CN1756545A - Use of omega-3-fatty acids in the treatment of diabetic patients - Google Patents

Abstract

The present invention relates to the use of essential fatty acids having a high content of ethyl eicosapentaenoate (EPA) or ethyl docosahexaenoate (DHA) for the prevention of cardiovascular disease in patients with diabetes.

Description

Application of omega-3-fatty acid in the treatment of diabetic patients

field of invention

The present invention relates to the application of a pharmaceutical composition containing ethyl esters of essential fatty acids derived from fish oil, especially a high concentration of (20:5ω3) eicosapentaenoic acid ( EPA) and (22:6ω3) a mixture of ethyl esters of docosahexaenoic acid (DHA).

Background of the invention

It is well known that certain essential fatty acids contained in fish oil can prevent and treat cardiovascular diseases, such as treating hypertension, thrombosis, hypercholesterolemia, arteriosclerosis, and cerebral infarction; preventing sudden death in patients after myocardial infarction; improving endothelial function and high blood pressure. It has therapeutic effect in lipidemia.

US patents US 5,502,077, US 5,656,667 and US 5,698,594 may be cited as examples. Prevention of cardiovascular disease, especially mortality in patients who have survived an acute myocardial infarction (AMI) hospitalization, is described in International Patent Application WO 00/48592.

The aforementioned prior art in particular provides information on fatty acids belonging to the omega-3 family, more specifically (20:5ω3) eicosapentaenoic acid (EPA) and (22:6ω3) docosahexaenoic acid ( DHA) in the treatment of the above diseases.

Prevention of fatty acid EPA production as a precursor to PGI 3 and TxA3 can be attributed to cyclooxygenase inhibition (similar effect to aspirin) and/or competition with arachidonic acid for the platelet aggregation and anticoagulant effects of this enzyme, Synthesis of PGE2 and TxA2, which are well-known platelet aggregation agents, is subsequently reduced.

On the other hand, the fatty acid DHA, which is the most important component in human brain lipids and is also a structural component of platelet cells, is indirectly involved in increasing platelet fluidity, thereby playing an important role in anticoagulant activity.

International patent application WO 89/11521 describes inter alia an industrial process for the extraction of mixtures with a high content of polyunsaturated acids, including EPA and DHA and their ethyl esters, from animal and/or vegetable oils, This document is incorporated herein by reference.

It is reported that fatty acid mixtures obtained according to WO89/11521, especially EPA/DHA, are particularly useful in the treatment of cardiovascular diseases.

However, current therapeutic approaches for human therapy have proven inadequate for patients with diabetes, especially those in whom cardiovascular disease also needs to be prevented at the same time. It is well known that patients with diabetes, especially with diabetes mellitus, are substantially at increased risk of cardiovascular disease and death.

Therefore, there remains a clear need for improved and effective treatment with drugs, especially for the prevention of recurrence of these diseases. It is an object of the present invention to provide such improved and effective treatments for diabetic patients.

Contents of the invention

The present invention thus proposes a new use of essential fatty acids having a high content of EPA-ethyl esters or DHA-ethyl esters or mixtures thereof in high concentrations for the preparation of medicaments for the treatment of patients suffering from diabetes. In particular, the present invention relates to methods of preventing cardiovascular disease in patients with diabetes.

For convenience of description, "EPA-ethyl ester" and "DHA-ethyl ester" are also referred to herein as "EPA" and "DHA".

In particular, the present invention relates to the preparation of essential fatty acids comprising a mixture of ethyl eicosapentaenoate (EPA) and ethyl docosahexaenoate (DHA) for the treatment of patients suffering from diabetes, preferably in the prevention of Use in diabetic patients with cardiovascular diseases, wherein the content of EPA and DHA in such mixtures is higher than 25% by weight.

The essential fatty acids of the present invention having a high content of EPA or DHA preferably contain more than 25% by weight, especially about 60 to about 100%, of such esters. These compounds can be obtained by known methods.

Among essential fatty acids with a high concentration of mixtures of EPA and DHA, it is preferred that such mixtures have an EPA and DHA content higher than 25% by weight, especially from about 30 to about 100% by weight, preferably about 85% by weight. In the EPA/DHA mixture, the preferred percentage of EPA is about 40-60% by weight and the preferred percentage of DHA is about 25-about 45-50%. In any event, the preferred ratio of EPA/DHA in such EPA/DHA mixtures is about 0.9/1.5.

Pharmacology

Diabetes has become an increasingly common disease worldwide. The incidence of diabetes is rapidly increasing and the number of individuals reported to have type 2 diabetes (80-90% of all diabetics) will reach 3 billion in 2025, accounting for 5.4% of the global population. Furthermore, cardiovascular disease is an important cause of morbidity and mortality in patients with diabetes. The risk of death from cardiovascular disease is 2-6 times higher in patients with diabetes than in non-diabetics. Currently more than 50% of diabetic patients die of coronary heart disease. In contrast to the non-diabetic population, CHD mortality did not decrease in the diabetic population. Type II diabetes eliminates women's defensive advantage in CHD mortality. The prognosis of coronary heart disease is worse in the diabetic population than in the non-diabetic population. Within 1 year after acute myocardial infarction, 44.2% of men with type 2 diabetes and 36.9% of women with type 2 diabetes died.

All manifestations of coronary heart disease are usually at least 2 times greater in patients with diabetes than in non-diabetic individuals. Furthermore, the close interrelationship between diabetes and cardiovascular disease (at least with coronary heart disease) has recently been elucidated. It has been demonstrated in numerous studies that 28% of patients with known coronary heart disease have diabetes and as many as 70% of patients with acute coronary syndrome have abnormal glucose metabolism in the form of diabetes or impaired glucose tolerance. The main risk factors for coronary heart disease in patients with diabetes are:

1. Unfavorable lipoprotein profile, characterized by increased serum triglycerides;

2. Elevated blood pressure;

3. Prone to thrombosis, including the following manifestations: high concentration of plasminogen activator-1 and cytokines;

4. Impaired endothelin-dependent vasodilation;

5. Abnormal cardiac self-discipline, leading to decreased ischemic pain sensation, high heart rate and decreased heart rate variability, thus increasing the risk of sudden death.

The efficacy of the treatment method of the present invention is confirmed by sufficient pre-clinical and clinical evidence:

1. EPA+DHA induces a reduction in triglycerides and very low-density lipoprotein cholesterol (VLDL) levels in patients with hypertriglyceridemia;

2. EPA+DHA does reduce blood pressure in patients with hypertension;

3. Dietary EPA and DHA regulate gene expression of platelet-derived growth factor-A and platelet-derived growth factor-B in human monocytes;

4. Supplementation with EPA+DHA alleviates the process of coronary atherosclerosis in patients with coronary heart disease;

5. EPA and DHA improved endothelial function in heart transplant recipients;

6. Experimental studies have confirmed the antiarrhythmic effect of EPA and DHA in several animal models, which may be caused by the specific regulation of ion current;

7. EPA and DHA increase the heart rate of healthy volunteers and myocardial infarction survivors;

8. EPA+DHA reduces the incidence of sudden death in myocardial infarction survivors.

The above evidence of reduction in risk factors indicates that the present invention provides a novel and valuable therapeutic approach for treating diabetic patients and especially for preventing cardiovascular disease in diabetic patients.

Accordingly, the present invention also provides a method for the treatment of diabetic patients, preferably patients with malnourished diabetes mellitus, and in particular for the prevention of cardiovascular disease in diabetic patients, preferably patients with malnourished diabetes mellitus, comprising treating Such patients are administered a therapeutically effective amount of a drug containing essential fatty acids with a high content of EPA-ethyl ester or DHA-ethyl ester or a mixture thereof at high concentrations.

The essential fatty acids of the present invention may have a high content, for example more than 25% by weight of EPA or DHA or a mixture thereof. However, EPA and DHA-ethyl ester are preferably present as a mixture in which the content of EPA and DHA is higher than 25% by weight, especially from about 30 to about 100% by weight, preferably about 85% by weight.

Based on the available evidence, a preferred aspect of the present invention is that an essential fatty acid containing a mixture of EPA and DHA having a titer of 85% by weight can be administered orally to a patient at a dose ranging from about 0.7 g to about 6 g per day, preferably about 6 g per day. 1g.

This amount of product as a mixture of EPA and DHA (or EPA alone or DHA alone) may be administered throughout the day in divided doses or preferably in a single dose in order to obtain the desired blood levels. Obviously, clinicians can consider adjusting the dosage of the product according to the patient's age, body weight and general condition.

The medicaments of the present invention, for example in the form of pharmaceutical compositions, can be prepared according to methods known in the art. The preferred route of administration is oral, however, the clinician may consider allowing alternative routes of administration, such as gastrointestinal.

Preferred variants of the invention are further defined in the dependent claims.

The following examples illustrate preferred formulations for oral administration, but do not limit the invention in any way.

capsule

Capsules with the following composition and each capsule containing 1 g of active ingredients (EPA and DHA, 85% titration) were prepared according to known pharmaceutical techniques.

Preparation 1

EPA-ethyl ester 525mg/capsule

DHA-ethyl ester 315mg/capsule

d-alpha tocopherol 41U/capsule

Gelatin 246mg/capsule

Glycerin 118mg/capsule

Ferric oxide 2.27mg/capsule

Yellow iron oxide 1.27mg/capsule

Preparation 2

Ethyl esters of polyunsaturated fatty acids and ethyl esters of omega-3 polyunsaturated esters

Content (eicosapentaenoic acid EPA, docosahexaenoic acid DHA) 1000mg

850mg

d-1-alpha tocopherol 0.3mg

Gelatin succinate 233mg

Glycerin 67mg

Sodium paraben 1.09mg

Sodium propylparaben 0.54mg

Claims (29)

1. the essential fatty acid that contains the mixture of EPA-E (EPA) and docosahexaenoic acid ethyl (DHA) is used for the treatment of the patient who suffers from diabetes in preparation, preferably suffer from application in the medicine of the cardiovascular disease among the patient of diabetes in prevention, wherein EPA and the DHA content in this class mixture is greater than 25% weight.

2. the application of claim 1, wherein said medicine are used for preventing suffering from the patient's of malnutrition type diabetes cardiovascular disease.

3. claim 1 or 2 application, wherein EPA and the DHA content in this class mixture is about about 100% weight of 30-.

4. claim 1 or 2 application, wherein EPA and the DHA content in this class mixture is about 85% weight.

5. any one application among the claim 1-4, wherein said medicine is used for oral administration.

6. the application of claim 4, wherein said medicine is used for oral administration, and dosage is about the about 6g of 0.7g-every day.

7. the application of claim 6, wherein EPA and the DHA ratio in EPA and DHA mixture is about 0.9/1.5.

8. the essential fatty acid that contains EPA-E (EPA) or docosahexaenoic acid ethyl (DHA) is used for the treatment of the patient who suffers from diabetes in preparation, preferably suffer from application in the medicine of the cardiovascular disease among the patient of diabetes in prevention, wherein the content of EPA and DHA is greater than 25% weight.

9. the application of claim 8, wherein said medicine are used for preventing suffering from the patient's of malnutrition type diabetes cardiovascular disease.

10. claim 8 or 9 application, wherein EPA or DHA content are about about 100% weight of 60-.

11. any one application among the claim 8-10, wherein said medicine is used for oral administration.

12. treatment suffers from the patient of diabetes, preferred malnutrition type diabetes, the patient who suffers from diabetes especially for prevention, the method of preferably suffering from patient's central vessel disease of malnutrition type diabetes, comprise the medicine that contains essential fatty acid of described patient being treated effective dose, described essential fatty acid contains the mixture of EPA-E (EPA) and docosahexaenoic acid ethyl (DHA), and wherein EPA and the DHA content in this class mixture is greater than 25% weight.

13. the method for claim 12, wherein EPA and the DHA content in this class mixture is about about 100% weight of 30-.

14. the method for claim 12, wherein EPA and the DHA content in this class mixture is about 85% weight.

15. claim 12,13 or 14 method are wherein by the described medicine of orally give.

16. the method for claim 14 wherein gives described medicine by oral dosage with the about 6g of about 0.7g-every day.

17. the method for claim 16, wherein the ratio of EPA/DHA in EPA and DHA mixture is about 0.9/1.5.

18. treatment suffers from the patient of diabetes, preferred malnutrition type diabetes, the patient who suffers from diabetes especially for prevention, the method of preferably suffering from patient's central vessel disease of malnutrition type diabetes, comprise the medicine that contains essential fatty acid of described patient being treated effective dose, described essential fatty acid contains the mixture of EPA-E (EPA) and docosahexaenoic acid ethyl (DHA), and wherein EPA and the DHA content in this class mixture is greater than 25% weight.

19. the method for claim 18, wherein EPA and the DHA content in this class mixture is about about 100% weight of 30-.

20. the method for claim 18, wherein EPA and the DHA content in this class mixture is about 85% weight.

21. claim 18,19 or 20 method are wherein by the described medicine of orally give.

22. the method for claim 20 wherein gives described medicine by oral dosage with the about 6g of about 0.7g-every day.

23. the method for claim 22, wherein the EPA/DHA ratio in EPA and DHA mixture is about 0.9/1.5.

24. treatment suffers from the patient of diabetes, preferred malnutrition type diabetes, the patient who suffers from diabetes especially for prevention, preferred malnutrition type suffers from the method for patient's central vessel disease of diabetes, comprise the medicine that contains essential fatty acid of described patient being treated effective dose, the content of EPA-E that described essential fatty acid has (EPA) or docosahexaenoic acid ethyl (DHA) is greater than 25% weight.

25. the method for claim 24, wherein the content of EPA or DHA is about about 100% weight of 60-.

26. the method for claim 24 or 25 is wherein by the described medicine of orally give.

27. treatment suffers from diabetes, the patient of preferred malnutrition type diabetes, the patient who suffers from diabetes especially for prevention, the method of preferably suffering from patient's central vessel disease of malnutrition type diabetes, comprise the medicine that contains essential fatty acid of described patient being treated effective dose, the content of EPA-E that described essential fatty acid has (EPA) or docosahexaenoic acid ethyl (DHA) is greater than 25% weight.

28. the method for claim 27, wherein EPA or DHA content are about about 100% weight of 60-.

29. the method for claim 27 or 28 is wherein by the described medicine of orally give.