EP2068861A2

EP2068861A2 - Compositions comprising omega-3 fatty acids, and their use in treating peripheral artery disease and intermittent claudication

Info

Publication number: EP2068861A2
Application number: EP07810680A
Authority: EP
Inventors: Roelof M.L. Rongen; Robert A. Ms. Shalwitz
Original assignee: Reliant Pharmaceuticals Inc
Current assignee: Reliant Pharmaceuticals Inc
Priority date: 2006-07-21
Filing date: 2007-07-23
Publication date: 2009-06-17
Also published as: WO2008011178A3; JP2009544701A; EP2068861A4; WO2008011178A2

Abstract

Compositions comprising omega-3 fatty acids, where the compositions are useful for treating intermittent claudication, preventing its further progression, and treating underlying conditions such as PAD that cause IC symptoms, methods of making such compositions, methods of using the compositions to treat intermittent claudication, and methods of using the compositions to treat any of the various underlying conditions that cause intermittent claudication.

Description

Compositions Comprising Omega-3 Fatty Acids, and Their Use In Treating Peripheral Artery Disease and Intermittent Claudication

RELATED APPLICATION DATA

[0001] This application claims priority from U.S. Provisional Application No. 60/832,135, which was filed on July 21, 2006, the contents of which are incorporated herein by reference.

Background of the Invention

1. Field of the Invention

[0002] The present invention relates, generally, to compositions comprising omega- 3 fatty acids, where the compositions are useful for treating peripheral artery disease and/or intermittent claudication. The present invention also includes pharmaceutical formulations made from the compositions, methods of making such formulations, methods of using the formulations to treat peripheral artery disease and/or intermittent claudication, and methods of using the formulations to treat any of the various underlying conditions that cause intermittent claudication, including peripheral artery disease.

2. Description of the Related Art

[0003] In humans, cholesterol and triglycerides are part of lipoprotein complexes in the bloodstream, and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions. Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL, and released into the plasma. High levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (a membrane complex for LDL-C) promote human atherosclerosis and decreased levels of HDL-C and its transport complex, apolipoprotein A, which are associated with the development of atherosclerosis. Further, cardiovascular morbidity and mortality in humans can vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.

[0004] 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), 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 lower serum triglycerides, increase serum HDL-cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor Vll-phospholipid complex. Further, omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.

[0005] One form of omega-3 fatty acid 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 acid 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.

[0006] Intermittent claudication (IC) is pain that occurs during exercise, particularly during walking. In IC, blood flow is sufficient to meet the needs of the patient at rest. When the patient exercises, however, the vessels are blocked and limit the free flow of blood. Oxygen supply, then, does not meet the exercising muscles' demands. In response to this higher demand, the body reduces chemicals that open blood vessels (e.g., nitric oxide) and increases chemicals that narrow blood vessels (thromboxane, serotonin, angiotensin II, endothelin, norepinephrine). There is also some evidence that blood cells may become abnormal and prone to forming clots. The result of these problems is pain during exercise, which is relieved only by rest. This pain frequently occurs in the calves, but can also occur in other muscles of the legs, or even in the arms. This leg pain occurs in one leg in 40% of patients, and in both legs in 60% of patients. The most frequently affected artery in IC is the popliteal artery, which leads off from the major artery in the thigh (called the femoral artery) and continues below the knee where it branches off and carries blood to the muscles in the calf and foot. [0007] Although IC is a symptom that may be caused by a number of different conditions, including neurological disorders, inflammatory diseases, and circulatory impairment, it is most often a symptom of peripheral arterial disease (PAD). IC occurs in between a third and half of PAD patients. In general, insufficient blood flow in the extremities can cause two forms of pain: intermittent claudication, which is pain that occurs during exercise, particularly in the legs; and ischemic rest pain, which occurs even when a patient is at rest, and indicates a more advanced state of PAD. If IC is allowed to progress to ischemic rest pain, the arteries can become so obstructed that ulcers and gangrene can develop, requiring amputation in severe cases. Other symptoms of ischemic rest pain can include withered calf muscles, hair loss over the toes and feet, thick toenails, shiny, tight skin, painful toe ulcers, and, in some cases, formation of blood clots in the arteries in the legs.

[0008] Peripheral artery disease (PAD) occurs when atherosclerosis (commonly called hardening of the arteries) affects the extremities, blocking arteries and obstructing oxygen-rich blood flow. It is most often caused by the same type of. plaque build-up that can develop in the arteries leading to the heart and brain. Further, PAD patients have the same risk of death from heart events or stroke as people with evident heart disease, even if no signs of heart disease are evident. PAD-related symptoms, such as IC, can significantly impair daily physical functioning. IC pain severely limits physical activity. IC also increases the risk for falling, usually because of unsteadiness, regardless of the severity of PAD. IC and PAD are also associated with mental decline, which mimics the addition of four or five years onto a person's age. Generally, the worse the leg condition, the poorer the overall health of the PAD patient.

[0009] Most of the IC medications currently available are aimed at relieving pain, improving function, and preventing progression that might lead to gangrene and amputation. This is usually accomplished with drugs that open blood vessels or prevent blood clots. Anti-platelet drugs are important agents for achieving these goals, but others are also being investigated. When the cause of the IC is PAD, treatment through diet and exercise are recommended, as well as smoking- cessation therapy. Treatment may be augmented with various pharmaceutical agents. Aspirin is the least intensive anti-platelet agent and is used for mild PAD. Clopidogrel (Plavix®) has been specifically approved for IC, and has other heart- protective properties. If the PAD is more severe, balloon angioplasty or bypass surgery may be recommended.

[0010] Prevention of heart disease and stroke are important treatment goals for IC₁ as is reduction of artery damage. These goals are frequently addressed by using agents that improve cholesterol and lipid levels.

[0011] Improving cholesterol and lipid levels are also very important where intermittent claudication is a symptom of PAD. Experts recommend that PAD patients be given the optimal treatments for managing any heart risk factors, as well as treatments for intermittent claudication, including lipid-lowering agents, angiotensin-converting enzyme (ACE) inhibitors, statins (which might also promote, growth of new blood vessels and therefore help prevent intermittent claudication), fibrates, nicotinic acid, intensive insulin control (in diabetic patients), and antiplatelet drugs (which may include aspirin, clopidogrel (Plavix), and ticlopidine (Ticlid)).

[0012] Various studies have been conducted to determine the effects of dietary supplementation with products such as fish oil on IC and its causes, including PVD and PAD.

[0013] Carrero, J., et al. "Daily Supplementation with (n-3) PUFAs, Oleic Acid, Folic Acid, and Vitamins B-6 and E Increases Pain-Free Walking Distance and Improves Risk Factors in Men with Peripheral Vascular Disease," J. Nutrition, Vol. 135, Issue 6 (June 2005) describes a study regarding the effects of daily dietary supplementation with 500 ml of a fortified dairy product containing 0.2 g eicosapentaenoic acid (EPA), 0.13 g docosahexaenoic acid (DHA)₁ 5.12 g oleic acid, 15O g folic acid, vitamin A, 1.5 mg vitamin B-6, vitamin D, and vitamin E on patients with peripheral vascular disease and intermittent claudication (PVD-IC). All patients were administered the antiplatelet agent triflusal, and the hemorrheologic agent pentoxifylline, and half of the patients also received the fortified dairy product. The study found that the patients who also received the fortified dairy product exhibited improvement in pain free walking distance and ankle-brachial pressure as compared to patients who did not. [0014] Various studies have found that dietary supplementation with (n-3) PUFAs (Somerfield, T. and Hiatt, W.R., "Omega-3 fatty acids for intermittent claudication [Cochrane review]," The Cochrane Library, Issue 3 (2004)), olive oil (Ramirez- Tortosa, M.C., et al., "Extra-virgin olive oil increases the resistance of LDL to oxidation more than refined olive oil in free-living men with peripheral vascular disease," J. Nutrition, Vol. 129: 2177-83 (1999)), sunflower oil (Aguilera, CM., et al., "Sunflower oil does not protect against LDL oxidation as virgin olive oil does in patients with peripheral vascular disease," Clin. Nutr, Vol. 23: 673-81), vitamin E (Kleijnen, J. and Mackerras, D., "Vitamin E for intermittent claudication [Cochrane review]," The Cochrane Library, Issue 3 (2004)), or folic acid and vitamin B-6 (Robinson, K., et al., "Low circulating folate and vitamin B-6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease," European COMAC Group, Circulation 97: 437-43 (1998)) provide beneficial effects to patients exhibiting intermittent claudication, but have not resulted in specific dietary supplementation guidelines.

[0015] The World Health Organization (WHO) Study Group Diet (2003), Technical Report Series No. 916, has generally recommended the regular consumption of fish to provide approximately 200 to 500 mg of EPA and DHA per week, in addition to limiting saturated fats, and increasing consumption of fruits and vegetables to obtain adequate levels of antioxidants and folate.

[0016] Pittler, M. H., and Ernst, E., "Complementary therapies for peripheral arterial disease: Systematic review," Atherosclerosis, Vol. 181: 1-7 (March 2005), reviews studies relating to the use of acupuncture, biofeedback, chelation therapy, CO₂- applications, garlic, gingko, omega-3 fatty acids, padma 28, and vitamin E as therapies for PAD, where all but one of the studies being reviewed included only patients with PAD in Fontaine stage Il (intermittent claudication). With respect to the omega-3 fatty acid study, it was found that there was no significant change in the pain free and maximal walking distances of the patients, and there was no evidence of improved clinical outcome for patients with intermittent claudication. [0017] Leng, G.C., et al., "Randomized controlled trial of gamma-linoleic acid and eicosapeπtaenoic acid in peripheral arterial disease," Clin. Nutr., 17(6): 265-71 (1998), studied the effect of administering fatty acids (capsules containing 280 mg gamma-linoleic acid (18:3n-6) and 45 mg eicosapentaenoic acid (20:5n-3)), versus placebo (capsules containing 500 mg sunflower oil) to patients with stable intermittent claudication over a two year period. It was found that there was a small reduction in non-fatal coronary events in the fatty acid group, but that there was no difference in pain-free walking distance, and the authors noted that similar studies of shorter duration produced consistent results.

[0018] Canadian Patent No. 2,291 ,959 relates to a nutraceutical composition for use in the treatment of occlusive vascular diseases, including components that have utility in the treatment of patients with coronary heart disease, cerebrovascular disease (where the patient has suffered at least one stroke), and peripheral vascular disease (where the patient suffers from intermittent claudication). The composition includes the metabolic enhancers L-camitine and coenzyme Q; the homocysteine- lowering vitamins folic acid, B6, and B12; LDL cholesterol-lowering amounts of nicotinic acid or slow release forms thereof; the antioxidants vitamin C, vitamin E, and selenium; and omega-3 polyunsaturated fatty acids.

[0019] PCT Published Application No. WO 01/084961 relates to preparations for use in preventing and/or treating vascular disorders, including three fractions. The first fraction comprises long chain polyunsaturated fatty acids. The second fraction comprises phospholipids, including at least two selected from the group consisting of phosphatidylserine, phosphatidylinositol, phosphatidylcholine, and phosphatidylethanolamine. The third fraction includes compounds that are a factor in methionine metabolism, including at least one selected from the group consisting of folic acid, vitamin B12, vitamin B6, magnesium, and zinc. The application is primarily directed to the treatment of vascular problems causing symptoms of dementia; however other problems include thromboangiitis obliterans and atherosclerosis obliterans.

[0020] U.S. Published Application No. 2002/0055539 relates to compositions and methods for treating or preventing cardiovascular conditions by intravascular administration of an omega fatty acid. The cardiovascular condition may be peripheral vascular disease. The compositions may include one or more omega-3 fatty acids, one or more omega-6 fatty acids, or a mixture of one or more omega-3 and one or more omega-6 fatty acids. In accordance with the methods of treatment, the composition is preferably administered intravascularly in close proximity to the site to be treated.

[0021] Accordingly, none of the above-mentioned techniques approaches provides compositions and methods for alleviating IC₁ and treating underlying conditions (such as PAD) that cause IC, by administering the compositions of the present invention containing omega-3 fatty acids, and optionally including one or more additional compounds.

[0022] There is clearly a great need in the art for compositions that are useful for treating IC, and its underlying causes (such as PAD), and methods for making same. Methods of treating intermittent claudication using the formulations are also needed. There is an especially great need in the art for additional treatments effective in alleviating the primary condition associated with IC, PAD.

Summary of the Invention

[0023] There is an unmet need in the art for compositions and methods of treating 1C, and the underlying conditions responsible for causing IC, such as PAD, using mixtures of omega-3 fatty acids that include highly concentrated levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably Lovaza® omega-3 fatty acids.

[0024] Further, there is an unmet need for a combination product that provides a single administration of highly concentrated amounts of omega-3 fatty acids (e.g., the Lovaza® omega-3 fatty acids) and optionally including one or more compounds useful for treating the underlying conditions responsible for causing IC, such as PAD. Such a combination product may be provided, for example, in a unit dosage. There is also an unmet need in the art for a method of administration of a single administration or unit dosage product. Moreover, there is an unmet need in the art for compositions including one or more compounds useful for treating the underlying conditions responsible for causing IC, such as PAD, and the Lovaza® omega-3 fatty acids, wherein the one or more compounds are combined with the Lovaza® omega- 3 acids to provide the specific therapeutic properties.

[0025] The present invention meets the unmet needs of the art, as well as others, by providing compositions containing omega-3 fatty acids that include highly concentrated levels of EPA and DHA₁ preferably Lovaza® omega-3 fatty acids, that can provide an effective treatment for IC and PAD, as well as any of the various underlying conditions that may produce IC as a symptom. These additional underlying conditions may include, but are not limited to, Charcot-Marie-Tooth syndrome, thromboangiitis obliterans (von Winiwarter-Buerger's disease), arteriosclerosis obliterans, and/or peripheral vascular disease. According to a particularly preferred embodiment, the underlying condition is PAD. According to a further embodiment, the omega-3 fatty acids are provided for co-administration, or as unit doses, with one or more compounds useful for treating the underlying conditions responsible for causing IC.

[0026] 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 intermittent claudication, while minimizing unwanted side effects.

[0027] One embodiment of the present invention provides a method of utilizing a composition comprising 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 experiencing intermittent claudication.

[0028] Another embodiment of the present invention is a oral formulation of natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof. In one aspect of the embodiment, the formulation is used in the treatment of subjects with intermittent claudication. [0029] Another subject of the invention is a method of relieving intermittent claudication in a patient suffering therefrom, by providing a composition comprising natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof, and thereafter administering the composition to the patient.

[0030] 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 intermittent claudication.

[0031] The compositions and methods of the present invention may further comprise co-administration of one or more additional compounds useful in the treatment of one or more of Charcot-Marie-Tooth syndrome, thromboangiitis obliterans (von Winiwarter-Buerger's disease), arteriosclerosis obliterans, peripheral vascular disease, and/or peripheral arterial disease. According to a particularly preferred embodiment, the compositions and methods of the present invention are useful in the treatment of PAD. Also included are unit dosage forms including the omega-3 fatty acids and said one or more additional compounds, and methods for administering same to a patient in need thereof.

[0032] These additional compounds may be selected from the group consisting of pentoxifylline, angiotensin-converting-enzyme (ACE) inhibitors, dyslipidemic agents, dihydropyridine calcium channel blockers, antiarrhythmic agents, azetidinone-based cholesterol absorption inhibitors, niacin and derivatives, PDE III inhibitors such as cilostazol, PPAR agonists/antagonists, bile acid sequestrants, antiplatelet drugs, and pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, and mixtures thereof.

[0033] In preferred embodiments the pharmaceutical compositions comprise Lovaza® omega-3 fatty acids, as described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594. In other preferred embodiments the pharmaceutical compositions comprise omega-3 fatty acids present in a concentration of at least

40% by weight as compared to the total fatty acid content of the composition. In still other preferred embodiments 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, and the EPA and DHA are in a weight ratio of EPArDHA 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.

[0034] Other novel features and advantages of the present invention will become apparent to those skilled in the art upon examination of the following or upon learning by practice of the invention.

Detailed Description of the Invention

[0035] The present invention relates to compositions comprising omega-3 fatty acids, methods of making same, and their use in relieving intermittent claudication (IC), and treating the underlying conditions that may produce IC as a symptom. Additional compounds useful in treating IC or the underlying conditions responsible for causing the IC symptoms may also be beneficially coadministered with the inventive compositions and pharmaceutical formulations, or may be provided in a unit dose form therewith. The underlying conditions that cause IC may include, but are not limited to, Charcot-Marie-Tooth syndrome, thromboangiitis obliterans (von Winiwarter-Buerger's disease), arteriosclerosis obliterans, peripheral vascular disease (PVD), and/or peripheral arterial disease (PAD). According to a particularly preferred embodiment, the compositions and methods of the present invention are useful in treating PAD.

1. Compositions Containing Omeqa-3 Fatty Acids

[0036] In preferred embodiments, the compositions of the present invention are useful for treating IC, and the underlying cause(s) thereof. These inventive compositions comprise Lovaza® omega-3 fatty acids, as described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594. In other preferred embodiments the compositions comprise omega-3 fatty acids present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition. In still other preferred embodiments 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, and 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 comprise pure EPA or pure DHA.

[0037] As used herein, the term "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. Examples of 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 a- 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. The 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).

[0038] Another preferred composition includes 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. Preferably, 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. Preferably 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. Preferably 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.

[0039] 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. This amount may be in one or more dosage forms, preferably one dosage form. 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.

[0040] The most preferred form of 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):

[0041] The active ingredients of the present invention, omega-3 fatty acids, may be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as "excipients"). Non-active ingredients, for example, 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. Thus, the non-active ingredients may include colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and xanthum gum. [0042] 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. The use of surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical arts, and as would be understood to one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof.

[0043] Preferably, the active ingredients are administered without the use of large amounts of surfactants. In preferred embodiments, if present at all, surfactants are present in amounts of less than 50% w/w based on the total weight of the solvent system in the dosage form(s), more preferably less that 40%, even more preferably less than 30%, and most preferably less than 20%. In one embodiment, the solvent system contains no surfactant.

[0044] As used herein, "solvent system" includes the omega-3 fatty acid oil. In other preferred embodiments, the weight ratio of omega-3 fatty acid oil to surfactant is at least 0.5 to 1..more preferably at least 0.7 to 1 , even more preferably at least 0.9 to 1 , and most preferably at least 1 to 1. In still other preferred embodiments, if present at all, the amount of hydrophilic solvent used in the solvent system is less than 20% w/w based on the total weight of the solvent system in the dosage form(s), more preferably less than 15%. In certain embodiments, the amount of hydrophilic solvent used in the solvent system is between 10 and 20% w/w. In other preferred embodiments, if present at all, the amount of hydrophilic solvent used in the solvent system is less than 10% w/w based on the total weight of the solvent system in the dosage form(s), more preferably less than 5%. In certain embodiments, the amount of hydrophilic solvent used in the solvent system is between 5 and 10% w/w.

[0045] The active ingredients of the present invention, omega-3 fatty acids, may optionally be co-administered with one or more additional compounds, or provided in a unit dose pharmaceutical formulation with one or more additional compounds,

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TECH/524774.1 where those additional compounds are useful in relieving IC, useful in preventing IC from progressing to ischemic rest pain, or are effective in treating any of the underlying conditions that result in IC. These underlying conditions may include PAD, PVD, arteriosclerosis obliterans, thromboangiitis obliterans (von Winiwarter- Buerger disease), or Charcot-Marie-Tooth syndrome. According to a particularly preferred embodiment, the active ingredients of the present invention are useful for treating PAD.

[0046] The additional compounds in accordance with the present invention may be selected from the group consisting of angiotensin-converting-enzyme (ACE) inhibitors; dyslipidemic agents (preferably including, but not limited to HMG CoA reductase inhibitors (statins) such as simvastatin, rosuvostatin, pravastatin, atorvastatin, lovastatin, and fluvastatin); dihydropyridine calcium channel blockers (preferably including, but not limited to, Bay K 8644, amlodipine (e.g., Norvasc®), felodipine (e.g., Plendil®), lacidipine (e.g., Lacipil®), lercanidipine (e.g., Zanidip®), nicardipine (e.g., Cardene®), nifedipine (e.g., Adalat®, Procardia®), nimodipine (e.g., Nimotop®), nisoldipine (e.g., Sular®), nitrendipine and isradipine (e.g., DynaCirc®)); antiarrhythmic agents (preferably including, but not limited to, quinidine, procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, encainide, flecainide, moricizine, propafenone, esmolol, propranolol, acebutolol, metoprolol, amiodarone, azimilide, bretylium, clofilium, dofetilide, ibutilide, sematilide, sotalol, verapamil, mebefradfil, diltiazem adenosine, and digoxin); azetidinone-based cholesterol absorption inhibitors (preferably including, but not limited to, ezetimibe, MD-0727, and SCH60663); niacin and derivatives (preferably including, but not limited to, nicotinamide); PPAR agonists/antagonists (preferably including, but not limited to, fenofibrate, tesaglitazar, naviglitizar, mivaglitazar, proglitazone, and rosiglitazone); bile acid sequestrants (preferably including, but not limited to, cholestyramine, cholestipol, and colesevelam); antiplatelet drugs (including, but not limited to, aspirin, clopidogrel, and ticlopidine); and pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, and mixtures thereof.

[0047] Other additional compounds that may optionally be combined with the omega-3 fatty acids of the present invention are available or are under investigation for use In relieving IC. These include pentoxifylline (Trental), cilostazol (Pletal), prostaglandins (including prostaglandin E1 and Beraprost), recombinant fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), naftidrofuryl (Nafronyl), levocarnitine (L-carnitine) and its derivative propionyl levocarnitine, E2F decoy, mesoglycan, and sex steroid hormones (including testosterone).

[0048] Also envisioned in accordance with the present invention is the use of similar compounds to those set forth above, which may be discovered in the future, or already existing compounds that may be approved for new uses in the future. Further envisioned is the optional inclusion of additional compounds useful in the treatment of conditions such as high blood pressure and diabetes, which are known to contribute to disorders of the circulatory system.

[0049] Where provided, these optional additional ingredients are useful in the treatment of IC, or any of the underlying conditions or diseases that cause IC as a symptom. These may include, but are not limited to, Charcot-Marie-Tooth syndrome, thromboangiitis obliterans (von Winiwarter-Buerger's disease), arteriosclerosis obliterans, peripheral vascular disease, and/or peripheral arterial disease.

[0050] As will be discussed in greater detail below, the optional additional ingredients, when provided, are including in amounts that are sufficient to provide relief of IC symptoms, and/or treat the underlying condition causing the patient to suffer IC. The optional additional ingredients are provided in amounts that are generally regarded as safe, and are effective in relieving IC and treating its underlying causes.

[0051] The composition comprising concentrated 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. However, 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. When form.

[0052] In some embodiments, the unit dose formulations of the present invention allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose, as compared to the formulations in the prior art. In other embodiments, the formulations of the present invention may allow for reduced dosages of the optional additional ingredients, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.

[0053] The present combinations of concentrated omega-3 fatty acids and one or more additional ingredients, taken from the list set forth above, may allow for a greater effect than any expected combined or additive effect of the compounds alone. Thus, the combined treatment using the active ingredients, separately or through the novel combination product of the present invention, may cause an unexpected increase in effect of the active ingredients. This may allow increased effectiveness with standard dosages, or, alternatively, may allow maintained effectiveness with reduced dosages of the active ingredients. It is well accepted in practice that an improved bioavailability or effectiveness of a drug or other active ingredient allows for an appropriate reduction in the daily dosage amount. Any undesirable side effects may also be reduced as a result of the lower dosage amount and the reduction in use of excipients (e.g., surfactants).

2. Methods of Treating IC and PAD

[0054] The compositions containing concentrated omega-3 fatty acids described above 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 PAD and/or from the symptoms of IC. The daily dosages of concentrated 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 concentrated omega-3 fatty acids may be used. The administration of the dosages is preferably effective in alleviating IC in a patient suffering therefrom, and/or is effective in treating the underlying condition(s) responsible for causing the IC, particularly PAD.

[0055] The compositions containing omega-3 fatty acids can optionally be coadministered with one or more additional compounds useful for alleviating IC, or treating the underlying condition(s) causing it. These underlying causes may include, but are not limited to, Charcot-Marie-Tooth syndrome, thromboangiitis obliterans (von Winiwarter-Buerger's disease), arteriosclerosis obliterans, peripheral vascular disease, and/or peripheral arterial disease. Administration of unit dose forms of the omega-3 fatty acids and one or more additional compounds is also contemplated in accordance with the present invention.

[0056] The one or more optional additional compounds are beneficially selected from pentoxifylline, angiotensin-converting-enzyme (ACE) inhibitors, dyslipidemic agents, dihydropyridine calcium channel blockers, antiarrhythmic agents, azetidinone-based cholesterol absorption inhibitors, niacin and derivatives, PDE III inhibitors such as cilostazol, PPAR agonists/antagonists, bile acid sequestrants, antiplatelet drugs, and pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, and mixtures thereof, although combination with other compounds used to treat high blood pressure, diabetes, or other conditions that contribute to disorders of the circulatory system is also envisioned in accordance with the present invention.

[0057] The co-administration of the concentrated omega-3 fatty acids of the present invention with one or more additional compounds listed above achieves results that are highly advantageous and beneficial to the pharmaceutical and medicinal arts. The increased efficacy of the combined treatment and/or combination product allows for a novel and more efficient pharmaceutical treatment for IC, and its underlying causes (such as PAD). [0058] The methods of treatment in accordance with the present invention include preferred embodiments wherein IC and its underlying causes, particularly PAD, are treated by administering a therapeutically effective combination of Lovaza and a PPAR agonist/antagonist (particularly fenofibrate), or a therapeutically effective combination of Lovaza and a dyslipidemic agent (particularly a statin), or a therapeutically effective combination of Lovaza and a sterol/stanol, or a therapeutically effective combination of Lovaza and a calcium channel blocker, or a therapeutically effective combination of Lovaza and a cholesterol absorption inhibitor, or a therapeutically effective combination of Lovaza and an antiarrhythmic agent. These methods will be discussed in further detail below.

a. Lovaza and a PPAR Agonist/Antagonist

[0059] The invention provides a novel method of treatment of subjects suffering from PAD and/or IC, comprising the administration of omega-3 fatty acids (preferably Lovaza® omega-3 fatty acids) and a PPAR agonist and/or antagonist, wherein omega-3 fatty acids are administered before, simultaneous to or after administration of the PPAR agonist and/or antagonist. A unit dose form containing both the omega- 3 fatty acids and the PPAR agonist/antagonist is specifically envisioned for use in accordance with the methods of the present invention.

[0060] As noted above, the treatment of a subject with both active ingredients allows a more effective treatment from the typical dosage amount of each drug or the option of decreasing the dosage amount of each drug while maintaining an effective treatment. The administration is preferably oral administration.

[0061] The present invention may incorporate now known or future known PPAR agonists and/or antagonists in an amount generally recognized as safe. The term "PPAR agonists and/or antagonists" includes, but is not limited to, PPAR-alpha, PPAR-gamma, PPAR-delta, PPAR-alpha/gamma, PPAR-gamma/delta, PPAR- alpha/delta, and PPAR-alpha/gamma/delta agonists and antagonists, as well as partial agonists and/or antagonists. Specific compounds include, but are not limited to, the fibrates, the thiazolidinediones, the non-thiazolidinediones and metaglidasen. Preferably, the compound is a fibrate, such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, most preferably fenofibrate.

[0062] The combination product of a PPAR agonist and/or antagonist and concentrated omega-3 fatty acids may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, or another solid oral dosage form, a liquid, a soft gel capsule or other convenient dosage form such as oral liquid in a capsule, as known in the art. In some embodiments, the capsule comprises a hard gelatin. The combination product may also be contained in a liquid suitable for injection or infusion.

[0063] Generally, the effect of the PPAR agonist and/or antagonist is dose dependent, i.e., the higher the dose, the greater the therapeutic affect. However, the effect of each PPAR agonist and/or antagonist is different, and therefore the level of therapeutic effect of PPAR agonist and/or antagonist cannot be necessarily be directly correlated to the level of therapeutic effects of other PPAR agonists and/or antagonists. However, those of ordinary skill in the art would understand the correct dosage to be given to a particular subject, based on experience and the seriousness of the condition.

[0064] The concentrated omega-3 fatty acids can be administered in a daily amount of from about 0.1 g to about 10 g, more preferably about 0.5 g to about 8 g, and most preferably from about 0.75 g to about 4 g. According to preferred embodiments, the PPAR agonist is fenofibrate, which can be administered in a daily amount of 300 mg or less of fenofibrate, preferably 200 mg or less, more preferably 160 mg or less, even more preferably 140 mg or less, most preferably 130 mg or less.

[0065] The daily dosages of PPAR agonist and/or antagonist and concentrated 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 preferably 1 to 2 times a day. The administration is preferably oral administration, although other forms of administration that provides a unit dosage of PPAR agonist and/or antagonist and concentrated omega-3 fatty acids may be used. [0066] In some embodiments, the formulations of the present invention allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose, as compared to the formulations in the prior art. In other embodiments, the formulations of the present invention may allow for reduced dosages of PPAR agonist and/or antagonist and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.

[0067] The combination of a PPAR agonist and/or antagonist and omega-3 fatty acids allows for a greater effect than the additive effect expected when the two drugs are combined. Thus, the combined treatment of the two active ingredients, separately or through the novel combination product of the present invention, causes an increase in effectiveness with standard dosages or maintained effectiveness with reduced dosages of the two active ingredients. Thus, the improved bioavailability or effectiveness of the two active ingredients allows for reduction in the daily dosage amount. The side effects may also be potentially reduced as a result of the lower dosage amount.

[0068] When used in accordance with the methods of the present invention, the PPAR agonist and/or antagonist may be administered in an amount more than, equal to or less than the conventional full-strength dose as a single-administered product. For example, the PPAR agonist and/or antagonist may be administered in an amount of from 10-100%, preferably about 25-100%, most preferably about 50- 80%, of the conventional full-strength dose as a single-administered product.

[0069] The administration of a combination of PPAR agonist and/or antagonist and concentrated omega-3 fatty acids therefore achieves results that are highly advantageous and beneficial in the treatment of IC. The possible increased efficacy of the combined treatment and combination product may allow for a novel and more efficient pharmaceutical treatment for IC and the underlying conditions that cause IC, including PAD. b. Lovaza with Dyslipidemic Agents

[0070] In another preferred embodiment, the invention relates to the administration of omega-3 fatty acids, preferably in the form of the Lovaza® omega-3 fatty acids, and a dyslipidemic agent, wherein the omega-3 fatty acids are administered simultaneously with administration of the dyslipidemic agent, e.g., as a single fixed dosage pharmaceutical composition or as separate compositions administered at the same time. Preferably, the administration of the dyslipidemic agent and the omega-3 fatty acids is effective in the treatment of IC and/or any its underlying causes, such as PAD.

[0071] The dyslipidemic agent is preferably a statin including, but not limited to, simvastatin, rosuvostatin, pravastatin, atorvastatin, lovastatin and fluvastatin. In particularly preferred embodiments, the statin used in combination with omega-3 fatty acids is simvastatin.

[0072] In other preferred embodiments, the administration comprises omega-3 fatty acids and a dyslipidemic agent, wherein the omega-3 fatty acids are administered apart from the administration of the dyslipidemic agent, but in a concomitant treatment regime. For example, the dyslipidemic agent may be administered weekly with daily intake of omega-3 fatty acids. One skilled in the art with the benefit of the present disclosure will understand that the precise dosage and schedule for the administration of the omega-3 fatty acids and the dyslipidemic agent will vary depending on numerous factors, such as, for example, the route of administration and the seriousness of the condition.

[0073] The present invention may incorporate now known or future known dyslipidemic agents in an amount generally recognized as safe. Preferred dyslipidemic agents include HMG CoA inhibitors, cholesterol absorption inhibitors, niacin and derivatives such as nicotinamide, fibrates, and bile acid sequestrants. There are currently six statins that are widely available: atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. A seventh statin, cerivastatin, has been removed from the U.S. market at the time of this writing. However, it is conceivable to one skilled in the art that cerivastatin may be used in conjunction with some embodiments of the present invention if cerivastatin is ultimately determined to be safe and effective.

[0074] Generally, the effect of the dyslipidemic agent is dose dependent, i.e., the higher the dose, the greater the therapeutic affect. However, the effect of each dyslipidemic agent is different, and therefore the level of therapeutic effect of one dyslipidemic agent cannot be necessarily be directly correlated to the level of therapeutic effects of other dyslipidemic agents. However, those of ordinary skill in the art would understand the correct dosage to be given to a particular subject, based on experience and the seriousness of the condition.

[0075] In one embodiment of the present invention, the statin can generally be present in an amount from about 0.5 mg to 80 mg, more preferably from about 1 mg to about 40 mg, and most preferably from about 5 mg to about 20 mg, per gram of omega-3 fatty acid. The daily dose may range from about 2 mg to about 320 mg, preferably about 4 mg to about 160 mg.

[0076] The daily dosages of dyslipidemic agent and concentrated 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 preferably 1 to 2 times a day. The administration is preferably oral administration, although other forms of administration that provides a unit dosage of dyslipidemic agent and concentrated omega-3 fatty acids may be used.

[0077] The combination product of a dyslipidemic agent and concentrated omega-3 fatty acids may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, or another solid oral dosage form, a liquid, a soft gel capsule or other convenient dosage form such as oral liquid in a capsule, as known in the art. In some embodiments, the capsule comprises a hard gelatin. The combination product may also be contained in a liquid suitable for injection or infusion.

[0078] In some embodiments, the formulations of the present invention allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose, as compared to the formulations in the prior art. In other embodiments, the formulations of the present invention may allow for reduced dosages of dyslipidemic agent and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.

[0079] The present combination of a dyslipidemic agent and concentrated omega-3 fatty acids may allow for a greater effect than any expected combined or additive effect of the two drugs alone. Thus, the combined treatment of the two active ingredients, separately or through the novel combination product of the present invention, may cause an unexpected increase in effect of the active ingredients that allows increased effectiveness with standard dosages or maintained effectiveness with reduced dosages of the two active ingredients. It is well accepted in practice that an improved bioavailability or effectiveness of a drug or other active ingredient allows for an appropriate reduction in the daily dosage amount. Any undesirable side effects may also be reduced as a result of the lower dosage amount and the reduction in excipients (e.g., surfactants).

[0080] The dyslipidemic agent may therefore be administered in an amount equal to or less than the conventional full-strength dose as a single-administered product. For example, the dyslipidemic agent may be administered in an amount of from 10- 100%, preferably about 25-100%, most preferably about 50-80%, of the conventional full-strength dose as a single-administered product.

[0081] The administration of a combination of dyslipidemic agent and concentrated omega-3 fatty acids (e.g., the Lovaza® omega-3 fatty acids), achieves results that are highly advantageous and beneficial in the treatment of IC. The possible increased efficacy of the combined treatment and combination product may allow for a novel and more efficient pharmaceutical treatment for IC and the underlying conditions that cause IC, including, but not limited to, PAD.

c. Lovaza with Sterol/Stanol [0082] According to another embodiment of the present invention, sterol and/or stanol is used in conjunction with the omega-3 fatty acids, preferably highly concentrated omega-3 fatty acids, most preferably in the form of the Lovaza® omega-3 fatty acids, for the treatment of IC and any underlying condition responsible for causing the IC symptoms in a patient, such as PAD. A combination product or unit dosage comprising one or more sterols and/or stanols and one or more omega-3 fatty acids is therefore provided in accordance with the present embodiment. In a further preferred embodiment, the Lovaza® omega-3 fatty acids are administered simultaneous to administration of a sterol or stanol.

[0083] The present invention may incorporate now known or future known sterol and/or stanol in an amount generally recognized as safe. For example, in some embodiments of the present invention the sterol includes sitosterol, campesterol, stigmasterol, avenasterol, brassicasterol, ergosterol, and lanosterol. In other embodiments of the present invention the stanol includes cholestanol, sitostanol, campestanol, stigmastanol, avenastanol, brassicastanol, ergostanol, and lanostanol. The sterols and/or stanols may be in unmodified or, preferably, in modified form, such as in the form of esters with glycerol such as mono-, di- and triglycerides, or primary alcohols such as fatty acid methyl esters and fatty acid ethyl esters. Preferably, the sterols and/or stanols are in the form of fatty acid esters (otherwise known simply as "sterol esters" or "stanol esters"). In particularly preferred embodiments, the sterol is sitosterol. In other particularly preferred embodiments of the present invention, the stanol is sitostanol.

[0084] The highly concentrated omega-3 fatty acids, preferably the Lovaza® omega- 3 acids, can be present in an amount from about 0.1 g to about 1O g, more preferably about 1 g to about 6 g, and most preferably from about 2 g to about 4 g. The stanols and/or sterols, whether unmodified or modified, can be present in an amount from about 0.1 g to about 10 g, more preferably about 0.5 g to about 4 g, and most preferably from about 1 g to about 3 g (this being the weight of the stanol and/or sterol alone, and not including the weight of any modifying agent, such as the fatty acid ester portion).

[0085] The daily dosages of sterol and/or stanol and highly concentrated omega-3 fatty acids, preferably the Lovaza® 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 preferably from 1 to 2 times a day. The administration is preferably oral administration, although other forms of administration that provide a unit dosage of sterol and/or stanol and highly concentrated omega-3 fatty acids may be used.

[0086] In some embodiments, the formulations of the present invention may allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose. In other embodiments, the formulations of the present invention may allow for reduced dosages of sterol and/or stanol and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.

[0087] The present combination of sterol and/or stanol and concentrated omega-3 fatty acids (e.g., the Lovaza® omega-3 acids), may allow for a greater effect than any expected combined or additive effect of the two drugs alone. Thus, the combined treatment of the two active ingredients, separately or through the novel combination product of the present invention, may cause an unexpected increase in effect of the active ingredients that allows increased effectiveness with standard dosages or maintained effectiveness with reduced dosages of the two active ingredients. It is well accepted in practice that an improved bioavailability or effectiveness of a drug or other active ingredient allows for an appropriate reduction in the daily dosage amount.

[0088] The administration of a combination of sterol and/or stanol and concentrated omega-3 fatty acids (e.g., the Lovaza® omega-3 fatty acids), achieves results that ^■ are highly advantageous and beneficial in the treatment of IC. The possible increased efficacy of the combined treatment and combination product may allow for a novel and more efficient pharmaceutical treatment for IC and the underlying conditions that cause IC. Such underlying conditions preferable include, but are not limited to, PAD.

d. Lovaza with Calcium Channel Blocker [0089] In still other preferred embodiments, the invention relates to treatment of

PAD and/or IC, or any other underlying condition that causes IC as a symptom, through the administration of omega-3 fatty acids, preferably in the form of the Lovaza® omega-3 fatty acids, and a dihydropyridine calcium channel blocker.

[0090] According to a first preferred embodiment, the Lovaza® omega-3 fatty acids are administered apart from the administration of the dihydropyridine calcium channel blocker. For example, isradipine may be administered once weekly (e.g., through an isradipine patch) with daily intake of omega-3 fatty acids (e.g., Lovaza® capsules). One skilled in the art with the benefit of the present disclosure will understand that the precise dosage and schedule for the administration of the Lovaza® omega-3 acids and the dihydropyridine calcium channel blocker will vary depending on numerous factors, such as, for example, the route of administration and the seriousness of the IC and underlying condition(s).

[0091] According to a second preferred embodiment, the Lovaza® omega-3 fatty acids are administered in conjunction with the administration of the dihydropyridine calcium channel blocker, and may optionally be administered in a unit dosage form. In some embodiments, more than one dihydropyridine calcium channel blocker are combined with amounts of omega-3 fatty acids.

[0092] The present invention may incorporate now known or future known dihydropyridine calcium channel blockers in an amount generally recognized as safe. For example, dihydropyridine calcium channel blockers include Bay K 8644, amlodipine, felodipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and isradipine. In a preferred embodiment, the dihydropyridine calcium channel blocker is isradipine.

[0093] The highly concentrated omega-3 fatty acids, preferably the Lovaza® omega- 3 fatty acids, can be present in an amount 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. When used in accordance with the present invention, the dihydropyridine calcium channel blocker can generally be present in an amount from about 0.5 mg to 100 mg. [0094] The combination product of dihydropyridine calcium channel blocker(s) and highly concentrated omega-3 fatty acids, preferably the Lovaza® omega-3 fatty acids, may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, a liquid, a soft gel capsule or other convenient dosage form such as oral liquid in a capsule, as known in the art. In some embodiments, the capsule is comprised of hard gelatin.

[0095] The daily dosages of dihydropyridine calcium channel blocker and highly concentrated 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, and the most preferable number of dosages from 1 to 2 times a day. The administration is preferably oral administration, although other forms of administration that provide a unit dosage of dihydropyridine calcium channel blocker and highly concentrated omega-3 fatty acids may be used.

[0096] In some embodiments, the formulations of the present invention allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose. In other embodiments, the formulations of the present invention may allow for reduced dosages of dihydropyridine calcium channel blocker and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.

[0097] The present combination of a dihydropyridine calcium channel blocker and concentrated omega-3 fatty acids may allow for a greater effect than any expected combined or additive effect of the compounds when used alone. Thus, the combined treatment of the active ingredients, separately or through the novel combination product of the present invention, may cause an unexpected increase in effect of the active ingredients that allows increased effectiveness with standard dosages or maintained effectiveness with reduced dosages of the two active ingredients. It is well accepted in practice that an improved bioavailability or effectiveness of a drug or other active ingredient allows for an appropriate reduction in the daily dosage amount. [0098] The administration of a combination of a dihydropyridine calcium channel blocker and concentrated omega-3 fatty acids achieves results that are highly advantageous and beneficial to the treatment of IC. The increased efficacy of the combined treatment and combination product allows for a novel and more efficient pharmaceutical treatment for IC, and an improved treatment for the underlying conditions that cause IC, which may include PAD, PVD, hypertriglyceridemia, hypertension, angina, heart failure, artherosclerotic disease and related conditions. According to a particularly preferred embodiment, the underlying condition is PAD. The compositions and methods of the present invention also beneficially prevent or reduce the incidence of cardiovascular and vascular events.

e. Lovaza with Cholesterol Absorption Inhibitor

[0099] According to a further embodiment of the present invention, the omega-3 fatty acids are administered in combination with an azetidinone-based cholesterol absorption inhibitor, preferably ezetimibe, with mixtures of omega-3 fatty acids that include highly concentrated levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably Lovaza® omega-3 fatty acids, for the treatment of IC₁ and the causes thereof. The invention also envisions a combination product or unit dosage comprising an azetidinone-based cholesterol absorption inhibitor, preferably ezetimibe, with mixtures of omega-3 fatty acids that include highly concentrated levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably Lovaza® omega-3 fatty acids. Preferred embodiments include methods of alleviating IC, and methods of treating underlying conditions that cause IC, such as PAD.

[0100] A particularly preferred azetidinone-based compound for use in compositions and methods of the present invention is ezetimibe or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug. Another preferred azetidinone-based cholesterol absorption inhibitor is the phenolic glucuronide of ezetimibe or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug. Two other ezetimibe related analogs and cholesterol absorption inhibitors for use in compositions and methods of the present invention, for example, are referred to in the literature as: 1) SCH 58053 or (+)-7-(4- chlorophenyl)-2-(4-flourophenyl)-7-hydroxy-3R-(4-hydroxyphenyl)- 2-a2aspiro[3,5] nonan-1-one) (see J. Lipid Res. 43:1864-1873(2002)) and 2) SCH 48461 or (3R)- 3Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (see J. Med. Chem., 41:973-980 (1998)).

[0101] Ezetimibe's mode of action involves the inhibition of cholesterol absorption and resorption in the intestinal tract. This mechanism of action also involves the increased excretions of cholesterol and its intestinally-generated metabolites in the feces. This effect of ezetimibe results in lowered body cholesterol levels, increased cholesterol synthesis, and decreased triglyceride synthesis. The increased cholesterol synthesis initially provides for the maintenance of cholesterol levels in the circulation, levels that eventually decline as the inhibition of cholesterol absorption and resorption continues. The overall effect of drug action is the lowering of cholesterol levels in the circulatory system and tissues of the body.

[0102] The highly concentrated omega-3 fatty acids, preferably the Lovaza® omega- 3 acids, can be present in an amount 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. In one embodiment of the present invention, the azetidinone-based cholesterol absorption inhibitor, preferably ezetimibe, can generally be administered in an amount from about 2 mg to 150 mg, more preferably from about 5 mg to about 100 mg, and even more preferably from about 10 mg to about 50 mg. ^■

[0103] The dosages of azetidinone-based cholesterol absorption inhibitor with mixtures of omega-3 fatty acids that include highly concentrated levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be administered together in from 1 to 10 dosages, with the preferred number of dosages from 1 to 4 times a day, and the most preferred number of dosages from 1 to 2 times a day. [0104] The combination product of an azetidinone-based cholesterol absorption inhibitor, preferably ezetimibe, with mixtures of omega-3 fatty acids that include highly concentrated levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably Lovaza® omega-3 fatty acids, may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, a liquid, a soft gel capsule or other convenient dosage form such as oral liquid in a capsule, as known in the art. In some embodiments, the capsule comprises hard gelatin.

[0105] In some embodiments, the combination of the present invention allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose, as compared to the formulations in the prior art. In other embodiments, the formulations of the present invention may allow for reduced dosages of an azetidinone-based cholesterol absorption inhibitor and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.

[0106] The present combination of azetidinone-based cholesterol absorption inhibitor with mixtures of omega-3 fatty acids that include highly concentrated levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may allow for a greater effect than any expected combined or additive effect of the two drugs alone. Thus, the combined treatment of the two active ingredients, separately or through the novel combination product of the present invention, may cause an unexpected increase in effect of the active ingredients that allows increased effectiveness with standard dosages or maintained effectiveness with reduced dosages of the two active ingredients. It is well accepted in practice that an improved bioavailability or effectiveness of a drug or other active ingredient allows for an appropriate reduction in the daily dosage amount. Any undesirable side effects may also be reduced as a result of the lower dosage amount and the reduction in excipients (e.g., surfactants).

[0107] The administration of a combination of an azetidinone-based cholesterol absorption inhibitor and concentrated omega-3 fatty acids achieves results that are highly advantageous and beneficial to the treatment of IC. The increased efficacy of the combined treatment and combination product allows for a novel and more efficient pharmaceutical treatment for IC, and an improved treatment for the underlying conditions that cause IC, which may include PAD, PVD, hypertriglyceridemia, hypertension, angina, heart failure, artherosclerotic disease and related conditions. According to a particularly preferred embodiment, the underlying condition is PAD. The compositions and methods of the present invention also beneficially prevent or reduce the incidence of cardiovascular and vascular events.

f. Lovaza with Antiarrhythmic Agents

[0108] In still further variations of the present invention, the administration of an antiarrhythmic agent with omega-3 fatty acids (e.g., Lovaza® omega-3 fatty acids) is contemplated. The combination may optionally be provided as a single administration or unit dosage form comprising an antiarrhythmic agent selected from the following: quinidine, procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, encainide, flecainide, moricizine, propafenone, esmolol, propranolol, acebutolol, metoprolol, amiodarone, azimilide, bretylium, clofilium, dofetilide, ibutilide, sematilide, sotalol, verapamil, mebefradfil, diltiazem adenosine and digoxin. In a preferred embodiment, the antiarrhythmic agent is propafenone. In further preferred embodiments the antiarrhythmic agent is Rhythmol®. The present invention may incorporate now known or future known antiarrhythmic agents in an amount generally recognized as safe.

[0109] The combination product of an antiarrhythmic agent and highly concentrated omega-3 fatty acids, preferably the Lovaza® omega-3 fatty acids, may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, a liquid, a soft gel capsule or other convenient dosage form such as oral liquid in a capsule, as known in the art. In some embodiments, the capsule is comprised of hard gelatin.

[0110] The daily dosages of an antiarrhythmic agent, preferably propafenone as Rhythmol®, and highly concentrated omega-3 fatty acids, preferably the Lovaza® 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, and the most preferred number of dosages from 1 to 2 times a day. The administration is preferably oral administration, although other forms of administration that provide a unit dosage of an antiarrhythmic agent, preferably propafenone as Rhythmol®, and highly concentrated omega-3 fatty acids, preferably the Lovaza® omega-3 acids, may be used.

[0111] In some embodiments, the formulations of the present invention may allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose. In other embodiments, the formulations of the present invention may allow for reduced dosages of an antiarrhythmic agent and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.

[0112] The present combination of an antiarrhythmic agent (e.g., propafenone as Rhythmol®) and concentrated omega-3 fatty acids (e.g., the Lovaza® omega-3 acids), may allow for a greater effect than any expected combined or additive effect of the two drugs alone. Thus, the combined treatment of the two active ingredients, separately or through the novel combination product of the present invention, may cause an unexpected increase in effect of the active ingredients that allows increased effectiveness with standard dosages or maintained effectiveness with reduced dosages of the two active ingredients. It is well accepted in practice that an improved bioavailability or effectiveness of a drug or other active ingredient allows for an appropriate reduction in the daily dosage amount.

[0113] The administration of a combination of an antiarrhythmic agent (e.g., propafenone as Rhythmol®) and concentrated omega-3 fatty acids (e.g., the Lovaza® omega-3 acids), achieves results that are highly advantageous and beneficial to the treatment of IC. The possible increased efficacy of the combined treatment and combination product may allow for a novel and more efficient pharmaceutical treatment for IC, and underlying conditions such as PAD.

3. Alternative Embodiments

[0114] Additional uses for the compositions and methods of the present invention, beyond treatment of intermittent claudication and its causes, are also envisioned. For example, and without limitation, the compositions of the present invention may also be useful in treating hypertriglyceridemia, hypercholesteremia, mixed dyslipidemia, vascular disease, artherosclerotic disease and related conditions, and in preventing or reducing cardiovascular and vascular events. The compositions may also be beneficially incorporated into preparations for use in the treatment of these and other conditions.

[0115] It will, of course, be appreciated that the above description has been given by way of example only and that modifications in detail may be made within the scope of the present invention.

[0116] Throughout this application, various patents and publications have been cited. The disclosures of these patents and publications in their entireties are hereby incorporated by reference into this application, in order to more fully describe the state of the art to which this invention pertains.

[0117] The invention is capable of considerable modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts having the benefit of this disclosure.

[0118] While the present invention has been described for what are presently considered the preferred embodiments, the invention is not so limited. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the detailed description provided above.

Claims

WHAT IS CLAIMED:

1. A method for treating peripheral artery disease (PAD) in a patient suffering therefrom, comprising the steps of: providing a composition comprising one or more omega-3 fatty acids; and administering the composition to the patient in an amount effective to treat PAD.

2. A method for treating intermittent claudication (IC) in a patient suffering therefrom, comprising the steps of: providing a composition comprising one or more omega-3 fatty acids; and administering the composition to the patient in an amount effective to treat IC.

3. The method of claim 2, wherein the method provides an effective treatment for underlying conditions or risk factors of IC.

4. The method of claim 3, wherein the underlying conditions or risk factors of IC are selected from the group consisting of PAD, Charcot-Marie-Tooth syndrome, thromboangiitis obliterans (von Winiwarter-Buerger's disease), arteriosclerosis obliterans, and peripheral vascular disease.

5. Use of one or more omega-3 fatty acids for manufacturing a medicament for treating IC and/or treating one or more underlying conditions or risk factors of IC.

6. The use of claim 5, wherein the one or more of the underlying conditions or risk factors of IC is selected from the group consisting of PAD, Charcot-Marie-Tooth syndrome, thromboangiitis obliterans (von Winiwarter-Buerger's disease), arteriosclerosis obliterans, and peripheral vascular disease.

7. The method or use of any one of claims 1-6, wherein the one or more omega- 3 fatty acids comprise EPA and DHA.

8. The method or use of any one of claims 1-7, wherein the one or more omega- 3 fatty acids is present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition.

9. The method or use of any one of claims 1-7, wherein the one or more omega- 3 fatty acids is present in a concentration of at least 80% by weight as compared to the total fatty acid content of the composition.

10. The method or use of any one of claims 1-9, wherein the one or more 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.

11. The method or use of any one of claims 1-9, wherein the one or more omega- 3 fatty acids comprise at least 80% by weight of EPA and DHA as compared to the total fatty acid content of the composition.

12. The method or use of any one of claims 1-11, wherein the one or more omega-3 fatty acids comprise about 40% to about 55% by weight of EPA as compared to the total fatty acid content of the composition.

13. The method or use of any one of claims 1-12, wherein the one or more omega-3 fatty acids comprise about 30% to about 60% by weight of DHA as compared to the total fatty acid content of the composition.

14. The method or use of any one of claims 1-13, wherein the one or more omega-3 fatty acids are selected from the group consisting of omega-3 polyunsaturated, long-chain fatty acids; esters of omega-3 fatty acids with glycerol; esters of omega-3 fatty acids and a primary, secondary or tertiary alcohol; and mixtures thereof.

15. The method or use of any one of claims 1-14, wherein the EPA and DHA are in a weight ratio of EPA.-DHA of from 1 :2 to 2:1.

16. The method or use of any one of claims 1-15, wherein the one or more omega-3 fatty acids are provided for co-administration with one or more additional compounds each selected from the group consisting of pentoxifylline, angiotensin- converting-enzyme (ACE) inhibitors, dyslipidemic agents, dihydropyridine calcium channel blockers, antiarrhythmic agents, azetidinone-based cholesterol absorption inhibitors, niacin and derivatives, PDE III inhibitors, PPAR agonists/antagonists, bile acid sequestrants, and antiplatelet drugs.