Journal of pharmaceutical sciences最新文献

A physiologically-based pharmacokinetic (PBPK) model was successfully developed to describe the absorption, distribution, metabolism, and excretion processes for the upadacitinib 15 mg, 30 mg, and 45 mg extended-release (ER) formulations. A prior numerical in vitro-in vivo correlation (IVIVC) was established for the 15 mg and 30 mg ER formulations. A novel dissolution method had to be developed to achieve adequate in vitro upadacitinib release from the 45 mg ER formulation. A PBPK model was developed and an IVIVC using the 15 mg, 30 mg, and 45 mg ER formulations was incorporated to establish a mechanistic IVIVC framework. Importantly, the more comprehensive mechanistic IVIVC model demonstrated robustness through both internal and external validation and was able to accurately predict in vivo upadacitinib exposures in a distinct clinical trial data set using the 45 mg ER tablet in vitro dissolution data. Further, the model was able to discriminate between 15 mg, 30 mg, and 45 mg exposures. As outlined and encouraged by regulatory guidances, this validated Level A mechanistic IVIVC can serve as a surrogate for bioavailability testing, be a screening tool for future upadacitinib formulation dissolution, and set clinically relevant dissolution acceptance criteria.

Cutaneous Candidiasis, a widespread opportunistic fungal infection primarily caused by Candida albicans, accounts for 1% of outpatient and 7% of inpatient dermatology consultations. The rise in antifungal resistance due to genetic mutations in Candida species has complicated therapeutic outcomes and increased mortality rates. This study aimed to develop a more effective topical therapy by formulating Luliconazole (LCZ), a potent imidazole antifungal limited by poor solubility and skin penetration, into a Transethosomal gel (LCZ-TEG) for enhanced delivery and efficacy. LCZ-loaded Transethosomes (LCZ-TESs) were developed and subsequently incorporated into a hydroxypropyl methylcellulose (HPMC) gel base. Utilizing a Box-Behnken design (BBD) within a Quality by Design (QbD) framework, the formulation was optimized by evaluating the impact of LCZ load, Tween 80 concentration, and ethanol content. The optimized LCZ-TEG formulation demonstrated a high correlation between predicted and experimental values, with a particle size (PS) of 111.90 nm, a polydispersity index (PDI) of 0.072, a zeta potential (ZP) of +49.40 mV, and a 95.00% drug entrapment efficiency (EE), with a sustained-release profile. Ex vivo studies indicated that the LCZ-TESs significantly outperformed free LCZ in skin permeation. This was corroborated by confocal laser scanning microscopy (CLSM), which revealed that LCZ-TESs exhibited stronger and deeper fluorescence signals, reaching a skin depth of 179 µm compared to only 84 µm for the rhodamine B-free solution. Furthermore, in vitro antifungal testing demonstrated a 1.40-fold increase in the zone of inhibition (ZOI) compared to the marketed Lucoz® cream. In vivo studies in a Candida-infected rat model showed a 1.50-fold reduction in treatment duration with the LCZ-TEG formulation. These findings suggest that the developed LCZ-TEG significantly improves the solubility, skin penetration, and antifungal efficacy of luliconazole, supporting its potential as a promising, efficient, and targeted therapy for Cutaneous Candidiasis.

Pharmacokinetic (PK) predictions in humans are important for both the parent compounds and their metabolites, as these predictions help decide whether to progress to human clinical trials. More human PK prediction studies have been conducted on unchanged compounds than on their metabolites. Human PK predictions are more complex for metabolites than for unchanged compounds due to the large number of metabolic enzymes involved and the need to consider species-related differences in these enzymes. Mice with humanized livers are expected to serve as simple and useful tools for assessing a wide range of metabolic enzymes. We confirmed the production of the metabolite formed from the oxidation of the alcohol group of the glucokinase activator, TMG-123, in humans; in addition, we conducted a predictive study on TMG-123 using chimeric mice. Furthermore, we identified the drug-metabolizing enzymes involved in this metabolic reaction. The in vivo production rate of GDI-1202 was 19.1% in humans, 17.0% in chimeric mice, and 5.0% in ICR mice. The main enzyme that metabolizes TMG-123 to GDI-1202 was found to be alcohol dehydrogenase (ADH)/aldehyde dehydrogenase (ALDH). Therefore, chimeric mice are effective animal models for predicting the PK of metabolites formed via the action of non-cytochrome P450 enzymes in humans.

Post-surgical breast cancer management remains limited by systemic toxicity, residual tumor burden, and infection risk. To address these issues, we developed an intelligent nanoplatform (MoOx@DOX@LNT) for the co-delivery of oxygen-deficient molybdenum oxide (MoOx) nanosheets and doxorubicin (DOX). This system enables simultaneous tumor eradication and prevention of bacterial colonization through NIR-II-triggered chemo-photothermal synergy. The hydrothermally synthesized MoOx nanosheets display strong NIR-II absorption and a high photothermal conversion efficiency of 44.88%. An electrostatic loading strategy achieved a high DOX payload of 82.14%, while the platform maintained good biocompatibility with > 90% viability in HEK293T cells at 400 µg mL⁻¹. Upon irradiation at 1,064 nm, MoOx@DOX@LNT rapidly induces localized hyperthermia and triggers spatiotemporally controlled DOX release. This combined action resulted in G₂/M phase arrest and extensive apoptosis/necrosis, effectively eliminating 93.73% of MCF-7 cells. Meanwhile, the photothermal effect potently disrupted bacterial membrane integrity and suppressed ATP synthesis, leading to the eradication of both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). By integrating precise tumor ablation with broad-spectrum antimicrobial prophylaxis, this multifunctional nanoplatform presents a clinically promising strategy for comprehensive postoperative breast cancer therapy.

Enumerating and sizing subvisible particles (SbVP) is an important aspect of ensuring pharmaceutical drug product (DP) quality. Existing SbVP characterization is limited by the destructive nature of testing methods and the need to withdraw solution from DP primary containers. Mie-Scattering light sheet (MSLS) SbVP analysis, a technology that measures scattering from a sheet of light projected directly through a DP primary container, has the potential to address these shortcomings. MSLS testing has previously been demonstrated on solutions of homogeneous polystyrene (PS) beads in standard DP vials. Proteinaceous SbVP inherent to DP biologics have heterogeneous size distribution, aspherical morphology, and lower optical contrast than bead standards. In the work described herein, the MSLS analyzer's ability to enumerate and size proteinaceous SbVP was evaluated. Use cases were developed to assess how proteinaceous SbVP suspended in solutions of monoclonal antibody (mAb) can be analyzed after exposure to agitation and storage with varied formulation pH. Measurement variability was assessed on scan-to-scan and container-to-container basis across the full functional range of the system (10 to 300,000 particles/mL). Results show the MSLS analyzer successfully elucidated SbVP growth dynamics while preserving the DP sample, enabling direct assessment of product stability. The sensitivity, working range, and accuracy of the MSLS analyzer for characterizing inherent particles were also presented, and future development direction discussed.

Purine derivatives are valuable anticancer agents, but their limited stability and poor tumor selectivity restrict therapeutic efficacy. This study aimed to overcome these barriers by designing a multifunctional radiotheranostic system integrating a methoxy-substituted purine derivative with silver nanoparticles. The methoxy-purine compound was synthesized, structurally characterized, and radiolabeled with iodine-131 via electrophilic substitution, while also serving as a reducing and stabilizing agent for the green synthesis of silver nanoparticles. The resulting [¹³¹I]I-MeO-Purine-AgNPs were evaluated for radiochemical purity, stability, cytotoxicity, and biodistribution in tumor-bearing mice. Both the free and nanoparticle forms showed high radiochemical purity exceeding 95% and remained stable for 24 hours. The nanoformulation demonstrated significantly improved tumor uptake and retention, with a tumor-to-muscle ratio of 6.57 ± 0.52 compared with 5.20 ± 0.41 for the free compound. Enhanced cytotoxicity resulted from the synergistic actions of the purine pharmacophore, iodine-131 radiotherapeutic emissions, and silver nanoparticle-mediated tumor targeting. These findings demonstrate that the [¹³¹I]I-MeO-Purine-AgNP construct provides a promising, stable, and targeted nano-radiopharmaceutical platform for simultaneous cancer diagnosis and therapy.