JP2009544701A - Compositions containing omega-3 fatty acids and their use to treat peripheral arterial injury and intermittent claudication - Google Patents

Abstract

  A composition comprising omega-3 fatty acids, useful for treating intermittent claudication, preventing its further progression, and treating potential conditions such as PAD causing IC symptoms, methods of making the compositions, A method of using the composition to treat intermittent claudication and a method of using the composition to treat any of a variety of potential conditions that cause intermittent claudication.

Description

(Related application data)
This application claims priority based on US Provisional Application No. 60 / 832,135, filed July 21, 2006, the contents of which are hereby incorporated by reference.

(Background of the Invention)
1. The present invention generally relates to compositions comprising omega-3 fatty acids useful for treating peripheral arterial disorders and / or intermittent claudication. The present invention includes a pharmaceutical composition made from the composition, a method of making the composition, a method of using the formulation to treat peripheral arterial disorders and / or intermittent claudication, and peripheral arterial disorders. Also included is a method of using the formulation to treat any of a variety of potential conditions that cause intermittent claudication.

2. Description of the Related Fields In humans, cholesterol and triglycerides are part of the lipoprotein complex in the bloodstream and, via ultracentrifugation, high density lipoprotein (HDL), intermediate density lipoprotein (IDL), low It can be separated into 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 of LDL-C) promote human atherosclerosis and are associated with the onset of atherosclerosis Promotes levels of HDL-C and its transport complex, apolipoprotein A. Furthermore, cardiovascular morbidity and mortality in humans varies proportionally with total-C and LDL-C levels, and inversely with HDL-C levels.

  Omega-3 fatty acids are known to lower serum triglycerides by inhibiting diacylglycerol acyltransferase (DGAT) and by stimulating peroxime and mitochondrial beta-oxidation. Fish oil, commonly referred to as fish oil, is an excellent source of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are known to regulate fatty acid metabolism. Omega-3 fatty acids have been found to have beneficial effects in risk factors for cardiovascular disease, particularly mild hypertension, hypertriglyceridemia, and in coagulation factor VII phospholipid complex activity. Omega 3 fatty acids lower serum triglycerides, increase serum HDL cholesterol, reduce systolic and diastolic blood pressure and pulse rate, and reduce the activity of blood coagulation factor VII phospholipid complexes. Furthermore, omega-3 fatty acids appear to be well tolerated without causing other serious side effects.

  One form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids derived from fish oil, including DHA and EPA, sold under the trademark “Lovaza” ®. Such forms of omega-3 fatty acids are described, for example, in US Pat. Nos. 5,502,077, 5,656,667, and 5,698,594, which are hereby incorporated by reference. Is described.

  Intermittent claudication (IC) is pain that occurs during exercise, especially during walking. In IC, blood flow is sufficient to meet the needs of a resting patient. However, when the patient moves, the blood vessels are occluded and the free flow of blood is restricted. And oxygen supply cannot meet the demands of the muscles to exercise. In response to this high demand, the body lowers chemicals that open blood vessels (eg, nitrate oxide) and increases chemicals that narrow blood vessels (thromboxane, serotonin, angiotensin II, endothelin, norepinephrine). There is some evidence that blood cells can become abnormal and tend to form clots. The result of these problems is pain during exercise, which can be relieved only by rest. This pain occurs frequently in the calf but can also occur in other muscles of the leg or even in the arms. This leg pain occurs on one leg in 40% of patients and on both legs in 60% of patients. The most frequently affected artery in IC is the popliteal artery, which begins at the main femoral artery (called the general artery) and continues under the knee, where it branches off, calf and leg muscles. To carry blood.

  IC is a symptom that can be caused by many different conditions, including neurological disorders, inflammatory diseases and circulatory disorders, but it is most often a symptom of peripheral arterial disease (PAD). IC occurs between one-third and half of PAD patients. In general, inadequate blood flow in the extremities results in two forms of pain, intermittent claudication (this is pain that occurs in the legs, especially during exercise) and ischemic resting pain (which is what the patient is resting on May also occur, indicating a more advanced state of PAD). When IC progresses to ischemic resting pain, arteries become blocked and can develop ulcers and necrosis, so severe cases require amputation. Other symptoms of ischemic resting pain include weak calf muscles, toe-to-leg hair loss, thick toenails, shiny hard skin, painful toe ulcers, and, in some cases, legs Clot formation in the arteries.

  Peripheral arterial injury (PAD) occurs when atherosclerosis (commonly referred to as arteriosclerosis) affects the extremities by blocking the arteries and preventing oxygen-rich blood flow. It is often caused by the same type of plaque accumulation that can occur in the arteries leading to the heart and brain. Furthermore, PAD patients have the same risk of heart events and stroke as patients with overt heart disease, even if no signs of heart disease are evident. PAD-related symptoms, such as IC, can significantly impair physical function from day to day. IC pain severely limits physical activity. ICs also usually have an increased risk of falling due to instability, regardless of the severity of PAD. IC and PAD are also associated with mental decline, which appears to add 4 or 5 years to the age of the individual. In general, the worse the leg condition, the more impaired the overall health of the PAD patient.

  Most of the currently available IC medications aim to relieve pain, improve function, and prevent progression that can lead to necrosis and amputation. This is usually done with drugs that open blood vessels or prevent clots. Antiplatelet drugs are important drugs to achieve these goals, but others are also being studied. When IC is caused by PAD, treatment through dietary restrictions and exercise is recommended, as is smoking cessation therapy. Treatment can be supplemented with a variety of medications. Aspirin is at least a potent antiplatelet agent and is used for moderate PAD. Clopidogrel (Plavix®) is specifically approved for ICs and has other cardiac protective functions. If PAD is more severe, balloon angioplasty or bypass surgery may be recommended.

  Prevention of heart disease and stroke is an important treatment goal for IC to reduce arterial damage. These objectives are often handled by using drugs that improve cholesterol and lipid concentrations.

  Improved cholesterol and lipid concentrations are also very important when intermittent claudication is a symptom of PAD. Experts have found that PAD patients are lipid lowering agents, angiotensin converting enzyme (ACE) inhibitors, statins (which can help promote new blood vessel growth and thereby prevent intermittent claudication), fibrates, nicotine What heart risks, as well as treatment of intermittent claudication, including acid, strong insulin regulation (in diabetics) and antiplatelet drugs (may include aspirin, clopidogrel (Plavix) and ticlopidine (Ticlid)) We recommend that you be given the best treatment to manage even the factors.

  Various studies have been conducted to determine the effects of dietary supplements with products such as fish oil on their causes including IC and PVD and PAD.

  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), 0.2 g eicosapentaenoic acid (EPA), 0.13 g docosahexaenoic acid (DHA) in patients with peripheral vascular disease and intermittent claudication (PVD-IC). Research on the effects of daily dietary supplements using 500 ml of dairy products with enhanced nutritional value containing 5.12 g oleic acid, 150 g folic acid, vitamin A, 1.5 mg vitamin B-6, vitamin D, and vitamin E Describe. All patients received the antiplatelet drug triflusal and the hemorrheologic agent pentoxifylline, and half of the patients received a more nutritious dairy product. This study found that patients who also received nutritious dairy products showed improvements in painless walking distance and ankle-brachial blood pressure compared to patients who did not.

  Various studies include (n-3) PUFA (Somerfield, T. and Hiatt, WR “Omega-3 fatty acids for intermittent claudication [Cochrane review]”, The Cochrane Library, Issue 3 (2004)), olive oil (Ramirez-Tortosa , MC 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 dietary supplements containing (1998)) is, gives a beneficial effect on patients who exhibit intermittent claudication, was found not to result in a specific dietary supplement guidelines.

  The World Health Organization (WHO) Study Group Diet (2003), Technical Report Series No. 916, generally limits saturated fats and appropriate levels of antioxidants and folic acid. In addition to increasing the consumption of fruits and vegetables to obtain salt, regular consumption of fish is recommended to provide 200 mg to 500 mg of EPA and DHA appropriately weekly.

Pittler, MH and Ernst, E.'s "Complementary therapies for peripheral arterial disease: Systematic review" Atherosclerosis, Vol. 181: 1-7 (March 2005) is acupuncture, biological self-regulation, chelation therapy as PAD treatment , CO ₂ application methods (CO ₂ -applications), garlic, ginkgo, omega-3 fatty acids, Padma 28 (Padma 28) and commented research on the use of vitamin E, all instead of one is the commentary has been studied Fonte Only patients with PAD in Fontaine stage II (intermittent claudication) were included. For omega-3 fatty acids, no significant change in the patient's painless maximum walking distance was found, and there was no evidence of improved clinical outcome in patients with intermittent claudication .

  Leng, GC et al., “Randomized controlled trial of gamma-linoleic acid and eicosapentaenoic acid in peripheral arterial disease” Clin. Nutr., 17 (6): 265-71 (1998) is a fatty acid (280 mg of gamma-linolenic acid (18 : 3n-6) and 45 mg eicosapentaenoic acid (20: 5n-3) capsule), versus placebo (500 mg sunflower oil capsule) without stable intermittent lameness The effect of administering to patients with depression over a period of 2 years was studied. It was found that there was a small alleviation of non-lethal coronary events in the fatty acid group, but there was no difference in walking distance without pain, and the authors found similar results from a similar study in a short period of time. Mentioned what to bring.

  Canadian Patent No. 2,291,959 describes coronary heart disease, cerebrovascular disease (where the patient suffers from at least one stroke), and peripheral vascular disease (where the patient suffers from intermittent claudication). The present invention relates to a nutritive composition for use in the treatment of vaso-occlusive diseases, comprising compounds useful for the treatment of patients who are suffering from The composition comprises metabolic enhancers, L-carnitine and coenzyme Q; homocysteine-lowering vitamins, folic acid, B6 and B12; LDL cholesterol-lowering amounts of nicotinic acid or sustained release forms thereof; antioxidants, vitamin C, Contains vitamin E and selenium; and omega-3 polyunsaturated fatty acids.

  Published PCT application No. WO 01/084961 relates to a preparation for use in preventing and / or treating vascular disorders, comprising three fractions. The first fraction contains long chain polyunsaturated fatty acids. The second fraction comprises a phospholipid containing at least two selected from the group consisting of phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine. The third fraction contains a compound that is a factor in methionine metabolism containing at least one selected from the group consisting of folic acid, vitamin B12, vitamin B6, magnesium and zinc. This application is primarily directed to the treatment of vascular problems that cause symptoms of dementia; however, other problems include obstructive thromboangitis and atherosclerosis.

  Published US Patent Application 2002/0055539 relates to compositions and methods for treating or preventing cardiovascular conditions by intravascular administration of omega fatty acids. The cardiovascular condition may be a peripheral vascular disease. The composition may comprise one or more omega-3 fatty acids, one or more omega-6 fatty acids, or a mixture of one or more omega-3 fatty acids and omega-6 fatty acids. With respect to the method of treatment, the composition is preferably administered intravascularly near the site to be treated.

  Thus, any of the above technical approaches is a composition for alleviating IC by administering a composition of the invention comprising omega-3 fatty acids and optionally containing one or more additional compounds. Products and methods, and compositions and methods for treating potential conditions that cause IC (eg, PAD) are not provided.

  There is a clear need in the art for compositions useful for treating IC and its potential causes (eg, PAD), and methods of making the same. There is also a need for a method of treating intermittent claudication with the formulation. There is a particularly great need in the art for the initial state associated with IC, the additional treatment effect to alleviate PAD.

US Pat. No. 5,502,077 US Pat. No. 5,656,667 US Pat. No. 5,698,594 Canadian Patent No. 2,291,959 WO01 / 084961 US Patent Application No. 2002/0055539

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) Somerfield, T. and Hiatt, W.R. "Omega-3 fatty acids for intermittent claudication [Cochrane review]" The Cochrane Library, Issue 3 (2004) 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) Aguilera, C.M., 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 Kleijnen, J. and Mackerras, D. “Vitamin E for intermittent claudication [Cochrane review]” The Cochrane Library, Issue 3 (2004) 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) World Health Organization (WHO) Study Group Diet (2003), Technical Report Series 916 Pittler, M.H. and Ernst, E., "Complementary therapies for peripheral arterial disease: Systematic review" Atherosclerosis, Vol. 181: 1-7 (March 2005) Leng, G.C., et al., `` Randomized controlled trial of gamma-linoleic acid and eicosapentaenoic acid in peripheral arterial disease '' Clin. Nutr., 17 (6): 265-71 (1998)

(Summary of the Invention)
IC and a mixture of omega-3 fatty acids, preferably Lovaza, containing high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to treat IC and potential conditions that cause IC, such as PAD There is an unmet need in the art for compositions and methods that use ® omega-3 fatty acids.

  In addition, high concentrations of omega-3 fatty acids (eg, Lovaza® omega-3 fatty acids) and optionally one or more compounds useful for treating potential conditions that cause IC, eg, PAD There is still an unmet need for a combination product that provides a single dose to contain. Such a combination may be provided, for example, in unit dosage. There is also an unmet need in the art for how to administer a single dose or unit dose product. Further, a composition comprising one or more compounds useful for treating potential conditions that cause IC, such as PAD, and Lovaza® omega-3 fatty acid, wherein the one Alternatively, there is a need that has not yet been addressed in the art for compositions where compounds are combined with Lovaza® omega-3 fatty acids to provide specific therapeutic characteristics.

  The present invention provides omega-3 fatty acids, preferably Lovaza®, including high levels of EPA and DHA, that can provide effective treatment for IC and PAD and any of a variety of potential conditions that can result in IC as a symptom. By providing a composition containing Omega 3 fatty acids, the unmet need in the art as well as other needs are met. These additional potential conditions include, but are not limited to, Charcot-Marie-Tooth syndrome, obstructive thromboangiitis (von Viniwalter-Bürger disease), obstructive arteriosclerosis and / or peripheral vascular disease. Including. For certain preferred embodiments, the potential condition is PAD. For further embodiments, omega-3 fatty acids are provided for co-administration with one or more compounds useful for treating potential conditions that cause IC, or as a unit dosage.

  The present invention also provides natural or synthetic omega-3 fatty acids and / or their pharmaceutically acceptable esters to provide an effective pharmaceutical treatment for intermittent claudication while minimizing undesirable side effects, Methods are provided that utilize compositions comprising inducers, conjugates, precursors or salts, or mixtures thereof.

  Other embodiments of the present invention provide natural or synthetic omega-3 fatty acids and / or their pharmaceutically acceptable esters, inducers, conjugates, precursors or in the treatment of subjects experiencing intermittent claudication Provide a salt, or a mixture thereof.

  Other embodiments of the invention are oral formulations of natural or synthetic omega-3 fatty acids and / or their pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts, or mixtures thereof. . In another aspect of the embodiments, the formulation is used for the treatment of subjects who suffer from intermittent claudication.

  Another subject of the invention provides compositions comprising natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof, Then, the composition is administered to a patient suffering from intermittent claudication to relieve intermittent claudication in the patient suffering from it.

  Another subject of the present invention treats intermittent claudication of natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts thereof, or mixtures thereof. For use in the manufacture of pharmaceuticals.

  The compositions and methods of the present invention comprise one of Charcot-Marie-Tooth syndrome, obstructive thromboangiitis (von Vinniwalter-Burger disease), obstructive arteriosclerosis, peripheral vascular disease and / or peripheral arterial disease. It may further include co-administration of one or more additional compounds useful for multiple treatments. With respect to certain preferred embodiments, the compositions and methods of the invention are useful for the treatment of PAD. Also included are unit dosage forms comprising omega-3 fatty acids and salts, one or more additional compounds, and methods of administering it to a patient in need thereof.

  These additional compounds include 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 their pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts, and mixtures thereof It may be selected from a group.

  In a preferred embodiment, the pharmaceutical composition comprises Lovaza® omega-3 fatty acids as described in US Pat. Nos. 5,502,077, 5,656,667, and 5,698,594. Including. In another preferred embodiment, the pharmaceutical composition comprises omega-3 fatty acids present at a concentration of about 40% by weight relative to the total fatty acid content of the composition. In yet another preferred embodiment, the omega-3 fatty acid comprises at least 50% by weight of EPA and DHA, based on the total fatty acid content of the composition, wherein EPA and DHA are 99: 1 by weight ratio of EPA: DHA. To 1:99, preferably 1: 4 to 4: 1, more preferably 1: 3 to 3: 1, and most preferably 1: 2 to 2: 1.

  Other new features and advantages of the present invention will be appreciated by those of ordinary skill in the art upon understanding the following test or practice of the present invention.

(Detailed description of the invention)
The present invention relates to compositions comprising omega-3 fatty acids, methods of making them, and their use in the relief of intermittent claudication (IC) and their use in the treatment of potential conditions that may result in IC. Additional compounds useful for treating IC or treating potential conditions that cause IC symptoms may also be beneficial for co-administration with the compositions and pharmaceutical formulations of the present invention. Or may be provided in a single dosage form containing them. Potential conditions that cause IC include, but are not limited to, Charcot-Marie-Tooth syndrome, obstructive thromboangiitis (von Viniwalter-Bürger disease), obstructive arteriosclerosis, peripheral vascular disease (PVD) ), And / or peripheral arterial disease (PAD). With regard to particularly preferred embodiments, the compositions and methods of the present invention are useful for treating PAD.

1. Compositions comprising omega-3 fatty acids In a preferred embodiment, the compositions of the present invention are useful for treating IC and its potential cause (s). These inventive compositions comprise Lovaza® omega-3 fatty acids as described in US Pat. Nos. 5,502,077, 5,656,667 and 5,698,594. In another preferred embodiment, the composition comprises omega-3 fatty acids present at a concentration of at least 40% by weight relative to the total amount of fatty acids in the composition. In yet another preferred embodiment, the omega-3 fatty acid comprises at least 50% per weight of EPA and DHA, relative to the total fatty acid content of the composition, and EPA and DHA are 99:99 by weight ratio of EPA: DHA. 1-1: 99, preferably 1: 4-4: 1, more preferably 1: 3-3: 1, and most preferably 1: 2-2: 1. The omega-3 fatty acid may comprise pure EPA or pure DHA.

  As used herein, the term “omega-3 fatty acid” refers to natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters, derivatives, conjugates thereof (eg, Zaloga et al., US Patent Application Publication No. 2004/0254357). Horrobin et al., US Pat. No. 6,245,811 (incorporated herein by reference), precursors or salts. Examples of omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated, long chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid; glycerol, For example, esters of mono-, di- and triglycerides with omega-3 fatty acids; and esters of omega-3 fatty acids with primary, secondary or tertiary alcohols, such as fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long chain fatty acids such as EPA or DHA, their triglycerides, their ethyl esters and mixtures thereof. The omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in pure form or as components of oils such as fish oil, but preferably Fish oil concentrate. Commercial examples of omega-3 fatty acids suitable for use in the present invention include Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England) and EPAX6000FA, EPAX5000TG EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare as, 1327 Lysaker, Norway).

  Other preferred compositions are at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, even more preferably at least 70% by weight, most preferably at least 80% by weight, Omega-3 fatty acids present at a concentration of at least 90% by weight. Preferably, the omega-3 fatty acid comprises at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, more preferably at least 70% by weight, most preferably at least 80% by weight, such as at least 84%. Including. Preferably, the omega-3 fatty acid is from 5% to about 100% by weight, more preferably from about 25% to about 75% by weight, even more preferably from about 40% to about 55% by weight, most preferably the weight of EPA. About 46%. Preferably, the omega-3 fatty acids are from about 5% to 100% by weight, more preferably from about 25% to about 75% by weight, even more preferably from 30% to about 60% by weight, most preferably per weight of DHA. Contains about 38%. All of the above percentages are by weight as compared to the total amount of fatty acids in the composition unless otherwise indicated.

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

The most preferred form of omega-3 fatty acid is Lovaza® omega-3 fatty acid (K85EE, Pronova Biocare AS, Lysaker, Norway) and preferably includes the following characteristics (before dosage form).

  The active ingredient of the present invention, omega-3 fatty acids, may be administered in combination with one or more inert pharmaceutical ingredients (commonly known as “excipients”). Non-active ingredients provide, for example, solubility, dispersibility, thickness, dilution, emulsification, stability, storage stability, protection, coloration, flavor and formability to the active ingredients and are safe, convenient or suitable for use. A suitable and effective preparation. Thus, the inactive ingredients include colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and xanthan gum. You can leave.

  Excipients are surfactants such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long chain fatty acids, polyoxyethylene castor oil, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, dicapryl Acid / propylene glycol dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, co-solvents such as ethanol, glycerol, polyethylene glycol and propylene glycol, oils such as coconut, olive or safflower oil Including. The use of surfactants, co-solvents, oils or combinations thereof is generally known in the pharmaceutical arts and, as will be appreciated by those skilled in the art, any suitable surfactant is identified in the present invention and its It can be used in combination with the embodiment.

  Preferably, the active ingredient is administered without the use of large amounts of surfactant. In preferred embodiments, when present, the surfactant is present in an amount of less than 50%, more preferably less than 40%, even more preferably 30%, based on the total weight of the solvent system of the dosage form (s). Less than, most preferably less than 20%. In one embodiment, the solvent form does not include a surfactant.

  As used herein, “solvent system” includes omega-3 fatty acids. In other embodiments, the weight ratio of omega-3 fatty acid 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 1. One to one. In still other preferred embodiments, when present, the amount of hydrophilic solvent used in the solvent system is less than 20% w / w, more preferably based on the total weight of the solvent system of the dosage form (s). Is 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, 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 of the dosage form (s), more preferably Less than 5%. In certain embodiments, the amount of hydrophilic solvent used in the solvent system is 5% to 10% w / w.

  The active ingredient of the present invention, omega-3 fatty acids, may be administered simultaneously with one or more additional compounds and may be provided in a unit dosage pharmaceutical formulation comprising one or more additional compounds, The additional compounds are useful to relieve IC, are useful to prevent IC from progressing to ischemic resting pain, or result in any potential condition leading to IC. It is effective to treat. These potential conditions may include PAD, PVD, obstructive arteriosclerosis, obstructive thromboangiitis (von Viniwalter-Burger disease), or Charcot-Marie-Tooth syndrome. According to certain preferred embodiments, the active ingredients of the present invention are useful for treating PAD.

  Additional compounds in accordance with the present invention include angiotensin converting enzyme (ACE) inhibitors; dyslipidemic drugs (preferably, but not limited to, HMG CoA reductase inhibitors (statins) such as simvastatin, rosuvastatin, Including pravastatin, atorvastatin, lovastatin, and fluvastatin; dihydropyridine calcium channel blockers (preferably, but not limited to, Bay K 8644, amlodipine (eg, Norvasc®), felodipine (eg, Plendil (eg Registered trademark)), lacidipine (eg, Lacipil®), lercanidipine (eg, Zanidip®), nicardipine (eg, Cardene®), nifedipine (eg, Adalat®, Procardia ( Registered trademark)), nimodipine (eg, Ni motop®), nisoldipine (eg, Sular®), nitrendipine and isradipine (eg, DynaCirc®); antiarrhythmic agents (preferably but not limited to quinidine, Procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, encainide, flecainide, moricidin, propaphenone, esmolol, propranolol, acebutolol, metoprolol, amiodarone, azimilide, bretylium, clofilium, dofetilide, verifilide, tibutiridol, mebefradfil), including diltiazem adenosine and digoxin); azetidinone-based cholesterol absorption inhibitors (preferably, but not limited to) Including ezetimibe, MD-0727 and SCH60663; niacin and derivatives (preferably including but not limited to nicotinamide); PPAR agonists / antagonists (preferably but not limited to fenofibrate) , Including 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. May be selected.

  Other additional compounds that may be used in combination with the omega-3 fatty acids of the present invention are those that are available or under investigation for use to moderate IC. These include pentoxifylline (Trental), cilostazol (Pletal), prostaglandins (including prostaglandin E1 and beraprost), recombinant fibroblast growth factor-2 (FGF-2), blood vessels Includes endothelial cell growth factor (VEGF), naphthidrofuryl (Nafronyl), levocarnitine (L-carnitine) and its derivatives propionyl levocarnitine, E2F decoy, mesoglycan and six steroid hormones (including testosterone) .

  Compounds similar to those described above are also envisioned with respect to the present invention and may be disclosed in the future or may already be present in the future with existing compounds. Good. Furthermore, the optional inclusion of additional compounds useful for the treatment of conditions such as hypertension and diabetes that are known to contribute to circulatory diseases is also envisaged.

  If provided, these optional additional ingredients are useful in the treatment of IC or any potential condition or disease that causes IC as a symptom. These include, but are not limited to, Charcot-Marie-Tooth syndrome, occlusive thromboangiitis (von Viniwalter-Burger disease), obstructive arteriosclerosis, peripheral vascular disease, and / or peripheral arterial disease .

  As will be described in more detail below, optional additional ingredients, if provided, provide relief of IC symptoms and / or treat potential conditions that cause the patient to suffer from IC. Contains enough to do. This optional additional ingredient is generally recognized as safe and is provided in an amount effective to alleviate the IC and treat its potential cause.

  Compositions containing concentrated omega-3 fatty acids can be prepared in the form of capsules, such as hard gelatin capsules; tablets; powders that can be dispersed in beverages; liquids; or soft gel capsules. The composition may also be contained in a liquid suitable for injection or infusion. However, the method of preparing the composition of the invention for administration is not limited to any particular dosage form. Rather, they can be prepared as any pharmaceutically acceptable dosage form, including other solid oral dosage forms, other liquid oral dosage forms, and any other suitable dosage form. . Where provided, one or more optional additional ingredients may also be provided in dosage forms containing omega-3 fatty acids to create a generic unit dosage form.

  In some embodiments, the unit dosage formulations of the present invention are improved for each active ingredient compared to prior art formulations, with one or both administered at a dose that exhibits conventional full efficacy. Make the effect possible. In other embodiments, the formulations of the present invention may allow reduced dosing of optional additional ingredients as compared to prior art formulations while still maintaining or further improving the effectiveness of each active ingredient. .

  This combination of concentrated omega-3 fatty acids and one or more additional ingredients selected from those listed above can be more effective than any combination or additional effects expected of the compound alone. Can be. Thus, combination therapy with active ingredients can lead to unexpected enhancements in the efficacy of the active ingredients separately or through the new combination of the present invention. This allows for an increased effect when using a standard dosage of the active ingredient or a sustained effect when using a reduced dosage. In practice, it is widely accepted that improved bioavailability or effect of drugs or other active ingredients allows for an appropriate reduction in daily dosage. Any undesirable side effects can also be mitigated as a result of low dosage and reduced use of excipients (eg, surfactants).

Methods of Treating IC and PAD The compositions comprising the concentrated omega-3 fatty acids described above are about 0.1 g to about 10 g, more preferably about 1 g to about patients suffering from PAD and / or patients suffering from symptoms of IC. It may be administered at a daily dose of about 6 g, most preferably about 2 g to about 4 g. The daily dose of concentrated omega-3 fatty acids may be administered from 1 to 10 doses, preferably from 1 to 4 doses per day, most preferably from 1 to 2 times per day. . The administration is preferably oral administration, although other dosage forms that provide a single dose of concentrated omega-3 fatty acids may be used. The administration of the preparation is preferably effective in alleviating the IC of patients suffering from IC and / or effective in treating the potential condition (s) that cause the IC, particularly PAD .

  A composition comprising omega-3 fatty acids can be administered simultaneously with one or more additional compounds that are effective in alleviating IC or effective in treating the potential condition (s) that cause it. Also good. These potential causes include, but are not limited to, Charcot-Marie-Tooth syndrome, obstructive thromboangiitis (von Viniwalter-Burger disease), obstructive arteriosclerosis, peripheral vascular disease and / or Peripheral artery disease is included. Administration of unit dosage forms of omega-3 fatty acids and one or more additional compounds is also contemplated for the present invention.

  One or more optional additional compounds include pentoxifylline, angiotensin converting enzyme (ACE) inhibitor, dyslipidemia, dihydropyridine calcium channel blocker, antiarrhythmic agent, azetidinone based cholesterol absorption inhibitor, From niacin and derivatives, PDE III inhibitors such as cilostazol, PPAR agonists / antagonists, bile acid sequestrants, antiplatelet drugs and their pharmaceutically acceptable esters, derivatives, conjugates, precursors or salts, and mixtures thereof Although advantageously selected, combinations with other compounds used to treat hypertension, diabetes or other conditions that contribute to circulatory disease are envisioned in the context of the present invention.

  Co-administration of the concentrated omega-3 fatty acids of the present invention with one or more additional compounds described above achieves very advantageous and beneficial results for the pharmaceutical and pharmaceutical fields. The increased efficacy of this combination therapy and combination product allows new and more effective pharmaceutical treatments for IC and its potential causes (eg PAD).

  The treatment method in accordance with the present invention is that IC and its potential causes, in particular PAD, is a therapeutically effective combination of Lovaza and a PPAR agonist / antagonist (especially fenofibrate), or Lovaza and a dyslipidemic drug (especially Statins), or Lovaza and sterol / stanol therapeutically effective combinations, or Lovaza and calcium channel blockers, or Lovaza and cholesterol absorption inhibitors. Preferred embodiments are those that are treated by administering an effective combination, or a therapeutically effective combination of Lovaza and an antiarrhythmic agent. These methods will be described in further detail below.

a. Lovaza and PPAR agonist / antagonists The present invention suffered from PDA and / or IC comprising administering omega-3 fatty acids (preferably Lovaza® omega-3 fatty acids) and PPAR agonists and / or antagonists A novel method of treatment of a subject is provided wherein the omega-3 fatty acid is administered before, simultaneously with or after administration of a PPAR agonist and / or antagonist. Unit dosage forms comprising both omega-3 fatty acids and PPAR agonist / antagonists are specifically envisioned for use with the methods of the present invention.

  As noted above, treatment of a subject with both active ingredients allows a more effective treatment than the typical dosage of each drug, or allows each drug dosage to be maintained while maintaining an effective treatment. Allows options to be reduced. Administration is preferably oral.

  The present invention may include currently known or future known PPAR agonists and / or antagonists in amounts generally recognized as safe. The term “PPAR agonist and / or antagonist” 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, fibrate, thiazolidinedione, non-thiazolidinedione and metaglidasen. Preferably, the compound comprises fibrates such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, most preferably fenofibrate.

  Combinations of PPAR agonists and / or antagonists and concentrated omega-3 fatty acids can be dispersed in capsules, tablets, powders or other solid oral dosage forms, solutions, softeners as known in the art. Other standard dosage forms such as gel capsules or oral liquids in capsules may be administered. In some embodiments, the capsule comprises hard gelatin. Combinations can also be included in liquids suitable for injection or infusion.

  In general, the effects of PPAR agonists and / or antagonists are dose dependent, ie higher doses have a better therapeutic effect. However, the effects of each PPAR agonist and / or antagonist are different, and thus the level of therapeutic effect of PPAR agonists and / or antagonists is not necessarily directly correlated with the level of therapeutic effect of other PPAR agonists and / or antagonists. You don't have to. However, one of ordinary skill in the art will understand the exact dosage to be given to a particular subject, depending on experience and the severity of the condition.

  Concentrated omega-3 fatty acids may be administered at a daily dose of about 0.1 g to about 10 g, more preferably about 0.5 g to about 8 g, and most preferably about 0.75 g to about 4 g. According to a preferred embodiment, the PPAR agonist is fenofibrate, 300 mg or less 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 daily doses may be administered.

  The daily dosage of the PPAR agonist and / or antagonist and concentrated omega-3 fatty acid is 1 to 10 dosages, preferably 1 to 4 dosages per day, most preferably once a day Two doses may be administered. The administration is preferably oral administration, although other dosage forms that provide a single dosage of PPAR agonist and / or antagonist and concentrated omega-3 fatty acids may be used.

  In other embodiments, the formulations of the present invention allow an improved effect of each active ingredient compared to prior art formulations, with one or both being administered at a dose that exhibits conventional full efficacy. To. In other embodiments, the formulations of the invention reduce PPAR agonists and / or antagonists and / or omega-3 fatty acids as compared to prior art formulations while maintaining or further improving the effectiveness of each active ingredient. May be possible.

  The combination of PPAR agonists and / or antagonists and omega-3 fatty acids allows for a greater effect than would be expected when combining the two drugs. Thus, the combination treatment of the two active ingredients can result in an increase in efficacy when using a standard dosage, or a reduced dosage of the two active ingredients, either separately or through a new combination of the invention. Causes sustained efficacy when used. Thus, the improved bioavailability or efficacy of the two active ingredients allows for a reduction in daily dosage. Side effects will also potentially be reduced as a result of lower dosages.

  When used in connection with the methods of the present invention, PPAR agonists and / or antagonists may be administered in an amount above, equal to, or below an amount that exhibits general full efficacy as a single dose product. For example, PPAR agonists and / or antagonists may be from 10% to 100%, preferably from about 25% to 100%, most preferably from about 50% to a dose that exhibits general full efficacy as a single dose product. It may be administered at 80%.

  Thus, administration of a combination of PPAR agonists and / or antagonists and concentrated omega-3 fatty acids achieves very advantageous and beneficial results in the treatment of IC. The possible increased efficacy of combination therapies and combinations may allow new and more effective pharmaceutical treatment of potential conditions that cause IC, including IC and PAD.

b. Lovaza and dyslipidemic drugs In another preferred embodiment, the invention provides for the administration of omega-3 fatty acids and dyslipidemic drugs, preferably in the dosage form of Lovaza® omega-3 fatty acids, said omega-3 It relates to administration wherein the fatty acids are administered simultaneously with the administration of the dyslipidemic drug, for example as a single stable dosage pharmaceutical composition or as separate compositions administered simultaneously. Preferably, administration of dyslipidemic drugs and omega-3 fatty acids is effective in treating IC and / or any of its potential causes, such as PAD.

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

  In other preferred embodiments, the administration comprises an omega-3 fatty acid and a dyslipidemic agent, wherein the omega-3 fatty acid is administered separately from the administration of the dyslipidemic agent, except in combination therapy treatment regimes. The For example, dyslipidemic drugs may be administered weekly with a daily intake of omega-3 fatty acids. Those of ordinary skill in the art who have the benefit of this disclosure will determine the exact dosing and schedule for administration of omega-3 fatty acids and dyslipidemic drugs depending on various factors, such as the severity of the route of administration and condition. Understand that it can change.

  The present invention may contain currently 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, fibrate and bile acid sequestrants. There are currently six widely available statins: atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. The seventh statin, cerivastatin, disappeared from the US market during this writing. However, one skilled in the art can envision that cerivastatin may be used in combination with some embodiments of the present invention if it is ultimately determined that it is safe and effective.

  In general, the effects of dyslipidemic drugs are dose-dependent, i.e., higher doses have a higher therapeutic effect. However, the effects of each dyslipidemic drug are different and therefore the level of therapeutic effect of one dyslipidemic drug need not necessarily be directly correlated with the level of therapeutic effect of other dyslipidemic drugs. Absent. However, one of ordinary skill in the art will understand the exact dosage to be given to a particular subject, depending on experience and the severity of the condition.

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

  Daily medications of dyslipidemic drugs and concentrated omega-3 fatty acids may be administered together from 1 to 10 times a day, with a preferred dosage of 1 to 4 times a day, most preferably 1 day. 1 to 2 times. The administration is preferably oral, although other dosage forms of administration that provide unit dosages of dyslipidemic drugs and concentrated omega-3 fatty acids may be used.

  Combinations of dyslipidemic drugs and concentrated omega-3 fatty acids can be used in capsules, tablets, powders that can be dispersed in liquids, or other solid oral dosage forms, solutions, soft gels, as is known in the art. It may be administered in capsules or other common dosage forms, such as oral solutions in capsules. In some embodiments, the capsule comprises hard gelatin. The combination may also be included in a solution suitable for injection or infusion.

  In some embodiments, the formulations of the present invention exhibit an improved effect of each active ingredient compared to prior art formulations, with one or both administered at a dose that exhibits conventional full efficacy. enable. In other embodiments, the formulations of the present invention have reduced dyslipidemic drugs and / or omega-3 fatty acids as compared to prior art formulations while maintaining or further improving the effectiveness of each active ingredient. Dosing may be possible.

  This combination of dyslipidemic drugs and concentrated omega-3 fatty acids may allow for an effect that is greater than the effect of any combination or additional effects expected with the two drugs alone. Thus, the combination treatment of the two active ingredients is maintained when using standard doses of the two active ingredients or using reduced dosages, either separately or through the new combination of the present invention. Can lead to an unexpected increase in the efficacy of the active ingredient, which allows for a positive effect. In practice, it is widely accepted that improved bioavailability or effect of drugs or other active ingredients allows for an appropriate reduction in daily dosage. Any undesirable side effects can also be mitigated as a result of low dosage and excipient (eg, surfactant) reduction.

  Thus, dyslipidemic drugs can be administered as a single dose product, generally in an amount equal to or less than the dose that exhibits full efficacy. For example, a dyslipidemic drug is typically 10% to 100%, preferably about 25% to 100%, most preferably about 50% to about 100% of the dose generally showing full efficacy as a single dose product. It may be administered in an amount of 80%.

  Administration of a combination of dyslipidemic drugs and concentrated omega-3 fatty acids (eg, Lovaza® omega-3 fatty acids) achieves very advantageous and beneficial results in the treatment of IC. This possible increased efficacy of combination therapies and combinations may allow new and more effective pharmaceutical treatment of IC and potential conditions that cause IC, including but not limited to PAD. .

c. Lovaza and sterols / stanols According to another embodiment of the present invention, sterols and / or stanols are omega-3 fatty acids, preferably for the treatment of potential conditions that cause IC and IC symptoms in patients, such as PAD. Is used in combination with high concentrations of omega-3 fatty acids, most preferably in the form of Lovaza® omega-3 fatty acids. Accordingly, a combination or single dose comprising one or more sterols and / or stanols and one or more omega-3 fatty acids is provided in connection with embodiments of the present invention. In a further preferred embodiment, Lovaza® omega-3 fatty acid is administered simultaneously with the administration of sterol or stanol.

  The present invention may include currently known or future known sterols and / or stanols in generally accepted amounts. For example, in some embodiments of the present invention, sterols include sitosterol, campesterol, stigmasterol, avenasterol, brajcasterol, ergosterol, and lanosterol. In other embodiments of the present invention, stanols include cholestanol, sitostanol, campestanol, stigmus stanol, avenastanol, brajcastanol, ergostanol and lanostanol. Sterols and / or stanols are in unmodified or preferably modified forms, for example in the form of esters containing glycerol such as mono-, di- and triglycerides, or in the form of primary alcohols such as fatty acid methyl esters and fatty acid ethyl esters It may be. Preferably, sterols and / or stanols are in the form of fatty acid esters (alternatively known simply as “sterol esters” or “stanol esters”). In a particularly preferred embodiment, the sterol is sitosterol. In another particularly preferred embodiment of the invention, the stanol is sitostanol.

  High concentrations of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, may be present in an amount of about 0.1 g to about 10 g, more preferably about 1 g to about 6 g, most preferably about 2 g to about 4 g. . Either unmodified or modified stanol and / or stenol is in an amount of about 0.1 g to about 10 g, more preferably about 0.5 g to about 4 g, and most preferably about 1 g to about 3 g. And / or may be present in the weight of stenol alone, not including the weight of other modifiers, such as fatty acid ester moieties.

  Daily administration of sterols and / or stanols and high concentrations of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, is preferably 1 to 10 times, most preferably 1 to 4 times per day, most preferably May be administered together once or twice per day. The administration is preferably oral, although other dosage forms that provide a single administration of sterol and / or stanol and high concentrations of omega-3 fatty acids may be used.

  In some embodiments, the formulations of the present invention may allow an improved effect of each active ingredient, with one or both being administered at a dose that exhibits conventional full efficacy. In other embodiments, the formulations of the present invention have reduced sterols and / or stanols and / or omega-3 fatty acids compared to prior art formulations while still maintaining or further improving the effectiveness of each active ingredient. Dosing may be possible.

  This combination of sterols and / or stanols and concentrated omega-3 fatty acids (eg Lovaza® omega-3 fatty acids) has a greater effect than either the expected combination effect or the additional effect of the two drugs alone. Can show. Thus, the combination therapy of the two active ingredients, either separately or through the new combination of the present invention, has an increased effect with standard dosing or a sustained effect with reduced dosing of the two active ingredients. It may cause an unexpected increase in the effect of the active ingredient. It is widely accepted that improved bioavailability or effect of drugs or other active ingredients allows for an appropriate reduction in daily dosage.

  Administration of a combination of sterols and / or stanols and concentrated omega-3 fatty acids (eg, Lovaza® omega-3 fatty acids) achieves very advantageous and beneficial results in the treatment of IC. This possible increased efficacy of combination therapies and combinations may allow new and more effective pharmaceutical treatment of IC and potential conditions that cause IC. Such potential conditions include, but are not limited to, preferably PAD.

Lovaza and Calcium Channel Blockers In yet another preferred embodiment, the present invention relates to PAD and POD through administration of omega-3 fatty acids, preferably in the form of Lovaza® omega-3 fatty acids, and dihydropyridine calcium channel blockers. It relates to the treatment of IC or any other potential condition that causes IC as a symptom.

  With respect to the first preferred embodiment, Lovaza® omega-3 fatty acid is administered separately from administration of the dihydropyridine calcium channel blocker. For example, isradipine (eg, through an isradipine patch) may be administered once a week in addition to daily intake of omega-3 fatty acids (eg, Lovaza® capsules). Those skilled in the art who benefit from this disclosure will know the exact dosing and regimen of Lovaza® omega-3 fatty acids and dihydropyridine calcium channel blockers, for example the route of administration and the severity of the IC or potential condition (symptoms). It will be appreciated that it will vary depending on many factors such as severity.

  With respect to the second preferred embodiment, Lovaza® omega-3 fatty acid may be administered in combination with administration of a dihydropyridine calcium channel blocker and administered in unit dosage form. In some embodiments, one or more dihydropyridine calcium channel blockers are combined with an amount of omega-3 fatty acids.

  The present invention may incorporate currently known or future known dihydropyridine calcium channel blockers in amounts generally accepted 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.

  A high concentration of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, is present in an amount of about 0.1 g to about 10 g, more preferably about 1 g to about 6 g, most preferably about 2 g to about 4 g. Also good. When used in connection with the present invention, the dihydropyridine calcium channel blocker may generally be present in an amount of about 0.5 g to 100 mg.

  Combinations of dihydropyridine calcium channel blocker (s) and high concentrations of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, can be dispersed in capsules, tablets, drinks as is known in the art. It may be administered in other standard dosage forms such as powders, solutions, soft gel capsules, or oral solutions in capsules. In some embodiments, the capsule consists of hard gelatin.

  Daily administration of dihydropyridine calcium channel blocker and high concentration omega-3 fatty acid is 1 to 10 doses, preferably 1 to 4 doses, most preferably 1 to 2 doses per day They may be administered together. Administration is preferably oral, although other dosage forms that provide a single dose of dihydropyridine calcium channel blocker and high concentration omega-3 fatty acids may be used.

  In some embodiments, the formulations of the present invention allow for an improved effect of each active ingredient, with one or both being administered at a dose that exhibits conventional full efficacy. In other embodiments, the formulations of the present invention have reduced dihydropyridine calcium channel blockers and / or omega-3 fatty acids as compared to prior art formulations while still maintaining or further improving the effect of each active ingredient. Dosing may be possible.

  This combination of dihydropyridine calcium channel blocker and concentrated omega-3 fatty acid may allow for greater effects than the combined effects or additional effects expected when used alone. Thus, the combination therapy of each active ingredient can be increased when using standard dosages of the two active ingredients separately or through the new combination of the invention, or when using reduced dosages. Allows a sustained effect. In practice, it is widely accepted that improved bioavailability or efficacy of drugs or other active ingredients allows for appropriate reductions in daily dosage.

  Administration of a combination of a dihydropyridine calcium channel blocker and concentrated omega-3 fatty acids achieves very advantageous and beneficial results in IC treatment. The increased efficacy of this combination therapy and combination has led to new and more effective pharmaceutical treatments for IC, as well as PAD, PVD, hypertriglyceridemia, hypertension, angina, heart failure, atherosclerosis and related conditions. Enables improved treatment of potential conditions that cause ICs to be included. For certain preferred embodiments, the potential condition is PAD. The compositions and methods of the present invention also advantageously prevent or reduce the occurrence of cardiovascular and vascular events.

e. Lovaza and cholesterol absorption inhibitors For further embodiments of the present invention, omega-3 fatty acids are administered in combination with azetidinone-based cholesterol absorption inhibitors, preferably ezetimibe, for the treatment of IC and their causes, It is administered with a mixture of omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably with Lovaza® omega-3 fatty acids. The present invention also provides a mixture of omega-3 fatty acids, preferably Lovaza®, containing high concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), including cholesterol absorption inhibitors based on azetidinone, preferably ezetimibe. Combinations or single doses with omega-3 fatty acids are also envisaged. Preferred embodiments include methods for alleviating IC and treating potential conditions that cause IC, such as PAD.

  Particularly preferred azetidinone-based compounds for use in the compositions and methods of the present invention are ezetimibe or a mixture of their stereoisomers, diastereomerically enriched, diastereomerically pure, enantiomerically enriched, or Enantiomerically pure isomers thereof, or prodrugs, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs. Other preferred azetidinone-based cholesterol absorption inhibitors are ezetimibe phenol glucuronides or mixtures of their stereoisomers, diastereomerically enriched, diastereomerically pure, enantiomerically enriched, enantiomerically pure These isomers, or a prodrug of the compound, a mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug. Two different ezetimibe-related analogues and cholesterol absorption inhibitors for the use of the compositions and methods of the present invention are described in the literature 1) SCH58053 or (+)-7- (4-chlorophenyl) -2- (4-fluoro Phenyl) -7-hydroxy-3R- (4-hydroxyphenyl) -2-azaspiro [3,5] nonan-1-one) (see J. Lipid Res. 43: 1864-1873 (2002)) and 2) See SCH48461 or (3R) -3phenylpropyl) -1, (4S) -bis (4-methoxyphenyl) -2-azetidinone (J. Med. Chem., 41: 973-980 (1998). ).

  The mode of action of ezetimibe is related to the inhibition of cholesterol absorption and intestinal reabsorption. This mechanism of action is also associated with increased excretion of cholesterol in excreta and its intermediates made in the gut. This effect of ezetimibe results in decreased body cholesterol levels, increased cholesterol synthesis, and decreased triglyceride synthesis. Increased cholesterol synthesis initially leads to the maintenance of cholesterol levels in the circulatory system, which eventually declines gently as inhibition of cholesterol absorption and reabsorption continues. The overall effect of drug action is a reduction in cholesterol levels in the body's circulatory system and tissues.

  A high concentration of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, is present in an amount of about 0.1 g to about 10 g, more preferably about 1 g to about 6 g, and most preferably about 2 g to about 4 g. It's okay. In one embodiment of the invention, the azetidinone-based cholesterol absorption inhibitor, preferably ezetimibe, is generally in an amount of about 2 mg to about 150 mg, more preferably about 5 mg to about 100 mg, and even more preferably about 10 mg to about 50 mg. May be present.

  Dosing of an azetidinone-based cholesterol absorption inhibitor with a mixture of omega-3 fatty acids containing high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is from 1 to 10 doses, preferably 1 dose per day The doses may be administered together from 1 to 4 doses, most preferably from 1 to 2 doses per day.

  Combination of an azetidinone-based cholesterol absorption inhibitor, preferably ezetimibe, with a mixture of omega-3 fatty acids containing high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably Lovaza® omega-3 fatty acids The product is administered in other standard dosage forms such as capsules, tablets, powders that can be dispersed in beverages, liquids, soft gel capsules, or oral liquids in capsules as is known in the art. May be. In some embodiments, the capsule comprises hard gelatin.

  In some embodiments, the combination of the present invention provides an improved effect of each active ingredient compared to prior art formulations, with one or both administered at a dose that exhibits conventional full efficacy. enable. In other embodiments, the formulations of the present invention comprise azetidinone-based cholesterol absorption inhibitors and / or omega-3 fatty acids as compared to prior art formulations while maintaining or further improving the effectiveness of each active ingredient. Reduced dosing may be possible.

  This combination of an azetidinone-based cholesterol absorption inhibitor and a mixture of omega-3 fatty acids containing high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is one of the expected combinations of the two drugs alone An effect larger than the above effect or an additional effect may be possible. Thus, the combination therapy of the two active ingredients, either separately or through the new combination of the present invention, when using a standard dose of the two active ingredients, or when using a reduced dosage Can lead to an unexpected enhancement in the efficacy of the active ingredient, allowing a sustained effect of In practice, it is widely accepted that an improved bioavailability or effect of a drug or other active ingredient can allow an appropriate reduction in daily dosage. Any undesirable side effects can also be mitigated as a result of low dosage and excipient (eg, surfactant) reduction.

  Administration of a combination of an azetidinone-based cholesterol absorption inhibitor and concentrated omega-3 fatty acids achieves very advantageous and beneficial results in IC treatment. The increased efficacy of this combination therapy and combination is a new and more effective pharmacological treatment for IC and PAD, PVD, hypertriglyceridemia, hypertension, angina, heart failure, atherosclerosis and related conditions Allows for improved treatment of potential conditions that cause ICs. For certain preferred embodiments, the potential condition is PAD. The compositions and methods of the present invention also advantageously prevent or reduce the occurrence of cardiovascular and vascular events.

f. Lovaza and antiarrhythmic agents In a further variation of the invention, administration of an antiarrhythmic agent and an omega-3 fatty acid (eg, Lovaza® omega-3 fatty acid) is contemplated. This combination includes the following: quinidine, procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, encainide, flecainide, moricidin, propaphenone, esmolol, propranolol, acebutolol, metoprolol, amiodarone, azimilide, bretylium, clifidolium, chilidoid, It may be provided as a single dose or unit dosage form comprising an antiarrhythmic agent selected from sematilide, sotalol, verapamil, mebefradfil, diltiazem adenosine or digoxin. In a preferred embodiment, the antiarrhythmic agent is propafenone. In a further preferred embodiment, the antiarrhythmic agent is Rhythmol®. The present invention may include currently known or future known antiarrhythmic agents in amounts generally accepted as safe.

  Combinations of antiarrhythmic drugs with high concentrations of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, can be dispersed in capsules, tablets, drinks, liquids, soft gel capsules, orally in capsules Other standard dosage forms, such as solutions, may be administered. In some embodiments, the capsule consists of hard gelatin.

  Daily administration of an antiarrhythmic drug, preferably propaphenone as Rhythmol® and high concentrations of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, is 1 to 10 doses, preferred doses are One to four times a day, the most preferred dosing frequency may be administered once to twice a day. Other dosage forms may be used that provide unit dosages of antiarrhythmic drugs, preferably propaphenone as Rhythmol® and high concentrations of omega-3 fatty acids, preferably Lovaza® omega-3 fatty acids, Administration is preferably oral.

  In some embodiments, the formulations of the present invention allow an improved effect of each active ingredient, with one or both being administered at a dose that exhibits conventional full efficacy. In other embodiments, the formulations of the present invention provide a reduced dosage of antiarrhythmic drugs and / or omega-3 fatty acids compared to prior art formulations while maintaining or further improving the effectiveness of each active ingredient. Can be possible.

  This combination of an antiarrhythmic drug (eg, propaphenone as Rhythmol®) and a high concentration of omega-3 fatty acids (eg, Lovaza® omega-3 fatty acids) is one that would be expected with two drugs alone Greater effects than combination effects or additional effects may be possible. Thus, the combination therapy of the two active ingredients, either separately or through the new combination of the present invention, when using a standard dose of the two active ingredients, or when using a reduced dosage Can lead to an unexpected enhancement in the efficacy of the active ingredient, allowing a sustained effect of In practice, it is widely accepted that an improved bioavailability or effect of a drug or other active ingredient can allow an appropriate reduction in daily dosage.

  Administration of this combination of antiarrhythmic drugs (eg, propaphenone as Rhythmol®) and high concentrations of omega-3 fatty acids (eg, Lovaza® omega-3 fatty acids) is very advantageous and beneficial in IC treatment To achieve a good result. The increased efficacy of this combination therapy and combination allows new and more effective pharmaceutical treatments for potential conditions such as IC and PAD.

3. Alternative Embodiments Additional uses of the compositions and methods of the invention other than intermittent claudication and the treatment of its cause are also envisioned. For example, but not limited to, the compositions of the present invention are also used to treat hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, vascular disease, atherosclerosis and related conditions, and It may be useful to prevent or reduce cardiovascular and vascular events. The composition can also be advantageously incorporated into preparations for use in the treatment of these and other conditions.

  It will of course be understood that the above description is given by way of example only and that modifications in detail may be made within the scope of the invention.

  Various patents and publications are cited throughout the application. The disclosures of those patents and publications are hereby incorporated by reference in their entirety to more fully describe the technical field to which this invention pertains.

  The present invention is capable of many variations, modifications and equivalents in form and function, as will occur to those skilled in the art having the benefit of this disclosure.

  Although the present invention is described with respect to presently preferred embodiments, the invention is not limited thereto. On the contrary, the invention extends to various modifications and equivalent substitutions that fall within the spirit and scope of the above detailed description.

Claims (16)

A method of treating PAD in a patient suffering from peripheral arterial injury (PAD) comprising:
Providing a composition comprising one or more omega-3 fatty acids;
Administering the composition to the patient in an amount effective to treat PAD. A method of treating IC in a patient suffering from intermittent claudication (IC) comprising:
Providing a composition comprising one or more omega-3 fatty acids;
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 potential IC conditions or risk factors.   The potential condition or risk factors for IC are selected from the group consisting of PAD, Charcot-Marie-Tooth syndrome, obstructive thromboangiitis (von viniferter-Burger disease), obstructive arteriosclerosis and peripheral vascular disease The method according to claim 3.   Use of one or more omega-3 fatty acids for the manufacture of a medicament for treating IC and / or treating a potential condition or risk factor of one or more ICs.   Potential conditions or risk factors for one or more ICs include PAD, Charcot-Marie-Tooth syndrome, obstructive thromboangiitis (von Viniwalter-Burger disease), obstructive arteriosclerosis and peripheral vascular disease 6. Use according to claim 5, wherein the use is selected from the group consisting of   7. A method or use according to any one of claims 1-6, wherein the one or more omega-3 fatty acids comprise EPA and DHA.   8. The method or any one of claims 1-7, wherein the one or more omega-3 fatty acids are present at a concentration of at least 40% by weight relative to the total fatty acid content of the composition. use.   8. The method or any one of claims 1-7, wherein the one or more omega-3 fatty acids are present at a concentration of at least 80% by weight relative to the total fatty acid content of the composition. use.   10. A method according to any one of the preceding claims, wherein the one or more omega-3 fatty acids comprise at least 50% EPA and DHA by weight relative to the total fatty acid content of the composition. Or use.   10. A method according to any one of the preceding claims, wherein the one or more omega-3 fatty acids comprise at least 80% EPA and DHA by weight relative to the total fatty acid content of the composition. Or use.   12. The method according to any one of the preceding claims, wherein the one or more omega-3 fatty acids comprise from about 40% to about 50% EPA by weight relative to the total fatty acid content of the composition. Method or use.   13. The method according to any one of the preceding claims, wherein the one or more omega-3 fatty acids comprise about 30% to about 60% DHA by weight relative to the total fatty acid content of the composition. Method or use.   One or more omega-3 fatty acids are omega-3 polyunsaturated, long chain fatty acids; esters of omega-3 fatty acids and glycerol; omega-3 fatty acids and esters of primary, secondary or tertiary alcohols; and mixtures thereof 14. The method or use according to any one of claims 1 to 13, wherein the method or use is selected from the group consisting of:   15. A method or use according to any one of the preceding claims, wherein EPA and DHA are in a weight ratio of EPA: DHA of 1: 2 to 2: 1.   One or more omega-3 fatty acids may be pentoxifylline, angiotensin converting enzyme (ACE) inhibitor, dyslipidemia, dihydropyridine calcium channel blocker, antiarrhythmic, azetidinone-based cholesterol absorption inhibitor, niacin and derivatives , A PDE III inhibitor, a PPAR agonist / antagonist, a bile acid sequester, and an antiplatelet agent, each provided for co-administration with one or more additional compounds selected from the group consisting of: Item 16. The method or use according to any one of Items 1 to 15.