Formulations and methods for treatment of metabolic syndrome
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Publication Number
US-9839644-B2
Publication Date
2017-12-12
Expiration Date
Abstract
Formulations and methods of providing an orally-active anti-metabolic disease Fixed Dose Combinations (FDC) for use as personalized medicine to treat different components of the Metabolic Syndrome or Insulin resistance syndrome such as Type II diabetes, Hypertension, Hyperlipidemia and Obesity are disclosed. Pharmaceutical compositions of anti-inflammatory and pancreatic beta-cell centric drug formulations and methods comprising of NSAIDS in general and selective Cox-2 inhibitors in particular and one or more anti-T2DM or anti-hypertensive or anti-hyperlipidemic or anti-obesity drugs formulated to exhibit pre-determined modified release kinetics to achieve therapeutic as well as kinetic synergies are disclosed.
Core Innovation
The invention provides orally administered fixed dose combinations for chronic treatment of Type II diabetes or a pre-diabetic condition in a mammal. The fixed dose combination includes metformin as a biguanide, celecoxib as a non-steroidal anti-inflammatory drug, and valsartan as an Angiotensin II Type 1 receptor blocker.
The described regimen includes specified drug-release and administration formats, including immediate release (IR), quick release (QR), delayed release (DR), and extended release (ER) formats. The document further describes releasing a dose of valsartan 6 hours after administering a dose of metformin.
The invention is supported with preclinical animal-study evidence in C57BL/6J DIO mice showing that co-administration of metformin, celecoxib, and sub-hypertensive valsartan improves non-fasting and fasting blood glucose rapidly and sustainably over days. The document also reports improvements in OGTT glucose tolerance.
Claims Coverage
The document includes two independent claims. Across both independent claims, the inventive features are built around combining metformin, celecoxib, and valsartan with defined fixed-dose formulation concepts and a specified timing relationship for delayed-release valsartan relative to metformin.
Chronic fixed dose combination of metformin, celecoxib, and valsartan
Orally administering on a chronic basis a fixed dose combination comprising metformin, celecoxib, and an Angiotensin II Type 1 receptor blocker (valsartan) to treat Type II diabetes or a pre-diabetic condition in a mammal.
Once-a-day management with IR/QR metformin-celecoxib and DR delayed-release valsartan
Daily oral administration in a human patient of a single dose combining sub-therapeutic celecoxib with therapeutic-dose metformin in immediate release (IR) or quick release (QR) form, together with sub-systolic blood pressure dose valsartan administered 6 hours later in delayed release (DR) form to manage non-fasting (fed) blood glucose levels for Type II diabetes or prediabetes.
Overall claim coverage centers on treating Type II diabetes or prediabetes with an oral fixed dose combination of metformin, celecoxib, and valsartan administered chronically or daily, with non-fasting glucose management specifically using IR/QR dosing for metformin-celecoxib and DR delayed-release valsartan after a defined 6-hour interval.
Stated Advantages
Improves non-fasting and fasting blood glucose rapidly and sustainably over days.
Improves OGTT glucose tolerance.
Provides a rationale for correcting pancreatic beta-cell dysfunction and hepatic insulin resistance.
Improves glycemic and related parameters including HbA1c, OGTT performance, beta-cell function, fasting and post-prandial glucose, acute insulin response and first phase insulin secretion, glucose excursion, and NAS activity scores in NASH/NAFLD patients.
Documented Applications
Managing non-fasting (fed) blood glucose levels in a human patient suffering from Type II diabetes or prediabetes using daily oral dosing with sub-therapeutic celecoxib, therapeutic metformin, and delayed-release valsartan administered after 6 hours.
Treating Type II diabetes or a pre-diabetic condition in a mammal by orally administering on a chronic basis a fixed dose combination of metformin, celecoxib, and valsartan.
Improving NASH/NAFLD-related outcomes using NAS activity scores in NASH/NAFLD patients as part of the disclosed glycemic/related parameter improvements.
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