Solubility and Pharmacokinetic Profile Improvement of Griseofulvin through Supercritical Carbon Dioxide-Assisted Complexation with HP-<i>γ</i>-Cyclodextrin

Abstract

Since griseofulvin was marketed as a non-polyene antifungal antibiotic drug in 1958, its poor water solubility has been an issue for its wide applications, and over the last sixty years, many attempts have been made to increase its water solubility; however, a significant result has yet to be achieved. Through supercritical carbon dioxide-assisted cyclodextrin complexation with the addition of a trace amount of water-soluble polymer surfactant, the griseofulvin inclusion complex with HP-γ-cyclodextrin was prepared and confirmed. The 1:2 ratio of griseofulvin and HP-γ-cyclodextrin in the complex was determined based on its NMR study. After complexation with HP-γ-cyclodextrin, griseofulvin’s water solubility was increased 477 times compared with that of griseofulvin alone, which is the best result thus far. The complex showed 90% of griseofulvin release in vitro in 10 min, in an in vivo dog pharmacokinetic study; the Cmax was increased from 0.52 µg/mL to 0.72 µg/mL, AUC0–12 was increased from 1.55 μg·h/mL to 2.75 μg·h/mL, the clearance was changed from 51.78 L/kg/h to 24.16 L/kg/h, and the half-life time was changed from 0.81 h to 1.56 h, indicating the obtained griseofulvin complex can be a more effective drug than griseofulvin alone.

Keywords

• griseofulvin
• HP-<i>γ</i>-cyclodextrin
• inclusion complex
• preparation
• water solubility
• in vitro and in vivo PK study