Title:A Lipid Base Formulation for Intramuscular Administration of a Novel Sulfur Donor for Cyanide Antagonism
Volume: 13
Issue: 8
Author(s): Kristof Kovacs, Prashanth K. Jayanna, Anna Duke, Brittany Winner, Melaeni Negrito, Siva Angalakurthi, Jorn C.C. Yu, Petra Füredi, Krisztina Ludányi, Peter Sipos, Gary A. Rockwood and Ilona Petrikovics
Affiliation:
Keywords:
Cyanide antagonism, in vitro/in vivo efficacy, parenteral, PEG-PE micelles, solubility enhancement, sulfur donor.
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.
