Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-β-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy

Abstract

Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 μg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8–12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving ¹H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-β-cyclodextrin (G₂-β-CD-Frax). Notably, G₂-β-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G₂-β-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G₂-β-CD-Frax (5 mg/kg) efficiently inhibited CCl₄-induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.

Keywords:

• Fraxinellone
• cyclodextrin derivatives
• oral bioavailability
• solubility
• hepatic fibrosis

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This research was supported by the National Natural Science Foundation of China (81703433 and 81703422) as well as the China Postdoctoral Science Foundation (2017M622381). Additional funding was acquired from the Key Scientific and Technological Project of Henan Province (202102310160 and 212102310323) and the Project of the Basic Research Fund of the Henan Institute of Medical and Pharmacological Sciences (2021BP0202).