Effect of hydrotropic substances on the complexation of sparingly soluble drugs with cyclodextrin derivatives and the influence of cyclodextrin complexation on the pharmacokinetics of the drugs.

The influence of hydrotropic compounds on complex formation by 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) was investigated with methyltestosterone (MeT). Various representatives of the lyotropic series were used for this purpose. Additive hydrotropic effects were observed for nicotinamide and urea, which disrupt the water structure, while structure formers such as sorbitol exerted negative effects. The effects of hydrotropic substances on the phase solubility relationship of MeT showed that inclusion complex formation with 2-HP-beta-CD depends on the degree of ordering of the solvent and is apparently subject to entropy effects. Combined systems comprising 2-HP-beta-CD and auxiliary substances with various underlying solubilizing principles were also investigated. Combination of 2-HP-beta-CD with conventional solubilizers, such as 1,2-propylene glycol or sodium deoxycholate, reduced the solubilization capacity of 2-HP-beta-CD. Competitive displacement of the inclusion molecule from its 2-HP-beta-CD complex by sodium deoxycholate suggested that cholesterol participates in the release mechanism of the inclusion molecule under in vivo conditions. The spontaneous release of complexed drug molecules could indirectly be shown on the basis of the spontaneous action of a complexed dihydropyridine derivative after iv administration in rats. The bioavailability of an investigational drug in cynomolgus monkeys could be enhanced sevenfold by inclusion complexation with 2-HP-beta-CD.