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Pharmaceutics, Volume 15, Issue 4 (April 2023) – 287 articles

Cover Story (view full-size image): Posterior segment eye diseases pose treatment challenges due to ocular barriers limiting drug penetration, residence time, and bioavailability. Current treatments require frequent dosing, including eye drops or intravitreal injections. Biodegradable nano-based drug delivery systems (DDS) offer a solution by staying in ocular tissues longer, passing through barriers for higher bioavailability, and being composed of biodegradable, nanosized polymers. This review examines DDS in ocular disease treatment, therapeutic challenges in posterior segment diseases, and the enhancement of treatment options through various biodegradable nanocarriers. A literature review from 2017 to 2023 highlights the rapid evolution of nano-based DDSs, promising to overcome current clinical challenges. View this paper
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21 pages, 8457 KiB  
Review
Natural Compounds: Co-Delivery Strategies with Chemotherapeutic Agents or Nucleic Acids Using Lipid-Based Nanocarriers
by Patrícia V. Teixeira, Eduarda Fernandes, Telma B. Soares, Filomena Adega, Carla M. Lopes and Marlene Lúcio
Pharmaceutics 2023, 15(4), 1317; https://doi.org/10.3390/pharmaceutics15041317 - 21 Apr 2023
Cited by 5 | Viewed by 1512
Abstract
Cancer is one of the leading causes of death, and latest predictions indicate that cancer- related deaths will increase over the next few decades. Despite significant advances in conventional therapies, treatments remain far from ideal due to limitations such as lack of selectivity, [...] Read more.
Cancer is one of the leading causes of death, and latest predictions indicate that cancer- related deaths will increase over the next few decades. Despite significant advances in conventional therapies, treatments remain far from ideal due to limitations such as lack of selectivity, non-specific distribution, and multidrug resistance. Current research is focusing on the development of several strategies to improve the efficiency of chemotherapeutic agents and, as a result, overcome the challenges associated with conventional therapies. In this regard, combined therapy with natural compounds and other therapeutic agents, such as chemotherapeutics or nucleic acids, has recently emerged as a new strategy for tackling the drawbacks of conventional therapies. Taking this strategy into consideration, the co-delivery of the above-mentioned agents in lipid-based nanocarriers provides some advantages by improving the potential of the therapeutic agents carried. In this review, we present an analysis of the synergistic anticancer outcomes resulting from the combination of natural compounds and chemotherapeutics or nucleic acids. We also emphasize the importance of these co-delivery strategies when reducing multidrug resistance and adverse toxic effects. Furthermore, the review delves into the challenges and opportunities surrounding the application of these co-delivery strategies towards tangible clinical translation for cancer treatment. Full article
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12 pages, 4047 KiB  
Article
In Situ Synthesis of a Tumor-Microenvironment-Responsive Chemotherapy Drug
by Xiupeng Wang, Ayako Oyane, Tomoya Inose and Maki Nakamura
Pharmaceutics 2023, 15(4), 1316; https://doi.org/10.3390/pharmaceutics15041316 - 21 Apr 2023
Cited by 2 | Viewed by 1318
Abstract
Current chemotherapy still suffers from unsatisfactory therapeutic efficacy, multi-drug resistance, and severe adverse effects, thus necessitating the development of techniques to confine chemotherapy drugs in the tumor microenvironment. Herein, we fabricated nanospheres of mesoporous silica (MS) doped with Cu (MS-Cu) and polyethylene glycol [...] Read more.
Current chemotherapy still suffers from unsatisfactory therapeutic efficacy, multi-drug resistance, and severe adverse effects, thus necessitating the development of techniques to confine chemotherapy drugs in the tumor microenvironment. Herein, we fabricated nanospheres of mesoporous silica (MS) doped with Cu (MS-Cu) and polyethylene glycol (PEG)-coated MS-Cu (PEG-MS-Cu) as exogenous copper supply systems to tumors. The synthesized MS-Cu nanospheres showed diameters of 30–150 nm with Cu/Si molar ratios of 0.041–0.069. Only disulfiram (DSF) and only MS-Cu nanospheres showed little cytotoxicity in vitro, whereas the combination of DSF and MS-Cu nanospheres showed significant cytotoxicity against MOC1 and MOC2 cells at concentrations of 0.2–1 μg/mL. Oral DSF administration in combination with MS-Cu nanospheres intratumoral or PEG-MS-Cu nanospheres intravenous administration showed significant antitumor efficacy against MOC2 cells in vivo. In contrast to traditional drug delivery systems, we herein propose a system for the in situ synthesis of chemotherapy drugs by converting nontoxic substances into antitumor chemotherapy drugs in a specific tumor microenvironment. Full article
(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition)
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22 pages, 4678 KiB  
Article
Influence of Solid Oral Dosage Form Characteristics on Swallowability, Visual Perception, and Handling in Older Adults
by Henriette Hummler, Susanne Page, Cordula Stillhart, Lisa Meilicke, Michael Grimm, Marwan Mannaa, Maik Gollasch and Werner Weitschies
Pharmaceutics 2023, 15(4), 1315; https://doi.org/10.3390/pharmaceutics15041315 - 21 Apr 2023
Cited by 2 | Viewed by 2227
Abstract
Swallowability, visual perception, and any handling to be conducted prior to use are all influence factors on the acceptability of an oral dosage form by the patient. Knowing the dosage form preferences of older adults, as the major group of medication end users, [...] Read more.
Swallowability, visual perception, and any handling to be conducted prior to use are all influence factors on the acceptability of an oral dosage form by the patient. Knowing the dosage form preferences of older adults, as the major group of medication end users, is needed for patient-centric drug development. This study aimed at evaluating the ability of older adults to handle tablets as well as to assess the anticipated swallowability of tablets, capsules, and mini tablets based on visual perception. The randomized intervention study included 52 older adults (65 to 94 years) and 52 younger adults (19 to 36 years). Within the tested tablets, ranging from 125 mg up to 1000 mg in weight and being of different shapes, handling was not seen as the limiting factor for the decision on appropriate tablet size. However, the smallest sized tablets were rated worst. According to visual perception, the limit of acceptable tablet size was reached at around 250 mg for older adults. For younger adults, this limit was shifted to higher weights and was dependent on the tablet shape. Differences in anticipated swallowability with respect to tablet shapes were most pronounced for tablets of 500 mg and 750 mg in weight, independent of the age category. Capsules performed worse compared to tablets, while mini tablets appeared as a possible alternative dosage form to tablets of higher weight. Within the deglutition part of this study, swallowability capabilities of the same populations were assessed and have been reported previously. Comparing the present results with the swallowing capabilities of the same populations with respect to tablets, it shows adults’ clear self-underestimation of their ability to swallow tablets independent of their age. Full article
(This article belongs to the Special Issue Advance in Development of Patient-Centric Dosage Form, 2nd Edition)
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18 pages, 22565 KiB  
Article
Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450
by Martina Medvedíková, Václav Ranc, Ján Vančo, Zdeněk Trávníček and Pavel Anzenbacher
Pharmaceutics 2023, 15(4), 1314; https://doi.org/10.3390/pharmaceutics15041314 - 21 Apr 2023
Viewed by 1163
Abstract
The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H2O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO3 (complex 1) or BF4 (complex 2) on the activities of different isoenzymes [...] Read more.
The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H2O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO3 (complex 1) or BF4 (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC50 values were 2.46 and 4.88 μM), CYP2C9 (IC50 values were 16.34 and 37.25 μM), and CYP2C19 (IC50 values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents. Full article
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69 pages, 17242 KiB  
Review
Chitosan: A Potential Biopolymer in Drug Delivery and Biomedical Applications
by Nimeet Desai, Dhwani Rana, Sagar Salave, Raghav Gupta, Pranav Patel, Bharathi Karunakaran, Amit Sharma, Jyotsnendu Giri, Derajram Benival and Nagavendra Kommineni
Pharmaceutics 2023, 15(4), 1313; https://doi.org/10.3390/pharmaceutics15041313 - 21 Apr 2023
Cited by 69 | Viewed by 8791
Abstract
Chitosan, a biocompatible and biodegradable polysaccharide derived from chitin, has surfaced as a material of promise for drug delivery and biomedical applications. Different chitin and chitosan extraction techniques can produce materials with unique properties, which can be further modified to enhance their bioactivities. [...] Read more.
Chitosan, a biocompatible and biodegradable polysaccharide derived from chitin, has surfaced as a material of promise for drug delivery and biomedical applications. Different chitin and chitosan extraction techniques can produce materials with unique properties, which can be further modified to enhance their bioactivities. Chitosan-based drug delivery systems have been developed for various routes of administration, including oral, ophthalmic, transdermal, nasal, and vaginal, allowing for targeted and sustained release of drugs. Additionally, chitosan has been used in numerous biomedical applications, such as bone regeneration, cartilage tissue regeneration, cardiac tissue regeneration, corneal regeneration, periodontal tissue regeneration, and wound healing. Moreover, chitosan has also been utilized in gene delivery, bioimaging, vaccination, and cosmeceutical applications. Modified chitosan derivatives have been developed to improve their biocompatibility and enhance their properties, resulting in innovative materials with promising potentials in various biomedical applications. This article summarizes the recent findings on chitosan and its application in drug delivery and biomedical science. Full article
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23 pages, 3204 KiB  
Review
Local Delivery and Controlled Release Drugs Systems: A New Approach for the Clinical Treatment of Periodontitis Therapy
by Mariacristina Amato, Simona Santonocito, Alessandro Polizzi, Gianluca Martino Tartaglia, Vincenzo Ronsivalle, Gaia Viglianisi, Cristina Grippaudo and Gaetano Isola
Pharmaceutics 2023, 15(4), 1312; https://doi.org/10.3390/pharmaceutics15041312 - 21 Apr 2023
Cited by 10 | Viewed by 2832
Abstract
Periodontitis is an inflammatory disease of the gums characterized by the degeneration of periodontal ligaments, the formation of periodontal pockets, and the resorption of the alveolar bone, which results in the destruction of the teeth’s supporting structure. Periodontitis is caused by the growth [...] Read more.
Periodontitis is an inflammatory disease of the gums characterized by the degeneration of periodontal ligaments, the formation of periodontal pockets, and the resorption of the alveolar bone, which results in the destruction of the teeth’s supporting structure. Periodontitis is caused by the growth of diverse microflora (particularly anaerobes) in the pockets, releasing toxins and enzymes and stimulating the immune system. Various approaches, both local and systemic, have been used to treat periodontitis effectively. Successful treatment depends on reducing bacterial biofilm, bleeding on probing (BOP), and reducing or eliminating pockets. Currently, the use of local drug delivery systems (LDDSs) as an adjunctive therapy to scaling and root planing (SRP) in periodontitis is a promising strategy, resulting in greater efficacy and fewer adverse effects by controlling drug release. Selecting an appropriate bioactive agent and route of administration is the cornerstone of a successful periodontitis treatment plan. In this context, this review focuses on applications of LDDSs with varying properties in treating periodontitis with or without systemic diseases to identify current challenges and future research directions. Full article
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10 pages, 4537 KiB  
Communication
Activation of Insulin Gene Expression via Transfection of a CRISPR/dCas9a System Using Magnetic Peptide-Imprinted Nanoparticles
by Mei-Hwa Lee, James L. Thomas, Chien-Yu Lin, Yi-Chen Ethan Li and Hung-Yin Lin
Pharmaceutics 2023, 15(4), 1311; https://doi.org/10.3390/pharmaceutics15041311 - 21 Apr 2023
Cited by 1 | Viewed by 1327
Abstract
A CRISPRa transcription activation system was used to upregulate insulin expression in HEK293T cells. To increase the delivery of the targeted CRISPR/dCas9a, magnetic chitosan nanoparticles, imprinted with a peptide from the Cas9 protein, were developed, characterized, and then bound to dCas9a that was [...] Read more.
A CRISPRa transcription activation system was used to upregulate insulin expression in HEK293T cells. To increase the delivery of the targeted CRISPR/dCas9a, magnetic chitosan nanoparticles, imprinted with a peptide from the Cas9 protein, were developed, characterized, and then bound to dCas9a that was complexed with a guide RNA (gRNA). The adsorption of dCas9 proteins conjugated with activators (SunTag, VPR, and p300) to the nanoparticles was monitored using both ELISA kits and Cas9 staining. Finally, the nanoparticles were used to deliver dCas9a that was complexed with a synthetic gRNA into HEK293T cells to activate their insulin gene expression. Delivery and gene expression were examined using quantitative real-time polymerase chain reaction (qRT-PCR) and staining of insulin. Finally, the long-term release of insulin and the cellular pathway related to stimulation by glucose were also investigated. Full article
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18 pages, 3742 KiB  
Article
Linker-Free Synthesis of Antimicrobial Peptides Using a Novel Cleavage Reagent: Characterisation of the Molecular and Ionic Composition by nanoESI-HR MS
by Roser Segovia, Mireia Díaz-Lobo, Yolanda Cajal, Marta Vilaseca and Francesc Rabanal
Pharmaceutics 2023, 15(4), 1310; https://doi.org/10.3390/pharmaceutics15041310 - 21 Apr 2023
Viewed by 2175
Abstract
The efficient preparation of novel bioactive peptide drugs requires the availability of reliable and accessible chemical methodologies together with suitable analytical techniques for the full characterisation of the synthesised compounds. Herein, we describe a novel acidolytic method with application to the synthesis of [...] Read more.
The efficient preparation of novel bioactive peptide drugs requires the availability of reliable and accessible chemical methodologies together with suitable analytical techniques for the full characterisation of the synthesised compounds. Herein, we describe a novel acidolytic method with application to the synthesis of cyclic and linear peptides involving benzyl-type protection. The process consists of the in situ generation of anhydrous hydrogen bromide and a trialkylsilyl bromide that acts as protic and Lewis acid reagents. This method proved to be useful to effectively remove benzyl-type protecting groups and cleave Fmoc/tBu assembled peptides directly attached to 4-methylbenzhydrylamine (MBHA) resins with no need for using mild trifluoroacetic acid labile linkers. The novel methodology was successful in synthesising three antimicrobial peptides, including the cyclic compound polymyxin B3, dusquetide, and RR4 heptapeptide. Furthermore, electrospray mass spectrometry (ESI-MS) is successfully used for the full characterisation of both the molecular and ionic composition of the synthetic peptides. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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17 pages, 2294 KiB  
Article
Cerium End-Deposited Gold Nanorods-Based Photoimmunotherapy for Boosting Tumor Immunogenicity
by Yanlin Feng, Yumei Xu, Zhaoyang Wen, Xin Ning, Jianlin Wang, Deping Wang, Jimin Cao and Xin Zhou
Pharmaceutics 2023, 15(4), 1309; https://doi.org/10.3390/pharmaceutics15041309 - 21 Apr 2023
Viewed by 1630
Abstract
Background: Triple-negative breast cancer (TNBC) was closely related to high metastatic risk and mortality and has not yet found a targeted receptor for targeted therapy. Cancer immunotherapy, especially photoimmunotherapy, shows promising potential in TNBC treatment because of great spatiotemporal controllability and non-trauma. However, [...] Read more.
Background: Triple-negative breast cancer (TNBC) was closely related to high metastatic risk and mortality and has not yet found a targeted receptor for targeted therapy. Cancer immunotherapy, especially photoimmunotherapy, shows promising potential in TNBC treatment because of great spatiotemporal controllability and non-trauma. However, the therapeutic effectiveness was limited by insufficient tumor antigen generation and the immunosuppressive microenvironment. Methods: We report on the design of cerium oxide (CeO2) end-deposited gold nanorods (CEG) to achieve excellent near-infrared photoimmunotherapy. CEG was synthesized through hydrolyzing of ceria precursor (cerium acetate, Ce(AC)3) on the surface of Au nanorods (NRs) for cancer therapy. The therapeutic response was first verified in murine mammary carcinoma (4T1) cells and then monitored by analysis of the anti-tumor effect in xenograft mouse models. Results: Under near-infrared (NIR) light irradiation, CEG can efficiently generate hot electrons and avoid hot-electron recombination to release heat and form reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and activating part of the immune response. Simultaneously, combining with PD-1 antibody could further enhance cytotoxic T lymphocyte infiltration. Conclusions: Compared with CBG NRs, CEG NRs showed strong photothermal and photodynamic effects to destroy tumors and activate a part of the immune response. Combining with PD-1 antibody could reverse the immunosuppressive microenvironment and thoroughly activate the immune response. This platform demonstrates the superiority of combination therapy of photoimmunotherapy and PD-1 blockade in TNBC therapy. Full article
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29 pages, 6477 KiB  
Article
Amphiphilic Polypeptides Obtained by Post-Polymerization Modification of Poly-l-Lysine as Systems for Combined Delivery of Paclitaxel and siRNA
by Apollinariia Dzhuzha, Erik Gandalipov, Viktor Korzhikov-Vlakh, Elena Katernyuk, Natalia Zakharova, Sergey Silonov, Tatiana Tennikova and Evgenia Korzhikova-Vlakh
Pharmaceutics 2023, 15(4), 1308; https://doi.org/10.3390/pharmaceutics15041308 - 21 Apr 2023
Cited by 2 | Viewed by 1449
Abstract
The development of effective anti-cancer therapeutics remains one of the current pharmaceutical challenges. The joint delivery of chemotherapeutic agents and biopharmaceuticals is a cutting-edge approach to creating therapeutic agents of enhanced efficacy. In this study, amphiphilic polypeptide delivery systems capable of loading both [...] Read more.
The development of effective anti-cancer therapeutics remains one of the current pharmaceutical challenges. The joint delivery of chemotherapeutic agents and biopharmaceuticals is a cutting-edge approach to creating therapeutic agents of enhanced efficacy. In this study, amphiphilic polypeptide delivery systems capable of loading both hydrophobic drug and small interfering RNA (siRNA) were developed. The synthesis of amphiphilic polypeptides included two steps: (i) synthesis of poly-αl-lysine by ring-opening polymerization and (ii) its post-polymerization modification with hydrophobic l-amino acid and l-arginine/l-histidine. The obtained polymers were used for the preparation of single and dual delivery systems of PTX and short double-stranded nucleic acid. The obtained double component systems were quite compact and had a hydrodynamic diameter in the range of 90–200 nm depending on the polypeptide. The release of PTX from the formulations was studied, and the release profiles were approximated using a number of mathematical dissolution models to establish the most probable release mechanism. A determination of the cytotoxicity in normal (HEK 293T) and cancer (HeLa and A549) cells revealed the higher toxicity of the polypeptide particles to cancer cells. The separate evaluation of the biological activity of PTX and anti-GFP siRNA formulations testified the inhibitory efficiency of PTX formulations based on all polypeptides (IC50 4.5–6.2 ng/mL), while gene silencing was effective only for the Tyr-Arg-containing polypeptide (56–70% GFP knockdown). Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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15 pages, 7315 KiB  
Article
Poly(l-Ornithine)-Based Polymeric Micelles as pH-Responsive Macromolecular Anticancer Agents
by Miao Pan, Chao Lu, Wancong Zhang, Huan Huang, Xingyu Shi, Shijie Tang and Daojun Liu
Pharmaceutics 2023, 15(4), 1307; https://doi.org/10.3390/pharmaceutics15041307 - 21 Apr 2023
Cited by 4 | Viewed by 1334
Abstract
Anticancer peptides and polymers represent an emerging field of tumor treatment and can physically interact with tumor cells to address the problem of multidrug resistance. In the present study, poly(l-ornithine)-b-poly(l-phenylalanine) (PLO-b-PLF) block copolypeptides were prepared [...] Read more.
Anticancer peptides and polymers represent an emerging field of tumor treatment and can physically interact with tumor cells to address the problem of multidrug resistance. In the present study, poly(l-ornithine)-b-poly(l-phenylalanine) (PLO-b-PLF) block copolypeptides were prepared and evaluated as macromolecular anticancer agents. Amphiphilic PLO-b-PLF self-assembles into nanosized polymeric micelles in aqueous solution. Cationic PLO-b-PLF micelles interact steadily with the negatively charged surfaces of cancer cells via electrostatic interactions and kill the cancer cells via membrane lysis. To alleviate the cytotoxicity of PLO-b-PLF, 1,2-dicarboxylic-cyclohexene anhydride (DCA) was anchored to the side chains of PLO via an acid-labile β-amide bond to fabricate PLO(DCA)-b-PLF. Anionic PLO(DCA)-b-PLF showed negligible hemolysis and cytotoxicity under neutral physiological conditions but recovered cytotoxicity (anticancer activity) upon charge reversal in the weakly acidic microenvironment of the tumor. PLO-based polypeptides might have potential applications in the emerging field of drug-free tumor treatment. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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22 pages, 1043 KiB  
Review
Stability of Oral Liquid Dosage Forms in Pediatric Cardiology: A Prerequisite for Patient’s Safety—A Narrative Review
by Carmen-Maria Jîtcă, George Jîtcă, Bianca-Eugenia Ősz, Amalia Pușcaș and Silvia Imre
Pharmaceutics 2023, 15(4), 1306; https://doi.org/10.3390/pharmaceutics15041306 - 21 Apr 2023
Viewed by 3933
Abstract
The development of safe and effective pediatric formulations is essential, especially in therapeutic areas such as pediatric cardiology, where the treatment requires multiple dosing or outpatient care. Although liquid oral dosage forms are considered the formulation of choice given the dose flexibility and [...] Read more.
The development of safe and effective pediatric formulations is essential, especially in therapeutic areas such as pediatric cardiology, where the treatment requires multiple dosing or outpatient care. Although liquid oral dosage forms are considered the formulation of choice given the dose flexibility and acceptability, the compounding practices are not endorsed by the health authorities, and achieving stability can be problematic. The purpose of this study is to provide a comprehensive overview of the stability of liquid oral dosage forms used in pediatric cardiology. An extensive review of the literature has been performed, with a particular focus on cardiovascular pharmacotherapy, by consulting the current studies indexed in PubMed, ScienceDirect, PLoS One, and Google Scholar databases. Regulations and guidelines have been considered against the studies found in the literature. Overall, the stability study is well-designed, and the critical quality attributes (CQAs) have been selected for testing. Several approaches have been identified as innovative in order to optimize stability, but opportunities to improve have been also identified, such as in-use studies and achieving dose standardization. Consequently, the information gathering and the results of the studies can be translated into clinical practice in order to achieve the desired stability of liquid oral dosage forms. Full article
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18 pages, 2028 KiB  
Article
Design, Evaluation and Comparison of Nanostructured Lipid Carriers and Chitosan Nanoparticles as Carriers of Poorly Soluble Drugs to Develop Oral Liquid Formulations Suitable for Pediatric Use
by Giulia Nerli, Lídia M. D. Gonçalves, Marzia Cirri, António J. Almeida, Francesca Maestrelli, Natascia Mennini and Paola A. Mura
Pharmaceutics 2023, 15(4), 1305; https://doi.org/10.3390/pharmaceutics15041305 - 21 Apr 2023
Cited by 4 | Viewed by 1498
Abstract
There is a serious need of pediatric drug formulations, whose lack causes the frequent use of extemporaneous preparations obtained from adult dosage forms, with consequent safety and quality risks. Oral solutions are the best choice for pediatric patients, due to administration ease and [...] Read more.
There is a serious need of pediatric drug formulations, whose lack causes the frequent use of extemporaneous preparations obtained from adult dosage forms, with consequent safety and quality risks. Oral solutions are the best choice for pediatric patients, due to administration ease and dosage-adaptability, but their development is challenging, particularly for poorly soluble drugs. In this work, chitosan nanoparticles (CSNPs) and nanostructured lipid carriers (NLCs) were developed and evaluated as potential nanocarriers for preparing oral pediatric solutions of cefixime (poorly soluble model drug). The selected CSNPs and NLCs showed a size around 390 nm, Zeta-potential > 30 mV, and comparable entrapment efficiency (31–36%), but CSNPs had higher loading efficiency (5.2 vs. 1.4%). CSNPs maintained an almost unchanged size, homogeneity, and Zeta-potential during storage, while NLCs exhibited a marked progressive Zeta-potential decrease. Drug release from CSNPs formulations (differently from NLCs) was poorly affected by gastric pH variations, and gave rise to a more reproducible and controlled profile. This was related to their behavior in simulated gastric conditions, where CSNPs were stable, while NLCs suffered a rapid size increase, up to micrometric dimensions. Cytotoxicity studies confirmed CSNPs as the best nanocarrier, proving their complete biocompatibility, while NLCs formulations needed 1:1 dilution to obtain acceptable cell viability values. Full article
(This article belongs to the Special Issue Development of Chitosan/Cyclodextrins in Drug Delivery Field)
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14 pages, 474 KiB  
Article
A Multi-Criteria Decision Aid Tool for Radiopharmaceutical Selection in Tau PET Imaging
by Ilker Ozsahin, Efe Precious Onakpojeruo, Berna Uzun, Dilber Uzun Ozsahin and Tracy A. Butler
Pharmaceutics 2023, 15(4), 1304; https://doi.org/10.3390/pharmaceutics15041304 - 21 Apr 2023
Cited by 2 | Viewed by 1538
Abstract
The accumulation of pathologically misfolded tau is a feature shared by a group of neurodegenerative disorders collectively referred to as tauopathies. Alzheimer’s disease (AD) is the most prevalent of these tauopathies. Immunohistochemical evaluation allows neuropathologists to visualize paired-helical filaments (PHFs)—tau pathological lesions, but [...] Read more.
The accumulation of pathologically misfolded tau is a feature shared by a group of neurodegenerative disorders collectively referred to as tauopathies. Alzheimer’s disease (AD) is the most prevalent of these tauopathies. Immunohistochemical evaluation allows neuropathologists to visualize paired-helical filaments (PHFs)—tau pathological lesions, but this is possible only after death and only shows tau in the portion of brain sampled. Positron emission tomography (PET) imaging allows both the quantitative and qualitative analysis of pathology over the whole brain of a living subject. The ability to detect and quantify tau pathology in vivo using PET can aid in the early diagnosis of AD, provide a way to monitor disease progression, and determine the effectiveness of therapeutic interventions aimed at reducing tau pathology. Several tau-specific PET radiotracers are now available for research purposes, and one is approved for clinical use. This study aims to analyze, compare, and rank currently available tau PET radiotracers using the fuzzy preference ranking organization method for enrichment of evaluations (PROMETHEE), which is a multi-criteria decision-making (MCDM) tool. The evaluation is based on relatively weighted criteria, such as specificity, target binding affinity, brain uptake, brain penetration, and rates of adverse reactions. Based on the selected criteria and assigned weights, this study shows that a second-generation tau tracer, [18F]RO-948, may be the most favorable. This flexible method can be extended and updated to include new tracers, additional criteria, and modified weights to help researchers and clinicians select the optimal tau PET tracer for specific purposes. Additional work is needed to confirm these results, including a systematic approach to defining and weighting criteria and clinical validation of tracers in different diseases and patient populations. Full article
(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)
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16 pages, 2864 KiB  
Article
Release of TGF-β3 from Surface-Modified PCL Fiber Mats Triggers a Dose-Dependent Chondrogenic Differentiation of Human Mesenchymal Stromal Cells
by Leonie Berten-Schunk, Yvonne Roger, Heike Bunjes and Andrea Hoffmann
Pharmaceutics 2023, 15(4), 1303; https://doi.org/10.3390/pharmaceutics15041303 - 21 Apr 2023
Cited by 3 | Viewed by 1405
Abstract
The design of implants for tissue transitions remains a major scientific challenge. This is due to gradients in characteristics that need to be restored. The rotator cuff in the shoulder, with its direct osteo-tendinous junction (enthesis), is a prime example of such a [...] Read more.
The design of implants for tissue transitions remains a major scientific challenge. This is due to gradients in characteristics that need to be restored. The rotator cuff in the shoulder, with its direct osteo-tendinous junction (enthesis), is a prime example of such a transition. Our approach towards an optimized implant for entheses is based on electrospun fiber mats of poly(ε-caprolactone) (PCL) as biodegradable scaffold material, loaded with biologically active factors. Chitosan/tripolyphosphate (CS/TPP) nanoparticles were used to load transforming growth factor-β3 (TGF-β3) with increasing loading concentrations for the regeneration of the cartilage zone within direct entheses. Release experiments were performed, and the concentration of TGF-β3 in the release medium was determined by ELISA. Chondrogenic differentiation of human mesenchymal stromal cells (MSCs) was analyzed in the presence of released TGF-β3. The amount of released TGF-β3 increased with the use of higher loading concentrations. This correlated with larger cell pellets and an increase in chondrogenic marker genes (SOX9, COL2A1, COMP). These data were further supported by an increase in the glycosaminoglycan (GAG)-to-DNA ratio of the cell pellets. The results demonstrate an increase in the total release of TGF-β3 by loading higher concentrations to the implant, which led to the desired biological effect. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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14 pages, 2153 KiB  
Article
Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer
by Quezia Lacerda, Hebah Falatah, Ji-Bin Liu, Corinne E. Wessner, Brian Oeffinger, Ankit Rochani, Dennis B. Leeper, Flemming Forsberg, Joseph M. Curry, Gagan Kaushal, Scott W. Keith, Patrick O’Kane, Margaret A. Wheatley and John R. Eisenbrey
Pharmaceutics 2023, 15(4), 1302; https://doi.org/10.3390/pharmaceutics15041302 - 21 Apr 2023
Cited by 3 | Viewed by 2191
Abstract
Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of [...] Read more.
Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O2 and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O2 and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation. Full article
(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)
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14 pages, 1516 KiB  
Article
Controlled Release of Flurbiprofen from 3D-Printed and Supercritical Carbon Dioxide Processed Methacrylate-Based Polymer
by Truc T. Ngo and Jae D. Kim
Pharmaceutics 2023, 15(4), 1301; https://doi.org/10.3390/pharmaceutics15041301 - 21 Apr 2023
Viewed by 1067
Abstract
The ability to engineer and predict drug release behavior during treatment is critical to the design and implementation of effective drug delivery systems. In this study, a drug delivery system consisting of a methacrylate-based polymer and flurbiprofen was studied, and its release profile [...] Read more.
The ability to engineer and predict drug release behavior during treatment is critical to the design and implementation of effective drug delivery systems. In this study, a drug delivery system consisting of a methacrylate-based polymer and flurbiprofen was studied, and its release profile in a controlled phosphate-buffered saline solution was characterized. The polymer, which was 3D printed and processed in supercritical carbon dioxide under different temperature and pressure settings, showed sustained drug release over a prolonged period. A computer algorithm was used to determine the drug release time duration before reaching steady state and the maximum drug release at steady state. Several empirical models were applied to fit the release kinetic data to gain information about the drug release mechanism. The diffusion coefficients for each system were also estimated using Fick’s law. Based on the results, the influence of supercritical carbon dioxide processing conditions on the diffusion behavior is interpreted, providing insights into the effective and tunable design of drug delivery systems for targeted treatment specifications. Full article
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18 pages, 2526 KiB  
Review
Microfluidic Liver-on-a-Chip for Preclinical Drug Discovery
by Jingyu Fu, Hailong Qiu and Cherie S. Tan
Pharmaceutics 2023, 15(4), 1300; https://doi.org/10.3390/pharmaceutics15041300 - 21 Apr 2023
Cited by 2 | Viewed by 1856
Abstract
Drug discovery is an expensive, long, and complex process, usually with a high degree of uncertainty. In order to improve the efficiency of drug development, effective methods are demanded to screen lead molecules and eliminate toxic compounds in the preclinical pipeline. Drug metabolism [...] Read more.
Drug discovery is an expensive, long, and complex process, usually with a high degree of uncertainty. In order to improve the efficiency of drug development, effective methods are demanded to screen lead molecules and eliminate toxic compounds in the preclinical pipeline. Drug metabolism is crucial in determining the efficacy and potential side effects, mainly in the liver. Recently, the liver-on-a-chip (LoC) platform based on microfluidic technology has attracted widespread attention. LoC systems can be applied to predict drug metabolism and hepatotoxicity or to investigate PK/PD (pharmacokinetics/pharmacodynamics) performance when combined with other artificial organ-on-chips. This review discusses the liver physiological microenvironment simulated by LoC, especially the cell compositions and roles. We summarize the current methods of constructing LoC and the pharmacological and toxicological application of LoC in preclinical research. In conclusion, we also discussed the limitations of LoC in drug discovery and proposed a direction for improvement, which may provide an agenda for further research. Full article
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16 pages, 3575 KiB  
Article
mTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4+CD57+ T Cells In Vivo and In Vitro
by Florence Herr, Manon Dekeyser, Jerome Le Pavec, Christophe Desterke, Andrada-Silvana Chiron, Karen Bargiel, Olaf Mercier, Amelia Vernochet, Elie Fadel and Antoine Durrbach
Pharmaceutics 2023, 15(4), 1299; https://doi.org/10.3390/pharmaceutics15041299 - 20 Apr 2023
Cited by 1 | Viewed by 898
Abstract
Calcineurin inhibitors have improved graft survival in solid-organ transplantation but their use is limited by toxicity, requiring a switch to another immunosuppressor in some cases. Belatacept is one option that has been shown to improve graft and patient survival despite being associated with [...] Read more.
Calcineurin inhibitors have improved graft survival in solid-organ transplantation but their use is limited by toxicity, requiring a switch to another immunosuppressor in some cases. Belatacept is one option that has been shown to improve graft and patient survival despite being associated with a higher risk of acute cellular rejection. This risk of acute cellular rejection is correlated with the presence of belatacept-resistant T cells. We performed a transcriptomic analysis of in vitro-activated cells to identify pathways affected by belatacept in belatacept-sensitive cells (CD4+CD57) but not in belatacept-resistant CD4+CD57+ T cells. mTOR was significantly downregulated in belatacept-sensitive but not belatacept-resistant T cells. The inhibition of mTOR strongly decreases the activation and cytotoxicity of CD4+CD57+ cells. In humans, the use of a combination of mTOR inhibitor and belatacept prevents graft rejection and decreases the expression of activation markers on CD4 and CD8 T cells. mTOR inhibition decreases the functioning of belatacept-resistant CD4+CD57+ T cells in vitro and in vivo. It could potentially be used in association with belatacept to prevent acute cellular rejection in cases of calcineurin intolerance. Full article
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12 pages, 2783 KiB  
Article
Imageable AuNP-ECM Hydrogel Tissue Implants for Regenerative Medicine
by Malka Shilo, Ester-Sapir Baruch, Lior Wertheim, Hadas Oved, Assaf Shapira and Tal Dvir
Pharmaceutics 2023, 15(4), 1298; https://doi.org/10.3390/pharmaceutics15041298 - 20 Apr 2023
Viewed by 1218
Abstract
In myocardial infarction, a blockage in one of the coronary arteries leads to ischemic conditions in the left ventricle of the myocardium and, therefore, to significant death of contractile cardiac cells. This process leads to the formation of scar tissue, which reduces heart [...] Read more.
In myocardial infarction, a blockage in one of the coronary arteries leads to ischemic conditions in the left ventricle of the myocardium and, therefore, to significant death of contractile cardiac cells. This process leads to the formation of scar tissue, which reduces heart functionality. Cardiac tissue engineering is an interdisciplinary technology that treats the injured myocardium and improves its functionality. However, in many cases, mainly when employing injectable hydrogels, the treatment may be partial because it does not fully cover the diseased area and, therefore, may not be effective and even cause conduction disorders. Here, we report a hybrid nanocomposite material composed of gold nanoparticles and an extracellular matrix-based hydrogel. Such a hybrid hydrogel could support cardiac cell growth and promote cardiac tissue assembly. After injection of the hybrid material into the diseased area of the heart, it could be efficiently imaged by magnetic resonance imaging (MRI). Furthermore, as the scar tissue could also be detected by MRI, a distinction between the diseased area and the treatment could be made, providing information about the ability of the hydrogel to cover the scar. We envision that such a nanocomposite hydrogel may improve the accuracy of tissue engineering treatment. Full article
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17 pages, 9050 KiB  
Article
Proliferative and Osteogenic Supportive Effect of VEGF-Loaded Collagen-Chitosan Hydrogel System in Bone Marrow Derived Mesenchymal Stem Cells
by Jeevithan Elango
Pharmaceutics 2023, 15(4), 1297; https://doi.org/10.3390/pharmaceutics15041297 - 20 Apr 2023
Cited by 6 | Viewed by 1338
Abstract
The use of hydrogel (HG) in regenerative medicine is an emerging field and thus several approaches have been proposed recently to find an appropriate hydrogel system. In this sense, this study developed a novel HG system using collagen, chitosan, and VEGF composites for [...] Read more.
The use of hydrogel (HG) in regenerative medicine is an emerging field and thus several approaches have been proposed recently to find an appropriate hydrogel system. In this sense, this study developed a novel HG system using collagen, chitosan, and VEGF composites for culturing mesenchymal stem cells (MSCs), and investigated their ability for osteogenic differentiation and mineral deposition. Our results showed that the HG loaded with 100 ng/mL VEGF (HG-100) significantly supported the proliferation of undifferentiated MSCs, the fibrillary filament structure (HE stain), mineralization (alizarin red S and von Kossa stain), alkaline phosphatase, and the osteogenesis of differentiated MSCs compared to other hydrogels (loaded with 25 and 50 ng/mL VEGF) and control (without hydrogel). HG-100 showed a higher VEGF releasing rate from day 3 to day 7 than other HGs, which substantially supports the proliferative and osteogenic properties of HG-100. However, the HGs did not increase the cell growth in differentiated MSCs on days 14 and 21 due to the confluence state (reach stationary phase) and cell loading ability, regardless of the VEGF content. Similarly, the HGs alone did not stimulate the osteogenesis of MSCs; however, they increased the osteogenic ability of MSCs in presence of osteogenic supplements. Accordingly, a fabricated HG with VEGF could be used as an appropriate system to culture stem cells for bone and dental regeneration. Full article
(This article belongs to the Special Issue Hydrogels in Drug Delivery: Progress and Challenges)
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17 pages, 4364 KiB  
Article
Formulation and Characterization of Electrospun Nanofibers for Melatonin Ocular Delivery
by Alessia Romeo, Adrienn Kazsoki, Safaa Omer, Balázs Pinke, László Mészáros, Teresa Musumeci and Romána Zelkó
Pharmaceutics 2023, 15(4), 1296; https://doi.org/10.3390/pharmaceutics15041296 - 20 Apr 2023
Cited by 3 | Viewed by 1509
Abstract
The poor ocular bioavailability of melatonin (MEL) limits the therapeutic action the molecule could exert in the treatment of ocular diseases. To date, no study has explored the use of nanofiber-based inserts to prolong ocular surface contact time and improve MEL delivery. Here, [...] Read more.
The poor ocular bioavailability of melatonin (MEL) limits the therapeutic action the molecule could exert in the treatment of ocular diseases. To date, no study has explored the use of nanofiber-based inserts to prolong ocular surface contact time and improve MEL delivery. Here, the electrospinning technique was proposed to prepare poly (vinyl alcohol) (PVA) and poly (lactic acid) (PLA) nanofiber inserts. Both nanofibers were produced with different concentrations of MEL and with or without the addition of Tween® 80. Nanofibers morphology was evaluated by scanning electron microscopy. Thermal and spectroscopic analyses were performed to characterize the state of MEL in the scaffolds. MEL release profiles were observed under simulated physiological conditions (pH 7.4, 37 °C). The swelling behavior was evaluated by a gravimetric method. The results confirmed that submicron-sized nanofibrous structures were obtained with MEL in the amorphous state. Different MEL release rates were achieved depending on the nature of the polymer. Fast (20 min) and complete release was observed for the PVA-based samples, unlike the PLA polymer, which provided slow and controlled MEL release. The addition of Tween® 80 affected the swelling properties of the fibrous structures. Overall, the results suggest that membranes could be an attractive vehicle as a potential alternative to liquid formulations for ocular administration of MEL. Full article
(This article belongs to the Special Issue Recent Development of Electrospinning for Drug Delivery, 3rd Edition)
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13 pages, 2720 KiB  
Article
Adoptive Transfer of Photosensitizer-Loaded Cytotoxic T Cells for Combinational Photodynamic Therapy and Cancer Immuno-Therapy
by André-René Blaudszun, Woo Jun Kim, Wooram Um, Hong Yeol Yoon, Man Kyu Shim and Kwangmeyung Kim
Pharmaceutics 2023, 15(4), 1295; https://doi.org/10.3390/pharmaceutics15041295 - 20 Apr 2023
Cited by 2 | Viewed by 1712
Abstract
Adoptive cell transfer (ACT) has shown remarkable therapeutic efficacy against blood cancers such as leukemia and lymphomas, but its effect is still limited due to the lack of well-defined antigens expressed by aberrant cells within tumors, the insufficient trafficking of administered T cells [...] Read more.
Adoptive cell transfer (ACT) has shown remarkable therapeutic efficacy against blood cancers such as leukemia and lymphomas, but its effect is still limited due to the lack of well-defined antigens expressed by aberrant cells within tumors, the insufficient trafficking of administered T cells to the tumor sites, as well as immunosuppression induced by the tumor microenvironment (TME). In this study, we propose the adoptive transfer of photosensitizer (PS)-loaded cytotoxic T cells for a combinational photodynamic and cancer immunotherapy. Temoporfin (Foscan®), a clinically applicable porphyrin derivative, was loaded into OT-1 cells (PS-OT-1 cells). The PS-OT-1 cells efficiently produced a large amount of reactive oxygen species (ROS) under visible light irradiation in a culture; importantly, the combinational photodynamic therapy (PDT) and ACT with PS-OT-1 cells induced significant cytotoxicity compared to ACT alone with unloaded OT-1 cells. In murine lymphoma models, intravenously injected PS-OT-1 cells significantly inhibited tumor growth compared to unloaded OT-1 cells when the tumor tissues were locally irradiated with visible light. Collectively, this study suggests that combinational PDT and ACT mediated by PS-OT-1 cells provides a new approach for effective cancer immunotherapy. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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26 pages, 11693 KiB  
Article
Hydroxyapatite Thin Films of Marine Origin as Sustainable Candidates for Dental Implants
by Gabriela Dorcioman, Valentina Grumezescu, George E. Stan, Mariana Carmen Chifiriuc, Gratiela Pircalabioru Gradisteanu, Florin Miculescu, Elena Matei, Gianina Popescu-Pelin, Irina Zgura, Valentin Craciun, Faik Nüzhet Oktar and Liviu Duta
Pharmaceutics 2023, 15(4), 1294; https://doi.org/10.3390/pharmaceutics15041294 - 20 Apr 2023
Cited by 5 | Viewed by 1989
Abstract
Novel biomaterials with promising bone regeneration potential, derived from rich, renewable, and cheap sources, are reported. Thus, thin films were synthesized from marine-derived (i.e., from fish bones and seashells) hydroxyapatite (MdHA) by pulsed laser deposition (PLD) technique. Besides the physical–chemical and mechanical investigations, [...] Read more.
Novel biomaterials with promising bone regeneration potential, derived from rich, renewable, and cheap sources, are reported. Thus, thin films were synthesized from marine-derived (i.e., from fish bones and seashells) hydroxyapatite (MdHA) by pulsed laser deposition (PLD) technique. Besides the physical–chemical and mechanical investigations, the deposited thin films were also evaluated in vitro using dedicated cytocompatibility and antimicrobial assays. The morphological examination of MdHA films revealed the fabrication of rough surfaces, which were shown to favor good cell adhesion, and furthermore could foster the in-situ anchorage of implants. The strong hydrophilic behavior of the thin films was evidenced by contact angle (CA) measurements, with values in the range of 15–18°. The inferred bonding strength adherence values were superior (i.e., ~49 MPa) to the threshold established by ISO regulation for high-load implant coatings. After immersion in biological fluids, the growth of an apatite-based layer was noted, which indicated the good mineralization capacity of the MdHA films. All PLD films exhibited low cytotoxicity on osteoblast, fibroblast, and epithelial cells. Moreover, a persistent protective effect against bacterial and fungal colonization (i.e., 1- to 3-log reduction of E. coli, E. faecalis, and C. albicans growth) was demonstrated after 48 h of incubation, with respect to the Ti control. The good cytocompatibility and effective antimicrobial activity, along with the reduced fabrication costs from sustainable sources (available in large quantities), should, therefore, recommend the MdHA materials proposed herein as innovative and viable solutions for the development of novel coatings for metallic dental implants. Full article
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19 pages, 1953 KiB  
Review
The Science of Selecting Excipients for Dermal Self-Emulsifying Drug Delivery Systems
by Daniélle van Staden, Richard K. Haynes and Joe M. Viljoen
Pharmaceutics 2023, 15(4), 1293; https://doi.org/10.3390/pharmaceutics15041293 - 20 Apr 2023
Cited by 1 | Viewed by 1772
Abstract
Self-emulsification is considered a formulation technique that has proven capacity to improve oral drug delivery of poorly soluble drugs by advancing both solubility and bioavailability. The capacity of these formulations to produce emulsions after moderate agitation and dilution by means of water phase [...] Read more.
Self-emulsification is considered a formulation technique that has proven capacity to improve oral drug delivery of poorly soluble drugs by advancing both solubility and bioavailability. The capacity of these formulations to produce emulsions after moderate agitation and dilution by means of water phase addition provides a simplified method to improve delivery of lipophilic drugs, where prolonged drug dissolution in the aqueous environment of the gastro-intestinal (GI) tract is known as the rate-limiting step rendering decreased drug absorption. Additionally, spontaneous emulsification has been reported as an innovative topical drug delivery system that enables successful crossing of mucus membranes as well as skin. The ease of formulation generated by the spontaneous emulsification technique itself is intriguing due to the simplified production procedure and unlimited upscaling possibilities. However, spontaneous emulsification depends solely on selecting excipients that complement each other in order to create a vehicle aimed at optimizing drug delivery. If excipients are not compatible or unable to spontaneously transpire into emulsions once exposed to mild agitation, no self-emulsification will be achieved. Therefore, the generalized view of excipients as inert bystanders facilitating delivery of an active compound cannot be accepted when selecting excipients needed to produce self-emulsifying drug delivery systems (SEDDSs). Hence, this review describes the excipients needed to generate dermal SEDDSs as well as self-double-emulsifying drug delivery systems (SDEDDSs); how to consider combinations that complement the incorporated drug(s); and an overview of using natural excipients as thickening agents and skin penetration enhancers. Full article
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25 pages, 5444 KiB  
Article
In Vivo Acute Toxicity and Immunomodulation Assessment of a Novel Nutraceutical in Mice
by Tatiana Onisei, Bianca-Maria Tihăuan, Georgiana Dolete, Mădălina Axinie (Bucos), Manuela Răscol and Gheorghița Isvoranu
Pharmaceutics 2023, 15(4), 1292; https://doi.org/10.3390/pharmaceutics15041292 - 20 Apr 2023
Viewed by 1047
Abstract
Achieving and maintaining a well-balanced immune system has righteously become an insightful task for the general population and an even more fundamental goal for those affected by immune-related diseases. Since our immune functions are indispensable in defending the body against pathogens, diseases and [...] Read more.
Achieving and maintaining a well-balanced immune system has righteously become an insightful task for the general population and an even more fundamental goal for those affected by immune-related diseases. Since our immune functions are indispensable in defending the body against pathogens, diseases and other external attacks, while playing a vital role in maintaining health and modulating the immune response, we require an on-point grasp of their shortcoming as a foundation for the development of functional foods and novel nutraceuticals. Seeing that immunoceuticals are considered effective in improving immune functions and reducing the incidence of immunological disorders, the main focus of this study was to assess the immunomodulatory properties and possible acute toxicity of a novel nutraceutical with active substances of natural origin on C57BL/6 mice for 21 days. We evaluated the potential hazards (microbial contamination and heavy metals) of the novel nutraceutical and addressed the acute toxicity according to OECD guidelines of a 2000 mg/kg dose on mice for 21 days. The immunomodulatory effect was assessed at three concentrations (50 mg/kg, 100 mg/kg and 200 mg/kg) by determining body and organ indexes through a leukocyte analysis; flow cytometry immunophenotyping of lymphocytes populations and their subpopulations (T lymphocytes (LyCD3+), cytotoxic suppressor T lymphocytes (CD3+CD8+), helper T lymphocytes (CD3+CD4+), B lymphocytes (CD3−CD19+) and NK cells (CD3−NK1.1.+); and the expression of the CD69 activation marker. The results obtained for the novel nutraceutical referred to as ImunoBoost indicated no acute toxicity, an increased number of lymphocytes and the stimulation of lymphocyte activation and proliferation, demonstrating its immunomodulatory effect. The safe human consumption dose was established at 30 mg/day. Full article
(This article belongs to the Special Issue Recent Advances in Oral Solid Dosages)
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22 pages, 4927 KiB  
Article
In Vitro Biotransformation and Anti-Inflammatory Activity of Constituents and Metabolites of Filipendula ulmaria
by Anastasia Van der Auwera, Laura Peeters, Kenn Foubert, Stefano Piazza, Wim Vanden Berghe, Nina Hermans and Luc Pieters
Pharmaceutics 2023, 15(4), 1291; https://doi.org/10.3390/pharmaceutics15041291 - 20 Apr 2023
Cited by 2 | Viewed by 1283
Abstract
(1) Background: Filipendula ulmaria (L.) Maxim. (Rosaceae) (meadowsweet) is widely used in phytotherapy against inflammatory diseases. However, its active constituents are not exactly known. Moreover, it contains many constituents, such as flavonoid glycosides, which are not absorbed, but metabolized in the colon by [...] Read more.
(1) Background: Filipendula ulmaria (L.) Maxim. (Rosaceae) (meadowsweet) is widely used in phytotherapy against inflammatory diseases. However, its active constituents are not exactly known. Moreover, it contains many constituents, such as flavonoid glycosides, which are not absorbed, but metabolized in the colon by gut microbiota, producing potentially active metabolites that can be absorbed. The aim of this study was to characterize the active constituents or metabolites. (2) Methods: A F. ulmaria extract was processed in an in vitro gastrointestinal biotransformation model, and the metabolites were characterized using UHPLC-ESI-QTOF-MS analysis. In vitro anti-inflammatory activity was evaluated by testing the inhibition of NF-κB activation, COX-1 and COX-2 enzyme inhibition. (3) Results: The simulation of gastrointestinal biotransformation showed a decrease in the relative abundance of glycosylated flavonoids such as rutin, spiraeoside and isoquercitrin in the colon compartment, and an increase in aglycons such as quercetin, apigenin, naringenin and kaempferol. The genuine as well as the metabolized extract showed a better inhibition of the COX-1 enzyme as compared to COX-2. A mix of aglycons present after biotransformation showed a significant inhibition of COX-1. (4) Conclusions: The anti-inflammatory activity of F. ulmaria may be explained by an additive or synergistic effect of genuine constituents and metabolites. Full article
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21 pages, 5257 KiB  
Article
Extracellular Vesicles and Their Mimetics: A Comparative Study of Their Pharmacological Activities and Immunogenicity Profiles
by Wei Heng Chng, Ram Pravin Kumar Muthuramalingam, Charles Kang Liang Lou, Silas New, Yub Raj Neupane, Choon Keong Lee, Ayca Altay Benetti, Chenyuan Huang, Praveen Thoniyot, Wei Seong Toh, Jiong-Wei Wang and Giorgia Pastorin
Pharmaceutics 2023, 15(4), 1290; https://doi.org/10.3390/pharmaceutics15041290 - 20 Apr 2023
Cited by 1 | Viewed by 1548
Abstract
Extracellular vesicles (EVs), which are miniaturised carriers loaded with functional proteins, lipids, and nucleic acid material, are naturally secreted by cells and show intrinsic pharmacological effects in several conditions. As such, they have the potential to be used for the treatment of various [...] Read more.
Extracellular vesicles (EVs), which are miniaturised carriers loaded with functional proteins, lipids, and nucleic acid material, are naturally secreted by cells and show intrinsic pharmacological effects in several conditions. As such, they have the potential to be used for the treatment of various human diseases. However, the low isolation yield and laborious purification process are obstacles to their translation for clinical use. To overcome this problem, our lab developed cell-derived nanovesicles (CDNs), which are EV mimetics produced by shearing cells through membrane-fitted spin cups. To evaluate the similarities between EVs and CDNs, we compare the physical properties and biochemical composition of monocytic U937 EVs and U937 CDNs. Besides having similar hydrodynamic diameters, the produced CDNs had proteomic, lipidomic, and miRNA profiles with key communalities compared to those of natural EVs. Further characterisation was conducted to examine if CDNs could exhibit similar pharmacological activities and immunogenicity when administered in vivo. Consistently, CDNs and EVs modulated inflammation and displayed antioxidant activities. EVs and CDNs both did not exert immunogenicity when administered in vivo. Overall, CDNs could serve as a scalable and efficient alternative to EVs for further translation into clinical use. Full article
(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)
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27 pages, 7036 KiB  
Article
Multicomponent Lipid Nanoparticles for RNA Transfection
by Nataliya Gretskaya, Mikhail Akimov, Dmitry Andreev, Anton Zalygin, Ekaterina Belitskaya, Galina Zinchenko, Elena Fomina-Ageeva, Ilya Mikhalyov, Elena Vodovozova and Vladimir Bezuglov
Pharmaceutics 2023, 15(4), 1289; https://doi.org/10.3390/pharmaceutics15041289 - 20 Apr 2023
Cited by 4 | Viewed by 1978
Abstract
Despite the wide variety of available cationic lipid platforms for the delivery of nucleic acids into cells, the optimization of their composition has not lost its relevance. The purpose of this work was to develop multi-component cationic lipid nanoparticles (LNPs) with or without [...] Read more.
Despite the wide variety of available cationic lipid platforms for the delivery of nucleic acids into cells, the optimization of their composition has not lost its relevance. The purpose of this work was to develop multi-component cationic lipid nanoparticles (LNPs) with or without a hydrophobic core from natural lipids in order to evaluate the efficiency of LNPs with the widely used cationic lipoid DOTAP (1,2-dioleoyloxy-3-[trimethylammonium]-propane) and the previously unstudied oleoylcholine (Ol-Ch), as well as the ability of LNPs containing GM3 gangliosides to transfect cells with mRNA and siRNA. LNPs containing cationic lipids, phospholipids and cholesterol, and surfactants were prepared according to a three-stage procedure. The average size of the resulting LNPs was 176 nm (PDI 0.18). LNPs with DOTAP mesylate were more effective than those with Ol-Ch. Core LNPs demonstrated low transfection activity compared with bilayer LNPs. The type of phospholipid in LNPs was significant for the transfection of MDA-MB-231 and SW 620 cancer cells but not HEK 293T cells. LNPs with GM3 gangliosides were the most efficient for the delivery of mRNA to MDA-MB-231 cells and siRNA to SW620 cells. Thus, we developed a new lipid platform for the efficient delivery of RNA of various sizes to mammalian cells. Full article
(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)
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13 pages, 2200 KiB  
Article
Experimental Elucidation of Templated Crystallization and Secondary Processing of Peptides
by Vivek Verma, Isha Bade, Vikram Karde and Jerry Y. Y. Heng
Pharmaceutics 2023, 15(4), 1288; https://doi.org/10.3390/pharmaceutics15041288 - 20 Apr 2023
Viewed by 1333
Abstract
The crystallization of peptides offers a sustainable and inexpensive alternative to the purification process. In this study, diglycine was crystallised in porous silica, showing the porous templates’ positive yet discriminating effect. The diglycine induction time was reduced by five-fold and three-fold upon crystallising [...] Read more.
The crystallization of peptides offers a sustainable and inexpensive alternative to the purification process. In this study, diglycine was crystallised in porous silica, showing the porous templates’ positive yet discriminating effect. The diglycine induction time was reduced by five-fold and three-fold upon crystallising in the presence of silica with pore sizes of 6 nm and 10 nm, respectively. The diglycine induction time had a direct relationship with the silica pore size. The stable form (α-form) of diglycine was crystallised in the presence of porous silica, with the diglycine crystals obtained associated with the silica particles. Further, we studied the mechanical properties of diglycine tablets for their tabletability, compactability, and compressibility. The mechanical properties of the diglycine tablets were similar to those of pure MCC, even with the presence of diglycine crystals in the tablets. The diffusion studies of the tablets using the dialysis membrane presented an extended release of diglycine through the dialysis membrane, confirming that the peptide crystal can be used for oral formulation. Hence, the crystallization of peptides preserved their mechanical and pharmacological properties. More data on different peptides can help us produce oral formulation peptides faster than usual. Full article
(This article belongs to the Special Issue Recent Advances in Secondary Processing of Pharmaceutical Powders)
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