Pharmaceutics

40 pages, 921 KB

Open AccessReview

Mechanisms and Therapeutic Targets of Botanicals Derived from Asteraceae Plant Species

by Aphelele Taliwe, Siphamandla Q. N. Lamula, Lisa V. Buwa-Komoreng and Vuyolwethu Khwaza

Pharmaceutics 2026, 18(6), 759; https://doi.org/10.3390/pharmaceutics18060759 (registering DOI) - 21 Jun 2026

The Asteraceae family represents one of the largest groups of medicinal plants, widely used in traditional medicine and increasingly investigated for its pharmacological potential. This review summarizes current evidence on the botanicals derived from Asteraceae plant species and their molecular mechanisms of action [...] Read more.

The Asteraceae family represents one of the largest groups of medicinal plants, widely used in traditional medicine and increasingly investigated for its pharmacological potential. This review summarizes current evidence on the botanicals derived from Asteraceae plant species and their molecular mechanisms of action against inflammation and cancer. Major classes of bioactive compounds in extracts are discussed in relation to their modulation of key signaling pathways and therapeutic targets such as NF-κB, MAPK, PI3K/Akt, COX-2, iNOS, and apoptotic regulators (Bax/Bcl-2, caspases). A literature search covering studies published between 2022 and 2026 was conducted. Evidence from in vitro, in vivo, and in silico studies demonstrates that Asteraceae-derived botanicals exert therapeutic effects through antioxidant activity, cytokine suppression, enzyme inhibition, and regulation of gene expression. Overall, the mechanistic insights presented herein support the rational use of Asteraceae medicinal plants and identify promising lead compounds for drug discovery and development. Full article

(This article belongs to the Special Issue Pharmaceutical Applications and Therapeutic Mechanisms of Substances from Plant Origin)

31 pages, 2178 KB

Open AccessArticle

Investigation of the Photoprotective Effects of Various Pigments Against Laser-Marking of Pharmaceutical Tablets

by Hadi Shammout, Béla Hopp, Judit Kopniczky, Tamás Smausz, Bence Sipos, Katalin Kristó, János Bohus, Orsolya Jójárt-Laczkovich, Flórián Benkő, Tamás Sovány and Krisztina Ludasi

Pharmaceutics 2026, 18(6), 758; https://doi.org/10.3390/pharmaceutics18060758 (registering DOI) - 21 Jun 2026

Abstract

Background/Objectives: With the increasing incidence of drug counterfeiting and the emergence of personalized medicine, the need for unique marking of solid dosage forms, e.g., tablets, has attracted considerable interest in the current research and development landscape. Besides traditional printing methods, laser marking [...] Read more.

Background/Objectives: With the increasing incidence of drug counterfeiting and the emergence of personalized medicine, the need for unique marking of solid dosage forms, e.g., tablets, has attracted considerable interest in the current research and development landscape. Besides traditional printing methods, laser marking offers several advantages, as it eliminates the need for organic solvents and enables the generation of precise patterns. However, laser exposure may raise safety concerns regarding the stability of photosensitive drugs in the irradiated dosage forms. Therefore, the aim of the present study was to test the photoprotective effect of titanium dioxide (TiO₂) and its various alternatives, e.g., talc, calcium carbonate (CaCO₃), zinc oxide (ZnO), and black iron oxide (Fe₃O₄), alongside a ready-to-use reference formulation, Opadry^® Brown, which contains TiO₂ (titanium-containing, TC) on nifedipine, a light-sensitive model drug. Methods: Laser marking or short-term laser ablation at different wavelengths (193 nm, 248 nm, 532 nm, and 781 nm) was applied to different coating formulations. As a positive control, prolonged exposure to daylight was applied. The properties and photostability of these formulations were evaluated using several analytical methods (i.e., surface profilometry, Raman spectroscopy, and high-performance liquid chromatography (HPLC)). Results: The TiO₂, ZnO, Fe₃O₄, and Opadry^® TC Brown coatings maintained their color during the long-term study under all conditions. Furthermore, the prepared formulations exhibited different ablation depths and morphological changes depending on the coating and laser type. HPLC measurements confirmed significant differences in the protective ability of various pigments against sunlight and different types of lasers. Nevertheless, the obtained Raman spectra were not in complete agreement with HPLC results, which can be attributed to spectral overlap between key nifedipine degradation markers and excipient signals in the tablet core. Conclusions: Overall, laser treatment of tablets containing photosensitive drugs may induce API decomposition; however, this effect can be minimized or avoided by careful selection of the appropriate combination of laser type and photoprotective pigment. Under the applied experimental conditions, Ti:Sa laser treatment was associated with the lowest degree of nifedipine degradation among all formulations, while ZnO-containing coatings demonstrated the most consistent photoprotective performance against the majority of the tested laser types, while Fe₃O₄-containing coatings provided superior protection during prolonged sunlight exposure and Nd:YAG laser irradiation. Full article

(This article belongs to the Special Issue Dosage Forms in Drug Delivery: State of the Art and Future Perspectives, 2nd Edition)

22 pages, 2946 KB

Open AccessArticle

A Systemically Administered Humanized Anti-Nav1.7 Antibody with Long-Lasting Analgesic Activity and Preserved Physiological Nociception

by Sosuke Yoneda, Daisuke Uta, Kana Yasufuku, Takuya Yamane, Saho Yoshioka, Keiko Takasu, Takaya Izumi, Sayaka Fujita, Daiki Nakamori, Shiori Kawasaki, Tatsuya Takahashi, Mai Yoshikawa, Koichi Ogawa and Erika Kasai

Pharmaceutics 2026, 18(6), 757; https://doi.org/10.3390/pharmaceutics18060757 (registering DOI) - 21 Jun 2026

Abstract

Background: Neuropathic pain remains difficult to treat because current analgesics often provide insufficient efficacy or dose-limiting adverse effects. Nav1.7 is genetically validated as a key regulator of human pain sensation, but the development of selective small-molecule Nav1.7 inhibitors has been limited by the [...] Read more.

Background: Neuropathic pain remains difficult to treat because current analgesics often provide insufficient efficacy or dose-limiting adverse effects. Nav1.7 is genetically validated as a key regulator of human pain sensation, but the development of selective small-molecule Nav1.7 inhibitors has been limited by the high similarity among voltage-gated sodium channel subtypes. Methods: We generated monoclonal antibodies selectively targeting Nav1.7, humanized them for therapeutic development, and evaluated their binding, selectivity, functional channel inhibition, systemic analgesic efficacy, and effects on neuronal activity in a rat model of partial sciatic nerve ligation-induced neuropathic pain. Results: The humanized antibodies showed high-affinity and selective binding to Nav1.7 and functionally inhibited the channel in cellular assays. After systemic administration to neuropathic pain model rats, the lead antibody produced robust analgesia lasting at least 96 h. Electrophysiological analyses demonstrated reduced mechanically evoked and spontaneous neuronal activity, and immunohistochemistry showed decreased mechanical stimulus-induced phosphorylation of extracellular signal-regulated kinase in dorsal root ganglion neurons. The antibodies did not impair physiological nociception or motor function under the tested conditions. Conclusions: These findings provide preclinical proof of concept that humanized anti-Nav1.7 antibodies can act as systemically administered, long-acting biologic analgesics for neuropathic pain while preserving normal nociceptive and motor functions. The clinical advancement of S-151128 further supports the translational potential of this modality. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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14 pages, 1345 KB

Open AccessArticle

A Functional Data Analysis-Based Framework for Modeling and Multi-Objective Optimization of Sustained-Release Drug Delivery Systems

by Hao Ren, Mengchen Han, Yuchao Qiao, Yu Cui, Chongqi Hao, Yiming Lou, Gaomin Jing, Qiankun Liu, Lang Yang, Li Zheng and Lixia Qiu

Pharmaceutics 2026, 18(6), 756; https://doi.org/10.3390/pharmaceutics18060756 (registering DOI) - 21 Jun 2026

Abstract

Objectives: An integrated methodological framework was developed for modeling and multiobjective optimization of sustained-release drug delivery systems. Methods: The cumulative release percentage was fitted as a function curve, and functional principal component analysis was subsequently used to transform the function curves [...] Read more.

Objectives: An integrated methodological framework was developed for modeling and multiobjective optimization of sustained-release drug delivery systems. Methods: The cumulative release percentage was fitted as a function curve, and functional principal component analysis was subsequently used to transform the function curves into functional principal component scores (FPCs). FPCs were then treated as dependent variables, while the proportions of the formulation factors were used as independent variables to construct Scheffé polynomial regression models. Finally, Non-dominated Sorting Genetic Algorithm III (NSGA-III) was applied to perform multi-objective optimization. Results: FPC1, FPC2, and FPC3 captured 95.18%, 4.39%, and 0.32% of the total variation, respectively. Corresponding Scheffé polynomial regression models were established, including quadratic models for FPC1 (adjusted R² = 0.751, AIC = 168.557) and FPC2 (adjusted R² = 0.592, AIC = 119.302), and a special cubic model for FPC3 (adjusted R² = 0.597, AIC = 64.574). The NSGA-III algorithm generated a Pareto optimal set, yielding stable formulation compositions with mean (SD) values of X₁ = 0.123 (0.015), X₂ = 0.821 (0.032), X₃ = 0.012 (0.017), and X₄ = 0.045 (0.015). The corresponding FPCs were −41.787 (2.544), 10.009 (0.168), and 8.264 (0.010) for FPCs1–FPCs3, respectively. The reconstructed cumulative release percentages were 42.471 (1.661), 52.623 (2.868), 69.942 (1.200), 84.275 (1.010), and 93.330 (0.832), demonstrating good agreement with the target release profiles. Conclusions: The integrated FDA–Scheffé–NSGA-III framework provides a robust and effective approach for accurately modeling release behavior and optimizing sustained-release formulations. Full article

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

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42 pages, 1251 KB

Open AccessReview

An Overview of Advanced Materials and Manufacturing Strategies for 3D-Printed Bioengineered Vascular Stents: Toward Next-Generation Drug Delivery Applications

by Faisal Khaled Aldawood

Pharmaceutics 2026, 18(6), 755; https://doi.org/10.3390/pharmaceutics18060755 (registering DOI) - 21 Jun 2026

Abstract

Additive manufacturing has emerged as a transformative technology for fabricating complex drug-eluting medical devices, offering unprecedented design freedom and functional integration capabilities. This comprehensive review systematically analyzes 3D printing technologies applied to pharmaceutical device manufacturing, focusing on drug-eluting vascular stents as a representative [...] Read more.

Additive manufacturing has emerged as a transformative technology for fabricating complex drug-eluting medical devices, offering unprecedented design freedom and functional integration capabilities. This comprehensive review systematically analyzes 3D printing technologies applied to pharmaceutical device manufacturing, focusing on drug-eluting vascular stents as a representative application. This review covers six primary additive manufacturing techniques, ranging from high-resolution vat photopolymerization (25 μm resolution) to direct energy deposition, with a focus on their capabilities for produce pharmaceutical devices with controlled drug release properties. Novel 4D/5D/6D printing technologies introduce stimuli-responsive behaviors enabling programmable drug release profiles and adaptive device functionality. Manufacturing process optimization reveals superior design flexibility compared to conventional methods, with 85–95% reduction in design iteration time and elimination of tooling costs for complex geometries. The material landscape encompasses traditional metals (316L stainless steel, cobalt–chromium), biodegradable polymers (polylactic acid, PLA; polycaprolactone, PCL; poly(lactic-co-glycolic acid), PLGA), shape-memory materials (i.e., polymers and alloys capable of recovering a pre-programmed shape upon exposure to a specific stimulus such as body temperature, moisture, or light), and advanced nanocomposites, each offering distinct drug-loading capacities (100–500 μg/cm²) and release kinetics. Critical challenges include standardization requirements (International Organization for Standardization (ISO) 5840 and American Society for Testing and Materials (ASTM) F2606), pharmaceutical-grade manufacturing protocols, and regulatory pathways for novel drug-device combinations. This review identifies key research priorities including development of biocompatible printing materials, accelerated drug release testing protocols, and scalable manufacturing processes suitable for medical device production. This analysis demonstrates that 3D printing enables integration of multiple pharmaceutical functions within single devices, controlled spatiotemporal drug delivery, and elimination of secondary manufacturing steps for drug coating processes, advancing the development of next-generation therapeutic medical devices. Full article

(This article belongs to the Special Issue Biomedical Applications: Advances in Bioengineering and Drug Delivery, 2nd Edition)

26 pages, 19471 KB

Open AccessArticle

Benzofuran-Annulated Naphthalimides Trigger Replication Stress, DNA Damage, and p53-Dependent Cell Cycle Arrest

by Zlatina Vlahova, Lazar Lazarov, Maria Petrova, Shazie Yusein-Myashkova, Jordana Todorova, Maria Schröder, Monika Mutovska, Stanimir Stoyanov, Yulian Zagranyarski and Iva Ugrinova

Pharmaceutics 2026, 18(6), 754; https://doi.org/10.3390/pharmaceutics18060754 (registering DOI) - 20 Jun 2026

Abstract

Background/Objectives: DNA-targeting small molecules that induce replication stress represent a promising strategy in anticancer drug development. 1,8-Naphthalimide (NI) derivatives are well-established DNA-intercalating agents, and heterocyclic annulation offers a rational approach to enhancing their potency and tumor selectivity. Here, we report the synthesis and [...] Read more.

Background/Objectives: DNA-targeting small molecules that induce replication stress represent a promising strategy in anticancer drug development. 1,8-Naphthalimide (NI) derivatives are well-established DNA-intercalating agents, and heterocyclic annulation offers a rational approach to enhancing their potency and tumor selectivity. Here, we report the synthesis and biological evaluation of a novel series of benzofuran-containing naphthalimide derivatives, with particular focus on the lead dinitro-substituted compound 5d. Methods: Cytotoxic activity was assessed using the MTT assay in A549 (p53 wild-type), H1299 (p53-null), and MRC-5 cells. Long-term antiproliferative effects were evaluated by clonogenic survival assay. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Replication stress and DNA damage were quantified by EdU incorporation and γH2AX immunofluorescence, respectively. Apoptosis was assessed by Annexin V/PI staining and caspase-3/7 activation assay. p53 nuclear accumulation and autophagy induction were evaluated by immunofluorescence and Western blot, using LC3 as an autophagic marker. Results: All compounds exhibited cytotoxic activity in the nanomolar range, with 5d emerging as the most potent and selective. Clonogenic survival was significantly reduced, indicating durable suppression of proliferative capacity. Treatment with 5d induced G₁ arrest in A549 cells and the accumulation of H1299 cells in G₂/M, consistent with p53-dependent and p53-independent checkpoint activation, respectively. EdU incorporation was markedly reduced, while γH2AX intensity increased, collectively supporting a replication stress-driven mechanism of DNA damage. Apoptosis was confirmed by increased Annexin V-positive populations and caspase-3/7 activation. LC3 puncta formation and LC3-I/LC3-II conversion were increased, indicating LC3 processing and autophagosome accumulation consistent with the activation of autophagy-related processes. Conclusions: 5d induces a cellular phenotype consistent with replication stress, including reduced EdU incorporation, γH2AX accumulation, cell cycle arrest, and apoptotic cell death in a p53 status-dependent manner. These findings establish benzofuran-annulated naphthalimides as a promising scaffold for the development of anticancer agents that exploit replication stress vulnerabilities in tumor cells. Full article

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

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25 pages, 1032 KB

Open AccessArticle

Mucoadhesive Nanostructured Lipid Carriers of Ketoconazole for Enhanced Dermal Delivery and Antifungal Activity: Formulation Optimization and In Vivo Evaluation

by Mashan Almutairi, Ahmed Adel Ali Youssef, Yazed S. Alsowaida, Ahmed Alobaida and Samir A. Ross

Pharmaceutics 2026, 18(6), 753; https://doi.org/10.3390/pharmaceutics18060753 (registering DOI) - 19 Jun 2026

Abstract

Background/Objective: Topical therapy remains a cornerstone in managing fungal infections due to the deep-seated nature of the pathogens and the persistence of the disease. Ketoconazole (KTZ) is a broad-spectrum antifungal agent, but its highly lipophilic nature presents considerable challenges in developing effective topical [...] Read more.

Background/Objective: Topical therapy remains a cornerstone in managing fungal infections due to the deep-seated nature of the pathogens and the persistence of the disease. Ketoconazole (KTZ) is a broad-spectrum antifungal agent, but its highly lipophilic nature presents considerable challenges in developing effective topical formulations. Additionally, oral KTZ has been subject to labeling restrictions and market withdrawal due to its association with severe hepatic adverse effects. This study was conducted to design, optimize, and evaluate KTZ-loaded nanolipid carriers (NLCs; KTZ-NLCs) as a delivery platform that could improve cutaneous bioavailability and enhance antifungal activity. Methods: The optimized KTZ-NLCs were further incorporated into a mucoadhesive system (KTZ-NLCs-C) through the inclusion of Carbopol^® 940 NF, aiming to improve the retention of the formulation on the skin surface. NLCs were characterized in terms of their physical appearance, particle size, polydispersity index, zeta potential, pH, viscosity, drug content, and entrapment efficiency. The optimized KTZ-NLC and KTZ-NLCs-C formulations were subsequently assessed for in vitro drug release, ex vivo skin permeation and deposition, as well as in vivo skin irritation. Results: In vitro release studies revealed that nanocarrier systems provided a sustained release of KTZ over 24 h. The ex vivo transdermal flux and permeability coefficient of KTZ from the lead KTZ-NLCs-C formulation were approximately 2.8-fold greater than those achieved with the marketed cream formulation. The in vivo skin irritation studies indicate that NLC-based formulations are suitable for topical applications. The lead formulation was stable for 90 days (the final time point evaluated) under refrigerated and room-temperature storage conditions. Conclusions: These findings suggest that the NLC-based system is a promising platform for the topical delivery of KTZ and has the potential to enhance the therapeutic outcomes for patients with superficial fungal infections. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Enhanced Transdermal and Dermal Delivery)

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27 pages, 3096 KB

Open AccessReview

Genetic Interruption of PD-1/PD-L1 as an Alternative Means for Immune Checkpoint Blockade in Cancer: A Review

by Dan Li, Jiao Lu, Qianru Li, Huan Deng and Songwei Tan

Pharmaceutics 2026, 18(6), 752; https://doi.org/10.3390/pharmaceutics18060752 (registering DOI) - 18 Jun 2026

Abstract

Background/Objectives: Immune checkpoints are critical regulatory pathways that maintain peripheral tolerance and prevent autoimmunity. Among these, the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis serves as a major inhibitory pathway that terminates T cell responses. While protein-based checkpoint blockade (ICB) targeting this axis [...] Read more.

Background/Objectives: Immune checkpoints are critical regulatory pathways that maintain peripheral tolerance and prevent autoimmunity. Among these, the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis serves as a major inhibitory pathway that terminates T cell responses. While protein-based checkpoint blockade (ICB) targeting this axis has revolutionized clinical cancer therapy, its clinical efficacy is frequently limited by low response rates, immune-related adverse events (irAEs), and the emergence of adaptive resistance. To break through these bottlenecks, genetic interruption has emerged as a high-precision alternative to modulate the PD-1/PD-L1 pathway at the nucleotide level. Methods: A comprehensive systematic review of literature was performed across major databases (PubMed, Web of Science), with a focus on high quality studies published up to 2026. Results: Direct genomic disruption via CRISPR/Cas9 and post-transcriptional silencing through RNA interference can effectively neutralize inhibitory signaling at its source. Recent advances demonstrate that targeting upstream regulatory nodes—including metabolic checkpoints (e.g., lactate metabolism) and biophysical mechanisms (e.g., liquid–liquid phase separation)—provides superior transcriptional control over PD-L1. Furthermore, engineering CAR-T cells with multiplex gene editing (e.g., TCR/B2M/PD-1 knockout) or localized scFv secretion significantly enhances antitumor potency while reducing systemic toxicity. Innovations in organ-targeted lipid nanoparticles and stimuli-responsive biomimetic carriers further address the delivery barriers in solid tumors. Conclusions: Gene therapy provides a high-precision platform for PD-1/PD-L1 modulation, offering a viable strategy to overcome adaptive resistance. Future clinical application depends on the refinement of safer editing tools, such as base editing, and the standardization of intelligent delivery systems to ensure controllable and scalable cancer immunotherapy. Full article

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

23 pages, 1370 KB

Open AccessArticle

A Novel Herbal Nano-Based Ear Drop with Ocimum gratissimum Essential Oil: An Alternative Strategy for Managing Otomycosis

by Bac V. G. Nguyen, Hoai Thu Le, Tien-Trung Dao, Quy-Nguyen Doan, Duc-Huy Pham, Nghi Bao Nguyen, Minh-Tri Le, Du-Thien Nguyen and Phuoc-Vinh Nguyen

Pharmaceutics 2026, 18(6), 751; https://doi.org/10.3390/pharmaceutics18060751 (registering DOI) - 18 Jun 2026

Abstract

Background/Objectives: Otomycosis is a recurrent fungal infection of the external auditory canal. This disease is difficult to manage with current antifungal agents due to irritation, ototoxicity risk, and emerging resistance. Natural essential oils have been proposed as alternatives, yet their clinical application [...] Read more.

Background/Objectives: Otomycosis is a recurrent fungal infection of the external auditory canal. This disease is difficult to manage with current antifungal agents due to irritation, ototoxicity risk, and emerging resistance. Natural essential oils have been proposed as alternatives, yet their clinical application in otic formulations remains limited due to their poor solubility and stability. In this study, we report the first ear-drop formulation combining microemulsified Ocimum gratissimum essential oil and acetic acid for otomycosis treatment. Methods: The essential oil was quality-validated with eugenol content superior to 60%. A systematic formulation study was performed, and the Tween 20/isopropanol (4:1, w/w) mixture was selected as the optimal surfactant system, yielding a stable microemulsion with high encapsulation efficiency (~98%) and relevant physicochemical stability (up to 28 days). The final formulation containing 1% acetic acid and 0.3% micro-emulsified essential oil met pharmacopeial requirements in terms of appearance, pH, viscosity, and microbial limits. Results: Importantly, this micro-emulsified eardrop demonstrated significantly greater in vitro antifungal activity than 3% boric acid and 2% acetic acid eardrops in twelve clinical fungal isolates from Vietnamese swimmers, especially on Curvularia, Cunninghamella, Aspergillus terreus, and Bipolaris. Although less pronounced than 1% clotrimazole, the finalized formulation demonstrates better antifungal kinetics and a broader activity spectrum. Conclusions: This work provides relevant experimental evidence on the use of Ocimum gratissimum essential oil in a microemulsion delivery system and demonstrates its efficacy against clinically relevant otomycosis pathogens. The results establish a foundation for future in vivo and clinical studies. Full article

(This article belongs to the Special Issue Nanoemulsions for Pharmaceutical and Biomedical Applications)

33 pages, 2033 KB

Open AccessReview

Medicinal Plant-Derived Exosome-like Nanoparticles: From Basic Research to Biomedical Applications

by Huan Deng, Yi-Wen Zhang, Qian-Fu Zhao and Zhi-Jun Huang

Pharmaceutics 2026, 18(6), 750; https://doi.org/10.3390/pharmaceutics18060750 (registering DOI) - 18 Jun 2026

Abstract

Plant-derived exosome-like nanoparticles (PELNs), a subset of extracellular vesicle (EV) secreted by plant cells, have emerged as revolutionary biomaterial with broad applications in biomedicine, agriculture, and nanotechnology. Structurally, PELNs feature a phospholipid bilayer homologous to plant cell membranes, encapsulating bioactive components such as [...] Read more.

Plant-derived exosome-like nanoparticles (PELNs), a subset of extracellular vesicle (EV) secreted by plant cells, have emerged as revolutionary biomaterial with broad applications in biomedicine, agriculture, and nanotechnology. Structurally, PELNs feature a phospholipid bilayer homologous to plant cell membranes, encapsulating bioactive components such as proteins, nucleic acids, lipids, and secondary metabolites. The native structure of PELNs endows them with enhanced bioavailability, reduced immunogenicity, and improved barrier penetration for precise tissue delivery. Recent studies highlight the cross-kingdom therapeutic potential of PELNs in mammals, including antitumor, anti-inflammatory, tissue repair, immunomodulation and so on. This review comprehensively summarized recent advancements in PELN research, including innovative isolation techniques, molecular characterization, their roles in drug delivery and disease therapy. We also discussed challenges in standardization, scalability, and regulatory frameworks which could provide future perspectives for translating PELNs into clinical and industrial applications. Full article

(This article belongs to the Special Issue Delivery System for Biomacromolecule Drugs: Design and Application, 2nd Edition)

19 pages, 6304 KB

Open AccessArticle

Preformulation Studies and Rational Design of an Ointment Containing a Postbiotic Metabolite of Procyanidins for Topical Use

by Tomasz Todryk, Monika Budnicka, Lukasz Pajchel, Hanna Kierońska, Maciej Dawidowski, Krzysztof Adam Stępień, Joanna Giebułtowicz, Sebastian Granica, Joanna Kolmas and Jakub P. Piwowarski

Pharmaceutics 2026, 18(6), 749; https://doi.org/10.3390/pharmaceutics18060749 - 18 Jun 2026

Abstract

Background: 5-(3′,4′-Dihydroxyphenyl)-γ-valerolactone (DHPV) is a postbiotic gut microbiota-derived flavanol metabolite with reported anti-inflammatory activity. Despite growing interest in its potential dermatological applications, its pharmaceutical properties and suitability for topical delivery have not been systematically investigated. This study aimed to perform the first comprehensive [...] Read more.

Background: 5-(3′,4′-Dihydroxyphenyl)-γ-valerolactone (DHPV) is a postbiotic gut microbiota-derived flavanol metabolite with reported anti-inflammatory activity. Despite growing interest in its potential dermatological applications, its pharmaceutical properties and suitability for topical delivery have not been systematically investigated. This study aimed to perform the first comprehensive preformulation and formulation-oriented evaluation of DHPV and to develop stable topical ointment formulations suitable for further dermatological research. Methods: The physicochemical properties of DHPV were characterized using powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), quantitative solubility assessment, and excipient compatibility studies. Based on the obtained preformulation data, two anhydrous ointment formulations containing DHPV were developed. The formulations were evaluated for homogeneity, rheological behavior, chemical stability under accelerated storage conditions, and in vitro drug release performance. Results: DHPV was identified as a crystalline compound with heterogeneous particle morphology and limited aqueous solubility. Quantitative solubility studies demonstrated the highest solubility in PEG 300 and glycol-based solvents. Compatibility testing revealed increased impurity formation in hydrophilic environments, whereas lipophilic excipients provided improved chemical stability. Both ointment formulations exhibited acceptable physical characteristics and maintained DHPV stability throughout accelerated storage. However, marked differences in release behavior were observed. The lipid–wax formulation showed significantly higher release rates, lower variability, and more reproducible release profiles than the petrolatum-based reference formulation, indicating more efficient diffusion of DHPV from the semisolid matrix. Conclusions: The physicochemical characteristics of DHPV strongly influence formulation design and performance. Anhydrous lipid-based systems provide a favorable environment for maintaining DHPV stability, while formulation composition significantly affects drug release. The developed lipid–wax formulation represents a promising platform for future skin permeation, pharmacodynamic, and efficacy studies. Full article

(This article belongs to the Special Issue Research on the Design, Development and Delivery of Topical Drugs)

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20 pages, 1262 KB

Open AccessArticle

Formulation and Evaluation of Fluconazole Containing Sodium Alginate/Methylcellulose-Based Buccal Films for Potential Treatment of Oral Candidiasis

by Adekunle Oduneye Odularu, Anuoluwapo Temitope Adesegun, Chukwuemeka Paul Azubuike and Oluwadamilola Miriam Kolawole

Pharmaceutics 2026, 18(6), 748; https://doi.org/10.3390/pharmaceutics18060748 - 18 Jun 2026

Abstract

Background/Objectives: Oral candidiasis is an infection of the oral cavity caused by Candida albicans. Mucoadhesive buccal films could adhere to the buccal mucosa for prolonged periods, improving the therapeutic outcomes of patients with oral candidiasis. This study aimed to develop and [...] Read more.

Background/Objectives: Oral candidiasis is an infection of the oral cavity caused by Candida albicans. Mucoadhesive buccal films could adhere to the buccal mucosa for prolonged periods, improving the therapeutic outcomes of patients with oral candidiasis. This study aimed to develop and evaluate the properties of fluconazole containing sodium alginate/methylcellulose-based buccal films for potential treatment of oral candidiasis. Methods: Drug-polymer compatibility was investigated using FT-IR spectrophotometry. Three optimised fluconazole films (F1 to F3) containing 1–1.6% sodium alginate and methylcellulose (1.6%) were formulated using the solvent-casting method. Their physicomechanical properties were characterised using standard protocols. Drug content and in vitro drug release profiles were evaluated using UV-visible spectroscopy; in vitro/ex vivo mucoadhesion studies were conducted using the shaking water bath technique, and their antifungal activity against Candida albicans was evaluated using the agar ditch method. Results: FT-IR data analysis revealed that sodium alginate, methylcellulose and fluconazole were compatible in the films. The films were off-white, smooth, peelable, thin, with satisfactory pH values, folding endurance, drug content, excellent zones of inhibition against Candida albicans (40 mm), controlled drug release profile (3.6–4.1 mg/cm² after 6 h), and they displayed Korsmeyer–Peppas drug release kinetics. Film F3 containing 1.6% sodium alginate and 1.6% of methylcellulose exhibited superior swelling index (70 ± 1%), tensile strength (0.68 ± 0.04 MPa) and in vitro/ex vivo mucoadhesion time (5.5 ± 0.3 h; 2.3 ± 0.3 h) relative to other studied films. Conclusions: The sodium alginate content of the films influenced their tensile and mucoadhesive properties. Film F3 was the most promising formulation for potential treatment of oral candidiasis. Full article

(This article belongs to the Section Biopharmaceutics)

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30 pages, 27534 KB

Open AccessArticle

Supercritical CO₂ Antisolvent-Micronised Naringin and Naringenin Alleviate Paclitaxel-Induced Pain Syndrome

by Gabriela Adriany Lisboa Zilli, Samara Cristina Mazon, Patricia Viera de Oliveira, Felipe Zaniol, Eulália Lopes da Silva Barros, Ângela Maria Lodi, Chaiane Lunelli Saretto, Hemyly Cardoso, Ana Lúcia Anversa Segatto, Sara Marchesan Oliveira, J. Vladimir Oliveira and Indiara Brusco

Pharmaceutics 2026, 18(6), 747; https://doi.org/10.3390/pharmaceutics18060747 - 17 Jun 2026

Abstract

Background/Objectives: Paclitaxel is a chemotherapy drug used to treat various tumours, but its use is often limited by an acute and chronic pain syndrome that is poorly managed. Naringin and its aglycone, naringenin, exhibit antioxidant, antitumour, anti-inflammatory, and antinociceptive effects, [...] Read more.

Background/Objectives: Paclitaxel is a chemotherapy drug used to treat various tumours, but its use is often limited by an acute and chronic pain syndrome that is poorly managed. Naringin and its aglycone, naringenin, exhibit antioxidant, antitumour, anti-inflammatory, and antinociceptive effects, making them potential alternative treatments. However, their low water solubility limits their oral bioavailability in humans. Micronisation in a supercritical medium reduces particle size and enhances the dissolution of compounds, offering a possible solution. In this study, we investigated whether micronising naringin and naringenin via supercritical technology could improve their dissolution and oral efficacy against paclitaxel-induced pain syndrome. Methods: Micronisation was performed using supercritical CO₂. Molecular docking was used to analyse the binding of naringin and naringenin to TRPV1, a key target for pain relief. Swiss mice were used in capsaicin (TRPV1 agonist)-induced nociception and paclitaxel-caused acute and chronic pain models. We assessed mechanical, cold, and heat sensitivity, potential adverse effects, and TRPV1 mRNA expression. Results: Micronisation improved the apparent dissolution profile of molecules. Docking results showed that naringin and naringenin bind to TRPV1. Both micronised compounds reduced capsaicin-induced nociception without affecting locomotion or body temperature. Micronised naringin and naringenin alleviated mechanical and cold allodynia, as well as thermal hyperalgesia in both acute and chronic paclitaxel-induced pain, outperforming their conventional forms. They also downregulated TRPV1 mRNA expression in the mice’s sciatic nerve. Conclusions: Taken together, these results show that supercritical micronisation improved the apparent dissolution and oral antinociceptive efficacy of naringin and naringenin, emphasising their potential as promising alternatives for managing paclitaxel-induced pain, with TRPV1 being a probable contributor to the observed antinociceptive effects. Full article

(This article belongs to the Special Issue Advances in Polymer-Based Devices and Platforms for Pain Management)

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19 pages, 2977 KB

Open AccessArticle

Thymoquinone-Loaded Electrospun Fibrous Mats as Advanced Wound Dressing Materials

by Magdalena Paczkowska-Walendowska, Elwira Sieniawska, Zbigniew Krasiński, Judyta Cielecka-Piontek and Krystyna Skalicka-Woźniak

Pharmaceutics 2026, 18(6), 746; https://doi.org/10.3390/pharmaceutics18060746 - 17 Jun 2026

Abstract

Background: Thymoquinone (TQ), a bioactive compound derived from Nigella sativa L., exhibits promising antioxidant, anti-inflammatory, and wound-healing properties; however, its clinical application is limited by poor solubility and instability. Methods: In this study, three electrospun nanofiber systems based on different polymeric matrices, PVP [...] Read more.

Background: Thymoquinone (TQ), a bioactive compound derived from Nigella sativa L., exhibits promising antioxidant, anti-inflammatory, and wound-healing properties; however, its clinical application is limited by poor solubility and instability. Methods: In this study, three electrospun nanofiber systems based on different polymeric matrices, PVP (N1), PVP/HPβCD (N2), and PVP/PCL (N3), were developed as potential wound dressing materials for controlled TQ delivery. Results: All formulations produced uniform nanofibrous structures with TQ molecularly dispersed within the polymer matrix, as confirmed by SEM, XRPD, and FTIR analyses. The composition of the nanofibers significantly influenced their physicochemical and functional properties. The N2 system, containing hydroxypropyl-β-cyclodextrin (HPβCD), exhibited the smallest fiber diameter (~208 nm), the fastest drug release, and enhanced antioxidant and anti-inflammatory activity due to improved TQ solubility. In contrast, the N3 system, incorporating polycaprolactone (PCL), formed thicker fibers (~1089 nm) and demonstrated sustained release behavior, the highest mucoadhesion, and the most pronounced wound-healing effect (90% closure after 24 h). Stability studies revealed that HPβCD significantly improved TQ resistance to thermal, humidity, and photolytic degradation, whereas the PVP-based system without stabilizers showed the lowest stability. Principal component analysis (PCA) confirmed that nanofiber performance is governed by two key factors: drug availability and sustained release combined with bioadhesion. Importantly, wound-healing efficiency correlated more strongly with the latter. Conclusions: The results demonstrate that rational design of polymer composition enables modulation of TQ delivery and biological response. Among the tested systems, PVP/PCL nanofibers appear to be the most promising candidates for wound-dressing applications due to their ability to provide sustained drug release and enhance tissue regeneration. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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26 pages, 19353 KB

Open AccessArticle

Development and Characterization of a Stable Oil-in-Water Nanoemulsion Using Impingement Jet Mixing and Lyophilization Techniques

by Anna Shao, Jingyan Zhang, Zhaowei Jin, Yao Li, Jialin Tang, Quanmin Chen, Hongbing Wu and Jeremy Guo

Pharmaceutics 2026, 18(6), 745; https://doi.org/10.3390/pharmaceutics18060745 - 17 Jun 2026

Abstract

Nanoemulsion (NEM) is an effective adjuvant and delivery system for vaccines and nucleic acids, capable of inducing immune responses against diverse pathogens. Background/Objectives: Conventional NEM manufacture uses multi-step operations, typically high-shear homogenization and then microfluidization (HSHM), thereby increasing process complexity and contamination [...] Read more.

Nanoemulsion (NEM) is an effective adjuvant and delivery system for vaccines and nucleic acids, capable of inducing immune responses against diverse pathogens. Background/Objectives: Conventional NEM manufacture uses multi-step operations, typically high-shear homogenization and then microfluidization (HSHM), thereby increasing process complexity and contamination risk. As water-rich colloidal dispersions, NEM is prone to microbial proliferation and droplet coalescence; freezing further disrupts microstructure, causing phase fusion and separation, so NEM adjuvants are often stored separately from antigens in multi-vial formats. Lyophilization could reduce cold-chain dependence and enable single-vial products, but there is no systematic study on lyoprotectants comparation and process optimization of lyophilized NEM. Methods: An impingement jet mixing (IJM) process was evaluated as a simplified, scalable route for NEM production. Key IJM parameters, including flow ratio, total flow rate, preparation temperature, microchannel type, and shear mode—were examined to match attributes of conventional HSHM. Lyophilized and reconstituted NEM were characterized by dynamic light scattering, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry and/or in vitro potency to inform lyoprotectant selection, and Taguchi Design of Experiment (DOE) methodology guided lyophilization processes. Results: IJM yielded NEM with droplet size, polydispersity index (PDI) and morphology comparable to HSHM, with higher throughput and fewer unit operations. Optimized lyophilization technique with designed lyoprotectant and process formed closed structures to prevent the easy-to-flow monolayer of the emulsion from fusing, producing robust and stable NEM. Conclusions: Coupling IJM with targeted lyophilization establishes a scalable, lower-risk manufacturing paradigm for NEM that preserves critical quality attributes, reduces cold-chain reliance and enables single-vial adjuvanted vaccine formats with tangible industrial and clinical benefits. Full article

(This article belongs to the Special Issue Advancements in Industrial Pharmaceutics: Innovations and Future Directions)

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32 pages, 1689 KB

Open AccessReview

Polymeric Micelle Systems for Oral Drug Delivery of Small Molecule Therapeutics

by Eungyeop Lee, Jum Bum Kwon, Hyuk Jun Cho, Mi Ran Woo, Dong Wuk Kim, Jong Oh Kim and Duhyeong Hwang

Pharmaceutics 2026, 18(6), 744; https://doi.org/10.3390/pharmaceutics18060744 - 16 Jun 2026

Abstract

Oral administration remains the most convenient and favored route for systemic delivery of small-molecule drugs, primarily due to patient compliance and the absence of invasive procedures. Yet, poor aqueous solubility, chemical/enzymatic instability, and limited permeability in the gastrointestinal (GI) tract often result in [...] Read more.

Oral administration remains the most convenient and favored route for systemic delivery of small-molecule drugs, primarily due to patient compliance and the absence of invasive procedures. Yet, poor aqueous solubility, chemical/enzymatic instability, and limited permeability in the gastrointestinal (GI) tract often result in low bioavailability (BA) of many therapeutic agents. Polymeric micelles formed from the self-assembly of amphiphilic block copolymers have gained considerable attention as a nanotechnology-driven solution to overcome these challenges. Their hydrophobic core–hydrophilic shell structure enables efficient encapsulation of poorly soluble small molecule drugs, providing protection from acidic or enzymatic degradation while potentially enhancing drug transport across the intestinal epithelium. This review examines the design principles, formulation strategies, and in vivo performance of polymeric micelles for oral delivery of small molecule drugs. We discuss strategies to improve micelle stability in the GI environment, including optimization of core hydrophobicity, kinetic stabilization, and corona engineering, and compare polymeric micelles with established alternatives such as self-micro emulsifying drug delivery system (SMEDDS) and amorphous solid dispersions (ASDs) across critical performance parameters. Despite decades of preclinical progress, no oral polymeric micelle formulation has reached regulatory approval, underscoring the persistent challenge of maintaining micellar structural integrity under the dynamic conditions of the GI environment. This review therefore examines not only the promise but also the structural vulnerabilities of oral micelles, proposing a stability-centered framework for interpreting micelle function under GI conditions. Finally, we discuss current translational challenges and suggest directions for future research toward clinical application of oral polymeric micelle systems. Full article

(This article belongs to the Special Issue Polymer Systems for Drug-Delivery Applications)

26 pages, 1343 KB

Open AccessReview

Interpreting the Black Box: Interpretable Machine Learning and Systems Pharmacology in Small-Molecule Therapeutics

by Huan Zhang, Yangyang Wang, Jihan Wang and Hui Li

Pharmaceutics 2026, 18(6), 743; https://doi.org/10.3390/pharmaceutics18060743 - 16 Jun 2026

Abstract

Small-molecule drug development faces high attrition rates driven by complex pharmacokinetics and unforeseen toxicities. While deep learning offers high predictive accuracy, its opaque “black-box” nature hinders mechanistic transparency, clinical trust, and regulatory approval. This review synthesizes how Interpretable Machine Learning, synergized with systems [...] Read more.

Small-molecule drug development faces high attrition rates driven by complex pharmacokinetics and unforeseen toxicities. While deep learning offers high predictive accuracy, its opaque “black-box” nature hinders mechanistic transparency, clinical trust, and regulatory approval. This review synthesizes how Interpretable Machine Learning, synergized with systems pharmacology, advances this paradigm by enhancing mechanistic transparency in drug development. By providing insights into algorithmic decisions, Interpretable Machine Learning helps researchers identify molecular features that are statistically associated with absorption, distribution, metabolism, and excretion optimization and preemptively mitigate toxicophores, while noting that these associations require experimental validation to establish genuine causality. Furthermore, integrating multi-omics data via Interpretable Machine Learning guides rational polypharmacology, bridging in silico target identification with “dry-wet loop” validations. Crucially, Interpretable Machine Learning accelerates clinical translation by discovering causal biomarkers, refining patient stratification, and generating transparent “Model Cards” to satisfy U.S. Food and Drug Administration/ European Medicines Agency regulations. We also discuss future challenges: data heterogeneity, out-of-distribution generalizability, and the evolution toward Causal Artificial Intelligence. Ultimately, the integration of Interpretable Machine Learning provides a framework for more transparent and evidence-based drug design, realizing the promise of precision medicine. Full article

(This article belongs to the Special Issue Advanced Algorithms for Small-Molecule Therapeutics Development)

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26 pages, 1440 KB

Open AccessReview

Magnetic Fields in Cancer Therapy: Mechanistic Insights, Signaling Pathways, and Evidence from Clinical and In Vitro Studies

by Sadettin Berkay Sarli and Asiye Busra Boz Er

Pharmaceutics 2026, 18(6), 742; https://doi.org/10.3390/pharmaceutics18060742 - 15 Jun 2026

Abstract

Magnetic fields (MFs) represent an emerging modality in cancer therapy, encompassing static, low-frequency, pulsed, and nanoparticle-mediated alternating fields. These interventions have demonstrated the capacity to modulate proliferation, apoptosis, ferroptosis, migration, and epithelial-to-mesenchymal transition (EMT) in tumor cells, often through reactive oxygen species (ROS) [...] Read more.

Magnetic fields (MFs) represent an emerging modality in cancer therapy, encompassing static, low-frequency, pulsed, and nanoparticle-mediated alternating fields. These interventions have demonstrated the capacity to modulate proliferation, apoptosis, ferroptosis, migration, and epithelial-to-mesenchymal transition (EMT) in tumor cells, often through reactive oxygen species (ROS) modulation, ion channel regulation, membrane receptor dynamics, and lysosomal membrane permeabilization. Magnetic nanoparticle hyperthermia (MHT) has reached clinical application, showing promising outcomes in glioblastoma and prostate cancer, while pulsed electromagnetic fields (PEMFs) and magneto-mechanical approaches are under preclinical investigation. The mechanistic diversity of MFs allows synergistic combination with chemotherapy, radiotherapy, and immunotherapy. However, parameter sensitivity, field standardization, and long-term safety remain challenges. Here, we review mechanistic insights, signaling pathways, and experimental and clinical evidence for MF-based cancer therapies, highlighting translational potential and the need for rigorous optimization to realize clinical efficacy. Full article

(This article belongs to the Special Issue Magnetic Materials for Biomedical Applications)

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45 pages, 11152 KB

Open AccessReview

Molecular Docking of Natural Compounds as DPP-4 Inhibitors in Type 2 Diabetes: A Comprehensive Review

by Justyna Baranowska, Anna Kiss and Łukasz Szeleszczuk

Pharmaceutics 2026, 18(6), 741; https://doi.org/10.3390/pharmaceutics18060741 - 15 Jun 2026

Abstract

Dipeptidyl peptidase-4 (DPP-4) is an established therapeutic target in the treatment of type 2 diabetes mellitus (T2DM), primarily due to its role in regulating incretin activity and glucose homeostasis. Although clinically approved DPP-4 inhibitors are widely used, their moderate efficacy has driven the [...] Read more.

Dipeptidyl peptidase-4 (DPP-4) is an established therapeutic target in the treatment of type 2 diabetes mellitus (T2DM), primarily due to its role in regulating incretin activity and glucose homeostasis. Although clinically approved DPP-4 inhibitors are widely used, their moderate efficacy has driven the search for novel compounds with improved properties. In this context, natural products have attracted considerable attention as a source of structurally diverse and biologically active molecules. At the same time, molecular docking has emerged as a key computational tool for the identification and evaluation of potential DPP-4 inhibitors. This review summarizes and critically analyzes current molecular docking studies of natural compounds targeting DPP-4. Over 150 studies were evaluated with respect to docking methodologies, selection of protein structures, and validation strategies. The results reveal substantial variability in computational protocols. Frequently used protein structures include ligand-bound DPP-4 models such as 1X70 and 6B1E. Among the investigated compounds, flavonoids represent the most extensively studied class, followed by alkaloids, phenolics, terpenoids, and peptides. Despite numerous reports of favorable binding interactions within the DPP-4 active site, many studies rely solely on docking results without further validation. The limited use of molecular dynamics simulations and experimental assays highlights a significant gap in the current literature. Overall, while molecular docking provides valuable preliminary insights, improved standardization and integration with complementary approaches are essential to enhance the reliability and translational relevance of in silico findings. Full article

(This article belongs to the Special Issue Studies of Protein–Ligand Interactions in the Evaluation of the Biological Activity of Compounds)

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