The Development Of Liquid Injectable Formulation For Water-insoluble Isosteviol Sodium By Using Co-solvent Technology

Isosteviol is extracted from steviosides, and isosteviol sodium(STVNa) is the sodium salt of isosteviol. STVNa has a great clinical potential for cardiovascular diseases, but its application is severely hampered by its low water-solubility. In the present study, an attempt has been made to develop a liquid formulation of STVNa for intravenous(i.v.) administration.Formulation parameters, including p H, type and content of excipients, were overall optimized to obtain a clear liquid formulation of STVNa with sufficient physi-chemical stabilities and acceptable safety for i.v. administration. In addition, we exploited an overall validated analysis method(including clarity, p H, volume, related substances, sterility, bacterial endotoxin and content) to detect the quality of STVNa. Preliminary safety was evaluated by hemolysis test and cytotoxicity assay.STVNa was easily and cost-effectively prepared using a solvent system composed of saline at p H 10.0, 25 %(v/v) of ethanol and 20 %(v/v) of propylene glycol,the concentration of STVNa was 20 mg/m L(STVNa injection), which showed high physi-chemical stabilities(i.e. no precipitation and generation of impurities) upon storage for at least 3 months. STVNa did not induce hemolytic effects up to 9.1 %(v/v) for 3 hours and significant cytotoxicity up to 50 μg/m L in H9C2 cells. After i.v. administration, no significant acute toxicities in Wistar rats received STVNa were observed. As far as we know, this is the first demonstration of a liquid formulation of STVNa suitable for i.v. administration.