Pharmaceutics

17 pages, 4849 KiB

Open AccessEditor’s ChoiceArticle

Solid Lipid Nanoparticles Loaded with Dexamethasone Palmitate for Pulmonary Inflammation Treatment by Nebulization Approach

by Hsin-Hung Chen, Chen-Hsiang Sang, Chang-Wei Chou, Yi-Ting Lin, Yi-Shou Chang and Hsin-Cheng Chiu

Pharmaceutics 2024, 16(7), 878; https://doi.org/10.3390/pharmaceutics16070878 - 29 Jun 2024

Viewed by 1372

Abstract

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this [...] Read more.

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this issue, the current study introduces solid lipid nanoparticles encapsulating hydrophobic dexamethasone palmitate (DXMS-Pal-SLNs) as an anti-inflammatory nanoplatform to treat pneumonia. The specialized nanoparticle formulation is characterized by high drug loading efficiency, low drug leakage and excellent colloidal stability in particular during nebulization and is proficiently designed to target alveolar macrophages in deep lung regions via local delivery with the nebulization administration. In vitro analyses revealed substantial reductions in the secretions of tumor necrosis factor-α and interleukin-6 from alveolar macrophages, highlighting the potential efficacy of DXMS-Pal-SLNs in alleviating pneumonia-related inflammation. Similarly, in vivo experiments showed a significant reduction in the levels of these cytokines in the lungs of mice experiencing lipopolysaccharide-induced pulmonary inflammation after the administration of DXMS-Pal-SLNs via nebulization. Furthermore, the study demonstrated that DXMS-Pal-SLNs effectively control acute infections without causing pulmonary infiltration or excessive recruitment of immunocytes in lung tissues. These findings highlight the potential of nebulized DXMS-Pal-SLNs as a promising therapeutic strategy for mitigating pneumonia-related inflammations. Full article

(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation)

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29 pages, 1354 KiB

Open AccessEditor’s ChoiceReview

Gene Therapy with Chitosan Nanoparticles: Modern Formulation Strategies for Enhancing Cancer Cell Transfection

by Varvara Antoniou, Elena A. Mourelatou, Eleftheria Galatou, Konstantinos Avgoustakis and Sophia Hatziantoniou

Pharmaceutics 2024, 16(7), 868; https://doi.org/10.3390/pharmaceutics16070868 - 27 Jun 2024

Cited by 2 | Viewed by 1079

Abstract

Gene therapy involves the introduction of exogenous genetic material into host tissues to modify gene expression or cellular properties for therapeutic purposes. Initially developed to address genetic disorders, gene therapy has expanded to encompass a wide range of conditions, notably cancer. Effective delivery [...] Read more.

Gene therapy involves the introduction of exogenous genetic material into host tissues to modify gene expression or cellular properties for therapeutic purposes. Initially developed to address genetic disorders, gene therapy has expanded to encompass a wide range of conditions, notably cancer. Effective delivery of nucleic acids into target cells relies on carriers, with non-viral systems gaining prominence due to their enhanced safety profile compared to viral vectors. Chitosan, a biopolymer, is frequently utilized to fabricate nanoparticles for various biomedical applications, particularly nucleic acid delivery, with recent emphasis on targeting cancer cells. Chitosan’s positively charged amino groups enable the formation of stable nanocomplexes with nucleic acids and facilitate interaction with cell membranes, thereby promoting cellular uptake. Despite these advantages, chitosan-based nanoparticles face challenges such as poor solubility at physiological pH, non-specificity for cancer cells, and inefficient endosomal escape, limiting their transfection efficiency. To address these limitations, researchers have focused on enhancing the functionality of chitosan nanoparticles. Strategies include improving stability, enhancing targeting specificity, increasing cellular uptake efficiency, and promoting endosomal escape. This review critically evaluates recent formulation approaches within these categories, aiming to provide insights into advancing chitosan-based gene delivery systems for improved efficacy, particularly in cancer therapy. Full article

(This article belongs to the Special Issue Cancer Gene Therapy with Non-Viral Nanocarriers, 2nd Edition)

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10 pages, 2992 KiB

Open AccessEditor’s ChoiceArticle

Histological Assessment of Respiratory Tract and Liver of BALB/c Mice Nebulized with Tocilizumab

by Paloma Jimena de Andres, Sergio Ferreiro, Angela Flores, Almudena Garcia and Cesar Henriquez-Camacho

Pharmaceutics 2024, 16(7), 862; https://doi.org/10.3390/pharmaceutics16070862 - 27 Jun 2024

Viewed by 822

Abstract

Pulmonary drug delivery offers a minimally invasive and efficient method for treating lung conditions, leveraging the lungs’ extensive surface area and blood flow for rapid drug absorption. Nebulized therapies aim to deliver drugs directly to the lung tissue. This study investigates the histological [...] Read more.

Pulmonary drug delivery offers a minimally invasive and efficient method for treating lung conditions, leveraging the lungs’ extensive surface area and blood flow for rapid drug absorption. Nebulized therapies aim to deliver drugs directly to the lung tissue. This study investigates the histological impact of nebulized tocilizumab—a monoclonal antibody targeting IL-6, traditionally administered intravenously for rheumatoid arthritis and severe COVID-19—on a murine model. Thirty BALB/c mice were nebulized with tocilizumab (10 mg, 5 mg, and 2.5 mg) and six controls were nebulized with saline solution. They were euthanized 48 h later, and their organs (lungs, nasal mucosa, and liver) were analyzed by a microscopic histological evaluation. The results indicate that all the mice survived the 48 h post-nebulization period without systemic compromise. The macroscopic examination showed no abnormalities, and the histopathological analysis revealed greater lung vascular changes in the control group than in the nebulized animals, which is attributable to the euthanasia with carbon dioxide. Additionally, increased alveolar macrophages were observed in the nebulized groups compared to controls. No significant histological changes were observed in the liver, indicating the safety of nebulized tocilizumab. In conclusion, these findings suggest the potential of nebulized tocilizumab for treating pulmonary inflammation, warranting further research to establish its efficacy and safety in clinical settings. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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17 pages, 5659 KiB

Open AccessEditor’s ChoiceArticle

Antimicrobial Peptide Screening for Designing Custom Bactericidal Hydrogels

by Matthias Recktenwald, Muskanjot Kaur, Mohammed M. Benmassaoud, Aryanna Copling, Tulika Khanna, Michael Curry, Dennise Cortes, Gilbert Fleischer, Valerie J. Carabetta and Sebastián L. Vega

Pharmaceutics 2024, 16(7), 860; https://doi.org/10.3390/pharmaceutics16070860 - 27 Jun 2024

Viewed by 1206

Abstract

Staphylococcus aureus (S. aureus) is an opportunistic pathogen that lives on surfaces and skin and can cause serious infections inside the body. Antimicrobial peptides (AMPs) are part of the innate immune system and can eliminate pathogens, including bacteria and viruses, and [...] Read more.

Staphylococcus aureus (S. aureus) is an opportunistic pathogen that lives on surfaces and skin and can cause serious infections inside the body. Antimicrobial peptides (AMPs) are part of the innate immune system and can eliminate pathogens, including bacteria and viruses, and are a promising alternative to antibiotics. Although studies have reported that AMP-functionalized hydrogels can prevent bacterial adhesion and biofilm formation, AMP dosing and the combined effects of multiple AMPs are not well understood. Here, three AMPs with different antibacterial properties were synthesized and the soluble minimum inhibitory concentrations (MICs) of each AMP against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) were determined. Hydrogels with immobilized AMPs at their MIC (DD₁₃-RIP 27.5 µM; indolicidin 43.8 µM; P10 120 µM) were effective in preventing MRSA adhesion and biofilm formation. Checkerboard AMP screens identified synergy between indolicidin (3.1 µM) and P10 (12.5 µM) based on soluble fractional inhibitory concentration indices (FICIs) against MRSA, and hydrogels formed with these AMPs at half of their synergistic concentrations (total peptide concentration, 7.8 µM) were highly efficacious in killing MRSA. Mammalian cells cultured atop these hydrogels were highly viable, demonstrating that these AMP hydrogels are biocompatible and selectively eradicate bacteria, based on soluble checkerboard-screening data. Full article

(This article belongs to the Special Issue Recent Advances in the Prevention and Eradication Strategies for Combating Biofilm-Related Infections)

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23 pages, 4798 KiB

Open AccessEditor’s ChoiceArticle

Imiquimod-Loaded Nanosystem for Treatment Human Papillomavirus-Induced Lesions

by Izamara Maocha, Beatriz Rosado, Jéssica Lopes-Nunes, Melanie Lopes, Joana Rolo, Bruno Pires, Eugénia Gallardo, Ana Palmeira-de-Oliveira, José Martinez-de-Oliveira, Rita Palmeira de Oliveira, Rui Medeiros and Carla Cruz

Pharmaceutics 2024, 16(7), 864; https://doi.org/10.3390/pharmaceutics16070864 - 27 Jun 2024

Cited by 2 | Viewed by 1148

Abstract

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via [...] Read more.

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via Toll-like receptors 7/8 when formulated in carriers, like nanogels, for topical use. An effective alternative to conventional therapies is the nanoparticle drug delivery system. We studied lipidic nanoparticles with IQ (Lipo IQ) and functionalized them with a DNA aptamer, AT11 (Lipo IQ AT11), to improve the selectivity for cervical cancer cells combined with the efficacy of essential oils. The formulations showed that the physicochemical properties are adequate for vaginal drug delivery and have antimicrobial activity at higher concentrations (with MIC₅₀ starting from 0.625%). The final formulations exhibited cytotoxicity in cancer cells, enhanced by essential oils without affecting healthy cells, resulting in less than 10% cell viability in HeLa cells and over 60% in NHDF cells. Essential oils potentiate Lipo IQ’s effectiveness, while AT11 increases the selectivity for cervical cancer cells. As suggested by the results of the permeation assay, the formulations were internalized by the cancer cells. Overall, the obtained results suggested that the synergistic effect of the essential oils and the nanosystem potentiate the cytotoxic effect of Lipo IQ and that Lipo IQ AT11 promotes selectivity towards cancer cells. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Aptamers as Novel Therapeutics)

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20 pages, 2426 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Polyvinyl Alcohol as Binder during Continuous Twin Screw Wet Granulation

by Phaedra Denduyver, Gudrun Birk, Alessandra Ambruosi, Chris Vervaet and Valérie Vanhoorne

Pharmaceutics 2024, 16(7), 854; https://doi.org/10.3390/pharmaceutics16070854 - 25 Jun 2024

Viewed by 1742

Abstract

Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2–40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during [...] Read more.

Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2–40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during TSWG, but the potential of other PVA grades—differing in polymerization and hydrolysis degree—has not yet been studied. Therefore, the aim of the current study was to evaluate the potential of different PVA grades as a binder during TSWG. The breakage and drying behavior during the fluidized bed drying of drug-loaded granules containing the PVA grades was also studied. Three PVA grades (4-88, 18-88, and 40-88) were characterized and their attributes were compared to previously investigated binders by Vandevivere et al. through principal component analysis. Three binder clusters could be distinguished according to their attributes, whereby each cluster contained a PVA grade and a previously investigated binder. PVA 4-88 was the most effective binder of the PVA grades for both a good water-soluble and water-insoluble formulation. This could be attributed to its high total surface energy, low viscosity, good wettability of hydrophilic and hydrophobic surfaces, and good wettability by water of the binder. Compared to the previously investigated binders, all PVA grades were more effective in the water-insoluble formulation, as they yielded strong granules (friability below 30%) at lower L/S-ratios. This was linked to the high dispersive surface energy of the high-energy sites on the surface of PVA grades and their low surface tension. During fluidized bed drying, PVA grades proved suitable binders, as the acetaminophen (APAP) granules were dried within a short time due to the low L/S-ratio, at which high-quality granules could be produced. In addition, no attrition occurred, and strong tablets were obtained. Based on this study, PVA could be the preferred binder during twin screw granulation due to its high binder effectiveness at a low L/S-ratio, allowing efficient downstream processing. However, process robustness must be controlled by the included excipients, as PVA grades are operating in a narrow L/S-ratio range. Full article

(This article belongs to the Special Issue Impact of Raw Material Properties on Solid Dosage Form Processes)

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21 pages, 3630 KiB

Open AccessEditor’s ChoiceArticle

Investigation of the Electrokinetic Potential of Granules and Optimization of the Pelletization Method Using the Quality by Design Approach

by Azza A. K. Mahmoud, Alharith A. A. Hassan, Dorina Gabriella Dobó, Krisztina Ludasi, László Janovák, Géza Regdon, Jr., Ildikó Csóka and Katalin Kristó

Pharmaceutics 2024, 16(7), 848; https://doi.org/10.3390/pharmaceutics16070848 - 22 Jun 2024

Cited by 1 | Viewed by 3800

Abstract

The preparation of pellets using a high-shear granulator in a rapid single-step is considered a good economic alternative to the extrusion spheronization process. As process parameters and material attributes greatly affect pellet qualities, successful process optimization plays a vital role in producing pellet [...] Read more.

The preparation of pellets using a high-shear granulator in a rapid single-step is considered a good economic alternative to the extrusion spheronization process. As process parameters and material attributes greatly affect pellet qualities, successful process optimization plays a vital role in producing pellet dosage forms with the required critical quality attributes. This study was aimed at the development and optimization of the pelletization technique with the Pro-CepT granulator. According to the quality by design (QbD) and screening design results, chopper speed, the volume of the granulating liquid, binder amount, and impeller speed were selected as the highest risk variables for a two-level full factorial design and central composite design, which were applied to the formula of microcrystalline cellulose, mannitol, and with a binding aqueous polyvinylpyrrolidone solution. The design space was estimated based on physical response results, including the total yield of the required size, hardness, and aspect ratio. The optimized point was tested with two different types of active ingredients. Amlodipine and hydrochlorothiazide were selected as model drugs and were loaded into an optimized formulation. The kinetics of the release of the active agent was examined and found that the results show a correlation with the electrokinetic potential because amlodipine besylate can be adsorbed on the surface of the MCC, while hydrochlorothiazide less so; therefore, in this case, the release of the active agent increases. The research results revealed no significant differences between plain and model drug pellets, except for hydrochlorothiazide yield percent, in addition to acceptable content uniformity and dissolution enhancement. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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46 pages, 3156 KiB

Open AccessEditor’s ChoiceReview

An Overview on the Physiopathology of the Blood–Brain Barrier and the Lipid-Based Nanocarriers for Central Nervous System Delivery

by Francesca Susa, Silvia Arpicco, Candido Fabrizio Pirri and Tania Limongi

Pharmaceutics 2024, 16(7), 849; https://doi.org/10.3390/pharmaceutics16070849 - 22 Jun 2024

Viewed by 1995

Abstract

The state of well-being and health of our body is regulated by the fine osmotic and biochemical balance established between the cells of the different tissues, organs, and systems. Specific districts of the human body are defined, kept in the correct state of [...] Read more.

The state of well-being and health of our body is regulated by the fine osmotic and biochemical balance established between the cells of the different tissues, organs, and systems. Specific districts of the human body are defined, kept in the correct state of functioning, and, therefore, protected from exogenous or endogenous insults of both mechanical, physical, and biological nature by the presence of different barrier systems. In addition to the placental barrier, which even acts as a linker between two different organisms, the mother and the fetus, all human body barriers, including the blood–brain barrier (BBB), blood–retinal barrier, blood–nerve barrier, blood–lymph barrier, and blood–cerebrospinal fluid barrier, operate to maintain the physiological homeostasis within tissues and organs. From a pharmaceutical point of view, the most challenging is undoubtedly the BBB, since its presence notably complicates the treatment of brain disorders. BBB action can impair the delivery of chemical drugs and biopharmaceuticals into the brain, reducing their therapeutic efficacy and/or increasing their unwanted bioaccumulation in the surrounding healthy tissues. Recent nanotechnological innovation provides advanced biomaterials and ad hoc customized engineering and functionalization methods able to assist in brain-targeted drug delivery. In this context, lipid nanocarriers, including both synthetic (liposomes, solid lipid nanoparticles, nanoemulsions, nanostructured lipid carriers, niosomes, proniosomes, and cubosomes) and cell-derived ones (extracellular vesicles and cell membrane-derived nanocarriers), are considered one of the most successful brain delivery systems due to their reasonable biocompatibility and ability to cross the BBB. This review aims to provide a complete and up-to-date point of view on the efficacy of the most varied lipid carriers, whether FDA-approved, involved in clinical trials, or used in in vitro or in vivo studies, for the treatment of inflammatory, cancerous, or infectious brain diseases. Full article

(This article belongs to the Special Issue Nanotechnology-Based Pharmaceutical Treatments)

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32 pages, 7459 KiB

Open AccessEditor’s ChoiceArticle

Polymeric Microneedles Enhance Transdermal Delivery of Therapeutics

by Hiep X. Nguyen, Thomas Kipping and Ajay K. Banga

Pharmaceutics 2024, 16(7), 845; https://doi.org/10.3390/pharmaceutics16070845 - 22 Jun 2024

Viewed by 1983

Abstract

This research presents the efficacy of polymeric microneedles in improving the transdermal permeation of methotrexate across human skin. These microneedles were fabricated from PLGA Expansorb^® 50-2A and 50-8A and subjected to comprehensive characterization via scanning electron microscopy, Fourier-transform infrared spectroscopy, and mechanical [...] Read more.

This research presents the efficacy of polymeric microneedles in improving the transdermal permeation of methotrexate across human skin. These microneedles were fabricated from PLGA Expansorb^® 50-2A and 50-8A and subjected to comprehensive characterization via scanning electron microscopy, Fourier-transform infrared spectroscopy, and mechanical analysis. We developed and assessed a methotrexate hydrogel for physicochemical and rheological properties. Dye binding, histological examinations, and assessments of skin integrity demonstrated the effective microporation of the skin by PLGA microneedles. We measured the dimensions of microchannels in the skin using scanning electron microscopy, pore uniformity analysis, and confocal microscopy. The skin permeation and disposition of methotrexate were researched in vitro. PLGA 50-8A microneedles appeared significantly longer, sharper, and more mechanically uniform than PLGA 50-2A needles. PLGA 50-8A needles generated substantially more microchannels, as well as deeper, larger, and more uniform channels in the skin than PLGA 50-2A needles. Microneedle insertion substantially reduced skin electrical resistance, accompanied by an elevation in transepidermal water loss values. PLGA 50-8A microneedle treatment provided a significantly higher cumulative delivery, flux, diffusion coefficient, permeability coefficient, and predicted steady-state plasma concentration; however, there was a shorter lag time than for PLGA 50-2A needles, base-treated, and untreated groups (p < 0.05). Conclusively, skin microporation using polymeric microneedles significantly improved the transdermal delivery of methotrexate. Full article

(This article belongs to the Special Issue Microarray Patches for Transdermal Drug Delivery)

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13 pages, 3238 KiB

Open AccessEditor’s ChoiceArticle

Derivatization of Hyaluronan to Target Neuroblastoma and Neuroglioma Expressing CD44

by Giau Van Vo, Kummara Madhusudana Rao, Ildoo Chung, Chang-Sik Ha, Seong Soo A. An and Yang H. Yun

Pharmaceutics 2024, 16(6), 836; https://doi.org/10.3390/pharmaceutics16060836 - 20 Jun 2024

Cited by 1 | Viewed by 1272

Abstract

Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to [...] Read more.

Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to be highly overexpressed in many breast cancers and other types of cancer cells. While CD44 has been documented to express low levels in normal adult neurons, astrocytes, and microglia, this receptor may be overexpressed by neuroblastoma and neuroglioma. If differential expression exists between normal and cancerous cells, hyaluronan (HA) could be a useful carrier that targets carcinomas. Thus, HA was conjugated with resveratrol (HA-R), and its efficacy was tested on cortical–neuroblastoma hybrid, neuroblastoma, and neuroglioma cells. Confocal and flow cytometry showed these cells express CD44 and are able to bind and uptake HA-R. The toxicity of HA-R correlated well with CD44 expression in this study. Therefore, conjugating resveratrol and other chemotherapeutics to HA could minimize the side effects for normal cells within the brain and nervous system and could be a viable strategy for developing targeted therapies. Full article

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

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10 pages, 1763 KiB

Open AccessEditor’s ChoiceArticle

The Distinctive Role of Gluconic Acid in Retarding Percutaneous Drug Permeation: Formulation of Lidocaine-Loaded Chitosan Nanoparticles

by Amnon C. Sintov

Pharmaceutics 2024, 16(6), 831; https://doi.org/10.3390/pharmaceutics16060831 - 19 Jun 2024

Viewed by 790

Abstract

The objective of the present investigation was to evidence the skin retardation phenomenon of lidocaine by gluconic acid as an inactive ingredient involved in citrate-crosslinking chitosan nanoparticles. Lidocaine hydrochloride was loaded in nanoparticles based on chitosan, fabricated by using a water-in-oil microemulsion as [...] Read more.

The objective of the present investigation was to evidence the skin retardation phenomenon of lidocaine by gluconic acid as an inactive ingredient involved in citrate-crosslinking chitosan nanoparticles. Lidocaine hydrochloride was loaded in nanoparticles based on chitosan, fabricated by using a water-in-oil microemulsion as a template and citric acid as an ionic cross-linker. Gluconic acid (pentahydroxy hexanoic acid) was added during the fabrication and compared with caproic acid, a non-hydroxy hexanoic acid. The chitosan nanoparticulate systems were characterized for mean particle size, particle size distribution, and zeta potential. The pentahydroxy hexanoic acid decreased the zeta potential to a significantly lower value than those obtained from both plain citrate and citrate–hexanoic acid formulations. The relatively lower value implies that gluconate ions are partly attached to the nanoparticle’s surface and mask its positively charged groups. It was also noted that the in vitro percutaneous permeation flux of lidocaine significantly decreased when gluconate-containing chitosan nanoparticles were applied, i.e., 6.1 ± 1.5 μg‧cm⁻²‧h⁻¹ without gluconic acid to 3.4 ± 2.3 μg‧cm⁻²‧h⁻¹ with gluconic acid. According to this result, it is suggested that gluconate ions played a role in retarding drug permeation through the skin, probably by calcium chelation in the stratum granulosum, which in turn stimulated lamellar body secretion, lipid synthesis, and intracellular release of Ca²⁺ from the endoplasmic reticulum. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition)

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23 pages, 7648 KiB

Open AccessEditor’s ChoiceArticle

Multistage Nanocarrier Based on an Oil Core–Graphene Oxide Shell

by Immacolata Tufano, Raffaele Vecchione, Valeria Panzetta, Edmondo Battista, Costantino Casale, Giorgia Imparato and Paolo Antonio Netti

Pharmaceutics 2024, 16(6), 827; https://doi.org/10.3390/pharmaceutics16060827 - 18 Jun 2024

Viewed by 1081

Abstract

Potent synthetic drugs, as well as biomolecules extracted from plants, have been investigated for their selectivity toward cancer cells. The main limitation in cancer treatment is the ability to bring such molecules within each single cancer cell, which requires accumulation in the peritumoral [...] Read more.

Potent synthetic drugs, as well as biomolecules extracted from plants, have been investigated for their selectivity toward cancer cells. The main limitation in cancer treatment is the ability to bring such molecules within each single cancer cell, which requires accumulation in the peritumoral region followed by homogeneous spreading within the entire tissue. In the last decades, nanotechnology has emerged as a powerful tool due to its ability to protect the drug during blood circulation and allow enhanced accumulation around the leaky regions of the tumor vasculature. However, the ideal size for accumulation of around 100 nm is too large for effective penetration into the dense collagen matrix. Therefore, we propose a multistage system based on graphene oxide nanosheet-based quantum dots (GOQDs) with dimensions that are 12 nm, functionalized with hyaluronic acid (GOQDs-HA), and deposited using the layer-by-layer technique onto an oil-in-water nanoemulsion (O/W NE) template that is around 100 nm in size, previously stabilized by a biodegradable polymer, chitosan. The choice of a biodegradable core for the nanocarrier is to degrade once inside the tumor, thus promoting the release of smaller compounds, GOQDs-HA, carrying the adsorbed anticancer compound, which in this work is represented by curcumin as a model bioactive anticancer molecule. Additionally, modification with HA aims to promote active targeting of stromal and cancer cells. Cell uptake experiments and preliminary penetration experiments in three-dimensional microtissues were performed to assess the proposed multistage nanocarrier. Full article

(This article belongs to the Special Issue Smart Nanocarriers for Drug Delivery in Cancer Therapy)

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20 pages, 2999 KiB

Open AccessEditor’s ChoiceArticle

Acid-Responsive Decomposable Nanomedicine Based on Zeolitic Imidazolate Frameworks for Near-Infrared Fluorescence Imaging/Chemotherapy Combined Tumor Theranostics

by Heze Guo, Vincent Mukwaya, Daikun Wu, Shuhan Xiong and Hongjing Dou

Pharmaceutics 2024, 16(6), 823; https://doi.org/10.3390/pharmaceutics16060823 - 18 Jun 2024

Viewed by 1188

Abstract

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and therapeutic drugs. While typically, similar hydrophilic molecules are encapsulated in either pure aqueous or organic environments, few studies have explored co-encapsulation of [...] Read more.

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and therapeutic drugs. While typically, similar hydrophilic molecules are encapsulated in either pure aqueous or organic environments, few studies have explored co-encapsulation of chemotherapeutic drugs and imaging agents with varying hydrophilicity and, consequently, constructed multifunctional ZIF-8 composite NPs for acid-responsive, near-infrared fluorescence imaging/chemotherapy combined tumor theranostics. Here, we present a one-pot method for the synthesis of uniform Cy5.5&DOX@ZIF-8 nanoparticles in mixed solvents, efficiently achieving simultaneous encapsulation of hydrophilic doxorubicin (DOX) and hydrophobic Cyanine-5.5 (Cy5.5). Surface decoration with dextran (Dex) enhanced colloidal stability and biocompatibility. The method significantly facilitated co-loading of Cy5.5 dyes and DOX drugs, endowing the composite NPs with notable fluorescent imaging capabilities and pH-responsive chemotherapy capacities. In vivo near-infrared fluorescence (NIRF) imaging in A549 tumor-bearing mice demonstrated significant accumulation of Cy5.5 at tumor sites due to enhanced permeability and retention (EPR) effects, with fluorescence intensities approximately 48-fold higher than free Cy5.5. Enhanced therapeutic efficiency was observed in composite NPs compared to free DOX, validating tumor-targeted capability. These findings suggest ZIF-8-based nanomedicines as promising platforms for multifunctional tumor theranostics. Full article

(This article belongs to the Topic Application of Nanomaterials and Nanobiotechnology in Cancer)

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14 pages, 8407 KiB

Open AccessEditor’s ChoiceArticle

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics)

by María José Rodríguez Fernández, Daniel Hernández, Brayan Javier Anaya, Dolores R. Serrano and Juan José Torrado

Pharmaceutics 2024, 16(6), 820; https://doi.org/10.3390/pharmaceutics16060820 - 17 Jun 2024

Viewed by 779

Abstract

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, [...] Read more.

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly (p < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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47 pages, 3150 KiB

Open AccessEditor’s ChoiceReview

Progress in Topical and Transdermal Drug Delivery Research—Focus on Nanoformulations

by Dominique Lunter, Victoria Klang, Adina Eichner, Sanela M. Savic, Snezana Savic, Guoping Lian and Franciska Erdő

Pharmaceutics 2024, 16(6), 817; https://doi.org/10.3390/pharmaceutics16060817 - 16 Jun 2024

Cited by 2 | Viewed by 2947

Abstract

Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The [...] Read more.

Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The skin is involved in body temperature regulation by the storage of fat and water. It is an interesting tissue in regard to the local and transdermal application of active ingredients for prevention or treatment of pathological conditions. Topical and transdermal delivery is an emerging route of drug and cosmetic administration. It is beneficial for avoiding side effects and rapid metabolism. Many pharmaceutical, technological and cosmetic innovations have been described and patented recently in the field. In this review, the main features of skin morphology and physiology are presented and are being followed by the description of classical and novel nanoparticulate dermal and transdermal drug formulations. The biophysical aspects of the penetration of drugs and cosmetics into or across the dermal barrier and their investigation in diffusion chambers, skin-on-a-chip devices, high-throughput measuring systems or with advanced analytical techniques are also shown. The current knowledge about mathematical modeling of skin penetration and the future perspectives are briefly discussed in the end, all also involving nanoparticulated systems. Full article

(This article belongs to the Special Issue Nanoparticles for Local Drug Delivery)

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54 pages, 4234 KiB

Open AccessEditor’s ChoiceReview

Lipid Biomimetic Models as Simple Yet Complex Tools to Predict Skin Permeation and Drug–Membrane Biophysical Interactions

by Eduarda Fernandes, Carla M. Lopes and Marlene Lúcio

Pharmaceutics 2024, 16(6), 807; https://doi.org/10.3390/pharmaceutics16060807 - 14 Jun 2024

Viewed by 929

Abstract

The barrier function of the skin is primarily determined by its outermost layer, the Stratum Corneum (SC). The SC consists of corneocytes embedded in a lipid matrix composed mainly of ceramides, cholesterol, and free fatty acids in equimolar proportions and is organised in [...] Read more.

The barrier function of the skin is primarily determined by its outermost layer, the Stratum Corneum (SC). The SC consists of corneocytes embedded in a lipid matrix composed mainly of ceramides, cholesterol, and free fatty acids in equimolar proportions and is organised in a complex lamellar structure with different periodicities and lateral packings. This matrix provides a diffusion pathway across the SC for bioactive compounds that are administered to the skin. In this regard, and as the skin administration route has grown in popularity, there has been an increase in the use of lipid mixtures that closely resemble the SC lipid matrix, either for a deeper biophysical understanding or for pharmaceutical and cosmetic purposes. This review focuses on a systematic analysis of the main outcomes of using lipid mixtures as SC lipid matrix models for pharmaceutical and cosmetic purposes. Thus, a methodical evaluation of the main outcomes based on the SC structure is performed, as well as the main recent developments in finding suitable new in vitro tools for permeation testing based on lipid models. Full article

(This article belongs to the Topic New Challenges in the Cosmetics Industry)

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17 pages, 2761 KiB

Open AccessEditor’s ChoiceReview

Development, Optimization, and Clinical Relevance of Lactoferrin Delivery Systems: A Focus on Ocular Delivery

by Erika Ponzini, Gloria Astolfi, Rita Grandori, Silvia Tavazzi and Piera Versura

Pharmaceutics 2024, 16(6), 804; https://doi.org/10.3390/pharmaceutics16060804 - 14 Jun 2024

Cited by 1 | Viewed by 1331

Abstract

Lactoferrin (Lf), a multifunctional protein found abundantly in secretions, including tears, plays a crucial role in ocular health through its antimicrobial, immunoregulatory, anti-inflammatory, and antioxidant activities. Advanced delivery systems are desirable to fully leverage its therapeutic potential in treating ocular diseases. The process [...] Read more.

Lactoferrin (Lf), a multifunctional protein found abundantly in secretions, including tears, plays a crucial role in ocular health through its antimicrobial, immunoregulatory, anti-inflammatory, and antioxidant activities. Advanced delivery systems are desirable to fully leverage its therapeutic potential in treating ocular diseases. The process of Lf quantification for diagnostic purposes underscores the importance of developing reliable, cost-effective detection methods, ranging from conventional techniques to advanced nano-based sensors. Despite the ease and non-invasiveness of topical administration for ocular surface diseases, challenges such as rapid drug elimination necessitate innovations, such as Lf-loaded contact lenses and biodegradable polymeric nanocapsules, to enhance drug stability and bioavailability. Furthermore, overcoming ocular barriers for the treatment of posterior segment disease calls for nano-formulations. The scope of this review is to underline the advancements in nanotechnology-based Lf delivery methods, emphasizing the pivotal role of multidisciplinary approaches and cross-field strategies in improving ocular drug delivery and achieving better therapeutic outcomes for a wide spectrum of eye conditions. Full article

(This article belongs to the Special Issue Application Progress of Lactoferrin in Biomedicine)

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21 pages, 4436 KiB

Open AccessEditor’s ChoiceArticle

Benznidazole-Loaded Polymeric Nanoparticles for Oral Chemotherapeutic Treatment of Chagas Disease

by Lucas Resende Dutra Sousa, Thays Helena Chaves Duarte, Viviane Flores Xavier, Aline Coelho das Mercês, Gabriel Maia Vieira, Maximiliano Delany Martins, Cláudia Martins Carneiro, Viviane Martins Rebello dos Santos, Orlando David Henrique dos Santos and Paula Melo de Abreu Vieira

Pharmaceutics 2024, 16(6), 800; https://doi.org/10.3390/pharmaceutics16060800 - 13 Jun 2024

Viewed by 1051

Abstract

Chagas disease (CD) is a worldwide public health problem. Benznidazole (BZ) is the drug used to treat it. However, in its commercial formulation, it has significant side effects and is less effective in the chronic phase of the infection. The development of particulate [...] Read more.

Chagas disease (CD) is a worldwide public health problem. Benznidazole (BZ) is the drug used to treat it. However, in its commercial formulation, it has significant side effects and is less effective in the chronic phase of the infection. The development of particulate systems containing BZ is therefore being promoted. The objective of this investigation was to develop polymeric nanoparticles loaded with BZ and examine their trypanocidal impact in vitro. Two formulas (BNP1 and BNP2) were produced through double emulsification and freeze drying. Subsequent to physicochemical and morphological assessment, both formulations exhibited adequate yield, average particle diameter, and zeta potential for oral administration. Cell viability was assessed in H9C2 and RAW 264.7 cells in vitro, revealing no cytotoxicity in cardiomyocytes or detrimental effects in macrophages at specific concentrations. BNP1 and BNP2 enhanced the effect of BZ within 48 h using a treatment of 3.90 μg/mL. The formulations notably improved NO reduction, particularly BNP2. The findings imply that the compositions are suitable for preclinical research, underscoring their potential as substitutes for treating CD. This study aids the quest for new BZ formulations, which are essential in light of the disregard for the treatment of CD and the unfavorable effects associated with its commercial product. Full article

(This article belongs to the Special Issue Nanoparticles: Technology and Therapeutic Applications in Human Infectious and Parasitic Diseases)

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19 pages, 4927 KiB

Open AccessEditor’s ChoiceArticle

Synthesis of Gd-DTPA Carborane-Containing Compound and Its Immobilization on Iron Oxide Nanoparticles for Potential Application in Neutron Capture Therapy

by Ilya V. Korolkov, Alexander Zaboronok, Kairat A. Izbasar, Zhangali A. Bekbol, Lana I. Lissovskaya, Alexandr V. Zibert, Rafael I. Shakirzyanov, Luiza N. Korganbayeva, Haolan Yang, Eiichi Ishikawa and Maxim V. Zdorovets

Pharmaceutics 2024, 16(6), 797; https://doi.org/10.3390/pharmaceutics16060797 - 12 Jun 2024

Viewed by 1167

Abstract

Cancer is one of the leading causes of global mortality, and its incidence is increasing annually. Neutron capture therapy (NCT) is a unique anticancer modality capable of selectively eliminating tumor cells within normal tissues. The development of accelerator-based, clinically mountable neutron sources has [...] Read more.

Cancer is one of the leading causes of global mortality, and its incidence is increasing annually. Neutron capture therapy (NCT) is a unique anticancer modality capable of selectively eliminating tumor cells within normal tissues. The development of accelerator-based, clinically mountable neutron sources has stimulated a worldwide search for new, more effective compounds for NCT. We synthesized magnetic iron oxide nanoparticles (NPs) that concurrently incorporate boron and gadolinium, potentially enhancing the effectiveness of NCT. These magnetic nanoparticles underwent sequential modifications through silane polycondensation and allylamine graft polymerization, enabling the creation of functional amino groups on their surface. Characterization was performed using Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), energy dispersive X-ray (EDX), dynamic light scattering (DLS), thermal gravimetric analysis (TGA), and transmission electron microscopy (TEM). ICP-AES measurements indicated that boron (B) content in the NPs reached 3.56 ppm/mg, while gadolinium (Gd) averaged 0.26 ppm/mg. Gadolinium desorption was observed within 4 h, with a peak rate of 61.74%. The biocompatibility of the NPs was confirmed through their relatively low cytotoxicity and sufficient cellular tolerability. Using NPs at non-toxic concentrations, we obtained B accumulation of up to 5.724 × 10¹⁰ atoms per cell, sufficient for successful NCT. Although limited by its content in the NP composition, the Gd amount may also contribute to NCT along with its diagnostic properties. Further development of the NPs is ongoing, focusing on increasing the boron and gadolinium content and creating active tumor targeting. Full article

(This article belongs to the Special Issue Development of Novel Tumor-Targeting Nanoparticles, 2nd Edition)

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12 pages, 3160 KiB

Open AccessEditor’s ChoiceReview

Nano-Delivery of Immunogenic Cell Death Inducers and Immune Checkpoint Blockade Agents: Single-Nanostructure Strategies for Enhancing Immunotherapy

by Yujeong Moon, Hanhee Cho and Kwangmeyung Kim

Pharmaceutics 2024, 16(6), 795; https://doi.org/10.3390/pharmaceutics16060795 - 12 Jun 2024

Cited by 3 | Viewed by 1232

Abstract

Cancer immunotherapy has revolutionized oncology by harnessing the patient’s immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically ‘cold’ tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers [...] Read more.

Cancer immunotherapy has revolutionized oncology by harnessing the patient’s immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically ‘cold’ tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers and advanced drug delivery systems represents a promising solution. This review discusses the development and application of various nanocarriers, including polymeric nanoparticles, liposomes, peptide-based nanoparticles, and inorganic nanoparticles, designed to deliver ICD inducers and ICBs effectively. These nanocarriers improve therapeutic outcomes by converting cold tumors into hot tumors, thus enhancing immune responses and reducing systemic toxicity. By focusing on single-nanoparticle systems that co-deliver both ICD inducers and ICBs, this review highlights their potential in achieving higher drug concentrations at tumor sites, improving pharmacokinetics and pharmacodynamics, and facilitating clinical translation. Future research should aim to optimize these nanocarrier systems for better in vivo performance and clinical applications, ultimately advancing cancer immunotherapy. Full article

(This article belongs to the Special Issue Nanomedicines in Cancer Therapy)

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22 pages, 11192 KiB

Open AccessEditor’s ChoiceArticle

Identification and Characterization of Critical Processing Parameters in the Fabrication of Double-Emulsion Poly(lactic-co-glycolic) Acid Microparticles

by Elizabeth R. Bentley, Stacia Subick, Michael Pezzillo, Stephen C. Balmert, Aidan Herbert and Steven R. Little

Pharmaceutics 2024, 16(6), 796; https://doi.org/10.3390/pharmaceutics16060796 - 12 Jun 2024

Viewed by 1849

Abstract

In the past several decades, polymeric microparticles (MPs) have emerged as viable solutions to address the limitations of standard pharmaceuticals and their corresponding delivery methods. While there are many preclinical studies that utilize polymeric MPs as a delivery vehicle, there are limited FDA-approved [...] Read more.

In the past several decades, polymeric microparticles (MPs) have emerged as viable solutions to address the limitations of standard pharmaceuticals and their corresponding delivery methods. While there are many preclinical studies that utilize polymeric MPs as a delivery vehicle, there are limited FDA-approved products. One potential barrier to the clinical translation of these technologies is a lack of understanding with regard to the manufacturing process, hindering batch scale-up. To address this knowledge gap, we sought to first identify critical processing parameters in the manufacturing process of blank (no therapeutic drug) and protein-loaded double-emulsion poly(lactic-co-glycolic) acid MPs through a quality by design approach. We then utilized the design of experiments as a tool to systematically investigate the impact of these parameters on critical quality attributes (e.g., size, surface morphology, release kinetics, inner occlusion size, etc.) of blank and protein-loaded MPs. Our results elucidate that some of the most significant CPPs impacting many CQAs of double-emulsion MPs are those within the primary or single-emulsion process (e.g., inner aqueous phase volume, solvent volume, etc.) and their interactions. Furthermore, our results indicate that microparticle internal structure (e.g., inner occlusion size, interconnectivity, etc.) can heavily influence protein release kinetics from double-emulsion MPs, suggesting it is a crucial CQA to understand. Altogether, this study identifies several important considerations in the manufacturing and characterization of double-emulsion MPs, potentially enhancing their translation. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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14 pages, 2993 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Novel Nasal Mucoadhesive Nanoformulations Containing Lipid-Soluble EGCG for Long COVID Treatment

by Nicolette Frank, Douglas Dickinson, Garrison Lovett, Yutao Liu, Hongfang Yu, Jingwen Cai, Bo Yao, Xiaocui Jiang and Stephen Hsu

Pharmaceutics 2024, 16(6), 791; https://doi.org/10.3390/pharmaceutics16060791 - 11 Jun 2024

Cited by 1 | Viewed by 1491

Abstract

Following recovery from the acute infection stage of the SARS-CoV-2 virus (COVID-19), survivors can experience a wide range of persistent Post-Acute Sequelae of COVID-19 (PASC), also referred to as long COVID. According to the US National Research Action Plan on Long COVID 2022, [...] Read more.

Following recovery from the acute infection stage of the SARS-CoV-2 virus (COVID-19), survivors can experience a wide range of persistent Post-Acute Sequelae of COVID-19 (PASC), also referred to as long COVID. According to the US National Research Action Plan on Long COVID 2022, up to 23.7 million Americans suffer from long COVID, and approximately one million workers may be out of the workforce each day due to these symptoms, leading to a USD 50 billion annual loss of salary. Neurological symptoms associated with long COVID result from persistent infection with SARS-CoV-2 in the nasal neuroepithelial cells, leading to inflammation in the central nervous system (CNS). As of today, there is no evidence that vaccines or medications can clear the persistent viral infection in olfactory mucosa. Recently published clinical data demonstrate that only 5% of long COVID anosmia patients have fully recovered during the past 2 years, and 10.4% of COVID patients are still symptomatic 18 months post-infection. Our group demonstrated that epigallocatechin-3-gallate-monopalmitate (EC16m) nanoformulations possess strong antiviral activity against human coronavirus, suggesting that this green-tea-derived compound in nanoparticle formulations could be developed as an intranasally delivered new drug targeting the persistent SARS-CoV-2 infection, as well as inflammation and oxidative stress in the CNS, leading to restoration of neurologic functions. The objective of the current study was to evaluate the mucociliary safety of the EC16m nasal nanoformulations and their efficacy against human coronavirus. Methods: Nanoparticle size and Zeta potential were measured using the ZetaView Nanoparticle Tracking Analysis system; mucociliary safety was determined using the MucilAir human nasal model; contact antiviral activity and post-infection inhibition against the OC43 viral strain were assessed by the TCID50 assay for cytopathic effect on MRC-5 cells. Results: The saline-based EC16 mucoadhesive nanoformulations containing 0.005 to 0.02% w/v EC16m have no significant difference compared to saline (0.9% NaCl) with respect to tissue integrity, cytotoxicity, and cilia beat frequency. A 5 min contact resulted in 99.9% inactivation of β-coronavirus OC43. OC43 viral replication was inhibited by >90% after infected MRC-5 cells were treated with the formulations. Conclusion: The saline-based novel EC16m mucoadhesive nasal nanoformulations rapidly inactivated human coronavirus with mucociliary safety properties comparable to saline, a solution widely used for nasal applications. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Targeted Drug Delivery Systems)

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26 pages, 4460 KiB

Open AccessEditor’s ChoiceArticle

A Physiologically Based Pharmacokinetic (PBPK) Study to Assess the Adjuvanticity of Three Peptides in an Oral Vaccine

by Leonor Saldanha, Ülo Langel and Nuno Vale

Pharmaceutics 2024, 16(6), 780; https://doi.org/10.3390/pharmaceutics16060780 - 8 Jun 2024

Viewed by 849

Abstract

Following up on the first PBPK model for an oral vaccine built for alpha-tocopherol, three peptides are explored in this article to verify if they could support an oral vaccine formulation as adjuvants using the same PBPK modeling approach. A literature review was [...] Read more.

Following up on the first PBPK model for an oral vaccine built for alpha-tocopherol, three peptides are explored in this article to verify if they could support an oral vaccine formulation as adjuvants using the same PBPK modeling approach. A literature review was conducted to verify what peptides have been used as adjuvants in the last decades, and it was noticed that MDP derivatives have been used, with one of them even being commercially approved and used as an adjuvant when administered intravenously in oncology. The aim of this study was to build optimized models for three MDP peptides (MDP itself, MTP-PE, and murabutide) and to verify if they could act as adjuvants for an oral vaccine. Challenges faced by peptides in an oral delivery system are taken into consideration, and improvements to the formulations to achieve better results are described in a step-wise approach to reach the most-optimized model. Once simulations are performed, results are compared to determine what would be the best peptide to support as an oral adjuvant. According to our results, MTP-PE, the currently approved and commercialized peptide, could have potential to be incorporated into an oral formulation. It would be interesting to proceed with further in vivo experiments to determine the behavior of this peptide when administered orally with a proper formulation to overcome the challenges of oral delivery systems. Full article

(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)

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21 pages, 6251 KiB

Open AccessEditor’s ChoiceArticle

Preparation and Evaluation of Inhalable Microparticles with Improved Aerodynamic Performance and Dispersibility Using L-Leucine and Hot-Melt Extrusion

by Jin-Hyuk Jeong, Ji-Su Kim, Yu-Rim Choi, Dae Hwan Shin, Ji-Hyun Kang, Dong-Wook Kim, Yun-Sang Park and Chun-Woong Park

Pharmaceutics 2024, 16(6), 784; https://doi.org/10.3390/pharmaceutics16060784 - 8 Jun 2024

Viewed by 1174

Abstract

Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility [...] Read more.

Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility while simultaneously maintaining the high aerodynamic performance of inhalable microparticles. This study explored using LEU in HME to improve dispersibility and maintain the high aerodynamic performance of inhalable microparticles. Formulations with crystalline itraconazole (ITZ) and LEU were made via co-jet milling and HME followed by jet milling. The LEU ratio varied, comparing solubility, homogenization, and aerodynamic performance enhancements. In HME, ITZ solubility increased, and crystallinity decreased. Higher LEU ratios in HME formulations reduced the contact angle, enhancing mass median aerodynamic diameter (MMAD) size and aerodynamic performance synergistically. Achieving a maximum extra fine particle fraction of 33.68 ± 1.31% enabled stable deep lung delivery. This study shows that HME combined with LEU effectively produces inhalable particles, which is promising for improved drug dispersion and delivery. Full article

(This article belongs to the Special Issue Dry Powders for Pulmonary Delivery: Device and Formulation Technologies for an Enhanced Lung Deposition, 2nd Edition)

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17 pages, 2526 KiB

Open AccessEditor’s ChoiceArticle

Geometry-Driven Fabrication of Mini-Tablets via 3D Printing: Correlating Release Kinetics with Polyhedral Shapes

by Young-Jin Kim, Yu-Rim Choi, Ji-Hyun Kang, Yun-Sang Park, Dong-Wook Kim and Chun-Woong Park

Pharmaceutics 2024, 16(6), 783; https://doi.org/10.3390/pharmaceutics16060783 - 8 Jun 2024

Cited by 1 | Viewed by 1079

Abstract

The aim of this study was to fabricate mini-tablets of polyhedrons containing theophylline using a fused deposition modeling (FDM) 3D printer, and to evaluate the correlation between release kinetics models and their geometric shapes. The filaments containing theophylline, hydroxypropyl cellulose (HPC), and EUDRAGIT [...] Read more.

The aim of this study was to fabricate mini-tablets of polyhedrons containing theophylline using a fused deposition modeling (FDM) 3D printer, and to evaluate the correlation between release kinetics models and their geometric shapes. The filaments containing theophylline, hydroxypropyl cellulose (HPC), and EUDRAGIT RS PO (EU) could be obtained with a consistent thickness through pre-drying before hot melt extrusion (HME). Mini-tablets of polyhedrons ranging from tetrahedron to icosahedron were 3D-printed using the same formulation of the filament, ensuring equal volumes. The release kinetics models derived from dissolution tests of the polyhedrons, along with calculations for various physical parameters (edge, SA: surface area, SA/W: surface area/weight, SA/V: surface area/volume), revealed that the correlation between the Higuchi model and the SA/V was the highest (R² = 0.995). It was confirmed that using 3D- printing for the development of personalized or pediatric drug products allows for the adjustment of drug dosage by modifying the size or shape of the drug while maintaining or controlling the same release profile. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of 3D Printing)

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27 pages, 6940 KiB

Open AccessEditor’s ChoiceArticle

Evidence That a Peptide-Drug/p53 Gene Complex Promotes Cognate Gene Expression and Inhibits the Viability of Glioblastoma Cells

by Ana Neves, Tânia Albuquerque, Rúben Faria, Cecília R. A. Santos, Eric Vivès, Prisca Boisguérin, Diana Carneiro, Daniel F. Bruno, Maria D. Pavlaki, Susana Loureiro, Ângela Sousa and Diana Costa

Pharmaceutics 2024, 16(6), 781; https://doi.org/10.3390/pharmaceutics16060781 - 8 Jun 2024

Viewed by 1172

Abstract

Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Conventional therapies are followed by poor patient survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Gene therapy has emerged as an exciting and innovative tool in cancer [...] Read more.

Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Conventional therapies are followed by poor patient survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Gene therapy has emerged as an exciting and innovative tool in cancer therapy. Its combination with chemotherapy has significantly improved therapeutic outcomes. In line with this, our team has developed temozolomide–transferrin (Tf) peptide (WRAP5)/p53 gene nanometric complexes that were revealed to be biocompatible with non-cancerous cells and in a zebrafish model and were able to efficiently target and internalize into SNB19 and U373 glioma cell lines. The transfection of these cells, mediated by the formulated peptide-drug/gene complexes, resulted in p53 expression. The combined action of the anticancer drug with p53 supplementation in cancer cells enhances cytotoxicity, which was correlated to apoptosis activation through quantification of caspase-3 activity. In addition, increased caspase-9 levels revealed that the intrinsic or mitochondrial pathway of apoptosis was implicated. This assumption was further evidenced by the presence, in glioma cells, of Bax protein overexpression—a core regulator of this apoptotic pathway. Our findings demonstrated the great potential of peptide TMZ/p53 co-delivery complexes for cellular transfection, p53 expression, and apoptosis induction, holding promising therapeutic value toward glioblastoma. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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15 pages, 4235 KiB

Open AccessEditor’s ChoiceArticle

Intranasal Delivery of Cell-Penetrating Therapeutic Peptide Enhances Brain Delivery, Reduces Inflammation, and Improves Neurologic Function in Moderate Traumatic Brain Injury

by Yaswanthi Yanamadala, Ritika Roy, Afrika Alake Williams, Navya Uppu, Audrey Yoonsun Kim, Mark A. DeCoster, Paul Kim and Teresa Ann Murray

Pharmaceutics 2024, 16(6), 774; https://doi.org/10.3390/pharmaceutics16060774 - 7 Jun 2024

Cited by 1 | Viewed by 1303

Abstract

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is [...] Read more.

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood–brain barrier (BBB), which prevents the passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal (IN) administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of proinflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance after TBI in KAFAK-treated mice. This study demonstrates KAFAK’s ability to cross the blood–brain barrier, to lower proinflammatory cytokines in vivo, and to restore function after a moderate TBI. Full article

(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics, 2nd Edition)

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21 pages, 1087 KiB

Open AccessEditor’s ChoiceArticle

Predicting ADMET Properties from Molecule SMILE: A Bottom-Up Approach Using Attention-Based Graph Neural Networks

by Alessandro De Carlo, Davide Ronchi, Marco Piastra, Elena Maria Tosca and Paolo Magni

Pharmaceutics 2024, 16(6), 776; https://doi.org/10.3390/pharmaceutics16060776 - 7 Jun 2024

Cited by 1 | Viewed by 1173

Abstract

Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims [...] Read more.

Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs). The model utilizes a graph-based representation of molecules directly derived from Simplified Molecular Input Line Entry System (SMILE) notation. Information is processed sequentially, from substructures to the whole molecule, employing a bottom-up approach. The developed GNN is tested and compared with existing approaches using six benchmark datasets and by encompassing regression (lipophilicity and aqueous solubility) and classification (CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition) tasks. Results show the effectiveness of our model, which bypasses the computationally expensive retrieval and selection of molecular descriptors. This approach provides a valuable tool for high-throughput screening, facilitating early assessment of ADMET properties and enhancing the likelihood of drug success in the development pipeline. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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26 pages, 1438 KiB

Open AccessEditor’s ChoiceReview

Design of Chitin Cell Culture Matrices for 3D Tissue Engineering: The Importance of Chitin Types, Solvents, Cross-Linkers, and Fabrication Techniques

by Turna Basak and Julia L. Shamshina

Pharmaceutics 2024, 16(6), 777; https://doi.org/10.3390/pharmaceutics16060777 - 7 Jun 2024

Cited by 2 | Viewed by 1283

Abstract

This review focuses on factors and the fabrication techniques affecting the microarchitecture of tissue engineering scaffolds from the second most abundant biopolymer, chitin. It emphasizes the unique potentiality of this polymer in tissue engineering (TE) applications and highlights the variables important to achieve [...] Read more.

This review focuses on factors and the fabrication techniques affecting the microarchitecture of tissue engineering scaffolds from the second most abundant biopolymer, chitin. It emphasizes the unique potentiality of this polymer in tissue engineering (TE) applications and highlights the variables important to achieve tailored scaffold properties. First, we describe aspects of scaffolds’ design, and the complex interplay between chitin types, solvent systems, additives, and fabrication techniques to incorporate porosity, with regard to best practices. In the following section, we provide examples of scaffolds’ use, with a focus on in vitro cell studies. Finally, an analysis of their biodegradability is presented. Our review emphasizes the potentiality of chitin and the pressing need for further research to overcome existing challenges and fully harness its capabilities in tissue engineering. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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14 pages, 2264 KiB

Open AccessEditor’s ChoiceArticle

Heparin Dosing Regimen Optimization in Veno-Arterial Extracorporeal Membrane Oxygenation: A Pharmacokinetic Analysis

by Julien Lanoiselée, Jérémy Mourer, Marie Jungling, Serge Molliex, Lise Thellier, Julien Tabareau, Emmanuelle Jeanpierre, Emmanuel Robin, Sophie Susen, Benoit Tavernier, André Vincentelli, Edouard Ollier and Mouhamed Djahoum Moussa

Pharmaceutics 2024, 16(6), 770; https://doi.org/10.3390/pharmaceutics16060770 - 6 Jun 2024

Viewed by 880

Abstract

Background. Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU/mL. Owing to heparin’s heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. [...] Read more.

Background. Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU/mL. Owing to heparin’s heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. The aim of this study was to build a pharmacokinetic model of heparin accounting for potential confounders, and derive an optimized dosing regimen for a given anti-Xa target. Methods. Adult patients undergoing VA-ECMO were included between January 2020 and June 2021. Anticoagulation was managed with an initial 100 IU/kg heparin loading dose followed by a continuous infusion targeting 0.2 to 0.7 IU/mL anti-Xa. The data were split into model development and model validation cohorts. Statistical analysis was performed using a nonlinear mixed effects modeling population approach. Model-based simulations were performed to develop an optimized dosing regimen targeting the desired anti-Xa. Results. A total of 74 patients were included, with 1703 anti-Xa observations. A single-compartment model best fitted the data. Interpatient variability for distribution volume was best explained by body weight, C-reactive protein and ECMO indication (post-cardiotomy shock or medical cardiogenic shock), and interpatient variability for elimination clearance was best explained by serum creatinine and C-reactive protein. Simulations using the optimized regimen according to these covariates showed accurate anti-Xa target attainment. Conclusion. In adult patients on VA-ECMO, heparin’s effect increased with serum creatinine and medical indication, whereas it decreased with body weight and systemic inflammation. We propose an optimized dosing regimen accounting for key covariates, capable of accurately predicting a given anti-Xa target. Full article

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23 pages, 19779 KiB

Open AccessEditor’s ChoiceArticle

Optimizing mRNA-Loaded Lipid Nanoparticles as a Potential Tool for Protein-Replacement Therapy

by Rocío Gambaro, Ignacio Rivero Berti, María José Limeres, Cristián Huck-Iriart, Malin Svensson, Silvia Fraude, Leah Pretsch, Shutian Si, Ingo Lieberwirth, Stephan Gehring, Maximiliano Cacicedo and Germán Abel Islan

Pharmaceutics 2024, 16(6), 771; https://doi.org/10.3390/pharmaceutics16060771 - 6 Jun 2024

Cited by 1 | Viewed by 3372

Abstract

Lipid nanoparticles (LNPs) tailored for mRNA delivery were optimized to serve as a platform for treating metabolic diseases. Four distinct lipid mixes (LMs) were formulated by modifying various components: LM1 (ALC-0315/DSPC/Cholesterol/ALC-0159), LM2 (ALC-0315/DOPE/Cholesterol/ALC-0159), LM3 (ALC-0315/DSPC/Cholesterol/DMG-PEG2k), and LM4 (DLin-MC3-DMA/DSPC/Cholesterol/ALC-0159). LNPs exhibited stability and homogeneity [...] Read more.

Lipid nanoparticles (LNPs) tailored for mRNA delivery were optimized to serve as a platform for treating metabolic diseases. Four distinct lipid mixes (LMs) were formulated by modifying various components: LM1 (ALC-0315/DSPC/Cholesterol/ALC-0159), LM2 (ALC-0315/DOPE/Cholesterol/ALC-0159), LM3 (ALC-0315/DSPC/Cholesterol/DMG-PEG2k), and LM4 (DLin-MC3-DMA/DSPC/Cholesterol/ALC-0159). LNPs exhibited stability and homogeneity with a mean size of 75 to 90 nm, confirmed by cryo-TEM and SAXS studies. High mRNA encapsulation (95–100%) was achieved. LNPs effectively delivered EGFP-encoding mRNA to HepG2 and DC2.4 cell lines. LNPs induced cytokine secretion from human peripheral blood mononuclear cells (PBMCs), revealing that LM1, LM2, and LM4 induced 1.5- to 4-fold increases in IL-8, TNF-α, and MCP-1 levels, while LM3 showed minimal changes. Reporter mRNA expression was observed in LNP-treated PBMCs. Hemotoxicity studies confirmed formulation biocompatibility with values below 2%. In vivo biodistribution in mice post intramuscular injection showed significant mRNA expression, mainly in the liver. The modification of LNP components influenced reactogenicity, inflammatory response, and mRNA expression, offering a promising platform for selecting less reactogenic carriers suitable for repetitive dosing in metabolic disease treatment. Full article

(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)

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18 pages, 809 KiB

Open AccessEditor’s ChoiceReview

The Integration of Advanced Drug Delivery Systems into Conventional Adjuvant Therapies for Peri-Implantitis Treatment

by Iria Seoane-Viaño, Mariola Seoane-Gigirey, Carlos Bendicho-Lavilla, Luz M. Gigirey, Francisco J. Otero-Espinar and Santiago Seoane-Trigo

Pharmaceutics 2024, 16(6), 769; https://doi.org/10.3390/pharmaceutics16060769 - 5 Jun 2024

Viewed by 1606

Abstract

Despite the high success rates of dental implants, peri-implantitis is currently the most common complication in dental implantology. Peri-implantitis has an inflammatory nature, it is associated with the accumulation of plaque in the peri-implant tissues, and its evolution can be progressive depending on [...] Read more.

Despite the high success rates of dental implants, peri-implantitis is currently the most common complication in dental implantology. Peri-implantitis has an inflammatory nature, it is associated with the accumulation of plaque in the peri-implant tissues, and its evolution can be progressive depending on various factors, comorbidities, and poor oral health. Prophylaxis and different treatment methods have been widely discussed in recent decades, and surgical and non-surgical techniques present both advantages and disadvantages. In this work, a literature review of different studies on the application of adjuvant treatments, such as local and systemic antibiotics and antiseptic treatments, was conducted. Positive outcomes have been found in the short (up to one year after treatment) and long term (up to ten years after treatment) with combined therapies. However, there is still a need to explore new therapies based on the use of advanced drug delivery systems for the effective treatment of peri-implantitis in the long term and without relapses. Hence, micro- and nanoparticles, implants, and injectable hydrogels, among others, should be considered in future peri-implantitis treatment with the aim of enhancing overall therapy outcomes. Full article

(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)

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13 pages, 2982 KiB

Open AccessEditor’s ChoiceArticle

Nanoliposomes Permeability in a Microfluidic Drug Delivery Platform across a 3D Hydrogel

by Corentin Peyret, Aleka Manousaki, Sabine Bouguet-Bonnet, Emmanuel Stratakis, Laura Sanchez-Gonzalez, Cyril J.F. Kahn and Elmira Arab-Tehrany

Pharmaceutics 2024, 16(6), 765; https://doi.org/10.3390/pharmaceutics16060765 - 4 Jun 2024

Viewed by 1090

Abstract

Nanoliposomes are nano-sized vesicles that can be used as drug delivery carriers with the ability to encapsulate both hydrophobic and hydrophilic compounds. Moreover, their lipid compositions facilitate their internalization by cells. However, the interaction between nanoliposomes and the membrane barrier of the human [...] Read more.

Nanoliposomes are nano-sized vesicles that can be used as drug delivery carriers with the ability to encapsulate both hydrophobic and hydrophilic compounds. Moreover, their lipid compositions facilitate their internalization by cells. However, the interaction between nanoliposomes and the membrane barrier of the human body is not well-known. If cellular tests and animal testing offer a solution, their lack of physiological relevance and ethical concerns make them unsuitable to properly mimic human body complexity. Microfluidics, which allows the environment of the human body to be imitated in a controlled way, can fulfil this role. However, existing models are missing the presence of something that would mimic a basal membrane, often consisting of a simple cell layer on a polymer membrane. In this study, we investigated the diffusion of nanoliposomes in a microfluidic system and found the optimal parameters to maximize their diffusion. Then, we incorporated a custom made GelMA with a controlled degree of substitution and studied the passage of fluorescently labeled nanoliposomes through this barrier. Our results show that highly substituted GelMA was more porous than lower substitution GelMA. Overall, our work lays the foundation for the incorporation of a hydrogel mimicking a basal membrane on a drug delivery microfluidic platform. Full article

(This article belongs to the Special Issue Novel Applications of Modern Excipients in Advanced Pharmaceutical Products)

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19 pages, 3674 KiB

Open AccessEditor’s ChoiceArticle

Antitumoral-Embedded Biopolymeric Spheres for Implantable Devices

by Valentina Grumezescu, Oana Gherasim, Bianca Gălățeanu and Ariana Hudiță

Pharmaceutics 2024, 16(6), 754; https://doi.org/10.3390/pharmaceutics16060754 - 3 Jun 2024

Viewed by 756

Abstract

The bioactive surface modification of implantable devices paves the way towards the personalized healthcare practice by providing a versatile and tunable approach that increase the patient outcome, facilitate the medical procedure, and reduce the indirect or secondary effects. The purpose of our study [...] Read more.

The bioactive surface modification of implantable devices paves the way towards the personalized healthcare practice by providing a versatile and tunable approach that increase the patient outcome, facilitate the medical procedure, and reduce the indirect or secondary effects. The purpose of our study was to assess the performance of composite coatings based on biopolymeric spheres of poly(lactide-co-glycolide) embedded with hydroxyapatite (HA) and methotrexate (MTX). Bio-simulated tests performed for up to one week evidenced the gradual release of the antitumor drug and the biomineralization potential of PLGA/HA-MTX sphere coatings. The composite materials proved superior biocompatibility and promoted enhanced cell adhesion and proliferation with respect to human preosteoblast and osteosarcoma cell lines when compared to pristine titanium. Full article

(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery, 3rd Edition)

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28 pages, 6006 KiB

Open AccessEditor’s ChoiceArticle

Design and Biocompatibility of Biodegradable Poly(octamethylene suberate) Nanoparticles to Treat Skin Diseases

by Dragana P. C. de Barros, Luís P. Fonseca, Luís G. Gonçalves, Diogo S. Serrano and Abel Oliva

Pharmaceutics 2024, 16(6), 753; https://doi.org/10.3390/pharmaceutics16060753 - 3 Jun 2024

Viewed by 894

Abstract

Biodegradable aliphatic polyester formulations as carriers for topical drug delivery show the potential to encapsulate structurally different therapeutic compounds. Poly(octamethylene suberate) (POS) nanoparticles (POS-NPs) were used as a matrix to encapsulate four therapeutic molecules used to treat skin disorders: caffeine (CF), quercetin (QR), [...] Read more.

Biodegradable aliphatic polyester formulations as carriers for topical drug delivery show the potential to encapsulate structurally different therapeutic compounds. Poly(octamethylene suberate) (POS) nanoparticles (POS-NPs) were used as a matrix to encapsulate four therapeutic molecules used to treat skin disorders: caffeine (CF), quercetin (QR), hydrocortisone (HC), and adapalene (AD). Hydrophobicity and chemical structure of bioactive compounds (BCs) influenced the physicochemical stability of drug-loaded nanoparticles. The particle size of drug-loaded nanoparticles was between 254.9 nm for the CF-POS-NP and 1291.3 for QR-POS-NP. Particles had a negative charge from −27.6 mV (QR) to −49.2 mV (HC). Drug loading content for all BC-POS-NPs varies between 36.11 ± 1.48% (CF-POS-NP) and 66.66 ± 4.87% (AD-POS-NP), and their entrapment efficiency is relatively high (28.30 ± 1.81% and 99.95 ± 0.04%, respectively). Calorimetric analysis showed the appearance of polymorphism for AD- and HC-loaded systems and the drug’s complete solubilisation into all nanoparticle formulations. FTIR and NMR spectra showed apparent drug incorporation into the polymer matrix of NPs. The encapsulation of BCs enhanced the antioxidative effect. The prepared POS nanoparticles’ cytotoxicity was studied using two dermal cell lines, keratinocyte (HaCaT) cells and fibroblasts (HDFn). The nanoparticle cytotoxic effect was more substantial on HaCaT cell lines. A reconstructed human epidermis (RHE) was successfully used to investigate the penetration of polymeric NPs. Based on permeation and histology studies, HC-POS-NPs and CF-POS-NPs were shown not to be suitable for dermal applications with the explored drug concentrations. AD presents a high permeation rate and no toxic impact on RHE. Full article

(This article belongs to the Special Issue Topical Drug Carriers: Recent Advances and Future Challenges)

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31 pages, 2372 KiB

Open AccessEditor’s ChoiceReview

Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds

by Danny Aljamal, Priya S. Iyengar and Tammy T. Nguyen

Pharmaceutics 2024, 16(6), 750; https://doi.org/10.3390/pharmaceutics16060750 - 2 Jun 2024

Cited by 1 | Viewed by 1128

Abstract

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound [...] Read more.

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds, 2nd Edition)

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34 pages, 2873 KiB

Open AccessEditor’s ChoiceReview

Chitosan Nanoparticles for Intranasal Drug Delivery

by Hossein Omidian, Erma J. Gill, Sumana Dey Chowdhury and Luigi X. Cubeddu

Pharmaceutics 2024, 16(6), 746; https://doi.org/10.3390/pharmaceutics16060746 - 31 May 2024

Cited by 1 | Viewed by 1891

Abstract

This manuscript explores the use of nanostructured chitosan for intranasal drug delivery, targeting improved therapeutic outcomes in neurodegenerative diseases, psychiatric care, pain management, vaccination, and diabetes treatment. Chitosan nanoparticles are shown to enhance brain delivery, improve bioavailability, and minimize systemic side effects by [...] Read more.

This manuscript explores the use of nanostructured chitosan for intranasal drug delivery, targeting improved therapeutic outcomes in neurodegenerative diseases, psychiatric care, pain management, vaccination, and diabetes treatment. Chitosan nanoparticles are shown to enhance brain delivery, improve bioavailability, and minimize systemic side effects by facilitating drug transport across the blood–brain barrier. Despite substantial advancements in targeted delivery and vaccine efficacy, challenges remain in scalability, regulatory approval, and transitioning from preclinical studies to clinical applications. The future of chitosan-based nanomedicines hinges on advancing clinical trials, fostering interdisciplinary collaboration, and innovating in nanoparticle design to overcome these hurdles and realize their therapeutic potential. Full article

(This article belongs to the Special Issue Recent Advances in Nanoparticles for Mucosal Drug Delivery)

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11 pages, 5736 KiB

Open AccessEditor’s ChoiceArticle

Co-Amorphization of Acemetacin with Basic Amino Acids as Co-Formers for Solubility Improvement and Gastric Ulcer Mitigation

by Jiayue Hou, Peixu Zhao, Yanfei Wang, Xiwei Jiang and Qiang Fu

Pharmaceutics 2024, 16(6), 745; https://doi.org/10.3390/pharmaceutics16060745 - 31 May 2024

Viewed by 949

Abstract

Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and [...] Read more.

Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and basic amino acids have the potential to protect the gastrointestinal tract. In order to develop a highly efficient and low-toxic ACM formulation, we prepared ACM CAM systems, with basic amino acids (lysine, arginine, and histidine) as co-formers, using a cryo-milling method. The solid-state behaviors of the ACM CAM systems were characterized by polarizing light microscopy, differential scanning calorimetry, and powder X-ray diffraction. Fourier transform infrared spectroscopy and molecular docking were carried out to understand the formation mechanism. Moreover, the gastro-protective effects of ACM CAM systems were evaluated in a rat gastric ulcer model. The results demonstrated that the CAM systems improved the dissolution rates of ACM compared with the neat amorphous counterpart. Furthermore, ACM CAM systems are significantly effective in mitigating the ACM-induced gastric ulcer in rats, and the ulcer inhibition rates were almost 90%. More importantly, this study provided a useful method for mitigating drug-induced gastrointestinal damage and broadened the applications of drug–amino acid CAM systems. Full article

(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)

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28 pages, 12497 KiB

Open AccessEditor’s ChoiceReview

Atomic Force Microscopy for the Study of Cell Mechanics in Pharmaceutics

by Henrik Siboni, Ivana Ruseska and Andreas Zimmer

Pharmaceutics 2024, 16(6), 733; https://doi.org/10.3390/pharmaceutics16060733 - 29 May 2024

Viewed by 1050

Abstract

Cell mechanics is gaining attraction in drug screening, but the applicable methods have not yet become part of the standardized norm. This review presents the current state of the art for atomic force microscopy, which is the most widely available method. The field [...] Read more.

Cell mechanics is gaining attraction in drug screening, but the applicable methods have not yet become part of the standardized norm. This review presents the current state of the art for atomic force microscopy, which is the most widely available method. The field is first motivated as a new way of tracking pharmaceutical effects, followed by a basic introduction targeted at pharmacists on how to measure cellular stiffness. The review then moves on to the current state of the knowledge in terms of experimental results and supplementary methods such as fluorescence microscopy that can give relevant additional information. Finally, rheological approaches as well as the theoretical interpretations are presented before ending on additional methods and outlooks. Full article

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18 pages, 10969 KiB

Open AccessEditor’s ChoiceArticle

Porous Chitosan/Hydroxyapatite Composite Microspheres for Vancomycin Loading and Releasing

by Meng-Ying Wu, Yi-Ting Kuo, I-Fang Kao and Shiow-Kang Yen

Pharmaceutics 2024, 16(6), 730; https://doi.org/10.3390/pharmaceutics16060730 - 29 May 2024

Viewed by 872

Abstract

Porous chitosan/hydroxyapatite (Chi-HAp) composite microspheres were prepared in an aqueous solution containing chitosan, calcium nitrate, and ammonium dihydrogen phosphate by using a hydrothermal method at various temperatures. The investigation indicated that temperature significantly impacted the final product’s appearance. Hydroxyapatite (HAp) coupled with dicalcium [...] Read more.

Porous chitosan/hydroxyapatite (Chi-HAp) composite microspheres were prepared in an aqueous solution containing chitosan, calcium nitrate, and ammonium dihydrogen phosphate by using a hydrothermal method at various temperatures. The investigation indicated that temperature significantly impacted the final product’s appearance. Hydroxyapatite (HAp) coupled with dicalcium phosphate dihydrate (DCPD) flakes were obviously found at 65 and 70 °C, while the latter gradually disappeared at higher temperatures. Conversely, synthesis at 90 °C led to smaller particle sizes due to the broken chitosan chains. The microspheres synthesized at 75 °C were selected for further analysis, revealing porous structures with specific surface areas of 36.66 m²/g, pores ranging from 3 to 100 nm, and pore volumes of 0.58 cm³/g. Vancomycin (VCM), an antibiotic, was then absorbed on and released from the microspheres derived at 75 °C, with a drug entrapment efficiency of 20% and a release duration exceeding 20 days. The bacteriostatic activity of the VCM/composite microspheres against Staphylococcus aureus increased with the VCM concentration and immersion time, revealing a stable inhibition zone diameter of approximately 4.3 mm from 24 to 96 h, and this indicated the retained stability and efficacy of the VCM during the encapsulating process. Full article

(This article belongs to the Special Issue Design of Mesoporous Materials for Biomedical Application)

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17 pages, 3570 KiB

Open AccessEditor’s ChoiceReview

Review of Prodrug and Nanodelivery Strategies to Improve the Treatment of Colorectal Cancer with Fluoropyrimidine Drugs

by Santu Sarkar, Sezgin Kiren and William H. Gmeiner

Pharmaceutics 2024, 16(6), 734; https://doi.org/10.3390/pharmaceutics16060734 - 29 May 2024

Cited by 1 | Viewed by 1333

Abstract

Fluoropyrimidine (FP) drugs are central components of combination chemotherapy regimens for the treatment of colorectal cancer (CRC). FP-based chemotherapy has improved survival outcomes over the last several decades with much of the therapeutic benefit derived from the optimization of dose and delivery. To [...] Read more.

Fluoropyrimidine (FP) drugs are central components of combination chemotherapy regimens for the treatment of colorectal cancer (CRC). FP-based chemotherapy has improved survival outcomes over the last several decades with much of the therapeutic benefit derived from the optimization of dose and delivery. To provide further advances in therapeutic efficacy, next-generation prodrugs and nanodelivery systems for FPs are being developed. This review focuses on recent innovative nanodelivery approaches for FP drugs that display therapeutic promise. We summarize established, clinically useful FP prodrug strategies, including capecitabine, which exploit tumor-specific enzyme expression for optimal anticancer activity. We then describe the use of FP DNA-based polymers (e.g., CF10) for the delivery of activated FP nucleotides as a nanodelivery approach with proven activity in pre-clinical models and with clinical potential. Multiple nanodelivery systems for FP delivery show promise in CRC pre-clinical models and we review advances in albumin-mediated FP delivery, the development of mesoporous silica nanoparticles, emulsion-based nanoparticles, metal nanoparticles, hydrogel-based delivery, and liposomes and lipid nanoparticles that display particular promise for therapeutic development. Nanodelivery of FPs is anticipated to impact CRC treatment in the coming years and to improve survival for cancer patients. Full article

(This article belongs to the Special Issue Recent Advances in Drug Delivery for the Treatment of Colorectal Cancer)

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12 pages, 1988 KiB

Open AccessEditor’s ChoiceArticle

Structural Optimization of Carboxy-Terminal Phenylalanine-Modified Dendrimers for T-Cell Association and Model Drug Loading

by Hiroya Shiba, Tomoka Hirose, Akinobu Sakai, Ikuhiko Nakase, Akikazu Matsumoto and Chie Kojima

Pharmaceutics 2024, 16(6), 715; https://doi.org/10.3390/pharmaceutics16060715 - 27 May 2024

Viewed by 1069

Abstract

Dendrimers are potent nanocarriers in drug delivery systems because their structure can be precisely controlled. We previously reported that polyamidoamine (PAMAM) dendrimers that were modified with 1,2-cyclohexanedicarboxylic acid (CHex) and phenylalanine (Phe), PAMAM-CHex-Phe, exhibited an effective association with various immune cells, including T-cells. [...] Read more.

Dendrimers are potent nanocarriers in drug delivery systems because their structure can be precisely controlled. We previously reported that polyamidoamine (PAMAM) dendrimers that were modified with 1,2-cyclohexanedicarboxylic acid (CHex) and phenylalanine (Phe), PAMAM-CHex-Phe, exhibited an effective association with various immune cells, including T-cells. In this study, we synthesized various carboxy-terminal Phe-modified dendrimers with different linkers using phthalic acid and linear dicarboxylic acids to determine the association of these dendrimers with Jurkat cells, a T-cell model. PAMAM-n-hexyl-Phe demonstrated the highest association with Jurkat T-cells. In addition, dendri-graft polylysine (DGL) with CHex and Phe, DGL-CHex-Phe, was synthesized, and its association with Jurkat cells was investigated. The association of DGL-CHex-Phe with T-cells was higher than that of PAMAM-CHex-Phe. However, it was insoluble in water and thus it is unsuitable as a drug carrier. Model drugs, such as protoporphyrin IX and paclitaxel, were loaded onto these dendrimers, and the most model drug molecules could be loaded into PAMAM-CHex-Phe. PTX-loaded PAMAM-CHex-Phe exhibited cytotoxicity against Jurkat cells at a similar level to free PTX. These results suggest that PAMAM-CHex-Phe exhibited both efficient T-cell association and drug loading properties. Full article

(This article belongs to the Special Issue Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 85th Birthday for His Outstanding Achievements in Advancing the Field of Dendrimers)

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13 pages, 635 KiB

Open AccessEditor’s ChoiceReview

Current Progress in Magnetic Resonance-Guided Focused Ultrasound to Facilitate Drug Delivery across the Blood-Brain Barrier

by Ying Meng, Lorraine V. Kalia, Suneil K. Kalia, Clement Hamani, Yuexi Huang, Kullervo Hynynen, Nir Lipsman and Benjamin Davidson

Pharmaceutics 2024, 16(6), 719; https://doi.org/10.3390/pharmaceutics16060719 - 27 May 2024

Cited by 2 | Viewed by 1589

Abstract

This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from [...] Read more.

This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from extensive pre-clinical studies, demonstrating a reassuring safety profile and paving the way for numerous translational clinical trials in Alzheimer’s disease, Parkinson’s disease, and primary and metastatic brain tumors. Future directions include improving ultrasound delivery devices, exploring alternative delivery approaches such as nanodroplets, and expanding the application to other neurological conditions. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Blood–Brain Barrier Disruption and Drug Delivery)

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17 pages, 3465 KiB

Open AccessEditor’s ChoiceArticle

In Vitro and In Vivo Synergetic Radiotherapy with Gold Nanoparticles and Docetaxel for Pancreatic Cancer

by Abdulaziz Alhussan, Nolan Jackson, Norman Chow, Ermias Gete, Nicole Wretham, Nancy Dos Santos, Wayne Beckham, Cheryl Duzenli and Devika B. Chithrani

Pharmaceutics 2024, 16(6), 713; https://doi.org/10.3390/pharmaceutics16060713 - 26 May 2024

Cited by 1 | Viewed by 1407

Abstract

This research underscores the potential of combining nanotechnology with conventional therapies in cancer treatment, particularly for challenging cases like pancreatic cancer. We aimed to enhance pancreatic cancer treatment by investigating the synergistic effects of gold nanoparticles (GNPs) and docetaxel (DTX) as potential radiosensitizers [...] Read more.

This research underscores the potential of combining nanotechnology with conventional therapies in cancer treatment, particularly for challenging cases like pancreatic cancer. We aimed to enhance pancreatic cancer treatment by investigating the synergistic effects of gold nanoparticles (GNPs) and docetaxel (DTX) as potential radiosensitizers in radiotherapy (RT) both in vitro and in vivo, utilizing a MIA PaCa-2 monoculture spheroid model and NRG mice subcutaneously implanted with MIA PaCa-2 cells, respectively. Spheroids were treated with GNPs (7.5 μg/mL), DTX (100 nM), and 2 Gy of RT using a 6 MV linear accelerator. In parallel, mice received treatments of GNPs (2 mg/kg), DTX (6 mg/kg), and 5 Gy of RT (6 MV linear accelerator). In vitro results showed that though RT and DTX reduced spheroid size and increased DNA DSBs, the triple combination of DTX/RT/GNPs led to a significant 48% (p = 0.05) decrease in spheroid size and a 45% (p = 0.05) increase in DNA DSBs. In vivo results showed a 20% (p = 0.05) reduction in tumor growth 20 days post-treatment with (GNPs/RT/DTX) and an increase in mice median survival. The triple combination exhibited a synergistic effect, enhancing anticancer efficacy beyond individual treatments, and thus could be employed to improve radiotherapy and potentially reduce adverse effects. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Diagnostics and Drug Delivery Therapy)

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24 pages, 7549 KiB

Open AccessEditor’s ChoiceArticle

Focused Ultrasound-Mediated Disruption of the Blood–Brain Barrier for AAV9 Delivery in a Mouse Model of Huntington’s Disease

by Bernie S. Owusu-Yaw, Yongzhi Zhang, Lilyan Garrett, Alvin Yao, Kai Shing, Ana Rita Batista, Miguel Sena-Esteves, Jaymin Upadhyay, Kimberly Kegel-Gleason and Nick Todd

Pharmaceutics 2024, 16(6), 710; https://doi.org/10.3390/pharmaceutics16060710 - 24 May 2024

Viewed by 1272

Abstract

Huntington’s disease (HD) is a monogenic neurodegenerative disorder caused by a cytosine–adenine–guanine (CAG) trinucleotide repeat expansion in the HTT gene. There are no cures for HD, but the genetic basis of this disorder makes gene therapy a viable approach. Adeno-associated virus (AAV)-miRNA-based therapies [...] Read more.

Huntington’s disease (HD) is a monogenic neurodegenerative disorder caused by a cytosine–adenine–guanine (CAG) trinucleotide repeat expansion in the HTT gene. There are no cures for HD, but the genetic basis of this disorder makes gene therapy a viable approach. Adeno-associated virus (AAV)-miRNA-based therapies have been demonstrated to be effective in lowering HTT mRNA; however, the blood–brain barrier (BBB) poses a significant challenge for gene delivery to the brain. Delivery strategies include direct injections into the central nervous system, which are invasive and can result in poor diffusion of viral particles through the brain parenchyma. Focused ultrasound (FUS) is an alternative approach that can be used to non-invasively deliver AAVs by temporarily disrupting the BBB. Here, we investigate FUS-mediated delivery of a single-stranded AAV9 bearing a cDNA for GFP in 2-month-old wild-type mice and the zQ175 HD mouse model at 2-, 6-, and 12-months. FUS treatment improved AAV9 delivery for all mouse groups. The delivery efficacy was similar for all WT and HD groups, with the exception of the zQ175 12-month cohort, where we observed decreased GFP expression. Astrocytosis did not increase after FUS treatment, even within the zQ175 12-month group exhibiting higher baseline levels of GFAP expression. These findings demonstrate that FUS can be used to non-invasively deliver an AAV9-based gene therapy to targeted brain regions in a mouse model of Huntington’s disease. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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27 pages, 4655 KiB

Open AccessEditor’s ChoiceReview

Complex Emulsions as an Innovative Pharmaceutical Dosage form in Addressing the Issues of Multi-Drug Therapy and Polypharmacy Challenges

by Naresh Yandrapalli

Pharmaceutics 2024, 16(6), 707; https://doi.org/10.3390/pharmaceutics16060707 - 24 May 2024

Viewed by 1357

Abstract

This review explores the intersection of microfluidic technology and complex emulsion development as a promising solution to the challenges of formulations in multi-drug therapy (MDT) and polypharmacy. The convergence of microfluidic technology and complex emulsion fabrication could herald a transformative era in multi-drug [...] Read more.

This review explores the intersection of microfluidic technology and complex emulsion development as a promising solution to the challenges of formulations in multi-drug therapy (MDT) and polypharmacy. The convergence of microfluidic technology and complex emulsion fabrication could herald a transformative era in multi-drug delivery systems, directly confronting the prevalent challenges of polypharmacy. Microfluidics, with its unparalleled precision in droplet formation, empowers the encapsulation of multiple drugs within singular emulsion particles. The ability to engineer emulsions with tailored properties—such as size, composition, and release kinetics—enables the creation of highly efficient drug delivery vehicles. Thus, this innovative approach not only simplifies medication regimens by significantly reducing the number of necessary doses but also minimizes the pill burden and associated treatment termination—issues associated with polypharmacy. It is important to bring forth the opportunities and challenges of this synergy between microfluidic-driven complex emulsions and multi-drug therapy poses. Together, they not only offer a sophisticated method for addressing the intricacies of delivering multiple drugs but also align with broader healthcare objectives of enhancing treatment outcomes, patient safety, and quality of life, underscoring the importance of dosage form innovations in tackling the multifaceted challenges of modern pharmacotherapy. Full article

(This article belongs to the Special Issue Micro- and Nano-Emulsions as Drug Delivery Systems)

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32 pages, 5508 KiB

Open AccessEditor’s ChoiceReview

Drug Development for Alzheimer’s and Parkinson’s Disease: Where Do We Go Now?

by Lisa Sequeira, Sofia Benfeito, Carlos Fernandes, Inês Lima, Joana Peixoto, Catarina Alves, Cláudia Sofia Machado, Alexandra Gaspar, Fernanda Borges and Daniel Chavarria

Pharmaceutics 2024, 16(6), 708; https://doi.org/10.3390/pharmaceutics16060708 - 24 May 2024

Cited by 4 | Viewed by 1632

Abstract

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an [...] Read more.

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases’ progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop new, disease-modifying drugs to treat AD and PD, describing as representative examples some advances in the development of drug candidates targeting oxidative stress and adenosine A2A receptors. Full article

(This article belongs to the Special Issue The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs)

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34 pages, 1507 KiB

Open AccessEditor’s ChoiceReview

Process Simulation of Twin-Screw Granulation: A Review

by Tony Bediako Arthur and Nejat Rahmanian

Pharmaceutics 2024, 16(6), 706; https://doi.org/10.3390/pharmaceutics16060706 - 24 May 2024

Cited by 1 | Viewed by 3619

Abstract

Twin-screw granulation has emerged as a key process in powder processing industries and in the pharmaceutical sector to produce granules with controlled properties. This comprehensive review provides an overview of the simulation techniques and approaches that have been employed in the study of [...] Read more.

Twin-screw granulation has emerged as a key process in powder processing industries and in the pharmaceutical sector to produce granules with controlled properties. This comprehensive review provides an overview of the simulation techniques and approaches that have been employed in the study of twin-screw granulation processes. This review discusses the major aspects of the twin-screw granulation process which include the fundamental principles of twin-screw granulation, equipment design, process parameters, and simulation methodologies. It highlights the importance of operating conditions and formulation designs in powder flow dynamics, mixing behaviour, and particle interactions within the twin-screw granulator for enhancing product quality and process efficiency. Simulation techniques such as the population balance model (PBM), computational fluid dynamics (CFD), the discrete element method (DEM), process modelling software (PMS), and other coupled techniques are critically discussed with a focus on simulating twin-screw granulation processes. This paper examines the challenges and limitations associated with each simulation approach and provides insights into future research directions. Overall, this article serves as a valuable resource for researchers who intend to develop their understanding of twin-screw granulation and provides insights into the various techniques and approaches available for simulating the twin-screw granulation process. Full article

(This article belongs to the Special Issue Pharmaceutical Solids: Advanced Manufacturing and Characterization)

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17 pages, 4839 KiB

Open AccessEditor’s ChoiceArticle

Risperidone-Loaded Nasal Thermosensitive Polymeric Micelles: Quality by Design-Based Formulation Study

by Bence Sipos, Gábor Katona and Ildikó Csóka

Pharmaceutics 2024, 16(6), 703; https://doi.org/10.3390/pharmaceutics16060703 - 24 May 2024

Cited by 1 | Viewed by 1034

Abstract

The current research aims to develop thermosensitive polymeric micelles loaded with risperidone for nasal administration, emphasizing the added benefits of their thermosensitive behavior under nasal conditions. An initial risk assessment facilitated the advanced development process, confirming that the key indicators of thermosensitivity were [...] Read more.

The current research aims to develop thermosensitive polymeric micelles loaded with risperidone for nasal administration, emphasizing the added benefits of their thermosensitive behavior under nasal conditions. An initial risk assessment facilitated the advanced development process, confirming that the key indicators of thermosensitivity were suitable for nasal application. The polymeric micelles exhibited an average size of 118.4 ± 3.1 nm at ambient temperature and a size of 20.47 ± 1.2 nm at 36.5 °C, in both cases in monodisperse distribution. Factors such as pH and viscosity did not significantly impact these parameters, demonstrating appropriate nasal applicability. The model formulations showed a rapid, burst-like drug release profile in vitro, accompanied by a quick and high permeation rate at nasal conditions. Overall, the Quality by Design-based risk assessment process led to the development of an advanced drug delivery system capable of administering risperidone through the nasal cavity. Full article

(This article belongs to the Special Issue Nasal Drug Delivery: Challenges and Future Opportunities)

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41 pages, 2380 KiB

Open AccessEditor’s ChoiceReview

Insight into the Functional Dynamics and Challenges of Exosomes in Pharmaceutical Innovation and Precision Medicine

by Anu Sharma, Anita Yadav, Aparajita Nandy and Subhadip Ghatak

Pharmaceutics 2024, 16(6), 709; https://doi.org/10.3390/pharmaceutics16060709 - 24 May 2024

Cited by 5 | Viewed by 1776

Abstract

Of all the numerous nanosized extracellular vesicles released by a cell, the endosomal-originated exosomes are increasingly recognized as potential therapeutics, owing to their inherent stability, low immunogenicity, and targeted delivery capabilities. This review critically evaluates the transformative potential of exosome-based modalities across pharmaceutical [...] Read more.

Of all the numerous nanosized extracellular vesicles released by a cell, the endosomal-originated exosomes are increasingly recognized as potential therapeutics, owing to their inherent stability, low immunogenicity, and targeted delivery capabilities. This review critically evaluates the transformative potential of exosome-based modalities across pharmaceutical and precision medicine landscapes. Because of their precise targeted biomolecular cargo delivery, exosomes are posited as ideal candidates in drug delivery, enhancing regenerative medicine strategies, and advancing diagnostic technologies. Despite the significant market growth projections of exosome therapy, its utilization is encumbered by substantial scientific and regulatory challenges. These include the lack of universally accepted protocols for exosome isolation and the complexities associated with navigating the regulatory environment, particularly the guidelines set forth by the U.S. Food and Drug Administration (FDA). This review presents a comprehensive overview of current research trajectories aimed at addressing these impediments and discusses prospective advancements that could substantiate the clinical translation of exosomal therapies. By providing a comprehensive analysis of both the capabilities and hurdles inherent to exosome therapeutic applications, this article aims to inform and direct future research paradigms, thereby fostering the integration of exosomal systems into mainstream clinical practice. Full article

(This article belongs to the Special Issue Extracellular Vesicle-Based Drug Delivery Systems)

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