Compositions of dimethyl trisulfide (DMTS) as a cyanide antidote
Inventors
Dixon, Hong • McDonough, Joseph A.
Assignees
Southwest Research Institute SwRI
Publication Number
US-12036187-B2
Publication Date
2024-07-16
Expiration Date
2040-03-10
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Abstract
The present disclosure is directed at compositions of dimethyl trisulfide (DMTS) suitable for use for treatment of cyanide intoxication. The compositions show particularly useful stability such that the DMTS remains stable for therapeutic use at the identified time periods. The compositions are therefore particularly suitable for use in autoinjectors.
Core Innovation
The invention provides stable pharmaceutical compositions of dimethyl trisulfide (DMTS) suitable for the treatment of cyanide intoxication. The compositions consist of DMTS in defined proportions with surfactants, optional sodium chloride, water, and optionally a water miscible organic solvent at low levels, forming microemulsions with DMTS droplet sizes between 1 nm and 100 nm. These compositions maintain high DMTS availability after prolonged storage, making them suitable for use in autoinjectors.
Cyanide intoxication presents a significant medical challenge due to its mechanism of inducing cellular hypoxia through inhibition of cytochrome c oxidase, hindering tissue oxygenation. Existing DMTS formulations have demonstrated efficacy but are plagued by stability issues, including decreased DMTS concentration over time due to factors such as precipitation and evaporation, limiting their shelf life and practical therapeutic use, especially in compact, ready-to-use devices like autoinjectors.
The disclosed compositions address these stability and solubility challenges by defining precise ranges for DMTS, surfactant, sodium chloride, water, and optional organic solvent, ensuring at least 90% or more of the DMTS remains available for therapeutic use when stored for up to 26 months at room temperature. This improvement renders DMTS-based antidotes more practical for field and emergency settings, particularly via administration in small-volume autoinjectors for rapid response to cyanide exposure.
Claims Coverage
There are three independent claims covering the composition, method of treating cyanide intoxication, and an autoinjector containing the composition.
Stable DMTS microemulsion composition
A composition comprising: - Dimethyl trisulfide present at 11 wt. % to 20 wt. %. - Sodium chloride from 1.0 wt. % to 10 wt. %. - One or more non-ionic surfactants at 22 wt. % to 45 wt. %. - The balance is water, and a water miscible organic solvent at up to and including 5000 ppm. The composition is a microemulsion with DMTS droplets sized from 1 nm to 100 nm, in a volume of 0.15 ml to 5.0 ml, and retains at least 90% of DMTS after storage at 20° C. to 25° C. in a sealed ampoule for up to 26 months.
Method for treating cyanide intoxication using solvent-free DMTS composition
A method of treating cyanide intoxication by administering to a subject a composition that is organic-solvent free (includes water miscible organic solvent up to 5000 ppm), which consists of: - Dimethyl trisulfide at 11 wt. % to 20 wt. %. - Sodium chloride at 1.0 wt. % to 10 wt. %. - One or more non-ionic surfactants at 22 wt. % to 45 wt. %. - The balance is water. The composition is a microemulsion (DMTS droplets 1 nm to 100 nm, 0.15 ml to 5.0 ml volume), and at least 90% or more of DMTS remains available after 26 months storage at 20° C. to 25° C.
Autoinjector containing stable DMTS composition
An autoinjector comprising an injection volume of 0.15 ml to 5.00 ml, configured to deliver a dose of a composition comprising: - Dimethyl trisulfide at 11 wt. % to 20 wt. %. - Sodium chloride at 1.0 wt. % to 10 wt. %. - One or more non-ionic surfactants at 22 wt. % to 45 wt. %. - The balance is water, optionally including a water miscible organic solvent at up to 5000 ppm. The composition is a microemulsion, with DMTS droplets 1 nm to 100 nm, and at least 90% of DMTS remains available after storage at 20° C. to 25° C. for up to 26 months in the sealed ampoule/autoinjector.
The inventive features cover a stable DMTS microemulsion composition, its solvent-free use for treating cyanide intoxication, and incorporation into an autoinjector, all ensuring extended DMTS stability and readiness for use.
Stated Advantages
The compositions provide enhanced stability, maintaining at least 90% or more of DMTS available for therapeutic use after storage at 20° C. to 25° C. for up to 26 months.
The formulations allow for higher DMTS concentrations in small volumes, suitable for use in compact autoinjectors and enabling effective treatment in emergency settings.
Compositions remain clear, do not precipitate, offer freeze-thaw stability, and can be sterilized by filtration, making them practical for clinical and field applications.
Documented Applications
Treatment of cyanide intoxication in subjects using DMTS compositions.
Formulation and use of stable DMTS compositions in autoinjectors for rapid administration.
Administration of the DMTS compositions by intramuscular, intravenous, intraosseous, subcutaneous injection, or through the nasal passage.
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