Pharmaceutics

14 pages, 1959 KiB

Open AccessEditor’s ChoiceArticle

Quantification of the Therapeutic Antibody Ocrelizumab in Mouse Brain Interstitial Fluid Using Cerebral Open Flow Microperfusion and Simultaneous Monitoring of the Blood–Brain Barrier Integrity

by Thomas Altendorfer-Kroath, Joanna Hummer, Denise Kollmann, Beate Boulgaropoulos, Reingard Raml and Thomas Birngruber

Pharmaceutics 2023, 15(7), 1880; https://doi.org/10.3390/pharmaceutics15071880 - 4 Jul 2023

Viewed by 2368

Abstract

The increasing relevance of improved therapeutic monoclonal antibodies (mAbs) to treat neurodegenerative diseases has strengthened the need to reliably measure their brain pharmacokinetic (PK) profiles. The aim of this study was, therefore, to absolutely quantify the therapeutic antibody ocrelizumab (OCR) as a model [...] Read more.

The increasing relevance of improved therapeutic monoclonal antibodies (mAbs) to treat neurodegenerative diseases has strengthened the need to reliably measure their brain pharmacokinetic (PK) profiles. The aim of this study was, therefore, to absolutely quantify the therapeutic antibody ocrelizumab (OCR) as a model antibody in mouse brain interstitial fluid (ISF), and to record its PK profile by using cerebral open flow microperfusion (cOFM). Further, to monitor the blood–brain barrier (BBB) integrity using an endogenous antibody with a similar molecular size as OCR. The study was conducted on 13 male mice. Direct and absolute OCR quantification was performed with cOFM in combination with zero flow rate, and subsequent bioanalysis of the obtained cerebral ISF samples. For PK profile recording, cerebral ISF samples were collected bi-hourly, and brain tissue and plasma were collected once at the end of the sampling period. The BBB integrity was monitored during the entire PK profile recording by using endogenous mouse immunoglobulin G1. We directly and absolutely quantified OCR and recorded its brain PK profile over 96 h. The BBB remained intact during the PK profile recording. The resulting data provide the basis for reliable PK assessment of therapeutic antibodies in the brain thus favoring the further development of therapeutic monoclonal antibodies. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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22 pages, 6315 KiB

Open AccessEditor’s ChoiceArticle

Multifunctional Polymeric Biodegradable and Biocompatible Coatings Based on Silver Nanoparticles: A Comparative In Vitro Study on Their Cytotoxicity towards Cancer and Normal Cell Lines of Cytostatic Drugs versus Essential-Oil-Loaded Nanoparticles and on Their Antimicrobial and Antibiofilm Activities

by Rebecca Alexandra Puiu, Alexandra Cătălina Bîrcă, Valentina Grumezescu, Liviu Duta, Ovidiu Cristian Oprea, Alina Maria Holban, Ariana Hudiță, Bianca Gălățeanu, Paul Cătălin Balaure, Alexandru Mihai Grumezescu and Ecaterina Andronescu

Pharmaceutics 2023, 15(7), 1882; https://doi.org/10.3390/pharmaceutics15071882 - 4 Jul 2023

Cited by 12 | Viewed by 2342

Abstract

We report on a comparative in vitro study of selective cytotoxicity against MCF7 tumor cells and normal VERO cells tested on silver-based nanocoatings synthesized by the matrix-assisted pulsed laser evaporation (MAPLE) technique. Silver nanoparticles (AgNPs) were loaded with five representative cytostatic drugs (i.e., [...] Read more.

We report on a comparative in vitro study of selective cytotoxicity against MCF7 tumor cells and normal VERO cells tested on silver-based nanocoatings synthesized by the matrix-assisted pulsed laser evaporation (MAPLE) technique. Silver nanoparticles (AgNPs) were loaded with five representative cytostatic drugs (i.e., doxorubicin, fludarabine, paclitaxel, gemcitabine, and carboplatin) and with five essential oils (EOs) (i.e., oregano, rosemary, ginger, basil, and thyme). The as-obtained coatings were characterized by X-ray diffraction, thermogravimetry coupled with differential scanning calorimetry, Fourier-transform IR spectroscopy, IR mapping, and scanning electron microscopy. A screening of the impact of the prepared nanocoatings on the MCF7 tumor and normal VERO cell lines was achieved by means of cell viability MTT and cytotoxicity LDH assays. While all nanocoatings loaded with antitumor drugs exhibited powerful cytotoxic activity against both the tumor and the normal cells, those embedded with AgNPs loaded with rosemary and thyme EOs showed remarkable and statistically significant selective cytotoxicity against the tested cancercells. The EO-loaded nanocoatings were tested for antimicrobial and antibiofilm activity against Staphylococcus aureus, Escherichia coli, and Candida albicans. For all studied pathogens, the cell viability, assessed by counting the colony-forming units after 2 and 24 h, was significantly decreased by all EO-based nanocoatings, while the best antibiofilm activity was evidenced by the nanocoatings containing ginger and thyme EOs. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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17 pages, 5911 KiB

Open AccessEditor’s ChoiceArticle

Liposome-Micelle-Hybrid (LMH) Carriers for Controlled Co-Delivery of 5-FU and Paclitaxel as Chemotherapeutics

by Md. Musfizur Hassan, Bilquis Romana, Guangzhao Mao, Naresh Kumar, Fabio Sonvico, Pall Thordarson, Paul Joyce, Kristen E. Bremmell, Timothy J. Barnes and Clive A. Prestidge

Pharmaceutics 2023, 15(7), 1886; https://doi.org/10.3390/pharmaceutics15071886 - 4 Jul 2023

Cited by 9 | Viewed by 4145

Abstract

Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low solubility or permeability and limited controlled release from nanocarriers), which reduces their effectiveness in new medicines. Anticancer drugs have several major limitations, which [...] Read more.

Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low solubility or permeability and limited controlled release from nanocarriers), which reduces their effectiveness in new medicines. Anticancer drugs have several major limitations, which include non-specificity, wide biological distribution, a short half-life, and systemic toxicity. Here, we investigate the potential of liposome-micelle-hybrid (LMH) carriers (i.e., drug-loaded micelles encapsulated within drug-loaded liposomes) to enhance the co-formulation and delivery of PTX and 5-FU, facilitating new delivery opportunities with enhanced chemotherapeutic performance. We focus on the combination of liposomes and micelles for co-delivery of PTX and 5_FU to investigate increased drug loading, improved solubility, and transport/permeability to enhance chemotherapeutic potential. Furthermore, combination chemotherapy (i.e., containing two or more drugs in a single formulation) may offer improved pharmacological performance. Compared with individual liposome and micelle formulations, the optimized PTX-5FU-LMH carriers demonstrated increased drug loading and solubility, temperature-sensitive release, enhanced permeability in a Caco-2 cell monolayer model, and cancer cell eradication. LMH has significant potential for cancer drug delivery and as a next-generation chemotherapeutic. Full article

(This article belongs to the Special Issue Advanced Liposomes for Drug Delivery)

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15 pages, 2065 KiB

Open AccessEditor’s ChoiceArticle

Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica

by Anand Chakroborty, Deiniol R. Pritchard, Marc E. Bouillon, Anna Cervi, Rolf Kraehenbuehl, Charlotte Wild, Caroline Fenn, Peter Holdsworth, Colin Capner, Gilda Padalino, Josephine E. Forde-Thomas, Joseph Payne, Brendan G. Smith, Maggie Fisher, Martina Lahmann, Mark S. Baird and Karl F. Hoffmann

Pharmaceutics 2023, 15(7), 1869; https://doi.org/10.3390/pharmaceutics15071869 - 3 Jul 2023

Cited by 1 | Viewed by 3085

Abstract

Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in [...] Read more.

Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in bulk from Hedera helix. Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC₅₀ obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). These data indicate that modified hederagenins display properties suitable for further investigations as candidate flukicides. Full article

(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)

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17 pages, 3714 KiB

Open AccessEditor’s ChoiceArticle

Study and Characterization of Polyvinyl Alcohol-Based Formulations for 3D Printlets Obtained via Fused Deposition Modeling

by Sofiya Ilieva, Dilyana Georgieva, Valentina Petkova and Milen Dimitrov

Pharmaceutics 2023, 15(7), 1867; https://doi.org/10.3390/pharmaceutics15071867 - 2 Jul 2023

Cited by 10 | Viewed by 2536

Abstract

Three-dimensional (3D) printing has emerged as a new promising technique for the production of personalized dosage forms and medical devices. Polyvinyl alcohol is prominently used as a source material to produce 3D-printed medicines via fused deposition modeling (FDM)—a technology that combines hot melt [...] Read more.

Three-dimensional (3D) printing has emerged as a new promising technique for the production of personalized dosage forms and medical devices. Polyvinyl alcohol is prominently used as a source material to produce 3D-printed medicines via fused deposition modeling (FDM)—a technology that combines hot melt extrusion and 3D printing. A preliminary screening of three grades of PVA indicated that partially hydrolyzed PVA with a molecular weight (MW) of 31,000–50,000 and plasticized with sorbitol was most suitable for 3D printing. Paracetamol was used as a model drug. The materials and the produced filaments were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The complex viscosity (η*) of the polymer melts was determined as a function of the angular frequency (ω) at the printing temperature to assess their printability. Three-dimensional printlets with a 40% infill exhibited an immediate release of the API, while tablets with a higher infill were prone to a prolonged release regardless of the filament drug loading. A factorial design was used to give more insight into the influence of the drug-loading of the filaments and the tablet infill as independent variables on the production of 3D printlets. The Pareto chart confirmed that the infill had a statistically significant effect on the dissolution rate after 45 min, which was chosen as the response variable. Full article

(This article belongs to the Special Issue Additive Manufacturing Approaches to Produce Drug Delivery Systems Volume II)

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25 pages, 1398 KiB

Open AccessEditor’s ChoiceReview

Incretins-Based Therapies and Their Cardiovascular Effects: New Game-Changers for the Management of Patients with Diabetes and Cardiovascular Disease

by Federico Bernardini, Annunziata Nusca, Federica Coletti, Ylenia La Porta, Mariagrazia Piscione, Francesca Vespasiano, Fabio Mangiacapra, Elisabetta Ricottini, Rosetta Melfi, Ilaria Cavallari, Gian Paolo Ussia and Francesco Grigioni

Pharmaceutics 2023, 15(7), 1858; https://doi.org/10.3390/pharmaceutics15071858 - 1 Jul 2023

Cited by 8 | Viewed by 3513

Abstract

Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials [...] Read more.

Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians’ knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies. Full article

(This article belongs to the Special Issue Effective Therapies for Diabetes)

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18 pages, 3569 KiB

Open AccessEditor’s ChoiceArticle

Dysregulation of Amino Acid Transporters in a Rat Model of TLR7-Mediated Maternal Immune Activation

by Eliza R. McColl, Jeffrey T. Henderson and Micheline Piquette-Miller

Pharmaceutics 2023, 15(7), 1857; https://doi.org/10.3390/pharmaceutics15071857 - 1 Jul 2023

Cited by 2 | Viewed by 2295

Abstract

Maternal immune activation (MIA) during pregnancy is linked to neurodevelopmental disorders in humans. Similarly, the TLR7 agonist imiquimod alters neurodevelopment in rodents. While the mechanisms underlying MIA-mediated neurodevelopmental changes are unknown, they could involve dysregulation of amino acid transporters essential for neurodevelopment. Therefore, [...] Read more.

Maternal immune activation (MIA) during pregnancy is linked to neurodevelopmental disorders in humans. Similarly, the TLR7 agonist imiquimod alters neurodevelopment in rodents. While the mechanisms underlying MIA-mediated neurodevelopmental changes are unknown, they could involve dysregulation of amino acid transporters essential for neurodevelopment. Therefore, we sought to determine the nature of such transporter changes in both imiquimod-treated rats and human placentas during infection. Pregnant rats received imiquimod on gestational day (GD)14. Transporter expression was measured in placentas and fetal brains via qPCR (GD14.5) and immunoblotting (GD16). To monitor function, fetal brain amino acid levels were measured by HPLC on GD16. Gene expression in the cortex of female fetal brains was further examined by RNAseq on GD19. In human placentas, suspected active infection was associated with decreased ASCT1 and SNAT2 protein expression. Similarly, in imiquimod-treated rats, ASCT1 and SNAT2 protein was also decreased in male placentas, while EAAT2 was decreased in female placentas. CAT3 was increased in female fetal brains. Consistent with this, imiquimod altered amino acid levels in fetal brains, while RNAseq demonstrated changes in expression of several genes implicated in autism. Thus, imiquimod alters amino acid transporter levels in pregnant rats, and similar changes occur in human placentas during active infection. This suggests that changes in expression of amino acid transporters may contribute to effects mediated by MIA toward altered neurodevelopment. Full article

(This article belongs to the Special Issue Drug Transporters: Regulation and Roles in Therapeutic Strategies)

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21 pages, 4321 KiB

Open AccessEditor’s ChoiceArticle

Assessment of Different Niosome Formulations for Optogenetic Applications: Morphological and Electrophysiological Effects

by José David Celdrán, Lawrence Humphreys, Desirée González, Cristina Soto-Sánchez, Gema Martínez-Navarrete, Iván Maldonado, Idoia Gallego, Ilia Villate-Beitia, Myriam Sainz-Ramos, Gustavo Puras, José Luis Pedraz and Eduardo Fernández

Pharmaceutics 2023, 15(7), 1860; https://doi.org/10.3390/pharmaceutics15071860 - 1 Jul 2023

Viewed by 2173

Abstract

Gene therapy and optogenetics are becoming promising tools for treating several nervous system pathologies. Currently, most of these approaches use viral vectors to transport the genetic material inside the cells, but viruses present some potential risks, such as marked immunogenicity, insertional mutagenesis, and [...] Read more.

Gene therapy and optogenetics are becoming promising tools for treating several nervous system pathologies. Currently, most of these approaches use viral vectors to transport the genetic material inside the cells, but viruses present some potential risks, such as marked immunogenicity, insertional mutagenesis, and limited insert gene size. In this framework, non-viral nanoparticles, such as niosomes, are emerging as possible alternative tools to deliver genetic material, avoiding the aforementioned problems. To determine their suitability as vectors for optogenetic therapies in this work, we tested three different niosome formulations combined with three optogenetic plasmids in rat cortical neurons in vitro. All niosomes tested successfully expressed optogenetic channels, which were dependent on the ratio of niosome to plasmid, with higher concentrations yielding higher expression rates. However, we found changes in the dendritic morphology and electrophysiological properties of transfected cells, especially when we used higher concentrations of niosomes. Our results highlight the potential use of niosomes for optogenetic applications and suggest that special care must be taken to achieve an optimal balance of niosomes and nucleic acids to achieve the therapeutic effects envisioned by these technologies. Full article

(This article belongs to the Special Issue Supramolecular Systems for Gene and Drug Delivery, 2nd Edition)

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23 pages, 5603 KiB

Open AccessEditor’s ChoiceArticle

Nano-Hydroxyapatite/PLGA Mixed Scaffolds as a Tool for Drug Development and to Study Metastatic Prostate Cancer in the Bone

by Annachiara Dozzo, Krishnakumar Chullipalliyalil, Michael McAuliffe, Caitriona M. O’Driscoll and Katie B. Ryan

Pharmaceutics 2023, 15(1), 242; https://doi.org/10.3390/pharmaceutics15010242 - 11 Jan 2023

Cited by 7 | Viewed by 4046

Abstract

(1) Background: Three-dimensional (3D) in vitro, biorelevant culture models that recapitulate cancer progression can help elucidate physio-pathological disease cues and enhance the screening of more effective therapies. Insufficient research has been conducted to generate in vitro 3D models to replicate the spread of [...] Read more.

(1) Background: Three-dimensional (3D) in vitro, biorelevant culture models that recapitulate cancer progression can help elucidate physio-pathological disease cues and enhance the screening of more effective therapies. Insufficient research has been conducted to generate in vitro 3D models to replicate the spread of prostate cancer to the bone, a key metastatic site of the disease, and to understand the interplay between the key cell players. In this study, we aim to investigate PLGA and nano-hydroxyapatite (nHA)/PLGA mixed scaffolds as a predictive preclinical tool to study metastatic prostate cancer (mPC) in the bone and reduce the gap that exists with traditional 2D cultures. (2) Methods: nHA/PLGA mixed scaffolds were produced by electrospraying, compacting, and foaming PLGA polymer microparticles, +/− nano-hydroxyapatite (nHA), and a salt porogen to produce 3D, porous scaffolds. Physicochemical scaffold characterisation together with an evaluation of osteoblastic (hFOB 1.19) and mPC (PC-3) cell behaviour (RT-qPCR, viability, and differentiation) in mono- and co-culture, was undertaken. (3) Results: The results show that the addition of nHA, particularly at the higher-level impacted scaffolds in terms of mechanical and degradation behaviour. The nHA 4 mg resulted in weaker scaffolds, but cell viability increased. Qualitatively, fluorescent imaging of cultures showed an increase in PC-3 cells compared to osteoblasts despite lower initial PC-3 seeding densities. Osteoblast monocultures, in general, caused an upregulation (or at least equivalent to controls) in gene production, which was highest in plain scaffolds and decreased with increases in nHA. Additionally, the genes were downregulated in PC3 and co-cultures. Further, drug toxicity tests demonstrated a significant effect in 2D and 3D co-cultures. (4) Conclusions: The results demonstrate that culture conditions and environment (2D versus 3D, monoculture versus co-culture) and scaffold composition all impact cell behaviour and model development. Full article

(This article belongs to the Special Issue In Vitro Cell Models in Regenerative Medicine)

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32 pages, 5946 KiB

Open AccessEditor’s ChoiceReview

Superparamagnetic Iron Oxide Nanoparticles (SPION): From Fundamentals to State-of-the-Art Innovative Applications for Cancer Therapy

by Thomas Vangijzegem, Valentin Lecomte, Indiana Ternad, Levy Van Leuven, Robert N. Muller, Dimitri Stanicki and Sophie Laurent

Pharmaceutics 2023, 15(1), 236; https://doi.org/10.3390/pharmaceutics15010236 - 10 Jan 2023

Cited by 101 | Viewed by 10703

Abstract

Despite significant advances in cancer therapy over the years, its complex pathological process still represents a major health challenge when seeking effective treatment and improved healthcare. With the advent of nanotechnologies, nanomedicine-based cancer therapy has been widely explored as a promising technology able [...] Read more.

Despite significant advances in cancer therapy over the years, its complex pathological process still represents a major health challenge when seeking effective treatment and improved healthcare. With the advent of nanotechnologies, nanomedicine-based cancer therapy has been widely explored as a promising technology able to handle the requirements of the clinical sector. Superparamagnetic iron oxide nanoparticles (SPION) have been at the forefront of nanotechnology development since the mid-1990s, thanks to their former role as contrast agents for magnetic resonance imaging. Though their use as MRI probes has been discontinued due to an unfavorable cost/benefit ratio, several innovative applications as therapeutic tools have prompted a renewal of interest. The unique characteristics of SPION, i.e., their magnetic properties enabling specific response when submitted to high frequency (magnetic hyperthermia) or low frequency (magneto-mechanical therapy) alternating magnetic field, and their ability to generate reactive oxygen species (either intrinsically or when activated using various stimuli), make them particularly adapted for cancer therapy. This review provides a comprehensive description of the fundamental aspects of SPION formulation and highlights various recent approaches regarding in vivo applications in the field of cancer therapy. Full article

(This article belongs to the Special Issue Magnetic Nanomaterials – a Promising Approach in Cancer Therapy)

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27 pages, 2214 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Intranasal Liposomes for Drug, Gene, and Vaccine Delivery

by Van-An Duong, Thi-Thao-Linh Nguyen and Han-Joo Maeng

Pharmaceutics 2023, 15(1), 207; https://doi.org/10.3390/pharmaceutics15010207 - 6 Jan 2023

Cited by 66 | Viewed by 9289

Abstract

Liposomes are safe, biocompatible, and biodegradable spherical nanosized vesicles produced from cholesterol and phospholipids. Recently, liposomes have been widely administered intranasally for systemic and brain delivery. From the nasal cavity, liposome-encapsulated drugs and genes enter the systemic circulation primarily via absorption in the [...] Read more.

Liposomes are safe, biocompatible, and biodegradable spherical nanosized vesicles produced from cholesterol and phospholipids. Recently, liposomes have been widely administered intranasally for systemic and brain delivery. From the nasal cavity, liposome-encapsulated drugs and genes enter the systemic circulation primarily via absorption in the respiratory region, whereas they can be directly transported to the brain via the olfactory pathway. Liposomes can protect drugs and genes from enzymatic degradation, increase drug absorption across the nasal epithelium, and prolong the residence time in the nasal cavity. Intranasal liposomes are also a potential approach for vaccine delivery. Liposomes can be used as a platform to load antigens and as vaccine adjuvants to induce a robust immune response. With the recent interest in intranasal liposome formulations, this review discusses various aspects of liposomes that make them suitable for intranasal administration. We have summarized the latest advancements and applications of liposomes and evaluated their performance in the systemic and brain delivery of drugs and genes administered intranasally. We have also reviewed recent advances in intranasal liposome vaccine development and proposed perspectives on the future of intranasal liposomes. Full article

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

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12 pages, 1823 KiB

Open AccessEditor’s ChoiceArticle

Tumor Treating Fields (TTFields) Induce Cell Junction Alterations in a Human 3D In Vitro Model of the Blood-Brain Barrier

by Ellaine Salvador, Theresa Köppl, Julia Hörmann, Sebastian Schönhärl, Polina Bugaeva, Almuth F. Kessler, Malgorzata Burek, Ralf-Ingo Ernestus, Mario Löhr and Carsten Hagemann

Pharmaceutics 2023, 15(1), 185; https://doi.org/10.3390/pharmaceutics15010185 - 4 Jan 2023

Cited by 20 | Viewed by 3431

Abstract

In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins [...] Read more.

In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies. Full article

(This article belongs to the Special Issue Targeting Cell Junctions for Therapy and Delivery)

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15 pages, 1108 KiB

Open AccessEditor’s ChoiceReview

Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

by Caroline P. Kerr, Joseph J. Grudzinski, Thanh Phuong Nguyen, Reinier Hernandez, Jamey P. Weichert and Zachary S. Morris

Pharmaceutics 2023, 15(1), 128; https://doi.org/10.3390/pharmaceutics15010128 - 30 Dec 2022

Cited by 19 | Viewed by 5537

Abstract

Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease [...] Read more.

Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention—a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

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14 pages, 5064 KiB

Open AccessEditor’s ChoiceArticle

Clay-Based Hydrogels as Drug Delivery Vehicles of Curcumin Nanocrystals for Topical Application

by Marco Ruggeri, Rita Sánchez-Espejo, Luca Casula, Raquel de Melo Barbosa, Giuseppina Sandri, Maria Cristina Cardia, Francesco Lai and César Viseras

Pharmaceutics 2022, 14(12), 2836; https://doi.org/10.3390/pharmaceutics14122836 - 17 Dec 2022

Cited by 21 | Viewed by 3272

Abstract

The poor water solubility of a significant number of active pharmaceutical ingredients (API) remains one of the main challenges in the drug development process, causing low bioavailability and therapeutic failure of drug candidates. Curcumin is a well-known Biopharmaceutics Classification System (BCS) class IV [...] Read more.

The poor water solubility of a significant number of active pharmaceutical ingredients (API) remains one of the main challenges in the drug development process, causing low bioavailability and therapeutic failure of drug candidates. Curcumin is a well-known Biopharmaceutics Classification System (BCS) class IV drug, characterized by lipophilicity and low permeability, which hampers topical bioavailability. Given these premises, the aim of this work was the design and the development of curcumin nanocrystals and their incorporation into natural inorganic hydrogels for topical application. Curcumin nanocrystals were manufactured by the wet ball milling technique and then loaded in clay-based hydrogels. Bentonite and/or palygorskite were selected as the inorganic gelling agents. Curcumin nanocrystal-loaded hydrogels were manufactured by means of a homogenization process and characterized with respect to their chemico-physical properties, in vitro release, antioxidant activity and skin permeation. The results highlighted that the presence of bentonite provided an increase of curcumin skin penetration and simultaneously allowed its radical scavenging properties, due to the desirable rheological characteristics, which should guarantee the necessary contact time of the gel with the skin. Full article

(This article belongs to the Special Issue Special Issue in Honor of Professor Carla Caramella)

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44 pages, 3907 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in the Biomedical Applications of Functionalized Nanogels

by Kannan Badri Narayanan, Rakesh Bhaskar and Sung Soo Han

Pharmaceutics 2022, 14(12), 2832; https://doi.org/10.3390/pharmaceutics14122832 - 16 Dec 2022

Cited by 23 | Viewed by 4709

Abstract

Nanomaterials have been extensively used in several applications in the past few decades related to biomedicine and healthcare. Among them, nanogels (NGs) have emerged as an important nanoplatform with the properties of both hydrogels and nanoparticles for the controlled/sustained delivery of chemo drugs, [...] Read more.

Nanomaterials have been extensively used in several applications in the past few decades related to biomedicine and healthcare. Among them, nanogels (NGs) have emerged as an important nanoplatform with the properties of both hydrogels and nanoparticles for the controlled/sustained delivery of chemo drugs, nucleic acids, or other bioactive molecules for therapeutic or diagnostic purposes. In the recent past, significant research efforts have been invested in synthesizing NGs through various synthetic methodologies such as free radical polymerization, reversible addition-fragmentation chain-transfer method (RAFT) and atom transfer radical polymerization (ATRP), as well as emulsion techniques. With further polymeric functionalizations using activated esters, thiol–ene/yne processes, imines/oximes formation, cycloadditions, nucleophilic addition reactions of isocyanates, ring-opening, and multicomponent reactions were used to obtain functionalized NGs for targeted delivery of drug and other compounds. NGs are particularly intriguing for use in the areas of diagnosis, analytics, and biomedicine due to their nanodimensionality, material characteristics, physiological stability, tunable multi-functionality, and biocompatibility. Numerous NGs with a wide range of functionalities and various external/internal stimuli-responsive modalities have been possible with novel synthetic reliable methodologies. Such continuous development of innovative, intelligent materials with novel characteristics is crucial for nanomedicine for next-generation biomedical applications. This paper reviews the synthesis and various functionalization strategies of NGs with a focus on the recent advances in different biomedical applications of these surface modified/functionalized single-/dual-/multi-responsive NGs, with various active targeting moieties, in the fields of cancer theranostics, immunotherapy, antimicrobial/antiviral, antigen presentation for the vaccine, sensing, wound healing, thrombolysis, tissue engineering, and regenerative medicine. Full article

(This article belongs to the Special Issue Natural and/or Synthetic-Based Nanostructured Systems as Drug Delivery Platforms)

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21 pages, 2992 KiB

Open AccessEditor’s ChoiceArticle

3D Printing of Paracetamol Suppositories: An Automated Manufacturing Technique for Individualized Therapy

by Vanessa Domsta, Julius Krause, Werner Weitschies and Anne Seidlitz

Pharmaceutics 2022, 14(12), 2676; https://doi.org/10.3390/pharmaceutics14122676 - 1 Dec 2022

Cited by 12 | Viewed by 6165

Abstract

Pharmaceutical compounding using the molding technique is the currently applied method for the on-demand manufacturing of suppositories and pessaries. Potential errors of this method are difficult to detect, and the possibilities of individualization of size and shape of the suppositories are limited. In [...] Read more.

Pharmaceutical compounding using the molding technique is the currently applied method for the on-demand manufacturing of suppositories and pessaries. Potential errors of this method are difficult to detect, and the possibilities of individualization of size and shape of the suppositories are limited. In this study, a syringe-based semi-solid 3D printing technique was developed for the manufacturing of suppositories in three different printing designs with the suppository bases polyethylene glycol (PEG) and hard fat (HF). The 3D printed suppositories were analyzed for their visual appearance, uniformity of mass and content, diametrical dimension, breaking force and release behavior and compared to suppositories of the same composition prepared by a commonly used molding technique. The results showed no adverse properties for the 3D printed suppositories compared to the molded ones. Moreover, the easy adaptation of shape using the 3D printing technique was demonstrated by the printing of different sizes and infill structures. Thus, 3D printing has great potential to complement the available manufacturing methods for compounded suppositories, as it represents an automated system for the individualized manufacturing of suppositories that meet patients’ needs. Full article

(This article belongs to the Special Issue Recent Non-oral Dosage Form Development: Focus on 3D-Printed Formulations)

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52 pages, 2030 KiB

Open AccessEditor’s ChoiceReview

Alternative Excipients for Protein Stabilization in Protein Therapeutics: Overcoming the Limitations of Polysorbates

by Angel J. Castañeda Ruiz, Maryam A. Shetab Boushehri, Tamara Phan, Stefan Carle, Patrick Garidel, Julia Buske and Alf Lamprecht

Pharmaceutics 2022, 14(12), 2575; https://doi.org/10.3390/pharmaceutics14122575 - 23 Nov 2022

Cited by 46 | Viewed by 11852

Abstract

Given their safety and efficiency in protecting protein integrity, polysorbates (PSs) have been the most widely used excipients for the stabilization of protein therapeutics for years. In recent decades, however, there have been numerous reports about visible or sub-visible particles in PS-containing biotherapeutic [...] Read more.

Given their safety and efficiency in protecting protein integrity, polysorbates (PSs) have been the most widely used excipients for the stabilization of protein therapeutics for years. In recent decades, however, there have been numerous reports about visible or sub-visible particles in PS-containing biotherapeutic products, which is a major quality concern for parenteral drugs. Alternative excipients that are safe for parenteral administration, efficient in protecting different protein drugs against various stress conditions, effective in protein stabilization in high-concentrated liquid formulations, stable under the storage conditions for the duration of the product’s shelf-life, and compatible with other formulation components and the primary packaging are highly sought after. The aim of this paper is to review potential alternative excipients from different families, including surfactants, carbohydrate- and amino acid-based excipients, synthetic amphiphilic polymers, and ionic liquids that enable protein stabilization. For each category, important characteristics such as the ability to stabilize proteins against thermal and mechanical stresses, current knowledge related to the safety profile for parenteral administration, potential interactions with other formulation components, and primary packaging are debated. Based on the provided information and the detailed discussion thereof, this paper may pave the way for the identification or development of efficient excipients for biotherapeutic protein stabilization. Full article

(This article belongs to the Special Issue Developing Peptide and Protein Drug Formulations)

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24 pages, 2630 KiB

Open AccessEditor’s ChoiceReview

Advancements in the Design and Development of Dry Powder Inhalers and Potential Implications for Generic Development

by Abhinav Ram Mohan, Qiang Wang, Sneha Dhapare, Elizabeth Bielski, Anubhav Kaviratna, Liangfeng Han, Susan Boc and Bryan Newman

Pharmaceutics 2022, 14(11), 2495; https://doi.org/10.3390/pharmaceutics14112495 - 17 Nov 2022

Cited by 17 | Viewed by 6293

Abstract

Dry powder inhalers (DPIs) are drug–device combination products where the complexity of the formulation, its interaction with the device, and input from users play important roles in the drug delivery. As the landscape of DPI products advances with new powder formulations and novel [...] Read more.

Dry powder inhalers (DPIs) are drug–device combination products where the complexity of the formulation, its interaction with the device, and input from users play important roles in the drug delivery. As the landscape of DPI products advances with new powder formulations and novel device designs, understanding how these advancements impact performance can aid in developing generics that are therapeutically equivalent to the reference listed drug (RLD) products. This review details the current understanding of the formulation and device related principles driving DPI performance, past and present research efforts to characterize these performance factors, and the implications that advances in formulation and device design may present for evaluating bioequivalence (BE) for generic development. Full article

(This article belongs to the Special Issue Dry Powders for Pulmonary Delivery: Device and Formulation Technologies for an Enhanced Lung Deposition)

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36 pages, 2843 KiB

Open AccessEditor’s ChoiceReview

Superparamagnetic Iron Oxide Nanoparticles for Immunotherapy of Cancers through Macrophages and Magnetic Hyperthermia

by Alexandre M. M. Dias, Alan Courteau, Pierre-Simon Bellaye, Evelyne Kohli, Alexandra Oudot, Pierre-Emmanuel Doulain, Camille Petitot, Paul-Michael Walker, Richard Decréau and Bertrand Collin

Pharmaceutics 2022, 14(11), 2388; https://doi.org/10.3390/pharmaceutics14112388 - 5 Nov 2022

Cited by 43 | Viewed by 6390

Abstract

Cancer immunotherapy has tremendous promise, but it has yet to be clinically applied in a wider variety of tumor situations. Many therapeutic combinations are envisaged to improve their effectiveness. In this way, strategies capable of inducing immunogenic cell death (e.g., doxorubicin, radiotherapy, hyperthermia) [...] Read more.

Cancer immunotherapy has tremendous promise, but it has yet to be clinically applied in a wider variety of tumor situations. Many therapeutic combinations are envisaged to improve their effectiveness. In this way, strategies capable of inducing immunogenic cell death (e.g., doxorubicin, radiotherapy, hyperthermia) and the reprogramming of the immunosuppressive tumor microenvironment (TME) (e.g., M2-to-M1-like macrophages repolarization of tumor-associated macrophages (TAMs)) are particularly appealing to enhance the efficacy of approved immunotherapies (e.g., immune checkpoint inhibitors, ICIs). Due to their modular construction and versatility, iron oxide-based nanomedicines such as superparamagnetic iron oxide nanoparticles (SPIONs) can combine these different approaches in a single agent. SPIONs have already shown their safety and biocompatibility and possess both drug-delivery (e.g., chemotherapy, ICIs) and magnetic capabilities (e.g., magnetic hyperthermia (MHT), magnetic resonance imaging). In this review, we will discuss the multiple applications of SPIONs in cancer immunotherapy, focusing on their theranostic properties to target TAMs and to generate MHT. The first section of this review will briefly describe immune targets for NPs. The following sections will deal with the overall properties of SPIONs (including MHT). The last section is dedicated to the SPION-induced immune response through its effects on TAMs and MHT. Full article

(This article belongs to the Special Issue Application of Nanomedicine in Immunotherapy: Recent Advances and Prospects)

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21 pages, 4816 KiB

Open AccessEditor’s ChoiceReview

Drug Stability: ICH versus Accelerated Predictive Stability Studies

by Olga González-González, Irving O. Ramirez, Bianca I. Ramirez, Peter O’Connell, Maria Paloma Ballesteros, Juan José Torrado and Dolores R. Serrano

Pharmaceutics 2022, 14(11), 2324; https://doi.org/10.3390/pharmaceutics14112324 - 28 Oct 2022

Cited by 113 | Viewed by 16986

Abstract

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and [...] Read more.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and the United States to facilitate the mutual acceptance of stability data that are sufficient for registration by the regulatory authorities in these jurisdictions. Overall, ICH stability studies involve a drug substance tested under storage conditions and assess its thermal stability and sensitivity to moisture. The long-term testing should be performed over a minimum of 12 months at 25 °C ± 2 °C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH. The intermediate and accelerated testing should cover a minimum of 6 months at 30 °C ± 2 °C/65% RH ± 5% RH (which is not necessary if this condition was utilized as a long-term one) and 40 °C ± 2 °C/75% RH ± 5% RH, respectively. Hence, the ICH stability testing for industrially fabricated medicines is rigorous and tedious and involves a long period of time to obtain preclinical stability data. For this reason, Accelerated Predictive Stability (APS) studies, carried out over a 3–4-week period and combining extreme temperatures and RH conditions (40–90 °C)/10–90% RH, have emerged as novel approaches to predict the long-term stability of pharmaceutical products in a more efficient and less time-consuming manner. In this work, the conventional ICH stability studies versus the APS approach will be reviewed, highlighting the advantages and disadvantages of both strategies. Furthermore, a comparison of the stability requirements for the commercialization of industrially fabricated medicines versus extemporaneous compounding formulations will be discussed. Full article

(This article belongs to the Special Issue Stability of Medicines and Novel Approaches for Predicting Drug Stability)

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31 pages, 2667 KiB

Open AccessEditor’s ChoiceReview

Drug Delivery Systems as a Strategy to Improve the Efficacy of FDA-Approved Alzheimer’s Drugs

by Débora Nunes, Joana A. Loureiro and Maria Carmo Pereira

Pharmaceutics 2022, 14(11), 2296; https://doi.org/10.3390/pharmaceutics14112296 - 26 Oct 2022

Cited by 38 | Viewed by 7053

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, with a high impact worldwide, accounting for more than 46 million cases. The continuous increase of AD demands the fast development of preventive and curative therapeutic strategies that are truly effective. The drugs [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia, with a high impact worldwide, accounting for more than 46 million cases. The continuous increase of AD demands the fast development of preventive and curative therapeutic strategies that are truly effective. The drugs approved for AD treatment are classified into acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The therapeutic effectiveness of those drugs is hindered by their restricted access to the brain due to the blood–brain barrier, low bioavailability, and poor pharmacokinetic properties. In addition, the drugs are reported to have undesirable side effects. Several drug delivery systems (DDSs) have been widely exploited to address these issues. DDSs serve as drug carriers, combining the ability to deliver drugs locally and in a targeted manner with the ability to release them in a controlled and sustained manner. As a result, the pharmacological therapeutic effectiveness is raised, while the unwanted side effects induced by the unspecific distribution decrease. This article reviews the recently developed DDSs to increase the efficacy of Food and Drug Administration-approved AD drugs. Full article

(This article belongs to the Special Issue Drug Targeting for CNS Disease)

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24 pages, 1110 KiB

Open AccessEditor’s ChoiceReview

Human Brain Organoids-on-Chip: Advances, Challenges, and Perspectives for Preclinical Applications

by Héloïse Castiglione, Pierre-Antoine Vigneron, Camille Baquerre, Frank Yates, Jessica Rontard and Thibault Honegger

Pharmaceutics 2022, 14(11), 2301; https://doi.org/10.3390/pharmaceutics14112301 - 26 Oct 2022

Cited by 27 | Viewed by 7848

Abstract

There is an urgent need for predictive in vitro models to improve disease modeling and drug target identification and validation, especially for neurological disorders. Cerebral organoids, as alternative methods to in vivo studies, appear now as powerful tools to decipher complex biological processes [...] Read more.

There is an urgent need for predictive in vitro models to improve disease modeling and drug target identification and validation, especially for neurological disorders. Cerebral organoids, as alternative methods to in vivo studies, appear now as powerful tools to decipher complex biological processes thanks to their ability to recapitulate many features of the human brain. Combining these innovative models with microfluidic technologies, referred to as brain organoids-on-chips, allows us to model the microenvironment of several neuronal cell types in 3D. Thus, this platform opens new avenues to create a relevant in vitro approach for preclinical applications in neuroscience. The transfer to the pharmaceutical industry in drug discovery stages and the adoption of this approach by the scientific community requires the proposition of innovative microphysiological systems allowing the generation of reproducible cerebral organoids of high quality in terms of structural and functional maturation, and compatibility with automation processes and high-throughput screening. In this review, we will focus on the promising advantages of cerebral organoids for disease modeling and how their combination with microfluidic systems can enhance the reproducibility and quality of these in vitro models. Then, we will finish by explaining why brain organoids-on-chips could be considered promising platforms for pharmacological applications. Full article

(This article belongs to the Special Issue Organoids and Spheroids for the Design and the Evaluation of Therapeutic Strategies)

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26 pages, 3976 KiB

Open AccessEditor’s ChoiceReview

Emerging Artificial Intelligence (AI) Technologies Used in the Development of Solid Dosage Forms

by Junhuang Jiang, Xiangyu Ma, Defang Ouyang and Robert O. Williams III

Pharmaceutics 2022, 14(11), 2257; https://doi.org/10.3390/pharmaceutics14112257 - 22 Oct 2022

Cited by 58 | Viewed by 12312

Abstract

Artificial Intelligence (AI)-based formulation development is a promising approach for facilitating the drug product development process. AI is a versatile tool that contains multiple algorithms that can be applied in various circumstances. Solid dosage forms, represented by tablets, capsules, powder, granules, etc., are [...] Read more.

Artificial Intelligence (AI)-based formulation development is a promising approach for facilitating the drug product development process. AI is a versatile tool that contains multiple algorithms that can be applied in various circumstances. Solid dosage forms, represented by tablets, capsules, powder, granules, etc., are among the most widely used administration methods. During the product development process, multiple factors including critical material attributes (CMAs) and processing parameters can affect product properties, such as dissolution rates, physical and chemical stabilities, particle size distribution, and the aerosol performance of the dry powder. However, the conventional trial-and-error approach for product development is inefficient, laborious, and time-consuming. AI has been recently recognized as an emerging and cutting-edge tool for pharmaceutical formulation development which has gained much attention. This review provides the following insights: (1) a general introduction of AI in the pharmaceutical sciences and principal guidance from the regulatory agencies, (2) approaches to generating a database for solid dosage formulations, (3) insight on data preparation and processing, (4) a brief introduction to and comparisons of AI algorithms, and (5) information on applications and case studies of AI as applied to solid dosage forms. In addition, the powerful technique known as deep learning-based image analytics will be discussed along with its pharmaceutical applications. By applying emerging AI technology, scientists and researchers can better understand and predict the properties of drug formulations to facilitate more efficient drug product development processes. Full article

(This article belongs to the Special Issue Recent Advances in Solid Dosage Form)

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17 pages, 2694 KiB

Open AccessEditor’s ChoiceReview

Blood–Brain Barrier Transport of Transferrin Receptor-Targeted Nanoparticles

by Maj Schneider Thomsen, Kasper Bendix Johnsen, Krzysztof Kucharz, Martin Lauritzen and Torben Moos

Pharmaceutics 2022, 14(10), 2237; https://doi.org/10.3390/pharmaceutics14102237 - 19 Oct 2022

Cited by 52 | Viewed by 6589

Abstract

The blood–brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes [...] Read more.

The blood–brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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51 pages, 8632 KiB

Open AccessEditor’s ChoiceReview

Updates on Responsive Drug Delivery Based on Liposome Vehicles for Cancer Treatment

by Maria P. Nikolova, Enamala Manoj Kumar and Murthy S. Chavali

Pharmaceutics 2022, 14(10), 2195; https://doi.org/10.3390/pharmaceutics14102195 - 15 Oct 2022

Cited by 82 | Viewed by 9568

Abstract

Liposomes are well-known nanoparticles with a non-toxic nature and the ability to incorporate both hydrophilic and hydrophobic drugs simultaneously. As modern drug delivery formulations are produced by emerging technologies, numerous advantages of liposomal drug delivery systems over conventional liposomes or free drug treatment [...] Read more.

Liposomes are well-known nanoparticles with a non-toxic nature and the ability to incorporate both hydrophilic and hydrophobic drugs simultaneously. As modern drug delivery formulations are produced by emerging technologies, numerous advantages of liposomal drug delivery systems over conventional liposomes or free drug treatment of cancer have been reported. Recently, liposome nanocarriers have exhibited high drug loading capacity, drug protection, improved bioavailability, enhanced intercellular delivery, and better therapeutic effect because of resounding success in targeting delivery. The site targeting of smart responsive liposomes, achieved through changes in their physicochemical and morphological properties, allows for the controlled release of active compounds under certain endogenous or exogenous stimuli. In that way, the multifunctional and stimuli-responsive nanocarriers for the drug delivery of cancer therapeutics enhance the efficacy of treatment prevention and fighting over metastases, while limiting the systemic side effects on healthy tissues and organs. Since liposomes constitute promising nanocarriers for site-targeted and controlled anticancer drug release, this review focuses on the recent progress of smart liposome achievements for anticancer drug delivery applications. Full article

(This article belongs to the Special Issue Advanced Liposomes for Drug Delivery)

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73 pages, 1350 KiB

Open AccessEditor’s ChoiceReview

Formulation of Dosage Forms with Proton Pump Inhibitors: State of the Art, Challenges and Future Perspectives

by Justyna Srebro, Witold Brniak and Aleksander Mendyk

Pharmaceutics 2022, 14(10), 2043; https://doi.org/10.3390/pharmaceutics14102043 - 25 Sep 2022

Cited by 30 | Viewed by 18290

Abstract

Since their introduction to pharmacotherapy, proton pump inhibitors (PPIs) have been widely used in the treatment of numerous diseases manifested by excessive secretion of gastric acid. Despite that, there are still unmet needs regarding their availability for patients of all age groups. Their [...] Read more.

Since their introduction to pharmacotherapy, proton pump inhibitors (PPIs) have been widely used in the treatment of numerous diseases manifested by excessive secretion of gastric acid. Despite that, there are still unmet needs regarding their availability for patients of all age groups. Their poor stability hinders the development of formulations in which dose can be easily adjusted. The aim of this review is to describe the discovery and development of PPIs, discuss formulation issues, and present the contemporary solutions, possibilities, and challenges in formulation development. The review outlines the physicochemical characteristics of PPIs, connects them with pharmacokinetic and pharmacodynamic properties, and describes the stability of PPIs, including the identification of the most important factors affecting them. Moreover, the possibilities for qualitative and quantitative analysis of PPIs are briefly depicted. This review also characterizes commercial preparations with PPIs available in the US and EU. The major part of the review is focused on the presentation of the state of the art in the development of novel formulations with PPIs covering various approaches employed in this process: nanoparticles, microparticles, minitablets, pellets, bilayer, floating, and mucoadhesive tablets, as well as parenteral, transdermal, and rectal preparations. It also anticipates further possibilities in the development of PPIs dosage forms. It is especially addressed to the researchers developing new formulations containing PPIs, since it covers the most important formulary issues that need to be considered before a decision on the selection of the formula is made. It may help in avoiding unnecessary efforts in this process and choosing the best approach. The review also presents an up-to-date database of publications focused on the pharmaceutical technology of formulations with PPIs. Full article

(This article belongs to the Special Issue Recent Advances in Solid Dosage Form)

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19 pages, 3444 KiB

Open AccessEditor’s ChoiceArticle

Curcumin-Loaded Mesoporous Silica Nanoparticles Dispersed in Thermo-Responsive Hydrogel as Potential Alzheimer Disease Therapy

by Tais de Cassia Ribeiro, Rafael Miguel Sábio, Marcela Tavares Luiz, Lucas Canto de Souza, Bruno Fonseca-Santos, Luis Carlos Cides da Silva, Márcia Carvalho de Abreu Fantini, Cleopatra da Silva Planeta and Marlus Chorilli

Pharmaceutics 2022, 14(9), 1976; https://doi.org/10.3390/pharmaceutics14091976 - 19 Sep 2022

Cited by 57 | Viewed by 5791

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes associated to AD. A thermo-responsive hydrogel is an interesting approach for facilitating the administration of the nanosystem via a nasal route, as well as for overcoming mucociliary clearance mechanisms. In light of this, MSN-CCM were dispersed in the hydrogel and evaluated through in vitro and in vivo assays. The MSNs and MSN-CCM were successfully characterized by physicochemical analysis and a high value of the CCM encapsulation efficiency (EE%, 87.70 ± 0.05) was achieved. The designed thermo-responsive hydrogel (HG) was characterized by rheology, texture profile analysis, and ex vivo mucoadhesion, showing excellent mechanical and mucoadhesive properties. Ex vivo permeation studies of MSN-CCM and HG@MSN-CCM showed high permeation values (12.46 ± 1.08 and 28.40 ± 1.88 μg cm⁻² of CCM, respectively) in porcine nasal mucosa. In vivo studies performed in a streptozotocin-induced AD model confirmed that HG@MSN-CCM reverted the cognitive deficit in mice, acting as a potential formulation in the treatment of AD. Full article

(This article belongs to the Special Issue Silica-Based Carriers for Drug Delivery)

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24 pages, 5531 KiB

Open AccessEditor’s ChoiceArticle

Optimization of Lipid Nanoparticles by Response Surface Methodology to Improve the Ocular Delivery of Diosmin: Characterization and In-Vitro Anti-Inflammatory Assessment

by Elide Zingale, Salvatore Rizzo, Angela Bonaccorso, Valeria Consoli, Luca Vanella, Teresa Musumeci, Angelo Spadaro and Rosario Pignatello

Pharmaceutics 2022, 14(9), 1961; https://doi.org/10.3390/pharmaceutics14091961 - 16 Sep 2022

Cited by 22 | Viewed by 4346

Abstract

Diosmin is a flavonoid with a great variety of biological activities including antioxidant and anti-inflammatory ones. Its cytoprotective effect in retinal pigment epithelium cells under high glucose conditions makes it a potential support in the treatment of diabetic retinopathy. Despite its benefits, poor [...] Read more.

Diosmin is a flavonoid with a great variety of biological activities including antioxidant and anti-inflammatory ones. Its cytoprotective effect in retinal pigment epithelium cells under high glucose conditions makes it a potential support in the treatment of diabetic retinopathy. Despite its benefits, poor solubility in water reduces its potential for therapeutic use, making it the biggest biopharmaceutical challenge. The design of diosmin-loaded nanocarriers for topical ophthalmic application represents a novelty that has not been yet explored. For this purpose, the response surface methodology (RSM) was used to optimize nanostructured lipid carriers (NLCs), compatible for ocular administration, to encapsulate diosmin and improve its physicochemical issues. NLCs were prepared by a simple and scalable technique: a melt emulsification method followed by ultrasonication. The experimental design was composed of four independent variables (solid lipid concentration, liquid lipid concentration, surfactant concentration and type of solid lipid). The effect of the factors was assessed on NLC size and PDI (responses) by analysis of variance (ANOVA). The optimized formulation was selected according to the desirability function (0.993). Diosmin at two different concentrations (80 and 160 µM) was encapsulated into NLCs. Drug-loaded nanocarriers (D-NLCs) were subjected to a physicochemical and technological investigation revealing a mean particle size of 83.58 ± 0.77 nm and 82.21 ± 1.12 nm, respectively for the D-NLC formulation prepared with diosmin at the concentration of 80 µM or 160 µM, and a net negative surface charge (−18.5 ± 0.60 and −18.0 ± 1.18, respectively for the two batches). The formulations were analyzed in terms of pH (6.5), viscosity, and adjusted for osmolarity, making them more compatible with the ocular environment. Subsequently, stability studies were carried out to assess D-NLC behavior under different storage conditions up to 60 days, indicating a good stability of NLC samples at room temperature. In-vitro studies on ARPE-19 cells confirmed the cytocompatibility of NLCs with retinal epithelium. The effect of D-NLCs was also evaluated in-vitro on a model of retinal inflammation, demonstrating the cytoprotective effect of D-NLCs at various concentrations. RSM was found to be a reliable model to optimize NLCs for diosmin encapsulation. Full article

(This article belongs to the Special Issue Advances in Formulation of Poorly Soluble Bioactive Compounds)

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45 pages, 3469 KiB

Open AccessEditor’s ChoiceReview

Microfluidic Manufacture of Lipid-Based Nanomedicines

by Karim Osouli-Bostanabad, Sara Puliga, Dolores R. Serrano, Andrea Bucchi, Gavin Halbert and Aikaterini Lalatsa

Pharmaceutics 2022, 14(9), 1940; https://doi.org/10.3390/pharmaceutics14091940 - 14 Sep 2022

Cited by 49 | Viewed by 8441

Abstract

Nanoparticulate technologies have revolutionized drug delivery allowing for passive and active targeting, altered biodistribution, controlled drug release (temporospatial or triggered), enhanced stability, improved solubilization capacity, and a reduction in dose and adverse effects. However, their manufacture remains immature, and challenges exist on an [...] Read more.

Nanoparticulate technologies have revolutionized drug delivery allowing for passive and active targeting, altered biodistribution, controlled drug release (temporospatial or triggered), enhanced stability, improved solubilization capacity, and a reduction in dose and adverse effects. However, their manufacture remains immature, and challenges exist on an industrial scale due to high batch-to-batch variability hindering their clinical translation. Lipid-based nanomedicines remain the most widely approved nanomedicines, and their current manufacturing methods remain discontinuous and face several problems such as high batch-to-batch variability affecting the critical quality attributes (CQAs) of the product, laborious multistep processes, need for an expert workforce, and not being easily amenable to industrial scale-up involving typically a complex process control. Several techniques have emerged in recent years for nanomedicine manufacture, but a paradigm shift occurred when microfluidic strategies able to mix fluids in channels with dimensions of tens of micrometers and small volumes of liquid reagents in a highly controlled manner to form nanoparticles with tunable and reproducible structure were employed. In this review, we summarize the recent advancements in the manufacturing of lipid-based nanomedicines using microfluidics with particular emphasis on the parameters that govern the control of CQAs of final nanomedicines. The impact of microfluidic environments on formation dynamics of nanomaterials, and the application of microdevices as platforms for nanomaterial screening are also discussed. Full article

(This article belongs to the Special Issue Engineering and Characterisation of Novel Nanomedicine Formulations)

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32 pages, 2308 KiB

Open AccessEditor’s ChoiceReview

Ocular Drug Delivery: Advancements and Innovations

by Bo Tian, Evan Bilsbury, Sean Doherty, Sean Teebagy, Emma Wood, Wenqi Su, Guangping Gao and Haijiang Lin

Pharmaceutics 2022, 14(9), 1931; https://doi.org/10.3390/pharmaceutics14091931 - 13 Sep 2022

Cited by 33 | Viewed by 5823

Abstract

Ocular drug delivery has been significantly advanced for not only pharmaceutical compounds, such as steroids, nonsteroidal anti-inflammatory drugs, immune modulators, antibiotics, and so forth, but also for the rapidly progressed gene therapy products. For conventional non-gene therapy drugs, appropriate surgical approaches and releasing [...] Read more.

Ocular drug delivery has been significantly advanced for not only pharmaceutical compounds, such as steroids, nonsteroidal anti-inflammatory drugs, immune modulators, antibiotics, and so forth, but also for the rapidly progressed gene therapy products. For conventional non-gene therapy drugs, appropriate surgical approaches and releasing systems are the main deliberation to achieve adequate treatment outcomes, whereas the scope of “drug delivery” for gene therapy drugs further expands to transgene construct optimization, vector selection, and vector engineering. The eye is the particularly well-suited organ as the gene therapy target, owing to multiple advantages. In this review, we will delve into three main aspects of ocular drug delivery for both conventional drugs and adeno-associated virus (AAV)-based gene therapy products: (1) the development of AAV vector systems for ocular gene therapy, (2) the innovative carriers of medication, and (3) administration routes progression. Full article

(This article belongs to the Special Issue Drug Delivery in Ophthalmology)

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21 pages, 2483 KiB

Open AccessEditor’s ChoiceReview

Recent Developments in Heteroatom/Metal-Doped Carbon Dot-Based Image-Guided Photodynamic Therapy for Cancer

by Rajkumar Sekar, Nagaraj Basavegowda, Saktishree Jena, Santhoshkumar Jayakodi, Pandian Elumalai, Amballa Chaitanyakumar, Prathap Somu and Kwang-Hyun Baek

Pharmaceutics 2022, 14(9), 1869; https://doi.org/10.3390/pharmaceutics14091869 - 5 Sep 2022

Cited by 35 | Viewed by 4209

Abstract

Carbon nanodots (CNDs) are advanced nanomaterials with a size of 2–10 nm and are considered zero-dimensional carbonaceous materials. CNDs have received great attention in the area of cancer theranostics. The majority of review articles have shown the improvement of CNDs for use in [...] Read more.

Carbon nanodots (CNDs) are advanced nanomaterials with a size of 2–10 nm and are considered zero-dimensional carbonaceous materials. CNDs have received great attention in the area of cancer theranostics. The majority of review articles have shown the improvement of CNDs for use in cancer therapy and bioimaging applications. However, there is a minimal number of consolidated studies on the currently developed doped CNDs that are used in various ways in cancer therapies. Hence, in this review, we discuss the current developments in different types of heteroatom elements/metal ion-doped CNDs along with their preparations, physicochemical and biological properties, multimodal-imaging, and emerging applications in image-guided photodynamic therapies for cancer. Full article

(This article belongs to the Special Issue Metal-Based Prodrugs and Nanoparticles in Cancer Therapy)

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30 pages, 4522 KiB

Open AccessEditor’s ChoiceReview

Polymeric Micelles for Breast Cancer Therapy: Recent Updates, Clinical Translation and Regulatory Considerations

by Vijayabhaskarreddy Junnuthula, Praveen Kolimi, Dinesh Nyavanandi, Sunitha Sampathi, Lalitkumar K. Vora and Sathish Dyawanapelly

Pharmaceutics 2022, 14(9), 1860; https://doi.org/10.3390/pharmaceutics14091860 - 3 Sep 2022

Cited by 70 | Viewed by 5815

Abstract

With the growing burden of cancer, parallel advancements in anticancer nanotechnological solutions have been witnessed. Among the different types of cancers, breast cancer accounts for approximately 25% and leads to 15% of deaths. Nanomedicine and its allied fields of material science have revolutionized [...] Read more.

With the growing burden of cancer, parallel advancements in anticancer nanotechnological solutions have been witnessed. Among the different types of cancers, breast cancer accounts for approximately 25% and leads to 15% of deaths. Nanomedicine and its allied fields of material science have revolutionized the science of medicine in the 21st century. Novel treatments have paved the way for improved drug delivery systems that have better efficacy and reduced adverse effects. A variety of nanoformulations using lipids, polymers, inorganic, and peptide-based nanomedicines with various functionalities are being synthesized. Thus, elaborate knowledge of these intelligent nanomedicines for highly promising drug delivery systems is of prime importance. Polymeric micelles (PMs) are generally easy to prepare with good solubilization properties; hence, they appear to be an attractive alternative over the other nanosystems. Although an overall perspective of PM systems has been presented in recent reviews, a brief discussion has been provided on PMs for breast cancer. This review provides a discussion of the state-of-the-art PMs together with the most recent advances in this field. Furthermore, special emphasis is placed on regulatory guidelines, clinical translation potential, and future aspects of the use of PMs in breast cancer treatment. The recent developments in micelle formulations look promising, with regulatory guidelines that are now more clearly defined; hence, we anticipate early clinical translation in the near future. Full article

(This article belongs to the Special Issue Development of Novel Tumor-Targeting Nanoparticles)

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23 pages, 1454 KiB

Open AccessEditor’s ChoiceReview

Non-Viral Delivery of CRISPR/Cas Cargo to the Retina Using Nanoparticles: Current Possibilities, Challenges, and Limitations

by Ahmed Salman, Ariel Kantor, Michelle E. McClements, Gemma Marfany, Sonia Trigueros and Robert E. MacLaren

Pharmaceutics 2022, 14(9), 1842; https://doi.org/10.3390/pharmaceutics14091842 - 1 Sep 2022

Cited by 23 | Viewed by 5102

Abstract

The discovery of the CRISPR/Cas system and its development into a powerful genome engineering tool have revolutionized the field of molecular biology and generated excitement for its potential to treat a wide range of human diseases. As a gene therapy target, the retina [...] Read more.

The discovery of the CRISPR/Cas system and its development into a powerful genome engineering tool have revolutionized the field of molecular biology and generated excitement for its potential to treat a wide range of human diseases. As a gene therapy target, the retina offers many advantages over other tissues because of its surgical accessibility and relative immunity privilege due to its blood–retinal barrier. These features explain the large advances made in ocular gene therapy over the past decade, including the first in vivo clinical trial using CRISPR gene-editing reagents. Although viral vector-mediated therapeutic approaches have been successful, they have several shortcomings, including packaging constraints, pre-existing anti-capsid immunity and vector-induced immunogenicity, therapeutic potency and persistence, and potential genotoxicity. The use of nanomaterials in the delivery of therapeutic agents has revolutionized the way genetic materials are delivered to cells, tissues, and organs, and presents an appealing alternative to bypass the limitations of viral delivery systems. In this review, we explore the potential use of non-viral vectors as tools for gene therapy, exploring the latest advancements in nanotechnology in medicine and focusing on the nanoparticle-mediated delivery of CRIPSR genetic cargo to the retina. Full article

(This article belongs to the Special Issue Oligonucleotides and Nucleic-Acid-Based Strategies to Address Therapeutic Challenges: From the Bench to the Bedside)

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26 pages, 591 KiB

Open AccessEditor’s ChoiceArticle

Adoption of Machine Learning in Pharmacometrics: An Overview of Recent Implementations and Their Considerations

by Alexander Janssen, Frank C. Bennis and Ron A. A. Mathôt

Pharmaceutics 2022, 14(9), 1814; https://doi.org/10.3390/pharmaceutics14091814 - 29 Aug 2022

Cited by 33 | Viewed by 5496

Abstract

Pharmacometrics is a multidisciplinary field utilizing mathematical models of physiology, pharmacology, and disease to describe and quantify the interactions between medication and patient. As these models become more and more advanced, the need for advanced data analysis tools grows. Recently, there has been [...] Read more.

Pharmacometrics is a multidisciplinary field utilizing mathematical models of physiology, pharmacology, and disease to describe and quantify the interactions between medication and patient. As these models become more and more advanced, the need for advanced data analysis tools grows. Recently, there has been much interest in the adoption of machine learning (ML) algorithms. These algorithms offer strong function approximation capabilities and might reduce the time spent on model development. However, ML tools are not yet an integral part of the pharmacometrics workflow. The goal of this work is to discuss how ML algorithms have been applied in four stages of the pharmacometrics pipeline: data preparation, hypothesis generation, predictive modelling, and model validation. We will also discuss considerations before the use of ML algorithms with respect to each topic. We conclude by summarizing applications that hold potential for adoption by pharmacometricians. Full article

(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)

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31 pages, 1481 KiB

Open AccessEditor’s ChoiceReview

How to Treat Melanoma? The Current Status of Innovative Nanotechnological Strategies and the Role of Minimally Invasive Approaches like PTT and PDT

by Joana Lopes, Cecília M. P. Rodrigues, Maria Manuela Gaspar and Catarina Pinto Reis

Pharmaceutics 2022, 14(9), 1817; https://doi.org/10.3390/pharmaceutics14091817 - 29 Aug 2022

Cited by 26 | Viewed by 4325

Abstract

Melanoma is the most aggressive type of skin cancer, the incidence and mortality of which are increasing worldwide. Its extensive degree of heterogeneity has limited its response to existing therapies. For many years the therapeutic strategies were limited to surgery, radiotherapy, and chemotherapy. [...] Read more.

Melanoma is the most aggressive type of skin cancer, the incidence and mortality of which are increasing worldwide. Its extensive degree of heterogeneity has limited its response to existing therapies. For many years the therapeutic strategies were limited to surgery, radiotherapy, and chemotherapy. Fortunately, advances in knowledge have allowed the development of new therapeutic strategies. Despite the undoubted progress, alternative therapies are still under research. In this context, nanotechnology is also positioned as a strong and promising tool to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve photothermal and photodynamic therapies outcomes. This review describes the latest advances in nanotechnology field in the treatment of melanoma from 2011 to 2022. The challenges in the translation of nanotechnology-based therapies to clinical applications are also discussed. To sum up, great progress has been made in the field of nanotechnology-based therapies, and our understanding in this field has greatly improved. Although few therapies based on nanoparticulate systems have advanced to clinical trials, it is expected that a large number will come into clinical use in the near future. With its high sensitivity, specificity, and multiplexed measurement capacity, it provides great opportunities to improve melanoma treatment, which will ultimately lead to enhanced patient survival rates. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Photothermal and Photodynamic Therapy)

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40 pages, 5626 KiB

Open AccessEditor’s ChoiceReview

Fluoroquinolones Hybrid Molecules as Promising Antibacterial Agents in the Fight against Antibacterial Resistance

by Ioana-Andreea Lungu, Octavia-Laura Moldovan, Victoria Biriș and Aura Rusu

Pharmaceutics 2022, 14(8), 1749; https://doi.org/10.3390/pharmaceutics14081749 - 22 Aug 2022

Cited by 62 | Viewed by 8735

Abstract

The emergence of bacterial resistance has motivated researchers to discover new antibacterial agents. Nowadays, fluoroquinolones keep their status as one of the essential classes of antibacterial agents. The new generations of fluoroquinolones are valuable therapeutic tools with a spectrum of activity, including Gram-positive, [...] Read more.

The emergence of bacterial resistance has motivated researchers to discover new antibacterial agents. Nowadays, fluoroquinolones keep their status as one of the essential classes of antibacterial agents. The new generations of fluoroquinolones are valuable therapeutic tools with a spectrum of activity, including Gram-positive, Gram-negative, and atypical bacteria. This review article surveys the design of fluoroquinolone hybrids with other antibacterial agents or active compounds and underlines the new hybrids’ antibacterial properties. Antibiotic fluoroquinolone hybrids have several advantages over combined antibiotic therapy. Thus, some challenges related to joining two different molecules are under study. Structurally, the obtained hybrids may contain a cleavable or non-cleavable linker, an essential element for their pharmacokinetic properties and mechanism of action. The design of hybrids seems to provide promising antibacterial agents helpful in the fight against more virulent and resistant strains. These hybrid structures have proven superior antibacterial activity and less susceptibility to bacterial resistance than the component molecules. In addition, fluoroquinolone hybrids have demonstrated other biological effects such as anti-HIV, antifungal, antiplasmodic/antimalarial, and antitumor activity. Many fluoroquinolone hybrids are in various phases of clinical trials, raising hopes that new antibacterial agents will be approved shortly. Full article

(This article belongs to the Special Issue Drug Targeting towards Fighting Pathogen Bacteria)

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36 pages, 15663 KiB

Open AccessEditor’s ChoiceReview

Innovations in Chewable Formulations: The Novelty and Applications of 3D Printing in Drug Product Design

by Lucía Rodríguez-Pombo, Atheer Awad, Abdul W. Basit, Carmen Alvarez-Lorenzo and Alvaro Goyanes

Pharmaceutics 2022, 14(8), 1732; https://doi.org/10.3390/pharmaceutics14081732 - 18 Aug 2022

Cited by 33 | Viewed by 15184

Abstract

Since their introduction, chewable dosage forms have gained traction due to their ability to facilitate swallowing, especially in paediatric, geriatric and dysphagia patients. Their benefits stretch beyond human use to also include veterinary applications, improving administration and palatability in different animal species. Despite [...] Read more.

Since their introduction, chewable dosage forms have gained traction due to their ability to facilitate swallowing, especially in paediatric, geriatric and dysphagia patients. Their benefits stretch beyond human use to also include veterinary applications, improving administration and palatability in different animal species. Despite their advantages, current chewable formulations do not account for individualised dosing and palatability preferences. In light of this, three-dimensional (3D) printing, and in particular the semi-solid extrusion technology, has been suggested as a novel manufacturing method for producing customised chewable dosage forms. This advanced approach offers flexibility for selecting patient-specific doses, excipients, and organoleptic properties, which are critical for ensuring efficacy, safety and adherence to the treatment. This review provides an overview of the latest advancements in chewable dosage forms for human and veterinary use, highlighting the motivations behind their use and covering formulation considerations, as well as regulatory aspects. Full article

(This article belongs to the Special Issue New Pharmaceutical Applications through 3D Printing Processes)

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28 pages, 3970 KiB

Open AccessEditor’s ChoiceReview

Beyond Formulation: Contributions of Nanotechnology for Translation of Anticancer Natural Products into New Drugs

by Rodrigo dos A. Miguel, Amanda S. Hirata, Paula C. Jimenez, Luciana B. Lopes and Leticia V. Costa-Lotufo

Pharmaceutics 2022, 14(8), 1722; https://doi.org/10.3390/pharmaceutics14081722 - 17 Aug 2022

Cited by 33 | Viewed by 4740

Abstract

Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, [...] Read more.

Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, which is quite curious since the research and development (R&D) course of nanoformulations are even more expensive and prone to failure than the conventional ones. Nonetheless, nanosystems are cost-effective and represent both novel and safer dosage forms with fewer side effects due to modification of pharmacokinetic properties and tissue targeting. In addition, nanotechnology-based drugs can contribute to dose modulation, reversion of multidrug resistance, and protection from degradation and early clearance; can influence the mechanism of action; and can enable drug administration by alternative routes and co-encapsulation of multiple active agents for combined chemotherapy. In this review, we discuss the contribution of nanotechnology as an enabling technology taking the clinical use of DOX and PTX as examples. We also present other nanoformulations approved for clinical practice containing different anticancer natural-product-derived drugs. Full article

(This article belongs to the Special Issue Recent Advances in Natural Product Drugs)

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23 pages, 1128 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches

by Alexander Batista-Duharte, Fakhri Hassouneh, Pablo Alvarez-Heredia, Alejandra Pera and Rafael Solana

Pharmaceutics 2022, 14(8), 1721; https://doi.org/10.3390/pharmaceutics14081721 - 17 Aug 2022

Cited by 23 | Viewed by 3925

Abstract

In recent years, the use of immune checkpoint inhibitors (ICIs) in combination with approved or experimental vaccines has proven to be a promising approach to improve vaccine immunogenicity and efficacy. This strategy seeks to overcome the immunosuppressive mechanisms associated with the vaccine response, [...] Read more.

In recent years, the use of immune checkpoint inhibitors (ICIs) in combination with approved or experimental vaccines has proven to be a promising approach to improve vaccine immunogenicity and efficacy. This strategy seeks to overcome the immunosuppressive mechanisms associated with the vaccine response, thereby achieving increased immunogenicity and efficacy. Most of the information on the use of ICIs combined with vaccines derives from studies on certain anti-tumor vaccines combined with monoclonal antibodies (mAbs) against either cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1). However, over the past few years, emerging strategies to use new-generation ICIs as molecular adjuvants are paving the way for future advances in vaccine research. Here, we review the current state and future directions of the use of ICIs in experimental and clinical settings, including mAbs and alternative new approaches using antisense oligonucleotides (ASOs), small non-coding RNAs, aptamers, peptides, and other small molecules for improving vaccine efficacy. The scope of this review mainly includes the use of ICIs in therapeutic antitumor vaccines, although recent research on anti-infective vaccines will also be addressed. Full article

(This article belongs to the Special Issue Design and Evaluation of Molecular Adjuvants for Human and Veterinary Vaccines)

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22 pages, 1817 KiB

Open AccessEditor’s ChoiceReview

Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases

by Jacob Helm, Ludger Schöls and Stefan Hauser

Pharmaceutics 2022, 14(8), 1708; https://doi.org/10.3390/pharmaceutics14081708 - 16 Aug 2022

Cited by 21 | Viewed by 5560

Abstract

Antisense oligonucleotides (ASOs) are single-stranded nucleic acid strings that can be used to selectively modify protein synthesis by binding complementary (pre-)mRNA sequences. By specific arrangements of DNA and RNA into a chain of nucleic acids and additional modifications of the backbone, sugar, and [...] Read more.

Antisense oligonucleotides (ASOs) are single-stranded nucleic acid strings that can be used to selectively modify protein synthesis by binding complementary (pre-)mRNA sequences. By specific arrangements of DNA and RNA into a chain of nucleic acids and additional modifications of the backbone, sugar, and base, the specificity and functionality of the designed ASOs can be adjusted. Thereby cellular uptake, toxicity, and nuclease resistance, as well as binding affinity and specificity to its target (pre-)mRNA, can be modified. Several neurodegenerative diseases are caused by autosomal dominant toxic gain-of-function mutations, which lead to toxic protein products driving disease progression. ASOs targeting such mutations—or even more comprehensively, associated variants, such as single nucleotide polymorphisms (SNPs)—promise a selective degradation of the mutant (pre-)mRNA while sparing the wild type allele. By this approach, protein expression from the wild type strand is preserved, and side effects from an unselective knockdown of both alleles can be prevented. This makes allele-specific targeting strategies a focus for future personalized therapies. Here, we provide an overview of current strategies to develop personalized, allele-specific ASO therapies for the treatment of neurodegenerative diseases, such Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3/MJD). Full article

(This article belongs to the Special Issue Oligonucleotides and Nucleic-Acid-Based Strategies to Address Therapeutic Challenges: From the Bench to the Bedside)

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14 pages, 2888 KiB

Open AccessEditor’s ChoiceArticle

Efficient Delivery of DNA Using Lipid Nanoparticles

by Lishan Cui, Serena Renzi, Erica Quagliarini, Luca Digiacomo, Heinz Amenitsch, Laura Masuelli, Roberto Bei, Gianmarco Ferri, Francesco Cardarelli, Junbiao Wang, Augusto Amici, Daniela Pozzi, Cristina Marchini and Giulio Caracciolo

Pharmaceutics 2022, 14(8), 1698; https://doi.org/10.3390/pharmaceutics14081698 - 15 Aug 2022

Cited by 30 | Viewed by 8398

Abstract

DNA vaccination has been extensively studied as a promising strategy for tumor treatment. Despite the efforts, the therapeutic efficacy of DNA vaccines has been limited by their intrinsic poor cellular internalization. Electroporation, which is based on the application of a controlled electric field [...] Read more.

DNA vaccination has been extensively studied as a promising strategy for tumor treatment. Despite the efforts, the therapeutic efficacy of DNA vaccines has been limited by their intrinsic poor cellular internalization. Electroporation, which is based on the application of a controlled electric field to enhance DNA penetration into cells, has been the method of choice to produce acceptable levels of gene transfer in vivo. However, this method may cause cell damage or rupture, non-specific targeting, and even degradation of pDNA. Skin irritation, muscle contractions, pain, alterations in skin structure, and irreversible cell damage have been frequently reported. To overcome these limitations, in this work, we use a microfluidic platform to generate DNA-loaded lipid nanoparticles (LNPs) which are then characterized by a combination of dynamic light scattering (DLS), synchrotron small-angle X-ray scattering (SAXS), and transmission electron microscopy (TEM). Despite the clinical successes obtained by LNPs for mRNA and siRNA delivery, little is known about LNPs encapsulating bulkier DNA molecules, the clinical application of which remains challenging. For in vitro screening, LNPs were administered to human embryonic kidney 293 (HEK-293) and Chinese hamster ovary (CHO) cell lines and ranked for their transfection efficiency (TE) and cytotoxicity. The LNP formulation exhibiting the highest TE and the lowest cytotoxicity was then tested for the delivery of the DNA vaccine pVAX-hECTM targeting the human neoantigen HER2, an oncoprotein overexpressed in several cancer types. Using fluorescence-activated cell sorting (FACS), immunofluorescence assays and fluorescence confocal microscopy (FCS), we proved that pVAX-hECTM-loaded LNPs produce massive expression of the HER2 antigen on the cell membrane of HEK-293 cells. Our results provide new insights into the structure–activity relationship of DNA-loaded LNPs and pave the way for the access of this gene delivery technology to preclinical studies. Full article

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

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22 pages, 2762 KiB

Open AccessEditor’s ChoiceReview

Alternative Antibiotics in Dentistry: Antimicrobial Peptides

by Alexandra Griffith, Akilah Mateen, Kenneth Markowitz, Steven R. Singer, Carla Cugini, Emi Shimizu, Gregory R. Wiedman and Vivek Kumar

Pharmaceutics 2022, 14(8), 1679; https://doi.org/10.3390/pharmaceutics14081679 - 12 Aug 2022

Cited by 24 | Viewed by 4719

Abstract

The rise of antibiotic resistant bacteria due to overuse and misuse of antibiotics in medicine and dentistry is a growing concern. New approaches are needed to combat antibiotic resistant (AR) bacterial infections. There are a number of methods available and in development to [...] Read more.

The rise of antibiotic resistant bacteria due to overuse and misuse of antibiotics in medicine and dentistry is a growing concern. New approaches are needed to combat antibiotic resistant (AR) bacterial infections. There are a number of methods available and in development to address AR infections. Dentists conventionally use chemicals such as chlorohexidine and calcium hydroxide to kill oral bacteria, with many groups recently developing more biocompatible antimicrobial peptides (AMPs) for use in the oral cavity. AMPs are promising candidates in the treatment of (oral) infections. Also known as host defense peptides, AMPs have been isolated from animals across all kingdoms of life and play an integral role in the innate immunity of both prokaryotic and eukaryotic organisms by responding to pathogens. Despite progress over the last four decades, there are only a few AMPs approved for clinical use. This review summarizes an Introduction to Oral Microbiome and Oral Infections, Traditional Antibiotics and Alternatives & Antimicrobial Peptides. There is a focus on cationic AMP characteristics and mechanisms of actions, and an overview of animal-derived natural and synthetic AMPs, as well as observed microbial resistance. Full article

(This article belongs to the Special Issue Biomaterials and Agents: Pharmaceutical and Biomedical Applications in Dental Research)

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19 pages, 1417 KiB

Open AccessEditor’s ChoiceArticle

Zinc(II), Palladium(II), and Metal-Free Phthalocyanines Bearing Nipagin-Functionalized Substituents against Candida auris and Selected Multidrug-Resistant Microbes

by Daniel Ziental, Dariusz T. Mlynarczyk, Emil Kolasinski, Emre Güzel, Jolanta Dlugaszewska, Łukasz Popenda, Stefan Jurga, Tomasz Goslinski and Lukasz Sobotta

Pharmaceutics 2022, 14(8), 1686; https://doi.org/10.3390/pharmaceutics14081686 - 12 Aug 2022

Cited by 17 | Viewed by 3214

Abstract

Due to the rapidly increasing problem of antibiotic resistance in recent years, the use of phthalocyanines as photosensitizers with their superior properties in photodynamic antimicrobial therapy (PACT) applications has become important. In this study, magnesium(II) 1,4,8,11,15,18,22,25-octakis(4-[4-butoxycarbonylphenoxy]butyloxy)phthalocyanine was used in the demetalation reaction in [...] Read more.

Due to the rapidly increasing problem of antibiotic resistance in recent years, the use of phthalocyanines as photosensitizers with their superior properties in photodynamic antimicrobial therapy (PACT) applications has become important. In this study, magnesium(II) 1,4,8,11,15,18,22,25-octakis(4-[4-butoxycarbonylphenoxy]butyloxy)phthalocyanine was used in the demetalation reaction in trifluoroacetic acid, and subsequently subjected to metalation reaction in dimethylformamide with zinc(II) acetate and bis(benzonitrile)palladium(II) chloride towards zinc(II) and palladium(II) derivatives. Three phthalocyanines, including a demetalated one as well as two metalated, in the core with zinc(II) and palladium(II) were characterized using 1D and 2D NMR spectroscopy and mass spectrometry. In addition, all macrocycles were subjected to absorption and emission studies as well as photostability tests. In a photochemical study, zinc(II) and palladium(II) phthalocyanine complexes appeared to be efficient singlet oxygen generators. There were noted quantum yields of singlet oxygen generation for zinc(II) phthalocyanine derivative in DMF and DMSO at 0.55 and 0.72, whereas for palladium(II) complex at 0.73 and 0.77, respectively. Liposomal formulations of phthalocyanine derivatives were prepared, and their activity was evaluated against a broad spectrum of antibiotic-resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (ESBL+), Candida albicans resistant to fluconazole, C. auris, and against dermatophytes. Phthalocyanine palladium(II) complex showed the highest bactericidal activity against all antibiotic-resistant microorganisms, including reducing C. auris growth at 3.54 log. Full article

(This article belongs to the Special Issue Antimicrobial Sonodynamic and Photodynamic Therapies)

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36 pages, 9740 KiB

Open AccessEditor’s ChoiceReview

Honey: An Advanced Antimicrobial and Wound Healing Biomaterial for Tissue Engineering Applications

by Joel Yupanqui Mieles, Cian Vyas, Enes Aslan, Gavin Humphreys, Carl Diver and Paulo Bartolo

Pharmaceutics 2022, 14(8), 1663; https://doi.org/10.3390/pharmaceutics14081663 - 10 Aug 2022

Cited by 69 | Viewed by 14112

Abstract

Honey was used in traditional medicine to treat wounds until the advent of modern medicine. The rising global antibiotic resistance has forced the development of novel therapies as alternatives to combat infections. Consequently, honey is experiencing a resurgence in evaluation for antimicrobial and [...] Read more.

Honey was used in traditional medicine to treat wounds until the advent of modern medicine. The rising global antibiotic resistance has forced the development of novel therapies as alternatives to combat infections. Consequently, honey is experiencing a resurgence in evaluation for antimicrobial and wound healing applications. A range of both Gram-positive and Gram-negative bacteria, including antibiotic-resistant strains and biofilms, are inhibited by honey. Furthermore, susceptibility to antibiotics can be restored when used synergistically with honey. Honey’s antimicrobial activity also includes antifungal and antiviral properties, and in most varieties of honey, its activity is attributed to the enzymatic generation of hydrogen peroxide, a reactive oxygen species. Non-peroxide factors include low water activity, acidity, phenolic content, defensin-1, and methylglyoxal (Leptospermum honeys). Honey has also been widely explored as a tissue-regenerative agent. It can contribute to all stages of wound healing, and thus has been used in direct application and in dressings. The difficulty of the sustained delivery of honey’s active ingredients to the wound site has driven the development of tissue engineering approaches (e.g., electrospinning and hydrogels). This review presents the most in-depth and up-to-date comprehensive overview of honey’s antimicrobial and wound healing properties, commercial and medical uses, and its growing experimental use in tissue-engineered scaffolds. Full article

(This article belongs to the Special Issue Biomaterials in Skin Wound Healing and Tissue Regenerations Volume II)

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24 pages, 5454 KiB

Open AccessEditor’s ChoiceArticle

Fabrication and Preliminary In Vitro Evaluation of 3D-Printed Alginate Films with Cannabidiol (CBD) and Cannabigerol (CBG) Nanoparticles for Potential Wound-Healing Applications

by Paraskevi Kyriaki Monou, Anastasia Maria Mamaligka, Emmanuil K. Tzimtzimis, Dimitrios Tzetzis, Souzan Vergkizi-Nikolakaki, Ioannis S. Vizirianakis, Eleftherios G. Andriotis, Georgios K. Eleftheriadis and Dimitrios G. Fatouros

Pharmaceutics 2022, 14(8), 1637; https://doi.org/10.3390/pharmaceutics14081637 - 5 Aug 2022

Cited by 34 | Viewed by 4594

Abstract

In this study, drug carrier nanoparticles comprised of Pluronic-F127 and cannabidiol (CBD) or cannabigerol (CBG) were developed, and their wound healing action was studied. They were further incorporated in 3D printed films based on sodium alginate. The prepared films were characterized morphologically and [...] Read more.

In this study, drug carrier nanoparticles comprised of Pluronic-F127 and cannabidiol (CBD) or cannabigerol (CBG) were developed, and their wound healing action was studied. They were further incorporated in 3D printed films based on sodium alginate. The prepared films were characterized morphologically and physicochemically and used to evaluate the drug release profiles of the nanoparticles. Additional studies on their water loss rate, water retention capacity, and 3D-printing shape fidelity were performed. Nanoparticles were characterized physicochemically and for their drug loading performance. They were further assessed for their cytotoxicity (MTT Assay) and wound healing action (Cell Scratch Assay). The in vitro wound-healing study showed that the nanoparticles successfully enhanced wound healing in the first 6 h of application, but in the following 6 h they had an adverse effect. MTT assay studies revealed that in the first 24 h, a concentration of 0.1 mg/mL nanoparticles resulted in satisfactory cell viability, whereas CBG nanoparticles were safe even at 48 h. However, in higher concentrations and after a threshold of 24 h, the cell viability was significantly decreased. The results also presented mono-disperse nano-sized particles with diameters smaller than 200 nm with excellent release profiles and enhanced thermal stability. Their entrapment efficiency and drug loading properties were higher than 97%. The release profiles of the active pharmaceutical ingredients from the films revealed a complete release within 24 h. The fabricated 3D-printed films hold promise for wound healing applications; however, more studies are needed to further elucidate their mechanism of action. Full article

(This article belongs to the Special Issue Printed Pharmaceuticals in Future Healthcare)

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28 pages, 1147 KiB

Open AccessEditor’s ChoiceReview

Orally Dispersible Dosage Forms for Paediatric Use: Current Knowledge and Development of Nanostructure-Based Formulations

by Andreea Cornilă, Sonia Iurian, Ioan Tomuță and Alina Porfire

Pharmaceutics 2022, 14(8), 1621; https://doi.org/10.3390/pharmaceutics14081621 - 3 Aug 2022

Cited by 28 | Viewed by 10574

Abstract

The paediatric population has always suffered from a lack of medicines tailored to their needs, especially in terms of accurate dosage, stability and acceptability. Orodispersible dosage forms have gone through a resurrection as an alternative to liquid formulations or fractioned solid formulations, although [...] Read more.

The paediatric population has always suffered from a lack of medicines tailored to their needs, especially in terms of accurate dosage, stability and acceptability. Orodispersible dosage forms have gone through a resurrection as an alternative to liquid formulations or fractioned solid formulations, although they are still subject to several inconveniences, among which the unpleasant taste and the low oral bioavailability of the API are the most significant hurdles in the way of achieving an optimal drug product. Nanostructures can address these inconveniences through their size and variety, owing to the plethora of materials that can be used in their manufacturing. Through the formation and functionalisation of nanostructures, followed by their inclusion in orodispersible dosage forms, safe, stable and acceptable medicines intended for paediatric use can be developed. Full article

(This article belongs to the Special Issue Development of Orally Dispersible Dosage Forms)

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18 pages, 5707 KiB

Open AccessEditor’s ChoiceArticle

Biomaterial-Mediated Protein Expression Induced by Peptide-mRNA Nanoparticles Embedded in Lyophilized Collagen Scaffolds

by Rik Oude Egberink, Helen M. Zegelaar, Najoua El Boujnouni, Elly M. M. Versteeg, Willeke F. Daamen and Roland Brock

Pharmaceutics 2022, 14(8), 1619; https://doi.org/10.3390/pharmaceutics14081619 - 2 Aug 2022

Cited by 15 | Viewed by 3736

Abstract

In our aging society, the number of patients suffering from poorly healing bone defects increases. Bone morphogenetic proteins (BMPs) are used in the clinic to promote bone regeneration. However, poor control of BMP delivery and thus activity necessitates high doses, resulting in adverse [...] Read more.

In our aging society, the number of patients suffering from poorly healing bone defects increases. Bone morphogenetic proteins (BMPs) are used in the clinic to promote bone regeneration. However, poor control of BMP delivery and thus activity necessitates high doses, resulting in adverse effects and increased costs. It has been demonstrated that messenger RNA (mRNA) provides a superior alternative to protein delivery due to local uptake and prolonged expression restricted to the site of action. Here, we present the development of porous collagen scaffolds incorporating peptide-mRNA nanoparticles (NPs). Nanoparticles were generated by simply mixing aqueous solutions of the cationic cell-penetrating peptide PepFect14 (PF14) and mRNA. Peptide-mRNA complexes were uniformly distributed throughout the scaffolds, and matrices fully preserved cell attachment and viability. There was a clear dependence of protein expression on the incorporated amount of mRNA. Importantly, after lyophilization, the mRNA formulation in the collagen scaffolds retained activity also at 4 °C over two weeks. Overall, our results demonstrate that collagen scaffolds incorporating peptide-mRNA complexes hold promise as off-the-shelf functional biomaterials for applications in regenerative medicine and constitute a viable alternative to lipid-based mRNA formulations. Full article

(This article belongs to the Special Issue Tissue Engineered Biomaterials and Drug Delivery Systems)

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38 pages, 1674 KiB

Open AccessEditor’s ChoiceReview

Lentiviral Vectors for Ocular Gene Therapy

by Yvan Arsenijevic, Adeline Berger, Florian Udry and Corinne Kostic

Pharmaceutics 2022, 14(8), 1605; https://doi.org/10.3390/pharmaceutics14081605 - 31 Jul 2022

Cited by 33 | Viewed by 5591

Abstract

This review offers the basics of lentiviral vector technologies, their advantages and pitfalls, and an overview of their use in the field of ophthalmology. First, the description of the global challenges encountered to develop safe and efficient lentiviral recombinant vectors for clinical application [...] Read more.

This review offers the basics of lentiviral vector technologies, their advantages and pitfalls, and an overview of their use in the field of ophthalmology. First, the description of the global challenges encountered to develop safe and efficient lentiviral recombinant vectors for clinical application is provided. The risks and the measures taken to minimize secondary effects as well as new strategies using these vectors are also discussed. This review then focuses on lentiviral vectors specifically designed for ocular therapy and goes over preclinical and clinical studies describing their safety and efficacy. A therapeutic approach using lentiviral vector-mediated gene therapy is currently being developed for many ocular diseases, e.g., aged-related macular degeneration, retinopathy of prematurity, inherited retinal dystrophies (Leber congenital amaurosis type 2, Stargardt disease, Usher syndrome), glaucoma, and corneal fibrosis or engraftment rejection. In summary, this review shows how lentiviral vectors offer an interesting alternative for gene therapy in all ocular compartments. Full article

(This article belongs to the Special Issue Drug Delivery in Ophthalmology)

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21 pages, 45400 KiB

Open AccessEditor’s ChoiceArticle

Influence of the Binder Jetting Process Parameters and Binder Liquid Composition on the Relevant Attributes of 3D-Printed Tablets

by Klemen Kreft, Zoran Lavrič, Tijana Stanić, Petra Perhavec and Rok Dreu

Pharmaceutics 2022, 14(8), 1568; https://doi.org/10.3390/pharmaceutics14081568 - 28 Jul 2022

Cited by 19 | Viewed by 4645

Abstract

Binder jetting has the potential to revolutionize the way we produce medicine. However, tablets produced by binder jetting technology can be quite fragile and hard to handle. In this study, the printing process and ink composition were examined to optimize the mechanical properties [...] Read more.

Binder jetting has the potential to revolutionize the way we produce medicine. However, tablets produced by binder jetting technology can be quite fragile and hard to handle. In this study, the printing process and ink composition were examined to optimize the mechanical properties of tablets. A model formulation containing the ketoprofen drug was developed and used as a base for optimization. Firstly, important printing parameters were identified with a fractional factorial design. Saturation and layer height critically influenced selected tablet properties. Relevant process parameters were optimized for tablet mechanical strength by using the D-optimization DoE approach. The best mechanical properties were achieved when saturation was set to 1 and layer height to 150 µm. On the other hand, binder ink composition did not appear to impact tablet mechanical strength as much as process parameters did. Three ethanol-water mixtures were tested at three tablet strength levels and no definitive conclusions could be drawn. The binder jetting process can be wasteful, especially if the unbound powder cannot be reused. To determine the suitability of powder blend recycling, the ketoprofen content was measured for 27 subsequent batches of tablets. While the trendline did indicate a slight reduction in ketoprofen content, the powder blend reuse can nevertheless be employed. Full article

(This article belongs to the Special Issue 3D Printing Technology for Pharmaceutical and Biomedical Application)

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19 pages, 3641 KiB

Open AccessEditor’s ChoiceArticle

mRNA-Loaded Lipid Nanoparticles Targeting Dendritic Cells for Cancer Immunotherapy

by Kosuke Sasaki, Yusuke Sato, Kento Okuda, Kazuki Iwakawa and Hideyoshi Harashima

Pharmaceutics 2022, 14(8), 1572; https://doi.org/10.3390/pharmaceutics14081572 - 28 Jul 2022

Cited by 47 | Viewed by 7554

Abstract

Dendritic cells (DCs) are attractive antigen-presenting cells to be targeted for vaccinations. However, the systemic delivery of mRNA to DCs is hampered by technical challenges. We recently reported that it is possible to regulate the size of RNA-loaded lipid nanoparticles (LNPs) to over [...] Read more.

Dendritic cells (DCs) are attractive antigen-presenting cells to be targeted for vaccinations. However, the systemic delivery of mRNA to DCs is hampered by technical challenges. We recently reported that it is possible to regulate the size of RNA-loaded lipid nanoparticles (LNPs) to over 200 nm with the addition of salt during their formation when a microfluidic device is used and that larger LNPs delivered RNA more efficiently and in greater numbers to splenic DCs compared to the smaller counterparts. In this study, we report on the in vivo optimization of mRNA-loaded LNPs for use in vaccines. The screening included a wide range of methods for controlling particle size in addition to the selection of an appropriate lipid type and its composition. The results showed a clear correlation between particle size, uptake and gene expression activity in splenic DCs and indicated that a size range from 200 to 500 nm is appropriate for use in targeting splenic DCs. It was also found that it was difficult to predict the transgene expression activity and the potency of mRNA vaccines in splenic DCs using the whole spleen. A-11-LNP, which was found to be the optimal formulation, induced better transgene expression activity and maturation in DCs and induced clear therapeutic antitumor effects in an E.G7-OVA tumor model compared to two clinically relevant LNP formulations. Full article

(This article belongs to the Special Issue Application of Nanomedicine in Immunotherapy: Recent Advances and Prospects)

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