Intravenous bufadienolides‐loaded lipid microspheres for improving chemical stability

Abstract

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 8C but 4510, 1717, and 3300 days at 25 8C, whereas for BU-S only 11, 3, and 10 days at 80 8C and 71, 18, and 49 days at 25 8C. 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 mg/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.

Bioavailability and pharmacokinetics of bufadienolides‐loaded lipid microspheres after different administrations to rats

“…Finally, the BU-LM is transferred to vials after adding nitrogen gas and sterilized in a 1218C rotating autoclave water steam bath for 10 min [9]. The BU-LM had a uniform milky appearance.…”

“…The mobile phase was a 45:55 v/v mixture of acetonitrile: water (pH 3.2) containing 0.5% potassium dihydrogen phosphate at a flow rate of 1.0 mL/min. The wavelength of the UV detector was set at 296 nm and the injection volume was 10 mL with the column temperature at 408C [9].…”

“…Bufadienolides-loaded lipid microsphere (BU-LM), has the particle size distribution and zeta potential of 173.2 AE 56.3 nm and À32.03 mV, respectively, by incorporating 87.0% of B, 91.6% of C, and 92.9% of R into the inner oil phase and the interfacial lecithin layer to protect bufadienolides from degradation. The degradation half-lives of B, C, and R could be increased 337.4-, 430.4-, and 371.1-fold compared with bufadienolides solution (BU-S) at 48C [9]. Now the objectives of this study were to compare the in vitro metabolism and stability of B, C, and R loaded in BU-LM and BU-S, to investigate the pharmacokinetics of bufadienolides between BU-LM and BU-S after intravenous administration in rats and to determine the bioavailability of BU-LM following IP, ID, and IG administrations.…”

Fabrication of multicomponent amorphous bufadienolides nanosuspension with wet milling improves dissolution and stability

“…Improvement of the dissolution behaviour of poorly water-soluble drugs should enhance their oral bioavailability and therapeutic efficiency. A very small number of studies have been undertaken to improve the solubility of bufadienolides, including with liposomes, nanostructured lipid carriers, lipid microspheres, lyophilized nanoemulsions and submicroemulsions [14][15][16][17]. However, these formulations have been largely restricted by two factors.…”

Formulation and preparation of a stable intravenous disulfiram‐loaded lipid emulsion

“…The O/W type lipid emulsion (LE), as an intravenous delivery system, has various therapeutic applications including incorporating water‐insoluble lipophilic drugs, reducing irritation, and reducing the side effects of a variety of potent drugs . Also, it has been reported to improve the chemical stability of drugs . The O/W type LE also has many appealing properties such as good biocompatibility, biodegradability, and physical stability, and it is relatively easy to produce on a large scale.…”