Oral Bioavailability and Pharmacodynamic Activity
of Hesperetin Nanocrystals Generated Using a Novel Bottom-up Technology
Ganesh Shete
Yogesh B. Pawar
Kaushik Thanki
Sanyog Jain
Arvind Kumar Bansal
10.1021/mp5008647.s001
https://acs.figshare.com/articles/journal_contribution/Oral_Bioavailability_and_Pharmacodynamic_Activity_of_Hesperetin_Nanocrystals_Generated_Using_a_Novel_Bottom_up_Technology/2180110
In 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 <i>in vitro</i> 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 <i>C</i><sub>max</sub> and oral bioavailability (AUC<sub>0–∞</sub>) 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.
2015-04-06 00:00:00
MCF
release rate enhancement
ROS
HRN nanocrystals
NSD formation
Hesperetin Nanocrystals Generated
AUC
bioavailability
reactive oxygen species