Formulations for parenteral administration of amino-substituted (E)-2, 6-dialkoxystyryl 4-substituted benzylsulfones
Inventors
Bell, Stanley C. • Maniar, Manoj
Assignees
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Publication Number
US-8476320-B2
Publication Date
2013-07-02
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 a compound of formula Ior 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 relates to aqueous parenteral compositions comprising an effective amount of the sodium salt of (E)-2,4,6-trimethoxystyryl-3-carboxymethylamino-4-methoxybenzylsulfone (ON 01910.Na) with a polyethylene glycol and a phosphate buffer. The compositions are characterized by a pH range of about 8 to about 14 and an aqueous osmolarity of 300 mOsm/kg, and the PEG component comprises PEG 300, PEG 400, PEG 600, or PEG 800 at 25% to 47.5% by weight.
The patent places emphasis on PEG-based parenteral vehicles for ON 01910.Na and states that stabilization occurs through reduced dielectric constant associated with these formulation conditions. A preferred higher pH of about 10 to about 13 is also described, together with a target osmolarity of about 300 mOsm/kg.
The document also describes illustrated (E)-2,4,6-trimethoxystyryl-3-benzylsulfone derivatives that vary the amide or functional group on the side chain while maintaining the (E)-styryl benzylsulfone framework. The claims focus on pharmaceutical aqueous compositions built around ON 01910.Na for parenteral administration and for prevention or treatment of a pathophysiological condition in a mammal.
Claims Coverage
The provided claims include two independent claims. Across them, the inventive coverage is centered on aqueous compositions containing ON 01910.Na, 25% to 47.5% by weight of PEG 300, PEG 400, PEG 600, or PEG 800, a phosphate buffer, a pH of about 8 to about 14, and an aqueous osmolarity of 300 mOsm/kg, with one claim directed to parenteral administration and the other to prevention or treatment of a pathophysiological condition in a mammal.
Aqueous parenteral ON 01910.Na with high-PEG phosphate buffer at 300 mOsm/kg
An aqueous composition for parenteral administration comprising an effective amount of a sodium salt of (E)-2,4,6-trimethoxystyryl-3-carboxymethylamino-4-methoxybenzylsulfone (ON 01910.Na) and 25% to 47.5% by weight of a polyethylene glycol comprising PEG 300, PEG 400, PEG 600, or PEG 800, and a phosphate buffer, wherein the composition is in a pH range of about 8 to about 14, and osmolarity of the aqueous composition is 300 mOsm/kg.
Mammal prevention or treatment composition with essentially ON 01910.Na, PEG, and phosphate buffer
A composition for prevention or treatment of a pathophysiological condition in a mammal consisting essentially of about 4% to about 10% by weight of sodium salt of (E)-2,4,6-trimethoxystyryl-3-carboxymethylamino-4-methoxybenzylsulfone (ON 01910.Na) and 25% to 47.5% by weight of a polyethylene glycol comprising PEG 300, PEG 400, PEG 600, or PEG 800, and a phosphate buffer, wherein the composition is in a pH range of about 8 to about 14, and osmolarity of the aqueous composition is 300 mOsm/kg.
The independent claims are directed to aqueous compositions containing ON 01910.Na with PEG 300, PEG 400, PEG 600, or PEG 800 and a phosphate buffer, constrained by pH about 8 to about 14 and aqueous osmolarity of 300 mOsm/kg. One claim covers parenteral administration, and the other covers prevention or treatment of a pathophysiological condition in a mammal with an essentially limited ON 01910.Na content.
Stated Advantages
Improving formulation stability and enabling parenteral delivery for conditions mediated by abnormal cell proliferation.
Stated formulation stabilization via reduced dielectric constant.
Documented Applications
Prevention or treatment of a pathophysiological condition in a mammal.
Parenteral administration using an aqueous composition comprising an effective amount of ON 01910.Na, a polyethylene glycol (PEG 300/400/600/800), and a phosphate buffer at about pH 8 to about 14 with osmolarity of 300 mOsm/kg.
ON 01910.Na IV infusion and associated clinical Phase I study in advanced solid tumors [procedural detail omitted for safety].
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