Formulation, preparation, and stability of intravenous bufadienolides‐loaded lipid microspheres

Abstract The purpose of this study was to develop a new formulation of intravenous lipid microspheres for bufadienolides (bufadienolides‐loaded lipid microspheres, BU‐LM) and investigate the stability of BU‐LM after dilution and long‐term storage. Photon correlation spectroscopy, electrophoretic light scattering, and light microscopy were used to evaluate the physical characteristics of BU‐LM. The chemical properties of bufadienolides were measured by high‐performance liquid chromatography. The optimum BU‐LM, consisting of 10% MCT, 3.0% Lipoid S75, 0.4% F68, 0.05% sodium oleate and 2.5% glycerol, was prepared by emulsification with a high‐speed shear mixing at 10 000 rpm for 12 min and a high‐pressure homogenization at 800 bar for 8 cycles at 30°C. The BU‐LM at pH 6.48, with the particle size distribution of 175.2 ± 57.3 nm, ζ‐potential of −32.10 mV, entrapment efficiency of 86.9%, 91.7%, 92.9%, and contents of 20.8%, 31.3%, 50.4% for B, C, R, respectively, was stable after sterilization in a 121°C rotating autoclave water steam bath for 10 min. Moreover, BU‐LM had sufficient physicochemical stability after dilution with 5% glucose injection and long‐term storage at 4 ± 2°C for 18 months. BU‐LM has a great potential for clinical applications as a new drug delivery system for bufadienolides. Practical applications: Bufadienolides, mainly composed of bufalin (B), cinobufagin (C), and resibufogenin (R) have poor aqueous solubility and are chemically unstable. Currently the main marketable products of bufadienolides are solution injections, which cause serious venous irritation and in this formulation, the drug is not protected from degradation. Lipid microspheres, with the unique properties of a low cost, low toxicity, good storage stability, easy to scale up production, sustained release and targeting effect, incorporate the drugs into the interior oil phase and the oil‐water interfacial film; thus a direct contact of the drug with body fluids and tissues is prevented, which increases the stability of the drugs and minimizes the possible side effects.