Pharmaceutical Research

, 35:229 | Cite as

Sustained Release from Ionic-Gradient Liposomes Significantly Decreases ETIDOCAINE Cytotoxicity

  • Juliana Damasceno Oliveira
  • Lígia Nunes de Morais Ribeiro
  • Gustavo Henrique Rodrigues da Silva
  • Bruna Renata Casadei
  • Verônica Muniz Couto
  • Elizabeth Ferreira Martinez
  • Eneida de PaulaEmail author
Research Paper



Etidocaine (EDC) is a long lasting local anesthetic, which alleged toxicity has restricted its clinical use. Liposomes can prolong the analgesia time and reduce the toxicity of local anesthetics. Ionic gradient liposomes (IGL) have been proposed to increase the upload and prolong the drug release, from liposomes.


First, a HPLC method for EDC quantification was validated. Then, large unilamellar vesicles composed of hydrogenated soy phosphatidylcholine:cholesterol with 250 mM (NH4)2SO4 - inside gradient - were prepared for the encapsulation of 0.5% EDC. Dynamic light scattering, nanotracking analysis, transmission electron microscopy and electron paramagnetic resonance were used to characterize: nanoparticles size, polydispersity, zeta potential, concentration, morphology and membrane fluidity. Release kinetics and in vitro cytotoxicity tests were also performed.


IGLEDC showed average diameters of 172.3 ± 2.6 nm, low PDI (0.12 ± 0.01), mean particle concentration of 6.3 ± 0.5 × 1012/mL and negative zeta values (−10.2 ± 0.4 mV); parameters that remain stable during storage at 4°C. The formulation, with 40% encapsulation efficiency, induced the sustained release of EDC (ca. 24 h), while reducing its toxicity to human fibroblasts.


A novel formulation is proposed for etidocaine that promotes sustained release and reduces its cytotoxicity. IGLEDC can come to be a tool to reintroduce etidocaine in clinical use.


drug-delivery etidocaine ionic gradient liposomes local anesthesia 





Drug delivery system


Dynamic light scattering




Electron paramagnetic resonance


Hydrogenated soy phosphatidylcholine


Half maximal inhibitory concentration of cell viability


Ionic gradient liposomes


Etidocaine-containing sulphate gradient liposomes


Local anesthetic


Large unilamellar vesicle


3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Nanotracking analysis


Transmission electron microscopy


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Juliana Damasceno Oliveira
    • 1
  • Lígia Nunes de Morais Ribeiro
    • 1
  • Gustavo Henrique Rodrigues da Silva
    • 1
  • Bruna Renata Casadei
    • 2
  • Verônica Muniz Couto
    • 1
  • Elizabeth Ferreira Martinez
    • 3
  • Eneida de Paula
    • 1
    Email author
  1. 1.Department of Biochemistry and Tissue Biology, Institute of BiologyUniversity of Campinas – UnicampCampinasBrazil
  2. 2.Department of BiophysicsFederal University of São Paulo – UNIFESP, São PauloSão PauloBrazil
  3. 3.Department of Oral PathologySão Leopoldo Mandic Institute and Research CenterSão PauloBrazil

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