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 other databases.
- Journal Rank: JCR - Q1 (Pharmacology & Pharmacy) / CiteScore - Q2 (Pharmaceutical Science)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 15.9 days after submission; acceptance to publication is undertaken in 3.5 days (median values for papers published in this journal in the second half of 2022).
- 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:
6.525 (2021);
5-Year Impact Factor:
7.227 (2021)
Latest Articles
New Insights into the Behavior of NHC-Gold Complexes in Cancer Cells
Pharmaceutics 2023, 15(2), 466; https://doi.org/10.3390/pharmaceutics15020466 (registering DOI) - 31 Jan 2023
Abstract
Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies have revealed that many cytotoxic gold compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin
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Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies have revealed that many cytotoxic gold compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin reductase (TrxR) inhibitors. Many other pathways have been supposed to be altered by gold coordination to protein targets. Within this frame, we have selected two gold(I) complexes based on aromatic ligands to be tested on cancer cells. Differently from bis [1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I) bromide (Au4BC), bis [1-methyl-3-acridineimidazolin-2-ylidene]gold(I) tetrafluoroborate (Au3BC) inhibited TrxR1 activity in vitro. Treatment of Huh7 hepatocellular carcinoma (HCC) cells, and MDA-MB-231 triple-negative breast cancer (TNBC) cells, with Au4BC inhibited cell viability, increased reactive oxygen species (ROS) levels, caused DNA damage, and induced autophagy and apoptosis. Notably, we found that, although Au3BC inhibited TrxR1 activity, no effect on the cell viabilities of HCC and BC cells was observed. At the molecular level, Au3BC induced a protective response mechanism in Huh7 and MDA-MB-231 cells, by inducing up-regulation of RAD51 and p62 protein expression, two proteins involved in DNA damage repair and autophagy, respectively. RAD51 gene knock-down in HCC cells increased cell sensitivity to Au3BC by significant reduction of cell viability, induction of DNA damage, and induction of apoptosis and autophagy. All together, these results suggest that the tested NHC-Gold complexes, Au3BC and Au4BC, showed different mechanisms of action, either dependent or independent of TrxR1 inhibition. As a result, Au3BC and Au4BC were found to be promising candidates as anticancer drugs for the treatment of HCC and BC.
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(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)
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Open AccessArticle
Quality by Design Assisted Optimization and Risk Assessment of Black Cohosh Loaded Ethosomal Gel for Menopause: Investigating Different Formulation and Process Variables
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, , , , , and
Pharmaceutics 2023, 15(2), 465; https://doi.org/10.3390/pharmaceutics15020465 (registering DOI) - 31 Jan 2023
Abstract
Black cohosh (Cimicifuga racemosa) (CR) is a popular herb and is medically lauded for ameliorating myriad symptoms associated with menopause. However, its pharmaceutical limitations and non-availability of a patient-compliant drug delivery approach have precluded its prevalent use. Henceforth, the current research
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Black cohosh (Cimicifuga racemosa) (CR) is a popular herb and is medically lauded for ameliorating myriad symptoms associated with menopause. However, its pharmaceutical limitations and non-availability of a patient-compliant drug delivery approach have precluded its prevalent use. Henceforth, the current research premise is aimed at developing an ethosomal gel incorporating triterpene enriched fraction (TEF) obtained from CR and evaluating its effectiveness through the transdermal application. TEF-loaded ethosomes were formulated using solvent injection, optimized and characterised. The optimized ethosomes were then dispersed into a polymeric gel base to form ethosomal gel which was further compared with the conventional gel by in-vitro and ex-vivo experiments. Here, the quality by design (QbD) approach was exploited for the optimization and development of ethosomal gel. The elements of QbD comprising initial risk assessment, design of experimentation (DoE), and model validation for the development of formulation have all been described in detail. The optimized ethosomes (F03) showed a nanometric size range, negative zeta potential and good entrapment. The in vitro release profile of gel revealed a burst release pattern following the Korsmeyer Peppas model having Fickian diffusion. The transdermal flux of ethosomal gel was observed to be more than that of conventional gel. Texture analysis and rheological characterization of the gel, revealed good strength showing shear thinning and pseudoplastic behaviour. The confocal microscope investigation revealed the deeper skin permeation of ethosomal gel than conventional gel. This result was further strengthened by DSC, IR and histological assessment of the animal skin (Wistar rat), treated with the optimized formulation. Conclusively, the implementation of QbD in the formulation resulted in a better understanding of the process and the product. It aids in the reduction of product variability and defects, hence improving product development efficiencies. Additionally, the ethosomal gel was found to be a more effective and successful carrier for TEF than the conventional gel through the transdermal route. Moreover, this demands an appropriate animal study, which is underway, for a stronger outcome.
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(This article belongs to the Special Issue Novel Drug Delivery Systems for Women's Health)
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Open AccessArticle
Application of Antiviral, Antioxidant and Antibacterial Glycyrrhiza glabra L., Trifolium pratense L. Extracts and Myristica fragrans Houtt. Essential Oil in Microcapsules
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, , , , and
Pharmaceutics 2023, 15(2), 464; https://doi.org/10.3390/pharmaceutics15020464 - 30 Jan 2023
Abstract
Viruses and bacteria can disrupt normal human functions; therefore, ways to use the beneficial properties of plants to promote health are constantly being researched. Plant materials that accumulate biologically active compounds can be used to create a new pharmaceutical form. This study aimed
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Viruses and bacteria can disrupt normal human functions; therefore, ways to use the beneficial properties of plants to promote health are constantly being researched. Plant materials that accumulate biologically active compounds can be used to create a new pharmaceutical form. This study aimed to investigate the biological activity of selected plant extracts and essential oil and to produce microcapsules. The main compounds in extracts and essential oil were determined using chromatographic methods, antioxidant activity was evaluated spectrophotometrically, antimicrobial activity was assessed by monitoring the growth of nine pathogens, and the antiviral effect on infected bird cells with coronavirus was evaluated. Trifolium pratense L. extract had the highest antioxidant (26.27 ± 0.31 and 638.55 ± 9.14 µg TE/g dw by the DPPH and ABTS methods, respectively) and antiviral activity (56 times decreased titre of virus). Liquorice extract expressed antibacterial activity against Gram-positive pathogens and the highest antioxidant activity using the FRAP method (675.71 ± 4.61 mg FS/g dw). Emulsion stability depended on excipients and their amount. Microcapsules with extracts and essential oil were 1.87 mm in diameter, and their diameter after swelling was increased more than two times in intestinal media, while less than 0.5 times in gastric media.
Full article
(This article belongs to the Special Issue Essential Oils in Pharmaceutical Products (Volume II))
Open AccessCommunication
Unveiling the Anti-Biofilm Property of Hydroxyapatite on Pseudomonas aeruginosa: Synthesis and Strategy
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, , , , and
Pharmaceutics 2023, 15(2), 463; https://doi.org/10.3390/pharmaceutics15020463 - 30 Jan 2023
Abstract
Biofilm-related nosocomial infections may cause a wide range of life-threatening infections. In this regard, Pseudomonas aeruginosa biofilm is becoming a serious health burden due to its capability to develop resistance to natural and synthetic drugs. The utilization of nanoparticles that inhibit biofilm formation
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Biofilm-related nosocomial infections may cause a wide range of life-threatening infections. In this regard, Pseudomonas aeruginosa biofilm is becoming a serious health burden due to its capability to develop resistance to natural and synthetic drugs. The utilization of nanoparticles that inhibit biofilm formation is one of the major strategies to control infections caused by biofilm-forming pathogens. Hydroxyapatite (HA) is a synthetic ceramic material having properties similar to natural bones. Herein, a co-precipitation method followed by microwave treatment was used to synthesize HA nanoparticles (HANPs). The resulting HANPs were characterized using X-ray diffraction and transmission electron microscopy. Then, their antibiofilm properties against P. aeruginosa ATCC 10145 were examined in vitro. The needle-shaped HANPs were 30 and 90 nm long in width and length, respectively. The synthesized HANPs inhibited the biofilm formation of P. aeruginosa ATCC 10145 in a concentration-dependent manner, which was validated by light and confocal laser scanning microscopy. Hence, this study demonstrated that HANPs could be used to control the biofilm-related infections of P. aeruginosa.
Full article
(This article belongs to the Special Issue Micro/Nanostructures and Micro/Nanodevices for Tissue Engineering and Biomedicine)
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Open AccessReview
Exosomes: The Role in Tumor Tolerance and the Potential Strategy for Tumor Therapy
Pharmaceutics 2023, 15(2), 462; https://doi.org/10.3390/pharmaceutics15020462 - 30 Jan 2023
Abstract
Drug and radiotherapy resistance is the primary cause of treatment failure and poor prognosis in patients with tumors. Exosomes are extracellular vesicles loaded with substances such as nucleic acids, lipids, and proteins that transmit information between cells. Studies have found that exosomes are
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Drug and radiotherapy resistance is the primary cause of treatment failure and poor prognosis in patients with tumors. Exosomes are extracellular vesicles loaded with substances such as nucleic acids, lipids, and proteins that transmit information between cells. Studies have found that exosomes are involved in tumor therapy resistance through drug efflux, promotion of drug resistance phenotypes, delivery of drug-resistance-related molecules, and regulation of anti-tumor immune responses. Based on their low immunogenicity and high biocompatibility, exosomes have been shown to reduce tumor therapy resistance by loading nucleic acids, proteins, and drugs inside xosomes or expressing tumor-specific antigens, target peptides, and monoclonal antibodies on their phospholipid bimolecular membranes. Consequently, future research on genetically engineered exosomes is expected to eliminate resistance to tumor treatment, improving the overall prognosis of patients with tumors.
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(This article belongs to the Section Drug Targeting and Design)
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CCR7 Mediates Dendritic-Cell-Derived Exosome Migration and Improves Cardiac Function after Myocardial Infarction
Pharmaceutics 2023, 15(2), 461; https://doi.org/10.3390/pharmaceutics15020461 - 30 Jan 2023
Abstract
Dendritic cells (DCs) play key roles in promoting wound healing after myocardial infarction (MI). Our previous studies have shown that exosomes derived from DCs (DEXs) could migrate to lymphoid tissue and improve cardiac function post-MI by activating CD4+ T cells; however, the
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Dendritic cells (DCs) play key roles in promoting wound healing after myocardial infarction (MI). Our previous studies have shown that exosomes derived from DCs (DEXs) could migrate to lymphoid tissue and improve cardiac function post-MI by activating CD4+ T cells; however, the mechanism of DEXs’ migration to lymphoid tissue and the improvement of cardiac function are still unknown. In our study, we found that CCR7 expression significantly increased in MI-DEXs compared with control-DEXs; meanwhile, CCL19 and CCL21, the ligands of CCR7, significantly increased in the serum of MI-model mice. Subsequently, we overexpressed and knocked down CCR7 in MI-DEXs and found that overexpressed CCR7 enhanced the migration of MI-DEXs to the spleen; however, CCR7 knockdown attenuated MI-DEXs’ migration according to near-IR fluorescence imaging. Furthermore, overexpressed CCR7 in MI-DEXs enhanced the MI-DEXs’ improvement of cardiac function after MI; however, CCR7-knockdown MI-DEXs attenuated this improvement. In addition, after DEXs’ migration to the spleen, MI-DEXs activated CD4+ T cells and induced the expression of IL-4 and IL-10, which were significantly increased in the MI-DEX group compared with the control group. In conclusion, CCR7 could mediate DEXs’ migration to the spleen and improve cardiac function after MI, and we found that the mechanism was partly via activation of CD4+ T cells and secretion of IL-4 and IL-10. Our study presented an innovative method for improving cardiac function by enhancing the migration ability of MI-DEXs after MI, while CCR7 could be a potential candidate for MI-DEX bioengineering to enhance migration.
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(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)
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Comparison of Seven Non-Linear Mixed Effect Model-Based Approaches to Test for Treatment Effect
Pharmaceutics 2023, 15(2), 460; https://doi.org/10.3390/pharmaceutics15020460 - 30 Jan 2023
Abstract
Analyses of longitudinal data with non-linear mixed-effects models (NLMEM) are typically associated with high power, but sometimes at the cost of inflated type I error. Approaches to overcome this problem were published recently, such as model-averaging across drug models (MAD), individual model-averaging (IMA),
[...] Read more.
Analyses of longitudinal data with non-linear mixed-effects models (NLMEM) are typically associated with high power, but sometimes at the cost of inflated type I error. Approaches to overcome this problem were published recently, such as model-averaging across drug models (MAD), individual model-averaging (IMA), and combined Likelihood Ratio Test (cLRT). This work aimed to assess seven NLMEM approaches in the same framework: treatment effect assessment in balanced two-armed designs using real natural history data with or without the addition of simulated treatment effect. The approaches are MAD, IMA, cLRT, standard model selection (STDs), structural similarity selection (SSs), randomized cLRT (rcLRT), and model-averaging across placebo and drug models (MAPD). The assessment included type I error, using Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) scores from 817 untreated patients and power and accuracy in the treatment effect estimates after the addition of simulated treatment effects. The model selection and averaging among a set of pre-selected candidate models were driven by the Akaike information criteria (AIC). The type I error rate was controlled only for IMA and rcLRT; the inflation observed otherwise was explained by the placebo model misspecification and selection bias. Both IMA and rcLRT had reasonable power and accuracy except under a low typical treatment effect.
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(This article belongs to the Special Issue Recent Advances in Population Pharmacokinetics and Pharmacodynamics)
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Monoclonal Antibodies, Gene Silencing and Gene Editing (CRISPR) Therapies for the Treatment of Hyperlipidemia—The Future Is Here
Pharmaceutics 2023, 15(2), 459; https://doi.org/10.3390/pharmaceutics15020459 - 30 Jan 2023
Abstract
Hyperlipidemia is a significant risk factor for atherosclerotic cardiovascular disease. Undertreatment of elevated lipids persists despite existing therapies. Here, we provide an update on monoclonal antibodies, gene silencing therapies, and gene editing techniques for the management of hyperlipidemia. The current era of cutting-edge
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Hyperlipidemia is a significant risk factor for atherosclerotic cardiovascular disease. Undertreatment of elevated lipids persists despite existing therapies. Here, we provide an update on monoclonal antibodies, gene silencing therapies, and gene editing techniques for the management of hyperlipidemia. The current era of cutting-edge pharmaceuticals targeting low density lipoprotein cholesterol, PCSK9, lipoprotein (a), angiopoietin-like 3, and apolipoprotein C3 are reviewed. We outline what is known, studies in progress, and futuristic goals. This review of available and upcoming biotechnological lipid therapies is presented for clinicians managing patients with familial hyperlipidemia, statin intolerance, hypertriglyceridemia, or elevated lipoprotein (a) levels.
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(This article belongs to the Section Biologics and Biosimilars)
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Open AccessArticle
Optimizing Dacarbazine Therapy: Design of a Laser-Triggered Delivery System Based on β-Cyclodextrin and Plasmonic Gold Nanoparticles
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, , , , , , , and
Pharmaceutics 2023, 15(2), 458; https://doi.org/10.3390/pharmaceutics15020458 - 30 Jan 2023
Abstract
Dacarbazine (DB) is an antineoplastic drug extensively used in cancer therapy. However, present limitations on its performance are related to its low solubility, instability, and non-specificity. To overcome these drawbacks, DB was included in β-cyclodextrin (βCD), which increased its aqueous solubility and stability.
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Dacarbazine (DB) is an antineoplastic drug extensively used in cancer therapy. However, present limitations on its performance are related to its low solubility, instability, and non-specificity. To overcome these drawbacks, DB was included in β-cyclodextrin (βCD), which increased its aqueous solubility and stability. This new β[email protected] complex has been associated with plasmonic gold nanoparticles (AuNPs), and polyethylene glycol (PEG) has been added in the process to increase the colloidal stability and biocompatibility. Different techniques revealed that DB allows for a dynamic inclusion into βCD, with an association constant of 80 M−1 and a degree of solubilization of 0.023, where βCD showed a loading capacity of 16%. The partial exposure of the NH2 group in the included DB allows its interaction with AuNPs, with a loading efficiency of 99%. The PEG-AuNPs-β[email protected] nanosystem exhibits an optical plasmonic absorption at 525 nm, a surface charge of −29 mV, and an average size of 12 nm. Finally, laser irradiation assays showed that DB can be released from this platform in a controlled manner over time, reaching a concentration of 56 μg/mL (43% of the initially loaded amount), which, added to the previous data, validates its potential for drug delivery applications. Therefore, the novel nanosystem based on βCD, AuNPs, and PEG is a promising candidate as a new nanocarrier for DB.
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(This article belongs to the Special Issue Recent Advances in Nanotechnology-Based Approaches for Pharmaceutical Applications)
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Synthesis, Molecular Docking, and Bioactivity Study of Novel Hybrid Benzimidazole Urea Derivatives: A Promising α-Amylase and α-Glucosidase Inhibitor Candidate with Antioxidant Activity
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, , , , , , , and
Pharmaceutics 2023, 15(2), 457; https://doi.org/10.3390/pharmaceutics15020457 (registering DOI) - 30 Jan 2023
Abstract
A novel series of benzimidazole ureas 3a–h were elaborated using 2-(1H-benzoimidazol-2-yl) aniline 1 and the appropriate isocyanates 2a–h. The antioxidant and possible antidiabetic activities of the target benzimidazole-ureas 3a–h were evaluated. Almost all compounds 3a–h displayed strong to moderate antioxidant
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A novel series of benzimidazole ureas 3a–h were elaborated using 2-(1H-benzoimidazol-2-yl) aniline 1 and the appropriate isocyanates 2a–h. The antioxidant and possible antidiabetic activities of the target benzimidazole-ureas 3a–h were evaluated. Almost all compounds 3a–h displayed strong to moderate antioxidant activities. When tested using the three antioxidant techniques, TAC, FRAP, and MCA, compounds 3b and 3c exhibited marked activity. The most active antioxidant compound in this family was compound 3g, which had excellent activity using four different methods: TAC, FRAP, DPPH-SA, and MCA. In vitro antidiabetic assays against α-amylase and α-glucosidase enzymes revealed that the majority of the compounds tested had good to moderate activity. The most favorable results were obtained with compounds 3c, 3e, and 3g, and analysis revealed that compounds 3c (IC50 = 18.65 ± 0.23 μM), 3e (IC50 = 20.7 ± 0.06 μM), and 3g (IC50 = 22.33 ± 0.12 μM) had good α-amylase inhibitory potential comparable to standard acarbose (IC50 = 14.21 ± 0.06 μM). Furthermore, the inhibitory effect of 3c (IC50 = 17.47 ± 0.03 μM), 3e (IC50 = 21.97 ± 0.19 μM), and 3g (IC50 = 23.01 ± 0.12 μM) on α-glucosidase was also comparable to acarbose (IC50 = 15.41 ± 0.32 μM). According to in silico molecular docking studies, compounds 3a–h had considerable affinity for the active sites of human lysosomal acid α-glucosidase (HLAG) and pancreatic α-amylase (HPA), indicating that the majority of the examined compounds had potential anti-hyperglycemic action.
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(This article belongs to the Special Issue Oxidative Stress and Inflammation: Novel Drug Formulation and Delivery Systems)
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Evaluation of a Medical Grade Thermoplastic Polyurethane for the Manufacture of an Implantable Medical Device: The Impact of FDM 3D-Printing and Gamma Sterilization
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, , , , , , , , and
Pharmaceutics 2023, 15(2), 456; https://doi.org/10.3390/pharmaceutics15020456 - 30 Jan 2023
Abstract
Three-dimensional printing (3DP) of thermoplastic polyurethane (TPU) is gaining interest in the medical industry thanks to the combination of tunable properties that TPU exhibits and the possibilities that 3DP processes offer concerning precision, time, and cost of fabrication. We investigated the implementation of
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Three-dimensional printing (3DP) of thermoplastic polyurethane (TPU) is gaining interest in the medical industry thanks to the combination of tunable properties that TPU exhibits and the possibilities that 3DP processes offer concerning precision, time, and cost of fabrication. We investigated the implementation of a medical grade TPU by fused deposition modelling (FDM) for the manufacturing of an implantable medical device from the raw pellets to the gamma (γ) sterilized 3DP constructs. To the authors’ knowledge, there is no such guide/study implicating TPU, FDM 3D-printing and gamma sterilization. Thermal properties analyzed by differential scanning calorimetry (DSC) and molecular weights measured by size exclusion chromatography (SEC) were used as monitoring indicators through the fabrication process. After gamma sterilization, surface chemistry was assessed by water contact angle (WCA) measurement and infrared spectroscopy (ATR-FTIR). Mechanical properties were investigated by tensile testing. Biocompatibility was assessed by means of cytotoxicity (ISO 10993-5) and hemocompatibility assays (ISO 10993-4). Results showed that TPU underwent degradation through the fabrication process as both the number-averaged (Mn) and weight-averaged (Mw) molecular weights decreased (7% Mn loss, 30% Mw loss, p < 0.05). After gamma sterilization, Mw increased by 8% (p < 0.05) indicating that crosslinking may have occurred. However, tensile properties were not impacted by irradiation. Cytotoxicity (ISO 10993-5) and hemocompatibility (ISO 10993-4) assessments after sterilization showed vitality of cells (132% ± 3%, p < 0.05) and no red blood cell lysis. We concluded that gamma sterilization does not highly impact TPU regarding our application. Our study demonstrates the processability of TPU by FDM followed by gamma sterilization and can be used as a guide for the preliminary evaluation of a polymeric raw material in the manufacturing of a blood contacting implantable medical device.
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(This article belongs to the Special Issue 3D Printing Technology for Pharmaceutical and Biomedical Application)
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Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model
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, , , , , , , , , , , , , , , and
Pharmaceutics 2023, 15(2), 455; https://doi.org/10.3390/pharmaceutics15020455 - 30 Jan 2023
Abstract
Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood–brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint
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Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood–brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A blood–brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10 µL/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly opened the BBB. BBB opening was confirmed visually and microscopically using Evans blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice’s survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome in order to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.
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(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)
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Open AccessArticle
Composition-Property Relationships of pH-Responsive Poly[(2-vinylpyridine)-co-(butyl methacrylate)] Copolymers for Reverse Enteric Coatings
by
and
Pharmaceutics 2023, 15(2), 454; https://doi.org/10.3390/pharmaceutics15020454 - 30 Jan 2023
Abstract
The taste-masking of bitter-tasting active pharmaceutical ingredients is key to ensuring patient compliance when producing oral pharmaceutical formulations. This is generally achieved via the incorporation of pH-responsive, reverse enteric polymers, that prevent the dissolution of the formulation in the oral environment, but rapidly
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The taste-masking of bitter-tasting active pharmaceutical ingredients is key to ensuring patient compliance when producing oral pharmaceutical formulations. This is generally achieved via the incorporation of pH-responsive, reverse enteric polymers, that prevent the dissolution of the formulation in the oral environment, but rapidly mediate it within the gastric environment. Reverse enteric polymers are commonly applied as coatings on oral dosage forms via spray atomisation (e.g., fluidised-bed spray coating), and generally exhibit the most efficient taste-masking. However, currently used reverse enteric coatings require high mass gains (% w/w) during coating to mediate taste-masking, and thereby exhibit delayed release within the gastric environment. Therefore, there remains a need for the development of new reverse enteric coatings, that can efficiently taste-mask at low mass gains and maintain rapid release characteristics within the gastric environment. Herein we report the synthesis and evaluation of a series of addition copolymers of 2-vinylpyridine and butyl methacrylate, methyl methacrylate and isobornyl methacrylate. The thermal, solubility, and water absorption properties of the copolymers were effectively tuned by altering the mol% fraction of the constitutive monomers. Based on their physical properties, selected copolymers were preliminarily evaluated for their compatibility with fluidised-bed spray coating, and effectiveness as taste-masking reverse enteric coatings. The copolymers poly[(2-vinylpyridine)-co-(butyl methacrylate)] (mol% ratio 40:60) and poly[(2-vinylpyridine)-co-(butyl methacrylate)-co-(methyl methacrylate)] (mol% ratio 40:50:10) were found to exhibit excellent taste-masking properties following fluidised-bed spray coating onto Suglets® sugar spheres. Suglets® bearing a film coating of either copolymer (5.2–6.5% w/w mass gain) were found to effectively impede the release of a model drug formulation for up to 72 h in a simulated salivary environment, and rapidly release it (<10 min) within a simulated gastric environment. The results demonstrated the potential of poly[(2-vinylpyridine)-co-(butyl methacrylate)] copolymers to form effectively taste-masked, reverse enteric dosage forms, and suggested that these copolymers may provide improved performance compared to currently available polymers.
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(This article belongs to the Special Issue Functional Polymeric Materials for Drug Delivery and Sustained Drug Release)
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Open AccessArticle
Biological Evaluation and In Vitro Characterization of ADME Profile of In-House Pyrazolo[3,4-d]pyrimidines as Dual Tyrosine Kinase Inhibitors Active against Glioblastoma Multiforme
by
, , , , , , , , , , , and
Pharmaceutics 2023, 15(2), 453; https://doi.org/10.3390/pharmaceutics15020453 - 30 Jan 2023
Abstract
The therapeutic use of tyrosine kinase inhibitors (TKIs) represents one of the successful strategies for the treatment of glioblastoma (GBM). Pyrazolo[3,4-d]pyrimidines have already been reported as promising small molecules active as c-Src/Abl dual inhibitors. Herein, we present a series of pyrazolo[3,4-
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The therapeutic use of tyrosine kinase inhibitors (TKIs) represents one of the successful strategies for the treatment of glioblastoma (GBM). Pyrazolo[3,4-d]pyrimidines have already been reported as promising small molecules active as c-Src/Abl dual inhibitors. Herein, we present a series of pyrazolo[3,4-d]pyrimidine derivatives, selected from our in-house library, to identify a promising candidate active against GBM. The inhibitory activity against c-Src and Abl was investigated, and the antiproliferative profile against four GBM cell lines was studied. For the most active compounds endowed with antiproliferative efficacy in the low-micromolar range, the effects toward nontumoral, healthy cell lines (fibroblasts FIBRO 2-93 and keratinocytes HaCaT) was investigated. Lastly, the in silico and in vitro ADME properties of all compounds were also assessed. Among the tested compounds, the promising inhibitory activity against c-Src and Abl (Ki 3.14 µM and 0.44 µM, respectively), the irreversible, apoptotic-mediated death toward U-87, LN18, LN229, and DBTRG GBM cell lines (IC50 6.8 µM, 10.8 µM, 6.9 µM, and 8.5 µM, respectively), the significant reduction in GBM cell migration, the safe profile toward FIBRO 2-93 and HaCaT healthy cell lines (CC50 91.7 µM and 126.5 µM, respectively), the high metabolic stability, and the excellent passive permeability across gastrointestinal and blood–brain barriers led us to select compound 5 for further in vivo assays.
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(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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Peptide Vaccines in Melanoma: Chemical Approaches towards Improved Immunotherapeutic Efficacy
Pharmaceutics 2023, 15(2), 452; https://doi.org/10.3390/pharmaceutics15020452 - 30 Jan 2023
Abstract
Cancer of the skin is by far the most common of all cancers. Although the incidence of melanoma is relatively low among skin cancers, it can account for a high number of skin cancer deaths. Since the start of deeper insight into the
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Cancer of the skin is by far the most common of all cancers. Although the incidence of melanoma is relatively low among skin cancers, it can account for a high number of skin cancer deaths. Since the start of deeper insight into the mechanisms of melanoma tumorigenesis and their strong interaction with the immune system, the development of new therapeutical strategies has been continuously rising. The high number of melanoma cell mutations provides a diverse set of antigens that the immune system can recognize and use to distinguish tumor cells from normal cells. Peptide-based synthetic anti-tumor vaccines are based on tumor antigens that elicit an immune response due to antigen-presenting cells (APCs). Although targeting APCs with peptide antigens is the most important assumption for vaccine development, peptide antigens alone are poorly immunogenic. The immunogenicity of peptide antigens can be improved not only by synthetic modifications but also by the assistance of adjuvants and/or delivery systems. The current review summarizes the different chemical approaches for the development of effective peptide-based vaccines for the immunotherapeutic treatment of advanced melanoma.
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(This article belongs to the Section Biologics and Biosimilars)
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Open AccessReview
Aspects of Nanotechnology for COVID-19 Vaccine Development and Its Delivery Applications
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, , , , , , , , , and
Pharmaceutics 2023, 15(2), 451; https://doi.org/10.3390/pharmaceutics15020451 - 30 Jan 2023
Abstract
Coronavirus, a causative agent of the common cold to a much more complicated disease such as “severe acute respiratory syndrome (SARS-CoV-2), Middle East Respiratory Syndrome (MERS-CoV-2), and Coronavirus Disease 2019 (COVID-19)”, is a member of the coronaviridae family and contains a positive-sense single-stranded
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Coronavirus, a causative agent of the common cold to a much more complicated disease such as “severe acute respiratory syndrome (SARS-CoV-2), Middle East Respiratory Syndrome (MERS-CoV-2), and Coronavirus Disease 2019 (COVID-19)”, is a member of the coronaviridae family and contains a positive-sense single-stranded RNA of 26–32 kilobase pairs. COVID-19 has shown very high mortality and morbidity and imparted a significantly impacted socioeconomic status. There are many variants of SARS-CoV-2 that have originated from the mutation of the genetic material of the original coronavirus. This has raised the demand for efficient treatment/therapy to manage newly emerged SARS-CoV-2 infections successfully. However, different types of vaccines have been developed and administered to patients but need more attention because COVID-19 is not under complete control. In this article, currently developed nanotechnology-based vaccines are explored, such as inactivated virus vaccines, mRNA-based vaccines, DNA-based vaccines, S-protein-based vaccines, virus-vectored vaccines, etc. One of the important aspects of vaccines is their administration inside the host body wherein nanotechnology can play a very crucial role. Currently, more than 26 nanotechnology-based COVID-19 vaccine candidates are in various phases of clinical trials. Nanotechnology is one of the growing fields in drug discovery and drug delivery that can also be used for the tackling of coronavirus. Nanotechnology can be used in various ways to design and develop tools and strategies for detection, diagnosis, and therapeutic and vaccine development to protect against COVID-19. The design of instruments for speedy, precise, and sensitive diagnosis, the fabrication of potent sanitizers, the delivery of extracellular antigenic components or mRNA-based vaccines into human tissues, and the administration of antiretroviral medicines into the organism are nanotechnology-based strategies for COVID-19 management. Herein, we discuss the application of nanotechnology in COVID-19 vaccine development and the challenges and opportunities in this approach.
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(This article belongs to the Special Issue Sustainable Materials and Technologies for Drug Delivery and Tissue Engineering)
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Open AccessArticle
Nanoseeded Desupersaturation and Dissolution Tests for Elucidating Supersaturation Maintenance in Amorphous Solid Dispersions
Pharmaceutics 2023, 15(2), 450; https://doi.org/10.3390/pharmaceutics15020450 - 30 Jan 2023
Abstract
The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on
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The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loading facilitated desupersaturation. Sol was the only effective nucleation inhibitor; the overall precipitation inhibition capability was ranked: Sol > HPMC > VA64. In the dissolution tests, only the Sol-based ASDs generated significant supersaturation, which decreased upon an increase in the nanoseed loading. This study has demonstrated the importance of using drug nanocrystals in lieu of conventional coarse crystals in desupersaturation and dissolution tests in ASD development.
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(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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Open AccessArticle
Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability
by
, , , , , and
Pharmaceutics 2023, 15(2), 449; https://doi.org/10.3390/pharmaceutics15020449 - 29 Jan 2023
Abstract
According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug
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According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug is also highly hygroscopic, thus showing stability problems. Another kind of worldwide prescribed drug is the non-steroidal anti-inflammatory drug (NSAID). These latter, on the contrary, show a low solubility profile; therefore, they must be administered at high doses, which increases the probability of secondary effects. In this work, novel drug-drug pharmaceutical solids combining MTF-NSAIDs have been synthesized in solution or by mechanochemical methods. The aim of this concomitant treatment is to improve the physicochemical properties of the parent active pharmaceutical ingredients. After a careful solid-state characterization along with solubility and stability studies, it can be concluded that the new molecular salt formulations enhance not only the stability of MTF but also the solubility of NSAIDs, thus giving promising results regarding the development of these novel pharmaceutical multicomponent solids.
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(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
Open AccessArticle
Honokiol-Loaded Nanoemulsion for Glioblastoma Treatment: Statistical Optimization, Physicochemical Characterization, and an In Vitro Toxicity Assay
by
, , , , , and
Pharmaceutics 2023, 15(2), 448; https://doi.org/10.3390/pharmaceutics15020448 - 29 Jan 2023
Abstract
Background: Glioblastoma (GBM) is an extremely invasive and heterogenous malignant brain tumor. Despite advances in current anticancer therapy, treatment options for glioblastoma remain limited, and tumor recurrence is inevitable. Therefore, alternative therapies or new active compounds that can be used as adjuvant therapy
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Background: Glioblastoma (GBM) is an extremely invasive and heterogenous malignant brain tumor. Despite advances in current anticancer therapy, treatment options for glioblastoma remain limited, and tumor recurrence is inevitable. Therefore, alternative therapies or new active compounds that can be used as adjuvant therapy are needed. This study aimed to develop, optimize, and characterize honokiol-loaded nanoemulsions intended for intravenous administration in glioblastoma therapy. Methods: Honokiol-loaded nanoemulsion was developed by incorporating honokiol into Lipofundin MCT/LCT 20% using a horizontal shaker. The Box–Behnken design, coupled with response surface methodology, was used to optimize the incorporation process. The effect of the developed formulation on glioblastoma cell viability was determined using the MTT test. Long-term and short-term stress tests were performed to evaluate the effect of honokiol on the stability of the oil-in-water system and the effect of different stress factors on the stability of honokiol, respectively. Its physicochemical properties, such as MDD, PDI, ZP, OSM, pH, and loading efficiency (LE%), were determined. Results: The optimized honokiol-loaded nanoemulsion was characterized by an MDD of 201.4 (0.7) nm with a PDI of 0.07 (0.02) and a ZP of −28.5 (0.9) mV. The LE% of honokiol was above 95%, and pH and OSM were sufficient for intravenous administration. The developed formulation was characterized by good stability and a satisfactory toxicity effect of the glioblastoma cell lines. Conclusions: The honokiol-loaded nanoemulsion is a promising pharmaceutical formulation for further development in the adjuvant therapy of glioblastoma.
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(This article belongs to the Special Issue Sustainable Materials and Technologies for Drug Delivery and Tissue Engineering)
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Open AccessReview
Natural Biopolymers as Smart Coating Materials of Mesoporous Silica Nanoparticles for Drug Delivery
Pharmaceutics 2023, 15(2), 447; https://doi.org/10.3390/pharmaceutics15020447 - 29 Jan 2023
Abstract
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In recent years, the functionalization of mesoporous silica nanoparticles (MSNs) with different types of responsive pore gatekeepers have shown great potential for the formulation of drug delivery systems (DDS) with minimal premature leakage and site-specific controlled release. New nanotechnological approaches have been developed
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In recent years, the functionalization of mesoporous silica nanoparticles (MSNs) with different types of responsive pore gatekeepers have shown great potential for the formulation of drug delivery systems (DDS) with minimal premature leakage and site-specific controlled release. New nanotechnological approaches have been developed with the objective of utilizing natural biopolymers as smart materials in drug delivery applications. Natural biopolymers are sensitive to various physicochemical and biological stimuli and are endowed with intrinsic biodegradability, biocompatibility, and low immunogenicity. Their use as biocompatible smart coatings has extensively been investigated in the last few years. This review summarizes the MSNs coating procedures with natural polysaccharides and protein-based biopolymers, focusing on their application as responsive materials to endogenous stimuli. Biopolymer-coated MSNs, which conjugate the nanocarrier features of mesoporous silica with the biocompatibility and controlled delivery provided by natural coatings, have shown promising therapeutic outcomes and the potential to emerge as valuable candidates for the selective treatment of various diseases.
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