European Journal of Pharmaceutical Sciences最新文献

Several studies have recommended the use of hydrogels for localized targeted delivery of chemotherapeutic drugs following tumor removal surgery. This approach aims to both fill the cavity and prevent cancer recurrence. The use of Multiphysics-based simulation emerges as a valuable strategy for minimizing experimental work, providing detailed insights into how drug release occurs in the tissue, and enabling the optimization of the design. In this study, we introduced a mathematical model, utilizing experimental data, to investigate the transport of liposomes carrying MZ1 from a thermosensitive hydrogel and their impact on the viability of breast cancer cells. The proposed comprehensive model considers not just the transport within the interstitial tissue, represented as a porous medium, but also the uptake by cells and its influence on cell viability, along with the potential lymphatic drainage. The six real patient-specific tumor shapes extracted from MRI scans were used to investigate how the size and form of the tumor can modify the transport pattern. The computational results revealed that the concentration of liposomes in the tissue is significantly influenced by their release from the hydrogel, which proved to be the limiting step. Liposome concentrations of approximately 0.1% weight were found to be sufficient in ensuring minimal cell survival in the vicinity of the tumor.

The exploration of three-dimensional (3D) printing inspired technologies in pharmaceutical compounding reveals a promising frontier in personalized medicine manufacture. This study focuses on the development of clopidogrel bisulphate tablets, with doses ranging from 2 mg to 20 mg per tablet, suitable for pediatric use. The study explored a semi-solid extrusion-based deposition technology already being used in compounding pharmacies across several European locations. The investigation explored various properties of two formulations of 1% and 2% clopidogrel gel tablets, with a specific focus on mass variation, drug content uniformity, in vitro drug release profiles, disintegration time, and stability. The mean weights of the smallest printed 200 mg tablets with 1% and 2% clopidogrel concentrations were 199.1 ± 4.6 mg and 201.0 ± 3.2 mg, respectively. For the largest printed 500 mg tablets with 1% and 2% concentrations, the mean weights were 499.3 ± 7.7 mg and 501.7 ± 6.5 mg, respectively. The mean clopidogrel content uniformity for 1% clopidogrel 200 mg and 500 mg tablets were 102.0 ± 1.8%and 96.6 ± 2.6%, respectively, and for 2% clopidogrel 200 mg and 500 mg were 102.6 ± 3.9% and 101.2 ± 1.6%, respectively, well within the acceptable acceptance value (AV) range of 3 to 12. Both 1% and 2% formulations of clopidogrel tablets exhibited rapid drug release, meeting the USP pharmacopeial target of 85% release in 15 minutes. All tablet sizes formulated at 1% and 2% concentrations met specified disintegration specifications. The stability assessment over three months revealed consistent pH values and assay results within target specifications for both clopidogrel formulations (93.5% for 1% formulation and 93.6% for 2% formulation). At three months, X-ray Diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) results demonstrated stability in clopidogrel tablets. In conclusion, a comprehensive evaluation of our developed clopidogrel tablets demonstrate their suitability for clinical use in an extemporaneous setting using the presented semi-solid extrusion-based automation technology.

Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining their association with dexamethasone-induced toxicity. Peak and trough concentrations were collected during the maintenance phase from pediatric ALL patients who received oral dexamethasone (6mg/m2/day). NONMEM was used to study the population pharmacokinetics including covariates. Pharmacokinetic (PK) and pharmacodynamic (PD) correlations between drug and its active metabolite exposure and adverse effects were examined. 382 samples (dexamethasone: n=191; 6β-hydroxydexamethasone: n=191) from 104 children (age range 3.0 -18.8 years) were collected. A one-compartment model described the data best. The estimated apparent dexamethasone total clearance was 26 L/h/70kg with 18% inter-individual variability, and an apparent volume of distribution of 123 L/70kg, yielding a half-life of 3.3 hours. Covariate analysis demonstrated that when asparaginase was co-administered, there was a 50% reduction in both the clearance of dexamethasone and the extent to which dexamethasone was metabolized to 6β-hydroxydexamethasone. A statistically significant but weak positive correlation was observed between dexamethasone drug exposure and fasting hunger scores. Dexamethasone exposure significantly increased with asparaginase co-administration by inhibition of the CYP3A4 pathway. Our study found a statistically significant but weak positive correlation between dexamethasone exposure and increased hunger. These results support the need for more studies on how to personalize dexamethasone dosing in pediatric ALL treatment and adjust doses to limit side effects, especially in case of co-medication.

Continuous spin-freeze-drying is an innovative pharmaceutical manufacturing approach offering real-time monitoring and control at the individual vial level, unlike conventional batch lyophilization. A central feature of this technology is spin-freezing, which involves rapidly spinning liquid-filled vials under a precisely controlled cold gas flow, resulting in a thin, uniform frozen product layer. Using a model peptide formulation, we investigated the impact of different cooling and crystallization rates on quality attributes (QA) and primary drying duration. Key QAs included monomer content, peptide assay, moisture content, and pore structure. The monomer content, peptide content, and primary drying duration remained consistent across all spin-freezing conditions. However, scanning electron microscopy (SEM) and Karl Fischer titration revealed that freezing parameters significantly influenced pore structure and residual moisture content. Samples with smaller pores displayed lower residual moisture, as larger surface areas facilitate moisture desorption. Variations in freezing parameters also significantly impacted desorption kinetics during secondary drying. Slower crystallization rates led to more cracks and less shrinkage in the cake structure, while faster rates resulted in more uniform, stable cakes. Although specific to the product under study, these findings highlight the crucial role of spin-freezing in enhancing freeze-drying efficiency and product quality of biopharmaceuticals.

Preclinical testing of new drug candidates frequently necessitates high-dose solution formulations to support robust testing in rodent models. This study aimed to expand the range of high solubilisation capacity formulations by exploring the solubilisation effects of the polymeric surfactant Soluplus® in combination with ionic surfactants. The interactions between Soluplus® and three ionic surfactants, sodium dodecyl sulfate, dioctyl sodium succinate, and sodium oleate, with a primary focus on solubility enhancement were investigated over a range of ionic surfactant concentrations. The solubilisation profiles for seven model drugs were obtained, and the vehicles were characterized by their visual characteristics, dynamic light scattering, and viscosity measurements. The solubilisation profiles were non-linear, indicating the formation of different colloidal species with individual solubilisation strengths depending on surfactant type and concentration, demonstrating substantial solubility enhancement. For certain drugs more than additive solubilisation, facilitated by synergistic interactions between Soluplus® and the ionic surfactants, was obtained. Overall, the solubility increase provided by the excipient combinations resulted in non-linear and drug specific solubilisation profiles. The non-linearities observed were reflected in visual observations of the vehicles appearance, DLS and viscosity measurements, which collectively indicated a change in polymer aggregation with increasing concentration of anionic surfactant. This investigation highlights that already low quantities of ionic surfactants introduced to Soluplus® may substantially enhance solubility, which offers a promising approach for further exploration in preclinical drug development where more conventional solubilising formulation strategies may fall short.

4-Bromo-N-(thiazol-2-yl)benzenesulfonamide (1) is enriched with bioactive components and is highlighted for its pharmacological properties. However, its pharmacokinetic characteristics are yet to be reported. The interaction of compound 1 with carrier proteins in the bloodstream is an important factor that affects its potential therapeutic efficacy. This study aimed to elucidate the pharmacokinetic mechanisms of compound 1 in relation to human serum albumin (HSA) using multi-spectroscopic and computational techniques. Its predicted drug-like properties revealed no mutagenicity, although potential hepatotoxicity and interactions with certain cytochrome P450 enzymes were observed. Spectroscopic analyses extensively provided the interaction between HSA and 1 through a static fluorescence quenching mechanism with spontaneous hydrophobic interactions and hydrogen bonding. The binding constant of the HSA‒1 complex was relatively moderate to strong at a level of 10⁶ M^-1. Various spectroscopic techniques including ultraviolet-visible, Fourier transform infrared, and circular dichroism spectroscopies indicated that its binding induced alteration in the α-helix content of HSA. Competitive binding and molecular docking studies designated the preferential binding of 1 to sub-structural domain IIA binding site I of HSA. Molecular dynamic simulations further illustrated the formation of a stable complex between 1 and HSA, accompanied by conformational changes in the protein. Importantly, esterase capacity of the HSA‒1 complex increased compared to the free HSA. Therefore, elucidation of the HSA‒1 binding mechanism provides valuable insights into the pharmacokinetics, suggesting potential benefits for the further development of 1 as a therapeutic agent.

Improving the solubility of poorly water-soluble drugs is essential for enhancing bioavailability, formulation flexibility and reducing patient-to-patient variability. The preparation of amorphous solid dispersions (ASDs) is an attractive strategy to formulate such drugs, leading to higher apparent water solubility and therefore higher bioavailability. For such ASDs, water-soluble polymer excipients, such as poly(vinyl pyrrolidone) (PVP) or poly(vinyl pyrrolidone-co-vinyl acetate) (P(VP-co-VA)), are employed to solubilize and stabilize the drug against crystallization. We posit that polymers bearing tertiary amides are particularly well suited to stabilizing drugs containing H-bond donors, as they offer strong H-bonding potential between the polymer and drug. The aim of this study was to compare new and established polymers with tertiary amides as excipients for ASDs. Experimental amphiphilic ABA triblock copolymers comprising poly(2-methyl-2-oxazoline) (pMeOx), poly(2-butyl-2-oxazoline) (pBuOx) and poly(2-butyl-2-oxazine) (pBuOzi) blocks, were compared with the established excipients, PVP and P(VP-co-VA). ASDs with indomethacin as the model drug were prepared at high drug loadings via hot melt extrusion. The extrudates were studied with DSC and PXRD, revealing the ASDs to be fully amorphous up to 75wt% indomethacin, independent of the polymer used. ¹³C CPMAS NMR provided insights into intermolecular associations as a function of drug loading, and suggested the presence of drug dimers at 75wt% drug loading in pMeOx-pBuOzi-pMeOx and pMeOx-pBuOx-pMeOx, which could affect physical stability. Independent of the polymers, the solid-state form of the drug in the ASD was found to affect the dissolution profile of the samples, insofar as the samples containing crystalline indomethacin showed slower dissolution than the fully amorphous ones. This study shows that the polymers comprising poly(2-oxazoline) and poly(2-oxazine) are effective polymers for ASD preparation, similar to PVP and P(VP-co-VA) which merits further investigations into these novel polymers for formulating ASDs.