Pillar[n]arenes versus cyclodextrins as supramolecular carriers for improved bioavailability: Idebenone as a model drug

• Pillararenes may improve drug bioavailability of poorly soluble drugs. • Pillararenes may have advantages over cyclodextrins for delivery of certain drugs. • For different applications, the same drug may benefit from a different macrocycle. • Pillararenes strongly complex Idebenone. The present study describes the ability of different water soluble pillararenes (PAs) to complex and solubilize Idebenone (IDE), as a model drug, and the results are compared to previously reported complexes of IDE with cyclodextrins (CDs). We show that P[5]As strongly bind IDE, with the CDs showing lower binding and P[6]As exhibiting the weakest binding. The differences between the weak and strong complexes reached above two orders of magnitude in the binding constants. The solubility-permeability interplay was then investigated to determine the best structures for potential improvement of bioavailability under different circumstances. For unsaturated solutions, using an in-vitro BBB permeability model, the highest permeability was obtained with the weakest complexes, demonstrating the solubility-permeability interplay whereby higher binding leads to lower permeability. However, when saturated solutions/suspensions were used, with the oral in-vitro permeapad® permeability model, stronger complexes led to higher permeation and drug flux. By comparing to cyclodextrins we show that PAs may be a significant addition to the CDs family, commonly used for bioavailability improvement in pharmaceutical applications.