Per-6-Thiolated Cyclodextrins: A Novel Type of Permeation Enhancing Excipients for BCS Class IV Drugs

• Published in: ACS applied materials & interfaces Vol. 12; no. 7; pp. 7942 - 7950
• Main Authors: Asim, Mulazim Hussain, Nazir, Imran, Jalil, Aamir, Laffleur, Flavia, Matuszczak, Barbara, Bernkop-Schnürch, Andreas
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 19.02.2020
• Subjects: alpha-cyclodextrin; Animals; bioadhesives; bioavailability; Biological Availability; Caco-2 Cells; Chromatography, High Pressure Liquid; Cyclodextrins - chemistry; cytotoxicity; Excipients - chemistry; Fourier transform infrared spectroscopy; furosemide; Furosemide - analogs & derivatives; Furosemide - chemistry; Furosemide - pharmacology; human cell lines; Humans; in vivo studies; intestinal mucosa; Intestinal Mucosa - drug effects; iodine; Magnetic Resonance Spectroscopy; moieties; mucus; Mucus - drug effects; nuclear magnetic resonance spectroscopy; oxidation; permeability; Pharmaceutical Preparations - metabolism; Rats; Rats, Sprague-Dawley; Rheology; Solubility; Spectroscopy, Fourier Transform Infrared; Sulfhydryl Compounds - chemistry; Swine; thiols; viscoelasticity; Viscosity; thiolated; solubility improvement; permeation enhancement; mucoadhesion; BCS Class IV drugs; thiolated cyclodextrin; per-6-thiolated cyclodextrin; thiomers
• ISSN: 1944-8244; 1944-8252; 1944-8252
• DOI: 10.1021/acsami.9b21335

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.