Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex.
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-beta-cyclodextrin (HP-beta-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-beta-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 11.2mM for RVC and RVC HP-beta-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 RVC HP-beta-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 RVC HP-beta-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation.
Department of Biochemistry, Institute of Biology, State University of Campinas, Campinas, SP, Brazil.
Daniele R
DR
de Araujo
Simone S
SS
Tsuneda
Cíntia M S
CM
Cereda
Fernanda
F
Del G F Carvalho
Paulo S C
PS
Preté
Sergio A
SA
Fernandes
Fabiano
F
Yokaichiya
Margareth K K D
MK
Franco
Irineu
I
Mazzaro
Leonardo F
LF
Fraceto
Angélica
A
de F A Braga
Eneida
E
de Paula
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002152:Calorimetry, Differential Scanning / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding / Q000379:methods*; D006461:Hemolysis / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning / Q000379:methods; D015394:Molecular Structure; D009407:Nerve Block; D017288:Pain Threshold / Q000187:drug effects; D000077212:Ropivacaine; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology; D012995:Solubility; D013237:Stereoisomerism; D013997:Time Factors; D014961:X-Ray Diffraction / Q000379:methods; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000577:Amides; D000779:Anesthetics, Local; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077212:Ropivacaine