Methods of treating heart failure with hibernating myocardium using modified forms of trimetazidine
Inventors
Patel, Jaikrishna • CHAMBERLIN, Paul
Assignees
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Publication Number
US-12076318-B2
Publication Date
2024-09-03
Expiration Date
Abstract
The invention provides methods of treatment of heart failure with hibernating myocardium using modified forms of trimetazidine, such as CV-8972 and CV-8814.
Core Innovation
The invention provides a method of reversing hibernating myocardium in a subject with heart failure by administering a compound represented by formula (X), or a pharmaceutically acceptable salt thereof. The treatment is directed to a subject having hibernating myocardium, with the goal of reversing that condition in the setting of heart failure.
A related embodiment provides the compound represented by formula (IX), or a pharmaceutically acceptable salt thereof, for reversing hibernating myocardium in a subject with heart failure. The described mechanism shifts myocardial metabolism from fatty-acid oxidation to glucose oxidation by inhibiting long-chain 3-ketoacyl-CoA thiolase, thereby supporting mitochondrial ATP production in low-oxygen or ischemic conditions.
The disclosed compounds include modified trimetazidine derivatives, including CV-8972 (formula X) and CV-8814 (formula IX), and are described as metabolized stepwise from CV-8972 to CV-8814 and then trimetazidine. This is described as yielding improved sustained levels and reduced side effects relative to unadulterated trimetazidine, and the document also defines pharmaceutically acceptable salts and provides pharmaceutical compositions for use, including oral dosage forms and formulations using hydroxypropyl methylcellulose (HPMC).
Claims Coverage
The patent includes two independent methods focused on reversing hibernating myocardium in a subject with heart failure by providing a specific modified trimetazidine derivative defined by formula (X) or formula (IX). The dependent claims add oral pharmaceutical compositions, dosage forms, erodible swelling polymer systems using HPMC, unit-dose constraints, and an ischemia association.
Reversing hibernating myocardium using formula (X) compound
Providing to a subject with hibernating myocardium a compound represented by formula (X) or a pharmaceutically acceptable salt thereof to reverse hibernating myocardium in a subject with heart failure.
Reversing hibernating myocardium using formula (IX) compound
Providing to a subject with hibernating myocardium a compound represented by formula (IX) or a pharmaceutically acceptable salt thereof to reverse hibernating myocardium in a subject with heart failure.
Oral administration of pharmaceutical composition
Administering the pharmaceutical composition orally as part of the method of reversing hibernating myocardium.
Dosage form selection for oral pharmaceutical composition
Using a pharmaceutical composition formulated in a dosage format selected from the group consisting of a tablet, troche, lozenge, aqueous suspension, oily suspension, emulsion, hard capsule, soft capsule, or syrup.
Erodible swelling polymer formulation in aqueous environment
Providing a pharmaceutical composition including a compound mixed with an erodible polymer that swells when the mixture is in an aqueous environment.
Hydroxypropyl methylcellulose as the erodible polymer
Using hydroxypropyl methylcellulose (HPMC) as the erodible polymer in the pharmaceutical composition that includes the compound mixture.
Unit dosage range for the compound amount
Providing a unit dosage containing about 10 mg to about 500 mg of the compound in the pharmaceutical composition.
Use for heart failure associated with ischemia
Reversing hibernating myocardium in a subject with heart failure when the method is associated with ischemia.
Defined compound-to-HPMC weight ratio
Providing a mixture containing the compound and HPMC at a specified weight ratio ranging from about 1:10 to about 10:1.
Overall, the claims cover two formula-defined embodiments for reversing hibernating myocardium in heart-failure subjects, with dependent coverage emphasizing oral pharmaceutical compositions, erodible swelling polymer systems including HPMC, and quantitative constraints such as unit-dose amounts and compound-to-HPMC weight ratios, including an ischemia association.
Stated Advantages
Improved sustained levels relative to unadulterated trimetazidine.
Reduced side effects relative to unadulterated trimetazidine.
Documented Applications
Treatment of heart failure associated with hibernating myocardium by reversing hibernating myocardium using modified trimetazidine derivatives (CV-8972 (formula X) and CV-8814 (formula IX)).
Treatment of heart failure associated with ischemia in the context of reversing hibernating myocardium.
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