Macrocycles as drug-enhancing excipients in pharmaceutical formulations

Abstract

The macrocycle families: cucurbit[n]urils, n-cyclodextrins, calix[n]arenes, and pillar[n]arenes (where n represents the number of subunits in each homologue) have shown considerable potential as drug-enhancing excipients for a range of pharmaceutical applications. Each macrocycle can form host–guest complexes with active pharmaceutical ingredients (API) where binding is stabilised by hydrophobic effects within each macrocycles’ cavity and through hydrogen bonds/ion–dipole bonds/electrostatic interactions at the macrocycles’ portals. Macrocycles have been shown to provide a range of benefits to API molecules, which include: increased drug solubility, taste masking, controlled and sustained drug release, improved chemical and physical drug stability, light activation of prodrugs, and shifts in drug functional group pKa values. The n-cyclodextrin family of macrocycles are already approved excipients for medicines, but for the other three macrocycle families, there are several gaps in knowledge that need to be addressed before they will be ready for first-in-human clinical trials. These include: comprehensive mapping of their interactions with other pharmaceutical excipients, their variable solubility, variability in their hydration levels in the solid state, short- and long-term safety, and the development of more pharmaceutical formulations.