Pharmaceutical compositions containing epa and cardiovascular drug, and method for preparing them

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition for reducing triglycerides in an individual in need thereof, wherein the pharmaceutical composition contains at least 95 wt % of EPA of total fatty acids present in the composition and HMG-CoA reductase inhibitor.

EFFECT: invention provides reducing triglycerides in the individual in need thereof.

28 cl, 1 ex, 4 dwg

 

PRIOR art

Cardiovascular diseases are one of the leading causes of death in the United States and most European countries. It is calculated that only in the United States more than 70 million people suffer from cardiovascular diseases or disorders, including as non-limiting examples of high blood pressure, coronary heart disease, dyslipidemia, congestive heart failure, and stroke.

ENTITY

In one of the embodiments the present invention relates to pharmaceutical compositions containing EPA and optionally one or more additional cardiovascular drugs. In another embodiment, the EPA comprises ethyl ester of eicosapentaenoic acid. In another embodiment, the composition essentially contains no amount of docosahexaenoic acid or its derivative (for example, ethyl-DHA), if any contains.

In other embodiments implementing the present invention relates to methods for treating and/or preventing associated with cardiovascular system diseases, including introduction to the needy in the individual a pharmaceutical composition or composition(s)contain(s) EPA and optionally one or more additional cardiovascular suck the East of funds.

In any of the above embodiments, the implementation of the EPA and additional cardiovascular agent(a) can be combined in a single unit dosage or can be formulated in the form of two to a variety of dosage units for a concerted, combined or simultaneous administration.

Below in this document are described in more detail these and other embodiments of the present invention.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 presents the effect of EPA, DHA and combined treatment on lipid peroxidation of membranes when the ratio of cholesterol to phospholipids and 1.0.

Figure 2 presents the effect of EPA, DHA and combined treatment on lipid peroxidation of membranes when the ratio of cholesterol to phospholipids of 0.5.

Figure 3 presents dependent cholesterol effect of EPA, DHA and combined treatment on lipid peroxidation of membranes.

Figure 4 presents the effect of EPA, DHA or EPA/DHA with atorvastatin (molar ratio 10:1) on the levels of lipid peroxides in cholesterol-enriched membranes (the ratio of cholesterol to phospholipids 1:1).

DETAILED DESCRIPTION

Although the present invention can be implemented in various forms, provided the following description of several embodiments is made with the understanding that the present description should rassmatrivati as an example of the invention, and it is not intended to limit the invention to the specific illustrated variants of the invention. Headings are provided for convenience and should not be construed as in any way limiting the invention. Embodiments of illustrated under any title, can be combined with the variants of implementation, illustrated under any other heading.

When using numeric values in different quantitative values specified in this application, unless specifically stated otherwise, they are shown as approximations as though the minimum and maximum values in these ranges was preceded by the word "approximately". Thus, to achieve essentially the same results as the specified value, you can use a small deviation from the specified value. A description of the ranges are shown as a continuous range including every value between the minimum and maximum values, as well as any ranges that can be formed from these values. Also herein described any and all relationships (and the ranges of any of these ratios), which can be created by dividing the numerical value in any other numerical value. Thus, the special is ialist will understand what numerical values provided in this document, you can definitely get many such ratios, ranges, and ranges of ratios, and in all cases such ratios, ranges, and ranges of ratios provided by various embodiments of the present invention.

Eicosapentaenoic acid

In one of the embodiments of the composition according to the invention as the active ingredient contain EPA. As used herein, the term "EPA" refers to eicosapentaenoic acid (for example, eicosa-5,8,11,14,17-pontenova acid and/or its pharmaceutically acceptable ether complex, derivative, conjugate or salt or mixture of any of the above. The term "pharmaceutically acceptable" in this context means that the substance does not cause unacceptable toxicity for the individual or interaction with other components of the composition.

In one embodiment, the implementation of the EPA contains a fully-CIS-eicosa-5,8,11,14,17-pontenova acid. In another embodiment, the EPA is in the form of ester of eicosapentaenoic acid (also referred to herein as E-EPA or ethyl-EPA). In another embodiment, the EPA contains a C1-C5-alkilany ether EPA. In another embodiment, the EPA contains methyl ester e is icosapentaenoic acid, propyl ester of eicosapentaenoic acid or butyl ester of eicosapentaenoic acid. In another embodiment, contains EPA ethyl ester completely CIS-eicosa-5,8,11,14,17-pentaenoic acid.

In another embodiment, contains EPA EPA lithium salt, mono-, di - or triglyceride EPA or any ester or salt of the EPA or the form of the free acid EPA. EPA also may be in the form of 2-substituted derivative or other derivative, which slows the rate of oxidation, but in other respects does not alter its biological action in any significant degree.

In one embodiment, the implementation of the EPA, which is present in the composition according to the invention contains ultra-pure EPA. As used herein, the term "ultrapure" against EPA relates to compositions containing at least 96% by weight of EPA (as the term "EPA" defined and illustrated in this document). Ultra-pure EPA may contain even more pure EPA, for example, at least 97% by weight of EPA or at least 98% by weight of EPA where EPA is any form of EPA, as specified in this document. Ultra-pure EPA, you can optionally specify (for example, the composition of impurities) through any of the EPA definitions provided in this document.

In another embodiment, the EPA provides to nyugat EPA-fatty acid, where EPA conjugated with another molecule EPA or another fatty acid. In one embodiment, the implementation of the conjugate EPA-fatty acid contains complex fluids formed EPA and EPA, or EPA, and the second fatty acid, as shown in structures (I) and (II). In one embodiment, the implementation of R1represents an acyl group of a fatty acid derived from EPA, and R2selected from H, acyl fatty acids with the number of carbon atoms from 12 to 30 with two or more CIS - or TRANS-double bonds and groups of fatty alcohols with a number of carbon atoms from 12 to 30, such as R1or different from him. R1and R2can occur from the EPA (EPA-EPA) or one may come from the EPA, and the second from the other fatty acids (EPA-fatty acid), for example, gamma-linolenic acid, di-Homo-gamma-linolenic acid, arachidonic acid, atenolol acid, stearidonic acid, docosapentaenoic acid n-3, etc). R3mainly represents hydrogen, a fully hydrocarbon or contains heteroatoms, and in one of the embodiments represents a C1-C4is an alkyl group.

Synthesis of conjugate complex diapir can be well-known in the field of ways, including, for example, use as rolled is atarov metals, chlorides of metals or organic acids; the use of chlorides of fatty acids, such as chloride EPA, chloride, γ-linolenic acid (chloride GLA), chloride di-Homo-γ-linolenic acid (chloride DGLA), linoleic acid chloride (chloride LA), chloride arachidonic acid (chloride AA), chloride conjugated linoleic acid (cLA chloride), chloride ALA, chloride STA chloride ETA, chloride DPA etc; and use as catalysts immobilized enzymes.

In another embodiment, the composition according to the present invention contains a complex mixture of diesters EPA-fatty acid. In a related embodiment, compositions of the present invention contains less than 20% of the conjugate EPA-DHA, less than 15% of the conjugate EPA-DHA, less than 10% of the conjugate EPA-DHA, less than 9% of the conjugate EPA-DHA, less than 8% of the conjugate EPA-DHA, less than 7% of the conjugate EPA-DHA, less than 6% of the conjugate EPA-DHA, less than 5% of the conjugate EPA-DHA, less than 4% of the conjugate EPA-DHA, less than 3% of the conjugate EPA-DHA, less than 2% of the conjugate EPA-DHA, less than 1% conjugate EPA-DHA, less than 0.5% of the conjugate EPA-DHA or less than 0.1% by weight of the conjugate EPA-DHA.

In another embodiment, the composition according to the present invention contains at least 96% of the conjugate EPA-fatty acid (e.g., EPA-EPA), at least 97% of the conjugate EPA-fatty acid, at least 98% of the conjugate EPA-fatty acid or at least 99% of the conjugate EPA-fatty acid. In another embodiment, the HDMI is tion of the present invention contains not more than 10%, no more than 9%, no more than 8%, no more than 7%not more than 6%not more than 5%, no more than 4%, no more than 3%, no more than 2%not more than 1% or not more than 0.6%, not more than 0,5%not more than 0,4%not more than 0,3%not more than 0.2, or less than 0.1% of any conjugate EPA-fatty acid, different from the complex diapir EPA-EPA.

In another embodiment, the EPA is present in the composition according to the invention in quantities of from about 50 mg to about 5,000 mg, from about 75 mg to about 2500 mg, or from about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, in listello 1025 mg, approximately 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, approximately 1550 mg, approximately 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, approximately 1675 mg, about 1700 mg, approximately 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, approximately 2050 mg, approximately 2075 mg, about 2100 mg, approximately 2125 mg, approximately 2150 mg, approximately 2175 mg, about 2200 mg, approximately 2225 mg, about 2250 mg, approximately 2275 mg, approximately 2300 mg, approximately 2325 mg, approximately 2350 mg, approximately 2375 mg, 2400 mg, approximately 2425 mg, approximately 2450 mg, approximately 2475 mg, or about 2500 mg

In one of the options, the ants implementation of the composition according to the invention contains not more than about 10%, not more than about 9%, not more than about 8%, not more than about 7%, not more than about 6%, not more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, not more than about 1%, or no more than about 0.5% by weight of docosahexaenoic acid or its derivative, such as ethyl-DHA (E-DHA) from all fatty acids, if any contains. In another embodiment, the composition according to the invention essentially contains no docosahexaenoic acid or its derivative, such as E-DHA. In another embodiment, the composition according to the invention does not contain DHA or E-DHA.

In another embodiment, the EPA comprises at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% by weight of all fatty acids present in the composition according to the invention.

In another embodiment, the composition according to the invention contains less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%less 4%less 3%less 2%less 1%less 0.5% or less than 0.25% of any fatty acid, is excellent from EPA or its derivative, by weight of the total composition or mass content of all fatty acids. Illustrative examples of fatty acids other than EPA include linoleic acid (LA) or its derivative, such as Tillyaeva acid, arachidonic acid (AA) or its derivative, such as ethyl-AA, docosahexaenoic acid (DHA) or its derivative, such as ethyl-DHA, alpha-linolenic acid (ALA) or its derivative, such as ethyl-ALA, stearidonic acid (STA) or its derivative, such as ethyl-SA, eicosatrienoic acid (ETA) or its derivative, such as ethyl-ETA, and/or docosapentaenoic acid (DPA) or its derivative, such as ethyl-DPA.

In another embodiment, the composition according to the invention has one or more of the following characteristics: (a) ethyl ester of eicosapentaenoic acid is at least 96%, at least 97% or at least 98% by weight of all fatty acids present in the composition; (b) the composition contains not more than 4%, no more than 3% or no more than 2% by weight of all fatty acids other than ethyl ester of eicosapentaenoic acid; (c) the composition contains not more than 0.6%, 0.5% or 0.4% of each individual fatty acids other than ethyl ester of eicosapentaenoic acid; (d) the refractive index of the composition is (20°C) from about 1 to about 2, from about 1.2 to the roughly 1.8 or from about 1.4 to about 1.5; (e) the specific gravity of the composition is (20°C) approximately 0.8 to approximately 1.0, from about 0.85 to about 0.95, or from about 0.9 to about 0,92; (f) the composition contains not more than 20 ppm, 15 ppm, or 10 ppm heavy metals, (g) the composition contains not more than 5 ppm, 4 ppm, 3 ppm or 2 ppm of arsenic and/or (h) peroxide value of the composition is not more than 5, 4, 3 or 2 mEq./kg

In another embodiment, the composition is suitable according to the invention contains at least essentially consists at least of, or consists of at least 95% of ethylacetophenone (EPA-E), from about 0.2% to about 0.5% of etilachetoachetate (ODTA-E), from about 0.05% to about 0.25% of ethylenediaminetetra (NDPA-E), from about 0.2% to about 0.45% of etilamfetamine (AA-E), from about 0.3% to about 0.5% of ethylacetoacetate (ETA-E) and from about 0.05 to% to about 0.32 per cent of ethylenediaminetetra (HPA-E), each by weight of all fatty acids present in the composition. In another embodiment, the composition is in a capsule shell. In another embodiment, the capsule shell contains no chemically modified gelatin.

In another embodiment, compositions that are suitable according to the invention contain at the ore, essentially consist of at least or consist of at least 95%, 96% or 97% of atransparent, from about 0.2% to about 0.5% of etilachetoachetate, from about 0.05% to about 0.25% of ethylenediaminetetra, from about 0.2% to about 0.45% of etilamfetamine, from about 0.3% to about 0.5% of ethylacetoacetate and from approximately 0.05% to approximately 0,32% ethyleneimine, each by weight of all fatty acids present in the composition. Optionally, the composition contains not more than about 0.06 percent, about 0.05% or about 0.04 percent by weight of DHA or its derivative, such as ethyl-DHA, from all present fatty acids. In one of the embodiments the composition essentially contains or does not contain any amount of DHA or its derivative, such as ethyl-DHA. In addition, the composition optionally contains one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5%, or not more than 0.05%. In another embodiment, the composition comprises from about 0.05% to about 0.4%, for example about 0.2% by weight of tocopherol. In another embodiment, from about 500 mg to about 1 g of the composition is provided in the capsule shell. In another embodiment is sushestvennee capsule shell contains no chemically modified gelatin.

In another embodiment, compositions that are suitable according to the invention contain at least essentially consist of at least or consist of at least 96% of atransparent, from about 0.22% to about 0.4% of etilachetoachetate, from about 0,075% to about 0.20% of ethylenediaminetetra, from about 0.25% to about 0.40% of etilamfetamine, from about 0.3% to about 0.4% of ethylacetoacetate and approximately 0,075% to approximately 0.25% of ethylenediaminetetra, each by weight of all fatty acids present in the composition. Optionally, the composition contains not more than about 0.06 percent, about 0.05% or about 0.04 percent by weight of DHA or its derivative, such as ethyl-DHA, from all present fatty acids. In one of the embodiments the composition essentially contains or does not contain any amount of DHA or its derivative, such as ethyl-DHA. In addition, the composition optionally contains one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5%, or not more than 0.05%. In another embodiment, the composition comprises from about 0.05% to about 0.4%, for example about 0.2% by weight of tocopherol. In another embodiment, the invention relative to the tsya to the dosage form, containing from about 500 mg to about 1 g of the above composition in the capsule shell. In one embodiment, the implementation of the dosage form is a containing gel or liquid capsule, and it is Packed in blister pack with number of capsules on the plate is about 1 to about 20.

In another embodiment, compositions that are suitable according to the invention contain at least essentially consist of at least or consist of at least 96%, 97% or 98% by weight of atransparent, from about 0.25% to about 0,38% by weight of etilachetoachetate, about 0.10% to about 0.15% by weight of ethylenediaminetetra, from about 0.25% to about 0.35 percent by weight etilamfetamine, approximately from 0.31% to approximately 0,38% by weight of ethylacetoacetate and from about 0.08% to about 0.20% of ethylenediaminetetra, each the weight of all fatty acids present in the composition. Optionally, the composition contains not more than about 0.06 percent, about 0.05% or about 0.04 percent by weight of DHA or its derivative, such as ethyl-DHA, from all present fatty acids. In one of the embodiments the composition essentially contains or does not contain any amount of DHA or its derivatives is one, such as ethyl-DHA. In addition, the composition optionally contains one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5%, or not more than 0.05%. In another embodiment, the composition comprises from about 0.05% to about 0.4%, for example about 0.2% by weight of tocopherol. In another embodiment, the invention relates to a dosage form containing from about 500 mg to about 1 g of the above composition in the capsule shell. In another embodiment, the capsule shell contains no chemically modified gelatin.

Cardiovascular drugs

In one embodiment, the implementation of the composition (or scheme of treatment with a joint introduction) according to the invention includes one or more additional cardiovascular drugs. One or more additional cardiovascular drugs can be combined with EPA or together can be entered with the EPA. Interchangeable terms "cardiovascular agent" or "cardiovascular medicine" in this document refer to a drug or agent that is capable of treating, preventing or reducing the risk of cardiovascular diseases or disorders or risk factors or symptoms in the individual. With techno-vascular equipment herein as non-limiting examples may include means, modulating cholesterol and triglyceride, means treating coronary heart disease, means treating hypertension or pulmonary arterial hypertension, tools, treating the atrial fibrillation or arrhythmia, means treating stroke, means treating ischemia, infarction, and/or means treating thrombosis.

Non-limiting examples of classes from which you can choose cardio-vascular equipment, suitable for use in the present invention include inhibitors of acyl-coenzyme A:cholesterylester (ACAT), including selective inhibitors of ACAT-1 AND ACAT-2 as well as dual inhibitors of ACAT-1 and ACAT-2, drugs that block alpha-adrenergicheskie receptors (alpha-blockers), alpha/beta blockers, inhibitors of angiotensin-converting enzyme (ACE), aldosterone antagonists, antagonists of angiotensin II receptors, antiarrhythmic agent, anticoagulants, antiplatelet tools the mimetics of the apolipoprotein A-1 (apoA-1), beta-blockers, amplifiers excretion of bile acids, calcium channel blockers, inhibitors of the protein-carrier esters of cholesterol to ApoB (CETP)inhibitors of cholesterol intake, diuretics, anti-dyslipidemia, receptor antagonists endothelin, fibrates, reductase inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), activators LCAT, inductors receptor is in LDL, the lipase inhibitors, inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2)inhibitors of microsomal protein carrier of triglycerides (MTP), platelet aggregation inhibitors, agonists and PPAR activators, including PPARγ agonists, PPARα agonists and dual agonists, PPAR α/γ, antisense RNA or Rnci PCSK9 inhibitors scaleability, inhibitors stvalentines, thrombolytics and activators of thyroid receptor beta.

Inhibitors of ACAT

Acyl-CoA:cholesterylester ("ACAT") is acyltransferase enzyme. In the biosynthesis of bile acids ACAT catalyzes the intracellular formation of esters of cholesterol from cholesterol. ACAT contributes to the accumulation of esters of cholesterol in the tissues of the blood vessels. Thus, means of inhibiting ACAT, suitable for the prevention or treatment of atherosclerosis. Non-limiting examples of suitable inhibitors include ACAT CI-1011 (avasimibe (Avasimibe), Pfizer), CS-505 (sulfate pactimibe (Pactimibe), Sankyo Pharma) or combinations thereof.

If desired, one or more inhibitors of ACAT, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 1000 mg, for example about 1 mg, about 5 mg, about 10 mg, about 20 mg, is roughly 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg

The ACE inhibitors

Angiotensin-I-converting enzyme (ACE) converts angiotensin I to angiotensin II and inhibits bradykinin. Due to the fact that increased levels of angiotensin II and decreased levels of bradykinin promote a range of cardiovascular diseases and disorders, means inhibiting ACE, suitable for prevented the I or treatment associated with cardiovascular system diseases, such as hypertension, heart failure, diabetic neuropathy and diabetes type 2. Non-limiting examples of suitable ACE inhibitors include captopril, enalapril, enalaprilat, trandolapril, moexipril, ramipril, inapril, perindopril, lisinopril, benazepril, fosinopril or combinations thereof.

If desired, one or more ACE inhibitors, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.5 mg to about 50 mg, for example, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, approximately 22 mg, approximately 23 mg, about 24 mg, about 25 mg, about 26 mg, approximately 27 mg, approximately 28 mg, approximately 29 mg, about 30 mg, about 3 mg, approximately 32 mg, approximately 33 mg, approximately 34 mg, about 35 mg, 36 mg, approximately 37 mg, 38 mg, approximately 39 mg, about 40 mg, about 41 mg, approximately 42 mg, approximately 43 mg, approximately 44 mg, about 45 mg, about 46 mg, approximately 47 mg, approximately 48 mg, approximately 49 mg or about 50 mg

The aldosterone antagonists

Aldosterone is a steroid hormone that promotes hypertension through inhibition of renal function. Thus, funding, competing with aldosterone for receptor mineralocorticoids, suitable for the prevention or treatment of hypertension. Non-limiting examples of suitable anti-aldosterone include eplerenone and aldacton or combinations thereof.

If desired, the aldosterone antagonists, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 5 mg to about 100 mg, for example about 5 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, AP is sustained fashion 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 or about 100 mg

Alpha blockers

Alpha-blockers, also called antagonists, alpha-adrenergic receptors, competing with adrenaline for binding to α-adrenergic receptors. The binding of epinephrine to these receptors leads to vasoconstriction and thus hypertension. Thus, funding, competing with adrenaline or block α-adrenergic receptors, which are suitable for preventing or treating hypertension. Non-limiting examples of suitable alpha-blockers include doxazosin, metildofu, clonidine, prazosin, terazosin, or combinations thereof.

Optionally, alpha-blockers, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.02 mg to about 0.5 mg, for example, approximately 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 2.5 mg, about 0.3 mg, about 3.5 mg, about 0.4 mg, about 4,5mg or about 0.5 mg; in the amount of from about 0.5 mg to about 15 mg, for example, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg, or in the amount from about 100 mg to about 500 mg, for example, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg or about 500 mg

Alpha/beta-blockers

If desired, one or more alpha/beta-blockers, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 25 mg, for example about 1 mg, about 2 mg, about 3 mg, about 3.125 mg, about 4 mg, about 5 mg, about 6 mg, arr is siteline 6.25 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, approximately 22 mg, approximately 23 mg, about 24, or about 25 mg of a non-limiting example of alpha/beta-blocker is carvedilol.

Antagonists of angiotensin II receptors

Antagonists of angiotensin II receptors, known blockers of the angiotensin receptor, ARB, antagonists AT1receptors or Sartana suitable for the treatment of hypertension, congestive heart failure and various other diseases and disorders. Non-limiting examples of antagonists of angiotensin II receptors include candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan or a combination thereof.

If desired, one or more antagonists of angiotensin II receptors, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 100 mg, for example about 1 mg, about 2 mg, about 3 mg, if listello 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 16 mg, about 20 mg, about 24 mg, about 25 mg, about 28 mg, about 30 mg, about 32 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg; in an amount from about 40 mg to about 320 mg, for example, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg; in an amount from about 200 mg to about 800 mg, for example, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 is g or about 800 mg

Antiarrhythmic agent

Antiarrhythmic medicines act, correcting abnormal heart rhythm and/or slowing the heart with too high heart rate. Non-limiting examples of suitable anti-arrhythmic means include adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, meksiletin, procainamide, quinidine gluconate, hydrochloride propafenone, cocaine or combinations thereof.

If desired, one or more antiarrhythmic drugs, as a rule, present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.1 mg to about 1500 mg, from about 1 mg to about 1200 mg, or from about 5 mg to about 1000 mg, for example, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 5 mg, about 6 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, AP is sustained fashion 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg or approximately 1500 mg

In another embodiment, one or more antiarrhythmic drugs may be present in amounts of from about 1 mg / ml to about 500 mg per ml, for example, approximately 1 mg name, approximately 2 mg per ml, about 3 mg per ml, about 4 mg per ml, about 5 mg / ml, about 6 mg / ml, about 10 mg / ml, about 25 mg / ml, about 50 mg / ml, about 75 mg / ml, about 80 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 225 mg / ml, about 250 mg per ml, about 275 mg / ml, about 300 mg / ml, about 325 mg per ml, about 350 mg / ml, about 375 mg per ml, about 400 mg / ml, about 425 mg per ml, about 450 mg / ml, about 475 mg / ml, or about 500 mg per ml

In another embodiment, antiarrhythmic agent are present in amounts of from about 0.01% to about 5%, for example, about 0.01%, about 0.02 percent, about 0.03%, about 0.04 percent, about 0.05%, about 0.06%of the approximately 0.07 per cent, approximately 0,08%, approximately 0,09%, about 0.1%, about 0.2%, approximately 0.3%, about 0.4%, about 0.5%, about 0.6%, of which approximately 0.7%, about 0.8%, about 0.9 percent, about 1%, about 1.1%, approximately 1.2%, about 1.3%, about 1.4%, CA is approximately 1,5%, roughly 1.6%, about 1.7%, about 1.8%, with an estimated 1.9%, approximately 2%, approximately 2.1%, about 2.2%, and approximately 2.3%, approximately 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8 per cent, around 2.9%, approximately 3%, approximately 3.1%, approximately 3.2 percent of approximately 3.3%, about 3.4%, approximately 3.5%, approximately 3.6%, approximately 3.7 percent, approximately 3.8 percent, approximately 3,9%, about 4%, approximately 4.1%, approximately 4.2%, about 4.3%, approximately 4.4%to approximately 4.5%, approximately 4.6 percent, approximately 4.7%, about 4.8%, about 4.9 percent, or approximately 5% by weight of the total composition.

Antiplatelet tools

Antiplatelet drugs inhibit platelet aggregation and thus resists the development of blood clots. Non-limiting examples of antiplatelet agents include ardeparin, aspirin, clopidogrel, danaparoid, dalteparin, danaparoid, ticlopidine, Cilostazol, abciximab, eptifibatide, tirofiban, defibrotide, enoxaparin, dipyridamole, Tinzaparin or combinations thereof.

If desired, one or more antiplatelet agents, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the implementation of the image is etenia) in an amount of from about 10 mg to about 100 mg, for example, about 10 mg, about 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg; in an amount from about 50 mg to about 300 mg, for example, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg

In another embodiment, one or more antiplatelet agents are present in amounts of from about 25 μg per ml to about 50 μg per ml, for example, about 25 µg per ml, about 30 μg per ml, approximately 35 µg per ml, about 40 μg per ml, about 45 μg per ml, or about 50 μg per ml; or in the amount of from about 1 mg per ml to about 2 mg per ml, for example, approximately 1 mg per ml, about 1.25 mg per ml, about 1.50 mg per ml, about 1.75 or about 2 mg per ml

Mimetics apo-1

Apolipoprotein A-1 ("apoA-1") is the primary protein component of serum HDL to cholesterol. Non-limiting examples of mimetics of apoA-1 is composed of ETC-216, ETC-588-liposome, ETC-642, trimeric apoA-1, CSL-111, APP018, back D-4F or combinations thereof.

If desired, one or more mimetics of apoA-1, typically present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.1 mg to about 1500 mg, from about 1 mg to about 1200 mg, or from about 5 mg to about 1000 mg, for example, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 5 mg, about 6 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, priblizitelen the 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, approximately 1125 mg, approximately 1150 mg, approximately 1175 mg, or about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg, or about 1500 mg

Beta-blockers

Beta-blockers block the response to beta-adrenergic nerves, which leads to the slowing of heart rate reduction and lower blood pressure. Non-limiting examples of suitable beta-blockers include acebutolol, atenolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, or combinations thereof.

If desired, one or more beta-blockers, usually present in whom is osili according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 1000 mg, from about 1 mg to about 750 mg, or from about 1 mg to about 500 mg, for example about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg or about 500 mg

Amplifiers excretion of bile acids

Amplifiers excretion of bile acids disrupt intestinal-hepatic circulation of bile acids by concatenating the components of bile acids in the gastrointestinal tract, making them after this newsseveral. Thus, amplifiers excretion of bile acids in addition to other diseases and disorders suitable for preventing or treating hyperlipidemia. Non-limiting examples of amplifiers excretion of bile acids include colesevelam HCl, colestipol, lo is rest and cholestyramine or combinations thereof.

If desired, one or more amplifiers excretion of bile acids typically present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 4 mg to about 32 mg, for example, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg, about 32 mg, or in the amount of from about 300 mg to about 4000 mg, for example, about 300 mg, about 325 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 625 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg, about 2000 mg, about 2250 mg, about 2500 mg, about 2750 mg, about 3000 mg, about 3250 mg, about 3500 mg, about or approximately 3750 4000 mg.

Calcium channel blockers

Calcium channel blockers due to their vasodilatory action suitable for the prevention or treatment of hypertension. Non-limiting examples of calcium channel blockers include nordip is h, diltiazem, butyrate clevidipine, isradipine, nimodipine, nisoldipine, verapamil, and besylate amlodipine or a combination thereof. Non-limiting examples of combination of calcium channel blockers include amlodipine, olmesartan, valsartan or combinations thereof.

If desired, one or more calcium channel blockers, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 10 mg, for example about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; in an amount from about 5 mg to about 34 mg, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 8.5 mg, about 9 mg, about 10 mg, about 15 mg, about 17.5 mg, about 20 mg, about to 22.5 mg, about 25 mg, about 25.5 mg, about 27.5 mg, about 30 mg, about 32,5 or approximately 34 mg; in an amount from about 10 mg to about 60 mg, for example, about 10 mg, about 15 mg, rough is about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg; in an amount of from about 20 mg to about 120 mg, for example, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110, about 120 mg; in an amount of from about 60 mg to about 420 mg, for example, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, approximately 340 mg, about 360 mg, about 380 mg, about 400, or about 420 mg.

In another embodiment, one or more calcium channel blockers are present in amounts of from about 0.05 mg per ml to about 2.5 mg per ml, for example, about 0.05 mg per ml, about 0.1 mg per ml, about 0.2 mg per ml, about 0.3 mg per ml, approximately what about 0.4 mg per ml, approximately 0.5 mg per ml, about 0.6 mg per ml, about 0.7 mg per ml, about 0.8 mg per ml, about 0.9 mg per ml, about 1.0 mg per ml, about 1.25 mg per ml, about 1.5 mg per ml, about 1.75 mg per ml, about 2.0 mg per ml, about 2.25 mg per ml, or about 2.5 mg per ml

Inhibitors of CETP

Protein-carrier esters of cholesterol ("CETP") plays an important role in the transfer of esters of cholesterol and triglycerides. Thus, inhibition of CETP also called protein-carrier plasma lipids suitable for the prevention or treatment of atherosclerosis and other cardiovascular diseases and disorders. Non-limiting examples of CETP inhibitors include torcetrapib, anacetrapib, JTT-705, BAY-60-5521, PF-3185043 and CP-800569 or combinations thereof.

One or more of CETP inhibitors, if desired, are present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount sufficient to provide an individual dose of approximately 25 mg per kg of body weight (mg / kg) to about 100 mg / kg, for example, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg per kg, approximately 45 mg / kg, about 50 mg per kg, about 55 mg per the g approximately 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg per kg, about 80 mg per kg, approximately 85 mg / kg, about 90 mg per kg, approximately 95 mg / kg, or about 100 mg per kg

In another embodiment, if desired, one or more of CETP inhibitors are present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount from about 100 mg to about 10 g, from about 500 mg to about 9 g, or from about 750 mg to about 5 g

Inhibitors of cholesterol intake

Absorption inhibitors of cholesterol reduce cholesterol chylomicrons and remnants of chylomicrons, preventing the capture michaelango of cholesterol from the small intestine. As a result, the liver is delivered fewer cholesterol and, thus, decrease LDL. Non-limiting examples of inhibitors of cholesterol intake include ezetimibe and simvastatin or combinations thereof.

If desired, one or more inhibitors of cholesterol intake, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from approximately 1 mg to approximately the 10 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, or in the amount of from about 10 to about 80 mg, for example, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg or about 80 mg

Diuretics

Diuretics increase urinary frequency, forcing diuresis. Some diuretics, also provides hypotensive effect. Non-limiting examples of diuretics include hydrochlorothiazide, torsemide, etakrinova acid, furosemide, triamterene, indapamide, chlorothiazide sodium, aliskiren or combinations thereof.

If desired, one or more diuretics, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of: (a) from about 0.25 mg to about 2.5 mg, for example, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, when listello 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5 mg; (b) in an amount of from about 5 mg to about 25 mg, for example about 5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22,5 mg or about 25 mg; (c) in an amount of from about 2 mg to about 100 mg, for example, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg; (d) from about 10 mg to about 50 mg, for example, approximately 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about to 22.5 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg; in an amount from about 5 mg to bring is Ino 60 mg, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg; (e) in an amount of from about 25 mg to about 100 mg, for example, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; in an amount from about 75 mg to about 300 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg; (f) from about 0.1 g to about 0.5 g, for example, about 0.1 g, about 0.2 g, about 0.3, about 0.4 g or about 0.5 g; or (g) in an amount of from about 1 mg / ml to about 10 mg per ml, for example, approximately 1 mg per ml, about 2 mg per ml, about 3 mg per ml, about 4 mg per ml, about 5 mg / ml, about 6 mg per ml, about 7 mg / ml, about 8 mg per ml, AP is sustained fashion 9 mg / ml or about 10 mg per ml

Anti-dyslipidemia

Dyslipidemia is a class of diseases including hyperlipidemia. Dyslipidemia of Fredrickson type I (sometimes referred to as syndrome Burger-Grutza, primary hyperlipoproteinemia or family hyperchylomicronemia) is characterized by elevated cholesterol levels, individuals with dyslipidemia of Fredrickson type IIa (also known as familial hypercholesterolaemia) observed elevated levels of LDL. Individuals with dyslipidemia of Fredrickson type IIb (familial combined hyperlipoproteinemia (FCH) or secondary combined hyperlipoproteinemia) observed elevated levels of LDL and VLDL. Dyslipidemia of Fredrickson type III (sometimes called beta illness or dysbetalipoproteinemia) is characterized by elevated levels of medium-density lipoproteins ("IDL"), while individuals with dyslipidemia of Fredrickson type IV (sometimes called "pure hypertriglyceridemia") observed elevated levels of VLDL. Individuals with dyslipidemia of Fredrickson type V see elevated levels of VLDL and chylomicrons.

Non-limiting examples of anti-dyslipidemia include antibody Angpt14, APA-01 (Phosphagenics), CRD 5 (ImaSight), NCX6560 (NicOx), Rnci PCSK9 (Alnylam), recombinant apoA-1 (SemBioSys Genetics), antibody to oxLDL (Genentech), APL180 (Novartis), APP018 (D4F) (Novartis), CER-002 (Cerenis Therapeutics), CP-800569 (Pfizer), GSK-256073 (GlaxoSmithKline), MB0811 (Metabasis), PF-3185043 (Pfizer), R7232 (Roche), rilapladib (GlaxoSmithKline), RVX-208 (Resverlogix), sabatera (Sobetirome) (QRX-431 (QuatRx)), anacetrapib (Merk), CSL111 (CSL Limited), darapladib (GlaxoSmithKline), eprotirome (Karo Bio), GFT505 (Genfit), MAHDL01 (by marzal Plant Pharma), MBX-8025 (Metabolex), PLX204 (Wyeth/Plexxikon), aleglitazar (Roche), dalcetrapib (Roche), SLx4090 (Surface Logix), varespladib (Anthera Pharmaceuticals), AEGR-733 (Aegerion), ABT-335 (Abbott Laboratories), AVE5530 (Sanofi-Aventis), LCP-AtorFen (LifeCycle Pharma), TRIA-662 (Cortria), fenofibrate, polipropilen, ezetimibe, colesevelam, laropiprant or a combination of any of the above.

If desired, one or more anti-dyslipidemia, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg, about 48 mg, about 50 mg, about 54 mg, about 55 mg, about 60 mg, about 65 mg, about 67 mg, about 70 mg, about 75 mg, about 80 is g, about 85 mg, about 87 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, approximately 107 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 134 mg, approximately 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, approximately 195 mg, about 200 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 500 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg

Receptor antagonists endothelin

The binding of endothelin-1 receptors endothelin A (ETA) or receptors e is dateline B (ETB) causes vasoconstriction in the lungs. Antagonists of endothelin receptors compete for binding to the endothelin-1, thus, weakening the vasoconstriction in the lungs. Thus, antagonists of endothelin receptors suitable for treatment of pulmonary hypertension. Non-limiting examples of antagonists of endothelin receptors include ambrisentan, bosentan, volibris, Tieling or combinations thereof.

If desired, one or more antagonists of endothelin receptors, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 10 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; in an amount from about 50 mg to about 250 mg, for example, approximately 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg

Inhibitors of HMG-CoA reductase

Reductase HMG-CoA (also known as HMGR) in the metabolic cascade products of cholesterol converts HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) to mevalonic acid (3,5-is hydroxy-3-methylpentanol acid). Inhibitors of HMG-CoA reductase, also called statins, inhibit the reductase HMG-CoA and, thus, reduce the production of cholesterol. As a result, the inhibitors of HMG-CoA reductase suitable for the treatment of several cardiovascular disorders, including, for example, hypercholesterolemia, hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, atherosclerosis. Non-limiting examples of inhibitors of HMG-CoA reductase, among others, include lovastatin, lovastatin + Niacin, mevastatin, pitavastatin, pravastatin, rosuvastatin, fluvastatin, atorvastatin, atorvastatin + besilate amlodipine, simvastatin, simvastatin + Niacin, ezetimibe and pravastatin.

If desired, one or more inhibitors of HMG-CoA reductase, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 5 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, approximately 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg

The LCAT activator

Lecithin-cholesterylester ("LCAT") converts the cholesterol ester cholesterol. Individuals with insufficient levels of LCAT in the tissues of the body accumulates neeterificirovannah cholesterol. This can lead to increased levels of HDL in the serum and, over time, to atherosclerosis. Thus, activators LCAT suitable for lower levels of HDL in savoretti for the treatment or prevention of atherosclerosis. Non-limiting examples of activators LCAT include the enzyme LCAT, recombinant LCAT, gene therapy tools, which contain the nucleic acid sequence encoding the sequence for the expression of LCAT, estrogen, estrogen analogues, and combinations thereof, for example as described in U.S. patent No. 6635614, fully incorporated herein by reference.

If desired, one or more activators LCAT, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount sufficient to increase the level of LCAT in the serum of the individual to the desired level. Individuals with abnormally low levels of serum LCAT you can enter the amount of the composition of the invention containing EPA and the enzyme LCAT, estrogen, estrogen analogues, or combinations thereof, sufficient to increase the level of LCAT in the serum of the subject to the normal levels, usually about 5 µg per ml or more. In another embodiment, individuals with approximately normal LCAT levels in serum can be treated with the composition according to the invention, containing EPA and the enzyme LCAT, estrogen, estrogen analogues, or combinations thereof in an amount sufficient to increase the level of LCAT in the serum approximately 6 µg per ml or more, priblizitelen is 7 µg per ml or more, about 8 µg per ml or more, about 9 μg per ml or more, or about 10 μg per ml or more.

Inducers of LDL receptors

The LDL receptors are proteins on the cell surface. Together with adapting receptors bind LDL free cholesterol LDL education covered clatrina vesicles, reducing the levels of LDL in serum. Therefore, tools that induce LDL receptor further reduce the levels of LDL in the serum and is suitable for the prevention or treatment of atherosclerosis. A non-limiting example of the LDL receptor is lactacystin.

If desired, one or more inducers of LDL receptors, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, will bring the flax 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg

Inhibitors of Lp-PLA2

The composition of the invention can contain one or more inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2). Lp-PLA2 hydrolyzes oxidized phospholipids in LDL with cholesterol. I believe that high levels of Lp-PLA2 trigger a cascade of inflammatory processes in atherosclerosis and lead to an increased risk of stroke. Thus, inhibitors of Lp-PLA2 suitable for slowing or preventing the development of atherosclerosis. Non-limiting examples inhib the tori Lp-PLA2 include rilapladib, darapladib and their combinations.

If desired, one or more inhibitors of Lp-PLA2 as a rule, present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, AP is sustained fashion 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg

Inhibitors of 5-lipoxygenase

Inhibitors of 5-lipoxygenase suitable in accordance with various embodiment of the invention. Non-limiting examples of inhibitors of 5-lipoxygenase include VIA-2291, MK-886, CMI 977, ABT-761, ZD2138, manapalan, zileuton, inhibitor of 5-LO 6, L-739010, CGS 22745, SC-45662, and combinations thereof.

Additional inhibitors of 5-lipoxygenase, suitable for use in accordance with the variants of implementation of the present invention, are described in the following patents and patent applications U.S., each of which, therefore, is totally incorporated herein by reference: U.S. 20050101659, U.S. 7026344, U.S. 7329682, U.S. 20040198768, U.S. 20090054519, U.S. 5112848, U.S. 5086052, U.S. 482828, U.S. 5208364, U.S. 4970210, U.S. 4794114, U.S. 4686231, U.S. 5134150, U.S. 5639782, U.S. 6239170, U.S. 20060106014, U.S. 5229386, U.S. 4673684, U.S. 6136839, U.S. 6090547, U.S. 6355434, U.S. 20090042849, U.S. 4731382, U.S. 4877881, U.S. 5130485, U.S. 5665752, U.S. 5723481, U.S. 5102897, U.S. 5234939, U.S. 5143928, U.S. 5217971, U.S. 4889941, U.S. 5234937, U.S. 5283361, U.S. 5232939, U.S. 5086064, U.S. 5208251, U.S. 5290800, U.S. 5006549, U.S. 5494927, U.S. 20040198800, U.S. 4719218, U.S. 4847270, U.S. 6121323, U.S. 20080226758, U.S. 20070218146, U.S. 4728656, U.S. 4835189, U.S. 5763673, U.S. 4835190, U.S. 5162365, U.S. 5985937, U.S. 6455541, U.S. 5534524, U.S. 2007013441, U.S. 20050267145, U.S. 4694018, U.S. 5260294, U.S. 5792776, U.S. 5530141, U.S. 5780503, U.S. 5093356, U.S. 5348957, U.S. 5384318, U.S. 568822, U.S. 20010009918, U.S. 20070219206, U.S. 20070225285, U.S. 20050267211, U.S. 20030162193, U.S. 20070173508, U.S. 20070066577, U.S. 5036067, U.S. 20030082108, U.S. 20090018170, U.S. 20070105866, U.S. 20070237848, U.S. 20070244185, U.S. 20080227807, U.S. 4728735, U.S. 4803279, U.S. 4962119, U.S. 5314898, U.S. 20070123522, U.S. 20070123522, U.S. 20070244128, U.S. 20070093524, U.S. 4602023, U.S. 4943587, U.S. 6025384, U.S. 20090118373, U.S. 5112868, U.S. 5254553, U.S. 5312821, U.S. 5635514, U.S. 7405302, U.S. 4624964, U.S. 4786755, U.S. 4933351, U.S. 5059609, U.S. 5442111, U.S. 5066668, U.S. 5292900, U.S. 5998451, U.S. 4851586, U.S. 5314900, U.S. 5447943, U.S. 6221880, U.S. 6262077, U.S. 6376528, U.S. 6569895, U.S. 4663347, U.S. 4975457, U.S. 4978679, U.S. 5703093, U.S. 5811432, U.S. 4822803, U.S. 5356921, U.S. 5750565, U.S. 4751310, U.S. 4816486, U.S. 5288751 U.S. 5298512, U.S. 5909734, U.S. 4745127, U.S. 5215986, U.S. 5270319, U.S. 5476944, U.S. 4939169, U.S. 6166031, U.S. 6696477, U.S. 6756399, U.S. 4931444, U.S. 5066658, U.S. 5248685, U.S. 5240929, U.S. 4861798, U.S. 4933329, U.S. 5008390, U.S. 5814648, U.S. 6939674, U.S. 5696141, U.S. 5434151, U.S. 20030216481, U.S. 20030232763, U.S. 20060177528, U.S. 20030235620, U.S. 20020177723, U.S. 5036105, U.S. 5504097, U.S. 5741809, U.S. 5459154, U.S. 5463083, U.S. 6420392, U.S. 5358938, U.S. 5326907, U.S. 6294574, U.S. 5648486, U.S. 5856323, U.S. 7387797, U.S. 4801611, U.S. 5530114, U.S. 7514469, U.S. 20010025040, U.S. 20020143033, U.S. 5665749, U.S. 20010009917, U.S. 20070049621, U.S. 20080280826, U.S. 5393923, U.S. 5114958, U.S. 5376670, U.S. 6217875, U.S. 5155122, U.S. 5288896, U.S. 6436924, U.S. 5256680, U.S. 7132441, U.S. 5145860, U.S. 5354768, U.S. 5698576, U.S. 7371874, U.S. 5068251, U.S. 5130483, U.S. 6177415, U.S. 5541218, U.S. 20070264361, U.S. 5284949, U.S. 4672075, U.S. 5212189, U.S. 5302597, U.S. 20080107757, U.S. 6620813, U.S. 5250565, U.S. 624012, U.S. 4732901, U.S. 5196431, U.S. 5340815, U.S. 5504108, U.S. 5220025, U.S. 5252562, U.S. 5420131, U.S. 5037837, U.S. 5081126, U.S. 5105020, U.S. 5187175, U.S. 5342838, U.S. 4755525, U.S. 5248682, U.S. 4963576, U.S. 5514703, U.S. 6194585, U.S. 6194585, U.S. 6291534, U.S. 4695586, U.S. 4971979, U.S. 6653311, U.S. 475554, U.S. 5147893, U.S. 4711903, U.S. 20040077691, U.S. 4695585, U.S. 2005009084, U.S. 5516789, U.S. 5512594, U.S. 20070202206, U.S. 6261607, U.S. 5350754, U.S. 6344563, U.S. 20040235807, U.S. 5064851, U.S. 5254581, U.S. 5288742, U.S. 5403859, U.S. 5407945, U.S. 20030008914, U.S. 5254731, U.S. 5318970, U.S. 5519022, U.S. 6174883, U.S. 6262073, U.S. 20040170974, U.S. 20070231345, U.S. 4985435, U.S. 5126365, U.S. 5234950, U.S. 5321025, U.S. 5484805, U.S. 5221677, U.S. 5280047, U.S. and U.S. 5300655 5359063.

If desired, one or more inhibitors of 5-lipoxygenase, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.01 mg to about 2500 mg, from about 0.1 mg to about 1500 mg, from about 1 mg to about 1200 mg, or from about 5 mg to about 1000 mg, for example, about 0.1 mg, about 0.5, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 m is, approximately 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, approximately 1150 mg, approximately 1175 mg, or about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, approximately 1550 mg, approximately 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, approximately 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, approx the positive 1975 mg, about 2000 mg, about 2025 mg, approximately 2050 mg, approximately 2075 mg, about 2100 mg, approximately 2125 mg, approximately 2150 mg, approximately 2175 mg, about 2200 mg, approximately 2225 mg, about 2250 mg, approximately 2275 mg, about 2300 mg, approximately 2325 mg, approximately 2350 mg, approximately 2375 mg, 2400 mg, approximately 2425 mg, approximately 2450 mg, approximately 2475 mg, or about 2500 mg

Inhibitors of microsomal protein carrier of triglycerides

Microsomal protein carrier of triglycerides ("MTTP" or "MTP") is a heterodimeric protein that is involved in the Assembly of lipoproteins. Thus, MTP inhibitors suitable for slowing or preventing the production of lipoproteins and, thus, cardiovascular diseases and disorders. Non-limiting examples of MTP inhibitors include SLx-4090, AEGR-733, implitapide, BMS-200150, CP-346086, JTT-130, dirlotapide and their combinations.

For more MTP inhibitors suitable for use in accordance with the variants of implementation of the present invention, are described in the following patents and patent applications U.S., each of which, therefore, is totally incorporated herein by reference: U.S. 20030166590, U.S. 6492365, U.S. 20040132779, U.S. 20040132745, U.S. 20050181376, U.S. 20030086912, U.S. 6767739, U.S. 20080249130, U.S. 2020028943, U.S. 5883099, U.S. 5739135, U.S. 5712279, U.S. 6034098, U.S. 5827875, U.S. 6066650, U.S. 5885983, U.S. 20060166999, U.S. 20070027183, U.S. 20020045271, U.S. 6288234, U.S. 20030109700, U.S. 20040014748, 6878707, 6218524, 5595872, U.S. 20080253985, U.S. 20080103122, U.S. 20050234073, U.S. 20050090426, U.S. 20040044008, U.S. 20090042835, U.S. 20040058908, U.S. 20060270655, U.S. 6369075, U.S. 20080241869, U.S. 20070093468, U.S. 20090054393, U.S. 20020132806, U.S. 20070088089, U.S. 20040033506, U.S. 20080161279, U.S. 20020161233, U.S. 20020042516, U.S. 20070093527, U.S. 6713489, U.S. 20060211020, U.S. 6617325, U.S. 6147214 and U.S. 20020032238.

In one of the embodiments, if desired, one or more MTP inhibitors, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount sufficient to provide an individual dose of about 1 μg per kg of body weight (mcg / kg) to about 100 μg per kg, for example, about 25 μg per kg, about 30 μg per kg, about 35 μg / kg, about 40 mg per kg, approximately 45 mg / kg, about 50 μg per kg, about 55 μg per kg, about 60 μg per kg, about 65 μg / kg, about 70 mg per kg, about 75 μg per kg, about 80 μg per kg, about 85 μg / kg, about 90 μg / kg, 95 μg / kg or about 100 μg per kg In another embodiment, if desired, one or more MTP inhibitors are present in the compositions according to the invention (or compatible with the STN administered with EPA according to other variants of the invention) in an amount of approximately from 30 μg to about 20 mg, from about 50 μg to about 15 mg, or from about 70 μg to about 10 mg

In another embodiment, if desired, one or more MTP inhibitors are present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.01 mg to about 2500 mg, from about 0.1 mg to about 1500 mg, from about 1 mg to about 1200 mg, or from about 5 mg to about 1000 mg, for example, about 0.1 mg, about 0.5, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 m is, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, approximately 1150 mg, approximately 1175 mg, or about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, approximately 1550 mg, approximately 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, approximately 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, approximately 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, approximately 2050 mg, approximately 2075 mg, about 2100 mg, approximately 2125 mg, approximately 2150 mg, when listello 2175 mg, approximately 2200 mg, approximately 2225 mg, about 2250 mg, approximately 2275 mg, about 2300 mg, approximately 2325 mg, approximately 2350 mg, approximately 2375 mg, 2400 mg, approximately 2425 mg, approximately 2450 mg, approximately 2475 mg, or about 2500 mg

Agonists and PPAR activators

Activated proliferation peroxisome receptor ("PPAR") is a nuclear receptor proteins that regulate gene expression by acting as transcription factors in combination with the retinoid X receptor ("RXR"). Thus, means inhibiting or activating PPAR suitable for modification in the expression of certain genes, including, for example, genes associated with metabolic disorders, such as hypercholesterolemia. Non-limiting examples of agonists and PPAR activators include fenofibrate, bezafibrat, ciprofibrate, clofibrate, gemfibrozil, CER-002, rosiglitazone, GW501516, RWJ 800025, KD-3010 and their combinations.

If desired, one or more agonists and/or PPAR activators, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.5 mg to about 4 mg, for example, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, PR is approximately 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, 2.75 mg, about 3 mg, about to 3.25 mg, about 3.5 mg, about 3.75 mg, or about 4 mg; or in the amount of from about 20 mg to about 120 mg, for example, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg

Inhibitors of sPLA2

The sPLA2 inhibitors suitable for use in accordance with the variations in implementation of the present invention. Non-limiting examples of sPLA2 inhibitors include LY 333013, varespladib, WA8242A, WA8242A2, WA8242B, A-0001 A-0002 and their combinations.

For more sPLA2 inhibitors suitable for use in accordance with the variants of implementation of the present invention, are described in the following patents and patent applications U.S., each of which, therefore, is totally incorporated herein by reference: U.S.6974831, U.S.6916840, U.S.6992100, U.S.6872743, U.S.20040063967, U.S.20040063941, U.S.20040092543, U.S.20040077704, U.S.6433001, U.S.20030153770, U.S.20030191175, U.S.6706752, U.S.6730694, U.S.20040059130, U.S.7026348, U.S.6608099, U.S.6340699, U.S.6252084, U.S.6635670, U.S.6939890, U.S.6930123, U.S.6713505, U.S.6274578, U.S.6451839, U.S.20040029948, U.S.20090062369, U.S.20030236232, U.S.7160909, U.S.6384041, U.S.6175021, U.S.6214876,U.S.20090131396, U.S.6353128, U.S.6407104, U.S.6274616, U.S.20030087944, U.S.5916922, U.S.20040198801, U.S.20080249027, U.S.7026318, U.S.6933313, U.S.20040087796, U.S.6391908, U.S.20030181454, U.S.6831095, U.S.6177426, U.S.20060116379, U.S.6472389, U.S.6797708, U.S.20090118503, U.S.20070249008, U.S.7087637, U.S.5919810, U.S.6828344, U.S.6916841, U.S.5654326, U.S.5641800, U.S.5733923, U.S.6534535, U.S.20050026988, U.S.6166062, U.S.5684034, U.S.7253194, U.S.20080045444, U.S.20040033995, U.S.20060235009, U.S.20090088427, U.S.7196103, U.S.20080317809, U.S.20090092595, U.S.20070037253, U.S.7098237, U.S.6140327, U.S.5972972, U.S.20040248898, U.S.6967200, U.S.20030092767, U.S.20040106669, U.S.20040077651, U.S.20050158401, U.S.6514984, U.S.20040102442, U.S.6610728, U.S.20030119860, U.S.6436983, U.S.6703385, U.S.6576654, U.S.7101875, U.S.6635771, U.S.6756376, U.S.6984735, U.S.6448284, U.S.6787545, U.S.6265591, U.S.6713645, U.S.6673781, U.S.6214855, U.S.6008231, U.S.6344467, U.S.6177440, U.S.6426344, U.S.7105514, U.S.6214991, U.S.20020169108, U.S.20060025348, U.S.20030008816, U.S.20090029917, U.S.6900208, U.S.6380397, U.S.7205329, U.S.5919943, U.S.7126010, U.S.7109231, U.S.6555568, U.S.6872557, U.S.7030112, U.S.7041695, U.S.7220756, U.S.7396838, U.S.6407261, U.S.6028116, U.S.5965619, U.S.6063818, U.S.5998477, U.S.6121321, U.S.6958348, U.S.7528112, U.S.6903104, U.S.6745133, U.S.6861436, U.S.5650374, U.S.6569539, U.S.6432987, U.S.5762413, U.S.7176281, U.S.7317009, U.S.7153854, U.S.20020110523, U.S.6776986, U.S.5948779, U.S.7449615, U.S.7531568, U.S.7476746, U.S.7491831, U.S.6231189, U.S.6987105, U.S.7300932, U.S.6962784, U.S.6248553, U.S.6255063, U.S.20070053912, U.S.6974831, U.S.20040063941, U.S.20040077704, U.S.20040248898, U.S.20040063967, U.S.6992100, U.S.20040092543, U.S.6916840, U.S.6433001, U.S.20070249008, U.S.20090092595, U.S.6872743, U.S.20070037253.

If desired, one or more sPLA2 inhibitors, usually present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.01 mg to about 2500 mg, about 0.1 mg to CA is approximately 1500 mg, from about 1 mg to about 1200 mg, or from about 5 mg to about 1000 mg, for example, about 0.1 mg, about 0.5, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 110 mg, approximately 1175 mg, or about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, approximately 1550 mg, approximately 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, approximately 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, approximately 2050 mg, approximately 2075 mg, about 2100 mg, approximately 2125 mg, approximately 2150 mg, approximately 2175 mg, about 2200 mg, approximately 2225 mg, about 2250 mg, approximately 2275 mg, about 2300 mg, approximately 2325 mg, approximately 2350 mg, approximately 2375 mg, 2400 mg, approximately 2425 mg, approximately 2450 mg, approximately 2475 mg, or about 2500 mg

Inhibitors scaleability

Skvalenepoksidazu, also called skvalenepoksidazu, catalyzes okelani the squalene in the cascade of the biosynthesis of cholesterol. Thus, means inhibiting skvalenepoksidazu suitable for preventing or slowing the production of cholesterol. Non-limiting examples of inhibitors scaleability include terbinafine, naftifine, amorolfine, butenafine, FR194738, NB-598, resveratrol (TRANS-3,4',5-trihydroxystilbene), epigallocatechin-3-O-gallate, S-allylcysteine, selenocysteine, alliin, diallyldisulfide, diallyldisulfide and their combinations.

If desired, one or more inhibitors scaleability typically present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount from about 100 mg to 250 mg, for example, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg; or in the amount of from about 0.5% to about 5% by weight of the composition, for example, about 0.5%, about 0.75 percent, approximately 1%, about 1.25%, about 1.5%, about 1.75%and approximately 2%, approximately of 2.25%, about 2.5%, 2.75%, about 3%, about 3.25%milkfat, approximately 3.5%, approximately 3,75%, approximately 4%, approximately 4.25 percent, approximately 4.5%, approximately 4.75% or about 5% by weight.

Thrombolite and

Thrombolytic drugs dissolve blood clots. Thus, thrombolytic drugs suitable for the treatment of cardiovascular diseases and disorders, including, among other things, for example, deep vein thrombosis, embolism of the lungs vessels, ischemic complications of unstable angina, myocardial infarction and venous thromboembolism. Non-limiting examples of thrombolytics include fondaparinux, dalteparin, enoxaparin, apixaban, PD-348292 and their combinations.

If desired, one or more thrombolytic drugs, as a rule, present in the composition according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount sufficient to provide a dose of approximately 0.5 mg per kg of body weight (mg / kg) to about 40 mg / kg, for example, approximately 0.5 mg per kg, about 1 mg / kg, about 2 mg / kg, about 3 mg per kg, about 4 mg / kg, about 5 mg / kg, about 6 mg per kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg to to the, approximately 21 mg / kg, about 22 mg per kg, approximately 23 mg / kg, about 24 mg / kg, about 25 mg per kg, approximately 26 mg / kg, approximately 27 mg / kg, about 28 mg per kg, approximately 29 mg / kg, about 30 mg per kg, approximately 31 mg / kg, about 32 mg per kg, approximately 33 mg / kg, approximately 34 mg / kg, about 35 mg per kg, approximately 36 mg / kg, approximately 37 mg on kg, approximately 38 mg / kg, approximately 39 mg / kg, or about 40 mg / kg or in total amount of from about 30 mg to about 3.5 g

In another embodiment, one or more thrombolytic drugs are present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount of from about 0.5 mg to about 2.5 mg, for example, 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5 mg; or in a quantity sufficient to provide approximately 60 international units per kg of body weight (IU / kg) to approximately 240 IU / kg, for example, 60 IU / kg, about 70 IU / kg, about 80 IU / kg, about 90 IU / kg, about 100 IU / kg,about 110 IU / kg, approximately 120 IU per kg, approximately 130 IU / kg, approximately 140 IU / kg, approximately 150 IU / kg, about 160 IU / kg, about 170 IU / kg, about 180 IU / kg, approximately 190 IU / kg, about 200 IU per kg, approximately 210 IU / kg, approximately 220 IU / kg, approximately 230 IU / kg or approximately 240 IU per kg

Other cardiovascular drugs

For prevention, inhibition or treatment of cardiovascular diseases or disorders are also suitable for other cardiovascular drugs. Non-limiting examples of other cardiovascular drugs include gemfibrozil, niaspan, orlistat, GFT14, AZD-2479, ETC-1001 and their combinations.

If desired, one or more of these other cardiovascular drugs may be present in compositions according to the invention (or they can jointly enter with EPA according to other variants of the invention) in an amount corresponding to the recommended or suggested dose for specific cardiovascular drugs(s). In a related embodiment, the cardiovascular agent(a) may be present in compositions according to the invention (or can jointly enter with EPA according to other variants of the invention) in an amount smaller than recommended, or suggested dose for a specific cardio-the vascular funds(a). For example, the composition according to the invention may contain EPA and one or more of these other cardiovascular funds in the amount of from about 5 mg to about 1500 mg, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 100 mg, approximately 1125 mg, approximately 1150 mg, approximately 1175 mg, or about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg, or about 1500 mg

The headings used to describe cardiovascular drugs in this document should not be construed as limiting in any way. Many cardiovascular drugs can have multiple mechanisms of action and can be described under one or more headings.

Salts and other derivatives

According to the invention it is possible to use a salt, hydrate, solvate, esters, amides, enantiomers, isomers, tautomers, polymorphic forms, proletarienne funds and derivatives of any of the above medicines, and they can be obtained by standard methods known to experts in the field of synthetic organic chemistry. See, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998) and Weisermel et al., Industrial Organic Chemistry (2002).

"Pharmaceutically acceptable salt" or "salt include a salt of a medicinal product derived from Mouravi is Noah, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, Anthranilic, mailaway, stearic, salicylic, p-hydroxybenzoic, phenylacetic, almond, monowai, methansulfonate, econsultancy, benzosulfimide, Pantothenic, toluensulfonate, 2-hydroxyethanesulfonic, sulfanilic, cyclohexanesulfonic, alginic, beta-hydroxybutiric, galacturonic and the galacturonic acids.

In one of the embodiments of salt accession acids obtained from the free base forms accepted methods, including the reaction of the free base with an appropriate acid. Suitable acid to obtain the salt of the accession of the acid include organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid and the like, and inorganic acids, for example hydrochloric acid, brough estevadeordal acid, sulfuric acid, nitric acid, phosphoric acid, etc.

In another embodiment, the salt of the accession of the bases obtained from the form of free acids conventional methods, including the reaction of the free acid with a suitable base.

In other embodiments, the implementation of salt accession acid again converted into the free base by treatment with a suitable base. In an additional embodiment, the salt of the accession acids represent a halogen salt, which is obtained using hydrochloric or Hydrobromic acids. In other embodiments, the implementation of basic salts are salts of alkali metals, e.g. sodium salt. In other embodiments, the implementation of salt accession grounds back is converted into the free base by treatment with a suitable acid.

In one embodiment, the implementation of the EPA and one or more cardiovascular drugs are present in the compositions according to the invention or their conjunction is introduced into the mass ratio of EPA:cardiovascular agent from about 1:1000 to about 1000:1, from about 1:500 to about 500:1, from about 1:100 to about 100:1, from about 1:50 to about 50:1, from about 1:25 to about 25:1, from about 1:10 to when listello 10:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1 to approximately 1:3 to about 3:1, from about 1:2 to about 2:1 or approximately 1:1.

Antiretroviral therapy is

In one of the embodiments the present invention relates to a method of treatment associated with cardiovascular system diseases, as defined herein, for example, dyslipidemia or hyperlipidemia, HIV-positive individual. In another embodiment, the method comprises co-administration or co-administration of a composition or compositions as described herein, with one or more protease inhibitors of HIV-1. Non-limiting examples of protease inhibitors of HIV-1 include APV, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir.

If desired, one or more protease inhibitors HIV-1 typically present in the compositions according to the invention (or their jointly administered with EPA according to other variants of the invention) in an amount from about 100 mg to about 2500 mg, for example, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, priblizitelen is 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 625 mg, about 650 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1825 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, or about 2500 mg; in an amount from about 200 mg to about 1000 mg, for example, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg; in an amount from about 50 mg to about 400 mg, for example, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg; in an amount from about 200 mg to about 1066 mg, for example, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, priblizitelen is 500 mg, approximately 533 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, or about 1066 mg; in an amount from about 50 mg to about 1200 mg, for example, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg, or in the amount of from about 15 mg per kg of body weight to about 40 mg per kg of body weight, for example, approximately 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg per kg, about 35 mg / kg, or about 40 mg per kg

Dosage forms

In one of the embodiments of the composition according to the invention are delivered orally. The terms "deliver oral" or "oral introduction" in the present who eat the document include any form of delivery of a therapeutic agent or composition thereof to the individual, where the agent or the composition is placed in the oral cavity of the individual, regardless of, swallow whether the agent or the composition or not. Thus, the "oral introduction" includes buccal and sublingual, and esophageal introduction.

In some embodiments, the implementation of the compositions according to the invention are in the form of solid dosage forms. Non-limiting examples of suitable solid dosage forms include tablets (for example, suspendiruemye tablets, raskusyvanii suspendiruemye tablets, bistrotdepierrerue tablets, chewable tablets, rasplavljajutsja tablets, effervescent tablets, bilayer tablets, etc.), caplet, capsules (for example, soft or hard gelatin capsules filled with solid and/or liquid), powder (for example, Packed powder, dosed powder or effervescent powder), pills, candies, Sasha, starch capsules, lozenges, pills, granules, microspheres encapsulated microspheres, powder aerosol formulations, or any other solid dosage form, suitably adapted for oral administration.

EPA and/or any other desired cardiovascular agent(a) can be combined in the same unit dosage or they can be formulated individually in separate unit dosage. The term"dosage form" and "unit dosage" in this document refer to the part of the pharmaceutical composition, containing a quantity of therapeutic agent that is suitable for a single injection to provide a therapeutic effect. Such unit dosage you can enter from one to several (i.e. from 1 to about 10, from 1 to 8, 1 to 6, 1 to 4 or 1 to 2) times a day or as many times as necessary to obtain a therapeutic response.

In one of the embodiments of the composition according to the invention contains one or more cardiovascular drugs, dispersed or suspended in the EPA, where the dispersion or suspension is in the capsule (e.g., gelatin or HPMC capsule), sachet or other dosage form or medium, as described herein. In another embodiment, dispersion or suspension are essentially homogeneous. In another embodiment, when it is desirable simultaneous introduction of two or more dosage units, EPA is in a first unit dosage, for example, in suspension in the capsule, and cardiovascular means is in a second unit dosage, for example, tablet. Optionally, the third composition may be any desired additional cardiovascular agent.

In another embodiment, the composition(s) according to the invention can be in the form of liquid dosage forms or drug f the RM for direct suction, and before ingestion can be mixed with food or drink. Non-limiting examples of suitable liquid dosage forms include solutions, suspensions, elixirs, syrups, liquid aerosol formulations, etc.

In one of the embodiments of the composition according to the invention after storage in a closed container, stored at room temperature, the cooling temperature (for example, from approximately 5 to approximately 5 to 10°C) or frozen for a period of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, demonstrates at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of active ingredient(s), source present in it.

In another embodiment, the invention relates to pharmaceutical compositions containing EPA and the cardiovascular agent (filler), encapsulated in a capsule shell, where the initial peroxide value of the filler is not more than about 10 mEq./kg, about 9 mg-EQ./kg, about 8 mg-EQ./kg, about 7 mg-EQ./kg, about 6 mg-EQ./kg, about 5 mEq./kg, about 4 mg-EQ./kg, about 3 mg-EQ./kg or about 2 mEq./kg, where, after storage of the composition at 23°C and 50% RH during the period priblizitelen is 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23 or about 24 months of the second peroxide value of ultra-pure EPA is not more than about 25 mEq./kg, about 24 mEq./kg, about 23 mEq./kg, about 22 mEq./kg, about 21 mEq./kg, about 20 mg-EQ./kg, about 19 mEq./kg, about 18 mEq./kg, about 17 mEq./kg, about 16 mEq./kg, about 15 mg-EQ./kg, about 14 mg-EQ./kg, about 13 mEq./kg, about 12 mg-EQ./kg, about 11 mEq./kg, about 10 mg-EQ./kg, about 9 mg-EQ./kg, about 8 mg-EQ./kg, about 7 mg-EQ./kg, about 6 mg-EQ./kg, about 5 mEq./kg, about 4 mg-EQ./kg, about 3 mg-EQ./kg or about 2 mEq./kg

When storing some pharmaceutical composition over time are destroyed. Debris can alter the efficiency of the composition, such as the er, as a result of delivering to the individual a smaller amount of the active ingredient than is recommended. About the products of the destruction of new drugs above certain thresholds must be notified in Food & Drug Administration (FDA) in accordance with current guidelines. Debris above a certain threshold quantities should be identified. Product destruction is "identified"when received its structural characteristics. For disintegration products above a certain amount, it is necessary to determine compliance with statutory requirements. For product destruction "is defined compliance"when identified and evaluated its biological safety.

In one of the embodiments of the composition according to the invention with a maximum daily dose of less than or equal to 1 gram after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 0.1% of any product destruction described for Food and Drug Administration (FDA). In another embodiment, the composition according to the invention with a maximum daily dose of more than 1 gram after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than compressedfile of 0.05% any product destruction not described for the FDA.

In one of the embodiments of the composition according to the invention with a maximum daily dose of less than 1 mg after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 1% of any unidentified product destruction. In another embodiment, the composition according to the invention with a maximum daily dose of less than 1 mg after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 5 μg any unidentified product destruction.

In one of the embodiments of the composition according to the invention with a maximum daily dose of from 1 mg to 10 mg after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 0.5% of any unidentified product destruction. In another embodiment, the composition according to the invention with a maximum daily dose of from 1 mg to 10 mg after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 20 μg any unidentified product destruction.

In one of the three embodiments of the composition according to the invention with a maximum daily dose of from 10 mg to 2 g after storage in light conditions, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 0.2% any unidentified product destruction. In another embodiment, the composition according to the invention with a maximum daily dose of from 10 mg to 2 g after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 2 mg of any unidentified product destruction.

In one of the embodiments of the composition according to the invention with a maximum daily dose > 2 g after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 0.1% of any unidentified product destruction.

In one of the embodiments of the composition according to the invention with a maximum daily dose of less than 10 mg after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 1% of any product destruction with indefinite compliance with statutory requirements. In another embodiment, the composition according to the invention with a maximum daily dose of less than 10 mg after storage in light conditions, heat is Denmark, humidity, acidic/basic hydrolysis and/or oxidative conditions, contain less than about 50 μg any product destruction with indefinite compliance.

In one of the embodiments of the composition according to the invention with a maximum daily dose of from 10 mg to 100 mg after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 0.5% of any product destruction with indefinite compliance with statutory requirements. In another embodiment, the composition according to the invention with a maximum daily dose of from 10 mg to 100 mg after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than approximately 200 µg of any product destruction with indefinite compliance.

In one of the embodiments of the composition according to the invention with a maximum daily dose from 100 mg to 2 g after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 0.2% any product destruction with indefinite compliance with statutory requirements. In another embodiment, to which notizie according to the invention with a maximum daily dose from 100 mg to 2 g after storage in light conditions, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 3 mg of any product destruction with indefinite compliance.

In one of the embodiments of the composition according to the invention with a maximum daily dose > 2 g after storage under conditions of light, heat, humidity, acid/basic hydrolysis and/or oxidative conditions, contain less than about 0.15% any product destruction with indefinite compliance.

In some embodiments, the implementation of the compositions according to the invention contain a stabilizing agent, which suppresses, prevents, inhibits or otherwise reduces the destruction of the active ingredient(s) during storage. For example, oxidative destruction of the EPA in the compositions according to the invention can be prevented or reduced by the presence of antioxidants. Non-limiting examples of suitable antioxidants include tocopherol, lecithin, citric acid and/or ascorbic acid. If desired, one or more antioxidants, usually present in the composition in amounts of from about 0.01% to about 0.1% by weight or approximately from 0.025% to about 0.05% by weight.

Excipients

The composition of the obreteniyu optionally contain one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" herein means any substance, not itself being a therapeutic agent, used as a carrier or Transporter for delivery of a therapeutic agent to the individual, or added to a pharmaceutical composition to improve its technological properties or stability during storage, or to provide or facilitate formation of a standard dose of the composition, and which does not cause unacceptable toxicity or interaction with other components in the composition.

The composition of the invention as an optional excipients, contain one or more pharmaceutically acceptable diluents. Suitable diluents illustrative, individually or in combination, include lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (for example, Solutab (Celutab™) and emdex (Emdex™)); mannitol; sorbitol; xylitol; dextrose (for example, carinoso (Cerelose™) 2000) and dextrose monohydrate; dihydrate dibasic calcium phosphate; based on the sucrose thinners; sugar confectionery; monohydrate nonoonono calcium sulphate; the dihydrate of calcium sulfate; trihydrate granular calcium lactate; dexterity; Inositol; solids hydrolyzed PLN the Cove; amylose; various types of pulp, including microcrystalline cellulose, food sources of α - and amorphous cellulose (e.g., Rexel (Rexcel™)and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone and the like, Such as diluent, if present, only approximately 5% to approximately 99%, from about 10% to about 85%, or from about 20% to about 80% by weight of the total composition.

The composition of the invention as an optional excipients, contain one or more pharmaceutically acceptable disintegrants. Suitable disintegrant, individually or in combination, include starches, including sodium starch glycolate (e.g., explotab (Explotab™) from PenWest) and pregelatinized corn starches (for example, national (National™) 1551, national (National™) 1550 and colocar (Colocorn™) 1500), clay (for example, wigum (Veegum™) HV), various types of cellulose, such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and carboxymethylcellulose sodium, croscarmellose sodium (e.g. Ac-Di-Sol™ from FMC), alginates, crosspovidone and gums such as agar, guar, xanthan gum, carob bean gum, gum karaya, pectin and tragacanthin gums. Such disintegrant, if present, usually segomotso from about 0.2% to about 30%, from about 0.2% to about 10%, or from about 0.2% to about 5% by weight of the total composition.

The composition of the invention optionally contain one or more antioxidants. Illustrative antioxidants include sodium ascorbate, and vitamin E (tocopherol). One or more antioxidants, if present, is typically present in the compositions according to the invention in amounts of about 0.001% to about 5%, about 0.005% to about 2.5%, or from about 0.01% to about 1% by weight.

The composition of the invention as an optional excipients, contain one or more pharmaceutically acceptable binding tools or adhesives. Such connecting means and adhesives can give sufficient connectivity tableting powder for normal processing, such as sizing, lubrication, compression and packaging, but can still allow the tablet to disintegrate and be absorbed composition after ingestion. Suitable connecting means and adhesives, individually or in combination, include gum Arabic; tragakant; sucrose; gelatin; glucose; starches, as non-limiting examples, such as petizione starches (for example, national (National™) 1511 and national (National™) 1500); different the e types of pulp, as non-limiting examples, such as methylcellulose, carmellose sodium (for example, tylose (Tylose™)); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (for example, klucel (Klucel™)and ethylcellulose (for example, ethocel (Ethocel™)). Such connecting means and/or adhesives, if present, only approximately 0.5% to approximately 25%, from about 0.75% to about 15% or from about 1% to about 10% by weight of the total composition.

The composition of the invention as an optional excipients, contain one or more pharmaceutically acceptable humidifiers. Non-limiting examples of surfactants that can be used as moisturizers in the compositions according to the invention include Quaternary ammonium compounds such as benzalkonium chloride, chloride benzene and chloride of cetylpyridinium, dioctylsulfosuccinate, simple alkylphenolate esters of polyoxyethylene, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (block copolymers of polyoxyethylene and polyoxypropylene), glycerides and oils and polyoxyethylene fatty acids, for example polyoxyethylene (8) Capri is new/capric mono - and diglycerides (e.g., Lubrizol (Labrasol™ from Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; ethers of polyoxyethylene and Akilov, for example, a simple ester of polyoxyethylene (20) and cetostearyl, esters of polyoxyethylene and fatty acids, for example polyoxyethylene(40)stearate, esters of polyoxyethylene and sorbitan, for example Polysorbate 20 and Polysorbate 80 (e.g., Tween™ 80 of ICI), esters of propylene glycol and fatty acids, for example propilenglikolstearat (for example, Lubrizol (Labrasol™) from Gattefosse), sodium lauryl sulfate, fatty acids and their salts, for example oleic acid, sodium oleate and triethanolamine, complex glyceriae esters of fatty acids, such as glycerylmonostearate, complex sorbitane esters, for example sorbitanoleat, servicemanual, servicemanagement and servicemonitor, tyloxapol and mixtures thereof. Such humidifiers, if present, only approximately 0.25% to approximately 15%, from about 0.4% to about 10% or from about 0.5% to about 5% by weight of the total composition.

The composition of the invention as an optional excipients, contain one or more pharmaceutically acceptable lubricants (including antiadhesive and/or promoting sliding means). Fit smasa the ing funds separately or in combination, include glycerinated (e.g., Compritol™ 888); stearic acid and its salts, including magnesium stearates (magnesium stearate), calcium and sodium, hydrogenated vegetable oil (e.g., sarotex (Sterotex™)); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (for example, carbowax (Carbowax™) 4000 and carbowax (Carbowax™) 6000); sodium oleate; sodium lauryl sulfate and lauryl magnesium. Such lubricant, if present, only approximately 0.1% to approximately 10%, from about 0.2% to about 8% or from about 0.25% to about 5% by weight of the total composition.

Suitable antiadhesive include talc, corn starch, DL-leucine, sodium lauryl sulfate, and metallic stearates. Talc is a parting agent or facilitate the sliding of the tool used, for example, to reduce sticking of the composition to the surfaces of equipment, as well as to reduce interference when mixing. Talc, if present, is from about 0.1% to about 10%, from about 0.25% to about 5% or from about 0.5% to about 2% by weight of the total composition. Promoting sliding means can be used to ensure the fluidity of orosco in solid compositions. Suitable promoting sliding means include colloidal silicon dioxide, starch, talc, rejonowy calcium phosphate, powdered cellulose, and magnesium trisilicate.

The compositions of the present invention optionally contain one or more flavorings, sweeteners and/or dyes. Flavoring agents suitable for the present invention as non-limiting examples include syrup of gum Arabic, alitum, anise, Apple, aspartame, banana, jelly with whipped cream, berry, black currant, butter, butter pecan, toffee, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, Cola, frozen cherries, frozen citrus, cyclamate, CIEMAT, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycerrhetinic, syrup of licorice (liquorice), grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, magnasweet (MagnaSweet®), maltol, mannitol, maple, menthol, mint, mint cream, berry mix, walnut, orange, peanut butter, pear, pepper mint, cream of peppermint, powder enlightenment (Prosweet®), raspberry, root beer, rum, saccharin, safrole, sorbitol, spicate mint, cream of spearmint, strawberry, strawberry cream, stevia, Sucralose, sucrose, Swiss cream, tagatose, Mandarin, thaumatin, candied fruits, vanilla, Greck the second nut, watermelon, cherries, Wintergreen, xylitol and combinations thereof, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, etc.

Sweeteners that can be used in the present invention include, for example, Acesulfame potassium (Acesulfame K), alitum, aspartame, cyclamate, CIEMAT, dextrose, isomalt, magnasweet (MagnaSweet®), ▫ maltitol, mannitol, neohesperidin DC, NOTAM, powder enlightenment (Prosweet®), saccharin, sorbitol, stevia, Sucralose, sucrose, tagatose, thaumatin, xylitol, etc.

Flavors, sweeteners and/or dyes may be present in the compositions according to the invention in any suitable amount, for example, from about 0.01% to about 10%, from about 0.1% to about 8% or from about 1% to about 5% by weight.

The composition of the invention optionally contain suspendisse tool. Non-limiting illustrative examples of suitable suspendida funds include silicon dioxide, bentonite, hydrated aluminum silicate (for example, kaolin and mixtures thereof. One or more suspendida funds optionally present in the compositions according to the invention in a total amount of from approximately 0.01% to approximately 3.0%, from about 0.1% to about 2.0% or approx the tion from 0.25% to approximately 1.0% by mass.

As is well known in this field, the above excipients can have multiple roles. For example, the starch can serve as a filler, as well as disintegrant. The above classification of excipients in no way should be considered as limiting. As can be easily understood by the person skilled in the art, excipients, in any way related to the categories, can also operate in various other categories of excipients.

Therapeutic methods

In various embodiments, the implementation of the compositions according to the invention is suitable for treatment and/or prevention associated with cardiovascular system diseases. The term "associated with cardiovascular system disease" herein refers to any disease or disturbance of the heart or blood vessels (i.e. arteries and veins) or any of their or symptom of any disease or condition that cause or contribute to cardiovascular disease. Non-limiting examples associated with cardiovascular system diseases and disorders include acute ischemic disorders of the heart, acute myocardial infarction, angina, chest pectoris, arrhythmia, atrial fibrillation, atherosclerosis, atrial fibrillation, heart failure, cardiovascular disease, chronic cardiac insufficient the durability, chronic stable angina, congestive heart failure, ischemic heart disease, atherosclerotic heart disease, deep vein thrombosis, diabetes, diabetes mellitus, diabetic neuropathy, diastolic dysfunction in individuals with diabetes, edema, primary arterial hypertension, the potential embolism blood vessels of the lungs, fatty liver disease, heart disease, heart failure, homozygous familial hypercholesterolemia (HoFH), homozygous familial sitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia in HIV-positive individuals, hypertension, hypertriglyceridemia, ischemic complications in unstable angina and myocardial infarction, low blood pressure, metabolic syndrome, mixed dyslipidemia, heart failure, moderate to mild, myocardial infarction, control of obesity, paroxysmal fibrillation/atrial flutter, paroxysmal supraventricular tachycardia (PSVT), very severe swelling or edema with rapid early platelet aggregation, primary hypercholesterolemia, primary hyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension, paroxysmal hemodynamically unstable ventricular tachycardia (VT), paroxysmal ventricular fibrillation, proximaldistal ventricular fibrillation (VF), a ruptured aneurysm, sitosterolemia, stroke, supraventricular tachycardia, symptomatic fibrillation/atrial flutter, tachycardia, type II diabetes, vascular disease, venous thrombosis, ventricular fibrillation and other cardiovascular disorders.

The term "treatment" in relation to these diseases or disorders as non-limiting examples include the containment of diseases or disorders, for example, stopping the development of the disease or disorder; the alleviation of diseases or disorders, for example, causing regression of the disease or disorder; or alleviating conditions caused by or resulting from diseases or disorders, for example, alleviation, prevention or treatment of symptoms or disorders. The term "prevention" in relation to the disease or impairment means preventing the early development of the disease, if it has not happened, preventing any disease or disorder of an individual who may be predisposed to the disorder or disease, but which have not yet diagnosed the presence of disorders or diseases, and/or preventing the further development of the diseases/disorders, if it is already present.

In some embodiments, the implementation of the compositions of the present invention can be entered with the topically or administered simultaneously with one or more additional cardiovascular agents. The terms "added together", "co-administration" and "administered simultaneously" is used herein interchangeably, and each include, for example, to the introduction of two or more tools (e.g., EPA or its derivative and cardiovascular drugs) at the same time, in one and the same unit dosing, one directly after the other, within five minutes of each other, within ten minutes of each other, within fifteen minutes of each other, within thirty minutes of each other, within one hours apart, within two hours of each other, within four hours of each other, within six hours of each other, within twelve hours of each other, within one day of each other, within one week of each other, within two weeks from each other, within one month of each other, within two months of each other, within six months of each other, within one year of each other, etc.

In one of the embodiments the present invention relates to a method of treatment associated with cardiovascular system diseases, including introduction to the needy in the individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (in the form of one unit of dosiro the project or as multiple dosage units), where improve one or more parameters of lipid compared with the parameters of the lipids obtained by the additive effects of treatment separately.

In a related embodiment, after treatment according to the present invention, for example, during a period of from about 1 to about 200 weeks, from about 1 to about 100 weeks, about 1 to about 80 weeks, from about 1 to about 50 weeks, about 1 to about 40 weeks, from about 1 to about 20 weeks, from about 1 to about 15 weeks, from about 1 to about 12 weeks, from about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the individual or group of individuals demonstrate one or more of the following outcomes:

(a) reduced triglyceride levels compared to baseline or placebo group;

(b) reduced levels of Apo B compared to baseline or placebo group;

(c) increased levels of HDL-C compared to baseline or placebo group;

(d) the absence of increased levels of LDL-C compared to baseline or placebo group;

(e) reduction of LDL-C compared to baseline or placebo group;

(f) reducing the levels of HDL-C compared to baseline or placebo group;

(g) reduction in vLDL levels compared to baseline or placebo group;

(h) increasing levels of apo A-I compared to baseline or placebo group;

(i) an increase in the ratio of apo A-I/apo B compared to baseline or placebo group;

(j) reducing the levels of lipoprotein A, compared with baseline or placebo group;

(k) increasing the number of LDL particles compared with baseline or placebo group;

(l) lowering the amount of LDL compared with baseline or placebo group;

(m) the reduction of cholesterol in residual particles compared to baseline or placebo group;

(n) reducing the oxidized LDL compared to baseline or placebo group;

(o) no change or decrease in the plasma glucose fasting (FPG) compared to baseline or placebo group;

(p) reduction of hemoglobin A1c(HbA1c) compared to baseline or placebo group;

(q) the reduction of insulin resistance in the model of homeostasis compared to recognize the essential level or group, placebo;

(r) a reduction in lipoprotein-associated phospholipase A2 compared to baseline or placebo group;

(s) reduction of intracellular adhesion molecule-1 compared to baseline or placebo group;

(t) a reduction in interleukin-6 compared to baseline or placebo group;

(u) the reduction of the inhibitor of plasminogen activator-1 compared to baseline or placebo group;

(v) reduction in high-sensitivity C-reactive protein (hsCRP) compared to baseline or placebo group;

(w) the increase of EPA in serum phospholipids compared with baseline or placebo group;

(x) the increase in EPA in erythrocyte membranes compared to baseline or placebo group; and/or

(y) a reduction or increase in one or more of the content in serum phospholipids and/or erythrocyte docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic acid (PA), stearidonic acid (SA) or oleic acid (OA) compared to baseline or a placebo group.

In one of the embodiments of the methods of the present invention include the measurement before dosing to the individual or group the individuals of the initial levels of one or more markers, specified in (a)-(y) above. In another embodiment, the methods include the introduction of individual compositions, as described herein, after determining the baseline levels of one or more markers listed in (a)-(y), and then an additional measuring the one or more tokens.

In another embodiment, after treatment with the composition of the present invention, for example, during a period of from about 1 to about 200 weeks, from about 1 to about 100 weeks, about 1 to about 80 weeks, from about 1 to about 50 weeks, about 1 to about 40 weeks, from about 1 to about 20 weeks, from about 1 to about 15 weeks, from about 1 to about 12 weeks, from about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week individual or group of individuals exhibit any 2 or more, any 3 or more, 4 or more, any 5 or more, any 6 or more, any 7 or more, any 8 or more, any 9 or more, any 10 or more, any 11 or more, any 12 or more, 13 or any more, any 14 or more, any 15 or more, any 16 or more, any 17 Il is more any 18 or more, 19 or any more, any 20 or more, 21 or any more, any 22 or more, 23 or any more, any 24 or more or all of 25 results (a)-(y)described immediately above.

In another embodiment, after treatment with the composition of the present invention, for example, during a period of from about 1 to about 200 weeks, from about 1 to about 100 weeks, about 1 to about 80 weeks, from about 1 to about 50 weeks, about 1 to about 40 weeks, from about 1 to about 20 weeks, from about 1 to about 15 weeks, from about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week individual or group of individuals demonstrates one or more of the following outcomes:

(a) reducing the level of triglycerides of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, p is at least about 55% or at least about 75% (change in absolute % or the change in average %) compared with the initial level or group, placebo;

(b) an increase of less than 30%, an increase of less than 20%increase less than 10%increase less than 5% or no increase levels of HDL-C or lowering levels of HDL-C at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (change in absolute % or the change in average %) compared to baseline or placebo group;

(c) essentially no change, no change or increase the levels of HDL-C at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% of the sludge is at least about 75% (change in absolute % or the change in average %) compared with the initial level or group, placebo;

(d) increased less than 60%, an increase of less than 50%, an increase of less than 40%, an increase of less than 30%, an increase of less than 20%, an increase of less than 15% or no increase levels of LDL-C or lowering of LDL-C of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 55% or at least about 75% (change in absolute % or the change in average %) compared to baseline or placebo group;

(e) reducing the levels of Apo B is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (change in absolute %or the change in average %) compared with the initial level or group, placebo;

(f) reduction in the levels of vLDL at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or change in the middle %) compared to baseline or placebo group;

(g) increasing levels of apo A-I at least approximately 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(h) the higher the ratio of apo A-I/apo B is at least about 5%, at least about 10%, at least about 15%, at least about the 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(i) reduced levels of lipoprotein (a) at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(j) reducing the average number of LDL particles is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least AP is sustained fashion by 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(k) the increase in the average particle size of LDL at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(l) the reduction of cholesterol in residual particles of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared with the original level of the Lee group, placebo;

(m) the reduction of oxidized LDL by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or change in the middle %) compared to baseline or placebo group;

(n) essentially no change, no change or decrease in the level of plasma glucose fasting (FPG) at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(o) essentially no change, no change or a decrease in hemoglobin A1c (HbA1cat least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% (change in absolute % or the change in average %) compared with the initial level or the group receiving the placebo;

(p) the reduction of the index of insulin resistance in the model of homeostasis at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(q) a reduction in lipoprotein-associated phospholipase A2, at least about 5%, at least about 10%, at least about 15%, at least about 20%, p is at least approximately 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(r) reduction of intracellular adhesion molecule-1, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(s) a reduction in interleukin-6 at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least bring the flax 50% or at least about 100% (change in absolute % or the change in average %) compared with the initial level or group, placebo;

(t) reduction inhibitor of plasminogen activator-1, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change in absolute % or the change in average %) compared to baseline or placebo group;

(u) reduction in high-sensitivity C-reactive protein (hsCRP) at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or at least about 100% (change absolute % or the change in average %) compared to baseline or placebo group;

(v) the increase of EPA in serum, plasma and/or RBC at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 100%, at least about 200%, or at least about 400% (change in absolute % or the change in average %) compared to baseline or a placebo group;

(w) the increase of EPA in serum phospholipids and/or erythrocyte membranes at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 100%at least about 200%, or at least about 400% (change in absolute % or the change in average %) compared to baseline or placebo group;

(x) a reduction or increase in one or more of DHA, DPA, AA, PA and/or OA in serum phospholipid and/or red blood cells at least PR is approximately 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (change in absolute % or the change in average %) compared with baseline or placebo group; and/or

(y) a reduction in total cholesterol at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (change in absolute % or the change in average %) compared to baseline or a placebo group.

In one of the embodiments of the methods of the present invention to include dispensing an individual or group of individuals measuring baseline levels of one or bore the channels at markers, specified in (a)-(y). In another embodiment, the methods include the introduction of a composition as described herein to the individual after determining the baseline levels of one or more markers listed in (a)-(y), and then conduct additional measurements of one or more markers that are measured at baseline, for comparison with him.

In another embodiment, after treatment with the composition of the present invention, for example, during a period of from about 1 to about 200 weeks, from about 1 to about 100 weeks, about 1 to about 80 weeks, from about 1 to about 50 weeks, about 1 to about 40 weeks, from about 1 to about 20 weeks, from about 1 to about 15 weeks, from about 1 to about 12 weeks, from about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the individual or group of individuals demonstrates any 2 or more, any 3 or more, 4 or more, any 5 or more, any 6 or more, any 7 or more, any 8 or more, any 9 or more, any 10 or more, any 11 or more, any 12 or more, 13 or any more, any 14 or more, dear to the e of 15 or more, any 16 or more, 17 or any more, any 18 or more, 19 or any more, any 20 or more, 21 or any more, any 22 or more, 23 or any more, any 24 or more or all 25 of outcomes (a)-(y)described immediately above.

Options (a)-(y) can be measured according to any clinically acceptable methodology. For example, triglycerides, total cholesterol, HDL-C and blood sugar on an empty stomach can be a sample of serum, and they can be analyzed by standard methods of photometry. VLDL-TG, LDL-C and VLDL-C can be calculated and determined with the use of fractionation of serum lipoproteins by preparative ultracentrifugation and subsequent quantitative analysis by refractometry or by means of analytical ultracentrifugation. Apo A1, Apo B and hsCRP can be determined in serum by standard methods nephelometry. Lipoprotein (a) can be identified in serum by standard methods turbidimetric immunoassay. The number of LDL particles and the particle size can be determined using spectrometry nuclear magnetic resonance (NMR). Residual lipoprotein and LDL-phospholipase A2 can be determined in serum or plasma with EDTA and serum, respectively, by means of enzymatic immunoproteasome. The levels of oxidized LDL molecules IU the cell adhesion-1 and interleukin-2 can be determined in serum by standard methods enzyme immunoassay. These methods are described in detail in standard manuals, for example, Tietz Fundamentals of Clinical Chemistry, 6thEd. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.

In a related embodiment, the reduction or increase of the parameters (a)-(y)above, is statistically significant.

In another embodiment, the present invention relates to a method for treatment of blood lipids, including introduction to the needy in this individual from 1 to a variety of dosage units containing composition or compositions as described herein. In another embodiment, the initial level of triglycerides in the individual being treated, prior to treatment composition of the present invention is greater than or equal to approximately 150 mg/DL, greater than or equal to about 175 mg/DL, greater than or equal to approximately 250 mg/DL or greater than or equal to about 500 mg/DL, for example, from about 200 mg/DL to about 2000 mg/DL, from about 300 to about 1800 mg/DL or approximately 500 mg/DL to about 1500 mg/DL.

In one of the embodiments of the methods of the present invention to include dispensing an individual or group of individuals measuring baseline levels of one or more markers listed in (a)-(y). In another embodiment, the methods include introduction the individual songs, as described herein, after determining the baseline levels of one or more markers listed in (a)-(y), and then conduct additional measurements of one or more markers that are measured at baseline, for comparison with him.

In one of the embodiments the present invention relates to a method of treatment or prevention of primary hypercholesterolemia and/or mixed dyslipidemia (Fredrickson types IIa and IIb) in need thereof of an individual including the introduction of individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described herein. In a related embodiment, the present invention relates to a method of reducing levels of triglycerides from the individual or individuals, when treated with statin monotherapy or Niacin extended action is believed to be low (hyperlipidemia Fredrickson type IV). Monotherapy statin or Niacin prolonged action believe inadequate when, for example, a level not HDL-C of the individual is not reduced or not reduced to the desired degree, LDL-C the individual has not improved or not improved to the desired extent, the level of HDL-C individuuma improved or not improved to the desired extent and/or triglyceride levels of the individual not improved or not improved to the desired extent.

In another embodiment, the present invention relates to a method of treating or preventing non-fatal myocardial infarction, including the introduction of individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this document.

In another embodiment, the present invention relates to a method of treating or preventing the risk of recurrent non-fatal myocardial infarction in individuals with myocardial infarction in the history of the disease, including the introduction of individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this document.

In another embodiment, the present invention relates to a method of slowing development or stimulation of the regression of atherosclerotic disease in need thereof of an individual including the introduction of individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this is the face of the document.

In another embodiment, the present invention relates to a method of treating obesity in need thereof of an individual including an introduction to the needy in the individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this document.

In another embodiment, the present invention relates to a method of treating or preventing very high levels of triglycerides in serum (e.g., hyperlipidemia type IV and V) in need thereof of an individual including the introduction of individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this document.

In another embodiment, the present invention relates to a method of treatment of individuals with very high levels of triglycerides in serum (e.g., more than 1000 mg/DL or more than 2000 mg/DL) and with the risk of pancreatitis, including the introduction of individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or in a single unit dosage, or VI is e multiple dosage units), as described in this document.

In another embodiment, the present invention relates to a method for preventing recurrence of stroke, including the introduction of the individual with stroke in the history of the composition or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this document.

In another embodiment, the present invention relates to a method of preventing the beginning and/or recurrence of cardiovascular disorders in the individual released from a period of instability after the cardiovascular angioplasty, including the introduction of individual compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this document.

In another embodiment, the present invention relates to a method of reducing levels of Apo-B and not HDL-cholesterol in a group of individuals with baseline LDL-cholesterol of at least 100 mg/DL, the source level is not HDL-cholesterol of at least 130 mg/DL and baseline triglyceride level of at least 200 mg/DL and reduced levels of Apo-B and not HDL-cholesterol in the group the individual is Oumou by administration of a composition or compositions, containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described in this document, the members of a group of individuals.

In another embodiment, the invention relates to a method of reducing levels of Apo-B in which a group of individuals, including the measurement of LDL-cholesterol, not HDL-cholesterol and triglycerides in individuals receiving a group of individuals with baseline LDL-cholesterol of at least 100 mg/DL, the source level is not HDL-cholesterol of at least 130 mg/DL and baseline triglyceride level of at least 200 mg/DL, and decreased levels of Apo-B in which a group of individuals through the introduction of group members, individuals compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described herein in an amount effective to reduce the levels of Apo-B in which a group of individuals in a statistically significant degree as compared with the control treatment, where avoiding the increase or statistically significant increase in the level of LDL-cholesterol.

In another embodiment, the invention relates to a method of reducing levels of Apo-B in which a group of individuals, including the obtaining of a group of individuals with baseline LDL-cholesterol of at least 100 mg/DL, the initial level is not HDL-cholesterol of at least 130 mg/DL and baseline triglyceride level of at least 200 mg/DL, reduced levels of Apo-B in which a group of individuals through the introduction of group members, individuals compositions or compositions containing EPA and one or more additional cardiovascular drugs (or as one unit dosage or multiple dosage units)as described herein in an amount effective to reduce the levels of Apo-B in which a group of individuals in a statistically significant degree as compared with the control treatment, and the definition lower levels of Apo-B in which a group of individuals.

In one of the embodiments of the composition according to the invention is administered to an individual in amounts sufficient to provide a daily dose of EPA from about 1 mg to about 10000 mg, from about 25 to about 5,000 mg, from about 50 to about 3,000 mg, from about 75 mg to about 2500 mg, or from about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, closer is the super 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, approximately 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, approximately 1150 mg, approximately 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, approximately 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, about 1400 mg, about 1425 mg, approximately 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, approximately 1550 mg, approximately 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, approximately 1675 mg, about 1700 mg, approximately 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, priblizitel is but 1925 mg, circa 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, approximately 2050 mg, approximately 2075 mg, about 2100 mg, approximately 2125 mg, approximately 2150 mg, approximately 2175 mg, about 2200 mg, approximately 2225 mg, about 2250 mg, approximately 2275 mg, about 2300 mg, approximately 2325 mg, approximately 2350 mg, approximately 2375 mg, 2400 mg, approximately 2425 mg, approximately 2450 mg, approximately 2475 mg, or about 2500 mg

In various embodiments of the invention described in this document, EPA, and optionally one or more additional cardiovascular drugs can be introduced in the form of jointly formulate one unit dosage or as a separate dosage units. When EPA and the optional one or more additional cardiovascular drugs administered together in the form of separate dosage units, each unit dosage you can enter individual essentially at the same time or substantially at different points in time. In one of the embodiments, when two or more separate dosage units must be administered daily, every unit dosing is possible to introduce individual within a period of approximately 24 hours, 18 hours, 12 hours, 10 hours, 8 cha is s, 6 hours, 4 hours, 2 hours, 1 hour or 0.5 hours.

In another embodiment, the EPA and one or more optional cardiovascular drugs can be entered sequentially. For example, EPA can enter the individual as one means during dispensing EPA. The dosing period may represent, for example, 1 day, 2 days, 4 days, 6 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. After any such period of dosing with the current introduction of the EPA or instead of EPA treatment, you can start introducing one or more additional cardiovascular drugs.

In another embodiment, the EPA is administered to the individual in the morning, for example, from about 4 o'clock in the morning until about 10 o'clock in the morning, from about 5 am to about 9 am or from about 6 am to about 8 am, and optional one or more cardiovascular drugs administered to the individual after noon or evening, for example, from about 13 hours to about 23, about 14 hours to about 22 hours, or from about 15 hours to about 21 hours, or Vice versa.

In another embodiment, the invention relates to the use of EPA and one or more cardiovascular drugs in p is receiving medicines to treat or prevent associated with cardiovascular system diseases, such as hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction and other cardiovascular disorders. In one of the embodiments the composition contains not more than 10% DHA, if any contains. In another embodiment, the composition essentially contains or does not contain DHA.

In another embodiment, the invention relates to a pharmaceutical composition comprising EPA and one or more cardiovascular drugs for the treatment and/or prevention associated with cardiovascular system diseases, where the composition contains not more than 10% DHA, if any contains. In a related embodiment, the composition essentially contains no DHA or does not contain DHA.

In one embodiment, the implementation of the individual being treated with the composition or by means of a treatment regimen specified in the present document is an individual with diabetes or prediabetes.

In one of the options for implementing any of the methods described herein, is used to treat or prevent an individual or individuals within the traditional Western diet. In one of the embodiments of the methods according to the invention include the step defined the self as being on a Western diet or a reasonable diet, and then the treatment of the individual, if the individual recognize consume a Western diet. The term "Western diet" in this document refers to a typical diet, in percent of total calories, consisting of approximately 45% to approximately 50% carbohydrate, from about 35 to about 40% fat and from about 10% to about 15% protein. Western diet can additionally be characterized by a relatively high consumption of raw and processed meats, sweets, products from refined grains and desserts, for example, when half or more or 70% or more of the calories come from these sources.

It should be understood that the specialists in this area is clear and provides for a wide range of changes and modifications of the embodiments described above. Thus, I believe that the above detailed description should be considered as illustrative and not as limiting, and that it should be understood that in order to determine the nature and scope of the invention, there is the following claims, including all equivalents.

It should be understood that the specialists in this field is obvious various changes and modifications of the preferred embodiments of the present invention described herein. Such changes and modifications can be made is TLAT without deviating from the essence and scope of the object of the present invention and without sacrificing its implied benefits. Thus, it is expected that such changes and modifications are provided in the attached claims.

EXAMPLES

Following non-limiting examples are provided for illustrative purposes only, and should not be construed as in any way limiting the invention.

Example 1

The experiment was carried out to test EPA, DHA, EPA + DHA with atorvastatin without in model membranes enriched in PUFA and cholesterol levels, reproducing the disease or condition high CV risk (i.e. hypocholesterolemia). As shown below, EPA demonstrates potent antioxidant effect in cholesterol-enriched membranes, which was superior antioxidant effect observed when using DHA. In addition, the combination of EPA and atorvastatin provided even greater antioxidant effect when compared to one EPA.

EPA and DHA were tested separately at a fixed concentration of 10.0 μm or in combination with the 5.65 microns and 4.35 microns (EPA and DHA, respectively), which is a molar ratio of 1.3:1. Individual and combined effect of these funds on the formation of lipid peroxides (LOOH) investigated when the molar relationship of cholesterol to phospholipid (C/P) of 0.5:1, and 1.0:1 and 1.5:1. The levels of lipid hydroperoxides was measured for EPA, DPH and EPA/DPH in cholesterol-enriched membranes obtained in the absence and the presence of atorvastatin.

1,2-talinolol-3-sn-phosphatidylcholine (DLPC) was obtained from Avanti Polar Lipids (Alabaster, AL) and were stored in chloroform (25 mg/ml) at -80°C. Cholesterol is received and stored in chloroform (10 mg/ml) at -20°C. the Color reagent CHOD-iodide (original solution)consisting of 0.2 M K2HPO4, 0,12 M KI, 0.15 mm NaN3, 10 μm of ammonium molybdate and 0.1 g/l benzalkonium chloride, obtained by the modified method based on El-Saadani et al. (El-Saadani M, Esterbauer H, El-Sayed M, Goher M, Nassar AY, Jurgens G. A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent. J Lipid Res 1989; 30:627-30). Before use in the experiment reagent CHOD activated by adding 24 μm ethylenediaminetetraacetic acid (EDTA), 20 μm bottled hydroxytoluene (BHT) and 0.2% Triton X-100. Atorvastatin was obtained in ethanol immediately before use in the experiment and were added together with the constituent lipids containing a fixed amount equimolar levels of EPA, DPH or EPA/DPH. Compounds and lipids were added in combination for obtaining a sample of the membrane to ensure full incorporation of lipid bilayers.

Samples of membranes composed of DLPC ± cholesterol with a molar relationship of cholesterol to phospholipid (C/P) in the range from 0.5 to 1.5, was obtained as follows. Components of lipids (in chloroform) was transferred into test tubes 13 x 100 mm and dried in the casing in a constant stream of gazoobraznogo the nitrogen with stirring in a centrifuge of the type "vortex". Lipid together was dried with EPA, DPH or EPA/DPH obtained in the absence or in the presence of equimolar levels of atorvastatin.

Residual solvent was removed by drying for at least 3 hours in vacuum. After drying each sample membrane resuspendable diffraction buffer (0.5 mm HEPES, 154 mm NaCl, pH 7.3) to obtain the final concentration of phospholipids 1.0 mg/ml was Obtained multilayer vesicles (MLV) by mixing in a centrifuge of the type "vortex" for 3 minutes at ambient temperature. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J. Mol. Biol. 1965; 13:238-52. Directly after the initial receipt of MLV were selected aliquots of each sample membrane for analysis of baseline lipid peroxidation (0 hour).

All samples of lipid membranes were subjected to the auto-oxidation of different duration by incubation at 37°C in an open water bath with stirring. Took a small aliquot of each sample at intervals of 24 hours and combined with 1.0 ml of the active dye CHOD-iodide. To ensure reading spectrophotometric data in the optimum range of optical density, the amount of samples taken to measure the formation of lipid peroxides, regulated by duration peroxidation and range from 100 to 10 ál. Test samples immediately p who could open the foil and incubated at room temperature for > 4 hours in the absence of light. Absorption was measured against the control CHOD at 365 nm using a spectrophotometer Beckman DU-640.

Colorimetric analysis CHOD based on the oxidation of iodide (I-) lipid hydroperoxides (LOOH) and is in accordance with the following reaction scheme:

LOOH + 2H++ 3I-→ LOH + H2O + I3-.

The number of anion triiodide (I3-)released in this reaction is directly proportional to the number of lipid hydroperoxides present in the sample membranes. The molar absorption coefficient (ε) I3-at 365 nm is 2.46×104M-1cm-1.

The results are presented in figures 1-4.

1. Pharmaceutical composition for lowering triglycerides in the individual in need thereof, where the pharmaceutical composition comprises at least 95% EPA, by weight of all fatty acids present in the composition and inhibitor of HMG-CoA reductase.

2. The composition according to claim 1, where the inhibitor of HMG-CoA reductase is selected from the group including amlodipine, atorvastatin, ezetimibe, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, or their pharmaceutically acceptable combination.

3. The composition according to claim 1, where EPA is present in an amount of from 100 mg to 1500 mg

4. The composition according to claim 1, where the composition comprises less than 0.5% DHA or its derivative of the mA is the CE of all fatty acids.

5. The composition according to claim 1, where the composition essentially contains no DHA or its derivative.

6. The composition according to claim 1, where the mass ratio of EPA to other fatty acids is at least about 96:4.

7. The composition according to claim 1, where EPA contains complex1-C5-alkilany ether.

8. The composition according to claim 7, where the complex C1-C5-alkilany ether contains ethyl ester of EPA.

9. The composition according to claim 1, where the composition contains less than 1% of Tocopherols by weight, if any, contains.

10. The composition according to claim 1, where the composition is orally deliverable dosage form.

11. The composition of claim 10, where the dosage form comprises a tablet, dripping, capsule, powder, tablet-candy, Sasha, a starch capsule, toffee, pill, granule, microgranule encapsulated microgranule or powder spray.

12. The composition according to claim 1, where the inhibitor of HMG-CoA reductase suspended in EPA.

13. The composition according to item 12, where the suspension is, in essence, is homogeneous.

14. The composition according to item 13, where the composition is in a capsule.

15. The composition according to claim 1, where the inhibitor of HMG-CoA reductase includes atorvastatin.

16. A method of reducing triglyceride levels in an individual in need thereof, comprising: identifying an individual in need of decreasing triglycerides, and the introduction of individual compositions containing less than the least of 95% ethyl-EPA by weight of all fatty acids, present in the composition, and inhibitor of HMG-CoA reductase.

17. The method according to clause 16, where the inhibitor of HMG-CoA reductase is selected from the group consisting of amlodipine, atorvastatin, ezetimibe, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, or their pharmaceutically acceptable combination.

18. The method according to clause 16, where the inhibitor of HMG-CoA reductase and EPA jointly administered as separate dosage units.

19. The method according to clause 16, where EPA and the inhibitor of HMG-CoA reductase formulated together and administered as a single unit dosing.

20. The method according to claim 19, where the unit dosage is administered from one to multiple times per day.

21. The method of reducing the glycerides in HIV+ individual, where the method includes the administration to an individual a pharmaceutical composition comprising the inhibitor of the protease of HIV-1 and at least 95% ethyl-EPA by weight of all fatty acids present in the pharmaceutical composition.

22. The method according to item 21, where the inhibitor of the protease of HIV-1 includes APV, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or a combination thereof.

23. A method of treating or preventing obesity in need thereof of an individual, where the method includes the administration to an individual a pharmaceutical composition that contains at least 95% ethyl-EPA by weight of all fatty acids present in the composition, and orlistat.

2. The method according to item 23, where EPA and orlistat is administered in a single unit dosage.

25. The method according to item 23, where EPA and orlistat jointly administered in separate dosage units.

26. A method of treating type II diabetes in need of this individual, where the method includes the administration to an individual a pharmaceutical composition that contains at least 95% EPA, by weight of all fatty acids present in the composition, and Metformin.

27. The method according to p, where EPA and Metformin administered in a single unit dosage.

28. The method according to p, where EPA and Metformin jointly administered in separate dosage units.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a liquid oral solution for treating angiotensin II mediated disorders and conditions, and to a method for preparing it. The liquid oral solution contains valsartan in the concentration of 5 mg/ml or less, a wetting agent, a preserving agent, a flavouring agent, a buffer system and water with pH of the solution making 4.5-5.9. The wetting agent is poloxamer 188 described by the structure HO(CH2CH2O)a(CH(CH3)CH2OH)b(CH2CH2O)cH, wherein a is equal to 75, b is equal to 30, and c is equal to 75, with average molecular weight 8350. The buffer system contains alkali citrates and citric acid, alkali acetates and acetic acid, alkali succinates and succinic acid, or any mixtures thereof. The method for preparing the above solution involves mixing the ingredients added then with valsartan when heated.

EFFECT: group of inventions provides preparing the liquid solution of valsartan with an extended storage period.

8 cl, 12 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclic azaindole-3-carboxamides of formula (I) in any of its stereoisomeric forms or in the form of a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them: wherein A is specified in O, S and C(Ra)2; Ra is specified in hydrogen and (C1-C4)-alkyl wherein the two groups Ra are independent from each other and may be identical or different; R is specified from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-CO-CuH2u- and R1-NH-CO-CuH2u-, wherein all the groups R are independent from each other and may be identical or different; R1 is specified from hydrogen, (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-; R10 is specified from hydrogen, (C1-C6)-alkyl-O-CO-; R20 is specified from phenyl which is optionally substituted by one or more identical or different substitutes specified in halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-; R30 is specified from (C3-C7)-cycloalkyl and phenyl, wherein phenyl is optionaly substituted by one or more identical or different substitutes specified in halogen and (C1-C6)-alkyl; R40 is specified in halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl-, hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O- and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, wherein all the substitutes R40 are independent from each other and may be identical or different; one of the groups Y1, Y2, Y3 and Y4 represents N, while the others are identical or different groups CH or CR40; n is specified in 0, 1, 2 and 3; p and q which are independent from each other and may be identical or different being specified in 2 and 3; n is specified in 0, 1 and 2, wherein all the values are independent from each other and may be identical or different; wherein all the alkyl groups are independently from each other optionally substituted by one or more fluorine atoms; wherein all the phenyl groups found in R and R40 are independently from each other optionally substituted by one or more identical or different substitutes specified in halogen and (C1-C4)-alkyl. Besides, the invention describes a method for preparing a compound of formula I, a pharmaceutical compositions having renin inhibitory activity and containing the compound of formula I and to using the compound of formula I for making a therapeutic preparation.

EFFECT: described and prepared are the new compounds that inhibit the enzyme renin, and modulate activity of the renin-angiotensin system, and are effective for treating the diseases such as, eg hypertension.

7 cl, 141 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 4-[3-(4-cyclopropanecarbonyl-piperazin-1-carbonyl)-4-fluor-benzyl]-2H-phthalazin-1-one in the form of a crystalline form L having characteristic peaks on an X-ray powder diffraction pattern presented in the patent claim, to methods for preparing the form L, pharmaceutical formulation containing the form L, and versions of using the form L and formulations containing the form L.

EFFECT: preparing the new crystalline form of the above compound which possesses poly-(ADP)polymerase (PARP) inhibitory activity The form L contains no solvent impurities that enables more accurate dosage of the active compound when treating the patient.

17 cl, 4 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: biotechnology.

SUBSTANCE: polypeptides for the prevention or treatment of myocardial hypertrophy correspond to sequences of amino acids SEQ ID NO:2-3, 5-8. The composition for prevention or treatment of myocardial hypertrophy comprises a polypeptide corresponding to sequences of amino acids SEQ ID NO:2-3, 5-8, and pharmaceutically acceptable additives. The method of production of the said polypeptides comprises a step of synthesis of the polypeptide with the amino acid sequence SEQ ID NO:2-3, 5-8 in a synthesizer of polypeptides or ligation of the corresponding nucleotide sequence with the vector to form a recombinant vector, transformation of the said recombinant vector into a host cell, induction of expression of the said polypeptide in the said host cell, and isolating of the said polypeptide.

EFFECT: invention enables to produce new polypeptides for prevention or treatment of myocardial hypertrophy.

12 cl, 6 dwg, 9 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: present group of inventions refers to medicine, particularly to therapy and neurology, and concerns treating the patients with neurological disorders, cerebral infarction and myocardial infarction. That is ensured by introducing an effective amount of a composition containing 4 to 14 ingredients of plant and animal origin, such as locoweed root, salvia miltiorrhiza bunge root, red peony root, hemlock parsley rhizome, Gynura pinnatifida root, Chinese peony root bark, rosewood, dry scorpions, snakeroot, sweet flag rhizome, leeches, ground beetles, cow bezoar and one of the preparations used in western medicine for treating the above disorders, such as an antiaggregant, anticoagulant and/or neuroprotectant.

EFFECT: invention provides an effective treatment of the above pathological conditions due to the antioxidant, anti-inflammatory and apoptosis-reducing effect of the composition that in turn is accompanied by improving cell viability and neuron proliferation, as well as reduced tissue ischemia.

9 cl, 6 ex, 4 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

Novel composition // 2483716

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and deals with pharmaceutical composition, which includes dipeptidyl peptidase IV (DPPIV) inhibitor, preferably vildagliptin in amount from 1.5 to 20% and metformin in amount from 80 to 98.5%. Active ingredients constitute from 60 to 98% of composition. Cellulose or its derivatives in amount from 1 to 20% is used as binding agent. Also described is method of obtaining said composition.

EFFECT: novel composition is claimed.

47 cl, 7 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to DGAT inhibitor of formula (I), its N-oxide, pharmaceutically acceptable salt and solvate, based on it pharmaceutical composition and its application for treatment of diseases, mediated by DGAT activity, such as obesity and diabetes. In general formula (I) A represents CH or N; X represents -C (=O)-C(=O); -O-C(=O)-; -NRX-C(=O)-; -Z1-C(O)-; -Z1-NRx-C(O)-; -C(O)-Z1-; -NRx-C(O)-Z1-; -S(=O)p-; -NRX-C(=S) -; Y represents NRx-C(=O)-Z2-; -NRx-C(=O)-Z2-NRy-; -NR*-C(=O)-Z2-NRy-C(=O)-; -NRx-C(=O)-Z2-NRy-C(=O)-O-; -NRx-C(O)-Z2-O-; -NRx-C(=O)-Z2-O-C(=O)-; -NRx-C(=O)-Z2-C(=O)-O-; -NRx-C(=O)-Z2-C(=O)-NRy-; -NRx-C(=O)-Z2-NRy-C(=O)-NRy-, -C(<))-Z2-; -C(=O)-NRx-Z2-; -C(=O)-NRx-Z2-O-; R1 represents C1-12alkyl, optionally substituted with cyano, C1-4alkyloxy, C1-4alkyloxy C1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl, C2-6alkinyl; C3-6cycloalkyl; adamantanyl; aryl1; aryl1C1-6alkyl; Het1; or HetC1-6alkyl, on condition that when Y represents -NRxC(=O)-Z2-; -NRx-C(=O)-Z2-NRy; -NRx-C(=O)-Z2-C(=O)-NRy-, -C(=O)Z2-; -NRx-C(=O)-Z2-NRy-C(=O)-NRy-; -C(=O)-NRx-Z2-; -C(=O)-NRx-O-Z2- or -C(=O)-NRx-Z2-NRy-; then R1 can also represent hydrogen; R2 represents R3; R3 represents phenyl, naphthalenyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle, containing 1 or 2 N atoms, where each of said cycles can optionally be substituted with, at least, one substituent, in particular, one-five substituents, said substituents represent halogen, C1-6alkyl, optionally substituted with hydroxy, polyhalogen C1-6alkyl, C1-6alkylthio, polyhalogen-C1-6alkyloxy, carboxyl, hydroxyl, C1-6alkylcarbonyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, nitro, R5R4N-C(=O)-; R5R4N-C1-6alkyl; HetC1-4alkyl, Het-C(=O)-C1-4alkyl, Het-C(=O)-; R8 represents hydrogen, halogen, C1-4alkyl, substituted with hydroxyl Values of other radicals are given in invention formula.

EFFECT: obtaining pharmaceutical composition for treatment of diseases, mediated by DGAT activity, such as obesity and diabetes.

31 cl, 5 tbl, 352 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a product containing an insulin response. A method for producing the product containing the insulin response involving mixing at least one polyphenol-containing herbal material specified in a group consisting of fruit, vegetables, tea, green tea, coffee, cocoa, chocolate and bark, and at least aqueous edible solvent for making the mixture; heating said mixture; adding at least one lactic acid bacilli strain specified in Lactobacillus plantarum, and optionally at least one protein source specified in a group including peptones, tryptones, yeast extracts and their combinations to said heated mixture for making the fermented mixture; and exposing said fermented mixture to the conditions suitable for fermentation for making the product reducing the insulin response, and optionally eliminating the Lactobacillus plantarum strain. The use of the product reducing the insulin response for preparing a composition for preventing or treating diabetes, metabolic syndrome, obesity and cardiovascular diseases.

EFFECT: product prepared by the method described above effectively reduces the insulin response.

15 cl, 7 dwg, 11 tbl

FIELD: chemistry.

SUBSTANCE: compounds activate glucokinase and can be used to prepare medicine for treating of metabolic disorders, for lowering blood glucose level, for treating hyperglycemia, for treating IGT, for treating Syndrome X, for treating impaired fasting glucose (IFG), for treating type 2 diabetes, for treating type 1 diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for treating dyslipidemia, for treating hyperlipidemia, for treating hypertension, for lowering food intake, for appetite regulation, for for treating obesity, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins. In compounds of formula , A denotes , R3 is selected from a group consisting of phenoxy and benzyloxy, each possibly substituted with one or more substitutes independently selected from R12; R12 is F, CI, Br, -CF3, -CN methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH3 or -S(O)2-CH3; R30 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy or cyclopropyl-methoxy, each possibly substituted with one or more substitutes independently selected from R12; R8 is methylthio, isopropylthio, ethylthio or 2-methylpropylthio, each substituted with one or more substitutes independently selected from R34; R34 is carboxy.

EFFECT: improved properties of the compound.

13 cl, 1 tbl, 242 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology and can be used for reduction of hypoglycemia acute exacerbation or severe hypoglycemia exacerbation in patients with type II diabetes after treatment with insulin. For this purpose vildagliptin or its salt is introduces to patient in combination with insulin.

EFFECT: invention ensures reduction of risk of hypoglycemia development, as well as necessity to apply several antihyperglycemic medications.

12 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical industry and concerns a composition for glucose delivery through an oral mucosa for increasing of glucose (sugar) blood level of an individual. The composition contains: a. effective amount of glucose, b. effective amount of sodium glycocholate, c. effective amount of a pharmaceutically acceptable carrier; the composition it is free from additional active pharmaceutical agents.

EFFECT: development of the effective method for increasing glucose (sugar) blood level.

13 cl, 9 ex, 4 tbl, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: medicine.

SUBSTANCE: present invention concerns new, selectable hybrid polypeptides expressing at least two hormonal activities containing a first biologically active module of a peptide hormone covalently bonded with at least one additional biologically active module of the peptide hormone.

EFFECT: polypeptides can be used as agents for treatment and prevention of metabolic diseases and disorders associated with overweight.

19 cl, 6 dwg, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: described is an effective low-toxicity agent, which is methyl ether of 2-cyano-3,12-dioxo-18βH-olean-1(2),11(9)-dien-30-ic acid of formula (I): having anti-oxidant, anti-inflammatory, neuroprotective, hypolipidemic, hypocholesterolemic, hypoglycemic, hepatoprotective and immunosuppressive activity.

EFFECT: agent has low toxicity and is synthesised based on readily available plant material.

1 cl, 13 ex, 16 tbl

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