Pharmaceutics

29 pages, 986 KB

Open AccessArticle

Impact of Compaction Parameters and Techniques on MUPS Tablets

by Daniel Robin Thio, Paul Wan Sia Heng and Lai Wah Chan

Pharmaceutics 2025, 17(10), 1347; https://doi.org/10.3390/pharmaceutics17101347 (registering DOI) - 18 Oct 2025

Background/Objectives: Compaction of sustained release coated pellets into tablets is associated with damage to the functional coat and loss in sustained release. The influences of precompression, trilayering, and tableting rate on the compaction of sustained release coated pellets into tablets are not well [...] Read more.

Background/Objectives: Compaction of sustained release coated pellets into tablets is associated with damage to the functional coat and loss in sustained release. The influences of precompression, trilayering, and tableting rate on the compaction of sustained release coated pellets into tablets are not well defined and were herein investigated to enhance the current limited understanding of these factors. Methods: Pellets coated with acrylic polymer (AC) or ethylcellulose (EC) were combined with filler material and compacted into multi-unit pellet system (MUPS) tablets prepared using different levels of precompression, as a trilayered MUPS tablet and at different tableting rates. The physical properties of the resulting MUPS tablets were evaluated. Trilayering was achieved by adding cushioning layers at the top and bottom of the MUPS tablet to avoid direct contact of pellets with punch surfaces. Results: With precompression, slightly stronger MUPS tablets were made compared to the tablets without precompression for EC pellets but not AC pellets. However, precompression led to a slight reduction in pellet coat damage for AC pellets but not EC pellets. Trilayering led to significant reductions in pellet coat damage and significant increases in tablet tensile strength. When EC pellets were lubricated with sodium stearyl fumarate, pellet coat damage was significantly lower. Increasing the tableting rate from 20 to 100 rpm did not result in increased pellet coat damage but in significantly weaker tablets due to the shorter dwell time. Conclusions: This study provides key insights on how compaction parameters and techniques could be altered to produce better MUPS tablets. Full article

(This article belongs to the Special Issue Feature Reviews in Pharmaceutical Technology, Manufacturing and Devices)

27 pages, 2871 KB

Open AccessArticle

Design of Polycation-Functionalized Resveratrol Nanocrystals for Intranasal Administration

by Angela Bonaccorso, Elide Zingale, Giuseppe Caruso, Anna Privitera, Claudia Carbone, Maria Josè Lo Faro, Filippo Caraci, Teresa Musumeci and Rosario Pignatello

Pharmaceutics 2025, 17(10), 1346; https://doi.org/10.3390/pharmaceutics17101346 (registering DOI) - 18 Oct 2025

Abstract

Background/Objectives: Nanocrystals (NCs) are a relatively underexplored yet adaptable platform with broad potential for various applications. Currently, the surface modification of NCs leads to the development of versatile platforms capable of enhancing targeted delivery potential and supporting the advancement of precision medicine. With [...] Read more.

Background/Objectives: Nanocrystals (NCs) are a relatively underexplored yet adaptable platform with broad potential for various applications. Currently, the surface modification of NCs leads to the development of versatile platforms capable of enhancing targeted delivery potential and supporting the advancement of precision medicine. With this in mind, this study focused on the design and surface functionalization of a resveratrol (RSV) NC selected for its antioxidant and neuroprotective effects. Methods: The design of the RSV NC was assessed by the Quality by Design approach. With the aim of intranasal administration, we assessed the RSV NC functionalization with a cationic poly (amino acid) belonging to the class of cell-penetrating peptides. Both naked and surface-modified RSV nanosuspensions were characterized in terms of mucoadhesion, behavior in artificial cerebrospinal fluid, crystallinity, solubility, and storage stability. The scavenging activity (%) of neat RSV and its nanosized forms was measured using the DPPH assay. Results: RSV NCs were successfully designed, producing truncated cubic crystals (~240 nm) with an ~80% drug content. Functionalization was efficiently achieved with poly-l-arginine hydrochloride as revealed by DSC and FTIR and resulted in a positively charged nanosuspension. Nanonization technology improved drug solubility in water and did not affect RSV scavenging activity. Technological characterization demonstrated that both nanosuspensions present suitable properties for intranasal administration in terms of particle size, mucoadhesive tendency, and stability in artificial cerebrospinal fluid. An MTT assay revealed the safety of all treatments in human microglia (HMC3) cells. Conclusions: RSV NCs’ functionalization enhanced their brain delivery potential, establishing a promising platform to improve therapeutic outcomes in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Nasal Nanotechnology: What Do We Know and What Is Yet to Come?)

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24 pages, 1845 KB

Open AccessArticle

Angiotensin II/Angiotensin I Ratio as a New Pharmacodynamic Parameter for Population Modelling in Healthy Adults and Children with Heart Failure Treated with Enalapril

by Melina Steichert, Willi Cawello, Bjoern B. Burckhardt, Fabian K. Suessenbach and Stephanie Laeer

Pharmaceutics 2025, 17(10), 1345; https://doi.org/10.3390/pharmaceutics17101345 (registering DOI) - 18 Oct 2025

Abstract

Background/Objectives: Since 2023, enalapril orodispersible minitablets have been approved in Europe for paediatric heart failure from birth, but no population pharmacodynamic analyses have yet been conducted in this patient group. The objectives were to investigate the effect of the active metabolite enalaprilat [...] Read more.

Background/Objectives: Since 2023, enalapril orodispersible minitablets have been approved in Europe for paediatric heart failure from birth, but no population pharmacodynamic analyses have yet been conducted in this patient group. The objectives were to investigate the effect of the active metabolite enalaprilat on the angiotensin II/angiotensin I ratio in children with heart failure and to determine potential differences compared to healthy adults. Methods: Population pharmacokinetic/pharmacodynamic analysis for healthy adults and population pharmacodynamic analysis for children with heart failure were performed using Monolix. Data were analyzed from 9 healthy adults after a single dose of enalapril and from 27 angiotensin-converting enzyme (ACE) inhibitor-naïve children with heart failure treated with enalapril orodispersible minitablets for up to one year in the ‘Labeling of Enalapril from Neonates up to Adolescents’ (LENA) studies. Results: For the relationship between enalaprilat and the angiotensin II/angiotensin I ratio, a maximum inhibition (I_max) model with full inhibition and sigmoidicity factor was selected for healthy adults and without sigmoidicity factor for children with heart failure. In children with heart failure, the population estimate for the baseline effect was higher (0.19 versus 0.043) and for the half-maximal inhibitory concentration lower (1.19 µg/L versus 30.01 µg/L) than in healthy adults. Four hours after a median initial dose of 0.06 mg/kg enalapril maleate, the angiotensin II/angiotensin I ratio decreased by a median of 79.3% in children with heart failure. Conclusions: Effective ACE inhibition can be assumed at the administered dose in children with heart failure. Population analyses suggest that children with heart failure may be more sensitive to enalaprilat than healthy adults. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

18 pages, 3836 KB

Open AccessArticle

Advanced Vaginal Nanodelivery of Losartan Potassium via PEGylated Zein Nanoparticles for Methicillin-Resistant Staphylococcus aureus

by Rofida Albash, Mariam Hassan, Ahmed M. Agiba, Haneen Waleed Mohamed, Mohamed Safwat Hassan, Roaa Mohamed Ali, Yara E. Shalabi, Hend Mahmoud Abdelaziz Omran, Moaz A. Eltabeeb, Jawaher Abdullah Alamoudi, Asmaa Saleh, Amira B. Kassem and Yasmina Elmahboub

Pharmaceutics 2025, 17(10), 1344; https://doi.org/10.3390/pharmaceutics17101344 (registering DOI) - 18 Oct 2025

Abstract

Background/Objectives: PEGylated zein nanoparticles (PZNs) loaded with losartan potassium (LOS) were developed as a repurposed treatment for vaginal methicillin-resistant Staphylococcus aureus (MRSA) infection. PZNs were prepared using the ethanol injection method with different types and amounts of Brij^® surfactant. Methods: The [...] Read more.

Background/Objectives: PEGylated zein nanoparticles (PZNs) loaded with losartan potassium (LOS) were developed as a repurposed treatment for vaginal methicillin-resistant Staphylococcus aureus (MRSA) infection. PZNs were prepared using the ethanol injection method with different types and amounts of Brij^® surfactant. Methods: The prepared formulations were optimized using a D-optimal mixture design via Design-Expert^® software version 13. The assessed responses included entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP). Results: The optimized PZNs, composed of 30 mg Brij^® O20 and 10 mg zein, exhibited spherical particles with an EE% of 90.58 ± 1.20%, PS of 200.81 ± 1.39 nm, PDI of 0.395 ± 0.01, and ZP of −36.59 ± 0.05 mV. Confocal laser scanning microscopy confirmed complete deposition of fluorescein-labeled PZNs within vaginal tissues. Ex vivo studies showed that PZNs resulted in prolonged permeation of LOS compared to the LOS solution. In a murine model of MRSA infection, the optimized PZNs demonstrated superior therapeutic efficacy over the LOS solution. Histopathological examinations confirmed the safety of the tested formulations. Conclusions: In conclusion, the optimized PZNs present a promising approach for the treatment of MRSA-related vaginal infections. Full article

(This article belongs to the Special Issue Advanced Nano-Formulations for Drug Delivery and Cancer Immunotherapy)

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15 pages, 837 KB

Open AccessArticle

Development of Practical Low-Volume Screening Method and Pharmacokinetic Simulation of Levofloxacin-Loaded Nanofiber Inserts for Sustained Ocular Therapy

by Houssam Aaref Abboud, Romána Zelkó and Adrienn Kazsoki

Pharmaceutics 2025, 17(10), 1343; https://doi.org/10.3390/pharmaceutics17101343 - 17 Oct 2025

Abstract

Background/Objectives: Ocular drug delivery faces significant challenges due to anatomical and physiological barriers that limit drug bioavailability, particularly with conventional eye drops. Levofloxacin (LEVO), a broad-spectrum antibiotic, is widely used in the treatment of bacterial conjunctivitis, but its therapeutic efficacy [...] Read more.

Background/Objectives: Ocular drug delivery faces significant challenges due to anatomical and physiological barriers that limit drug bioavailability, particularly with conventional eye drops. Levofloxacin (LEVO), a broad-spectrum antibiotic, is widely used in the treatment of bacterial conjunctivitis, but its therapeutic efficacy is hindered by rapid precorneal clearance and short residence time. Methods: This study introduces a biorelevant 2 mL dissolution model to simulate ocular conditions better and evaluate the release kinetics of LEVO-loaded nanofibrous ophthalmic inserts. Compared to the conventional 40 mL setup, the 2 mL system demonstrated a slower and more sustained drug release profile, with kinetic modeling confirming a more controlled release behavior. Difference and similarity factor analysis further validated the distinct release profiles, highlighting the impact of dissolution volume on release dynamics. Results: Preliminary pharmacokinetic modeling suggested that the nanofiber inserts, particularly when applied twice daily, maintained levofloxacin concentrations above minimum inhibitory and bactericidal levels for extended durations across three bacterial strains (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus), potentially outperforming traditional eye drops. Conclusions: These findings suggest that small-volume dissolution testing may provide a more realistic method for evaluating ophthalmic insert formulations, though in vivo validation is needed. Moreover, the nanofibrous inserts show potential as a sustained-release alternative that warrants further investigation to improve patient compliance and therapeutic outcomes in ocular disease management. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 3rd Edition)

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41 pages, 990 KB

Open AccessReview

In Vitro Skin Models as Non-Animal Methods for Dermal Drug Development and Safety Assessment

by Viviana Stephanie Costa Gagosian, Raquel Coronel, Bruna Caroline Buss, Maria Luiza Ferreira dos Santos, Isabel Liste, Berta Anta and Leonardo Foti

Pharmaceutics 2025, 17(10), 1342; https://doi.org/10.3390/pharmaceutics17101342 - 17 Oct 2025

Abstract

Research on in vitro skin models has advanced remarkably, driven by a better understanding of the skin and the search for more ethical and efficient methods. The development of these models was initially motivated by the need for reduced animal testing and a [...] Read more.

Research on in vitro skin models has advanced remarkably, driven by a better understanding of the skin and the search for more ethical and efficient methods. The development of these models was initially motivated by the need for reduced animal testing and a faster and more ethical approach for the safety evaluation of cosmetic and pharmaceutical products. Stricter regulations and growing ethical awareness have driven further evolution, resulting in more refined and reliable methods. Diversity of cell types is crucial to replicating the complexity of human skin, including epithelial, dendritic, endothelial, and adipose cells, providing environments that closely mimic the physiological skin environment. This allows for more precise studies on skin interactions with cosmetic, dermatological, and pharmaceutical products. In vitro skin models have applications in toxicity testing, dermatological product evaluation, skin ageing studies, and drug research, reducing dependence on animal testing. This review presents a look at the different types of in vitro skin models developed for various applications, with a brief look at their strengths and drawbacks. Models developed for disease-specific applications are also covered. Techniques such as bioprinting and organ-on-a-chip have revolutionised the manufacturing of these models. Challenges persist, such as the need to improve vascularisation and faithfully replicate skin architecture. The promising future of these models points to an exciting path forward for dermatological research and the cosmetic industry. This review addresses the history and regulations of skin models, explores various skin models, and highlights the most recent advances, outlining future perspectives and offering a comprehensive overview. Full article

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16 pages, 1507 KB

Open AccessArticle

Escitalopram Dose Optimization During Pregnancy: A PBPK Modeling Approach

by Seo-Yeon Choi, Eunsol Yang and Kwang-Hee Shin

Pharmaceutics 2025, 17(10), 1341; https://doi.org/10.3390/pharmaceutics17101341 - 17 Oct 2025

Abstract

Background/Objectives: Escitalopram, a first-line antidepressant, is primarily metabolized by CYP2C19. Its pharmacokinetics are altered during pregnancy. This study aims to predict maternal and fetal exposure to escitalopram during pregnancy and to propose safe and effective dosing strategies using physiologically based pharmacokinetic (PBPK) [...] Read more.

Background/Objectives: Escitalopram, a first-line antidepressant, is primarily metabolized by CYP2C19. Its pharmacokinetics are altered during pregnancy. This study aims to predict maternal and fetal exposure to escitalopram during pregnancy and to propose safe and effective dosing strategies using physiologically based pharmacokinetic (PBPK) modeling. Methods: Predictive PBPK models for escitalopram were developed in nonpregnant women, pregnant women, and the fetoplacental unit using the Simcyp^® simulator. Additional models incorporating CYP2C19 phenotypes were constructed. Model performance was evaluated using visual predictive checks and by comparing predicted-to-observed ratios for the maximum plasma concentration (C_max) and the area under the curve (AUC), within an acceptance criterion of 0.7–1.3. Results: Escitalopram concentrations at doses of 10–20 mg declined with advancing gestation. The cord-to-maternal concentration ratio was approximately 0.70 for both doses. Simulations of maternal and fetoplacental PBPK models across CYP2C19 phenotypes showed that most observed concentrations fell within the 95% confidence intervals of the predictions. Based on the therapeutic range attained and the maintenance of steady-state exposure, a once-daily 20 mg escitalopram dose was predicted to be appropriate during pregnancy. Conclusions: These findings suggest that a once-daily 20 mg dose appears optimal during pregnancy, highlighting the need to consider the gestational stage and CYP2C19 phenotype in dose optimization. Full article

(This article belongs to the Special Issue Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling and Applications)

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32 pages, 9810 KB

Open AccessArticle

Silver(I) Complexes Bearing S-Alkyl Thiosalicylic Acid Derivatives: DNA/BSA Binding and Antitumor Activity In Vitro and In Vivo

by Jovana Marinković, Milena Jurišević, Marina Jovanović, Miloš Milosavljević, Ivan Jovanović, Snežana Jovanović Stević, Marina Vesović, Miloš Nikolić, Nikola Nedeljković, Ana Živanović, Dušan Tomović, Andriana Bukonjić, Gordana Radić and Nevena Gajović

Pharmaceutics 2025, 17(10), 1340; https://doi.org/10.3390/pharmaceutics17101340 - 16 Oct 2025

Abstract

Background/Objectives: In recent years, silver complexes have shown strong antibacterial, antifungal, and antitumor activity with high selectivity toward cancer cells. Their cytotoxic effects are mainly linked to apoptosis induction, DNA damage, and enzyme inhibition, while the antitumor activity of silver(I) complexes with S-alkyl [...] Read more.

Background/Objectives: In recent years, silver complexes have shown strong antibacterial, antifungal, and antitumor activity with high selectivity toward cancer cells. Their cytotoxic effects are mainly linked to apoptosis induction, DNA damage, and enzyme inhibition, while the antitumor activity of silver(I) complexes with S-alkyl thiosalicylic acid derivatives remains unexplored. Methods: Silver(I) complexes with S-alkyl derivatives of thiosalicylic acid (C1–C5) were obtained through the direct reaction of silver(I) nitrate, the corresponding ligand of thiosalicylic acid, and a sodium hydroxide solution. The interactions between the complexes and CT-DNA/BSA were studied using UV-Vis, fluorescence spectroscopy, and molecular docking studies. The cytotoxic capacity of the newly synthesized complexes was assessed by an MTT assay. Results: Complexes C1–C5 exhibited strong cytotoxicity against murine and human breast (4T1, MDA-MB-468), colon (CT26, HCT116), and lung (LLC1, A549) cancer cell lines. The C3 complex significantly diminished tumor progression in an orthotropic mammary carcinoma model while demonstrating good systemic tolerance. Conclusions: The tested complex C3 triggered apoptosis in 4T1 cells by altering the delicate balance between pro- and anti-apoptotic Bcl-2 family members, increasing reactive oxygen species (ROS) levels, and reducing mitochondrial membrane depolarization. Moreover, the C3 arrested the 4T1 cell cycle in G0/G1 phase, decreasing the expression of cyclin D3 and increasing the expression of p16, p21, and p27. Full article

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

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24 pages, 4333 KB

Open AccessArticle

Development of Co-Amorphous Systems for Inhalation Therapy—Part 2: In Silico Guided Co-Amorphous Rifampicin–Moxifloxacin and –Ethambutol Formulations

by Eleonore Fröhlich, Noon Sharafeldin, Valerie Reinisch, Nila Mohsenzada, Stefan Mitsche, Hartmuth Schröttner and Sarah Zellnitz-Neugebauer

Pharmaceutics 2025, 17(10), 1339; https://doi.org/10.3390/pharmaceutics17101339 - 16 Oct 2025

Abstract

Background/Objectives: Tuberculosis (TB) remains a global health challenge due to long treatment durations, poor adherence, and growing drug resistance. Inhalable co-amorphous systems (COAMS) offer a promising strategy for targeted pulmonary delivery of fixed-dose combinations, improving efficacy and reducing systemic side effects. Methods: [...] Read more.

Background/Objectives: Tuberculosis (TB) remains a global health challenge due to long treatment durations, poor adherence, and growing drug resistance. Inhalable co-amorphous systems (COAMS) offer a promising strategy for targeted pulmonary delivery of fixed-dose combinations, improving efficacy and reducing systemic side effects. Methods: Our in-house-developed machine learning (ML) tool identified two promising API-API combinations for TB therapy, rifampicin (RIF)–moxifloxacin (MOX) and RIF–ethambutol (ETH). Physiologically based pharmacokinetic (PBPK) modeling was used to estimate therapeutic lung doses of RIF, ETH, and MOX following oral administration. Predicted lung doses were translated into molar ratios, and COAMS of RIF-ETH and RIF-MOX at both model-predicted (1:1) and PBPK-informed ratios were prepared by spray drying and co-milling, followed by comprehensive physicochemical and aerodynamic characterization. Results: RIF-MOX COAMS could be prepared in all molar ratios tested, whereas RIF-ETH failed to result in COAMS for therapeutically relevant molar ratios. Spray drying and ball milling successfully produced stable RIF-MOX formulations, with spray drying showing superior behavior in terms of morphology (narrow particle size distribution; lower Sauter mean diameter), aerosolization performance (fine particle fraction above 74% for RIF and MOX), and dissolution. Conclusions: This study demonstrated that PBPK modeling and ML are useful tools to develop COAMS for pulmonary delivery of active pharmaceutical ingredients (APIs) routinely applied through the oral route. It was also observed that COAMS may be less effective when the therapeutic lung dose ratio significantly deviates from the predicted 1:1 molar ratio. This suggests the need for alternative delivery strategies in such cases. Full article

(This article belongs to the Special Issue New Platform for Tuberculosis Treatment)

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19 pages, 1775 KB

Open AccessArticle

From Mechanochemically Driven Complexation and Multimodal Characterization to Stability and Toxicological Insight: A Study of Cinnarizine–β-Cyclodextrins Complexes

by David Klarić, Lucija Kutleša, Mario Jug and Nives Galić

Pharmaceutics 2025, 17(10), 1338; https://doi.org/10.3390/pharmaceutics17101338 - 16 Oct 2025

Abstract

Background: Cinnarizine (CIN) is a poorly soluble drug used in the treatment of vestibular disorders. Its solubility can be improved by complexation with cyclodextrins (CDs). This study focused on the preparation of 1:1 CIN/CD complexes with β-cyclodextrin (βCD) and its derivatives hydroxypropyl-β-cyclodextrin (HPβCD) [...] Read more.

Background: Cinnarizine (CIN) is a poorly soluble drug used in the treatment of vestibular disorders. Its solubility can be improved by complexation with cyclodextrins (CDs). This study focused on the preparation of 1:1 CIN/CD complexes with β-cyclodextrin (βCD) and its derivatives hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD) by mechanical activation. Methods: Complexes were obtained under optimized grinding conditions using a high-energy vibrational mill with ZrO₂ grinding media. Solid products were characterized by DSC, TGA, XRPD, and FTIR spectroscopy. Dissolution studies were performed in phosphate buffer (pH 4.5). The effect of βCD and HPβCD on CIN stability was assessed under hydrolytic (acidic, neutral, and basic) and oxidative conditions. A stability-indicating UHPLC-DAD-HRMS method was developed and validated, enabling CIN quantification in the presence of degradation products, whose structures were proposed based on HRMS/MS data. Potential toxicity, bioaccumulation, and mutagenicity of degradation products were predicted using QSAR modeling. Accelerated stability studies (40 °C, 75% RH) were conducted to evaluate long-term stability. Results: Solid-state analyses confirmed CIN/CD interactions in the ground products. The highest dissolution efficiency was observed for CIN/HPβCD complexes, while CD complexation did not alter CIN permeability in biomimetic membrane assays. CIN and its complexes demonstrated satisfactory chemical stability, with no degradation products detected under accelerated conditions. Conclusions: Solid-state complexes of CIN with CDs enhanced dissolution without compromising stability, supporting their potential as promising candidates for novel pharmaceutical formulations. Full article

(This article belongs to the Special Issue Solid Dispersions for Drug Delivery: Development, Preparation and In Vitro/In Vivo Characterization)

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24 pages, 2998 KB

Open AccessArticle

Drug-Integrating Amphiphilic Nano-Assemblies: 3. PEG-PPS/Palmitate Nanomicelles for Sustained and Localized Delivery of Dexamethasone in Cell and Tissue Transplantations

by Giulio Palummieri, Saeida Saadat, Sung-Ting Chuang, Peter Buchwald and Diana Velluto

Pharmaceutics 2025, 17(10), 1337; https://doi.org/10.3390/pharmaceutics17101337 - 16 Oct 2025

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Abstract

Background: Glucocorticoids are an important class of therapeutics used in a variety of applications, including allotransplantations. Dexamethasone (Dexa) is well-known for its strong anti-inflammatory, immunosuppressive, and anticancer properties. However, its clinical use is often limited by its poor water solubility, poor pharmacokinetics, and [...] Read more.

Background: Glucocorticoids are an important class of therapeutics used in a variety of applications, including allotransplantations. Dexamethasone (Dexa) is well-known for its strong anti-inflammatory, immunosuppressive, and anticancer properties. However, its clinical use is often limited by its poor water solubility, poor pharmacokinetics, and high likelihood of systemic side effects. Methods: To address the issues, we tested a combined strategy where our original Drug-Integrating Amphiphilic Nano-Assemblies (DIANAs), a class of self-assembling polymeric nanoparticles designed for controlled drug release, were used to solubilize and deliver dexamethasone palmitate (DexP), a hydrophobic prodrug of dexamethasone. Results: The palmitate chains of the prodrug can form strong van der Waals interactions with the hydrophobic moieties of the PEG-PPS block copolymer used here. In water, this resulted in the self-assembling of stable dexamethasone palmitate–PEG–PPS nanomicelles, termed DexP-nMICs, with a 25 nm average diameter that slowly released Dexa over more than two weeks. Conclusions: Here we demonstrated that DexP-nMICs can carry elevated amounts of Dexa—increasing its solubility in water—prolong circulation in its pharmacologically active form in vivo and provide passive targeting to inflammation sites. The anti-inflammatory efficacy of DexP-nMICs was first confirmed in vitro on stimulated macrophages, demonstrating a significant reduction in cytokine secretion. An allogeneic mouse skin transplant model, used to assess the therapeutic potential of DexP-nMICs in vivo, confirmed its ability to provide graft-targeted delivery and prolong graft survival as compared to the unformulated parent drug. Therefore, DexP-nMICs are a promising candidate for sustained and localized use of anti-inflammatory drugs in cell and tissue transplantations. Full article

(This article belongs to the Special Issue Applications of Nanomaterials in Immunotherapies)

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42 pages, 1602 KB

Open AccessReview

Exosome-Based Drug Delivery: A Next-Generation Platform for Cancer, Infection, Neurological and Immunological Diseases, Gene Therapy and Regenerative Medicine

by Dolores R. Serrano, Francisco Juste, Brayan J. Anaya, Bianca I. Ramirez, Sergio A. Sánchez-Guirales, John M. Quispillo, Ester M. Hernandez, Jesus A. Simon, Jose M. Trallero, Celia Serrano, Satyavati Rawat and Aikaterini Lalatsa

Pharmaceutics 2025, 17(10), 1336; https://doi.org/10.3390/pharmaceutics17101336 - 15 Oct 2025

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Abstract

Exosomes, naturally derived extracellular vesicles, have emerged as powerful bio-nanocarriers in precision medicine. Their endogenous origin, biocompatibility, and ability to encapsulate and deliver diverse therapeutic payloads position them as transformative tools in drug delivery, gene therapy, and regenerative medicine. This review presents a [...] Read more.

Exosomes, naturally derived extracellular vesicles, have emerged as powerful bio-nanocarriers in precision medicine. Their endogenous origin, biocompatibility, and ability to encapsulate and deliver diverse therapeutic payloads position them as transformative tools in drug delivery, gene therapy, and regenerative medicine. This review presents a comprehensive analysis of exosome-based therapeutics across multiple biomedical domains, including cancer, neurological and infectious diseases, immune modulation, and tissue repair. Exosomes derived from stem cells, immune cells, or engineered lines can be loaded with small molecules, RNA, or CRISPR-Cas systems, offering highly specific and low-immunogenic alternatives to viral vectors or synthetic nanoparticles. We explore endogenous and exogenous loading strategies, surface functionalization techniques for targeted delivery, and innovations that allow exosomes to traverse physiological barriers such as the blood–brain barrier. Furthermore, exosomes demonstrate immunomodulatory and regenerative properties in autoimmune and degenerative conditions, with promising roles in skin rejuvenation and cosmeceuticals. Despite their potential, challenges remain in large-scale production, cargo loading efficiency, and regulatory translation. Recent clinical trials and industry efforts underscore the accelerating momentum in this field. Exosomes represent a promising platform in precision medicine, though further standardization and validation are required before widespread clinical use. This review offers critical insights into current technologies, therapeutic mechanisms, and future directions to unlock the full translational potential of exosomes in clinical practice. Full article

(This article belongs to the Special Issue Vesicle-Based Drug Delivery Systems)

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19 pages, 3879 KB

Open AccessArticle

Expanded Nanofibrous Polymeric Mats Incorporating Tetracycline-Loaded Silica Mesoporous Nanoparticles for Antimicrobial Applications

by Federico Fookes, Silvestre Bongiovanni Abel, Josefa F. Martucci, Diana Estenoz, Gustavo A. Abraham and Carlos A. Busatto

Pharmaceutics 2025, 17(10), 1335; https://doi.org/10.3390/pharmaceutics17101335 - 15 Oct 2025

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Abstract

Background/Objectives: In this work, expanded electrospun poly(vinyl alcohol) (PVA) nanofiber mats incorporating tetracycline-loaded mesoporous silica nanoparticles (MSNs) were fabricated for antimicrobial wound dressing applications. Methods: MSNs with high surface area were synthesized and efficiently loaded with tetracycline, achieving sustained drug release. These nanoparticles [...] Read more.

Background/Objectives: In this work, expanded electrospun poly(vinyl alcohol) (PVA) nanofiber mats incorporating tetracycline-loaded mesoporous silica nanoparticles (MSNs) were fabricated for antimicrobial wound dressing applications. Methods: MSNs with high surface area were synthesized and efficiently loaded with tetracycline, achieving sustained drug release. These nanoparticles were then embedded into both conventional (2D) and gas-expanded (3D) electrospun PVA mats. Results: The gas-foaming process significantly enhanced the mat’s thickness, promoting improved nanoparticle loading and diffusion properties. Physicochemical characterization confirmed the structural integrity, thermal stability, and successful drug incorporation within the hybrid scaffolds. Antimicrobial tests against Escherichia coli and Staphylococcus aureus demonstrated excellent bactericidal effects, with superior inhibition observed in 3D mats due to their higher drug loading capacity and faster drug release related to the expanded structure. Conclusions: These results highlight the potential of combining electrospinning, gas expansion, and nanocarriers to engineer advanced, drug-loaded fibrous scaffolds for wound healing. Full article

(This article belongs to the Special Issue Application of Electrohydrodynamic Techniques for Delivery of Therapeutic Agents)

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17 pages, 5535 KB

Open AccessArticle

Lipid Nanoparticle-Mediated RNAi Against GIPC1 Overcomes Chemoresistance in Pancreatic Ductal Adenocarcinoma

by Vijay Sagar Madamsetty, Hari Krishnareddy Rachamala, Shamit Kumar Dutta, Enfeng Wang, Krishnendu Pal and Debabrata Mukhopadhyay

Pharmaceutics 2025, 17(10), 1334; https://doi.org/10.3390/pharmaceutics17101334 - 15 Oct 2025

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Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive tumor biology, poor vascularization, dense stromal barriers, and profound resistance to chemotherapy. GAIP-interacting protein C-terminus 1 (GIPC1), a PDZ-domain-containing adaptor protein, is highly overexpressed in PDAC and plays [...] Read more.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive tumor biology, poor vascularization, dense stromal barriers, and profound resistance to chemotherapy. GAIP-interacting protein C-terminus 1 (GIPC1), a PDZ-domain-containing adaptor protein, is highly overexpressed in PDAC and plays a critical role in tumor progression and chemoresistance. This study aimed to develop and evaluate a novel tumor-targeted liposomal siRNA delivery system (LGIPCsi) to silence GIPC1 and enhance the therapeutic efficacy of gemcitabine (GEM) in PDAC; Methods: LGIPCsi nanoparticles were synthesized and optimized for physicochemical stability, siRNA complexation efficiency, and tumor-targeting capability. Their therapeutic efficacy was assessed using in vitro pancreatic cancer cell models and in vivo orthotopic and patient-derived xenograft (PDX) models of PDAC. Biodistribution, tumor uptake, and antitumor efficacy were evaluated following systemic administration. Combination studies were performed to assess the synergistic effects of LGIPCsi and GEM; Results: GIPC1 silencing significantly sensitized pancreatic cancer cells to GEM, resulting in enhanced inhibition of tumor cell proliferation in vitro. In vivo, systemic administration of LGIPCsi achieved efficient intratumoral delivery of siGIPC1, leading to marked tumor growth suppression. Combination therapy with GEM and LGIPCsi produced synergistic antitumor effects, with substantial tumor regression compared to monotherapy groups. Importantly, no significant systemic toxicity was observed in treated animals; Conclusions: This study identifies GIPC1 as a promising therapeutic target in PDAC and demonstrates that tumor-targeted siRNA nanomedicine can effectively overcome chemoresistance when combined with standard chemotherapy. The LGIPCsi platform offers a rational and translational strategy to enhance treatment efficacy in PDAC through targeted RNAi-based combination therapy. Full article

(This article belongs to the Special Issue Hybrid Nanoparticles for Cancer Therapy)

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12 pages, 1116 KB

Open AccessArticle

A Four-Layer Numerical Model for Transdermal Drug Delivery: Parameter Optimization and Experimental Validation Using a Franz Diffusion Cell

by Fjola Jonsdottir, O. I. Finsen, B. S. Snorradottir and S. Sigurdsson

Pharmaceutics 2025, 17(10), 1333; https://doi.org/10.3390/pharmaceutics17101333 - 14 Oct 2025

Viewed by 331

Abstract

Background/Objectives: A mechanistic understanding of transdermal drug delivery relies on accurately capturing the layered structure and barrier function of the skin. This study presents a four-layer numerical model that explicitly includes the donor compartment, stratum corneum (SC), viable skin (RS), and receptor compartment. [...] Read more.

Background/Objectives: A mechanistic understanding of transdermal drug delivery relies on accurately capturing the layered structure and barrier function of the skin. This study presents a four-layer numerical model that explicitly includes the donor compartment, stratum corneum (SC), viable skin (RS), and receptor compartment. Methods: The model is based on Fickian diffusion and incorporates interfacial partitioning and mass transfer resistance. It is implemented using the finite element method in MATLAB and calibrated through nonlinear least-squares optimization against experimental data from Franz diffusion cell studies using porcine skin. Validation was performed using receptor concentration profiles over time and final drug content in the SC and RS layers, assessed via tape stripping and residual skin analysis. Results: The model provided excellent agreement with experimental data. For diclofenac, the optimized partition coefficient at the SC–RS interface was close to unity, indicating minimal interfacial discontinuity and that a simplified three-layer model may be sufficient for this compound. Conclusions: The proposed four-layer framework provides a physiologically informed and generalizable platform for simulating transdermal drug delivery. It enables spatial resolution, mechanistic interpretation, and flexible adaptation to other drugs and formulations, particularly those with significant interfacial effects or limited lipophilicity. Full article

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

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19 pages, 880 KB

Open AccessReview

Therapeutic and Formulation Innovations in the Management of Canine Otitis Externa

by Yunmei Song, Sangseo Kim, Songhita Mukhopadhyay, Souha H. Youssef, Jin Quan Eugene Tan, Emily Josephine Weir, Stephen W. Page and Sanjay Garg

Pharmaceutics 2025, 17(10), 1332; https://doi.org/10.3390/pharmaceutics17101332 - 14 Oct 2025

Viewed by 248

Abstract

Canine Otitis Externa (COE) is a challenging otological disorder in dogs which causes significant irritation and discomfort. This comprehensive review provides an extensive analysis of COE with emphasis on the fundamentals of the condition, starting with the basic anatomy of the canine external [...] Read more.

Canine Otitis Externa (COE) is a challenging otological disorder in dogs which causes significant irritation and discomfort. This comprehensive review provides an extensive analysis of COE with emphasis on the fundamentals of the condition, starting with the basic anatomy of the canine external ear canal, followed by pathophysiology and diagnosis of COE. Furthermore, novel therapeutic interventions, formulation considerations, and challenges, with the perspective of future directions in the field of COE management, are described. Diagnostic models, including clinical examination, cytology, and susceptibility tests, are presented to provide an overview of the processes involved in detecting and selecting appropriate therapies for the management of COE. Moreover, this paper describes the limitations of current therapies with considerations for the selection of alternative novel treatments such as aromatherapy, acupuncture, bacteriophages, nutraceuticals, and nanomedicines. This review places particular emphasis on the pharmaceutical formulation of topical products used for COE treatment. Various factors, including osmotic pressure, safety profile, viscosity, bioadhesion, and formulation pH, must be considered when developing topical preparations. These parameters are critical in formulation development to enhance therapeutic outcomes and minimise potential side effects. Finally, potential advancements in COE management are highlighted, including the integration of microbial genomics and the significance of managing the microbiota. Overall, this review serves as a valuable resource for those interested in the future of topical treatment of COE by providing a deep understanding of diagnostic, therapeutic, and medical interventions for effective management. Full article

(This article belongs to the Special Issue Innovations in Drug Delivery, Pharmacometrics, and Clinical Studies in Veterinary Medicine)

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26 pages, 1856 KB

Open AccessReview

Extracellular Vesicles and Nanoparticles in Regenerative and Personalised Medicine: Diagnostic and Therapeutic Roles—A Narrative Review

by Elena Silvia Bernad, Ingrid-Andrada Vasilache, Robert Leonard Bernad, Lavinia Hogea, Dragos Ene, Florentina Duica, Bogdan Tudora, Sandor Ianos Bernad, Marius Lucian Craina, Loredana Mateiovici and Răzvan Ene

Pharmaceutics 2025, 17(10), 1331; https://doi.org/10.3390/pharmaceutics17101331 - 14 Oct 2025

Viewed by 345

Abstract

Background: Degenerative, metabolic and oncologic diseases are scarcely amenable to the complete reconstruction of tissue structure and functionalities using common therapeutic modalities. On the nanoscale, extracellular vesicles (EVs) and nanoparticles (NPs) have emerged as attractive candidates in regenerative and personalised medicine. However, EV [...] Read more.

Background: Degenerative, metabolic and oncologic diseases are scarcely amenable to the complete reconstruction of tissue structure and functionalities using common therapeutic modalities. On the nanoscale, extracellular vesicles (EVs) and nanoparticles (NPs) have emerged as attractive candidates in regenerative and personalised medicine. However, EV transfection is hindered by its heterogeneity and low yield, while NPs suffer from cytotoxicity, immunogenicity, and long-term safety issues. Scope of Review: This review synthesises data from over 180 studies as part of a narrative synthesis, critically evaluating the disease-specific utility, mechanistic insights, and translational obstacles. The focus is laid on comparative cytotoxicity profiles, the capacities of hybrid EV–NP systems to circumvent mutual shortcomings, and the increasing impact of artificial intelligence (AI) on predictive modelling, as well as toxicity appraisal and manufacturing. Key Insights: EVs have inherent biocompatibility, immune evasive and organotropic signalling functions; NPs present structural flexibility, adjustable physicochemical properties, and industrial scalability. Common molecular pathways for NP toxicity, such as ROS production, MAPK and JAK/STAT activation, autophagy, and apoptosis, are significant biomarkers for regulatory platforms. Nanotechnological and biomimetic nanocarriers incorporate biological tropism with engineering control to enhance therapeutic efficacy, as well as their translational potential. AI approaches can support rational drug design, promote reproducibility across laboratories, and meet safe-by-design requirements. Conclusions: The intersection of EVs, NPs and AI signifies a turning point in regenerative nanomedicine. To advance this field, there is a need for convergence on experimental protocols, the adoption of mechanistic biomarkers, and regulatory alignment to ensure reproducibility and clinical competence. If realised, these endeavours will not only transition nanoscale medicament design from experimental constructs into reliable and patient-specific tools for clinical trials, but we also have the strong expectation that they could revolutionise future treatments of challenging human disorders. Full article

(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)

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22 pages, 2797 KB

Open AccessArticle

Carbon Dots with Tunable Charge as Mucus-Penetrating Gene Carriers

by Samuel Arca, Clea Witjaksono, Françoise Pons and Luc Lebeau

Pharmaceutics 2025, 17(10), 1330; https://doi.org/10.3390/pharmaceutics17101330 - 14 Oct 2025

Viewed by 351

Abstract

Background/Objectives: Local delivery of gene therapy products through the airways shows great promise for the treatment of a number of serious lung diseases, but its effectiveness is hampered by the mucus layer protecting the lung epithelium in the trachea and bronchi. Methods: To [...] Read more.

Background/Objectives: Local delivery of gene therapy products through the airways shows great promise for the treatment of a number of serious lung diseases, but its effectiveness is hampered by the mucus layer protecting the lung epithelium in the trachea and bronchi. Methods: To overcome this barrier, we engineered carbon dots (CDs) with mucus penetrating properties. Results: The CDs were synthesized by solvothermal treatment of citric acid and branched polyethyleneimine, and functionalized with maleamic acid groups to create cationic mucoinert nanoparticles with tunable charge. We characterized their interactions with a mucus model through turbidity and transport measurements, and assessed their impact on the viscoelastic properties of the biopolymer. We then demonstrated that the carriers are effective at delivering pDNA to a variety of cell models in vitro. In particular, mucus-producing Calu-3 cells cultured at the air–liquid interface (ALI) were used as a discriminating model to evaluate intracellular delivery of the genetic cargo through a thick layer of mucus at the cell surface. Conclusions: The functionalization of CDs with maleamic acid groups resulted in a 1000- to 10,000-fold increase in transfection efficiency in the mucus-producing model, offering new opportunities for lung gene therapy. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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20 pages, 4947 KB

Open AccessArticle

Engineered Liposomal Delivery of Human ACE2 Across the Blood–Brain Barrier Attenuated Neurogenic Hypertension

by Yue Shen, Richard Nii Lante Lamptey, Gowthami Reddy Mareddy, Bivek Chaulagain, Jagdish Singh and Chengwen Sun

Pharmaceutics 2025, 17(10), 1329; https://doi.org/10.3390/pharmaceutics17101329 - 14 Oct 2025

Viewed by 285

Abstract

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf [...] Read more.

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf receptor binding at the BBB and penetratin (Pen), a cell-penetrating peptide, to enhance neuronal uptake. Methods: This study evaluated the efficacy of Tf-Pen-liposomes in delivering angiotensin-converting enzyme 2 (ACE2) or EGFP (control) genes across the BBB in rats. In addition, the therapeutic effect of intravenous administration of Tf-Pen-Lip carrying plasmid DNA encoding ACE2 (Tf-Pen-Lip-pACE2) was tested in a neurogenic hypertension model induced by intracerebroventricular (ICV) infusion of angiotensin II (Ang II) via osmotic pump implantation and brain cannulation. Results: Conjugation with Tf and Pen significantly enhanced liposome-mediated gene transfection in cultured cells and increased transport across an in vitro BBB model. In vivo, intravenous administration of Tf-Pen-Lip-pACE2 or Tf-Pen-Lip-pGFP successfully elevated ACE2 or EGFP expression, respectively, in the hypothalamic paraventricular nucleus (PVN). Chronic ICV infusion of Ang II produced a sustained increase in blood pressure and heart rate, accompanied by sympathetic overactivation and elevated arginine vasopressin (AVP) secretion, hallmarks of neurogenic hypertension. Notably, intravenous Tf-Pen-Lip-pACE2 treatment dramatically attenuated Ang II–induced neurogenic hypertension, whereas Tf-Pen-Lip-pGFP had no effect on pressor responses, sympathetic activity, or AVP secretion. Conclusions: This dual-functionalized liposomal delivery system effectively transported the ACE2 gene across the BBB into the brain, increased ACE2 expression, and markedly attenuated neurogenic hypertension following systemic administration. Full article

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

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20 pages, 652 KB

Open AccessReview

Short Peptides as Excipients in Parenteral Protein Formulations: A Mini Review

by Dorian Migoń, Zbigniew Jaremicz and Wojciech Kamysz

Pharmaceutics 2025, 17(10), 1328; https://doi.org/10.3390/pharmaceutics17101328 - 13 Oct 2025

Viewed by 501

Abstract

Biopharmaceutical medicines represent one of the most dynamic sectors of the pharmaceutical industry, with therapeutic proteins forming the largest and most important group. Their structural complexity and inherent sensitivity to chemical and physical stressors, however, continue to pose major challenges for formulation development [...] Read more.

Biopharmaceutical medicines represent one of the most dynamic sectors of the pharmaceutical industry, with therapeutic proteins forming the largest and most important group. Their structural complexity and inherent sensitivity to chemical and physical stressors, however, continue to pose major challenges for formulation development and long-term stability. Short peptides have emerged as a promising yet underutilized class of excipients for protein-based drug products. Their modular architecture allows for precise tuning of physicochemical properties such as polarity, charge distribution, and hydrogen-bonding potential, thereby offering advantages over single amino acids. Experimental studies indicate that short peptides can serve multiple functions: stabilizers, antioxidants, viscosity-lowering agents, and as lyo/cryoprotectants or bulking agents in lyophilized formulations. Notably, the relatively small and chemically defined space of short peptides—approximately 400 possible dipeptides and 8000 tripeptides—makes them particularly amenable to systematic screening and computational modeling. This enables rational identification of candidates with tailored excipient functions. This review summarizes current knowledge on the use of short peptides as excipients in parenteral protein formulations, with a focus on their functional versatility and potential for rational design in future development. Full article

(This article belongs to the Section Biopharmaceutics)

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45 pages, 2530 KB

Open AccessReview

Unique Features and Collateral Immune Effects of mRNA-LNP COVID-19 Vaccines: Plausible Mechanisms of Adverse Events and Complications

by János Szebeni

Pharmaceutics 2025, 17(10), 1327; https://doi.org/10.3390/pharmaceutics17101327 - 13 Oct 2025

Viewed by 242

Abstract

A reassessment of the risk-benefit balance of the two lipid nanoparticle (LNP)-based vaccines, Pfizer’s Comirnaty and Moderna’s Spikevax, is currently underway. While the FDA has approved updated products, their administration is recommended only for individuals aged 65 years or older and for those [...] Read more.

A reassessment of the risk-benefit balance of the two lipid nanoparticle (LNP)-based vaccines, Pfizer’s Comirnaty and Moderna’s Spikevax, is currently underway. While the FDA has approved updated products, their administration is recommended only for individuals aged 65 years or older and for those aged 6 months or older who have at least one underlying medical condition associated with an increased risk of severe COVID-19. Among other factors, this change in guidelines reflect an expanded spectrum and increased incidence of adverse events (AEs) and complications relative to other vaccines. Although severe AEs are relatively rare (occurring in <0.5%) in vaccinated individuals, the sheer scale of global vaccination has resulted in millions of vaccine injuries, rendering post-vaccination syndrome (PVS) both clinically significant and scientifically intriguing. Nevertheless, the cellular and molecular mechanisms of these AEs are poorly understood. To better understand the phenomenon and to identify research needs, this review aims to highlight some theoretically plausible connections between the manifestations of PVS and some unique structural properties of mRNA-LNPs. The latter include (i) ribosomal synthesis of the antigenic spike protein (SP) without natural control over mRNA translation, diversifying antigen processing and presentation; (ii) stabilization of the mRNA by multiple chemical modification, abnormally increasing translation efficiency and frameshift mutation risk; (iii) encoding for SP, a protein with multiple toxic effects; (iv) promotion of innate immune activation and mRNA transfection in off-target tissues by the LNP, leading to systemic inflammation with autoimmune phenomena; (v) short post-reconstitution stability of vaccine nanoparticles contributing to whole-body distribution and mRNA transfection; (vi) immune reactivity and immunogenicity of PEG on the LNP surface increasing the risk of complement activation with LNP disintegration and anaphylaxis; (vii) GC enrichment and double proline modifications stabilize SP mRNA and prefusion SP, respectively; and (viii) contaminations with plasmid DNA and other organic and inorganic elements entailing toxicity with cancer risk. The collateral immune anomalies considered are innate immune activation, T-cell- and antibody-mediated cytotoxicities, dissemination of pseudo virus-like hybrid exosomes, somatic hypermutation, insertion mutagenesis, frameshift mutation, and reverse transcription. Lessons from mRNA-LNP vaccine-associated AEs may guide strategies for the prediction, prevention, and treatment of AEs, while informing the design of safer next-generation mRNA vaccines and therapeutics. Full article

(This article belongs to the Special Issue Development of Nucleic Acid Delivery System)

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29 pages, 1315 KB

Open AccessReview

Targeting the Eye: RNA-Based Therapies, Interferences, and Delivery Strategies

by Mohammed S. Abdel-Raziq Hassan, Cheng Zhong, Fatma Hassan and S. Kevin Li

Pharmaceutics 2025, 17(10), 1326; https://doi.org/10.3390/pharmaceutics17101326 - 13 Oct 2025

Viewed by 512

Abstract

Recent advances in molecular biology have led to the development of RNA-based therapeutics, offering significant promise for treating various eye diseases. Current RNA therapeutics include RNA aptamers, antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and messenger RNA (mRNA) that can target specific genetic [...] Read more.

Recent advances in molecular biology have led to the development of RNA-based therapeutics, offering significant promise for treating various eye diseases. Current RNA therapeutics include RNA aptamers, antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and messenger RNA (mRNA) that can target specific genetic and molecular pathways involved in eye disorders. In addition to their potential in therapy, RNA technologies have also provided tools for mechanistic studies to improve the understanding of eye diseases, expanding the possibilities of RNA-based treatments. Despite the utility of RNA in studying eye disease mechanisms and its potential in disease treatment, only a few RNA-based therapies have been approved for posterior eye diseases. This paper reviews RNA interference and related ocular delivery and posterior eye diseases, focusing on the use of RNA aptamers, siRNA, short hairpin RNA (shRNA), and microRNA (miRNA). Approaches using RNA to advance our understanding of eye diseases and disease treatments, particularly in the posterior segment of the eye, are discussed. It is concluded that RNA therapeutics offer a novel approach to treating a variety of eye diseases by targeting their molecular causes. siRNA, shRNA, miRNA, and ASO can directly silence disease-driving genes, while RNA aptamers bind to specific targets. Although many RNA-based therapies are still in experimental stages, they hold promise for conditions such as age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, and inherited retinal disorders. Effective delivery methods and long-term safety are key challenges that need to be addressed for these treatments to become widely available. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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27 pages, 1204 KB

Open AccessReview

Orally Dispersible Swallowed Topical Corticosteroids in Eosinophilic Esophagitis: A Paradigm Shift in the Management of Esophageal Inflammation

by Alberto Barchi, Marina Girelli, Antonio Ventimiglia, Francesco Vito Mandarino, Silvio Danese, Sandro Passaretti, Mona-Rita Yacoub, Serena Nannipieri, Ambra Federica Ciliberto, Luca Albarello, Alessandra Bartolucci, Edoardo Vespa and Giuseppe Dell’Anna

Pharmaceutics 2025, 17(10), 1325; https://doi.org/10.3390/pharmaceutics17101325 - 13 Oct 2025

Viewed by 390

Abstract

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease of the esophagus within the type 2 inflammatory spectrum, characterized by progressive tissue remodeling driven by uncontrolled inflammation. Its incidence and prevalence are rising sharply, likely reflecting environmental triggers acting on genetic and epigenetic susceptibility. [...] Read more.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease of the esophagus within the type 2 inflammatory spectrum, characterized by progressive tissue remodeling driven by uncontrolled inflammation. Its incidence and prevalence are rising sharply, likely reflecting environmental triggers acting on genetic and epigenetic susceptibility. Therapeutic options have expanded rapidly, with recent approvals of new topical steroidal formulations together with biologic compounds. Proton pump inhibitors (PPIs), older swallowed topical corticosteroid (STC), and dietary interventions remain in use but are limited by suboptimal adherence and treatment discontinuation. This has driven a shift toward advanced orally dispersible STCs formulations—most notably budesonide orally dispersible tablets (BOT), budesonide oral suspension (BOS), and fluticasone orally dispersible tablets (FOT). BOT, the most extensively studied, achieves high rates of histologic and clinical remission, with favorable safety and superior adherence compared to earlier STCs formulations. This comprehensive overview focuses on following key research findings and novelty aspects of new treatments: (a) optimized esophageal targeting through orally dispersible or viscous formulations of STC, enhancing mucosal contact time and improving drug delivery to affected tissues compared to older formulations; (b) robust evidence for both induction and maintenance rates of remission, with data extending up to nearly 2 years and showing stable efficacy across clinical, histologic, and endoscopic endpoints; (c) effectiveness in STC-refractory patients, with BOT showing benefit even in those previously unresponsive to older STC formulations. This review synthesizes evidence of steroid therapy in EoE, from pharmacological aspects to clinical efficacy from randomized trials and emerging real-world studies, highlighting its impact on EoE management and outlining future therapeutic directions. Full article

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

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3 pages, 972 KB

Open AccessCorrection

Correction: Mandal et al. Modified Linear Peptides Effectively Silence STAT-3 in Breast Cancer and Ovarian Cancer Cell Lines. Pharmaceutics 2023, 15, 666

by Dindyal Mandal, Sandeep Lohan, Muhammad Imran Sajid, Abdulelah Alhazza, Rakesh Kumar Tiwari, Keykavous Parang and Hamidreza Montazeri Aliabadi

Pharmaceutics 2025, 17(10), 1324; https://doi.org/10.3390/pharmaceutics17101324 - 13 Oct 2025

Viewed by 211

Abstract

In the original publication [...] Full article

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

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20 pages, 5106 KB

Open AccessArticle

Phase I Clinical Study with the GRPR-Antagonist [^99mTc]Tc-DB8 for SPECT Imaging of Prostate Cancer: Does the Injected Peptide Mass Make a Difference?

by Anna Orlova, Anastasia Rybina, Anna Medvedeva, Roman Zelchan, Olga Bragina, Liubov Tashireva, Maria Larkina, Ruslan Varvashenya, Nadejda Lushnikova, Panagiotis Kanellopoulos, Theodosia Maina, Berthold A. Nock, Vladimir Tolmachev and Vladimir Chernov

Pharmaceutics 2025, 17(10), 1323; https://doi.org/10.3390/pharmaceutics17101323 - 12 Oct 2025

Viewed by 494

Abstract

Background/Objectives: The gastrin-releasing peptide receptor (GRPR) shows high-density expression in prostate cancer (PCa), especially in the early stages of the disease. The introduction of a safe radiotracer for assessing GRPR-expression in PCa may serve as an alternative or complementary tracer to PSMA-directed [...] Read more.

Background/Objectives: The gastrin-releasing peptide receptor (GRPR) shows high-density expression in prostate cancer (PCa), especially in the early stages of the disease. The introduction of a safe radiotracer for assessing GRPR-expression in PCa may serve as an alternative or complementary tracer to PSMA-directed probes for patients with insufficient PSMA expression. In the present study, the tolerability and safety, biodistribution, and dosimetry of the new GRPR-targeting radiopeptide [^99mTc]Tc-DB8 were investigated for the first time in male PCa patients. A mass escalation study was performed, aiming to improve tumor-to-background contrast and, thereby, to enhance diagnostic accuracy. Methods: Sixteen male patients were enrolled in a single-center diagnostic open-label exploratory Phase I clinical trial. Patients were administered a single intravenous injection of 40, 80, or 120 µg of [^99mTc]Tc-DB8 peptide (n = 5–6) and underwent whole-body planar imaging (anterior and posterior) 2, 4, 6, and 24 h post-injection (pi) and SPECT-CT acquisition 2, 4, and 6 h pi. Results: Administration of [^99mTc]Tc-DB8 was well tolerated at all tested peptide masses. The effective dose did not differ significantly between the injected peptide mass and was 0.005 ± 0.003 mSv/MBq. High activity uptake was observed in the pancreas and kidneys, which 3-fold decreased with an increasing injected peptide mass from 40 to 120 µg. The activity uptake in primary tumors did not differ significantly between cohorts injected with different peptide masses [SUV_max 1.65–9.96]. The tumor-to-muscle ratios increased with time and were the highest for the cohort injected with 120 µg of peptide, 7.2 ± 3.1 (4.64-11-25) at 4 h pi. Conclusions: Single intravenous administration of [^99mTc]Tc-DB8, for visualization of GRPR expression in PCa using SPECT imaging was well tolerated in a peptide mass range of 40–120 µg. An injected peptide mass of 80–120 µg/patient and SPECT acquisition 2–4 h pi were found to be optimal for further clinical studies due to the significantly lower activity accumulation in the pancreas and kidneys. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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21 pages, 1300 KB

Open AccessReview

Cancer Cell Membrane-Coated NPs as a Biomimetic Strategy for Precision Tumor Therapy

by Junyi Lin, Wei Li, Alaa R. Aboushanab and Jingjing Sun

Pharmaceutics 2025, 17(10), 1322; https://doi.org/10.3390/pharmaceutics17101322 - 11 Oct 2025

Viewed by 530

Abstract

Cancer treatment remains challenging due to the complexity of the tumor microenvironment, which promotes tumor heterogeneity and contributes to the development of multidrug resistance, ultimately hindering drug delivery and reducing therapeutic efficacy. In recent years, biomimetic nanocarriers have emerged as promising tools to [...] Read more.

Cancer treatment remains challenging due to the complexity of the tumor microenvironment, which promotes tumor heterogeneity and contributes to the development of multidrug resistance, ultimately hindering drug delivery and reducing therapeutic efficacy. In recent years, biomimetic nanocarriers have emerged as promising tools to address these challenges. Among them, cancer cell membrane (CCM)-coated nanoparticles (CCM-NPs) have attracted increasing attention due to their unique advantages, including homologous targeting, prolonged circulation mediated by self-recognition, and enhanced tumor penetration. Moreover, CCM-NPs can serve as versatile platforms for tumor vaccines by leveraging their inherent tumor-associated antigens and immunomodulatory potential. By leveraging CCMs to functionalize NPs, researchers have developed innovative approaches to improve drug delivery, enhance tumor immunotherapy, and optimize cancer vaccine efficacy. Despite these advancements, a comprehensive review summarizing the latest progress in CCM-based biomimetic nanocarriers for tumor treatment is lacking. This review integrates recent advances in CCM-NPs for targeted drug delivery and cancer vaccination, and discusses their fabrication, characterization, mechanisms and applications across multiple cancer types, which provides timely insights to guide their future development in precision tumor therapy. Full article

(This article belongs to the Special Issue Innovative Drug Delivery Strategies for Targeted Cancer Immunotherapy)

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21 pages, 2142 KB

Open AccessReview

Advances in Nasal Biopharmaceutics to Support Product Development and Therapeutic Needs

by Ben Forbes, Lucy Goodacre, Alison B. Lansley, Andrew R. Martin, Helen Palmer, Claire Patterson, Chris Roe and Regina Scherließ

Pharmaceutics 2025, 17(10), 1321; https://doi.org/10.3390/pharmaceutics17101321 - 11 Oct 2025

Viewed by 326

Abstract

Background/Objectives: Nasal biopharmaceutics is the scientific understanding of product and patient factors that determine the rate and extent of drug exposure following nasal administration. The authors considered whether current biopharmaceutics tools are fit for the current and future needs of nasal product development [...] Read more.

Background/Objectives: Nasal biopharmaceutics is the scientific understanding of product and patient factors that determine the rate and extent of drug exposure following nasal administration. The authors considered whether current biopharmaceutics tools are fit for the current and future needs of nasal product development and regulation. Methods: The limitations of current methods were critically assessed, unmet needs were highlighted, and key questions were posed to guide future directions in biopharmaceutics research. Results: The emergence of physiologically based biopharmaceutics models for nasal delivery has the potential to drive the scientific understanding of nasal delivery. Simulations can guide formulation and device development, inform dose selection and generate mechanistic insights. Developments in modeling need to be complemented by advances in experimental systems, including the use of realistic or idealized nasal casts to estimate the regional deposition of nasal sprays and refined in vitro cell culture models to study nasal drug absorption and the influence of mucus. Similarly, improvements are needed to address the practicalities of using animals in non-clinical studies of nasal drug delivery, and greater clinical use of gamma scintigraphy/magnetic resonance imaging is recommended to measure the delivery and nasal retention of different formulations in humans. Conclusions: Nasal drug delivery is a rapidly growing field and requires advances in nasal biopharmaceutics to support product innovation. Key needs are (i) validated clinically relevant critical product attributes for product performance and (ii) established links between how patients administer the product and where in the nose it deposits and dissolves in order to act or be absorbed, leading to its desired clinical effect. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments, 3rd Edition)

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10 pages, 1043 KB

Open AccessCommunication

Preliminary In Vivo Ocular Tolerance Assessment of a Cefuroxime Sodium Suspension in Self-Emulsifying Oil

by Katarzyna Krzemińska, Eliza Wolska, Juliusz Chorążewicz and Małgorzata Sznitowska

Pharmaceutics 2025, 17(10), 1320; https://doi.org/10.3390/pharmaceutics17101320 - 11 Oct 2025

Viewed by 272

Abstract

Cefuroxime sodium (CEF) is a second-generation cephalosporin that remains unstable in an aqueous environment. The answer to this low stability may be self-emulsifying oils, which are isotropic mixtures of oil and surfactants, in which the stability of CEF has already been proven. Self-emulsifying [...] Read more.

Cefuroxime sodium (CEF) is a second-generation cephalosporin that remains unstable in an aqueous environment. The answer to this low stability may be self-emulsifying oils, which are isotropic mixtures of oil and surfactants, in which the stability of CEF has already been proven. Self-emulsifying oils are well known for their ability to enhance the solubility and bioavailability of lipophilic drugs. This research presents a preliminary in vivo study of an innovative approach to develop eye drops in the form of a self-emulsifying oil (SEO) containing suspended water-labile antibiotic cefuroxime sodium. Such a concept has never been explored before. Upon contact with tear fluid, the preparation rapidly forms an emulsion, allowing for the rapid dissolution of the antibiotic. The aim of the study was to assess the tolerability of such eye drops. CEF (5% w/w) was suspended in SEO carriers, prepared by dissolving surfactants (Tween 20; 5% w/w) in Miglyol. The in vivo evaluation was conducted on rabbits after two once-a-day applications of the eye drops. The study demonstrated the safety of both the SEO-placebo and the SEO containing suspended CEF. The formulations did not affect the appearance of the cornea and iris. During the observations, only changes in the conjunctiva of the eye were noted, which manifested as conjunctival hyperemia. The result of the Draize test was an average of 3.3 points out of 110 possible points, which classifies the CEF-SEO suspension as minimally irritating. Full article

(This article belongs to the Special Issue Advances in Emulsifying Drug Delivery Systems)

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21 pages, 3438 KB

Open AccessArticle

Research on Enhancing the Solubility and Bioavailability of Canagliflozin Using Spray Drying Techniques with a Quality-by-Design Approach

by Ji Ho Lee, Seong Uk Choi, Tae Jong Kim, Na Yoon Jeong, Hyun Seo Paeng and Kyeong Soo Kim

Pharmaceutics 2025, 17(10), 1319; https://doi.org/10.3390/pharmaceutics17101319 - 11 Oct 2025

Viewed by 280

Abstract

Objectives: The objective of this study was to enhance the solubility and bioavailability of canagliflozin (CFZ) using a spray drying technique with a Quality-by-Design (QbD) approach. Methods: The formulation of CFZ-loaded solid dispersions (CFZ-SDs) was optimized using a Box–Behnken design (BBD) [...] Read more.

Objectives: The objective of this study was to enhance the solubility and bioavailability of canagliflozin (CFZ) using a spray drying technique with a Quality-by-Design (QbD) approach. Methods: The formulation of CFZ-loaded solid dispersions (CFZ-SDs) was optimized using a Box–Behnken design (BBD) with three factors at three levels, resulting in a total of fifteen experiments, including three central point replicates. The design space was determined using the BBD, and the optimized CFZ-SD was evaluated for reproducibility, morphology, and physical properties and subjected to in vitro and in vivo tests. Results: The optimal values for each X factor were identified using a response optimization tool, achieving a yield (Y1) of 62.8%, a solubility (Y2) of 9941 μg/mL, and a particle size (Y3) of 5.89 μm, all of which were within the 95% prediction interval (PI). Additionally, amorphization induced by spray drying was confirmed for the optimized CFZ-SD using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) analyses. In in vitro dissolution tests, the final dissolution rate of the CFZ-SD increased 3.58-fold at pH 1.2 and 3.84-fold at pH 6.8 compared to an Invokana^® tablet. In addition, relative to CFZ, it showed an 8.67-fold and 8.85-fold increase at pH 1.2 and pH 6.8, respectively. The in vivo pharmacokinetic behavior of CFZ and the CFZ-SD was evaluated in Sprague–Dawley rats following oral administration at a dose of 5 mg/kg. The AUC of the CFZ-SD increased 1.9-fold compared to that of CFZ. Conclusions: In this study, a solid dispersion (SD) formulation of CFZ, a BCS class IV SGLT2 inhibitor, was developed and optimized using a QbD approach to enhance solubility and oral bioavailability. Full article

(This article belongs to the Special Issue Methods of Potentially Improving Drug Permeation and Bioavailability)

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27 pages, 6020 KB

Open AccessArticle

Engineered Nanobody-Bearing Extracellular Vesicles Enable Precision Trop2 Knockdown in Resistant Breast Cancer

by Jassy Mary S. Lazarte, Mounika Aare, Sandeep Chary Padakanti, Arvind Bagde, Aakash Nathani, Zachary Meeks, Li Sun, Yan Li and Mandip Singh

Pharmaceutics 2025, 17(10), 1318; https://doi.org/10.3390/pharmaceutics17101318 - 11 Oct 2025

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Abstract

Background/Objectives: Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in a broad spectrum of epithelial malignancies but minimally expressed in normal tissues, has emerged as a clinically relevant prognostic biomarker and therapeutic target, particularly in breast cancer. This study aims [...] Read more.

Background/Objectives: Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in a broad spectrum of epithelial malignancies but minimally expressed in normal tissues, has emerged as a clinically relevant prognostic biomarker and therapeutic target, particularly in breast cancer. This study aims to develop an enhanced way of targeting Trop2 expression in tumors and blocking it using extracellular vesicles (EVs) bioengineered to express a nanobody sequence against Trop2 (NB60 E). Methods: Here, a plasmid construct was designed to express the Trop2 sequence, NB60, flanked with HA tag and myc epitope and a PDGFR transmembrane domain in the C-terminal region, and was transfected into HEK293T cells for EVs isolation. The potency of NB60 E to knock down Trop2 in letrozole-resistant breast cancer cells (LTLT-Ca and MDA-MB-468 cells) was initially investigated. Thereafter, the effects of NB60 E on the cell viability and downstream signaling pathway of Trop2 via MTT assay and Western blotting were determined. Lastly, we also examined whether NB60 E treatment in Jurkat T cells affects IL-6, TNF-α, and IL-2 cytokine production by enzyme-linked immunosorbent assay (ELISA). Results: Results revealed treatment with NB60 E significantly reduced surface Trop2 expression across both cell lines by 23.5 ± 1.5% in MDA-MB-468, and 61.5 ± 1.5% in LTLT-Ca, relative to the HEK293T-derived control EVs (HEK293T E). NB60 E treatment resulted in a marked reduction in LTLT-Ca cell viability by 52.8 ± 0.9% at 48 h post-treatment. This was accompanied by downregulation of key oncogenic signaling molecules: phosphorylated ERK1/2 (p-ERK 1/2) decreased by 30 ± 4%, cyclin D1 by 67 ± 11%, phosphorylated STAT3 (p-STAT3) by 71.8 ± 1.6%, and vimentin by 40.8 ± 1.4%. ELISA analysis revealed significant decreases in IL-6 (−57.5 ± 1.5%, 7.4 ± 0.35 pg/mL) and TNF-α (−32.1 ± 0.3%, 6.1 ± 1.2 pg/mL) levels, coordinated by an increase in IL-2 secretion (22.1 ± 2.7%, 49.2 ± 1.1 pg/mL). Quantitative analysis showed marked reductions in the number of nodes (−45 ± 4.4%), junctions (−55 ± 3.5%), and branch points (−38 ± 1.2%), indicating suppression of angiogenic capacity. In vivo experiment using near-infrared Cy7 imaging demonstrated rapid and tumor-selective accumulation of NB60 E within 4 h post-administration, followed by efficient systemic clearance by 24 h. The in vivo results demonstrate the effectiveness of NB60 E in targeting Trop2-enriched tumors while being efficiently cleared from the system, thus minimizing off-target interactions with normal cells. Lastly, Trop2 expression in LTLT-Ca tumor xenografts revealed a significant reduction of 41.0 ± 4% following NB60 E treatment, confirming efficient targeted delivery. Conclusions: We present a first-in-field NB60 E-grafted EV therapy that precisely homes to Trop2-enriched breast cancers, silences multiple growth-and-invasion pathways, blocks angiogenesis, and rewires cytokine crosstalk, achieving potent antitumor effects with self-clearing, biomimetic carriers. Our results here show promising potential for the use of NB60 E as anti-cancer agents, not only for letrozole-resistant breast cancer but also for other Trop2-expressing cancers. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)

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Pharmaceutics, Volume 17, Issue 10 (October 2025) – 110 articles

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