Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-09-17
2002-04-23
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S617000, C424S626000, C424S639000, C424S655000
Reexamination Certificate
active
06376549
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutical compounds formulated in conjugation with dietary supplements; and to methods of using the resulting compositions for the treatment of a number of conditions. Particularly, this invention relates to metformin-containing pharmaceutical compositions and to methods of using the same for the treatment of diabetes and a number of symptoms which precede and/or accompany diabetes.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a mammalian condition in which the amount of glucose in the blood plasma is abnormally high. Elevated glucose levels in some instances can lead to higher than normal amounts of a particular hemoglobin, HbA1c. This condition can be life-threatening and high glucose levels in the blood plasma (hyperglycemia) can lead to a number of chronic diabetes syndromes, for example, atherosclerosis, microangiopathy, kidney disorders or failure, cardiac disease, diabetic retinopathy and other ocular disorders, including blindness.
Diabetes mellitus is known to affect at least 10 million Americans, and millions more may unknowingly have the disease. There are two forms of the disease. In the form of this disease known as Type II, non-insulin dependent diabetes (NIDDM) or adult-onset (as opposed to juvenile diabetes or Type I), the pancreas often continues to secrete normal amounts of insulin. However, this insulin is ineffective in preventing the symptoms of diabetes which include cardiovascular risk factors such as hyperglycemia, impaired carbohydrate (particularly glucose) metabolism, glycosuria, decreased insulin sensitivity, centralized obesity hypertriglyceridemia, low HDL levels, elevated blood pressure and various cardiovascular effects attending these risk factors. Many of these cardiovascular risk factors are known to precede the onset of diabetes by as much as a decade. These symptoms, if left untreated, often lead to severe complications, including premature atherosclerosis, retinopathy, nephropathy, and neuropathy. Insulin resistance is believed to be a precursor to overt NIDDM and strategies directed toward ameliorating insulin resistance may provide unique benefits to patients with NIDDM.
Current drugs used for managing Type II diabetes and its precursor syndromes, such as insulin resistance, fall within five classes of compounds: the biguanides, thiazolidinediones, the sulfonylureas, benzoic acid derivatives and &agr;-glucosidase inhibitors. The biguanides, e.g., metformin, are believed to prevent excessive hepatic gluconeogenesis. The thiazolidinediones are believed to act by increasing the rate of peripheral glucose disposal. The sulfonylureas, e.g., tolbutamide and glyburide, the benzoic acid derivatives, e.g. repaglinide, and the &agr;-glucosidase inhibitors, e.g. acarbose, lower plasma glucose primarily by stimulating insulin secretion.
Among biguanides useful as diabetic therapeutic agents, metformin has proven particularly successful. Metformin is an anti-diabetic agent that acts by reducing glucose production by the liver and by decreasing intestinal absorption of glucose. It is also believed to improve the insulin sensitivity of tissues elsewhere in the body (increases peripheral glucose uptake and utilization). Metformin improves glucose tolerance in impared glucose tolerant (IGT) subjects and NIDDM subjects, lowering both basal and postprandial plasma glucose.
Unlike sulfonylureas, metformin does not produce hypoglycemia in either diabetic or non-diabetic subjects. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. Metformin also has a favorable effect on serum lipids, which are often abnormal in NIDDM patients. In clinical studies, particularly when baseline levels of lipids were abnormally elevated, metformin lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels.
Currently, there is no composition for the treatment of diabetes, its precursor syndromes and related sequelae that combines metformin with bioavailable elemental nutritional supplements such as vanadium, magnesium and chromium as well as other non-elemental nutritional palliatives which are effective in managing diabetes, its precursors, and sequelae.
DESCRIPTION OF THE INVENTION
The present invention provides for metformin-containing compositions containing one or more nutritional supplements in an amount sufficient to produce a desirable effect, such as bioavailable sources of vanadium, chromium, magnesium, vitamin E, lipoic acid, folate and the like. Additionally, compositions of the present invention may contain aspirin. The present invention improves upon current regimens for treating diabetes with metformin, by exploiting the insulin-like effects of vanadium and chromium and also by providing a source of magnesium, which is so often deficient in people with diabetes. Also provided are methods for the treatment of diabetes and conditions attending or commonly preceding diabetes, comprising administration of an effective amount of the aforementioned compositions.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided compositions comprising metformin, one or more of a bioavailable source of chromium, vanadium or magnesium and pharmaceutically acceptable salts thereof; and a physiologically acceptable carrier.
In another aspect of the present invention, there are provided compositions comprising, in addition to the aforementioned components, an effective amount of one or more additional anti-diabetic agents such as insulin, a thiazolidinedione, a sulfonylurea, a benzoic acid derivative, an &agr;-glucosidase inhibitor, exendin-4, or the like. As will be apprecitated by those skilled in the art, the effective amount of each of these components will vary by the patient and severity of condition being treated. Thus, any determination as to the effective amount will be made by the treating professional.
Metformin (N,N-dimethylimidodicarbonimidicdiamide; 1,1-dimethylbiguanide; N,N-dimethylbiguanide; N,N-dimethyldiguanide; N′-dimehtylguanylguanidine) is commonly administered as metformin HCl. This as well as all other useful forms of metformin are contemplated for use in the practice of the present invention. Generally, a fixed dosage regimen is individualized for the management of hyperglycemia in diabetes mellitus with metformin HCl or any other pharmacologic agent. Individualization of dosage is made on the basis of both effectiveness and tolerance, while generally not exceeding the maximum recommended daily dose of 2550 mg. In one embodiment of the present invention, compositions comprise in the range of about 100 mg up to about 2550 mg per daily dose. In some embodiments of the invention, doseages may be less than 100 mg per day when administered with higher amounts of bioavailable forms of two or more of chromium, vanadium or magnesium.
Thiazolidinediones contemplated for use in the practice of the present invention include troglitazone, and the like. Effective amounts of troglitazone, when used alone, range from about 10 mg up to about 800 mg per daily dose and a commensurate range is contemplated for use in the present invention. In a preferred aspect of the present invention, the composition comprises from about 100 mg to about 600 mg of troglitazone per daily dose.
As readily recognized by those of skill in the art, a variety of sulfonylureas are useful for the treatment of diabetes. Exemplary sulfonylureas contemplated for use in the practice of the present invention (with typical daily dosages indicated in parentheses) include acetohexamide (in the range of about 250 up to about 1500 mg), chlorpropamide (in the range of about 100 up to about 500mg), tolazimide (in the range of about 100 up to about 1000 mg), tolbutamide (in the range of about 500 up to about 3000 mg), gliclazide (in the range of about 80 up to about 320 mg), glipizide (in the range of about 5 up to about 40 mg), glipizide GITS (in
Fine Stuart A.
Kinsella Kevin J.
Akesis Pharmaceuticals, Inc.
Criares Theodore J.
Foley Hoag & Eliot LLP
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