Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing.
It is well known that cyclodextrins can enhance the permeation of poorly soluble drugs through biological membranes. However, the permeability will decrease if cyclodextrin is added in excess of the concentration needed to solvate the drug. The mechanism of cyclodextrin effect on drug permeability has not been fully explained. The effect of cyclodextrins can not be explained as solely due to increased solubility of the drug in the aqueous donor phase nor can it be explained by assuming that cyclodextrins act as classical permeation enhancers, i.e. by decreasing the barrier function of the lipophilic membrane. In the present work we have modeled the effect of cyclodextrins in terms of mixed barrier consisting of both diffusion and membrane controlled diffusion, where the diffusion of the drug in the aqueous diffusion layer is significantly slower than in the bulk of the donor. This diffusion model is described by simple mathematical equation where the properties of the system are expressed in terms of two constants P(M)/Kd and M1/2. Data for the permeation of hydrocortisone through hairless mouse skin in the presence of various cyclodextrins, and cyclodextrin polymer mixtures, were fitted to obtain values for these two constants. The rise in flux with increased cyclodextrin complex concentration and fall with excess cyclodextrin was accurately predicted. Data for the permeation of drugs through semi-permeable cellophane membrane could also be fitted to the equation. It was concluded that cyclodextrins act as permeation enhancers carrying the drug through the aqueous barrier, from the bulk solution towards the lipophilic surface of biological membranes, where the drug molecules partition from the complex into the lipophilic membrane.
Másson
M
M
Department of Pharmacy, University of Iceland, Hofsvallagata 53, P.O Box 7210, IS-107 Reykjavik, Iceland.
Loftsson
T
T
Másson
G
G
Stefánsson
E
E
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics; D002463:Cell Membrane Permeability / Q000187:drug effects; D002476:Cellophane; D003505:Cyclodextrins / Q000494:pharmacology*; D003907:Dexamethasone / Q000493:pharmacokinetics; D004058:Diffusion; D015194:Diffusion Chambers, Culture; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008432:Mathematical Computing; D008567:Membranes, Artificial; D051379:Mice; D008812:Mice, Hairless; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D003505:Cyclodextrins; D008567:Membranes, Artificial; D003907:Dexamethasone; D002476:Cellophane; D006854:Hydrocortisone