MXPA05009432A

MXPA05009432A - Use of omega-3-fatty acids in the treatment of diabetic patients.

Info

Publication number: MXPA05009432A
Application number: MXPA05009432A
Authority: MX
Inventors: Verboom Cees-Nico
Original assignee: Solvay Pharm Gmbh
Priority date: 2003-03-05
Filing date: 2004-03-02
Publication date: 2005-11-23
Also published as: JP2006519244A; AU2004216856A1; EP1603551A2; WO2004078166A2; CN1756545A; CA2515328A1; BRPI0408006A; WO2004078166A3

Abstract

The invention concerns the use of essential fatty acids with a high content in eicosapentaenoic acid ethyl ester (EPA) or docosahexaenoic acid ethyl ester (DHA) useful for preventing of cardiovascular events in patients with diabetes mellitus.

Description

USE OF OMEGA-3 FATTY ACIDS IN THE TREATMENT OF DIABETIC PATIENTS DESCRIPTION OF THE INVENTION This invention relates to the use of a pharmaceutical composition containing essential fatty acid ethyl esters originating from fish oil, in particular as a high concentration mixture of ethyl esters of eicosapentaenoic acid (EPA) (20: 5? 3) and docosahexaenoic acid (DHA) (22: 6? 3) in patients who suffer from diabetes. It is well known that some essential fatty acids found in fish oil have a therapeutic effect in the prevention and treatment of cardiovascular disorders, such as in the treatment of hypertension, thrombosis, hypercholesterolemia, arteriosclerosis, cerebral infarction, death prevention sudden in patients after myocardial infarction, improvement of endothelial function and hyperlipedemies. The Patents of E.U.A. 5,502,077; 5,656,667 and 5,698,594 can be indicated as examples. The prevention of cardiovascular events, especially mortality in patients who have survived the hospitalization phase of acute myocardial infarction (AMI), is described in the international patent application WO 00/48592. The prior art mentioned above in particular provides knowledge about the usefulness of the fatty acids belonging to the family? -3, more specifically eicosapentaenoic acid (EPA) (20: 5? 3) and docosahexaenoic acid (DHA) (22 : 6? 3) in the treatment of the disorders mentioned above. The fatty acid EPA, is a precursor of PGI3 and TxA3, exerts an effect of prevention of platelet aggregation and an antithrombotic effect that can be attributed to the inhibition of cyclooxygenase (effect similar to that of aspirin) or competition with arachidonic acid for this enzyme, with subsequent reduction in the synthesis of PGE2 and TxA2, which are well known platelet aggregation agents. On the other hand, the fatty acid DHA is the most important component of brain lipids in man and, in addition, it is a structural component of platelet cells and indirectly intervenes in the increase in platelet fluidity and thus plays an important role in the antithrombotic activity. The international patent application WO 89/11521, the description of which is hereby incorporated by reference, describes in particular an industrial process for extracting mixtures with a high content of polyunsaturated acids including EPA and DHA and their ethyl esters from animal or vegetable oils. The mixtures of fatty acids, especially EPA / DHA that are obtained according to O 89/11521 are reported to be particularly useful in the treatment of cardiovascular diseases. However, current methods of treatment used in human therapy have shown that it is insufficient in patients who have diabetes mellitus, particularly in those patients in whom it is also desired to avoid cardiovascular events. It is well known that patients with diabetes, in particular with diabetes mellitus, are at a substantially increased risk of cardiovascular events and death. Therefore, there is still a substantial need for improved and effective treatments with drugs, in particular to avoid such recurrence. Therefore, the object of this invention is to provide such improved and effective treatment for diabetic patients. Therefore, this invention suggests the novel use of essential fatty acids with a high content of ethyl ester of EPA or of DHA ethyl ester or a mixture with a high concentration thereof, in the preparation of a medicament useful for the treatment of patients suffering from diabetes. In particular, the invention is related to the prevention of cardiovascular events in patients who have diabetes mellitus. For ease of description, the terms "ethyl ester of EPA" and "ethyl ester of DHA" are also indicated herein as "EPA" and "DHA". In particular, this invention relates to the use of essential fatty acids containing a mixture of ethyl ester of eicosapentaenoic acid (EPA) and ethyl ester of docosahexaenoic acid (DHA) in the preparation of a drug useful for the treatment of patients suffering from diabetes , preferably to prevent cardiovascular events in patients who have diabetes, wherein the content of EPA and DHA in such a mixture is greater than 25% by weight. An essential fatty acid with a high content of EPA or DHA, according to the present invention, preferably contains more than 25% by weight, in particular from about 60 to about 100% of said ester. These compounds can be obtained by known methods. In an essential fatty acid with a high concentration mixture of EPA and DHA, said mixture preferably has an EPA and DHA content greater than 25% by weight, in particular from approximately 30 to approximately 100% by weight, preferably about 85% by weight. In the EPA / DHA blend, EPA is preferably present in a percentage of about 40 to 60% by weight, and DHA preferably in a percentage of about 25 to about 45-50%. In any case, the preferred proportion of EPA / DHA in such EPA / DHA mixture is approximately 0.9 / 1.5.

PHARMACOLOGY Diabetes mellitus has become a disease with a higher prevalence worldwide. The prevalence of diabetes increases rapidly and the number of individuals with type II diabetes (80-90% of all diabetics) has been predicted to reach 300 million by the year 2025, constituting 5.4% of the world population. In addition, cardiovascular events are important contributors in morbidity and mortality in patients with diabetic diseases. The risk of death from cardiovascular diseases, in patients with diabetes, is 2 to 6 times that found among people without diabetes. Currently, more than 50% of diabetic patients die of coronary heart disease. In contrast to non-diabetic persons, coronary cardiac mortality has not decreased in diabetic persons. Type II diabetes eliminates the protective advantage of the female sex against Mortality due to coronary cardxopathy. The prognosis after an event of coronary cardxopathy is poorer in diabetic people than in people or diabetics. Within 1 year after acute myocardial infarction, 44.2% of type II diabetic men and 36.9% of type II diabetic women die. All manifestations of coronary heart disease are at least twice as common as in patients with diabetes compared in non-diabetic individuals. In addition, the close relationships between diabetes and cardiovascular disease, not at least coronary artery disease, have recently been elucidated. It has been shown in several studies that 28% of patients with known coronary artery disease have diabetes and that up to 70% of patients with acute coronary syndromes have abnormal glucose metabolism, either in the form of diabetes or impaired glucose tolerance. The main risk factors for coronary heart disease in patients with diabetes are: 1. an unfavorable liprotein profile, characterized by increased serum triglycerides (triacylglycerides); 2. increased blood pressure; 3. predisposition to thrombus formation, which include the following manifestations: concentrations Elevated Plasminogen-1 Activator and Cytokines; 4. damage of endothelin-dependent vasodilation; 5. Autonomic cardiac damage that leads to decreased ischemic pain perception, increased heart rate and decreased heart rate variability, which in turn increases the risk of sudden death. The effectiveness of the treatment, according to the present invention is demonstrated by the preclinical and clinical broad tests: 1. EPA plus DHA induce a reduction in the concentrations of triglycerides and cholesterol with very low density lipoprotein (VLDL) in patients with hypertriglyceridemia; 2. EPA plus DHA lower blood pressure in patients with hypertension; 3. EPA and DHA in the diet down regulate the expression of platelet-derived growth factor A genes and platelet-derived growth factor B in human mononuclear cells; 4. Supplementation with EPA plus DHA mitigates the development of coronary atherosclerosis in patients with coronary heart disease; 5. EPA and DHA improve endothelial function in cardiac transplant recipients; 6. Experimental studies have shown that EPA and DHA are antiarrhythmic in several animal models, probably due to specific modulation of ion currents; 7. EPA and DHA increase heart rate variability in healthy volunteers and survivors of myocardial infarction; 8. EPA plus DHA decrease the incidence of sudden death in survivors of myocardial infarction. The tests mentioned before reduction of risk factors demonstrate that the present invention provides a new and valuable therapeutic tool for the treatment of diabetic patients, and in particular to avoid cardiovascular events in diabetic patients. Accordingly, this invention also provides a method for treating diabetic patients, preferably patients with diabetes mellitus and in particular to prevent cardiovascular events in diabetic patients, preferably in patients with diabetes mellitus, which comprises administering to said patient a therapeutically effective amount of a medicine that contains essential fatty acids with a high content of ethyl ester of EPA or ethyl ester of DHA or a mixture of high concentration thereof. The essential fatty acids, according to the invention, can have a high content, for example more than 25% by weight of EPA or DHA, or in a mixture thereof. However, the ethyl ester of EPA and DHA is preferably present as a mixture thereof with an EPA and DHA content greater than 25% by weight, in particular from approximately 30% to approximately 100% by weight, preferably approximately 85% by weight. Based on the available tests, according to a preferred aspect of the invention, the dosage of an essential fatty acid containing a mixture of EPA and DHA with a titer of 85% by weight for oral administration to a patient, can vary from about 0.7 g to about 6 g daily, preferably about 1 g daily. This amount of product as a mixture of EPA and DHA (or amount of EPA alone or of DHA alone) can be administered in several divided doses during the day or preferably in a single administration in order to obtain the desired blood level. Obviously, this is at the discretion of the doctor who can adjust the amount of product that is administered according to the age, weight and general conditions of the patient.

The medicament, for example in the form of a pharmaceutical composition, according to this invention, can be prepared according to methods known in the art. The preferred route of administration is oral (buccal), however, alternative routes of administration are left, for example, parenterally, at the discretion of the doctor. Preferred variables of the present invention are further defined in the dependent claims. The following examples illustrate preferred formulations for oral administration, but are not intended to limit the invention in any way.

Gelatin Capsules According to known pharmaceutical techniques, capsules are prepared having a composition indicated in the following and containing 1 g of active ingredient (EPA and DHA, 85% title).

Formulation 1 EPA ethyl ester 525 mg / capsule DHA ethyl ester 315 mg / capsule d-o¡ tocoperol 4UI mg / gelatin capsule 246 mg / capsule glycerol 118 mg / capsule red iron oxide 2.27 mg / capsule yellow iron oxide 1.27 mg / capsule Formulation 2 ethyl esters of 1000 mg polyunsaturated fatty acids containing ethyl esters of polyunsaturated esters? 3 (EPA eicosapentaenoic, DHA docosahexaenoic), 850 mg dl-oí-tocopherol 0.3 mg gelatin succinate 233 mg glycerol 67 mg sodium p-oxybenzoate 1.09 mg propyrosodium p-oxobenzoate 0.54 mg

Claims

CLAIMS 1. The use of essential fatty acids containing a mixture of ethyl ester of eicosapentaenoic acid (EPA) and ethyl ester of docosahexaenoic acid (DHA) in the preparation of a medicament useful for the treatment of patients suffering from diabetes, preferably for avoid cardiovascular events in patients who have diabetes, wherein the content of EPA and DHA in said mixture is greater than 25% by weight. 2. The use as described in claim 1, wherein the medicament is useful to prevent cardiovascular events in a patient who has diabetes mellitus. 3. Use as described in the claim 1 or 2, wherein the EPA and DHA content in said mixture is from about 30 to about 100% by weight. 4. The use as described in claim 1 or 2, wherein the content of EPA and DHA in said mixture is about 85% by weight. 5. The use as described in any of claims 1 to 4, wherein the medicament is for oral administration. 6. The use as described in claim 4, wherein the medicament is for oral administration, a dosage of about 0.7 g to about 6 g daily. 7. The use as described in claim 6, wherein the ratio of EPA and DHA in the mixture of EPA and DHA is about 0.9 / 1.5. 8. The use of essential fatty acids containing ethyl ester of eicosapentaenoic acid (EPA) or ethyl ester of docosahexaenoic acid (DHA) in the preparation of a medicament useful for the treatment of patients suffering from diabetes, preferably to avoid cardiovascular events in patients who have diabetes, where the content of EPA and DHA is greater than 25% by weight. 9. The use as described in claim 8, wherein the medicament is useful to prevent cardiovascular events in a patient who has diabetes mellitus. The use as described in claim 8 or 9, wherein the content of EPA or DHA is from about 60 to about 100% by weight. 11. The use as described in any of claims 8 to 10, wherein the medicament is for oral administration. 12. A method for the treatment of patients suffering from diabetes, preferably diabetes mellitus, in particular to prevent cardiovascular events in patients who have diabetes, preferably in a patient who has diabetes mellitus, which comprises administering to the patient a therapeutically effective amount of a medicament containing essential fatty acids containing a mixture of ethyl ester of eicosapentaenoic acid (EPA) ) and docosahexaenoic acid ethyl ester (DHA) wherein the content of EPA and DHA in said mixture is greater than 25% by weight. The method as described in claim 12, wherein the content of EPA and DHA in said mixture is from about 30 to about 100% by weight. 1 . The method as described in claim 12, wherein the content of EPA and DHA in said mixture is about 85% by weight. 15. The method as described in claim 12, 13 or 14, wherein the medicament is administered orally. The method as described in claim 14, wherein the medicament is orally administered at a dosage of about 0.7 g to about 6 g daily. 17. The method as described in claim 16, wherein the proportion of EPA / DHA in the EPA and DHA mixture is approximately 0.9 / 1.5. 18. A method for the treatment of patients suffering from diabetes, preferably diabetes mellitus, in particular to prevent cardiovascular events in patients who have diabetes, preferably in a patient who has diabetes mellitus, which comprises administering to the patient a therapeutically effective amount of a medicament containing essential fatty acids containing a mixture of ethyl ester of eicosapentaenoic acid (DPA) and ethyl ester of docosa-dopaenoic acid (DHA), wherein the content of EPA and DHA in said mixture is greater than 25% by weight. The method as described in claim 18, wherein the content of EPA and DHA in said mixture is from about 30 to about 100% by weight. The method as described in claim 18, wherein the EPA and DHA content in said mixture is about 85% by weight. The method as described in claim 18, 19 or 20, wherein the medicament is administered orally. 22. The method as described in claim 20, wherein the medicament is administered orally at a dosage of about 0.7 g a approximately 6 g daily. The method as described in claim 22, wherein the ratio of EPA / DHA in the mixture of EPA and DHA is about 0.9 / 1.5. 24. A method for the treatment of patients suffering from diabetes, preferably diabetes mellitus, in particular to prevent cardiovascular events in patients who have diabetes, preferably in a patient who has diabetes mellitus, which comprises administering to the patient a therapeutically effective amount of a medicament containing essential fatty acids with a content of ethyl ester of eicosapentaenoic acid (EPA) or of ethyl ester of docosahexaenoic acid (DHA) greater than 25% by weight. 25. The method as described in claim 24, wherein the content of EPA or DHA is from about 60 to about 100% by weight. 26. The method as described in claim 24 or 25, wherein the medicament is administered orally. 27. A method for the treatment of patients suffering from diabetes, preferably diabetes mellitus, in particular to prevent cardiovascular events in patients who have diabetes, preferably in a patient who has diabetes mellitus, comprising administering to the patient a therapeutically effective amount of a medicament containing essential fatty acids with a content of ethyl ester of eicosapentaenoic acid (EPA) or ethyl ester of docosahexaenoic acid (DHA) greater than 25% by weight. The method as described in claim 27, wherein the content of EPA or DHA is from about 60 to about 100% by weight. 29. The method as described in claim 27 or 28, wherein the medicament is administered orally.