Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates, generally, to compositions comprising omega- 3 fatty acids, where the compositions are useful for treating resistant hypertension.
• the present invention also includes pharmaceutical formulations made from the compositions, methods of making such formulations and methods of using the formulations to treat resistant hypertension.
• Hypertension is a dangerous condition which increases heart activity and contributes to atherosclerosis. Hypertension increases the risk of heart disease and stroke, which are the first- and third-leading causes of death among Americans. High blood pressure also can result in other conditions, such as congestive heart failure, kidney disease, and blindness.
• a blood pressure level of 140/90 rnmHg (systolic/diastolic) or higher is considered “high.”
• About two-thirds of people over 65 have hypertension.
• reduction of blood pressure levels may be achieved by lifestyle changes, such as weight reduction, dietary sodium reduction, exercise, moderation of alcohol consumption and smoking cessation.
• lifestyle changes are not suitable or adhered to, or more intervention is needed.
• drug treatment is prescribed.
• a large number of drugs are currently available for reducing blood pressure.
• more than two-thirds of hypertensive individuals cannot be controlled on one drug, and require two or more antihypertensive agents chosen from different classes.
• three or more antihypertensive drugs may be utilized.
• the use of at least a second antihypertensive drug is recommended when use of a single agent is inadequate to achieve the goal blood pressure levels, for example when blood pressure is greater than 20 mmHg above the systolic goal or 10 mmHg above the diastolic goal.
• JNC 7 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
• Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting diacylglycerol acyltransferase (DGAT) and by stimulating peroxisomal and mitochondrial beta oxidation.
• Marine oils also commonly referred to as fish oils, are a good source of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) 1 which have been found to regulate lipid metabolism.
• Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation * factor VII phospholipid complex activity.
• omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
• One form of omega-3 fatty acids is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA that is sold under the trademark Lovaza®. Such a form of omega-3 fatty acids is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, each of which is incorporated herein by reference. These patents disclose the use of such a concentrated form of omega-3 fatty acids in the treatment of hypertension.
• Various studies have been conducted to determine the effects of dietary supplementation with omega-3 fatty acids on hypertensive patients that are being treated with more than one hypertension medication. The results of such studies have been mixed.
• the average baseline blood pressure for the four groups was 135.9/75.4 mmHg for the control group, 132.1/75.2 mmHg in the fish diet group, 137.6/78.3 mmHg in the weight loss group, and 132.1/74.9 mmHg in the fish diet + weight loss group.
• the study found that the incorporation of a daily meal of fish rich in omega-3 fatty acids into a reduced-fat, energy-restricted diet In obese treated hypertensive subjects resulted in additive effects on blood pressure reduction.
• Gray et al., Pharmacother. 1996, 16(2):295-300 examined the effects of omega-3 fatty acid supplementation on blood pressure controls in 19 subjects whose blood pressure was not optimally controlled with antihypertensive agents.
• the subjects received either 18 g of menhaden oil (containing 25% omega-3 fatty acids) or 18 g of com oil placebo.
• Subjects in the placebo group had an average baseline supine blood pressure of 151/93 mmHg in the placebo group, and 151/97 mmHg in the fish oil group.
• Subjects receiving fish oil had a significant reduction in blood pressure by 4 weeks of treatment, but the decrease was less pronounced after 8 weeks.
• omega-3 fatty acids may be useful for treating resistant hypertension. There is a need in the art for treatments for resistant hypertension.
• the present invention meets the unmet needs of the art, as well as others, by providing compositions containing natural or synthetic omega-3 fatty acids, and/or
• TECH/52477L1 their pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts, or mixtures thereof, as an effective treatment for resistant hypertension.
• the present invention also provides natural or synthetic omega-3 fatty acids, and/or their pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts, or mixtures thereof, to provide an effective pharmaceutical treatment for resistant hypertension, while minimizing unwanted side effects.
• One embodiment of the present invention provides a method of utilizing natural or synthetic omega-3 fatty acids, and/or their pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts, or mixtures thereof, in the treatment of subjects with resistant hypertension.
• 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 thereof, or mixtures thereof, wherein the formulation is used tn the treatment of subjects with resistant hypertension.
• Another subject of the invention is a method of reducing blood pressure in a patient suffering from resistant hypertension, comprising administering natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof.
• Another subject of the invention is a method of controlling blood pressure in a patient suffering from resistant hypertension, comprising administering natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof.
• Another subject of the invention is the use of natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof, for the manufacture of a medicament for treating resistant hypertension.
• Another subject of . the invention is a method of treating resistant hypertension in a subject group, comprising administering to the subject group natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof.
• Another subject of the invention is a method of treating resistant hypertension in a subject group, comprising administering to the subject group natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof, wherein after administration to the subject group the blood pressure of the subject group is reduced in a statistically significant amount as compared to a control group.
• the present invention relates to compositions comprising omega-3 fatty acids, methods of making same, and their use in treating resistant hypertension.
• the omega-3 fatty acids comprise Lovaza® omega-3 fatty acids, as described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594.
• the omega-3 fatty acids are present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition.
• the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA as compared to the total fatty acid content of the composition.
• the EPA and DHA are in a weight ratio of EPA'.DHA of from 99:1 to 1:99, preferably from 1:4 to 4:1, more preferably from 1:3 to 3:1 , and most preferably from 1:2 to 2:1.
• the omega-3 fatty acids may also comprise pure EPA or pure DHA.
• omega-3 fatty acids includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Patent No. 6,245,811, each hereby incorporated by reference), precursors or salts thereof and mixtures thereof.
• omega-3 fatty acid oils include but are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ⁇ - linolenic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary alcohol 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, triglycerides thereof, ethyl esters thereof and mixtures thereof.
• omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in their pure form or as a component of an oil such as fish oil, preferably purified fish oil concentrates.
• Commercial examples of omega-3 fatty acids suitable for use in the invention include lncromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG.
• EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE Pronova Biocare a.s., 1327 Lysaker, Norway).
• omega-3 fatty acids present in a concentration of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80% by weight, or even at least 90% by weight.
• the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight.
• the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 40 to about 55% by weight, and most preferably about 46% by weight of EPA.
• the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 30 to about 60% by weight, and most preferably about 38% by weight of DHA. All percentages above are by weight as compared to the total fatty acid content in the composition, unless otherwise indicated. The percentage by weight may be based on the free acid or ester forms, although it is preferably based on the ethyl ester form of the omega-3 fatty acids even if other forms are utilized in accordance with the present invention.
• the omega-3 fatty acids can be present in an amount from about 350 mg to about 10 grams, more preferably about 500 mg to about 6 grams, and most preferably from about 750 mg to about 4 grams.
• the omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
• chemical antioxidants such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil
• lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
• omega-3 fatty acids is Lovaza® omega-3 fatty acids (K85EE, Pronova Biocare A.S., Lysaker, Norway) and preferably comprises the following characteristics (per dosage form):
• the active ingredients of the present invention may be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as "excipients").
• Non-active ingredients serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and fashion the active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.
• Excipients include surfactants, such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene- polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, cosolvents such ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oils.
• surfactants such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicapry
• compositions and methods of the present invention may further comprise co-administration of one or more additional compounds useful in the treatment of hypertension.
• unit dosage forms including the natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof, and said one or more additional compounds, and methods for administering same to a patient in need thereof.
• additional compounds may be one or more, preferably two or more, most preferably three or more different compounds each independently selected from the classes of diuretics, aldosterone receptor blockers, beta-blockers, combined alpha- and beta-blockers, ACE inhibitors, angiotensin Il antagonists, calcium channel blockers, alpha-1 blockers, central alpha-2 agonists, and direct vasodilators.
• at least one of the additional compounds is a diuretic.
• the additional compounds include at least three different types of compounds indicated above, including a diuretic. Already-existing treatment with three different types of compounds including a diuretic is typically found in subjects having resistant hypertension.
• the composition comprising omega-3 fatty acids may be prepared in the form of a capsule, such as a hard gelatin capsule; a tablet; a powder that can be dispersed in a beverage; a liquid; or a soft gel capsule.
• the composition may also be contained in a liquid suitable for injection or infusion.
• the methods of preparing the inventive compositions for administration are not to be limited to any particular dosage form. Rather, they may be prepared as any pharmaceutically acceptable dosage form, including other solid oral dosage forms, other liquid oral dosage forms, and any other suitable dosage forms.
• the one or more optional additional ingredients may also be provided in the dosage form with the omega-3 fatty acids, so as to create a convenient unit dose form.
• the omega-3 fatty acids can be administered in a daily amount of from about 0.1 g to about 10 g, more preferably about 1 g to about 6 g, and most preferably from about 2 g to about 4 g, to a patient suffering from resistant hypertension.
• the daily dosages of omega-3 fatty acids can be administered together in from 1 to 10 dosages, with the preferred number of dosages from 1 to 4 times a day, most preferred 1 to 2 times a day.
• the administration is preferably oral administration, although other forms of administration that provide a unit dosage of omega-3 fatty acids may be used.
• the administration of the dosages is preferably effective in lowering blood pressure levels, more preferably effective in controlling blood pressure.
• treatment in accordance with the present invention reduces systolic blood pressure levels to under 140 mmHg and/or reduces diastolic blood pressure levels to under 90 mmHg.
• Blood pressure levels may be measured in accordance with any recognized method in the art, such as but not limited to, supine, sitting, upright, standing or 24-hr ambulatory.

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• 2007
  • 2007-07-23 JP JP2009521786A patent/JP2009544702A/ja active Pending
  • 2007-07-23 WO PCT/US2007/016527 patent/WO2008011179A2/en active Application Filing
  • 2007-07-23 EP EP07810681A patent/EP2049098A2/de not_active Withdrawn

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