Pharmaceutics

0 pages, 1856 KiB

Open AccessArticle

Comparative Evaluation of Gelatin and HPMC Inhalation Capsule Shells Exposed to Simulated Humidity Conditions

by Sabrina Magramane, Nikolett Kállai-Szabó, Dóra Farkas, Károly Süvegh, Romána Zelkó and István Antal

Pharmaceutics 2025, 17(7), 877; https://doi.org/10.3390/pharmaceutics17070877 - 3 Jul 2025

Abstract

Background/Objectives: This study investigates the impact of high humidity (25 °C, 75% relative humidity) on gelatin and hydroxypropyl methylcellulose (HPMC) capsules used in dry powder inhalers (DPIs), focusing on moisture dynamics, structural responses, and mechanical performance, with an emphasis on understanding how [...] Read more.

Background/Objectives: This study investigates the impact of high humidity (25 °C, 75% relative humidity) on gelatin and hydroxypropyl methylcellulose (HPMC) capsules used in dry powder inhalers (DPIs), focusing on moisture dynamics, structural responses, and mechanical performance, with an emphasis on understanding how different capsule types respond to prolonged exposure to humid conditions. Methods: Capsules were exposed to controlled humidity conditions, and moisture uptake was measured via thermal analysis. Visual observations of silica bead color changes were performed to assess moisture absorption, while surface wettability was measured using the sessile drop method. Hardness testing, mechanical deformation, and puncture tests were performed to evaluate structural and mechanical changes. Positron annihilation lifetime spectroscopy (PALS) was used to analyze free volume expansion. Results: HPMC capsules exhibited rapid moisture uptake, attributed to their lower equilibrium moisture content and ability to rearrange dynamically, preventing brittleness. In contrast, gelatin capsules showed slower moisture absorption but reached higher equilibrium levels, resulting in plasticization and softening. Mechanical testing showed that HPMC capsules retained structural integrity with minimal deformation, while gelatin capsules became softer and exhibited reduced puncture resistance. Structural analysis revealed greater free volume expansion in HPMC capsules, consistent with their amorphous nature, compared with gelatin’s semi-crystalline matrix. Conclusions: HPMC capsules demonstrated superior humidity resilience, making them more suitable for protecting moisture-sensitive active pharmaceutical ingredients (APIs) in DPI formulations. These findings underline the importance of appropriate storage conditions, as outlined in the Summary of Product Characteristics, to ensure optimal capsule performance throughout patient use. Full article

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

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0 pages, 11210 KiB

Open AccessArticle

Perspectives on the pH-Influenced Design of Chitosan–Genipin Nanogels for Cell-Targeted Delivery

by Julieta D. Glasman, Agustina Alaimo, Cecilia Samaniego López, María Edith Farías, Romina B. Currá, Diego G. Lamas and Oscar E. Pérez

Pharmaceutics 2025, 17(7), 876; https://doi.org/10.3390/pharmaceutics17070876 - 3 Jul 2025

Abstract

Background: Chitosan (CS) crosslinked with genipin (GNP) provides a mild, non-toxic route to generate nanogels (NGs) with enhanced integrity and colloidal stability. Objectives: To develop and characterise CS-GNP NG as a novel platform for targeted cellular delivery, optimising design through physicochemical [...] Read more.

Background: Chitosan (CS) crosslinked with genipin (GNP) provides a mild, non-toxic route to generate nanogels (NGs) with enhanced integrity and colloidal stability. Objectives: To develop and characterise CS-GNP NG as a novel platform for targeted cellular delivery, optimising design through physicochemical characterisation and biocompatibility evaluation. Methods: NGs were synthesised under optimised conditions by adjusting the pH of the CS solution, followed by high-intensity ultrasound (HIUS) to achieve disaggregation. Physicochemical characterisation was carried out using UV-Vis spectroscopy, FTIR, dynamic light scattering (DLS), and scanning electron microscopy (SEM). Rheological studies and SAXS analysis assessed structural properties. Biocompatibility was evaluated via MTT assay, and internalisation was monitored by fluorescence microscopy on mammalian cell lines. Results: NG formation was highly pH-dependent, with optimal configuration at pH 4.5, yielding stable, uniformly sized particles (~200 nm, ζ-potential +29 mV). Kinetic modelling showed a sigmoidal formation pattern, suggesting nucleation, growth, and stabilisation. FTIR confirmed covalent bonding between CS and GNP via primary amide bonds and Schiff bases. Rheology indicated pseudoplastic behaviour, and SAXS revealed a compact network formation. Biocompatibility assays confirmed non-cytotoxicity below 100 µg/mL and efficient cellular uptake. Conclusions: This study presents a rapid, reproducible protocol for generating colloidally stable, biocompatible NGs suitable for drug delivery. Full article

(This article belongs to the Special Issue Biomaterial-Based Nanoencapsulation Systems for Drug Protection and Controlled Release)

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0 pages, 4426 KiB

Open AccessArticle

Laser Microinterferometry for API Solubility and Phase Equilibria: Darunavir as a Case Example

by Veronika Makarova, Mark Mandrik and Sergey Antonov

Pharmaceutics 2025, 17(7), 875; https://doi.org/10.3390/pharmaceutics17070875 - 3 Jul 2025

Abstract

Background: The solubility and phase behavior of APIs are crucial for the development of medicines and ensuring their stability. However, conventional experimental approaches often do not allow for the precise determination of phase transitions and solubility limits, especially for poorly soluble compounds. Purpose: [...] Read more.

Background: The solubility and phase behavior of APIs are crucial for the development of medicines and ensuring their stability. However, conventional experimental approaches often do not allow for the precise determination of phase transitions and solubility limits, especially for poorly soluble compounds. Purpose: The aim of this study was to demonstrate the possibility of using the laser microinterferometry method, traditionally used to define the phase equilibria of polymer systems, to determine the thermodynamic solubility of the APIs. Methods: Using laser microinterferometry, the thermodynamic solubility and phase behavior of amorphous darunavir were determined in various pharmaceutical solvents, including vaseline and olive oils, water, glycerol, alcohols (methanol, ethanol, isopropanol), glycols (propylene glycol, polyethylene glycol 400, polypropylene glycol 425, polyethylene glycol 4000), and ethoxylated polyethylene glycol ether obtained from castor oil in the temperature range of 25–130 °C. Dissolution kinetics was estimated at 25 °C. Hansen solubility parameter calculations were also performed for comparison. Results: Darunavir is practically insoluble in olive and vaseline oils. In water and glycerol, an amorphous equilibrium with an upper critical solution temperature was observed, and phase diagrams were constructed for the first time. In alcohols, glycols, and ethoxylated polyethylene glycol ether obtained from castor oil, darunavir showed high solubility, accompanied by the formation of crystalline solvates. Kinetic evaluation showed that the dissolution rate of darunavir in methanol is four times faster than in ethanol and thirty times faster than in isopropanol. Comparison of the obtained data with previously published and calculated values of solubility parameters demonstrates a good correlation. Conclusions: Laser microinterferometry has been demonstrated as a potential tool for determining the thermodynamic solubility of APIs. This method allows for directly observing the dissolution process, determining the solubility limits, and detecting phase transitions. These studies are necessary for selecting appropriate excipients, preventing the formation of undesirable solvates and predicting formulation stability, which are all critical factors in early-stage drug development and pharmaceutical formulation design. Full article

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

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0 pages, 1018 KiB

Open AccessArticle

The Influence of Moisturizer Co-Application Protocols on In Vitro Penetration of Betamethasone in Porcine Skin

by Daiane L. Rost, Geisa N. Barbalho, Jayanaraian F. M. Andrade, Marcilio Cunha-Filho, Guilherme M. Gelfuso and Tais Gratieri

Pharmaceutics 2025, 17(7), 874; https://doi.org/10.3390/pharmaceutics17070874 - 3 Jul 2025

Abstract

Background/Objectives: The treatment of atopic dermatitis frequently involves using a topical corticosteroid and a moisturizer. While the sequential application of these products is a common dermatological practice, their influence on drug penetration remains poorly understood. There is no clear evidence on how hydration, [...] Read more.

Background/Objectives: The treatment of atopic dermatitis frequently involves using a topical corticosteroid and a moisturizer. While the sequential application of these products is a common dermatological practice, their influence on drug penetration remains poorly understood. There is no clear evidence on how hydration, application sequence, and massage affect cutaneous drug delivery. Hence, this study aimed to evaluate the effects of formulation type, moisturizer composition, application sequence, and mechanical stimulation on betamethasone dipropionate (BET) cutaneous penetration. Methods: Two commercial formulations (cream and ointment) of BET were evaluated in different experimental conditions, including drug application combined with moisturizers (Cetaphil^®, as an emollient; Nivea^®, as an occlusive) pre- or post-application, with or without a 30 s massage. In vitro skin penetration assays were conducted for 12 h using porcine skin mounted in modified Franz diffusion cells. BET levels were extracted from the skin layers and quantified by HPLC. Results: The cutaneous BET penetration was strongly influenced by the application sequence, type of moisturizer, and mechanical stimuli. Pre-application of an occlusive or emollient moisturizer, followed by 30 s physical stimuli, significantly enhanced drug retention in the stratum corneum. For the cream, pre-application of moisturizers followed by massage notably increased BET levels in both the stratum corneum and viable skin. Conversely, post-application of moisturizers hindered BET absorption. The ointment showed limited penetration across all conditions, with no drug detected in the viable skin. Conclusions: The results showed pre-hydrating the skin, combined with a 30 s massage, was the best strategy for BET diffusion into the skin following cream administration. The formulation type and the order of application directly influence the effectiveness of drug therapy and the topical absorption of BET. Full article

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

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18 pages, 1061 KiB

Open AccessArticle

Design of Clofazimine-Loaded Lipid Nanoparticles Using Smart Pharmaceutical Technology Approaches

by Helena Rouco, Nicola Filippo Virzì, Carolina Menéndez-Rodríguez, Carmen Potel, Patricia Diaz-Rodriguez and Mariana Landin

Pharmaceutics 2025, 17(7), 873; https://doi.org/10.3390/pharmaceutics17070873 - 2 Jul 2025

Abstract

Background/Objectives: Clofazimine (CFZ) is a versatile antimicrobial active against several bacterial species, although its reduced aqueous solubility and the occurrence of side effects limit its use. Nanostructured lipid carriers (NLCs) constitute an interesting approach to increase drug bioavailability and safety. However, the [...] Read more.

Background/Objectives: Clofazimine (CFZ) is a versatile antimicrobial active against several bacterial species, although its reduced aqueous solubility and the occurrence of side effects limit its use. Nanostructured lipid carriers (NLCs) constitute an interesting approach to increase drug bioavailability and safety. However, the development of nanoparticle-based formulations is challenging. In the present work, a combination of smart pharmaceutical technology approaches was proposed to develop CFZ-loaded NLCs, taking advantage of previous knowledge on NLCs screening. Methods: A design space previously established using Artificial Intelligence (AI) tools was applied to develop CFZ-loaded NLC formulations. After formulation characterization, Neurofuzzy Logic (NFL) and in silico docking simulations were employed to enhance the understanding of lipid nanocarriers. Then, the performance of formulations designed following NFL guidelines was characterized in terms of biocompatibility, using murine fibroblasts, and antimicrobial activity against several strains of Staphylococcus aureus. Results: The followed approach enabled CFZ-loaded NLC formulations with optimal properties, including small size and high antimicrobial payload. NFL was useful to investigate the existing interactions between NLC components and homogenization conditions, that influence CFZ-loaded NLCs’ final properties. Also, in silico docking simulations were successfully applied to examine interactions and affinity between the drug and the lipid matrix components. Finally, the designed CFZ-loaded formulations demonstrated suitable biocompatibility, together with antimicrobial activity. Conclusions: The implementation of smart strategies during nanoparticle-based therapeutics development, such as those described in this manuscript, would enable the more efficient design of new systems for suitable antimicrobial delivery. Full article

(This article belongs to the Special Issue Smart Pharmaceutical Technologies for Drug Delivery and Tissue Engineering)

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28 pages, 5527 KiB

Open AccessArticle

Oral Metronomic Delivery of Atorvastatin and Docetaxel via Transporter-Targeted Nanoemulsions Enhances Antitumor Efficacy and Immune Modulation in Colon Cancer

by Laxman Subedi, Arjun Dhwoj Bamjan, Susmita Phuyal, Bikram Khadka, Mansingh Chaudhary, Ki-Taek Kim, Ki Hyun Kim, Jung-Hyun Shim, Seung-Sik Cho, Ji Eun Yu and Jin Woo Park

Pharmaceutics 2025, 17(7), 872; https://doi.org/10.3390/pharmaceutics17070872 - 2 Jul 2025

Abstract

Background/Objectives: This study aimed to enhance the oral delivery and therapeutic synergy of atorvastatin (AT) and docetaxel (DT) through a metronomic schedule using a transporter-targeted nanoemulsion (NE), with the goal of improving antitumor efficacy and immune modulation. Methods: AT and DT [...] Read more.

Background/Objectives: This study aimed to enhance the oral delivery and therapeutic synergy of atorvastatin (AT) and docetaxel (DT) through a metronomic schedule using a transporter-targeted nanoemulsion (NE), with the goal of improving antitumor efficacy and immune modulation. Methods: AT and DT were co-encapsulated in a NE system (AT/DT-NE#E) incorporating deoxycholic acid–DOTAP (D-TAP), biotin-conjugated phospholipid (Biotin-PE), and d-α-tocopherol polyethylene glycol succinate (TPGS) to exploit bile acid and multivitamin transport pathways and inhibit P-glycoprotein efflux. The optimized NE was characterized physicochemically and evaluated for permeability in artificial membranes and Caco-2/HT29-MTX-E12 monolayers. Pharmacokinetics, tumor suppression, and immune cell infiltration were assessed in vivo using rat and CT26.CL25 mouse models. Results: AT/DT-NE#E showed enhanced permeability of AT and DT by 45.7- and 43.1-fold, respectively, across intestinal cell models and improved oral bioavailability by 118% and 376% compared to free drugs. In vivo, oral metronomic AT/DT-NE#E reduced tumor volume by 65.2%, outperforming intravenous AT/DT. Combination with anti-PD1 therapy achieved a 942% increase in tumor suppression over the control, accompanied by marked increases in tumor-infiltrating CD45⁺, CD4⁺CD3⁺, and CD8⁺CD3⁺ T cells. Conclusions: Oral metronomic administration of AT/DT via a dual-transporter-targeted NE significantly improves drug absorption, tumor inhibition, and immune response. This strategy presents a safe and effective approach for colon cancer therapy, particularly when combined with immunotherapy. Full article

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

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2 pages, 118 KiB

Open AccessEditorial

Editorial for the Special Issue “Mathematical Modelling in Drug Delivery”

by Fjóla Jónsdóttir

Pharmaceutics 2025, 17(7), 871; https://doi.org/10.3390/pharmaceutics17070871 - 2 Jul 2025

Abstract

This Special Issue highlights the essential role of mathematical modelling in pharmaceutical research, particularly in the development and optimization of drug delivery systems [...] Full article

19 pages, 2810 KiB

Open AccessArticle

In Vitro Assessment of a Doubly Adjuvanted Self-Emulsified Nanoemulsion as a Delivery Vehicle for Antigenic Proteins

by Evgenia Tsanaktsidou, Maritsa Margaroni, Evdokia Karagouni, Costas Kiparissides and Olga Kammona

Pharmaceutics 2025, 17(7), 870; https://doi.org/10.3390/pharmaceutics17070870 - 2 Jul 2025

Abstract

Background/Objectives: Leishmaniasis is a prevailing infectious disease transmitted via infected phlebotomine sandflies. The lack of an efficient vaccine with respect to immunogenic antigens and adjuvanted delivery systems impedes its control. Following the induction of immune responses in mice vaccinated with multi-epitope Leishmania peptides [...] Read more.

Background/Objectives: Leishmaniasis is a prevailing infectious disease transmitted via infected phlebotomine sandflies. The lack of an efficient vaccine with respect to immunogenic antigens and adjuvanted delivery systems impedes its control. Following the induction of immune responses in mice vaccinated with multi-epitope Leishmania peptides (LeishPts) encapsulated in doubly adjuvanted self-nanoemulsifying drug delivery systems (ST-SNEDDSs), this study aims to assess ST-SNEDDS-based nanoemulsions as vehicles for the delivery of antigenic proteins. Methods: Model antigens (e.g., BSA-FITC, OVA) were encapsulated in ST-SNEDDS after being complexed with the cationic phospholipid dimyristoyl phosphatidylglycerol (DMPG) via hydrophobic ion pairing. The nanoemulsions were characterized with respect to droplet diameter, zeta potential, stability, protein loading, protein release from the nanodroplets in different release media and cell uptake. Results: Both model antigens exhibited high encapsulation efficiency (>95%) and their release from the nanodroplets was shown to be strongly affected by the type of release medium (e.g., PBS, FBS 10% v/v) and the ratio of its volume to that of the oily phase, in agreement with predictions of protein release. Protein-loaded nanoemulsion droplets labeled with Cy-5 were found to be efficiently taken up by macrophages (J774A.1) in vitro. However, no colocalization of the labeled nanodroplets and BSA-FITC could be observed. Conclusions: It was revealed that in contrast with LeishPts, whole protein molecules may not be appropriate antigenic cargo for ST-SNEDDS formulations due to the rapid protein release from the nanodroplets in release media simulating in vitro culture and in vivo conditions such as FBS 10% v/v. Full article

(This article belongs to the Special Issue The Development of Drug Delivery Systems and Pharmaceutical Formulations for the Treatment of Infectious Diseases)

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26 pages, 4933 KiB

Open AccessArticle

Antimicrobial and Anti-Inflammatory Activity of N-(2-Bromo-phenyl)-2-hydroxy-benzamide Derivatives and Their Inclusion Complexes

by Ioana Maria Carmen Ienașcu, Adina Căta, Antonina Evelina Lazăr, Nick Samuel Țolea, Gerlinde Rusu, Paula Sfîrloagă, Cristina Moşoarcă, Adriana Aurelia Chiș, Claudiu Morgovan, Corina Danciu, Delia Muntean, Iuliana Popescu and Raluca Pop

Pharmaceutics 2025, 17(7), 869; https://doi.org/10.3390/pharmaceutics17070869 - 2 Jul 2025

Abstract

Background/Objectives: In order to enhance the biological activity, novel complexes of N-(2-bromo-phenyl)-2-hydroxy-benzamide derivatives and β-cyclodextrin were obtained. Methods: The inclusion complexes were characterized using spectral and thermal analyses. The antimicrobial activity was determined using the disk diffusion agar method, and [...] Read more.

Background/Objectives: In order to enhance the biological activity, novel complexes of N-(2-bromo-phenyl)-2-hydroxy-benzamide derivatives and β-cyclodextrin were obtained. Methods: The inclusion complexes were characterized using spectral and thermal analyses. The antimicrobial activity was determined using the disk diffusion agar method, and completed with the minimum inhibitory concentration (MIC) values obtained by the broth microdilution method. The in vitro anti-inflammatory activity was evaluated using the protease inhibition assay. Results: The computed supramolecular architectures of the inclusion complexes showed that the most stable molecular arrangements correspond to the models in which the N-(2-bromo-phenyl)-2-hydroxy-benzamide derivatives are partially included in the cyclodextrin cavity. The antimicrobial screening showed that the compounds were active against Gram-positive bacteria (MIC = 2.5–5.0 mg/mL). Also, the evaluation of the proteinase inhibitory activity showed that the IC₅₀ values of the title compounds (0.04–0.07 mg/mL) were much lower than that of the acetylsalicylic acid (0.4051 ± 0.0026 mg/mL) used as positive control, proving their superior efficiency in inhibiting trypsin activity. Conclusions: The complexation proved to be beneficial for both antimicrobial and anti-inflammatory effects. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Pharmaceutical Applications)

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19 pages, 2844 KiB

Open AccessArticle

Chitosan Nanoparticles Enhance the Antiproliferative Effect of Lapachol in Urothelial Carcinoma Cell Lines

by Tatiane Roquete Amparo, Kamila de Fátima da Anunciação, Tamires Cunha Almeida, Lucas Resende Dutra Sousa, Viviane Flores Xavier, Janaína Brandão Seibert, Ana Paula Moreira Barboza, Paula Melo de Abreu Vieira, Orlando David Henrique dos Santos, Glenda Nicioli da Silva and Geraldo Célio Brandão

Pharmaceutics 2025, 17(7), 868; https://doi.org/10.3390/pharmaceutics17070868 - 2 Jul 2025

Abstract

Backgroud/Objectives: Lapachol is a naturally occurring prenylated naphthoquinone with antiproliferative effects. However, its clinical application remains limited due to several factors, including poor water solubility, low bioavailability, and adverse effects. The development of chitosan-based nanoparticles holds promise in overcoming these challenges and has [...] Read more.

Backgroud/Objectives: Lapachol is a naturally occurring prenylated naphthoquinone with antiproliferative effects. However, its clinical application remains limited due to several factors, including poor water solubility, low bioavailability, and adverse effects. The development of chitosan-based nanoparticles holds promise in overcoming these challenges and has emerged as a potential nanocarrier for cancer therapy, including bladder cancer. The objective of this study was to develop and evaluate the effects of chitosan nanoparticles on bladder tumor cell lines. Methods: The nanoemulsion was prepared using the hot homogenization method, while the chitosan nanoparticles were obtained through the ionic gelation technique. The nanoformulations were characterized in terms of particle size and polydispersity index (PDI) using photon correlation spectroscopy, and zeta potential by electrophoretic mobility. Encapsulation efficiency was determined by ultracentrifugation, and the drug release was analyzed using the dialysis method. The antineoplastic potential was assessed using the MTT assay, and the safety profile was assessed through ex vivo analysis. Cellular uptake was determined by fluorescence microscopy. Results: The study demonstrated that both the chitosan-based nanoemulsion and nanospheres encapsulating lapachol exhibited appropriate particle sizes (around 160 nm), high encapsulation efficiency (>90%), and a controlled release profile (Korsmeyer–Peppas model). These nanoemulsion systems enhanced the antiproliferative activity of lapachol in bladder tumor cells, with the nanospheres showing superior cellular uptake. Histopathological analysis indicated the safety of the formulations when administered intravesically. Conclusions: The results suggest that chitosan nanoparticles may represent a promising alternative for bladder cancer treatment. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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13 pages, 653 KiB

Open AccessReview

Topical Percutaneous Drug Delivery for Allergic Diseases: A Novel Strategy for Site-Directed Pharmacologic Modulation

by Mitsuhiro Kamimura, Hiroaki Todo, Kenji Sugibayashi and Koichiro Asano

Pharmaceutics 2025, 17(7), 867; https://doi.org/10.3390/pharmaceutics17070867 - 2 Jul 2025

Abstract

Topical percutaneous drug delivery has recently emerged as a novel strategy for the treatment of allergic diseases, offering targeted drug delivery to mucosal tissues adjacent to the skin. Unlike conventional topical approaches that act on the skin surface or mucosal membranes, topical percutaneous [...] Read more.

Topical percutaneous drug delivery has recently emerged as a novel strategy for the treatment of allergic diseases, offering targeted drug delivery to mucosal tissues adjacent to the skin. Unlike conventional topical approaches that act on the skin surface or mucosal membranes, topical percutaneous drug delivery enables non-invasive pharmacologic modulation of deeper structures such as the conjunctiva, nasal mucosa, and trachea. This review explores the rationale, pharmacokinetic foundation, clinical data, and future prospects of transdermal therapy in allergic conjunctivitis, allergic rhinitis, and asthma-related cough. In allergic conjunctivitis, eyelid-based transdermal delivery of antihistamines such as diphenhydramine and epinastine has shown rapid and long-lasting symptom relief, with epinastine cream recently approved in Japan following a randomized controlled trial (RCT) demonstrating its efficacy. Preclinical and clinical pharmacokinetic studies support the eyelid’s unique permeability and sustained drug release profile, reinforcing its utility as a delivery site for ocular therapies. In allergic rhinitis, diphenhydramine application to the nasal ala demonstrated symptomatic improvement in patients intolerant to intranasal therapies, though anatomical separation from the inflamed turbinates may limit consistent efficacy. Similarly, cervical tracheal application of steroids and antihistamines has shown potential benefit in asthma-related cough, especially for patients refractory to inhaled treatments, despite anatomical and depth-related limitations. Overall, site-specific anatomy, skin permeability, and disease localization are critical factors in determining therapeutic outcomes. While trans-eyelid therapy is supported by robust data, studies on the nasal ala and trachea remain limited to small-scale pilot trials. No major adverse events have been reported with nasal or tracheal application, but eyelid sensitivity requires formulation caution. To validate this promising modality, further RCTs, pharmacokinetic analyses, and formulation optimization are warranted. Topical percutaneous drug delivery holds potential as a non-invasive, site-directed alternative for managing allergic diseases beyond dermatologic indications. Full article

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

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20 pages, 2643 KiB

Open AccessArticle

Applying Unbiased, Functional Criteria Allows Selection of Novel Cyclic Peptides for Effective Targeted Drug Delivery to Malignant Prostate Cancer Cells

by Anna Cohen, Maysoon Kashkoosh, Vipin Sharma, Akash Panja, Sagi A. Shpitzer, Shay Golan, Andrii Bazylevich, Gary Gellerman, Galia Luboshits and Michael A. Firer

Pharmaceutics 2025, 17(7), 866; https://doi.org/10.3390/pharmaceutics17070866 - 1 Jul 2025

Abstract

Background: Metastatic prostate cancer (mPrC), with a median survival of under 2 years, represents an important unmet medical need which may benefit from the development of more effective targeted drug delivery systems. Several cell surface receptors have been identified as candidates for targeted [...] Read more.

Background: Metastatic prostate cancer (mPrC), with a median survival of under 2 years, represents an important unmet medical need which may benefit from the development of more effective targeted drug delivery systems. Several cell surface receptors have been identified as candidates for targeted drug delivery to mPrC cells; however, these receptors were selected for their overabundance on PrC cells rather than for their suitability for targeted delivery and uptake of cytotoxic drug payloads. Methods: We describe a novel, unbiased strategy to isolate peptides that fulfill functional criteria required for effective intracellular drug delivery and the specific cytotoxicity of PrC cells without prior knowledge of the targeted receptor. Phage clones displaying 7-mer cyclic peptides were negatively selected in vivo and then positively biopanned through a series of parent and drug-resistant mPrC cells. Peptides from the internalized clones were then subjected to a panel of biochemical and functional tests that led to the selection of several peptide candidates. Results: The selected peptides do not bind PSMA. Peptide-drug conjugates (PDCs) incorporating one of the peptides selectively killed wild-type and drug-resistant PrC cell lines and patient PrC cells but not normal prostate tissue cells in vitro. The PDC also halted the growth of PC3 tumors in a xenograft model. Conclusions: Our study demonstrates that adding unbiased, functional criteria into drug carrier selection protocols can lead to the discovery of novel peptides with appropriate properties required for effective targeted drug delivery into target cancer cells. Full article

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

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24 pages, 1670 KiB

Open AccessReview

Could Sodium-Glucose Co-Transporter-2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists Play a Role in Gout Treatment?

by Dan Kaufmann and Naomi Schlesinger

Pharmaceutics 2025, 17(7), 865; https://doi.org/10.3390/pharmaceutics17070865 - 30 Jun 2025

Abstract

Gout, a metabolic and autoinflammatory disease, is the most common form of inflammatory arthritis worldwide. Hyperuricemia may result in monosodium urate (MSU) crystals forming and depositing in joints and surrounding tissues, triggering an autoinflammatory response. Effective urate-lowering therapies, as well as anti-inflammatory medications, [...] Read more.

Gout, a metabolic and autoinflammatory disease, is the most common form of inflammatory arthritis worldwide. Hyperuricemia may result in monosodium urate (MSU) crystals forming and depositing in joints and surrounding tissues, triggering an autoinflammatory response. Effective urate-lowering therapies, as well as anti-inflammatory medications, are used to treat gout. Over the past few decades, new antihyperglycemic drug classes with different modes of action have been added to treat hyperglycemia in type 2 diabetes mellitus (T2DM). Two of these drug classes, sodium–glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have reduced cardiovascular and renal events and mortality. Several clinical studies have demonstrated that SGLT2 inhibitors possess urate-lowering properties, which may be beneficial for treating gout patients, particularly those with comorbid T2DM. Regarding SGLT2 inhibitors, some researchers have suggested that their benefits are partly explained by their ability to reduce serum urate (SU) levels, probably through increased urinary uric acid excretion. The effect of GLP-1 RA on SU levels and urinary excretion of uric acid in humans is unclear. This paper reviews the mechanisms of action of SGLT2 inhibitors and GLP-1RA, both approved and in development. Additionally, it examines what is known about their structure–activity relationships, uricosuric effects, pharmacokinetic profiles, and adverse effects. Full article

(This article belongs to the Special Issue Recent Advances in Inhibitors for Targeted Therapies)

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18 pages, 5655 KiB

Open AccessArticle

Trans-p-Coumaryl Alcohol as a Bioactive Compound and Anti-Inflammatory Agent in Wannachawee Recipe for Psoriasis

by Supreeya Tantipat, Kongkiat Trisuwan, Phraepakaporn Kunnaja, Seewaboon Sireeratawong, Surapol Natakankitkul, Surasak Imiam and Sunee Chansakaow

Pharmaceutics 2025, 17(7), 864; https://doi.org/10.3390/pharmaceutics17070864 - 30 Jun 2025

Abstract

Background/Objectives: Wannachawee recipe (WCR) has been listed in the Hospital Traditional Medicine Formulary and has been used as a Thai medicine to treat psoriasis in the Thai Traditional Medicine Clinic of Prapokklao Hospital since 2006. Previous reports have found that WCR demonstrates [...] Read more.

Background/Objectives: Wannachawee recipe (WCR) has been listed in the Hospital Traditional Medicine Formulary and has been used as a Thai medicine to treat psoriasis in the Thai Traditional Medicine Clinic of Prapokklao Hospital since 2006. Previous reports have found that WCR demonstrates good results for the treatment of patients with psoriasis. Among 136 Thai psoriasis patients who received WCR, 92.80% responded well. Although WCR is effective, there is still a lack of scientific data, especially relating to the bioactive compound in WCR. Therefore, this study aims to evaluate the phytochemicals in WCR via bioassay-guided isolation. Methods: In this study, the WCR was extracted via decoction with water, in a process based on traditional Thai medicine. The water extract was concentrated and dried using a spray dryer. The crude water extract was isolated using the partition technique with organic solvents, namely petroleum ether and ethyl acetate. These fractions were then separated and tested for anti-inflammatory activity using the bioassay-guided fractionation method. Results: Two particular types of pro-inflammatory cytokines are involved in inflammation and are among the factors that cause psoriasis—TNF-α and IL-6. Thus, we evaluated the isolated samples in terms of anti-inflammatory activity. The isolation resulted in two pure compounds—p-coumaryl aldehyde and trans-p-coumaryl alcohol. In the efficacy test of the isolated compounds, compared to the standard indomethacin at the same concentration of 12.5 ug/mL, trans-p-coumaryl alcohol was found to have the best efficacy, inhibiting TNF-α by 29.28% and IL-6 by 36.75%, with the standard compound showing inhibitions rates of 15.80% for TNF-α and 27.44% for IL-6. Conclusions: This study is the first report to identify the bioactive compound of WCR as trans-p-coumaryl alcohol or 4-hydroxycinnamyl alcohol. Full article

(This article belongs to the Special Issue Natural Pharmaceuticals Focused on Anti-inflammatory Activities)

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17 pages, 1482 KiB

Open AccessArticle

Nasal Residence Depending on the Administered Dosage Form: Impact of Formulation Type on the In Vivo Nasal Retention Time of Drugs in Rats

by Daisuke Inoue, Yoshihiro Seto and Hideto To

Pharmaceutics 2025, 17(7), 863; https://doi.org/10.3390/pharmaceutics17070863 - 30 Jun 2025

Abstract

Background/Objectives: The precise control of drug absorption through the nasal mucosa following intranasal administration can be achieved through optimal formulation development that considers the nasal retention properties of the administered dosage form. This study aimed to quantitatively elucidate the effect of formulation [...] Read more.

Background/Objectives: The precise control of drug absorption through the nasal mucosa following intranasal administration can be achieved through optimal formulation development that considers the nasal retention properties of the administered dosage form. This study aimed to quantitatively elucidate the effect of formulation type on nasal residence time in vivo. Methods: The nasal residence behavior of various formulation types, including solutions, particulates, and powders, was estimated in rats. Furthermore, the effect of mucoadhesive polymers on the nasal residence time was investigated using gel and powder dosage forms of sodium alginate. Results: The nasal retention behavior of the formulation in the nasal cavity differed depending on the dosage form. The polystyrene microparticles and lactose powder, a non-adhesive powder, were quickly eliminated into the nasopharynx, whereas the solution remained in the nasal cavity longer than the other formulations. The clearance behavior of the solution was investigated, and it was found that the solution was quickly transported to the stomach without being retained in the esophagus. The disappearance of the gel and powder with the mucoadhesive polymer was different, with the powder clearing faster. This difference in clearance is thought to be due to the powder being cleared before dissolving and diffusing into the nasal mucus. Conclusions: It has been clearly shown that the nasal residence behavior differed depending on the dosage forms. The addition of mucoadhesive polymers was effective in improving the nasal residence of the drug, and more-effective formulations for nasal application can be developed by combining optimal dosage forms, such as powders and gels. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments, 2nd Edition)

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34 pages, 3876 KiB

Open AccessArticle

pH Gradient-Driven Loading of Doxorubicin into Niosomes: A Comparative Study Using Bromocresol Green as a Visual Indicator

by Mohammed Altaee, Ahmed Mostafa Faheem and Amal Ali Elkordy

Pharmaceutics 2025, 17(7), 862; https://doi.org/10.3390/pharmaceutics17070862 - 30 Jun 2025

Abstract

Background: The active (remote) loading of drugs into nanoparticulate systems via the pH gradient technique has been proven highly successful in liposomes, as numerous formulations have reached the market. However, this is not the case for niosomes, as the full potential of [...] Read more.

Background: The active (remote) loading of drugs into nanoparticulate systems via the pH gradient technique has been proven highly successful in liposomes, as numerous formulations have reached the market. However, this is not the case for niosomes, as the full potential of this area remains largely undiscovered. The purpose of this research is to study the effect of different co-surfactants (Cremophor RH 40, Cremophor ELP and Solutol HS-15) on stabilising the niosomal membrane to enable the creation of a pH gradient. Methods: For visualisation of pH gradients, pH indicator bromocresol green (BCG) was used as a novel encapsulated model molecule to visually investigate the ability of niosomes to entrap drugs through active loading. Thereafter, the optimised BCG niosomal formulation was applied to encapsulate a therapeutic drug molecule, doxorubicin, via pH gradient active loading. Niosomes were formulated via thin-film hydration using Span 60, cholesterol, with or without co-surfactants. Thin films were hydrated with either Trizma buffer or HEPES buffer for BCG, or ammonium sulfate for doxorubicin. The niosomes’ outer membrane pH was adjusted via either the addition of HCl or citric acid in the case of BCG, or by passing the niosomes through a Sephadex G50 gel column, pre-equilibrated with PBS or Trizma buffer, in the case of doxorubicin. Results: Niosomes formulated with Span 60 and cholesterol could not be formed at acidic pH and thus could not create a pH gradient. All three co-surfactants, when added to Span 60 and cholesterol, stabilised the niosomes and enabled them to form a pH gradient. Niosomes (after size reduction) containing Solutol HS-15 showed significantly higher entrapment efficiency of BCG when compared to Cremophor RH 40 and Cremophor ELP (67.86% vs. 15.57% vs. 17.81%, respectively, with sizes of 159.6 nm, 177.9 nm and 219.1 nm, respectively). The use of HEPES buffer resulted in a higher EE of BCG compared to Trizma buffer (72.85% vs. 67.86%) and achieved a size of 283.4 nm. The Solutol HS-15 containing formulation has exhibited 68.28% EE of doxorubicin with ammonium sulfate as the inner buffer, while the external buffer was Trizma with a size of 241.1 nm after extrusion. Conclusions: Niosomal formulations containing Solutol HS-15 are highly promising for remote drug loading. The novel use of BCG for studying pH gradient and drug loading into niosomes has proved beneficial and successful. Full article

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

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17 pages, 4243 KiB

Open AccessArticle

Molecular Target Identification of Gossypol Against Cervical Cancer Based on Target Fishing Technology

by Jinyan Li, Rayisa Asat, Wenying Li, Parwen Parhat, Yue Ma, Yinglan Ma and Min Li

Pharmaceutics 2025, 17(7), 861; https://doi.org/10.3390/pharmaceutics17070861 - 30 Jun 2025

Abstract

Objectives: This study aims to investigate the impact of Gossypol on human cervical cancer cells and elucidate its mechanism of action to establish a foundation for further clinical investigations. Methods: Cell proliferation, migration, and invasion were evaluated through CCK−8, wound healing, [...] Read more.

Objectives: This study aims to investigate the impact of Gossypol on human cervical cancer cells and elucidate its mechanism of action to establish a foundation for further clinical investigations. Methods: Cell proliferation, migration, and invasion were evaluated through CCK−8, wound healing, and Transwell assays. Fe₃O₄-BP-Gossypol (Fe₃O₄@Gossypol) conjugates were synthesized by linking Fe₃O₄ with Gossypol using benzophenone crosslinking. Successful conjugation was confirmed through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and ultraviolet–visible spectrophotometry (UV-Vis). Subsequent to co-incubation with HeLa cell lysates, Fe₃O₄@Gossypol complexes facilitated the magnetic enrichment and purification of target proteins, which were identified using high-resolution mass spectrometry (HR-MS). The identified targets underwent KEGG pathway and GO analyses, followed by molecular docking with Gossypol. HeLa cells were exposed to Gossypol at concentrations of 7.48, 14.96, and 29.92 μmol·L⁻¹ for 48 h, and protein expression levels were quantified via Western blotting. Results: Gossypol notably suppressed cervical cancer cell proliferation, migration, and invasion. The integration of target fishing, network pharmacology, and molecular docking highlighted PIK3R2, MAPK1, and GRB2 as potential therapeutic targets. Western blot analysis revealed a dose-dependent reduction in PIK3R2, GRB2, and MAPK1 expression in Gossypol-treated groups compared to controls (p < 0.05). Conclusions: Gossypol may exhibit anti-cervical cancer effects by modulating the PI3K/AKT signaling pathway. Full article

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21 pages, 2401 KiB

Open AccessArticle

Co-Formulation of Iron Oxide and PLGA Nanoparticles to Deliver Curcumin and IFNα for Synergistic Anticancer Activity in A375 Melanoma Skin Cancer Cells

by Magdi Abobaker, Mershen Govender and Yahya E. Choonara

Pharmaceutics 2025, 17(7), 860; https://doi.org/10.3390/pharmaceutics17070860 - 30 Jun 2025

Abstract

Background/Objectives: Skin cancer remains a significant global health issue, driving the development of new treatment strategies to improve clinical outcomes and prevent recurrence. Traditional monotherapies often face obstacles such as bioactive resistance, prompting interest in combination therapies that enhance efficacy, while minimizing [...] Read more.

Background/Objectives: Skin cancer remains a significant global health issue, driving the development of new treatment strategies to improve clinical outcomes and prevent recurrence. Traditional monotherapies often face obstacles such as bioactive resistance, prompting interest in combination therapies that enhance efficacy, while minimizing side effects. This study investigated the use of a co-nanoparticle approach of iron oxide nanoparticles (NPs) surface-functionalized with curcumin (Cur-FeONPs) delivered with prolonged-release interferon alpha (IFNα)-loaded PLGA NPs (IFNα-PLGANPs) for the synergistic treatment of malignant melanoma tested in A375 cells. Methods: Extensive in vitro characterization studies of the Cur-FeONPs and IFNα-PLGANPs were performed, including zeta-size profiling, morphological studies, and structural validation, in addition to cytotoxicity assessments on A375 melanoma and NIH-3T3 fibroblast cells. Results: The Cur-FeONP and IFNα-PLGANPs synthesis processes yielded NPs with an average size of 111.0 nm and 97.0 nm, respectively. Morphological and structural validation studies determined the successful synthesis of the nanoparticulate systems, with cell viability analyses displaying significant cytotoxicity against A375 melanoma cells for the combination treatment, when compared to the individual platforms, with a minimal effect on NIH-3T3 fibroblast cells. Conclusions: The results of this study present a promising synergistic approach for enhanced anticancer activity in A375 melanoma skin cancer cells, providing a potential platform for future preclinical and clinical studies. Full article

(This article belongs to the Special Issue Nano-Drug Delivery Systems for Targeting the Tumor Microenvironment and Simultaneously Overcoming Drug Resistance Properties)

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29 pages, 1100 KiB

Open AccessReview

Application of Gene Therapy to Oral Diseases

by Seiichi Yamano, Kenji Inoue and Yoichiro Taguchi

Pharmaceutics 2025, 17(7), 859; https://doi.org/10.3390/pharmaceutics17070859 - 30 Jun 2025

Abstract

Gene therapy has emerged as a promising therapeutic approach across various oral diseases. This review examines current applications and future prospects of gene therapy in dentistry, focusing on five key areas: oral cancer, cancer-related pain, xerostomia (dry mouth), dental caries, and periodontal disease. [...] Read more.

Gene therapy has emerged as a promising therapeutic approach across various oral diseases. This review examines current applications and future prospects of gene therapy in dentistry, focusing on five key areas: oral cancer, cancer-related pain, xerostomia (dry mouth), dental caries, and periodontal disease. Recent advances in viral and non-viral vectors have enabled more efficient gene delivery systems, with particular success in cancer pain management through µ-opioid receptor gene transfer and xerostomia treatment using aquaporin-1 gene therapy. For periodontal applications, gene therapy strategies include both immunomodulation and tissue regeneration approaches using growth factors like platelet-derived growth factor and bone morphogenetic proteins. While significant progress has been made, particularly in treating radiation-induced xerostomia and oral cancer pain, challenges remain in vector optimization and delivery methods. Clinical trials, predominantly in Phase I, indicate both the potential and current limitations of gene therapy in oral healthcare. This review synthesizes current evidence and outlines future directions for gene therapy applications in oral medicine and dentistry. Full article

(This article belongs to the Special Issue Drug Delivery and Pharmacokinetics in Oral Medicine and Dental Infection, 2nd Edition)

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