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Pharmaceutics
Volume 15
Issue 1
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Pharmaceutics, Volume 15, Issue 1 (January 2023) – 304 articles

Cover Story (view full-size image): The efficacy of therapeutic antibodies has been limited in solid tumors due to the poor distribution of antibodies within tumor tissues. We have reported that the combination of ultrasound-responsive nanobubbles (NBs) and therapeutic ultrasound (TUS) increases the efficiency of the delivery of macromolecular drugs to target tissues. In this study, we developed therapeutic antibody-modified NBs using an Fc-binding polypeptide that can quickly load antibodies to nanocarriers and assessed the utility of combining the NBs and TUS as an antibody delivery system. The combination system can enable efficient antibody drug delivery to tumors, while retaining the original antibody activity. Hence, this system has the potential to maximize the therapeutic effects in antibody therapy for solid tumors. View this paper
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13 pages, 4120 KiB  
Article
Fractal Kinetic Implementation in Population Pharmacokinetic Modeling
by Woojin Jung, Hyo-jeong Ryu, Jung-woo Chae and Hwi-yeol Yun
Pharmaceutics 2023, 15(1), 304; https://doi.org/10.3390/pharmaceutics15010304 - 16 Jan 2023
Viewed by 2112
Abstract
Compartment modeling is a widely accepted technique in the field of pharmacokinetic analysis. However, conventional compartment modeling is performed under a homogeneity assumption that is not a naturally occurring condition. Since the assumption lacks physiological considerations, the respective modeling approach has been questioned, [...] Read more.
Compartment modeling is a widely accepted technique in the field of pharmacokinetic analysis. However, conventional compartment modeling is performed under a homogeneity assumption that is not a naturally occurring condition. Since the assumption lacks physiological considerations, the respective modeling approach has been questioned, as novel drugs are increasingly characterized by physiological or physical features. Alternative approaches have focused on fractal kinetics, but evaluations of their application are lacking. Thus, in this study, a simulation was performed to identify desirable fractal-kinetics applications in conventional modeling. Visible changes in the profiles were then investigated. Five cases of finalized population models were collected for implementation. For model diagnosis, the objective function value (OFV), Akaike’s information criterion (AIC), and corrected Akaike’s information criterion (AICc) were used as performance metrics, and the goodness of fit (GOF), visual predictive check (VPC), and normalized prediction distribution error (NPDE) were used as visual diagnostics. In most cases, model performance was enhanced by the fractal rate, as shown in a simulation study. The necessary parameters of the fractal rate in the model varied and were successfully estimated between 0 and 1. GOF, VPC, and NPDE diagnostics show that models with the fractal rate described the data well and were robust. In the simulation study, the fractal absorption process was, therefore, chosen for testing. In the estimation study, the rate application yielded improved performance and good prediction–observation agreement in early sampling points, and did not cause a large shift in the original estimation results. Thus, the fractal rate yielded explainable parameters by setting only the heterogeneity exponent, which reflects true physiological behavior well. This approach can be expected to provide useful insights in pharmacological decision making. Full article
(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process (Volume II))
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19 pages, 2856 KiB  
Article
Design, Development, and Optimisation of Smart Linker Chemistry for Targeted Colonic Delivery—In Vitro Evaluation
by Heba S. Abd-Ellah, Ramesh Mudududdla, Glen P. Carter and Jonathan B. Baell
Pharmaceutics 2023, 15(1), 303; https://doi.org/10.3390/pharmaceutics15010303 - 16 Jan 2023
Cited by 1 | Viewed by 2122
Abstract
Drug targeting is necessary to deliver drugs to a specific site of action at a rate dictated by therapeutic requirements. The pharmacological action of a drug can thereby be optimised while minimising adverse effects. Numerous colonic drug delivery systems have been developed to [...] Read more.
Drug targeting is necessary to deliver drugs to a specific site of action at a rate dictated by therapeutic requirements. The pharmacological action of a drug can thereby be optimised while minimising adverse effects. Numerous colonic drug delivery systems have been developed to avoid such undesirable side effects; however, these systems lack site specificity, leaving room for further improvement. The objective of the present study was to explore the potential of amino-alkoxycarbonyloxymethyl (amino-AOCOM) ether prodrugs as a general approach for future colonic delivery. To circumvent inter- and intra-subject variabilities in enzyme activities, these prodrugs do not rely on enzymes but rather are activated via a pH-triggered intramolecular cyclisation–elimination reaction. As proof of concept, model compounds were synthesised and evaluated under various pH conditions, simulating various regions of the gastrointestinal tract (GIT). Probe 15 demonstrated excellent stability under simulated stomach- and duodenum-like conditions and protected 60% of the payload in a small intestine-like environment. Moreover, 15 displayed sustained release at colonic pH, delivering >90% of the payload over 38 h. Mesalamine (Msl) prodrugs 21 and 22 were also synthesised and showed better stability than probe 15 in the simulated upper GIT but relatively slower release at colonic pH (61–68% of Msl over 48 h). For both prodrugs, the extent of release was comparable to that of the commercial product Asacol. This study provides initial proof of concept regarding the use of a cyclisation-activated prodrug for colon delivery and suggests that release characteristics still vary on a case-by-case basis. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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12 pages, 1674 KiB  
Article
The Combined Anti-Tumor Efficacy of Bioactive Hydroxyapatite Nanoparticles Loaded with Altretamine
by Yahia Alghazwani, Krishnaraju Venkatesan, Kousalya Prabahar, Mohamed El-Sherbiny, Nehal Elsherbiny and Mona Qushawy
Pharmaceutics 2023, 15(1), 302; https://doi.org/10.3390/pharmaceutics15010302 - 16 Jan 2023
Cited by 4 | Viewed by 2017
Abstract
In the current study, the combined anti-tumor efficacy of bioactive hydroxyapatite nano- particles (HA-NPs) loaded with altretamine (ALT) was evaluated. The well-known fact that HA has great biological compatibility was confirmed through the findings of the hemolytic experiments and a maximum IC50 [...] Read more.
In the current study, the combined anti-tumor efficacy of bioactive hydroxyapatite nano- particles (HA-NPs) loaded with altretamine (ALT) was evaluated. The well-known fact that HA has great biological compatibility was confirmed through the findings of the hemolytic experiments and a maximum IC50 value seen in the MTT testing. The preparation of HA-NPs was performed using the chemical precipitation process. An in vitro release investigation was conducted, and the results demonstrated the sustained drug release of the altretamine-loaded hydroxyapatite nanoparticles (ALT-HA-NPs). Studies using the JURKAT E6.1 cell lines MTT assay, and cell uptake, as well as in vivo pharmacokinetic tests using Wistar rats demonstrated that the ALT-HA-NPs were easily absorbed by the cells. A putative synergism between the action of the Ca2+ ions and the anticancer drug obtained from the carrier was indicated by the fact that the ALT-HA-NPs displayed cytotoxicity comparable to the free ALT at 1/10th of the ALT concentration. It has been suggested that a rise in intracellular Ca2+ ions causes cells to undergo apoptosis. Ehrlich’s ascites model in Balb/c mice showed comparable synergistic efficacy in a tumor regression trial. While the ALT-HA-NPs were able to shrink the tumor size by six times, the free ALT was only able to reduce the tumor volume by half. Full article
(This article belongs to the Special Issue Recent Advances in Long-Acting Drug Delivery and Formulations)
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17 pages, 2515 KiB  
Article
Antiadherent AgBDC Metal–Organic Framework Coating for Escherichia coli Biofilm Inhibition
by Ana Arenas-Vivo, Vanessa Celis Arias, Georgiana Amariei, Roberto Rosal, Isabel Izquierdo-Barba, Tania Hidalgo, María Vallet-Regí, Hiram I. Beltrán, Sandra Loera-Serna and Patricia Horcajada
Pharmaceutics 2023, 15(1), 301; https://doi.org/10.3390/pharmaceutics15010301 - 16 Jan 2023
Cited by 3 | Viewed by 2526
Abstract
Surface microbial colonization and its potential biofilm formation are currently a major unsolved problem, causing almost 75% of human infectious diseases. Pathogenic biofilms are capable of surviving high antibiotic doses, resulting in inefficient treatments and, subsequently, raised infection prevalence rates. Antibacterial coatings have [...] Read more.
Surface microbial colonization and its potential biofilm formation are currently a major unsolved problem, causing almost 75% of human infectious diseases. Pathogenic biofilms are capable of surviving high antibiotic doses, resulting in inefficient treatments and, subsequently, raised infection prevalence rates. Antibacterial coatings have become a promising strategy against the biofilm formation in biomedical devices due to their biocidal activity without compromising the bulk material. Here, we propose for the first time a silver-based metal–organic framework (MOF; here denoted AgBDC) showing original antifouling properties able to suppress not only the initial bacterial adhesion, but also the potential surface contamination. Firstly, the AgBDC stability (colloidal, structural and chemical) was confirmed under bacteria culture conditions by using agar diffusion and colony counting assays, evidencing its biocide effect against the challenging E. coli, one of the main representative indicators of Gram-negative resistance bacteria. Then, this material was shaped as homogeneous spin-coated AgBDC thin film, investigating its antifouling and biocide features using a combination of complementary procedures such as colony counting, optical density or confocal scanning microscopy, which allowed to visualize for the first time the biofilm impact generated by MOFs via a specific fluorochrome, calcofluor. Full article
(This article belongs to the Special Issue Sustainable Materials and Technologies for Drug Delivery and Tissue Engineering)
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14 pages, 2229 KiB  
Review
A New Challenge for the Old Excipient Calcium Carbonate: To Improve the Dissolution Rate of Poorly Soluble Drugs
by Valeria Ambrogi
Pharmaceutics 2023, 15(1), 300; https://doi.org/10.3390/pharmaceutics15010300 - 16 Jan 2023
Cited by 2 | Viewed by 3178
Abstract
Calcium carbonate is an excipient traditionally used in solid dosage forms with several functions such as a diluent, a quick dissolution agent, a buffer and an opacifier. Recently, many other challenges have arisen for calcium carbonate and, among them, the possibility of using [...] Read more.
Calcium carbonate is an excipient traditionally used in solid dosage forms with several functions such as a diluent, a quick dissolution agent, a buffer and an opacifier. Recently, many other challenges have arisen for calcium carbonate and, among them, the possibility of using it as an excipient for improving the dissolution rate of poorly soluble drugs. As a consequence of their poor solubility in biological fluids, many active ingredients suffer from low and erratic bioavailability when administered by the oral route and thus, many formulation strategies and excipients have been proposed to overcome this problem. Among them, calcium carbonate has been proposed as an excipient for improving dissolution rates. Calcium carbonate has many interesting characteristics, in fact it dissolves quickly in gastric fluid, is inexpensive and is safe. It exists in different polymorphic forms and in porous morphology and recently a porous functionalized calcium carbonate has been proposed as a new excipient. This review is the first overview on the use of calcium carbonate as an excipient for improving drug dissolution rates. The drug loading procedure, the physical characterization of the drug/CaCO3 samples and their dissolution profiles will be described. Moreover, the possible mechanisms of dissolution improvement, such as the presence of the drug in amorphous or polymorphic forms, in small crystals, and the effects of CaCO3 dissolution in acidic medium will be discussed. Different polymorphic forms of calcium carbonate and the presence of porosity and functionalization will be analyzed as well and their effects on dissolution rates will be discussed. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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23 pages, 2114 KiB  
Article
Therapeutic Drug Monitoring of Tacrolimus Based on Volumetric Absorptive Microsampling Technique (VAMS) in Renal Transplant Pediatric Recipients—LC-MS/MS Method Development, Hematocrit Effect Evaluation, and Clinical Application
by Arkadiusz Kocur, Dorota Marszałek, Jacek Rubik, Agnieszka Czajkowska and Tomasz Pawiński
Pharmaceutics 2023, 15(1), 299; https://doi.org/10.3390/pharmaceutics15010299 - 16 Jan 2023
Cited by 5 | Viewed by 3001
Abstract
Tacrolimus (TAC) is post-transplant pharmacotherapy’s most widely used immunosuppressant. In routine clinical practice, frequent uncomfortable venipuncture is necessary for whole-blood (WB) collection to check trough TAC levels. Volumetric absorptive microsampling (VAMS) is an alternative strategy to WB collection. In this study, we aimed [...] Read more.
Tacrolimus (TAC) is post-transplant pharmacotherapy’s most widely used immunosuppressant. In routine clinical practice, frequent uncomfortable venipuncture is necessary for whole-blood (WB) collection to check trough TAC levels. Volumetric absorptive microsampling (VAMS) is an alternative strategy to WB collection. In this study, we aimed to validate and develop a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for TAC quantification in WB and VAMS samples. After extraction with water and protein precipitation, the samples were directly analyzed using LC-MS/MS. Whole-blood and VAMS capillary-blood samples were collected from 50 patients treated with TAC during the follow-up visits. The cross-correlation between the developed methods was evaluated using Passing–Bablok regression and a Bland–Altman bias plot. The matrix effect (ME) and carry-over were insignificant for both scenarios. There was a high correlation between the processes and no significant clinical deviation. LC-MS/MS methods were successfully developed and validated in the 0.5–60 ng/mL calibration range. This study demonstrated and confirmed the utility of VAMS-based TAC monitoring in the pediatric population. This is the first study to directly develop and validate the VAMS LC-MS/MS method for evaluating the hematocrit effect in the pediatric population. The statistical correlation between immunochemical and VAMS-based methods was satisfactory. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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26 pages, 1520 KiB  
Review
Exosomes-Based Nanomedicine for Neurodegenerative Diseases: Current Insights and Future Challenges
by Amanda Cano, Álvaro Muñoz-Morales, Elena Sánchez-López, Miren Ettcheto, Eliana B. Souto, Antonio Camins, Mercè Boada and Agustín Ruíz
Pharmaceutics 2023, 15(1), 298; https://doi.org/10.3390/pharmaceutics15010298 - 16 Jan 2023
Cited by 8 | Viewed by 3222
Abstract
Neurodegenerative diseases constitute a group of pathologies whose etiology remains unknown in many cases, and there are no treatments that stop the progression of such diseases. Moreover, the existence of the blood–brain barrier is an impediment to the penetration of exogenous molecules, including [...] Read more.
Neurodegenerative diseases constitute a group of pathologies whose etiology remains unknown in many cases, and there are no treatments that stop the progression of such diseases. Moreover, the existence of the blood–brain barrier is an impediment to the penetration of exogenous molecules, including those found in many drugs. Exosomes are extracellular vesicles secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Due to their natural origin and molecular similarities with most cell types, exosomes have emerged as promising therapeutic tools for numerous diseases. Specifically, neurodegenerative diseases have shown to be a potential target for this nanomedicine strategy due to the difficult access to the brain and the strategy’s pathophysiological complexity. In this regard, this review explores the most important biological-origin drug delivery systems, innovative isolation methods of exosomes, their physicochemical characterization, drug loading, cutting-edge functionalization strategies to target them within the brain, the latest research studies in neurodegenerative diseases, and the future challenges of exosomes as nanomedicine-based therapeutic tools. Full article
(This article belongs to the Special Issue Controlled Release of Nanostructured Drug Systems (Volume II))
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16 pages, 2210 KiB  
Article
The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants
by Philipp F. Popp, Tania Lozano-Cruz, Franziska Dürr, Addis Londaitsbehere, Johanna Hartig, Francisco Javier de la Mata, Rafael Gómez, Thorsten Mascher and Ainhoa Revilla-Guarinos
Pharmaceutics 2023, 15(1), 297; https://doi.org/10.3390/pharmaceutics15010297 - 16 Jan 2023
Viewed by 1409
Abstract
The threat of antimicrobial-resistant bacteria is ever increasing and over the past-decades development of novel therapeutic counter measurements have virtually come to a halt. This circumstance calls for interdisciplinary approaches to design, evaluate and validate the mode of action of novel antibacterial compounds. [...] Read more.
The threat of antimicrobial-resistant bacteria is ever increasing and over the past-decades development of novel therapeutic counter measurements have virtually come to a halt. This circumstance calls for interdisciplinary approaches to design, evaluate and validate the mode of action of novel antibacterial compounds. Hereby, carbosilane dendritic systems that exhibit antimicrobial properties have the potential to serve as synthetic and rationally designed molecules for therapeutic use. The bow-tie type topology of BDTL049 was recently investigated against the Gram-positive model organism Bacillus subtilis, revealing strong bactericidal properties. In this study, we follow up on open questions concerning the usability of BDTL049. For this, we synthesized a fluorescent-labeled version of BDTL049 that maintained all antimicrobial features to unravel the interaction of the compound and bacterial membrane. Subsequently, we highlight the bacterial sensitivity against BDTL049 by performing a mutational study of known resistance determinants. Finally, we address the cytotoxicity of the compound in human cells, unexpectedly revealing a high sensitivity of the eukaryotic cells upon BDTL049 exposure. The insights presented here further elaborate on the unique features of BDTL049 as a promising candidate as an antimicrobial agent while not precluding that further rounds of rational designing are needed to decrease cytotoxicity to ultimately pave the way for synthetic antibiotics toward clinical applicability. Full article
(This article belongs to the Special Issue Application of Nanoparticles and Dendrimers for Treating Infectious Diseases)
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21 pages, 3836 KiB  
Article
Coatings of Cyclodextrin/Citric-Acid Biopolymer as Drug Delivery Systems: A Review
by Karen Escobar, Karla A. Garrido-Miranda, Ruth Pulido, Nelson Naveas, Miguel Manso-Silván and Jacobo Hernandez-Montelongo
Pharmaceutics 2023, 15(1), 296; https://doi.org/10.3390/pharmaceutics15010296 - 16 Jan 2023
Cited by 6 | Viewed by 2849
Abstract
In the early 2000s, a method for cross-linking cyclodextrins (CDs) with citric acid (CTR) was developed. This method was nontoxic, environmentally friendly, and inexpensive compared to the others previously proposed in the literature. Since then, the CD/CTR biopolymers have been widely used as [...] Read more.
In the early 2000s, a method for cross-linking cyclodextrins (CDs) with citric acid (CTR) was developed. This method was nontoxic, environmentally friendly, and inexpensive compared to the others previously proposed in the literature. Since then, the CD/CTR biopolymers have been widely used as a coating on implants and other materials for biomedical applications. The present review aims to cover the chemical properties of CDs, the synthesis routes of CD/CTR, and their applications as drug-delivery systems when coated on different substrates. Likewise, the molecules released and other pharmaceutical aspects involved are addressed. Moreover, the different methods of pretreatment applied on the substrates before the in situ polymerization of CD/CTR are also reviewed as a key element in the final functionality. This process is not trivial because it depends on the surface chemistry, geometry, and physical properties of the material to be coated. The biocompatibility of the polymer was also highlighted. Finally, the mechanisms of release generated in the CD/CTR coatings were analyzed, including the mathematical model of Korsmeyer–Peppas, which has been dominantly used to explain the release kinetics of drug-delivery systems based on these biopolymers. The flexibility of CD/CTR to host a wide variety of drugs, of the in situ polymerization to integrate with diverse implantable materials, and the controllable release kinetics provide a set of advantages, thereby ensuring a wide range of future uses. Full article
(This article belongs to the Special Issue Recent Advances in Polymeric Delivery Vehicles for Controlled and Sustained Drug Release)
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17 pages, 2953 KiB  
Article
Eudraguard® Natural and Protect: New “Food Grade” Matrices for the Delivery of an Extract from Sorbus domestica L. Leaves Active on the α-Glucosidase Enzyme
by Maria Rosaria Lauro, Patrizia Picerno, Silvia Franceschelli, Michela Pecoraro, Rita Patrizia Aquino and Rosario Pignatello
Pharmaceutics 2023, 15(1), 295; https://doi.org/10.3390/pharmaceutics15010295 - 16 Jan 2023
Cited by 3 | Viewed by 1499
Abstract
(1) Background: Eudraguard® Natural (EN) and Protect (EP) are polymers regulated for use in dietary supplements in the European Union and the United States to carry natural products, mask unpleasant smells and tastes, ameliorate product handling, and protect products from moisture, light, [...] Read more.
(1) Background: Eudraguard® Natural (EN) and Protect (EP) are polymers regulated for use in dietary supplements in the European Union and the United States to carry natural products, mask unpleasant smells and tastes, ameliorate product handling, and protect products from moisture, light, and oxidation. Moreover, EN and EP can control the release of encapsulated compounds. The aim of this work was the development, preparation, and control of Eudraguard® spray-drying microparticles to obtain powders with easy handling and a stable dietary supplement containing a polar functional extract (SOE) from Sorbus domestica L. leaves. (2) Methods: SOE was characterized using HPLC, NMR, FTIR, DSC, and SEM methods. Furthermore, the SOE’s antioxidant/free radical scavenging activity, α-glucosidase inhibition, MTT assay effect on viability in normal cells, and shelf life were evaluated in both the extract and final formulations. (3) Results: The data suggested that SOE, rich in flavonoids, is a bioactive and safe extract; however, from a technological point of view, it was sticky, difficult to handle, and had low aqueous solubility. Despite the fact that EN and EP may undergo changes with spray-drying, they effectively produced easy-to-handle micro-powders with a controlled release profile. Although EN had a weaker capability to coat SOE than EP, EN acted as a substrate that was able to swell, drawing in water and improving the extract solubility and dissolution/release; however, EP was also able to carry the extract and provide SOE with controlled release. (4) Conclusion: Both Eudraguard® products were capable of carrying SOE and improving its antioxidant and α-glucosidase inhibition activities, as well as the extract stability and handling. Full article
(This article belongs to the Special Issue Herbal Extracts and Natural Compounds: Nutraceutical and Pharmaceutical Aspects Volume II)
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22 pages, 2419 KiB  
Review
Insights into Asymmetric Liposomes as a Potential Intervention for Drug Delivery Including Pulmonary Nanotherapeutics
by Yaqeen Nadheer Al Badri, Cheng Shu Chaw and Amal Ali Elkordy
Pharmaceutics 2023, 15(1), 294; https://doi.org/10.3390/pharmaceutics15010294 - 15 Jan 2023
Cited by 11 | Viewed by 2889
Abstract
Liposome-based drug delivery systems are nanosized spherical lipid bilayer carriers that can encapsulate a broad range of small drug molecules (hydrophilic and hydrophobic drugs) and large drug molecules (peptides, proteins, and nucleic acids). They have unique characteristics, such as a self-assembling bilayer vesicular [...] Read more.
Liposome-based drug delivery systems are nanosized spherical lipid bilayer carriers that can encapsulate a broad range of small drug molecules (hydrophilic and hydrophobic drugs) and large drug molecules (peptides, proteins, and nucleic acids). They have unique characteristics, such as a self-assembling bilayer vesicular structure. There are several FDA-approved liposomal-based medicines for treatment of cancer, bacterial, and viral infections. Most of the FDA-approved liposomal-based therapies are in the form of conventional “symmetric” liposomes and they are administered mainly by injection. Arikace® is the first and only FDA-approved liposomal-based inhalable therapy (amikacin liposome inhalation suspension) to treat only adults with difficult-to-treat Mycobacterium avium complex (MAC) lung disease as a combinational antibacterial treatment. To date, no “asymmetric liposomes” are yet to be approved, although asymmetric liposomes have many advantages due to the asymmetric distribution of lipids through the liposome’s membrane (which is similar to the biological membranes). There are many challenges for the formulation and stability of asymmetric liposomes. This review will focus on asymmetric liposomes in contrast to conventional liposomes as a potential clinical intervention drug delivery system as well as the formulation techniques available for symmetric and asymmetric liposomes. The review aims to renew the research in liposomal nanovesicle delivery systems with particular emphasis on asymmetric liposomes as future potential carriers for enhancing drug delivery including pulmonary nanotherapeutics. Full article
(This article belongs to the Special Issue Dry Powders for Pulmonary Delivery: Device and Formulation Technologies for an Enhanced Lung Deposition)
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9 pages, 516 KiB  
Article
Change of CGRP Plasma Concentrations in Migraine after Discontinuation of CGRP-(Receptor) Monoclonal Antibodies
by Bianca Raffaelli, Maria Terhart, Mira Pauline Fitzek, Kristin Sophie Lange, Jasper Mecklenburg, Lucas Hendrik Overeem, Anke Siebert, Elisabeth Storch and Uwe Reuter
Pharmaceutics 2023, 15(1), 293; https://doi.org/10.3390/pharmaceutics15010293 - 15 Jan 2023
Cited by 3 | Viewed by 2182
Abstract
Discontinuation of treatment with monoclonal antibodies (mAb) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway leads to an increase in migraine frequency. We aimed to assess changes in free and total CGRP plasma concentrations after the discontinuation of CGRP(-receptor) mAbs. This prospective analysis included [...] Read more.
Discontinuation of treatment with monoclonal antibodies (mAb) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway leads to an increase in migraine frequency. We aimed to assess changes in free and total CGRP plasma concentrations after the discontinuation of CGRP(-receptor) mAbs. This prospective analysis included 59 patients with migraine (n = 25 erenumab, n = 25 galcanezumab, n = 9 fremanezumab) who discontinued mAbs after ≥8 months of treatment. Patients were visited at the time of the last mAb injection (V1) and 16 weeks later (V2). For control, 30 migraine patients without preventive drug therapy were included. We measured free CGRP plasma concentrations in the erenumab and fremanezumab group and total CGRP concentrations in the galcanezumab group. Free CGRP plasma concentrations did not change after treatment discontinuation [erenumab: V1 31.2 pg/mL (IQR 25.8–45.6), V2 30.3 pg/mL (IQR 22.9–47.6), p = 0.65; fremanezumab V1 29.4 pg/mL (IQR 16.4–61.9), V2 34.4 (19.2–62.0), p = 0.86]. Controls had similar CGRP values of 32.6 pg/mL (IQR 21.3–44.6). Total CGRP concentrations in the galcanezumab group were 5439.3 pg/mL (2412.7–6338.1) at V1, and decreased to 1853.2 pg/mL (1136.5–3297.0) at V2 (p < 0.001). Cessation of treatment with CGRP(-R) mAbs did not have an impact on the free-circulating CGRP concentrations. Total CGRP decreased significantly after three months of treatment discontinuation. Full article
(This article belongs to the Section Biologics and Biosimilars)
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16 pages, 5856 KiB  
Article
Liposomal Iron Oxide Nanoparticles Loaded with Doxorubicin for Combined Chemo-Photothermal Cancer Therapy
by Taehoon Park, Reeju Amatya, Kyoung Ah Min and Meong Cheol Shin
Pharmaceutics 2023, 15(1), 292; https://doi.org/10.3390/pharmaceutics15010292 - 15 Jan 2023
Cited by 12 | Viewed by 2351
Abstract
Iron oxide nanoparticle (IONP) possesses unique advantages over other nanoparticles in the use of cancer imaging and therapy. Specifically, it has drawn great attention in the emerging research field of photothermal cancer therapy. Herein, we developed doxorubicin (DOX)-loaded liposomal IONP (Lipo-IONP/DOX) and evaluated [...] Read more.
Iron oxide nanoparticle (IONP) possesses unique advantages over other nanoparticles in the use of cancer imaging and therapy. Specifically, it has drawn great attention in the emerging research field of photothermal cancer therapy. Herein, we developed doxorubicin (DOX)-loaded liposomal IONP (Lipo-IONP/DOX) and evaluated in vitro and in vivo their applicability for combined chemo-photothermal cancer therapy. The Lipo-IONP was synthesized by the thin-film evaporation method. The prepared Lipo-IONP was observed as about a 240 nm-sized agglomerate of globular-shaped nanoparticles. The TEM and FT-IR data evidenced the successful formation of liposomal IONP. The superparamagnetic property of the Lipo-IONP was confirmed by the SQUID analysis. The DSC data showed a transition temperature of about 47–48 °C for the mixed lipids composing the Lipo IONP, and the DOX release studies revealed the feasibility of induced burst release of DOX by laser irradiation. The Lipo-IONP/DOX possessed a plasma half-life of 42 min, which could ensure sufficient circulation time for magnetic tumor targeting. The in vivo magnetic targeting enabled a significant increase (6.3-fold) in the tumor accumulation of Lipo-IONP/DOX, leading to greater photothermal effects. Finally, the preliminary efficacy study evidenced the applicability as well as the safety of the Lipo-IONP/DOX for use in combined chemo-photothermal cancer therapy. Overall, the study results demonstrated that the Lipo-IONP/DOX might serve as an effective and safe agent for combined chemo-photothermal cancer therapy. Full article
(This article belongs to the Special Issue Advances in Cancer Nanotechnology for Photodynamic and Photothermal Therapy)
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30 pages, 946 KiB  
Article
Combined Use of Antimicrobial Peptides with Antiseptics against Multidrug-Resistant Bacteria: Pros and Cons
by Maria S. Zharkova, Aleksey S. Komlev, Tatiana A. Filatenkova, Maria S. Sukhareva, Elizaveta V. Vladimirova, Andrey S. Trulioff, Dmitriy S. Orlov, Alexander V. Dmitriev, Anna G. Afinogenova, Anna A. Spiridonova and Olga V. Shamova
Pharmaceutics 2023, 15(1), 291; https://doi.org/10.3390/pharmaceutics15010291 - 14 Jan 2023
Cited by 1 | Viewed by 2232
Abstract
Antimicrobial peptides (AMPs) are acknowledged as a promising template for designing new antimicrobials. At the same time, existing toxicity issues and limitations in their pharmacokinetics make topical application one of the less complicated routes to put AMPs-based therapeutics into actual medical practice. Antiseptics [...] Read more.
Antimicrobial peptides (AMPs) are acknowledged as a promising template for designing new antimicrobials. At the same time, existing toxicity issues and limitations in their pharmacokinetics make topical application one of the less complicated routes to put AMPs-based therapeutics into actual medical practice. Antiseptics are one of the common components for topical treatment potent against antibiotic-resistant pathogens but often with toxicity limitations of their own. Thus, the interaction of AMPs and antiseptics is an interesting topic that is also less explored than combined action of AMPs and antibiotics. Herein, we analyzed antibacterial, antibiofilm, and cytotoxic activity of combinations of both membranolytic and non-membranolytic AMPs with a number of antiseptic agents. Fractional concentration indices were used as a measure of possible effective concentration reduction achievable due to combined application. Cases of both synergistic and antagonistic interaction with certain antiseptics and surfactants were identified, and trends in the occurrence of these types of interaction were discussed. The data may be of use for AMP-based drug development and suggest that the topic requires further attention for successfully integrating AMPs-based products in the context of complex treatment. AMP/antiseptic combinations show promise for creating topical formulations with improved activity, lowered toxicity, and, presumably, decreased chances of inducing bacterial resistance. However, careful assessment is required to avoid AMP neutralization by certain antiseptic classes in either complex drug design or AMP application alongside other therapeutics/care products. Full article
(This article belongs to the Special Issue Recent Advances in Prevention and Treatment of Infectious Diseases)
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24 pages, 7183 KiB  
Article
Hyaluronic Acid-Modified Cisplatin-Encapsulated Poly(Lactic-co-Glycolic Acid) Magnetic Nanoparticles for Dual-Targeted NIR-Responsive Chemo-Photothermal Combination Cancer Therapy
by Huai-An Chen, Yu-Jen Lu, Banendu Sunder Dash, Yin-Kai Chao and Jyh-Ping Chen
Pharmaceutics 2023, 15(1), 290; https://doi.org/10.3390/pharmaceutics15010290 - 14 Jan 2023
Cited by 12 | Viewed by 2578
Abstract
Combination chemo-photothermal therapy with nanomaterials can reduce the dose of chemotherapeutic drugs required for effective cancer treatment by minimizing toxic side effects while improving survival times. Toward this end, we prepare hyaluronic acid (HA)-modified poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (MNP) for the CD44 [...] Read more.
Combination chemo-photothermal therapy with nanomaterials can reduce the dose of chemotherapeutic drugs required for effective cancer treatment by minimizing toxic side effects while improving survival times. Toward this end, we prepare hyaluronic acid (HA)-modified poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (MNP) for the CD44 receptor-mediated and magnetic field-guided dual-targeted delivery of cisplatin (CDDP). By co-encapsulating the CDDP and oleic acid-coated iron oxide MNP (IOMNP) in PLGA, the PMNPc was first prepared in a single emulsification/solvent evaporation step and successively surface modified with chitosan and HA to prepare the HA/PMNPc. Spherical HA/PMNPc nanoparticles of ~300 nm diameter can be prepared with 18 and 10% (w/w) loading content of CDDP and IOMNP and a pH-sensitive drug release to facilitate the endosomal release of the CDDP after intracellular uptake. This leads to the higher cytotoxicity of the HA/PMNPc toward the U87 glioblastoma cells than free CDDP with reduced IC50, a higher cell apoptosis rate, and the enhanced expression of cell apoptosis marker proteins. Furthermore, the nanoparticles show the hyperthermia effect toward U87 after short-term near-infrared (NIR) light exposure, which can further elevate the cell apoptosis/necrosis rate and upregulate the HSP70 protein expression due to the photothermal effects. The combined cancer therapeutic efficacy was studied in vivo using subcutaneously implanted U87 cells in nude mice. By using dual-targeted chemo-photothermal combination cancer therapy, the intravenously injected HA/PMNPc under magnetic field guidance and followed by NIR laser irradiation was demonstrated to be the most effective treatment modality by inhibiting the tumor growth and prolonging the survival time of the tumor-bearing nude mice. Full article
(This article belongs to the Special Issue Recent Advances in Pharmaceutical Applications of Functionalized Polysaccharides and Their Derivatives)
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15 pages, 2135 KiB  
Article
Enhancing Intradermal Delivery of Lidocaine by Dissolving Microneedles: Comparison between Hyaluronic Acid and Poly(Vinyl Pyrrolidone) Backbone Polymers
by Delly Ramadon, Lissa Florencia Putri Sutrisna, Yahdiana Harahap, Kurnia Sari Setio Putri, Fathin Ulayya, Pietradewi Hartrianti, Qonita Kurnia Anjani and Ryan F. Donnelly
Pharmaceutics 2023, 15(1), 289; https://doi.org/10.3390/pharmaceutics15010289 - 14 Jan 2023
Cited by 8 | Viewed by 3096
Abstract
Lidocaine hydrochloride (LiH), an amide-type local anesthetic agent, is commonly used in dermatological procedures. LiH is categorized as a BCS (biopharmaceutics classification system) class III group, which has high solubility and poor permeability. It should be noted that, in this context, LiH is [...] Read more.
Lidocaine hydrochloride (LiH), an amide-type local anesthetic agent, is commonly used in dermatological procedures. LiH is categorized as a BCS (biopharmaceutics classification system) class III group, which has high solubility and poor permeability. It should be noted that, in this context, LiH is intended as a local anesthetic, so the level of LiH in systemic circulation should be minimized to avoid toxicity and unwanted side effects such as hypotension and bradycardia. This study aimed to formulate and evaluate LiH-loaded dissolving microneedles (DMNs) with different polymer bases. Moreover, an in vitro permeation study using Franz diffusion cells and in vivo study were also performed. LiH-loaded DMNs were prepared using polymer groups of poly(vinyl pyrrolidone) (PVP-K30) and hyaluronic acid (HA). DMNs were created using the micro-molding method with centrifugation. The formulations selected based on the evaluation were F3 (HA 10%) and F5 (PVP-K30 25%). Based on the in vitro permeation study, the amount of drug permeated and deposited in the skin at F3 (HA 10%) was 247.1 ± 41.85 and 98.35 ± 12.86 μg, respectively. On the other hand, the amount of drug permeated and deposited in the skin at F5 (PVP-K30 25%) was 277.7 ± 55.88 and 59.46 ± 9.25 μg, respectively. Our in vivo drug-permeation study showed that only one rat from the PVP-K30 polymer group—with a concentration of 150.32 ng/mL—was detected on rat plasma. Therefore, LiH can be formulated into a DMN and can be deposited in the skin with a safe concentration of the drug permeating into systemic circulation. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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13 pages, 3992 KiB  
Article
Stimuli-Responsive Triblock Terpolymer Conversion into Multi-Stimuli-Responsive Micelles with Dynamic Covalent Bonds for Drug Delivery through a Quick and Controllable Post-Polymerization Reaction
by Eva Hlavatovičová, Roberto Fernandez-Alvarez, Katarzyna Byś, Sami Kereïche, Tarun K. Mandal, Leonard Ionut Atanase, Miroslav Štěpánek and Mariusz Uchman
Pharmaceutics 2023, 15(1), 288; https://doi.org/10.3390/pharmaceutics15010288 - 14 Jan 2023
Cited by 5 | Viewed by 1906
Abstract
Stimuli-responsive copolymers are of great interest for targeted drug delivery. This study reports on a controllable post-polymerization quaternization with 2-bromomethyl-4-fluorophenylboronic acid of the poly(4-vinyl pyridine) (P4VP) block of a common poly(styrene)-b-poly(4-vinyl pyridine)-b-poly(ethylene oxide) (SVE) triblock terpolymer in order to [...] Read more.
Stimuli-responsive copolymers are of great interest for targeted drug delivery. This study reports on a controllable post-polymerization quaternization with 2-bromomethyl-4-fluorophenylboronic acid of the poly(4-vinyl pyridine) (P4VP) block of a common poly(styrene)-b-poly(4-vinyl pyridine)-b-poly(ethylene oxide) (SVE) triblock terpolymer in order to achieve a selective responsivity to various diols. For this purpose, a reproducible method was established for P4VP block quaternization at a defined ratio, confirming the reaction yield by 11B, 1H NMR. Then, a reproducible self-assembly protocol is designed for preparing stable micelles from functionalized stimuli-responsive triblock terpolymers, which are characterized by light scattering and by cryogenic transmission electron microscopy. In addition, UV-Vis spectroscopy is used to monitor the boron-ester bonding and hydrolysis with alizarin as a model drug and to study encapsulation and release of this drug, induced by sensing with three geminal diols: fructose, galactose and ascorbic acid. The obtained results show that only the latter, with the vicinal diol group on sp2-hybridized carbons, was efficient for alizarin release. Therefore, the post-polymerization method for triblock terpolymer functionalization presented in this study allows for preparation of specific stimuli-responsive systems with a high potential for targeted drug delivery, especially for cancer treatment. Full article
(This article belongs to the Special Issue Application of Polymeric Micelles for Drug and Gene Delivery)
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16 pages, 4094 KiB  
Article
The Anti-Tubercular Aminolipopeptide Trichoderin A Displays Selective Toxicity against Human Pancreatic Ductal Adenocarcinoma Cells Cultured under Glucose Starvation
by Johanes K. Kasim, Jiwon Hong, Anthony J. R. Hickey, Anthony R. J. Phillips, John A. Windsor, Paul W. R. Harris, Margaret A. Brimble and Iman Kavianinia
Pharmaceutics 2023, 15(1), 287; https://doi.org/10.3390/pharmaceutics15010287 - 14 Jan 2023
Viewed by 1412
Abstract
Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we [...] Read more.
Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidence that it is also selectively toxic against BxPC-3 and PANC-1 human pancreatic ductal adenocarcinoma cells cultured under glucose deprivation. This has critical implications for the pancreatic ductal adenocarcinoma, which is characterized by nutrient deprivation due to its hypovascularized network. We have also successfully simplified the trichoderin A peptide backbone, allowing greater accessibility to the peptide for further biological testing. In addition, we also conducted a preliminary investigation into the role of peptide lipidation at the N-terminus. This showed that analogues with longer fatty acyl chains exhibited superior cytotoxicity than those with shorter acyl chains. Further structural optimization of trichoderin A is anticipated to improve its biological activity, whilst ongoing mechanistic studies to elucidate its intracellular mechanism of action are conducted in parallel. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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38 pages, 802 KiB  
Review
Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency
by Androulla N. Miliotou, Parthena F. Foltopoulou, Alexandra Ingendoh-Tsakmakidis, Asterios S. Tsiftsoglou, Ioannis S. Vizirianakis, Ioannis S. Pappas and Lefkothea C. Papadopoulou
Pharmaceutics 2023, 15(1), 286; https://doi.org/10.3390/pharmaceutics15010286 - 14 Jan 2023
Cited by 2 | Viewed by 3192
Abstract
Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase [...] Read more.
Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase (COX) assembly protein, have been implicated in the mitochondrial disorder fatal infantile cardioencephalomyopathy with COX deficiency. Since an effective treatment is still missing, a protein replacement therapy (PRT) was explored using protein transduction domain (PTD) technology. Therefore, the human recombinant full-length mitochondrial protein Sco2, fused to TAT peptide (a common PTD), was produced (fusion Sco2 protein) and successfully transduced into fibroblasts derived from a SCO2/COX-deficient patient. This PRT contributed to effective COX assembly and partial recovery of COX activity. In mice, radiolabeled fusion Sco2 protein was biodistributed in the peripheral tissues of mice and successfully delivered into their mitochondria. Complementary to that, an mRNA-based therapeutic approach has been more recently considered as an innovative treatment option. In particular, a patented, novel PTD-mediated IVT-mRNA delivery platform was developed and applied in recent research efforts. PTD-IVT-mRNA of full-length SCO2 was successfully transduced into the fibroblasts derived from a SCO2/COX-deficient patient, translated in host ribosomes into a nascent chain of human Sco2, imported into mitochondria, and processed to the mature protein. Consequently, the recovery of reduced COX activity was achieved, thus suggesting the potential of this mRNA-based technology for clinical translation as a PRT for metabolic/genetic disorders. In this review, such research efforts will be comprehensibly presented and discussed to elaborate their potential in clinical application and therapeutic usefulness. Full article
(This article belongs to the Special Issue mRNA-Based Protein Replacement Therapy)
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25 pages, 4986 KiB  
Article
Development of Guar Gum Hydrogel Containing Sesamol-Loaded Nanocapsules Designed for Irritant Contact Dermatitis Treatment Induced by Croton Oil Application
by Vinicius Costa Prado, Kauani Moenke, Bárbara Felin Osmari, Natháli Schopf Pegoraro, Sara Marchesan Oliveira and Letícia Cruz
Pharmaceutics 2023, 15(1), 285; https://doi.org/10.3390/pharmaceutics15010285 - 14 Jan 2023
Cited by 4 | Viewed by 1797
Abstract
Irritant contact dermatitis is usually treated with corticosteroids, which cause expressive adverse effects. Sesamol is a phenolic compound with anti-inflammatory and antioxidant properties. This study was designed to evaluate a hydrogel containing sesamol-loaded ethylcellulose nanocapsules for the treatment of irritant contact dermatitis. The [...] Read more.
Irritant contact dermatitis is usually treated with corticosteroids, which cause expressive adverse effects. Sesamol is a phenolic compound with anti-inflammatory and antioxidant properties. This study was designed to evaluate a hydrogel containing sesamol-loaded ethylcellulose nanocapsules for the treatment of irritant contact dermatitis. The nanocapsules presented a size in the nanometric range, a negative zeta potential, a sesamol content close to the theoretical value (1 mg/mL), and a 65% encapsulation efficiency. Nanoencapsulation protected sesamol against UVC-induced degradation and increased the scavenging activity assessed by ABTS and DPPH radicals. The hydrogels were prepared by thickening the nanocapsule suspensions with guar gum (2.5%). The hydrogels maintained the nanometric size of the nanocapsules and a sesamol content of approximately 1 mg/g. The HET-CAM assay classified the hydrogels as nonirritating. The in vitro release of the hydrogel containing sesamol in the nanoencapsulated form demonstrated an initial burst effect followed by a prolonged sesamol release and a lower skin permeation in comparison with the hydrogel containing free sesamol. In addition, it exhibited the best anti-inflammatory effect in the irritant contact dermatitis model induced by croton oil, reducing ear edema and inflammatory cells infiltration, similar to dexamethasone (positive control). Therefore, the hydrogel containing sesamol in the nanoencapsulated form seemed to have a therapeutic potential in treating irritant contact dermatitis. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Applications: Latest Advances and Prospects)
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14 pages, 2259 KiB  
Article
The Influence of Blonanserin Supersaturation in Liquid and Silica Stabilised Self-Nanoemulsifying Drug Delivery Systems on In Vitro Solubilisation
by Amalie Møller, Hayley B. Schultz, Tahlia R. Meola, Paul Joyce, Anette Müllertz and Clive A. Prestidge
Pharmaceutics 2023, 15(1), 284; https://doi.org/10.3390/pharmaceutics15010284 - 14 Jan 2023
Viewed by 1845
Abstract
Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study [...] Read more.
Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study aimed to understand the influence of supersaturated drug load on blonanserin solubilisation from liquid and silica solidified supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) during in vitro lipolysis. Stable liquid super-SNEDDS with varying drug loads (90–300% of the equilibrium solubility) were solidified by imbibition into porous silica microparticles (1:1 lipid: silica ratio). In vitro lipolysis revealed greater blonanserin solubilisation from liquid super-SNEDDS compared to solid at equivalent drug saturation levels, owing to strong silica-BLON/lipid interactions, evidenced by a significant decrease in blonanserin solubilisation upon addition of silica to a digesting liquid super-SNEDDS. An increase in solid super-SNEDDS drug loading led to increased solubilisation, owing to the increased drug:silica and drug:lipid ratios. Solidifying SNEDDS with silica enables the fabrication of powdered formulations with higher blonanserin loading and greater stability than liquid super-SNEDDS, however at the expense of drug solubilisation. These competing parameters need careful consideration in designing optimal super-SNEDDS for pre-clinical and clinical application. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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19 pages, 3176 KiB  
Article
Combinational Inhibition of P-Glycoprotein-Mediated Etoposide Transport by Zosuquidar and Polysorbate 20
by Rasmus Blaaholm Nielsen, René Holm, Ils Pijpers, Jan Snoeys, Ulla Gro Nielsen and Carsten Uhd Nielsen
Pharmaceutics 2023, 15(1), 283; https://doi.org/10.3390/pharmaceutics15010283 - 14 Jan 2023
Cited by 2 | Viewed by 1554
Abstract
P-glycoprotein (P-gp) limits the oral absorption of drug substances. Potent small molecule P-gp inhibitors (e.g., zosuquidar) and nonionic surfactants (e.g., polysorbate 20) inhibit P-gp by proposedly different mechanisms. Therefore, it was hypothesised that a combination of zosuquidar and polysorbate 20 may potentiate inhibition [...] Read more.
P-glycoprotein (P-gp) limits the oral absorption of drug substances. Potent small molecule P-gp inhibitors (e.g., zosuquidar) and nonionic surfactants (e.g., polysorbate 20) inhibit P-gp by proposedly different mechanisms. Therefore, it was hypothesised that a combination of zosuquidar and polysorbate 20 may potentiate inhibition of P-gp-mediated efflux. P-gp inhibition by zosuquidar and polysorbate 20 in combination was assessed in a calcein-AM assay and in a transcellular etoposide permeability study in MDCKII-MDR1 and Caco-2 cells. Furthermore, solutions of etoposide, zosuquidar, and polysorbate 20 were orally administered to Sprague Dawley rats. Zosuquidar elicited a high level of nonspecific adsorption to various labware, which significantly affected the outcomes of the in vitro studies. Still, at certain zosuquidar and polysorbate 20 concentrations, additive P-gp inhibition was observed in vitro. In vivo, however, oral etoposide bioavailability decreased by coadministration of both zosuquidar and polysorbate 20 when compared to coadministration of etoposide with zosuquidar alone. For future formulation development, the present study provided important and novel knowledge about nonspecific zosuquidar adsorption, as well as insights into combinational P-gp inhibition by a third-generation P-gp inhibitor and a P-gp-inhibiting nonionic surfactant. Full article
(This article belongs to the Special Issue Innovative In Vitro/In Silico Approaches to Drug Permeation and Absorption: The Highway to Implement the 3Rs Principles in Drug Development)
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24 pages, 11108 KiB  
Review
Extracellular Vesicles for Dental Pulp and Periodontal Regeneration
by Hongbin Lai, Jiaqi Li, Xiaoxing Kou, Xueli Mao, Wei Zhao and Lan Ma
Pharmaceutics 2023, 15(1), 282; https://doi.org/10.3390/pharmaceutics15010282 - 14 Jan 2023
Cited by 9 | Viewed by 2453
Abstract
Extracellular vesicles (EVs) are lipid bound particles derived from their original cells, which play critical roles in intercellular communication through their cargoes, including protein, lipids, and nucleic acids. According to their biogenesis and release pathway, EVs can be divided into three categories: apoptotic [...] Read more.
Extracellular vesicles (EVs) are lipid bound particles derived from their original cells, which play critical roles in intercellular communication through their cargoes, including protein, lipids, and nucleic acids. According to their biogenesis and release pathway, EVs can be divided into three categories: apoptotic vesicles (ApoVs), microvesicles (MVs), and small EVs (sEVs). Recently, the role of EVs in oral disease has received close attention. In this review, the main characteristics of EVs are described, including their classification, biogenesis, biomarkers, and components. Moreover, the therapeutic mechanism of EVs in tissue regeneration is discussed. We further summarize the current status of EVs in pulp/periodontal tissue regeneration and discuss the potential mechanisms. The therapeutic potential of EVs in pulp and periodontal regeneration might involve the promotion of tissue regeneration and immunomodulatory capabilities. Furthermore, we highlight the current challenges in the translational use of EVs. This review would provide valuable insights into the potential therapeutic strategies of EVs in dental pulp and periodontal regeneration. Full article
(This article belongs to the Special Issue Biomaterials and Agents: Pharmaceutical and Biomedical Applications in Dental Research)
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27 pages, 1386 KiB  
Systematic Review
Herbal Products and Their Active Constituents for Diabetic Wound Healing—Preclinical and Clinical Studies: A Systematic Review
by Anna Herman and Andrzej Przemysław Herman
Pharmaceutics 2023, 15(1), 281; https://doi.org/10.3390/pharmaceutics15010281 - 14 Jan 2023
Cited by 10 | Viewed by 3394
Abstract
The purpose of this review is to provide verified data on the current knowledge acquired in preclinical and clinical studies regarding topically used herbal products and their active constituents (formulations and dressings) with diabetic wound healing activity. Moreover, herbal products and their active [...] Read more.
The purpose of this review is to provide verified data on the current knowledge acquired in preclinical and clinical studies regarding topically used herbal products and their active constituents (formulations and dressings) with diabetic wound healing activity. Moreover, herbal products and their active constituents used for diabetic wound infections, and various cellular and molecular mechanisms of their actions will also be described. The electronic databases were searched for articles published from 2012 to 2022. Publications with oral or systemic administration of herbal products in diabetic wound healing, published before 2012, available only as an abstract, or in languages other than English were excluded from the study. The 59 articles comparing topically used herbal products in diabetic wound healing treatment versus control treatments (placebo or active therapy) were selected. Herbal products through different mechanisms of action, including antimicrobial, anti-inflammatory, antioxidant activity, stimulation of angiogenesis, production of cytokines and growth factors, keratinocytes, and fibroblast migration and proliferation may be considered as an important support during conventional therapy or even as a substitute for synthetic drugs used for diabetic wound treatment. Full article
(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)
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42 pages, 6320 KiB  
Review
Isolation, Detection and Analysis of Circulating Tumour Cells: A Nanotechnological Bioscope
by Upama Das, Soumyabrata Banik, Sharmila Sajankila Nadumane, Shweta Chakrabarti, Dharshini Gopal, Shama Prasada Kabekkodu, Pornsak Srisungsitthisunti, Nirmal Mazumder and Rajib Biswas
Pharmaceutics 2023, 15(1), 280; https://doi.org/10.3390/pharmaceutics15010280 - 13 Jan 2023
Cited by 2 | Viewed by 2914
Abstract
Cancer is one of the dreaded diseases to which a sizeable proportion of the population succumbs every year. Despite the tremendous growth of the health sector, spanning diagnostics to treatment, early diagnosis is still in its infancy. In this regard, circulating tumour cells [...] Read more.
Cancer is one of the dreaded diseases to which a sizeable proportion of the population succumbs every year. Despite the tremendous growth of the health sector, spanning diagnostics to treatment, early diagnosis is still in its infancy. In this regard, circulating tumour cells (CTCs) have of late grabbed the attention of researchers in the detection of metastasis and there has been a huge surge in the surrounding research activities. Acting as a biomarker, CTCs prove beneficial in a variety of aspects. Nanomaterial-based strategies have been devised to have a tremendous impact on the early and rapid examination of tumor cells. This review provides a panoramic overview of the different nanotechnological methodologies employed along with the pharmaceutical purview of cancer. Initiating from fundamentals, the recent nanotechnological developments toward the detection, isolation, and analysis of CTCs are comprehensively delineated. The review also includes state-of-the-art implementations of nanotechnological advances in the enumeration of CTCs, along with future challenges and recommendations thereof. Full article
(This article belongs to the Special Issue Tissue Diagnosis, Phototherapy and Drug Delivery)
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3 pages, 2399 KiB  
Correction
Correction: Zare et al. Encapsulation of miRNA and siRNA into Nanomaterials for Cancer Therapeutics. Pharmaceutics 2022, 14, 1620
by Mina Zare, Rakesh Pemmada, Maya Madhavan, Aswathy Shailaja, Seeram Ramakrishna, Sumodan Padikkala Kandiyil, James M. Donahue and Vinoy Thomas
Pharmaceutics 2023, 15(1), 279; https://doi.org/10.3390/pharmaceutics15010279 - 13 Jan 2023
Viewed by 1173
Abstract
In the original publication [...] Full article
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15 pages, 3149 KiB  
Article
The Effect of the Particle Size Reduction on the Biorelevant Solubility and Dissolution of Poorly Soluble Drugs with Different Acid-Base Character
by Dóra Csicsák, Rita Szolláth, Szabina Kádár, Rita Ambrus, Csilla Bartos, Emese Balogh, István Antal, István Köteles, Petra Tőzsér, Vivien Bárdos, Péter Horváth, Enikő Borbás, Krisztina Takács-Novák, Bálint Sinkó and Gergely Völgyi
Pharmaceutics 2023, 15(1), 278; https://doi.org/10.3390/pharmaceutics15010278 - 13 Jan 2023
Cited by 5 | Viewed by 4778
Abstract
Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal tract is a crucial parameter, because it can greatly influence the bioavailability. This work provides a comprehensive [...] Read more.
Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal tract is a crucial parameter, because it can greatly influence the bioavailability. This work provides a comprehensive investigation of the effect of the particle size, pH, biorelevant media and polymers (PVA and PVPK-25) on the solubility and dissolution of drug formulations using three model compounds with different acid-base characteristics (papaverine hydrochloride, furosemide and niflumic acid). It was demonstrated that micronization does not change the equilibrium solubility of a drug, but it results in a faster dissolution. In contrast, nanonization can improve the equilibrium solubility of a drug, but the selection of the appropriate excipient used for nanonization is essential, because out of the two used polymers, only the PVPK-25 had an increasing effect on the solubility. This phenomenon can be explained by the molecular structure of the excipients. Based on laser diffraction measurements, PVPK-25 could also inhibit the aggregation of the particles more effectively than PVA, but none of the polymers could hold the nanonized samples in the submicron range until the end of the measurements. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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35 pages, 4503 KiB  
Review
Microneedle-Mediated Transdermal Delivery of Biopharmaceuticals
by Hiep X. Nguyen and Chien N. Nguyen
Pharmaceutics 2023, 15(1), 277; https://doi.org/10.3390/pharmaceutics15010277 - 13 Jan 2023
Cited by 16 | Viewed by 7010
Abstract
Transdermal delivery provides numerous benefits over conventional routes of administration. However, this strategy is generally limited to a few molecules with specific physicochemical properties (low molecular weight, high potency, and moderate lipophilicity) due to the barrier function of the stratum corneum layer. Researchers [...] Read more.
Transdermal delivery provides numerous benefits over conventional routes of administration. However, this strategy is generally limited to a few molecules with specific physicochemical properties (low molecular weight, high potency, and moderate lipophilicity) due to the barrier function of the stratum corneum layer. Researchers have developed several physical enhancement techniques to expand the applications of the transdermal field; among these, microneedle technology has recently emerged as a promising platform to deliver therapeutic agents of any size into and across the skin. Typically, hydrophilic biomolecules cannot penetrate the skin by passive diffusion. Microneedle insertion disrupts skin integrity and compromises its protective function, thus creating pathways (microchannels) for enhanced permeation of macromolecules. Microneedles not only improve stability but also enhance skin delivery of various biomolecules. Academic institutions and industrial companies have invested substantial resources in the development of microneedle systems for biopharmaceutical delivery. This review article summarizes the most recent research to provide a comprehensive discussion about microneedle-mediated delivery of macromolecules, covering various topics from the introduction of the skin, transdermal delivery, microneedles, and biopharmaceuticals (current status, conventional administration, and stability issues), to different microneedle types, clinical trials, safety and acceptability of microneedles, manufacturing and regulatory issues, and the future of microneedle technology. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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16 pages, 3777 KiB  
Article
Synergistic Pro-Apoptotic Effect of a Cyclic RGD Peptide-Conjugated Magnetic Mesoporous Therapeutic Nanosystem on Hepatocellular Carcinoma HepG2 Cells
by Xuanping Zhao, Chuan Liu, Zichao Wang, Yingyuan Zhao, Xuyang Chen, Haizhen Tao, Hong Chen, Xueqin Wang and Shaofeng Duan
Pharmaceutics 2023, 15(1), 276; https://doi.org/10.3390/pharmaceutics15010276 - 13 Jan 2023
Cited by 3 | Viewed by 1974
Abstract
Numerous nanocarriers have been developed to deliver drugs for the treatment of hepatocellular carcinoma. However, the lack of specific targeting ability, the low administration efficiency, and insufficient absorption by hepatocellular carcinoma cells, severely limits the therapeutic effect of the current drugs. Therefore, it [...] Read more.
Numerous nanocarriers have been developed to deliver drugs for the treatment of hepatocellular carcinoma. However, the lack of specific targeting ability, the low administration efficiency, and insufficient absorption by hepatocellular carcinoma cells, severely limits the therapeutic effect of the current drugs. Therefore, it is still of great clinical significance to develop highly efficient therapies with few side effects for the treatment of hepatocellular carcinoma. Herein, we developed a highly effective nanocarrier, cyclic RGD peptide-conjugated magnetic mesoporous nanoparticles (RGDSPIO@MSN NPs), to deliver the chemotherapeutic drug doxorubicin (DOX) to human hepatocellular carcinoma HepG2 cells, and further explored their synergistic apoptosis-promoting effects. The results showed that the prepared RGDSPIO@MSN NPs had good stability, biosafety and drug-loading capacity, and significantly improved the absorption of DOX by HepG2 cells, and that the RGDSPIO@MSN@DOX NPs could synergistically promote the apoptosis of HepG2 cells. Thus, this cyclic RGD peptide-modified magnetic mesoporous silicon therapeutic nanosystem can be regarded as a potentially effective strategy for the targeted treatment of hepatocellular carcinoma. Full article
(This article belongs to the Special Issue Polymer Nanoparticles for the Delivery of Anticancer Drugs, 2nd Edition)
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16 pages, 660 KiB  
Review
Chemopreventive and Anticancer Role of Resveratrol against Oral Squamous Cell Carcinoma
by Giuseppe Angellotti, Giulia Di Prima, Elena Belfiore, Giuseppina Campisi and Viviana De Caro
Pharmaceutics 2023, 15(1), 275; https://doi.org/10.3390/pharmaceutics15010275 - 13 Jan 2023
Cited by 15 | Viewed by 2219
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most prevailing and aggressive head and neck cancers, featuring high morbidity and mortality. The available conventional treatments suffer from several adverse effects and are often inefficient in terms of their survival rates. Thus, seeking [...] Read more.
Oral squamous cell carcinoma (OSCC) is one of the most prevailing and aggressive head and neck cancers, featuring high morbidity and mortality. The available conventional treatments suffer from several adverse effects and are often inefficient in terms of their survival rates. Thus, seeking novel therapeutic agents and adjuvants is of the utmost importance for modern society. Natural polyphenolic compounds have recently emerged as promising chemopreventive and anticancer agents. Specifically, the natural compound resveratrol (RSV) has recently gained momentum for this purpose. RSV is useful for treating OSCC due to its antiproliferative, antimetastatic, and proapoptotic effects. Additionally, RSV acts against tumor cells while synergically cooperating with chemotherapeutics, overcoming drug resistance phenomena. Despite these wide-spectrum effects, there are few specific investigations regarding RSV’s effects against OSCC animal models that consider different routes and vehicles for the administration of RSV. Interestingly, an injectable RSV-loaded liposome-based formulation was proven to be effective against both in vitro and in vivo OSCC models, demonstrating that the development of RSV-loaded drug delivery systems for systemic and/or loco-regional applications may be the turning point in oral cancer treatment, leading to benefits from both RSV’s properties as well as from targeted delivery. Given these premises, this review offers a comprehensive overview of the in vitro and in vivo effects of RSV and its main derivative, polydatin (PD), against OSCC-related cell lines and animal models, aiming to guide the scientific community in regard to RSV and PD use in the treatment of oral precancerous and cancerous lesions. Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies, 2nd Edition)
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