Preparation of Ginkgolide Solid Dispersions with Low-Molecular-Weight Chitosan and Assessment of their Protective Effect on Isoproterenol- Induced Myocardial Injury.

BACKGROUND

Ginkgolides are widely used in cardio-protective therapy; however, poor bioavailability currently limits their application.

OBJECTIVE

The purpose of this study was to demonstrate whether solid dispersions prepared with Low- Molecular-Weight Chitosan (LMWC) could improve the protective effect of ginkgolides on Myocardial Injury (MI).

METHODS

Ginkgolide Solid Dispersions (GKSD) were prepared with LMWC. Their properties were then characterized using differential scanning calorimetry, X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. In vivo pharmacokinetic studies were performed in rats, and the protective effect of GKSD on MI was investigated by western blotting and immunohistochemical analyses.

RESULTS

Drug dissolution testing showed that GDSD were released at a significantly higher rate than ginkgolides, dissolved by alternative methods, suggesting that LMWC facilitates the release of ginkgolides. Differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, and Fourier transform infrared spectroscopy all showed that GKSD was amorphous. In-vivo testing revealed larger AUC0-t, higher Cmax, and shorter Tmax for GKSD compared to that in original ginkgolides. Myocardial injury was induced in rats with isoproterenol to test the protective effect of GKSD. GKSD alleviated MI and reduced myocardial fibrosis, as observed by Hematoxylin and Eosin staining. Compared with the crude drug group, the secretion of malonyl dialdehyde and nitric oxide and expression of NOX-2 and NOX-4 were lower. The activities of the cardiac marker enzymes SOD, CAT, GPX, GPX-1, and GSH were higher in GKSD-administered rats, indicating a beneficial effect of GKSD in eliminating free radicals during myocardial injury. Additionally, western blotting and immunohistochemical analysis showed that GKSD markedly reduced the expression of signaling proteins RHOA, ROCK1, ROCK2, and RAC1.

CONCLUSION

Solid dispersions prepared with low molecular weight chitosan improved the oral bioavailability of ginkgolide and enhanced its protective effect on myocardial injury.