Therapeutic formulations and methods
Inventors
Patterson, Steven Earl • Nagasawa, Herbert Tsukasa • Vince, Robert • Monteil, Alexandre
Assignees
National Institutes of Health NIH
Publication Number
US-9757354-B2
Publication Date
2017-09-12
Expiration Date
2036-06-08
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Abstract
The invention provides compositions and methods for treating cyanide poisoning.
Core Innovation
The invention provides compositions and methods for treating cyanide poisoning by improving the endogenous cyanide detoxification pathways through supplying a prodrug substrate and developing a formulation suitable for rapid intramuscular administration. Specifically, the invention identifies a sulfanegen formulation that is well tolerated, has acceptable thermal stability, and is effective in lethal models of cyanide toxicity. This formulation comprises sulfanegen lysine, lysine hydrochloride, and water.
The problem being solved is the limitation of existing cyanide antidotes such as hydroxocobalamin and the combination of sodium nitrite and sodium thiosulfate, which require intravenous administration over extended periods, making them unsuitable for mass casualty settings. Additionally, the endogenous substrate 3-mercaptopyruvate (3-MP) for the cyanide detoxifying enzyme 3-mercaptopyruvate sulfurtransferase has poor stability, limiting its therapeutic use. Prior formulations like sulfanegen sodium have insufficient aqueous solubility for intramuscular use and analogs like sulfanegen triethanolamine have poor thermal stability. Thus, there is a need for a sulfanegen formulation that achieves sufficient solubility, stability, and suitability for intramuscular administration.
Claims Coverage
The patent includes multiple independent claims covering pharmaceutical compositions and methods related to sulfanegen lysine formulations for cyanide poisoning treatment. The main inventive features are centered on composition, formulation method, administration, and kit preparations.
Pharmaceutical composition comprising sulfanegen lysine, lysine hydrochloride, and water
The invention provides a pharmaceutical composition comprising sulfanegen lysine, lysine hydrochloride, and water, wherein the molar ratio of sulfanegenic acid to lysine is about 1:2 and the molar ratio of sulfanegenic acid to lysine to lysine hydrochloride is about 1:2:0.4. The composition is formulated for intramuscular, intravenous, or intraosseous administration and maintains a pH between about 4 and 5.
Pharmaceutical composition prepared by combining sulfanegenic acid or sulfanegen lysine with lysine and lysine hydrochloride solutions or solids
The patent claims pharmaceutical compositions prepared by combining sulfanegenic acid or sulfanegen lysine with aqueous solutions containing lysine and lysine hydrochloride or by combining solid forms of sulfanegenic acid, lysine, and lysine hydrochloride with water to produce stable compositions suitable for treating cyanide poisoning.
Methods of preparing and administering sulfanegen lysine formulations
Methods include combining a solution prepared from water, lysine, and lysine hydrochloride with sulfanegenic acid solid to provide a resulting solution that can be administered to an animal, with administration occurring at times at least one hour or at least fifteen hours following combination. The invention also covers methods combining water with sulfanegenic acid solid, lysine solid, and lysine hydrochloride solid to provide a solution for administration.
Kits for treating cyanide poisoning
The invention includes kits comprising (a) a solution of water, lysine, and lysine hydrochloride; (b) sulfanegenic acid solid; and instructions for combining these to make a composition suitable for treating cyanide poisoning. Another kit comprises sulfanegenic acid solid, lysine solid, and lysine hydrochloride solid with instructions for combining them with water for the same purpose.
Nanoparticle formulations comprising sulfanegen lysine and lysine hydrochloride
The patent claims nanoparticles comprising sulfanegen lysine and lysine hydrochloride, including nanoparticle suspensions comprising multiple such nanoparticles and pharmaceutical compositions containing these nanoparticles with pharmaceutically acceptable carriers.
Overall, the claims cover novel sulfanegen lysine-based pharmaceutical compositions with defined molar ratios and pH ranges, methods for their preparation and administration, kits for onsite formulation, and nanoparticle formulations, all directed to effective and stable treatments for cyanide poisoning suitable for intramuscular and other routes.
Stated Advantages
The sulfanegen lysine salt has high aqueous solubility (approximately 1.05 M) suitable for intramuscular administration in small volumes.
The lysine salt formulation shows excellent thermal stability, remaining stable as a dry powder for at least one year.
The formulation is well tolerated in animal models with acceptable pH buffering using lysine hydrochloride, reducing injection site acidity and improving absorption.
The sulfanegen lysine formulation is effective in lethal murine and rabbit models of cyanide toxicity, demonstrated by high survival rates and rapid return of cyanide and lactate levels to baseline.
Documented Applications
Prophylactic or therapeutic treatment of cyanide poisoning in animals, including mammals such as humans.
Use in emergency or mass casualty settings requiring rapid antidote administration by intramuscular, intravenous, or intraosseous routes.
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