Stabilization of Teniposide in Aqueous Mixtures of Detergent-Phospholipid

Abstract

Teniposide-containing mixed micelles and liposomes consisting of detergent and phospholipid were investigated and compared for their teniposide latency as functions of the mixed micellar preparation method, stabilizers, type of detergent, lipid composition and serum proteins after storage at 10°C, 23°C, and 45°C or/and freezing and freeze-drying. There was no significant difference in teniposide loss from liposomes obtained using different micellar preparation methods. Sugars, dextrose or sorbitol, had no effect on teniposide loss from liposome but stabilized teniposide micelles. Glutamic acid had no effect on teniposide loss from micelles but increased the loss from liposomes. The presence of cholesterol in bile salt-egg PC micelles had little effect on teniposide loss at 10°C but generally increased it at 23°C, and 45°C, while bile salt-egg PC-cholesterol (9:9:1) liposomes were more stable than bile salt-egg PC liposomes. In contrast, teniposide loss from bile salt-egg PC-egg PE (2:1:1) liposomes or bile salt-egg PC-egg PA (16:15:1) micelles and liposomes increased remarkedly, probably due to the surface charge and/or the destabilization of PC bilayer. However, bile salt-egg PC-soy PC (2:1:1) micelles and liposomes lost less amounts of teniposide under the same storage conditions. Further, the stability of teniposide was greatly increased by neutral detergents (e.g., CHAPS or octylglucoside). The losses of teniposide from CHAPS- or octylglucoside-egg PC micelles and liposomes after six months’ storage at the ambient temperature were approximately 16% and 10%, respectively. Teniposide-micelles and liposomes, prepared in the presence of serum or serum protein, were more stable than CHAPS- or octylglucoside-egg PC liposomes. Teniposide was physically stable for at least 12 months when micelles were stored as the frozen or freeze-dried state. This result suggested that long-term storage for teniposide in neutral detergent-egg PC-soy PC micelles may be feasible in the presence of serum proteins.