Cyclodextrin-based in situ gel systems: Their benefits and limitations for drug delivery

The inherent limitations of conventional dosage forms, particularly for ocular and nasal administration, necessitate advanced drug delivery systems. In situ gelling systems and cyclodextrins (CDs) individually offer significant advantages, while their combination provides a synergistic platform. CD-based in situ gels combine the inclusion complexation ability of CDs with the sol-gel transition properties of stimuli-responsive polymers, enhancing the solubility, stability, and residence time of poorly soluble drugs across various mucosal routes. CDs improve drug availability and protect labile molecules, whereas in situ gels prolong retention and enable sustained release at the application site. Current formulation strategies include the integration of free CDs, drug/CD inclusion complexes, and CD-conjugated polymer networks, each exerting distinct effects on gelation behavior, drug loading, release, and permeation. However, system complexity introduces challenges in formulation optimization, drug-release control, and safety assessment. This review highlights the formulation strategies and pharmaceutical applications of CD-based in situ gels, with particular emphasis on the interplay among CD incorporation, polymer design, gelation mechanisms, drug-release behavior, therapeutic benefits, and inherent limitations across different delivery routes. Finally, the key challenges and future perspectives for translating these systems into clinically applicable formulations are discussed.