Pharmaceutics

2 pages, 528 KiB

Open AccessCorrection

Correction: Zaman et al. Synthesis and Evaluation of Thiol-Conjugated Poloxamer and Its Pharmaceutical Applications. Pharmaceutics 2021, 13, 693

by Muhammad Zaman, Sadaf Saeed, Rabia Imtiaz Bajwa, Muhammad Shafeeq Ur Rahman, Saeed Ur Rahman, Muhammad Jamshaid, Muhammad F. Rasool, Abdul Majeed, Imran Imran, Faleh Alqahtani, Sultan Alshehri, Abdullah F. AlAsmari, Nemat Ali and Mohammed S. Alasmari

Pharmaceutics 2024, 16(5), 690; https://doi.org/10.3390/pharmaceutics16050690 - 20 May 2024

Viewed by 692

Abstract

In the original publication, there was a mistake in one author name, Mohammed Alasmari should be Mohammed S [...] Full article

(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)

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12 pages, 1602 KiB

Open AccessArticle

Development of a Web Application for Simulating Plasma Drug Concentrations in Patients with Zolpidem Intoxication

by Hwa Jun Cha, Sungpil Han, Kwan Cheol Pak and Hyungsub Kim

Pharmaceutics 2024, 16(5), 689; https://doi.org/10.3390/pharmaceutics16050689 - 20 May 2024

Viewed by 1131

Abstract

Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) [...] Read more.

Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) model was established using digitized data obtained from twenty-three healthy volunteers after a single oral administration of zolpidem. Based on the final PK model, a web application was developed using open-source R packages such as rxode2, nonmem2rx, and shiny. The final model was a one-compartment model with first-order absorption and elimination with PK parameters, including clearance (CL, 16.9 L/h), absorption rate constant (K_a, 5.41 h⁻¹), volume of distribution (V_d, 61.7 L), and lag time (ALAG, 0.394 h). Using the established population PK model in the current study, we developed a web application that enables users to simulate plasma zolpidem concentrations and visualize their profiles. This user-friendly web application may provide essential clinical information to physicians, ultimately helping in the management of patients with zolpidem intoxication. Full article

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

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16 pages, 812 KiB

Open AccessSystematic Review

Polymer Matrix and Manufacturing Methods in Solid Dispersion System for Enhancing Andrographolide Solubility and Absorption: A Systematic Review

by Pratchaya Tipduangta, Sunee Chansakaow, Pimpimon Tansakul, Rungarun Meungjai and Piyameth Dilokthornsakul

Pharmaceutics 2024, 16(5), 688; https://doi.org/10.3390/pharmaceutics16050688 - 20 May 2024

Viewed by 1182

Abstract

Background: Andrographolide (ADG) has poor aqueous solubility and low bioavailability. This study systematically reviews the use of solid dispersion (SD) techniques to enhance the solubility and absorption of ADG, with a focus on the methods and polymers utilized. Methodology: We searched electronic databases [...] Read more.

Background: Andrographolide (ADG) has poor aqueous solubility and low bioavailability. This study systematically reviews the use of solid dispersion (SD) techniques to enhance the solubility and absorption of ADG, with a focus on the methods and polymers utilized. Methodology: We searched electronic databases including PubMed, Web of Science, Scopus^®, Embase and ScienceDirect Elsevier^® up to November 2023 for studies on the solubility or absorption of ADG in SD formulations. Two reviewers independently reviewed the retrieved articles and extracted data using a standardized form and synthesized the data qualitatively. Results: SD significantly improved ADG solubility with up to a 4.7-fold increase and resulted in a decrease in 50% release time (T_1/2) to less than 5 min. SD could also improve ADG absorption, as evidenced by higher C_max and AUC and reduced T_max. Notably, Soluplus-based SDs showed marked solubility and absorption enhancements. Among the five SD techniques (rotary evaporation, spray drying, hot-melt extrusion, freeze drying and vacuum drying) examined, spray drying emerged as the most effective, enabling a one-step process without the need for post-milling. Conclusions: SD techniques, particularly using Soluplus and spray drying, effectively enhance the solubility and absorption of ADG. This insight is vital for the future development of ADG-SD matrices. Full article

(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology, 3rd Edition)

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13 pages, 3134 KiB

Open AccessArticle

Formulation of Ascorbic Acid and Betaine-based Therapeutic Deep Eutectic System for Enhanced Transdermal Delivery of Ascorbic Acid

by Ji-Eun Song, Seung-Hyun Jun, Joo-Yeon Ryoo and Nae-Gyu Kang

Pharmaceutics 2024, 16(5), 687; https://doi.org/10.3390/pharmaceutics16050687 - 20 May 2024

Cited by 1 | Viewed by 1398

Abstract

L-ascorbic acid (AA), a potent antioxidant, is commonly used topically in the pharmaceutical and cosmetic fields. However, the incorporation of AA into topical formulations is difficult because of its highly unstable nature and relatively poor skin permeability. In this study, we propose [...] Read more.

L-ascorbic acid (AA), a potent antioxidant, is commonly used topically in the pharmaceutical and cosmetic fields. However, the incorporation of AA into topical formulations is difficult because of its highly unstable nature and relatively poor skin permeability. In this study, we propose an alternative strategy for improving the solubility and topical delivery of AA through its conversion to a therapeutic deep eutectic system (THEDES). AA and betaine (Bet)-based THEDESs were prepared at certain molar ratios and characterized using polarized optical microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. Solubility tests showed that AA in the form of THEDES was readily soluble in various polyols (glycerin, 1,3-butylene glycol, dipropylene glycol, and 1,3-propanediol) at a high concentration (approximately 40%). Furthermore, compared to AA alone or the physical mixture of AA and Bet, AA-based THEDES significantly enhanced AA delivery through porcine skin. In an in vivo human study, THEDES-containing serum reduced the markers of aging and induced an even skin tone. These findings indicate the utility of AA and Bet-based THEDES as novel transdermal delivery systems for AA. Furthermore, our approach also showed good extension to developing gluconolactone, a well-known natural antioxidant, and Bet-based THEDES, showing potential application in transdermal delivery systems. Full article

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

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11 pages, 1536 KiB

Open AccessArticle

Comparative Study of 5-Aminolevulinic Acid-Mediated Photodynamic Therapy and the Loop Electrosurgical Excision Procedure for the Treatment of Cervical High-Grade Squamous Intraepithelial Lesions

by Xiaoyun Wang, Xiaoming Xu, Yaxi Ma, Yixin Tang and Zheng Huang

Pharmaceutics 2024, 16(5), 686; https://doi.org/10.3390/pharmaceutics16050686 - 20 May 2024

Cited by 1 | Viewed by 1370

Abstract

The loop electrosurgical excision procedure (LEEP) is a common treatment for cervical intraepithelial neoplasia (CIN). Photodynamic therapy (PDT) mediated by 5-aminolevulinic acid (ALA) is a non-invasive modality that has been used for treating precancerous diseases and HPV infections. This comparative study evaluated the [...] Read more.

The loop electrosurgical excision procedure (LEEP) is a common treatment for cervical intraepithelial neoplasia (CIN). Photodynamic therapy (PDT) mediated by 5-aminolevulinic acid (ALA) is a non-invasive modality that has been used for treating precancerous diseases and HPV infections. This comparative study evaluated the efficacy and safety of ALA PDT and the LEEP in the treatment of cervical high-grade squamous intraepithelial lesions (HSILs). Patient records were reviewed and HSIL patients with HPV infections (24–51 years old) who underwent PDT or LEEP treatment were selected. Efficacy was analyzed blindly based on HPV-DNA, cytology, and colposcopy-directed biopsy obtained at 6 months after treatment. Treatment-related discomfort and side effects were also analyzed. Cure rates of 88.1% and 70.0% were achieved for the PDT group and LEEP group (p < 0.05), respectively. HPV-negative conversion rates of 81.0% and 62.0% were achieved for the PDT group and LEEP group (p < 0.05), respectively. The overall lesion remission rate of the PDT group was 19% higher than that of the LEEP group. The incidence of side effects was much lower in the PDT group. These results show that ALA PDT is a feasible non-invasive treatment for cervical HSIL. Full article

(This article belongs to the Special Issue Photodynamic Therapy: Recent Progress and Development)

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13 pages, 1219 KiB

Open AccessArticle

Integrating Clopidogrel’s First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite

by Zorica Pejčić, Valentina Topić Vučenović, Branislava Miljković and Katarina M. Vučićević

Pharmaceutics 2024, 16(5), 685; https://doi.org/10.3390/pharmaceutics16050685 - 20 May 2024

Viewed by 1210

Abstract

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85–90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, [...] Read more.

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85–90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants’ data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM^® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (K_tr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study’s generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (F_iaM_st1 and F_iaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA. Full article

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

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20 pages, 2000 KiB

Open AccessArticle

Novel Efficient Lipid-Based Delivery Systems Enable a Delayed Uptake and Sustained Expression of mRNA in Human Cells and Mouse Tissues

by Artem G. Fedorovskiy, Denis N. Antropov, Anton S. Dome, Pavel A. Puchkov, Daria M. Makarova, Maria V. Konopleva, Anastasiya M. Matveeva, Eugenia A. Panova, Elena V. Shmendel, Mikhail A. Maslov, Sergey E. Dmitriev, Grigory A. Stepanov and Oleg V. Markov

Pharmaceutics 2024, 16(5), 684; https://doi.org/10.3390/pharmaceutics16050684 - 19 May 2024

Viewed by 2687

Abstract

Over the past decade, mRNA-based therapy has displayed significant promise in a wide range of clinical applications. The most striking example of the leap in the development of mRNA technologies was the mass vaccination against COVID-19 during the pandemic. The emergence of large-scale [...] Read more.

Over the past decade, mRNA-based therapy has displayed significant promise in a wide range of clinical applications. The most striking example of the leap in the development of mRNA technologies was the mass vaccination against COVID-19 during the pandemic. The emergence of large-scale technology and positive experience of mRNA immunization sparked the development of antiviral and anti-cancer mRNA vaccines as well as therapeutic mRNA agents for genetic and other diseases. To facilitate mRNA delivery, lipid nanoparticles (LNPs) have been successfully employed. However, the diverse use of mRNA therapeutic approaches requires the development of adaptable LNP delivery systems that can control the kinetics of mRNA uptake and expression in target cells. Here, we report effective mRNA delivery into cultured mammalian cells (HEK293T, HeLa, DC2.4) and living mouse muscle tissues by liposomes containing either 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) or the newly applied 1,30-bis(cholest-5-en-3β-yloxycarbonylamino)-9,13,18,22-tetraaza-3,6,25,28-tetraoxatriacontane tetrahydrochloride (2X7) cationic lipids. Using end-point and real-time monitoring of Fluc mRNA expression, we showed that these LNPs exhibited an unusually delayed (of over 10 h in the case of the 2X7-based system) but had highly efficient and prolonged reporter activity in cells. Accordingly, both LNP formulations decorated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG₂₀₀₀) provided efficient luciferase production in mice, peaking on day 3 after intramuscular injection. Notably, the bioluminescence was observed only at the site of injection in caudal thigh muscles, thereby demonstrating local expression of the model gene of interest. The developed mRNA delivery systems hold promise for prophylactic applications, where sustained synthesis of defensive proteins is required, and open doors to new possibilities in mRNA-based therapies. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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22 pages, 5653 KiB

Open AccessEditor’s ChoiceArticle

Effects of Nozzle Retraction Elimination on Spray Distribution in Middle-Posterior Turbinate Regions: A Comparative Study

by Amr Seifelnasr, Xiuhua Si and Jinxiang Xi

Pharmaceutics 2024, 16(5), 683; https://doi.org/10.3390/pharmaceutics16050683 - 19 May 2024

Cited by 1 | Viewed by 1010

Abstract

The standard multi-dose nasal spray pump features an integrated actuator and nozzle, which inevitably causes a retraction of the nozzle tip during application. The retraction stroke is around 5.5 mm and drastically reduces the nozzle’s insertion depth, which further affects the initial nasal [...] Read more.

The standard multi-dose nasal spray pump features an integrated actuator and nozzle, which inevitably causes a retraction of the nozzle tip during application. The retraction stroke is around 5.5 mm and drastically reduces the nozzle’s insertion depth, which further affects the initial nasal spray deposition and subsequent translocation, potentially increasing drug wastes and dosimetry variability. To address this issue, we designed a new spray pump that separated the nozzle from the actuator and connected them with a flexible tube, thereby eliminating nozzle retraction during application. The objective of this study is to test the new device’s performance in comparison to the conventional nasal pump in terms of spray generation, plume development, and dosimetry distribution. For both devices, the spray droplet size distribution was measured using a laser diffraction particle analyzer. Plume development was recorded with a high-definition camera. Nasal dosimetry was characterized in two transparent nasal cavity casts (normal and decongested) under two breathing conditions (breath-holding and constant inhalation). The nasal formulation was a 0.25% w/v methyl cellulose aqueous solution with a fluorescent dye. For each test case, the temporospatial spray translocation in the nasal cavity was recorded, and the final delivered doses were quantified in five nasal regions. The results indicate minor differences in droplet size distribution between the two devices. The nasal plume from the new device presents a narrower plume angle. The head orientation, the depth at which the nozzle is inserted into the nostril, and the administration angle play crucial roles in determining the initial deposition of nasal sprays as well as the subsequent translocation of the liquid film/droplets. Quantitative measurements of deposition distributions in the nasal models were augmented with visualization recordings to evaluate the delivery enhancements introduced by the new device. With an extension tube, the modified device produced a lower spray output and delivered lower doses in the front, middle, and back turbinate than the conventional nasal pump. However, sprays from the new device were observed to penetrate deeper into the nasal passages, predominantly through the middle-upper meatus. This resulted in consistently enhanced dosing in the middle-upper turbinate regions while at the cost of higher drug loss to the pharynx. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration, 2nd Edition)

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19 pages, 3305 KiB

Open AccessArticle

Investigation of Hydrocolloid Plant Polysaccharides as Potential Candidates to Mimic the Functions of MUC5B in Saliva

by Christina Winter, Carolin Tetyczka, Duy Toan Pham, Dagmar Kolb, Gerd Leitinger, Sandra Schönfelder, Olaf Kunert, Tanja Gerlza, Andreas Kungl, Franz Bucar and Eva Roblegg

Pharmaceutics 2024, 16(5), 682; https://doi.org/10.3390/pharmaceutics16050682 - 18 May 2024

Cited by 1 | Viewed by 1304

Abstract

The successful substitution of complex physiological fluids, such as human saliva, remains a major challenge in drug development. Although there are a large number of saliva substitutes on the market, their efficacy is often inadequate due to short residence time in the mouth, [...] Read more.

The successful substitution of complex physiological fluids, such as human saliva, remains a major challenge in drug development. Although there are a large number of saliva substitutes on the market, their efficacy is often inadequate due to short residence time in the mouth, unpleasant mouthfeel, or insufficient protection of the teeth. Therefore, systems need to be identified that mimic the functions of saliva, in particular the salivary mucin MUC5B and the unique physiological properties of saliva. To this end, plant extracts known to contain hydrocolloid polysaccharides and to have mucus-forming properties were studied to evaluate their suitability as saliva substitutes. The aqueous plant extracts of Calendula officinalis, Fucus sp. thalli, and lichenan from Lichen islandicus were examined for composition using a range of techniques, including GC-MS, NMR, SEC, assessment of pH, osmolality, buffering capacity, viscoelasticity, viscoelastic interactions with human saliva, hydrocolloid network formation, and in vitro cell adhesion. For this purpose, a physiologically adapted adhesive test was developed using human buccal epithelial cells. The results show that lichenan is the most promising candidate to mimic the properties of MUC5B. By adjusting the pH, osmolality, and buffering capacity with K₂HPO₄, it was shown that lichenan exhibited high cell adhesion, with a maximum detachment force that was comparable to that of unstimulated whole mouth saliva. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of Plant Extracts, 2nd Edition)

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13 pages, 981 KiB

Open AccessArticle

A Sensitive Liquid Chromatography–Tandem Mass Spectrometry Method for Measuring Fosfomycin Concentrations in Human Prostatic Tissue

by Matteo Conti, Beatrice Giorgi, Rossella Barone, Milo Gatti, Pier Giorgio Cojutti and Federico Pea

Pharmaceutics 2024, 16(5), 681; https://doi.org/10.3390/pharmaceutics16050681 - 17 May 2024

Viewed by 980

Abstract

The aim of this study was to develop and validate a fast and sensitive bioanalytical method for the accurate quantification of fosfomycin concentrations in human prostatic tissue. The sample preparation method only required milligrams of tissue sample. Each sample was mixed with two [...] Read more.

The aim of this study was to develop and validate a fast and sensitive bioanalytical method for the accurate quantification of fosfomycin concentrations in human prostatic tissue. The sample preparation method only required milligrams of tissue sample. Each sample was mixed with two times its weight of water and homogenized. A methanol solution that was three times the volume of the internal standard (fosfomycin-13C3) was added, followed by vortex mixing and centrifugation. After its extraction from the homogenized prostatic tissue, fosfomycin was quantified by means of a liquid chromatography–tandem mass spectrometry (LC-MS/MS) triple quadrupole system operating in negative electrospray ionization and multiple reaction monitoring detection mode. The analytical procedure was successfully validated in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, and stability, according to EMA guidelines. The validation results, relative to three QC levels, were 9.9% for both the within-day and inter-day accuracy (BIAS%); 9.8% for within-day precision; and 9.9 for between-day precision. A marked matrix effect was observed in the measurements but was corrected by normalization with the internal standard. The average total recovery was high (approximatively 97% at the three control levels). The dynamic range of the method was 0.1–20 μg/g (R² of 0.999). Negligible carry-over was observed after the injection of highly concentrated samples. F in the sample homogenate extracts was stable at 10 °C and 4 °C for at least 24 h. In the tissue sample freeze–thaw experiments, a significant decrease in F concentrations was observed after only two cycles from −80 °C to room temperature. The novel method was successfully applied to measure fosfomycin in prostatic tissue samples collected from 105 patients undergoing prostatectomy. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring, 2nd Edition)

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18 pages, 2158 KiB

Open AccessReview

Spray-Dried Nanolipid Powders for Pulmonary Drug Delivery: A Comprehensive Mini Review

by Mahmoud H. Abu Elella, Arwa Omar Al Khatib and Hisham Al-Obaidi

Pharmaceutics 2024, 16(5), 680; https://doi.org/10.3390/pharmaceutics16050680 - 17 May 2024

Cited by 1 | Viewed by 1273

Abstract

Lung diseases have received great attention in the past years because they contribute approximately one-third of the total global mortality. Pulmonary drug delivery is regarded as one of the most appealing routes to treat lung diseases. It addresses numerous drawbacks linked to traditional [...] Read more.

Lung diseases have received great attention in the past years because they contribute approximately one-third of the total global mortality. Pulmonary drug delivery is regarded as one of the most appealing routes to treat lung diseases. It addresses numerous drawbacks linked to traditional dosage forms. It presents notable features, such as, for example, a non-invasive route, localized lung drug delivery, low enzymatic activity, low drug degradation, higher patient compliance, and avoiding first-pass metabolism. Therefore, the pulmonary route is commonly explored for delivering drugs both locally and systemically. Inhalable nanocarrier powders, especially, lipid nanoparticle formulations, including solid-lipid and nanostructured-lipid nanocarriers, are attracting considerable interest in addressing respiratory diseases thanks to their significant advantages, including deep lung deposition, biocompatibility, biodegradability, mucoadhesion, and controlled drug released. Spray drying is a scalable, fast, and commercially viable technique to produce nanolipid powders. This review highlights the ideal criteria for inhalable spray-dried SLN and NLC powders for the pulmonary administration route. Additionally, the most promising inhalation devices, known as dry powder inhalers (DPIs) for the pulmonary delivery of nanolipid powder-based medications, and pulmonary applications of SLN and NLC powders for treating chronic lung conditions, are considered. Full article

(This article belongs to the Special Issue Novel Dry Powder Formulation and Delivery Systems)

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11 pages, 1641 KiB

Open AccessEditor’s ChoiceArticle

Suitable Promoter for DNA Vaccination Using a pDNA Ternary Complex

by Tomoaki Kurosaki, Hiroki Nakamura, Hitoshi Sasaki and Yukinobu Kodama

Pharmaceutics 2024, 16(5), 679; https://doi.org/10.3390/pharmaceutics16050679 - 17 May 2024

Cited by 1 | Viewed by 1094

Abstract

In this study, we evaluated the effect of several promoters on the transfection activity and immune-induction efficiency of a plasmid DNA (pDNA)/polyethylenimine/γ-polyglutamic acid complex (pDNA ternary complex). Model pDNAs encoding firefly luciferase (Luc) were constructed with several promoters, such as simian virus 40 [...] Read more.

In this study, we evaluated the effect of several promoters on the transfection activity and immune-induction efficiency of a plasmid DNA (pDNA)/polyethylenimine/γ-polyglutamic acid complex (pDNA ternary complex). Model pDNAs encoding firefly luciferase (Luc) were constructed with several promoters, such as simian virus 40 (SV40), eukaryotic elongation factor 1 alpha (EF1), cytomegalovirus (CMV), and chicken beta actin hybrid (CBh) (pSV40-Luc, pEF1-Luc, pCMV-Luc, and pCBh-Luc, respectively). Four types of pDNA ternary complexes, each with approximately 145-nm particle size and −30-mV ζ-potential, were stably constructed. The pDNA ternary complex containing pSV40-Luc showed low gene expression, but the other complexes containing pEF1-Luc, pCMV-Luc, and pCBh-Luc showed high gene expression in DC2.4 cells and spleen after intravenous administration. After immunization using various pDNA encoding ovalbumin (OVA) such as pEF1-OVA, pCMV-OVA, and pCBh-OVA, only the pDNA ternary complex containing pCBh-OVA showed significant anti-OVA immunoglobulin G (IgG) induction. In conclusion, our results showed that the CBh promoter is potentially suitable for use in pDNA ternary complex-based DNA vaccination. Full article

(This article belongs to the Special Issue Plasmid DNA for Gene Therapy and DNA Vaccine Applications, 2nd Edition)

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28 pages, 16246 KiB

Open AccessArticle

Automated Non-Sterile Pharmacy Compounding: A Multi-Site Study in European Hospital and Community Pharmacies with Pediatric Immediate Release Propranolol Hydrochloride Tablets

by Niklas Sandler Topelius, Farnaz Shokraneh, Mahsa Bahman, Julius Lahtinen, Niko Hassinen, Sari Airaksinen, Soumya Verma, Ludmila Hrizanovska, Jana Lass, Urve Paaver, Janika Tähnas, Catharina Kern, Frederic Lagarce, Dominic Fenske, Julia Malik, Holger Scherliess, Sara P. Cruz, Mattias Paulsson, Jan Dekker, Katja Kammonen, Maria Rautamo, Hendrik Lück, Antoine Pierrot, Stephanie Stareprawo, Marija Tubic-Grozdanis, Stefanie Zibolka, Uli Lösch, Martina Jeske, Ulrich Griesser, Karin Hummer, Andreas Thalmeier, Anna Harjans, Alexander Kruse, Ralph Heimke-Brinck, Karim Khoukh and Fabien Bruno Show full author list Hide full author list

Pharmaceutics 2024, 16(5), 678; https://doi.org/10.3390/pharmaceutics16050678 - 17 May 2024

Viewed by 2010

Abstract

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and [...] Read more.

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend^® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies. Full article

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

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13 pages, 604 KiB

Open AccessEditor’s ChoicePerspective

Therapeutic Drug Monitoring and Biomarkers; towards Better Dosing of Antimicrobial Therapy

by Eman Wehbe, Asad E. Patanwala, Christine Y. Lu, Hannah Yejin Kim, Sophie L. Stocker and Jan-Willem C. Alffenaar

Pharmaceutics 2024, 16(5), 677; https://doi.org/10.3390/pharmaceutics16050677 - 17 May 2024

Viewed by 1384

Abstract

Due to variability in pharmacokinetics and pharmacodynamics, clinical outcomes of antimicrobial drug therapy vary between patients. As such, personalised medication management, considering both pharmacokinetics and pharmacodynamics, is a growing concept of interest in the field of infectious diseases. Therapeutic drug monitoring is used [...] Read more.

Due to variability in pharmacokinetics and pharmacodynamics, clinical outcomes of antimicrobial drug therapy vary between patients. As such, personalised medication management, considering both pharmacokinetics and pharmacodynamics, is a growing concept of interest in the field of infectious diseases. Therapeutic drug monitoring is used to adjust and individualise drug regimens until predefined pharmacokinetic exposure targets are achieved. Minimum inhibitory concentration (drug susceptibility) is the best available pharmacodynamic parameter but is associated with many limitations. Identification of other pharmacodynamic parameters is necessary. Repurposing diagnostic biomarkers as pharmacodynamic parameters to evaluate treatment response is attractive. When combined with therapeutic drug monitoring, it could facilitate making more informed dosing decisions. We believe the approach has potential and justifies further research. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)

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15 pages, 3372 KiB

Open AccessArticle

Poly(acrylic acid)/Poly(vinyl alcohol) Microarray Patches for Continuous Transdermal Delivery of Levodopa and Carbidopa: In Vitro and In Vivo Studies

by Yaocun Li, Lalitkumar K. Vora, Jiawen Wang, Akmal Hidayat Bin Sabri, Andrew Graham, Helen O. McCarthy and Ryan F. Donnelly

Pharmaceutics 2024, 16(5), 676; https://doi.org/10.3390/pharmaceutics16050676 - 17 May 2024

Cited by 1 | Viewed by 3597

Abstract

Levodopa (LD) has been the most efficacious medication and the gold standard therapy for Parkinson’s disease (PD) for decades. However, its long-term administration is usually associated with motor complications, which are believed to be the result of the fluctuating pharmacokinetics of LD following [...] Read more.

Levodopa (LD) has been the most efficacious medication and the gold standard therapy for Parkinson’s disease (PD) for decades. However, its long-term administration is usually associated with motor complications, which are believed to be the result of the fluctuating pharmacokinetics of LD following oral administration. Duodopa^® is the current option to offer a continuous delivery of LD and its decarboxylase inhibitor carbidopa (CD); however, its administration involves invasive surgical procedures, which could potentially lead to lifelong complications, such as infection. Recently, dissolving microarray patches (MAPs) have come to the fore as an alternative that can bypass the oral administration route in a minimally invasive way. This work explored the potential of using dissolving MAPs to deliver LD and CD across the skin. An acidic polymer poly(acrylic acid) (PAA) was used in the MAP fabrication to prevent the potential oxidation of LD at neutral pH. The drug contents of LD and CD in the formulated dissolving MAPs were 1.82 ± 0.24 and 0.47 ± 0.04 mg/patch, respectively. The in vivo pharmacokinetic study using female Sprague–Dawley^® rats (Envigo RMS Holding Corp, Bicester, UK) demonstrated a simultaneous delivery of LD and CD and comparable AUC values between the dissolving MAPs and the oral LD/CD suspension. The relative bioavailability for the dissolving MAPs was calculated to be approximately 37.22%. Accordingly, this work highlights the use of dissolving MAPs as a minimally invasive approach which could potentially bypass the gastrointestinal pathway and deliver both drugs continuously without surgery. Full article

(This article belongs to the Special Issue Emerging Trends and Translational Challenges in Drug and Vaccine Delivery, 2nd Edition)

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27 pages, 5074 KiB

Open AccessEditor’s ChoiceReview

Strategies to Improve the Transdermal Delivery of Poorly Water-Soluble Non-Steroidal Anti-Inflammatory Drugs

by Alexandra Balmanno, James R. Falconer, Halley G. Ravuri and Paul C. Mills

Pharmaceutics 2024, 16(5), 675; https://doi.org/10.3390/pharmaceutics16050675 - 16 May 2024

Cited by 1 | Viewed by 1746

Abstract

The transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has the potential to overcome some of the major disadvantages relating to oral NSAID usage, such as gastrointestinal adverse events and compliance. However, the poor solubility of many of the newer NSAIDs creates challenges in [...] Read more.

The transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has the potential to overcome some of the major disadvantages relating to oral NSAID usage, such as gastrointestinal adverse events and compliance. However, the poor solubility of many of the newer NSAIDs creates challenges in incorporating the drugs into formulations suitable for application to skin and may limit transdermal permeation, particularly if the goal is therapeutic systemic drug concentrations. This review is an overview of the various strategies used to increase the solubility of poorly soluble NSAIDs and enhance their permeation through skin, such as the modification of the vehicle, the modification of or bypassing the barrier function of the skin, and using advanced nano-sized formulations. Furthermore, the simple yet highly versatile microemulsion system has been found to be a cost-effective and highly successful technology to deliver poorly water-soluble NSAIDs. Full article

(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Improvement of Drug Bioavailability)

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37 pages, 2329 KiB

Open AccessReview

Novel Drug Delivery Systems: An Important Direction for Drug Innovation Research and Development

by Qian Chen, Zhen Yang, Haoyu Liu, Jingyuan Man, Ayodele Olaolu Oladejo, Sally Ibrahim, Shengyi Wang and Baocheng Hao

Pharmaceutics 2024, 16(5), 674; https://doi.org/10.3390/pharmaceutics16050674 - 16 May 2024

Cited by 2 | Viewed by 5662

Abstract

The escalating demand for enhanced therapeutic efficacy and reduced adverse effects in the pharmaceutical domain has catalyzed a new frontier of innovation and research in the field of pharmacy: novel drug delivery systems. These systems are designed to address the limitations of conventional [...] Read more.

The escalating demand for enhanced therapeutic efficacy and reduced adverse effects in the pharmaceutical domain has catalyzed a new frontier of innovation and research in the field of pharmacy: novel drug delivery systems. These systems are designed to address the limitations of conventional drug administration, such as abbreviated half-life, inadequate targeting, low solubility, and bioavailability. As the disciplines of pharmacy, materials science, and biomedicine continue to advance and converge, the development of efficient and safe drug delivery systems, including biopharmaceutical formulations, has garnered significant attention both domestically and internationally. This article presents an overview of the latest advancements in drug delivery systems, categorized into four primary areas: carrier-based and coupling-based targeted drug delivery systems, intelligent drug delivery systems, and drug delivery devices, based on their main objectives and methodologies. Additionally, it critically analyzes the technological bottlenecks, current research challenges, and future trends in the application of novel drug delivery systems. Full article

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

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14 pages, 4408 KiB

Open AccessArticle

Deep Learning Insights into the Dynamic Effects of Photodynamic Therapy on Cancer Cells

by Md. Atiqur Rahman, Feihong Yan, Ruiyuan Li, Yu Wang, Lu Huang, Rongcheng Han and Yuqiang Jiang

Pharmaceutics 2024, 16(5), 673; https://doi.org/10.3390/pharmaceutics16050673 - 16 May 2024

Viewed by 1624

Abstract

Photodynamic therapy (PDT) shows promise in tumor treatment, particularly when combined with nanotechnology. This study examines the impact of deep learning, particularly the Cellpose algorithm, on the comprehension of cancer cell responses to PDT. The Cellpose algorithm enables robust morphological analysis of cancer [...] Read more.

Photodynamic therapy (PDT) shows promise in tumor treatment, particularly when combined with nanotechnology. This study examines the impact of deep learning, particularly the Cellpose algorithm, on the comprehension of cancer cell responses to PDT. The Cellpose algorithm enables robust morphological analysis of cancer cells, while logistic growth modelling predicts cellular behavior post-PDT. Rigorous model validation ensures the accuracy of the findings. Cellpose demonstrates significant morphological changes after PDT, affecting cellular proliferation and survival. The reliability of the findings is confirmed by model validation. This deep learning tool enhances our understanding of cancer cell dynamics after PDT. Advanced analytical techniques, such as morphological analysis and growth modeling, provide insights into the effects of PDT on hepatocellular carcinoma (HCC) cells, which could potentially improve cancer treatment efficacy. In summary, the research examines the role of deep learning in optimizing PDT parameters to personalize oncology treatment and improve efficacy. Full article

(This article belongs to the Special Issue Multicomponent Nanomedicines for Photodynamic Diagnosis and Photodynamic Therapy)

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15 pages, 23424 KiB

Open AccessEditor’s ChoiceArticle

The Proteasome Inhibitor CEP-18770 Induces Cell Death in Medulloblastoma

by Swastina Nath Varma, Shany Ye, Sara Ferlin, Charley Comer, Kian Cotton and Maria Victoria Niklison-Chirou

Pharmaceutics 2024, 16(5), 672; https://doi.org/10.3390/pharmaceutics16050672 - 16 May 2024

Viewed by 1283

Abstract

Medulloblastomas (MBs) represent the most prevalent malignant solid tumors in kids. The conventional treatment regimen for MBs includes surgical removal of the tumor, followed by radiation and chemotherapy. However, this approach is associated with significant morbidity and detrimental side effects. Consequently, there is [...] Read more.

Medulloblastomas (MBs) represent the most prevalent malignant solid tumors in kids. The conventional treatment regimen for MBs includes surgical removal of the tumor, followed by radiation and chemotherapy. However, this approach is associated with significant morbidity and detrimental side effects. Consequently, there is a critical demand for more precise and less harmful treatments to enhance the quality of life for survivors. CEP-18770, a novel proteasome inhibitor that targets the 20S subunit, has emerged as a promising candidate, due to its anticancer activity in metastatic solid tumors and multiple myeloma, coupled with an acceptable safety profile. In this study, we aimed to assess the anticancer efficacy of CEP-18770 by employing a variety of MB patient-derived cells and cell lines. Our preclinical investigations revealed that CEP-18770 effectively inhibits proteasome activity and induces apoptosis in MBs cells. Furthermore, we discovered that CEP-18770 and cisplatin, a current component of MB therapy, exhibit a synergistic apoptotic effect. This paper shows that CEP-18770 holds potential as an adjunctive treatment for MB tumors, thereby paving the way for more targeted and less toxic therapeutic strategies. Full article

(This article belongs to the Special Issue Brain Tumors Treatment: Current and Future Challenges from Drug Formulations to Delivery Methods)

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20 pages, 7283 KiB

Open AccessArticle

Synergistic Enhancement of Targeted Wound Healing by Near-Infrared Photodynamic Therapy and Silver Metal–Organic Frameworks Combined with S- or N-Doped Carbon Dots

by Maja D. Nešić, Iva A. Popović, Jelena Žakula, Lela Korićanac, Jelena Filipović Tričković, Ana Valenta Šobot, Maria Victoria Jiménez, Manuel Algarra, Tanja Dučić and Milutin Stepić

Pharmaceutics 2024, 16(5), 671; https://doi.org/10.3390/pharmaceutics16050671 - 16 May 2024

Viewed by 1572

Abstract

The literature data emphasize that nanoparticles might improve the beneficial effects of near-infrared light (NIR) on wound healing. This study investigates the mechanisms of the synergistic wound healing potential of NIR light and silver metal–organic frameworks combined with nitrogen- and sulfur-doped carbon dots [...] Read more.

The literature data emphasize that nanoparticles might improve the beneficial effects of near-infrared light (NIR) on wound healing. This study investigates the mechanisms of the synergistic wound healing potential of NIR light and silver metal–organic frameworks combined with nitrogen- and sulfur-doped carbon dots (AgMOFsN-CDs and AgMOFsS-CDs, respectively), which was conducted by testing the fibroblasts viability, scratch assays, biochemical analysis, and synchrotron-based Fourier transform infrared (SR-FTIR) cell spectroscopy and imaging. Our findings reveal that the combined treatment of AgMOFsN-CDs and NIR light significantly increases cell viability to nearly 150% and promotes cell proliferation, with reduced interleukin-1 levels, suggesting an anti-inflammatory response. SR-FTIR spectroscopy shows this combined treatment results in unique protein alterations, including increased α-helix structures and reduced cross-β. Additionally, protein synthesis was enhanced upon the combined treatment. The likely mechanism behind the observed changes is the charge-specific interaction of N-CDs from the AgMOFsN-CDs with proteins, enhanced by NIR light due to the nanocomposite’s optical characteristics. Remarkably, the complete wound closure in the in vitro scratch assay was achieved exclusively with the combined NIR and AgMOFsN-CDs treatment, demonstrating the promising application of combined AgMOFsN-CDs with NIR light photodynamic therapy in regenerative nanomedicine and tissue engineering. Full article

(This article belongs to the Special Issue Advances in Targeted Photodynamic Therapy Based on Nanotechnology)

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38 pages, 8003 KiB

Open AccessReview

A Review of Recent Developments in Biopolymer Nano-Based Drug Delivery Systems with Antioxidative Properties: Insights into the Last Five Years

by Magdalena Stevanović and Nenad Filipović

Pharmaceutics 2024, 16(5), 670; https://doi.org/10.3390/pharmaceutics16050670 - 16 May 2024

Cited by 5 | Viewed by 1914

Abstract

In recent years, biopolymer-based nano-drug delivery systems with antioxidative properties have gained significant attention in the field of pharmaceutical research. These systems offer promising strategies for targeted and controlled drug delivery while also providing antioxidant effects that can mitigate oxidative stress-related diseases. Generally, [...] Read more.

In recent years, biopolymer-based nano-drug delivery systems with antioxidative properties have gained significant attention in the field of pharmaceutical research. These systems offer promising strategies for targeted and controlled drug delivery while also providing antioxidant effects that can mitigate oxidative stress-related diseases. Generally, the healthcare landscape is constantly evolving, necessitating the continual development of innovative therapeutic approaches and drug delivery systems (DDSs). DDSs play a pivotal role in enhancing treatment efficacy, minimizing adverse effects, and optimizing patient compliance. Among these, nanotechnology-driven delivery approaches have garnered significant attention due to their unique properties, such as improved solubility, controlled release, and targeted delivery. Nanomaterials, including nanoparticles, nanocapsules, nanotubes, etc., offer versatile platforms for drug delivery and tissue engineering applications. Additionally, biopolymer-based DDSs hold immense promise, leveraging natural or synthetic biopolymers to encapsulate drugs and enable targeted and controlled release. These systems offer numerous advantages, including biocompatibility, biodegradability, and low immunogenicity. The utilization of polysaccharides, polynucleotides, proteins, and polyesters as biopolymer matrices further enhances the versatility and applicability of DDSs. Moreover, substances with antioxidative properties have emerged as key players in combating oxidative stress-related diseases, offering protection against cellular damage and chronic illnesses. The development of biopolymer-based nanoformulations with antioxidative properties represents a burgeoning research area, with a substantial increase in publications in recent years. This review provides a comprehensive overview of the recent developments within this area over the past five years. It discusses various biopolymer materials, fabrication techniques, stabilizers, factors influencing degradation, and drug release. Additionally, it highlights emerging trends, challenges, and prospects in this rapidly evolving field. Full article

(This article belongs to the Special Issue Biopolymers for Biomedical and Pharmaceutical Applications)

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23 pages, 7853 KiB

Open AccessArticle

Gold Nanoparticles: Tunable Characteristics and Potential for Nasal Drug Delivery

by Aida Maaz, Ian S. Blagbrough and Paul A. De Bank

Pharmaceutics 2024, 16(5), 669; https://doi.org/10.3390/pharmaceutics16050669 - 16 May 2024

Viewed by 1223

Abstract

A general procedure to prepare gold nanourchins (GNUs) via a seed-mediated method was followed using dopamine hydrochloride as a reducing agent and silver nitrate salt (AgNO₃) as a shape-directing agent. The novelty of this study comes from the successful incorporation of [...] Read more.

A general procedure to prepare gold nanourchins (GNUs) via a seed-mediated method was followed using dopamine hydrochloride as a reducing agent and silver nitrate salt (AgNO₃) as a shape-directing agent. The novelty of this study comes from the successful incorporation of the prepared gold urchins as an aqueous suspension in a nasal pressurized metered dose inhaler (pMDI) formulation and the investigation of their potential for olfactory targeting for direct nose-to-brain drug delivery (NTBDD). The developed pMDI formulation was composed of 0.025% w/w GNUs, 2% w/w Milli-Q water, and 2% w/w EtOH, with the balance of the formulation being HFA134a propellant. Particle integrity and aerosolization performance were examined using an aerosol exposure system, whereas the nasal deposition profile was tested in a sectioned anatomical replica of human nasal airways. The compatibility of the gold dispersion with the nasal epithelial cell line RPMI 2650 was also investigated in this study. Colloidal gold was found to be stable following six-month storage at 4 °C and during the lyophilization process utilizing a pectin matrix for complete re-dispersibility in water. The GNUs were intact and discrete following atomization via a pMDI, and 13% of the delivered particles were detected beyond the nasal valve, the narrowest region in the nasal cavity, out of which 5.6% was recovered from the olfactory region. Moreover, the formulation was found to be compatible with the human nasal epithelium cell line RPMI 2650 and excellent cell viability was observed. The formulated GNU-HFA-based pMDI is a promising approach for intranasal drug delivery, including deposition in the olfactory region, which could be employed for NTBDD applications. Full article

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

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24 pages, 7324 KiB

Open AccessReview

Self-Immolative Domino Dendrimers as Anticancer-Drug Delivery Systems: A Review

by Karolina Kędra, Ewa Oledzka and Marcin Sobczak

Pharmaceutics 2024, 16(5), 668; https://doi.org/10.3390/pharmaceutics16050668 - 16 May 2024

Viewed by 1224

Abstract

Worldwide cancer statistics have indicated about 20 million new cancer cases and over 10 million deaths in 2022 (according to data from the International Agency for Research on Cancer). One of the leading cancer treatment strategies is chemotherapy, using innovative drug delivery systems [...] Read more.

Worldwide cancer statistics have indicated about 20 million new cancer cases and over 10 million deaths in 2022 (according to data from the International Agency for Research on Cancer). One of the leading cancer treatment strategies is chemotherapy, using innovative drug delivery systems (DDSs). Self-immolative domino dendrimers (SIDendr) for triggered anti-cancer drugs appear to be a promising type of DDSs. The present review provides an up-to-date survey on the contemporary advancements in the field of SIDendr-based anti-cancer drug delivery systems (SIDendr-ac-DDSs) through an exhaustive analysis of the discovery and application of these materials in improving the pharmacological effectiveness of both novel and old drugs. In addition, this article discusses the designing, chemical structure, and targeting techniques, as well as the properties, of several SIDendr-based DDSs. Approaches for this type of targeted DDSs for anti-cancer drug release under a range of stimuli are also explored. Full article

(This article belongs to the Special Issue Design of Novel Polymeric Systems for Controlled Drug Delivery, 2nd Edition)

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17 pages, 5630 KiB

Open AccessArticle

Swelling, Rupture and Endosomal Escape of Biological Nanoparticles Per Se and Those Fused with Liposomes in Acidic Environment

by Natalia Ponomareva, Sergey Brezgin, Ivan Karandashov, Anastasiya Kostyusheva, Polina Demina, Olga Slatinskaya, Ekaterina Bayurova, Denis Silachev, Vadim S. Pokrovsky, Vladimir Gegechkori, Evgeny Khaydukov, Georgy Maksimov, Anastasia Frolova, Ilya Gordeychuk, Andrey A. Zamyatnin Jr., Vladimir Chulanov, Alessandro Parodi and Dmitry Kostyushev

Pharmaceutics 2024, 16(5), 667; https://doi.org/10.3390/pharmaceutics16050667 - 16 May 2024

Cited by 1 | Viewed by 1844

Abstract

Biological nanoparticles (NPs), such as extracellular vesicles (EVs), exosome-mimetic nanovesicles (EMNVs) and nanoghosts (NGs), are perspective non-viral delivery vehicles for all types of therapeutic cargo. Biological NPs are renowned for their exceptional biocompatibility and safety, alongside their ease of functionalization, but a significant [...] Read more.

Biological nanoparticles (NPs), such as extracellular vesicles (EVs), exosome-mimetic nanovesicles (EMNVs) and nanoghosts (NGs), are perspective non-viral delivery vehicles for all types of therapeutic cargo. Biological NPs are renowned for their exceptional biocompatibility and safety, alongside their ease of functionalization, but a significant challenge arises when attempting to load therapeutic payloads, such as nucleic acids (NAs). One effective strategy involves fusing biological NPs with liposomes loaded with NAs, resulting in hybrid carriers that offer the benefits of both biological NPs and the capacity for high cargo loads. Despite their unique parameters, one of the major issues of virtually any nanoformulation is the ability to escape degradation in the compartment of endosomes and lysosomes which determines the overall efficiency of nanotherapeutics. In this study, we fabricated all major types of biological and hybrid NPs and studied their response to the acidic environment observed in the endolysosomal compartment. In this study, we show that EMNVs display increased protonation and swelling relative to EVs and NGs in an acidic environment. Furthermore, the hybrid NPs exhibit an even greater response compared to EMNVs. Short-term incubation of EMNVs in acidic pH corresponding to late endosomes and lysosomes again induces protonation and swelling, whereas hybrid NPs are ruptured, resulting in the decline in their quantities. Our findings demonstrate that in an acidic environment, there is enhanced rupture and release of vesicular cargo observed in hybrid EMNVs that are fused with liposomes compared to EMNVs alone. This was confirmed through PAGE electrophoresis analysis of mCherry protein loaded into nanoparticles. In vitro analysis of NPs colocalization with lysosomes in HepG2 cells demonstrated that EMNVs mostly avoid the endolysosomal compartment, whereas hybrid NPs escape it over time. To conclude, (1) hybrid biological NPs fused with liposomes appear more efficient in the endolysosomal escape via the mechanism of proton sponge-associated scavenging of protons by NPs, influx of counterions and water, and rupture of endo/lysosomes, but (2) EMNVs are much more efficient than hybrid NPs in actually avoiding the endolysosomal compartment in human cells. These results reveal biochemical differences across four major types of biological and hybrid NPs and indicate that EMNVs are more efficient in escaping or avoiding the endolysosomal compartment. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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24 pages, 2540 KiB

Open AccessReview

Lymph Node-on-Chip Technology: Cutting-Edge Advances in Immune Microenvironment Simulation

by Qi Wang, Yuanzhan Yang, Zixuan Chen, Bo Li, Yumeng Niu and Xiaoqiong Li

Pharmaceutics 2024, 16(5), 666; https://doi.org/10.3390/pharmaceutics16050666 - 16 May 2024

Cited by 1 | Viewed by 2178

Abstract

Organ-on-a-chip technology is attracting growing interest across various domains as a crucial platform for drug screening and testing and is set to play a significant role in precision medicine research. Lymph nodes, being intricately structured organs essential for the body’s adaptive immune responses [...] Read more.

Organ-on-a-chip technology is attracting growing interest across various domains as a crucial platform for drug screening and testing and is set to play a significant role in precision medicine research. Lymph nodes, being intricately structured organs essential for the body’s adaptive immune responses to antigens and foreign particles, are pivotal in assessing the immunotoxicity of novel pharmaceuticals. Significant progress has been made in research on the structure and function of the lymphatic system. However, there is still an urgent need to develop prospective tools and techniques to delve deeper into its role in various diseases’ pathological and physiological processes and to develop corresponding immunotherapeutic therapies. Organ chips can accurately reproduce the specific functional areas in lymph nodes to better simulate the complex microstructure of lymph nodes and the interactions between different immune cells, which is convenient for studying specific biological processes. This paper reviews existing lymph node chips and their design approaches. It discusses the applications of the above systems in modeling immune cell motility, cell–cell interactions, vaccine responses, drug testing, and cancer research. Finally, we summarize the challenges that current research faces in terms of structure, cell source, and extracellular matrix simulation of lymph nodes, and we provide an outlook on the future direction of integrated immune system chips. Full article

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

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14 pages, 4371 KiB

Open AccessArticle

Antibiotic Loaded Phytosomes as a Way to Develop Innovative Lipid Formulations of Polyene Macrolides

by Svetlana S. Efimova and Olga S. Ostroumova

Pharmaceutics 2024, 16(5), 665; https://doi.org/10.3390/pharmaceutics16050665 - 16 May 2024

Viewed by 4026

Abstract

Background: The threat of antibiotic resistance of fungal pathogens and the high toxicity of the most effective drugs, polyene macrolides, force us to look for new ways to develop innovative antifungal formulations. Objective: The aim of this study was to determine how the [...] Read more.

Background: The threat of antibiotic resistance of fungal pathogens and the high toxicity of the most effective drugs, polyene macrolides, force us to look for new ways to develop innovative antifungal formulations. Objective: The aim of this study was to determine how the sterol, phospholipid, and flavonoid composition of liposomal forms of polyene antibiotics, and in particular, amphotericin B (AmB), affects their ability to increase the permeability of lipid bilayers that mimic the membranes of mammalian and fungal cells. Methods: To monitor the membrane permeability induced by various polyene-based lipid formulations, a calcein leakage assay and the electrophysiological technique based on planar lipid bilayers were used. Key results: The replacement of cholesterol with its biosynthetic precursor, 7-dehydrocholesterol, led to a decrease in the ability of AmB-loaded liposomes to permeabilize lipid bilayers mimicking mammalian cell membranes. The inclusion of plant flavonoid phloretin in AmB-loaded liposomes increased the ability of the formulation to disengage a fluorescent marker from lipid vesicles mimicking the membranes of target fungi. I–V characteristics of the fungal-like lipid bilayers treated with the AmB phytosomes were symmetric, demonstrating the functioning of double-length AmB pores and assuming a decrease in the antibiotic threshold concentration. Conclusions and Perspectives: The therapeutic window of polyene lipid formulations might be expanded by varying their sterol composition. Polyene-loaded phytosomes might be considered as the prototypes for innovative lipid antibiotic formulations. Full article

(This article belongs to the Special Issue Emerging Pharmaceutical Strategies against Infectious Diseases)

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29 pages, 5918 KiB

Open AccessArticle

In Vitro and In Vivo Evaluation of the Effects of Drug 2c and Derivatives on Ovarian Cancer Cells

by Marianna Maddaloni, Rossella Farra, Barbara Dapas, Fulvia Felluga, Fabio Benedetti, Federico Berti, Sara Drioli, Mattia Vidali, Maja Cemazar, Urska Kamensek, Claudio Brancolini, Erminio Murano, Francesca Maremonti, Mario Grassi, Alice Biasin, Flavio Rizzolio, Enrico Cavarzerani, Bruna Scaggiante, Roberta Bulla, Andrea Balduit, Giuseppe Ricci, Gabriella Zito, Federico Romano, Serena Bonin, Eros Azzalini, Gabriele Baj, Domenico Tierno and Gabriele Grassi Show full author list Hide full author list

Pharmaceutics 2024, 16(5), 664; https://doi.org/10.3390/pharmaceutics16050664 - 15 May 2024

Viewed by 1494

Abstract

Background: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting [...] Read more.

Background: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins. Methods: 2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery. Results: 2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers. Conclusion: Our data strongly support the potential therapeutic value of 2c/derivatives in OC. Full article

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20 pages, 1786 KiB

Open AccessReview

Progress of Antimicrobial Mechanisms of Stilbenoids

by Xiancai Li, Yongqing Li, Binghong Xiong and Shengxiang Qiu

Pharmaceutics 2024, 16(5), 663; https://doi.org/10.3390/pharmaceutics16050663 - 15 May 2024

Cited by 1 | Viewed by 1162

Abstract

Antimicrobial drugs have made outstanding contributions to the treatment of pathogenic infections. However, the emergence of drug resistance continues to be a major threat to human health in recent years, and therefore, the search for novel antimicrobial drugs is particularly urgent. With a [...] Read more.

Antimicrobial drugs have made outstanding contributions to the treatment of pathogenic infections. However, the emergence of drug resistance continues to be a major threat to human health in recent years, and therefore, the search for novel antimicrobial drugs is particularly urgent. With a deeper understanding of microbial habits and drug resistance mechanisms, various creative strategies for the development of novel antibiotics have been proposed. Stilbenoids, characterized by a C₆–C₂–C₆ carbon skeleton, have recently been widely recognized for their flexible antimicrobial roles. Here, we comprehensively summarize the mode of action of stilbenoids from the viewpoint of their direct antimicrobial properties, antibiofilm and antivirulence activities and their role in reversing drug resistance. This review will provide an important reference for the future development and research into the mechanisms of stilbenoids as antimicrobial agents. Full article

(This article belongs to the Topic Challenges and Future Prospects of Antibacterial Therapy)

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20 pages, 3609 KiB

Open AccessEditor’s ChoiceArticle

An Investigation into the Effects of Processing Factors on the Properties and Scaling-Up Potential of Propranolol-Loaded Chitosan Nanogels

by Hei Ming Kenneth Ho, Richard M. Day and Duncan Q. M. Craig

Pharmaceutics 2024, 16(5), 662; https://doi.org/10.3390/pharmaceutics16050662 - 15 May 2024

Viewed by 868

Abstract

Chitosan-triphosphate (TPP) nanogels are widely studied drug delivery carrier systems, typically prepared via a simple mixing process. However, the effects of the processing factors on nanogel production have not been extensively explored, despite the importance of understanding and standardising such factors to allow [...] Read more.

Chitosan-triphosphate (TPP) nanogels are widely studied drug delivery carrier systems, typically prepared via a simple mixing process. However, the effects of the processing factors on nanogel production have not been extensively explored, despite the importance of understanding and standardising such factors to allow upscaling and commercial usage. This study aims to systematically evaluate the effects of various fabrication and processing factors on the properties of nanogels using a Design of Experiment approach. Hydrodynamic size, polydispersity index (PDI), zeta potential, and encapsulation efficiency were determined as the dependent factors. The temperature, stirring rate, chitosan grade, crosslinker choice, and the interaction term between temperature and chitosan grade were found to have a significant effect on the particle size, whereas the effect of temperature and the addition rate of crosslinker on the PDI was also noteworthy. Moreover, the addition rate of the crosslinker and the volume of the reaction vessel were found to impact the encapsulation efficiency. The zeta potential of the nanogels was found to be governed by the chitosan grade. The optimal fabrication conditions for the development of medium molecular weight chitosan and TPP nanogels included the following: the addition rate for TPP solution was set at 2 mL/min, while the solution was then stirred at a temperature of 50 °C and a stirring speed of 600 rpm. The volume of the glass vial used was 28 mL, while the stirrer size was 20 mm. The second aim of the study was to evaluate the potential for scaling up the nanogels. Size and PDI were found to increase from 128 nm to 151 nm and from 0.232 to 0.267, respectively, when the volume of the reaction mixture was increased from 4 to 20 mL and other processing factors were kept unchanged. These results indicate that caution is required when scaling up as the nanogel properties may be significantly altered with an increasing production scale. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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14 pages, 1225 KiB

Open AccessEditor’s ChoiceReview

Beyond Traditional Sunscreens: A Review of Liposomal-Based Systems for Photoprotection

by Júlio Abreu Miranda, Yasmin Ferreira da Cruz, Ícaro Chaves Girão, Fabia Julliana Jorge de Souza, Wógenes Nunes de Oliveira, Éverton do Nascimento Alencar, Lucas Amaral-Machado and Eryvaldo Sócrates Tabosa do Egito

Pharmaceutics 2024, 16(5), 661; https://doi.org/10.3390/pharmaceutics16050661 - 15 May 2024

Cited by 1 | Viewed by 1581

Abstract

Sunscreen products are essential for shielding the skin from ultraviolet (UV) radiation, a leading cause of skin cancer. While existing products serve this purpose, there is a growing need to enhance their efficacy while minimizing potential systemic absorption of UV filters and associated [...] Read more.

Sunscreen products are essential for shielding the skin from ultraviolet (UV) radiation, a leading cause of skin cancer. While existing products serve this purpose, there is a growing need to enhance their efficacy while minimizing potential systemic absorption of UV filters and associated toxicological risks. Liposomal-based formulations have emerged as a promising approach to address these challenges and develop advanced photoprotective products. These vesicular systems offer versatility in carrying both hydrophilic and lipophilic UV filters, enabling the creation of broad-spectrum sunscreens. Moreover, their composition based on phospholipids, resembling that of the stratum corneum, facilitates adherence to the skin’s surface layers, thereby improving photoprotective efficacy. The research discussed in this review underscores the significant advantages of liposomes in photoprotection, including their ability to limit the systemic absorption of UV filters, enhance formulation stability, and augment photoprotective effects. However, despite these benefits, there remains a notable gap between the potential of liposomal systems and their utilization in sunscreen development. Consequently, this review emphasizes the importance of leveraging liposomes and related vesicular systems as innovative tools for crafting novel and more efficient photoprotective formulations. Full article

(This article belongs to the Special Issue Nano-Based Drug Delivery System: Recent Developments and Future Prospects)

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Pharmaceutics, Volume 16, Issue 5 (May 2024) – 120 articles

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