Pharmaceutics

24 pages, 2223 KB

Open AccessArticle

Stability Assessment of Compounded Niaprazine Oral Solutions to Support an Evidence-Based Beyond-Use Date

by Antonio Lopalco, Borja Martínez-Alonso, Marina Cortellino, Cosimo Annese, Alexia Barbarossa, Catiana Mirgaldi, Angela Sanrocco, Stefania Antonacci, Sergio Fontana, Angela Assunta Lopedota and Nunzio Denora

Pharmaceutics 2026, 18(8), 1006; https://doi.org/10.3390/pharmaceutics18081006 (registering DOI) - 14 Aug 2026

Abstract

Background/Objectives: Niaprazine is widely used for the management of sleep disorders in pediatric and geriatric patients; however, no commercially available oral liquid formulation is currently available in Italy, making extemporaneous compounding necessary. In routine practice, the beyond-use date (BUD) is often limited [...] Read more.

Background/Objectives: Niaprazine is widely used for the management of sleep disorders in pediatric and geriatric patients; however, no commercially available oral liquid formulation is currently available in Italy, making extemporaneous compounding necessary. In routine practice, the beyond-use date (BUD) is often limited to 30 days, potentially affecting therapeutic continuity. This study aimed to evaluate the chemical, physical, and microbiological stability of a compounded niaprazine syrup to support evidence-based BUD and to assess the suitability of selected ready-to-use compounding vehicles for preparing alternative niaprazine oral liquid formulations. Methods: A niaprazine syrup (3 mg·mL⁻¹) was prepared in a sucrose-based vehicle acidified with tartaric acid and preserved with potassium sorbate. Chemical stability of niaprazine was evaluated by high-performance liquid chromatography coupled with diode array detector (HPLC-DAD), whose specificity was confirmed by forced degradation studies. Stability was monitored for up to 9 months at 4–8, 25, and 40 °C and confirmed after 12 months by HPLC-DAD and mass spectrometry (MS). Physical stability of the formulation was monitored by pH and visual inspection up to 12 months. Microbiological quality was assessed for 2 months at 4–8 and 25 °C according to the European Pharmacopoeia. In parallel, four selected ready-to-use compounding vehicles were evaluated for their suitability to prepare stable niaprazine oral liquid formulations. Results: Niaprazine concentrations in the syrup remained within pharmacopeial acceptance limits (±10%) at all temperatures, although a decrease was observed under accelerated conditions (40 °C). pH remained stable (≤0.5-unit variation) and the formulation stayed clear and homogeneous throughout the study, with only minor visual changes after prolonged storage at 40 °C. Statistically significant differences (p < 0.05) were observed in both the HPLC-DAD and HPLC-MS datasets. Microbiological testing confirmed compliance up to 2 months at 4–8 and 25 °C (TAMC ≤ 10³ CFU/mL; TYMC ≤ 10² CFU/mL; Escherichia coli absent). Comparable chemical and physical stability was observed for three of the four formulations prepared with the ready-to-use vehicles over at least two months. Conclusions: The compounded niaprazine syrup demonstrated chemical, physical, and microbiological stability under refrigerated and room-temperature storage, supporting evidence-based beyond-use dating of up to two months under the tested conditions. Ready-to-use vehicles may represent a practical complementary approach, offering standardized alternatives for the preparation of niaprazine oral liquid formulations. Full article

(This article belongs to the Special Issue Pharmacy Compounding of Personalized Preparation for Specific Patients: Challenges and Advantages, 2nd Edition)

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19 pages, 1581 KB

Open AccessReview

Machine Learning for Valproic Acid Therapy: A Scoping Review of Pharmacokinetic-Prediction Models and Pharmacokinetic-Informed Clinical Outcome Models

by Janthima Methaneethorn, Supavadee Aramvith, Wanaporn Charoenchokthavee, Sohaib Habiballah, Khanita Duangchaemkarn and Brad Reisfeld

Pharmaceutics 2026, 18(8), 1005; https://doi.org/10.3390/pharmaceutics18081005 - 14 Aug 2026

Abstract

Background/Objectives: Population pharmacokinetics (PopPK) has been used to aid valproic acid (VPA) dose individualization. However, this approach faces limitations owing to the complexity and high dimensionality of datasets. Machine learning (ML) can handle these challenges. However, the comparative evaluation of these ML [...] Read more.

Background/Objectives: Population pharmacokinetics (PopPK) has been used to aid valproic acid (VPA) dose individualization. However, this approach faces limitations owing to the complexity and high dimensionality of datasets. Machine learning (ML) can handle these challenges. However, the comparative evaluation of these ML algorithms and their practical application in optimizing VPA therapy have not yet been established. This review aims to summarize the current evidence, identify research gaps, and outline ML applications for VPA in clinical practice. Methods: PubMed, ScienceDirect, Scopus, the Association for Computing Machinery (ACM) Digital Library, and IEEE Xplore were searched from inception to October 2025. Eligible studies included original research articles using ML models to predict VPA pharmacokinetics or clinical outcomes (e.g., seizure control). Data on study design, population characteristics, features, predicted targets, ML algorithms, validation method, and model performance metrics were extracted. Results: Eleven studies were included. Most studies were retrospective, single-center designs. Ensemble tree-based models such as Random Forest, CatBoost, Gradient Boosted Regression Trees, and other ensemble methods, were consistently among the top-performing algorithms. Final models retained 3 to 19 input features, with daily dose, albumin, and body weight being the most common predictors. Only five studies performed external validation, limiting the generalizability of the models. Conclusions: Current VPA ML models demonstrated promising predictive performance. Nonetheless, most models are retrospective and single-center, with only limited external validation. Future VPA ML studies should use multicenter datasets and apply external evaluation to enhance model generalizability for clinical use. Full article

(This article belongs to the Topic New Approaches to Machine Learning Parameters in Pharmacology and Pharmacotherapy for Drug Targeting and Precision Medicine)

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23 pages, 4213 KB

Open AccessReview

Azithromycin in Dentistry: From Systemic Antibiotic to a Candidate for Local Therapeutic Delivery

by Jakub Kwiatek, Magdalena Paczkowska-Walendowska and Judyta Cielecka-Piontek

Pharmaceutics 2026, 18(8), 1004; https://doi.org/10.3390/pharmaceutics18081004 - 14 Aug 2026

Abstract

Azithromycin is widely used in dentistry as a systemic antibiotic, particularly for odontogenic infections and as an alternative in patients with β-lactam hypersensitivity. Beyond its antimicrobial activity, azithromycin possesses unique pharmacokinetic, anti-inflammatory, immunomodulatory, and anti-biofilm properties. Together with growing concerns regarding antimicrobial resistance [...] Read more.

Azithromycin is widely used in dentistry as a systemic antibiotic, particularly for odontogenic infections and as an alternative in patients with β-lactam hypersensitivity. Beyond its antimicrobial activity, azithromycin possesses unique pharmacokinetic, anti-inflammatory, immunomodulatory, and anti-biofilm properties. Together with growing concerns regarding antimicrobial resistance and antibiotic stewardship, these characteristics have stimulated interest in local drug-delivery strategies that may reduce systemic antibiotic exposure while maintaining therapeutic efficacy. This narrative review evaluates the rationale, potential clinical applications, and current evidence supporting local azithromycin delivery in dentistry. The available literature on azithromycin pharmacology, systemic dental use, immunomodulatory mechanisms, biofilm-related effects, local drug-delivery systems, safety, and regulatory considerations was critically reviewed. Current evidence suggests that locally delivered azithromycin may achieve high drug concentrations at the target site, enhance anti-biofilm activity, modulate local inflammation, and minimize systemic exposure. Potential applications include periodontitis, peri-implant diseases, persistent endodontic infections, oral surgery, and regenerative procedures such as bone augmentation and maxillary sinus floor elevation. Emerging delivery platforms, such as hydrogels, thermoresponsive gels, nanoparticles, and chitosan-based systems, further support the feasibility of this approach. Experimental findings also indicate that azithromycin may inhibit osteoclast activity, suggesting additional benefits for bone preservation and regenerative healing. Despite these promising findings, current evidence remains limited and is derived mainly from preclinical studies and small clinical investigations. Further translational research and well-designed randomized controlled trials are needed to establish the safety, efficacy, and optimal clinical role of locally delivered azithromycin in evidence-based dental practice. Full article

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

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20 pages, 10102 KB

Open AccessArticle

Hyaluronic Acid Hydrogel Incorporating Dexpanthenol-Engineered Extracellular Vesicles for Accelerated Wound Closure and Mitigated Secondary Infection Risk

by Hyeyoung Shin, Juwon Youn, Chang Kyu Lee, Seungwoon Baik, Tae-Keun Ahn and Dong Keun Han

Pharmaceutics 2026, 18(8), 1003; https://doi.org/10.3390/pharmaceutics18081003 - 13 Aug 2026

Abstract

Background: Loss of epithelial integrity leaves the wound bed open to opportunistic bacterial colonization, and the risk of secondary infection persists for as long as the defect remains unclosed. Wound dressings must therefore provide an immediate external barrier while accelerating restoration of the [...] Read more.

Background: Loss of epithelial integrity leaves the wound bed open to opportunistic bacterial colonization, and the risk of secondary infection persists for as long as the defect remains unclosed. Wound dressings must therefore provide an immediate external barrier while accelerating restoration of the skin’s own barrier. This study aims to develop and evaluate a bioactive nanotechnological platform comprising dexpanthenol (Dxp)-engineered extracellular vesicles (EVs) embedded within cross-linked hyaluronic acid hydrogels (HA@Dxp-engineered EVs) for targeted wound treatment and protection against external contaminants. Methods: EVs were engineered via exogenous (extrusion; Exo EV) and endogenous (co-incubation; Endo EV) strategies to encapsulate Dxp. The physicochemical properties of the HA@Dxp-engineered EV systems were characterized, and their therapeutic efficacy was validated through in vitro assays, including fibroblast migration and endothelial tube formation, and in vivo using a full-thickness excisional wound model in mice. Results: Both engineering strategies successfully encapsulated Dxp while preserving the structural integrity of the EVs. The HA hydrogel enabled sustained EV release and provided a physical barrier. In vitro, HA@Endo EVs significantly promoted fibroblast proliferation, migration, and the formation of mature capillary-like networks in HUVECs compared to controls. In vivo, the HA@Endo EV group demonstrated accelerated wound closure, achieving 99.88% healing by day 10, and promoted tissue remodeling with upregulated expression of COL1A1, VEGF, and HIF-1α. Conclusions: The HA@Endo EV system provides a dual-action strategy against secondary infection risk. It supplies an immediate physical barrier over the wound bed and simultaneously accelerates re-epithelialization, thereby shortening the interval during which the tissue remains exposed. Full article

(This article belongs to the Special Issue Development of New Nanotechnological Systems Loaded with Drugs for Infectious Disease Application, 2nd Edition)

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39 pages, 105461 KB

Open AccessArticle

Precision Drug Delivery of LY-11h for Acute Myeloid Leukemia Treatment Using Machine Learning-Assisted Hot Melt Extrusion and 3D-Printed Technologies

by Lianghao Huang, Danhui Li, Tiantian Yang, Weiwei Yang, Minqing Zhu, Xia Zhao and Jiaxiang Zhang

Pharmaceutics 2026, 18(8), 1002; https://doi.org/10.3390/pharmaceutics18081002 - 13 Aug 2026

Abstract

Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy, and LY-11h is a novel acylhydrazide-based histone deacetylase inhibitor with promising therapeutic potential for AML. However, its poor aqueous solubility, limited intestinal dissolution, and narrow therapeutic window hinder oral formulation [...] Read more.

Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy, and LY-11h is a novel acylhydrazide-based histone deacetylase inhibitor with promising therapeutic potential for AML. However, its poor aqueous solubility, limited intestinal dissolution, and narrow therapeutic window hinder oral formulation development and motivate the development of dosage forms with flexible dose-design capabilities. Herein, an integrated hot-melt extrusion (HME)–fused deposition modeling (FDM) strategy was developed to convert LY-11h into printable amorphous solid dispersion (ASD) dosage forms. Methods: HPMC-AS was used as a pH-responsive carrier to enhance intestinal release while restricting premature gastric release, and HPC-EF was incorporated to improve filament processability. Single-factor and DoE studies identified critical formulation and process variables and established formulation–process–property relationships, while machine learning further modeled nonlinear interactions and guided optimization. In-line near-infrared spectroscopy combined with polarized light microscopy enabled real-time monitoring of LY-11h amorphization and melt homogenization during HME. Results: ExtraTrees and Bagging models showed promising predictive performance for key filament properties, and PAT-stage validation confirmed strong agreement with experimental values. The 15 DoE-designed ASD filaments were successfully fabricated into FDM-printed tablets with reproducible geometry. Equilibrium-solubility and in vitro dissolution studies demonstrated enhanced intestinal-pH solubility and reproducible pH-responsive release. Conclusions: Collectively, these findings establish a technological proof of concept for the manufacture of LY-11h dosage forms with adjustable formulation and geometric attributes. Further in vivo pharmacokinetic studies are required to determine whether these manufacturing capabilities translate into predictable dose–exposure relationships and individualized dose control. Full article

(This article belongs to the Special Issue Advances in AI-Driven Drug Delivery Systems)

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21 pages, 2223 KB

Open AccessArticle

Physiologically Based Pharmacokinetic Modeling of Di(2-ethylhexyl) Adipate and Its Primary Metabolite, Mono(2-ethylhexyl) Adipate, in Rats, Incorporating Circulatory Topology-Based Multi-Tissue Metabolism and Lymphatic Absorption

by Eunsuk Yang, Yoo-Seong Jeong, Minsang Kim, Seungchan Kim and Suk-Jae Chung

Pharmaceutics 2026, 18(8), 1001; https://doi.org/10.3390/pharmaceutics18081001 - 13 Aug 2026

Abstract

Background/Objectives: Di(2-ethylhexyl) adipate (DEHA), a biocompatible ester plasticizer, has gained interest as a potential pharmaceutical excipient, yet its pharmacokinetics remain poorly characterized. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), in [...] Read more.

Background/Objectives: Di(2-ethylhexyl) adipate (DEHA), a biocompatible ester plasticizer, has gained interest as a potential pharmaceutical excipient, yet its pharmacokinetics remain poorly characterized. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), in rats by integrating in vitro, in vivo, in silico, and physiological data. Methods: In vitro hydrolysis was evaluated across tissues using bis-(p-nitrophenyl) phosphate (BNPP) to distinguish BNPP-sensitive and -insensitive metabolism, and tissue-specific clearances were extrapolated to the whole body using a circulatory topology-based framework accounting for sequential extraction across tissues, venous blood, and lungs. Results: Both adipates underwent rapid BNPP-sensitive hydrolysis across multiple tissues, whereas DEHA additionally exhibited BNPP-insensitive metabolism. The framework yielded reasonable estimates of the observed arterial clearance in vivo. Following oral administration, DEHA showed a reproducible double-peak plasma profile, with lymphatic transport identified as the predominant absorption route responsible for the prolonged terminal phase. The final model adequately reproduced the plasma and mesenteric lymph concentration-time profiles of DEHA and MEHA following both intravenous and oral administration. Conclusions: By integrating multi-tissue metabolism, circulatory topology, and lymphatic absorption, this study provides a quantitative framework applicable to rapidly hydrolyzed, highly lipophilic ester compounds, including pharmaceutical excipients and ester prodrugs. Full article

(This article belongs to the Special Issue Advances in Physiologically-Based Pharmacokinetic Modeling)

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19 pages, 26637 KB

Open AccessArticle

Biomimetic ZIF-8 Nanoplatform for Enhanced Therapeutic Efficacy of Combined Phototherapy and Chemotherapy Against Hepatocellular Carcinoma

by Xinlei Lin, Shaoteng Huang, Ning Zheng, Wenjie Yao, Mingbo Zhang, Qingqing Tu, Longhua Shen, Tao Wang, Gang Niu, Fang Wang, Junyang Zhuang, Yang Chen and Ning Li

Pharmaceutics 2026, 18(8), 1000; https://doi.org/10.3390/pharmaceutics18081000 - 13 Aug 2026

Abstract

Background: Hepatocellular carcinoma (HCC) remains challenging to treat because of the limited therapeutic efficacy and insufficient selectivity of conventional therapies. To overcome these limitations, multifunctional nanoplatforms integrating biomimetic strategies and combination therapy have attracted increasing attention. Single-modality therapies are often limited by [...] Read more.

Background: Hepatocellular carcinoma (HCC) remains challenging to treat because of the limited therapeutic efficacy and insufficient selectivity of conventional therapies. To overcome these limitations, multifunctional nanoplatforms integrating biomimetic strategies and combination therapy have attracted increasing attention. Single-modality therapies are often limited by insufficient therapeutic efficacy and restricted mechanisms of action, highlighting the need for biomimetic nanoplatforms that integrate combination therapeutic strategies for enhanced antitumor performance. Methods: Herein, a biomimetic strategy-based nanoplatform (DI-ZM) was constructed via a combination of ZIF-8 biomineralization, physical adsorption of dihydroartemisinin (DHA) and indocyanine green (ICG), followed by HepG2 cell membrane coating to achieve homologous interaction. This design enables integrated chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) within a single system. Results: The resulting DI-ZM nanoparticles exhibited a hydrodynamic diameter of approximately ~200 nm with good colloidal stability and high drug-loading capacity. Under 808 nm laser irradiation, DI-ZM achieved a temperature elevation to ~66 °C within 5 min, together with efficient ROS generation. Compared with uncoated nanoparticles, the biomimetic membrane coating significantly enhanced cellular uptake and homologous targeting ability, as confirmed by CLSM and flow cytometry analysis. Benefiting from the biomimetic membrane coating, DI-ZM further exhibited improved homologous targeting and cellular uptake, which contributed to enhanced intracellular ROS generation. This was accompanied by significant mitochondrial membrane depolarization and apoptosis rates exceeding 80% in HepG2 cells under laser irradiation, ultimately resulting in markedly enhanced cytotoxicity. In addition, the biomimetic membrane coating also enabled efficient penetration of DI-ZM into multicellular tumor spheroids, indicating its improved tumor-penetration capability. In vivo antitumor studies further revealed effective tumor suppression with a tumor inhibition rate of approximately 97%, along with acceptable systemic tolerance in HepG2 tumor-bearing mice. Conclusion: The biomimetic membrane-coated ZIF-8 nanoplatform integrating chemotherapy with ICG-mediated phototherapy (photothermal and photodynamic therapy) provides an effective strategy for the combination therapy against HCC. Full article

(This article belongs to the Special Issue Emerging Trends and Advancements in Anticancer Photodynamic Therapy: Innovative Delivery Systems, Translational Insights, and Breakthroughs)

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33 pages, 5189 KB

Open AccessReview

Nanotechnology in Pediatric Neurology: Applications and Innovations

by Raluca Ioana Teleanu, Ioana Alexandra Lungescu, Adelina-Gabriela Niculescu, Ana Cojocaru, Radu Ștefan Perjoc, Bianca Teodora Chenescu, Eugenia Roza, Oana Aurelia Vladâcenco, Alexandru Mihai Grumezescu and Daniel Mihai Teleanu

Pharmaceutics 2026, 18(8), 999; https://doi.org/10.3390/pharmaceutics18080999 - 13 Aug 2026

Abstract

Nanotechnology is rapidly transforming the perspective on pediatric neurology, enabling diagnostic, therapeutic, and monitoring strategies tailored to the unique features of neurological illnesses in children. This review acknowledges the problems caused by delays in diagnosis, the limitations of conventional procedures, and the need [...] Read more.

Nanotechnology is rapidly transforming the perspective on pediatric neurology, enabling diagnostic, therapeutic, and monitoring strategies tailored to the unique features of neurological illnesses in children. This review acknowledges the problems caused by delays in diagnosis, the limitations of conventional procedures, and the need for new, focused approaches, highlighting recent advances in nanoscale materials and smart nanocarriers. Specifically, this paper summarizes advances in nanomaterials that can overcome physiological barriers, such as the developing blood–brain barrier (BBB) and age-dependent pharmacokinetics. We discuss innovations in stimuli-responsive delivery systems, theranostic platforms, and multimodal nanohybrids designed for precise targeting and real-time treatment monitoring. Special emphasis is placed on pediatric-specific considerations, including developmental differences in immune and metabolic responses, the necessity for age-adjusted dosing, and the potential long-term safety implications of nanoparticle exposure. Transformative applications are explored in various pediatric neurological conditions, including brain tumors, epilepsy, neurodevelopmental disorders, and rare degenerative diseases, emphasizing both achievements and challenges in translation. This paper evaluates various regulatory, ethical, and societal factors, alongside the integration of converging technologies such as AI-driven nanoparticle optimization, brain organoids, and digital twins to accelerate personalized therapy development. Conclusively, this paper emphasizes the importance of interdisciplinary collaboration, pediatric-focused clinical trial designs, and sustained investment to fully realize the potential of nanotechnology in improving neurological outcomes for children. Full article

(This article belongs to the Special Issue Advances and Challenges in Nanomedicine: Translating Nanotechnology into Therapeutics for Cancer, Neurodegenerative, and Infectious Diseases)

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17 pages, 11901 KB

Open AccessArticle

Potential of Fenofibric Acid as Topical Eye Drops for Management of Dry Eye Syndrome

by Guilin Tan, Miao Chen, Peng Xie, Chengying Bian, Weizhuo Wang, Shaoqun Wu, Yuanhui Jin and Lingyun Cheng

Pharmaceutics 2026, 18(8), 998; https://doi.org/10.3390/pharmaceutics18080998 - 13 Aug 2026

Abstract

Background/Objectives: Ocular surface inflammation has been identified as a key causative factor for dry eye. The current study investigates the feasibility, safety, and efficacy of fenofibric acid (FFA) as a topical eye drops in controlling ocular surface inflammation. Methods: FFA was tested [...] Read more.

Background/Objectives: Ocular surface inflammation has been identified as a key causative factor for dry eye. The current study investigates the feasibility, safety, and efficacy of fenofibric acid (FFA) as a topical eye drops in controlling ocular surface inflammation. Methods: FFA was tested for its dissolution profile and its cytotoxicity in vitro, and its permeability through ocular surface tissues was tested ex vivo. A safe dose was tested on the Sprague–Dawley (SD) rat eye as an eyedrop for ocular safety and ocular pharmacokinetics. The efficacy was tested on a benzalkonium chloride (BAC)-induced dry eye model in the SD rats. The outcome measurements were analyzed against the untouched contralateral eyes of the animals. Results: The study found that FFA had a similar dissolution profile in PBS (phosphate-buffered saline) as is in saline; however, the saturated concentration in PBS was 81 times higher. FFA had an IC50 (half maximal inhibitory concentration) of 282.4 µM on HCECs (human corneal epithelium cells). The FFA permeation rate for the cornea was 1.77 × 10⁻⁶ µg/cm²/min, 4.95 × 10⁻⁶ µg/cm²/min for the conjunctiva, and 11.32 × 10⁻⁶ µg/cm²/min for the complex of the sclera/choroid. A regimen of twice-a-day eyedrops (500 µg/mL) demonstrated good ocular safety and therapeutic efficacy on the BAC-induced dry eye model in SD rats, with significant effects on the reduction in corneal edema and on preventing the loss of goblet cells from dry eye pathology. Conclusions: These findings strongly suggest that FFA eye drops at a concentration of 500 µg/mL may effectively control ocular surface inflammation and relieve dry-eye discomfort. Full article

(This article belongs to the Special Issue Ocular Drug Delivery Systems and Formulations)

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20 pages, 35150 KB

Open AccessArticle

Nuciferine-Loaded Lipid Nanoparticle Microneedles Alleviate Intervertebral Disc Degeneration by Restoring Nucleus Pulposus Cell Homeostasis

by Yifan Ding, Genchun Wang, Yucheng Wang, Songwei Tan and Yixin Cai

Pharmaceutics 2026, 18(8), 997; https://doi.org/10.3390/pharmaceutics18080997 - 13 Aug 2026

Abstract

Background/Objectives: Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain and disability. Nuciferine, a natural alkaloid with mitochondrial protective activity, shows therapeutic potential for IDD. However, the avascular nature of intervertebral discs limits effective drug delivery. This study [...] Read more.

Background/Objectives: Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain and disability. Nuciferine, a natural alkaloid with mitochondrial protective activity, shows therapeutic potential for IDD. However, the avascular nature of intervertebral discs limits effective drug delivery. This study aimed to develop a hierarchical stimuli-responsive microneedle (MN) system for localized nuciferine delivery. Methods: Nuciferine-loaded lipid nanoparticles (LNPs) were embedded in a phenylboronic acid-modified hyaluronic acid (HA-PBA) matrix to construct functional MNs. LNP characteristics and drug release were evaluated under physiological and simulated degenerative conditions. The effects of released LNPs on nucleus pulposus cell (NPC) viability, mitophagy, oxidative stress, and extracellular matrix homeostasis were assessed in vitro. Therapeutic efficacy was further evaluated in a rat IDD model. Results: Nuciferine-loaded LNPs had a mean size of 86.54 nm, PDI of 0.108, and encapsulation efficiency of 75.65%. The HA-PBA MNs showed minimal drug release at pH 7.4 but markedly accelerated release under dual stimuli (100 μM H₂O₂ and pH 5.0). Released LNPs maintained NPC viability above 90%, enhanced mitophagy by increasing LC3B-II and decreasing P62, and alleviated oxidative damage and extracellular matrix imbalance. In vivo, MN treatment significantly preserved the disc height index and improved Pfirrmann grades compared with the IDD group (p < 0.05). Conclusions: The hierarchical stimuli-responsive MN system enables localized, pathological microenvironment-responsive nuciferine delivery and protects against IDD by promoting mitophagy, reducing oxidative damage, and restoring extracellular matrix homeostasis. This strategy provides a potential approach for localized treatment of IDD. Full article

(This article belongs to the Special Issue Functional Nanomaterials in Pharmaceutics: Current Uses and Potential Applications, 2nd Edition)

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32 pages, 2440 KB

Open AccessReview

Kaempferol’s Therapeutic Applications and Mechanistic Insights in Ocular Diseases: Current Progress, Challenges, and Translational Opportunities

by Zhirui Ma, Dazheng Zhang, Xinyu Chen and Fuwen Zhang

Pharmaceutics 2026, 18(8), 996; https://doi.org/10.3390/pharmaceutics18080996 - 12 Aug 2026

Abstract

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological [...] Read more.

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions—anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory—by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development. Full article

(This article belongs to the Special Issue Natural Products Drug Discovery and Their Pharmacological Applications)

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50 pages, 4050 KB

Open AccessReview

Experimental Models and Nanotechnology-Based Platforms in Oral Squamous Cell Carcinoma: From Tumor Biology to Translational Applications

by Patricia Rodríguez Carballido, João P. N. Silva, Andrea Cunha and Patrícia M. A. Silva

Pharmaceutics 2026, 18(8), 995; https://doi.org/10.3390/pharmaceutics18080995 - 12 Aug 2026

Abstract

Oral cancer, predominantly represented by oral squamous cell carcinoma (OSCC), remains a major global health burden due to its aggressive clinical behavior, high recurrence rates, and limited improvement in survival over recent decades. Despite advances in treatment modalities, patient outcomes remain poor largely [...] Read more.

Oral cancer, predominantly represented by oral squamous cell carcinoma (OSCC), remains a major global health burden due to its aggressive clinical behavior, high recurrence rates, and limited improvement in survival over recent decades. Despite advances in treatment modalities, patient outcomes remain poor largely due to late diagnosis, therapeutic resistance, and profound tumor heterogeneity. In particular, metabolic reprogramming has emerged as a central hallmark of oral carcinogenesis, enabling tumor cells to adapt to hypoxic and nutrient-deprived microenvironments while promoting proliferation, invasion, and treatment resistance. Traditional experimental models, including two-dimensional cell cultures and in vivo animal models, have provided important mechanistic insights. However, they fail to fully recapitulate the metabolic, structural, and cellular complexity of human tumors. Consequently, there is growing interest in more physiologically relevant platforms, such as three-dimensional spheroids, organoids, and patient-derived models, which better preserve tumor architecture and microenvironmental interactions. In parallel, multi-omics approaches are increasingly being integrated to dissect the molecular and metabolic complexity of oral cancer at unprecedented resolutions, while nanotechnology-based systems are emerging as promising tools for targeted drug delivery and improved therapeutic precision. This review discusses experimental models in oral cancer research, focusing on their ability to capture metabolic alterations and tumor heterogeneity. We further highlight their translational potential together with multi-omics integration and nanotechnology-based strategies for improving biomarker discovery, therapeutic stratification, and the development of more effective treatment approaches. Full article

(This article belongs to the Special Issue Nano-Drug Delivery Systems: Tackling Cancer Metabolism and Drug Resistance)

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31 pages, 2030 KB

Open AccessArticle

Membrane Interfacial Organization Determines the Functional Performance of Liposomal Linezolid

by Vadim Avdeev, Ilya Kolmogorov, Tatyana Tyulkova, Galina Mozhokina, Anastasia Samoilova, Anastasia Gaida, Anna Skuredina, Natalia Belogurova, Natalia Klyachko, Alexey Doroshenko, Irina Le-Deygen and Irina Vasilieva

Pharmaceutics 2026, 18(8), 994; https://doi.org/10.3390/pharmaceutics18080994 - 11 Aug 2026

Abstract

Background: Despite extensive development of liposomal antibiotics, the structural determinants governing their stability, release, and biological activity remain poorly understood. This study investigated how the cholesterol content and drug-to-lipid ratio affect membrane organization and thereby determine the physicochemical and biological properties of linezolid-loaded [...] Read more.

Background: Despite extensive development of liposomal antibiotics, the structural determinants governing their stability, release, and biological activity remain poorly understood. This study investigated how the cholesterol content and drug-to-lipid ratio affect membrane organization and thereby determine the physicochemical and biological properties of linezolid-loaded liposomes. Methods: Nine liposomal formulations, varying in their cholesterol content (10–30 wt%) and drug-to-lipid ratios (1–5%), were prepared by thin-film hydration. Membrane organization was analyzed by ATR-FTIR spectroscopy and principal component analysis. Liposomes were further characterized by particle size, ζ-potential, encapsulation efficiency, storage stability, in vitro release in phosphate buffer with and without bovine serum albumin, antibacterial activity against B. subtilis, and antimycobacterial activity in an ex vivo PBMC-derived Mycobacterium tuberculosis granuloma model. Results: The cholesterol content and drug-to-lipid ratio markedly altered membrane interfacial organization, particularly the hydration of the carbonyl and phosphate regions. These structural changes correlated with differences in storage stability, protein-responsive release, and antibacterial activity. Functional behavior was non-monotonic, as 30-L showed the highest overall storage stability, while the apparent release depended jointly on the cholesterol content, drug loading, and medium. BSA altered the composition-dependent release pattern instead of producing a uniform effect. In the exploratory granuloma model, the formulations 10-S, 10-L, and 30-M reduced M. tuberculosis CFU by >99%, whereas free linezolid produced approximately 60% inhibition. Conclusions: Membrane interfacial organization is a key determinant of the functional performance of liposomal linezolid, establishing a structure–property–function relationship that provides a mechanistic basis for the rational design of liposomal antibiotic delivery systems for tuberculosis therapy. Full article

(This article belongs to the Special Issue Engineering and Characterisation of Novel Nanomedicine Formulations, 3rd Edition)

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20 pages, 5427 KB

Open AccessArticle

Thermoresponsive Solid Dispersion to Enhance Dissolution Profile of Atorvastatin Calcium: An Industrially Sustainable Alternative to Conventional Approaches

by Abdelrahman Y. Sherif and Mohamed A. Ibrahim

Pharmaceutics 2026, 18(8), 993; https://doi.org/10.3390/pharmaceutics18080993 - 11 Aug 2026

Abstract

Background: Poor aqueous solubility of therapeutic molecules remains a limitation in the pharmaceutical development of lipophilic drugs. This requires formulation approaches that provide the desired therapeutic efficacy while being industry-friendly. This study aimed to optimize a thermoresponsive solid dispersion containing atorvastatin calcium [...] Read more.

Background: Poor aqueous solubility of therapeutic molecules remains a limitation in the pharmaceutical development of lipophilic drugs. This requires formulation approaches that provide the desired therapeutic efficacy while being industry-friendly. This study aimed to optimize a thermoresponsive solid dispersion containing atorvastatin calcium to enhance its dissolution performance. Methods: Various nonaqueous solvents were screened to select a thermo-modulating agent. A central composite design was employed to investigate the impact of Pluronic F-68 concentration (5–15% w/w) and atorvastatin calcium concentration (5–10% w/w) on phase transition temperature and phase transition interval. Molecular interactions were assessed by Fourier-transform infrared spectroscopy. The in vitro dissolution of the optimized thermoresponsive solid dispersion was assessed using a USP Apparatus II dissolution test. Results: Propylene glycol was identified as the optimal thermo-modulating agent, forming a rigid carrier through hydrogen bonding with Pluronic F-68. The optimized thermoresponsive solid dispersion consisted of 10.07% w/w Pluronic F-68 and 9.98% w/w atorvastatin calcium. It converted to a solution state at 32 °C. At physiological temperature, the phase transition interval was 111.66 s. Dissolution studies demonstrated that the thermoresponsive solid dispersion enhanced the dissolution profile of atorvastatin calcium within 5 min, 96.6 ± 1.2% compared to 13.8 ± 4.2% for the raw drug. A comparison of process characteristics indicated fewer unit operations and no organic-solvent requirement relative to conventional techniques. Conclusions: This approach enhances dissolution performance and eliminates the need for organic solvents through simple manufacturing processes. Full article

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

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24 pages, 1856 KB

Open AccessArticle

Design-Expert^® Optimization of Tamoxifen-Loaded Transethosomal Gels: A Promising Transdermal System with Cytotoxicity and Stability Validation

by Reem Abou Assi, Ahmed Bassam Farhan, Karam Abdullah Darweesh, Amira H. Hassan and Siok Yee Chan

Pharmaceutics 2026, 18(8), 992; https://doi.org/10.3390/pharmaceutics18080992 - 11 Aug 2026

Abstract

Background: This study evaluates transdermal delivery of tamoxifen (TXN) as an alternative to the oral route of administration in treating breast cancer, which is the leading cause of cancer-related death in women globally. Oral TXN, a Class II drug, is associated with [...] Read more.

Background: This study evaluates transdermal delivery of tamoxifen (TXN) as an alternative to the oral route of administration in treating breast cancer, which is the leading cause of cancer-related death in women globally. Oral TXN, a Class II drug, is associated with first-pass metabolism and serious side effects, including secondary cancers. Objectives: To enhance transdermal delivery, lipid-based transethosomes (TRS) were formulated using three different 2⁴ factorial designs with various non-ionic surfactants, including Tween 20^®, Span 20^®, and Span 80^®. Methods: Optimized TRS formulations were incorporated into HPMC-based gels and characterized for morphology, drug content, pH, viscosity, spreadability, ex vivo skin penetration, and deposition. Additionally, cytotoxicity and stability were assessed. Results: All TXN-TRS gels were suitable for transdermal use; however, Span 20^®-based TRS gel demonstrated the highest skin penetration (40.3 ± 1.5 µg/cm²), representing a 127-fold enhancement rate compared with the non-ethosomal TXN gel. In line with the enhanced penetration profile, cellular studies on MCF-7 cells showed concentration-dependent cytotoxicity, reaching 91.24 ± 1.01% inhibition at 2% w/w after 72 h, with an IC₅₀ value of 0.85 ± 0.02% w/w. Stability testing showed all formulations were more stable under refrigeration than at dry room temperature storage, supporting their potential as preclinical transdermal tamoxifen delivery platforms. Conclusions: Span 20^®-based TXN transethosomal gel markedly enhanced skin penetration while maintaining potent cytotoxic activity, supporting its further preclinical evaluation as a promising transdermal alternative to oral tamoxifen. Full article

(This article belongs to the Special Issue Engineering of Advanced Nanocarriers and Extracellular Vesicle Systems for Precision Drug Delivery)

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40 pages, 1448 KB

Open AccessReview

Lipid Nanoparticles for Gene Therapy: Unresolved Challenges in Manufacturing, Transdermal Delivery, Machine Learning, Endosomal Escape, and the Protein Corona

by Ognjen Milić, Sanela M. Savić, Melanija Zurković, Boban Stanojević and Snežana Savić

Pharmaceutics 2026, 18(8), 991; https://doi.org/10.3390/pharmaceutics18080991 - 11 Aug 2026

Abstract

Lipid nanoparticles (LNPs) are now the leading delivery platform for nucleic acid therapeutics, but progress in the field is measured almost entirely by physicochemical and computational proxies rather than by functional properties that determine therapeutic outcomes. This review examines six interconnected areas of [...] Read more.

Lipid nanoparticles (LNPs) are now the leading delivery platform for nucleic acid therapeutics, but progress in the field is measured almost entirely by physicochemical and computational proxies rather than by functional properties that determine therapeutic outcomes. This review examines six interconnected areas of LNP development: microfluidic manufacturing, lyophilization, transdermal microneedle delivery, machine learning-guided formulation design, endosomal escape biology, and protein corona-mediated organ targeting. Although these areas are often discussed separately, they are linked by a common gap between routinely measured physicochemical or computational endpoints and the biological outcomes that determine therapeutic performance. A recently developed antifouling coating substantially reduced microfluidic channel fouling under the tested conditions, although its scalability remains to be validated. Lyophilization, by contrast, still requires formulation specific re-optimization for each new lipid composition, which remains an important barrier to clinical translation. In microneedle-based delivery, physicochemical integrity after fabrication is routinely treated as a proxy for therapeutic function, although, to our knowledge, no published study has directly compared endosomal escape capacity before and after microneedle fabrication. In machine learning, model accuracy is limited primarily by fragmented, outcome-biased training data rather than by algorithm design. Independent measurements of endosomal escape efficiency converge on a low ceiling whose biological origin, whether lipid-specific or inherent to the mechanism, remains unknown. For organ-selective targeting, one mechanistic account rests on a hypothesis tested in advance; another, equally prominent, has not been shown to have been anticipated rather than reconstructed after the fact. Closing this gap is now the field’s central methodologically priority. Full article

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

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22 pages, 1837 KB

Open AccessReview

Beyond Composition: Structure–Activity Relationships in Bioactive Deep Eutectic Systems

by Paulina Hernández, Catherine Klein, Paola R. Campodónico and Belén Olivares

Pharmaceutics 2026, 18(8), 990; https://doi.org/10.3390/pharmaceutics18080990 - 11 Aug 2026

Abstract

Deep eutectic systems (DESs) have evolved from sustainable solvent alternatives to promising bioactive platforms with reported antimicrobial, anti-inflammatory, regenerative, cryoprotective, and cytoprotective properties. However, despite the growing number of biological studies, the mechanistic basis of these effects remains poorly understood because biological activity [...] Read more.

Deep eutectic systems (DESs) have evolved from sustainable solvent alternatives to promising bioactive platforms with reported antimicrobial, anti-inflammatory, regenerative, cryoprotective, and cytoprotective properties. However, despite the growing number of biological studies, the mechanistic basis of these effects remains poorly understood because biological activity is still interpreted predominantly from the chemical identity of the hydrogen-bond donor and acceptor, rather than from the supramolecular organization of the eutectic system itself. This review is intended to provide anyone interested in the biomedical and pharmaceutical applications of DESs with a conceptual framework for understanding how supramolecular organization may influence the biological performance of DES-based systems, without requiring extensive expertise in physical chemistry. It critically analyzes the current evidence linking DES structure with biological function. The literature reveals that many reported biological responses cannot be fully explained by the properties of the individual constituents alone, supporting the existence of emergent physicochemical behavior associated with eutectic formation. Current evidence further demonstrates that DESs are dynamic supramolecular systems characterized by hydrogen-bond networks, nanoscale heterogeneity, hydration-dependent structural rearrangement, and persistent local organization under biologically relevant conditions. These structural features generate localized physicochemical microenvironments capable of modulating membrane organization, protein hydration, osmotic balance, and biomolecular interactions, providing a plausible mechanistic basis for the diverse biological effects reported to date. Our analysis also highlights a fundamental disconnect between the extensive physicochemical characterization of DESs and the predominantly composition-based interpretation of their biological activity. While conventional Quantitative Structure–Activity Relationship (QSAR) approaches rely on molecular descriptors of individual components, they fail to capture the higher levels of organization that characterize these dynamic multicomponent systems. Based on concepts established in supramolecular chemistry, self-assembled biomaterials, colloidal science, and soft matter, we propose a Hierarchical Structure–Activity Relationship (H-SAR) framework in which biological activity emerges from successive levels of organization extending from molecular composition and hydrogen-bond networks to nanostructural organization, hydration-dependent restructuring, localized physicochemical microenvironments, and biological interfaces. This framework provides a mechanistic basis for interpreting DES bioactivity and could offer a conceptual roadmap for the rational design, predictive modeling, and biomedical translation of next-generation bioactive deep eutectic systems. Full article

(This article belongs to the Special Issue Sustainable Nanotechnologies Derived from Renewable Resources for Advanced Drug Design, Delivery and Therapy)

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26 pages, 6600 KB

Open AccessArticle

Novel BODIPY-Loaded Liposomes Enhance Cellular Uptake and PDT Efficacy in 2D and 3D Models

by Federica Randisi, Miryam Chiara Malacarne, Francesco Milano, Lucrezia Cappon, Vincenzo De Leo, Emanuela Marras, Davide Odorico, Enrico Caruso and Marzia Bruna Gariboldi

Pharmaceutics 2026, 18(8), 989; https://doi.org/10.3390/pharmaceutics18080989 - 11 Aug 2026

Abstract

Background: Photodynamic therapy (PDT) is a cancer treatment that combines a photosensitizer (PS), light, and oxygen to generate reactive oxygen species (ROS), leading to tumor cell death. PDT efficacy depends largely on PS accumulation within tumors, prompting the development of third-generation PSs [...] Read more.

Background: Photodynamic therapy (PDT) is a cancer treatment that combines a photosensitizer (PS), light, and oxygen to generate reactive oxygen species (ROS), leading to tumor cell death. PDT efficacy depends largely on PS accumulation within tumors, prompting the development of third-generation PSs and nanotechnology-based delivery systems. Among these, BODIPYs (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) are promising PSs due to their favorable photophysical properties, while liposomes improve drug delivery, cellular uptake, and sustained release profiles. This study describes the synthesis of two novel BODIPY derivatives differing in the position of a methyl ester group on the meso-phenyl ring, their incorporation into liposomes, and evaluation of PDT efficacy. Methods: Cellular uptake of BODIPY-loaded liposomes, intracellular ROS generation, apoptosis, necrosis, and lipid peroxidation were assessed by flow cytometry in colorectal and ovarian cancer cell lines. The antitumor activity of the liposomal formulations was further evaluated in both 2D and 3D models using MTT and clonogenic assays. The involvement of ferroptosis and necroptosis in PDT-induced cell death was also investigated. Results: Liposomal formulations significantly enhanced cellular uptake compared with free compounds. Following light activation, both formulations induced potent antitumor effects through multiple cell death mechanisms, including canonical and non-canonical pathways, and maintained strong efficacy in 3D tumor spheroids. Conclusions: Liposome-encapsulated BODIPYs represent promising PDT agents by improving cellular uptake and eliciting robust antitumor activity through complementary cell death mechanisms. Furthermore, the methyl ester substituent on the meso-phenyl ring provides a versatile platform for future conjugation with targeting ligands, supporting the development of third-generation, tumor-targeted photosensitizers and warranting further preclinical investigation. Full article

(This article belongs to the Special Issue Photodynamic Therapy: Innovative Materials, Advanced Delivery Systems, and Clinical Translation)

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20 pages, 1474 KB

Open AccessArticle

Comparison of Metrics for Investigating Bioequivalence in Onset of Action in Incurred Bioequivalence Studies

by Paulo Paixao, Esperanza González-Rojano, Dolores Ochoa, Francisco Abad-Santos, Manuel Roman, Víctor Mangas-Sanjuan, John Gordon and Alfredo García-Arieta

Pharmaceutics 2026, 18(8), 988; https://doi.org/10.3390/pharmaceutics18080988 - 10 Aug 2026

Abstract

Background: In those products where onset of action is clinically relevant, different metrics have been proposed to demonstrate bioequivalence, and different metrics, statistical methods and acceptance criteria have been employed in the United States, the European Union and Canada in the past. Recently, [...] Read more.

Background: In those products where onset of action is clinically relevant, different metrics have been proposed to demonstrate bioequivalence, and different metrics, statistical methods and acceptance criteria have been employed in the United States, the European Union and Canada in the past. Recently, a harmonised approach has been recommended by the ICH M13A guideline. Methods: This work investigates the outcomes of several metrics in studies conducted in the Clinical Trials Unit of Hospital Universitario de La Princesa, Madrid, Spain, from 2000 to 2016, to identify the most adequate metric to reflect the onset of action. Results: An optimal single metric cannot be identified in these studies. The metrics show very high variability in most cases, making the conclusion of bioequivalence very unlikely with the usual sample sizes required for demonstration of bioequivalence based on Cmax and AUC. This is particularly evident if 90% confidence intervals are required to aim at inference of the study results to the whole population. Optimisation of the sampling times around tmax may be needed to reduce variability and increase reliability of the estimations. Conclusions: pAUC and tmax have been considered acceptable metrics under the ICH M13A guideline. For tmax, a non-parametric 90% confidence interval of the difference between the two formulations within a widened acceptance range may be sufficient for concluding BE in the early onset of action. Regarding pAUC, its high intra-subject variability can be addressed with the current scaling. Full article

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 3rd Edition)

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