Two phase bioactive formulations of bis-quaternary pyridinium oxime sulfonate salts
Inventors
Dixon, Hong • McDonough, Joseph A • Cabell, Larry Allen • Underwood, Patricia
Assignees
Southwest Research Institute SwRI • United States Department of the Army
Publication Number
US-8722706-B2
Publication Date
2014-05-13
Expiration Date
2028-08-15
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Abstract
The present invention relates to two phase systems of a bioactive ingredient in particle form that has limited or no solubility in a liquid medium, which provides stability to the bioactive ingredient that is similar to the bioactive ingredient when in the solid state. The bioactive ingredient may be capable of therapeutically treating for the presence of a cholinesterase inhibitor. The bio active ingredient comprises 1,1′-methlyenebis[4-[(hydroxyimino)methyl]-pyridinium]dimethanesulfonate.
Core Innovation
The invention relates to two phase systems comprising a bioactive ingredient in particle form with limited or no solubility in a liquid medium, thereby providing stability to the bioactive ingredient similar to that of the solid state. The bioactive ingredient includes bis-quaternary pyridinium-aldoxime salts such as 1,1'-methylenebis[4-[(hydroxyimino)methyl]-pyridinium]dimethanesulfonate, which are useful for treating exposure to cholinesterase inhibitors.
The problem addressed is the instability and short shelf life of formulations of small bioactive molecules, which often require refrigeration and lose pharmaceutical effectiveness when dissolved. Current solutions like freeze-dried formulations, encapsulation, and suspensions have drawbacks such as interference with in vivo performance or lack of stability.
The invention provides compositions where bis-quaternary pyridinium-2-aldoxime salts are formed into particles of 1 nm to 100 microns diameter and combined with liquids in which the particles have solubility less than or equal to 10% by weight. These two-phase systems preserve bioactivity and stability akin to that of the solid state, allowing for improved therapeutic treatment of cholinesterase inhibitor intoxication.
Claims Coverage
The patent includes multiple claims with one independent claim defining the composition of a bis-quaternary pyridinium-2-aldoxime salt in a liquid, with additional dependent claims specifying solubility ranges and chemical group specifics.
Composition of bis-quaternary pyridinium-2-aldoxime salt in liquid medium
The composition comprises a bis-quaternary pyridinium-2-aldoxime salt combined in a liquid medium.
Controlled particle solubility
The salt particles have solubility in the liquid limited to a range between 0.00% to 10% by weight, including narrower specified ranges (0.01% to 1.00%, and 0.00% to 0.05%).
Particle concentration in the liquid
The salt is present in the liquid at concentrations from 0.01% to 80% by weight.
Substituent identity on pyridinium ring
The chemical substituent R1 on the pyridinium ring is specified as a methyl group, with reference to the chemical formula.
The claims cover compositions comprising bis-quaternary pyridinium-2-aldoxime salt particles with controlled solubility and concentration in a liquid medium, including specific chemical substituents to achieve stable, two-phase bioactive formulations.
Stated Advantages
The two-phase systems provide stability to the bioactive ingredient similar to the solid state, overcoming issues related to short shelf life and the need for refrigeration.
The formulation avoids loss of pharmaceutical effectiveness associated with fully dissolved solutions.
The bioactive particulate in limited solubility liquids can maintain injectability through fine needles and excellent stability at elevated temperatures.
Documented Applications
Therapeutic treatment of intoxication in humans or animals due to exposure to cholinesterase inhibitors, including phosphorous-containing cholinesterase inhibitors such as organophosphates and carbamates.
Use as antidotal or prophylactic agents administered parenterally or orally for treatment of cholinesterase inhibitor poisoning.
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