Biguanide compositions and methods of treating metabolic disorders
Inventors
Baron, Alain D. • Fineman, Mark S. • Beeley, Nigel R. A.
Assignees
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Publication Number
US-11065215-B2
Publication Date
2021-07-20
Expiration Date
Abstract
Provided herein are methods for treating certain conditions, including diabetes, obesity, and other metabolic diseases, disorders or conditions by administrating a composition comprising a biguanide or related heterocyclic compound, e.g., metformin. Also provided herein are biguanide or related heterocyclic compound compositions, and methods for the preparation thereof for use in the methods of the present invention. Also provided herein are compositions comprising metformin and salts thereof and methods of use.
Core Innovation
The invention relates to treating a disorder of glucose metabolism in a patient by administering a pharmaceutical dosage form comprising metformin or a salt thereof. The dosage form is adapted to have an onset of release of metformin or a salt thereof distal of the duodenum, and the approach is designed to provide at least 20% less relative bioavailability of metformin as measured by plasma area under curve (AUC) compared to an immediate release composition having the same amount of metformin or a salt thereof.
The disclosed compositions and dosage forms are further characterized by targeted intestinal delivery to modulate enteroendocrine hormones. The pharmacological effect is associated with chemosensory receptor activation, including bitter receptor activation, and the document describes modulation of enteroendocrine hormones such as GLP-1, GLP-2, oxyintomodulin, PYY, and GIP, as well as other mediators including insulin, glucagon, CCK, ghrelin, amylin, and uroguanylin.
The disclosure also emphasizes structural and chemical embodiments of biguanide-related heterocyclic compounds, including metformin and salts of metformin, with extensive structural definitions using multiple generic formulas and variable substituents. Variants are described as cisoid conformation fixing or ring rigidifying variants, and the formulations include options for salt forms and dosage form design, with performance targets including reduced or minimized systemic bioavailability and delayed release onset by intestinal region, pH, or timed onset.
Claims Coverage
The document provides one independent claim. The independent claim covers a method for treating a disorder of glucose metabolism using metformin or a salt in a distal-of-duodenum release dosage form that yields a defined reduction in relative bioavailability based on plasma AUC, together with a daily dose range; dependent claims refine quantitative thresholds, plasma concentration targets, pH-dependent release onset ranges, and specific treated conditions and salt identities.
Distal-of-duodenum onset of release for metformin
A method administering to a patient a pharmaceutical dosage form comprising metformin or a salt thereof, wherein the dosage form is adapted to have an onset of release of the metformin or salt distal of the duodenum.
At least 20% less relative bioavailability by plasma AUC versus immediate release
The dosage form provides at least 20% less relative bioavailability of metformin as measured by plasma area under curve (AUC) resulting from administration of the dosage form, compared to an immediate release composition having the same amount of metformin or salt thereof.
Daily dose between about 1500 mg and about 2000 mg
The method specifies that the daily dose of metformin or the salt thereof is between about 1500 mg and about 2000 mg.
At least 50% less relative bioavailability versus immediate release
Dependent refinement providing at least 50% less relative bioavailability of metformin versus an immediate release composition containing the same amount of metformin or its salt.
Plasma concentration threshold below about 1.0 μg/mL
Dependent refinement lowering a patient’s circulating plasma concentration of metformin to below about 1.0 μg/mL.
pH-defined onset of release beginning about pH 6.0 to about pH 7.0
Dependent refinement in which the onset of release of metformin or a salt thereof begins at an onset of release within about pH 6.0 to about pH 7.0.
Treating gestational diabetes as the glucose metabolism disorder
Dependent refinement treating gestational diabetes as the disorder of glucose metabolism.
Metformin hydrochloride as the metformin salt
Dependent refinement using metformin or a salt thereof in the form of metformin hydrochloride.
Overall, the claim coverage centers on distal-of-duodenum release of metformin or a salt, achieving at least 20% less relative bioavailability measured by plasma AUC relative to an immediate release composition, and using a daily dose between about 1500 mg and about 2000 mg. Dependent claims further narrow the bioavailability reduction magnitude, impose plasma concentration thresholds, refine release onset characteristics including pH ranges, and specify gestational diabetes and metformin hydrochloride.
Stated Advantages
Provides at least 20% less relative bioavailability of metformin as measured by plasma area under curve (AUC) compared to an immediate release composition with the same amount of metformin or a salt.
Delivers metformin with an onset of release distal of the duodenum.
Provides at least 50% less relative bioavailability versus an immediate release composition.
Lowers circulating plasma concentration of metformin to below about 1.0 μg/mL.
Reduced metformin systemic exposure as indicated by at least 20% less relative bioavailability measured by plasma AUC compared to an immediate release composition.
Preservation of meal-enhanced gut hormone responses (PYY/GLP-1) alongside reduced metformin systemic exposure, as described in the documented clinical study.
Lowered metformin systemic exposure (AUC/Cmax) while effects on glucose/insulin are described in the documented evaluation.
Documented Applications
Treating a disorder of glucose metabolism in a patient in need thereof, including diabetes and gestational diabetes.
Clinical evaluation comparing EFB0026 and EFB0027, described as showing reduced metformin systemic exposure (AUC/Cmax) while preserving meal-enhanced gut hormone responses (PYY/GLP-1) and described effects on glucose/insulin.
A separate 12-week randomized double-blind placebo-controlled multicenter trial design for EFB0027 in type 2 diabetes mellitus with endpoints including HbA1c and PK/PD biomarkers.
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