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Sustained Release from Ionic-Gradient Liposomes Significantly Decreases ETIDOCAINE Cytotoxicity

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Abbreviations

Cho:

Cholesterol

DDS:

Drug delivery system

DLS:

Dynamic light scattering

EDC:

Etidocaine

EPR:

Electron paramagnetic resonance

HSPC:

Hydrogenated soy phosphatidylcholine

IC50 :

Half maximal inhibitory concentration of cell viability

IGL:

Ionic gradient liposomes

IGLEDC :

Etidocaine-containing sulphate gradient liposomes

LA:

Local anesthetic

LUV:

Large unilamellar vesicle

MTT:

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

NTA:

Nanotracking analysis

TEM:

Transmission electron microscopy

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Author information

Authors and Affiliations

  1. Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas – Unicamp, P.O. Box – 6109, CEP, Campinas, SP, 13083-862, Brazil

    Juliana Damasceno Oliveira, Lígia Nunes de Morais Ribeiro, Gustavo Henrique Rodrigues da Silva, Verônica Muniz Couto & Eneida de Paula

  2. Department of Biophysics, Federal University of São Paulo – UNIFESP, São Paulo, São Paulo, Brazil

    Bruna Renata Casadei

  3. Department of Oral Pathology, São Leopoldo Mandic Institute and Research Center, Campinas, São Paulo, Brazil

    Elizabeth Ferreira Martinez

Authors
  1. Juliana Damasceno Oliveira
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  2. Lígia Nunes de Morais Ribeiro
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  3. Gustavo Henrique Rodrigues da Silva
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  4. Bruna Renata Casadei
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  5. Verônica Muniz Couto
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  6. Elizabeth Ferreira Martinez
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  7. Eneida de Paula
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Correspondence to Eneida de Paula.

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Oliveira, J.D., Ribeiro, L.N.d., Rodrigues da Silva, G.H. et al. Sustained Release from Ionic-Gradient Liposomes Significantly Decreases ETIDOCAINE Cytotoxicity. Pharm Res 35, 229 (2018). https://doi.org/10.1007/s11095-018-2512-4

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  • DOI: https://doi.org/10.1007/s11095-018-2512-4

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