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

ABSTRACT: The purpose of the study was to develop a per-6-thiolated ?-cyclodextrin (?-CD) by substituting all primary hydroxyl groups of ?-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 ?-CD were replaced by iodine, followed by substitution with -SH groups. The structure of per-6-thiolated ?-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 ?-CD oligomer displayed 4244 ± 402 ?mol/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 ?-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 ?-CD. The addition of per-6-thiolated ?-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 ?-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 ?-CD. These results indicate that per-6-thiolated ?-CD would be a promising auxiliary agent for the mucosal delivery of, in particular, BCS Class IV drugs.

SUBMITTER: Asim MH

PROVIDER: S-EPMC7205388 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Asim Mulazim Hussain MH Nazir Imran I Jalil Aamir A Laffleur Flavia F Matuszczak Barbara B Bernkop-Schnürch Andreas A

ACS applied materials & interfaces 20200206 7

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 <sup>1</sup>H NMR spectroscopy. The per-6-thiolated was ...[more]

PMID: 31985207

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Project description:Cyclodextrins are a family of cyclic oligosaccharides with widespread usage in medicine, industry and basic sciences owing to their ability to solubilize and stabilize guest compounds. In medicine, cyclodextrins primarily act as a complexing vehicle and consequently serve as powerful drug delivery agents. Recently, uncomplexed cyclodextrins have emerged as potent therapeutic compounds in their own right, based on their ability to sequester and mobilize cellular lipids. In particular, 2-hydroxypropyl-?-cyclodextrin (HP?CD) has garnered attention because of its cholesterol chelating properties, which appear to treat a rare neurodegenerative disorder and to promote atherosclerosis regression related to stroke and heart disease. Despite the potential health benefits, use of HP?CD has been linked to significant hearing loss in several species, including humans. Evidence in mice supports a rapid onset of hearing loss that is dose-dependent. Ototoxicity can occur following central or peripheral drug delivery, with either route resulting in the preferential loss of cochlear outer hair cells (OHCs) within hours of dosing. Inner hair cells and spiral ganglion cells are spared at doses that cause ~85% OHC loss; additionally, no other major organ systems appear adversely affected. Evidence from a first-to-human phase 1 clinical trial mirrors animal studies to a large extent, indicating rapid onset and involvement of OHCs. All patients in the trial experienced some permanent hearing loss, although a temporary loss of function can be observed acutely following drug delivery. The long-term impact of HP?CD use as a maintenance drug, and the mechanism(s) of ototoxicity, are unknown. ?-cyclodextrins preferentially target membrane cholesterol, but other lipid species and proteins may be directly or indirectly involved. Moreover, as cholesterol is ubiquitous in cell membranes, it remains unclear why OHCs are preferentially susceptible to HP?CD. It is possible that HP?CD acts upon several targets-for example, ion channels, tight junctions (TJ), membrane integrity, and bioenergetics-that collectively increase the sensitivity of OHCs over other cell types.

Dataset Information

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

Publications

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

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