Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
Inventors
Baron, Alain D. • Fineman, Mark S. • Beeley, Nigel R. A.
Assignees
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Publication Number
US-10159658-B2
Publication Date
2018-12-25
Expiration Date
Abstract
Compositions and methods comprising at least one biguanide compound and at least one statin combined with at least one additional active agent in fixed dose combinations are provided for reducing cardiometabolic risk, and for the treatment of cardiovascular disease, wherein the biguanide compound is formulated for delayed release.
Core Innovation
The invention relates to reducing cardiometabolic risk by administering a combination dosage form that includes at least one biguanide compound, at least one statin, and at least one additional active agent. The biguanide compound is formulated for delayed release, and the delayed-release biguanide has reduced average systemic bioavailability as compared to an immediate-release formulation having an equivalent amount of the biguanide compound.
The disclosed combinations are fixed-dose combination therapies for treating or preventing cardiovascular disease and for reducing cardiometabolic risk. The additional active agents can include antihypertensives, anti-platelet agents, diuretics, bile acid sequestrants, oral anti-diabetics, incretin modulators, anti-obesity agents, and anti-atherosclerotics.
The delayed-release concept includes targeting release to parts of the gastrointestinal tract, including small intestine and distal small intestine, using enteric/pH-targeting and delayed-release systems. The disclosure includes enteric coatings and pH-dependent release in a pH range that supports release beyond the stomach and proximal small intestine.
Claims Coverage
The document includes one independent claim that covers a method of reducing cardiometabolic risk using a fixed combination dosage form with a delayed-release biguanide having reduced average systemic bioavailability relative to an immediate-release formulation, in combination with a statin and at least one additional active agent.
Reducing cardiometabolic risk with delayed-release biguanide reduced bioavailability in a fixed combination
A method of reducing cardiometabolic risk by administering a combination dosage form comprising at least one biguanide compound, at least one statin, and at least one additional active agent, wherein the biguanide compound is formulated for delayed release and has reduced average systemic bioavailability as compared to an immediate-release formulation having an equivalent amount of the biguanide compound.
Claim coverage centers on a delayed-release biguanide with reduced average systemic bioavailability in a fixed-dose combination that also includes a statin and at least one additional active agent to reduce cardiometabolic risk.
Stated Advantages
Reduced metformin plasma exposure, including reductions in AUC and Cmax, compared with immediate-release.
Preservation of gut hormone responses including PYY and GLP-1.
Similar glucose-lowering efficacy despite lower systemic metformin exposure.
Improved gastrointestinal tolerability in delayed-release groups based on reported adverse events.
Improved GI tolerability via reduced systemic exposure (lower mean plasma AUC and Cmax).
Broadens use in patients with contraindications to systemic biguanide exposure.
Documented Applications
Reducing cardiometabolic risk in a patient in need thereof by administering a delayed-release biguanide combination dosage form including at least one statin and at least one additional active agent.
Clinical evaluation of delayed-release metformin versus immediate-release and extended-release metformin formulations in randomized crossover studies and a phase 2 trial design, reporting effects on plasma exposure, gut hormone responses (PYY, GLP-1), glucose-lowering efficacy, and gastrointestinal tolerability.
Treating or preventing cardiovascular disease using fixed-dose combination therapies that reduce cardiometabolic risk.
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