Pharmaceutical Research最新文献

Introduction: Vancomycin is an antimicrobial agent for treating central nervous system (CNS) infections caused by Gram-positive bacteria. Due to practical and ethical reasons, it is difficult to evaluate vancomycin exposure in cerebrospinal fluid (CSF) and its relationship with therapeutic outcomes. Therefore, alternative methodologies are required. We developed a physiologically based pharmacokinetic (PBPK) model to characterize vancomycin exposure in plasma and CSF in patients with ventriculitis enrolled in a therapeutic drug monitoring program.

Methodology: PBPK modeling and simulation were conducted using PK-Sim® version 11.3. A PBPK model was constructed to simulate vancomycin exposure in plasma and CSF. Physicochemical parameters of vancomycin were incorporated into a large molecule model, and tissue distribution was described using the Rodgers-Rowland model.

Results: The final PBPK model incorporated vancomycin's low brain permeability by adjusting the CSF-to-plasma partition coefficient to 0.17. Model validation was performed using data from 33 patients with ventriculitis under external ventricular drainage. The dosing regimen consisted of a 30 mg/kg loading dose followed by a continuous intravenous infusion of 60 mg/kg/day. Mean simulated vancomycin concentrations in plasma and CSF were 32 mg/L and 7.2 mg/L, respectively. The predicted CSF/plasma concentration ratio was 0.22, which closely matched the observed ratio of 0.17.

Conclusion: Vancomycin penetration into the CNS is low and variable, highlighting the importance of therapeutic drug monitoring and individualized therapy in patients with ventriculitis. In the future, this model may facilitate the selection of optimal dosing regimens by simulating alternative dosing strategies and establishing PK/PD relationships for CNS infections.

Introduction: Diabetic foot ulcers are a major complication of diabetes, driven by inflammation, oxidative stress, and poor vascular function. Naringenin, a citrus flavonoid, addresses these factors but has low solubility and stability. We developed a Na-AMPS hydrogel dressing to enhance its delivery under diabetic-like conditions.

Methods: A Na-AMPS hydrogel containing 0.02%(w/w) naringenin was formulated and assessed for rheological and adhesive properties, drug release, and biological activity in HUVEC and HDFa cells. Cytotoxicity (XTT), reactive oxygen species (ROS), mitochondrial membrane potential (TMRM), cytokine levels (IL-6, IL-8, MMP-9, TGF-β), and wound closure (scratch assay) were measured.

Results/discussion: Naringenin modestly reduced the hydrogel elastic modulus (15,791.5 ± 1965 Pa at 30 Hz) without affecting adhesion. Release studies showed rapid drug release from solution but sustained release from hydrogels (17.88 ± 2.61% over 24 h). Under hyperglycaemic and pro-inflammatory conditions, naringenin significantly decreased ROS in HUVECs (41,030.58 ± 2737 to 31,778.74 ± 1822 AU; p < 0.001) and HDFa cells (38,188.13 ± 4593 to 29,950.94 ± 1426 AU; p < 0.05). Naringenin improved mitochondrial membrane potential in both cell types (p < 0.05-0.01) and attenuated pro-inflammatory cytokines. IL-6 decreased in HUVECs (39.40 ± 5.02 to 27.15 ± 3.10 pg/mL; p < 0.01) and HDFa cells (40.05 ± 2.23 to 16.41 ± 1.27 pg/mL; p < 0.0001). In HDFa's, MMP-9 was reduced (403.43 ± 18.70 to 195.33 ± 11.02 pg/mL; p < 0.0001), while in HUVECs, wound closure was enhanced.

Conclusion: Naringenin-loaded Na-AMPS hydrogels demonstrated sustained release, suitable mechanical properties, and significant antioxidant, anti-inflammatory, and wound healing effects. These findings highlight their therapeutic potential for diabetic wounds treatment.

Background and purpose: Studies have documented that continuous infusion is superior to bolus infusion in providing longer time with drug concentration above the minimal inhibitory concentration (T > MIC). This porcine study compared steady-state penicillin concentrations in oropharyngeal and frontal sinus tissues following intravenous bolus and continuous administration. EXPERIMENTAL APPROACH: Twelve pigs were randomized to receive either intravenous bolus (Group BI) or continuous (Group CI) infusion of penicillin (1.2 g). Doses were administered at 0, 6, and 12 h, with sampling from 12 to 18 h. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues, with simultaneous plasma sampling. The primary endpoints were T > MIC for two MIC targets (0.125 (low target) and 0.5 (high target) μg/mL) and attainment of ≥ 50%T > MIC treatment target.

Key results: No statistically significant differences were found between Group BI and CI for either MIC target. The ≥ 50%T > MIC target was achieved in all compartments except for the high MIC target in oropharyngeal tissue in Group CI (46%). although no statistical significance, T > MIC in oropharyngeal tissue tended to be longer in Group BI (low target: 98%; high target: 74%) compared with Group CI (low target: 68%; high target: 46%) (p = 0.07 and p = 0.19, respectively).

Conclusion and implication: Penicillin bolus and continuous infusion resulted in comparable T > MIC in oropharyngeal and frontal sinus tissues. However, bolus infusion showed a higher likelihood of attaining ≥ 50%T > MIC in oropharyngeal tissue. These findings are specific to the porcine model and dosing regimens used and cannot be directly extrapolated to humans.

Lipid nanoparticles (LNPs) have emerged as a versatile delivery platform for improving pharmacokinetic performance, protecting nucleic acid cargo, and enabling tissue- and cell-specific targeting. Continued advancement of LNP-based therapeutics requires a deeper understanding of how raw material quality, formulation parameters, nanoparticle architecture, and biological context collectively influence clinical performance. In this Perspective, we discuss key challenges, practical insights, and lessons learned from ongoing LNP development efforts, with emphasis on characterization strategies, delivery specificity, scale-up considerations, long-term stability, and emerging applications of artificial intelligence. We highlight the importance of rational design principles, robust and reproducible manufacturing practices, comprehensive analytical characterization, and innovative approaches to support the next generation of LNP technologies.

Background: Protein N-glycosylation is one of the critical quality attributes of monoclonal antibody (mAb). Evaluating its scalability and batch-to-batch consistency is essential for ensuring process robustness and product safety and efficacy.

Results: This study revealed that Project A exhibited significant scale differences in galactosylation ratio during process development and scale-up, with galactosylation levels in 2 L bioreactors being significantly greater than those in shake flasks and 200 L single-use bioreactors. We investigated the cause of this phenomenon and determined that the elevated galactosylation in 2 L bioreactor was due to the leaching of 0.05 μM to 0.06 μM manganese ions from the stainless-steel components in the 2 L glass bioreactor. These scale differences can be eliminated by adding 0.2 μM MnCl₂ · 4H₂O. Second, for projects with lower galactosylation levels, this paper suggests the use of shake flasks instead of bioreactors to guide the process scale-up of mAb glycosylation, thereby reducing trial-and-error costs and the production costs associated with replacing glass bioreactors with single-use bioreactors. Notably, the scale differences in mAb galactosylation observed in Project A do not apply to Project B, which showed no scale effect, indicating that this phenomenon may be more applicable to cell lines that are more sensitive to metal ions.

Conclusions: These findings demonstrate that metal ion leaching presents a substantial challenge to the process consistency of mAb. We have proposed a series of targeted and practical solutions to address the issue of "equipment and material leaching" during the production of mAb glycosylation amplification.

Purpose: Plant-derived nanoparticles (PdNPs) have garnered increasing attention as versatile tools for nucleic acid delivery, and they have been investigated for the transdermal delivery of encapsulated nucleic acids. However, not all PdNPs have high skin penetration enhancement ability. Surface modification of PdNPs with cell penetration peptides (CPPs) can enable skin penetration, with the Tat-peptide selected as a suitable CPP. In the present study, the feasibility of enhancing skin penetration was evaluated using grapefruit-derived nanoparticles (GNPs) modified with stearylated Tat-peptide (STR-Tat).

Methods: The surface modification of GNPs with STR-Tat was conducted using a simple mixing method of synthesized STR-Tat with GNPs. Changes in particle size and zeta-potential of STR-Tat-GNPs were measured. In addition, in vivo skin penetration experiments were conducted as well as investigating cellular uptake and cell toxicity to determine the effect of surface modification on the skin penetration ability of GNPs.

Results: A positive zeta potential was observed for STR-Tat-GNPs, whereas GNPs had a negative zeta potential. In addition, increased cellular uptake was confirmed for STR-Tat-GNPs without extensive cell toxicity. DiI-derived fluorescence was observed in hair follicles and at deeper sites of the dermis when DiI-labelled STR-Tat-GNPs were applied on mouse back skin in in vivo conditions.

Conclusion: A simple mixing procedure of STR-Tat enhanced the skin penetration ability of a lipophilic dye initially associated with GNPs without cellular toxicity. Therefore, this approach may be applicable for providing plant-derived particles, which are expected to be an effective vehicle for nucleic acid delivery with high skin penetration ability.

Purpose: This study investigates the thermodynamic behaviour and solubilization efficiency of micellar systems composed of Triton X-100, Triton X-165, and Brij C10, individually and in mixtures, using ketoprofen as a poorly water-soluble model drug (BCS class II). The aim was to clarify the relationship between micellar stability, molecular interactions, and drug solubilization.

Methods: Critical micelle concentrations (cmc) were determined by fluorescence spectroscopy with pyrene as a probe. Non-ideality of mixed micelles was analysed by Rubingh's model, Regular Solution Theory, and the Margules function. Thermodynamic parameters (g^E, s^E, h^E) were derived, and ketoprofen solubilization was quantified by HPLC as molar solubilization ratio (MSR) and excess solubilization parameters.

Results: Brij C10 exhibited the lowest cmc, reflecting strong hydrophobic contributions. Binary systems containing Brij C10 with Triton X-100 or X-165 showed pronounced synergism, indicated by negative β and gᴱ values. Triton-only systems behaved nearly ideally. Brij C10 alone provided the highest MSR, while binary Triton-Brij mixtures displayed partial antagonism in ΔMSR despite favourable thermodynamic stabilization. The ternary system was thermodynamically stable but less effective for ketoprofen solubilization due to packing constraints.

Conclusions: Micellar stability and solubilization efficiency are not always correlated. Brij-rich micelles showed superior ketoprofen solubilization, whereas overly stabilized ternary systems limited drug loading. These findings highlight the need to balance stability and flexibility when designing micellar carriers for hydrophobic BCS class II drugs.

Background: Understanding the transport of nanoparticles within blood vessels and their distribution in tumor tissues is crucial for the successful implementation of nanotechnological strategies in clinical practice. Although numerous studies have examined nanoparticle transport in blood flow, none have comprehensively investigated all the sequential steps a nanoparticle must undergo prior to internalization by target cells.

Methods: A computational framework was developed in COMSOL Multiphysics to simulate nanoparticle (NP) transport from systemic administration through to tumor cell internalization. The model integrates three coupled stages: (1) NP movement within a non-Newtonian blood flow; (2) trans-endothelial transport; and (3) NP motion within the tumor stroma, incorporating affinity forces to capture ligand-receptor interactions. The tumor geometry was reconstructed, including cancer cells and fibroblasts, to reproduce physiological porosity. Multiple case studies were conducted to evaluate the impact of particle density, injection velocity, and size on NP biodistribution.

Results: The computational model effectively simulates nanoparticle transport across all stages. Notably, it is the first model in the literature to incorporate the affinity of functionalized nanoparticles, which facilitates ligand-receptor interactions for targeted delivery. Simulation outcomes indicate that a low Stokes number is critical for ensuring a higher percentage of particles reach the end of the capillary network. Furthermore, surface modification of nanoparticles with ligands promotes more specific distribution within the stroma, reducing the percentage of nanoparticles that fail to reach target cells by approximately 50% CONCLUSIONS: A novel and comprehensive computational model has been developed to include the entire process of nanoparticle distribution following systemic administration, including specific recognition by cellular receptors.

Background: Anemia is a common and debilitating complication in patients with chronic kidney disease (CKD), often managed with erythropoiesis-stimulating agents. While PEGylation extends drug half-life, it may alter pharmacodynamics, requiring careful dose optimization. This study applies a middle-out translational pharmacokinetic/pharmacodynamic modeling approach, aligned with Model-Informed Drug Development principles, to evaluate two pegylated recombinant human erythropoietin candidates (PEG-EPO 32 kDa and PEG-EPO 40 kDa) and guide dose selection for CKD patients.

Methods: A semi-mechanistic pharmacokinetic/pharmacodynamic model developed in rabbits was extrapolated to humans using allometric scaling for pharmacokinetics and physiological adaptation for pharmacodynamics. The model was verified using intravenous data from Mircera®. Simulations were conducted in virtual CKD stage 4 and 5 populations to predict hemoglobin (Hb) trajectories over 90 days of dosing. Clinical thresholds were applied to assess efficacy and safety.

Results: Simulations with 0.6 µg/kg Q2W reproduced Mircera® profiles but showed higher proportions of patients exceeding Hb safety thresholds (> 11 g/dL in stage 4, > 9 g/dL in stage 5) for both PEG-EPOs. Dose reduction to 0.4 µg/kg Q2W aligned Hb responses with Mircera®, reducing the risk of excessive Hb elevation.

Conclusions: Middle-out modeling successfully predicted clinical performance of PEG-EPO candidates and identified 0.4 µg/kg Q2W as optimal starting dose for clinical trials. PEG-EPO 32 kDa and 40 kDa emerges as a promising candidate for further development. This study exemplifies the value of MIDD in optimizing dose selection, enhancing translational relevance, and de-risking early clinical evaluation of long-acting erythropoiesis-stimulating agents in CKD.