Pharmaceutics

21 pages, 2359 KB

Open AccessArticle

TDMQ20 as A Drug Candidate for Wilson’s Disease: Comparison with D-Penicillamine, Trientine, and Tetrathiomolybdate In Vitro and In Mice

by Yingshan Zhu, Weiling Peng, Guangwei Liu, Longxin Li, Zikang Zhou, Michel Nguyen, Anne Robert, Yan Liu and Bernard Meunier

Pharmaceutics 2025, 17(9), 1237; https://doi.org/10.3390/pharmaceutics17091237 - 22 Sep 2025

Viewed by 228

Abstract

Background/Objectives: The lifelong treatment of Wilson’s disease (WD) currently relies on copper chelators with relatively poor metal specificity, which frequently exhibit serious adverse effects. There is a real medical need for a specific copper chelator to regulate the copper excess efficiently, at [...] Read more.

Background/Objectives: The lifelong treatment of Wilson’s disease (WD) currently relies on copper chelators with relatively poor metal specificity, which frequently exhibit serious adverse effects. There is a real medical need for a specific copper chelator to regulate the copper excess efficiently, at lower doses than those used for penicillamine (DPA) or trientine (TETA), and with lower toxicity in long-term treatments. Methods: The efficiency of the specific Cu(II) chelator named TDMQ20 was evaluated by oral treatment of TX mice, used as a WD model, and compared with those of DPA, TETA, and also tetrathiomolybdate (bcTTM). We documented TDMQ20′s ability to (i) decrease the hepatic copper load, (ii) increase the amount and ferroxidase activity of ceruloplasmin (CP), and (iii) regulate liver proteins that are impaired in WD mice. Results: Compared to the other copper chelators, TDMQ20 was the only one that efficiently mediated excretion of Cu and restoration of active ceruloplasmin levels at doses 8 times lower than DPA. Such efficacy is related to the design of this chelator, which specifically coordinates Cu(II) as a discrete and soluble complex. Conversely, DPA, TETA, and bcTTM give rise to various complexes with copper ions, often with oligomeric or cluster structures that can be retained in blood circulation or sequestered by proteins. Conclusions: Taking into consideration all the advantages of TDMQ20 compared to other ligands, including its lack of toxicity during long-term administration in mice, the drug candidate TDMQ20 appears to be a first-class challenger to the currently used treatments, i.e., DPA, TETA, and bcTTM. Full article

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

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25 pages, 3340 KB

Open AccessArticle

Daunomycin Nanocarriers with High Therapeutic Payload for the Treatment of Childhood Leukemia

by Rosa M. Giráldez-Pérez, Elia M. Grueso, Antonio J. Montero-Hidalgo, Cristina Muriana-Fernández, Edyta Kuliszewska, Raúl M. Luque and Rafael Prado-Gotor

Pharmaceutics 2025, 17(9), 1236; https://doi.org/10.3390/pharmaceutics17091236 - 22 Sep 2025

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Abstract

Background/Objectives: Malignant neoplasms in children include leukemias. The main types are B-cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML). Treatments are expensive, which is a particular problem in low-income countries. The main objective of this work was to develop specific [...] Read more.

Background/Objectives: Malignant neoplasms in children include leukemias. The main types are B-cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML). Treatments are expensive, which is a particular problem in low-income countries. The main objective of this work was to develop specific nanosystems with small amounts of drug, allowing for affordable treatments. To this end, we designed ternary gold nanosystems (Au@16-Ph-16/DNA–Dauno) composed of daunomycin, a DNA biopolymer as a stabilizer, and the cationic surfactant gemini (TG) as a compacting agent for the DNA–daunomycin complex. Methods: Fluorescence, UV–visible, and CD spectroscopy, DLS and zeta potential, cell viability assays, TEM, AFM, and confocal microscopy were used to characterize and optimize nanocomposites. Results: The nanoparticles (Au@TG) obtained were small, stable, and highly charged in solution, allowing for optimal absorption and efficacy, capable of inducing the aggregation of the ternary nanosystem upon entering the cell, further enhancing its anticancer effect. Using nanoparticles, treatments can be redirected to the site of action, increasing the solubility and stability of the drug, minimizing the side effects of traditional treatments, and helping to overcome resistance to chemotherapy Conclusions: A significant decrease in the growth of pediatric B-ALL-derived cell lines (SEM and SUP-B15), constituting a potential and more affordable therapy for this type of pathology. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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30 pages, 1599 KB

Open AccessArticle

Development and Evaluation of a Modified Fixed-Dose Combination Antihypertensive Tablet Containing S-Amlodipine Besylate: A Bioequivalence and Stability Study

by Hyeon Woo Moon, Jin-Hyuk Jeong and Chun-Woong Park

Pharmaceutics 2025, 17(9), 1235; https://doi.org/10.3390/pharmaceutics17091235 - 22 Sep 2025

Viewed by 155

Abstract

Background/Objectives: Fixed-dose combination (FDC) antihypertensive medications containing olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide are widely used for the treatment of essential hypertension. Although effective, the use of racemic amlodipine, which contains both active S(−)-amlodipine and inactive R(+)-amlodipine, has been associated [...] Read more.

Background/Objectives: Fixed-dose combination (FDC) antihypertensive medications containing olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide are widely used for the treatment of essential hypertension. Although effective, the use of racemic amlodipine, which contains both active S(−)-amlodipine and inactive R(+)-amlodipine, has been associated with dose-dependent adverse effects, such as peripheral edema. S-amlodipine, a pharmacologically active enantiomer, provides comparable antihypertensive efficacy at half the dose with a lower incidence of side effects. Methods: In this study, a modified FDC formulation was developed by replacing racemic amlodipine with S-amlodipine to enhance tolerability while maintaining therapeutic efficacy. Results: A bilayer tablet design was employed to minimize the formation of impurities and ensure formulation stability, which was confirmed under stress and accelerated conditions. In vitro dissolution testing demonstrated pharmaceutical equivalence with the marketed reference FDC, and an in vivo pharmacokinetic study confirmed bioequivalence. Conclusions: These results suggest that the newly developed S-amlodipine besylate-containing FDC tablet is a viable alternative to existing olmesartan/amlodipine/hydrochlorothiazide combinations, offering comparable efficacy and pharmacokinetic properties with the potential for improved safety and patient adherence in the management of hypertension. Full article

(This article belongs to the Special Issue Advancements in Tablet Formulation and Technological Innovations in Pharmaceutical Manufacturing)

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22 pages, 7468 KB

Open AccessArticle

Laponite^®-Based Smart Hydrogels for Sustained Topical Delivery of Silver Sulfadiazine: A Strategy for the Treatment of Contaminated or Biofilm-Forming Wounds

by Jonas Lira do Nascimento, Michely Conceição Viana da Costa, Leticia Farias de Macêdo, Luiz Henrique Chaves de Macêdo, Ricardo Olímpio de Moura, Tomás Jeferson Alves de Mélo, Wilma Raianny Vieira da Rocha, Ana Cristina Figueiredo de Melo Costa, José Lamartine Soares-Sobrinho and Dayanne Tomaz Casimiro da Silva

Pharmaceutics 2025, 17(9), 1234; https://doi.org/10.3390/pharmaceutics17091234 - 22 Sep 2025

Viewed by 324

Abstract

Background/Objectives: Silver sulfadiazine (AgSD) is widely used in the topical treatment of burns and infected wounds, but its conventional formulations present drawbacks such as poor water solubility, the need for multiple daily applications, and patient discomfort. To overcome these limitations, this study [...] Read more.

Background/Objectives: Silver sulfadiazine (AgSD) is widely used in the topical treatment of burns and infected wounds, but its conventional formulations present drawbacks such as poor water solubility, the need for multiple daily applications, and patient discomfort. To overcome these limitations, this study aimed to develop and evaluate Laponite^® (LAP)-based hydrogels loaded with AgSD for controlled release and enhanced antimicrobial and antibiofilm efficacy, offering a promising alternative for the treatment of contaminated or biofilm-forming wounds. Methods: Laponite^®-based hydrogels containing 1% and 1.2% AgSD (LAP@AgSD) were prepared using a one-pot method. The formulations were characterized rheologically, thermally, and structurally. In vitro drug release was assessed using Franz diffusion cells, and mathematical modeling was applied to determine release kinetics. Antibacterial and antibiofilm activities were evaluated against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa using standardized microbiological methods. Results: LAP@AgSD hydrogels exhibited pseudoplastic behavior, high structural integrity, and enhanced thermal stability. In vitro release assays revealed a sustained release profile, best fitted by the Weibull model, indicating diffusion-controlled mechanisms. Antibacterial assays demonstrated concentration-dependent activity, with LAP@AgSD 1.2% showing superior efficacy over LAP@AgSD 1% and comparable performance to the commercial silver sulfadiazine cream (CC-AgSD). Biofilm inhibition was significant for all formulations, with CC-AgSD 1% exhibiting the highest immediate activity, while LAP@AgSD 1.2% provided sustained antibiofilm potential. Conclusions: LAP-based hydrogels are promising smart delivery systems for AgSD, combining mechanical robustness, controlled drug release, and effective antibacterial and antibiofilm activities. These findings support their potential use in topical therapies for infected and chronic wounds, particularly where biofilm formation is a challenge. Full article

(This article belongs to the Special Issue Hydrogels-Based Drug Delivery System for Wound Healing)

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15 pages, 2111 KB

Open AccessArticle

Predictive Modeling of Drug Product Stability in Pharmaceutical Blister Packs

by Jan Pech, Christoph Kaminski, Matthias Markus, Werner Hoheisel, Roman Heumann, Judith Winck and Markus Thommes

Pharmaceutics 2025, 17(9), 1233; https://doi.org/10.3390/pharmaceutics17091233 - 22 Sep 2025

Viewed by 268

Abstract

Background/Objectives: The principal function of pharmaceutical blister packaging is to provide protection for the drug product. Moisture is regarded as a critical factor in the physical and chemical aging of drug products. The present work proposes a modeling framework to predict the performance [...] Read more.

Background/Objectives: The principal function of pharmaceutical blister packaging is to provide protection for the drug product. Moisture is regarded as a critical factor in the physical and chemical aging of drug products. The present work proposes a modeling framework to predict the performance of tablet blister materials based on the moisture uptake profile of the drug product as well as degradation characteristics of the drug substance, while the consumption of water due to degradation is included. Methods: The model incorporates three kinetic superimposed processes that define moisture uptake and drug stability. The processes of permeation, sorption and degradation are each described with a rate constant. Based on a mass balance, these rate processes are interconnected and the relative humidity in the blister cavity is predicted. Results: In a case study, the model was applied to demonstrate the feasibility of predicting the stability of blistered tablets. By establishing a correlation between the moisture uptake of the tablet and the drug stability demonstrated in the model, it was feasible to predict the drug content over shelf life. Conclusions: Modeling of the drug stability of blister-packed products enables a rational packaging which offers novel possibilities for reducing material in order to avoid overpackaging of pharmaceutical products. As some of the commonly used barrier materials are considered to not be sustainable, this model can be used to consider a rationally justified reduction or even abandonment of the barrier materials. Full article

(This article belongs to the Special Issue Stability of Medicines and Novel Approaches for Predicting Drug Stability)

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18 pages, 1178 KB

Open AccessArticle

Optimisation of Medicine Compounding Using Quality by Design Approach: Case Studies of Two Aqueous Cream Formulations

by Okhee Yoo, Wenting Li, Siyu Ruan, Elizabeth Syme, Alisha Rodrigo, Connelia Locher, Sharmin Sultana and Lee Yong Lim

Pharmaceutics 2025, 17(9), 1232; https://doi.org/10.3390/pharmaceutics17091232 - 22 Sep 2025

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Abstract

Background/Objectives: Quality-by-Design (QbD) is a proactive, risk-based, regulatory-endorsed approach to the development and manufacture of medicinal products but is rarely applied to medicines compounded by pharmacists. This study aims to apply the QbD approach to optimise the compounding processes for the aqueous [...] Read more.

Background/Objectives: Quality-by-Design (QbD) is a proactive, risk-based, regulatory-endorsed approach to the development and manufacture of medicinal products but is rarely applied to medicines compounded by pharmacists. This study aims to apply the QbD approach to optimise the compounding processes for the aqueous cream and cetomacrogol cream formulations listed in the Australian Pharmaceutical Formulary and Handbook (APF). Methods: The creams were prepared by varying the process conditions, including oil and water phase temperatures, stirring speed, cooling environment temperature, and the temperature at the end of stirring. Thirty-two samples of each cream type were prepared using combinations of processing conditions defined by a three-level factorial design. The viscosity, spreadability and creaming index of samples were assessed as response variables, and results were analysed using Stat-Ease 360© software to determine the optimal processing conditions for the two creams. To validate the predictive model and assess further cream stability, triplicate creams of each formulation were prepared using the optimised conditions and evaluated for dynamic viscosity, spreadability and creaming index. Results: Optimal conditions for aqueous cream involved heating the oil and water phases to 60 °C and 80 °C, respectively, followed by stirring the two phases at 250 rpm at 10 °C until cooling to 50 °C. For cetomacrogol cream, optimal compounding required heating the oil and water phases to 70 °C and 75 °C, respectively, with stirring the two phases at 220 rpm at ambient temperature (25 °C) until cooling to 40 °C. The conditions predicted by the models successfully yielded creams that met all specified targets. Creams compounded under optimal conditions exhibited well-defined oil droplets, with uniform droplet size in aqueous cream and mild size heterogeneity in cetomacrogol cream. Freeze-thaw testing demonstrated that both optimised creams were stable with no observable phase separation. Conclusions: This study demonstrates that a systematic experimental approach to optimising compounding parameters for the APF aqueous cream and cetomacrogol cream resulted in high-quality, stable, and reproducible products. Formulary guidelines, such as the APF, could benefit from adopting QbD approaches to improve the standardisation of compounding instructions in pharmacy practice. Full article

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

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19 pages, 1260 KB

Open AccessReview

Emerging Approaches for the Discovery of Lipid-Based RNA Delivery Systems

by Paul Meers

Pharmaceutics 2025, 17(9), 1231; https://doi.org/10.3390/pharmaceutics17091231 - 22 Sep 2025

Viewed by 346

Abstract

This brief review is a non-comprehensive look at some of the important aspects of lipidic nucleic acid delivery systems with a focus on RNA. In the context of this review on lipid-based formulation, nucleic acids are one of the key cargoes. Here, a [...] Read more.

This brief review is a non-comprehensive look at some of the important aspects of lipidic nucleic acid delivery systems with a focus on RNA. In the context of this review on lipid-based formulation, nucleic acids are one of the key cargoes. Here, a brief historical background is given, highlighting a few of the key newly developing approaches to aid formulation design. These new techniques are discussed within a framework of “bottom-up” (rational) versus “top-down” (combinatorial) design. Evolving areas of interest that are discussed include multiplexed formulation and efficacy testing, new principles established in the role of the protein corona, details of the biophysical mechanism of delivery and machine learning approaches to design. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of Vesicle and Nanocarrier Delivery Strategies)

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23 pages, 10763 KB

Open AccessArticle

Enhanced Efinaconazole Permeation and Activity Against Trichophyton rubrum and Trichophyton mentagrophytes with a Self-Nanoemulsifying Drug Delivery System

by Seo Wan Yun, Jeong Gyun Lee, Chul Ho Kim and Kyeong Soo Kim

Pharmaceutics 2025, 17(9), 1230; https://doi.org/10.3390/pharmaceutics17091230 - 22 Sep 2025

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Abstract

Background: Onychomycosis responds poorly to topical therapy, and efinaconazole (EFN) has low aqueous solubility. Methods: This study aimed to develop a 10% w/w EFN self-nanoemulsifying system (SNEDDS) with improved solubility, permeation, antifungal activity, and stability. Excipients were screened by [...] Read more.

Background: Onychomycosis responds poorly to topical therapy, and efinaconazole (EFN) has low aqueous solubility. Methods: This study aimed to develop a 10% w/w EFN self-nanoemulsifying system (SNEDDS) with improved solubility, permeation, antifungal activity, and stability. Excipients were screened by EFN saturation solubility. An MCT oil/Solutol HS 15/Labrafil M2125 CS SNEDDS (5/75/20, w/w) was optimized via a pseudo-ternary diagram. Characterization included droplet size, PDI, and zeta potential, morphology, and drug–excipient compatibility. Solubility was measured across pH. Permeation of EFN SNEDDS vs. EFN suspension was tested by Franz diffusion cells. Antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes was assessed by paper-disc diffusion, and hyphal damage on human nails was examined by SEM. Stability was studied for six months under room, accelerated, and stress conditions. Results: The optimized SNEDDS formed sub-50 nm droplets with low polydispersity and favourable zeta potential. Solubility was maintained across pH, and cumulative permeation increased 13.6-fold versus suspension. Paper-disc assays showed larger inhibition zones at lower EFN doses. SEM on human nails revealed marked hyphal destruction. TEM confirmed spherical nanoemulsion droplets. FT-IR showed no new peaks, supporting compatibility. Particle size, PDI, zeta potential, and drug content remained stable over six months under all storage conditions. Conclusions: A 10% w/w EFN SNEDDS enhanced solubility, transungual permeation, and antifungal efficacy while maintaining robust stability, supporting its potential as an ethanol-free therapy for onychomycosis. Full article

(This article belongs to the Special Issue Research on the Development of Semi-Solid Pharmaceutical Dosage Forms and Self-Emulsifying Drug Delivery Systems)

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24 pages, 2737 KB

Open AccessArticle

Antiviral Activity of Liposomes Containing Natural Compounds Against CHIKV

by Marília Freitas Calmon, Luiza Araújo Gusmão, Thalles Fernando Rocha Ruiz, Guilherme Rodrigues Fernandes Campos, Gabriela Miranda Ayusso, Tamara Carvalho, Isabella do Vale Francisco Bortolato, Pâmela Joyce Previdelli Conceição, Sebastião Roberto Taboga, Ana Carolina Gomes Jardim, Andres Merits, Paula Rahal and Antonio Claudio Tedesco

Pharmaceutics 2025, 17(9), 1229; https://doi.org/10.3390/pharmaceutics17091229 - 22 Sep 2025

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Abstract

Background/Objectives: Chikungunya virus (CHIKV), a mosquito-borne single-stranded RNA virus belonging to the genus Alphavirus (family Togaviridae), causes large-scale outbreaks. However, no specific treatment for CHIKV infections is currently available. Berberine and emodin are plant-derived compounds with anti-CHIKV activities. This study aimed to [...] Read more.

Background/Objectives: Chikungunya virus (CHIKV), a mosquito-borne single-stranded RNA virus belonging to the genus Alphavirus (family Togaviridae), causes large-scale outbreaks. However, no specific treatment for CHIKV infections is currently available. Berberine and emodin are plant-derived compounds with anti-CHIKV activities. This study aimed to evaluate the antiviral efficacy of liposomes containing berberine (LB) or emodin (LE) against CHIKV in vitro, since nanocarriers incorporating zwitterionic polymers are known to enhance the biostability, biocompatibility, and therapeutic efficacy of drug candidates. Methods: Liposomes were synthesized and characterized, and cell viability was assessed to determine appropriate concentrations for subsequent assays. Confocal microscopy, antiviral assays, and western blotting were performed in BHK-21 and Huh7 cells. Results: In BHK-21 and Huh7 cells, LB and LE were well tolerated at concentrations of 5 and 10 µM, respectively. In both cell types, liposomes were internalized; LE was predominantly localized in the cytoplasm, whereas LB was also detected in the nucleus. EGCG, used as a standard drug against CHIKV in antiviral assays, exhibited virucidal activity and inhibited RNA replication and multiple stages of the CHIKV replication cycle in BHK-21 and Huh7 cells. Both the nanoformulations and EGCG consistently suppressed the expression of CHIKV replicase and virion proteins. Conclusions: These findings highlight the potential of berberine- and emodin-loaded liposomes as antiviral agents against CHIKV infection. 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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17 pages, 1231 KB

Open AccessArticle

Indirect Modeling of Post-Prandial Intestinal Lymphatic Uptake of Halofantrine Using PBPK Approaches: Limitations and Implications

by Malaz Yousef, Farag E. S. Mosa, Khaled H. Barakat, Neal M. Davies and Raimar Löbenberg

Pharmaceutics 2025, 17(9), 1228; https://doi.org/10.3390/pharmaceutics17091228 - 22 Sep 2025

Viewed by 215

Abstract

Background/Objectives: Despite the recognized importance and distinctive characteristics of the intestinal lymphatic pathway in drug absorption, its pharmacokinetic modeling remains largely unexplored. This study aimed to address this gap by developing a physiologically based pharmacokinetic model (PBPK) to represent the oral lymphatic uptake [...] Read more.

Background/Objectives: Despite the recognized importance and distinctive characteristics of the intestinal lymphatic pathway in drug absorption, its pharmacokinetic modeling remains largely unexplored. This study aimed to address this gap by developing a physiologically based pharmacokinetic model (PBPK) to represent the oral lymphatic uptake of halofantrine following a fatty meal. Methods: Using GastroPlus™ 9.8.3 and published literature data, halofantrine absorption, distribution, metabolism, and elimination in both fasting and fed states were modeled. As the used software does not directly simulate intestinal lymphatic transport, lymphatic involvement in the fed state was examined indirectly through parameter adjustments such as first-pass metabolism, pKa-driven solubility changes, and bile-salt-mediated solubilization, with the aid of molecular dynamics simulations under post-prandial pH. Results: The pharmacokinetic models revealed a reduction in the first-pass effect of halofantrine in the fed state compared to that in the fasting state. While adjustments in metabolism kinetics sufficed for constructing a representative PBPK model in the fasting state, capturing the fed-state profile required both modifications to metabolism kinetics and other parameters related to the structural rearrangements of halofantrine driven by the changes in intestinal pH following food intake. These changes were confirmed using molecular dynamics simulations of halofantrine in pHs reflecting the post-prandial conditions. Conclusions: This study underscores the need for further exploration and direct modeling of intestinal lymphatic uptake via PBPK models, highlighting its underexplored status in simulation algorithms. Moreover, the importance of integrating representative physicochemical factors for drugs, particularly in post-prandial conditions or lipid formulations, is evident. Overall, these findings contribute to advancing predictive regulatory and developmental considerations in drug development using post hoc analyses. Full article

(This article belongs to the Special Issue In Silico Pharmacokinetic and Pharmacodynamic (PK-PD) Modeling)

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24 pages, 2434 KB

Open AccessArticle

Therapeutic Approach Based on Nanotechnology with Chitosan-Coated Zein Nanoparticles Containing Quercetin Against Resistant Klebsiella pneumoniae Clinical Isolates

by Azael Francisco Silva-Neto, Maria Anndressa Alves Agreles, Ana Alice Venancio Correia, Hanne Lazla Rafael de Queiroz Macêdo, Alane Rafaela de Carvalho Amaral, Alexsandra Maria Lima Scavuzzi, João Victor de Oliveira Alves, Ana Catarina Souza Lopes, Márcia Vanusa da Silva, Maria Tereza dos Santos Correia, Isabella Macário Ferro Cavalcanti and Luís André de Almeida Campos

Pharmaceutics 2025, 17(9), 1227; https://doi.org/10.3390/pharmaceutics17091227 - 22 Sep 2025

Viewed by 327

Abstract

Background/Objectives: The study developed, characterized, and evaluated the toxicity, antibacterial and antibiofilm activity of quercetin encapsulated in chitosan-coated zein nanoparticles (QUER-ZNP-CH). Methods: QUER-ZNP-CH were prepared by the nanoprecipitation method and characterized by physicochemical analyses, stability (12 months), and release kinetics. Toxicity was evaluated [...] Read more.

Background/Objectives: The study developed, characterized, and evaluated the toxicity, antibacterial and antibiofilm activity of quercetin encapsulated in chitosan-coated zein nanoparticles (QUER-ZNP-CH). Methods: QUER-ZNP-CH were prepared by the nanoprecipitation method and characterized by physicochemical analyses, stability (12 months), and release kinetics. Toxicity was evaluated through hemocompatibility and a Tenebrio molitor larval model. Antibacterial activity (MIC/MBC, CLSI) and antibiofilm potential (crystal violet assay) were tested against resistant Klebsiella pneumoniae strains. Results: The nanoparticles were prepared, and physicochemical analyses revealed chemical interactions, efficient encapsulation of the drug, and thermal stability. The formulations remained stable over 12 months, and the release kinetics demonstrated controlled release for 72 h. No hemotoxic profile was observed and there was 95% survival of Tenebrio molitor larvae after treatment with QUER-ZNP-CH. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of QUER-ZNP-CH revealed enhanced antibacterial activity of QUER, as indicated by a 32 to 64-fold reduction in the MIC and MBC values. The biofilm inhibition potential of QUER-ZNP-CH showed 60–100% inhibition and 25–95% eradication in concentrations from 0.12 to 62.5 μg/mL. Conclusions: Thus, this nanotechnology-based formulation suggests potential for the treatment of bacterial infections caused by multidrug-resistant K. pneumoniae strains. Full article

(This article belongs to the Special Issue Smart Materials for Advanced Drug Delivery Systems and Pharmaceutical Applications)

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15 pages, 2933 KB

Open AccessArticle

Development of Liposomal Formulations for 1,4-bis-L/L Methionine-Conjugated Mitoxantrone–Amino Acid Conjugates to Improve Pharmacokinetics and Therapeutic Efficacy

by Ting-Lun Yang, Tsai-Kun Li and Chin-Tin Chen

Pharmaceutics 2025, 17(9), 1226; https://doi.org/10.3390/pharmaceutics17091226 - 21 Sep 2025

Viewed by 196

Abstract

Background: 1,4-bis-L/L methionine–conjugated mitoxantrone–amino acid conjugate (L/LMet-MAC) inhibits topoisomerase IIα and enhances tumor cytotoxicity, but its short half-life limits therapeutic application. Objective: To improve the pharmacokinetics and antitumor efficacy of L/LMet-MAC through liposomal encapsulation. Methods: PEGylated DSPC liposomes containing EPG or prepared via [...] Read more.

Background: 1,4-bis-L/L methionine–conjugated mitoxantrone–amino acid conjugate (L/LMet-MAC) inhibits topoisomerase IIα and enhances tumor cytotoxicity, but its short half-life limits therapeutic application. Objective: To improve the pharmacokinetics and antitumor efficacy of L/LMet-MAC through liposomal encapsulation. Methods: PEGylated DSPC liposomes containing EPG or prepared via the ammonium sulfate gradient method were employed to encapsulate L/LMet-MAC. Encapsulation efficiency, drug-to-lipid ratio, and serum stability were assessed. Pharmacokinetics, antitumor efficacy, and systemic safety were further evaluated in vivo. Results: L/LMet-MAC encapsulated in PEGylated DSPC liposomes containing EPG or prepared using the ammonium sulfate gradient method has high encapsulation efficiency. Further studies show that PEGylated DSPC liposomes prepared with the ammonium sulfate gradient approach display an efficient D/L ratio and serum stability as well as improved pharmacokinetics and enhanced antitumor efficacy while mitigating the side effects of L/LMet-MAC. Conclusions: PEGylated DSPC liposomes prepared using an ammonium sulfate gradient showed favorable performance for delivering L/LMet-MAC. Full article

(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation)

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22 pages, 14728 KB

Open AccessArticle

Evaluating Optical Coherence Tomography and X-Ray Computed Tomography to Measure Tablet Film Coat Thickness

by Emily Sanchez, Trent Eastman, Jennifer Potter and Robert Meyer

Pharmaceutics 2025, 17(9), 1225; https://doi.org/10.3390/pharmaceutics17091225 - 20 Sep 2025

Viewed by 238

Abstract

Background/Objective: Film coatings are vital components of many pharmaceutical products consumed orally in solid dosage form, and the optimization of the film coating unit operation is critical to the success of these products. It is essential to maintain adequate film coat thickness on [...] Read more.

Background/Objective: Film coatings are vital components of many pharmaceutical products consumed orally in solid dosage form, and the optimization of the film coating unit operation is critical to the success of these products. It is essential to maintain adequate film coat thickness on tablets to ensure the elegance, mechanical integrity, and controlled-release functionality of active pharmaceutical ingredients. We aim to evaluate techniques for measuring the film coat thickness of tablets in the pharmaceutical drug product development space as current research primarily focuses on in-line methods at the manufacturing scale. Methods: A total of four tablet types, varying in size, shape, and coating thickness were assessed using Optical Coherence Tomography and X-ray Computed Tomography. The data was then compared to baseline reference values gathered by examining tablets with a Confocal Microscope. A second trial was performed using an alternative Optical Coherence Tomography instrument to verify the accuracy of the data. The methods were also evaluated on additional criteria utilizing a Pugh Matrix. Results: The initial Optical Coherence Tomography yielded measurements that were inconsistent with the values provided by the control for three of the four tablet types; however, the follow-up study provided values within an acceptable range. The X-ray Computed Tomography also provided accurate measurements but presented challenges for precision in relation to the instrument’s resolution capabilities. Based on the assessment of selected criteria, Optical Coherence Tomography is ideal for all clear-coated tablets, while X-ray Computed Tomography is better suited for small tablets with either opaque or clear coats. Conclusions: Optical Coherence Tomography, X-ray Computed Tomography, and the use of a Confocal Microscope are all viable methods for measuring the film coat thickness of tablets. Method selection is not absolute and depends on factors such as safety, ease of use, adaptability, and tablet characteristics. The results of this study will help provide guidance for selecting the most appropriate method for measuring the film coat thickness of a specific tablet. Full article

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

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16 pages, 3320 KB

Open AccessArticle

A Comprehensive Physiologically Based Pharmacokinetic Framework of Ofloxacin: Predicting Disposition in Renal Impairment

by Ammara Zamir, Muhammad Fawad Rasool, Iltaf Hussain, Sary Alsanea, Samiah A. Alhabardi and Faleh Alqahtani

Pharmaceutics 2025, 17(9), 1224; https://doi.org/10.3390/pharmaceutics17091224 - 20 Sep 2025

Viewed by 829

Abstract

Background: In the last several years, “physiologically based pharmacokinetic (PBPK) modeling” has gathered significant emphasis in the modeling of drug absorption, disposition, and metabolism. This research study aims to elaborate the plasma/serum concentration–time profiles and pharmacokinetics (PK) of ofloxacin by establishing a [...] Read more.

Background: In the last several years, “physiologically based pharmacokinetic (PBPK) modeling” has gathered significant emphasis in the modeling of drug absorption, disposition, and metabolism. This research study aims to elaborate the plasma/serum concentration–time profiles and pharmacokinetics (PK) of ofloxacin by establishing a PBPK model in healthy subjects and those suffering from renal impairment (RI). Methods: A comprehensive literature analysis was conducted to screen out all the systemic PK profiles and parameters specific to ofloxacin, followed by their implementation in PK-Sim^® version 12 software. This model-driven approach begins by developing the model in healthy populations using both intravenous (IV) and per-oral (PO) routes and then extrapolating it to the diseased population. The model evaluation was then strengthened for different PK variables such as the maximal plasma/serum concentration (C_max), the area under the curve from 0 to t (AUC_0–t), and plasma/serum clearance (CL) by employing various metrics such as predicted/observed ratios (R_pre/obs), visual predictive checks, the average fold error (AFE), root mean squared error (RMSE), and mean absolute error (MAE). Results: The AFE, RSME, and MAE for C_max in RI were 1.10, 0.22, and 0.16, respectively, which fell within the acceptable simulated error range. Furthermore, dosage adjustments for individuals with mild, moderate, and severe RI were presented by box-whisker plots to compare their systemic exposure with that of the healthy population. Conclusions: These model predictions have confirmed the PK variations in ofloxacin, which may assist the clinicians in optimizing dosage schedules in healthy and various categories of RI populations. Full article

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

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33 pages, 2619 KB

Open AccessReview

Precision Adjuvant Strategies in Vaccine Development for Substance Use Disorders: Variability and Mechanistic Insights

by Yuanzhi Bian, Qiaoqiao Ci, Xin M. Luo and Chenming Zhang

Pharmaceutics 2025, 17(9), 1223; https://doi.org/10.3390/pharmaceutics17091223 - 20 Sep 2025

Viewed by 382

Abstract

Substance use disorders (SUDs) remain a major global health challenge with limited treatment options and high relapse rates. Vaccines that induce drug-sequestering antibodies have shown promise, but their efficacy is hindered by the poor immunogenicity of small-molecule haptens. Adjuvants, substances that enhance immune [...] Read more.

Substance use disorders (SUDs) remain a major global health challenge with limited treatment options and high relapse rates. Vaccines that induce drug-sequestering antibodies have shown promise, but their efficacy is hindered by the poor immunogenicity of small-molecule haptens. Adjuvants, substances that enhance immune responses, are critical for overcoming this limitation and improving vaccine efficacy. This review synthesizes over two decades of preclinical and clinical research to guide rational adjuvant design for SUD vaccines. Five major adjuvant classes are examined: aluminum-salt adjuvants, emulsion adjuvants, toll-like receptor (TLR) agonists, protein immunopotentiators, and cytokine modulators. Their physicochemical properties, innate immune activation profiles, and applications in nicotine, stimulant, and opioid vaccines are discussed. Comparative analyses reveal pronounced drug-specific and carrier-specific variability. Case studies illustrate the superior performance of a complementary TLR-agonist pair in a nicotine nanovaccine versus its limited effect in oxycodone vaccines. They also reveal the differential efficacy of an oil-in-water emulsion adjuvant across antigen types. Four principles emerge: (i) no adjuvant is universally optimal; (ii) drug pharmacology influences immune signaling; (iii) adjuvant-carrier compatibility is important; (iv) complementary adjuvant pairings often outperform single agents. These insights support a precision-vaccinology paradigm that tailors adjuvant strategies to each drug class and the delivery vehicle, advancing the development of next-generation SUD vaccines. Full article

(This article belongs to the Section Biopharmaceutics)

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22 pages, 2896 KB

Open AccessArticle

Integrating In Vitro BE Checker with In Silico Physiologically Based Biopharmaceutics Modeling to Predict the Pharmacokinetic Profiles of Oral Drug Products

by Takuto Niino, Takato Masada, Toshihide Takagi, Makoto Kataoka, Hiroyuki Yoshida, Shinji Yamashita and Atsushi Kambayashi

Pharmaceutics 2025, 17(9), 1222; https://doi.org/10.3390/pharmaceutics17091222 - 20 Sep 2025

Viewed by 186

Abstract

Objective: The objective of this study was to develop a Physiologically Based Biopharmaceutics Modeling (PBBM) framework that can predict PK profiles in humans based on data generated from the BE Checker. Methods: Metoprolol and dipyridamole were selected as model drugs. A [...] Read more.

Objective: The objective of this study was to develop a Physiologically Based Biopharmaceutics Modeling (PBBM) framework that can predict PK profiles in humans based on data generated from the BE Checker. Methods: Metoprolol and dipyridamole were selected as model drugs. A mathematical model was developed to describe drug dissolution, membrane permeation, and dynamic changes in pH and fluid volume within the BE Checker system. Using data generated under various experimental conditions, dissolution rate constants were estimated. For dipyridamole, the precipitation rate constant was also estimated, assuming simultaneous dissolution and precipitation processes. The estimated parameters were subsequently incorporated into the human PBBM to simulate PK profiles. Finally, the predictive accuracy of PK parameters such as Cmax and AUC was assessed. Results: For metoprolol, the PK profiles using the paddle revolution rates of 100 and 200 rpm closely matched the observed human data, particularly for Cmax and AUC, a key indicator of BE. In the case of dipyridamole, accurate predictions of the mean human PK profile were achieved when using BE Checker data obtained under high paddle speed (200 rpm) and longer pre-FaSSIF infusion times (20–30 min). Conversely, simulations based on lower paddle speed (50 rpm) and shorter pre-FaSSIF infusion time (10 min) underestimated plasma concentrations in humans. Conclusions: These findings suggest that the combination of BE Checker data acquired under high agitation conditions and the in silico mathematical model developed in this study enables accurate prediction of average human PK profiles. Full article

(This article belongs to the Special Issue Recent Advances in Physiologically Based Biopharmaceutics Modeling)

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30 pages, 11101 KB

Open AccessArticle

Influence of Processing and Stabilizer Selection on Microstructure, Stability and Rheology of Emulsion-Based Semisolid Formulations

by Ruochen Yang, Xin Yi Tee, Sendhil Kumar Poornachary, Elena Simone and Pui Shan Chow

Pharmaceutics 2025, 17(9), 1221; https://doi.org/10.3390/pharmaceutics17091221 - 20 Sep 2025

Viewed by 197

Abstract

Background/Objectives: Emulsion-based semisolid formulations are important delivery systems for many applications, including pharmaceuticals, cosmetics and food. The manufacturing process for such formulations typically involves a series of heating, cooling, mixing and emulsification steps. Stabilizing agents are usually included in such formulations, as [...] Read more.

Background/Objectives: Emulsion-based semisolid formulations are important delivery systems for many applications, including pharmaceuticals, cosmetics and food. The manufacturing process for such formulations typically involves a series of heating, cooling, mixing and emulsification steps. Stabilizing agents are usually included in such formulations, as emulsions are intrinsically unstable and are prone to various destabilization mechanisms. Precise control of each processing parameter and the selection of an appropriate stabilizing agent are essential for delivering products with long-term stability and the desired properties. In this study, the effects of emulsification temperature and the selection of the stabilizing agent on key product attributes were investigated to enable improved design and optimization of both the formulation and manufacturing process. Methods: Model emulsion systems containing propylene glycol (PG) as the dispersed phase and mineral oil as the continuous phase were prepared at different emulsification temperatures to cover both pre-crystallization and post-crystallization regimes. Three stabilizing agents, namely mono-and-diglyceride (MDG), neat monoglyceride (MG) and neat diglyceride (DG), were studied. Their crystallization behavior was first examined to determine crystallization temperatures and crystal morphologies. The resulting emulsion samples were then characterized in terms of their microstructure, physical stability and rheological properties. Results: The emulsions prepared under post-crystallization conditions exhibited better physical stability, higher rheological parameters (crossover stress and viscosity) and a more rigid microstructure compared to those formed under pre-crystallization conditions, regardless of the stabilizer used. Rheological properties were found to corelate well with physical stability. In the pre-crystallization regime, poor stability could partially be mitigated by lowering the emulsification temperature. MG was generally more effective than DG in stabilizing the emulsions and led to higher rheological properties, despite both crystallizing into the same polymorph within the system. This difference in performance was attributed to variations in the crystal morphology and spatial distribution within the emulsion. Notably, the MG-stabilized emulsions also displayed a self-hardening effect during storage. Conclusions: The selection of the appropriate stabilizing agents and processing conditions tailored to the specific system is critical for the successful manufacture of emulsion-based semisolid products with an optimized performance. Full article

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

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26 pages, 1179 KB

Open AccessReview

Novel Strategies for Androgenetic Alopecia Therapy: Integrating Multifunctional Plant Extracts with Nanotechnology for Advanced Cutaneous Drug Delivery

by Ruohan Diao, Meiqi Sun, Ningxin Zhang, Xinqian Liu and Ping Song

Pharmaceutics 2025, 17(9), 1220; https://doi.org/10.3390/pharmaceutics17091220 - 19 Sep 2025

Viewed by 525

Abstract

Androgenetic alopecia (AGA), the most common form of hair loss, imposes considerable psychosocial and medical burdens. Current topical treatments are limited by suboptimal efficacy, slow onset, side effects, and poor patient adherence. Although numerous reviews have explored natural plant-based strategies for managing AGA, [...] Read more.

Androgenetic alopecia (AGA), the most common form of hair loss, imposes considerable psychosocial and medical burdens. Current topical treatments are limited by suboptimal efficacy, slow onset, side effects, and poor patient adherence. Although numerous reviews have explored natural plant-based strategies for managing AGA, most offer fragmented evidence with limited systematic correlation between mechanistic studies and clinical outcomes concerning single plant constituents. This review critically synthesizes recent pharmaceutical advances in AGA therapy, with a focus on the synergistic potential of multifunctional plant extracts integrated with nanotechnology enhanced cutaneous delivery systems. We begin by examining the mechanistic basis of AGA pathogenesis and the limitations of existing treatments to identify unmet therapeutic needs. Next, we systematically evaluate plant extracts supported by robust in vitro, in vivo, and clinical evidence for their anti-androgenic, anti-inflammatory, antioxidative, and anti-apoptotic properties. Finally, we address key biopharmaceutical challenges in transdermal delivery for AGA and discuss how nanocarriers can overcome these barriers to improve local drug bioavailability and target specificity. By bridging phytochemistry and nanomedicine, this review provides novel insights and a pharmaceutics-oriented framework aimed at developing safer, more effective, and patient-compliant topical therapies for AGA. Full article

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

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17 pages, 9815 KB

Open AccessArticle

Pinostilbene as a Potential Cytotoxic Agent in Cancer Cell Lines: Improvement of Solubility and Stability by Cyclodextrin Encapsulation

by Irene Conesa, Silvia Navarro-Orcajada, Francisco José Vidal-Sánchez, Elena Torralba-Antón, Marta Carrión-Espinosa, Adrián Matencio and José Manuel López-Nicolás

Pharmaceutics 2025, 17(9), 1219; https://doi.org/10.3390/pharmaceutics17091219 - 19 Sep 2025

Viewed by 299

Abstract

Background/Objectives: Pinostilbene is a naturally occurring methoxylated stilbene with many beneficial health properties, including antioxidant, antimicrobial and neuroprotective activities. This stilbene has also been shown to possess anticancer or cytotoxic activity in some cancers. As in the case of other stilbenes, pinostilbene is [...] Read more.

Background/Objectives: Pinostilbene is a naturally occurring methoxylated stilbene with many beneficial health properties, including antioxidant, antimicrobial and neuroprotective activities. This stilbene has also been shown to possess anticancer or cytotoxic activity in some cancers. As in the case of other stilbenes, pinostilbene is very labile, degrades rapidly under stress conditions and is poorly water-soluble, which poses a drawback to its use as a drug. This work aims to provide further insights into its cytotoxicity activity in a colon cancer cell line and to overcome its physicochemical limitations by encapsulating the molecule in cyclodextrins. Methods: The anticancer activity was evaluated in vitro in Caco-2 colorectal cells using the neutral red assay. Subsequently, a screening of cyclodextrins was carried out to determine the one with the highest encapsulation constant, as well as the encapsulation stoichiometry, using fluorescence spectroscopy and molecular docking predictions. The formation of the inclusion complexes was checked by differential scanning calorimetry and scanning electron microscopy. The protective effect of cyclodextrins on pinostilbene release was monitored through spectrophotometric measurements over time. Results: Pinostilbene showed in vitro cytotoxicity activity in Caco-2 colorectal cells by the neutral red assay. This study revealed that the cyclodextrin with the highest encapsulation constant was the hydroxypropyl-β-cyclodextrin (K_F = 10,074.45 ± 503.72 M⁻¹), and the encapsulation stoichiometry was 1:1. DSC and SEM assays confirmed the formation of these inclusion complexes. Cyclodextrins were able to satisfactorily reduce pinostilbene degradation from 31% to less than 15% after 3 months, as well as increase its water solubility up to 10 times and enhance its release as a function of the pH of the medium. Conclusions: Pinostilbene is a promising drug candidate with strong in vitro antiproliferative activity. Many of its physicochemical limitations can be overcome with cyclodextrins, which opens the door to its future use in the pharmaceutical and food industries. Full article

(This article belongs to the Special Issue Carbohydrate-Based Carriers for Drug Delivery, 2nd Edition)

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31 pages, 8942 KB

Open AccessArticle

Formulation Studies on Microemulsion-Based Polymer Gels Loaded with Voriconazole for the Treatment of Skin Mycoses

by Michał Gackowski, Anna Froelich, Oliwia Kordyl, Jolanta Długaszewska, Dorota Kamińska, Raphaël Schneider and Tomasz Osmałek

Pharmaceutics 2025, 17(9), 1218; https://doi.org/10.3390/pharmaceutics17091218 - 18 Sep 2025

Viewed by 282

Abstract

Background: Skin mycoses affect approximately 10% of the global population, and the range of effective topical antifungal agents remains limited. Voriconazole (VRC) is a broad-spectrum triazole with proven efficacy against drug-resistant fungal infections. This study aimed to develop and optimize VRC-loaded microemulsion (ME) [...] Read more.

Background: Skin mycoses affect approximately 10% of the global population, and the range of effective topical antifungal agents remains limited. Voriconazole (VRC) is a broad-spectrum triazole with proven efficacy against drug-resistant fungal infections. This study aimed to develop and optimize VRC-loaded microemulsion (ME) polymer gels (Carbopol^®-based) for cutaneous delivery. Selected formulations also contained menthol (2%) as a penetration enhancer and potential synergistic antifungal agent. Methods: A comprehensive screening was performed using pseudoternary phase diagrams to identify stable oil/surfactant/co-surfactant/water systems. Selected MEs were prepared with triacetin, Etocas™ 35, and Transcutol^®, then gelled with Carbopol^®. Formulations were characterized for pH, droplet size, polydispersity index (PDI), and viscosity. In vitro VRC release was assessed using diffusion cells, while ex vivo permeation and skin deposition studies were conducted on full-thickness human skin. Rheological behavior (flow curves, yield stress) and texture (spreadability) were evaluated. Antifungal activity was tested against standard strain of Candida albicans and clinical isolates including a fluconazole-resistant strain. Results: The optimized ME (pH ≈ 5.2; droplet size ≈ 2.8 nm) was clear and stable with both VRC and menthol. Gelation produced non-Newtonian, shear-thinning hydrogels with low thixotropy, favorable for topical application. In ex vivo studies, performed with human skin, both VRC-loaded gels deposited the drug in the epidermis and dermis, with no detectable amounts in the receptor phase after 24 h, indicating retention within the skin. Menthol increased VRC deposition. Antifungal testing showed that VRC-containing gels produced large inhibition zones against C. albicans, including the resistant isolate. The VRC–menthol gel exhibited significantly greater inhibition zones than the VRC-only gel, confirming synergistic activity. Conclusions: ME-based hydrogels effectively delivered VRC into the skin. Menthol enhanced drug deposition and demonstrated synergistic antifungal activity with voriconazole. Full article

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

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18 pages, 3383 KB

Open AccessArticle

Selective Inhibition of Yersinia enterocolitica Type III Secretion by Lindera obtusiloba Extract and Cinnamtannin B1

by Jin-Hee Yoo and Tae-Jong Kim

Pharmaceutics 2025, 17(9), 1217; https://doi.org/10.3390/pharmaceutics17091217 - 18 Sep 2025

Viewed by 213

Abstract

Background/Objectives: Selective inhibition of bacterial virulence factors is a promising strategy to convert pathogenic bacteria into non-pathogenic commensals, circumventing the challenge of antibiotic resistance. This approach enables the host immune system to eliminate virulence-attenuated pathogens. Methods: In this study, we evaluated [...] Read more.

Background/Objectives: Selective inhibition of bacterial virulence factors is a promising strategy to convert pathogenic bacteria into non-pathogenic commensals, circumventing the challenge of antibiotic resistance. This approach enables the host immune system to eliminate virulence-attenuated pathogens. Methods: In this study, we evaluated the effects of Lindera obtusiloba Blume extract and cinnamtannin B1, the active component of the ethyl acetate fraction, on the type III secretion system (T3SS) of Yersinia enterocolitica. Results: The ethyl acetate fraction, at 100 mg/L, effectively suppressed all three T3SS components—the flagellar, Ysa, and Ysc T3SSs. Cinnamtannin B1, isolated from the ethyl acetate fraction through separation and identified through nuclear magnetic resonance spectrometer analysis, significantly inhibited flagellar and Ysa T3SS secretion, while selectively inhibiting expression of key effector proteins YopH and YopO in the Ysc T3SS. Additionally, cinnamtannin B1 reduced Y. enterocolitica-induced RAW 264.7 macrophage mortality and prevented poly (ADP-ribose) polymerase degradation, a marker of apoptosis. Conclusions: These findings suggest cinnamtannin B1 from L. obtusiloba as a selective T3SS-targeting compound with mechanistic potential for anti-virulence intervention. Further in vivo validation will be necessary to evaluate its therapeutic applicability. Full article

(This article belongs to the Special Issue Natural Products with Antimicrobial Activity and Their Pharmaceutical Delivery Systems)

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23 pages, 1914 KB

Open AccessReview

Nanoformulation-Based Transdermal Drug Delivery: A Paradigm Shift in Antiparasitic Therapy for Zoonotic Diseases

by Yuan Zhao, Ruoxuan Xiu, Chengxiang Wang, Junqi Wang, Dawei Guo, Wanhe Luo, Shanxiang Jiang, Zhiyi Ge and Xiuge Gao

Pharmaceutics 2025, 17(9), 1216; https://doi.org/10.3390/pharmaceutics17091216 - 18 Sep 2025

Viewed by 288

Abstract

Nanoparticle-based transdermal drug delivery systems (TDDS) have emerged as a revolutionary approach for antiparasitic therapy, addressing key challenges such as poor bioavailability, systemic toxicity, and drug resistance. This review highlights the advancements in nanotechnology-driven TDDS for combating zoonotic parasitic diseases, including leishmaniasis, malaria, [...] Read more.

Nanoparticle-based transdermal drug delivery systems (TDDS) have emerged as a revolutionary approach for antiparasitic therapy, addressing key challenges such as poor bioavailability, systemic toxicity, and drug resistance. This review highlights the advancements in nanotechnology-driven TDDS for combating zoonotic parasitic diseases, including leishmaniasis, malaria, and infections treated by broad-spectrum drugs like ivermectin and albendazole. By leveraging nanocarriers such as liposomes, nanoemulsions, and microneedles, which enhance skin permeation, enable controlled drug release, and improve targeting specificity. For instance, deformable transfersomes and ethosomes achieve high transdermal efficiency without chemical adjuvants, while microneedle arrays physically bypass the stratum corneum for precise delivery. Furthermore, sustained-release hydrogels and stimuli-responsive nanoparticles optimize therapeutic efficacy and reduce adverse effects. Despite promising results, clinical translation faces challenges in manufacturing scalability, long-term safety, and accessibility in resource-limited settings. Future directions include bioinspired nanocarriers, artificial intelligence (AI)-driven design, and integration with global health initiatives like “One Health”, all aimed at ensuring equitable implementation. This review highlights the transformative potential of nanotechnology in achieving sustainable antiparasitic solutions for zoonotic diseases. Full article

(This article belongs to the Special Issue Application of Nanoparticles and Dendrimers for Treating Infectious Diseases)

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24 pages, 2844 KB

Open AccessArticle

Theranostic Potential of a New ⁶⁴Cu-Labeled NOTA-R954 Peptide Conjugate for Kinin B1R Expressing Prostate Cancer

by Sadaf Ghanaatgar Kasbi, Martin Savard, Frédéric Couture, Céléna Dubuc, Véronique Dumulon-Perreault, Marie-Edith Nepveu-Traversy, Samia Ait-Mohand, Robert Sabbagh, Sameh Geha, Brigitte Guérin, Yves Dory and Fernand Gobeil

Pharmaceutics 2025, 17(9), 1215; https://doi.org/10.3390/pharmaceutics17091215 - 18 Sep 2025

Cited by 1 | Viewed by 401

Abstract

Background/Objectives: This study explores the potential of the inducible G protein-coupled kinin B1 receptor (B1R) as a target for the diagnosis and treatment of prostate cancer (PCa) and aims to develop the first theranostic agent targeting hB1R for both molecular imaging and [...] Read more.

Background/Objectives: This study explores the potential of the inducible G protein-coupled kinin B1 receptor (B1R) as a target for the diagnosis and treatment of prostate cancer (PCa) and aims to develop the first theranostic agent targeting hB1R for both molecular imaging and radionuclide therapy. Methods: B1R expression was analyzed via qPCR and immunohistochemistry in human PCa cells and tissues specimens. A novel ⁶⁴Cu/NOTA-conjugated peptide analog of the potent B1R antagonist R954 was synthetized and evaluated in vitro and in vivo. Results: B1R was confirmed to be expressed (RNA, protein) by varying degrees in all PCa cell lines and tissues investigated, with protein level significantly correlating with tumor grades. This finding was supported by similar analyses from the TCGA and MSKCC databases. In vitro, the ⁶⁴Cu/NOTA-βAla-R954 conjugate showed nanomolar affinity/potency at hB1R, complete plasma stability over 24 h, significant cellular uptake (up to 33% of ID at 24 h), and dose-dependent anti-clonal growth effects. In vivo, the radioconjugate remained stable in circulation for up to 90 min and was primarily excreted intact via the kidneys following IV administration. Intravenous ⁶⁴Cu/NOTA-βAla-R954 (7.5 MBq) effectively detected subcutaneous PCa xenografts via µPET imaging in male athymic nude mice. At a single higher dose (65 MBq; 50 µg/kg), it significantly reduced tumor growth without observable toxicity. This antitumor effect was associated with increased apoptosis (active caspase-3) and reduced proliferation (Ki67), as shown by immunohistochemistry. In contrast, the nonradioactive ^NatCu/NOTA-βAla-R954 had no therapeutic effect at the same dose. Conclusions: Our findings provide proof-of-concept for the potential theranostic use of ⁶⁴Cu/NOTA-R954 in PCa, and potentially other types of B1R-positive solid cancers. Full article

(This article belongs to the Special Issue Cutting-Edge Drug Delivery and Nanomedicine: Innovations in Hybrid Systems, Theranostics and Targeted Therapies)

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19 pages, 3900 KB

Open AccessArticle

Industrial Sustainable Decrystallizing Formulation to Enhance Dissolution of Candesartan Cilexetil: Overcoming Limitations of Traditional Solid Dispersion Approaches

by Mohamed A. Ibrahim, Abdelrahman Y. Sherif and Doaa Hasan Alshora

Pharmaceutics 2025, 17(9), 1214; https://doi.org/10.3390/pharmaceutics17091214 - 17 Sep 2025

Viewed by 398

Abstract

Background/Objectives: Conventional solid dispersion methods face significant industrial limitations, including thermal degradation, residual organic solvents, and complex preparation processes. This study presents a novel decrystallizing formulation using poloxamer and propylene glycol that remains solid during storage but liquefies at physiological temperature (37 [...] Read more.

Background/Objectives: Conventional solid dispersion methods face significant industrial limitations, including thermal degradation, residual organic solvents, and complex preparation processes. This study presents a novel decrystallizing formulation using poloxamer and propylene glycol that remains solid during storage but liquefies at physiological temperature (37 °C). Methods: Decrystallizing formulations containing various poloxamer types (407 and 188) at different concentrations (5–25% w/w) were prepared and assessed for decrystallization temperature, decrystallization time, and drug solubility. The optimal formulation was further characterized using FTIR analysis, as well as in vitro liquefaction performance and dissolution studies. Finally, the industrial sustainability of the decrystallizing formulation was assessed against conventional methods. Results: Poloxamer 407 exhibited higher decrystallization temperature, longer decrystallization time, and superior solubilization capacity compared to Poloxamer 188. Maximum drug solubility (5.51 ± 0.08 mg/g) was achieved at 20% w/w of poloxamer 407 with a decrystallization temperature of 37 °C, and it took 216 s for decrystallization. FTIR spectroscopy confirmed hydrogen bonding interactions, which are responsible for temperature-dependent phase transitions. The decrystallizing formulation showed remarkable improvement in dissolution efficiency (80.6 ± 3.9%) compared to the raw drug (1.8 ± 0.8%), a physical mixture (11.1 ± 6.0%), and a marketed tablet (30.8 ± 2.2%). Conclusions: The current decrystallizing formulation offers a promising approach for improving the bioavailability of poorly water-soluble drugs and tackling the limitations of conventional methods. Moreover, it provides additional advantages in terms of industrial sustainability for continuous production compared to conventional approaches. Full article

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

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17 pages, 4531 KB

Open AccessArticle

Glycyrrhiza uralensis Polysaccharide Gold Nanoparticles as Antigen Carriers and Potential Adjuvant to DC Vaccines

by Yanan Zhao, Ming Song, Yilizilan Dilixiati, Shanshan Cai, Reyilanmu Maisaidi, Patanmu Aili, Jinyao Li, Lili Han and Adila Aipire

Pharmaceutics 2025, 17(9), 1213; https://doi.org/10.3390/pharmaceutics17091213 - 17 Sep 2025

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Abstract

Background: Cervical cancer is the fourth leading cause of death among women worldwide, with human papillomavirus (HPV) identified as a major contributing factor. This study investigates the immunostimulatory activity and antigen delivery efficiency of Glycyrrhiza uralensis polysaccharide gold nanoparticles (GUPS-AuNPs) and assesses [...] Read more.

Background: Cervical cancer is the fourth leading cause of death among women worldwide, with human papillomavirus (HPV) identified as a major contributing factor. This study investigates the immunostimulatory activity and antigen delivery efficiency of Glycyrrhiza uralensis polysaccharide gold nanoparticles (GUPS-AuNPs) and assesses the antitumor efficacy of an HPV dendritic cell (DC) vaccine using GUPS-AuNPs as a delivery system. Methods: GUPS-AuNPs were synthesized via a green reduction method and characterized using advanced techniques, including SEM, EDS, TEM, UV, and FT-IR spectroscopy. DCs served as the primary experimental model, with flow cytometry employed to evaluate the immunostimulatory activity and antigen delivery effectiveness of GUPS-AuNPs. Additionally, a TC-1 tumor-bearing mouse model was established to assess the immunostimulatory and antitumor effects of the HPV-DC vaccine facilitated by GUPS-AuNPs. Results: The synthesized GUPS-AuNPs exhibited a particle size of 120.77 ± 3.13 nm, a surface charge of −11.9 ± 2.1 mV, and excellent stability. Flow cytometry analysis demonstrated that GUPS-AuNPs significantly enhanced DC maturation and promoted T cell proliferation. Furthermore, antigen delivery experiments revealed that GUPS-AuNPs improved the antigen capture capabilities of DCs. Confocal imaging confirmed that GUPS-AuNPs extended the intracellular retention time of antigens. In vivo studies showed that the HPV-DC vaccine formulated with GUPS-AuNPs as carriers effectively suppressed tumor growth, elevated the populations of CD4⁺ T and CD8⁺ T cells in the spleen, and induced a robust antigen-specific immune response. Conclusions: GUPS-AuNPs effectively enhance DC maturation and antigen delivery, significantly boosting the adaptive immune response triggered by HPV vaccines and leading to the inhibition of tumor progression. This research introduces GUPS-AuNPs as a novel, safe, and efficient antigen delivery platform with promising potential for vaccine development. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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44 pages, 1527 KB

Open AccessReview

Targeting the Oral Mucosa: Emerging Drug Delivery Platforms and the Therapeutic Potential of Glycosaminoglycans

by Bruno Špiljak, Maja Somogyi Škoc, Iva Rezić Meštrović, Krešimir Bašić, Iva Bando and Ivana Šutej

Pharmaceutics 2025, 17(9), 1212; https://doi.org/10.3390/pharmaceutics17091212 - 17 Sep 2025

Viewed by 605

Abstract

Research into oral mucosa-targeted drug delivery systems (DDS) is rapidly evolving, with growing emphasis on enhancing bioavailability and precision targeting while overcoming the unique anatomical and physiological barriers of the oral environment. Despite considerable progress, challenges such as enzymatic degradation, limited mucosal penetration, [...] Read more.

Research into oral mucosa-targeted drug delivery systems (DDS) is rapidly evolving, with growing emphasis on enhancing bioavailability and precision targeting while overcoming the unique anatomical and physiological barriers of the oral environment. Despite considerable progress, challenges such as enzymatic degradation, limited mucosal penetration, and solubility issues continue to hinder therapeutic success. Recent advancements have focused on innovative formulation strategies—including nanoparticulate and biomimetic systems—to improve delivery efficiency and systemic absorption. Simultaneously, smart and stimuli-responsive materials are emerging, offering dynamic, environment-sensitive drug release profiles. One particularly promising area involves the application of glycosaminoglycans, a class of naturally derived polysaccharides with excellent biocompatibility, mucoadhesive properties, and hydrogel-forming capacity. These materials not only enhance drug residence time at the mucosal site but also enable controlled release kinetics, thereby improving therapeutic outcomes. However, critical research gaps remain: standardized, clinically meaningful mucoadhesion/permeation assays and robust in vitro–in vivo correlations are still lacking; long-term stability, batch consistency of GAGs, and clear regulatory classification (drug, device, or combination) continue to impede scale-up and translation. Patient-centric performance—palatability, mouthfeel, discreet wearability—and head-to-head trials versus standard care also require systematic evaluation to guide adoption. Overall, converging advances in GAG-based films, hydrogels, and nanoengineered carriers position oral mucosal delivery as a realistic near-term option for precision local and selected systemic therapies—provided the field resolves standardization, stability, regulatory, and usability hurdles. Full article

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

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15 pages, 1257 KB

Open AccessArticle

Amino Compound-Synthesized Gold Nanoparticles for SARS-CoV-2 Antigen Delivery

by Layane Souza Rego, Marianna Teixeira Pinho Favaro, Monica Josiane Rodrigues-Jesus, Robert Andreata-Santos, Luiz Mário Ramos Janini, Marcelo Martins Seckler, Luis Carlos de Souza Ferreira and Adriano Rodrigues Azzoni

Pharmaceutics 2025, 17(9), 1211; https://doi.org/10.3390/pharmaceutics17091211 - 17 Sep 2025

Viewed by 334

Abstract

Background: Gold nanoparticles (AuNPs) are a promising platform for vaccine antigen delivery due to their ability to stimulate both innate and adaptive immune responses. These effects depend strongly on physicochemical properties such as size, polydispersity, morphology, and surface charge, which are in turn [...] Read more.

Background: Gold nanoparticles (AuNPs) are a promising platform for vaccine antigen delivery due to their ability to stimulate both innate and adaptive immune responses. These effects depend strongly on physicochemical properties such as size, polydispersity, morphology, and surface charge, which are in turn determined by the synthesis method. While amino acids are often used as capping agents for AuNPs, their direct use as both reducing and stabilizing agents has been rarely investigated. Objectives: This study aimed to establish an ultrasound-assisted method for synthesizing AuNPs using amino compounds as both reducing and stabilizing agents, and assess their physicochemical characteristics, antigen-binding capacity, and immunogenicity. Methods: AuNPs were synthesized using L-cysteine, L-arginine, and cysteamine as dual reducing/stabilizing agents under ultrasonic conditions. The nanoparticles were combined with a recombinant receptor-binding domain (RBD) of SARS-CoV-2 and evaluated in mice for their ability to induce antibody responses. Results: The synthesized AuNPs exhibited hydrodynamic diameters ranging from 6.3 to 12.4 nm and zeta potentials from −40.5 to +36.5 mV, depending on the amino compound used. All formulations elicited robust anti-RBD IgG responses, but virus neutralization activity varied significantly. Notably, AuNP–arginine induced the strongest neutralizing response despite lower adsorption capacity and stability, suggesting that epitope preservation and antigen presentation quality were more decisive than antigen density. Conclusions: These findings underscore the importance of nanoparticle design in optimizing antigen presentation and highlight the potential of amino compound-synthesized AuNPs as effective antigen delivery vehicles for future vaccine development. Full article

(This article belongs to the Special Issue Application of Nanoparticles and Dendrimers for Treating Infectious Diseases)

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19 pages, 3561 KB

Open AccessArticle

Enhancing Oral Absorption of an Ester Prodrug by Coating Drug Crystals with Binary Lipid Systems and Evaluating the Influence of Compositions

by Xiaowei Dong, Tao Zhang, Hellen L. Moreno Sanchez, Jaylen C. Mans, Sung Hun Bae and Liangqiao Bian

Pharmaceutics 2025, 17(9), 1210; https://doi.org/10.3390/pharmaceutics17091210 - 17 Sep 2025

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Abstract

Background/Objectives: Prodrug strategies are a vital aspect of drug development, with ester prodrugs particularly notable for modifying parent drug properties through ester functional groups to enhance oral absorption. However, ester prodrugs are prone to hydrolysis by water and enzymes, making stability in [...] Read more.

Background/Objectives: Prodrug strategies are a vital aspect of drug development, with ester prodrugs particularly notable for modifying parent drug properties through ester functional groups to enhance oral absorption. However, ester prodrugs are prone to hydrolysis by water and enzymes, making stability in the gastrointestinal (GI) tract prior to absorption a key challenge. Few formulation strategies effectively address this degradation issue. We recently introduced binary lipid systems (BLS), comprising a lipid and a water-soluble surfactant only that form stable microemulsions. This study aimed to explore the application of BLS for enhancing the oral absorption of ester prodrugs by coating drug crystals with BLS in solid granules and study the impact of the compositions of BLS on oral absorption. Methods: Olmesartan medoxomil (OLM), a methyl ester prodrug of olmesartan (OL), was selected as a model drug. Various lipids were combined with TPGS to form BLS and used to prepare OLM solid granules containing OLM crystals. Results: Among the tested formulations, OLM MCM-TPGS granules significantly enhanced drug release and protected OLM from enzyme-mediated degradation in two-step dissolution studies with esterase. Pharmacokinetic and tissue distribution studies in rats confirmed that OLM MCM-TPGS granules improved oral absorption by 145% and increased tissue uptake compared to OLM powder. Conclusions: This approach overcomes solubility limitations when using lipids and surfactants as excipients, enabling high drug loading in solid dosage forms and expanding the utility of lipids and surfactants for water-insoluble drugs. This novel formulation strategy holds great potential for enhancing oral absorption of ester prodrugs, representing a significant advancement in formulation technologies and offering more effective and versatile drug delivery solutions. Full article

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

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18 pages, 2506 KB

Open AccessArticle

Salt Cocrystallization—A Method to Improve Solubility and Bioavailability of Dihydromyricetin

by Jingping Li, Xinke Chen, Yanan Liu and Caiwu Jiang

Pharmaceutics 2025, 17(9), 1209; https://doi.org/10.3390/pharmaceutics17091209 - 17 Sep 2025

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Abstract

Objectives: This study aimed to find salts with similar pharmacological effects designed as cocrystals to improve the aqueous solubility and bioavailability of dihydromyricetin (DMY). Methods: A salt-cocrystal solvate (DMY-CIP·C₂H₆O) of dihydromyricetin and ciprofloxacin hydrochloride (CIP) was successfully [...] Read more.

Objectives: This study aimed to find salts with similar pharmacological effects designed as cocrystals to improve the aqueous solubility and bioavailability of dihydromyricetin (DMY). Methods: A salt-cocrystal solvate (DMY-CIP·C₂H₆O) of dihydromyricetin and ciprofloxacin hydrochloride (CIP) was successfully prepared via solvent evaporation method, and further characterized using powder X-ray diffraction, thermal analysis, and infrared spectroscopy. The solubility, stability, bioavailability, and in vitro antimicrobial efficacy of the cocrystal were also studied. Results: The cocrystal could increase the solubility of DMY in water and greatly improve the absorption of DMY in vivo (8-fold enhancement in relative bioavailability). In addition, the in vitro antimicrobial efficacy of the cocrystal was comparable to that of CIP, which is a great improvement for DMY. However, due to the formation of cocrystals with salts, the humidity stability of DMY is reduced and it should not be stored in high-humidity environments. Conclusions: These findings demonstrate that cocrystallization with water-soluble salts represents an effective strategy for optimizing the pharmaceutical properties of poorly soluble compounds. Full article

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

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21 pages, 1382 KB

Open AccessArticle

Formulation and Comparative Characterization of SLNs and NLCs for Targeted Co-Delivery of Paclitaxel and Hydroxytyrosol Carboxylic Acid Esters Against Triple-Negative Breast Cancer

by Elena Peira, Simona Sapino, Daniela Chirio, Fabio Bucciol, Flavia Turku, Emanuela Calcio Gaudino, Giancarlo Cravotto, Chiara Riganti and Marina Gallarate

Pharmaceutics 2025, 17(9), 1208; https://doi.org/10.3390/pharmaceutics17091208 - 16 Sep 2025

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Abstract

Background: The management of triple-negative breast cancer (TNBC) remains a therapeutic challenge due to the presence of multidrug resistance (MDR) and hypoxia-induced chemoresistance, both of which substantially reduce the efficacy of conventional chemotherapy. Although certain natural compounds have shown the ability to modulate [...] Read more.

Background: The management of triple-negative breast cancer (TNBC) remains a therapeutic challenge due to the presence of multidrug resistance (MDR) and hypoxia-induced chemoresistance, both of which substantially reduce the efficacy of conventional chemotherapy. Although certain natural compounds have shown the ability to modulate these resistance mechanisms, their clinical application is hindered by poor solubility and limited bioavailability. Among such phenolic compounds, 7-hydroxytyrosol (HTyr)—a phenolic compound from olive oil and olive leaves—has been reported to modulate hypoxia-inducible factor-1 (HIF-1). Methods: In this study, we developed hyaluronic acid (HA)-decorated solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for the targeted and synergistic co-delivery of paclitaxel (PTX) and hydroxytyrosol carboxylic acid esters (C_n-HTyrCA), precursors that share the antioxidant biphenolic moiety with HTyr. Results: Among the formulations tested, SLNs of trilaurin (TL) exhibited the highest entrapment efficiency (EE%), optimal average particle size, Zeta potential, and good colloidal stability. Of the synthesized C_n-HTyrCA derivatives, C₈- and C₁₀-HTyrCA showed superior loading capacity. In vitro release profiles indicated a sustained drug release pattern for both nanoparticles. HA decoration led to a marked increase in particle size and induced a shift in surface charge, confirming successful decoration and suggesting enhanced targeting potential via HA-CD44 interaction. Cytotoxicity assays conducted on MDA-MB-231 cells showed that PTX-loaded TL-SLNs exerted enhanced antitumor activity, particularly when HA-decorated, and a synergistic effect was observed upon co-administration with SLNs loaded with C₈-HTyrCA. Conclusions: Overall, our findings support the potential of SLN as a promising strategy to overcome key resistance mechanisms in TNBC, enabling reduced chemotherapeutic dosing and improving therapeutic outcomes. Full article

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

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Pharmaceutics, Volume 17, Issue 9 (September 2025) – 149 articles

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