RESUMEN
In this paper, we shed light on the potential of Pluronic® mixed micelles in lung delivery of poorly water-soluble drugs. To this purpose, Pluronic® P123/F127 mixed micelles (PMM), exhibiting superior stability in biological fluids, were loaded with budesonide (BUD), a model hydrophobic corticosteroid, and fully investigated focusing on their stability in pulmonary-relevant media, transport through the mucus barrier and aerodynamic behaviour in vitro. Then, lung bio-distribution and efficacy were evaluated in vivo, after intra-tracheal administration in rats. PMM showed excellent stability in saline, mucin, artificial airway mucus and simulated interstitial lung fluid. Likely due to their small size coupled with the hydrophilic biofouling shell, PMM did not interact with mucin and consequently diffused through artificial mucus. BUD was loaded with high efficiency in PMM and released at sustained rate in artificial mucus. BUD-PMM dispersion in saline was efficiently delivered through a common jet nebulizer without aggregation. After intratracheal administration in rats, PMM labelled with Rhodamine B persisted in the lung up to 24â¯h, while serum levels rapidly dropped. Finally, the effects of BUD-PMM in a rat model of lung inflammation induced by intra-tracheal aerosolization of lipopolysaccharide (LPS) from E. coli were investigated. Of note, a single intra-tracheal aerosolization of BUD-PMM significantly reduced bronchoalveolar neutrophil infiltration and the expression of protein/enzymes derived from the arachidonic acid cascade induced by LPS, whereas a control BUD aqueous suspension showed a weaker effect. Overall, this study demonstrates that inhalable formulations of PMM can be considered as a platform for local delivery of hydrophobic drugs at lungs worth of further consideration.
Asunto(s)
Budesonida/administración & dosificación , Sistemas de Liberación de Medicamentos , Pulmón/metabolismo , Poloxámero/química , Administración por Inhalación , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Budesonida/química , Budesonida/farmacocinética , Modelos Animales de Enfermedad , Portadores de Fármacos/química , Interacciones Hidrofóbicas e Hidrofílicas , Lipopolisacáridos/toxicidad , Masculino , Micelas , Nebulizadores y Vaporizadores , Tamaño de la Partícula , Neumonía/tratamiento farmacológico , Ratas , Ratas Wistar , Factores de Tiempo , Distribución TisularRESUMEN
Budesonide (BUD) is a glucocorticoid widely used for the treatment of ulcerative colitis. In this work, we propose the study of the system BUD-HP-ß-CD inclusion complex incorporated into PL 407 and PL407-PL403 thermoreversible hydrogels, considering physico-chemical and pharmaceutical aspects. Complexation between BUD and HP-ß-CD was confirmed by phase solubility studies (1:1 stoichiometry, Kc=8662.8 M(-1)), DSC, FTIR and microscopy analyzes. BUD solubility in simulated upper and lower colon fluids was improved in a dependence of HP-ß-CD and PL 407 or PL407-PL403 association. Micellar hydrodynamic diameter studies showed the interaction between HP-ß-CD and PL blocks, as well as the reorganization of the micellar system in the presence of BUD and its inclusion complex. Micellization temperature (Tm) was not shifted, but sol-gel phase transition studies showed that in the presence of BUD, HP-ß-CD or BUD:HP-ß-CD complex, the association PL407-PL403 favored the gel formation close to the physiological temperature. Physico-chemical and in vitro release assays studies revealed no competitive displacement of BUD from the HP-ß-CD cavity evoked by PL407 or PL407-PL403 addition. These findings point out the BUD-HP-ß-CD in PL-based hydrogels as strategies for future investigations on development of new pharmaceutical formulations for the treatment of ulcerative colitis.