Phenytoin-loaded lipid-core nanocapsules improve the technological properties and in vivo performance of fluidised bed granules.

Abstract

Lipid-core nanocapsules (LNCs) were recently reported by our group as a suitable binder system to produce fluidised bed granules. However, there is still a lack of knowledge about the influence of using these nanocarriers loaded with a drug on the properties of the granules and their in vivo performance. Therefore, this study was designed to produce innovative fluidised bed granules containing phenytoin-loaded LNCs (LNCPHT) as a strategy to evaluate the influence of the presence of the drug-loaded nanocarriers on their in vitro and in vivo properties. Granules were produced using a mixture of maltodextrin and phenytoin (1:0.004 w/w) as substrate. They were prepared by fluid bed granulation using water or LNCPHT as the liquid binder, affording good yields (73-82%) of granules with low moisture content (<5%). Granules prepared with LNCPHT had larger mean size (122μm) compared to maltodextrin primary particles (50μm) due to the formation of solid bridges. Moreover, the use of LNCPHT as the liquid binder improved their powder flow properties. The nanocarriers were recovered after aqueous dispersion (3.00mg.mL-1 of PHT) with a redispersibility close to 90%. After reconstitution in water, granules containing LNCPHT showed an improved dissolution behaviour compared to those prepared without them. In addition, they showed a higher mucoadhesive effect due to a combined effect of the LNCPHT and maltodextrin in the interactions with porcine intestinal mucosa. Regarding the in vivo studies, granules containing the combination of non-encapsulated PHT and PHT-loaded lipid-core nanocapsules increased the latency to seizures compared to placebo granules, showing effective anticonvulsant effect in mice. In conclusion, the use of drug-loaded nanocapsules as binder is an encouraging approach to produce fluidised bed mucoadhesive granules with improved technological properties and in vivo performance.