Pharmaceutics

16 pages, 373 KiB

Open AccessArticle

Stability and Dissolution Behavior Changes After Drug Compounding for Pediatric Cardiovascular Pharmacotherapy

by Jumpei Saito, Akimasa Yamatani, Yuna Kojima, Masayoshi Nakakuni, Kosuke Nakano, Kaoru Hirose, Hidefumi Nakamura, Takehisa Hanawa and Miki Akabane

Pharmaceutics 2025, 17(4), 535; https://doi.org/10.3390/pharmaceutics17040535 (registering DOI) - 19 Apr 2025

Abstract

Background: Compounding is performed to adjust dosages and support medication for children. In Japan, tablets are crushed, diluted with lactose, and stored in bottles or sachets until use, but the stability and impact on dissolution of the ingredients after crushing have not been [...] Read more.

Background: Compounding is performed to adjust dosages and support medication for children. In Japan, tablets are crushed, diluted with lactose, and stored in bottles or sachets until use, but the stability and impact on dissolution of the ingredients after crushing have not been evaluated. Methods: Using a database established by the National Center for Child Health and Development in collaboration with 11 medical facilities, the status of tablet crushing was investigated. Commonly compounded drugs were selected as the target drugs. The selected drugs were sieved through a 500 μm mesh after crushing and diluted with lactose hydrate. The stability at 25 ± 2 °C/60 ± 5% relative humidity and the dissolution of the ingredients were evaluated after storing them for up to 120 days under the following conditions: (I) stored in a closed polycarbonate bottle (closed), (II) bottle opened once a day (in-use), or (III) stored in a laminated cellophane and polyethylene sachet (laminated). The changes in the ingredient content and dissolution behavior were evaluated in accordance with the Japanese Pharmacopoeia. Results: Five cardiovascular drugs (amlodipine besylate, carvedilol, propranolol hydrochloride, hydrochlorothiazide, and tadalafil) were selected as target drugs. No more than 10% change in ingredient content was observed for all five formulations compared to day 0. In addition, no related substances (impurities) were detected at more than 0.01%. There was no change in the dissolution rate of the samples after 120 days of storage under each storage condition. Conclusions: The five cardiovascular drugs commonly compounded for children in Japan maintained their pharmaceutical quality after compounding, even after long-term storage. Full article

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

17 pages, 8542 KiB

Open AccessArticle

A Convenient Strategy for Studying Antibody Aggregation and Inhibition of Aggregation: Characterization and Simulation

by Yibo Guo, Xi Chen, Guchen Fang, Xuejun Cao and Junfen Wan

Pharmaceutics 2025, 17(4), 534; https://doi.org/10.3390/pharmaceutics17040534 (registering DOI) - 19 Apr 2025

Abstract

: Background/Objectives: Protein aggregation, particularly the aggregation of antibody-based drugs, has long been a significant challenge in downstream processes and formulation. While the inhibitory effects of excipients on aggregation have been extensively studied using early experimental characterization methods, complete formulation research requires [...] Read more.

: Background/Objectives: Protein aggregation, particularly the aggregation of antibody-based drugs, has long been a significant challenge in downstream processes and formulation. While the inhibitory effects of excipients on aggregation have been extensively studied using early experimental characterization methods, complete formulation research requires significant amounts of antibodies and time, resulting in high research costs. Methods: This study proposed a quick and small-scale position-restrained simulation method which elucidated the mechanism of the reversible self-association (RSA) of antibodies and the influence of excipients on RSA under different conditions. We also validated the rationality of rapid and small-scale simulations through long-term (>1 μs) and large-scale (>1,000,000 atoms) simulations. Results: Through combing with simple stability characterization, the effects of different excipients on monomer residual content and the trend shown with concentration changes after thermal incubation were found to be similar to those observed in the simulations. Additionally, the formulation proposed by the simulations was validated using experimental characterization. Conclusions: Simulations and experiments revealed the mechanism and showed consistent trends, providing better understanding for aggregation research. Full article

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

17 pages, 759 KiB

Open AccessArticle

Investigation of Nano Spray-Dried, Hyaluronic Acid-Modified Polymeric Micelles for Nasal Administration

by Bence Sipos, Levente Mayer, Mária Budai-Szűcs, Gábor Katona, Rita Ambrus and Ildikó Csóka

Pharmaceutics 2025, 17(4), 533; https://doi.org/10.3390/pharmaceutics17040533 (registering DOI) - 18 Apr 2025

Abstract

Background/Objectives: The combination of nanomedicine with nasal administration is of paramount importance in current research and development. Polymeric micelles coated with hyaluronic acid may be a suitable solution to enhance drug release and permeation whilst properly adhering to the nasal mucosa, increasing [...] Read more.

Background/Objectives: The combination of nanomedicine with nasal administration is of paramount importance in current research and development. Polymeric micelles coated with hyaluronic acid may be a suitable solution to enhance drug release and permeation whilst properly adhering to the nasal mucosa, increasing residence time. Methods: Solid state characterization included morphology and laser diffraction-based size analysis and X-ray powder diffraction. The characterization of dispersed polymeric micelles in aqueous media was performed based on dynamic light scattering and determining the solubility enhancement related factors such as encapsulation efficiency and thermodynamic solubility. In vitro nasal drug release and permeability studies were also conducted to characterize the different hyaluronic acid-modified polymeric micelles. Quantitative measurements were carried out via liquid chromatography. Results: Concentration dependence on hyaluronic acid was found during all measurements, with one formulation candidate overcoming the others. With a high yield above 80%, monodispersed particles were formulated with an approximately 4 µm particle size in uniform distribution and spherical morphology. The small micelle size (107.3 nm) in uniform manner led to a high encapsulation efficiency above 80% and released the drug amount above 70% in 15 min. High drug permeation was also achieved compared with the initial active substance by itself. Conclusions: A value-added polymeric micelle formulation was developed with rapid drug release and permeation kinetics alongside its high mucoadhesion. Full article

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

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24 pages, 6587 KiB

Open AccessArticle

Salicylic Acid-Mediated Silver Nanoparticle Green Synthesis: Characterization, Enhanced Antimicrobial, and Antibiofilm Efficacy

by Jingqing Zhang, Yuxu Chen, Yuanyu Xu, Zhimin Zhao and Xinjun Xu

Pharmaceutics 2025, 17(4), 532; https://doi.org/10.3390/pharmaceutics17040532 - 18 Apr 2025

Abstract

Objectives: Silver nanoparticles (AgNPs) were synthesized via an easy and rapid biogenic synthesis approach, utilizing the dual capabilities of salicylic acid as both a reducing and capping agent. Methods: The characterization of Salicylic Acid-Mediated Silver Nanoparticle (SA-AgNPs) was conducted using a variety of [...] Read more.

Objectives: Silver nanoparticles (AgNPs) were synthesized via an easy and rapid biogenic synthesis approach, utilizing the dual capabilities of salicylic acid as both a reducing and capping agent. Methods: The characterization of Salicylic Acid-Mediated Silver Nanoparticle (SA-AgNPs) was conducted using a variety of techniques, including ultraviolet-visible spectroscopy, dynamic light scattering, scanning electron microscopy combined with energy dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, as well as thermogravimetric analysis paired with differential scanning calorimetry. Results: SA-AgNPs demonstrated significant antibacterial properties against both Gram-positive (methicillin-resistant Staphylococcus epidermidis, Staphylococcus aureus, Cutibacterium acnes, methicillin-resistant Staphylococcus aureus) and Gram-negative (Escherichia coli), with minimum inhibitory concentrations (MICs) of 8, 9, 8, 4, and 6 μg/mL, respectively. At a concentration of 32 μg/mL, SA-AgNPs exhibited 99.9% killing efficiency against Escherichia coli (E. coli), Cutibacterium acnes (C. acnes), and methicillin-resistant Staphylococcus aureus (MRSA), within 4, 16, and 12 h, respectively. At the same concentration, SA-AgNPs effectively inhibited 95.61% of MRSA biofilm formation. SA-AgNPs induced the leakage of intracellular macromolecular substances by increasing the membrane permeability, which ultimately caused bacterial apoptosis. Conclusions: Overall, this study presents a fast and environmentally friendly approach for synthesizing SA-AgNPs, with potential applications as nano antibiotics antibacterial coatings for implantable medical devices and wound dressings. Full article

(This article belongs to the Special Issue Nanotechnology in Antibacterial Drug Delivery)

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20 pages, 2054 KiB

Open AccessArticle

Matrix Approach Assessment of Cabotegravir Drug–Drug Interactions with OAT1/OAT3 Substrates and UGT1A1/UGT1A9 Inhibitors Using Physiologically-Based Pharmacokinetic Modeling

by Helen Tracey, Simon T. Bate, Susan Ford, Parul Patel, Jackie Bloomer, Aarti Patel and Kunal S. Taskar

Pharmaceutics 2025, 17(4), 531; https://doi.org/10.3390/pharmaceutics17040531 - 18 Apr 2025

Abstract

Background/Objective: Cabotegravir (CAB), available as an oral tablet and as a long-acting (LA) nanosuspension for intramuscular injection, is approved as a combination therapy for the treatment, and as a monotherapy for the prevention, of HIV-1 infection. People living with HIV may receive multiple [...] Read more.

Background/Objective: Cabotegravir (CAB), available as an oral tablet and as a long-acting (LA) nanosuspension for intramuscular injection, is approved as a combination therapy for the treatment, and as a monotherapy for the prevention, of HIV-1 infection. People living with HIV may receive multiple concomitant medications, with the associated risk of drug–drug interactions (DDIs). CAB is an inhibitor of OAT1/OAT3 renal transporters and a substrate of the UDP-glucuronosyltransferase enzymes UGT1A1 and 1A9, in vitro. While the effect of induction of UGT1A1/UGT1A9 on CAB exposure had been investigated in the clinic, the effect of the risk of DDIs with CAB via inhibition of these enzymes, or as an inhibitor of OAT1/OAT3 transporters, had not been evaluated. Methods: A physiologically-based pharmacokinetic (PBPK) model was developed and verified for orally dosed CAB to investigate the DDI risks associated with CAB, using a matrix approach to extensively qualify the PBPK platform and the substrates and/or inhibitors of either OAT1/OAT3 or UGT1A1/UGT1A9. The effect of uncertainties in in vitro inhibition values for OAT1/OAT3 was assessed via sensitivity analysis. Results: A mean increase of less than 25% in systemic exposure for OAT1/OAT3 substrates was predicted, with the potential for an increase of up to 80% based on the sensitivity analysis. On co-dosing with UGT1A1/UGT1A9 inhibitors, the predicted mean increase in CAB exposure was within 11%. Conclusions: PBPK modelling indicated that clinically relevant DDIs are not anticipated with OAT1/3 substrates or UGT1A1/1A9 inhibitors and CAB. With maximal exposure of the LA formulation of CAB being lower than the oral, the results of these simulations can be extrapolated to LA injectable dosing. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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22 pages, 5552 KiB

Open AccessArticle

Conjugation of Glycine max (L.) Merrill Oligopeptide with Monosaccharides: A Novel Approach for Stability and Efficacy in Cosmeceutical Applications

by Wantida Chaiyana, Sudarat Jiamphun, Rewat Phongphisutthinant, Supakit Chaipoot and Pairote Wiriyacharee

Pharmaceutics 2025, 17(4), 530; https://doi.org/10.3390/pharmaceutics17040530 (registering DOI) - 17 Apr 2025

Abstract

Background/Objectives: Conjugation techniques are increasingly valued in food chemistry for enhancing sensory properties, nutritional profiles, and bioactivity, with potential applications in cosmeceuticals. This study aimed to investigate the potential of Glycine max (L.) Merrill oligopeptide–monosaccharide conjugates as active ingredients in cosmeceuticals, emphasizing [...] Read more.

Background/Objectives: Conjugation techniques are increasingly valued in food chemistry for enhancing sensory properties, nutritional profiles, and bioactivity, with potential applications in cosmeceuticals. This study aimed to investigate the potential of Glycine max (L.) Merrill oligopeptide–monosaccharide conjugates as active ingredients in cosmeceuticals, emphasizing their biological activities and stability. Methods: G. max isolate was prepared and subsequently hydrolyzed using alcalase to obtain the oligopeptide (OP). The OP was then conjugated with allulose (AL) or mannose (MN) through a controlled humid-dry heating process to produce the conjugates, OPA and OPM, respectively. Their biological activities, including antioxidant, anti-tyrosinase, anti-collagenase, anti-elastase, and anti-hyaluronidase properties, were assessed and compared to the individual components. Additionally, the irritation potential was evaluated using the hen’s egg test on chorioallantoic membrane (HET-CAM). The stability was examined under varying pH levels, temperatures, and light conditions based on their biological activity profiles. Results: OPA demonstrated the highest antioxidant activity, showing the lowest DPPH^• IC₅₀ value of 198.6 ± 2.7 µg/mL along with a strong ferric reducing power of 1.37 ± 0.04 µg FeSO₄/g sample. Besides, OPM showed superior tyrosinase inhibition on both L-tyrosine and L-DOPA substrates, highlighting its potential for skin whitening. Both OPA and OPM significantly enhanced collagenase inhibition, supporting their anti-aging potential. All samples were non-irritating in the HET-CAM test. The conjugates (OPA and OPM) demonstrated enhanced stability against pH, heat, and light compared to OP, AL, and MN. Conclusions: Oligopeptide–monosaccharide conjugation not only improved bioactivity but also enhanced biological stability, suggesting their potential for use in cosmeceutical applications. Full article

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

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35 pages, 4183 KiB

Open AccessReview

New Direction in Antimicrobial Delivery System: Preparation and Applications of Hydrogel Microspheres

by Jiapeng Li, Guotao Wei, Yihao Yuan, Ling Wang, Miaohan Qiu, Bo Li, Ruofei Ma, Jiawei Wu and Ziyi Shen

Pharmaceutics 2025, 17(4), 529; https://doi.org/10.3390/pharmaceutics17040529 - 17 Apr 2025

Abstract

Antimicrobial delivery systems have undergone extensive development, yet conventional carriers still exhibit limitations such as low loading capacity, inadequate controlled release mechanisms, and cytotoxicity. Recent studies have increasingly demonstrated the potential of Hydrogel Microspheres (HMSs) for antimicrobial delivery. These microspheres exhibit small dimensions, [...] Read more.

Antimicrobial delivery systems have undergone extensive development, yet conventional carriers still exhibit limitations such as low loading capacity, inadequate controlled release mechanisms, and cytotoxicity. Recent studies have increasingly demonstrated the potential of Hydrogel Microspheres (HMSs) for antimicrobial delivery. These microspheres exhibit small dimensions, high drug-loading capacity, and the ability to achieve deep-targeted delivery, complemented by adjustable physicochemical properties and biocompatibility that create favorable conditions for antimicrobial transportation. This review systematically examines HMS preparation strategies, characteristic properties, transported antimicrobials, and therapeutic applications. Particular emphasis is placed on critical preparation parameters governing HMS performance, especially those influencing drug delivery dynamics. We conclude by addressing current challenges and proposing actionable strategies for material optimization and clinical translation. This work aims to advance HMS-based antimicrobial delivery systems for more effective infection control. Full article

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

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20 pages, 1129 KiB

Open AccessReview

Harnessing Extracellular Vesicles for Targeted Drug Delivery in Ovarian Cancer

by Jang-Hyuk Yun, Yoo Rim Noh, Seongkyeong Yoo, Soohyun Park, Yunsup Choi, Jiyeon An and Iljin Kim

Pharmaceutics 2025, 17(4), 528; https://doi.org/10.3390/pharmaceutics17040528 - 17 Apr 2025

Abstract

Ovarian cancer remains one of the most lethal gynecologic malignancies, primarily due to late-stage diagnosis, high recurrence rates, and the development of chemoresistance. Although targeted therapies have improved patient outcomes, their efficacy is often limited by off-target toxicity and acquired drug resistance. Extracellular [...] Read more.

Ovarian cancer remains one of the most lethal gynecologic malignancies, primarily due to late-stage diagnosis, high recurrence rates, and the development of chemoresistance. Although targeted therapies have improved patient outcomes, their efficacy is often limited by off-target toxicity and acquired drug resistance. Extracellular vesicles (EVs), nanoscale vesicles naturally released by cells, have emerged as promising carriers for precision drug delivery. This review provides a comprehensive overview of recent advances in EV-based therapeutic strategies for ovarian cancer, including the delivery of chemotherapeutic agents, nucleic acid therapeutics, and immunomodulatory molecules. We further explore innovative engineering approaches to enhance targeting specificity, such as surface modification, cell source selection, biomaterial integration, and magnetic nanoparticle-assisted delivery. Key translational challenges in bringing EV-based therapies to clinical application are also addressed. Collectively, these insights underscore the transformative potential of EV-based platforms in advancing targeted and personalized treatment for ovarian cancer. Full article

(This article belongs to the Special Issue Extracellular Vesicle-Based Delivery System for Cancer and Neurodegenerative Disease Treatment)

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25 pages, 6293 KiB

Open AccessArticle

A Fungistatic Strategy Using a Shear-Thinning pH-Responsive CMCS-OHA-Lp/Lr Hydrogel for Vulvovaginal Candidiasis

by Yuanmin Zhao, Xiu Yang, Jiale Han, Chaoqi Huang, Mengliu Shao, Yan Yang, Qingliang Yang and Gensheng Yang

Pharmaceutics 2025, 17(4), 527; https://doi.org/10.3390/pharmaceutics17040527 - 17 Apr 2025

Abstract

Background: Vulvar vaginal candidiasis (VVC) is a type of vaginitis resulting from a Candida infection of the vaginal mucosa. Traditional treatments using antibiotics often lead to resistance and disrupt the vaginal microenvironment, causing ongoing problems for patients. In response to these challenges, [...] Read more.

Background: Vulvar vaginal candidiasis (VVC) is a type of vaginitis resulting from a Candida infection of the vaginal mucosa. Traditional treatments using antibiotics often lead to resistance and disrupt the vaginal microenvironment, causing ongoing problems for patients. In response to these challenges, this study introduces a multifunctional intelligent responsive probiotic hydrogel designed to modulate the vaginal microecological environment to combat Candida albicans infection. Methods: The innovative CMCS-OHA-Lp/Lr hydrogel was formulated using oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CMCS) as carriers, incorporating Lactobacillus plantarum (Lp) and Lactobacillus rhamnosus (Lr) as active components. Comprehensive characterization of the CMCS-OHA-Lp/Lr hydrogel revealed its chemical structure, rheological properties, rapid self-healing properties, gel degradation, and the release of lactobacilli in vitro. Results: The findings demonstrated that the hydrogel’s cross-linking conferred significant physical properties. In addition, the in vitro release study of Lactobacillus showed that the cumulative release rates of Lp and Lr in the medium with pH 5.5 were 83.50 ± 2.70% and 73.31 ± 2.22%, which proved the pH-responsive release characteristics of probiotics in acidic vaginal environments. Furthermore, the storage activity of Lactobacillus indicated that the survival rates of the CMCS-OHA-Lp and CMCS-OHA-Lr hydrogels were 86.90 ± 0.20% and 85.50 ± 0.56%, respectively, proving that encapsulation within the hydrogels significantly enhanced the storage stability of probiotics. In vivo studies further confirmed that the hydrogel alleviated vulval edema symptoms and reduced C. albicans colonies in the vagina, thereby mitigating vaginal inflammation. Conclusions: In conclusion, this pH-responsive, self-healing, and shear-thinning hydrogel offers a promising approach for the clinical treatment of VVC and serves as an effective probiotic delivery vehicle. Full article

(This article belongs to the Special Issue Application of Stimuli-Sensitive Hydrogel for the Treatment of Human and Animal Diseases)

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22 pages, 45418 KiB

Open AccessArticle

Development of an Ophthalmic Hydrogel to Deliver MG53 and Promote Corneal Wound Healing

by Heather L. Chandler, Sara Moradi, Spencer W. Green, Peng Chen, Christopher Madden, Luxi Zhang, Zhentao Zhang, Ki Ho Park, Jianjie Ma, Hua Zhu and Katelyn E. Swindle-Reilly

Pharmaceutics 2025, 17(4), 526; https://doi.org/10.3390/pharmaceutics17040526 - 16 Apr 2025

Abstract

Background/Objective: A clinical need exists for more effective therapeutics and sustained drug delivery systems to promote ocular surface healing. This study tested the hypothesis that a novel biodegradable, thermoresponsive hydrogel loaded with the human recombinant (rh)MG53 protein, which we have demonstrated to promote [...] Read more.

Background/Objective: A clinical need exists for more effective therapeutics and sustained drug delivery systems to promote ocular surface healing. This study tested the hypothesis that a novel biodegradable, thermoresponsive hydrogel loaded with the human recombinant (rh)MG53 protein, which we have demonstrated to promote corneal healing without fibrosis, would exhibit safety and biocompatibility in vitro and in vivo. Methods: Hydrogel optimization was performed based on varying concentrations of poloxamer 407, poloxamer 188, and hydroxypropyl methylcellulose. Hydrogels were characterized and potential toxicity was evaluated in vitro in cultured corneal epithelium, fibroblasts, and endothelium. In vivo safety and tolerability were assessed in mice and hydrogels were used to evaluate corneal healing following alkali injury. Results: The optimized hydrogel formulation did not result in any detrimental changes to the corneal cells and released functional rhMG53 protein for at least 24 h. In vivo rhMG53-loaded hydrogels improved re-epithelialization, reduced stromal opacification and vascularization, and promoted corneal nerve density. Mechanistically, rhMG53 reduced vascular endothelial cell migration and tube formation by inhibiting pSTAT3 signaling. Conclusions: Taken together, our poloxamer-based thermoresponsive hydrogel effectively released rhMG53 protein and enhanced multiple corneal healing outcomes. Full article

(This article belongs to the Special Issue Advances in Drug Delivery Systems for the Treatment of Chronic Wound Healing)

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2 pages, 470 KiB

Open AccessCorrection

Correction: Donthi et al. Dasatinib-Loaded Topical Nano-Emulgel for Rheumatoid Arthritis: Formulation Design and Optimization by QbD, In Vitro, Ex Vivo, and In Vivo Evaluation. Pharmaceutics 2023, 15, 736

by Mahipal Reddy Donthi, Ranendra Narayan Saha, Gautam Singhvi and Sunil Kumar Dubey

Pharmaceutics 2025, 17(4), 525; https://doi.org/10.3390/pharmaceutics17040525 - 16 Apr 2025

Abstract

In the original publication [...] Full article

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16 pages, 10030 KiB

Open AccessArticle

Population Pharmacokinetic Modeling of Total and Unbound Pamiparib in Glioblastoma Patients: Insights into Drug Disposition and Dosing Optimization

by Charuka Wickramasinghe, Seongho Kim, Yuanyuan Jiang, Xun Bao, Yang Yue, Jun Jiang, Amy Hong, Nader Sanai and Jing Li

Pharmaceutics 2025, 17(4), 524; https://doi.org/10.3390/pharmaceutics17040524 - 16 Apr 2025

Abstract

Background: This study aimed to develop a population pharmacokinetic (PK) model that characterized the plasma concentration–time profiles of the total and unbound pamiparib, a PARP inhibitor, in glioblastoma patients and identified patient factors influencing the PK. Methods: The total and unbound pamiparib plasma [...] Read more.

Background: This study aimed to develop a population pharmacokinetic (PK) model that characterized the plasma concentration–time profiles of the total and unbound pamiparib, a PARP inhibitor, in glioblastoma patients and identified patient factors influencing the PK. Methods: The total and unbound pamiparib plasma concentration data were obtained from 41 glioblastoma patients receiving 60 mg of pamiparib twice daily. Nonlinear mixed-effects modeling was performed using Monolix (2024R1) to simultaneously fit the total and unbound drug plasma concentration data. The covariate model was developed by covariate screening using generalized additive modeling followed by stepwise covariate modeling. Model simulations were performed following oral doses of 10–60 mg BID. Results: The total and unbound pamiparib plasma concentration–time profiles were best described by a one-compartment model with first-order absorption and elimination. Creatinine clearance and age were the significant covariates on the apparent volume of distribution (V/F) and apparent clearance (CL/F), respectively, explaining ~22% and ~5% of IIV of V/F and CL/F. Population estimates of the absorption rate constant (Ka), V/F, CL/F, and unbound fraction for the total drug were 1.58 h⁻¹, 44 L, 2.59 L/h, and 0.041. Model simulations suggested that doses as low as 20 mg BID may be adequate for therapeutic effects in a general patient population, assuming that a target engagement ratio (i.e., unbound C_ss,min/IC50) of 5 or above is sufficient for full target engagement. Conclusions: The total and unbound pamiparib plasma PK are well characterized by a linear one-compartment model, with creatinine clearance as the significant covariate on V/F. Model simulations support further clinical investigation into dose reduction to optimize the benefit-to-risk ratio of pamiparib, particularly in combination therapies. Full article

(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)

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21 pages, 3534 KiB

Open AccessArticle

Chitosan-Stabilized Lipid Vesicles with Indomethacin for Modified Release with Prolonged Analgesic Effect: Biocompatibility, Pharmacokinetics and Organ Protection Efficacy

by Angy Abu Koush, Eliza Gratiela Popa, Beatrice Rozalina Buca, Cosmin Gabriel Tartau, Iulian Stoleriu, Ana-Maria Raluca Pauna, Liliana Lacramioara Pavel, Paula Alina Fotache and Liliana Mititelu Tartau

Pharmaceutics 2025, 17(4), 523; https://doi.org/10.3390/pharmaceutics17040523 - 16 Apr 2025

Abstract

Background/Objectives: Indomethacin (IND) is a widely used non-steroidal anti-inflammatory drug (NSAID) effective in managing pain and inflammation. However, its therapeutic use is often limited by gastrointestinal irritation and low bioavailability. This study aimed to evaluate the biocompatibility, release kinetics, and analgesic potential [...] Read more.

Background/Objectives: Indomethacin (IND) is a widely used non-steroidal anti-inflammatory drug (NSAID) effective in managing pain and inflammation. However, its therapeutic use is often limited by gastrointestinal irritation and low bioavailability. This study aimed to evaluate the biocompatibility, release kinetics, and analgesic potential of IND-loaded chitosan (CHIT)-stabilized lipid vesicles (IND-ves) in comparison to free IND, focusing on their in vivo effects and impact on somatic nociceptive reactivity in mice. Methods: IND-ves were prepared using a molecular droplet self-assembly technique, followed by CHIT coating to enhance stability and control drug release. Mice were administered either free IND or IND-ves, and various physiological parameters, including liver and kidney function, oxidative stress markers, immune cell activity, and histopathological changes in key organs, were assessed. Plasma drug release kinetics and analgesic effects were evaluated using the tail-flick test. Results: Both IND and IND-ves demonstrated good biocompatibility, with no significant changes in hematological, biochemical, or immunological profiles. IND-ves exhibited a sustained release profile, with drug release initiating at 30 min and peaking at 3 h, while free IND displayed a rapid release and potential gastric mucosal damage. IND-ves did not induce oxidative stress or inflammation and maintained organ integrity, particularly protecting against gastric injury. Additionally, the prolonged release profile of IND-ves contributed to extended analgesic effects in the tail-flick test. Conclusions: CHIT-stabilized lipid vesicles offer a promising drug delivery system for IND, enhancing drug release, prolonging analgesic efficacy, and minimizing gastrointestinal irritation. These findings suggest that IND-ves could serve as a safer and more effective alternative for NSAID therapy. Full article

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

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10 pages, 1976 KiB

Open AccessArticle

In Vitro Toxicity of Cetalkonium Chloride on Corneal Epithelial Cells

by Joo-Hee Park and Choul Yong Park

Pharmaceutics 2025, 17(4), 522; https://doi.org/10.3390/pharmaceutics17040522 - 16 Apr 2025

Abstract

Objective: To investigate the toxicity of cetalkonium chloride (CKC) on primary cultured human corneal epithelial cells (HCECs). Methods: HCECs were subjected to various concentrations (0.03125 × 10⁻⁴ to 2.0 × 10⁻⁴% (w/v)) of CKC for durations [...] Read more.

Objective: To investigate the toxicity of cetalkonium chloride (CKC) on primary cultured human corneal epithelial cells (HCECs). Methods: HCECs were subjected to various concentrations (0.03125 × 10⁻⁴ to 2.0 × 10⁻⁴% (w/v)) of CKC for durations ranging from 24 to 72 h. Cell viability was evaluated using the CCK-8 kit along with live and dead cell staining. Intracellular reactive oxygen species (ROS) levels were measured 20 min following CKC exposure. Observations of changes in cell morphology, cytoplasmic actin filaments, and mitochondrial distribution were conducted using immunocytochemistry and MitoTracker assays. Protein expression levels related to cell survival pathways, including mTOR, ERK, Akt, Bcl-xL, and BAX, were examined via Western blot analysis. Results: CKC exhibited dose-dependent toxicity in HCECs. Exposure to CKC concentrations below 0.125 × 10⁻⁴% resulted in no significant decrease in HCEC viability for up to 72 h. Conversely, exposure to CKC at concentrations of 1.0 × 10⁻⁴% or higher led to significantly decreased HCEC viability. Following exposure to higher concentrations of CKC, elevated levels of intracellular ROS and LDH release were observed. This toxicity was further characterized by decreased levels of phosphorylated mTOR, phosphorylated Akt, phosphorylated ERK, and Bcl-xL, as well as an increase in BAX expression. As the CKC concentration increased, HCECs decreased in size, and mitochondria displayed a loss of characteristic punctate staining. Conclusions: Our findings indicated that exposure to CKC caused significant toxicity in HCECs, which varied with concentration and duration of exposure. This toxicity was associated with an increase in ROS, mitochondrial alterations, and a decline in activity of the cell survival pathways. Full article

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22 pages, 15268 KiB

Open AccessArticle

Pickering Double Emulsions Stabilized with Chitin Nanocrystals and Myristic Acid-Functionalized Silica Nanoparticles for Curcumin and Chlorogenic Acid Co-Delivery

by Javier Paredes-Toledo, Javier Herrera, Javier Morales, Paz Robert, Joaquín Gómez-Estaca and Begoña Giménez

Pharmaceutics 2025, 17(4), 521; https://doi.org/10.3390/pharmaceutics17040521 - 16 Apr 2025

Abstract

Background/Objectives: Double emulsions (DEs) enable the simultaneous encapsulation of water-soluble and oil-soluble bioactive compounds. Their stability can be enhanced through Pickering stabilization, where solid particles are irreversibly anchored at the interfaces, forming a steric barrier. This study aimed to evaluate the release [...] Read more.

Background/Objectives: Double emulsions (DEs) enable the simultaneous encapsulation of water-soluble and oil-soluble bioactive compounds. Their stability can be enhanced through Pickering stabilization, where solid particles are irreversibly anchored at the interfaces, forming a steric barrier. This study aimed to evaluate the release behavior of curcumin and chlorogenic acid (CA) in Pickering DEs formulated with chitin nanocrystals (ChNCs) stabilizing the outer interface (DE-ChNC) and both ChNCs and myristic acid-functionalized silica nanoparticles (SNPs-C14) stabilizing the outer and inner interfaces (DE-ChNC-C14) under in vitro gastrointestinal digestion. Methods: The optimal homogenization parameters (time and speed) for stabilizing the external interface with ChNCs were determined using a statistical design. Pickering DEs were characterized (droplet size and size distribution, microstructure, creaming, encapsulation efficiency and stability, rheological behavior) and subjected to the INFOGEST digestion method. Results: ChNCs effectively maintained the droplet size, microstructure, and ζ-potential, preventing coalescence and creaming while enhancing viscosity and gel-like behavior, contributing to improved physical stability. The CA encapsulation efficiency was higher in DE-ChNC-C14 (91.4%) than in DE-ChNC (45.0%) due to the presence of SNPs-C14 at the inner interface, which improved CA retention during storage. CA was gradually released from DE-ChNC-C14 throughout digestion, with bioaccessibility similar to that of the control DE (stabilized with conventional emulsifiers; ~60%). Curcumin bioaccessibility in the Pickering DEs was relatively high (~40%) but lower than in the control DE, as the ChNCs reduced lipid digestion and curcumin bioaccessibility. Conclusions: ChNCs and SNPs-C14 effectively stabilized the outer and inner interfaces of DEs, enabling the simultaneous release of water-soluble and oil-soluble bioactives with health benefits. Full article

(This article belongs to the Special Issue Recent Advances in Nanodelivery Systems for Plant and Food Derivatives, 2nd Edition)

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17 pages, 2217 KiB

Open AccessReview

Targeting DLL3: Innovative Strategies for Tumor Treatment

by Hui Wang, Tong Zheng, Dan Xu, Chao Sun, Daqing Huang and Xiongxiong Liu

Pharmaceutics 2025, 17(4), 520; https://doi.org/10.3390/pharmaceutics17040520 - 16 Apr 2025

Abstract

Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with [...] Read more.

Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with therapies targeting DLL3 for cancer treatment. The biological characteristics of DLL3 and its role in the Notch signaling pathway are introduced first, delving into the role of DLL3 in tumorigenesis and cancer progression. Next, current therapeutic approaches targeting DLL3 are described, including antibody–drug conjugates, T cell engagers, chimeric antigen receptor T cells, and radiopharmaceutical therapy, highlighting their effectiveness and safety in clinical trials. Despite the promising prospects, difficulties remain in the use of DLL3 as a therapeutic target due to tumor heterogeneity, the development of resistance, potential adverse effects, and barriers to patient stratification. Therefore, the potential of combination therapies, the use of innovative drug delivery systems, and ongoing clinical trial advancements are also discussed. Finally, the potential of DLL3-targeted therapies is summarized, highlighting the importance of multidisciplinary research to guide the clinical application and optimization of this emerging treatment strategy. These approaches might provide new therapeutic options, potentially starting a new era in cancer treatment. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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21 pages, 4883 KiB

Open AccessArticle

Osteogenic and Antibacterial Response of Levofloxacin-Loaded Mesoporous Nanoparticles Functionalized with N-Acetylcysteine

by Alberto Polo-Montalvo, Natividad Gómez-Cerezo, Mónica Cicuéndez, Blanca González, Isabel Izquierdo-Barba and Daniel Arcos

Pharmaceutics 2025, 17(4), 519; https://doi.org/10.3390/pharmaceutics17040519 - 15 Apr 2025

Abstract

Background/Objectives: Bone infection is one of the most prevalent complications in orthopedic surgery. This pathology is mostly due to bacterial pathogens, among which S. aureus stands out. The formation of a bacterial biofilm makes systemic treatment with antibiotics ineffective. Herein we propose [...] Read more.

Background/Objectives: Bone infection is one of the most prevalent complications in orthopedic surgery. This pathology is mostly due to bacterial pathogens, among which S. aureus stands out. The formation of a bacterial biofilm makes systemic treatment with antibiotics ineffective. Herein we propose a nanosystem composed of mesoporous bioactive glass nanoparticles (MBGN) loaded with levofloxacin and functionalized with N-acetylcysteine (NAC), aiming to offer an alternative to current treatments. These nanoparticles would present antibacterial activity able to disintegrate the biofilm and regenerate the peri-implantar osseous tissue. Methods: MBGN of composition 82.5 SiO₂—17.5 CaO have been synthesized, loaded with levofloxacin, and functionalized with NAC (MBGN-L-NAC). The antimicrobial activity against mature S. aureus biofilms and bioactivity of the nanosystem have been evaluated, as well as its biocompatibility and ability to promote murine pre-osteoblastic MC3T3-E1 differentiation. Results: MBGNs exhibited high surface areas and radial mesoporosity, allowing up to 23.1% (% w/w) of levofloxacin loading. NAC was covalently bound keeping the mucolytic thiol group, SH, available. NAC and levofloxacin combination enhances the activity against S. aureus by disrupting mature biofilm integrity. This nanosystem was biocompatible with pre-osteoblasts, enhanced their differentiation towards a mature osteoblast phenotype, and promoted bio-mimetic mineralization under in vitro conditions. MBGN-L-NAC nanoparticles induced greater osteogenic response of osteoprogenitor cells through increased alkaline phosphatase expression, increased mineralization, and stimulation of pre-osteoblast nodule formation. Conclusions: MBGN-L-NAC exhibits a more efficient antibacterial activity due to the biofilm disaggregation exerted by NAC, which also contributes to enhance the osteoinductive properties of MBGNs, providing a potential alternative to conventional strategies for the management of bone infections. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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17 pages, 8557 KiB

Open AccessArticle

Intracellular Protein Binding of Zr-89 Oxine Cell Labeling for PET Cell Tracking Studies

by Emmanuel Nyong, Yutaka Kurebayashi, Kingsley O. Asiedu, Peter L. Choyke and Noriko Sato

Pharmaceutics 2025, 17(4), 518; https://doi.org/10.3390/pharmaceutics17040518 - 15 Apr 2025

Abstract

Background/Objectives: ⁸⁹Zr-oxine is an ex vivo cell labeling agent that enables cells to be tracked in vivo by positron emission tomography (PET) over a period of up to two weeks. To better understand where ⁸⁹Zr-oxine binds within cellular components, factors [...] Read more.

Background/Objectives: ⁸⁹Zr-oxine is an ex vivo cell labeling agent that enables cells to be tracked in vivo by positron emission tomography (PET) over a period of up to two weeks. To better understand where ⁸⁹Zr-oxine binds within cellular components, factors affecting labeling and intracellular distribution of ⁸⁹Zr were examined. Methods: Mouse primary T cells, natural killer cells, dendritic cells, and monocytes, and cell lines EL4 (mouse lymphoma), DC2.4 (mouse dendritic cell), Kit225K6 (human T cell leukemia) and MC38 (mouse colon adenocarcinoma) were labeled with ⁸⁹Zr-oxine or ¹¹¹In-oxine and protein binding within the cellular compartments, the labeling thresholds, and radioactivity retention were subsequently determined. Results: Cell incorporation of ⁸⁹Zr-oxine (27.8–71.8 kBq/10⁶ cells) positively correlated with cellular size and protein mass. Most (>97%) ⁸⁹Zr was protein-bound and primarily localized in the cytoplasm, membrane, and nuclear fractions (>81%) with distribution patterns varying by cell type. By contrast, ¹¹¹In-oxine showed lower protein-binding activity of approximately 59–65%, with 62–65% of ¹¹¹In localized in the cytoplasm. Autoradiography of electrophoresed subcellular fractionated cell samples indicated stable binding by ⁸⁹Zr-oxine to proteins in all subcellular fractions but unstable protein binding by ¹¹¹In. Saturation studies showed that ⁸⁹Zr-oxine labeling was saturable, and further labeling reduced cellular retention. Biodistribution of dendritic cells labeled with either ⁸⁹Zr-oxine or ¹¹¹In-oxine indicated greater retention of ⁸⁹Zr in the labeled cells in vivo than ¹¹¹In. Conclusions: ⁸⁹Zr-oxine stably binds many intracellular proteins and shows much higher and more stable protein binding than ¹¹¹In-oxine. Intracellular protein binding of ⁸⁹Zr accounts for the ability of ⁸⁹Zr-oxine labeling to successfully track cells in vivo long-term on PET. Full article

(This article belongs to the Section Gene and Cell Therapy)

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18 pages, 1541 KiB

Open AccessArticle

Stability and Efficacy of Mucoadhesive Eye Drops Containing Olopatadine HCl: Physicochemical, Functional, and Preclinical In Vivo Assessment

by Anđelka Račić, Veljko Krstonošić, Ana Micov, Uroš Pecikoza, Vladimir Dobričić, Erna Turković and Danina Krajišnik

Pharmaceutics 2025, 17(4), 517; https://doi.org/10.3390/pharmaceutics17040517 - 15 Apr 2025

Abstract

Background: The incorporation of polymers into drug delivery vehicles has been shown to be an effective strategy to prolong the residence time of active ingredients in the precorneal tear film and to increase ocular bioavailability. Objectives: The aim of this study was to [...] Read more.

Background: The incorporation of polymers into drug delivery vehicles has been shown to be an effective strategy to prolong the residence time of active ingredients in the precorneal tear film and to increase ocular bioavailability. Objectives: The aim of this study was to develop novel, viscous eye drops containing olopatadine (OCH) as the active ingredient, polysaccharides hydroxypropyl guar gum (HPG), and sodium hyaluronate (SH), individually, and in combination as functional polymers. Methods: Viscous eye drops containing 0.1% OCH in combination with HPG (0.25%) and SH (0.4%), were prepared and evaluated for their physicochemical properties, rheological behavior, mucoadhesion, and preliminary stability. A novel rheological method was used to evaluate the resistance of the eye drops under simulated blinking conditions. In vivo efficacy was evaluated using an ocular itch test in mice to compare the formulations with a commercial product. Results: The formulations remained stable and transparent, with physicochemical parameters within acceptable ranges. Rheological studies confirmed pseudoplastic flow, with the HPG-SH combination exhibiting enhanced viscosity and shear-thinning properties for prolonged retention in the eye. Mucoadhesion was highest in SH-HPG formulations. During simulated blinking cycles, eye drops containing a combination of SH and HPG polymers fully regained their initial viscosity during the resting periods. Preliminary stability studies indicate that the formulated eye drops exhibit satisfactory physicochemical stability under various storage conditions. In vivo, OCH-SH and OCH-HPG-SH drops provided prolonged antipruritic and analgesic effects compared to the reference product. Conclusions: Polysaccharide-based innovative formulations improve OCH retention, enhancing therapeutic efficacy and patient compliance in the treatment of allergic conjunctivitis. Full article

(This article belongs to the Special Issue Biomedical Applications: Advances in Bioengineering and Drug Delivery)

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