​Safety Evaluation of Andrographolide-nanosuspensions

Abstract

Background: Andrographolide (ANDRO) is a hydrophobic drug, which faces the problem of limited absorption due to poor water solubility. The current research prepared andrographolide nanosuspensions (ANDRO-NS) and examined in vivo toxicity for mice. Methods: ANDRO-NS were prepared by anti-solvent precipitation method, transmission electron micrographs, granularity analysis and in vitro release were used to characterize the ANDRO-NS, we evaluate the safety of the ANDRO-NS by using the acute toxicity test, local irritation test and chronic toxicity test. Result: The particle size of ANDRO-NS was (568.51±13.74 nm). The LD50 for ANDRO-NS was 548.91 mg/kg after oral administration to KM mice with a 95% CI of 468.19-645.03 mg/kg. The white blood cell counts and hemoglobin levels for the experimental groups were lower than controls receiving only saline. Serum aspartate transaminase, creatinine and blood urea nitrogen levels were greater than controls after 7 and 14 days of once-daily administration. After 14 days of administration, the platelet counts as well asalanine transaminase levels were, in addition, Histological observations indicated that interstitial kidney tissues were wider than controls and showed episodic bleeding after 7 days of administration. The highest dose administered also resulted in the dilation and blood engorgement of the central hepatic veins with some severed hepatic cords. Mice receiving the lowest dose of ANDRO-NS we administered appeared healthy and similar to controls receiving saline only. Following 14 days of administration, we found significant vacuolar degeneration of renal tubular epithelial cells and glomerular atrophy for the high-dose group as well as edema and necrosis in liver cells. The medium-dose group displayed kidney interstitial tissue widening with scattered bleeding, inflammatory cell infiltration and hepatocyte edema. The low-dose group displayed dilated renal tubules and irregularly-arranged liver cells as well as bleeding in the hepatic sinusoids. Therefore, short-term administration of andrographolide suspensions resulted in inflammation and time- and dose-dependent toxic effects on the kidneys and liver.