The
purpose of the study was to develop a per-6-thiolated α-cyclodextrin
(α-CD) by substituting all primary hydroxyl groups of α-CD
with thiol groups and to assess its solubility-improving and permeation-enhancing
properties for a BCS Class IV drug in vitro as well as in vivo. The
primary hydroxyl groups of α-CD were replaced by iodine, followed
by substitution with −SH groups. The structure of per-6-thiolated
α-CD was approved by FT-IR and 1H NMR spectroscopy.
The per-6-thiolated was characterized for thiol content, −SH
stability, cytotoxicity, and solubility-improving properties by using
the model BCS Class IV drug furosemide (FUR). The mucoadhesive properties
of the thiolated oligomer were investigated via viscoelastic measurements
with porcine mucus, whereas permeation-enhancing features were evaluated
on the Caco-2 cell monolayer and rat gut mucosa. Furthermore, oral
bioavailability studies were performed in rats. The per-6-thiolated α-CD
oligomer displayed 4244 ± 402 μmol/g thiol groups. These
−SH groups were stable at pH ≤ 4, exhibiting a pK
a value of 8.1, but subject to oxidation at
higher pH. Per-6-thiolated α-CD was not cytotoxic to Caco-2
cells in 0.5% (m/v) concentration within 24 h. It improved the solubility
of FUR in the same manner as unmodified α-CD. The addition of
per-6-thiolated α-CD (0.5% m/v) increased the mucus viscosity
up to 5.8-fold at 37 °C within 4 h. Because of the incorporation
in per-6-thiolated α-CD, the apparent permeability coefficient
(P
app) of FUR was 6.87-fold improved on
the Caco-2 cell monolayer and 6.55-fold on the intestinal mucosa.
Moreover, in vivo studies showed a 4.9-fold improved oral bioavailability
of FUR due to the incorporation in per-6-thiolated α-CD. These
results indicate that per-6-thiolated α-CD would be a promising
auxiliary agent for the mucosal delivery of, in particular, BCS Class
IV drugs.
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