title: Physico-chemical characterization of disoxaril-dimethyl-beta-cyclodextrin inclusion complex and in vitro permeation studies.
abstract: In this work we evaluated the ability of 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-Cyd) to include the anti-rhinovirus drug Disoxaril (WIN 51711), increasing its water solubility and stability. The complex, prepared by kneading method, was characterized in the solid state by differential scanning calorimetry and in aqueous solution using circular dichroism and NMR spectroscopy. The formation of 1:1 and 1:2 drug-Cyd complexes was hypothesized. Stability constants for both complexes were determined on the basis of an Ap-type phase solubility diagrams and evidenced a very high stability for the 1:1 complex. Thermodynamic parameters of the binding process showed the existence of classical hydrophobic interactions in the 1:1 complex with the formation of a less ordered system after complexation. An enthalpic contribution rather than an entropic one accompanied the association of the second Cyd molecule. DM-beta-Cyd was able to significantly increase water solubility of WIN 51711, from 0.000123 to 0.47142 mg/ml. Free drug shows a very low water stability, it is completely hydrolyzed after 36 h in PBS (pH 7.0), at 4 degrees C. In the presence of DM-beta-Cyd only a 10% of WIN 51711 was degraded, to the same conditions, after 12 days. DM-beta-Cyd increases the permeation of WIN 51711 across excised bovine nasal mucosa mounted on Franz cells, with respect to the free drug. Nevertheless, the permeation process had a lag time of 2 h so that the drug might assure its pharmacological activity on the outer surface of the mucosa. In vivo studies on rabbits evidenced that WIN 51711 is well tolerated, having no observable effect on the nasal mucosa following repeated administration.
authors.affiliation: Pharmaco-Chemical Department, Faculty of Pharmacy, University of Messina, Viale Annunziata I, 98168 Messina, Italy. cventura@pharma.unime.it
authors.forename: Cinzia Anna
authors.initials: CA
authors.lastname: Ventura
authors.forename: Ignazio
authors.initials: I
authors.lastname: Giannone
authors.forename: Teresa
authors.initials: T
authors.lastname: Musumeci
authors.forename: Rosario
authors.initials: R
authors.lastname: Pignatello
authors.forename: Lorella
authors.initials: L
authors.lastname: Ragni
authors.forename: Carla
authors.initials: C
authors.lastname: Landolfi
authors.forename: Claudio
authors.initials: C
authors.lastname: Milanese
authors.forename: Donatella
authors.initials: D
authors.lastname: Paolino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Puglisi
mesh_terms: D000818:Animals; D002417:Cattle; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D004355:Drug Stability; D057927:Hydrophobic and Hydrophilic Interactions; D007555:Isoxazoles / Q000008:administration & dosage* / Q000737:chemistry; D007700:Kinetics; D009297:Nasal Mucosa / Q000473:pathology; D011817:Rabbits; D012995:Solubility; D013057:Spectrum Analysis; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D007555:Isoxazoles; D047392:beta-Cyclodextrins; D014867:Water; C045978:disoxaril