title: Synthesis and characterization of thiolated β-cyclodextrin as a novel mucoadhesive excipient for intra-oral drug delivery.
abstract: The objective of the present study was to synthesize and characterize cysteamine conjugated β-cyclodextrin (β-CD-Cys) as a novel mucoadhesive oligomeric excipient for intra-oral drug delivery. β-CD-Cys conjugates were obtained in a two-step synthetic pathway, whereby, vicinal diol groups of the oligomer were oxidized using increasing concentrations of sodium-per-iodate (NaIO4), prior to the covalent coupling of cysteamine via reductive amination. Quantification of immobilized thiol groups through Ellman's test revealed 561.56 ± 81 μmol/g, 1054.26 ± 131 μmol/g and 1783.92 ± 201 μmol/g of free thiol groups attached to the oligomer backbone depending on the extent of oxidation. β-CD-Cys conjugates at concentrations of 0.5% (m/v) showed no toxic effects on Caco-2 cells within 72 h. Furthermore, β-CD-Cys conjugates displayed a 4-fold improved water solubility compared to the parent oligomer. β-CD-Cys conjugates (β-CD-Cys561, β-CD-Cys1054 and β-CD-Cys1783) showed 2.86-, 15.09- and 49.08-fold improved retention time on porcine intestinal mucosa and 9.66-, 16.43- and 34.51-fold improved on the porcine buccal mucosa, respectively. Formation of inclusion complexes of miconazole nitrate and β-CD-Cys1054 resulted in 150-fold increased solubility of miconazole nitrate. According to these results, it seems that β-CD-Cys conjugates might provide a new promising tool for delivery of poorly water soluble therapeutic agents, such as miconazole nitrate for intra-oral delivery.
authors.affiliation: Center for Chemistry and Biomedicine, Center for Molecular Bioscience (CMBI), Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ijaz
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Matuszczak
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Pancasila University, Srengseng Sawah, Jagakarsa, 16240 Jakarta Selatan, Indonesia.
authors.forename: Deni
authors.initials: D
authors.lastname: Rahmat
authors.affiliation: Center for Chemistry and Biomedicine, Center for Molecular Bioscience (CMBI), Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Arshad
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Center for Chemistry and Biomedicine, Center for Molecular Bioscience (CMBI), Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Bonengel
authors.affiliation: Center for Chemistry and Biomedicine, Institute of Analytical Chemistry and Radiochemistry, Leopold-Franzens University, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Shah
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Center for Chemistry and Biomedicine, Institute of Analytical Chemistry and Radiochemistry, Leopold-Franzens University, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Huck
authors.affiliation: Center for Chemistry and Biomedicine, Center for Molecular Bioscience (CMBI), Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000269:Adhesives / Q000138:chemical synthesis / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D018938:Caco-2 Cells; D003543:Cysteamine / Q000138:chemical synthesis / Q000737:chemistry*; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008825:Miconazole / Q000008:administration & dosage*; D009061:Mouth Mucosa / Q000378:metabolism; D012995:Solubility; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013552:Swine; D047392:beta-Cyclodextrins / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000269:Adhesives; D000935:Antifungal Agents; D004337:Drug Carriers; D013438:Sulfhydryl Compounds; D047392:beta-Cyclodextrins; D003543:Cysteamine; D008825:Miconazole; C031215:betadex
keywords: Cyclomaltoheptaose (PubChem CID: 444041); Cysteamine (PubChem CID: 6058); Inclusion complex; Intra-oral drug delivery; Miconazole nitrate (PubChem CID: 68553); Mucoadhesion; Sodium cyanotrihydridoborate (PubChem CID: 20587905); Sodium metaperiodate (PubChem CID: 23667635); Thiolated oligomer; β-Cyclodextrin