Cyclodextrins as multifunctional supramolecular carriers in ocular drug delivery

Topical and non-invasive ocular drug delivery remains challenged by the rapid precorneal clearance, ocular epithelial and blood-retinal barriers, and poor aqueous solubility resulting in less than 5% bioavailability. Often, there is requirement for irritant cosolvents or invasive intravitreal routes of administration. Cyclodextrins (CDs) have been known to improve solubility, but the supramolecular aspects of CDs have not been fully incorporated into the treatment of various diseases. In this review, the supramolecular aspects of CDs as drug delivery systems are discussed, with the emphasis being the relationship between the structure and host-guest thermodynamics and the efficacy, safety, and translational potential of CDs in the treatment of various ocular diseases. Recent developments in native and modified CDs, most specifically hydroxypropyl-β-CD (HPβCD), sulfobutyl ether-β-CD (SBEβCD), and γ-CD, are reviewed in the context of inclusion complexes, nanoaggregates, nanosponges, pseudopolyrotaxane hydrogels, nanofibers, and in situ gelling systems. The mechanistic influences on solubility, stability, corneal and scleral permeability, residence time, and controlled release are correlated with therapeutic outcomes in dry eye disease, uveitis, ocular infections, glaucoma, and non-invasive posterior segment delivery. In contrast to previous reviews that focused on CDs as solubilizers, this review highlights CDs as multifunctional supramolecular carriers that modulate solubility, permeability, and release kinetics while improving ocular tolerability. The review provides a disease-driven, mechanism-based framework for CD selection and integrates computational and regulatory perspectives to facilitate rational and clinical-ready design.