Compositions and methods for treating metabolic disorders
Inventors
Baron, Alain D. • Fineman, Mark S. • Beeley, Nigel R. A.
Assignees
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Publication Number
US-10201511-B2
Publication Date
2019-02-12
Expiration Date
Abstract
Methods for improving the gastrointestinal tolerability of biguanide compounds and for treating metabolic disorders and/or inducing weight loss in patients in need thereof, particularly in individuals having a contraindication for treatment with biguanide compounds, are provided comprising administering delayed release formulations of such biguanide compounds, including metformin, targeted to the small intestine.
Core Innovation
The invention relates to compositions and methods for treating metabolic disorders by orally administering biguanide compounds selected from metformin, phenformin, buformin and imeglimin in delayed-release formulations adapted to minimize systemic bioavailability. The delayed-release formulation is characterized by reduced relative bioavailability compared to an immediate-release composition having the same amount of the biguanide compound.
The problem addressed is gastrointestinal intolerance and gastrointestinal complications resulting from biguanide administration, including the risk associated with patients who have contraindications for biguanides. The approach is to reduce systemic exposure so that therapeutic benefit can be obtained with minimized systemic bioavailability, including luminal or gut triggers of enteroendocrine hormone release such as GLP-1 and PYY.
The disclosure further specifies pharmacokinetic and bioavailability targets intended to correlate with improved gastrointestinal tolerability, including reduced relative bioavailability of at least 20%, reduced plasma exposure metrics such as plasma AUC0-36 and Cmax, and limits on circulating plasma concentrations. Broad formulation and delivery approaches are described to achieve delayed release, including enteric coatings with pH thresholds, timed release systems, and multicomponent or bilayer designs, including combinations of immediate-release and extended-release.
Claims Coverage
The document provides one independent claim with multiple inventive features. The claim centers on improving gastrointestinal tolerability and/or reducing gastrointestinal complications by combining a selected biguanide, a delayed-release formulation with minimized systemic bioavailability, a quantified reduction versus immediate release, and a patient population defined by contraindications across several metabolic disorders.
Improving gastrointestinal tolerability with delayed-release biguanide in contraindicated patients
Orally administering a therapeutically effective amount of a biguanide compound selected from metformin, phenformin, buformin and imeglimin in a delayed-release formulation adapted to minimize systemic bioavailability to a patient having a metabolic disorder, where the patient has a contraindication for the biguanide compound and the goal is improving gastrointestinal tolerability and/or reducing gastrointestinal complications.
At least 20% reduced relative bioavailability versus immediate release
Using the delayed-release formulation such that it has reduced relative bioavailability of at least 20% compared to an immediate-release composition having the same amount of the biguanide compound.
Patient metabolic disorder scope for the method
Applying the method to a patient having a metabolic disorder selected from obesity, dislipidemia, hyperglycemia, type II diabetes, prediabetes, gestational diabetes, and polycystic ovary syndrome.
Overall, the claim coverage is directed to an oral method using selected biguanides in delayed-release formulations that minimize systemic bioavailability, with a stated minimum reduction in relative bioavailability versus immediate release, for patients with defined metabolic disorders who have contraindications, aiming to improve gastrointestinal tolerability and/or reduce gastrointestinal complications.
Stated Advantages
Improving gastrointestinal tolerability of biguanide administration.
Reducing gastrointestinal complications resulting from biguanide administration.
Reducing systemic bioavailability to address patients with biguanide contraindications.
Fewer gastrointestinal and nervous system adverse events for delayed-release versus immediate-release.
Comparable meal-enhanced gut hormones (PYY, GLP-1) and glucose-lowering effects despite reduced systemic exposure.
Documented Applications
Treating metabolic disorders including obesity, dislipidemia, hyperglycemia, type II diabetes, prediabetes, gestational diabetes, and polycystic ovary syndrome by orally administering a delayed-release biguanide formulation to patients with biguanide contraindications.
Metformin delayed-release versus immediate-release comparison, including pharmacokinetic and pharmacodynamic evaluation and safety/tolerability outcomes, and evaluation of meal-enhanced gut hormones (PYY, GLP-1) and glucose-lowering effects.
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