Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-05-13
1999-07-13
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514634, A61K 3116, A61K 31155
Patent
active
059227699
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of a combination consisting of glibenclamide and metformin in one specific ratio as medicament for the treatment of diabetes mellitus of type II.
Non-insulin dependent diabetes of type II (NID) is known to be a frequent metabolic disease and the main cause of hyperglycemia. In recent years, diabetes mellitus of type II has been proved to be a heterogeneous disease, with complex, unclarified metabolic aspects, which disease is characterized by three main metabolic abnormalities contributing to hyperglycemia: the partial or complete decrease in insulin secretion, the resistance of the peripheral tissues to insulin and the increased hepatic production of glucose in fasting conditions.
Diet and physical exertion are unanimously recognized to be the foundation of the therapy of diabetes of type II: both of them lead to a reduction in insulin-resistance and, in the long run, to an improvement in the pancreas secretive deficit.
However, these provisions are insufficient and a pharmacological aid with oral hypoglycemic agents is necessary. At present, the two main families of oral hypoglycemic agents available are sulfonylureas and biguanides.
The use of sulfonylureas and biguanides in monotherapy, in most cases, allows to obtain an effective glycometabolic control for some years, if an appropriate diet and behavioural regimen are kept. Nevertheless, the efficacy of the therapy with oral hypoglycemic agents can decrease with time.
After a positive starting response which can last 4-5 years, monotherapy becomes ineffective in a considerable percentage of patients. These are the so-called "secondary failures" of the therapy with oral hypoglycemic agents. Such a failure is estimated to occur each year in 5-10% of the patients under therapy with sulfonylureas, therefore after 10 years, only 50% of the patients still show a satisfactory response.
The secondary failure in patients under treatment with metformin appears to have an incidence superimposable to the above mentioned one.
Recent studies show that besides a qualitative/quantitative deficiency of insulin secretion, the combined occurrence of insulin-resistance conditions is at the bottom of NID diabetes.
Since sulfonylureas are capable of stimulating insulin release, but are not capable of acting on insulin resistance, and biguanides are able to act on insulin resistance, whereas they are not able to stimulate insulin secretion, the therapeutical rationale of said studies suggested the use of combined formulations of medicaments capable of finding a remedy for both the deficiency in insulin secretion and the insulin-resistance condition.
Vigneri et al. (Diabete & Metabolisme, 1991, (17), 232-234), faced the problem of secondary failure to sulfonylurea therapy in NID diabetes. The authors proposed a combination of glibenclamide-metformin in a daily dosage of 15 mg and 1500 mg, respectively, in alternative to insulin therapy in addition to glibenclamide.
The combined therapy (sulfonylurea+biguanide) plays therefore a specifically important therapeutical role, since it allows to obtain an effective metabolic control in those patients with diabetes of type II, in which the therapy with only sulfonylureas or only biguanides becomes ineffective with time.
Two biguanides are used in the oral therapy of diabetes of type II: phenformin and metformin. Although the former is still widely used, a number of data in literature clearly show that metformin exerts an effective normoglycemic action with no risk of lactic acidosis in the patients, as it can occur in some cases when using phenformin. Therefore, it is generally accepted that metformin is the preferred biguanide in the therapy of diabetes of type II.
The Applicant found, during clinical experiments, that the sulfonylurea maximum daily dose considered optimum for the most severe, barely controllable cases is 15 mg. However, such a dose has to be combined with a biguanide maximum daily dose of 15,00 mg in order to obtain the maximum therapeutical effect together with the reducti
REFERENCES:
BIOSCI Rep, 9(3). 1989. 347-350., XP000570541 Al-Ahmend F A A et al: Interaction Between Diazepam and Oral Antidiabetic Agents on Serum Glucose Insulin and Chromium Levels in Rats see abstract.
Diabete Metabol., 1991, 17/1 BIS (232-234), France, XP000570538 Vigneri R. et al:, "Treatment of NIDDM patients with secondary failure to glyburide: comparison of the addition of either metformin or bed-time NPH insulin to glyburide" cited in the application see p. 233, col. 1, paragraph 3.
Barelli Giulio
De Regis Massimo
Abiogen Pharma s.r.l.
Henley III Raymond
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