Formulations with enhanced stability and bioavailability for administration of (E)-2,6-dialkoxystyryl 4-substituted benzylsulfones
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Publication Number
US-10098862-B1
Publication Date
2018-10-16
Expiration Date
Abstract
Pharmaceutical compositions of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof are described as well as methods of their use.
Core Innovation
The invention relates to a pharmaceutical composition comprising (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof, formulated with basic pre-treated low molecular weight polyethylene glycol. The composition is characterized by an undiluted pH of about 11.0 to about 14.0 and a water or aqueous solution content of less than 5%.
The pharmaceutical compositions are positioned to improve stability and impurity profiles compared to non-pH-adjusted or buffered PEG formulations, while also aiming to enhance oral bioavailability. The compositions use basic pretreated PEG with low water content and substantially no added buffer, and include embodiments for oral and parenteral administration.
The document describes therapeutic context for treating cancer or proliferative disorders, including hematological cancers and solid tumors. It further discusses oral bifurcated dosing regimens timed relative to meals to reduce urothelial toxicity.
Claims Coverage
The document provides two independent claims. Across the independent claims, the inventive features focus on the composition’s drug identity plus basic pre-treated low molecular weight PEG at a defined undiluted pH with very low water content, and on a two-dose oral regimen timed relative to breakfast and lunch.
Basic pre-treated low molecular weight PEG at undiluted pH and low water
The pharmaceutical composition comprises (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof, basic pre-treated low molecular weight polyethylene glycol, undiluted pH of about 11.0 to about 14.0, and less than 5% water or aqueous solution.
Meal-timed oral two-dose regimen for abnormal cell proliferation
Orally administering (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt to a patient in need thereof, comprising orally administering a first dose of 840 mg approximately 1-2 hours before breakfast and a second dose of 280 mg about 2 hours after lunch, or administering a first dose of 560 mg approximately 1-2 hours before breakfast and a second dose of 280-560 mg about 2 hours after lunch.
Overall, claim coverage centers on formulating rigosertib sodium salt with basic pre-treated low molecular weight PEG at an undiluted pH of about 11.0 to about 14.0 with less than 5% water or aqueous solution, and on treating abnormal cell proliferation via a timed oral regimen with specified mg amounts relative to breakfast and lunch.
Stated Advantages
Improves stability and impurity profiles versus non-pH-adjusted or buffered PEG formulations.
Enhances oral bioavailability or oral exposure.
Reduces urothelial toxicity using a timed, bifurcated oral dosing regimen.
Documented Applications
Treating conditions mediated by abnormal cell proliferation by administering an oral regimen of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt.
Treating cancer or proliferative disorders, including hematological cancers (MDS, AML) and solid tumors, with described oral and parenteral dosage-form embodiments.
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