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