Parenteral dosage form development and testing of dimethyl trisulfide, as an antidote candidate to combat cyanide intoxication

Abstract

This study focused on the solubility enhancement and the in vivo antidotal efficacy testing of a new potential cyanide (CN) countermeasure, dimethyl trisulfide (DMTS). Various FDA approved cyclodextrins (HPβCD, RMβCD, HPγCD), cosolvents (ethanol, polyethylene glycols, propylene glycol), surfactants (cremophor EL, cremophor RH 40, sodium cholate, sodium deoxycholate, polysorbate 80) and their combinations were applied. Based on the solubility enhancing potential of the tested systems, polysorbate 80 was chosen for further in vivo efficacy studies. A composition comprising 15% polysorbate 80 and 50 mg/ml DMTS with the applied DMTS dose of 100 mg/kg provided a therapeutic antidotal protection of 3.4 × LD₅₀. For comparison, the present therapy of sodium thiosulfate (TS) with the dose of 100 mg/kg provided only 1.1 × LD₅₀ protection, and at the dose of 200 mg/kg, the LD₅₀ was enhanced by 1.3 times. No difference in the therapeutic protection by DMTS was detected when the concentration of polysorbate 80 was increased to 20% (3.2 × LD₅₀ protection). These data demonstrate the potential importance of DMTS as a CN countermeasure, and the formulation comprising polysorbate 80 provides the base of an injectable intramuscular dosage form that can later serve as a CN antidotal kit suitable for mass scenario.

Keywords:

• Cyanide antagonism
• solubility enhancement
• sulfur donor

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This research was supported by the CounterACT Program, National Institutes of Health Office of the Director, and the National Institute of Allergy and Infectious Diseases, Inter Agency Agreement Number Y1-OD-1561–01/A120-B.P2011–01, and the USAMRICD under the auspices of the US Army Research Office of Scientific Services Program Contract No. W911NF-11-D-0001 and the Robert A. Welch Foundation (x-001) at Sam Houston State University, Huntsville, TX.

Relating to DMTS, the following two patents have been submitted: ILONA PETRIKOVICS (SHSU), KRISTOF KOVACS (SHSU), FORMULATIONS OF DIMETHYLTRISULFIDE FOR USE AS A CYANIDE ANTIDOTE (2014, March), Provisional Patent#: 14/685,014 pending; ILONA PETRIKOVICS (SHSU), GARY ROCKWOOD (ICD) and STEVEN BASKIN (ICD). DIMETHYL TRISULFIDE AS A POTENTIAL CYANIDE ANTIDOTE. PENDING US PATENT APPLICATION, 14/685,008."