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Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-β-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy
- Source :
- Drug Delivery, article-version (VoR) Version of Record, Drug Delivery, Vol 28, Iss 1, Pp 1890-1902 (2021)
- Publication Year :
- 2021
-
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.
- Subjects :
- Liver Cirrhosis
Male
FRAX
Cell Survival
Chemistry, Pharmaceutical
Drug Compounding
Pharmaceutical Science
RM1-950
Pharmacology
Mice
Drug Stability
Oral administration
Fibrosis
Animals, Outbred Strains
Medicine
Animals
Humans
hepatic fibrosis
Dictamnus
Rats, Wistar
Maltose
Fraxinellone
Benzofurans
chemistry.chemical_classification
Cyclodextrins
Cyclodextrin
biology
Dose-Response Relationship, Drug
business.industry
cyclodextrin derivatives
solubility
General Medicine
biology.organism_classification
medicine.disease
Bioavailability
Rats
Disease Models, Animal
Drug Liberation
chemistry
oral bioavailability
Therapeutics. Pharmacology
Caco-2 Cells
business
Hepatic fibrosis
Research Article
Subjects
Details
- ISSN :
- 15210464
- Volume :
- 28
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Drug delivery
- Accession number :
- edsair.doi.dedup.....6c71a6bce922e63a3fc0250ab2a7809b