Methotrexate-Cyclodextrin Systems: Molecular Recognition, Formulation Design, and Translational Perspectives
Abstract
Methotrexate (MTX) remains central to the treatment of rheumatoid arthritis and several malignancies, yet its use is complicated by dose-dependent toxicity, variable oral exposure, photolability, and pH-dependent solubility. Cyclodextrins (CDs) can alter the molecular environment of MTX, but the literature often conflates true inclusion complexes with formulations in which CD merely forms part of a larger carrier. This review critically distinguishes direct MTX-CD complexes, dosage forms built from a preformed complex, CD-containing carriers without direct evidence of cavity occupancy, and covalent MTX-CD conjugates. Particular attention is given to binding stoichiometry, apparent association constants, guest orientation, preparation methods, and the evidence needed to establish inclusion. Both solution-state host-guest association and isolated solid products are considered; however, solid-state changes are treated as supportive evidence rather than as stand-alone proof of cyclodextrin cavity occupancy. Among the limited head-to-head comparisons of native cyclodextrins, β-CD generally showed more favorable MTX recognition than α- or γ-CD, although the magnitude of this difference is method- and condition-dependent. Complexation can improve dissolution, photostability, and oral or local delivery; however, greater solubilization does not necessarily enhance membrane transport. In carrageenan hydrogels, β-CD increased MTX loading and release while reducing membrane permeation,…
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