Clonidine complexation with hydroxypropyl-beta-cyclodextrin: From physico-chemical characterization to in vivo adjuvant effect in local anesthesia

M. PICKHOLZ; L. F. CABECA; E. DE PAULA; M.F. MARTINI; FRANCO M.K.D; LIMIA C.E.G; MA BRAGA; YOKAICHIYA F; SILVA C.M.G.

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2016 vol. 119 p. 27 - 36

0731-7085

Clonidine (CND), an alpha-2-adrenergic agonist, is used as an adjuvant with local anesthetics. In this work,we describe the preparation and characterization of an inclusion complex of clonidine in hydroxypropylbeta-cyclodextrin (HP--CD), as revealed by experimental (UV?vis absorption, SEM, X-ray diffraction,DOSY- and ROESY-NMR) and theoretical (molecular dynamics) approaches. CND was found to bindto HP--CD (Ka = 20 M−1) in 1:1 stoichiometry. X-ray diffractograms and SEM images provided evidenceof inclusion complex formation, which was associated with changes in the diffraction patternsof the pure compounds. NMR experiments revealed changes in the chemical shift of H3HP--CD hydrogens( = 0.026 ppm) that were compatible with the insertion of CND in the hydrophobic cavity ofthe cyclodextrin. Molecular dynamics simulation with the three CND species that exist at pH 7.4revealed the formation of intermolecular hydrogen bonds, especially for the neutral imino form ofCND, which favored its insertion in the HP--CD cavity. In vitro assays revealed that complexationretarded drug diffusion without changing the intrinsic toxicity of clonidine, while in vivo tests in ratsshowed enhanced sensory blockade after the administration of 0.15% CND, with the effect decreasingin the order: CND:HP--CD + bupivacaine > CND + bupivacaine > bupivacaine > CND:HP--CD > clonidine.The findings demonstrated the suitability of the complex for use as a drug delivery system for clinicaluse in antinociceptive procedures, in association with local anesthetics.