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Oral Bioavailability and Pharmacodynamic Activity of Hesperetin Nanocrystals Generated Using a Novel Bottom-up Technology
journal contribution
posted on 2015-04-06, 00:00 authored by Ganesh Shete, Yogesh B. Pawar, Kaushik Thanki, Sanyog Jain, Arvind Kumar BansalIn the present study, nanocrystalline
solid dispersion (NSD) was
developed to enhance the release rate and oral bioavailability of
hesperetin (HRN). NSD of HRN was prepared using a novel bottom-up
technology platform. It is a spray drying based technology to generate
solid particles, containing drug nanocrystals dispersed in small molecule
excipients. HRN and mannitol were used in a 5:5 ratio, and an average
crystallite size of HRN in NSD with mannitol was found to be 137.3
± 90.0 nm. An in vitro release study revealed
a statistically significant release rate enhancement for HRN nanocrystals
(46.3 μg/mL/min) as compared to that of the control (29.5 μg/mL/min).
Further, a comparative oral bioavailability study of NSD and control
in Sprague–Dawley rats established significant improvement
in Cmax and oral bioavailability (AUC0–∞) by 1.79- and 2.25-fold, respectively, for
HRN nanocrystals. The findings of oral bioavailability were corroborated
by intestinal uptake and Caco-2 cell uptake studies, wherein HRN,
when administered in nanocrystalline form, showed higher penetration
in intestinal mucosa and higher uptake in Caco-2 cells. Finally, the
therapeutic efficacy of HRN nanocrystals was tested by a reactive
oxygen species (ROS) generation assay and carrageenan induced anti-inflammatory
model. HRN nanocrystals markedly inhibited ROS generation in MCF-7
cells, and carrageenan induced inflammation in rats. The process of
NSD formation was found to be based on classical nucleation theory
wherein mannitol contributed to NSD formation by acting as a plasticizer
and crystallization inducer, and by providing sites for heterogeneous
nucleation/crystallization.