In vitro and in vivo evaluation of a posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex.

Abstract

Posaconazole (PCZ) is a triazole antifungal agent with an extended spectrum of antifungal activity. It is approved for the prophylaxis of invasive fungal infections in patients with neutropenia or in hematopoietic stem cell transplant recipients undergoing high-dose immunosuppressive therapy for graft-vs-host disease, and for the treatment of fungal infections. However, its pharmacological effects are severely limited owing to its poor solubility and low bioavailability. In order to solve these problems, a sulfobutyl ether-β-cyclodextrin compound was used to prepare an intramuscular injection to improve the bioavailability of posaconazole. The extracorporeal dissolution rate of posaconazole was markedly improved by this inclusion complex with >90% being released within 5 min, and the in vivo pharmacokinetics were studied using a HPLC/MS/MS method for quantifying posaconazole and the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex in rat blood. Posaconazole and an internal standard, itraconazole, were extracted by protein precipitation using acetonitrile. The concentration range of posaconazole was 0.05-4.0 μg/mL with good linearity (r = 0.9980), the peak concentrations of pure posaconazole and the inclusion complex were 0.565 ± 0.102 μg/mL and 1.12 ± 0.091 μg/mL, the values for AUC0-t were 12.2 ± 2.5 and 19.9 ± 2.5 μg h/mL, and the values for AUC0-∞ were 16.4 ± 3.2 and 25.0 ± 3.5 μg h/mL, respectively. The main pharmacokinetics parameters showed significant differences (P<0.01). Compared with pure posaconazole, the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex markedly improved the bioavailability of posaconazole.