Pharmaceutics

18 pages, 4388 KiB

Open AccessArticle

Synthesis and Characterization of Thiolated Nanoparticles Based on Poly (Acrylic Acid) and Algal Cell Wall Biopolymers for the Delivery of the Receptor Binding Domain from SARS-CoV-2

by Ileana García-Silva, Susan Farfán-Castro, Sergio Rosales-Mendoza and Gabriela Palestino

Pharmaceutics 2024, 16(7), 891; https://doi.org/10.3390/pharmaceutics16070891 (registering DOI) - 2 Jul 2024

Viewed by 162

Abstract

The COVID-19 pandemic required great efforts to develop efficient vaccines in a short period of time. However, innovative vaccines against SARS-CoV-2 virus are needed to achieve broad immune protection against variants of concern. Polymeric-based particles can lead to innovative vaccines, serving as stable, [...] Read more.

The COVID-19 pandemic required great efforts to develop efficient vaccines in a short period of time. However, innovative vaccines against SARS-CoV-2 virus are needed to achieve broad immune protection against variants of concern. Polymeric-based particles can lead to innovative vaccines, serving as stable, safe and immunostimulatory antigen delivery systems. In this work, polymeric-based particles called thiolated PAA/Schizo were developed. Poly (acrylic acid) (PAA) was thiolated with cysteine ethyl ester and crosslinked with a Schizochytrium sp. cell wall fraction under an inverse emulsion approach. Particles showed a hydrodynamic diameter of 313 ± 38 nm and negative Zeta potential. FT-IR spectra indicated the presence of coconut oil in thiolated PAA/Schizo particles, which, along with the microalgae, could contribute to their biocompatibility and bioactive properties. TGA analysis suggested strong interactions between the thiolated PAA/Schizo components. In vitro assessment revealed that thiolated particles have a higher mucoadhesiveness when compared with non-thiolated particles. Cell-based assays revealed that thiolated particles are not cytotoxic and, importantly, increase TNF-α secretion in murine dendritic cells. Moreover, immunization assays revealed that thiolated PAA/Schizo particles induced a humoral response with a more balanced IgG2a/IgG1 ratio. Therefore, thiolated PAA/Schizo particles are deemed a promising delivery system whose evaluation in vaccine prototypes is guaranteed. Full article

(This article belongs to the Special Issue Advanced Polymeric Materials as Therapeutic Agents)

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33 pages, 2541 KiB

Open AccessReview

The Evolving Paradigm of Antibody–Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases

by Peyton High, Cara Guernsey, Shraddha Subramanian, Joan Jacob and Kendra S. Carmon

Pharmaceutics 2024, 16(7), 890; https://doi.org/10.3390/pharmaceutics16070890 (registering DOI) - 2 Jul 2024

Viewed by 231

Abstract

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody–drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with [...] Read more.

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody–drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs. Full article

(This article belongs to the Special Issue Next-Generation Antibody-Drug Conjugates (ADCs))

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5 pages, 211 KiB

Open AccessEditorial

Recent Advances in the Development of Hybrid Drugs

by Tânia S. Morais

Pharmaceutics 2024, 16(7), 889; https://doi.org/10.3390/pharmaceutics16070889 (registering DOI) - 1 Jul 2024

Viewed by 193

Abstract

In the search for innovative, selective, effective, and safer treatment strategies, hybrid drugs have gained worldwide momentum [...] Full article

(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)

21 pages, 1745 KiB

Open AccessReview

From Tyrosine Kinases to Tyrosine Phosphatases: New Therapeutic Targets in Cancers and Beyond

by Yu Zhou, Zhimeng Yao, Yusheng Lin and Hao Zhang

Pharmaceutics 2024, 16(7), 888; https://doi.org/10.3390/pharmaceutics16070888 (registering DOI) - 1 Jul 2024

Viewed by 208

Abstract

Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) regulate the level of tyrosine phosphorylation in proteins. PTKs are key enzymes that catalyze the transfer of an ATP phosphoric acid to a tyrosine residue on target protein substrates. Protein tyrosine phosphatases (PTPs) are [...] Read more.

Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) regulate the level of tyrosine phosphorylation in proteins. PTKs are key enzymes that catalyze the transfer of an ATP phosphoric acid to a tyrosine residue on target protein substrates. Protein tyrosine phosphatases (PTPs) are responsible for the dephosphorylation of tyrosine residues and play a role in countering PTK overactivity. As widespread oncogenes, PTKs were once considered to be promising targets for therapy. However, tyrosine kinase inhibitors (TKIs) now face a number of challenges, including drug resistance and toxic side effects. Treatment strategies now need to be developed from a new perspective. In this review, we assess the current state of TKIs and highlight the role of PTPs in cancer and other diseases. With the advances of allosteric inhibition and the development of multiple alternative proprietary drug strategies, the reputation of PTPs as “undruggable” targets has been overturned, and they are now considered viable therapeutic targets. We also discuss the strategies and prospects of PTP-targeted therapy, as well as its future development. Full article

(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors, 2nd Edition)

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24 pages, 5887 KiB

Open AccessReview

Advancing Tumor Therapy: Development and Utilization of Protein-Based Nanoparticles

by Shirin Khakpour, Nushin Hosano, Zahra Moosavi-Nejad, Amir A. Farajian and Hamid Hosano

Pharmaceutics 2024, 16(7), 887; https://doi.org/10.3390/pharmaceutics16070887 (registering DOI) - 1 Jul 2024

Viewed by 244

Abstract

Protein-based nanoparticles (PNPs) in tumor therapy hold immense potential, combining targeted delivery, minimal toxicity, and customizable properties, thus paving the way for innovative approaches to cancer treatment. Understanding the various methods available for their production is crucial for researchers and scientists aiming to [...] Read more.

Protein-based nanoparticles (PNPs) in tumor therapy hold immense potential, combining targeted delivery, minimal toxicity, and customizable properties, thus paving the way for innovative approaches to cancer treatment. Understanding the various methods available for their production is crucial for researchers and scientists aiming to harness these nanoparticles for diverse applications, including tumor therapy, drug delivery, imaging, and tissue engineering. This review delves into the existing techniques for producing PNPs and PNP/drug complexes, while also exploring alternative novel approaches. The methods outlined in this study were divided into three key categories based on their shared procedural steps: solubility change, solvent substitution, and thin flow methods. This classification simplifies the understanding of the underlying mechanisms by offering a clear framework, providing several advantages over other categorizations. The review discusses the principles underlying each method, highlighting the factors influencing the nanoparticle size, morphology, stability, and functionality. It also addresses the challenges and considerations associated with each method, including the scalability, reproducibility, and biocompatibility. Future perspectives and emerging trends in PNPs’ production are discussed, emphasizing the potential for innovative strategies to overcome current limitations, which will propel the field forward for biomedical and therapeutic applications. Full article

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

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13 pages, 1548 KiB

Open AccessArticle

Enhanced Oral Efficacy of Semaglutide via an Ionic Nanocomplex with Organometallic Phyllosilicate in Type 2 Diabetic Rats

by Gyu Lin Kim, Jae Geun Song and Hyo-Kyung Han

Pharmaceutics 2024, 16(7), 886; https://doi.org/10.3390/pharmaceutics16070886 (registering DOI) - 30 Jun 2024

Viewed by 291

Abstract

This study aimed to develop an effective oral formulation of semaglutide, a glucagon-like peptide-1 receptor agonist, using an organometallic phyllosilicate-based colonic delivery system. The core nanocomplex (AMP-Sema) of 3-aminopropyl-functionalized magnesium phyllosilicate (AMP) and semaglutide was prepared via electrostatic interactions. Subsequently, AMP-Sema was coated [...] Read more.

This study aimed to develop an effective oral formulation of semaglutide, a glucagon-like peptide-1 receptor agonist, using an organometallic phyllosilicate-based colonic delivery system. The core nanocomplex (AMP-Sema) of 3-aminopropyl-functionalized magnesium phyllosilicate (AMP) and semaglutide was prepared via electrostatic interactions. Subsequently, AMP-Sema was coated with a polymer showing pH-dependent solubility (Eudragit^® S100) for preferential colonic delivery. The surface-coated nanoparticles (EAMP-Sema) showed a narrow size distribution, and the encapsulated semaglutide maintained its conformational stability. The pH-dependent drug release property of EAMP-Sema yielded around 20% and 62% drug release at pH 1.2 and 7.4, respectively. The nanoparticles exhibited significantly decreased size and surface charge at pH 7.4, which indicated the pH-dependent dissolution of the coating layer. Furthermore, EAMP-Sema effectively improved the membrane permeability and metabolic stability of semaglutide in the gastrointestinal tract. It protected the encapsulated drugs from proteolysis in simulated intestinal fluids and increased drug transport by 2.5-fold in Caco-2 cells. Consequently, orally administered EAMP-Sema (equivalent to 8 mg/kg of semaglutide) showed significant therapeutic benefits, yielding effective glycemic control and weight loss in high-fat diet/streptozotocin (40 mg/kg)-induced type 2 diabetic rats. These results demonstrate that EAMP-Sema could improve the efficacy of orally administered semaglutide by enhancing the GI stability and cellular uptake of protein drugs. Full article

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

22 pages, 9614 KiB

Open AccessArticle

Investigating Laser Ablation Process Parameters for the Fabrication of Customized Microneedle Arrays for Therapeutic Applications

by Faisal Khaled Aldawood, Abhay Andar and Salil Desai

Pharmaceutics 2024, 16(7), 885; https://doi.org/10.3390/pharmaceutics16070885 (registering DOI) - 30 Jun 2024

Viewed by 289

Abstract

Microneedles are an innovation in the field of medicine that have the potential to revolutionize drug delivery, diagnostics, and cosmetic treatments. This innovation provides a minimally invasive means to deliver drugs, vaccines, and other therapeutic substances into the skin. This research investigates the [...] Read more.

Microneedles are an innovation in the field of medicine that have the potential to revolutionize drug delivery, diagnostics, and cosmetic treatments. This innovation provides a minimally invasive means to deliver drugs, vaccines, and other therapeutic substances into the skin. This research investigates the design and manufacture of customized microneedle arrays using laser ablation. Laser ablation was performed using an ytterbium laser on a polymethyl methacrylate (PMMA) substrate to create a mold for casting polydimethylsiloxane (PDMS) microneedles. An experimental design was conducted to evaluate the effect of process parameters including laser pulse power, pulse width, pulse repetition, interval between pulses, and laser profile on the desired geometry of the microneedles. The analysis of variance (ANOVA) model showed that lasing interval, laser power, and pulse width had the highest influence on the output metrics (diameter and height) of the microneedle. The microneedle dimensions showed an increase with higher pulse width and vice versa with an increase in pulse interval. A response surface model indicated that the laser pulse width and interval (independent variables) significantly affect the response diameter and height (dependent variable). A predictive model was generated to predict the microneedle topology and aspect ratio varying from 0.8 to 1.5 based on the variation in critical input process parameters. This research lays the foundation for the design and fabrication of customized microneedles based on variations in specific input parameters for therapeutic applications in dermal sensors, drug delivery, and vaccine delivery. Full article

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

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11 pages, 944 KiB

Open AccessArticle

Altered Expression of BCRP Impacts Fetal Accumulation of Rosuvastatin in a Rat Model of Preeclampsia

by Wanying Dai and Micheline Piquette-Miller

Pharmaceutics 2024, 16(7), 884; https://doi.org/10.3390/pharmaceutics16070884 (registering DOI) - 30 Jun 2024

Viewed by 324

Abstract

Expression of the breast cancer resistance protein (BCRP/ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE. While many drugs are substrates of this important efflux transporter, the impact of PE associated BCRP downregulation [...] Read more.

Expression of the breast cancer resistance protein (BCRP/ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE. While many drugs are substrates of this important efflux transporter, the impact of PE associated BCRP downregulation on maternal and fetal drug exposure has not been investigated. Using the PE rat model, we performed a pharmacokinetic study with rosuvastatin (RSV), a BCRP substrate, to investigate this impact. PE was induced in rats during gestational days (GD) 13 to 16 with daily low-dose endotoxin. On GD18, RSV (3 mg/kg) was administrated intravenously, and rats were sacrificed at time intervals between 0.5 and 6 h. As compared to controls, placental expression of Bcrp and Oatp2b1 significantly decreased in PE rats. A corresponding increase in RSV levels was seen in fetal tissues and amniotic fluid of the PE group (p < 0.05), while maternal plasma concentrations remained unchanged from the controls. An increase in Bcrp expression and decreased RSV concentration were seen in the livers of PE dams. This suggests that PE-mediated transporter dysregulation leads to significant changes in the maternal and fetal RSV disposition. Overall, our findings demonstrate that altered placental expression of transporters in PE can increase fetal accumulation of their substrates. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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17 pages, 5453 KiB

Open AccessArticle

Process-Induced Crystal Surface Anisotropy and the Impact on the Powder Properties of Odanacatib

by Isha Bade, Vikram Karde, Luke Schenck, Marina Solomos, Margaret Figus, Chienhung Chen, Stephanus Axnanda and Jerry Y. Y. Heng

Pharmaceutics 2024, 16(7), 883; https://doi.org/10.3390/pharmaceutics16070883 (registering DOI) - 30 Jun 2024

Viewed by 202

Abstract

Crystalline active pharmaceutical ingredients with comparable size and surface area can demonstrate surface anisotropy induced during crystallization or downstream unit operations such as milling. To the extent that varying surface properties impacts bulk powder properties, the final drug product performance such as stability, [...] Read more.

Crystalline active pharmaceutical ingredients with comparable size and surface area can demonstrate surface anisotropy induced during crystallization or downstream unit operations such as milling. To the extent that varying surface properties impacts bulk powder properties, the final drug product performance such as stability, dissolution rates, flowability, and dispersibility can be predicted by understanding surface properties such as surface chemistry, energetics, and wettability. Here, we investigate the surface properties of different batches of Odanacatib prepared through either jet milling or fast precipitation from various solvent systems, all of which meet the particle size specification established to ensure equivalent biopharmaceutical performance. This work highlights the use of orthogonal surface techniques such as Inverse Gas Chromatography (IGC), Brunauer–Emmett–Teller (BET) surface area, contact angle, and X-ray Photoelectron Spectroscopy (XPS) to demonstrate the effect of processing history on particle surface properties to explain differences in bulk powder properties. Full article

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

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29 pages, 3024 KiB

Open AccessReview

Zirconium 89 and Copper 64 for ImmunoPET: From Antibody Bioconjugation and Radiolabeling to Molecular Imaging

by Laure Badier and Isabelle Quelven

Pharmaceutics 2024, 16(7), 882; https://doi.org/10.3390/pharmaceutics16070882 (registering DOI) - 30 Jun 2024

Viewed by 232

Abstract

Immunotherapy has transformed cancer treatment. Nevertheless, given the heterogeneity of clinical efficacy, the multiplicity of treatment options available and the possibility of serious adverse effects, selecting the most effective treatment has become the greatest challenge. Molecular imaging offers an attractive way for this [...] Read more.

Immunotherapy has transformed cancer treatment. Nevertheless, given the heterogeneity of clinical efficacy, the multiplicity of treatment options available and the possibility of serious adverse effects, selecting the most effective treatment has become the greatest challenge. Molecular imaging offers an attractive way for this purpose. ImmunoPET provides specific imaging with positron emission tomography (PET) using monoclonal antibodies (mAb) or its fragments as vector. By combining the high targeting specificity of mAb and the sensitivity of PET technique, immunoPET could noninvasively and dynamically reveal tumor antigens expression and provide theranostic tools of several types of malignancies. Because of their slow kinetics, mAbs require radioelements defined by a consistent half-life. Zirconium 89 (⁸⁹Zr) and Copper 64 (⁶⁴Cu) are radiometals with half-lives suitable for mAb labeling. Radiolabeling with a radiometal requires the prior use of a bifunctional chelate agent (BFCA) to functionalize mAb for radiometal chelation, in a second step. There are a number of BFCA available and much research is focused on antibody functionalization techniques or on develo** the optimum chelating agent depending the selected radiometal. In this manuscript, we present a critical account of radiochemical techniques with radionuclides ⁸⁹Zr and ⁶⁴Cu and their applications in preclinical and clinical immuno-PET imaging. Full article

(This article belongs to the Special Issue Promising Radiopharmaceuticals in Oncological Therapy)

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18 pages, 3601 KiB

Open AccessArticle

Toward Personalized Salbutamol Therapy: Validating Virtual Patient-Derived Population Pharmacokinetic Model with Real-World Data

by Lara Marques and Nuno Vale

Pharmaceutics 2024, 16(7), 881; https://doi.org/10.3390/pharmaceutics16070881 (registering DOI) - 30 Jun 2024

Viewed by 266

Abstract

Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. [...] Read more.

Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. Herein, we developed a popPK model for salbutamol, a short-acting β₂-agonist (SABA) used in asthma treatment, to identify key patient characteristics that influence treatment response. To do so, synthetic data from physiologically-based pharmacokinetic (PBPK) models was employed, followed by an external validation using real patient data derived from an equivalent study. Thirty-two virtual patients were included in this study. A two-compartment model, with first-order absorption (no delay), and linear elimination best fitted our data, according to diagnostic plots and selection criteria. External validation demonstrated a strong agreement between individual predicted and observed values. The incorporation of covariates into the basic structural model identified a significant impact of age on clearance (Cl) and intercompartmental clearance (Q); gender on Cl and the constant rate of absorption (ka); race on Cl; and weight on Cl in the volume of distribution of the peripheral compartment (V2). This study addresses critical challenges in popPK modeling, particularly data scarcity, incompleteness, and homogeneity, in traditional clinical trials, by leveraging synthetic data from PBPK modeling. Significant associations between individual characteristics and salbutamol’s PK parameters, here uncovered, highlight the importance of personalized therapeutic regimens for optimal treatment outcomes. Full article

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

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20 pages, 6116 KiB

Open AccessArticle

Cationic Liposomes Carrying HPV16 E6-siRNA Inhibit the Proliferation, Migration, and Invasion of Cervical Cancer Cells

by Luz Victoria Sánchez-Meza, Ciresthel Bello-Rios, Josimar O. Eloy, Yazmín Gómez-Gómez, Marco Antonio Leyva-Vázquez, Raquel Petrilli, María Josefa Bernad-Bernad, Alfredo Lagunas-Martínez, Luis Alberto Medina, Janeth Serrano-Bello, Jorge Organista-Nava and Berenice Illades-Aguiar

Pharmaceutics 2024, 16(7), 880; https://doi.org/10.3390/pharmaceutics16070880 (registering DOI) - 29 Jun 2024

Viewed by 392

Abstract

The E6 and E7 oncoproteins of high-risk types of human papillomavirus (HR-HPV) are crucial for the development of cervical cancer (CC). Small interfering RNAs (siRNAs) are explored as novel therapies that silence these oncogenes, but their clinical use is hampered by inefficient delivery [...] Read more.

The E6 and E7 oncoproteins of high-risk types of human papillomavirus (HR-HPV) are crucial for the development of cervical cancer (CC). Small interfering RNAs (siRNAs) are explored as novel therapies that silence these oncogenes, but their clinical use is hampered by inefficient delivery systems. Modification (pegylation) with polyethylene glycol (PEG) of liposomal siRNA complexes (siRNA lipoplexes) may improve systemic stability. We studied the effect of siRNA targeting HPV16 E6, delivered via cationic liposomes (lipoplexes), on cellular processes in a cervical carcinoma cell line (CaSki) and its potential therapeutic use. Lipoplexes-PEG-HPV16 E6, composed of DOTAP, Chol, DOPE, and DSPE-PEG2000 were prepared. The results showed that pegylation (5% DSPE-PEG2000) provided stable siRNA protection, with a particle size of 86.42 ± 3.19 nm and a complexation efficiency of over 80%; the siRNA remained stable for 30 days. These lipoplexes significantly reduced HPV16 E6 protein levels and restored p53 protein expression, inhibiting carcinogenic processes such as proliferation by 25.74%, migration (95.7%), and cell invasion (97.8%) at concentrations of 20 nM, 200 nM, and 80 nM, respectively. In conclusion, cationic lipoplexes-PEG-HPV16 E6 show promise as siRNA carriers for silencing HPV16 E6 in CC. Full article

(This article belongs to the Section Drug Targeting and Design)

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18 pages, 2273 KiB

Open AccessArticle

Investigation of Factors Influencing the Effectiveness of Deformable Nanovesicles for Insulin Nebulization Inhalation

by **ghan Yu, Yingying Meng, Zhiyang Wen, Yu Jiang, Yiyue Guo, Simeng Du, Yuling Liu and Xuejun **a

Pharmaceutics 2024, 16(7), 879; https://doi.org/10.3390/pharmaceutics16070879 (registering DOI) - 29 Jun 2024

Viewed by 331

Abstract

Nebulized inhalation offers a noninvasive method for delivering drugs to treat both local respiratory and systemic diseases. In this study, insulin was used as a model drug to design a series of deformable nanovesicles (DNVs) with key quality attributes, including particle size, deformability, [...] Read more.

Nebulized inhalation offers a noninvasive method for delivering drugs to treat both local respiratory and systemic diseases. In this study, insulin was used as a model drug to design a series of deformable nanovesicles (DNVs) with key quality attributes, including particle size, deformability, and drug load capacity. We investigated the effects of these properties on aerosol generation, macrophage phagocytosis, and bloodstream penetration. The results showed that deformability improved nebulization performance and reduced macrophage phagocytosis, benefiting local and systemic delivery. However, the advantage of DNVs for transmembrane penetration was not evident in the alveolar epithelium. Within the size range of 80–490 nm, the smaller the particle size of IPC-DNVs, the easier it is to evade clearance by macrophages and the more effective the in vivo hypoglycemic efficacy will be. In the drug load range of 3–5 mg/mL, a lower drug load resulted in better hypoglycemic efficacy. The area above the blood glucose decline curve with time (AAC) of nebulized DNVs was 2.32 times higher than that of the insulin solution, demonstrating the feasibility and advantages of DNVs in the pulmonary delivery of biomacromolecule drugs. This study provides insights into the construction and formulation optimization of pulmonary delivery carriers. Full article

(This article belongs to the Special Issue Pharmaceutical Manufacturing Process of Inhaled Drugs)

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17 pages, 1389 KiB

Open AccessArticle

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

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

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

Viewed by 278

Abstract

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

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

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

14 pages, 4848 KiB

Open AccessArticle

Impact of V9302, a Competitive Antagonist of Transmembrane Glutamine Flux on Reversal of Resistance in Breast Cancer Cell Lines

by Nikoletta Szemerédi, Zsuzsanna Schelz, Dária Antónia Horvath, Bálint Rácz, András G. Szatmári, Hiba F. Muddather, Noémi Bózsity, István Zupkó and Gabriella Spengler

Pharmaceutics 2024, 16(7), 877; https://doi.org/10.3390/pharmaceutics16070877 (registering DOI) - 29 Jun 2024

Viewed by 428

Abstract

Chemotherapy is a known treatment modality that improves the long-term survival of breast cancer patients. However, due to the resistance to numerous anticancer drugs, alternative chemotherapeutic strategies are required. Regarding antimetabolic drugs, several compounds have proven anticancer properties, such as statins. The present [...] Read more.

Chemotherapy is a known treatment modality that improves the long-term survival of breast cancer patients. However, due to the resistance to numerous anticancer drugs, alternative chemotherapeutic strategies are required. Regarding antimetabolic drugs, several compounds have proven anticancer properties, such as statins. The present study aimed to investigate the in vitro effects of V9302, a competitive antagonist of glutamine flux, on different subtypes of breast cancers (estrogen, progesterone, and HER2 receptor-positive or negative, and Pgp-negative and Pgp-overexpressing). The interactions of V9302 with standard chemotherapeutic drugs (doxorubicin and cisplatin) were also determined by MTT staining on breast cancer cell lines. Furthermore, the influence of V9302 on the cell cycle of MCF-7 and its Pgp-overexpressing counterpart KCR was monitored by flow cytometry. It was shown that V9302 exerted synergistic interactions with doxorubicin in all breast cancer cell lines. In cell cycle analysis, the KCR cell line was more sensitive to V9302. After 48 h, cell proliferation was completely blocked, and elevated G1, suppressed S, and decreased G2/M could be detected. Inhibition of glutamate transport can be assumed to block resistance related to Pgp. Full article

(This article belongs to the Special Issue Novel Approaches in the Search for Active Compounds in Drug Discovery and Development)

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15 pages, 2576 KiB

Open AccessArticle

Palmitoylethanolamide-Incorporated Elastic Nano-Liposomes for Enhanced Transdermal Delivery and Anti-Inflammation

by Chuanpeng Ren, Yanyun Ma, Yizhen Wang, Dan Luo, Yanhan Hong, **nyuan Zhang, Hexiang Mei and Wei Liu

Pharmaceutics 2024, 16(7), 876; https://doi.org/10.3390/pharmaceutics16070876 (registering DOI) - 29 Jun 2024

Viewed by 232

Abstract

Palmitoylethanolamide (PEA) exhibits multiple skincare functions such as anti-nociceptive and anti-inflammatory effects. However, its topical application is limited due to its difficulty in bypassing the stratum corneum barrier, relatively low bioavailability, and low stability. Herein, elastic nano-liposomes (ENLs) with excellent deformability and elasticity [...] Read more.

Palmitoylethanolamide (PEA) exhibits multiple skincare functions such as anti-nociceptive and anti-inflammatory effects. However, its topical application is limited due to its difficulty in bypassing the stratum corneum barrier, relatively low bioavailability, and low stability. Herein, elastic nano-liposomes (ENLs) with excellent deformability and elasticity were utilized as a novel drug delivery system to encapsulate PEA to overcome the abovementioned issues and enhance the biological effects on the skin. ENL was prepared with phosphatidylcholine, cholesterol, and cetyl-PG hydroxyethyl palmitamide with a molar ratio mimicking skin epidermal lipids, and PEA was loaded. The PEA-loaded ENL (PEA-ENL) demonstrated efficient transdermal delivery and enhanced skin retention, with negligible cytotoxicity toward HaCaT cells and no allergic reaction in the human skin patch test. Notably, PEA-ENL treatment increased cell migration and induced significant regulation in the expression of genes associated with anti-nociceptive, anti-inflammatory, and skin barrier repair. The mechanism of the anti-nociceptive and anti-inflammatory effects of PEA was further investigated and explained by molecular docking site analysis. This novel PEA-ENL, with efficient transdermal delivery efficiency and multiple skincare functionalities, is promising for topical application. Full article

(This article belongs to the Special Issue Transport of Drugs through Biological Barriers—an Asset or Risk)

19 pages, 3700 KiB

Open AccessReview

The Advances in Phospholipids-Based Phase Separation Gels for the Sustained Release of Peptides, Proteins, and Chemotherapeutics

by Jianxia Dong, Xueru Zhou, Qing Li, Ruohui Zheng, **g Chen, Yuzhe Liu, **n Tong, Zhuoya Wan and Tao Gong

Pharmaceutics 2024, 16(7), 875; https://doi.org/10.3390/pharmaceutics16070875 (registering DOI) - 29 Jun 2024

Viewed by 173

Abstract

Implantable drug delivery systems formed upon injection offer a host of advantages, including localized drug administration, sustained release, minimized side effects, and enhanced patient compliance. Among the various techniques utilized for the development of in situ forming drug implants, solvent-induced phase inversion emerges [...] Read more.

Implantable drug delivery systems formed upon injection offer a host of advantages, including localized drug administration, sustained release, minimized side effects, and enhanced patient compliance. Among the various techniques utilized for the development of in situ forming drug implants, solvent-induced phase inversion emerges as a particularly promising approach. However, synthetic polymer-based implants have been associated with undesirable effects arising from polymer degradation. In response to this challenge, a novel category of drug delivery systems, known as phospholipids-based phase separation gels (PPSGs), has emerged. These gels, characterized by their low initial viscosity, exhibit injectability and undergo rapid transformation into in situ implants when exposed to an aqueous environment. A typical PPSG formulation comprises biodegradable components, such as phospholipids, pharmaceutical oil, and a minimal amount of ethanol. The minimized organic solvents in the composition show good biocompatibility. And the relatively simple composition holds promise for industrial-scale manufacturing. This comprehensive review provides an overview of the principles and advancements in PPSG systems, with specific emphasis on their suitability as drug delivery systems for a wide range of active pharmaceutical ingredients (APIs), spanning from small molecules to peptides and proteins. Additionally, we explore the critical parameters and underlying principles governing the formulation of PPSG-based drug delivery strategies, offering valuable insights on optimization strategies. Full article

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

15 pages, 3845 KiB

Open AccessArticle

A Second Wind for Inorganic APIs: Leishmanicidal and Antileukemic Activity of Hydrated Bismuth Oxide Nanoparticles

by Andriy Grafov, Ana Flávia da Silva Chagas, Alice de Freitas Gomes, Wessal Ouedrhiri, Pierfrancesco Cerruti, Maria Cristina Del Barone, Breno de Souza Mota, Carlos Eduardo de Castro Alves, Anny Maíza Vargas Brasil, Antonia Maria Ramos Franco Pereira and Gemilson Soares Pontes

Pharmaceutics 2024, 16(7), 874; https://doi.org/10.3390/pharmaceutics16070874 (registering DOI) - 29 Jun 2024

Viewed by 332

Abstract

American cutaneous leishmaniasis is a disease caused by protozoa of the genus Leishmania. Currently, meglumine antimoniate is the first-choice treatment for the disease. The limited efficacy and high toxicity of the drug results in the necessity to search for new active principles. Nanotechnology [...] Read more.

American cutaneous leishmaniasis is a disease caused by protozoa of the genus Leishmania. Currently, meglumine antimoniate is the first-choice treatment for the disease. The limited efficacy and high toxicity of the drug results in the necessity to search for new active principles. Nanotechnology is gaining importance in the field, since it can provide better efficacy and lower toxicity of the drugs. The present study aimed to synthesize, characterize, and evaluate the in vitro leishmanicidal and antileukemic activity of bismuth nanoparticles (BiNPs). Promastigotes and amastigotes of L. (V.) guyanensis and L. (L.) amazonensis were exposed to BiNPs. The efficacy of the nanoparticles was determined by measurement of the parasite viability and the percentage of infected cells, while the cytotoxicity was characterized by the colorimetry. BiNPs did not induce cytotoxicity in murine peritoneal macrophages and showed better efficacy in inhibiting promastigotes (IC50 < 0.46 nM) and amastigotes of L. (L.) amazonensis. This is the first report on the leishmanicidal activity of Bi-based materials against L. (V.) guayanensis. BiNPs demonstrated significant cytotoxic activity against K562 and HL60 cells at all evaluated concentrations. While the nanoparticles also showed some cytotoxicity towards non-cancerous Vero cells, the effect was much lower compared to that on cancer cells. Treatment with BiNPs also had a significant effect on inhibiting and reducing colony formation in HL60 cells. These results indicate that bismuth nanoparticles have the potential for an inhibitory effect on the clonal expansion of cancer cells. Full article

(This article belongs to the Special Issue Biodegradable Nanomaterials for Targeted Drug Delivery)

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20 pages, 8172 KiB

Open AccessArticle

Oxyresveratrol in Breast Cancer Cells: Synergistic Effect with Chemotherapeutics Doxorubicin or Melphalan on Proliferation, Cell Cycle Arrest, and Cell Death

by Carlos Luan Alves Passos, Christian Ferreira, Aline Gabrielle Alves de Carvalho, Jerson Lima Silva, Rafael Garrett and Eliane Fialho

Pharmaceutics 2024, 16(7), 873; https://doi.org/10.3390/pharmaceutics16070873 (registering DOI) - 29 Jun 2024

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Abstract

Breast cancer is the second most common type of cancer in the world. Polyphenols can act at all stages of carcinogenesis and oxyresveratrol (OXY) promising anticancer properties, mainly associated with chemotherapy drugs. The aim of this study was to investigate the effect of [...] Read more.

Breast cancer is the second most common type of cancer in the world. Polyphenols can act at all stages of carcinogenesis and oxyresveratrol (OXY) promising anticancer properties, mainly associated with chemotherapy drugs. The aim of this study was to investigate the effect of OXY with doxorubicin (DOX) or melphalan (MEL), either isolated or associated, in MCF-7 and MDA-MB-231 breast cancer cells. Our results showed that OXY, DOX, and MEL presented cytotoxicity, in addition to altering cell morphology. The synergistic association of OXY + DOX and OXY + MEL reduced the cell viability in a dose-dependent manner. The OXY, DOX, or MEL and associations were able to alter the ROS production, ∆Ψm, and cell cycle; DOX and OXY + DOX led the cells to necrosis. Furthermore, OXY and OXY + MEL were able to lead the cells to apoptosis and upregulate caspases-3, -7, -8, and -9 in both cells. LC-HRMS showed that 7-deoxidoxorubicinone and doxorubicinol, responsible for the cardiotoxic effect, were not identified in cells treated with the OXY + DOX association. In summary, our results demonstrate for the first time the synergistic effect of OXY with chemotherapeutic agents in breast cancer cells, offering a new strategy for future animal studies. Full article

(This article belongs to the Special Issue Natural Products for Anticancer Application)

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12 pages, 762 KiB

Open AccessArticle

Pharmacokinetic Evaluation of Oral Viscous Budesonide in Paediatric Patients with Eosinophilic Oesophagitis in Repaired Oesophageal Atresia

by Raffaele Simeoli, Sebastiano A. G. Lava, Alessandro Di Deo, Marco Roversi, Sara Cairoli, Renato Tambucci, Francesca Rea, Monica Malamisura, Giulia Angelino, Isabella Biondi, Alessandra Simonetti, Paola De Angelis, Carlo Dionisi Vici, Paolo Rossi, Giuseppe Pontrelli, Oscar Della Pasqua and Bianca Maria Goffredo

Pharmaceutics 2024, 16(7), 872; https://doi.org/10.3390/pharmaceutics16070872 (registering DOI) - 28 Jun 2024

Viewed by 277

Abstract

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and [...] Read more.

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression. Full article

(This article belongs to the Special Issue Pediatric Drug Formulations)

19 pages, 3932 KiB

Open AccessArticle

Development, Characterization, and Evaluation of Potential Systemic Toxicity of a Novel Oral Melatonin Formulation

by Catalina N. Cheaburu-Yilmaz, Kemal Atmaca, Onur Yilmaz and Hilmi Orhan

Pharmaceutics 2024, 16(7), 871; https://doi.org/10.3390/pharmaceutics16070871 (registering DOI) - 28 Jun 2024

Viewed by 255

Abstract

The need to create safe materials for biomedical and pharmaceutical applications has become a significant driving force for the development of new systems. Therefore, a chitosan-coated copolymer of itaconic acid, acrylic acid, and N-vinyl caprolactam (IT-AA-NVC) was prepared by radical polymerization and subsequent [...] Read more.

The need to create safe materials for biomedical and pharmaceutical applications has become a significant driving force for the development of new systems. Therefore, a chitosan-coated copolymer of itaconic acid, acrylic acid, and N-vinyl caprolactam (IT-AA-NVC) was prepared by radical polymerization and subsequent coating via nanoprecipitation to give a system capable of sustained delivery of melatonin. Although melatonin brings undoubted benefits to the human body, aspects of the optimal dose, route, and time of administration for the obtaining of suitable treatment outcomes remain under discussion. The entrapment of melatonin in biocompatible polymeric systems can prevent its oxidation, decrease its toxicity, and provide an increased half-life, resulting in an enhanced pharmacokinetic profile with improved patient compliance. The structures of the biopolymer and conjugate were proven by FTIR, thermal properties were tested by DSC, and the morphologies were followed by SEM. The loading efficiency and in vitro release profile were studied by means of HPLC, and a delayed release profile with an initial burst was obtained. The potential systemic toxicity of the formulation was studied in vivo; a mild hepatotoxicity was observed following administration of the melatonin-loaded formulation to mice, both by histopathology and blood clinical biochemistry. Histopathology showed a mild nephrotoxicity as well; however, kidney clinical biochemistry did not support this. Full article

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

22 pages, 7688 KiB

Open AccessArticle

IDO1 Inhibitor RY103 Suppresses Trp-GCN2-Mediated Angiogenesis and Counters Immunosuppression in Glioblastoma

by Zikang **ng, Xuewen Li, Zhen Ning Tony He, **n Fang, Heng Liang, Chunxiang Kuang, Aiying Li and Qing Yang

Pharmaceutics 2024, 16(7), 870; https://doi.org/10.3390/pharmaceutics16070870 (registering DOI) - 28 Jun 2024

Viewed by 238

Abstract

Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while [...] Read more.

Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while IDO1 has also been suggested to be related to tumor angiogenesis. Herein, we aim to clarify the potential role of IDO1 in glioma angiogenesis and the mechanism behind it. Bioinformatic analyses showed that the expressions of IDO1 and angiogenesis markers VEGFA and CD34 were positively correlated and increased with pathological grade in glioma. IDO1-overexpression-derived-tryptophan depletion activated the general control nonderepressible 2 (GCN2) pathway and upregulated VEGFA in glioma cells. The tube formation ability of angiogenesis model cells could be inhibited by IDO1 inhibitors and influenced by the activity and expression of IDO1 in condition medium. A significant increase in serum VEGFA concentration and tumor CD34 expression was observed in IDO1-overexpressing GL261 subcutaneous glioma-bearing mice. IDO1 inhibitor RY103 showed positive anti-tumor efficacy, including the anti-angiogenesis effect and upregulation of natural killer cells in GL261 glioma-bearing mice. As expected, the combination of RY103 and anti-angiogenesis agent sunitinib was proved to be a better therapeutic strategy than either monotherapy. Full article

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

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37 pages, 1361 KiB

Open AccessReview

Emerging Trends in the Treatment of Skin Disorders by Herbal Drugs: Traditional and Nanotechnological Approach

by Rutvi Agrawal, Priyanka Jurel, Rohitas Deshmukh, Ranjit Kumar Harwansh, Akash Garg, Ashwini Kumar, Sudarshan Singh, Ajay Guru, Arun Kumar and Vinoth Kumarasamy

Pharmaceutics 2024, 16(7), 869; https://doi.org/10.3390/pharmaceutics16070869 (registering DOI) - 28 Jun 2024

Viewed by 203

Abstract

Since the earliest days, people have been employing herbal treatments extensively around the world. The development of phytochemical and phytopharmacological sciences has made it possible to understand the chemical composition and biological properties of a number of medicinal plant products. Due to certain [...] Read more.

Since the earliest days, people have been employing herbal treatments extensively around the world. The development of phytochemical and phytopharmacological sciences has made it possible to understand the chemical composition and biological properties of a number of medicinal plant products. Due to certain challenges like large molecular weight and low bioavailability, some components of herbal extracts are not utilized for therapeutic purposes. It has been suggested that herbal medicine and nanotechnology can be combined to enhance the benefits of plant extracts by lowering dosage requirements and adverse effects and increasing therapeutic activity. Using nanotechnology, the active ingredient can be delivered in an adequate concentration and transported to the targeted site of action. Conventional therapy does not fulfill these requirements. This review focuses on different skin diseases and nanotechnology-based herbal medicines that have been utilized to treat them. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside, 2nd Edition)

29 pages, 1087 KiB

Open AccessReview

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

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

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

Viewed by 229

Abstract

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

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

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

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17 pages, 992 KiB

Open AccessArticle

Influence of the Acceptor Fluid on the Bupivacaine Release from the Prospective Intra-Articular Methylcellulose Hydrogel

by Dorota Wójcik-Pastuszka, Anna Frąk and Witold Musiał

Pharmaceutics 2024, 16(7), 867; https://doi.org/10.3390/pharmaceutics16070867 - 27 Jun 2024

Viewed by 193

Abstract

Injections are one way of delivering drugs directly to the joint capsule. Employing this possibility, local anesthetic, such as bupivacaine (Bu), in the form of the suspension can be administered. The aim of this work was to propose a methylcellulose-based hydrogel-incorporated bupivacaine for [...] Read more.

Injections are one way of delivering drugs directly to the joint capsule. Employing this possibility, local anesthetic, such as bupivacaine (Bu), in the form of the suspension can be administered. The aim of this work was to propose a methylcellulose-based hydrogel-incorporated bupivacaine for intra-articular injections and to study the release kinetics of the drug from the hydrogel to different acceptor media, reflecting the synovial fluid of a healthy joint and the synovial fluid of an inflamed joint. The drug release studies were performed employing the flow apparatus. The drug was released to four different acceptor fluids: phosphate buffer pH = 7.4 (PBS7.4), phosphate buffer pH = 6.8 (PBS6.8), phosphate buffer pH = 7.4 with the high-molecular-weight sodium hyaluronate (PBS7.4H), and phosphate buffer pH = 6.8 with the low-molecular-weight sodium hyaluronate (PBS6.8L). The investigation was carried out at the temperature of 37 °C. The absorbance of the Bu released was measured at the wavelength of 262 nm every 2 min for 24 h. The release profiles of Bu to the acceptor media PBS7.4, PBS6.8, PBS7.4H, and PBS6.8L were described best by the first-order kinetics and the second-order equation. According to these models, the release rate constants were the highest when Bu was released to the fluid PBS7.4 and were k₁ = (7.20 ± 0.01) × 10⁻⁵ min⁻¹ and k₂ = (3.00 ± 0.04) × 10⁻⁶ mg⁻¹ × min⁻¹, respectively. The relative viscosity of the acceptor medium, its pH, and the addition of high-molecular-weight or low-molecular-weight sodium hyaluronate (HAH or HAL) to the acceptor fluid influenced the drug dissolution. The release of Bu into the medium reflecting healthy synovial fluid takes a different pattern from its release into the fluid of an inflamed joint. Full article

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

23 pages, 1532 KiB

Open AccessArticle

Formulation and Evaluation of pH-Modulated Amorphous Solid Dispersion-Based Orodispersible Tablets of Cefdinir

by Yahya Alhamhoom, Thanusha Kumaraswamy, Avichal Kumar, Shivakumar Hagalavadi Nanjappa, Sanjana S. Prakash, Mohamed Rahamathulla, Kamal Y. Thajudeen, Mohammed Muqtader Ahmed and Thippeswamy Boreddy Shivanandappa

Pharmaceutics 2024, 16(7), 866; https://doi.org/10.3390/pharmaceutics16070866 - 27 Jun 2024

Viewed by 220

Abstract

Cefdinir (CEF) is a semi-synthetic third-generation broad-spectrum oral cephalosporin that exhibits poor solubility at lower pH values. Considering this, pH-modulated CEF solid dispersions (ASDs) were produced by solvent evaporation method employing various hydrophilic carriers and alkalizers. Among different carriers, ASDs produced using PEG [...] Read more.

Cefdinir (CEF) is a semi-synthetic third-generation broad-spectrum oral cephalosporin that exhibits poor solubility at lower pH values. Considering this, pH-modulated CEF solid dispersions (ASDs) were produced by solvent evaporation method employing various hydrophilic carriers and alkalizers. Among different carriers, ASDs produced using PEG 6000 with meglumine as alkalizer were found to significantly increase (p < 0.005) the drug solubility (4.50 ± 0.32 mg/mL) in pH 1.2. Fourier transform infrared spectrophotometry confirmed chemical integrity of CEF while differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) indicated CEF was reduced to an amorphous state in ASD8. Antimicrobial assay performed by well diffusion method against Staphylococcus aureus (MTCC96) and Escherichia coli (MTCC118) demonstrated significantly superior (p < 0.001) efficacy of CEFSD compared to CEF. The porous orodispersible tablets (ODTs) of ASD8 (batch F5) were developed by incorporating ammonium bicarbonate as a subliming agent by direct compression, followed by vacuum drying displayed quick disintegration (27.11 ± 1.96 s) that met compendial norms and near-complete dissolution (93.85 ± 1.27%) in 30 min. The ODTs of ASD8 appear to be a promising platform to mitigate the pH-dependent solubility and dissolution issues associated with CEF in challenging physiological pH conditions prevalent in stomach. Thus, ODTs of ASD8 are likely to effectively manage various infections and avoid development of drug-resistant strains, thereby improving the curing rates. Full article

(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)

28 pages, 1133 KiB

Open AccessReview

Immunotherapies Targeting Tumor-Associated Macrophages (TAMs) in Cancer

by Mei-Ye Li, Wei Ye and Ke-Wang Luo

Pharmaceutics 2024, 16(7), 865; https://doi.org/10.3390/pharmaceutics16070865 - 27 Jun 2024

Viewed by 359

Abstract

Tumor-associated macrophages (TAMs) are one of the most plentiful immune compositions in the tumor microenvironment, which are further divided into anti-tumor M1 subtype and pro-tumor M2 subtype. Recent findings found that TAMs play a vital function in the regulation and progression of tumorigenesis. [...] Read more.

Tumor-associated macrophages (TAMs) are one of the most plentiful immune compositions in the tumor microenvironment, which are further divided into anti-tumor M1 subtype and pro-tumor M2 subtype. Recent findings found that TAMs play a vital function in the regulation and progression of tumorigenesis. Moreover, TAMs promote tumor vascularization, and support the survival of tumor cells, causing an impact on tumor growth and patient prognosis. Numerous studies show that reducing the density of TAMs, or modulating the polarization of TAMs, can inhibit tumor growth, indicating that TAMs are a promising target for tumor immunotherapy. Recently, clinical trials have found that treatments targeting TAMs have achieved encouraging results, and the U.S. Food and Drug Administration has approved a number of drugs for use in cancer treatment. In this review, we summarize the origin, polarization, and function of TAMs, and emphasize the therapeutic strategies targeting TAMs in cancer treatment in clinical studies and scientific research, which demonstrate a broad prospect of TAMs-targeted therapies in tumor immunotherapy. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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23 pages, 859 KiB

Open AccessArticle

Imiquimod-Loaded Nanosystem for Treatment Human Papillomavirus-Induced Lesions

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

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

Viewed by 219

Abstract

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

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

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

21 pages, 9327 KiB

Open AccessArticle

Development of a Versatile Nanostructured Lipid Carrier (NLC) Using Design of Experiments (DoE)—Part II: Incorporation and Stability of Butamben with Different Surfactants

by Ananda P. Matarazzo, Carlos A. Rios, Gabriela Gerônimo, Roberta Ondei, Eneida de Paula and Márcia C. Breitkreitz

Pharmaceutics 2024, 16(7), 863; https://doi.org/10.3390/pharmaceutics16070863 - 27 Jun 2024

Viewed by 232

Abstract

Nanostructured lipid carriers (NLCs) are typically composed of liquid lipids, solid lipids, and surfactants, enabling the encapsulation of lipophilic drugs. Butamben is a Class II anesthetic drug, according to the Biopharmaceutical Classification System (BCS); it has a log P of 2.87 and is [...] Read more.

Nanostructured lipid carriers (NLCs) are typically composed of liquid lipids, solid lipids, and surfactants, enabling the encapsulation of lipophilic drugs. Butamben is a Class II anesthetic drug, according to the Biopharmaceutical Classification System (BCS); it has a log P of 2.87 and is considered a ‘brick dust’ (poorly water-soluble and poorly lipid-soluble) drug. This characteristic poses a challenge for the development of NLCs, as they are not soluble in the liquid lipid present in the NLC core. In a previous study, we developed an NLC core consisting of a solid lipid (Crodamol^TM CP), a lipophilic liquid with medium polarity (SR^TM Lauryl lactate), and a hydrophilic excipient (SR^TM DMI) that allowed the solubilization of ‘brick dust’ types of drugs, including butamben. In this study, starting from the NLC core formulation previously developed we carried out an optimization of the surfactant system and evaluated their performance in aqueous medium. Three different surfactants (Crodasol^TM HS HP, Synperonic^TM PE/F68, and Croduret^TM 40) were studied and, for each of them, a 2³ factorial design was stablished, with total lipids, % surfactant, and sonication time (min) as the input variables and particle size (nm), polydispersity index (PDI), and zeta potential (mV) as the response variables. Stable NLCs were obtained using Crodasol^TM HS HP and Synperonic^TM PE/F68 as surfactants. Through a comparison between NLCs developed with and without SR^TM DMI, it was observed that besides hel** the solubilization of butamben in the NLC core, this excipient helped in stabilizing the system and decreasing particle size. NLCs containing Crodasol^TM HS HP and Synperonic^TM PE/F68 presented particle size values in the nanometric scale, PDI values lower than 0.3, and zeta potentials above |10|mV. Concerning NLCs’ stability, SBTB-NLC with Synperonic^TM PE/F68 and butamben demonstrated stability over a 3-month period in aqueous medium. The remaining NLCs showed phase separation or precipitation during the 3-month analysis. Nevertheless, these formulations could be freeze-dried after preparation, which would avoid precipitation in an aqueous medium. Full article

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

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10 pages, 2992 KiB

Open AccessArticle

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

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

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

Viewed by 236

Abstract

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

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

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

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