European Journal of Pharmaceutics and Biopharmaceutics最新文献

The integration of multiple therapeutic agents within a single nano-drug carrier holds promise for advancing anti-tumor therapies, despite challenges posed by their diverse physicochemical properties. This study introduces a novel multi-stage microfluidic co-encapsulation platform designed to address these challenges. By carefully orchestrating the nano-precipitation process sequence, this platform achieves sequential encapsulation of two drugs with markedly different physicochemical characteristics. Using the multi-stage microfluidic TrH chip, hybrid nanoparticles (HNPs) loaded with paclitaxel (PTX)-simvastatin (SV), PTX-lenvatinib (LV), and SV-LV were synthesized. Unlike conventional Bulk methods and existing commercial microfluidic Tesla and Baffle chips, the HNPs produced here exhibit a core-shell structure and uniform particle size distribution, crucial for enhancing drug delivery efficacy. Notably, this method achieves nearly 100 % encapsulation efficiency for both drugs across a dual-drug feed ratio range from 1:4 to 4:1. Drug loading efficiencies were quantified for PTX-SV/HNPs (14.97 ± 1.19 %), PTX-LV/HNPs (16.58 ± 0.69 %), and SV-LV/HNPs (19.21 ± 2.38 %). PTX-SV/HNPs demonstrated sequential release characteristics of SV and PTX, as confirmed by in vitro drug release experiments. Significantly, PTX-SV/HNPs exhibited superior cytotoxicity against HepG2 cells compared to individual PTX and SV treatments, underscoring their potential in cancer therapy. In conclusion, the developed multi-stage microfluidic platform represents a robust strategy for co-encapsulating drugs with substantial physicochemical disparities, thereby offering a promising avenue for advancing multi-drug delivery in nanomedicine applications.

Transdermal drug delivery presents a compelling alternative to both needle injection and oral ingestion of medication, as it enhances patient adherence and convenience through its non-invasive and painless administration method. The use of microneedles penetrates the barrier of the stratum corneum, facilitating the sustained delivery of drugs across the skin. However, their efficacy has been limited by the slow diffusion of molecules and often requires external triggers. Herein, a lightweight and minimized 3D-printed microneedle array is introduced, employing a cymbal-type ultrasound transducer, as the external engine for deeper and faster transdermal drug delivery. A theoretical finite element model was developed and the optimization design was conducted for structural parameters. The optimized assembled prototype was fabricated using high-precision 3D printing and weighs only 20 g. In vivo experiments using a diabetic mouse model demonstrate that local insulin delivery with CyMA achieves systemic effects comparable to intraperitoneal administration. Such compact and effective microneedle delivery technology offers considerable promise therapeutic applications on the skin and intraoral use.

This study focuses on developing, characterizing, and evaluating lycopene nanomicelles formulations for their therapeutic potential in treating acute inflammation and obesity. Lycopene, a hydrophobic carotenoid with potent antioxidant, anti-inflammatory, and anticancer properties, faces challenges in bioavailability due to its poor solubility. To address this, the study utilized nanocarrier systems like liposomes, nanoparticles, and nanoemulsions to enhance the solubility, stability, and bioavailability of lycopene. The lycopene nanomicelles demonstrated significant anti-inflammatory and anticancer activities through multiple mechanisms. It inhibited the NF-κB pathway, reducing the expression of pro-inflammatory mediators, and modulated apoptotic pathways, leading to increased apoptosis and reduced cell proliferation in cancer cells. Furthermore, lycopene enhanced phase II detoxifying enzymes activity, interfered with gap junction communication, and potentially improved DNA repair mechanisms, contributing to its anticancer efficacy. In vivo studies revealed that lycopene nanomicelles effectively reduced leukocyte and neutrophil counts in an acute inflammation model, especially at higher doses, highlighting its potential as a nanodrug for inflammation management. However, the study found no significant alteration in triglyceride levels, indicating a need for further investigation into the effects of lycopene and its nanostructured forms on lipid metabolism. Biochemical analyses showed variations in liver enzyme levels, suggesting protective effects on the liver but also indicating potential pancreatic activity or stress and low glucose levels. These findings underscore the necessity for comprehensive safety evaluations. Overall, this research underscores the promising therapeutic applications of lycopene nanomicelles in inflammation and cancer while emphasizing the importance of addressing safety and metabolic effects for effective clinical translation.

Throughout history, psychedelic compounds have been used for religious, spiritual and recreational purposes. A plethora of studies have reported the use of psychedelic compounds in the treatment of various conditions, such as alcoholism, addictions, depressive state to borderline schizophrenia, personality disorder, among other mental disorders. Psychedelic microdosing, a common technique in recent years, involves the consumption of small doses of psychedelic drugs for therapeutic purposes. This study investigated the potential of hydrogel-forming microarray patches (HF-MAPs) to deliver N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and mescaline (MES) in small doses through the skin. To this purpose, HF-MAPs were prepared using poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP), using citric acid as the crosslinker. Two different reservoirs, containing PVP and PVA as the main components and poly(ethylene)glycol 400 (PEG400) and glycerol as plasticising agents, were used to deliver all the drugs from the HF-MAPs. Franz cells studies in excised neonatal porcine skin demonstrated that the permeation of DMT, 5-MeO-DMT and MES was better from the PEG400 reservoir, showing a permeation of 60.71 %, 59.61 % and 41.85 % respectively. Pharmacokinetic studies in rats showed that HF-MAP technology as a strategy for microdosing psychedelic compounds was also demonstrated with DMT. AUC_t0-final for the HF-MAP cohort (7186 ± 1296 ng/mL*h) was significantly greater than the IM cohort (1803 ± 53.25 ng/mL*h) (p = 0.0020), with a relative bioavailability of ∼ 72 %. Considering their pharmacokinetic profile, the frequency of DMT dosing could be reduced with HF-MAP when compared to the IM route.

Oral delivery of peptide drugs remains one of the most formidable challenges in the frontier of pharmaceutical research. Peptide drugs typically suffer from exceptionally low oral bioavailability, primarily attributed to rigorous enzymatic degradation within the gastrointestinal (GI) tract, limited ability to traverse the enterocyte barrier, and significant first-pass hepatic metabolism. Absorption of peptide drugs via the lymphatic route could potentially bypass intracellular lysosome degradation and hepatic first-pass metabolism. In this study, we present a strategy to enhance the lymphatic absorption of the model peptide leuprolide (LEU) by diverting its intracellular trafficking towards the endoplasmic-reticulum (ER)-Golgi pathway. Complexes were formed between LEU and lipophilic excipient and then formulated as an oral emulsion. We observed that the penetration of LEU in the emulsion across the Caco-2 cell monolayer model was diverted from the endosome-lysosome pathway, and LEU entered the bloodstream via the mesenteric lymph nodes (MLNs). The data obtained illustrates that the lipophilic LEU complexes could improve enterocyte permeability and bypass lysosomal degradation, and the change of absorption pathway may reduce hepatic first pass metabolism.

Compatibility of parenteral nutrition admixture (PNA) and intravenous medications (IVMs) is a major consideration for clinicians and clinical pharmacists, especially when concurrent administration of PNA with IVMs is unavoidable. This is relatively common in children and neonates, where limited vascular access can be challenging. The purpose of this paper is to create a risk assessment tool that will assist clinical judgment in evaluating the potential incompatibility risk between PNA media and the IVMs when they are administered together through the same intravenous line. The tool will help to provide a more structured approach for healthcare professionals involved in the provision and administration of PNA to assess the risk of incompatibility of IVMs with PNA media.

Albendazole, an anthelmintic recognized by the World Health Organization as an essential medicine, is known to have limitations in solubility and bioavailability. To improve these properties, binary and ternary multicomponent systems were designed employing different combinations of albendazole desmotropes with maltodextrin and aspartic acid. The impact of these systems in solution was evaluated through phase solubility analysis. Moreover, solid systems were produced using the kneading method and evaluated with a combination of techniques, including dissolution tests, Fourier-Transform infrared spectroscopy, X-ray powder diffraction, and scanning electron microscopy. These studies demonstrated that multicomponent systems had higher solubility than free desmotropes, with the system formulated using solid form II of albendazole exhibiting the most significant improvement. Additionally, the dissolution percentage of each solid system in simulated gastric fluid was significantly increased. It can therefore be concluded that these innovative systems offer promising alternatives for improving the oral bioavailability of albendazole, generating significant interest in the pharmaceutical field.

Background: Given the challenges of pediatric antibacterial therapy, it is crucial to formulate antibiotics with a lower potential for interaction with dietary interventions and tailor them for optimal administration in children. Chemometric methods allow us to analyze multiple interrelated variables simultaneously and uncover correlations.

Aim: We applied a chemometric approach to examine how food, beverages, antacids, and mineral supplements affect antibiotic bioavailability in adults and children, aiming to explore relationships between antibiotic structure, physicochemical properties, and post-meal changes in pharmacokinetic (PK) parameters.

Methods: We selected 95 antibacterial drugs for analysis, including beta-lactams (32), quinolones (25), macrolides (13), tetracyclines (16), and others (9). The input dataset comprised information from published clinical trials, chemical records, and calculations. We constructed hierarchical partial least squares (PLS) models with changes in PK parameters (ΔAUC, ΔC_max, ΔT_max, and Δ t ½) as response parameters and nine groups of molecular descriptors (M1-M9) as predictor parameters. We performed analyses separately in children and adults for different dietary interventions.

Results: In the final 10 PLS models, significant components explained 61-90% and 10.3-54.4% of the variance in the predictor and response parameter sets, respectively. We obtained 59 significant positive and negative correlations between antibiotic structure or physicochemical properties (molecular descriptors) and action in the human body in the presence of food, antacids, or mineral supplements (changes in PK parameters), of which 41 concern pediatric patients.

Conclusions: Chemometric methods can be helpful and valuable in investigating the interactions between antibiotics and dietary interventions. Using chemometrics may pave the way for formulating antibiotics for children with a lower potential to interact with food.

Nanocrystalline formulations typically contain stabilizing additives to minimize the risk of particle growth or agglomeration. This risk is particularly relevant when the nanosuspension is converted into a solid drug product as the original state of the nanosuspension should be restored upon redispersion of the drug product in vivo. In this work, the behavior of different nonionic and anionic surfactants in solid nanocrystalline formulations and their effects on redispersibility under biorelevant conditions were investigated. For this purpose, nanocrystalline formulations of basic (itraconazole, ritonavir), acidic (naproxen), and neutral (fenofibrate) API containing nonionic polymers acting as steric stabilizers combined either with anionic (sodium dodecyl sulfate, deoxycholate sodium, docusate sodium) or non-ionic surfactants (polysorbate 80, vitamin E-TPGS) were manufactured by nano-milling. These formulations were turned into a solid drug product by lyophilization and their redispersibility was tested by dispersing them in biorelevant media with different pH values and by characterizing their particle size distribution (PSD) and surface charge. In the absence of an anionic surfactant, it was difficult to achieve particle sizes below 500 nm. However, formulations stabilized anionically were at risk of agglomeration in gastric media. For basic API, the agglomeration was reversible for formulations containing sodium deoxycholate after increasing the pH from acidic to neutral levels, but it was found to be irreversible for those containing sodium dodecyl sulfate and docusate sodium. In summary, the type of anionic stabilizer and its interplay with the physicochemical properties of the API (basic, acidic, or neutral) should be considered in the development of solid nanocrystal formulations.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) represents a spectrum of potentially fatal conditions that currently lack effective drug treatment. Recent researches suggest that Fibroblast Growth Factor 21 (FGF21) may protect against ALI/ARDS. However, the clinical use of FGF21 is limited by its rapid degradation, restricted targeting capabilities, and numerous adverse effects. Addressing this challenge, the study employs a pH-responsive nanoparticle delivery system known as Hexahistidine-metal Assembly (HmA) for administering FGF21. The entrapment efficiency (EE%) and loading capacity (LCwt%) of HmA exceed 90 % and 35 %, respectively, while the HmA@FGF21 nanoparticles exhibit an average size of 130 nm, a PDI value of approximately 0.28, and a zeta potential of 24 mV. In animal experiments, HmA@FGF21 administered in lipopolysaccharide (LPS)-induced lung injury significantly exceed those of standalone FGF21, including mitigating the pathological manifestations and reducing the wet/dry ratio, total protein concentration, and overall cell count in BALF of ALI, whether administered via the airway or intravenously. This therapeutic approach therefore shows promise for precise delivery of FGF21 to the lungs to treat ALI, and may offer a novel, and efficient method for delivery of potential pharmacological agents to address other lung diseases.