Pharmaceutics

23 pages, 1943 KiB

Open AccessArticle

Potentials and Challenges in Development of Vesicular Phospholipid Gel as a Novel Dermal Vehicle for Thymol

by Sabina Keser, Zora Rukavina, Marica Jozić, Lea Pavlović-Mitrović, Magda Vodolšak, Kristina Kranjčec, Darija Stupin Polančec, Gordana Maravić-Vlahoviček, Jasmina Lovrić, Maja Šegvić Klarić and Željka Vanić

Pharmaceutics 2025, 17(7), 854; https://doi.org/10.3390/pharmaceutics17070854 (registering DOI) - 29 Jun 2025

Abstract

Background/Objectives: Thymol, one of the main compounds of thyme essential oil, has shown promising effects in treating various skin disorders owing to its anti-inflammatory, antimicrobial and antioxidative activities. Due to its limited solubility in water, thymol is commonly used in higher concentrations to [...] Read more.

Background/Objectives: Thymol, one of the main compounds of thyme essential oil, has shown promising effects in treating various skin disorders owing to its anti-inflammatory, antimicrobial and antioxidative activities. Due to its limited solubility in water, thymol is commonly used in higher concentrations to achieve a suitable therapeutic effect, which can consequently lead to skin irritation. To overcome these limitations, we incorporated thymol into a vesicular phospholipid gel (VPG), a novel semisolid dermal vehicle consisting of highly concentrated dispersion of phospholipid vesicles (liposomes). Methods: Thymol was successfully loaded into two VPGs differing in bilayer fluidity, which were characterized for the physicochemical and rheological properties, storage stability, in vitro release, ex vivo skin permeability, in vitro compatibility with epidermal cells, wound healing potential, and antibacterial activity against skin-relevant bacterial strains. Results: High pressure homogenization method enabled preparation of VPG-liposomes of neutral surface charge in the size range 140–150 nm with polydispersity indexes below 0.5. Both types of VPGs exhibited viscoelastic solid-like structures appropriate for skin administration and ensured skin localization of thymol. Although both types of VPGs enabled prolonged release of thymol, the presence of cholesterol in the VPG increased the rigidity of the corresponding liposomes and further slowed down thymol release. Conclusions: Loading of thymol into VPGs significantly reduced its cytotoxicity toward human keratinocytes in vitro even at very high concentrations, compared to free thymol. Moreover, it facilitated in vitro wound healing activity, proving its potential as a vehicle for herbal-based medicines. However, the antibacterial activity of thymol against Staphylococcus aureus and methicillin-resistant S. aureus was hindered by VPGs, which represents a challenge in their development. Full article

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

► Show Figures

Figure 1

37 pages, 5939 KiB

Open AccessArticle

Optimizing Burn Wound Healing: The Critical Role of pH and Rheological Behavior in Plant-Derived Topical Formulations

by Oana-Janina Roșca, Georgeta-Hermina Coneac, Roxana Racoviceanu, Alexandru Nistor, Ioana-Viorica Olariu, Ana-Maria Cotan, Roxana Negrea-Ghiulai, Cristina Adriana Dehelean, Lavinia Lia Vlaia and Codruța Marinela Șoica

Pharmaceutics 2025, 17(7), 853; https://doi.org/10.3390/pharmaceutics17070853 (registering DOI) - 29 Jun 2025

Abstract

Background: In burn injuries, wound healing effectiveness is complex and influenced significantly by the local biochemical environment and the physicochemical properties of topical preparations. pH lesions modulation can influence protection barrier integrity, inflammatory responses, and microbial colonization. Their antioxidant, antimicrobial, and anti-inflammatory properties, [...] Read more.

Background: In burn injuries, wound healing effectiveness is complex and influenced significantly by the local biochemical environment and the physicochemical properties of topical preparations. pH lesions modulation can influence protection barrier integrity, inflammatory responses, and microbial colonization. Their antioxidant, antimicrobial, and anti-inflammatory properties, of the topical formulations enriched with plant extracts have demonstrated promising results. Objective: The aim of the study was to develop and characterize topical oleogel and hydrogel formulations containing ethanolic and hydroalcoholic extracts of medicinal plants (Boswellia serrata, Ocimum basilicum, Sambucus nigra, and Galium verum), and to evaluate the impact of their physicochemical properties, rheological behavior, in contrast with the wound pH modulation, and healing efficacy in an experimental burn model. Methods: Second-degree burns were induced uniformly on Wistar rats using the validated RAPID-3D device. All formulations were applied daily for 21 days, and wound healing was assessed through several measurements specific to the wound surface, skin temperature, pH, and, last but not least, histological analyses. Formulations’ physicochemical and rheological properties, including pH, viscosity, and spreadability, were also analyzed and systematically characterized. Results: Oleogel formulations demonstrated superior wound healing performance compared to hydrogels. Formulations containing Boswellia serrata and Ocimum basilicum extracts significantly reduced wound size, inflammation, and melanin production by days 9 and 21 (p < 0.05). The beneficial outcomes correlated strongly with formulation acidity (pH < 6), high viscosity, and enhanced thixotropic behavior, indicating improved adherence and sustained bioactive compound release. Histological evaluations confirmed enhanced epithelialization and reduced inflammation. Conclusions: Particularly Boswellia serrata and Ocimum basilicum in oleogel formulations in ethanolic solvent effectively modulated wound pH, enhanced topical adherence, and improved burn wound healing. These findings highlight their potential clinical application and justify further clinical investigations. Full article

(This article belongs to the Special Issue Controlled-Release Drug Delivery Systems for Anti-Inflammatory and Wound Healing Action)

25 pages, 6059 KiB

Open AccessArticle

Comparative Evaluation of β-Cyclodextrin Inclusion Complexes with Eugenol, Eucalyptol, and Clove Essential Oil: Characterisation and Antimicrobial Activity Assessment for Pharmaceutical Applications

by Alina Ionela Stancu, Magdalena Mititelu, Anton Ficai, Lia-Mara Ditu, Mihaela Buleandră, Irinel Adriana Badea, Elena Pincu, Marius Constantin Stoian, Oana Brîncoveanu, Adina Boldeiu and Eliza Oprea

Pharmaceutics 2025, 17(7), 852; https://doi.org/10.3390/pharmaceutics17070852 (registering DOI) - 29 Jun 2025

Abstract

Clove essential oil (Eugenia caryophyllata essential oil, ECEO) is known for its high eugenol content and notable antimicrobial properties. However, the volatility and instability of its active compounds hinder broader pharmaceutical applications. Methods: This study characterised the chemical composition of ECEO and [...] Read more.

Clove essential oil (Eugenia caryophyllata essential oil, ECEO) is known for its high eugenol content and notable antimicrobial properties. However, the volatility and instability of its active compounds hinder broader pharmaceutical applications. Methods: This study characterised the chemical composition of ECEO and comparatively evaluated four β-cyclodextrin (β-CD) encapsulation methods: kneading, co-precipitation, lyophilisation, and co-precipitation–lyophilisation for eugenol, eucalyptol, and ECEO. Encapsulation efficiency, physicochemical properties, and antimicrobial potential were assessed. Analytical techniques included Gas Chromatography–Mass Spectrometry (GC-MS), Headspace GC-MS (HS-GC-MS), Differential Scanning Calorimetry (DSC), Job’s method, and Dynamic Light Scattering (DLS). Results: GC-MS identified eugenol (90.67%), eugenyl acetate (4.77%), and (E)–β-caryophyllene (3.98%) as major components of ECEO, while HS-GC-MS indicated a slightly reduced eugenol content (86.46%). The kneading method yielded the highest encapsulation efficiency for eugenol, whereas the co-precipitation–lyophilisation method was optimal for eucalyptol. DSC thermograms confirmed complex formation, and DLS analysis revealed nanostructures averaging 186.4 nm in diameter (PDI = 0.298). Antimicrobial assays showed MIC values ranging from 0.039 mg/mL to 10,000 mg/mL. Notably, ECEO and its β-CD complex displayed enhanced efficacy against Escherichia coli (0.039 mg/mL), surpassing the reference antibiotic gentamicin (0.049 mg/mL). Conclusions: β-Cyclodextrin encapsulation significantly enhances the stability and bioactivity of volatile antimicrobial compounds, thereby supporting their potential integration into advanced essential oil-based pharmaceutical formulations. Full article

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

► Show Figures

Figure 1

15 pages, 3669 KiB

Open AccessArticle

Effect of Hepatic Impairment on the Pharmacokinetics of Baicalin in Rats: Critical Roles of Gut Microbiota and Hepatic Transporters

by Ping Li, Yihua Tian, Hong Wang, Yuting Ji, Huiying Zeng, Shengman Zhang, Xiuli Gao and Xiaoyan Chen

Pharmaceutics 2025, 17(7), 851; https://doi.org/10.3390/pharmaceutics17070851 (registering DOI) - 29 Jun 2025

Abstract

Background: Baicalin (BG) has been used in the treatment of many diseases. However, the effect of hepatic insufficiency on its pharmacokinetics has not been reported, and there is a lack of clinical guidance for the use of BG in patients with hepatic [...] Read more.

Background: Baicalin (BG) has been used in the treatment of many diseases. However, the effect of hepatic insufficiency on its pharmacokinetics has not been reported, and there is a lack of clinical guidance for the use of BG in patients with hepatic impairment. Methods: Carbon tetrachloride (CCl₄)-induced rat models were used to simulate hepatic failure patients to assess the effect of hepatic impairment on the pharmacokinetics and distribution of BG. In vitro metabolism and transporter studies were employed to elucidate the potential mechanisms. Results: After intragastric administration of 10 mg/kg of BG, the peak plasma concentration and exposure (AUC_0–t) of BG decreased by 64.6% and 52.6%, respectively, in CCl₄-induced rats. After intravenous administration, the AUC_0–t decreased by 73.6%, and unlike in the control group, the second absorption peak of BG was not obvious in the concentration–time curve of CCl₄-induced rats. The cumulative excretion of BG in the feces increased, but that in the bile decreased. In vivo data indicated that the absorption and enterohepatic circulation of BG were affected. In vitro studies found that the hydrolysis of BG to the aglycone baicalein decreased significantly in the intestinal tissues and contents of the CCl₄-induced rats. And BG was identified as a substrate for multiple efflux and uptake transporters, such as breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), organic anion transporting polypeptides (OATP1B1, 1B3, 2B1), and organic anion transporters (OATs). The bile acids accumulated by liver injury inhibited the uptake of BG by OATPs, especially that by OATP2B1. Conclusions: Hepatic impairment reduced BG hydrolysis by intestinal microflora and inhibited its transporter-mediated biliary excretion, which synergistically led to the attenuation of the enterohepatic circulation of BG, which altered its pharmacokinetics. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

► Show Figures

Figure 1

26 pages, 889 KiB

Open AccessReview

Cutting-Edge Approaches in the Co-Amorphization Process

by Azza A. K. Mahmoud, Géza Regdon, Jr. and Katalin Kristó

Pharmaceutics 2025, 17(7), 850; https://doi.org/10.3390/pharmaceutics17070850 (registering DOI) - 29 Jun 2025

Abstract

Background: Recently, the co-amorphization method has been widely used to refine the bioavailability characteristics of poorly soluble drugs in addition to overcoming the drawbacks of other traditional amorphization techniques. Objectives: The main aim of this systematic review is to present an extensive outline [...] Read more.

Background: Recently, the co-amorphization method has been widely used to refine the bioavailability characteristics of poorly soluble drugs in addition to overcoming the drawbacks of other traditional amorphization techniques. Objectives: The main aim of this systematic review is to present an extensive outline of different co-former classes, co-former selection, and evaluation of produced co-amorphous systems. Methods: The systematic research was carried out based on three different databases, including PubMed, Scopus, and Web of Science time using co-amorphous, co-former, and drug as keywords. The selected papers were written in the English language and published between 2016 and 2024, and they focused on the co-amorphous systems, while articles discussing other amorphization techniques and crystallization processes were excluded. Results: 127 peer-reviewed articles were selected and summarized. Conclusions: This paper revealed that amino acid is the most commonly used co-former, specifically arginine with acidic drugs and tryptophan with acidic and basic drugs, and it reported other co-formers that were used and different co-amorphous systems with their dissolution behaviour and stabilities, and different computational tools that were applied in the selection of co-former and process result evaluation. Full article

(This article belongs to the Special Issue Advances in Analysis and Modeling of Solid Drug Product)

► Show Figures

Figure 1

25 pages, 13580 KiB

Open AccessFeature PaperArticle

Development of Low-Dose Disulfiram Rectal Suppository Intended for Application in Post-Treatment Lyme Disease Syndrome

by Beáta-Mária Benkő, Bálint-Imre Szabó, Szabina Kádár, Edina Szabó, Gergő Tóth, Lajos Szente, Péter Tonka-Nagy, Romána Zelkó and István Sebe

Pharmaceutics 2025, 17(7), 849; https://doi.org/10.3390/pharmaceutics17070849 (registering DOI) - 28 Jun 2025

Abstract

Background/Objectives: Early diagnosis and oral or, in severe cases, intravenous antibiotics are usually effective for Lyme disease, but some patients have persistent symptoms unresponsive to standards of care, requiring alternative therapies. Disulfiram (DIS), a drug for alcoholism, is under investigation as a [...] Read more.

Background/Objectives: Early diagnosis and oral or, in severe cases, intravenous antibiotics are usually effective for Lyme disease, but some patients have persistent symptoms unresponsive to standards of care, requiring alternative therapies. Disulfiram (DIS), a drug for alcoholism, is under investigation as a potential adjunctive treatment, but its low bioavailability, rapid metabolism, and safety concerns urge the development of improved formulations for clinical translation. Methods: Screening dissolution and permeation studies were investigated for vehicle and excipient selection, following the pharmacopeia perspectives to develop and optimize the low-dose DIS rectal suppository intended for application in post-treatment Lyme disease syndrome (PTLDS). Further characterizations were carried out by differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy. Results: Cyclodextrin (CD) encapsulation was investigated to improve the aqueous solubility of the hydrophobic drug. The dissolution of DIS from fatty base suppository was very slow; it was remarkably improved by the molecular encapsulation of the drug with CDs. The dissolution of DIS from a water-soluble base was more favorable, but incomplete. In the polyethylene glycol (PEG) based suppositories, the addition of CDs already in a physical mixture ensured the dissolution of the drug. The presented drug delivery system relates to a novel preparation for rectal administration comprising a low-dose disulfiram with improved solubility and permeability by the PEG and hydroxypropyl-β-cyclodextrin (HPBCD) synergistic matrix. Conclusions: The rectal dosage form containing the drug and CD in the physical mixture is advantageous, avoiding the hepatic first-pass effect, minimizing dose-limiting toxicity, simplifying production, and fasting the availability of the repositioned drug. Full article

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

24 pages, 2105 KiB

Open AccessArticle

Process Development for GMP-Grade Full Extract Cannabis Oil: Towards Standardized Medicinal Use

by Maria do Céu Costa, Ana Patrícia Gomes, Iva Vinhas, Joana Rosa, Filipe Pereira, Sara Moniz, Elsa M. Gonçalves, Miguel Pestana, Mafalda Silva, Luís Monteiro Rodrigues, Anthony DeMeo, Logan Marynissen, António Marques da Costa, Patrícia Rijo and Michael Sassano

Pharmaceutics 2025, 17(7), 848; https://doi.org/10.3390/pharmaceutics17070848 (registering DOI) - 28 Jun 2025

Abstract

Background/Objectives: The industrial extraction and purification processes of Cannabis sativa L. compounds are critical steps in creating formulations with reliable and reproducible therapeutic and sensorial attributes. Methods: For this study, standardized preparations of chemotype I were chemically analyzed, and the sensory attributes were [...] Read more.

Background/Objectives: The industrial extraction and purification processes of Cannabis sativa L. compounds are critical steps in creating formulations with reliable and reproducible therapeutic and sensorial attributes. Methods: For this study, standardized preparations of chemotype I were chemically analyzed, and the sensory attributes were studied to characterize the extraction and purification processes, ensuring the maximum retention of cannabinoids and minimization of other secondary metabolites. The industrial process used deep-cooled ethanol for selective extraction. Results: Taking into consideration that decarboxylation occurs in the process, the cannabinoid profile composition was preserved from the herbal substance to the herbal preparations, with wiped-film distillation under deep vacuum conditions below 0.2 mbar, as a final purification step. The profiles of the terpenes and cannabinoids in crude and purified Full-spectrum Extract Cannabis Oil (FECO) were analyzed at different stages to evaluate compositional changes that occurred throughout processing. Subjective intensity and acceptance ratings were received for taste, color, overall appearance, smell, and mouthfeel of FECO preparations. Conclusions: According to sensory analysis, purified FECO was more accepted than crude FECO, which had a stronger and more polarizing taste, and received higher ratings for color and overall acceptance. In contrast, a full cannabis extract in the market resulted in lower acceptance due to taste imbalance. The purification process effectively removed non-cannabinoids, improving sensory quality while maintaining therapeutic potency. Terpene markers of the flower were remarkably preserved in SOMAÍ’s preparations’ fingerprint, highlighting a major qualitative profile reproducibility and the opportunity for their previous separation and/or controlled reintroduction. The study underscores the importance of monitoring the extraction and purification processes to optimize the cannabinoid content and sensory characteristics in cannabis preparations. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology in Portugal)

► Show Figures

Graphical abstract

14 pages, 1055 KiB

Open AccessReview

Tear Film and Keratitis in Space: Fluid Dynamics and Nanomedicine Strategies for Ocular Protection in Microgravity

by Ryung Lee, Rahul Kumar, Jainam Shah, Joshua Ong, Ethan Waisberg and Alireza Tavakkoli

Pharmaceutics 2025, 17(7), 847; https://doi.org/10.3390/pharmaceutics17070847 (registering DOI) - 28 Jun 2025

Abstract

Spaceflight-associated dry eye syndrome (SADES) has been reported among astronauts during both International Space Station (ISS) and Space Transportation System (STS) missions. As future missions extend beyond low Earth orbit, the physiological challenges of spaceflight include microgravity, radiation, and environmental stressors, which may [...] Read more.

Spaceflight-associated dry eye syndrome (SADES) has been reported among astronauts during both International Space Station (ISS) and Space Transportation System (STS) missions. As future missions extend beyond low Earth orbit, the physiological challenges of spaceflight include microgravity, radiation, and environmental stressors, which may further exacerbate the development of ocular surface disease. A deeper understanding of the underlying pathophysiology, along with the exploration of innovative countermeasures, is critical. In this review, we examine nanomedicine as a promising countermeasure for managing ophthalmic conditions in space, with the goal of enhancing visual health and mission readiness for long-duration exploration-class missions. Full article

(This article belongs to the Special Issue Drug Delivery Systems for Ocular Diseases)

► Show Figures

Figure 1

14 pages, 1243 KiB

Open AccessReview

Tertiary Amine Oxide-Containing Zwitterionic Polymers: From Material Design to Biomedical Applications

by Jian Shen, Tao Sun and Yunke Bi

Pharmaceutics 2025, 17(7), 846; https://doi.org/10.3390/pharmaceutics17070846 (registering DOI) - 27 Jun 2025

Abstract

Tertiary amine oxide (TAO)-containing zwitterionic polymers are a class of zwitterionic materials formed by the oxidation of tertiary amine groups. In recent years, polymers such as poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) (OPDEA) have gained significant attention due to their unique antifouling properties, dynamic cell membrane affinity, [...] Read more.

Tertiary amine oxide (TAO)-containing zwitterionic polymers are a class of zwitterionic materials formed by the oxidation of tertiary amine groups. In recent years, polymers such as poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) (OPDEA) have gained significant attention due to their unique antifouling properties, dynamic cell membrane affinity, and responsiveness to microenvironments. These characteristics have made them promising candidates in drug delivery, antibiofouling, and precision therapy. Compared to traditional polyethylene glycol (PEG), these polymers not only exhibit long-circulation properties but can also overcome biological barriers through active transport mechanisms, making them a research hotspot in the field of next-generation biomaterials. This review comprehensively summarizes the recent advancements in this field, covering aspects such as the synthesis, properties, applications, and mechanisms of TAO-containing zwitterionic polymers. Full article

► Show Figures

Figure 1

33 pages, 5649 KiB

Open AccessArticle

A Semi-Mechanistic Mathematical Model of Immune Tolerance Induction to Support Preclinical Studies of Human Monoclonal Antibodies in Rats

by Paridhi Gupta, Josiah T. Ryman, Vibha Jawa and Bernd Meibohm

Pharmaceutics 2025, 17(7), 845; https://doi.org/10.3390/pharmaceutics17070845 (registering DOI) - 27 Jun 2025

Abstract

Background/Objectives: The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens [...] Read more.

Background/Objectives: The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. Here, we report on the development of a semi-mechanistic modeling approach that quantitatively integrates pharmacokinetic and immunogenicity assessments from immune tolerance induction studies to provide a framework for the simulation-based evaluation of different immune induction scenarios for the maintenance of prolonged immune tolerance towards human mAbs. Methods: The integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach combined a semi-mechanistic model of the adaptive immune system to predict ADA formation kinetics with a population pharmacokinetic model to assess the impact of the time course of the ADA magnitude on the PK of erenumab in rats. Model-derived erenumab concentration–time profiles served as input for a quantitative system pharmacology-style semi-mechanistic model of the adaptive immune system to conceptualize the ADA response as a function of the kinetics of CD4⁺ T helper cells and T regulatory cells. Results: The model adequately described the observed ADA magnitude–time profiles in all treatment groups and reasonably simulated the kinetics of selected immune cells responsible for ADA formation. It also successfully captured the impact of tacrolimus/sirolimus immunomodulation on ADA formation, demonstrating that the regimen effectively suppressed ADA formations and induced immune tolerance. Conclusions: This work demonstrates the utility of modeling approaches to integrate pharmacokinetic and immunogenicity assessment data for the prospective planning of long-term toxicology studies to support the preclinical development of mAbs. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

► Show Figures

Figure 1

19 pages, 4597 KiB

Open AccessArticle

Influence of the pH Synthesis of Fe₃O₄ Magnetic Nanoparticles on Their Applicability for Magnetic Hyperthermia: An In Vitro Analysis

by Bárbara Costa, Eurico Pereira, Vital C. Ferreira-Filho, Ana Salomé Pires, Laura C. J. Pereira, Paula I. P. Soares, Maria Filomena Botelho, Fernando Mendes, Manuel P. F. Graça and Sílvia Soreto Teixeira

Pharmaceutics 2025, 17(7), 844; https://doi.org/10.3390/pharmaceutics17070844 (registering DOI) - 27 Jun 2025

Abstract

Nanotechnology, specifically magnetic nanoparticles (MNPs), is revolutionizing cancer treatment. Magnetic hyperthermia is a treatment that, using MNPs, can selectively kill cancer cells without causing damage to the surrounding tissues. Background/Objectives: This work aimed to analyze how the synthesis conditions, namely, how the [...] Read more.

Nanotechnology, specifically magnetic nanoparticles (MNPs), is revolutionizing cancer treatment. Magnetic hyperthermia is a treatment that, using MNPs, can selectively kill cancer cells without causing damage to the surrounding tissues. Background/Objectives: This work aimed to analyze how the synthesis conditions, namely, how the pH of the reaction can influence the magnetic properties of Fe₃O₄ nanoparticles for magnetic hyperthermia, using the hydrothermal synthesis. Methods: For the hydrothermal synthesis, FeCl₃·6H₂O and FeCl₂·4H₂O were mixed with different quantities of NaOH to adjust the pH. After obtaining a black precipitate, the samples were placed in an autoclave at 200 °C for 60 h, followed by a washing and drying phase. The obtained MNPs were analyzed using X-Ray Diffraction (XRD), Transmission Electron Microscopy, a Superconducting Quantum Interference Device, Specific Absorption Rate analysis, and cytotoxicity assays. Results: Different MNPs were analyzed (9.06 < pH < 12.75). The XRD results showed the presence of various iron oxide phases (magnetite, maghemite, and hematite), resulting from the oxidization of the iron phases present in the autoclave. In terms of the average particle size, it was verified that, by increasing the pH value, the size decreases (from 53.53 nm to 9.49 nm). Additionally, MNPs possess a superparamagnetic behaviour with high SAR values (above 69.3 W/g). Conclusions: It was found that the pH of the reaction can influence the size, morphology, magnetization, and thermal efficiency of the MNP. The MNP with the highest composition of Fe₃O₄ was synthesized with a pH of 12.75, with a cubic morphology and a SAR value of 92.7 ± 3.2 W/g. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Magnetic Gels)

► Show Figures

Graphical abstract

16 pages, 1327 KiB

Open AccessArticle

Therapeutic Evaluation Punica granatum Peel Powder for the Ailment of Inflammatory Bowel Disorder in NCM460 Cell Line and in Albino Rats

by Parikshit Roychowdhury, Gyanendra Kumar Prajapati, Rupesh Singh, Prasanna Gurunath, Ramesh C, Gowthamarajan Kuppuswamy and Anindita De

Pharmaceutics 2025, 17(7), 843; https://doi.org/10.3390/pharmaceutics17070843 (registering DOI) - 27 Jun 2025

Abstract

Background: Ulcerative colitis (UC) is a chronic inflammatory condition associated with the colon and rectum, often predisposing individuals to inflammatory bowel disease-related colorectal cancer (IBD-CRC). Current therapeutic options for UC, including corticosteroids and immunosuppressive drugs, pose significant side effects. Punica granatum peel powder [...] Read more.

Background: Ulcerative colitis (UC) is a chronic inflammatory condition associated with the colon and rectum, often predisposing individuals to inflammatory bowel disease-related colorectal cancer (IBD-CRC). Current therapeutic options for UC, including corticosteroids and immunosuppressive drugs, pose significant side effects. Punica granatum peel powder (PPPG), a traditional herbal remedy in Ayurveda medicine for colitis, exhibits promising therapeutic effects with a favorable safety profile. Objectives: This study aims to explore the therapeutic potential and mechanism of action of a modified PPPG formulation in UC treatment. Methods: Using NCM460 cells and an acetic acid-induced UC murine model, the efficacy of modified PPPG was evaluated. Results: Therapy with modified PPPG significantly improved UC-associated symptoms, such as improvements in body weight, colon length, and disease activity index, as validated by histological examination. Transcriptomic sequencing identified downregulation of the IL-6/STAT3 signaling pathway and reduced inflammatory markers like p-NF-κB, IL-1β, and NLRP3 on PPPG therapy. Conclusions: These findings suggest that modified PPPG holds promise as a novel therapeutic strategy for UC intervention, targeting key inflammatory pathways implicated in UC pathogenesis and potentially mitigating the risk of IBD-CRC. Full article

(This article belongs to the Section Clinical Pharmaceutics)

► Show Figures

Graphical abstract

19 pages, 8298 KiB

Open AccessArticle

Screening for Polymorphism, Cyclodextrin Complexation, and Co-Crystallization of the Non-Steroidal Anti-Inflammatory Drug Fenbufen: Isolation and Characterization of a Co-Crystal and an Ionic Co-Crystal of the API with a Common Coformer

by Hannah M. Frösler, Neo Refiloe Mancapa, Laura Catenacci, Milena Sorrenti, Maria Cristina Bonferoni and Mino R. Caira

Pharmaceutics 2025, 17(7), 842; https://doi.org/10.3390/pharmaceutics17070842 (registering DOI) - 27 Jun 2025

Abstract

Background/Objectives: Increasing the solid-state landscape of an active pharmaceutical ingredient (API) by generating new crystalline forms (e.g., polymorphs, cyclodextrin (CD) inclusion complexes, co-crystals, and salts) can yield products with significantly enhanced biopharmaceutical properties (especially increased water solubility), thereby improving API delivery and [...] Read more.

Background/Objectives: Increasing the solid-state landscape of an active pharmaceutical ingredient (API) by generating new crystalline forms (e.g., polymorphs, cyclodextrin (CD) inclusion complexes, co-crystals, and salts) can yield products with significantly enhanced biopharmaceutical properties (especially increased water solubility), thereby improving API delivery and extending its lifetime. The aim of this study was the isolation of new solid forms of the poorly water-soluble non-steroidal anti-inflammatory drug fenbufen (FBF), for which relatively few solid phases have been reported to date. Further motivation for the study is the recent finding that it has potential for repurposing to treat acute pancreatitis. Methods: Interventions for generating new solid forms of FBF included (a) polymorph screening with a variety of solvent media, (b) attempts to form solid inclusion complexes with the native cyclodextrins α-, β-, and γ-CD using various preparative methods, and (c) co-crystallization with a series of coformers to produce co-crystals and/or molecular salts. Results: No new polymorphic forms of FBF were identified, but screening with CDs resulted in isolation and characterization of a new solid inclusion complex with γ-CD. However, co-crystallization of FBF with the water-soluble coformer isonicotinamide yielded two new products, namely a 1:1 co-crystal and an unusual multi-component ionic co-crystal, whose aqueous solubility indicated significant enhancement of FBF solubility. Conclusions: Due to its extremely low water solubility, FBF presented challenges during the study aimed at modifying its crystalline form. However, two new supramolecular forms, a co-crystal and an ionic co-crystal, were isolated, the latter phase having potential for further formulation owing to its significantly enhanced solubility. Full article

(This article belongs to the Special Issue Recent Insights Concerning the Use of Supramolecular Systems for Biomedical Applications)

► Show Figures

Figure 1

31 pages, 1459 KiB

Open AccessReview

Insights on Natural Membrane Characterization for the Rational Design of Biomimetic Drug Delivery Systems

by Daniela Donghia, Sara Baldassari, Giuliana Drava, Giorgia Ailuno and Gabriele Caviglioli

Pharmaceutics 2025, 17(7), 841; https://doi.org/10.3390/pharmaceutics17070841 (registering DOI) - 27 Jun 2025

Abstract

Cell membranes are vital for living organisms and serve as a dynamic barrier between the internal and external environments. They are composed of a complex lipid bilayer embedded with proteins, allowing them to perform multiple functions like maintaining the cell structure, regulating which [...] Read more.

Cell membranes are vital for living organisms and serve as a dynamic barrier between the internal and external environments. They are composed of a complex lipid bilayer embedded with proteins, allowing them to perform multiple functions like maintaining the cell structure, regulating which substances enter or leave the cell, and intercellular communication. Cellular functions are inherently linked to their membrane properties, and the heterogeneous nature of cell membranes makes the study of their physico-chemical properties extremely challenging. This review is intended to provide a comprehensive overview of the composition and physical features of the cell membrane, by focusing on the lipid and protein composition, and on the physical properties (like membrane stiffness or fluidity), highlighting how these characteristics influence cell functions. An insight into the similarities and differences from the membranes of extracellular vesicles (naturally secreted by almost all cell types) is also provided. The understanding of the physico-chemical properties of cell membranes might find application in different therapeutic fields, like disease diagnosis and development of novel drug delivery systems. Therefore, an overview of the literature works describing the rational design of biomimetic drug delivery systems is presented, focusing on the choice of lipid components, frequently inspired by the study of the composition of naturally secreted exosomes, and on the physical characterization of the systems. In the future, in-depth study of biologic vesicles might lead to the development of promising formulation for drug delivery, possibly enhancing the therapeutic outcomes of many pathologies, like cancer. Full article

(This article belongs to the Special Issue Membrane Transport and Drug Permeation)

► Show Figures

Graphical abstract

16 pages, 2226 KiB

Open AccessArticle

Design of Geraniol-Loaded Nanocapsules for Use Against Salmonella Infantis: Evaluation in an In Vitro Poultry Model

by Karla S. Garcia-Salazar, Hector J. Leon-Solano, Jesus A. Maguey-Gonzalez, Juan D. Latorre, Raquel López-Arellano, Elvia A. Morales Hipólito, Roberto Díaz-Torres, Miguel Morales Rodríguez, Alma Vázquez-Durán, Guillermo Tellez-Isaias, Abraham Méndez-Albores, Bruno Solis-Cruz and Daniel Hernandez-Patlan

Pharmaceutics 2025, 17(7), 840; https://doi.org/10.3390/pharmaceutics17070840 (registering DOI) - 27 Jun 2025

Abstract

Background/Objectives: Salmonella Infantis (S. Infantis) is a bacterium that has gained importance in public health over the last decade due to its high pathogenicity and resistance to antibiotics. Therefore, the objective of the present study was to present key considerations [...] Read more.

Background/Objectives: Salmonella Infantis (S. Infantis) is a bacterium that has gained importance in public health over the last decade due to its high pathogenicity and resistance to antibiotics. Therefore, the objective of the present study was to present key considerations for the design and development of geraniol-loaded nanocapsules for its delivery in the drinking water or feed of broiler chickens and to evaluate its potential as an antimicrobial agent against S. Infantis using a standard in vitro microplate assay and a model that simulates the pH and feed conditions of the crop of broiler chickens. Methods: Using a 3^k factorial experimental design, geraniol nanocapsule-based formulations were selected, and their antimicrobial activity was evaluated in in vitro models. Results: The results demonstrated that geraniol alone exhibits antimicrobial action against S. Infantis mainly due to its lipophilicity, hydrophobicity and the presence of the hydroxyl group found in its chemical structure, but when formulated in nanocapsular systems, the interaction of its components tends to reduce its antimicrobial action, especially the mixture of Tween 80:Span 80 and Miglyol^® 810N. Furthermore, the use of the in vitro model that simulates the crop of broiler chickens demonstrated that the formulation also has interactions with the feed components, completely nullifying the antimicrobial action of geraniol compared to that obtained in the in vitro microplate model. Conclusions: Preformulation studies during the development of nanocapsule-based formulations should be considered for the correct selection of the components of a formulation to ensure its effectiveness, without only considering the physicochemical and stability properties of these as is frequently seen in studies. Full article

(This article belongs to the Special Issue Applications of Nanotechnology in Veterinary Drug Delivery)

► Show Figures

Graphical abstract

17 pages, 1424 KiB

Open AccessReview

Challenges in the Investigation of Therapeutic Equivalence of Locally Applied/Locally Acting Drugs in the Gastrointestinal Tract: The Rifaximin Case

by Georgia Tsakiridou, Antigoni Maria Papanastasiou, Panagiotis Efentakis, Maria Faidra Galini Angelerou and Lida Kalantzi

Pharmaceutics 2025, 17(7), 839; https://doi.org/10.3390/pharmaceutics17070839 (registering DOI) - 27 Jun 2025

Abstract

Background: Locally acting gastrointestinal (GI) drugs present challenges for generic drug development because traditional bioequivalence measures, which rely on systemic drug levels, do not reflect local efficacy. This review examines regulatory guidelines for establishing therapeutic equivalence for such drugs, using rifaximin—a minimally absorbed, [...] Read more.

Background: Locally acting gastrointestinal (GI) drugs present challenges for generic drug development because traditional bioequivalence measures, which rely on systemic drug levels, do not reflect local efficacy. This review examines regulatory guidelines for establishing therapeutic equivalence for such drugs, using rifaximin—a minimally absorbed, gut-localized antibiotic—as a case study. Methods: We reviewed bioequivalence guidelines from the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA), along with the literature on rifaximin’s biopharmaceutical and clinical properties, to identify strategies and challenges for establishing equivalence for locally acting GI drugs. Results: Rifaximin exemplifies the limitations of standard bioequivalence methods: as a Biopharmaceutics Classification System (BCS) class IV drug with minimal absorption and low solubility, in vitro dissolution may not predict local drug availability. Clinical endpoint trials (e.g., traveler’s diarrhea, hepatic encephalopathy, IBS-D) are resource-intensive and insensitive to formulation differences. Pharmacokinetic (PK) studies in healthy volunteers show low, variable plasma levels, which may inaccurately discriminate between formulations. The EMA requires evidence of non-saturable absorption to accept PK data, a difficult-to-establish but potentially irrelevant criterion. Differences between FDA and EMA approaches highlight a lack of harmonization, complicating global generic development. Conclusions: A tailored, multifaceted approach is needed to demonstrate bioequivalence for GI-localized drugs like rifaximin. This case underscores the need for more sensitive surrogate methods (e.g. advanced in vitro or pharmacodynamic models) and flexible regulatory criteria. Harmonization across international guidelines and innovative bioequivalence study designs are key to facilitating the approval of safe and effective generic alternatives in this drug class. Full article

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)

► Show Figures

Figure 1

24 pages, 2380 KiB

Open AccessArticle

Development and Characterization of a New Oral Antileishmanial Bis(pyridine-2-Carboxamidine) Drug Through Innovative Dissolution Testing in Biorelevant Media Combined with Pharmacokinetic Studies

by Almudena Laguna, Borja Martínez-Alonso, Víctor Guarnizo-Herrero, J. Jonathan Nué-Martinez, Christophe Dardonville, Santiago Torrado-Santiago and Carlos Torrado-Salmerón

Pharmaceutics 2025, 17(7), 838; https://doi.org/10.3390/pharmaceutics17070838 (registering DOI) - 26 Jun 2025

Abstract

Background/Objectives: Currently there are very few effective oral antileishmanial treatments. In this study we evaluated a new bis(pyridine-2-carboxamidine) antileishmanial drug (JNII40_base) and its hydrochloride salt (JNII40_HCl). Methods: The characterization studies performed allowed us to determine the crystallinity, hydration water, and presence [...] Read more.

Background/Objectives: Currently there are very few effective oral antileishmanial treatments. In this study we evaluated a new bis(pyridine-2-carboxamidine) antileishmanial drug (JNII40_base) and its hydrochloride salt (JNII40_HCl). Methods: The characterization studies performed allowed us to determine the crystallinity, hydration water, and presence of hydrogen bonds in these drugs. Different dissolution methods were employed to predict intestinal absorption. A high-performance liquid chromatography–mass spectrophotometry (HPLC-MS/MS) method was developed for the determination of JNII40 in plasma. Results: Pharmacokinetic studies in rats of JNII40_base at 100 and 20 mg/kg, and JNII40_HCl at 20 mg/kg, showed a non-linear pharmacokinetic at high doses. An innovative biorelevant medium of phosphate buffer pH 6.8 with polysorbate 80 at 0.6% (w/v) showed high concentration values for JNII40_base at 30 min, which predicts good intestinal absorption. These results were consistent with the bioavailability data, which exhibited a significant (p < 0.05) increase in maximum plasma concentration (C_max) and a slight delay in time to maximum (T_max) compared to JNII40_HCl. Furthermore, the sustained release of JNII40_base in this biorelevant media was related to high plasma concentration values at 24 h (C_24h) observed in bioavailability studies. These plasma concentrations of JNII40_base were above the half-maximal inhibitory concentration (IC₅₀) against promastigote and amastigote forms of Leishmania donovani, which is indicative of effectiveness and should reduce the occurrence of drug resistance during treatments. Conclusions: The bioavailability and pharmacokinetic data support the consideration of this drug for further in vivo studies as an oral antileishmanial treatment. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

► Show Figures

Graphical abstract

18 pages, 1859 KiB

Open AccessArticle

PET and SPECT Tracer Development via Copper-Mediated Radiohalogenation of Divergent and Stable Aryl-Boronic Esters

by Austin Craig, Frederik J. Sachse, Markus Laube, Florian Brandt, Klaus Kopka and Sven Stadlbauer

Pharmaceutics 2025, 17(7), 837; https://doi.org/10.3390/pharmaceutics17070837 (registering DOI) - 26 Jun 2025

Abstract

Background/Objectives: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly sensitive clinical imaging modalities, frequently employed in conjunction with magnetic resonance imaging (MRI) or computed tomography (CT) for diagnosing a wide range of disorders. Efficient and robust radiolabeling methods [...] Read more.

Background/Objectives: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly sensitive clinical imaging modalities, frequently employed in conjunction with magnetic resonance imaging (MRI) or computed tomography (CT) for diagnosing a wide range of disorders. Efficient and robust radiolabeling methods are needed to accommodate the increasing demand for PET and SPECT tracer development. Copper-mediated radiohalogenation (CMRH) reactions enable rapid late-stage preparation of radiolabeled arenes, yet synthetic challenges and radiolabeling precursors’ instability can limit the applications of CMRH approaches. Methods: A series of aryl-boronic acids were converted into their corresponding aryl-boronic acid 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] and aryl-boronic acid 1,1,2,2-tetrapropylethylene glycol esters [ArB(Ppin)s] as stable and versatile precursor building blocks for radiolabeling via CMRH. General protocols for the preparation of ¹⁸F-labeled and ¹²³I-labeled arenes utilizing CMRH of these substrates were developed and applied. The radiochemical conversions (RCC) were determined by radio-(U)HPLC. Results: Both ArB(Epin)s and ArB(Ppin)s-based radiolabeling precursors were prepared in a one-step synthesis with chemical yields of 49–99%. Radiolabeling of the aryl-boronic esters with fluorine-18 or iodine-123 via CMRH furnished the corresponding radiolabeled arenes with RCC of 7–99% and 10–99%, respectively. Notably, a radiohalogenated prosthetic group containing a vinyl sulfone motif was obtained with an activity yield (AY) of 18 ± 3%, and applied towards the preparation of two clinically relevant PET tracers. Conclusions: This approach enables the synthesis of stable radiolabeling precursors and thus provides increased versatility in the application of CMRH, thereby supporting the development of novel PET and SPECT radiotracers. Full article

(This article belongs to the Section Clinical Pharmaceutics)

► Show Figures

Figure 1

11 pages, 8421 KiB

Open AccessArticle

A Metalless and Fungicide-Free Material Against Candida: Glass-Loaded Hydrogels

by Gabrielle Caroline Peiter, Elane da Silva Salvador, Fabián Ccahuana Ayma, Kádima Nayara Teixeira, Silvia Jaerger, Rafael A. Bini, Cleverson Busso, Rodrigo José de Oliveira and Ricardo Schneider

Pharmaceutics 2025, 17(7), 836; https://doi.org/10.3390/pharmaceutics17070836 (registering DOI) - 26 Jun 2025

Abstract

Background/Objectives: We report the antifungal potential of transition metal-free borophosphate glass-loaded hydrogels (BGHs) with different phosphorus/boron molar ratios (P/B = 2, 1, and 0.5) against Candida species. Candida yeasts pose a significant health risk as they can cause infections, systemic diseases, and even [...] Read more.

Background/Objectives: We report the antifungal potential of transition metal-free borophosphate glass-loaded hydrogels (BGHs) with different phosphorus/boron molar ratios (P/B = 2, 1, and 0.5) against Candida species. Candida yeasts pose a significant health risk as they can cause infections, systemic diseases, and even potentially fatal complications in immunocompromised individuals. Methods: The antifungal activity of BGH was evaluated against Candida albicans, Candida tropicalis, Candida krusei, and Candida glabrata using kinetic growth analysis, the agar well diffusion method, the minimum inhibitory concentration, the minimum fungicidal concentration, and scanning electron microscopy. Results: All BGH formulations effectively inhibited yeast growth at various concentrations, with results comparable to commercial miconazole gel (CMG). Hydrogels with P/B ratios of 0.5 and 1 produced larger inhibition zones than CMG, except against C. glabrata. However, BGHs with a P/B ratio of 0.5 at 3% and 5% (w/w) demonstrated relevant antifungal activity, especially against C. albicans and C. tropicalis. Conclusions: These findings highlight the promising antifungal potential of borophosphate glass-based hydrogels, particularly those with high boron content. Their efficacy against multiple Candida species suggests they could serve as an alternative to conventional antifungal agents. Full article

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

► Show Figures

Figure 1

Journal Description

Pharmaceutics

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI