Background: Hesperetin (HSP) is a low water-soluble flavanone aglycone with low
Objectives: This study aimed at enhancing the hepatoprotective effects of HSP by a combinatory
technique based on solid dispersions of co-crystals of HSP.
Methods: Co-crystals were prepared using citric acid, tartaric acid, caffeine and isonicotinamide (INM)
using two methods of solvent evaporation and co-grinding. The solid dispersion of co-crystals with
different ratio of INM, PVP K30 and drug was prepared by the solvent evaporation method. The
resulting material was characterized by DSC, XRD, FTIR and SEM, their saturated solubility and
dissolution rate were compared to the pure drug. Finally, liver toxicity was induced in rats by carbon
tetrachloride (CCl4) and mice were treated with different formulations of HSP. The liver function was
tested by measurement of glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase
(SGOT), serum alkaline phosphatase (ALP) and bilirubin as well as histopathological tests.
Results: Although saturation solubility of HSP was enhanced about 5 times by co-crystals of HSP/INM
(1:2), solid dispersions of the co-crystals of HSP obtained from PVP K30 and INM enhanced it up to
200 folds. Functional parameters of liver in rats pretreated with a solid dispersion of co-crystals of HSP
were significantly lower than those with pure HSP and co-crystals of INM/HSP with 2:1 ratio. Furthermore,
this formulations reduced liver damage effectively compared with the CCL4 group.
Conclusion: Solid dispersion of HSP co-crystals synergistically attenuates hepatic toxicity of carbon
tetrachloride oxidative stress in rats more effectively than its solid dispersions or co-crystals alone.