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Cyclodextrins in Antiviral Therapeutics and Vaccines -
Recent advances in co-amorphous drug formulations -
LipoParticles: Lipid-Coated PLA Nanoparticles Enhanced In Vitro mRNA Transfection Compared to Liposomes -
Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region -
NK cell-based cancer immunotherapy with nanoparticles
Journal Description
Pharmaceutics
Pharmaceutics
is a peer-reviewed, open access journal on the science and technology of pharmaceutics and biopharmaceutics, and is published monthly online by MDPI. The Spanish Society of Pharmaceutics and Pharmaceutical Technology (SEFIG), Pharmaceutical Solid State Research Cluster (PSSRC), Academy of Pharmaceutical Sciences (APS) and Korean Society of Pharmaceutical Sciences and Technology (KSPST) are affiliated with Pharmaceutics and their members receive a discount on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and many other databases.
- Journal Rank: JCR - Q1 (Pharmacology & Pharmacy) / CiteScore - Q2 (Pharmaceutical Science)
- Rapid Publication: manuscripts are peer-reviewed and a first decision provided to authors approximately 13.5 days after submission; acceptance to publication is undertaken in 3.7 days (median values for papers published in this journal in the first half of 2021).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Companion journal: Future Pharmacology
Impact Factor:
6.321 (2020)
;
5-Year Impact Factor:
6.734 (2020)
Latest Articles
Solid and Semisolid Innovative Formulations Containing Miconazole-Loaded Solid Lipid Microparticles to Promote Drug Entrapment into the Buccal Mucosa
Pharmaceutics 2021, 13(9), 1361; https://doi.org/10.3390/pharmaceutics13091361 (registering DOI) - 29 Aug 2021
Abstract
The currently available antifungal therapy for oral candidiasis (OC) has various limitations restricting its clinical use, such as short retention time, suboptimal drug concentration and low patients compliance. These issues could be overcome using micro or nanotechnology. In particular, solid lipid microparticles (SLMs)
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The currently available antifungal therapy for oral candidiasis (OC) has various limitations restricting its clinical use, such as short retention time, suboptimal drug concentration and low patients compliance. These issues could be overcome using micro or nanotechnology. In particular, solid lipid microparticles (SLMs) resulted as a particularly promising penetration enhancer carrier for lipophilic drugs, such as the antifungal miconazole (MCZ). Based on these considerations, cetyl decanoate (here synthesized without the use of metal catalysis) was employed together with 1-hexadecanol to prepare MCZ-loaded SLMs. These resulted in a powder composed of 45–300 µm diameter solid spherical particles, able to load a high amount of MCZ in the amorphous form and characterized by a melting temperature range perfectly compatible with oromucosal administration (35–37 °C). Moreover, when compared to Daktarin® 2% oral gel in ex vivo experiments, SLMs were able to increase up to three-fold MCZ accumulation into the porcine buccal mucosa. The prepared SLMs were then loaded into a buccal gel or a microcomposite mucoadhesive buccal film and evaluated in terms of MCZ permeation and/or accumulation into porcine buccal mucosa by using lower doses than the conventional dosage form. The promising results obtained highlighted an enhancement in terms of MCZ accumulation even at low doses. Furthermore, the prepared buccal film was eligible as stable, reproducible and also highly mucoadhesive. Therefore, the formulated SLMs represent a penetration enhancer vehicle suitable to reduce the dose of lipophilic drugs to be administered to achieve the desired therapeutic effects, as well as being able to be effectively embedded into easily administrable solid or semisolid dosage forms.
Full article
(This article belongs to the Special Issue Polymeric Systems to Enhance Drug Penetration and/or Permeation through Biomembranes)
Open AccessArticle
Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
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, , , , , , , , and
Pharmaceutics 2021, 13(9), 1360; https://doi.org/10.3390/pharmaceutics13091360 (registering DOI) - 29 Aug 2021
Abstract
Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of
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Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.
Full article
(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)
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Open AccessArticle
The Therapeutic Effect of Second Near-Infrared Absorbing Gold Nanorods on Metastatic Lymph Nodes via Lymphatic Delivery System
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, , , , , , , and
Pharmaceutics 2021, 13(9), 1359; https://doi.org/10.3390/pharmaceutics13091359 (registering DOI) - 28 Aug 2021
Abstract
Photothermal therapy has been established recently as a non-invasive treatment protocol for cancer metastatic lymph nodes. Although this treatment approach shows efficient tumour ablation towards lymph node metastasis, the monitoring and reporting of treatment progress using the lymphatic delivery channel still need to
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Photothermal therapy has been established recently as a non-invasive treatment protocol for cancer metastatic lymph nodes. Although this treatment approach shows efficient tumour ablation towards lymph node metastasis, the monitoring and reporting of treatment progress using the lymphatic delivery channel still need to be explored. Herein, we investigated the anti-tumour effect of pegylated gold nanorods with a high aspect ratio (PAuNRs) delivered via the lymphatic route in a mouse model. In this study, breast carcinoma (FM3A-Luc) cells were inoculated in the subiliac lymph node (SiLN) to induce metastasis in the proper axillary lymph node (PALN). The treatment was initiated by injecting the PAuNRs into the accessory axillary lymph node (AALN) after tumour metastasis was confirmed in the PALN followed by external NIR laser irradiation under a temperature-controlled cooling system. The anti-tumour impact of the treatment was evaluated using an in vivo bioluminescence imaging system (IVIS). The results showed a time-dependent reduction in tumour activity with significant treatment response. Tumour growth was inhibited in all mice treated with PAuNRs under laser irradiation; results were statistically significant (** p < 0.01) even after treatment was concluded on day 3. We believe that this non-invasive technique would provide more information on the dynamics of tumour therapy using the lymphatically administered route in preclinical studies.
Full article
(This article belongs to the Special Issue Application of Gold Nanoparticles and Gold-Based Polymer Composites in Biomedicine)
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Infection Responsive Smart Delivery of Antibiotics Using Recombinant Spider Silk Nanospheres
Pharmaceutics 2021, 13(9), 1358; https://doi.org/10.3390/pharmaceutics13091358 (registering DOI) - 28 Aug 2021
Abstract
Frequent and inappropriate usage of antibiotics has changed the natural evolution of bacteria by reducing susceptibility and increasing resistance towards antibacterial agents. New resistance mechanisms evolved in the response to host defenses and pharmaceutical interventions are threatening our ability to treat common infections,
[...] Read more.
Frequent and inappropriate usage of antibiotics has changed the natural evolution of bacteria by reducing susceptibility and increasing resistance towards antibacterial agents. New resistance mechanisms evolved in the response to host defenses and pharmaceutical interventions are threatening our ability to treat common infections, resulting in increased mortality. In the face of this rising epidemic, antibiotic drug discovery, which has long been overlooked by big pharma, is reaching a critical low. Thus, the development of an infection-responsive drug delivery system, which may mitigate multidrug resistance and preserve the lifetime of our current antibiotic arsenal, has garnered the attention of both popular science and funding agencies. The present work describes the development of a thrombin-sensitive linker embedded into a recombinant spider silk copolymer to create a nanosphere drug delivery vehicle. Recent studies have suggested that there is an increase in thrombin-like activity during Staphylococcus aureus infection; thus, drug release from this new “smart” nanosphere can be triggered in the presence of infection. A thrombin sensitive peptide (TSP) was synthesized, and the thrombin cleavage sensitivity was determined by HPLC. The results showed no cleavage of the peptide when exposed to human serum whereas the peptide was cleaved when incubated with S. aureus exudate. Subsequently, the peptide was coupled with a silk copolymer via EDC-NHS chemistry and formulated into nanospheres encapsulating antibiotic vancomycin. These nanospheres were evaluated for in vitro infection-responsive drug release and antimicrobial activity. Finally, the drug responsive nanospheres were assessed for efficacy in an in vivo septic arthritis model. Our study provides evidence that the protein conjugate was enzyme responsive and can be used to formulate targeted drug release to combat infections against multidrug-resistant bacterial strains.
Full article
(This article belongs to the Special Issue Advanced Polymeric-Based Nanocarriers for Drug Delivery and Theranosis)
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Open AccessArticle
Atrial Natriuretic Peptide Antibody-Functionalised, PEGylated Multiwalled Carbon Nanotubes for Targeted Ischemic Stroke Intervention
Pharmaceutics 2021, 13(9), 1357; https://doi.org/10.3390/pharmaceutics13091357 (registering DOI) - 28 Aug 2021
Abstract
Stroke is one of the major causes of disability and the second major cause of death around the globe. There is a dire need for an ultrasensitive detection tool and an effective and efficient therapeutic system for both detection and treatment of stroke
[...] Read more.
Stroke is one of the major causes of disability and the second major cause of death around the globe. There is a dire need for an ultrasensitive detection tool and an effective and efficient therapeutic system for both detection and treatment of stroke at its infancy stage. Carbon nanotubes are promising nanomaterials for tackling these challenges. The loading of dexamethasone and decoration of PEGylated multiwalled carbon nanotube with atrial natriuretic peptide (ANP) antibody and fluorescein isothiocyanate for targeting ischemic site in the rat stroke model is presented here. Functionalisation of carbon nanotubes with dexamethasone (DEX), polyethylene glycol (PEG), fluorescein isothiocyanate (FITC), and ANP antibody caused a 63-fold increase in the D band intensity as illustrated by Raman. The characteristic band intensity increase was observed at 1636 nm following functionalisation of carbon nanotubes with polyethylene glycol and dexamethasone as confirmed by Fourier Transform Infrared. These findings have demonstrated the coupling capability of atrial natriuretic peptide antibody to DEX-PEG-CNTs. The baseline plasma atrial natriuretic peptide levels were ranging from 118 to 135.70 pg/mL prior to surgery and from 522.09 to 552.37 following common carotid artery occlusion. A decrease in atrial natriuretic peptide levels to 307.77 was observed when the rats were treated with FITC-DEX-PEG-ANP-CNTs, PEG-CNTs and DEX with a significant drop in the FITC-DEX-PEG-ANP-CNTs treated group. Fluorescence was detected in FITC-DEX-PEG-CNTs and FITC-DEX-PEG-ANP-CNTs treated ischemic stroke rats. The highest fluorescence intensity was reported in plasma (2179) followed by the kidney (1563) and liver (1507). These findings suggest a beneficial role that is played by the FITC-DEX-PEG-ANP-CNTs in the reduction of inflammation in the ischemic stroke induced rats that could induce a successful treatment of ischemic stroke.
Full article
(This article belongs to the Special Issue Peptide-Based Drug Delivery Systems)
Open AccessArticle
Anti-Cancer Nanopowders and MAPLE-Fabricated Thin Coatings Based on SPIONs Surface Modified with Paclitaxel Loaded β-Cyclodextrin
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, , , , , , , , , and
Pharmaceutics 2021, 13(9), 1356; https://doi.org/10.3390/pharmaceutics13091356 (registering DOI) - 28 Aug 2021
Abstract
Globally, cancer is the second most common cause of death, and Europe accounts for almost 25% of the global cancer burden, although its people make up only 10% of the world’s population. Conventional systemically administered anti-cancer drugs come with important drawbacks such as
[...] Read more.
Globally, cancer is the second most common cause of death, and Europe accounts for almost 25% of the global cancer burden, although its people make up only 10% of the world’s population. Conventional systemically administered anti-cancer drugs come with important drawbacks such as inefficiency due to poor bioavailability and improper biodistribution, severe side effects associated with low therapeutic indices, and the development of multidrug resistance. Therefore, smart nano-engineered targeted drug-delivery systems with tailored pharmacokinetics and biodistribution which can selectively deliver anti-cancer agents directly to the tumor site are the solution to most difficulties encountered with conventional therapeutic tools. Here, we report on the synthesis, physicochemical characterization, and in vitro evaluation of biocompatibility and anti-tumor activity of novel magnetically targetable SPIONs based on magnetite (Fe3O4) nanoparticles’ surface modified with β-cyclodextrin (CD) and paclitaxel (PTX)–guest–host inclusion complexes (Fe3O4@β-CD/PTX). Both pristine Fe3O4@β-CD nanopowders and PTX-loaded thin films fabricated by MAPLE technique were investigated. Pristine Fe3O4@β-CD and Fe3O4@β-CD/PTX thin films were physicochemically characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), thermal analysis, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The biocompatibility of bare magnetic nanocomposite thin films was evaluated by MTT cell viability assay on a normal 3T3 osteoblast cell line culture and by measuring the level of NO in the culture medium. No significant modifications, neither in cell viability nor in NO level, could be observed, thereby demonstrating the excellent biocompatibility of the SPIONs thin films. Inverted phase-contrast microscopy showed no evident adverse effect on the morphology of normal osteoblasts. On the other hand, Fe3O4@β-CD/PTX films decreased the cell viability of the MG-63 osteosarcoma cell line by 85%, demonstrating excellent anti-tumor activity. The obtained results recommend these magnetic hybrid films as promising candidates for future delivery, and hyperthermia applications in cancer treatment.
Full article
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))
Open AccessArticle
Orally Administered Natural Lipid Nanoparticle-Loaded 6-Shogaol Shapes the Anti-Inflammatory Microbiota and Metabolome
Pharmaceutics 2021, 13(9), 1355; https://doi.org/10.3390/pharmaceutics13091355 (registering DOI) - 28 Aug 2021
Abstract
The past decade has seen increasing interest in microbiota-targeting therapeutic strategies that aim to modulate the gut microbiota’s composition and/or function to treat chronic diseases, such as inflammatory bowel disease (IBD), metabolic symptoms, and obesity. While targeting the gut microbiota is an innovative
[...] Read more.
The past decade has seen increasing interest in microbiota-targeting therapeutic strategies that aim to modulate the gut microbiota’s composition and/or function to treat chronic diseases, such as inflammatory bowel disease (IBD), metabolic symptoms, and obesity. While targeting the gut microbiota is an innovative means for treating IBD, it typically requires an extended treatment time, hampering its potential application. Herein, using an established natural-lipid nanoparticle (nLNP) platform, we demonstrate that nLNPs encapsulated with the drug candidate 6-shogaol (6S/nLNP) distinctly altered microbiota composition within one day of treatment, significantly accelerating a process that usually requires five days using free 6-shogaol (6S). In addition, the change in the composition of the microbiota induced by five-day treatment with 6S/nLNP was maintained for at least 15 days (from day five to day 20). The consequent alteration in the fecal metabolic profile stemming from this compositional change manifested as functional changes that enhanced the in vitro anti-inflammatory and wound-healing efficacy of macrophage cells (Raw 264.7) and epithelial cells (Caco-2 BBE1), respectively. Further, this metabolic compositional change, as reflected in an altered metabolic profile, promoted a robust anti-inflammatory effect in a DSS-induced mouse model of acute colitis. Our study demonstrates that, by near-instantly modulating microbiota composition and function, an nLNP-based drug-delivery platform might be a powerful tool for treating ulcerative colitis.
Full article
(This article belongs to the Special Issue Encapsulation of Single or Multiple Molecules in Nano- and Microparticles for Drug Delivery)
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Surface-Tailored Zein Nanoparticles: Strategies and Applications
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, , , , , and
Pharmaceutics 2021, 13(9), 1354; https://doi.org/10.3390/pharmaceutics13091354 (registering DOI) - 28 Aug 2021
Abstract
Plant-derived proteins have emerged as leading candidates in several drug and food delivery applications in diverse pharmaceutical designs. Zein is considered one of the primary plant proteins obtained from maize, and is well known for its biocompatibility and safety in biomedical fields. The
[...] Read more.
Plant-derived proteins have emerged as leading candidates in several drug and food delivery applications in diverse pharmaceutical designs. Zein is considered one of the primary plant proteins obtained from maize, and is well known for its biocompatibility and safety in biomedical fields. The ability of zein to carry various pharmaceutically active substances (PAS) position it as a valuable contender for several in vitro and in vivo applications. The unique structure and possibility of surface covering with distinct coating shells or even surface chemical modifications have enabled zein utilization in active targeted and site-specific drug delivery. This work summarizes up-to-date studies on zein formulation technology based on its structural features. Additionally, the multiple applications of zein, including drug delivery, cellular imaging, and tissue engineering, are discussed with a focus on zein-based active targeted delivery systems and antigenic response to its potential in vivo applicability.
Full article
(This article belongs to the Special Issue Nanotecnology and Natural Products: Plant Bioactive Compounds for Drug Delivery)
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Open AccessReview
Combination Therapy of Navitoclax with Chemotherapeutic Agents in Solid Tumors and Blood Cancer: A Review of Current Evidence
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, , , , , and
Pharmaceutics 2021, 13(9), 1353; https://doi.org/10.3390/pharmaceutics13091353 (registering DOI) - 28 Aug 2021
Abstract
Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family
[...] Read more.
Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.
Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies)
Open AccessArticle
Antimicrobial Properties of Lepidium sativum L. Facilitated Silver Nanoparticles
Pharmaceutics 2021, 13(9), 1352; https://doi.org/10.3390/pharmaceutics13091352 (registering DOI) - 27 Aug 2021
Abstract
Antibiotic resistance toward commonly used medicinal drugs is a dangerously growing threat to our existence. Plants are naturally equipped with a spectrum of biomolecules and metabolites with important biological activities. These natural compounds constitute a treasure in the fight against multidrug-resistant microorganisms. The
[...] Read more.
Antibiotic resistance toward commonly used medicinal drugs is a dangerously growing threat to our existence. Plants are naturally equipped with a spectrum of biomolecules and metabolites with important biological activities. These natural compounds constitute a treasure in the fight against multidrug-resistant microorganisms. The development of plant-based antimicrobials through green synthesis may deliver alternatives to common drugs. Lepidium sativum L. (LS) is widely available throughout the world as a fast-growing herb known as garden cress. LS seed oil is interesting due to its antimicrobial, antioxidant, and anti-inflammatory activities. Nanotechnology offers a plethora of applications in the health sector. Silver nanoparticles (AgNP) are used due to their antimicrobial properties. We combined LS and AgNP to prevent microbial resistance through plant-based synergistic mechanisms within the nanomaterial. AgNP were prepared by a facile one-pot synthesis through plant-biomolecules-induced reduction of silver nitrate via a green method. The phytochemicals in the aqueous LS extract act as reducing, capping, and stabilizing agents of AgNP. The composition of the LS-AgNP biohybrids was confirmed by analytical methods. Antimicrobial testing against 10 reference strains of pathogens exhibited excellent to intermediate antimicrobial activity. The bio-nanohybrid LS-AgNP has potential uses as a broad-spectrum microbicide, disinfectant, and wound care product.
Full article
(This article belongs to the Special Issue Focus on Antibiotics – New Challenges and Steps Forward in Discovery and Development)
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Viscoelastic and Deformation Characteristics of Structurally Different Commercial Topical Systems
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, , , , , and
Pharmaceutics 2021, 13(9), 1351; https://doi.org/10.3390/pharmaceutics13091351 (registering DOI) - 27 Aug 2021
Abstract
Rheological characteristics and shear response have potential implication in defining the pharmaceutical equivalence, therapeutic equivalence, and perceptive equivalence of commercial topical products. Three creams (C1 and C3 as oil-in-water and C2 as water-in-oil emulsions), and two gels (G1 and G2 carbomer-based) were characterized
[...] Read more.
Rheological characteristics and shear response have potential implication in defining the pharmaceutical equivalence, therapeutic equivalence, and perceptive equivalence of commercial topical products. Three creams (C1 and C3 as oil-in-water and C2 as water-in-oil emulsions), and two gels (G1 and G2 carbomer-based) were characterized using the dynamic range of controlled shear in steady-state flow and oscillatory modes. All products, other than C3, met the Critical Quality Attribute criteria for high zero-shear viscosity (η0) of 2.6 × 104 to 1.5 × 105 Pa∙s and yield stress (τ0) of 55 to 277 Pa. C3 exhibited a smaller linear viscoelastic region and lower η0 (2547 Pa∙s) and τ0 (2 Pa), consistent with lotion-like behavior. All dose forms showed viscoelastic solid behavior having a storage modulus (G′) higher than the loss modulus (G″) in the linear viscoelastic region. However, the transition of G′ > G″ to G″ > G′ during the continual strain increment was more rapid for the creams, elucidating a relatively brittle deformation, whereas these transitions in gels were more prolonged, consistent with a gradual disentanglement of the polymer network. In conclusion, these analyses not only ensure quality and stability, but also enable the microstructure to be characterized as being flexible (gels) or inelastic (creams).
Full article
(This article belongs to the Special Issue Pharmaceutics 2020 Young Investigators' Contributions Collection)
Open AccessArticle
Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions
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, , , , , and
Pharmaceutics 2021, 13(9), 1350; https://doi.org/10.3390/pharmaceutics13091350 (registering DOI) - 27 Aug 2021
Abstract
Zoledronic acid (ZOL) is used as a bone-specific antiresorptive drug with antimyeloma effects. Adverse drug reactions (A.D.R.) are associated with ZOL-therapy, whose mechanics are unknown. ZOL is a nitrogen-containing molecule whose structure shows similarities with nucleotides, ligands of ATP-sensitive K+ (KATP) channels.
[...] Read more.
Zoledronic acid (ZOL) is used as a bone-specific antiresorptive drug with antimyeloma effects. Adverse drug reactions (A.D.R.) are associated with ZOL-therapy, whose mechanics are unknown. ZOL is a nitrogen-containing molecule whose structure shows similarities with nucleotides, ligands of ATP-sensitive K+ (KATP) channels. We investigated the action of ZOL by performing in vitro patch-clamp experiments on native KATP channels in murine skeletal muscle fibers, bone cells, and recombinant subunits in cell lines, and by in silico docking the nucleotide site on KIR and SUR, as well as the glibenclamide site. ZOL fully inhibited the KATP currents recorded in excised macro-patches from Extensor digitorum longus (EDL) and Soleus (SOL) muscle fibers with an IC50 of 1.2 ± 1.4 × 10−6 and 2.1 ± 3.7 × 10−10 M, respectively, and the KATP currents recorded in cell-attached patches from primary long bone cells with an IC50 of 1.6 ± 2.8 × 10−10 M. ZOL fully inhibited a whole-cell KATP channel current of recombinant KIR6.1-SUR2B and KIR6.2-SUR2A subunits expressed in HEK293 cells with an IC50 of 3.9 ± 2.7 × 10−10 M and 7.1 ± 3.1 × 10−6 M, respectively. The rank order of potency in inhibiting the KATP currents was: KIR6.1-SUR2B/SOL-KATP/osteoblast-KATP > KIR6.2-SUR2A/EDL-KATP >>> KIR6.2-SUR1 and KIR6.1-SUR1. Docking investigation revealed that the drug binds to the ADP/ATP sites on KIR6.1/2 and SUR2A/B and on the sulfonylureas site showing low binding energy <6 Kcal/mol for the KIR6.1/2-SUR2 subunits vs. the <4 Kcal/mol for the KIR6.2-SUR1. The IC50 of ZOL to inhibit the KIR6.1/2-SUR2A/B channels were correlated with its musculoskeletal and cardiovascular risks. We first showed that ZOL blocks at subnanomolar concentration musculoskeletal KATP channels and cardiac and vascular KIR6.2/1-SUR2 channels.
Full article
(This article belongs to the Special Issue In Silico Pharmacology for Evidence-Based and Precision Medicine)
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Inclusion of Medium-Chain Triglyceride in Lipid-Based Formulation of Cannabidiol Facilitates Micellar Solubilization In Vitro, but In Vivo Performance Remains Superior with Pure Sesame Oil Vehicle
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, , , , , , , , , , and
Pharmaceutics 2021, 13(9), 1349; https://doi.org/10.3390/pharmaceutics13091349 (registering DOI) - 27 Aug 2021
Abstract
Oral sesame oil-based formulation facilitates the delivery of poorly water-soluble drug cannabidiol (CBD) to the lymphatic system and blood circulation. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD. In this work, the performance of lipid-based formulations with
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Oral sesame oil-based formulation facilitates the delivery of poorly water-soluble drug cannabidiol (CBD) to the lymphatic system and blood circulation. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD. In this work, the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle has been tested in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and MLNs, but with reduced variability. MCT improves the emulsification and micellar solubilization of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle.
Full article
(This article belongs to the Special Issue Special Issue in Honor of Retired Professor and Former Dean Dr. Kishor M. Wasan: The Current State of Pharmaceutical Sciences and Its Promising Future)
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Plate-Like Alginate Microparticles with Disulfiram–SPIO–Coencapsulation: An In Vivo Study for Combined Therapy on Ovarian Cancer
Pharmaceutics 2021, 13(9), 1348; https://doi.org/10.3390/pharmaceutics13091348 (registering DOI) - 27 Aug 2021
Abstract
Disulfiram is a drug used to support the treatment of chronic alcoholism. Recently, it has been found to have an off-label ability to inhibit the growth of ovarian cancer cells. However, the original formulation was designed for use via oral administration, which is
[...] Read more.
Disulfiram is a drug used to support the treatment of chronic alcoholism. Recently, it has been found to have an off-label ability to inhibit the growth of ovarian cancer cells. However, the original formulation was designed for use via oral administration, which is not suitable to be given by a direct spray on the affected area. Therefore, in this study, we designed and prepared alginate (ALG) microparticles loaded with disulfiram and superparamagnetic iron oxide (cross-linking disulfiram/SPIO/ALG MPs), which have great potential application for inhibiting the growth of ovarian cancer simultaneously via two treatments, i.e., chemotherapy and hyperthermia. The drug-encapsulating alginate microparticles were prepared using an electrospray system and then cross-linked with calcium chloride ions. The particles were observed by optical microscopy and scanning electron microscopy, and found to be approximately 200 μm in diameter. The disc-shape morphology of the microparticles could be controlled by up to 95%. The drug-encapsulation efficiency of the microparticles reached 98%, and the suppression of tumor growth for the free-form disulfiram-treated group and disulfiram/SPIO/ALG MPs-treated group were 48.2% and 55.9% of tumor volume reduction, respectively, compared with a cisplatin-treated group. A hyperthermic effect can be achieved by applying a magnetic field to oscillate SPIO. The results of this study showed that these cross-linking disulfiram/SPIO/ALG MPs are potential drug carriers for the treatment of ovarian cancer.
Full article
(This article belongs to the Special Issue Porous Micro and Nanoparticles for Drug Delivery)
Open AccessArticle
Lung Targeted Lipopolymeric Microspheres of Dexamethasone for the Treatment of ARDS
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, , , , , , and
Pharmaceutics 2021, 13(9), 1347; https://doi.org/10.3390/pharmaceutics13091347 (registering DOI) - 27 Aug 2021
Abstract
Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ
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Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ side effects arising from frequent and chronic use of dexamethasone, we designed biodegradable, lung-targeted microspheres with sustained release profiles. Dexamethasone-loaded lipopolymeric microspheres of PLGA (Poly Lactic-co-Glycolic Acid) and DPPC (Dipalmitoylphosphatidylcholine) stabilized with vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate) were prepared by a single emulsion technique that had a mean diameter of 8.83 ± 0.32 μm and were spherical in shape as revealed from electron microscopy imaging. Pharmacokinetic and biodistribution patterns studied in the lungs, liver, and spleen of Wistar rats showed high selectivity and targeting efficiency for the lung tissue (re 13.98). As a proof-of-concept, in vivo efficacy of the microspheres was tested in the lipopolysaccharide-induced ARDS model in rats. Inflammation markers such as IL-1β, IL-6, and TNF-α, quantified in the bronchoalveolar lavage fluid indicated major improvement in rats treated with dexamethasone microspheres by intravenous route. Additionally, the microspheres substantially inhibited the protein infiltration, neutrophil accumulation and lipid peroxidation in the lungs of ARDS bearing rats, suggesting a reduction in oxidative stress. Histopathology showed decreased damage to the pulmonary tissue upon treatment with the dexamethasone-loaded microspheres. The multipronged formulation technology approach can thus serve as a potential treatment modality for reducing lung inflammation in ARDS. An improved therapeutic profile would help to reduce the dose, dosing frequency and, eventually, the toxicity.
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(This article belongs to the Special Issue Microencapsulation for the Therapeutic Delivery of Drugs)
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A New Approach to Atopic Dermatitis Control with Low-Concentration Propolis-Loaded Cold Cream
by
, , , , , , , , , , and
Pharmaceutics 2021, 13(9), 1346; https://doi.org/10.3390/pharmaceutics13091346 (registering DOI) - 27 Aug 2021
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease that is difficult to treat. Traditional cold cream, a water-in-oil emulsion made from beeswax, is used to alleviate AD symptoms in clinical practice, although its effectiveness has not been scientifically proven. The addition of
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Atopic dermatitis (AD) is a chronic inflammatory skin disease that is difficult to treat. Traditional cold cream, a water-in-oil emulsion made from beeswax, is used to alleviate AD symptoms in clinical practice, although its effectiveness has not been scientifically proven. The addition of propolis has the potential to impart anti-inflammatory properties to cold cream. However, in high concentrations, propolis can trigger allergic reactions. Thus, the objective of this work was to develop a cold cream formulation based on purified beeswax containing the same amount of green propolis present in raw beeswax. The impact of adding this low propolis concentration to cold cream on AD control was evaluated in patients compared to cold cream without added propolis (CBlank). Raw beeswax was chemically characterized to define the propolis concentration added to the propolis-loaded cold cream (CPropolis). The creams were characterized as to their physicochemical, mechanical, and rheological characteristics. The effect of CPropolis and CBlank on the quality of life, disease severity, and skin hydration of patients with AD was evaluated in a triple-blind randomized preclinical study. Concentrations of 34 to 120 ng/mL of green propolis extract reduced TNF-α levels in LPS-stimulated macrophage culture. The addition of propolis to cold cream did not change the cream’s rheological, mechanical, or bioadhesive properties. The preclinical study suggested that both creams improved the patient’s quality of life. Furthermore, the use of CPropolis decreased the disease severity compared to CBlank.
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(This article belongs to the Special Issue Skin Immunomodulation: Impact on Diseases and Treatments)
Open AccessReview
Liposome Photosensitizer Formulations for Effective Cancer Photodynamic Therapy
Pharmaceutics 2021, 13(9), 1345; https://doi.org/10.3390/pharmaceutics13091345 (registering DOI) - 27 Aug 2021
Abstract
Photodynamic therapy (PDT) is a promising non-invasive strategy in the fight against that which circumvents the systemic toxic effects of chemotherapeutics. It relies on photosensitizers (PSs), which are photoactivated by light irradiation and interaction with molecular oxygen. This generates highly reactive oxygen species
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Photodynamic therapy (PDT) is a promising non-invasive strategy in the fight against that which circumvents the systemic toxic effects of chemotherapeutics. It relies on photosensitizers (PSs), which are photoactivated by light irradiation and interaction with molecular oxygen. This generates highly reactive oxygen species (such as 1O2, H2O2, O2, ·OH), which kill cancer cells by necrosis or apoptosis. Despite the promising effects of PDT in cancer treatment, it still suffers from several shortcomings, such as poor biodistribution of hydrophobic PSs, low cellular uptake, and low efficacy in treating bulky or deep tumors. Hence, various nanoplatforms have been developed to increase PDT treatment effectiveness and minimize off-target adverse effects. Liposomes showed great potential in accommodating different PSs, chemotherapeutic drugs, and other therapeutically active molecules. Here, we review the state-of-the-art in encapsulating PSs alone or combined with other chemotherapeutic drugs into liposomes for effective tumor PDT.
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(This article belongs to the Special Issue Special Issue in Honor of Dr. Michael Weber’s 70th Birthday: Photodynamic Therapy: Rising Star in Pharmaceutical Applications)
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Open AccessReview
Black Phosphorus, an Emerging Versatile Nanoplatform for Cancer Immunotherapy
Pharmaceutics 2021, 13(9), 1344; https://doi.org/10.3390/pharmaceutics13091344 (registering DOI) - 27 Aug 2021
Abstract
Black phosphorus (BP) is one of the emerging versatile nanomaterials with outstanding biocompatibility and biodegradability, exhibiting great potential as a promising inorganic nanomaterial in the biomedical field. BP nanomaterials possess excellent ability for valid bio-conjugation and molecular loading in anticancer therapy. Generally, BP
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Black phosphorus (BP) is one of the emerging versatile nanomaterials with outstanding biocompatibility and biodegradability, exhibiting great potential as a promising inorganic nanomaterial in the biomedical field. BP nanomaterials possess excellent ability for valid bio-conjugation and molecular loading in anticancer therapy. Generally, BP nanomaterials can be classified into BP nanosheets (BPNSs) and BP quantum dots (BPQDs), both of which can be synthesized through various preparation routes. In addition, BP nanomaterials can be applied as photothermal agents (PTA) for the photothermal therapy (PTT) due to their high photothermal conversion efficiency and larger extinction coefficients. The generated local hyperpyrexia leads to thermal elimination of tumor. Besides, BP nanomaterials are capable of producing singlet oxygen, which enable its application as a photosensitizer for photodynamic therapy (PDT). Moreover, BP nanomaterials can be oxidized and degraded to nontoxic phosphonates and phosphate under physiological conditions, improving their safety as a nano drug carrier in cancer therapy. Recently, it has been reported that BP-based PTT is capable of activating immune responses and alleviating the immunosuppressive tumor microenvironment by detection of T lymphocytes and various immunocytokines, indicating that BP-based nanocomposites not only serve as effective PTAs to ablate large solid tumors but also function as an immunomodulation agent to eliminate discrete tumorlets. Therefore, BP-mediated immunotherapy would provide more possibilities for synergistic cancer treatment.
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(This article belongs to the Special Issue Nanomaterials: Immunological Perspective)
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Open AccessArticle
Assessing Lymphatic Uptake of Lipids Using Magnetic Resonance Imaging: A Feasibility Study in Healthy Human Volunteers with Potential Application for Tracking Lymph Node Delivery of Drugs and Formulation Excipients
by
, , , , , , , , , , and
Pharmaceutics 2021, 13(9), 1343; https://doi.org/10.3390/pharmaceutics13091343 (registering DOI) - 27 Aug 2021
Abstract
Dietary lipids and some pharmaceutical lipid excipients can facilitate the targeted delivery of drugs to the intestinal lymphatics. Here, the feasibility of magnetic resonance imaging (MRI) for imaging lipid uptake into the intestinal lymphatics was assessed, shedding light on which lymph nodes can
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Dietary lipids and some pharmaceutical lipid excipients can facilitate the targeted delivery of drugs to the intestinal lymphatics. Here, the feasibility of magnetic resonance imaging (MRI) for imaging lipid uptake into the intestinal lymphatics was assessed, shedding light on which lymph nodes can be targeted using this approach. Three healthy male volunteers were scanned at 3.0 T at baseline, 120, 180, 240, and 300 min post high-fat meal. A sagittal multi-slice image was acquired using a diffusion-weighted whole-body imaging sequence with background suppression (DWIBS) (pre inversion TI = 260 ms). Changes in area, major, and minor axis length were compared at each time point. Apparent diffusion coefficient (ADC) was calculated (b = 0 and 600 s/mm2) across eight slices. An average of 22 nodes could be visualised across all time points. ADC increased at 120 and 180 min compared to the baseline in all three participants by an average of 9.2% and 6.8%, respectively. In two participants, mean node area and major axis lengths increased at 120 and 180 min relative to the baseline. In conclusion, the method described shows potential for repeated lymph node measurements and the tracking of lipid uptake into the lymphatics. Further studies should focus on methodology optimisation in a larger cohort.
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(This article belongs to the Special Issue Recent Approaches for Lymphatic Drug Delivery)
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Open AccessArticle
Mass Spectrometric Quantification of the Antimicrobial Peptide Pep19-2.5 with Stable Isotope Labeling and Acidic Hydrolysis
by
, , , , and
Pharmaceutics 2021, 13(9), 1342; https://doi.org/10.3390/pharmaceutics13091342 (registering DOI) - 27 Aug 2021
Abstract
Sepsis is the number one cause of death in intensive care units. This life-threatening condition is caused by bacterial infections and triggered by endotoxins of Gram-negative bacteria that leads to an overreaction of the immune system. The synthetic anti-lipopolysaccharide peptide Pep19-2.5 is a
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Sepsis is the number one cause of death in intensive care units. This life-threatening condition is caused by bacterial infections and triggered by endotoxins of Gram-negative bacteria that leads to an overreaction of the immune system. The synthetic anti-lipopolysaccharide peptide Pep19-2.5 is a promising candidate for the treatment of sepsis as it binds sepsis-inducing lipopolysaccharides and thus prevents initiation of septic shock. For clinical evaluation precise quantification of the peptide in blood and tissue is required. As the peptide is not extractable from biological samples by commonly used methods there is a need for a new analysis method that does not rely on extraction of the peptide. In order to quantify the peptide by mass spectrometry, the peptide was synthesized containing 13C9,15N1-labeled phenylalanine residues. This modification offers high stability during acidic hydrolysis. Following acidic hydrolysis of the samples, the concentration of 13C9,15N1-labeled phenylalanine determined by LC-MS could be unambiguously correlated to the content of Pep19-2.5. Further experiments validated the accuracy of the data. Moreover, the quantification of Pep19-2.5 in different tissues (as studied in Wistar rats) was shown to provide comparable results to the results obtained with radioactively-labeled (14C) Pep19-2.5- Radioactive labeling is considered as the gold standard for quantification of compounds that refrain from reliable extraction methods. This novel method represents a valuable procedure for the determination of Pep19-2.5 and sticky peptides with unpredictable extraction properties in general.
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(This article belongs to the Special Issue Quantification of Therapeutic Peptides by LC-MS)
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