Drug permeation through biomembranes: cyclodextrins and the unstirred water layer

Abstract

Surface of the living epithelia is covered with mucus, a gel-like fluid containing mainly water (90-98%) and mucin (2-5%). This aqueous gel-like matrix forms an unstirred water layer (UWL) creating an aqueous diffusion barrier that hampers drug permeation through mucosal barriers. Frequently, the UWL is the main drug permeation barrier, especially in the case of small-molecular-weight lipophilic drugs. Under such conditions drug permeation can often be enhanced by forming water-soluble drug/cyclodextrin complexes. Cyclodextrins enhance drug delivery through biomembranes by increasing drug permeation through the UWL, that is, by increasing the availability of dissolved drug molecules juxtaposed to the membrane surface. Cyclodextrins only enhance drug permeation when the UWL contributes to the permeation barrier. Cyclodextrins do not enhance drug permeation when the permeation resistance of the UWL is much less than that of the membrane itself. The effect depends also on the physicochemical properties of the drug. As a rule the best results are obtained for lipophilic drugs that are poorly soluble in water, that form water-soluble complexes with cyclodextrins and that possess, as dissolved drug molecules, relatively high permeability through lipophilic biomembranes. It is extremely important to optimize drug vehicles with regard to the amount of cyclodextrin. Too much or too little cyclodextrin will lead to less than optimal drug availability. Good understanding of cyclodextrin complexation and how cyclodextrin affect drug permeation through biomembranes is essential for successful development of cyclodextrin-containing drug formulations.