International Journal of Pharmaceutics最新文献

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.

Successful development of direct-compression formulations can be hindered by poor compactibility of active pharmaceutical ingredients active pharmaceutical ingredients (APIs), necessitating rational formulation strategies. This work presents a neural network model trained on a large tableting dataset comprising over 200 formulations prepared from 33 powders, including 17 APIs, to predict tablet tensile strength across the full compaction pressure range directly from material properties and formulation composition for binary mixtures. The predictive accuracy of the neural network model was compared to a mixing rule based on tabletability parameters. The neural network outperformed the power-law mixing rule for binary mixtures, demonstrating particular strength for APIs with poor compaction behavior and for mixtures where the mixing-rule approach could not be applied due to the inability to produce intact compacts from pure components. The model also exhibits permutation invariance and only requires 3-5 g of material for the compaction characterization for a new powder, necessary for making model predictions.

Bevacizumab is a monoclonal antibody used intravitreally as an anti-VEGF therapy for some ocular diseases. However, this type of treatment presents some limitations, such as the invasiveness of its administration and the need for frequent injections due to the clearance of the antibody from the vitreous chamber. Semi-solid lipid implants emerge as an attractive possibility for the sustained release of biological drugs like bevacizumab, so they could have great potential for the subsequent treatment of VEGF-dependent degenerative retinal pathologies, such as proliferative diabetic retinopathy or neovascular age-related macular degeneration. In this work, injectable lipid implants were designed based on the lipids Precirol® ATO 5, Tefose® 63, Geleol^TM, and Tefose® 1500. The implants were easy to manufacture by melting and mixing. The surface of the implants was characterized by scanning electron microscopy, while the distribution of bevacizumab inside was characterized by confocal Raman mapping microscopy. Subsequently, the state of the antibody after release was evaluated by Raman Spectroscopy and Attenuated Total Reflection Infrared spectroscopy, showing an unaltered quaternary structure. Furthermore, the implants were able to sustain the antibody release for almost 40 days. Biocompatibility was assessed by assay with ARPE-19 cells. Finally, the calorimetry assay allowed us to refine the best possible formulation for further studies. This type of implant showed suitable properties as a potential therapeutic platform for the treatment of neovascular age-related macular degeneration and proliferative diabetic retinopathy, being injectable, easy to make, homogeneous, having sustained release and being biocompatible.

For nearly eight decades, the evaluation of disintegration performance has relied on a single disintegration time (DT) value, which serves as the sole pass or fail criterion for drug products. Although practical for regulatory compliance, this endpoint-based metric offers limited scientific insight into the underlying physical breakdown of the tablet matrix. In this study, the dynamic evolution of the gap height between the disk and mesh in the USP〈701〉 disintegration apparatus was monitored using a state-of-the-art non-contact distance sensor, enabling the construction of disintegration profiles that function as a mechanical fingerprint of the dosage form. Simvastatin 20mg tablets from six different brands were investigated, encompassing both originator and generic alternatives, and the resulting gap height profiles clearly discriminate among brands in terms of formulation-dependent disintegration behaviour. Within the measurable range, the erosion interface was found to propagate linearly towards the tablet core at a constant velocity, supporting the interpretation of the process as governed by linear erosion-controlled kinetics, in which the erosion rate and liquid ingress are synchronised. By linking the observed erosion velocity to the rate of surface area generation, this profiling approach provides the physical parameters needed to improve dissolution models within the Noyes-Whitney framework. The results demonstrate the potential of upgrading the conventional USP disintegration setup into an effective Process Analytical Technology tool for formulation development and quality assessment.

Oral administration is regarded as the most common and convenient drug delivery route. However, numerous drugs face challenges such as poor solubility, limited permeability, instability, and first-pass metabolism, which hinder intestinal absorption and therefore limit their clinical application. Niosomes, vesicular structures self-assembled from non-ionic surfactants and cholesterol, offer a promising strategy for enhancing oral bioavailability. This review gathers findings from recent studies to examine how key vesicle properties, such as surfactant type and ratio, cholesterol content, particle size, and surface charge, affect the oral pharmacokinetics of drugs (area under plasma concentration-time curve, C_max, and T_max). The effect of surface modification approaches, such as PEGylation and chitosan coating, on enhancing mucosal adhesion, enzymatic resistance, and sustained release has been reviewed. The main mechanisms involved in the ability of niosomes to enhance the oral drug absorption, including enhanced endocytosis, modulation of tight junctions to improve paracellular drug absorption, and elevated lymphatic transport via chylomicron formation and M-cell transcytosis, are also outlined. Characterization of niosomes required for oral administration, including particle size measurement, drug release behavior, stability evaluation in gastrointestinal media, and complementary evaluations such as cytotoxicity and mucoadhesion, is also summarized. Furthermore, we discussed evidence of intact vesicle absorption, safety issues, and regulatory challenges. This review provides a perspective for future research and a deeper understanding of niosomes' in vivo behavior, which could be used as a comprehensive guide to design and optimize oral niosomal formulations.

Water-in-oil-in-water (w₁/O/W₂) double emulsions can compartmentalize hydrophilic actives at high aqueous loadings, but osmotic gradients and interfacial transport often drive premature leakage. This remains a key limitation for high-payload hydrophilic formulations exposed to dilution or osmotic shocks during handling, reconstitution, or administration. Here, we engineer wax-shelled, gel-cored w₁/O/W₂ double emulsions designed under iso-osmotic conditions to combine storage-stable retention at 25°C (fully solid wax state) with temperature-activated permeability at a high internal water fraction (70%). Double emulsions were prepared with a polyacrylate-gelled inner aqueous phase and either liquid oil or semi-crystalline wax as the middle phase, and characterized by confocal microscopy, release assays (NaCl conductimetry and metformin dialysis/UV at 37°C, with additional 25°C datasets for wax systems), Weibull kinetic modelling (and early-time power-law analysis at 25°C), and oscillatory rheology. Iso-osmotic formulation enabled high initial encapsulation and preserved internal compartmentalization. Release profiles revealed two regimes: minimal leakage at low temperature and a marked increase in permeability upon heating, consistent with barrier-controlled transport. Compared with liquid oil, wax systems provided stronger retention but exhibited partial trapping after triggering. Finally, a CaCl₂/alginate external gelation model coupled to rheology quantified the triggered sol/gel transition and the mechanical response of wax-based double-emulsion assemblies under thermal stimulation and compressive loading.

Central nervous system diseases (CNSDs) pose a significant therapeutic challenge, largely due to the restrictive blood-brain barrier (BBB). While nanocarriers like liposomes, polymeric nanoparticles, and exosomes have been explored for brain delivery, carbon dots (CDs) have emerged as a particularly promising platform. These carbon-based nanomaterials offer advantages such as small size, excellent biocompatibility, and versatile surface chemistry, enabling precise functionalization. Compared to liposomes and polymer nanoparticles, CDs exhibit superior size uniformity, photophysical properties, and chemical stability. Unlike exosomes, they are synthetically controllable, scalable for mass production, and amenable to precise surface modification. A key advantage lies in their ability to cross the BBB via specific molecular mechanisms, such as receptor‑mediated transcytosis, when conjugated with targeting ligands (e.g., transferrin, lactoferrin, or cell‑penetrating peptides). This allows for disease-specific targeting, for instance, of amyloid-β plaques in Alzheimer's or overexpressed receptors in brain tumors. CDs can serve as intrinsic therapeutics or as drug carriers. However, their clinical translation depends on addressing critical issues of long-term safety, potential neurotoxicity (such as inducing oxidative stress and inflammation), and biodegradability. This review systematically summarizes the synthesis methods and functionalization strategies of CDs, alongside the molecular mechanisms underlying their BBB penetration. It focuses on their therapeutic potential for CNSDs, providing a comparative analysis with other common nanocarriers. Furthermore, it evaluates the current research and improvement strategies concerning CDs toxicity, biocompatibility, and long-term safety. Finally, the review outlines ongoing challenges and future directions for the field.