Pharmaceutics

Article

13 pages, 1154 KiB

Open AccessEditor’s ChoiceArticle

The Role of a Cholecystokinin Receptor Antagonist in the Management of Chronic Pancreatitis: A Phase 1 Trial

by Victor Ciofoaia, Wenqiang Chen, Bakain W. Tarek, Martha Gay, Narayan Shivapurkar and Jill P. Smith

Pharmaceutics 2024, 16(5), 611; https://doi.org/10.3390/pharmaceutics16050611 - 30 Apr 2024

Viewed by 1443

Abstract

Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We [...] Read more.

Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We previously showed that the CCK-receptor antagonist called proglumide could decrease inflammation, acinar-ductal metaplasia, and fibrosis in murine models of CP. We hypothesized that proglumide would be safe and diminish pain caused by CP. A Phase 1 open-labeled safety study was performed in subjects with clinical and radiographic evidence of CP with moderate to severe pain. After a 4-week observation period, the subjects were treated with proglumide in 400 mg capsules three times daily (1200 mg per day) by mouth for 12 weeks, and then subjects returned for a safety visit 4 weeks after the discontinuation of the study medication. The results of three pain surveys (Numeric Rating Scale, COMPAT-SF, and NIH PROMIS) showed that the patients had significantly less pain after 12 weeks of proglumide compared to the pre-treatment observation phase. Of the eight subjects in this study, two experienced nausea and diarrhea with proglumide. These side effects resolved in one subject with doses reduced to 800 mg per day. No abnormalities were noted in the blood chemistries. A blood microRNA blood biomarker panel that corresponded to pancreatic inflammation and fibrosis showed significant improvement. We conclude that proglumide is safe and well tolerated in most subjects with CP at a dose of 1200 mg per day. Furthermore, proglumide therapy may have a beneficial effect by decreasing pain associated with CP. Full article

(This article belongs to the Special Issue New Pharmaceutical Targets to Counteract Chronic Inflammation)

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16 pages, 6430 KiB

Open AccessEditor’s ChoiceArticle

Linseed Oil-Based Oleogel Vehicles for Hydrophobic Drug Delivery—Physicochemical and Applicative Properties

by Sonia Kudłacik-Kramarczyk, Anna Drabczyk, Alicja Przybyłowicz and Marcel Krzan

Pharmaceutics 2024, 16(5), 600; https://doi.org/10.3390/pharmaceutics16050600 - 29 Apr 2024

Viewed by 929

Abstract

In this study, a methodology for synthesizing oleogels based on linseed oil and emulsifiers, such as beeswax and Tween 20 and Tween 80, was developed. Linseed oil served as the main oil phase, while beeswax acted as a gelling and emulsifying agent. Tween [...] Read more.

In this study, a methodology for synthesizing oleogels based on linseed oil and emulsifiers, such as beeswax and Tween 20 and Tween 80, was developed. Linseed oil served as the main oil phase, while beeswax acted as a gelling and emulsifying agent. Tween compounds are non-ionic surfactants composed of hydrophobic and hydrophilic parts, allowing for the formation of a stable system with promising properties. Surface wetting analysis of the obtained oleogels, FT-IR spectroscopy, and determination of relative and absolute humidity over time, as well as optical microscope analysis and rheological analysis of the obtained oleogels, were conducted as part of the research. The results indicate that increasing the amount of Tween 20 decreases the hydrophilicity of the oleogel, while Tween 80 exhibits the opposite effect. Surface energy analysis suggests that a higher content of Tween 20 may lead to a reduction in the surface energy of the oleogels, which may indicate greater material stability. Changes in relative humidity and FT-IR spectral analysis confirm the influence of emulsifiers on the presence of characteristic functional groups in the structure of the oleogels. Additionally, microscopic analysis suggests that an emulsifier with a longer hydrophobic tail leads to a denser material structure. Full article

(This article belongs to the Special Issue Functional Biomaterials in Biomedical Applications)

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24 pages, 3776 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Surfactant Spheroidal Micelle Structure for Pharmaceutical Applications: A Novel Analytical Framework

by Liberato De Caro, Thibaud Stoll, Arnaud Grandeury, Fabia Gozzo and Cinzia Giannini

Pharmaceutics 2024, 16(5), 604; https://doi.org/10.3390/pharmaceutics16050604 - 29 Apr 2024

Viewed by 938

Abstract

We introduce an innovative theoretical framework tailored for the analysis of Pair Distribution Function (PDF) data derived from Small-Angle X-ray Scattering (SAXS) measurements of core-shell micelles. The new approach involves the exploitation of the first derivative of the PDF and the derivation of [...] Read more.

We introduce an innovative theoretical framework tailored for the analysis of Pair Distribution Function (PDF) data derived from Small-Angle X-ray Scattering (SAXS) measurements of core-shell micelles. The new approach involves the exploitation of the first derivative of the PDF and the derivation of analytical equations to solve the core-shell micelle structure under the hypothesis of a spheroidal shape. These analytical equations enable us to determine the micelle’s aggregation number, degree of ellipticity, and contrast in electron density between the core-shell and shell-buffer regions after having determined the whole micelle size and its shell size from the analysis of the first derivative of the PDF. We have formulated an overdetermined system of analytical equations based on the unknowns that characterize the micelle structure. This allows us to establish a Figure of Merit, which is utilized to identify the most reliable solution within the system of equations. Full article

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18 pages, 10346 KiB

Open AccessEditor’s ChoiceArticle

Development of 5-Fluorouracil/pH-Responsive Adjuvant-Embedded Extracellular Vesicles for Targeting α_vβ₃ Integrin Receptors in Tumors

by Jiseung Kim, Eunsol Lee and Eun Seong Lee

Pharmaceutics 2024, 16(5), 599; https://doi.org/10.3390/pharmaceutics16050599 - 29 Apr 2024

Viewed by 1123

Abstract

To selectively target and treat murine melanoma B16BL6 tumors expressing α_vβ₃ integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic [...] Read more.

To selectively target and treat murine melanoma B16BL6 tumors expressing α_vβ₃ integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic arginine-glycine-aspartic acid peptide (cRGD, serving as a tumor-targeting ligand), and 5-fluorouracil (5-FU, employed as a model antitumor drug). The pH-responsive adjuvant, essential for modulating drug release, was synthesized by chemically conjugating 3-(diethylamino)propylamine (DEAP) to deoxycholic acid (DOCA, a lipophilic substance capable of integrating into EVs’ membranes), denoted as DEAP-DOCA. The DOCA, preactivated using N-(2-aminoethyl)maleimide (AEM), was chemically coupled with the thiol group of the cRGD-DOCA through the thiol–maleimide click reaction, resulting in the formation of cRGD-DOCA. Subsequently, DEAP-DOCA, cRGD-DOCA, and 5-FU were efficiently incorporated into EVs using a sonication method. The resulting tumor-targeting EVs, expressing cRGD ligands, demonstrated enhanced in vitro/in vivo cellular uptake specifically for B16BL6 tumors expressing α_vβ₃ integrin receptors. The ionization characteristics of the DEAP in DEAP-DOCA induced destabilization of the EVs membrane at pH 6.5 through protonation of the DEAP substance, thereby expediting 5-FU release. Consequently, an improvement in the in vivo antitumor efficacy was observed for B16BL6 tumors. Based on these comprehensive in vitro/in vivo findings, we anticipate that this EV system holds substantial promise as an exceptionally effective platform for antitumor therapeutic delivery. Full article

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

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15 pages, 2699 KiB

Open AccessEditor’s ChoiceArticle

Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery

by Xiaolin Xu, Shasha Gao, Qindan Zuo, Jiahao Gong, Xinhao Song, Yongshi Liu, Jing Xiao, Xiaofeng Zhai, Haifeng Sun, Mingzhi Zhang, Xiuge Gao and Dawei Guo

Pharmaceutics 2024, 16(5), 601; https://doi.org/10.3390/pharmaceutics16050601 - 29 Apr 2024

Viewed by 1109

Abstract

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the [...] Read more.

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of −31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake. Full article

(This article belongs to the Special Issue Lipid/Polymer-Based Drug Delivery Systems)

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15 pages, 3790 KiB

Open AccessEditor’s ChoiceArticle

Targeted Thrombolysis with Magnetic Nanotherapeutics: A Translational Assessment

by Ming-Lu Lin, Siao-Yun Wu, Jyh-Ping Chen, Yi-Ching Lu, Shih-Ming Jung, Shiaw-Pyng Wey, Tony Wu and Yunn-Hwa Ma

Pharmaceutics 2024, 16(5), 596; https://doi.org/10.3390/pharmaceutics16050596 - 27 Apr 2024

Viewed by 975

Abstract

Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently [...] Read more.

Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently attached to chitosan-coated magnetic nanoparticles (chitosan-MNP-rtPA). The thrombolytic activity of a chitosan-MNP-rtPA was preserved by protection from an endogenous plasminogen activator inhibitor-1 (PAI-1) in whole blood and after circulation in vivo, as examined by thromboelastometry. Single-photon emission computed tomography (SPECT) demonstrated real-time retention of a ^99mTc-MNP-rtPA induced by magnet application in a rat embolic model; an 80% reduction in rtPA dosage for a chitosan-MNP-rtPA with magnetic guidance was shown to restore blood flow. After treatment, iron deposition was observed in the reticuloendothelial systems, with portal edema and neutrophil infiltration in the liver at a ten-fold higher dose but not the regular dose. Nevertheless, no liver or renal toxicity was observed at this higher dose. In conclusion, the liver may still be the major deposit site of rtPA nanocomposites after targeted delivery; chitosan-coated MNPs are potentially amenable to target therapeutics with parenteral administration. Full article

(This article belongs to the Special Issue Recent Advances in Biomedical Applications of Magnetic Nanomaterials)

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19 pages, 5058 KiB

Open AccessEditor’s ChoiceArticle

Development and Efficacy Evaluation of Innovative Cosmetic Formulations with Caryocar brasiliense Fruit Pulp Oil Encapsulated in Freeze-Dried Liposomes

by Letícia Kakuda, Patrícia M. B. G. Maia Campos and Wanderley P. Oliveira

Pharmaceutics 2024, 16(5), 595; https://doi.org/10.3390/pharmaceutics16050595 - 27 Apr 2024

Cited by 1 | Viewed by 1320

Abstract

Encapsulation and drying technologies allow the engineering of innovative raw materials from plant biodiversity, with potential applications in pharmaceutical and cosmetic fields. Lipid-based nanoencapsulation stands out for its efficiency, ease of production, and versatility in encapsulating substances, whether hydrophilic or lipophilic. This work [...] Read more.

Encapsulation and drying technologies allow the engineering of innovative raw materials from plant biodiversity, with potential applications in pharmaceutical and cosmetic fields. Lipid-based nanoencapsulation stands out for its efficiency, ease of production, and versatility in encapsulating substances, whether hydrophilic or lipophilic. This work aimed at encapsulating pequi oil in liposomes and freeze-dried liposomes to enhance its stability and functional benefits, such as skin hydration and anti-aging effects, for use in innovative cosmetic formulations. Pequi oil—extracted from the Caryocar brasiliense fruit pulp, a plant species from Brazilian plant biodiversity—is rich in secondary metabolites and fatty acids. Liposomes and dried liposomes offer controlled production processes and seamless integration into cosmetic formulations. The physicochemical analysis of the developed liposomes confirmed that the formulations are homogeneous and electrokinetically stable, as evidenced by consistent particle size distribution and zeta potential values, respectively. The gel-type formulations loaded with the dried liposomes exhibit enhanced skin hydration, improved barrier function, and refined microrelief, indicating improvements in skin conditions. These results highlight the potential of dried liposomes containing pequi oil for the development of innovative cosmeceutical products. This research contributes to the valorization of Brazilian biodiversity by presenting an innovative approach to leveraging the dermatological benefits of pequi oil in cosmetic applications. Full article

(This article belongs to the Special Issue Spray Drying and Encapsulation of Pharmaceuticals and Phytopharmaceuticals)

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18 pages, 7262 KiB

Open AccessEditor’s ChoiceArticle

QbD Approach-Based Preparation and Optimization of Hydrophobic Ion-Pairing Complex of Lysozyme with Sodium Dodecyl Sulphate to Enhance Stability in Lipid-Based Carriers

by Alharith A. A. Hassan, Tamás Sovány, Krisztián Pamlényi, Martin Deák, Viktória Hornok, Edit Csapó, Géza Regdon, Jr., Ildikó Csóka and Katalin Kristó

Pharmaceutics 2024, 16(5), 589; https://doi.org/10.3390/pharmaceutics16050589 - 26 Apr 2024

Viewed by 1109

Abstract

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the [...] Read more.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods. Full article

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

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17 pages, 13528 KiB

Open AccessEditor’s ChoiceArticle

Taste-Masked Pellets of Warfarin Sodium: Formulation towards the Dose Personalisation

by Lakija Kovalenko, Kirils Kukuls, Marta Berga and Valentyn Mohylyuk

Pharmaceutics 2024, 16(5), 586; https://doi.org/10.3390/pharmaceutics16050586 - 26 Apr 2024

Viewed by 1386

Abstract

The bitter drug, warfarin, has a narrow therapeutic index (NTI) and is used in paediatrics and geriatrics. The aim of this feasibility study was to formulate the taste-masked warfarin-containing pellets to be applicable for dose personalisation and to improve patient compliance, as well [...] Read more.

The bitter drug, warfarin, has a narrow therapeutic index (NTI) and is used in paediatrics and geriatrics. The aim of this feasibility study was to formulate the taste-masked warfarin-containing pellets to be applicable for dose personalisation and to improve patient compliance, as well as to investigate the effect of the core type (PharSQ^® Spheres M, CELPHERE™ CP-507, and NaCl) on the warfarin release from the Kollicoat^® Smartseal taste-masking-coated pellets. The cores were successfully drug-loaded and coated in a fluid-bed coater with a Wurster insert. An increase in particle size and particle size distribution was observed by optical microscopy. In saliva-simulated pH, at the Kollicoat^® Smartseal level of 2 mg/cm², none of the pellets demonstrated drug release, confirming their efficient taste-masking. However, in a stomach-simulated pH, a faster drug release was observed from PharSQ^® Spheres M- and CELPHERE™ CP-507-coated pellets in comparison with NaCl cores. Additional experiments allowed us to explain the slower drug release from NaCl-containing pellets because of the salting-out effect. Despite the successful taste masking, the drug release from pellets was relatively slow (not more than 91% per 60 min), allowing for further formulation improvements. Full article

(This article belongs to the Special Issue Dosage Form Design for Oral Administration)

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20 pages, 2459 KiB

Open AccessEditor’s ChoiceArticle

Co-Delivery of an Innovative Organoselenium Compound and Paclitaxel by pH-Responsive PCL Nanoparticles to Synergistically Overcome Multidrug Resistance in Cancer

by Daniela Mathes, Letícia Bueno Macedo, Taís Baldissera Pieta, Bianca Costa Maia, Oscar Endrigo Dorneles Rodrigues, Julliano Guerin Leal, Marcelo Wendt, Clarice Madalena Bueno Rolim, Montserrat Mitjans and Daniele Rubert Nogueira-Librelotto

Pharmaceutics 2024, 16(5), 590; https://doi.org/10.3390/pharmaceutics16050590 - 26 Apr 2024

Viewed by 1159

Abstract

In this study, we designed the association of the organoselenium compound 5′-Seleno-(phenyl)-3′-(ferulic-amido)-thymidine (AFAT-Se), a promising innovative nucleoside analogue, with the antitumor drug paclitaxel, in poly(ε-caprolactone) (PCL)-based nanoparticles (NPs). The nanoprecipitation method was used, adding the lysine-based surfactant, 77KS, as a pH-responsive adjuvant. The [...] Read more.

In this study, we designed the association of the organoselenium compound 5′-Seleno-(phenyl)-3′-(ferulic-amido)-thymidine (AFAT-Se), a promising innovative nucleoside analogue, with the antitumor drug paclitaxel, in poly(ε-caprolactone) (PCL)-based nanoparticles (NPs). The nanoprecipitation method was used, adding the lysine-based surfactant, 77KS, as a pH-responsive adjuvant. The physicochemical properties presented by the proposed NPs were consistent with expectations. The co-nanoencapsulation of the bioactive compounds maintained the antioxidant activity of the association and evidenced greater antiproliferative activity in the resistant/MDR tumor cell line NCI/ADR-RES, both in the monolayer/two-dimensional (2D) and in the spheroid/three-dimensional (3D) assays. Hemocompatibility studies indicated the safety of the nanoformulation, corroborating the ability to spare non-tumor 3T3 cells and human mononuclear cells of peripheral blood (PBMCs) from cytotoxic effects, indicating its selectivity for the cancerous cells. Furthermore, the synergistic antiproliferative effect was found for both the association of free compounds and the co-encapsulated formulation. These findings highlight the antitumor potential of combining these bioactives, and the proposed nanoformulation as a potentially safe and effective strategy to overcome multidrug resistance in cancer therapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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17 pages, 8529 KiB

Open AccessEditor’s ChoiceArticle

Mass Production of Rg1-Loaded Small Extracellular Vesicles Using a 3D Bioreactor System for Enhanced Cardioprotective Efficacy of Doxorubicin-Induced Cardiotoxicity

by Yunfeng Di, Shuang Zhao, Huilan Fan, Wei Li, Guangjian Jiang, Yong Wang, Chun Li, Wei Wang and Jingyu Wang

Pharmaceutics 2024, 16(5), 593; https://doi.org/10.3390/pharmaceutics16050593 - 26 Apr 2024

Viewed by 1159

Abstract

Background: Small extracellular vesicles (sEVs) obtained from human umbilical cord mesenchymal stromal cells (MSCs) have shown cardioprotective efficacy in doxorubicin-induced cardiotoxicity (DIC). However, their clinical application is limited due to the low yield and high consumption. This study aims to achieve large-scale production [...] Read more.

Background: Small extracellular vesicles (sEVs) obtained from human umbilical cord mesenchymal stromal cells (MSCs) have shown cardioprotective efficacy in doxorubicin-induced cardiotoxicity (DIC). However, their clinical application is limited due to the low yield and high consumption. This study aims to achieve large-scale production of sEVs using a three-dimensional (3D) bioreactor system. In addition, sEVs were developed to deliver Ginsenoside Rg1 (Rg1), a compound derived from traditional Chinese medicine, Ginseng, that has cardioprotective properties but limited bioavailability, to enhance the treatment of DIC. Methods: The 3D bioreactor system with spinner flasks was used to expand human umbilical cord MSCs and collect MSC-conditioned medium. Subsequently, sEVs were isolated from the conditioned medium using differential ultra-centrifugation (dUC). The sEVs were loaded with Ginsenoside Rg1 by electroporation and evaluated for cardioprotective efficacy using Cell Counting Kit-8 (CCK-8) analysis, Annexin V/PI staining and live cell count of H9c2 cells under DIC. Results: Using the 3D bioreactor system with spinner flasks, the expansion of MSCs reached ~600 million, and the production of sEVs was up to 2.2 × 10¹² particles in five days with significantly reduced bench work compared to traditional 2D flasks. With the optimized protocol, the Ginsenoside Rg1 loading efficiency of sEVs by electroporation was ~21%, higher than sonication or co-incubation. Moreover, Rg1-loaded sEVs had attenuated DOX-induced cardiotoxicity with reduced apoptosis compared to free Ginsenoside Rg1 or sEVs. Conclusions: The 3D culture system scaled up the production of sEVs, which facilitated the Rg1 delivery and attenuated cardiomyocyte apoptosis, suggesting a potential treatment of DOX-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Advances in Exosomes in Drug Delivery Systems)

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23 pages, 6324 KiB

Open AccessEditor’s ChoiceArticle

Investigating the Influence of Processing Conditions on Dissolution and Physical Stability of Solid Dispersions with Fenofibrate and Mesoporous Silica

by Ana Baumgartner, Nina Dobaj and Odon Planinšek

Pharmaceutics 2024, 16(5), 575; https://doi.org/10.3390/pharmaceutics16050575 - 24 Apr 2024

Cited by 2 | Viewed by 881

Abstract

The study aimed to enhance the solubility of the poorly water-soluble drug, fenofibrate, by loading it onto mesoporous silica, forming amorphous solid dispersions. Solid dispersions with 30% fenofibrate were prepared using the solvent evaporation method with three solvents (ethyl acetate, acetone, and isopropanol) [...] Read more.

The study aimed to enhance the solubility of the poorly water-soluble drug, fenofibrate, by loading it onto mesoporous silica, forming amorphous solid dispersions. Solid dispersions with 30% fenofibrate were prepared using the solvent evaporation method with three solvents (ethyl acetate, acetone, and isopropanol) at different temperatures (40 °C, boiling point temperature). Various characteristics, including solid-state properties, particle morphology, and drug release, were evaluated by different methods and compared to a pure drug and a physical mixture of fenofibrate and silica. Results revealed that higher solvent temperatures facilitated complete amorphization and rapid drug release, with solvent choice having a lesser impact. The optimal conditions for preparation were identified as ethyl acetate at boiling point temperature. Solid dispersions with different fenofibrate amounts (20%, 25%, 35%) were prepared under these conditions. All formulations were fully amorphous, and their dissolution profiles were comparable to the formulation with 30% fenofibrate. Stability assessments after 8 weeks at 40 °C and 75% relative humidity indicated that formulations prepared with ethyl acetate and at 40 °C were physically stable. Interestingly, some formulations showed improved dissolution profiles compared to initial tests. In conclusion, mesoporous silica-based solid dispersions effectively improved fenofibrate dissolution and demonstrated good physical stability if prepared under appropriate conditions. Full article

(This article belongs to the Special Issue Mesoporous Silica-Based Materials in Drug Delivery and Controlled Release)

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13 pages, 1331 KiB

Open AccessEditor’s ChoiceArticle

Pharmaceutical Compounding in Veterinary Medicine: Suspension of Itraconazole

by Gema J. Cabañero-Resta, Bárbara Sánchez-Dengra, Alejandro Ruiz-Picazo, Marival Bermejo, Virginia Merino, Isabel Gonzalez-Alvarez and Marta Gonzalez-Alvarez

Pharmaceutics 2024, 16(5), 576; https://doi.org/10.3390/pharmaceutics16050576 - 24 Apr 2024

Viewed by 1133

Abstract

Itraconazole is a drug used in veterinary medicine for the treatment of different varieties of dermatophytosis at doses between 3–5 mg/kg/day in cats. Nevertheless, in Spain, it is only available in the market as a 52 mL suspension at 10 mg/mL. The lack [...] Read more.

Itraconazole is a drug used in veterinary medicine for the treatment of different varieties of dermatophytosis at doses between 3–5 mg/kg/day in cats. Nevertheless, in Spain, it is only available in the market as a 52 mL suspension at 10 mg/mL. The lack of alternative formulations, which provide sufficient formulation to cover the treatment of large animals or allow the treatment of a group of them, can be overcome with compounding. For this purpose, it has to be considered that itraconazole is a weak base, class II compound, according to the Biopharmaceutics Classification System, that can precipitate when reaching the duodenum. The aim of this work is to develop alternative oral formulations of itraconazole for the treatment of dermatophytosis. Several oral compounds of itraconazole were prepared and compared, in terms of dissolution rate, permeability, and stability, in order to provide alternatives to the medicine commercialized. The most promising formulation contained hydroxypropyl methylcellulose and β-cyclodextrin. This combination of excipients was capable of dissolving the same concentration as the reference product and delaying the precipitation of itraconazole upon leaving the stomach. Moreover, the intestinal permeability of itraconazole was increased more than two-fold. Full article

(This article belongs to the Special Issue Dose Optimization of Traditional and New Drug Formulations in Veterinary and Human Medicine)

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14 pages, 2158 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Drug Blood-Brain-Barrier Permeability Using a Microfluidic Chip

by Jung Yoon Yang, Dae-Seop Shin, Moonkyu Jeong, Seong Soon Kim, Ha Neul Jeong, Byung Hoi Lee, Kyu-Seok Hwang, Yuji Son, Hyeon-Cheol Jeong, Chi-Hoon Choi, Kyeong-Ryoon Lee and Myung Ae Bae

Pharmaceutics 2024, 16(5), 574; https://doi.org/10.3390/pharmaceutics16050574 - 23 Apr 2024

Cited by 1 | Viewed by 1933

Abstract

The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a [...] Read more.

The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a variety of in vitro methods to reduce the quantities of drug candidates needed in preclinical and clinical trials. Most prior studies have relied on animal or cell-culture models, which do not fully recapitulate the human BBB. The development of microfluidic models of human-derived BBB cells could address this issue. We analyzed a model for predicting BBB permeability using the Emulate BBB-on-a-chip machine. Ten compounds were evaluated, and their permeabilities were estimated. Our study demonstrated that the permeability trends of ten compounds in our microfluidic-based system resembled those observed in previous animal and cell-based experiments. Furthermore, we established a general correlation between the partition coefficient (

K_{p}

) and the apparent permeability (

P_{a p p}

). In conclusion, we introduced a new paradigm for predicting BBB permeability using microfluidic-based systems. Full article

(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)

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15 pages, 1963 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of the Transport and Binding of Dopamine-Loaded PLGA Nanoparticles for the Treatment of Parkinson’s Disease Using In Vitro Model Systems

by Karin Danz, Jana Fleddermann, Marcus Koch, Elena Fecioru, Lorenz Maahs, Nicole Kinsinger, Johannes Krämer, Annette Kraegeloh and Sylvia Wagner

Pharmaceutics 2024, 16(5), 571; https://doi.org/10.3390/pharmaceutics16050571 - 23 Apr 2024

Viewed by 966

Abstract

The treatment of Parkinson’s disease has been moving into the focus of pharmaceutical development. Yet, the necessity for reliable model systems in the development phase has made research challenging and in vivo models necessary. We have established reliable, reproducible in vitro model systems [...] Read more.

The treatment of Parkinson’s disease has been moving into the focus of pharmaceutical development. Yet, the necessity for reliable model systems in the development phase has made research challenging and in vivo models necessary. We have established reliable, reproducible in vitro model systems to evaluate the binding and transport of dopamine-loaded PLGA nanoparticles for the treatment of Parkinson’s disease and put the results in context with comparable in vivo results. The in vitro models have provided similar results concerning the usability of the investigated nanoparticles as the previously used in vivo models and thus provide a good alternative in line with the 3R principles in pharmaceutical research. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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19 pages, 8253 KiB

Open AccessEditor’s ChoiceArticle

Nucleolin-Targeting AS1411 Aptamer-Conjugated Nanospheres for Targeted Treatment of Glioblastoma

by Kyeongjin Seo, Kihwan Hwang, Kyung Mi Nam, Min Ju Kim, Yoon-Kyu Song and Chae-Yong Kim

Pharmaceutics 2024, 16(4), 566; https://doi.org/10.3390/pharmaceutics16040566 - 21 Apr 2024

Viewed by 1823

Abstract

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in [...] Read more.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres (100–300 nm in size) loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than non-specific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study reveals the potential for anti-cancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labeling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier allowing for the precise targeting of tumors. This combination has the potential to produce anti-tumor effects in the active targeted therapy of GBM. Full article

(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)

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14 pages, 4213 KiB

Open AccessEditor’s ChoiceArticle

Modulating the Nature of Ionizable Lipids and Number of Layers in Hyaluronan-Decorated Lipid Nanoparticles for In Vitro Delivery of RNAi

by Victor Passos Gibson, Houda Tahiri, Claudia Gilbert, Chun Yang, Quoc Thang Phan, Xavier Banquy and Pierre Hardy

Pharmaceutics 2024, 16(4), 563; https://doi.org/10.3390/pharmaceutics16040563 - 20 Apr 2024

Cited by 1 | Viewed by 1402

Abstract

Lipid nanoparticles (LNPs) have established their position as nonviral vectors for gene therapy. Tremendous efforts have been made to modulate the properties of LNPs to unleash their full clinical potential. Among the strategies being pursued, the layer-by-layer (LbL) technique has gained considerable attention [...] Read more.

Lipid nanoparticles (LNPs) have established their position as nonviral vectors for gene therapy. Tremendous efforts have been made to modulate the properties of LNPs to unleash their full clinical potential. Among the strategies being pursued, the layer-by-layer (LbL) technique has gained considerable attention in the biomedical field. Illuminated by our previous work, here we investigate if the LbL approach could be used to modify the LNP cores formulated with three different ionizable lipids: DODMA, MC3, and DODAP. Additionally, we wondered if more than three layers could be loaded onto LNPs without disrupting their gene transfection ability. Taking advantage of physicochemical analysis, as well as uptake and gene silencing studies, we demonstrate the feasibility of modifying the surface of LNPs with the LbL assembly. Precisely, we successfully modified three different LNPs using the layer-by-layer strategy which abrogated luciferase activity in vitro. Additionally, we constructed a 5×-layered HA-LNP containing the MC3 ionizable lipid which outperformed the 3×-layered counterpart in transfecting miRNA-181-5p to the pediatric GBM cell line, as a proof-of-concept in vitro experiment. The method used herein has been proven reproducible, of easy modification to adapt to different ionizable lipid-containing LNPs, and holds great potential for the translation of RNA-based therapeutic strategies. Full article

(This article belongs to the Special Issue New Nano-Systems for Imaging, Diagnostics, and Drug Delivery)

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21 pages, 3239 KiB

Open AccessEditor’s ChoiceArticle

Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice

by Lina Zhou, Sandip Godse, Namita Sinha, Sunitha Kodidela, Udai Singh and Santosh Kumar

Pharmaceutics 2024, 16(4), 555; https://doi.org/10.3390/pharmaceutics16040555 - 19 Apr 2024

Viewed by 1349

Abstract

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using [...] Read more.

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders. Full article

(This article belongs to the Special Issue Next Generation of PLGA-Based Nanoparticles as Drug Delivery Systems for Biomedical Applications)

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20 pages, 7878 KiB

Open AccessEditor’s ChoiceArticle

Host–Guest Complexation of Itraconazole with Cyclodextrins for Bioavailability Enhancement

by Lenuţa-Maria Şuta, Amalia Ridichie, Adriana Ledeţi, Claudia Temereancă, Ionuţ Ledeţi, Delia Muntean, Matilda Rădulescu, Renata-Maria Văruţ, Claudia Watz, Florentin Crăineanu, Denisa Ivan, Gabriela Vlase and Lavinia Stelea

Pharmaceutics 2024, 16(4), 560; https://doi.org/10.3390/pharmaceutics16040560 - 19 Apr 2024

Viewed by 1046

Abstract

Itraconazole is an antifungal agent included in the triazole pharmacological classification that belongs to the BCS class II, characterized by a low solubility in an aqueous medium (of 1 ng/mL, at neutral pH), which is frequently translated in a low oral bioavailability but [...] Read more.

Itraconazole is an antifungal agent included in the triazole pharmacological classification that belongs to the BCS class II, characterized by a low solubility in an aqueous medium (of 1 ng/mL, at neutral pH), which is frequently translated in a low oral bioavailability but with a high permeability. In this sense, it is necessary to find solutions to increase/improve the solubility of itraconazole in the aqueous environment. The main purpose of this study is the preparation and analysis of five different guest–host inclusion complexes containing intraconazole. Initially, a blind docking process was carried out to determine the interactions between itraconazole and the selected cyclodextrins. The second step of the study was to find out if the active pharmaceutical ingredient was entrapped in the cavity of the cyclodextrin, by using spectroscopic and thermal techniques. Also, the antifungal activity of the inclusion complexes was studied to examine if the entrapment of itraconazole influences the therapeutic effect. The results showed that the active substance was entrapped in the cavity of the cyclodextrins, with a molar ratio of 1:3 (itraconazole–cyclodextrin), and that the therapeutic effect was not influenced by the entrapment. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Delivery, 2nd Edition)

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18 pages, 4654 KiB

Open AccessEditor’s ChoiceArticle

Polymeric Amorphous Solid Dispersions of Dasatinib: Formulation and Ecotoxicological Assessment

by Katarina Sokač, Martina Miloloža, Dajana Kučić Grgić and Krunoslav Žižek

Pharmaceutics 2024, 16(4), 551; https://doi.org/10.3390/pharmaceutics16040551 - 18 Apr 2024

Viewed by 1702

Abstract

Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). [...] Read more.

Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). Drug amorphization was induced in a planetary ball mill by solvent-free co-grinding, facilitating mechanochemical activation. This process resulted in the formation of amorphous solid dispersions (ASDs). The ASD capsules exhibited a notable enhancement in the release rate of DAS compared to capsules containing the initial drug. Given that anticancer drugs often undergo limited metabolism in the body with unchanged excretion, the ecotoxicological effect of the native form of DAS was investigated as well, considering its potential accumulation in the environment. The highest ecotoxicological effect was observed on the bacteria Vibrio fischeri, while other test organisms (bacteria Pseudomonas putida, microalgae Chlorella sp., and duckweed Lemna minor) exhibited negligible effects. The enhanced drug release not only contributes to improved oral absorption but also has the potential to reduce the proportion of DAS that enters the environment through human excretion. This comprehensive approach highlights the significance of integrating advances in drug development while considering its environmental implications. Full article

(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)

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18 pages, 3752 KiB

Open AccessEditor’s ChoiceArticle

Early Detection of Myeloid-Derived Suppressor Cells in the Lung Pre-Metastatic Niche by Shortwave Infrared Nanoprobes

by Jake N. Siebert, Jay V. Shah, Mei Chee Tan, Richard E. Riman, Mark C. Pierce, Edmund C. Lattime, Vidya Ganapathy and Prabhas V. Moghe

Pharmaceutics 2024, 16(4), 549; https://doi.org/10.3390/pharmaceutics16040549 - 17 Apr 2024

Viewed by 1545

Abstract

Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support [...] Read more.

Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support the colonization and growth of circulating tumor cells, a key component of which is the myeloid-derived suppressor cell (MDSC). Therefore, the MDSC has been identified as a potential biomarker for PMN formation, the detection of which would enable clinicians to proactively treat metastases. However, there is currently no technology capable of the in situ detection of MDSCs available in the clinic. Here, we propose the use of shortwave infrared-emitting nanoprobes for the tracking of MDSCs and identification of the PMN. Our rare-earth albumin nanocomposites (ReANCs) are engineered to bind the Gr-1 surface marker of murine MDSCs. When delivered intravenously in murine models of breast cancer with high rates of metastasis, the targeted ReANCs demonstrated an increase in localization to the lungs in comparison to control ReANCs. However, no difference was seen in the model with slower rates of metastasis. This highlights the potential utility of MDSC-targeted nanoprobes to assess PMN development and prognosticate disease progression. Full article

(This article belongs to the Special Issue Cancer Nanomedicine—from the Bench to the Bedside, 2nd Edition)

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23 pages, 5698 KiB

Open AccessEditor’s ChoiceArticle

Preparation and Characterization of Polymeric Microparticles Based on Poly(ethylene brassylate-co-squaric Acid) Loaded with Norfloxacin

by Alexandru-Mihail Șerban, Isabella Nacu, Irina Rosca, Alina Ghilan, Alina Gabriela Rusu, Loredana Elena Niță, Raluca Nicoleta Darie-Niță and Aurica P. Chiriac

Pharmaceutics 2024, 16(4), 550; https://doi.org/10.3390/pharmaceutics16040550 - 17 Apr 2024

Cited by 1 | Viewed by 1046

Abstract

In recent years, increasing interest has been accorded to polyester-based polymer microstructures, driven by their promising potential as advanced drug delivery systems. This study presents the preparation and characterization of new polymeric microparticles based on poly(ethylene brassylate-co-squaric acid) loaded with norfloxacin, a broad-spectrum [...] Read more.

In recent years, increasing interest has been accorded to polyester-based polymer microstructures, driven by their promising potential as advanced drug delivery systems. This study presents the preparation and characterization of new polymeric microparticles based on poly(ethylene brassylate-co-squaric acid) loaded with norfloxacin, a broad-spectrum antibiotic. Polymacrolactone was synthesised in mild conditions through the emulsion polymerization of bio-based and renewable monomers, ethylene brassylate, and squaric acid. The microparticles were obtained using the precipitation technique and subsequently subjected to comprehensive characterization. The impact of the copolymer/drug ratio on various properties of the new system was systematically evaluated, confirming the structure of the copolymer and the encapsulation of norfloxacin. The microspheres are approximately spherical and predominantly homogeneously distributed. The average hydrodynamic diameter of the microparticles falls between 400 and 2000 nm, a decrease that is observed with the increase in norfloxacin content. All samples showed good encapsulation efficiency and drug loading capacity, with the highest values obtained for microparticles synthesised using an equal ratio of copolymer and drug. In vitro drug release results disclose that norfloxacin molecules are released in a sustained biphasic manner for up to 24 h. Antimicrobial activity was also studied, with samples showing very good activity against E. coli and moderate activity against S. aureus and E. faecalis. In addition, HDFA human fibroblast cell cultures demonstrated the cytocompatibility of the microparticles. Full article

(This article belongs to the Special Issue Recent Advances in Carriers for Drug Delivery: From Structures to Functionality)

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20 pages, 2311 KiB

Open AccessEditor’s ChoiceArticle

LDLR-Mediated Targeting and Productive Uptake of siRNA-Peptide Ligand Conjugates In Vitro and In Vivo

by Baptiste Broc, Karine Varini, Rose Sonnette, Belinda Pecqueux, Florian Benoist, Maxime Masse, Yasmine Mechioukhi, Géraldine Ferracci, Jamal Temsamani, Michel Khrestchatisky, Guillaume Jacquot and Pascaline Lécorché

Pharmaceutics 2024, 16(4), 548; https://doi.org/10.3390/pharmaceutics16040548 - 17 Apr 2024

Viewed by 1702

Abstract

Small RNA molecules such as microRNA and small interfering RNA (siRNA) have become promising therapeutic agents because of their specificity and their potential to modulate gene expression. Any gene of interest can be potentially up- or down-regulated, making RNA-based technology the healthcare breakthrough [...] Read more.

Small RNA molecules such as microRNA and small interfering RNA (siRNA) have become promising therapeutic agents because of their specificity and their potential to modulate gene expression. Any gene of interest can be potentially up- or down-regulated, making RNA-based technology the healthcare breakthrough of our era. However, the functional and specific delivery of siRNAs into tissues of interest and into the cytosol of target cells remains highly challenging, mainly due to the lack of efficient and selective delivery systems. Among the variety of carriers for siRNA delivery, peptides have become essential candidates because of their high selectivity, stability, and conjugation versatility. Here, we describe the development of molecules encompassing siRNAs against SOD1, conjugated to peptides that target the low-density lipoprotein receptor (LDLR), and their biological evaluation both in vitro and in vivo. Full article

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

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15 pages, 2928 KiB

Open AccessEditor’s ChoiceArticle

Cryo-Milled β-Glucan Nanoparticles for Oral Drug Delivery

by Guanyu Chen, Yi Liu, Darren Svirskis, Hongyu Li, Man Ying, Weiyue Lu and Jingyuan Wen

Pharmaceutics 2024, 16(4), 546; https://doi.org/10.3390/pharmaceutics16040546 - 16 Apr 2024

Viewed by 1230

Abstract

Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a [...] Read more.

Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a novel nanoparticulate drug delivery system for the oral delivery of gemcitabine to improve its oral bioavailability. In this study, gemcitabine-loaded β-glucan NPs were fabricated using a film-casting method followed by a freezer-milling technique. As a result, the NPs showed a small particle size of 447.6 ± 14.2 nm, and a high drug entrapment efficiency of 64.3 ± 2.1%. By encapsulating gemcitabine into β-glucan NPs, a sustained drug release profile was obtained, and the anomalous diffusion release mechanism was analyzed, indicating that the drug release was governed by diffusion through the NP matrix as well as matrix erosion. The drug-loaded NPs had a greater ex vivo drug permeation through the porcine intestinal epithelial membrane compared to the plain drug solution. Cytotoxicity studies showed a safety profile of the β-glucan polymers, and the IC_50s of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL⁻¹ and 306.1 ± 46.3 ng·mL⁻¹, respectively. Additionally, the LD₅₀ of BALB/c nude mice was determined as 204.17 mg/kg in the acute toxicity studies. Notably, pharmacokinetic studies showed that drug-loaded β-glucan NPs could achieve a 7.4-fold longer T_1/2 and a 5.1-fold increase in oral bioavailability compared with plain drug solution. Finally, in vivo pharmacodynamic studies showed the promising capability of gemcitabine-loaded β-glucan NPs to inhibit the 4T1 breast tumor growth, with a 3.04- and 1.74-fold reduction compared to the untreated control and drug solution groups, respectively. In conclusion, the presented freezer-milled β-glucan NP system is a suitable drug delivery method for the oral delivery of gemcitabine and demonstrates a promising potential platform for oral chemotherapy. Full article

(This article belongs to the Special Issue Advances in Oral Administration)

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18 pages, 4092 KiB

Open AccessEditor’s ChoiceArticle

First Generic Teriparatide: Structural and Biological Sameness to Its Reference Medicinal Product

by Jimena Fernández-Carneado, Mariona Vallès-Miret, Sílvia Arrastia-Casado, Ana Almazán-Moga, Maria J. Macias, Pau Martin-Malpartida, Marta Vilaseca, Mireia Díaz-Lobo, Mayte Vazquez, Rosa M. Sanahuja, Gemma Gambús and Berta Ponsati

Pharmaceutics 2024, 16(4), 537; https://doi.org/10.3390/pharmaceutics16040537 - 13 Apr 2024

Viewed by 1649

Abstract

Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential [...] Read more.

Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential similarity between synthetic teriparatide BGW and the reference medicinal product (RMP), and thus to ensure the development of the first generic teriparatide drug. Hence, an extensive side-by-side comparative exercise, focusing on structural and biological activity, was performed using a wide range of state-of-the-art orthogonal methods. Nuclear magnetic resonance (NMR), ion mobility–mass spectrometry (IM–MS), UV, circular dichroism (CD) and Fourier transform infrared (FTIR) demonstrated the structural similarity between teriparatide BGW and the RMP. Comparative cell-based bioassays showed that the synthetic and recombinant peptides have identical behaviors. Teriparatide BGW, as a generic drug, provides an available treatment option for patients with osteoporosis and offers clinical benefits identical to those provided by the RMP. Full article

(This article belongs to the Section Biologics and Biosimilars)

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22 pages, 4338 KiB

Open AccessEditor’s ChoiceArticle

Non-Invasive Delivery of Negatively Charged Nanobodies by Anodal Iontophoresis: When Electroosmosis Dominates Electromigration

by Phedra Firdaws Sahraoui, Oscar Vadas and Yogeshvar N. Kalia

Pharmaceutics 2024, 16(4), 539; https://doi.org/10.3390/pharmaceutics16040539 - 13 Apr 2024

Viewed by 1256

Abstract

Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged [...] Read more.

Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged M7D12H nanobody and a series of negatively charged variants with single amino acid substitutions. Surprisingly, M7D12H and its variants were only delivered transdermally by anodal iontophoresis. In contrast, transdermal permeation after cathodal iontophoresis and passive diffusion was <LOQ. The anodal iontophoretic delivery of these negatively charged proteins was achieved because electroosmosis was the dominant electrotransport mechanism. Cutaneous deposition after the anodal iontophoresis of M7D12H_WT (wild type), and the R54E and K65E variants, was statistically superior to that after cathodal iontophoresis (6.07 ± 2.11, 9.22 ± 0.80, and 14.45 ± 3.45 μg/cm², versus 1.12 ± 0.30, 0.72 ± 0.27, and 0.46 ± 0.07 µg/cm², respectively). This was not the case for S102E, where cutaneous deposition after anodal and cathodal iontophoresis was 11.89 ± 0.87 and 8.33 ± 2.62 µg/cm², respectively; thus, a single amino acid substitution appeared to be sufficient to impact the iontophoretic transport of a 17.5 kDa protein. Visualization studies using immunofluorescent labeling showed that skin transport of M7D12H_WT was achieved via the intercellular and follicular routes. Full article

(This article belongs to the Special Issue Transdermal Delivery: Challenges and Opportunities)

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19 pages, 4137 KiB

Open AccessEditor’s ChoiceArticle

Investigation of Photodynamic Therapy Promoted by Cherenkov Light Activated Photosensitizers—New Aspects and Revelations

by Lisa Hübinger, Kerstin Wetzig, Roswitha Runge, Holger Hartmann, Falk Tillner, Katja Tietze, Marc Pretze, David Kästner, Robert Freudenberg, Claudia Brogsitter and Jörg Kotzerke

Pharmaceutics 2024, 16(4), 534; https://doi.org/10.3390/pharmaceutics16040534 - 13 Apr 2024

Viewed by 956

Abstract

This work investigates the proposed enhanced efficacy of photodynamic therapy (PDT) by activating photosensitizers (PSs) with Cherenkov light (CL). The approaches of Yoon et al. to test the effect of CL with external radiation were taken up and refined. The results were used [...] Read more.

This work investigates the proposed enhanced efficacy of photodynamic therapy (PDT) by activating photosensitizers (PSs) with Cherenkov light (CL). The approaches of Yoon et al. to test the effect of CL with external radiation were taken up and refined. The results were used to transfer the applied scheme from external radiation therapy to radionuclide therapy in nuclear medicine. Here, the CL for the activation of the PSs (psoralen and trioxsalen) is generated by the ionizing radiation from rhenium-188 (a high-energy beta-emitter, Re-188). In vitro cell survival studies were performed on FaDu, B16 and 4T1 cells. A characterization of the PSs (absorbance measurement and gel electrophoresis) and the CL produced by Re-188 (luminescence measurement) was performed as well as a comparison of clonogenic assays with and without PSs. The methods of Yoon et al. were reproduced with a beam line at our facility to validate their results. In our studies with different concentrations of PS and considering the negative controls without PS, the statements of Yoon et al. regarding the positive effect of CL could not be confirmed. There are slight differences in survival fractions, but they are not significant when considering the differences in the controls. Gel electrophoresis showed a dominance of trioxsalen over psoralen in conclusion of single and double strand breaks in plasmid DNA, suggesting a superiority of trioxsalen as a PS (when irradiated with UVA). In addition, absorption measurements showed that these PSs do not need to be shielded from ambient light during the experiment. An observational test setup for a PDT nuclear medicine approach was found. The CL spectrum of Re-188 was measured. Fluctuating inconclusive results from clonogenic assays were found. Full article

(This article belongs to the Special Issue Photodynamic Therapy in Cancer: Principles, State of the Art, and Future Directions)

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20 pages, 2693 KiB

Open AccessEditor’s ChoiceArticle

A Novel Class of Human ADAM8 Inhibitory Antibodies for Treatment of Triple-Negative Breast Cancer

by Nora D. Mineva, Stefania Pianetti, Sonia G. Das, Srimathi Srinivasan, Nicolas M. Billiald and Gail E. Sonenshein

Pharmaceutics 2024, 16(4), 536; https://doi.org/10.3390/pharmaceutics16040536 - 13 Apr 2024

Cited by 1 | Viewed by 1492

Abstract

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and [...] Read more.

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange–mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent, 2nd Edition)

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14 pages, 2287 KiB

Open AccessEditor’s ChoiceArticle

Interaction of γ-Polyglutamic Acid/Polyethyleneimine/Plasmid DNA Ternary Complexes with Serum Components Plays a Crucial Role in Transfection in Mice

by Tomotaka Ko, Shintaro Fumoto, Tomoaki Kurosaki, Moe Nakashima, Hirotaka Miyamoto, Hitoshi Sasaki and Koyo Nishida

Pharmaceutics 2024, 16(4), 522; https://doi.org/10.3390/pharmaceutics16040522 - 9 Apr 2024

Cited by 1 | Viewed by 887

Abstract

Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such [...] Read more.

Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such as γ-polyglutamic acid (γ-PGA), can prevent cytotoxicity and hemagglutination. However, the role of interactions between these complexes and serum components in in vivo gene transfer remains unclear. In this study, we analyzed the contribution of serum components to in vivo gene transfer using PEI/plasmid DNA binary complexes and γ-PGA/PEI/plasmid DNA ternary complexes. In binary complexes, heat-labile components in the serum greatly contribute to the hepatic and splenic gene expression of the luciferase gene. In contrast, serum albumin and salts affected the hepatic and splenic gene expression in the ternary complexes. Changes in physicochemical characteristics, such as increased particle size and decreased absolute values of ζ-potential, might be involved in the enhanced gene expression. These findings would contribute to a better understanding of in vivo non-viral gene transfer using polymers, such as PEI and γ-PGA. Full article

(This article belongs to the Section Gene and Cell Therapy)

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10 pages, 706 KiB

Open AccessEditor’s ChoiceCommunication

Therapeutic Aqueous Humor Concentrations of Latanoprost Attained in Rats by Administration in a Very-High-Molecular-Weight Hyaluronic Acid Eye Drop

by Kazunari Higa, Reona Kimoto, Takashi Kojima, Murat Dogru, Wolfgang G. K. Müller-Lierheim and Jun Shimazaki

Pharmaceutics 2024, 16(4), 523; https://doi.org/10.3390/pharmaceutics16040523 - 9 Apr 2024

Cited by 1 | Viewed by 898

Abstract

The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA [...] Read more.

The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA (LPvHiHA), commercial LP (cLP), and diluted LP (dLP)) and after instilling the eye drops, the aqueous humor (AH) was collected at 0.5, 1, 2, 4, and 6 h to measure the LP concentration using an enzyme-linked immunosorbent assay (ELISA). Although the LP concentration in the LPvHiHA eye drop formulation was 3.57 times lower than in the commercial eye drops used (cLP), the LP concentration in the AH following LPvHiHA administration reached a value close to that of cLP. The cLP was diluted to the same concentration of LP as in the LPvHiHA eye drops for the dLP group, but the LP concentration in the AH of these animals was lower than that of the LPvHiHA rats at all time points. The higher LP concentration in the AH of the LPvHiHA rats suggests that vHiHA may aid the transport of LP across the ocular surface epithelium. Full article

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

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14 pages, 7480 KiB

Open AccessEditor’s ChoiceArticle

Size Tuning of Mesoporous Silica Adjuvant for One-Shot Vaccination with Long-Term Anti-Tumor Effect

by Xiupeng Wang, Yu Sogo and Xia Li

Pharmaceutics 2024, 16(4), 516; https://doi.org/10.3390/pharmaceutics16040516 - 8 Apr 2024

Viewed by 1230

Abstract

Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect [...] Read more.

Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect by one-shot vaccination. This strategy is based on the size-dependent immunostimulation mechanism of mesoporous silica particles. Hollow mesoporous silica (HMS) nanoparticles enhance the antigen uptake with dendritic cells around the immunization site in vivo. In contrast, hierarchically porous silica (HPS) microparticles prolong cancer antigen retention and release in vivo. The size tuning of the mesoporous silica adjuvant prepared by combining both nanoparticles and microparticles demonstrates the immunological properties of both components and has a long-term anti-tumor effect after one-shot vaccination. One-shot vaccination with HMS-HPS-ovalbumin (OVA)-Poly IC (PIC, a TLR3 agonist) increases CD4⁺ T cell, CD8⁺ T cell, and CD86⁺ cell populations in draining lymph nodes even 4 months after vaccination, as well as effector memory CD8⁺ T cell and tumor-specific tetramer⁺CD8⁺ T cell populations in splenocytes. The increases in the numbers of effector memory CD8⁺ T cells and tumor-specific tetramer⁺CD8⁺ T cells indicate that the one-shot vaccination with HMS-HPS-OVA-PIC achieved the longest survival time after a challenge with E.G7-OVA cells among all groups. The size tuning of the mesoporous silica adjuvant shows promise for one-shot vaccination that mimics multiple clinical vaccinations in future cancer immunoadjuvant development. This study may have important implications in the long-term vaccine design of one-shot vaccinations. Full article

(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)

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14 pages, 14092 KiB

Open AccessEditor’s ChoiceArticle

Polydopamine-Modified Copper Coordination Mesoporous Silica Nanoparticles Loaded with Disulfiram for Synergistic Chemo-Photothermal Therapy

by Junhong Ling, Yingying Cai, Haozhan Feng, Zhen Liu and Xiao-kun Ouyang

Pharmaceutics 2024, 16(4), 512; https://doi.org/10.3390/pharmaceutics16040512 - 7 Apr 2024

Cited by 2 | Viewed by 1390

Abstract

Disulfiram (DSF) degrades to diethyldithiocarbamate (DTC) in vivo and coordinates with copper ions to form CuET, which has higher antitumor activity. In this study, DSF@CuMSN-PDA nanoparticles were prepared using mesoporous silica with copper ions, DSF as a carrier, and polydopamine (PDA) as a [...] Read more.

Disulfiram (DSF) degrades to diethyldithiocarbamate (DTC) in vivo and coordinates with copper ions to form CuET, which has higher antitumor activity. In this study, DSF@CuMSN-PDA nanoparticles were prepared using mesoporous silica with copper ions, DSF as a carrier, and polydopamine (PDA) as a gate system. The nanoparticles selectively released CuET into tumor tissue by taking advantage of the tumor microenvironment, where PDA could be degraded. The release ratio reached 79.17% at pH 5.0, indicating pH-responsive drug release from the nanoparticles. The PDA-gated system provided the nanoparticles with unique photothermal conversion performance and significantly improved antitumor efficiency. In vivo, antitumor experiments showed that the designed DSF@CuMSN-PDA nanoparticles combined with near-infrared light (808 nm, 1 W/cm²) irradiation effectively inhibited tumor growth in HCT116 cells by harnessing the combined potential of chemotherapy and photothermal therapy; a synergistic effect was achieved. Taken together, these results suggest that the designed DSF@CuMSN-PDA construct can be employed as a promising candidate for combined chemo-photothermal therapy. Full article

(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)

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21 pages, 3557 KiB

Open AccessEditor’s ChoiceArticle

Effect of Micromixer Design on Lipid Nanocarriers Manufacturing for the Delivery of Proteins and Nucleic Acids

by Enrica Chiesa, Alessandro Caimi, Marco Bellotti, Alessia Giglio, Bice Conti, Rossella Dorati, Ferdinando Auricchio and Ida Genta

Pharmaceutics 2024, 16(4), 507; https://doi.org/10.3390/pharmaceutics16040507 - 7 Apr 2024

Cited by 1 | Viewed by 1311

Abstract

Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, [...] Read more.

Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, precise and reproducible nanoparticle attributes. The present work aims to assess the effect of different micromixer geometries on the manufacturing of lipid nanocarriers taking into account the influence on the mixing efficiency by changing the fluid–fluid interface and indeed the mass transfer. Since the geometry of the adopted micromixer varies from those already published, a Design of Experiment (DoE) was necessary to identify the operating (total flow, flow rate ratio) and formulation (lipid concentration, lipid molar ratios) parameters affecting the nanocarrier quality. The suitable application of the platform was investigated by producing neutral, stealth and cationic liposomes, using DaunoXome^®, Myocet^®, Onivyde^® and Onpattro^® as the benchmark. The effect of condensing lipid (DOTAP, 3–10–20 mol%), coating lipids (DSPE-PEG550 and DSPE-PEG2000), as well as structural lipids (DSPC, eggPC) was pointed out. A very satisfactory encapsulation efficiency, always higher than 70%, was successfully obtained for model biomolecules (myoglobin, short and long nucleic acids). Full article

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

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16 pages, 3464 KiB

Open AccessEditor’s ChoiceArticle

Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation

by Yong-Kyun Kim, Kyeong-Min Jo, Jae-Ha Lee, Ji-Hoon Jang, Eun-Jun Choe, Gaeun Kang, Dae-Young Zang and Dong-Hwan Lee

Pharmaceutics 2024, 16(4), 499; https://doi.org/10.3390/pharmaceutics16040499 - 5 Apr 2024

Viewed by 1182

Abstract

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK [...] Read more.

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations. Full article

(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)

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29 pages, 1791 KiB

Open AccessEditor’s ChoiceArticle

Comparative Fitting of Mathematical Models to Carvedilol Release Profiles Obtained from Hypromellose Matrix Tablets

by Tadej Ojsteršek, Franc Vrečer and Grega Hudovornik

Pharmaceutics 2024, 16(4), 498; https://doi.org/10.3390/pharmaceutics16040498 - 4 Apr 2024

Viewed by 917

Abstract

The mathematical models available in DDSolver were applied to experimental dissolution data obtained by analysing carvedilol release from hypromellose (HPMC)-based matrix tablets. Different carvedilol release profiles were generated by varying a comprehensive selection of fillers and carvedilol release modifiers in the formulation. Model [...] Read more.

The mathematical models available in DDSolver were applied to experimental dissolution data obtained by analysing carvedilol release from hypromellose (HPMC)-based matrix tablets. Different carvedilol release profiles were generated by varying a comprehensive selection of fillers and carvedilol release modifiers in the formulation. Model fitting was conducted for the entire relevant dissolution data, as determined by using a paired t-test, and independently for dissolution data up to approximately 60% of carvedilol released. The best models were selected based on the residual sum of squares (RSS) results used as a general measure of goodness of fit, along with the utilization of various criteria for visual assessment of model fit and determination of the acceptability of estimated model parameters indicating burst release or lag time concerning experimental dissolution results and previous research. In addition, a model-dependent analysis of carvedilol release mechanisms was carried out. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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19 pages, 3966 KiB

Open AccessEditor’s ChoiceArticle

Membrane-Fusing Vehicles for Re-Sensitizing Transporter-Mediated Multiple-Drug Resistance in Cancer

by Sahel Vahdati and Alf Lamprecht

Pharmaceutics 2024, 16(4), 493; https://doi.org/10.3390/pharmaceutics16040493 - 2 Apr 2024

Cited by 1 | Viewed by 1009

Abstract

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three [...] Read more.

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC₅₀ value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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20 pages, 5222 KiB

Open AccessEditor’s ChoiceArticle

Unraveling Drug Delivery from Cyclodextrin Polymer-Coated Breast Implants: Integrating a Unidirectional Diffusion Mathematical Model with COMSOL Simulations

by Jacobo Hernandez-Montelongo, Javiera Salazar-Araya, Elizabeth Mas-Hernández, Douglas Soares Oliveira and Juan Paulo Garcia-Sandoval

Pharmaceutics 2024, 16(4), 486; https://doi.org/10.3390/pharmaceutics16040486 - 2 Apr 2024

Viewed by 1272

Abstract

Breast cancer ranks among the most commonly diagnosed cancers worldwide and bears the highest mortality rate. As an integral component of cancer treatment, mastectomy entails the complete removal of the affected breast. Typically, breast reconstruction, involving the use of silicone implants (augmentation mammaplasty), [...] Read more.

Breast cancer ranks among the most commonly diagnosed cancers worldwide and bears the highest mortality rate. As an integral component of cancer treatment, mastectomy entails the complete removal of the affected breast. Typically, breast reconstruction, involving the use of silicone implants (augmentation mammaplasty), is employed to address the aftermath of mastectomy. To mitigate postoperative risks associated with mammaplasty, such as capsular contracture or bacterial infections, the functionalization of breast implants with coatings of cyclodextrin polymers as drug delivery systems represents an excellent alternative. In this context, our work focuses on the application of a mathematical model for simulating drug release from breast implants coated with cyclodextrin polymers. The proposed model considers a unidirectional diffusion process following Fick’s second law, which was solved using the orthogonal collocation method, a numerical technique employed to approximate solutions for ordinary and partial differential equations. We conducted simulations to obtain release profiles for three therapeutic molecules: pirfenidone, used for preventing capsular contracture; rose Bengal, an anticancer agent; and the antimicrobial peptide KR-12. Furthermore, we calculated the diffusion profiles of these drugs through the cyclodextrin polymers, determining parameters related to diffusivity, solute solid–liquid partition coefficients, and the Sherwood number. Finally, integrating these parameters in COMSOL multiphysics simulations, the unidirectional diffusion mathematical model was validated. Full article

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

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30 pages, 6228 KiB

Open AccessEditor’s ChoiceArticle

The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine

by Khairulanwar Burhanuddin, Afzal Mohammed and Raj K. S. Badhan

Pharmaceutics 2024, 16(4), 489; https://doi.org/10.3390/pharmaceutics16040489 - 2 Apr 2024

Viewed by 1407

Abstract

The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity [...] Read more.

The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity on amlodipine pharmacokinetics and the need for dose adjustment has not been studied previously. This study applied the physiologically based pharmacokinetic modelling and established a paediatric obesity population to assess the impact of obesity on amlodipine pharmacokinetics in children and explore the possible dose adjustments required to reach the same plasma concentration as non-obese paediatrics. The difference in predicted maximum concentration (C_max) and area under the curve (AUC) were significant between children with and without obesity across the age group 2 to 18 years old when a fixed-dose regimen was used. On the contrary, a weight-based dose regimen showed no difference in C_max between obese and non-obese from 2 to 9 years old. Thus, when a fixed-dose regimen is to be administered, a 1.25- to 1.5-fold increase in dose is required in obese children to achieve the same C_max concentration as non-obese children, specifically for children aged 5 years and above. Full article

(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)

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20 pages, 5181 KiB

Open AccessEditor’s ChoiceArticle

Ionic Liquid Transdermal Patches of Two Active Ingredients Based on Semi-Ionic Hydrogen Bonding for Rheumatoid Arthritis Treatment

by Faxing Zhang, Lu Li, Xinyuan Zhang, Hongyu Yang, Yingzhen Fan, Jian Zhang, Ting Fang, Yaming Liu, Zhihao Nie and Dongkai Wang

Pharmaceutics 2024, 16(4), 480; https://doi.org/10.3390/pharmaceutics16040480 - 1 Apr 2024

Cited by 1 | Viewed by 1370

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to deformities and disabilities in patients. Conventional treatment focuses on delaying progression; therefore, new treatments are necessary. The present study reported a novel ionic liquid transdermal platform for efficient RA treatment, and the [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to deformities and disabilities in patients. Conventional treatment focuses on delaying progression; therefore, new treatments are necessary. The present study reported a novel ionic liquid transdermal platform for efficient RA treatment, and the underlying mechanism was elucidated using FTIR, ¹H-NMR, Raman, XPS, and molecular simulations. The results showed that the reversibility of the semi-ionic hydrogen bonding facilitated high drug loading and enhanced drug permeability. Actarit’s drug loading had an approximately 11.34-times increase. The in vitro permeability of actarit and ketoprofen was improved by 5.46 and 2.39 times, respectively. And they had the same significant effect in vivo. Furthermore, through the integration of network pharmacology, Western blotting (WB), and radiology analyses, the significant osteoprotective effects of SIHDD-PSA (semi-ionic H-bond double-drug pressure-sensitive adhesive transdermal patch) were revealed through the modulation of the JAK-STAT pathway. The SIHDD-PSA significantly reduced paw swelling and inflammation in the rat model, and stimulatory properties evaluation confirmed the safety of SIHDD-PSA. In conclusion, these findings provide a novel approach for the effective treatment of RA, and the semi-ionic hydrogen bonding strategy contributes a new theoretical basis for developing TDDS. Full article

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

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14 pages, 3576 KiB

Open AccessEditor’s ChoiceArticle

Influenza Virus Inactivated by Heavy Ion Beam Irradiation Stimulates Antigen-Specific Immune Responses

by Kai Schulze, Ulrich Weber, Christoph Schuy, Marco Durante and Carlos Alberto Guzmán

Pharmaceutics 2024, 16(4), 465; https://doi.org/10.3390/pharmaceutics16040465 - 27 Mar 2024

Cited by 1 | Viewed by 2000

Abstract

The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation [...] Read more.

The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation can affect surface-exposed antigen, thereby reducing vaccine efficacy. Gamma rays have been used in the past to inactivate viruses. We recently proposed that high-energy heavy ions may be more suitable as an inactivation method because they increase the damage ratio between the viral nucleic acid and surface proteins. Here, we demonstrate that irradiation of the influenza virus using heavy ion beams constitutes a suitable method to develop effective vaccines, since immunization of mice by the intranasal route with the inactivated virus resulted in the stimulation of strong antigen-specific humoral and cellular immune responses. Full article

(This article belongs to the Special Issue Emerging Pharmaceutical Strategies against Infectious Diseases)

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18 pages, 3281 KiB

Open AccessEditor’s ChoiceArticle

AmBisome^® Formulations for Pediatrics: Stability, Cytotoxicity, and Cost-Effectiveness Studies

by Guendalina Zuccari, Carla Villa, Valentina Iurilli, Paola Barabino, Alessia Zorzoli, Danilo Marimpietri, Debora Caviglia and Eleonora Russo

Pharmaceutics 2024, 16(4), 466; https://doi.org/10.3390/pharmaceutics16040466 - 27 Mar 2024

Viewed by 1639

Abstract

Liposomal amphotericin B (Ambisome^®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be [...] Read more.

Liposomal amphotericin B (Ambisome^®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be challenging due to the spontaneous tendency of amphotericin B to form aggregates with different biological activity. In this study, the colloidal stability of the liposomes and the chemical stability of amphotericin B were investigated over time at storage conditions. Three liposomal formulations of amphotericin B at 4.0 mg/mL, 2.0 mg/mL, and 0.2 mg/mL were prepared and assayed for changes regarding the dimensional distribution, zeta potential, drug aggregation state, and onset of by-products. Our analyses highlighted that the most diluted formulation, kept at room temperature, showed the greatest changes in the aggregation state of the drug and accordingly the highest cytotoxicity. These findings are clinically relevant since the lower dosages are addressed to the more vulnerable patients. Therefore, the centralization of the dilution of AmBisome^® at the pharmacy is of fundamental importance for assuring patient safety, and at the same time for reducing medication waste, as we demonstrated using the cost-saving analysis of drug expense per therapy carried out at the G. Gaslini children hospital. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Strategies for the Treatment of Pediatric Diseases)

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19 pages, 2919 KiB

Open AccessEditor’s ChoiceArticle

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

by Tomas L. Roldan, Shike Li, Christophe Guillon, Ned D. Heindel, Jeffrey D. Laskin, In Heon Lee, Dayuan Gao and Patrick J. Sinko

Pharmaceutics 2024, 16(4), 471; https://doi.org/10.3390/pharmaceutics16040471 - 27 Mar 2024

Viewed by 1644

Abstract

NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in [...] Read more.

NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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18 pages, 9211 KiB

Open AccessEditor’s ChoiceArticle

Nanonization and Deformable Behavior of Fattigated Peptide Drug in Mucoadhesive Buccal Films

by Woojun Kim, Hai V. Ngo, Hy D. Nguyen, Ji-Min Park, Kye Wan Lee, Chulhun Park, Jun-Bom Park and Beom-Jin Lee

Pharmaceutics 2024, 16(4), 468; https://doi.org/10.3390/pharmaceutics16040468 - 27 Mar 2024

Cited by 1 | Viewed by 1234

Abstract

This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) [...] Read more.

This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) were developed. Additionally, a deformable variant of LON (d-LON) was originally developed by incorporating l-α-phosphatidylcholine into LON as an edge activator. The physicochemical properties of LON and d-LON, encompassing particle size, zeta potential, and deformability index (DI), were evaluated. MBFs containing LEU, LOC, and NPs (LON, d-LON) were prepared using the solvent casting method by varying the ratio of Eudragit RLPO and hydroxypropyl methylcellulose, with propylene glycol used as a plasticizer. The optimization of MBF formulations was based on their physicochemical properties, including in vitro residence time, dissolution, and permeability. The dissolution results demonstrated that the conjugation of oleic acid to LEU exhibited a more sustained LEU release pattern by cleaving the ester bond of the conjugate, as compared to the native LEU, with reduced variability. Moreover, the LOC and its self-assembled NPs (LON, d-LON), equivalent to 1 mg LEU doses in MBF, exhibited an amorphous state and demonstrated better permeability through the nanonization process than LEU alone, regardless of membrane types. The incorporation of lauroyl-L-carnitine into the films as a permeation enhancer synergistically augmented drug permeability. Most importantly, the d-LON-loaded buccal films showed the highest permeability, due to the deformability of NPs. Overall, MBF-containing peptide NPs and permeation enhancers have the potential to replace parenteral LEU administration by improving LEU druggability and patient compliance. Full article

(This article belongs to the Special Issue Mucoadhesive and Mucosal Drug Delivery Systems, 2nd Edition)

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14 pages, 4006 KiB

Open AccessEditor’s ChoiceArticle

The Impact of Polymers on Enzalutamide Solid Self-Nanoemulsifying Drug Delivery System and Improved Bioavailability

by Su-Min Lee, Jeong-Gyun Lee, Tae-Han Yun, Chul-Ho Kim, Jung-Hyun Cho and Kyeong-Soo Kim

Pharmaceutics 2024, 16(4), 457; https://doi.org/10.3390/pharmaceutics16040457 - 26 Mar 2024

Cited by 1 | Viewed by 1403

Abstract

Enzalutamide (ENZ), marketed under the brand name Xtandi^® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. [...] Read more.

Enzalutamide (ENZ), marketed under the brand name Xtandi^® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. In previous studies, a liquid self-nanoemulsifying drug delivery system (L-SNEDDS) containing ENZ was developed among various solubilization technologies. However, powder formulations that included colloidal silica rapidly formed crystal nuclei in aqueous solutions, leading to a significant decrease in dissolution. Consequently, this study evaluated the efficacy of adding a polymer as a recrystallization inhibitor to a solid SNEDDS (S-SNEDDS) to maintain the drug in a stable, amorphous state in aqueous environments. Polymers were selected based on solubility tests, and the S-SNEDDS formulation was successfully produced via spray drying. The optimized S-SNEDDS formulation demonstrated through X-ray diffraction and differential scanning calorimetry data that it significantly reduced drug crystallinity and enhanced its dissolution rate in simulated gastric and intestinal fluid conditions. In an in vivo study, the bioavailability of orally administered formulations was increased compared to the free drug. Our results highlight the effectiveness of solid-SNEDDS formulations in enhancing the bioavailability of ENZ and outline the potential translational directions for oral drug development. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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21 pages, 3903 KiB

Open AccessEditor’s ChoiceArticle

Daptomycin Liposomes Exhibit Enhanced Activity against Staphylococci Biofilms Compared to Free Drug

by Foteini Gkartziou, Maria Plota, Charikleia Kypraiou, Iti Gauttam, Fevronia Kolonitsiou, Pavlos Klepetsanis, Iris Spiliopoulou and Sophia G. Antimisiaris

Pharmaceutics 2024, 16(4), 459; https://doi.org/10.3390/pharmaceutics16040459 - 26 Mar 2024

Viewed by 1061

Abstract

The purpose of the present study was to investigate the anti-staphylococcal activity of liposomal daptomycin against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin-resistant. Neutral and negatively charged daptomycin-loaded liposomes were prepared using three methods, namely, thin-film [...] Read more.

The purpose of the present study was to investigate the anti-staphylococcal activity of liposomal daptomycin against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin-resistant. Neutral and negatively charged daptomycin-loaded liposomes were prepared using three methods, namely, thin-film hydration (TFH), a dehydration–rehydration vesicle (DRV) method, and microfluidic mixing (MM); moreover, they were characterized for drug encapsulation (EE%), size distribution, zeta-potential, vesicle stability, drug release, and drug integrity. Interestingly, whilst drug loading in THF and DRV nanosized (by extrusion) vesicles was around 30–35, very low loading (~4%) was possible in MM vesicles, requiring further explanatory investigations. Liposomal encapsulation protected daptomycin from degradation and preserved its bioactivity. Biofilm mass (crystal violet, CV), biofilm viability (MTT), and growth curve (GC) assays evaluated the antimicrobial activity of neutral and negatively charged daptomycin-liposomes towards planktonic bacteria and biofilms. Neutral liposomes exhibited dramatically enhanced inhibition of bacterial growth (compared to the free drug) for all species studied, while negatively charged liposomes were totally inactive. Biofilm prevention and treatment studies revealed high antibiofilm activity of liposomal daptomycin. Neutral liposomes were more active for prevention and negative charge ones for treating established biofilms. Planktonic bacteria as well as the matured biofilms of low daptomycin-susceptible, methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) strains were almost completely eradicated by liposomal-daptomycin, indicating the need for their further exploration as antimicrobial therapeutics. Full article

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

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28 pages, 3797 KiB

Open AccessEditor’s ChoiceArticle

Gold(I) and Silver(I) Complexes Containing Hybrid Sulfonamide/Thiourea Ligands as Potential Leishmanicidal Agents

by Alice P. Borges, Malu M. S. Obata, Silvia H. Libardi, Rafael O. Trevisan, Victor M. Deflon, Ulrich Abram, Francis B. Ferreira, Luiz Antônio S. Costa, Antonio O. T. Patrocínio, Marcos V. da Silva, Júlio C. Borges and Pedro I. S. Maia

Pharmaceutics 2024, 16(4), 452; https://doi.org/10.3390/pharmaceutics16040452 - 25 Mar 2024

Viewed by 1132

Abstract

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from [...] Read more.

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from M^I metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HL^R) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with Ag^I and Au^I, leading to the formation of complexes of composition [M(HL^R)₂]X (M = Ag or Au; X = NO₃⁻ or Cl⁻). All compounds were characterized by FTIR, ¹H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of Metal Complexes and Derived Materials)

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27 pages, 4839 KiB

Open AccessEditor’s ChoiceArticle

Investigating the Effects of Mixing Dynamics on Twin-Screw Granule Quality Attributes via the Development of a Physics-Based Process Map

by Lalith Kotamarthy, Subhodh Karkala, Ashley Dan, Andrés D. Román-Ospino and Rohit Ramachandran

Pharmaceutics 2024, 16(4), 456; https://doi.org/10.3390/pharmaceutics16040456 - 25 Mar 2024

Viewed by 1236

Abstract

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing [...] Read more.

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism. Full article

(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)

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14 pages, 16075 KiB

Open AccessEditor’s ChoiceArticle

Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury

by Takuma Ikeda, Masahito Kawabori, Yuyuan Zheng, Sho Yamaguchi, Shuho Gotoh, Yo Nakahara, Erika Yoshie and Miki Fujimura

Pharmaceutics 2024, 16(4), 446; https://doi.org/10.3390/pharmaceutics16040446 - 23 Mar 2024

Cited by 3 | Viewed by 2362

Abstract

Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous [...] Read more.

Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 10⁸ exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers. Full article

(This article belongs to the Special Issue Pharmaceutical Formulations and Bioavailability Enhancement Techniques for Transmucosal Drug Delivery)

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12 pages, 3738 KiB

Open AccessEditor’s ChoiceArticle

Mannose-Decorated Solid-Lipid Nanoparticles for Alveolar Macrophage Targeted Delivery of Rifampicin

by Hriday Bera, Caizhu Zhao, Xidong Tian, Dongmei Cun and Mingshi Yang

Pharmaceutics 2024, 16(3), 429; https://doi.org/10.3390/pharmaceutics16030429 - 20 Mar 2024

Viewed by 1603

Abstract

Alveolar macrophages play a vital role in a variety of lung diseases, including tuberculosis. Thus, alveolar macrophage targeted anti-tubercular drug delivery through nanocarriers could improve its therapeutic response against tuberculosis. The current study aimed at exploring the efficacy of glyceryl monostearate (GMS)-based solid-lipid [...] Read more.

Alveolar macrophages play a vital role in a variety of lung diseases, including tuberculosis. Thus, alveolar macrophage targeted anti-tubercular drug delivery through nanocarriers could improve its therapeutic response against tuberculosis. The current study aimed at exploring the efficacy of glyceryl monostearate (GMS)-based solid-lipid nanoparticles (SLNs) and their mannose functionalized forms on the alveolar macrophage targeting ability of an anti-tubercular model drug, rifampicin (Rif). Rif-loaded SLNs were accomplished by the solvent diffusion method. These carriers with unimodal particle size distribution (~170 nm) were further surface-modified with mannose via Schiff-base reaction, leading to slight enhancement of particle diameter and a decline of drug loading capacity. The encapsulated Rif, which was molecularly dispersed within the matrices as indicated by their XRD patterns, was eluted in a sustained manner with an initial burst release effect. The uptake efficiency of mannose-modified SLNs was remarkably higher than that of corresponding native forms on murine macrophage Raw 264.7 cells and human lung adenocarcinoma A549 cells. Eventually, the mannose-modified SLNs showed a greater cytotoxicity on Raw 264.7 and A549 cells relative to their unmodified forms. Overall, our study demonstrated that mannose modification of SLNs had an influence on their uptake by alveolar macrophages, which could provide guidance for the future development of alveolar macrophage targeted nanoformulations. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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24 pages, 3524 KiB

Open AccessEditor’s ChoiceArticle

NLC-Based Sunscreen Formulations with Optimized Proportion of Encapsulated and Free Filters Exhibit Enhanced UVA and UVB Photoprotection

by Margarete M. de Araújo, Andressa C. Schneid, Mariana S. Oliveira, Samuel V. Mussi, Miller N. de Freitas, Flávia C. Carvalho, Edson A. Bernes Junior, Renato Faro and Hatylas Azevedo

Pharmaceutics 2024, 16(3), 427; https://doi.org/10.3390/pharmaceutics16030427 - 20 Mar 2024

Cited by 3 | Viewed by 1950

Abstract

The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced [...] Read more.

The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced and prolonged photoprotection. This work investigated novel sunscreen formulations and their UV protection effects by encapsulating Uvinul^® A, Tinosorb^® S, and Uvinul^® T150 into nanostructured lipid carriers (NLCs) based on bacuri butter and raspberry seed oil. First, the impact of critical formulation and process parameters on NLCs’ particle size was evaluated using a 2² Face Centered Central Composite Design. Then, formulations were evaluated in terms of critical quality factors, in vitro skin permeation, and in vitro and in vivo photoprotection activities. The developed NLCs-containing formulations exhibited appropriate size (122–135 nm), PdI (<0.3), encapsulation efficiency (>90%), and drug content (>80%), which were preserved for at least 90 days under different stability conditions. Moreover, these NLCs-based formulations had equivalent skin permeation to emulsion-based controls, and the addition of NLCs into sunscreen cream bases in the optimum proportion of 20% (w/w) resulted in enhanced UVA and UVB photoprotection levels, despite a 10% reduction in the total filters content. Altogether, these results describe the application of nanoencapsulated organic UV filters in innovative sunscreen formulations to achieve superior photoprotection and cosmeceutical properties. Full article

(This article belongs to the Special Issue Quality Requirements for Nanomedicines: From Early Development to the Market)

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