A lipid base formulation for intramuscular administration of a novel sulfur donor for cyanide antagonism

Kristof Kovacs, Prashanth K. Jayanna, Anna Duke, Brittany Winner, Melaeni Negrito, Siva Angalakurthi, Jorn C C Yu, Petra Füredi, K. Ludányi, Peter Sipos, Gary A. Rockwood, Ilona Petrikovics

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

This study represents a new formulation of the novel Cyanide (CN) antidote, Dimethyl trisulfide (DMTS), for intramuscular administration. This is a naturally occurring organosulfur molecule with the capability of reacting with CN more efficiently than the present sulfur donor type CN therapy of Thiosulfate (TS). Two types of micelles (PEG2000-DSPE and PEG2000-DSPE/TPGS) were prepared and tested for their ability to encapsulate the liquid, highly lipophilic and volatile drug, DMTS. The micellar encapsulation for DMTS does not only eliminate the possible muscle necrosis at the injection sites, but the rate of evaporation within the micelles is suppressed, that can provide a level of stability for the formulation. The method of micelle preparation was optimized and it was demonstrated that the PEG2000-DSPE preparation can dissolve up to 2.0 mg/ml of the antidote candidate. Keeping the injection volume minimized this could provide a maximum DMTS dose of 12.5 mg/kg. However, even this low dose of DMTS showed a remarkable in vivo therapeutic efficacy (2 X LD50 protection) in a mice model when injected intramuscularly. These in vitro and in vivo findings proved the efficacy of DMTS in combating CN intoxication, and the presented work gives valuable insight to micelle preparation and sets the bases for a more advanced future formulation of DMTS.

Original languageEnglish
Pages (from-to)1351-1357
Number of pages7
JournalCurrent Drug Delivery
Volume13
Issue number8
DOIs
Publication statusPublished - Dec 1 2016

Keywords

  • Cyanide antagonism
  • In vitro/in vivo efficacy
  • Parenteral
  • PEG-PE micelles
  • Solubility enhancement
  • Sulfur donor

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmaceutical Science

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    Kovacs, K., Jayanna, P. K., Duke, A., Winner, B., Negrito, M., Angalakurthi, S., Yu, J. C. C., Füredi, P., Ludányi, K., Sipos, P., Rockwood, G. A., & Petrikovics, I. (2016). A lipid base formulation for intramuscular administration of a novel sulfur donor for cyanide antagonism. Current Drug Delivery, 13(8), 1351-1357. https://doi.org/10.2174/1567201813666160321115851