WO2008058358A2

WO2008058358A2 - Descriptive report of the patent of invention of the medicament 'rosuvastatin + metformin' in combined form for cardiovascular diseases.

Info

Publication number: WO2008058358A2
Application number: PCT/BR2007/000349
Authority: WO
Inventors: Walter Santos Junior
Original assignee: Walter Santos Junior
Priority date: 2006-11-16
Filing date: 2007-11-14
Publication date: 2008-05-22
Also published as: BRMU8602999U; WO2008058358A3

Abstract

The patent of invention of the medicament 'rosuvastatin + metformin' in combined form for cardiovascular diseases, is resumed to combination of two medicaments used against the cardiovascular diseases which are main causes of death in globalized world. There are neat correlation between the ponderal again and the weight excess with risk of cardiovascular illness. The weight excess predisposes to these ilnesses due to abnormalities in the metabolism of the lipids, glucose and arterial pressure. The resistance to insulin/ hyperinsulinemia seems to be an risk factors. independent risk factors associated as the obesity, hyperlipidemia and hypertension, either in men or in women. The insulin and the growth factors similar to insulin estimulate activity of the smooth muscle cells and are involved in the atherogenese and even in the reestenose that follows to coronary repair by the angioplasty. Other insulin effects are related to the mechanisms that contribute for the development either of the hypertension or of the dyslipidemia. The patent of invention of the medicament ' rosuvastatin + metformin' in combined form for cardiovascular diseases, diminishes the insulin resistance, arterial pressure, ponderal gain and improves the lipidic profile of these patients, reducing so much the probability of cardiovascular events and consequently the death of this sort.

Description

DESCRIPTIVE REPORT OF THE PATENT OF INVENTION OF THE MEDICAMENT "ROSUVASTATIN + METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES.

The systematic study of central obesity and insulinic resistance in the population will show us in near future a cluster of highly harmful clinical events to our cardiovascular system, brain - vascular, not to mention on the augmented risk and of the inexorable evolution onto diabetes. The individuals with superior distribution fat (neck, shoulder and abdomen) present higher risk for the development of mellitus diabetes, hypertension and cardiovascular show a higher risk onto developing the diabetes mellitus, hypertension and cardiovascular disease.

The association among hypertriglycerides, obesity, hyperinsulinemia, insulin resistance, intolerance to glucose, hypertension and the coronary disease have been the reasons of studies since 1960. The combination of abdominal obesity and heart disease can be partially explained by the commitment in the glucose homeostasis and insulin as well as lipid and lipoproteins related (Bjorntorp)

BJORNTORP E COLS, who first related the relation between central obesity with augmented risk of diabetes and cardiovascular disease (DCD) in both men and women. The relation between the degree of obesity and the incidence of heart disease was established in 1983 when were published the results of evolution of 5.209 men and women who took part in Framingham study.

Although the obesity shows itself as an independent risk factor for coronary heart disease (CHD), it is important to lay stress on the existence of strong association among obesity, dyslipidemia, arterial hypertension, intolerance to glucose, and left ventricular hypertrophy. Finally, the association between obesity and the occurrence of stroke vascular disease ( SVD) was also demonstrated in Framingham by HURBERT e COLS. Particularly, in women, these investigators have demonstrated that the obesity contributes form in a remarkable for the risk of AVC. Particularly in women, these investigators have demonstrated that the obesity contributes remarkably for the risk of SVD.

Though several studies have demonstrated in the last few decades a

- neat association between severe obesity and lager mortality, till recently, there are still controversies as to the real damages of an overweight of slight or moderate degree and particularly as to the ideal weight that predispose to the longevity.

In more recent studies, the inclusion of a great number of patients and segment for periods superior to five years have permitted to establish a clear a relation between adiposity excess and the rise of mortality that arise principally from lesions in the vascular system. In fact, the obesity associates very often with conditions such as dyslipidemia, diabetes and arterial hypertension which favor the occurrence of cardiovascular events, particularly the coronary ones.

Since it was described by JEAN VAGUE, in 1974, the abdominal obesity has repeatedly associated independently to hypertension, diabetes and dyslipidemia, even in individuals who do not present weight excess.

The resistance to insulin can be defined whit a condition in which occurs lesser glucose utilization in reply to the insulin action in the peripheral tissues.

In this condition the lesser comsumption of glucose causes its serum levels to elevate, entailing major stimulus for the production of insulin and hyperinsulinemia. The visceral abdominal fat shows itself as metabolically very active tissue, presenting high rate of renewal. Concerning the lipόlise the visceral fat tissue, shows it self more sensitive to the lipolidica action of the catecholamines than to the antilipolitica action of insulin.

The free fatty acids liberated from the visceral fat get to the liver by the portal system. A larger hepatic volum of free fatty acids has, as consequences, reduction in the capitation and degradation of insulin and augment in the hepatic production of very low density lipoproteins ( VLDL) rich in triglycerides. The larger production of VLDL leads to the larger conversion of low density lipoproteins (LDL)₁ with elevated atherogenic potency, and to the reduction in the serum levels of high density lipoproteins (HDL). In addition, the accumulation of free fatty acids in the liver entails rise neoglucogenese that result in the larger hepatic production of glucose even in the presence of insulin serum levels, normally capable to inhibit it. This characterizes the hepatic resistance to the insulin action. Parallelly, the free fatty acids and triglycerides in major quantities in the systemic circulation reach the skeleton muscle and reduce the captation of glucose induced by the insulin, favoring the elevation of the glucose serum levels. Initially, the major quantity of free fatty acids and the more elevated glicemia estimulate the insulin production. The pancreas chronic exposure to the free fatty acids, by means of a phenomenon known as lipotoxicity, results in the reduction of the insulin pancreatica secretion, being even to provoke the appearing of type 2 diabetes. It is well known that, acting I the central nerve system, the hyperinsulinemia acts rising the activity of the sympathetic nervous system, generating a hyperadrenergico state that promotes vasoconstriction in the musculature contributing for the elevation of the arterial pressure levels. Besides, either the insulin or the rise of the sympathetic activity can estimulate the renal reabsorption of sodium, which, in turn also contributes for the elevation of arterial pressure.

THE PATENT OF INVENTION OF THE MEDICAMENT "ROSUVASTATIN + METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES, interacts as follows:

The metformin (drawing 01 picture 01) is a compound of the biguanides group which augments the sensitivity of insulin in the peripheral tissues, mainly the liver. The reduction of glycemic provoked by metformin (drawing 01 figure 01) is due specially to the diminution of the glucose hepatic production. It is not associated to the rise of weight, being able, inclusively to determine the reduction from two to three kilos during the first six months of treatment. It reduces the triglycerides from 10 to 15% and also from the plasminogen activator inhibitor 1 In the UKPDS, the metformin ( drawing 01 picture 01) was the only medication that determined significative reduction of incidence of cardiovascular complications in obese patients, inclusively myocardial infarction and death.

The most frequent adverse effects are: abdominal discomfort and diarrhea, that are usually slight and transitory. Less than 5% of the patients do not tolerate metformin (drawing 01 picture 01). Lactic acidosis is rare (about three cases per 100.000 patients/year), particulary if respected its counter- indications.

THE PATENT OF INVENTION OF THE MEDICAMENT "ROSUVASTATIN + METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES, can be utilized as follows:

The metformin ( figure 01 picture 01) is counter-indicated in patients with renal insufficiency ( creatinine > 1 ,5 mg/dl in men and >1 ,4 mg/dl in women). Congestive cardiac insufficiency, chronic hepatic illness ( transaminases > 3 times the superior limit of normality) and abusive use of alcohol. The medicament must be interrupted during the surgical procedures, radiographies with use of serious medical contrast and I intercurrence. The use of estatinas-inhibitors of the 3 - hydroxy -3 - methylglutaryl coenzyme A reductase rosuvastatin (drawing 01 figure 02) is beneficial for treatment of the lipoproteins anormalities and for primary and secondary prevention of DAC in patients DM type , even in subjects with normal plasmatic levels of LDL-c since the plasmatic levels of HDL - c are below the normal and are present hypertrigliceridemia.

The levels of apolipoprotein B diminishe by the treatment with estatinas because of the reduction in the synthesis in combination with the augment of the depuration of the plasmatic LDL, resulting in subsequent lipoproteic degration. Consequently, the number of particles of LDL diminishe by the augment by the synthesis of cholesterol particles of cholesterol of the lipoproteins of very low density reduces.

After ingestion by oral via in the active form with peaks of plasmatic levels occurring 5 hours after the administration, it is a selective and potent competitive inhibitor of the HMG-CoA redutase, the rosuvastatin (drawing 01 figure 02), carries out its modifier effects of lipids of two ways: it rises the number of hepatic LDL receptors in the cellular surface augment the capitation and the catabolism of the LDL, and inhibiting the VLDL hepatic synthesis, reducing , then, total number of both.

The rosuvastatin (drawing 01 figure 02) demonstrated to reduce the normal and elevated concentrations of LDL - c. The LDL that are formed from the very low density lipoprotein (VDL) and its catabolism occurs predominantly by the receptor of high afinity LDL. The mechanism of reductor effect of LDL of the rosuvastatin (drawing 01 figure 02) can involve the reduction of VLDL - c cholesterol concentration and the reduction of the LDL receptor, which leads to the reduction of production and the rise of the LDL - c catabolism. The counter-indications consist of hypersensitivity to active principles or to any of the excipients, active hepatic dysfunction or persistent and unexplainable elevation of the serum transaminases, pregnancy and lactation.

Claims

THE PATENT OF INVENTION OF THE MEDICAMENT " ROSUVASTATIN + METFORMIN" IN COMBINED FORM FOR CARDIOVASCULAR DISEASES, characterizes by utilizing more precauciously the strategics of intensive treatment, as treatment combined with metformin (drawing 01 + figure 01) and rosuvastatin ( drawing 01 + figure 02) in a combined formulation, where the pharmacocinetic proprieties of these of drugs back up the co-administration of salts. The metformin ( drawing 01 figure 01) in addition to proportioning a major control of the inherent metabolic alterations to the obese patients, reduces the levels of arterial pressure performing a synergism with the rosuvastatin ( drawing 01 figure 02) in a major global metabolic control.