Pharmaceutical Research最新文献

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.

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.

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: 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.

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.

Objectives: Carbamazepine (CBZ) is a drug that exists in multiple crystal forms and hydrates. In this study, CBZ was used as the model drug, and an attempt was made to regulate the crystal form and morphology of the drug using the DES system. The effects of deep eutectic solvents (DESs) on the crystal form of CBZ were systematically investigated.

Methods: The solubility of CBZ in different DES mass ratios was determined. Single crystals of the CBZ crystal form VI were prepared and the structure were analyzed. The differences between the new crystal form of CBZ and other crystal forms have been discussed. Molecular electrostatic potential surface (MEPS), Hirshfeld surface (HS), and molecular dynamics calculation (MD) were conducted to elucidate these phenomena at the molecular level.

Results: Form VI was successfully obtained under specific experimental conditions. The constitute and mass ratio of DES in methanol solution and the degree of supersaturation were found to influence the morphology of form VI.

Conclusions: The new crystal form VI of CBZ was obtained through the DES solvent system. The existence of DES can alter the interactions between molecules, thereby providing the possibility for the formation of new crystal forms and morphologies.

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.

Objective: The effectiveness of pressurized metered-dose inhalers (pMDIs) relies on correct inhalation technique. While prior studies investigated idealized breathing, the impact of real-life irregularities remains less understood. This study explores how real-life irregularities-pausing, coughing, and premature exhalation-alter aerosol transport and deposition in the airways.

Methods: Large-eddy simulations combined with a discrete phase model were performed on a realistic male airway geometry extending from the oral cavity to the fourth bronchial generation. Computational predictions were validated against in vitro experiments conducted under constant inhalation.

Results: Breathing irregularities substantially modified airflow dynamics and shifted deposition toward the upper airways. Coughing generated the strongest vortical structures and turbulence, followed by premature exhalation. Deposition in the left lung decreased from 19.9% during standard COPD inhalation to 2.1% during exhalation and 0.9% during coughing, while mouth-throat deposition increased to 35.2% during coughing compared to 14.5% under the COPD baseline condition. Exhalation caused higher overall particle loss (27.9%) than coughing (24.1%), but coughing produced more pronounced inertial impaction in the upper airways. Fine particles (< 2 µm) were largely exhaled (approximately 80%), whereas particles in the 2-5 µm range-considered optimal for deep lung delivery-were redirected and lost under disturbed flow conditions.

Conclusions: Irregular breathing patterns markedly decrease deep lung deposition and increase upper airway losses. Repeated puffs without adequate intervals may exacerbate this problem, leading to excessive upper-airway deposition and increasing the likelihood of side effects. These findings provide guidance for physicians to tailor puff number and timing, improving therapeutic efficacy while minimizing risks to patient safety.

Objective: The purpose of this study is to analyze the impact of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) transport characteristics of drugs on their intracerebral distribution in male cynomolgus monkeys.

Methods: Steady-state concentrations of 15 drugs (13 drugs and 2 compounds) transported by passive diffusion or via solute carrier (SLC) and/or ATP-binding cassette (ABC) transporters were measured in the frontal cortex interstitial fluid (ISF), lateral ventricular cerebrospinal fluid (CSF) and lumbar CSF of monkey brain by means of microdialysis and lumbar puncture methods. The values of brain ISF (or CSF)/plasma unbound concentration ratio (K_p,uu) were calculated to quantify the intracerebral distribution characteristics.

Results: The K_{p,uu,ISF,cortex} values of substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)were much lower than unity. The ISF concentration of these drugs were increased by the co-administration of elacridar, suggesting active efflux of these drugs at the BBB. Contrary to expectations, some of P-gp substrates were efficiently distributed into the brain with K_{p,uu,ISF,cortex} > 2. The lateral ventricular CSF concentrations of drugs tended to be higher than the ISF concentrations, while the lumbar CSF concentrations were comparable to the ISF concentrations.

Conclusion: The results of this study suggest that the intracerebral distribution of the test drugs from the blood in the monkey brain should consider the contribution of influx transporters as well as efflux transporters. In addition, the lumbar CSF concentrations of the test drugs appear to be a useful surrogate marker of the ISF concentrations.

Purpose: Drying is widely used to enhance the storage stability of biologic drug products which are susceptible to degradation in aqueous solutions. Compared to conventional freeze-drying, spray drying offers continuous, high-throughput manufacturing. Stabilizing excipients are critical for protecting proteins from stresses during drying and storage. This study evaluated the potential of polysaccharide- and protein-lysate-based polymeric excipients as alternatives to commonly used stabilizers such as trehalose and mannitol, using bovine serum albumin (BSA) as a model protein.

Methods: Spray-dried BSA formulations were prepared with (2-hydroxypropyl)-β-cyclodextrin (HPβCD), hydrolyzed gelatin, dextran 20 kDa, or sodium carboxymethyl cellulose (NaCMC) polymers, either alone or in combination with trehalose or mannitol. Protein stability was assessed by monitoring monomer loss under stressed storage (40°C, 3 months). Crystallinity and changes in the secondary structure were analyzed using powder X-ray diffraction (PXRD) and solid-state Fourier transform infrared spectroscopy (ssFTIR), respectively. Particle size and size distribution, surface morphology and reconstitution time were also evaluated.

Results: Spray-dried BSA formulations containing HPβCD or hydrolyzed gelatin, either alone or with sugars, exhibited lower monomer loss than the trehalose- or mannitol-only formulations. In contrast, formulations with Dextran 20 kDa and NaCMC showed poor stability. PXRD revealed progressive sodium chloride crystallization during storage. ssFTIR detected secondary structure changes in the BSA over 3 months. The spray-dried powders with polysaccharides generally showed longer reconstitution times than those with polymers.

Conclusion: HPβCD and hydrolyzed gelatin improved the physical stability of spray-dried BSA compared to sugar excipients, which highlights their potential use as stabilizing additives.