RESUMEN
The challenge of bacterial infection increases the risk of mortality and morbidity in acute and chronic wound healing. Silver nanoparticles (Ag NPs) are a promising new version of conventional antibacterial nanosystem to fight against the bacterial resistance in concern of the drug discovery void. However, there are several challenges in controlling the size and colloidal stability of Ag NPs, which readily aggregate or coalesce in both solid and aqueous state. In this study, a template-guided synthesis of ultrafine Ag NPs of around 2 nm using water-soluble and biocompatible γ-cyclodextrin metal-organic frameworks (CD-MOFs) is reported. The CD-MOF based synthetic strategy integrates AgNO3 reduction and Ag NPs immobilization in one pot achieving dual functions of reduced particle size and enhanced stability. Meanwhile, the synthesized Ag NPs are easily dispersible in aqueous media and exhibit effective bacterial inhibition. The surface modification of cross-linked CD-MOF particles with GRGDS peptide boosts the hemostatic effect that further enhances wound healing in synergy with the antibacterial effect. Hence, the strategy of ultrafine Ag NPs synthesis and immobilization in CD-MOFs together with GRGDS modification holds promising potential for the rational design of effective wound healing devices.
Asunto(s)
Antibacterianos/farmacología , Ciclodextrinas/química , Nanopartículas del Metal/química , Estructuras Metalorgánicas/farmacología , Oligopéptidos/química , Tamaño de la Partícula , Plata/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Ciclodextrinas/síntesis química , Hemostasis , Nanopartículas del Metal/ultraestructura , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/ultraestructura , Pruebas de Sensibilidad Microbiana , Ratas Sprague-Dawley , Dispersión del Ángulo Pequeño , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Staphylococcus aureus/efectos de los fármacos , Termogravimetría , Difracción de Rayos XRESUMEN
One unusual and challenging scientific field that has received only cursory attention to date is the three-dimensional (3D) microstructure and spatial distribution of drug(s) and formulation materials in solid dosage forms. This study aims to provide deeper insight into the relationships between the microstructure of multiple-unit pellet system (MUPS) tablets and the spatial distribution of the active pharmaceutical ingredient (API) and excipients to facilitate the design of quantitative models for drug delivery systems. Synchrotron radiation X-ray microcomputed tomography (SR-µCT) was established as a 3D structure elucidation technique, which, in conjunction with liquid chromatography coupled to mass spectrometry (LC-MS) or liquid chromatography with evaporative light-scattering detector (LC-ELSD) enables chemical analysis of tablets. On the basis of the specific interior construction of theophylline MUPS tablets, the spatial distribution of materials was acquired by quantifying microregion samples that had been validated by SR-µCT for their locations in the MUPS tablets. The 3D structure of the MUPS tablets was catalogued as three structural domains: a matrix layer (ML), a protective cushion layer (PCL), and pellets (PL). Compared with the components in the ML, components in the PL had a larger proportion of theophylline, sucrose, and diethyl phthalate and a smaller proportion of lactose and sodium lauryl sulfate, whereas glyceryl monostearate was found to account for a large portion of the PCL. Microstructural characterization-guided zonal chemical determination represents a new approach for quality assessment and the development of drug delivery systems with in-depth insight into their constituent layers on a new scale.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ciencia de los Materiales/métodos , Comprimidos/química , Teofilina/química , Microtomografía por Rayos X/métodosRESUMEN
Defining and visualizing the three-dimensional (3D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography (SR-µCT). In situ formed 3D structures at different in vitro drug release states were characterized comprehensively. A distinct movement pattern of NaCl crystals from the push layer to the drug layer was observed, beneath the semi-permeable coating in the desiccated tablet samples. The 3D structures at different dissolution time revealed that the pushing upsurge in the bilayer osmotic pump tablet was directed via peripheral "roadways". Typically, different regions of the osmotic front, infiltration region, and dormant region were classified in the push layer during the dissolution of drug from tablet samples. According to the observed 3D microstructures, a "subterranean river model" for the drug release mechanism has been defined to explain the drug release mechanism.
RESUMEN
The multiple-unit sustained-release (MUSR) dosage forms containing numerous sustained-release subunits present a reliable choice for oral formulation of controlled release systems. As a typical MUSR, the metoprolol succinate sustained-release tablet is an advanced system with limited researches devoted to relating its structure to the drug release phase other than the preparation process and modulation to the release behaviors. This research details a three-dimension method to image the internal structure and detail drug release features of commercial metoprolol succinate sustained-release tablets and component individual single pellets. As such, a new perspective for MUSR dosage form is provided. Using high energy synchrotron radiation X-ray microcomputed tomography (SR-µCT), the in-situ structure parameters were obtained nondestructively. It was demonstrated that the average number of spherical pellets in a tablet was 853 ± 12 (n = 3). The average volume of the pellets was 0.09 ± 0.01 mm3, the diameter was 0.55 ± 0.03 mm, and the sphericity was 0.87 ± 0.06. These data reflected the numerical features of pellets in MUSR tablets, which were helpful for reverse engineering to MUSR. Based on the three dimensional model generated by image processing and analysis software, the pellet structures were divided into three layers of typical depot sustained release system: pellet core, drug-containing layer and outer film. The dynamic structural features determined refer to the changes of structures in pellets during in vitro drug release, with evidence that the coating layer on the pellets maintained a spherical morphology whilst numerous valleys appeared on the surface. The material constitution and distribution in coating layer were evaluated by synchrotron radiation-based Fourier transform infrared mapping and results indicated a composition of hydroxypropyl methylcellulose dispersed in ethyl cellulose. Knowledge of these structural characteristics confirmed that the mechanism of sustained drug release was membrane controlled and consistent with the drug release profiles. In conclusion, the structural investigation provided knowledge of the intrinsic quality of metoprolol succinate sustained-release tablets and offers guidance for reverse engineering of MUSR.
RESUMEN
The aim of this study was to investigate the release behaviors of sinomenine hydrochloride loaded via in situ hexagonal liquid crystal (ISH), and its potential to improve the local bioavailability in knee joints of sinomenine hydrochloride (SMH) after intra-articular administration. The ISH was prepared by a liquid precursor mixture containing phytantriol (PT), Vitamin E acetate (VEA), ethanol (ET), and water. The in vitro release profiles revealed a sustained release of SMH from the optimized ISH formula (PT/VEA/ET/water, 60.8:3.2:16.0:20.0, w/w/w/w), which was selected for the in vivo pharmacokinetics and preliminary pharmacodynamics studies. In both healthy and adjuvant-induced arthritis (AA) rats, the SMH loaded ISH showed significantly smaller SMH AUC0-∞ in plasma (P < 0.01), and higher SMH concentration in synoviums (2Ë168 h) than that of SMH solution, indicating that the ISH significantly reduced the leakage of SMH into systemic circulation. The t1/2α of SMH loaded ISH in the knee joints of AA rats, was longer (13.42 h) than that of healthy rats (1.34 h) (P < 0.05), most likely that in vivo drug release behavior of SMH loaded ISH was affected by the physiological environment of the joint. It was found that the SMH loaded ISH could benefit AA-rats by suppressing the level of IL-1ß in comparison to SMH solutions. The results of the histopathology of knee joints in AA rats displayed that the SMH loaded ISH might be suitable for the development of treatment strategies for rheumatoid arthritis diseases.
Asunto(s)
Cristales Líquidos/química , Morfinanos/administración & dosificación , Animales , Antiinflamatorios/farmacología , Liberación de Fármacos , Alcoholes Grasos/química , Inyecciones Intraarticulares , Interleucina-1beta/metabolismo , Articulaciones/patología , Morfinanos/sangre , Morfinanos/química , Morfinanos/farmacocinética , Ratas , Pruebas de Irritación de la Piel , Membrana Sinovial/metabolismoRESUMEN
Rationale: Targeted delivery of therapeutic drugs or imaging agents to injured blood vessels via nanocarriers is likely to be dependent on the particle shape, yet cubic nanoparticle carriers have not been reported for vascular targeting. Here, we demonstrate that cuboidal cyclodextrin frameworks possess superior hemostasis effect and injured vessels targeting compared with spherical counterpart. Methods: Cuboidal and biocompatible γ-cyclodextrin metal-organic frameworks (CD-MOFs) are synthesized, tethered via crosslinking and surface modification with GRGDS peptide (GS5-MOFs). The specific interactions of cubic GS5-MOF nanoparticles with activated platelets were investigated by in vitro platelet aggregation assay and atomic force microscopy measurements (AFM). The hemostatic capacity and injured vessel targeting efficacy were evaluated in vivo. Results: Cuboidal GS5-MOF nanoparticles exhibit enhanced adhesion and aggregation with activated platelets in vitro under static condition and a physiologically relevant flow environment. The cubic GS5-MOF nanoparticles show efficient hemostatic effects with bleeding time and blood loss decrease of 90% and strong injured vessel targeting in vivo, markedly superior to spherical γ-CD nanosponges with the same chemical composition. Conclusions: These results clearly highlight the contribution of the cuboidal shape of GS5-MOFs to the enhanced aggregation of activated platelets and high targeting to damaged vessels. The cuboidal nanoparticle system provides an innovative delivery platform for the treatment and diagnosis of vascular diseases.
Asunto(s)
Plaquetas/metabolismo , Ciclodextrinas/farmacología , Sistemas de Liberación de Medicamentos/métodos , Hemorragia/terapia , Compuestos Organometálicos/farmacología , Agregación Plaquetaria , Nanomedicina Teranóstica/métodos , Animales , Adhesión Celular , Ciclodextrinas/administración & dosificación , Ciclodextrinas/síntesis química , Modelos Animales de Enfermedad , Hemostasis , Ratones , Oligopéptidos/administración & dosificación , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/síntesis química , Ratas Sprague-Dawley , Resultado del Tratamiento , Enfermedades Vasculares/diagnósticoRESUMEN
The microsphere was a primary particulate system for taste-masking with unique structural features defined by production process. In this article, ibuprofen lipid microspheres of octadecanol and glycerin monostearate were prepared to mask the undesirable taste of ibuprofen via three kinds of spray congealing processes, namely, air-cooling, water-cooling and citric acid solution-cooling. The stereoscopic and internal structures of ibuprofen microspheres were quantitatively analyzed by synchrotron radiation X-ray micro-computed tomography (SR-µCT) to establish the relationship between the preparation process and microsphere architectures. It was found that the microstructure and morphology of the microspheres were significantly influenced by preparation processes as the primary factors to determine the release profiles and taste-masking effects. The sphericity of ibuprofen microspheres congealed in citric acid solution was higher than that of other two and its morphology was more regular than that being congealed in air or distilled water, and the contact angles between congealing media and melted ibuprofen in octadecanol and glycerin monostearate well demonstrated the structure differences among microspheres of three processes which controlled the release characteristics of the microspheres. The structure parameters like porosity, sphericity, and radius ratio from quantitative analysis were correlated well with drug release behaviors. The results demonstrated that the exterior morphology and internal structure of microspheres had considerable influences on the drug release behaviors as well as taste-masking effects.
RESUMEN
Cyclodextrins nanosponges (CD-NSPs) are highly microporous crosslinked polymers with potential applications in the delivery of small and macro-molecular therapeutic agents. Despite the potent host-guest inclusion property, their inherent lack of cellular binding ability has limited applications in drug delivery. Herein, we functionalized the surface of ß-cyclodextrin nanosponge (ß-CD-NSP) with cholesterol, which is endogenous physiological molecules, widely distributed in all cells, and responsible for cell interactions and protein binding. The surface grafting of synthesized ß-CD-NSP was confirmed with spectroscopic, microscopic, thermogravimetric, and chromatographic techniques. Moreover, ß-CD-NSP was found to be safe in cytotoxicity assay. Doxorubicin (Dox) was selected as a model drug for drug adsorption study of cholesterol hydrogen succinate (CHS) grafted ß-CD-NSP. The cellular uptake of NSP was found to be enhanced after CHS modification confirmed by confocal laser scanning microscopy (CLSM). Thus, proposed CHS modified ß-CD-NSP system could be used as a site-specific drug delivery carrier.