Physico-chemical characterization of benzocaine-β-cyclodextrin inclusion complexes

Local anesthetics are able to induce pain relief by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nervous impulse. Benzocaine (BZC) is a local anesthetic whose low water-solubility limits its application to topical formulations. The present work focuses on the characterization of inclusion complexes of BZC in P-cyclodextrin (P-CD). Differential scanning calorimetry and electron microscopy gave evidences of the formation and the morphology of the complex. Fluorescence spectroscopy showed a BZC/beta-CD 1:1 stoichiometry. Phase-solubility diagrams allowed the determination of the association constants between BZC and P-CD (549 M-1) and revealed that a three-fold increase in BZC solubility can be reached upon complexation with P-CD. The details of BZC/beta-CD molecular interaction were analyzed by H-1 2D NMR allowing the proposition of an inclusion model for BZC into P-CD where the aromatic ring of the anesthetic is located near the head of the P-CD cavity. Moreover, in preliminary toxicity studies, the complex seems to be less toxic than BZC alone, since it induced a decrease in the in vitro oxidation of human hemoglobin. These results suggest that the BZC/beta-CD complex represents an effective novel formulation to enhance BZC solubility in water, turning it promising for use outside its traditional application, i.e., in infiltrative anesthesia. (c) 2005 Elsevier B.V. All rights reserved.