title: Oral bioavailability and pharmacodynamic activity of hesperetin nanocrystals generated using a novel bottom-up technology.
abstract: 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 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.
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Shete
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Yogesh B
authors.initials: YB
authors.lastname: Pawar
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Thanki
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Sanyog
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Arvind Kumar
authors.initials: AK
authors.lastname: Bansal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry; D001682:Biological Availability; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002351:Carrageenan / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D018360:Crystallography, X-Ray; D005260:Female; D006569:Hesperidin / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D008353:Mannitol / Q000737:chemistry; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013818:Thermogravimetry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D008353:Mannitol; D002351:Carrageenan; D006569:Hesperidin; C013015:hesperetin
keywords: bioavailability enhancement; hesperetin; nanocrystalline solid dispersion; nanocrystals; release rate improvement