Formulations for parenteral administration of (e)-2, 6-dialkoxystyryl 4-substituted benzylsulfones
Inventors
Bell, Stanley C. • Wong, Albert • Maniar, Manoj
Assignees
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Publication Number
US-8063109-B2
Publication Date
2011-11-22
Expiration Date
Abstract
Formulations are provided for parenteral administration of (amino substituted (e)-2,6-dialkoxystyryl 4-substituted benzylsulfones and the sodium and potassium salts thereof for the prevention and/or treatment of conditions mediated by abnormal cell proliferation. Composition for parenteral administration are provided which comprise an effective amount of compound of formula I or a compound of formula IIa and at least about 50% by weight of at least one water soluble polymer selected from the group consisting essentially of polyethylene glycol (PEG), poly-oxyethylene, poly-oxyethylene-poly-oxypropylene copolymers, polyglycerol, polyvinylalcohol, polyvinylpyrrolidone (PVP), polyvinylpyridine N-oxide, copolymer of vinylpyridine N-oxide and vinylpyridine.
Core Innovation
The invention is directed to styryl-benzylsulfone compounds represented by formulas VI-XXI and their salts, including (E)-2,4,6-trimethoxystyryl-3-carboxymethylamino-4-methoxybenzylsulfone, identified as ON 01910 and ON 01910.Na. The patent content also centers on aqueous pharmaceutical compositions for parenteral administration and for prevention or treatment of a pathophysiological condition, using an aqueous composition comprising an effective amount of ON 01910.Na and a polyethylene glycol system selected from PEG 300, PEG 400, PEG 600, or PEG 800, together with a buffer adjusted to a pH in the range of about 7.1 to about 10.
The disclosed formulations define pharmaceutical compositions that include ON 01910.Na in specified weight percentages or dosage amounts, combined with polyethylene glycol and buffer conditions. In one embodiment, the composition consists essentially of about 4% to about 10% by weight of ON 01910.Na and at least about 50% by weight of polyethylene glycol selected from PEG 300, PEG 400, PEG 600 or PEG 800, with a buffer in a pH range of about 7.1 to about 10.
In another embodiment, the invention provides a composition comprising about 25 mg to about 125 mg of ON 01910.Na per ml in 100% PEG-400. The document includes specific formulation embodiments using ON 01910.Na with PEG, including PEG 400, and reports Phase I clinical relevance and safety observations in intravenous infusion dosing.
Claims Coverage
The claim set provided contains three independent claims, anchored to ON 01910.Na and formulated with polyethylene glycol and a buffer at pH about 7.1 to about 10. Across the independent claims, the main inventive features focus on aqueous parenteral composition with high PEG mass fraction, a prevention or treatment composition for a mammal with a "consisting essentially of" limitation and defined wt% ranges, and a specific 100% PEG-400 formulation with a dosage-concentration range per ml.
Aqueous parenteral composition with ON 01910.Na, PEG and buffered pH
An aqueous composition for parenteral administration comprising an effective amount of ON 01910.Na and at least 50% by weight of polyethylene glycol comprising PEG 300, PEG 400, PEG 600 or PEG 800 and a buffer in a pH range of about 7.1 to about 10.
Prevention or treatment composition for mammal consisting essentially of ON 01910.Na, PEG and buffered pH
A composition for prevention or treatment of a pathophysiological condition in a mammal consisting essentially of about 4% to about 10% by weight of ON 01910.Na and at least about 50% by weight of polyethylene glycol comprising PEG 300, PEG 400, PEG 600 or PEG 800 and a buffer in a pH range of about 7.1 to about 10.
100% PEG-400 composition with ON 01910.Na dosage concentration range
A composition which comprises about 25 mg to about 125 mg of ON 01910.Na per ml in 100% PEG-400.
Overall, the independent claims collectively cover ON 01910.Na as the active sodium salt incorporated into aqueous, polyethylene-glycol-based buffered compositions for parenteral administration and for prevention or treatment of a pathophysiological condition, with key differentiators being the quantitative PEG mass fraction, buffer pH range, "consisting essentially of" component limitation for the mammal indication, and a specific 100% PEG-400 formulation with a defined ON 01910.Na mg/ml range.
Stated Advantages
Improved solubility and stability of ON 01910.Na in PEG-based aqueous/parenteral vehicle systems.
Unexpected stabilization associated with reduced formulation dielectric constant.
Formulation performance enabling parenteral administration, including intravenous infusion safety observations in a Phase I study.
Documented Applications
Parenteral administration of an aqueous composition comprising ON 01910.Na with polyethylene glycol and buffer (pH about 7.1 to about 10).
Prevention or treatment of a pathophysiological condition in a mammal, including cancer-related indications discussed in the document.
Parenteral administration via intravenous infusion in the context of a Phase I clinical study.
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