, Kaiyin Zhang, Xiaohui Chen, Haifeng Mao, Yixin Chen and Yongcheng Zhu

Pharmaceutics 2025, 17(6), 766; https://doi.org/10.3390/pharmaceutics17060766 - 10 Jun 2025

Abstract

Background/Objectives: This study aims to develop and evaluate neutrophil-membrane-coated nanoparticles (Siv@NMs) encapsulating sivelestat for the treatment of sepsis-induced endothelial injury. Leveraging the intrinsic chemotactic properties of neutrophil membranes, Siv@NMs are engineered to achieve site-specific delivery of sivelestat to damaged endothelia, thereby overcoming [...] Read more.

Background/Objectives: This study aims to develop and evaluate neutrophil-membrane-coated nanoparticles (Siv@NMs) encapsulating sivelestat for the treatment of sepsis-induced endothelial injury. Leveraging the intrinsic chemotactic properties of neutrophil membranes, Siv@NMs are engineered to achieve site-specific delivery of sivelestat to damaged endothelia, thereby overcoming the limitations of conventional therapies in mitigating endothelial dysfunction and multiorgan failure associated with sepsis. Methods: Siv@NMs were synthesized through a combination of ultrasonication and extrusion techniques to encapsulate sivelestat within neutrophil-membrane-derived vesicles. Comprehensive physicochemical characterization included analysis of particle size distribution, zeta potential, and encapsulation efficiency. Stability profiles and controlled release kinetics were systematically evaluated under simulated conditions. In vitro investigations encompassed (1) endothelial cell biocompatibility assessment via cytotoxicity assays, (2) investigation of the targeting efficiency in suppressing endothelial neutrophil extracellular trap generation during inflammation, and (3) ROS-scavenging capacity quantification using flow cytometry with DCFH-DA fluorescent probes. In vivo therapeutic efficacy was validated using a cecal ligation and puncture (CLP) sepsis mouse model, with multiparametric monitoring of endothelial function, inflammatory markers, ROS levels, and survival outcomes. Results: The optimized Siv@NMs exhibited an average particle size of approximately 150 nm, and a zeta potential of −10 mV was achieved. Cellular studies revealed that (1) Siv@NMs selectively bound to inflammatory endothelial cells with minimal cytotoxicity, and (2) Siv@NMs significantly reduced ROS accumulation in endothelial cells subjected to septic stimuli. In vitro experiments demonstrated that Siv@NMs treatment markedly attenuated endothelial injury biomarkers’ expression (ICAM-1 and iNOS), suppressed formation of neutrophil extracellular traps, and improved survival rates compared to treatment with free sivelestat. Conclusions: The neutrophil-membrane-coated nanoparticles loaded with sivelestat present a breakthrough strategy for precision therapy of sepsis-associated endothelial injury. This bioengineered system synergistically combines targeted drug delivery with multimodal therapeutic effects, including ROS mitigation, anti-inflammatory action, and endothelial protection. These findings substantiate the clinical translation potential of Siv@NMs as a next-generation nanotherapeutic for sepsis management. Full article

(This article belongs to the Special Issue ROS-Mediated Nano Drug Delivery for Antitumor Therapy)

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14 pages, 492 KiB

Open AccessArticle

Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog

by Kumar Kulldeep Niloy, Jamie Horn, Nazmul H. Bhuiyan, Khaled A. Shaaban, Suhas S. Bhosale, Thomas E. Prisinzano, Jon S. Thorson, Jurgen Rohr and Markos Leggas

Pharmaceutics 2025, 17(6), 765; https://doi.org/10.3390/pharmaceutics17060765 - 10 Jun 2025

Abstract

Background: Mithramycin (MTM) is a polyketide anti-cancer natural product previously identified as an EWS-FLI1 inhibitor. This oncogenic transcription factor is a canonical target for drug development in Ewing sarcoma. However, poor pharmacokinetics have been identified as a critical liability of MTM, preventing [...] Read more.

Background: Mithramycin (MTM) is a polyketide anti-cancer natural product previously identified as an EWS-FLI1 inhibitor. This oncogenic transcription factor is a canonical target for drug development in Ewing sarcoma. However, poor pharmacokinetics have been identified as a critical liability of MTM, preventing its further development. Through semisynthetic chemical modifications, we identified mithramycin SA-Trp (MTMSA-Trp) as being a pharmacologically superior congener. To explore their pharmacokinetic (PK) differences, this study examined the plasma PKs and plasma protein binding (PPB) of MTM and MTMSA-Trp in mice, rats, and monkeys. Methods: Protein binding was investigated by rapid equilibrium dialysis in plasma from mice, rats, monkeys, and humans. The pharmacokinetics were investigated at milligram- and microgram-level doses in mice and rats. The pharmacokinetics in monkeys were investigated using the cassette dosing approach at two microgram-level doses. The MTMSA-Trp pharmacokinetic linearity was evaluated in mice at 0.3, 1, 3, and 10 mg/kg doses. All samples were analyzed using LC-MS/MS. Results: Plasma protein binding was higher for MTMSA-Trp (1–4% unbound) than for MTM (10–30% unbound) across species, except in athymic nude mice (1–4% unbound and <1% for mithramycin and MTMSA-Trp, respectively). In mice and rats, MTMSA-Trp had significantly lower clearance than MTM at both milligram and microgram doses; however, the difference in plasma exposure was more pronounced at milligram doses. Consistent with the rodent PK results, cassette microdosing in monkeys showed that the clearance of MTMSA-Trp was lower than that of MTM, but the differences were less pronounced. In the dose proportionality study, MTMSA-Trp showed linear pharmacokinetics at 1, 3, and 10 mg/kg doses. Conclusions: MTMSA-Trp has significantly lower clearance than MTM in rodent models. This is a significant improvement compared to the parent drug, MTM, and warrants further evaluation of PKs in non-rodent models to enable the prediction of MTMSA-Trp PK in humans. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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25 pages, 3318 KiB

Open AccessReview

Solute–Vehicle–Skin Interactions and Their Contribution to Pharmacokinetics of Skin Delivery

by Pronalis Tapfumaneyi, Khanh Phan, Yicheng Huang, Kewaree Sodsri, Sarika Namjoshi, Howard Maibach and Yousuf Mohammed

Pharmaceutics 2025, 17(6), 764; https://doi.org/10.3390/pharmaceutics17060764 - 10 Jun 2025

Abstract

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients [...] Read more.

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients is a delicate balance between the molecular properties of the drug, the skin properties of the patients, and the formulation properties. Understanding this interplay can aid in the development of products applied to the skin. The kinetics of percutaneous absorption and an understanding of the rate-limiting steps involved can facilitate the optimization of these systems and enhance the degree to which skin drug delivery can be achieved. Solute–vehicle, vehicle–skin, and solute–skin interactions contribute notably to product release as well as the rate of absorption and diffusion across skin layers. These interactions alter the degree of permeation by interfering with the skin barrier or solubility and thermodynamic activity of the active pharmaceutical ingredient. This article aims to provide a concise understanding of some of the factors involved in the skin absorption of topical products, i.e., the pharmacokinetics of percutaneous absorption as well as the solute–vehicle–skin interactions that determine the rate of release of products and the degree of drug diffusion across the skin. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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5 pages, 177 KiB

Open AccessEditorial

Editorial for Special Issue ‘Engineering and Characterisation of Novel Nanomedicine Formulations, 2nd Edition’

by Raquel Fernández-García, Francisco Bolás-Fernández and Ana Isabel Fraguas-Sánchez

Pharmaceutics 2025, 17(6), 763; https://doi.org/10.3390/pharmaceutics17060763 - 10 Jun 2025

Abstract

Nanomedicine applies nanotechnology to revolutionise healthcare through the development of systems at the nanoscale (below 1000 nm) to enhance drug delivery [...] Full article

(This article belongs to the Special Issue Engineering and Characterisation of Novel Nanomedicine Formulations, 2nd Edition)

19 pages, 3044 KiB

Open AccessArticle

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

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

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

Abstract

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

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

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

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16 pages, 2647 KiB

Open AccessReview

Etrog Citron (Citrus medica) as a Novel Source of Antimicrobial Agents: Overview of Its Bioactive Phytochemicals and Delivery Approaches

by Arik Dahan, Ludmila Yarmolinsky, Faina Nakonechny, Olga Semenova, Boris Khalfin and Shimon Ben-Shabat

Pharmaceutics 2025, 17(6), 761; https://doi.org/10.3390/pharmaceutics17060761 - 9 Jun 2025

Abstract

The rising prevalence of bacterial antibiotic resistance remains a significant challenge, while many existing antibacterial agents exhibit limited efficacy and notable adverse effects. Edible plants offer a promising avenue for developing novel antimicrobial drugs and preservatives. Etrog citron (Citrus medica L.) and [...] Read more.

The rising prevalence of bacterial antibiotic resistance remains a significant challenge, while many existing antibacterial agents exhibit limited efficacy and notable adverse effects. Edible plants offer a promising avenue for developing novel antimicrobial drugs and preservatives. Etrog citron (Citrus medica L.) and its bioactive phytochemicals have demonstrated activity against various pathogenic microorganisms. However, the potential application of these compounds is hindered by factors such as poor solubility, limited bioavailability, and unclear mechanisms of action. This review consolidates key findings on the antimicrobial properties of extracts and essential oils derived from different parts of Citrus medica, emphasizing strategies for improving the delivery of these bioactive compounds. Full article

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23 pages, 2242 KiB

Open AccessReview

The Role of Nanoparticle Elasticity on Biological Hydrogel Penetration

by Chathuri I. Sodimanage and Marc Schneider

Pharmaceutics 2025, 17(6), 760; https://doi.org/10.3390/pharmaceutics17060760 - 9 Jun 2025

Abstract

The latest advancements in nanomedicine have led to increased therapeutic efficacy and reduced complications. However, nanoparticle penetration is significantly influenced by biological hydrogels, such as mucus, the extracellular matrix, biofilms, and nucleoporins. Solely modifying well-studied physicochemical properties like size, charge, and surface chemistry [...] Read more.

The latest advancements in nanomedicine have led to increased therapeutic efficacy and reduced complications. However, nanoparticle penetration is significantly influenced by biological hydrogels, such as mucus, the extracellular matrix, biofilms, and nucleoporins. Solely modifying well-studied physicochemical properties like size, charge, and surface chemistry is insufficient to fully elucidate or overcome these barriers. Recent studies have investigated the impact of particle elasticity, a relatively unexplored yet crucial physicochemical property influencing many biological processes. Hence, it is important to explore the impact of particle elasticity on penetrating biological hydrogels. This review examines biological hydrogels’ structural and functional features as diffusion barriers, provides an overview of particle elasticity, key elasticity measurement techniques, and explores strategies for elasticity modulation in nanoparticles, such as composition, crosslinking density, and structural design. Furthermore, nanoparticle penetration mechanisms, influenced by particle deformability, hydrogel mesh size, and adhesive interactions, are investigated by integrating theoretical and experimental findings. The evaluation of experimental data reveals the commonly observed particle elasticity trends in mucus penetration, extracellular matrix permeation, and corneal penetration of nanoparticles. Overall, this review offers valuable insights into designing next-generation nanomedicines capable of overcoming biological barriers. Full article

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

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29 pages, 7587 KiB

Open AccessArticle

Considerations Regarding the Cytotoxicity of Certain Classes of Fungal Polyketides—Potential Raw Materials for Skincare Products for Healthy and Diseased Skin

by Daniela Albisoru, Nicoleta Radu, Raluca Senin, Mihai Dan Caramihai, Mihaela Begea, Oksana Mulesa, Viviana Roman and Marinela Bostan

Pharmaceutics 2025, 17(6), 759; https://doi.org/10.3390/pharmaceutics17060759 - 9 Jun 2025

Abstract

Background: This study investigates the cytotoxicity of microbial polyketides biosynthesized by Monascus species through both in silico and in vitro approaches. Methods: Six main know Monascus-derived polyketides were analysed in silico an an vitro. Results: In silico tests reveal [...] Read more.

Background: This study investigates the cytotoxicity of microbial polyketides biosynthesized by Monascus species through both in silico and in vitro approaches. Methods: Six main know Monascus-derived polyketides were analysed in silico an an vitro. Results: In silico tests reveal that the main derived compounds exhibit lipophilic properties, indicating their potential suitability as active ingredients in dermato-cosmetic formulations. In silico tests revealed significant flexibility and high degrees of unsaturation for some Monascus-derived polyketides, suggesting a broad interaction potential and a propensity for chemical instability. In silico permeability tests indicated low epidermal penetration. Cytotoxicity assays conducted in vitro on a HaCaT cell line revealed varying levels of cytotoxicity among the three classes of fungal polyketides. Yellow polyketides derived from Monascus purpureus and Monascus ruber exhibited moderate cytotoxicity, while orange polyketides derived from the same strains showed low cytotoxicity. Red, orange, and yellow polyketides derived from a high-productive Monascus sp. genus showed low or negligible cytotoxicity. After 48 h of exposure, the cytotoxic profiles of all Monascus polyketides remained relatively stable. The IC₅₀ values obtained through linear or nonlinear models supplied by EXCEL MS Office or for the Systat programme indicated moderate-to-low cytotoxicity for polyketides derived from Monascus ruber and Monascus purpureus. The bioproducts derived from high-productive Monascus sp. exhibited weak or negligible cytotoxicity. Conclusions: The results obtained suggest that the Monascus-derived polyketides possess promising properties for therapeutic and cosmetic applications, but their chemical stability must be considered in the case of dermatological formulations. Full article

(This article belongs to the Special Issue Skin Care Products for Healthy and Diseased Skin)

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55 pages, 2462 KiB

Open AccessReview

Natural Products for Improving Soft Tissue Healing: Mechanisms, Innovations, and Clinical Potential

by Adina Alberts, Ioana Alexandra Lungescu, Adelina-Gabriela Niculescu and Alexandru Mihai Grumezescu

Pharmaceutics 2025, 17(6), 758; https://doi.org/10.3390/pharmaceutics17060758 - 8 Jun 2025

Abstract

Scar development is a notable clinical and aesthetic issue in soft tissue healing, frequently compromising functionality and quality of life. Conventional treatments demonstrate limited efficacy in avoiding fibrosis and facilitating regenerative repair. Nevertheless, natural compounds have surfaced as viable alternatives owing to their [...] Read more.

Scar development is a notable clinical and aesthetic issue in soft tissue healing, frequently compromising functionality and quality of life. Conventional treatments demonstrate limited efficacy in avoiding fibrosis and facilitating regenerative repair. Nevertheless, natural compounds have surfaced as viable alternatives owing to their biocompatibility, multitarget bioactivity, and historical application in traditional medicine. This review examines the therapeutic potential of plant-derived substances, marine agents, and microbial metabolites in influencing critical stages of wound healing, including inflammation, oxidative stress, fibroblast activation, and extracellular matrix remodeling. While these agents have demonstrated beneficial effects in preclinical models, their direct impact on functional or aesthetic clinical outcomes remains under investigation. We propose a hierarchical framework linking molecular mechanisms to clinical endpoints, suggesting that improvements at the cellular and molecular level may eventually support better healing quality. Natural bioactives, especially when integrated into advanced delivery systems such as hydrogels and nanocarriers, show promise for enhancing the regenerative microenvironment. By contextualizing these mechanisms within real-world therapeutic goals, this review highlights both the potential and limitations of natural products in the pursuit of improved soft tissue healing. Further translational research is needed to determine how modulation of these processes may reduce scarring and approach clinically meaningful outcomes. Full article

(This article belongs to the Special Issue Naturally Derived Materials-Based Drug Delivery Systems and Their Biomedical Applications)

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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 - 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 - 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 - 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 - 7 Jun 2025

Viewed by 354

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, 552 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 - 7 Jun 2025

Viewed by 161

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)

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21 pages, 1718 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 - 7 Jun 2025

Viewed by 114

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 [...] 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)

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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

Viewed by 316

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

Viewed by 346

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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24 pages, 2775 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

Viewed by 156

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 [...] 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)

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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

Viewed by 225

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

Viewed by 334

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

Viewed by 333

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

Viewed by 333

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

Viewed by 214

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

Viewed by 204

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

Viewed by 206

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

Viewed by 241

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

Viewed by 158

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

Viewed by 319

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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