International Journal of Pharmaceutics最新文献

Diabetic foot ulcers are a severe complication of diabetes mellitus, characterized by chronicity and high risk of infection. Their effective management requires wound-specific dressings, as no universal system adequately addresses the full spectrum of wounds. Hydrogel dressings offer promising local therapeutic strategies; however, materials combining mechanical robustness, prolonged drug release, and microenvironment modulation remain limited. Herein, we present a rational design strategy for a physically crosslinked, multi-component PVA-based hydrogel membrane incorporating metformin hydrochloride (MET) as the active pharmaceutical ingredient. Although conventionally administered orally, MET has been increasingly recognized for its anti-inflammatory and pro-regenerative properties, supporting its repurposing for localized wound applications. The developed dressings were comprehensively characterized in terms of rheology, pH modulation, morphology (optical microscopy, SEM), mechanical performance, liquid uptake, MET release, cytocompatibility, and in vitro antibacterial and anti-inflammatory activity. An optimized hydrogel formulation based on PVA (Mw ∼ 195,000 Da) and six freeze-thaw cycles (-80 °C/∼22 °C) exhibited high elasticity (ε > 380%), tensile strength (σ ∼ 0.23 MPa), and minimal permanent deformation (ε ≤ 3%). It enabled prolonged MET release over 72 h while maintaining a mildly acidic environment (pH ∼ 5.5-6.3) favorable for wound healing. Compared with commercial drug-free hydrogel dressings, the optimized formulation showed superior mechanical strength, pH-modulating capacity, antibacterial activity against Escherichia coli and Pseudomonas aeruginosa, as well as attenuation of IL-6 expression in LPS-stimulated keratinocytes, indicating anti-inflammatory activity. Collectively, these findings highlight the early-stage potential of MET-loaded solid-sheet hydrogels as multifunctional dressings for chronic, low-exudate diabetic foot ulcers.

Tofacitinib citrate (TC), a selective inhibitor of Janus kinase 1/3 (JAK1/3), has gained attention as a potential treatment option for vitiligo, although systemic adverse effects remain a concern with oral therapy. To address this limitation, the current study focused on the development of a tofacitinib citrate-loaded nanoemulsion (TC-NE) incorporating black seed oil (BSO), a major source of thymoquinone (TQ), which was engineered under the shed of D-Optimal statistical mixture design using a high-energy ultrasonication method. TC-NE exhibited a droplet size of 41.68 ± 0.2  nm, a PDI of 0.132 ± 0.004, and a zeta (ζ) potential of -31.9 ± 0.057  mV. Later, TC-NE was transformed into tofacitinib citrate-loaded nanoemulgel (TC-NEG) and characterized under a set of stringent in vitro and in vivo parameters for pharmaceutical and therapeutic efficacy analysis. Additionally, molecular docking studies revealed strong binding affinities of TC and TQ with JAK1 and JAK3 receptors, yielding docking scores of -8.339 kcal/mol and 6.092 kcal/mol for TC, and -9.36 kcal/mol and -7.31 kcal/mol for TQ, respectively. Next, the therapeutic efficacy of TC-NEG was tested against monobenzone-induced experimental vitiligo in C57BL/6 male mice. It demonstrated superior worth in the vitiligo area scoring index (VASI), melanogenesis, and attenuation of oxidative stress markers. Following this, TC-NEG also demonstrated noteworthy melanogenic activity in histological sections, Fontana-Masson (F-M) staining, and Lillie staining. TC-NEG caused significant down-regulation of JAK1 (One-way ANOVA, P < 0.001) and JAK3 (One-way ANOVA, P < 0.0001) in experimental vitiligo. Next, the relative transcriptional levels of JAK1, JAK3, and IFN-γ were also measured using the RT-PCR technique. Treatment with TC-NEG produced marked suppression of JAK1, JAK3, and IFN-γ gene expressions by 3.47-fold, 4.3-fold, and 3.65-fold in experimental vitiligo. Hence, TC-NEG enriched with TQ provided synergistic efficacy against experimental vitiligo due to diminution of oxidative stress, reduction in melanocyte damage, and augmentation of anti-inflammatory activity owing to inhibition of pro-inflammatory JAK/STAT pathway. In conclusion, TC-NEG may be a promising therapeutic modality for translating into a clinically viable pharmaceutical product.

Oral drug administration, preferred for patient compliance and convenience, encounters significant bioavailability challenges arising from complex physicochemical, physiological, and formulation-related barriers. Traditional models for evaluating absorption exhibit limitations in physiological relevance and predictive accuracy. This review critically examines evolving methodologies for oral drug absorption assessment, from classical permeability assays to emerging predictive platforms, emphasizing integration of mechanistic research with predictive modeling to advance intelligent platforms and clinical translation. While classical permeability models including parallel artificial membrane permeability assay (PAMPA), Caco-2, Ussing chambers, and intestinal perfusion remain indispensable for early screening, their limited physiological relevance and inability to elucidate mechanistic pathways constrain predictive accuracy. Mechanistic approaches such as lymphatic transport studies and advanced tracking techniques using fluorescence, Single Photon Emission Computed Tomography (SPECT), or Positron Emission Tomography (PET) imaging reveal critical biological pathways but suffer from scalability challenges. Emerging platforms provide transformative potential, as organoid-on-a-chip offer physiologically relevant and high-throughput alternatives, while integrated computational modeling enables multiscale prediction, from molecular interactions to systemic pharmacokinetics. Future oral absorption assessment requires converging in vitro biomimetics, computational modeling, and Artificial intelligence (AI) within unified platforms. Achieving this requires standardized in vitro models, robust data integration, and alignment with regulatory to accelerate translational drug development.

Manganese-based nanozymes have garnered significant research interest owing to their unique physicochemical properties. Their structures and morphologies can be precisely tailored, offering broad applicability. These materials exhibit novel magnetic and optical characteristics, endowing them with substantial potential in magnetic and optical applications. Furthermore, they have demonstrated excellent catalytic activity alongside favorable biodegradability, establishing a robust foundation for their utilization in catalysis and biomedicine. This review systematically summarizes the synthesis methodologies, catalytic mechanisms, biomedical applications, and future prospects of manganese-based nanozymes. It particularly highlights their applications and underlying mechanisms in tumor therapy and biosensing and detection. Future research endeavors should prioritize optimizing synthesis protocols, expanding the scope of application domains, and exploring their potential in areas such as drug delivery, biosensing, and environmental monitoring.

Fully synthetic exosome-mimetics (FSEMs) represent a nature-inspired drug delivery system designed to replicate the key physicochemical and biological properties of natural exosomes, while offering the potential to address limitations in scalability and reproducibility associated with natural exosomes. In this study, we prepared FSEMs at the laboratory scale. We loaded them with (-)-epigallocatechin-3-gallate (EGCG) and microRNA-23a (miR-23a), aiming to co-deliver therapeutic small molecules and nucleic acids for the treatment of melanoma. FSEMs were fabricated using three methods: thin-film hydration, ethanol injection, and microfluidics. They were surface-functionalized with either CD9, a tetraspanin involved in membrane fusion, or TSP-1, an adhesion protein promoting cellular interactions. Through physicochemical characterization via dynamic light scattering, we found that FSEMs were ∼ 100 nm in size, of low polydispersity (∼0.2) and showed a negative zeta potential (∼-55 mV). Both EGCG and miR-23a were efficiently encapsulated. SDS-PAGE analysis confirmed successful protein incorporation and correct positioning. In vitro release studies showed minimal premature leakage, supporting their suitability for cellular uptake-mediated delivery. When tested on melanoma cells (MDA-MB-435) and progenitor human dermal fibroblasts (FE002-SK2), FSEMs selectively killed melanoma cells while sparing fibroblasts. Importantly, EGCG within FSEMs was more effective than the free compound. Compared to conventional DOTAP-based liposomes, FSEMs were more selective and induced less off-target cytotoxicity. This study presents a proof-of-concept for fully synthetic, protein-functionalized FSEMs as dual carriers for both chemical and gene-based agents, offering a safer and potentially more effective alternative to traditional cationic liposomes. These results lay the groundwork for future in vivo validation and translational cancer research.

Inhalation-based delivery can efficiently transport monoclonal antibodies (mAbs) to the lungs for respiratory and other diseases. While several attempts have been made to develop inhaled formulations of mAbs in the nebulized or dry powder form, these formulations typically rely on high quantities of sugar stabilizers. While sugars can stabilize the mAbs during processing and storage, they are characterized by high hygroscopicity, which could hamper product physical stability in certain drug product configurations and requires aggressive moisture protection during storage and use. The addition of stabilizing excipients like sugars may also lead to a higher powder burden for high-dose therapies. Additionally, sugars may react adversely with certain mAbs via reactions such as the Maillard reaction. This study aimed at delivering mAbs in -lipid-based formulations and abrogate potential storage issues that limit typical sugar-based formulations by reducing hygroscopicity and cohesivity while maintaining high doses of the mAb. The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation. Anti-streptavidin IgG1 antibody was used as a model biologic and a series of formulations were prepared using one representative lipid, amino acid, and surfactant in different compositions. A "mixture design of experiments" was utilized to identify stability and dose constraints using these excipients when processed via spray drying. Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability. The prepared IgG powders exhibited excellent aerosol performance, with over 80 % fine particle fraction and more than 85 % emitted fraction. The powders also had reduced moisture sorption relative to control powders. Additionally, size exclusion chromatography showed that the powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity). These findings suggest lipid-based mAb formulations can provide enhanced physical stability to the protein, while exhibiting superior aerosol performance and hence may offer promise for dry powder inhaled therapies.

Brain-targeted drug delivery is crucial both for achieving highly efficient treatment of brain-related diseases and for avoiding severe side effects of systemic drug distribution. However, such obstacles from the administration site to the brain as mucus clearance and blood brain barrier challenge the practical applications. Herein we propose dual drug-loaded chromatophore nanorockets (CNs) driven by F_OF₁-ATPase motors to promote brain targetability for orthotopic glioma therapy. The F_OF₁-ATPase motor-embedded CNs were obtained from Thermus thermophilus, after which two drugs (temozolomide and curcumin) were successfully loaded onto the chromatophores. Both the in vitro and in vivo studies revealed that the established CNs played a key role in enhancing the nasal mucus penetration and in improving the brain targeting and glioma therapy. This study demonstrates that the chromatophore nanorockets with F_OF₁-ATPase motors is a promising alternative to powerfully deliver drugs intranasally for glioma therapy.

Poly (lactic-co-glycolic acid) (PLGA) microspheres are widely used for controlled drug delivery, but the drug existing state in the microspheres significantly influences the characteristics of microspheres. The focus of the present study was to formulate meloxicam injectable sustained release microspheres (MLX-MS) and to investigate the influence of the drug existing state within the microspheres on the release properties, degradation and to evaluate the intra-articular (IA) treatment efficacy of osteoarthritis (OA). Different MLX-MS were prepared by changing drug existing forms (microcrystal, particle and molecular state) by the method of cosolvent combination or micronized drug and they were characterized by scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS), X-ray diffraction (XRD) and in vitro release. The therapeutic effect of MLX-MS was investigated using OA rabbits after IA injection. The degradation, drug retention, and pharmacodynamics were also assessed. The results highlighted that the release and degradation of MLX-MS in the joint cavity were directly correlated to the drug existing state. This study offers crucial insights for developing sustained-release injectable MLX-MS, the microspheres with drug existing in molecular state (Mol-MS) were the optimum formulation which can provide sustained release and more effective therapy of joint inflammation.

Urolithin A (UA), a metabolite of ellagitannins produced by gut microbiota, exhibits a range of beneficial biological activities, particularly its ability to promote mitophagy, indicating its potential for treating ischemic stroke. However, its therapeutic efficacy is limited by poor solubility. In this study, we developed triphenylphosphonium (TPP)-modified UA nanoparticles, utilizing DSPE-PEG as a stabilizer and co-loading borneol (BO) as a permeation enhancer. The resultant UA-BO-TPP-NPs exhibited an average particle size of 172.2 nm, a zeta potential of -2.24 mV, and a substantial drug payload of 39.52%. UA-BO-TPP-NPs demonstrated commendable stability in diverse physiological media and during storage. In vitro experiments showed that UA-BO-TPP-NPs significantly enhanced cellular uptake and achieved high mitochondrial co-localization under both normal conditions and oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. UA-BO-TPP-NPs markedly reduced intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels while increasing adenosine triphosphate (ATP) content in human brain microvascular endothelial cells (HBMEC) and SH-SY5Y cells. Furthermore, intravenously injected UA-BO-TPP-NPs effectively accumulated in the brains of rats after cerebral ischemia-reperfusion (I/R) compared to conventional UA-NPs. Consistently, UA-BO-TPP-NPs significantly reduced brain infarction, increased survival rates, preserved blood-brain barrier (BBB) integrity, inhibited oxidative stress, and ameliorated neurological function in cerebral I/R rats. In summary, UA-BO-TPP-NPs effectively delivered encapsulated UA to mitochondria and demonstrated superior therapeutic efficacy in cerebral I/R rats, highlighting the potential for treating ischemic stroke.

D100B is a first-in-class small-molecule activator of AMP-activated protein kinase (AMPK) that specifically targets the lysosomal pool, enabling precise metabolic regulation with lower systemic toxicity. Despite its favorable solubility and stability, D100B exhibits extremely poor oral bioavailability due to strong mucoadhesion and extensive retention within the intestinal mucus. Electrostatic and hydrophobic interactions between D100B and mucin were found to severely hinder its diffusion and epithelial absorption. To overcome this limitation, a PEGylated self-nanoemulsifying system (PSNE) was developed to reduce mucin binding and enhance mucus penetration. The optimized PSNE displayed uniform nanoscale droplets, sustained drug release, and significantly improved diffusion in simulated mucus. In Caco-2/HT29-MTX co-culture monolayers, PSNE significantly enhanced epithelial transport, while pharmacokinetic evaluation demonstrated a 2.66-fold increase in oral bioavailability compared with the unformulated drug. Overall, this study establishes a mucus-barrier-focused formulation strategy that may be applicable for improving the oral delivery of amphiphilic compounds whose absorption is compromised by mucus-mediated retention.