Formulation of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone with enhanced stability and bioavailability
Inventors
Assignees
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Publication Number
US-11382877-B2
Publication Date
2022-07-12
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, 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
A pharmaceutical composition is provided that includes (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof, together with basic pre-treated low molecular weight polyethylene glycol comprising one or more of PEG 200, PEG 300, PEG 400, PEG 600, and/or PEG 800. The composition further includes an undiluted pH of about 11.0 to about 14.0 and less than 5% water or aqueous solution.
A method is provided for treating conditions mediated by abnormal cell proliferation by administering an effective amount of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt to a patient in need thereof. The treatment is specifically directed to hematological cancer, and in further embodiments the hematological cancer is selected from AML and MDS.
An oral dosing regimen is provided with a first dose of 70-840 mg approximately 1-2 hours before breakfast and a second dose of 70-560 mg administered in the fasting state about 6 to about 8 hours after the first dose. Further embodiments include multi-week dosing and combination with azacitidine starting at day 8 for one week.
Claims Coverage
The independent claims cover two related inventive aspects: a specific pharmaceutical composition and an oral treatment method for abnormal cell proliferation. Across these independents, there are six main inventive features.
Basic pre-treated low molecular weight polyethylene glycol composition with active and salts
A pharmaceutical composition comprising (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof, and basic pre-treated low molecular weight polyethylene glycol comprising one or more of PEG 200, PEG 300, PEG 400, PEG 600, and/or PEG 800.
Undiluted basic pH about 11.0 to about 14.0
The pharmaceutical composition includes an undiluted pH of about 11.0 to about 14.0.
Less than 5% water or aqueous solution
The pharmaceutical composition includes less than 5% water or aqueous solution.
Oral two-dose regimen before breakfast and fasting state
A method of treating conditions mediated by abnormal cell proliferation comprising administering an effective amount of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt by orally administering a first dose of 70-840 mg approximately 1-2 hours before breakfast, and a second dose of 70-560 mg administered in the fasting state about 6 to about 8 hours after the first dose.
Treatment of abnormal cell proliferation
A method of treating conditions mediated by abnormal cell proliferation comprising administering an effective amount of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt to a patient in need thereof.
First and second dose magnitudes within the specified dose ranges
The regimen specifies first dose values within 70-840 mg and second dose values within 70-560 mg, aligned with the stated timing of approximately 1-2 hours before breakfast and about 6 to about 8 hours after the first dose in the fasting state.
Overall, claim coverage is anchored in the defined pharmaceutical composition and is extended to an oral treatment method for abnormal cell proliferation using a two-dose regimen with defined dose ranges and timing relative to breakfast and fasting.
Stated Advantages
Improves stability/impurity control.
Improves oral bioavailability compared with non–pH-adjusted or PEG/buffer formulations.
Reduces impurity levels over long-term storage.
Enhances oral exposure (e.g., increased dog oral absorption / exposure such as Cmax and AUC).
Improves pharmacokinetic/exposure performance in high-pH filled capsules versus non–pH-adjusted softgels.
Reduces urinary adverse events and urothelial toxicity incidence.
Documented Applications
Treatment of conditions mediated by abnormal cell proliferation, including hematological cancer selected from AML and MDS, using oral administration of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt.
Combination treatment with azacitidine starting at day 8 for one week, together with the specified dosing regimen.
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