title: Influence of cyclodextrins and chitosan, separately or in combination, on glyburide solubility and permeability.
abstract: The effect of chitosan and of different concentrations of beta- or hydroxypropyl-beta-cyclodextrins, separately or in various (w/w) combinations, on the dissolution characteristics of glyburide (an oral hypoglycemic agent subject to incomplete and variable bioavailability) and on its permeability through Caco-2 cells has been investigated. Cyclodextrins (and particularly the hydroxypropyl-derivative, in virtue of its higher water solubility) were clearly more effective than chitosan in enhancing the drug dissolution properties: the aqueous glyburide solubility was improved 40-fold in the presence of 25 mM hydroxypropyl-beta-cyclodextrin, 25-fold in the presence of 13 mM beta-cyclodextrin (saturation solubility) and only 3-fold in the presence of chitosan at its saturation concentration (0.5% w/v). When chitosan and cyclodextrin were simultaneously present, a strong reduction of the cyclodextrin solubilizing efficiency towards the drug was observed, and it was attributed to a possible competition effect of polymer and glyburide for the interaction with the macrocycle. By contrast, permeation studies revealed that chitosan was more powerful than cyclodextrins in enhancing the glyburide permeability through Caco-2 cells. This was probably in virtue of the polymer's favourable effect on the tight junctions opening, as demonstrated by the significant decrease in the transepithelial electrical resistance recorded in its presence. Moreover, interestingly, when using the carriers together, conversely from solubility studies, a significant (P < 0.05) synergistic effect in enhancing glyburide apparent permeability was revealed in permeation experiments.
authors.affiliation: Laboratoire de Pharmacotechnie et Biopharmacie, Faculté de Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris Cedex, France.
authors.forename: N
authors.initials: N
authors.lastname: Zerrouk
authors.forename: G
authors.initials: G
authors.lastname: Corti
authors.forename: S
authors.initials: S
authors.lastname: Ancillotti
authors.forename: F
authors.initials: F
authors.lastname: Maestrelli
authors.forename: M
authors.initials: M
authors.lastname: Cirri
authors.forename: P
authors.initials: P
authors.lastname: Mura
mesh_terms: D000465:Algorithms; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry*; D004553:Electric Conductivity; D005079:Excipients; D005905:Glyburide / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010539:Permeability; D012995:Solubility
chemical_list: D003505:Cyclodextrins; D005079:Excipients; D007004:Hypoglycemic Agents; D048271:Chitosan; D007770:L-Lactate Dehydrogenase; D005905:Glyburide