Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reissue Patent
2000-07-05
2001-08-14
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S634000
Reissue Patent
active
RE037330
ABSTRACT:
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 reduction of untoward effects.
At present 4 combinations are marketed which use a combination of metformin with glibenclamide (Table 1). In the first combination, glibenclamide dose is 2.5 mg and metformin (expressed as the hydrochloride) dose is 500 mg for each tablet, namely a weight ratio of 1:200. In the other combinations, doses are respectively: 2.5 mg of glibenclamide and 400 mg of metformin, namely a weight ratio of 1:160.
TABLE I
Ready-to-use preparations of sulfonylurea (S) -
Metformin (M) available at present:
Name
Manufacturer
S (dose/cp)
M (dose/cp)
Glucomide
Lipha
Glibenclamide
Metformin
(2.5 mg)
(500 mg)
Glibomet
Guidotti
Glibenclamide
Metformin
(2.5 mg)
(400 mg)
Suguan M
Hoechst
Glibenclamide
Metformin
(2.5 mg)
(400 mg)
Bi-Euglucon M
Boehringer M
Glibenclamide
Metformin
(2.5 mg)
(400 mg)
It should be noted, however, that none of these formulations attain the optimum therapeutical effect due to the quantitative unbalance of the medicaments in combination. In fact, using the above mentioned formulations, in order to obtain the sulfonylurea maximum dose of 15 mg, which we consider optimum for the most severe, barely controllable cases, 6 tablets of the medicament should be taken, thus receiving 2400-3000 mg of metformin, which is a dose markedly higher than the maximum one we recommend (1500 mg).
Therefore, the still unsolved problem is to find a combination capable of obtaining the maximum increase in the therapeutical effect with balanced doses of the single medicaments, thereby decreasing in parallel their untoward effects.
Such a research is of paramount importance, taking into account that in diabetes of type II it is often necessary to progressively increase with time the hypoglycemic medicament doses.
The present invention solves the problem to provide medicament effective for the treatment of diabetes mellitus of type II in cases of secondary failure to a combination of glibenclamide-metformin currently used in therapy.
ABSTRACT OF THE INVENTION
Now it has been found that a combination of glibenclamide and metformin (expressed as the hydrochloride) in a 1:100 weight ratio, so as to allow a daily administration of 15 mg of glibenclamide and 1500 mg of metformin, is suitable to the preparation of a medicament useful for the treatment of diabetes mellitus of type II at any time of the progression of the disease, from its onset to the most severe cases.
Therefore, it is an object of the present invention the use of the above mentioned combination in admixture with conventional carriers and excipients for the preparation of a medicament for the treatment of diabetes mellitus of type II, particularly in the cases “secondary failure” to a combination of glibenclamide-metformin currently used in therapy.
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Summary of Velussi et al., M. Velussi, A. M. Cernigoi e coll., Glibenclamide+metformina, Clin. Ter. 141: 483-492, 1992.
Hermann et al., “Effects of Metformin and Glibenclamide Alone and in Combination on Serum Lipids and Lipoproteins in Patients with Non-Insulin-Dependent Diabetees Mellitus”, Diabete and Metabolisme, vol. 17, pp. 174-179, 1991.
Herman et al., Comparative Efficacy of Metformin and Glibenclamide in Patents with Non-Insulin-Dependent Diabetes Mellitus, Dibete and Metabolisme, vol. 17, pp. 201-208, 1991.
Marena et al., Metabolic Effects of Metformin Addition to Chronic Glibenclamide Treatment in Type 2 Diabetes, Diabete and Metabolisme, vol. 20, pp. 15-19, 1994.
Al-Ahmend F AA et al.: “Interaction Between Diazepam and Oral Antidiabetic Agents on Serum Glucose Insulin and Chromium Levels in Rats”, BIOSCI Resp, 9(3), 1989 pp. 347-350.
R. Vigneri et al., Treatment of NIDDM patients with secondary failure to glyburide: comparison of the addi
Barelli Giulio
De Regis Massimo
Abiogen Pharma S.p.A.
Henley III Raymond
Millen White Zelano & Branigan P.C.
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