Intravenous bufadienolides‐loaded lipid microspheres for improving chemical stability

This study focused on the degradation kinetics of bufalin (B), cinobufagin (C), and resibufogenin (R) in bufadienolides‐loaded lipid microsphere (BU‐LM) and bufadienolides‐loaded aqueous solution (BU‐S). The chemical stability of bufadienolides both in BU‐LM and BU‐S at different pH values and temperatures was monitored by HPLC. Photon correlation spectroscopy and electrophoretic light scattering technology were used to evaluate the physical characteristic of BU‐LM. Under the most stable pH range of 6.0-6.5, the half‐lives of B, C, and R in BU‐LM were 22, 15, and 20 days at 80 °C but 4510, 1717, and 3300 days at 25 °C, whereas for BU‐S only 11, 3, and 10 days at 80 °C and 71, 18, and 49 days at 25 °C. The results indicated that BU‐LM significantly increased the chemical stability of bufadienolides, especially at low temperatures. The degradation of bufadienolides took place mostly in the aqueous phase and the diffusion process of bufadienolides from the oil phase through the interfacial layer to the aqueous phase was the rate‐limiting step for the drug degradation. A low temperature slowed down of the diffusion rate leading to a slower degradation and longer half‐lives. Among the three bufadienolides in BU‐LM, C was protected from degradation to the greatest extent. Practical applications: Bufadienolides, consisting of bufalin (B), cinobufagin (C), and resibufogenin (R) have poor aqueous solubility between 20 and 60 µg/mL and are easily degradable by acids or bases. Here we propose a new strategy to overcome stability problems by using lipid microspheres (LM) as the drug vehicle. By incorporating the drugs into the interior oil phase and the oil-water interfacial film, a direct contact of the drug with body fluids and tissues is avoided. Thus the drug is protected from degradation and possible side effects are minimized. Our results indicate that BU‐LM significantly increased the chemical stability of bufadienolides, especially at low temperatures. Among the three bufadienolides in BU‐LM, C was protected from degradation to the greatest extent.