Cyclodextrins and Drug Membrane Permeation: Thermodynamic Considerations

Abstract

Cyclodextrins are hydrophilic oligosaccharides that can increase aqueous solubility of lipophilic drugs through formation of water-soluble drug/cyclodextrin complexes. Although the complexes are hydrophilic, and as such do not permeate biological membranes, the complexes are known to enhance drug permeation through lipophilic membranes and improve drug bioavailability after, for example, oral administration. However, it is not clear how cyclodextrins enhance the permeation. An artificial biomembrane (PermeaPad®) was used to study the effect of donor medium composition on drug permeation. It was observed that in aqueous solutions the hydrophilic cyclodextrins behave not like disperse systems but rather like organic cosolvents such as ethanol, increasing the solubility without having significant effect on the molecular mobility and ability of lipophilic drug molecules to partition into the lipophilic membrane. Also, that partition of dissolved drug molecules from the aqueous exterior into the membrane is at its maximum when their thermodynamic activity is at its maximum. In other words, that drug flux from aqueous cyclodextrin solutions through lipophilic membranes depends on both the concentration and the thermodynamic activity of dissolved drug. Maximum flux is obtained when both the drug concentration and thermodynamic activity of the dissolved drug molecules are at their maximum value.

Keywords: Complexation; Cyclodextrin(s); Formulation vehicle; Membrane transport; Partition coefficient(s); Permeability coefficient(s); Preformulation; Solubilization; Thermodynamics.