Pharmaceutics最新文献

Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of a drug, while pharmacodynamics focuses on the effects of the drug on the body [...].

Background: Thyroid cancer (TC) is the most prevalent endocrine malignancy, and is categorized into well-differentiated and aggressive anaplastic types. Novel therapeutic modalities are needed for TC. Nanomedicine is a promising strategy for the development of precision medicine. In this context, we investigated the use of nanogels (NGs) to deliver agents with different physicochemical properties, specifically the hydrophilic agent doxorubicin (DOX) and the hydrophobic compound curcumin (CUR), in TC cell lines. Methods: Nα-9-fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) peptide-based NGs loaded with DOX and CUR were formulated using the solvent-switch method. DOX-loaded NGs were previously characterized. CUR-loaded NGs were characterized through rheology, scanning electron microscopy (SEM), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), and Fourier transform infrared (FT-IR) spectroscopy. Confocal microscopy, q-RT-PCR, and ATP lite assays were performed to evaluate the uptake and delivery of DOX- and CUR-loaded NGs on TC cell lines. Results: CUR-loaded NGs exhibited a mean diameter of approximately 204.3 nm and a zeta potential of -34.6 mV, indicative of a good stability. In vitro release studies revealed a sustained release profile of CUR over 72 h. Functional analyses demonstrated that Fmoc-FF-loaded NGs were internalized into TC cell lines. They were primarily localized in the cytoplasm rather than in early endosomes, thereby ensuring intracellular stability. Furthermore, Fmoc-FF NGs reduced the nuclear uptake kinetics of DOX in TC cells, suggesting a potential reduction in dose-limiting toxicity. Comparative studies with CUR-loaded NGs revealed similar internalization and delayed nuclear uptake, highlighting the efficacy of Fmoc-FF NGs in delivering hydrophobic agents. Conclusions: Overall, the data suggest that Fmoc-FF NGs represent a promising strategy for delivering agents with diverse physicochemical properties in TC, enhancing their efficacy and safety and warranting further investigation.

Background/Objectives: The purpose of this study was to create bile acid-containing liposomes to improve methotrexate blood-brain barrier penetration and to assess the liposome transportation mechanism across the blood-brain barrier. Methods: The improvement of liposome penetration was investigated utilizing human brain microvascular endothelial cells in an in vitro blood-brain barrier model. Using confocal laser scanning microscopy (CLSM) and flow cytometry, liposomes were labeled with fluorescent phospholipids to facilitate their passage across the blood-brain barrier. Results: The produced liposomes with bile acid exhibited a negative surface charge and an average particle size of between 30 and 148 nm. According to an in vitro blood-brain barrier penetration study, the methotrexate penetration was increased by liposomes containing 1% glycocholic acid but not by liposomes containing taurocholic acid. For transport pathway evaluation across the blood-brain barrier of these liposomes, CLSM revealed that fluorescent liposomes were present inside cells treated with specific endocytosis inhibitors, indicating that the cellular internalization of the particles was not involved in endocytosis. Conclusions: Liposomes supplemented with 1% glycocholic acid could enhance the penetration of methotrexate across the blood-brain barrier, while taurocholic acid could not. The transport of liposomes with 1% glycocholic acid across the blood-brain barrier occurs via the transcellular pathway through which it penetrates cells. In contrast, the paracellular pathway was a minor pathway.

Background: It has been documented that radiation can influence the pharmacokinetics of chemotherapy drugs, yet the underlying mechanisms remain poorly understood. In clinical practice, a considerable number of cancer patients undergo radiotherapy, and those with comorbid hypertension required antihypertensive drugs, including valsartan, an angiotensin II receptor blocker. However, there is no research investigating whether radiotherapy poses a risk of altering the pharmacokinetics. Objective: The objective of this study is to investigate the impact of X-ray abdominal irradiation on the pharmacokinetics of valsartan and to preliminarily elucidate the underlying mechanism. Methods: The pharmacokinetics of valsartan after X-ray irradiation was investigated in rats and in vitro by detecting the concentration of valsartan in biological samples by LC-MS/MS. The oxidative stress in the intestine and the mRNA expression of partial transporters and Nrf2 in the liver and small intestine were detected by biochemical reagent kit or RT-qPCR. Results: In vivo studies showed that X-ray irradiation resulted in a significant decrease in the AUC and C_max of valsartan, and the cumulative fractional excretion of valsartan in bile and urine, although there was no significant change in fecal excretion. In vitro studies showed that the uptake of valsartan by both intestine and Caco-2 cells decreased after irradiation, and the cellular uptake could be restored by Mrp2 inhibitor MK571. The levels of GSH, SOD, and CAT in the intestine decreased after irradiation. The mRNA expressions of Mrp2 and P-gp in the intestine or Caco-2 cells were significantly upregulated after irradiation while there was a downregulation of Mrp2 and oatp1b2 in liver. Nrf2 and HO-1 in the intestine were also significantly upregulated, which clarified the involvement of Mrp2 and the possible molecular mechanism. Conclusions: Abdominal X-ray irradiation can cause oxidative stress and upregulate intestinal Mrp2, which may be related to oxidative stress and upregulation of Nrf2, reducing intestinal absorption of valsartan and leading to a significant decrease in the blood concentration of valsartan.

Amorphous solid dispersion (ASD) is one of the most important enabling formulation technologies for the development of poorly soluble drugs. Because of its thermodynamically unstable nature in both solid and wet states, the evaluation and optimization of the formulation performance involves some difficulties. The dissolution process is sensitively influenced by various factors, including the applied dose, medium composition, and pH. Supersaturated solutions can cause liquid-liquid phase separation (LLPS) and/or crystallization, which complicates the comprehension of the dissolution process. However, LLPS should be evaluated carefully because it is closely related to oral absorption. As LLPS concentration is analogous to amorphous solubility, it can be a key factor in predicting oral absorption from ASDs, if absorption is limited by solubility. Moreover, LLPS droplets are expected to increase transmembrane flux by increasing the drug concentration near the epithelial cell membrane. In this review, recently updated knowledge on the dissolution, membrane permeation, and oral absorption behaviors of ASDs is discussed with an emphasis on LLPS behavior.

Eczema is a complex autoimmune condition characterised mainly by inflammation and skin lesions along with physical and psychological comorbidities. Although there have been significant advances in understanding the mechanisms behind atopic dermatitis, conventionally available treatments yield inconsistent results and have some unintended consequences. In today's digital age, where knowledge is just a click away, natural-based supplements have been on the rise for a more "natural" treatment towards any type of disease. Natural compounds, particularly derived from medicinal plants, have piqued significant interest in the development of herbal remedies for chronic inflammatory skin conditions. Among many compounds, flavonoids have shown promise in treating eczema due to their strong anti-inflammatory, antioxidant, and anti-allergic properties, making them helpful in preventing allergic reactions, inflammation, and skin irritation. This review highlights the therapeutic potential of flavonoid-based bioactive compounds to manage eczema, emphasising the mechanisms of action. Additionally, providing a comprehensive analysis of the potential of emerging and established compounds, while bridging a gap between traditional and modern medicine. Flavonoids offer a variety of opportunities for further research and innovative formulations that can maximise its full benefits. Further combination of flavonoids with various approaches such as nanoencapsulation for enhanced bioavailability, hydrogel-based delivery systems for a controlled release, and additive manufacturing for personalised topical formulations, could align with future precision medicine needs.

Background/Objectives: Angiogenesis plays a crucial role in tumor development and is a driving force for the aggressiveness of several types of cancer. Our team developed a novel series of thiosemicarbazone-containing quinazoline derivatives, TSC1-TSC10, as potential VEGFR2 inhibitors with proven anti-angiogenic and antiproliferative potential. Methods: The TSC1-TSC10 series was synthesized and characterized by spectral data. Extensive methodology was applied both in vitro (Alamar Blue assay, Scratch assay, CAM assay, and VEGFR2 kinase assay) and in silico (docking studies, MDs, and MM-PBSA) for the confirmation of the biological potential. Results: TSC10 emerged as the most promising compound, with a favorable cytotoxic potential across the cell panel (Ea.Hy296, HaCaT, and A375) in agreement with the in vitro VEGFR2 kinase assay (IC₅₀ = 119 nM). A comparable motility reduction in the vascular endothelial cells to that of the reference drug sorafenib was provided by TSC10, with a similar anti-angiogenic potential in the more complex in ovo model of the CAM assay. The in silico experiments confirmed the successful accommodation of the active site of the kinase domain similar to sorafenib for the entire TSC1-TSC10 series, providing valuable key insight into the complex stability driving force for the evaluated compounds. Conclusions: The in vitro evaluations of the biological potential correlated with the in silico predictions by computer-aided complex simulations provided a solid confirmation of the initial hypothesis for the TSC1-TSC10 series.

Background/Objectives: EPICERTIN, a biotherapeutic candidate for mucosal healing in inflammatory bowel disease (IBD) and other mucosal disorders, was subjected to an extensive long-term stability program to evaluate its molecular stability and physicochemical properties. Additionally, a forced degradation assessment was conducted to identify EPICERTIN's degradation products under various conditions, including thermal stress, pH variations, agitation, and oxidation. Methods: The stability of EPICERTIN drug substance (DS), formulated in phosphate-buffered saline (PBS) at 1 mg/mL and stored at 5 °C and 25 °C/60% relative humidity (RH), was monitored over a 2-year period, referencing relevant regulatory guidelines. Evaluations of EPICERTIN DS over the 24-month period included assessment of purity by SDS-PAGE and size exclusion high performance liquid chromatography (SEC-HPLC), identity by electrospray ionization mass spectrometry (ESI-MS) intact mass analysis and Western blotting, and potency by GM1-binding KDEL-detection ELISA (GM1/KDEL ELISA). The forced degradation patterns were analyzed by assessing purity (using SEC-HPLC and SDS-PAGE), potency (via GM1/KDEL ELISA), and intact mass (via ESI-MS). Results: The results overall support that EPICERTIN DS remains stable for 2 years under the tested conditions. The forced degradation assessment effectively identified degradation products, particularly under conditions of high temperatures (above 40 °C for 24 h), low pH values (pH 1 and 4), and oxidation upon exposure to 2% H₂O₂. Conclusions: These findings highlight EPICERTIN's robust long-term stability in PBS formulation, reinforcing its potential as a viable drug candidate for the treatment of IBD.

Gels constitute a versatile class of materials with considerable potential for applications in both technical and medical domains. Physicochemical property characterization is a critical evaluation method for gels. Common characterization techniques include pH measurement, structural analysis, mechanical property assessment, rheological analysis, and phase transition studies, among others. While numerous research articles report characterization results, few reviews comprehensively summarize the appropriate numerical ranges for these properties. This lack of standardization complicates harmonized evaluation methods and hinders direct comparisons between different gels. To address this gap, it is essential to systematically investigate characterization methods and analyze data from the extensive body of literature on gels. In this review, we provide a comprehensive summary of general characterization methods and present a detailed analysis of gel characterization data to support future research and promote standardized evaluation protocols.

Background/Objectives: Drug repurposing explores new applications for approved medications, such as simvastatin (SV), a lipid-lowering drug that has shown anticancer potential but is limited by solubility and side effects. This study aims to enhance SV delivery and efficacy against lung cancer cells using bioactive lipid nanoparticles formulated with plant-derived monoterpenes as both nanostructuring agents and anticancer molecules. Methods: Lipid nanoparticles were produced by ultrasonication and characterized for morphology, size, zeta potential, and polydispersity index (PDI). Monoterpenes (linalool-LN-, limonene, 1,8-cineole) or Crodamol^® were used as liquid lipids. Encapsulation efficiency (EE), release profiles, stability, biocompatibility, protein adsorption, cytotoxicity, and anticancer effects were evaluated. Results: The nanoparticles exhibited high stability, size: 94.2 ± 0.9-144.0 ± 2.6 nm, PDI < 0.3, and zeta potential: -4.5 ± 0.7 to -16.3 ± 0.8 mV. Encapsulation of SV in all formulations enhanced cytotoxicity against A549 lung cancer cells, with NLC/LN/SV showing the highest activity and being chosen for further investigation. Sustained SV release over 72 h and EE > 95% was observed for NLC/LN/SV. SAXS/WAXS analysis revealed that LN altered the crystallographic structure of nanoparticles. NLC/LN/SV demonstrated excellent biocompatibility and developed a thin serum protein corona in vitro. Cellular studies showed efficient uptake by A549 cells, G0/G1 arrest, mitochondrial hyperpolarization, reactive oxygen species production, and enhanced cell death compared to free SV. NLC/LN/SV more effectively inhibited cancer cell migration than free SV. Conclusions: NLC/LN/SV represents a promising nanocarrier for SV repurposing, combining enhanced anticancer activity, biocompatibility, and sustained stability for potential lung cancer therapy.