title: Cyclodextrins and chitosan derivatives in sublingual delivery of low solubility peptides: A study using cyclosporin A, alpha-cyclodextrin and quaternary chitosan N-betainate.
abstract: Systemic drug delivery through intraoral membranes may offer a promising administration route for lipophilic peptide drugs. The aim of the present study was to investigate the effect of alpha-cyclodextrin (alpha-CD) and a novel chitosan derivative, chitosan N-betainate (CH), on sublingual absorption of a hydrophobic model peptide cyclosporin A (CsA), and the effect of temperature on the complexation of CsA with alpha-CD. Complexation of CsA with alpha-CD was studied using the phase-solubility method. Sublingual absorption of CsA was studied by administration of solid CsA/alpha-CD complex (with and without CH solution), solid CsA/alpha-CD/CH formulation and solid plain CsA to rabbits. The solubility of CsA in aqueous alpha-CD solution (14%) increased with decreasing temperature; the solubility of CsA at room temperature, +5 and +1 degrees C was 1.2, 12 and 19mg/ml, respectively. The bioavailability of CsA after administration of plain CsA, solid CsA/alpha-CD and solid CsA/alpha-CD/CH (0.6+/-0.5, 1.4+/-0.7 and 1.7+/-0.8%, respectively; mean+/-S.D.) was further increased when solid CsA/alpha-CD was administered together with CH solution (3.2+/-2.2%). The present study shows that decreased temperature can be effectively utilized to produce CsA/alpha-CD complexes. It was also shown that alpha-CD and CH may be advantageous in sublingual delivery of lipophilic peptides, although the absolute bioavailability remains low.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, Finland. janne.mannila@pharm.monash.edu.au
authors.forename: Janne
authors.initials: J
authors.lastname: Mannila
authors.forename: Kristiina
authors.initials: K
authors.lastname: Järvinen
authors.forename: Jukka
authors.initials: J
authors.lastname: Holappa
authors.forename: Laura
authors.initials: L
authors.lastname: Matilainen
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.forename: Pekka
authors.initials: P
authors.lastname: Jarho
mesh_terms: D000286:Administration, Sublingual; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001622:Betaine / Q000031:analogs & derivatives / Q000737:chemistry; D001682:Biological Availability; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003080:Cold Temperature; D003505:Cyclodextrins / Q000737:chemistry*; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D006207:Half-Life; D008297:Male; D010455:Peptides / Q000493:pharmacokinetics*; D011817:Rabbits; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D047391:alpha-Cyclodextrins / Q000737:chemistry
chemical_list: D003505:Cyclodextrins; D010455:Peptides; D047391:alpha-Cyclodextrins; C546228:chitosan N-betainate; D001622:Betaine; D016572:Cyclosporine; D048271:Chitosan