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-11759441-B2
Publication Date
2023-09-19
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 concerns a method for treating diabetes in a patient in need thereof by administering a pharmaceutical dosage form comprising metformin or a salt thereof. The pharmaceutical dosage form is adapted to have an onset of release downstream of the duodenum and 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 disclosure also describes pharmaceutical dosage forms configured for downstream intestinal release using onset of release that can be associated with pH-triggered conditions and with release onset timing as the dosage form transits through defined intestine regions. Release may be targeted to downstream of the duodenum and downstream of the ileum, and can include enteric release and modified, controlled, sustained, extended, or timed release systems.
The document also describes compositions and treatment approaches involving biguanide and related heterocyclic compounds, including metformin and metformin salts, together with structural Formula definitions for multiple biguanide or heterocycle families. The disclosure includes variants that rigidify or fix a cisoid conformation and discusses reduced systemic exposure and modulation of hormone profiles, including GLP-1, GLP-2, GIP, PYY, CCK, oxytonomodulin, insulin, C-peptide, ghrelin, glucagon, amylin, and uroguanylin.
Claims Coverage
The consolidated claim coverage includes 1 independent claim focused on a downstream-of-duodenum metformin dosage form that reduces relative bioavailability versus immediate release and specifies a daily dose range. Dependent claims further define metformin form, pH-based onset, stronger bioavailability reduction levels, plasma concentration thresholds, and downstream release locations such as the ileum.
Downstream duodenum onset with reduced relative bioavailability for metformin
A method for treating diabetes by administering a pharmaceutical dosage form comprising metformin or a salt thereof, adapted to have an onset of release downstream of the duodenum and to provide at least 20% less relative bioavailability of metformin as measured by plasma AUC compared to an immediate release composition having the same amount of metformin or a salt thereof, with a daily dose between 1500 mg and 2000 mg of metformin.
Metformin hydrochloride form
The metformin or a salt thereof is metformin hydrochloride.
pH-based release onset around pH 6.0
The pharmaceutical dosage form begins release of metformin or a salt thereof at about pH 6.0.
At least 30% less relative bioavailability versus immediate release
The pharmaceutical dosage form is configured to deliver at least 30% lower relative bioavailability of metformin than an immediate release composition containing the same amount of metformin or a salt thereof.
Plasma concentration below 1.0 μg/mL
Administration of the pharmaceutical dosage form results in a circulating plasma concentration of metformin below 1.0 μg/mL.
Release onset after passing the ileum
The pharmaceutical dosage form is configured to release metformin or a salt of metformin after passing the ileum, with the onset of release downstream of the ileum.
Overall, the claim set is directed to modified-release metformin treatment for diabetes using downstream-of-duodenum release and reduced relative bioavailability measured by plasma AUC, with dependent refinements including metformin hydrochloride, pH-based onset release conditions, stronger relative bioavailability reduction targets, plasma concentration thresholds, and release onset downstream of specific intestinal regions such as the ileum.
Stated Advantages
Reducing systemic metformin absorption by providing at least 20% less relative bioavailability of metformin as measured by plasma area under curve (AUC) compared to an immediate release composition.
Maintaining meal-induced enteroendocrine hormone responses, including GLP-1 and PYY, while reducing metformin plasma exposure.
Reported reduction of metformin plasma AUC/Cmax with preserved GLP-1/PYY responses compared to a standard composition.
At least 30% less relative bioavailability of metformin as measured by plasma area under curve (AUC) versus an immediate release composition having the same amount of metformin or a salt thereof.
Reduced relative bioavailability can be at least 30% (and further, per dependent claim sets).
Reduced systemic exposure of metformin, quantified as at least 20% less relative bioavailability based on plasma area under curve (AUC) versus immediate release.
Further reduction in systemic exposure as at least 30% less relative bioavailability versus immediate release (as recited in dependent claim language).
Documented Applications
Treating diabetes in a patient in need thereof using a downstream-release metformin or salt pharmaceutical dosage form with reduced metformin relative bioavailability versus immediate release.
Evaluating metformin formulations designed to reduce systemic metformin absorption while preserving meal-induced enteroendocrine hormone responses, including the Example 4 comparison and the proposed clinical trial framework in Example 5.
Treatment of diabetes in a patient in need thereof using metformin or a salt thereof administered as a downstream-release pharmaceutical dosage form.
Treating diabetes in a patient in need thereof using the described metformin-containing pharmaceutical dosage form with downstream-of-duodenum release onset and reduced relative bioavailability.
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