MXPA06007962A - Composition for treating dyslipidaemia and protecting diabetic patients from cardiovascular risks. - Google Patents

Abstract

The present invention is related to the pharmaceutical industry in general, and to the industry for manufacturing pharmaceutical products intended to prevent diabetic patients from cardiovascular risks. The advantages of the present composition compared to further drugs are that it reduces collateral effects caused by drugs for controlling both pathologies; it reduces cardiovascular risks, as well as side effects caused by the formula components; it achieves other synergystics effects by combining an antidiabetic agent along with a dyslipidaemic agent. The inventive composition consists in the combination of (i) a hypoglycemic agent, (ii) a hypolipemiant agent and (iii) a vitamin. ?? ?? ?? ??.

Description

COMPOSITION FOR THE MANAGEMENT OF DISLIPIDEMIA AND CARDIOVASCULAR RISK PROTECTION IN PATIENTS DIABETICS FIELD OF THE INVENTION The present invention is related to the pharmaceutical industry in general and to the pharmaceutical manufacturing industry for the protection of vascular risks and dyslipidemia in diabetic subjects.

BACKGROUND OF THE INVENTION In patients with type 2 diabetes mellitus it is very common to find clinical pictures of mixed hyperlipidemia, characterized by an increase in low density lipoproteins (LDL), high concentration of triglycerides (TGs) and low concentration of high density lipoproteins (HDL). ) (Farnier M., Picard S. (2001) Diabetes: statins, fibrates or both? Curr Atheroescler Rep 3: 19-28). In addition, other metabolic abnormalities such as the predominance of small particles of low density LDL (Packard O et al., 2000). The role of small, low density lipoprotein (LDL): a new look. / Nt J Card / o / 74 (s pp.1): 17S-22S) as well as an increase in the glycosylation of LDL (Bucala R. et al., 1994) Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency, Proc Natl Acad Sci.91: 9441-9445), increases the atherogenic risk in these patients. The glycemic control seems to improve, but it does not normalize these alterations.

Thiazolidinediones (TZDs) are insulin sensitizers widely used in the treatment of patients with type 2 diabetes (Lebovitz HE et al., 2001. Rosiglitazone monotherapy is effective in patients with type 2 diabetes J Clin Endocrinol Metab.86: 280-288.). Fibrates are cholesterol-lowering agents that lower TG levels and increase HDL levels (Staels B. et al., 1998. Mechanism of action of fibrates on lipid and lipoprotein metabolism, Circulation.98: 2088-2093). Indi idually, both TZDs and fibrates increase HDL levels, thus decreasing morbidity and mortality due to cardiovascular disease. Statins are other antihyperlipidemic agents that can be used to improve the dyslipidemia picture, these agents have shown their efficiency to reduce mortality and morbidity related to atherosclerosis in patients with diabetes (Sacks FM et al., 1996). on coronary events after myocardial infarction in patients with moderate cholesterol, N EngIMed.335: 1001-1009).

Some studies have shown that monotherapy with statins or fibrates can improve the lipid profile in patients with diabetes mellitus type 2, however, they affect different aspects of lipoprotein metabolism, which makes it very complicated to modify the lipid profile only with monotherapy , for which the American Diabetes Association has suggested the use of combinatorial therapy to obtain better results (Diabetes Care Association, 2001. Management of dyslipidemia in adults with diabetes (Position State-ment), Diabetes Care.24 (Suppl. 1): 58-61.).

An effective therapeutic alternative for the treatment of mixed hyperlipidemia is the combination of statins with fibrates.

Within these have been developed combinations of lovastatin and gemfibrozil (Pierce LR et al. (1990) .Myopathy and rabhdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA.264: 71-75), pravastatin and gemfibrozil (Athyros V. et al. (1994). Combined treatment with pravastatin and gem-fibrozil in patients with refractory familial combined hyperlipidaemia. Drug Invest.7: 134-142.), Simvastatin and ciprofibrate (Kontopoulus A. etal. (1996). simvastatin and ciprofibrate alone and in combination on apolipoprotein-B-containing lipoproteins on low density lipoproteins subfraction distribution in patients with familial combined hyperlipidaemia and coronary artery disease. Coron Artery Dis.7: 843-850), bezafibrate and simvastatin (Kehely A. et al., 1995) Combined bezafibrate and simvastatin treatment for mixed hyperlipidemia. QJM.88: 421-427), atorvastatin and fenofibrate (Kiortisis DN et al., (2000). Efficacy of combination of atorvastatin and micronized fenofibrate in the treatment of severe mixed hyperlipidemia. Eur J Clin Pharmacol.56: 631-635, Athyros V.G. et al. (2001). Statin-fibrate combinations in patients with combined hyperlipidemia. Atheroesclerosis.155: 243-244.).

Then, the combination therapy of statins with fibrates has been widely explored, however it has not been accepted due to the problems concerning adverse side effects, mainly myopathy, reported with the use of the combination lovastatin-gemfibrozil.

Another combination of statins with fibrates is represented by the use of cerivastatin with gemfibrozil. From this combination, some adverse effects related to the toxicity of cerivastatin have been reported, since the majority of deaths from myopathy and rab-domiolysis reported in the United States have been associated with the use of said statin (OZcan, O., Mediha, B., Veli, G., Yucel, U., Burak, K., Sule, K. A case with severe rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy: A case report, The Journal of Vascular Disease 2000) The combination of a hypoglycemic agent with an antilomaging agent is currently being investigated, especially for the treatment of diabetic patients who also have hyperlipidemia. Jain et al (Jain A. K. et al. (1985), Diabetes.34: 294-) used the combination of a sulphonylurea (hypoglycaemic) and a halogen-tato (antihyperlipidemic) with good results.

The combination of hypoglycaemic agents with lipid-lowering agents has also been proposed. Within these combinations one that has been studied is that of rosiglitazone with fenofibrate. Rosigli-tazone is an insulin sensitizer used in the treatment of type 2 diabetes mellitus. Fibrates are anti-hyperlipiderant agents that lower TG levels and increase HDL levels. Individually, fibrates and TZDs generally raise HDL levels, however there are reports of patients treated with the combination TZDs-Fibrates in which a decrease in HDL levels has been observed.

Bonhome et al. in their patent USPTO 6,372,790 claim the use of the combination of metformin with fibrates in the treatment of diabetic patients, said combination shows the following disadvantages. Metformin although it is widely used for the treatment of type 2 diabetes mellitus can reduce levels of vitamin B12 and increase homocysteine levels (Wulffelé M.G. (2003). Effect of short-term treatment with metformin on serum concentration trations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. Internal J! Med.254: 455-463.) Thus represented a cardiovascular disease risk factor (Hoogeveen E.K. et al. (2000). Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5- year-follow-up of the Hom study. Circulation.101: 1506-1511). On the other hand, with the use of fenofibrate and bezafibrate, a 40% increase in homocysteine levels has been observed (Dierkes J. et al., 2004.) The effect of fibrates and other lipid-lowering drugs on plasma homocysteine levéis Expert Opin Drug Saf.3: 101-111; Melenovsky V. et al (2003). Effect of folie acid on fenofibrate-induced elevation of homocysteine and cysteine. Am Hearth J.146: 110; Mayer O. et al (2003). Fenofibrate-induced hyperhomocysteinemia may be prevented by folate coadministration. Eur J Clin Pharmacol.59: 367-371), increasing the risk of cardiovascular disease.

De Silva et al., (De Silva S.R. (1979), Diabetes and Metabolism.5: 223-229) proposed the combination of metformin and clofibrate. With this combination a decrease in glucose levels was obtained, however the results were not very convincing in terms of the decrease in cholesterol and triglyceride levels.

Normen et al., (Ormen L. et al., (2004) Combination therapy with fenofibrate and rosiglitazone paradoxically lowers serum HDL cholesterol, Diabetes Care.27: 2241-2242) studied the effect of the combination of a TZDs (rosigli-tazone) ) and a fibrate (fenofibrate) in HDL levels of different types of patients.

The diabetic patient is exposed to a high risk of developing micro and macrovascular diseases, which can be prevented by strict control of blood glucose levels and maintenance of normal lipid levels. In this case, the ideal would be to have a medication that has an important effect on both morbidities.

Of all the antidiabetic agents that exist at the moment, only metformia and pioglitazone have proven to have an effect on the lipid profile, however the use of metformin is limited to low doses since in high doses it produces harmful effects to the patient. organism. Due to this, the alternative has been to use combinations of metformin with other agents in order to reduce the doses and therefore the adverse effects. In this sense, the most advisable to produce a beneficial effect in the treatment of mixed dyslipidemia in diabetic patients is to use a hypolipidemic agent in combination with metformin. Among the wide range of existing agents, the most recommended for use in diabetic patients with dyslipidemia is fenofibrate since it has an effect on the typical dyslipidemia of this type of patients.

OBJECTIVES OF THE INVENTION One of the objectives of the invention is to make possible the management of dyslipidemia in patients with diabetes by decreasing the side effects of the consumption of drugs that control one and the other table.

Another objective of the present invention is to make possible a pharmaceutical composition that also reduces the cardiovascular risks also achieving a decrease in the side effects of the components of the formula.

Still another objective is to achieve other synergistic effects of the combination of an antidiabetic agent and a dyslipidemic agent.

Other objects and advantages of the present invention may be apparent from the study of the following description and the accompanying examples for illustrative purposes only and not limitation.

BRIEF DESCRIPTION OF THE INVENTION The product of this patent is a combination therapy that protects diabetic patients against the risk of cardiovascular disease.

The therapy consists of a cholesterol reducer (fenofibrate) plus an antidiabetic agent (metformin) and a reducer of homocysteine (folic acid) levels.

Fenofibrate causes a decrease in total cholesterol, triglycerides and LDL levels and increases HDL levels; which helps significantly reduce risk and controls cardiovascular disease.

Metformin acts as an antidiabetic agent, in addition to decreasing body weight and improving endothelial function.

Both drugs have in common as an adverse effect elevating the levels of homocysteine, a sulfur amino acid that has been strongly associated with cardiovascular events in such a way that to use this combination it is important to add a third agent that decreases the levels of this amino acid. This effect is achieved by the addition of certain vitamins, among which the one with the greatest effect is folic acid.

Thus, there is a complete combination therapy for the treatment and prevention of cardiovascular disease for diabetic patients, having a synergistic beneficial effect in reducing the risk factors of atherosclerosis and cardiovascular disease.

In order to better understand the characteristics of the invention, the present description is accompanied, as an integral part thereof, by the present detailed description, which is illustrative but not limitative, which is explained below.

DETAILED DESCRIPTION OF THE INVENTION As already mentioned above, the product of this patent is a combination therapy that protects diabetic patients against the risk of cardiovascular disease. A composition including only one or two of the components that were located after multiple tests with the currently used doses, have side effects that together are controlled by the use of lower doses of metformin and fenofibrate plus the addition of folic acid . This is one of the synergistic effects provided by the present invention.

The combination is carefully planned to attack different alterations that occur in the diabetic patient. All these alterations lead to a very high risk of the occurrence of cardiovascular disease. In addition, because they are agents with different mechanisms, but complement each other, they allow them to be used in smaller doses with the consequent reduction of adverse events.

The fenofibrate present in the combination modifies the lipid profile of the patient, decreasing the levels of total cholesterol, triglycerides, and LDL, in addition to increasing HDL.

A fundamental aspect in the use of fenofibrate is the presentation of it. Fenofibrate is a compound with low solubility, which decreases its physiological efficiency. Therefore, in the combination motif of the present invention, it was decided to use micronized fenofibrate. The micronization process favors the solubility and therefore the absorption and the therapeutic effect of fenofibrate. The composition uses micronized fenofibrate with a particle size of 5-10 μm.

The combination therapy also contains metformin whose main effect is on the decrease of glucose and glycosylated hemoglobin, in addition to slightly decrease body weight, improve endothelial function and reduction of LDL and total cholesterol levels.

Although the benefits of fenofibrate and metformin mentioned above have been widely supported, both have the drawback of raising homocysteine levels. Therefore, folic acid was added to our combination, which effectively reduced homocysteine levels produced by the administration of metformin and fenofibrate. The combination with folic acid also provides a protective effect to the endothelial lesion, a common factor in the atherogenesis of patients with cardiovascular risk factors and dyslipidemia.

When testing metformin and fenofibrate, it was determined that the best relationship between these is between a weight: weight ratio of 1: 1 to 20: 1.

A preferred pharmaceutical composition comprises the following ratio of components, between 100 and 1000 mg of metformin or its pharmacologically acceptable salt; between 50 and 600 mg of fenofibrate and between 0.8 to 8 mg of folic acid. In other words, a quantitative composition such as the following: Metformin 60 - 80% Fenofibrate 25 - 33% Folic Acid 0.4 - 0.9% In its most preferred composition, it is established that it comprises 500 mg of metformin or its pharmacologically acceptable salt, 200 mg of fenofibrate and 5 mg of folic acid, that is: Metformin 70.92% Fenofibrate 28.37% Folic acid 00.71% The invention has been described sufficiently so that a person with average knowledge in the art can reproduce and obtain the results mentioned in the present invention. However, any person skilled in the art field of the present invention may be able to make modifications not described in the present application, however, if for the application of these modifications in a certain composition or in the manufacturing process thereof, the subject matter claimed in the following claims is required, said structures should be understood within the scope of the invention.

Claims (8)

R E I V I N D I C A C I O N S Having sufficiently described the invention, it is considered as a novelty and therefore it is claimed as property what is expressed and contained in the following claim clauses.

1. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients characterized by being formed by (i) a hypoglycemic agent (ii) a lipid-lowering agent and (ii) a vitamin.

2. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients as claimed in the preceding claim, further characterized in that the hypoglycaemic agent is metformin in the form of a pharmacologically acceptable salt such as metformin hydrochloride.

3. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients as claimed in claim 1 or 2, also characterized in that the lipid-lowering agent is a fibrate, such as fenofibrate.

4. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients as claimed in the previous claim, also characterized in that the fenofibrate is found in the micronized composition at a particle size of between 5 and 10 μ.

5. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients as claimed in any of the preceding claims, characterized also because the vitamin is selected from vitamin B6, B12 and folic acid.

6. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients as claimed in any of the preceding claims, characterized in that the weight: weight ratio between metformin and fibrate is in the range of 1: 1 and 20: 1.

7. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients as claimed in any of the preceding claims, further characterized because its quantitative composition is as follows: Metformin 60-80% Fenofibrate 25-33% Folic Acid 0.4 - 0.9%

8. Pharmaceutical composition for the management of dyslipidemia and protection of cardiovascular risk in diabetic patients as claimed in any of claims 1 to 6, further characterized because its quantitative composition is as follows: Metformin 70.92% Fenofibrate 28.37% Folic acid 00.71% SUMMARY The present invention is related to the pharmaceutical industry in general and to the pharmaceutical manufacturing industry for the protection of vascular risks and dyslipidemia in diabetic subjects. The advantages of the present composition with respect to other medicines used for the management of such pictures, lie in that it diminishes the collateral effects of the consumption of medicines that control both tables; it decreases the cardiovascular risks also achieving a decrease in the side effects of the components of the formula and achieves other synergistic effects of the combination of an antidiabetic agent and a dyslipidemic agent. Said composition consists of the combination of (i) a hypoglycemic agent (ii) a lipid-lowering agent and (iii) a vitamin.