JP2009544702A - Omega-3 fatty acids for the treatment of resistant hypertension - Google Patents

Abstract

  A composition comprising omega-3 fatty acids for treating resistant hypertension, for lowering blood pressure of a patient suffering from resistant hypertension and / or for suffering from resistant hypertension Compositions useful for the control of blood pressure are provided. The composition is also a method of treating resistant hypertension in a patient in a subject group suffering from resistant hypertension, wherein the subject group has a statistically significant amount of blood pressure compared to a control group. It is also useful for methods that only reduce.

Description

(Related application)
This application claims priority from US Provisional Application No. 60 / 83,156, filed July 21, 2006, the contents of which are hereby incorporated by reference.

(Field of Invention)
The present invention generally relates to compositions comprising omega-3 fatty acids that are useful for the treatment of resistant hypertension. The present invention also relates to a pharmaceutical preparation produced from the composition, a method for producing such a preparation, and a method for treating resistant hypertension using the preparation.

  Hypertension is a dangerous condition that increases cardiac activity and causes atherosclerosis. Hypertension increases the risk of heart disease and stroke, the first and third leading cause of death in Americans. Hypertension can also lead to other symptoms such as congestive heart failure, kidney disease and blindness.

  According to the National Institutes of Health, blood pressure levels above 140/90 mmHg (systolic / diastolic) are considered “high”. About two-thirds of people over the age of 65 have hypertension. In many people, a reduction in blood pressure levels can be achieved by changing lifestyle such as weight loss, dietary sodium loss, exercise, alleviation of alcohol consumption, and smoking cessation. However, for some people, lifestyle changes are not appropriate or do not persist, or require further interference. These patients are prescribed medication.

  Currently, many drugs for lowering blood pressure are commercially available. However, more than two-thirds of people with hypertension cannot be controlled with one drug and require two or more hypertensive agents selected from different types. In hypertensive patients that target low blood pressure or have substantially high blood pressure, three or more hypertensive agents may be used. If the use of a single drug is inappropriate to achieve the target blood pressure level, for example if the blood pressure is 20 mmHg or more higher than the systolic target or 10 mmHg or higher than the diastolic target The use of two antihypertensive drugs is recommended.

  In particular, persistent hypertension is resistant hypertension. The Joint US Committee's 7th report on prevention, detection, evaluation and treatment of hypertension (usually known as “JNC7”) (published by the American Heart, Lung and Blood Association in August 2004) Essential hypertension is defined as "a disease in which the target blood pressure cannot be achieved in a patient who fully performs an appropriate dosing regimen of three drugs, including diuretics".

  Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting diacylglycerol acyltransferase (DGAT) and stimulating peroxomar and mitochondrial beta-oxidation. Fish oil (commonly referred to as fish oil) has been found to be an excellent source of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and regulate lipid metabolism. Omega-3-fatty acids have been found to have an effective action on risk factors for cardiovascular disease, especially mild hypertension, hypertriglyceridemia, and on coagulation factor VII phospholipid complex activity. Furthermore, omega-3 fatty acids appear to be well tolerated without causing severe side effects.

  One form of omega-3 fatty acids is a concentrate of omega-3 long chain polyunsaturated fatty acids derived from DHA and EPA-containing fish oil, which is commercially available under the registered trademark (Lovaza). Such forms of omega-3 fatty acids are described, for example, in US Pat. Nos. 5,050,077 and 5,698,594, the contents of which are hereby incorporated by reference. These patents disclose the use of such concentrated forms of omega-3 fatty acids in the treatment of hypertension.

  Various studies have been done to determine the effects of nutritional supplements containing omega-3 fatty acids on hypertensive patients being treated with multiple hypertensive drugs. The results of such studies are summarized.

  Lungershausen et al., J. Hypertension 1994, 12: 1041-1045 evaluated the effect of omega-3 fatty acid supplements on blood pressure in hypertension treated with diuretics, beta-blockers or both. 43 of essential hypertension without complications controlled by taking beta blockers only (n = 29), diuretics only (n = 3) or a mixture of beta blockers and diuretics (n = 11) One patient was subjected to a cross-over experiment in which either placebo (4 g corn oil) or fish oil (4 g Lovaza®, containing 85% EPA and DHA) was administered. All participants had been taking antihypertensive drugs for at least one year and had satisfactory control in all cases. Pre-medication baseline blood pressure levels averaged 172/103 mmHg in the first corn oil group and 173/103 mmHg in the first Lovaza® group. From this experiment, it can be seen that systolic blood pressure and diastolic blood pressure are significantly lower in each group during the period of supplementing omega-3 fatty acids.

  Wing et al., J. Hypertension 1990, 8: 339-343 tested the effect of dietary supplements containing fish oil on blood pressure in 20 treated hypertensive patients with controlled blood pressure. Of the patients taking the three hypertension drugs, 2 were beta blockers, diuretics and nifedipine or prazosin, and 3 were ACE inhibitors, diuretics and beta blockers or nifedipine. Patients received either placebo (15 g olive oil) or fish oil (Lipitac® containing 30% EPA and DHA) in a crossover experiment. The patient's mean pre-test blood pressure was 144.7 / 84.5 mmHg. The experiment failed to reveal the difference in blood pressure between the two phases of treatment with fish oil and olive oil.

  Woodman et al., Am. J. Clin. Nutr. 2002, 76: 1007-1015, tests whether either purified EPA or purified DHA treatment has a differential effect on the blood pressure of treated hypertensive patients. did. 51 patients were subjected to a single arm experiment in which 4 g of purified (about 96%) EPA, purified (about 92%) DHA or olive oil placebo was administered once a day for 6 weeks. 24 of the subjects used three or more antihypertensive drugs. Average baseline blood pressure was 135.9 / 73.0 mmHg in the olive oil group. There were no significant differences in baseline systolic or diastolic blood pressure between groups. In comparing changes in the olive oil group, there was no significant change in systolic or diastolic blood pressure in either the EPA or DHA groups.

  Bao et al., Hypertension 1998, 32: 710-717 tested the effects of fish-centered diet and weight loss on blood pressure in overweight hypertensive patients. 4 groups of patients: control group; group of fish-centered diets where patients eat fish meal (about 3.65 g omega-3 fatty acids) daily; weight loss group; or fish diet + weight loss group Randomly divided. 2 out of 16 subjects in the control group, 1 out of 17 subjects in the fish-centered diet group, 1 out of 16 subjects in the weight-loss group, and fish-centered diet + weight loss One of the 14 subjects in the group took 3 or more antihypertensive drugs. The mean baseline blood pressure for group 4 is 135.9 / 75.4 mmHg for the subject group, 132.1 / 75.2 mmHg for the fish-centered diet group, and 137.6 / 78.3 mmHg for the weight loss group. It was 132.1 / 74.9 mmHg in the fish-centered diet + weight loss group. In this experiment, it was found that adding a fish meal rich in omega-3 fatty acids daily into a low-fat, energy-restricted diet for obesity-treated hypertensive subjects has an additional effect on reducing blood pressure.

  Gray et al., Pharmacother. 1996, 16 (2): 295-300 show the effect of omega-3 fatty acid supplements on blood pressure control in 19 subjects whose blood pressure is not effectively controlled with antihypertensive drugs. Tested. Subjects received either 18 g herring oil (containing 25% omega-3 fatty acids) or 18 g corn oil placebo. Subjects in the placebo group had an average baseline supine blood pressure of 151/93 mmHg and in the fish oil group it was 151/97 mmHg. Subjects who took fish oil had a significant decrease in blood pressure by the end of the 4th week of treatment, but the decrease was not appreciable after 8 weeks.

Lungershausen et al., J. Hypertension 1994, 12: 1041-1045. Wing et al., J. Hypertension 1990, 8: 339-343. Woodman et al., Am. J. Clin. Nutr. 2002, 76: 1007-1015. Bao et al., Hypertension 1998, 32: 710-717. Gray et al., Pharmacother. 1996, 16 (2): 295-300.

Problems to be solved by the invention

  None of the above references disclose that omega-3 fatty acids are useful for the treatment of resistant hypertension. There is a need in the art for the treatment of resistant hypertension.

  The present invention relates to compositions containing natural or synthetic omega-3 fatty acids and / or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof, for the treatment of resistant hypertension. By providing it as a novel therapeutic agent, it fulfills unmet needs in the field as well as other needs.

  The present invention provides natural or synthetic omega-3 fatty acids and / or pharmaceutically acceptable esters, derivatives, conjugates thereof to provide an effective pharmaceutical treatment of resistant hypertension while minimizing undesirable side effects. A gate, precursor or salt, or a mixture thereof is also provided.

  One embodiment of the present invention provides a natural or synthetic omega-3 fatty acid and / or a pharmaceutically acceptable ester, derivative, conjugate, precursor or salt thereof, or in the treatment of a subject with resistant hypertension, or A method of utilizing the mixture is provided.

  Another embodiment of the present invention is an oral formulation of natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts, or mixtures thereof, Formulations for use in the treatment of subjects with resistant hypertension are provided.

  Another object of the present invention is a method for lowering blood pressure in a patient suffering from resistant hypertension, comprising natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates thereof. Administering a gate, precursor or salt, or a mixture thereof.

Another object of the present invention is a method for controlling blood pressure in a patient suffering from resistant hypertension, comprising a natural or synthetic omega-3 fatty acid or a pharmaceutically acceptable ester, derivative thereof, Administering a conjugate, precursor or salt, or a mixture thereof.

  Another object of the present invention is to produce a natural or synthetic omega-3 fatty acid or a pharmaceutically acceptable ester, derivative, conjugate, precursor, or precursor for the manufacture of a medicament for the treatment of resistant hypertension. The use of salts or mixtures thereof.

  Another object of the present invention is a method of treating resistant hypertension in a subject group, comprising natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors thereof. Or a method comprising administering a salt, or a mixture thereof.

  Another object of the invention includes administering to a subject group a natural or synthetic omega-3 fatty acid or a pharmaceutically acceptable ester, derivative, conjugate, precursor or salt thereof, or a mixture thereof. A method for treating resistant hypertension in the group, wherein after administration to the subject group, the blood pressure of the subject group is reduced to a statistically significant degree as compared to the control group.

  Other novel features and advantages of the invention will become apparent from the following tests of the invention or from practice of the invention.

  The present invention relates to omega-3 fatty acids, a process for their preparation and their use in the treatment of resistant hypertension.

  In some preferred embodiments, the omega-3 fatty acid comprises Lovaza® omega-3 fatty acid, as described in US Pat. Nos. 5,050,077, 5,656,667, and 5,698,594. In other preferred embodiments, the omega-3 fatty acid is present at a concentration of at least 40% by weight relative to the total fatty acid content of the composition. In yet another preferred embodiment, the omega-3 fatty acid comprises at least 50% by weight EPA and DHA compared to the total fatty acid content of the composition. EPA and DHA have an EPA: DHA weight ratio of 99: 1 to 1:99, preferably 1: 4 to 4: 1, more preferably 1: 3 to 3: 1, most preferably 1: 2 to 2: 1. The omega-3 fatty acid may also be pure EPA or pure DHA.

  As used herein, the term “omega-3 fatty acids” refers to natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates thereof (eg, Zaloga et al., US Patent Application Publications). 2004/0254357 and Horrobin et al., US Pat. No. 6,245,811, each of which is hereby incorporated by reference), precursors or salts, or mixtures thereof. Examples of omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated long chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and α-linolenic acid; mono-, di- -And esters of omega-3 fatty acids with glycerol such as tri-glycerides; and esters of omega-3 fatty acids with primary, secondary or tertiary alcohols, such as fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long chain fatty acids such as EPA or DHA, their triglycerides, their ethyl esters and mixtures thereof. Omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof may be used in their pure form or as components of oils such as fish oils, preferably refined fish oil concentrates. it can. Commercial examples of omega-3 fatty acids suitable for use in the present invention include Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525, and E5015 (UK, Yorkshire, Croda International PLC) and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Norway, Lysaker, Pronova Biocare as).

  Another preferred composition comprises omega-3 fatty acids at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, even more preferably at least 70% by weight, most preferably at least 80%. Includes those formulated at a concentration of weight percent, or at least 90 weight percent. Preferably, the omega-3 fatty acid comprises at least 50 wt%, more preferably at least 60 wt%, even more preferably at least 70 wt%, most preferably at least 80 wt%, such as about 84 wt% EPA and DHA. . Preferably, the omega-3 fatty acid contains about 5 to about 100% by weight of EPA, more preferably about 25 to about 75% by weight, even more preferably about 40 to about 55% by weight, and most preferably about 46% by weight EPA. Including. Preferably, the omega-3 fatty acid contains about 5 to about 100% by weight of DHA, more preferably about 25 to about 75% by weight, even more preferably about 30 to about 60% by weight, and most preferably about 38% by weight DHA. Including. All percentages given above are by weight relative to the total fatty acid content in the composition, unless otherwise specified. The weight percent is based on the form of the free acid or ester, but is preferably based on the form of the ethyl ester of omega-3 fatty acid, even if other forms are utilized in accordance with the present invention.

  The omega-3 fatty acid may be present in an amount of about 350 mg to about 10 g, more preferably about 500 mg to about 6 g, and most preferably about 750 mg to about 4 g. This amount may be formulated in one or more dosage forms, preferably in one dosage form. Omega-3 fatty acid compositions optionally include chemical antioxidants such as alpha tocopherol, oils such as soybean oil and partially hardened edible oil, fractionated coconut oil, lubricants such as lecithin, and mixtures thereof. Also good.

The most preferred form of omega-3 fatty acid is Lovaza® omega-3 fatty acid (K85EE, Norway, Lysaker, Pronova Biocare AS), consisting of the following properties (per dosage form):

  The active ingredient of the present invention, omega-3 fatty acids, may be administered in combination with one or more non-active pharmaceutical ingredients (also commonly referred to herein as “excipients”). . For example, inactive ingredients solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor and shape active ingredients, safe and convenient to use It helps to make an applicable and effective formulation that would otherwise be acceptable.

  Excipients are propylene glycol monocaprylate, a mixture of glycerol and polyethylene glycol esters of long chain fatty acids, polyethoxylated castor oil, glycerol ester, oleyl macrogol glyceride, propylene glycol monolaurate, propylene glycol dicaprylate / dicolarate Surfactants such as polyethylene-polypropylene glycol copolymers and polyoxyethylene sorbitan monooleate, co-solvents such as ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oil. The use of surfactants, co-solvents, oils or combinations thereof is well known in the pharmaceutical arts and, as those skilled in the art can appreciate, any suitable surfactant is used in combination with the present invention and embodiments thereof. be able to.

  The compositions and methods of the present invention may further comprise administering together one or more additional compounds useful for the treatment of hypertension. Unit dosage forms comprising natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof, and one or more additional compounds also comprise Also encompassed are methods of administration to a patient in need thereof.

  These additional compounds may be one or more, preferably two or more, most preferably three or more different compounds, each of which is independently a diuretic Aldosterone receptor blockers, beta blockers, combined alpha- and beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, alpha-1 blockers, central alpha-2 agonists, and direct acting blood vessels Selected from the group of extenders. Preferably, the at least one additional compound is a diuretic. More preferably, the additional compounds include at least three different types of compounds as described above, including diuretics. Existing treatments using three different types of compounds, including diuretics, are typically found in subjects with resistant hypertension.

  The present invention also includes the use of compounds similar to those described above that may be found in future or existing compounds that may be approved for the treatment of hypertension in the future.

  Compositions containing omega-3 fatty acids can be prepared in the form of capsules such as hard gelatin capsules; tablets; powders that can be dispersed in beverages; liquids; or soft gel capsules. The composition may also contain a liquid suitable for injection or infusion. However, the preparation of the composition of the present invention for administration is not limited to a specific dosage form. Furthermore, the composition may be prepared as any pharmaceutically acceptable dosage form, including other solid oral dosage forms, other liquid oral dosage forms, and any suitable dosage form. If provided, one or more additional optional excipients may be provided in the dosage form with the omega-3 fatty acid, and a convenient unit dosage form may be discovered.

  Omega-3 fatty acids are administered to patients suffering from resistant hypertension in a daily dosage of about 0.1 g to about 10 g, more preferably about 1 g to about 6 g, most preferably about 2 g to about 4 g. can do. The daily dose of omega-3 fatty acids can be administered together in 1 to 10 dosage forms, preferably 1 to 4 times daily, most preferably 1 to 2 times daily. Administration is preferably oral administration, although other dosage forms that provide unit doses of omega-3 fatty acids may be used. Administration of the dose is preferably effective in lowering blood pressure levels, more preferably effective in controlling blood pressure. Treatment according to the present invention reduces systolic blood pressure levels to 140 mmHg or less and / or reduces diastolic blood pressure levels to 90 mmHg or less.

  The blood pressure level is measured by any method recognized in the art such as, but not limited to, blood pressure measurement in a supine, sitting, upright, standing or 24-hour free action. be able to.

  Throughout this application, various patents and publications are cited. The disclosures of these patents and publications are hereby incorporated by reference.

  Since those skilled in the relevant arts to which this disclosure will benefit will contemplate substantial modifications, changes and equivalents in form and function, the invention also includes such modifications, variations and equivalents.

  Although the invention has been described with reference to the presently preferred embodiments, it is not limited thereto. On the contrary, the present invention includes various modifications and equivalent changes within the spirit and scope of the above detailed description of the invention.

Claims (20)

Its treatment in patients suffering from resistant hypertension,
Providing a composition comprising one or more omega-3 fatty acids;
Administering the composition to a patient in an amount effective to treat resistant hypertension. A method for lowering blood pressure in a patient suffering from resistant hypertension, comprising:
Providing a composition comprising one or more omega-3 fatty acids;
Administering the composition to a patient in an amount effective to lower blood pressure.   3. The method of claim 2, wherein the treatment reduces systolic blood pressure to 140 mmHg or less and / or diastolic blood pressure to 90 mmHg or less. A method of controlling blood pressure in a patient suffering from resistant hypertension comprising:
Providing a composition comprising one or more omega-3 fatty acids;
Administering the composition to a patient in an amount effective to control blood pressure.   Use of one or more omega-3-fatty acids for the manufacture of a medicament for its treatment in a patient suffering from resistant hypertension. A method of treating resistant hypertension in a subject group of patients suffering from resistant hypertension comprising:
Providing a composition comprising one or more omega-3 fatty acids;
Administering the composition to a subject group in an amount effective to treat resistant hypertension in the subject group. A method of treating resistant hypertension in a subject group of patients suffering from resistant hypertension comprising:
Providing a composition comprising one or more omega-3 fatty acids;
Administering the composition to a subject group, wherein the blood pressure of the subject group has dropped to a statistically significant amount relative to the control group after administration to the subject group.   8. The method or use according to any one of claims 1 to 7, wherein the one or more omega-3 fatty acids comprises EPA and DHA.   9. The method or use according to any one of claims 1 to 8, wherein the one or more omega-3 fatty acids are present at a concentration of at least 40% by weight relative to the total fatty acid content of the composition.   9. The method or use according to any one of claims 1 to 8, wherein the one or more omega-3 fatty acids are present at a concentration of at least 80% by weight relative to the total fatty acid content of the composition.   11. A method or use according to any one of the preceding claims, wherein the one or more omega-3 fatty acids comprise at least 50% by weight EPA and DHA, relative to the total fatty acid content of the composition.   11. A method or use according to any one of the preceding claims, wherein the one or more omega-3 fatty acids comprise at least 80% by weight of EPA and DHA relative to the total fatty acid content of the composition.   13. The method according to any one of claims 1 to 12, wherein the one or more omega-3 fatty acids comprise about 40% to about 55% by weight EPA relative to the total fatty acid content of the composition. use.   14. The method according to any one of claims 1 to 13, wherein the one or more omega-3 fatty acids comprise from about 30% to about 60% by weight DHA relative to the total fatty acid content of the composition. use.   One or more omega-3 fatty acids are omega-3 polyunsaturated long chain fatty acids; esters of omega-3 fatty acids with glycerol; and esters of omega-3 fatty acids with primary, secondary or tertiary alcohols; and 15. A method or use according to any one of claims 1 to 14 selected from the group consisting of mixtures thereof.   16. The method or use according to any one of claims 1 to 15, wherein the EPA and DHA have an EPA: DHA weight ratio of 1: 2 to 2: 1.   17. A method or use according to any one of claims 1 to 16, wherein the composition further comprises one or more additional compounds useful for the treatment of hypertension.   The one or more additional compounds are respectively diuretics, aldosterone receptor blockers, beta blockers, alpha- and beta combination blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, alpha- 18. The method of claim 17, wherein the method is selected from the group consisting of a 1 blocker, a central alpha-2 agonist, and a direct acting vasodilator.   19. A method according to claim 17 or 18, wherein the one or more additional compounds comprise at least three different types of additional compounds useful for the treatment of hypertension.   20. The method of claim 19, wherein at least one of the three types of additional compounds is a diuretic.