Biguanide compositions and methods of treating metabolic disorders
Inventors
Baron, Alain D. • Fineman, Mark S. • Beeley, Nigel R.
Assignees
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Publication Number
US-10668031-B2
Publication Date
2020-06-02
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 metformin-based pharmaceutical compositions for treating diabetes, including biguanide or related heterocyclic compositions, formulated as pharmaceutical dosage forms. A central theme is reducing systemic exposure by providing an enteric-coated dosage form whose metformin release is adapted to begin in the intestinal environment rather than immediately after administration.
The dosage form comprises metformin or a salt thereof and is adapted to have an onset of release at about pH 5.5 or above. The resulting pharmacokinetic outcome is expressed as 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 further describes release-location options, including upper versus lower intestine and specific intestinal regions, and chemical frameworks for biguanide or related heterocyclic compounds, including metformin series and rigidified or cisoid-fixing variants. Optional inclusion of additional agents to modulate enteroendocrine hormones is also described.
Claims Coverage
The independent claim content centers on treating diabetes with an enteric-coated metformin dosage form having release onset at about pH 5.5 or above and reduced relative bioavailability measured by plasma AUC versus an immediate release composition. Additional features include higher bioavailability reduction thresholds, a plasma concentration cutoff, metformin hydrochloride, and optional combination with lorcaserin.
Enteric-coated metformin dosage form with release onset at pH 5.5 or above
A method for treating diabetes by administering a pharmaceutical dosage form comprising metformin or a salt thereof, wherein the dosage form comprises an enteric coating and is adapted to have an onset of release of metformin or the salt thereof at about pH 5.5 or above.
Reduced relative bioavailability versus immediate release by plasma AUC
The enteric-coated dosage form provides 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.
Increased relative bioavailability reduction thresholds
The pharmaceutical dosage form provides at least 30% less relative bioavailability, and in further refinements at least 50% less relative bioavailability, compared to an immediate release composition having the same amount of metformin or a metformin salt thereof.
Plasma concentration cutoff
The method provides a circulating plasma concentration of metformin resulting from administration of the pharmaceutical dosage form below about 0.5 μg/mL.
Metformin hydrochloride salt selection
The method uses metformin hydrochloride as the metformin or a salt thereof.
Combination with lorcaserin as an antiobesity agent
The method is carried out where the antiobesity agent is lorcaserin.
Overall, the claim coverage centers on enteric-coated metformin dosage forms whose release begins at about pH 5.5 or above and which achieve reduced systemic exposure quantified as decreased relative bioavailability by plasma AUC versus an immediate release composition. The independent and dependent features further include higher reduction thresholds, a plasma concentration cutoff, metformin hydrochloride, and lorcaserin.
Stated Advantages
Reduced systemic exposure measured by plasma area under curve (AUC).
At least 20% less relative bioavailability of metformin as measured by plasma AUC compared to an immediate release composition.
At least 30% less relative bioavailability compared to an immediate release composition.
At least 50% less relative bioavailability compared to an immediate release composition.
Circulating plasma metformin concentration is below about 0.5 μg/mL.
Documented Applications
Treating diabetes in a patient in need thereof by administering an enteric-coated metformin-containing pharmaceutical dosage form adapted to have an onset of release at about pH 5.5 or above and to provide reduced relative bioavailability versus immediate release.
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