Abstract
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 pKa 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 (Papp) 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.
Highlights
For drug delivery, oral drug administration is the most appropriate route with a high patient compliance
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
Thiolated CDs moved into the limelight of pharmaceutical research because of their mucoadhesive behavior by the formation of disulfide bonds with mucus glycoproteins.[7−10] thiolated oligo- and polymers in general are well-known for their permeationenhancing properties,[11] thiolated CDs have not been so far tested for these properties
Summary
Oral drug administration is the most appropriate route with a high patient compliance. Cannot be delivered orally because of poor solubility and low drug absorption in the intestine leading to an insufficient bioavailability.[1] more than 90% of drugs approved since 1995 show either poor solubility or poor permeability or both.[2] Strategies to address these formulation challenges include the co-administration of auxiliary agents, improving drug solubility, and enhancing membrane permeability. Among those auxiliary agents that exhibit solubilityimproving properties are cyclodextrins (CDs) being in focus of research for many decades. Thiolated CDs moved into the limelight of pharmaceutical research because of their mucoadhesive behavior by the formation of disulfide bonds with mucus glycoproteins.[7−10] thiolated oligo- and polymers in general are well-known for their permeationenhancing properties,[11] thiolated CDs have not been so far tested for these properties
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