Cyclodextrins and chitosan derivatives in sublingual delivery of low solubility peptides: A study using cyclosporin A, α-cyclodextrin and quaternary chitosan N-betainate

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 19 mg/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. (C) 2009 Elsevier B.V. All rights reserved.