In-vitro Evaluation of Biphenylyl Acetic Acid-β-Cyclodextrin Conjugates as Colon-targeting Prodrugs: Drug Release Behaviour in Rat Biological Media

Biphenylyl acetic acid was selectively conjugated to one of the primary hydroxyl groups of beta-cyclodextrin through an ester- or amide-linkage, and the physicochemical properties (aqueous solubility and hydrolysis) were investigated. Aqueous solubility of the conjugates was lower than those of either drug or parent beta-cyclodextrin. The amide conjugate was stable in aqueous solution and in rat biological fluids and gastrointestinal contents. The ester conjugate was hydrolysed to beta-cyclodextrin and biphenylyl acetic acid at moderate rates resulting in a V-shaped rate-pH profile in aqueous solution. The ester conjugate released the drug preferentially when incubated with the contents of caecum or colon, whereas no appreciable drug release was observed on incubation with contents of stomach or intestine, nor on incubation with intestinal or liver homogenates, nor on incubation with rat blood. The present results suggest that the ester-type drug conjugate of beta-cyclodextrin may serve as a colon-targeting prodrug.