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Preclinical Evaluation of Ropivacaine in 2 Liposomal Modified Systems

Rennó, Carolina C. MSc*; Papini, Juliana Z. B. PhD*; Cereda, Cintia Maria Saia PhD; Martinez, Elizabeth PhD; Montalli, Victor Angelo PhD; de Paula, Eneida PhD; Pedrazzoli Júnior, José PhD*; Calafatti, Silvana Aparecida PhD*; Tofoli, Giovana Radomille PhD

doi: 10.1213/ANE.0000000000003837
Preclinical Pharmacology: Original Laboratory Research Report

BACKGROUND: Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations.

METHODS: The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer.

RESULTS: Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system.

CONCLUSIONS: All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.

From the *São Francisco University, UNIFAG, Bragança Paulista, São Paulo, Brazil

Laboratory of Inflammation, São Leopoldo Mandic Institute and Research Center, Campinas, São Paulo, Brazil

Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, São Paulo, Brazil.

Published ahead of print 28 August 2018.

Accepted for publication August 28, 2018.

Funding: This work was supported by the Fundação de Amparo á Pesquisa do Estado de São Paulo (No. 2014/14457-5).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Giovana Radomille Tofoli, PhD, Institute and Research Center São Leopoldo Mandic, Rua José Rocha Junqueira 13, Campinas, São Paulo 13045-75, Brazil. Address e-mail to

Copyright © 2018 International Anesthesia Research Society
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