Formulation of (e)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone with enhanced stability and bioavailability
Inventors
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Publication Number
US-12156856-B2
Publication Date
2024-12-03
Expiration Date
Abstract
Pharmaceutical compositions of (E)-2,4,6-trimethoxy styryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof are described as well as methods of their use, and a dose regimen of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt to reduce the incidence of urothelial toxicity.
Core Innovation
The invention describes stable high-pH undiluted liquid formulations of rigosertib sodium (ON 01910.Na) with a basic pre-treated low molecular weight polyethylene glycol, aiming to improve storage stability and the impurity profile. The formulations are characterized as undiluted high pH (pH 11.0 to 14.0) and are substantially free of added buffer, using minimal water.
The described approach includes oral and parenteral pharmaceutical composition options for rigosertib sodium in liquid form, including liquid-filled hard/enteric capsules and softgels. The disclosure provides stability and total impurities comparisons between regular and high-pH formulations and includes dog pharmacokinetic information intended to support increased oral bioavailability.
The disclosure further describes oral fasting dosing regimens for treating cancer, including a first dose administered approximately 1 to 2 hours before breakfast and a second dose administered about 6 to about 8 hours after the first dose while the patient is fasting. It also outlines multi-week intermittent dosing and combination use with azacitidine starting on day 8.
Claims Coverage
The independent claims cover two inventive aspects: treating a solid tumor cancer with rigosertib sodium using an orally administered, fasting-state two-dose regimen with specific dose timing; and specifying non-small cell lung cancer as the solid tumor cancer being treated. Across the identified independent claims, five inventive features are directly supported.
Fasting-state oral first and second doses timed to breakfast
Orally administering a first dose approximately 1 to 2 hours before breakfast and a second dose about 6 to about 8 hours after the first dose in a fasting state.
840 mg first dose with 280 mg second dose
Administering an effective amount by orally giving a first dose of 840 mg approximately 1 to 2 hours before breakfast and a second dose of 280 mg about 6 to about 8 hours after the first dose in a fasting state.
560 mg first dose with 280 to 560 mg second dose
Administering an effective amount by orally giving a first dose of 560 mg approximately 1 to 2 hours before breakfast and a second dose of 280 to 560 mg about 6 to about 8 hours after the first dose in a fasting state.
Non-small cell lung cancer limitation
Limiting the method such that the solid tumor cancer is non-small cell lung cancer.
Azacitidine combination with multi-week on/off scheduling and day-based start
Further comprising administering azacitidine starting at day 8 in combination with a regimen in which the rigosertib sodium is administered for three weeks followed by one week off.
Overall, the claim coverage centers on administering rigosertib sodium to treat solid tumor cancer using orally dosed first and second administrations timed relative to breakfast while the patient is fasting. The coverage also includes explicit refinement to non-small cell lung cancer and an explicitly described azacitidine combination regimen with multi-week dosing and day-based initiation.
Stated Advantages
Improves storage stability and impurity profile through stable high-pH undiluted liquid formulations.
Increases oral bioavailability, supported by dog pharmacokinetic results.
Reduces urinary adverse events when using fasting oral dosing regimens and intermittent scheduling.
Documented Applications
Treating a solid tumor cancer by administering (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt using an orally timed, fasting-state dosing regimen.
Treating non-small cell lung cancer as a specific solid tumor cancer.
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