European Journal of Pharmaceutical Sciences最新文献

Background: Topical tacrolimus offers potent anti-inflammatory effects across a spectrum of ocular surface diseases, but its ophthalmic use has been limited by formulation challenges. This study evaluated 0.015% tacrolimus/hydroxypropyl-β-cyclodextrin eye drops (TCD) long-term performance.

Methods: In a prospective, open-label, sequential design, 56 patients treated ≥6 months with 0.03% tacrolimus ethanol-based formulation (TE) were switched to TCD and followed for 12 months. Assessments of efficacy and safety at baseline (TE) and month 12 (TCD) included distance best-corrected visual acuity, slit-lamp grading of conjunctival and corneal signs, Oxford staining, tear meniscus height, non-invasive break-up time, ocular redness, intraocular pressure, NEI VFQ-25 (National Eye Institute Visual Function Questionnaire) scores, symptom visual analog scales, adherence, and concomitant corticosteroid use. In addition, a comparative evaluation of microbiological stability in use was performed for both eye drops.

Results: Concomitant corticosteroids declined from 21.4% to 5%; two-thirds of eyes maintained or improved visual acuity; ≥80% showed stable or improved (TMH: tear meniscus height; p<0.0001) corneal/conjunctival. Tear meniscus height increased significantly (median 0.25 to 0.29 mm; p<0.0001), while break-up time and intraocular pressure remained stable. VFQ-25 total score rose from 82.8 to 87.8 (p<0.001); burning, photophobia and foreign-body sensation decreased (p<0.05), thereby promoting adherence to treatment. Both tacrolimus formulations were similarly contaminated due to improper manipulation by the patients.

Conclusions: The 0.015% tacrolimus/HPβCD formulation proves efficacy, and safety over 12 months for the treatment of diverse ocular inflammatory conditions, delivering sustained clinical stability and patient-reported benefits with reduced steroid reliance.

Liver ischemia-reperfusion injury (IRI) drives graft dysfunction and postsurgical morbidity. We show that hepatocellular MST1 is markedly upregulated in IRI and exacerbates damage by blocking PINK1-dependent mitophagy. Defective mitochondrial clearance causes mtDNA leakage, which activates macrophage cGAS-STING signaling and fuels inflammatory injury. Curcumin inhibits this MST1-PINK1 axis, restoring mitophagy and limiting mtDNA release. To translate these insights, we engineered Curcumin@EV@Se-stem-cell-derived extracellular vesicles surface-modified with diselenide-PEG for ROS-responsive, "stealth" delivery. In oxygen-glucose deprivation/reoxygenation models, Curcumin@EV@Se improved hepatocyte viability, preserved mitochondrial potential, reduced ROS and inflammatory cytokines, and promoted reparative/angiogenic programs. In a murine hepatic IRI model, systemic Curcumin@EV@Se decreased necrosis and TUNEL positivity and improved serum transaminases and histology, indicating enhanced liver function and regeneration. These data identify MST1-mediated mitophagy blockade with secondary cGAS-STING activation as a central pathogenic axis in IRI and present Curcumin@EV@Se as a mechanism-guided therapy that restores mitochondrial quality control and dampens innate immune activation, with translational promise for liver transplantation and acute hepatic injury.

Uterine cancer is a major global health problem and treatment frequently includes invasive surgery that severely compromises fertility. Current systemic chemotherapeutic drugs, such as paclitaxel (PCX) and carboplatin (CBP), lack an established standard protocol and their efficacy is limited. This study focuses on the development of a personalized, local drug delivery system for the treatment of uterine cancer. The intrauterine devices (IUDs) were prepared using polycaprolactone (PCL) filaments containing PCX and CBP complexed to Cyclodextrin (CD) to enhance the stability and solubility of the drugs during the printing process. The Fused Filament Fabrication (FFF) type 3D printing technique, owing to its precise computer-aided layer deposition, successfully provided a platform for geometric and dosage personalization, achieving high dimensional accuracy. Physicochemical characterization studies showed that CD inclusion complexes maintained drug stability during the printing process, confirmed by the absence of free crystalline drug. Furthermore, drug:CD complexes significantly enhanced the mechanical properties of PCL, thereby increasing strength and toughness, which are critical for intrauterine stability. In vitro release studies demonstrated a sustained, controlled release profile, exceeding 80% over 9 months for PCX and 4 months for CBP. Cytotoxicity studies showed that drug-free IUDs were non-cytotoxic and non-genotoxic to healthy L929 mouse fibroblast cells. Furthermore, in vivo studies demonstrated that IUDs did not cause dermal irritation. The drug-containing IUDs were found to be at least as effective as the drug solution on HEC-1B endometrial cancer cells. Lastly, ex vivo studies confirmed favorable bioadhesion of IUDs and high drug retention within uterine tissue. All these findings validate the FFF-type 3D printing as a promising and flexible approach for preparing personalized, biocompatible, and effective local drug delivery systems for the treatment of uterine cancer.

Overexpression of MERTK and FLT3 plays a crucial role in activating signal transduction pathways in various human hematological malignancies. These signaling pathways have been extensively studied and have shown significant potential as a promising therapeutic target for the treatment of acute myeloid leukemia (AML). In this study, we employed a modern medicinal chemistry approach, hybridizing machine learning (ML) with a bioisosterism strategy, to design and synthesize a new series of pyrrolo[2,3-d] pyridine derivatives as potent dual inhibitors of MERTK and FLT3. Through successive structure-activity relationship (SAR) studies, we successfully identified the lead compound 31l as a highly potent and selective MERTK/FLT3 dual inhibitor. Compound 31l exhibited remarkable kinase inhibitory activity against MERTK and FLT3 with IC₅₀ values of 2.58 and 0.86 nM, respectively, and potential anti-proliferative activity against MOLM-13 cell lines (IC₅₀ value of 7.50 nM). Furthermore, compound 31l displayed a favorable metabolic stability profile in both human and mouse liver microsome screens and an oral bioavailability of 56%. This finding suggests that lead compound 31l is a promising tool for further optimization and development as a potential MERTK/FLT3 dual inhibitor anti-AML drug candidate.

The therapeutic potential of inhaled biologics is limited by protein instability during aerosolization, which can cause aggregation and increase immunogenicity risks. This study aims to identify key molecular and formulation parameters that minimize the aggregation of antibody Fab fragments during vibrating mesh nebulization. A set of 14 engineered Fabs with a broad range of melting temperatures (T_m 60-90°C) were nebulized using two different commercial vibrating mesh devices. We systematically assessed the impact of Fab thermostability, protein concentration (10-80 mg/mL), formulation excipients, and nebulizer device on the formation of high molecular weight species (HMWS) and subvisible particles (SVP). Aerosol characteristics, including fine particle fraction (FPF) and output rate, were also evaluated. High intrinsic thermostability and high protein concentration were identified as the two most critical factors for preventing aggregation. Fabs with a T_m above 80°C demonstrated exceptional stability with negligible aggregation. We attribute this effect to a correlation of high T_m with a higher resistance against unfolding and therefore a better tolerance against nebulization-induced stresses, in particular air/liquid interfacial stress. Counterintuitively, increasing the protein concentration from 10 mg/mL to 80 mg/mL suppressed aggregation for all Fabs, which had the highest benefit for Fabs with lower thermostability. This effect can at least in part be explained by a saturation of the air/liquid interface at higher Fab concentrations. While higher concentrations modestly reduced nebulizer output rates, the overall inhalable protein output (mg protein/min) was significantly enhanced. In comparison, full-length monoclonal antibodies showed poor aerosolization performance at high concentrations. Our findings provide clear guidance for developing inhaled Fab therapeutics. To ensure stability and minimize aggregation, priority should be given to selecting Fabs with high thermostability (T_m > 80°C) and formulating them at high concentrations (≥ 40 mg/mL). These strategies are expected to mitigate aggregation-induced immunogenicity and concomitant safety risks, facilitating the development of the next generation of inhaled protein drugs.