Stable aqueous formulation of (E)-4-carboxystyryl-4-chlorobenzyl sulfone
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Publication Number
US-9060967-B2
Publication Date
2015-06-23
Expiration Date
Abstract
An aqueous pharmaceutical solution composition comprising between about 20 mg/ml to about 100 mg/ml of a radioprotective α,β-unsaturated aryl sulfone, a cosolvent comprising polyethylene glycol (PEG), polypropylene glycol, polyglycerol, DMA, propylene glycol, glycerol, ethanol, sorbitol, isopropyl alcohol, or a combination thereof in an amount between about 25% and about 90% w/v, and a water soluble Vitamin E derivative, wherein the composition has a pH within the range of about 7.0 to about 9.5.
Core Innovation
The invention provides an aqueous pharmaceutical solution composition for radioprotection that addresses pH-sensitive aqueous degradation of an α,β-unsaturated aryl sulfone radioprotective compound. The degradation is associated with nucleophilic Michael addition at the styryl sulfone double bond, and aqueous formulations are stabilized to maintain the radioprotective compound in a defined pH environment.
The composition centers on combining the radioprotective compound of formula (I) in an E steric configuration, or a salt thereof, with at least one cosolvent and a stabilizing agent that is Vitamin E TPGS. Water-soluble Vitamin E derivatives are used as stabilizing agents together with specified cosolvents, buffering agents, and a pH window within about 7.0 to about 9.5.
The disclosure further characterizes the radioprotective compound, including solubility, pKa, and stability trends, and discusses polyform and polymorphs. Comparative formulation data indicate improved stability when Vitamin E TPGS is included versus formulations without TPGS, and the document also provides mouse efficacy study context for radioprotection and radiomitigation using ON 01210.Na formulated as an aqueous pharmaceutical solution.
Claims Coverage
The independent claim coverage presents four core inventive features: a radioprotective compound of formula (I) or a salt in aqueous solution at a defined concentration range, specified cosolvents in a defined amount range, Vitamin E TPGS as the stabilizing agent, and a defined pH range of about 7.0 to about 9.5. Dependent claims further narrow the compound identity to specific salt forms and add narrower quantitative formulation ranges, buffer selection, and additional stability and delivery context constraints.
Aqueous radioprotective solution composition with E configured formula (I) compound or salt
An aqueous pharmaceutical solution composition comprising between about 20 mg/ml to about 100 mg/ml of a radioprotective compound having the formula (I), wherein R1 and R3 are hydrogen, R2 is halogen, R4 is carboxy, the steric configuration around the double bond is E, or a salt thereof.
Specified cosolvent system in high proportion
At least one cosolvent comprising polyethylene glycol (PEG), polypropylene glycol, polyglycerol, DMA, propylene glycol, glycerol, ethanol, sorbitol, isopropyl alcohol, or a combination thereof in an amount between about 25% and about 90% w/v.
Vitamin E TPGS as stabilizing agent
A stabilizing agent which is Vitamin E TPGS.
pH window for stabilization of the aqueous solution
The composition has a pH within the range of about 7.0 to about 9.5.
Across the claim coverage presented, the invention is defined by an aqueous pharmaceutical solution of an E-configured formula (I) radioprotective compound or salt with a specified high-percentage cosolvent system, Vitamin E TPGS as the stabilizing agent, and a controlled pH range about 7.0 to about 9.5. Dependent refinements include narrowing to ON 01210.Na and adding buffer selection and narrower quantitative stability-relevant ranges.
Stated Advantages
Improved stability when Vitamin E TPGS is included versus formulations without TPGS.
Documented Applications
Mouse efficacy study context for radioprotection and radiomitigation using ON 01210.Na formulation.
Subcutaneous and oral administration are referenced in the mouse efficacy study context.
Administration via an auto-injecting device is described as a narrower context in a dependent claim refinement.
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