Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-β-cyclodextrin inclusion complex

Abstract

Ropivacaine (RVC) is an enantiomerically pure local anesthetic (LA) largely used in surgical procedures, which presents physico-chemical and therapeutic properties similar to those of bupivacaine (BPV), but associated to less systemic toxicity. This study focuses on the development and pharmacological evaluation of a RVC in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-β-CD (9.46 M−1) and showed an increase on RVC solubility upon complexation. Release kinetics revealed a decrease on RVC release rate and reduced hemolytic effects after complexation (onset at 3.7 mM and 11.2 mM for RVC and RVCHP-β-CD, respectively) were observed. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray analysis (X-ray) showed the formation and the morphology of the complex. Nuclear magnetic resonance (NMR) and job-plot experiments afforded data regarding inclusion complex stoichiometry (1:1) and topology. Sciatic nerve blockade studies showed that RVCHP-β-CD was able to reduce the latency without increasing the duration of motor blockade, but prolonging the duration and intensity of the sensory blockade (p < 0.001) induced by the LA in mice. These results identify the RVCHP-β-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation.