Stable pharmaceutical compositions and methods for using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a pharmaceutical composition used for treating or preventing a cardiovascular disease in an individual in need thereof and containing at least 95% ethyleicosapentaenoate (ethyl-EPA) encased in a capsule containing gelatine, glycerol, sorbitol, maltitol and purified water, wherein the composition has an initial peroxide number of no more than 5 mEq/kg and the second peroxide number of no more than 8 mEq/kg if stored at 25°C and relative humidity (RH) of 60% for 6 months.

EFFECT: invention refers to a method of treating or preventing the cardiovascular diseases involving administering a therapeutically effective amount of this composition into the individual in need thereof.

18 cl, 4 ex, 4 tbl, 3 dwg

 

The CLAIM TO PRIORITY

This application claims the priority of provisional patent application U.S. 61/173763, filed on April 29, 2009, the contents of which are fully incorporated into the present application by reference.

BACKGROUND of the INVENTION

Esters of mixtures of omega-3 fatty acids, as a rule, placed in gelatin capsules of the type 2a, including gelatin (~43,4%), glycerol (~20%) and water (~36.6 percent) that does not cause stability issues throughout the storage period. At the same time, to encapsulate reactive ingredients used chemically modified gelatin, for example succinycholine/succinylcholine gelatin, and the use of such derivatives gelatin has not received approval in the U.S. and other markets.

The INVENTION

The inventors have unexpectedly found that eicosapentaenoic acid (EPA) high purity are more susceptible to oxidative breakdown than the mixture of ethyl esters of omega-3 acids. In various embodiments implementing the present invention relates to pharmaceutical compositions comprising fatty acid or its derivative, encased in a shell of a capsule, which opposes, impedes, impairs or prevents the oxidation of fatty acid or a derivative of a fatty acid, for example, to a greater extent h is m it provides a standard capsule shell type IIa. In a related embodiment, among the fatty acids include eicosapentaenoic acid (EPA), or derivatives of EPA, such as the ethyl eicosapentaenoate (ethyl-EPA or E-EPA). In another embodiment, the number of fatty acids is an ultra-pure EPA.

In one of the embodiments the invention relates to a pharmaceutical composition comprising ultra-pure EPA, encapsulated in the shell of a capsule, where ultra-pure EPA has a source of peroxide number not more than 5 mEq/kg, and during storage of the composition at 23°C and 50% relative humidity for a certain period of time secondary peroxy number of ultra-pure EPA does not exceed about 20 mEq/kg

In other embodiments implementing the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure EPA), encapsulated in the shell of a capsule, comprising a film-forming material and a hygroscopic plasticizer, where the mass ratio of film-forming material and a hygroscopic plasticizer is not less than about 2.5:1. In addition, the capsule shell may optionally include non-hygroscopic plasticizer. In one of the embodiments, the capsule does not contain chemically modified gelatin, for example succinylamino or succinylcholine gelatin.

In another group of variationsummary the present invention relates to methods of treating or preventing diseases, associated with the cardiovascular system, using the compositions of the present invention.

These and other embodiments of the present invention will be more fully disclosed below in the text of the application.

A BRIEF description of the ILLUSTRATIVE MATERIAL

In Fig.1 shows the dissolution profile of the composition enclosed in a capsule of the present invention, containing ~500 mg E-EPA, compared with a composition containing EPA per capsule from succinylamino gelatin.

In Fig.2 shows the bioavailability 300 mg EPA capsules from succinylamino gelatin.

In Fig.3 shows the bioavailability of the composition in capsules AMR101 of the present invention, containing ~500 mg E-EPA.

DETAILED description of the INVENTION

Although it is possible embodiment of the present invention in various forms, the description below of several embodiments is made with the understanding that the present text should be considered as a description of typical embodiments of the invention, and it is not intended to limit the invention to the specific implementation options listed in the description. Sections of text created for convenience only, and should not be considered as any limitation of the scope of the invention. Embodiments of described in any of sections, can be combined with options for domestic who, given in any other sections.

It is believed that used in this application the numerical values describing different quantitative values, unless otherwise stated explicitly, are approximate, as if the minimum and maximum values specified ranges was preceded by the word "about". This can be applied to minor deviations from the specified values to achieve almost the same results as in the case of these quantities. In addition, the above ranges are continuous and include all values between the specified minimum and maximum value, as well as any ranges that can be formed such values. In addition, in the present description of the disclosed without exception, all ratio (and the ranges of these ratios) that can be obtained by dividing the numerical values on the other numerical values. Accordingly, the person skilled in the art will understand that many of these ratios, ranges, and ranges of ratios can be uniquely obtained from the above in the application of the numerical values, and in all cases these ratios, ranges, and ranges of ratios represent various embodiments of the present invention.

Polyunsaturated fatty acids

In one of the embodiments of the composition of the present invention comprise as an active ingredient of polyunsaturated fatty acids. In another embodiment, the compositions of the present invention comprise as an active ingredient EPA. The term "EPA" in this application refers to eicosapentaenoic acid (for example, eicosa-5,8,11,14,17-pentaenoic acid) and/or pharmaceutically acceptable esters, derivatives, conjugates or salts or mixtures of any of these compounds.

In one embodiment, the implementation of the EPA includes a fully-CIS eicosa-5,8,11,14,17-pontenova acid. In another embodiment, the EPA has the form of ether eicosapentaenoic acid. In the following embodiment, the EPA comprises C1-C5alkilany ether EPA. In another embodiment, the EPA comprises ethyl ester eicosapentaenoic acid, methyl ester eicosapentaenoic acid, propyl ester eicosapentaenoic acid or butyl ether eicosapentaenoic acid. In yet another embodiment, the EPA comprises ethyl ester completely CIS eicosa-5,8,11,14,17-pentaenoic acid.

In other embodiments, implementation of the EPA includes ethyl-EPA, EPA lithium salt, mono-, di - or triglycerides EPA, or any other esters or salts EPA, or EPA in the form of the free acid. EPA can so is e to be of the form 2-substituted derivative or other derivative, which has a lower oxidation rate, but no other significant changes in its biological action.

The term "pharmaceutically acceptable" in the context of the present invention means a substance designated by this term, does not have unacceptable toxicity to the subject and not interacting with other components of the composition.

In one embodiment, the implementation of the EPA, as part of the composition of the present invention, includes an ultra-pure EPA. The term "tube" as used in this application with respect to EPA, refers to compositions containing at least 96 wt.% EPA (where the term "EPA" defined and illustrated in the proposal). Ultra-pure EPA may include more pure EPA, for example, contains not less than 97 wt.% EPA or at least 98 wt.% EPA where EPA refers to any form of EPA described in the proposal. Ultra-pure EPA, you can optionally specify (for example, the profile of contamination) in accordance with any of the descriptions EPA stated in the text of the application.

In other embodiments, implementation of the EPA is present in the composition according to the present invention in an amount of from about 50 mg to about 5,000 mg, from about 75 mg to about 2500 mg, about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, CA the RNC 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, about 525 mg, about 550 mg, about 575 mg, about 600, about 625 mg, about 650 mg, about 675 mg, about 700 mg to about 725 mg, about 750 mg to 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 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg to about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg to 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, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, approximately 2175 mg, about 2200 mg, approximately 2225 mg to about 2250 mg, approximately 2275 mg, about 2300 mg, approximately 2325 mg, about 2350 mg, about 2375 mg, PR is about 2400 mg, approximately 2425 mg, about 2450 mg, approximately 2475 mg, or about 2500 mg

In various embodiments, implementation of EPA (e.g. E-EPA or ultra-pure E-EPA) can be one or more antioxidants. Non-limiting examples of suitable antioxidants include tocopherol, lecithin, citric acid and/or ascorbic acid. One or more antioxidants, if their presence is desirable, as a rule, are contained in EPA in the amount of from about 0.01% to about 0.1% by weight or from approximately 0.025% to about 0.05% by weight.

In one of the embodiments the composition according to the present invention in total contains not more than about 10 wt.%, not more than about 9 wt.%, no more than about 8 wt.%, no more than about 7 wt.%, no more than about 6 wt.%, no more than about 5 wt.%, no more than about 4 wt.%, no more than about 3 wt.%, no more than about 2 wt.%, no more than about 1 wt.%, not more than about 0.5 wt.% docosahexaenoic acid or its derivatives, for example, E-DHA, from the total amount of fatty acids, if DHA or its derivatives generally present in the composition. In another embodiment, the composition according to the present invention contains almost no docosahexaenoic acid or its derivatives, such as E-DHA. In yet another embodiment, the composition according to the present invention does not contain d is Kazakstani acid or E-DHA.

In another embodiment, the EPA is present in amount of at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.% or 100 wt.% from the total amount of all fatty acids present in the composition according to the present invention.

In another embodiment, the composition according to the present invention contains a total of less than 30 wt.%, less than 20 wt.%, less than 10 wt.%, less than 9 wt.%, less than 8 wt.%, less than 7 wt.%, less than 6 wt.%, less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.5 wt.% or less than 0.25 wt.% from the total mass of the composition or of the total fatty acids, any fatty acids that are not EPA or its derivatives. Illustrative examples of fatty acids that are not EPA include linoleic acid (LA) or its derivatives, for example Tillyaeva acid, arachidonic acid (AA) or its derivatives, for example ethyl-AA, docosahexaenoic acid (DHA) or its derivatives, for example ethyl-DHA, alpha-linolenic acid (ALA) or its derivatives, for example ethyl-ALA, stearidonic (6,9,12,15-octatetraene acid) (STA) or its derivatives, for example ethyl-STA, eicosatrienoic the Yu acid (ETA) or its derivatives, for example ethyl-ETA and/or docosapentaenoic acid (DPA) or its derivatives, for example ethyl-DPA.

In another embodiment, the composition according to the present invention has one or more of the following characteristics: (a) ethyl ester of eicosapentaenoic acid is at least 96 wt.%, at least 97 wt.% or at least 98 wt.% from all of the fatty acids in the composition; (b) the composition in total, contains not more than 4 wt.%, not more than 3 wt.% or not more than 2 wt.% fatty acids that are not ethyl ester of eicosapentaenoic acid; (c) the composition contains not more than 0.6 wt.%, 0.5 wt.% or 0.4 wt.% any individual fatty acid, which is not ethyl ester of eicosapentaenoic acid; (d) the composition has a refractive index (at 20°C) from about 1 to about 2, from about 1.2 to about 1.8, or from about 1.4 to about 1.5; (e) the composition has a density (at 20°C) from about 0.8 to about 1.0, from about 0.85 to about 0.95 to, or from about 0.9 to about 0,92; (f) the composition contains not more than 20, 15 or 10 parts per million of heavy metals; (g) the composition contains not more than 5, 4, 3 or 2 parts per million of arsenic compounds and/or (h) peroxide number of the composition is not more than 5, 4, 3 or 2 mEq/kg

In another embodiment, the composition is applicable in this image the shadow, includes, consists essentially of or consists of at least 95 wt.% the ethyl of eicosapentaenoate (EPA-E), from about 0.2 wt.% to about 0.5 wt.% the ethyl of octadecatetraenoic (ODTA-E), from about 0.05 wt.% up to about 0.25 wt.% the ethyl of nonacceptance (NDPA-E), from about 0.2 wt.% to about 0.45 wt.% ethyl arachidonate (AA-E), from about 0.3 wt.% to about 0.5 wt.% the ethyl of eicosatetraenoate (ETA-E) and from about 0.05 wt.% to about 0.32 wt.% ethylenediaminetetra (HPA-E). In another embodiment, the composition is placed in the shell of the capsule. In yet another embodiment, the capsule shell contains no chemically modified gelatin.

In the following embodiment, a composition applicable in the present invention, includes, consists essentially of or consists of at least 95, 96 or 97 wt.% the ethyl of eicosapentaenoate, from about 0.2 wt.% to about 0.5 wt.% the ethyl of octadecatetraenoic, from about 0.05 wt.% up to about 0.25 wt.% the ethyl of nonacceptance, from about 0.2 wt.% to about 0.45 wt.% ethyl arachidonate, from about 0.3 wt.% to about 0.5 wt.% the ethyl of eicosatetraenoate and from about 0.05 wt.% to about 0.32 wt.% the ethyl of genaratepreloader. Optionally, the composition contains not more than about 0.06 wt.%, about 0.05 wt.% or about 0.04 wt.% DHA or its derivatives, for example ethyl-DHA. In one of variationsummary composition does not contain or do not contain DHA or its derivatives, for example ethyl-DHA. In addition, the composition optionally includes one or more antioxidants (e.g. tocopherol) in an amount not exceeding about 0.5%, or not exceeding 0.05%. In another embodiment, the composition includes from about 0.05% to about 0.4%, for example, about 0.2 wt.% tocopherol. In another embodiment, from about 500 mg to about 1 g of the composition is enclosed in the shell of a capsule. In yet another embodiment, the capsule shell contains no chemically modified gelatin.

In the following embodiment, a composition applicable in the present invention, includes, consists essentially of or consists of at least 96 wt.% the ethyl of eicosapentaenoate, from about 0.22 wt.% up to about 0.4 wt.% the ethyl of octadecatetraenoic, from some of 0.075 wt.% to about 0.20 wt.% the ethyl of nonacceptance, from about 0.25 wt.% to about 0.40 wt.% ethyl arachidonate, from about 0.3 wt.% up to about 0.4 wt.% the ethyl of eicosatetraenoate and from some of 0.075 wt.% up to about 0.25 wt.% the ethyl of genaratepreloader. Optionally, the composition contains not more than about 0.06 wt.%, about 0.05 wt.% or about 0.04 wt.% DHA or its derivatives, for example ethyl-DHA. In one of the embodiments the composition does not contain or do not contain DHA or its derivatives, for example ethyl-DHA. Also, the composition optionally includes one or more antioxidants (e.g. tocopherol) in an amount not exceeding about 0.5%, or not exceeding 0.05%. In another embodiment, the composition includes from about 0.05% to about 0.4%, for example, about 0.2 wt.% tocopherol. In another embodiment, the invention relates to a dosage form, comprising from about 500 mg to about 1 g of the above composition in the shell of the capsule. In one embodiment, the implementation of this dosage form is a capsule containing a gel or liquid, which are Packed in blister packing from about 1 to about 20 capsules per leaf.

In yet another embodiment, the composition applicable in the present invention, includes, consists essentially of or consists of at least 96, 97, or 98 wt.% the ethyl of eicosapentaenoate, from about 0.25 wt.% to about 0.38 wt.% the ethyl of octadecatetraenoic, from about 0.10 wt.% to about 0.15 wt.% the ethyl of nonacceptance, from about 0.25 wt.% to about 0.35 wt.% ethyl arachidonate, from about 0.31 wt.% to about 0.38 wt.% the ethyl of eicosatetraenoate and from about 0.08 wt.% to about 0.20 wt.% the ethyl of genaratepreloader. Optionally, the composition contains not more than about 0.06 wt.%, about 0.05 wt.% or about 0.04 wt.% DHA or its derivatives, e.g. the ethyl-DHA. In one of the embodiments the composition does not contain or do not contain DHA or its derivatives, for example ethyl-DHA. In addition, the composition optionally includes one or more antioxidants (e.g. tocopherol) in an amount not exceeding about 0.5%, or not exceeding 0.05%. In another embodiment, the composition includes from about 0.05% to about 0.4%, for example, about 0.2 wt.% tocopherol. In another embodiment, the invention relates to a dosage form, comprising from about 500 mg to about 1 g of the above composition in the shell of the capsule. In another embodiment, this capsule shell contains no chemically modified gelatin.

In various embodiments implementing the invention relates to polyunsaturated fatty acid such as EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in a shell pharmaceutical capsules. In one of the embodiments, the capsule would prevent, impede, reduce or prevent oxidation of the fatty acid or derivative fatty acids. In another embodiment, the capsule would prevent, impede, reduce or prevent oxidation of the polyunsaturated fatty acid or its derivative to a greater extent than a standard gelatin capsule type IIa. In another VA who ianthe implementation capsule does not contain chemically modified gelatin, for example succinylamino, succinylamino, ftorirovannogo, carbonyliron and/or phenol carbonyliron gelatin.

In another embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of the capsules described in the present invention and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, moreover, during storage of the composition at 23°C and 50% relative humidity during the period, equal to about 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, secondary peroxy number of ultra-pure EPA does not exceed about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 22 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 mEq/kg, about 17 mEq/kg, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 m is HF/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

"The source of peroxide number" and "secondary peroxy number" can be measured in any suitable way, for example with the application of standard techniques U. S, PhEur or JP. As a rule, prepare a large number of the encapsulated compositions of the EPA, where each composition containing EPA, encapsulate approximately the same time. Immediately after producing from the received party select one or more of the capsules, the capsules open and measure the peroxide number EPA, receiving a secondary source of peroxide number. Around the same time from a common party selected a second group of samples consisting of one or more capsules, and put them in the desired storage conditions for the desired period of time. At the end of the desired period of time capsules open and almost immediately after that determine the peroxide number EPA, receiving the average value of the secondary peroxide number. Then you can compare the original and secondary peroxide numbers. In one variant of implementation "source of peroxide number" and "secondary peroxy number determined with the use of a large number of unit dosage forms encapsulated EPA, where each of the units to the new form of drug was encapsulated (i.e., the capsule was filled with EPA and sealed) within the same 60-day period, the same 30-day period, the same 20-day period, the same 10-day period, the same 5-day period or the same 1-day period.

In another embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of the capsules described in the present invention and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, moreover, during storage of the composition at 25°C and a relative humidity of 60% during the period, equal to about 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, secondary peroxy number of specified composition does not exceed about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 22 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 mEq/kg, about 17 mEq/kg, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

In the following embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of the capsules described in the present invention, and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, moreover, during storage of the composition at 30°C and a relative humidity of 65% during the period, equal to about 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, secondary peroxy number of specified composition does not exceed about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 22 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 mEq/kg, about 17 makuch, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

In the following embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of the capsules described in the present invention, and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, moreover, during storage of the composition at 40°C and a relative humidity of 75% during the period, equal to about 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, secondary peroxy number of specified composition does not exceed about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 22 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 makuch, about 17 mEq/kg, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

In yet another embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of a capsule, and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, where the capsule comprises a film-forming material and a plasticizer in a weight ratio of not less than about 1.75:1 and where during storage of the composition at 23°C and 50% relative humidity during the period, equal to about 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, secondary peroxy number of specified composition does not exceed about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 2 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 mEq/kg, about 17 mEq/kg, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

In another embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of a capsule, and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, where the capsule comprises a film-forming material and a plasticizer in a weight ratio of not less than about 1.75:1 and where during storage of the composition at 25°C and a relative humidity of 60% during the period, equal to about 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, secondary peroxy number of specified composition will not exceed Iset about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 22 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 mEq/kg, about 17 mEq/kg, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

In the following embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of a capsule, and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, where the capsule comprises a film-forming material and a plasticizer in a weight ratio of not less than about 1.75:1 and where during storage of the composition at 30°C and a relative humidity of 65% during the period, equal to about 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, who am, secondary peroxy number of specified composition does not exceed about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 22 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 mEq/kg, about 17 mEq/kg, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

In yet another embodiment, the invention relates to pharmaceutical compositions comprising EPA (e.g. E-EPA or ultra-pure E-EPA), encapsulated in the shell of a capsule, and having a source of peroxide number of less than about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg, where the capsule comprises a film-forming material and a plasticizer in a weight ratio of not less than about 1.75:1 and where during storage of the composition at 40°C and a relative humidity of 75% during the period, equal to about 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, which is but 18, about 19, about 20, about 21, about 22, about 23 or about 24 months, secondary peroxy number of specified composition does not exceed about 25 mEq/kg, about 24 mEq/kg, about 23 mEq/kg, about 22 mEq/kg, about 21 mEq/kg, about 20 mEq/kg, about 19 mEq/kg, about 18 mEq/kg, about 17 mEq/kg, about 16 mEq/kg, about 15 mEq/kg, about 14 mEq/kg, about 13 mEq/kg, about 12 mEq/kg, about 11 mEq/kg, about 10 mEq/kg, about 9 mEq/kg, about 8 mEq/kg, about 7 mEq/kg, about 6 mEq/kg, about 5 mEq/kg, about 4 mEq/kg, about 3 mEq/kg or about 2 mEq/kg

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label number (i.e., the original number) of EPA or E-EPA, where in the case of storage of the composition at 23°C and 50% relative humidity during the period, equal to about 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, the composition contains at least about 97 wt.%, about 98 wt.%, approximately 99 m is SS.%, about 99.5 wt.%, about 99.7 wt.%, about 99.9 wt.% or almost all, or 100 wt.% specified on the label the amount of EPA or E-EPA.

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label number (i.e., the original number) of EPA or E-EPA, where in the case of storage of the composition at 25°C and a relative humidity of 60% during the period, equal to about 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, the composition contains at least about 97 wt.%, about 98 wt.%, about 99 wt.%, about 99.5 wt.%, about 99.7 wt.%, about 99.9 wt.% or almost all, or 100 wt.% specified on the label the amount of EPA or E-EPA.

In the following embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where in the case of storage of the composition at 30°C and a relative humidity of 65% during the period, equal to about 1, primer is 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, the composition contains at least about 97 wt.%, about 98 wt.%, about 99 wt.%, about 99.5 wt.%, about 99.7 wt.%, about 99.9 wt.% or almost all, or 100 wt.% specified on the label the amount of EPA or E-EPA.

In yet another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where in the case of storage of the composition at 40°C and a relative humidity of 75% during the period, equal to about 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, the composition contains at least about 97 wt.%, about 98 wt.%, about 99 wt.%, about 99.5 wt.%, about 99.7 wt.%, about 99.8 wt.%, about 99.9 wt.% or almost all, or 100 wt.% indicated on the labels to the number of EPA or E-EPA.

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA containing specified on the label the amount of EPA or E-EPA, where during storage of the composition at 23°C and 50% relative humidity during the period, equal to about 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, the composition contains not more than about 0.5%, less than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products. The term "decay product" in the context of this application means "impurity resulting from a chemical transformations in the composition that occurred during the production and/or storage of the composition under the action of, for example, light, temperature, pH, or water in the reaction with excipients and/or because of a system emergency closure of the container. The term "specified decay product" in the context of this application means "decay product, identified or neidentificata the tion, which is individually listed and limited to specific eligibility criteria in the product specification for this product.

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where during storage of the composition at 25°C and a relative humidity of 60% during the period, equal to about 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, the composition contains not more than about 0.5%, less than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where during storage of the composition at 30°C and a relative humidity of 65% during the period, equal to about 1 or, 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, no more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where during storage of the composition at 40°C and a relative humidity of 75% during the period, equal to about 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, not more than p is kerno to 0.15%, no more than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where the capsule contains a film-forming material, a hygroscopic plasticizer and a non-hygroscopic plasticizer and during storage of the composition at 23°C and 50% relative humidity during the period, equal to about 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, not more than approximately 0.05% or contains almost no degradation products and/or specified degradation products.

In another embodiment, the invention relates to pharmaceutical compositions, including in kapsulirovannyh EPA (for example, E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where the capsule contains a film-forming material, a hygroscopic plasticizer and a non-hygroscopic plasticizer and during storage of the composition at 25°C and a relative humidity of 60% during the period, equal to about 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In the following embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where the capsule contains a film-forming material, a hygroscopic plasticizer and a non-hygroscopic plasticizer and during storage of the composition at 30°C and 65% relative humidity for a period equal to p is kerno 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, no more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In yet another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where the capsule contains a film-forming material, a hygroscopic plasticizer and a non-hygroscopic plasticizer and during storage of the composition at 40°C and a relative humidity of 75% during the period, equal to about 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, the specified com is azizia contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), no more than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where the capsule contains a film-forming material and a plasticizer in a weight ratio of from about 2.5:1 to about 10:1 and during storage of the composition at 23°C and 50% relative humidity during the period, equal to about 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, no more than about 0.05% or contains almost no degradation products and/or specified degradation products.

In another embodiment, the invention relates the I to the pharmaceutical composition, comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing the specified label number EPA, where the capsule contains a film-forming material and a plasticizer in a weight ratio of from about 2.5:1 to about 10:1 and during storage of the composition at 25°C and a relative humidity of 60% during the period, equal to about 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, not more than approximately 0.05% or contains almost no degradation products and/or specified degradation products.

In the following embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where the capsule contains a film-forming material and a plasticizer in a weight ratio of from about 2.5:1 to about 10:1 and during storage of the composition at 30°C and relative activities is Noah humidity of 65% during the period, equal to about 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, the composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), not more than about 0.25%of not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In yet another embodiment, the invention relates to a pharmaceutical composition comprising encapsulated EPA (e.g. E-EPA or ultra-pure E-EPA) containing specified on the label the amount of EPA or E-EPA, where the capsule contains a film-forming material and a plasticizer in a weight ratio of from about 2.5:1 to about 10:1 and during storage of the composition at 40°C and a relative humidity of 75% during the period, equal to about 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 mosalam, this composition contains not more than about 0.5% (by weight of the specified amount of EPA or E-EPA), less than about 0.25 per cent, not more than approximately 0.15%, less than about 0.125 per cent, not more than about 0.1%, less than about 0,075%, less than about 0.05% or contains almost no degradation products and/or specified degradation products.

In another embodiment, the present invention relates to pharmaceutical compositions comprising from about 0.5 grams to about 1.5 grams of EPA (e.g. E-EPA or ultra-pure E-EPA), where the specified amount of EPA or E-EPA encapsulated in the pharmaceutical capsule, and in the case of storage at a temperature of from 15°C to 30°C over a period of approximately 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, at least about 97%, about 98%, about 99%, approximately 99.5%, about 99.6% and about 99.7% with about 99,8%, about 99.9 percent or nearly all of the specified number EPA is still present in the composition. In a related embodiment, for a specified period of storage of the composition is not achieved date expiration date indicated on the package.

In various embodiments, the implementation of the capsule shell, suitable for use in the present invention, includes one or more film-forming materials, one or more plasticizers and, optionally, a solution of the tel (for example, water). In a related embodiment, the film-forming material comprises gelatin. In another embodiment, the plasticizer comprises a hygroscopic and/or non-hygroscopic plasticizer. In yet another embodiment, the capsule shell consists of film-forming material, a hygroscopic plasticizer, non-hygroscopic plasticizer and a solvent.

In another embodiment, the capsule shell comprises from about 30 wt.% to about 70 wt.% or from about 40 wt.% to about 65 wt.% film-forming material, from about 15 wt.% to about 40 wt.% or from about 20 wt.% to about 35 wt.% one or more plasticizers and from about 3 wt.% to about 15 wt.% or from about 5 wt.% up to about 10 wt.% solvent, such as water. Capsules, optionally, may also contain additives, such as dyes, flavoring additives, preservatives, dezintegriruetsja tools, surfactants, flavors, sweeteners, etc.

Capsules suitable for use in various embodiments, implementation of the present invention include film-forming material such as gelatin. Gelatin is usually produced from by-products of animal origin that contain collagen, for example, bone, skin and connective tissue. Ways to get gelatin from animal offal is all right known in the art. In various embodiments, the implementation of the gelatin may be a gelatin, obtained by alkaline treatment, gelatin obtained by acid treatment, a chemically modified gelatin or mixtures thereof. Methods of obtaining gelatin during alkaline treatment, acid treatment, as well as chemically modified gelatin known in the art and described, for example, in the application Nakamura et al., U. S. 2003/0195246 fully incorporated into the present application by reference.

Film-forming materials may also include, for example, hydrocolloids not of animal origin, such as carrageenan, ethers alkilirovanny or hydroxyacetylamino cellulose, starch, alpha-starch, hydroxyalkyl starch, sodium alginate, sodium salt of a copolymer of gelatin and acrylic acid.

In another embodiment, the film-forming material can include a mixture with a mass ratio of from 20:80 to about 80:20, for example a mixture with a mass ratio of 60:40 hydroxypropylmethylcellulose and polyvinyl alcohol (for example, saponified approximately 70-90%, for example approximately 88,0%; and having a viscosity of from about 30 to about 50, for example about 45,0 CP). In another embodiment, the film-forming material can include a mixture with a mass ratio of from 20:80 to about 80:20, for example from the masses is the best ratio of 60:40, hydroxyethyl cellulose and polyvinyl alcohol (for example, saponified about 70-99,9%, for example approximately 98.5%; and having a viscosity of from about 2 to about 30, for example about 5.5 centipoise).

Suitable capsule shell may optionally be included as an integral part of the film-forming material is a gel filler that reduces the elasticity. Gel filler that reduces elasticity, may include starch, starch derivatives such as starch with a high amylose content, oxidized starch esters, starch, starch, starch, treated with acid, ethers, starch, hydrolyzed starch, hydrolyzed and hydrogenated starch, the starch is treated with enzymes and modified cellulose or other natural or modified natural biopolymers, such as bacterial polysaccharides, vegetable gums or other selection of plants, including alginates, carrageenan, guar gum, gum Arabic, gum, ghatti, gum karaya, gum tragakant, pectins, gum tamarind, xanthan gum and dextrans, and synthetic polymers, for example polymers with carbon chain vinyl and acrylic type, or chains containing heteroatoms, such polyoxide or polyamines including polyethylene oxide, polypropyleneoxide, polyoxyl the ilen, polytrimethylene, block copolymers of ethylene oxide, block copolymers of polyethylene oxide, polivinilbutilovy ether, polyethylenimine, polyacrylic acid, polyacrylamide, polymethacrylic acid, polymethacrylamide, poly(N,N-dimethylacrylamide), poly(N-izopropilakrilamid), poly(N-acrylamid), poly(N-methacrylamide), acrylic copolymers, polyvinyl acetate-polyvinyl alcohol, a copolymer of polyvinyl acetate and vinyl alcohol, polyvinylpyrrolidone, N-organic N-ethylpyrrolidin, N-vinyl pyrrolidone, sarcosinates anhydride, polivinilatsetalnye and polyvinylpyrrolidon. Starch or other gel fillers that reduce the elasticity, can be added to the composition in amounts from about 8% to about 30% by weight, for example from about 10% to about 16% by weight.

Shell capsules, suitable for use in various embodiments, implementation of the present invention may include one or more plasticizers, such as hygroscopic and/or hygroscopic plasticizers. Non-limiting examples of suitable hygroscopic plasticizers include glycerin, sorbitol and alkalophile (for example, propylene glycol and polyethylene glycols of low molecular weight). Non-limiting examples of suitable non-hygroscopic plasticizers include partially digidrirovanny of hereroland the th glucose syrup, ▫ maltitol, maltose, lactic, xylitol, aritra and polyethylene glycols with an average molecular weight from about 400 to about 6000.

In one of the embodiments, the mass ratio of hygroscopic and non-hygroscopic plasticizer plasticizer in the capsule shell, suitable for use in compositions of the present invention, is from about 1:1 to about 8:1, from about 2:1 to about 6:1, from about 3:1 to about 5:1, for example about 4:1, approximately 4,25:1, about 4.5:1, or approximately of 4.75:1.

In another embodiment, the mass ratio of gelatin and glycerin in the shell of a capsule suitable for use in compositions of the present invention, is from about 2.5:1 to about 10:1, from about 3.5:1 to about 9:1, from about 4:1 to about 8:1, from about 5:1 to about 7:1, for example, at least about 2.6:1, at least about 2.7:1, at least about 2.8:1, at least about 2.9:1, at least about 3:1, at least about 3.1:1, at least about 3.2:1, at least about 3.3:1, at least about 3.4:1, at least about 3.5:1, at least about 3.6:1, at least about 3.7:1, at least about 3.8:1, at least about 3.9:1, at least about 4.0:1, at least about 4,1:1, at least about 4.2:1, at least about a 4.3:1, at least, the example is about a 4.4:1, at least about 4.5:1, at least about 4.6:1, at least approximately 4.7:1, at least about 4.8:1, at least about 4.9:1, at least about 5,0:1, at least approximately 5.1:1, or at least approximately 5.2:1.

In another embodiment, the ratio of the mass of film-forming material (e.g., gelatin) to the total weight of the plasticizer in a suitable enclosure of the capsule is from about 1.75 to about 5, from about 1,78 up to about 3 or from about 1.8 to about 2.5, for example, at least about 1,76 at least about 1,77 at least about 1,78 at least about 1,79 at least about 1,80, at least about 1,81 at least about 1,82, at least about 1.83 or at least about 1,84.

In yet another embodiment, the shell of a capsule according to the present invention: (1) the mass ratio of gelatin and glycerin is from about 2.5:1 to about 10:1, from about 3.5:1 to about 9:1, from about 4:1 to about 8:1, from about 5:1 to about 7:1, for example, at least about 2.6:1, at least about 2.7:1, at least about 2.8:1, at least about 2.9:1, at least about 3:1, at least about 3.1:1, at least about 3.2:1, at least about 3.3:1, at least about 3.4:1, at least about 3.5:1, at least about 3.6:1, at least about 3.7:1, at least primerno,8:1, at least about 3.9:1, at least about 4.0:1, at least about 4,1:1, at least about 4.2:1, at least about a 4.3:1, at least about 4.4:1, at least about 4.5:1, at least about 4.6:1, at least approximately 4.7:1, at least about 4.8:1, at least about 4.9:1, at least about 5,0:1, at least approximately 5.1:1, or at least approximately 5.2:1 and/or (2) the ratio of the mass of gelatin and the total mass of the plasticizer is from around 1.75:1 to about 5:1, from about 1,78:1 to about 3:1 or from about 1.8:1 to about 2.5:1, for example at least approximately to 1.76:1, at least about 1,77:1, at least about 1,78:1, at least about 1,79:1, at least about 1.8:1, at least about 1,81 at least about 1,82, at least about 1.83 or at least about 1,84.

In one embodiment, the implementation of the capsule shell comprises one or more of the following components: gelatin in an amount of from about 50 wt.% to about 70 wt.%; glycerin in an amount of from about 5 wt.% to about 15 wt.%; sorbitol in an amount of from about 15 wt.% to about 25 wt.%; and/or ▫ maltitol in an amount of from about 3 wt.% up to about 10 wt.% of the mass of the nonaqueous components. This capsule can also include from about 2 wt.% to about 16 wt.% solvent, such as water.

In another variant implementation, the surveillance capsule shell, suitable for use in the compositions of the present invention, can be obtained with the use of gel mass which includes from about 40 wt.% to about 50 wt.% gelatin, from about 2 wt.% to about 12 wt.% glycerin, from about 10 wt.% up to about 20 wt.% solution of sorbitol, from about 2 wt.% up to about 10 wt.% syrup maldita, and from about 20 wt.% to about 35 wt.% water. In one embodiment, the implementation of the capsule shell, suitable for use in the compositions of the present invention, can be obtained with the use of gel mass containing about 45 wt.% gelatin, about 7 wt.% glycerin, about 17 wt.% solution of sorbitol (for example, 30% water), about 6 wt.% syrup maldita (for example, 15%-32% of water), and about 25 wt.% water. Capsules obtained from such a gel mass may be dried to a final moisture content from about 2% to about 12%. The capsules thus obtained, which contain EPA (e.g. E-EPA or ultra-pure E-EPA) and methods of their use in the treatment of diseases associated with the cardiovascular system, represent another group of embodiments of the present invention. The composition of the capsules described in this application can optionally include a coating, for example, from enteric polymer or wax coating.

In one variant the implementation of the composition according to the present invention provides a relatively fast dissolution profile, while maintaining excellent stability of the encapsulated substances (e.g., EPA). In a related embodiment, the composition according to the present invention has a dissolution profile (data on the device for the study of dissolution in the rotating dialysis cell (RDC) under the conditions described below), characterized by one or more of the following options: (1) at least about 20%, at least about 23%, or at least about 25% E-EPA is dissolved within 10 minutes; (2) at least about 45%, at least about 50% or at least about 55% E-EPA is dissolved within 30 minutes; (3) at least about 80%, at least about 82%, or at least about 85%, or at least about 87% E-EPA is dissolved within 60 minutes; and/or (4) at least about 95%, at least about 97%, or 100% E-EPA is dissolved in 100 minutes. In a related embodiment, the filler capsule continues to maintain its stability, peroxide number, given in the text of this specification.

In another embodiment, the composition according to the present invention provides a relatively short Tmaxwhile maintaining excellent stability of the encapsulated substances (e.g., EPA). In a related embodiment, the composition according to the present invention with the introduction of the su is the target shows T maxfor EPA less than 6 hours, less than, 5.8 hours, less than 5.6 hours, less than 5.4 hours or less 5.2 hours, for example from about 4.8 hours to approximately 5.2 hours. In a related embodiment, the filler capsule continues to maintain its stability, peroxide number, given in the text of this specification.

In one of the embodiments the invention relates to a method of treatment and/or prevention of diseases associated with the cardiovascular system, with the use described in the application of the composition. The term "disease associated with the cardiovascular system" refers in this application to any disease or disorder of the heart or blood vessels (i.e., arteries and veins) or to any symptom of such disease. The term "disease associated with the cardiovascular system" in this application refers to any disease or disorder of the heart or blood vessels (i.e., arteries or veins) or any symptom of such disease, or any disease or condition that causes cardiovascular disease or encourages it. Non-limiting examples of cardiovascular and related diseases include acute cases of cardiac ischemia, acute myocardial infarction, angina, chest pectoris, arrhythmia, atrial fibrillation, atherosclerosis, arterial fibrillation,heart failure, cardiovascular disease, chronic heart disease, chronic stable angina, congestive heart failure, coronary artery disease, coronary heart disease, deep vein thrombosis, diabetes, diabetes mellitus, diabetic neuropathy, diastolic dysfunction in subjects with diabetes, edema, primary arterial hypertension, pulmonary embolism, fatty liver, heart disease, heart failure, homozygous familial hypercholesterolemia (HoFH), homozygous familial sitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia in HIV-positive subjects, hypertension, hypertriglyceridemia, ischemic complications in unstable angina and myocardial infarction, low blood pressure, metabolic syndrome, mixed dyslipidaemia, heart failure, mild to moderate, myocardial infarction, treatment of obesity, paroxysmal atrial/arterial fibrillation/fibrillation paroxysmal supraventricular tachycardia (PSVT), edema in severe or rapidly evolving form, platelet aggregation, primary hypercholesterolemia, primary hyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension, recurrent hemodynamically unstable ventricular, tachycardia is (VT), recurrent ventricular arrhythmia, recurrent ventricular fibrillation (VF), ruptured aneurysm, sitosterolemia, stroke, supraventricular tachycardia, symptomatic atrial/atrial fibrillation, tachycardia, type II diabetes, vascular diseases, venous thrombosis, ventricular fibrillation and other cardiovascular diseases.

The term "treatment" in relation to a given disease or disorder includes, but is not limited to, suppression of the disease or disorder, for example the termination of development of the disease or disorder; the alleviation of diseases or disorders, for example by initiating reverse the disease or disorder; or alleviating a condition caused or resulting from the disease or disorder, such as relief, prevention or treatment of symptoms of the disease or disorder. The term "prevention" in relation to a given disease or disorder means: preventing the onset of disease, if it had not been observed previously, preventing diseases or disorders in a subject which may be predisposed to this disorder or disease, but which until now has not been diagnosed with this illness or disease, and/or prevent further development is Alemania/disorder if it already exists.

In one of the embodiments the present invention relates to a method of improving the lipid composition of the blood, including the introduction of a subject or group of subjects, if necessary, the pharmaceutical compositions described in this application. In another embodiment, the subject or group of subjects include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/or very high levels of triglycerides.

In another embodiment, subjected to treatment of a subject or group of subjects has a source level of triglycerides (or average initial level of triglycerides in the case of a group of subjects) after a meal or on an empty stomach, not less than about 300 mg/DL, not less than about 400 mg/DL, not less than about 500 mg/DL, not less than about 600 mg/DL, not less than about 700 mg/DL, not less than about 800 mg/DL, not less than about 900 mg/DL, not less than about 1000 mg/DL, not less than about 1100 mg/DL, not less than about 1200 mg/DL, not less than about 1300 mg/DL, not less than about 1400 mg/DL, not less than about 1500 mg/DL, for example, from about 400 mg/DL to about 2500 mg/DL, from about 450 mg/DL to about 2000 mg/DL, or from about 500 mg/DL to about 1500 mg/DL.

In another embodiment, the subject or group of subjects who are treated with methods of the present invention, is anee were subjected to treatment with Lovaza® and they have increased or did not decrease the levels of LDL-C and/or non-HDL-C. In one of these embodiments cease therapy with the use of Lovaza® and override its method of treatment according to the present invention.

In another embodiment, the subject or group of subjects who are exposed to the treatment method according to the present invention, show the original absolute level of free EPA in plasma shock (or the average value of this level in the case of a group of subjects), no more than about 0.70 nmol/ml, not more than about of 0.65 nmol/ml, not more than about of 0.60 nmol/ml, not more than about 0.55 nmol/ml, not more than about 0.50 nmol/ml, no more than about 0.45 nmol/ml, or not more than about 0.40 nmol/ml In another embodiment, the subject or group of subjects who are exposed to the treatment method according to the present invention, demonstrate the initial level of free EPA in plasma shock (or the average value of this level), expressed as a percentage of the total content of free fatty acids, less than about 3%, no more than about 2.5%, less than about 2%, no more than about 1.5%, less than about 1%, no more than about 0.75%, not more than about 0.5%, no more than about 0.25 per cent, not more than approximately 0.2% or no more than approximately 0.15%. In one of these embodiments, the content of free EPA in plasma and/or the total content of fatty acids determined before therapy.

In another embodiment, when bject or group of subjects, which are subject to treatment by the methods of the present invention, demonstrate the source of absolute total content of fatty acids in the plasma of fasting (or the average value of this parameter) is not more than about 250 nmol/ml, not more than about 200 nmol/ml, less than about 150 nmol/ml, not more than about 100 nmol/ml, or not more than about 50 nmol/ml

In another embodiment, the subject or group of subjects who are treated with methods of the present invention, demonstrate the initial level of EPA in plasma, serum or plasma membrane of red blood cells on an empty stomach no more than about 70 μg/ml, less than about 60 μg/ml, less than about 50 μg/ml, less than about 40 μg/ml, less than about 30 μg/ml or less than about 25 mg/ml

In the following embodiment, the methods of the present invention include phase measurement of the initial lipid profile of a subject (or the average for a group of subjects) before starting therapy. In another embodiment, the methods of the present invention include the stage of identification of the subject or group of subjects having one or more of the following parameters: baseline non-HDL-C from about 200 mg/DL to about 400 mg/DL, for example not less than about 210 mg/DL, not less than about 220 mg/DL, not less than about 230 mg/DL, not less than about 240 mg/is l, not less than about 250 mg/DL, not less than about 260 mg/DL, not less than about 270 mg/DL, not less than about 280 mg/DL, not less than about 290 mg/DL, or at least about 300 mg/DL; initial total cholesterol level from about 250 mg/DL to about 400 mg/DL, for example not less than about 260 mg/DL, not less than about 270 mg/DL, not less than about 280 mg/DL, or at least about 290 mg/DL; the initial level of vLDL-C from about 140 mg/DL to about 200 mg/DL, for example not less than about 150 mg/DL, not less than about 160 mg/DL, not less than about 170 mg/DL, not less than about 180 mg/DL or at least about 190 mg/DL; baseline HDL-C from about 10 to about 60 mg/DL, for example not more than about 40 mg/DL, less than about 35 mg/DL, less than about 30 mg/DL, no more than about 25 mg/DL, not more than about 20 mg/DL, or less than about 15 mg/DL; and/or baseline LDL-C from about 50 to about 300 mg/DL, for example not less than about 100 mg/DL, not less than about 90 mg/DL, not less than about 80 mg/DL, not less than about 70 mg/DL, not less than about 60 mg/DL or at least about 50 mg/DL.

In one of the embodiments of the composition of the present invention Packed in blister packaging. In another embodiment, the blister pack include PCTFE (polychlorotrifluoroethylene) (for example, 50 μm), transparent PVC laminated (for example, 190 μm) using a sticky substance on the water is again, which thermally sealed with aluminum foil.

In a related embodiment, when the treatment method according to the present invention, for example, during the period of from about 1 to about 200 weeks, from about 1 to about 100 weeks, from about 1 to about 80 weeks, from about 1 to about 50 weeks, from 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, from about 1 to about 5 weeks, from about 1 to about 2 weeks or about 1 week, the subject or group of subjects demonstrates one or more of the following results:

(a) reducing the level of triglycerides compared to baseline or the parallel group receiving placebo;

(b) reduced levels of Apo B compared with the initial level or parallel group receiving placebo;

(c) increasing levels of HDL-C compared to baseline levels or parallel group receiving placebo;

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

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

(f) reducing the levels of non-HDL-C compared to baseline levels or parallel group, receive the lice placebo;

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

(h) increasing levels of apo A-I compared with the original level or parallel group receiving placebo;

(i) an increase in the ratio of apo A-I/apo B compared with the initial level or parallel group receiving placebo;

(j) reducing levels of lipoprotein A in comparison with the initial level or parallel group receiving placebo;

(k) a reduction in the number of LDL particles compared with the initial level or parallel group receiving placebo;

(l) the increase in the average size of LDL compared with the initial level or parallel group receiving placebo;

(m) the reduction remantic (residual) particles of cholesterol compared to baseline levels or parallel group receiving placebo;

(n) reducing the oxidized LDL compared with the initial level or parallel group receiving placebo;

(o) no change or a decrease in the level of plasma glucose fasting (FPG) compared to baseline or the parallel group receiving placebo;

(p) reduction of hemoglobin A1c(HbA1ccompared with the initial level or parallel group receiving placebo;

(q) the reduction results in a homeostatic model of insulin resistance compared to IP the one level or parallel group, placebo;

(r) reduction of lipoprotein-associated phospholipase A2 in comparison with the initial level or parallel group receiving placebo;

(s) lower levels of intracellular adhesion molecule-1 compared to the baseline level or the parallel group receiving placebo;

(t) lower levels of interleukin-6 in comparison with the initial level or parallel group receiving placebo;

(u) lower levels of inhibitor-1 plasminogen activator compared with the initial level or parallel group receiving placebo;

(v) reduction results highly sensitive analysis of C-reactive protein (hsCRP) in comparison with the initial level or parallel group receiving placebo;

(w) increasing levels of EPA in serum phospholipids compared with the initial level or parallel group receiving placebo;

(x) the increase in the content of EPA in the membrane of red blood cells compared with the initial level or parallel group receiving placebo;

(y) decrease or increase in the levels of phospholipids in the serum and/or red blood cells of one or more of the following substances docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic acid (PA), stearidonic acid (SA) or oleic acid (OA) is compared with the initial level or parallel group, receiving placebo.

In one of the embodiments of the methods of the present invention include the measurement of initial level of one of more markers listed above in paragraphs.(a)-(y) before the introduction of the composition to a subject or group of subjects. In another embodiment, these methods include the introduction of the subject compositions of the present invention once the initial levels of one or more markers listed in paragraphs.(a)-(y), with the subsequent implementation of the additional dimensions of the specified one or more tokens.

In another embodiment, when the treatment composition of the present invention, for example, during the period of from about 1 to about 200 weeks, from about 1 to about 100 weeks, from about 1 to about 80 weeks, from about 1 to about 50 weeks, from 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, from about 1 to about 5 weeks, from about 1 to about 2 weeks or about 1 week, the subject or group of subjects 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, Luba is 12 or more, any 13 or more, 14 or any more, any 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 the above results (a)-(y).

In the following embodiment, when the treatment composition of the present invention the subject or group of subjects demonstrates one or more of the following results:

(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%, at least about 55% or at least approximately 75% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(b) less than 30% increase, less than 20% increase, less than 10% increase less than 5% increase or no increase in the levels of non-HDL-C, or reducing levels of non-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 primer is 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 75% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(c) the almost complete absence of 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% or at least about 75% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(d) less than 60% increase, less than 50% increase, less than 40% increase, less than 30% increase, less than 20% increase, less than 10% increase less than 5% increase or no increase levels of LDL-C or reduction 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 what and 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(e) reducing the levels of Apo B, 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 approximately 75% (specific % change or average % change) compared to baseline or the parallel group receiving 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% (specific % changes or average % change) compared to baseline or the parallel group receiving placebo;

(g) increasing levels of apo A-I, at least about 5%, at least about 10%, at least about 15%, at least about 20%, the AK 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(h) increasing the ratio of apo A-I/apo B, 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 approximately 100% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(i) reducing the 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% (specific % changes or average % change) compared to baseline or the parallel group receiving placebo;

(j) a reduction in the number of LDL particles, 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(k) the increase in the average size of LDL particles, 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% (specific % changes or average % change) compared to baseline or the parallel group receiving placebo;

(l) reducing remantic (residual) cholesterol particles, 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(m) is the reduced levels of oxidized 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% (specific % change or average % change) compared to the original or the parallel group receiving placebo;

(n) the almost complete absence of change, no change or a 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(o) the almost complete absence of change, no change or a decrease in hemoglobin A1c(HbA1c) 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%, to the to a minimum, about 45% or at least about 50% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(p) the reduction factor in the homeostatic model of insulin resistance, 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(q) reduction of lipoprotein-associated phospholipase A2, 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(r) lower levels of intracellular adhesion molecule-1, at least about 5%, at least about 10%, at least about 15%, at least note the RNO 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(s) lower levels of 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 about 50% or at least about 100% (specific % changes or average % change) compared to baseline or the parallel group receiving placebo;

(t) lower levels of inhibitor-1 plasminogen activator, 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(u) the reduction results vysokochuvstvitel the analysis of 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% (specific % change or average % change) compared to the original or the parallel group receiving placebo;

(v) the increase in the content of EPA in serum, plasma 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(w) increasing levels of EPA in serum phospholipids and/or the membrane of red blood cells, 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 PR is about 50%, at least about 100%, at least about 200%, or at least about 400% (specific % change or average % change) compared to baseline or the parallel group receiving placebo;

(x) a reduction or increase in the levels of phospholipids in the serum and/or red blood cells of one or more of the following substances DHA, DPA, AA, PA and/or OA, 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% (specific % change or average % change) compared to baseline or the parallel group receiving placebo; and/or

(y) the reduction of 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 approximately 75% (specific % change or average % change) compared to baseline or the parallel group receiving placebo./p>

In one of the embodiments of the methods of the present invention include the measurement of initial levels of one or more of the markers described above in paras.(a)-(y), before the introduction of the compositions of the present invention to a subject or group of subjects. In another embodiment, these methods include the introduction of the subject disclosed in this application of the composition after determining the baseline levels of one or more of the markers described in paras.(a)-(y), with the subsequent implementation of re-measuring one or more markers that have been measured source level, in order to compare with him.

In another embodiment, when the treatment composition of the present invention, for example, during the period of from about 1 to about 200 weeks, from about 1 to about 100 weeks, from about 1 to about 80 weeks, from about 1 to about 50 weeks, from 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, from about 1 to about 5 weeks, from about 1 to about 2 weeks or about 1 week, the subject or group of subjects 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 bol is e, 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, 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 the above results (a)-(y).

Options (a)-(y) can be measured by any clinically acceptable method. For example, for the determination of triglycerides, total cholesterol, HDL-C and fasting blood sugar can be extracted serum sample and to carry out his analysis by standard photometric methods. The content of VLDL-TG, LDL-C and VLDL-C can be calculated or determined by fractionation of lipoproteins preparative ultracentrifugation followed by quantitative analysis using refractometry or methods of analytical ultracentrifugation. Apo A1, Apo B and hsCRP can be determined in serum samples using standard values method. The content of A lipoprotein can be determined in serum using a standard turbidimetric immunoassay techniques. The number and size of LDL particles can be determined using nuclear magnetic resonance (NMR). Remnant lipoproteins and LDL-phospholipase A2 can be determined from EDTA plasma or serum and serum, respectively, using IU the odik enzyme immunolabeling. The levels of oxidized LDL, intracellular adhesion molecule-1 and interleukin-2 can be determined in serum samples using standard techniques of enzyme immunoassay. These methods are described in detail in standard manuals such as Tietz Fundamentals of Clinical Chemistry, 6thEd. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.

In one embodiment, the implementation of agents do not eat during the period of up to 12 hours before sampling of blood, for example, within about 10 hours.

In another embodiment, the present invention relates to a method of treatment or prevention of primary hypercholesterolemia and/or mixed dyslipidemia (types IIa and IIb according to Fredrickson) the patient requiring such treatment, comprising administration to a patient one or more compositions disclosed in this application. In a related embodiment, the present invention relates to a method of lowering the levels of triglycerides in a subject or subjects, if monotherapy with use of drugs of the statin or Niacin prolonged action deemed to be sufficient with hyperlipidemia type IV according to Fredrickson).

In another embodiment, the present invention relates to a method of treatment or prevention of the risk of recurrent non-fatal myocardial infarction in a patient with a history in which arcta infarction, includes introduction to the patient one or more compositions disclosed in this application.

In the following embodiment, the present invention relates to a method of slowing the progression or promote regression of atherosclerotic disease in a patient, which is necessary, involving the introduction of a needy patient one or more compositions disclosed in this application.

In the following embodiment, the present invention relates to a method of treatment or prophylaxis of very high levels of triglycerides in serum (e.g., hyperlipidemia types IV and V) patients who need it, including the introduction of a needy patient one or more compositions disclosed in this application.

In yet another embodiment, the present invention relates to a method of treatment of subjects with very high levels of triglycerides in serum (e.g., more than 1000 mg/DL or more than 2000 mg/DL), in which there is a risk of pancreatitis, including introduction to the patient one or more compositions of the present invention.

In one of the embodiments the composition of the present invention is administered to a subject in an amount sufficient to provide a daily intake of eicosapentaenoic acid from about 1 mg to about 10,000 mg, 25 m is to about 5000 mg, from about 50 to about 3000 mg, from about 75 to about 2500 mg, or from about 100 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, approximately 525 mg, about 550 mg, about 575 mg, about 600, about 625 mg, about 650 mg, about 675 mg, about 700 mg to about 725 mg, about 750 mg to 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, about 1175 mg, about 1200 mg, about 1225 mg to about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg to 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, about 2050 mg, CA the RNO 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, approximately 2175 mg, about 2200 mg, approximately 2225 mg to about 2250 mg, approximately 2275 mg, about 2300 mg, approximately 2325 mg, about 2350 mg, about 2375 mg to about 2400 mg, about 2425 mg, about 2450 mg, approximately 2475 mg, or about 2500 mg

In yet another embodiment, any of the methods disclosed in this application is used for the treatment or prophylaxis of a subject or subjects with the traditional Western diet. In one of the embodiments of the methods of the present invention include the stage of identification of the subject as the subject with the traditional Western diet, or entity with appropriate diet, with subsequent treatment of the subject, if it can be attributed to consumers the traditional Western diet. The term "traditional Western diet" in this application refers primarily to a standard diet consisting of (in percent of total calories) from about 45% to about 50% hydrocarbons, from about 35% to about 40% fat and from about 10% to about 15% protein. Additionally or alternatively, the traditional Western diet can be characterized by a relatively high consumption of raw meat and meat dishes, sweets, refined grains, and desserts, nab the emer more than 50%, more than 60% or 70% of the total calories coming from these sources.

EXAMPLES

The following examples serve only illustrative purposes, and should not be construed as any limitation of the scope of the invention.

EXAMPLE 1

Prepared test composition (TC), including ultra-pure ethyl-EPA (>96% E-EPA, ~3% related fatty acids (no DHA) and ~0,2% alpha tocoferol), and filled her soft gelatin shell capsule (~500 mg per capsule), made from a gel comprising gelatin (~44%), glycerol (~7%), sorbitol solution (~17%), the solution maldita, gelatin and purified water. Received comparative composition (CC), including the same filler that test composition, but enclosed in a capsule type IIa, made from a gel comprising glycerol (~20%), gelatin (43.4%) and water (~36.6 percent).

Then the tested compositions and comparative compositions were placed in plastic bags that are tightly closed and stored either at 25°C/Rel. Mois. 60% or 30°C/Rel. Mois. 65% for 1, 3 or 6 months. When the specified time capsule was opened and was determined peroxide number of the contents of the capsules. The results are shown in table 1 (average for capsules from three different parties).

Table 1
Perox the derivative number (mEq/kg) after storage
TrackEx.value1 month3 months6 months
Store at 25°C/Rel. Mois. 60%
TC1,6-3,23,4
CC1,9-3,49,6
Storage at 30°C/Rel. Mois. 65%
TC1,62,03,64,8
CC1,81,93,512,5

As can be seen from table 1, the filler of the tested compositions demonstrated significantly smaller peroxide number after 6 months of storage at both storage conditions. For the described studies have not observed significant differences between the fillers tested the composition and comparative compositions from the point of view of efficiency actions EPA-E and related compounds.

EXAMPLE 2

Received the test compositions and the comparative composition of example 1 was Packed in a blister (50 μm PCTFE, laminated 190 μm transparent PVC using the adhesive composition is water-based and sealed with aluminum foil when heated). Then Packed the tested compositions and comparative compositions were stored either at 25°C/Rel. Mois. 60% or 40°C/Rel. Mois. 70% for 1, 3, 6, 12 or 36 months. Upon completion of the specified shelf life capsules opened and defined the peroxide number of the contents of capsules, where the measurement results are shown in table 2 (mean values for three different parties).

Table 2
Peroxide number (mEq/kg) after storage
Ex. value1 month3 months6 months9 months12 months
Store at 25°C/Rel. Mois. 60%
TC2,5-1,12,12,2 of 5.4
CC2,6-5,18,3the 9.711,1
Storage at 40°C/Rel. Mois. 75%
TC2,52,13,2a 4.9--
CC2,63,410,618,8--

As can be seen from table 2, the test composition shows a much smaller peroxide number after 3, 6, 9 and 12 months of storage at 25°C/Rel. Mois. 60% and after 1, 3 and 6 months of storage at 40°C/Rel. Mois. 75% than comparative compositions.

At 40°C test composition showed an average decrease in the efficiency of E-EPA 0.30% per month, while the comparative composition showed an average decrease in the efficiency of E-EPA 0.44% per month. However, similar results were not obtained for the same batches of capsules in example 1 (capsules were stored not in blister packs in the Oh form). In addition, determination of related substances is not demonstrated any increase in the number of related compounds, which could not be attributed to normal variations of the analysis results.

When building peroxide numbers in a linear dependence of the average tilt angles of the lines for the tested compositions in experiment 1 (without blister packaging) and in experiment 2 (in blister pack) were similar, indicating that the package probably does not contribute to the prevention of oxidation.

Table 3
Peroxide number: the slope of the linear dependency of example 1 and example 2
Test trackComparative composition
The angle of inclination (mEq/kg/month)The angle of inclination (mEq/kg/month)
Example 1Example 2Example 1Example 2
25°C/Rel. Mois. 60%0,33 0,351,451,03
40°C/Rel. Mois. 75%0,560,661,813,00

EXAMPLE 3

Conducted test on the dissolution of the capsules of example 1, containing 500 mg of E-EPA, using the methodology developed by the rotating dialysis cell, described in Yamazaki et al.,Dissolution tests by RDC method for soft gelatin capsules containing ethyl icosapentate, Pharmaceutical Technology, Japan 15: 595-603 (1999). Following test conditions:

Cell RDC:Pharma Test
The rotation speed of the stirrer:100 rpm
Temperature:37°C
Filter:Hydrophobic filter sheets Millipore
Internal environment:Dezintegriruetsja environment JP pH1,2
External environmentAbsolute ethanol
Sampling:5 ml, selection on 10, 20, 30, 40, 60, 100 and 120 minutes

Analysis of samples was performed using standard the solution in ethanol with a concentration of 0.5 mg/ml, calculating the amount of dissolved product in each of the specified points in time. There was obtained a good solubility profile with a value of Q85about 60 minutes, and the resulting profile was similar to the profile obtained Yamazaki (data JP; capsules of succinylamino gelatin). The solubility profile of the capsules composition of the present invention was determined using the method of using the mixer in a medium containing SDS buffer and IPA (the mixer rotation speed of 100 rpm, 1000 ml, 37°C). The samples were taken at certain intervals of time and analyzed relative to a standard solution (9.5 mg/ml in methanol) using HPLC. All the data shown in Fig.1.

EXAMPLE 4

Data on bioavailability was obtained for shells of the capsules of example 1, containing 500 mg of E-EPA (AMR101), and compared with the data published Yamazaki to 300 mg capsules Epadel (succinycholine gelatin; Comparitor 1 and Comparitor 2). Table 4 shows the data Tmaxand the degree of dissolution after 60 min (in percent). Full profiles bioavailability for EPA in succinycholine capsules and capsules AMR101 shown in Fig. 2 and 3, respectively.

Table 4
The degree of dissolution and Tmax
The degree of dilution h is cut 60 min Tmax (h)
Comparitor 11776
Comparitor 22756
AMR1013875
1Capsule shell = 220 mg; content = 323 mg;
2Capsule shell = 134 mg; content = 327 mg;
3Average results for three batches of capsules, defined by RDC at a pH of 1.2

As can be seen from table 4, the capsule AMR101 provide a greater degree of dissolution of E-EPA in 60 minutes and have a shorter Tmax by comparison with the known from the literature data for Epadel capsules from succinylamino gelatin.

1. Pharmaceutical composition for treating or preventing diseases associated with the cardiovascular system of a subject in need thereof, comprising at least 95% of ethylacetophenone (ethyl-EPA) concluded in the shell of a capsule comprising gelatin, glycerine, sorbitol, ▫ maltitol and purified water, where the composition has a peroxide source number is not more than 5 mEq/kg and during storage of the composition at 25°C and relative humidity (RH) 60% within 6 months, the composition has a second peroxide number not Bo is her 8 mEq/kg

2. The pharmaceutical composition according to p. 1 containing less than about 1% of any individual fatty acid, which is not ethylacetophenone.

3. The pharmaceutical composition according to p. 1 containing less than about 0.5% of any individual fatty acid, which is not ethylacetophenone.

4. The pharmaceutical composition according to p. 1 containing less than about 0.3% DHA(docosahexaenoic acid) if it is included in the composition.

5. The pharmaceutical composition according to p. 4, which essentially does not contain DHA (docosahexaenoic acid).

6. The pharmaceutical composition according to p. 1 containing from about 0.1 wt.% to about 1 wt.% the antioxidant.

7. The pharmaceutical composition according to p. 6, where the antioxidant is tocopherol.

8. The pharmaceutical composition according to p. 1, where during storage of the composition at 25°C and a relative humidity of 60% within 6 months, the composition has a secondary peroxide number not more than 7 mEq/kg

9. The pharmaceutical composition according to p. 1, where during storage of the composition at 25°C and a relative humidity of 60% within 6 months, the composition has a secondary peroxy number of ethyl-EPA (ethyl-eicosapentaenoate) not more than 6 mEq/kg

10. The pharmaceutical composition according to any one of paragraphs.1-9, where gelatin and glycerin are present in a ratio of about 6:1.

11. The pharmaceutical composition will love PP.1-9, where gelatin and sorbitol are present in a ratio of about 2.6:1.

12. The pharmaceutical composition according to p. 10, where gelatin and sorbitol are present in a ratio of about 2.6:1.

13. The pharmaceutical composition according to any one of paragraphs.1-9 or 12, where the glycerol and sorbitol are present in a ratio of about 0.4:1.

14. The pharmaceutical composition according to p. 10, where the glycerol and sorbitol are present in a ratio of about 0.4:1.

15. The pharmaceutical composition according to p. 11, where the glycerol and sorbitol are present in a ratio of about 0.4:1.

16. A method of treating or preventing diseases associated with the cardiovascular system of a subject in need thereof, comprising administration to the subject a therapeutically effective amount of a composition according to any one of paragraphs.1-15.

17. The method according to p. 16, where the disease is associated with cardiovascular system, selected from acute cases of cardiac ischemia, acute myocardial infarction, angina pectoris, arrhythmia, atrial fibrillation, atherosclerosis, arterial fibrillation, heart failure, cardiovascular disease, chronic heart failure, chronic stable angina, congestive heart failure, coronary artery disease, coronary heart disease, deep vein thrombosis, diabetes, diabetes mellitus, diabetic neuropathy, diastolic dysfunction with whom bjectiv with diabetes, swelling, primary arterial hypertension, pulmonary embolism, fatty liver, heart disease, heart failure, homozygous familial hypercholesterolemia (HoFH), homozygous familial sitosterolemia, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, ischemic complications in unstable angina and myocardial infarction, low blood pressure, metabolic syndrome, mixed dyslipidaemia, heart failure, mild to moderate, myocardial infarction, platelet aggregation, primary hypercholesterolemia, primary hyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension, recurrent hemodynamically unstable ventricular tachycardia (VT), recurrent ventricular arrhythmias, recurrent ventricular fibrillation (VF), ruptured aneurysm, sitosterolemia, stroke, supraventricular tachycardia, symptomatic atrial/atrial fibrillation, tachycardia, type II diabetes, vascular diseases, venous thromboembolism and ventricular arrhythmias.

18. The method according to p. 17, where the disease is associated with cardiovascular system, is a hypertriglyceridemia.



 

Same patents:

FIELD: medicine.

SUBSTANCE: according to a known method of treating the liver disease accompanying type 2 diabetes mellitus involving the baseline therapy of diabetes mellitus and prescribed hepatoprotectors, the above hepatoprotector is presented by Mexicor in a daily therapeutically effective dose of not less than 16 weeks. The therapeutically effective dose of Mexicor makes 100 mg 4 times a day.

EFFECT: higher clinical effectiveness ensured by eliminating the liver disease more prominently, reducing the length of treatment, normalising the liver function test results over a short period of time, and avoiding any side effects.

2 cl, 2 tbl

Pcsk9 vaccine // 2538162

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to immunology and biotechnology. Presented is an immunogen for inducing an immune response to the PCSK9 protein, containing the PCSK9 antigen peptide specified in a group consisting of the disclosed SEQ ID NO: 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 314, 318 and 319, containing the amino acid sequence TRFHRQ, and SEQ ID NO: 182, 183, 184, 185, 186, 187, 188, 317, 401, 402 and 403, containing the amino acid sequence SIPWNLE, wherein the above PCSK9 peptide is conjugated with an immunogenic carrier specified in CRM197 or a Qbeta viral-like particle (VLP). Described is a composition for inducing the immune response to the PCSK9 protein containing at least two immunogens in immunologically effective amounts, wherein the first immunogen represents the above immunogen. Disclosed is a composition for inducing the immune response to the PCSK9 protein containing at least two immunogens in the immunologically effective amounts, wherein the first immunogen is specified in a group of immunogens containing the amino acid sequence SIPWNLE, and wherein the second immunogen is specified in a group of immunogens containing the amino acid sequence TRFHRQ; and wherein the composition can additionally contain at least one adjuvant. What is also presented is a pharmaceutical composition for preventing, treating or relieving PCSK9-related disorders containing: the above immunogen in a therapeutically effective amount, or one of the above compositions, and a pharmaceutically acceptable excipient.

EFFECT: invention enables preparing the effective vaccine for the disorders related to a reaction of the PCSK9 protein and its LDLR receptor.

24 cl, 19 dwg, 6 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrazolopyridine derivatives of formula (I) , a based pharmaceutical composition, and using them for treating and/or preventing disorders or conditions related to nictonamide adenine dinucleotide phosphatoxidase (NADPH-oxidase), as well as to a method for preparing them and an intermediate of formula (VIII) . In general formula (I), G1 is specified in H; and optionally substituted heteroaryl-C1-C6-alkyl; G2 is specified in H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-heterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G3 is specified in H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy, optionally substituted alkoxy-C1-C6-alkyl; optionally substituted carbonyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted C1-C6-alkylaryl: optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-hterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G4 is specified in -NR2-C(O)-R1 and -(CHR3)m-(CH2)n-R4, G5 represents H.

EFFECT: preparing the pharmaceutical composition for treating and/or preventing the disorders and conditions related to nictonamide adenine dinucleotide phosphatoxidase.

16 cl, 3 tbl, 87 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to endocrinology, and can be used for treating non-alcoholic liver disease accompanying type 2 diabetes mellitus. The declared preparation Mexicor provides reducing manifestations of cytolysis and cholestasis, decreasing the steatosis index, enables improving metabolic lipid and glycaemic values and reducing insulin resistance. Mexicor is applied in a daily therapeutically effective dose of 100 mg 4 times a day for at least 16 weeks.

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2 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition contains aleglitezar or its sodium salt in a dose of 0.01 to 0.9 mg.

EFFECT: pharmaceutical composition of aleglitezar is used for treating or preventing type II diabetes mellitus or cardiovascular diseases.

32 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biotechnology. Characterised is application of therapeutically efficient quantity of peptide GGF2, which contains domain, similar to epidermal growth factor (EGF-like), in treatment or prevention of heart failure in mammal by injection of said peptide every 48 hours in dose, which constitutes from approximately 0.001 mg/kg to approximately 10 mg/kg.

EFFECT: invention improves therapeutic effect with introduction of neuroregulin with minimisation of any potential side effects.

14 cl, 15 dwg, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to compositions containing vasoactive intestinal peptide (VIP) or its fragments, and to application of such compositions in treatment of aorta fibrosis.

EFFECT: group of inventions is effective in treatment and prophylaxis of aorta fibrosis.

10 cl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics and represents a pharmaceutical composition for parenteral administration containing sub-micron particles of dosocahexaenoic acid ester dispersed in a water phase with the use of mixture of at least two surfactants specified in a) at least one fatty acid polyoxyethylene ester and b) at least one phospholipide derivative, as well as a method for preparing the above pharmaceutical composition.

EFFECT: invention provides higher pharmacological activity.

14 cl, 3 dwg, 3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: what is presented is a fused protein that is a Notch1 antagonist, which consists of a human Fc region fused with the EGF-like repeat 1-13 of Notch1 or the EGF-like repeat 1-24 of Notch1. Fc-portion is localised on a carboxy-terminal portion of the EGF-repeat. There are described a pharmaceutical composition for the protein-based Notch signal transmission inhibition and using it for preparing the pharmaceutical composition for treating an individual suffering from: tumour; ovarian cancer; metabolic disorder; vascular proliferative retinopathy. What is presented is using the fused protein for producing the pharmaceutical composition for inhibition: angiogenesis in the individual; physiological lymphangiogenesis or pathological lymphangiogenesis in the individual; tumour deposits in the individual.

EFFECT: using the invention provides the proteins expressed in a supernatant at a level by several times more than the fused protein containing the EGF-like repeats 1-36 of Notch1; they penetrate into the tumour better, maintain a ligand-binding ability with the fused protein containing the repeats 1-24, binds to DLL4 and JAG1, whereas the fused protein containing the repeats 1-13 only binds to DLL4, but not to JAG1 that can find application in therapy of various diseases related to the Notch1 activity.

18 cl, 124 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention represents an agent for preventing and treating prostatitis and prostate adenoma in the form of a capsule, which contains doxazosin, diisopropylammonium dichroloacetate, afobazol, copper glycinate, vitamin E (d-alpha tocopherol acetate), zinc glycinate; L-Glutamine; L-Alanine; L-Arginine and excipients: corn starch and talc.

EFFECT: extended range of products for treating and preventing prostatitis and prostate adenoma.

4 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: therapeutically effective amount of ethyl methyl hydroxypyridine succinate and calcium atorvastatin, as well as additives in the form of lactose and magnesium stearate are encapsulated in gelatine. Ethyl methyl hydroxypyridine succinate and magnesium stearate is placed into an inner smaller gelatine capsule inside a main outer gelatine capsule containing atorvastatin, lactose and magnesium strearate. The ingredient ratio in the inner capsule makes, wt %: Ethyl methyl hydroxypyridine succinate 96.2-98.6; magnesium stearate 1.4-3.8, and the ingredient ratio in the outer capsule makes, wt %: calcium atorvastatin 10.0-45.0; lactose 52.0-89.0; magnesium stearate 1.0-3.8.

EFFECT: method enables providing the higher pharmaceutical effectiveness of the preparation and prolonging the shelf-life by preventing atorvastatin degradation.

3 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention represents pharmaceutical composition for correction and therapy of manifestations of amyloid intoxication in patients with brain pathologies, which are characterised by the fact that it contains melatonin 3-10 mg and memantine 5-300 mg.

EFFECT: effective treatment of patients, including cases of moderate cognitive disorders.

4 cl, 2 ex, 6 tbl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, particularly to a method for preparing an agent possessing an antiulcerogenic action. A method for preparing the agent possessing the antiulcerogenic action by extracting the aspen bark in 40% ethanol by the multi-step reverse-flow extraction followed by purification, vacuum concentration and drying in a vacuum chamber; the prepared dry extract is added with the Ludipress extract in the specific environment and used to fill solid gelatine capsules.

EFFECT: preparing the agent possessing the antiulcerogenic action.

15 dwg

FIELD: medicine.

SUBSTANCE: composition containing curcumine, an acid specified in a group consisting of citric acid, malic acid, acetic acid, tartaric acid, lactic acid, alginic acid or a mixture thereof, and an edible emulsifying agent with specific characteristics and taken in a certain amount wherein the above composition is applicable as a therapeutic agent. The composition containing curcumine, the edible emulsifying agent or a mixture thereof, the acid specified in a group consisting of citric acid, malic acid, acetic acid, tartaric acid, lactic acid, alginic acid or a mixture thereof taken in certain proportions, and additionally encapsulated into a gelatine capsule, wherein the above composition is applicable for treating or preventing an inflammation and/or diseases caused by the inflammation.

EFFECT: compositions improve the curcumine bioavailability effectively.

13 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: perorally delivered pharmaceutical composition contains a compound, which inhibits a protein of family Bcl-2, in particular ABT-263, a slightly soluble in lipids antioxidant, selected from the group, which consists of sulphites, bisulphites, metabisulphites, thiosulphates and their mixtures, and an in fact non-aqueous lipid carrier, which includes a phospholipid, a non-phospholipid surface-active substance and a solubilising component, which includes one or more glycols, glycolides and/or glyceride compounds, where the said compound ABT-263 and the said antioxidant are in a solution in the lipid carrier.

EFFECT: composition is suitable for peroral introduction to an individual who requires it for treatment of a disease, characterised by superexpression of one or some antiapoptotic proteins of family Bcl-2, for example cancer.

28 cl, 2 dwg, 17 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid pharmaceutical product for oral administration which contains a photosensitiser representing a compound of general formula I:

wherein R1 represents a substituted or unsubstituted unbranched, branched or cyclic alkyl group, and each R2 independently represents a hydrogen atom or optionally a substituted alkyl group or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient. The above pharmaceutical product is presented in the form of a tablet, a pill or a capsule having an enteric and gastroresistant coating, or in the form of the tablet or the capsule containing a number of balls, drops, granules or mini-pills with an enteric and gastroresistant coating. The above coating disintegrates in the lower gastrointestinal tract. The invention also refers to using the above photosensitiser in preparing the solid pharmaceutical product applicable in photodynamic treatment or diagnostics of a cancer condition in the lower gastrointestinal tract. What is also described is a photodynamic method of treating or diagnosing the cancer condition in the lower gastrointestinal tract by administering the solid pharmaceutical product containing the photosensitiser.

EFFECT: invention provides photosensitiser delivery to the lower gastrointestinal tract, and homogenous distribution of the photosensitiser in the target region, thereby improving the response to photodynamic treatment or diagnostics.

20 cl, 2 dwg, 2 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of cosmetology, namely to a cosmetic composition for peroral introduction, which contains a combination of lycopene, vitamin C, vitamin E and at least one polyphenol compound, obtained from pine bark, in which the ratio of weight content of polyphenol compound to the sum of weight contents of lycopene, vitamin C and vitamin E constitutes from 0.3 to 0.7, as s single active ingredient.

EFFECT: invention is intended for prevention and/or treatment of wrinkles in the area of eyes and mouth angles, small wrinkles, eye bags and dark circles under eyes.

22 cl, 2 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to preparation of encapsulated protein-containing products. The method producing protein-containing products involves preparing internal contents with a protein component, followed by encapsulation of the internal contents to obtain a protein-containing product with a shell. Said internal contents have a ratio of protein to salt mixture of (1-11):(1.0-4); the salts used are soluble calcium salts, barium salts or mixtures thereof and pH corrector salts with the ratio (1.0-3.0):(1-2). The internal contents are encapsulated through a sodium alginate solution 0.5…3.0%. Also disclosed is an encapsulated protein-containing product. The product has an alginic shell based on calcium, barium or mixture thereof with the ratio of internal contents to the shell of 100:(20-50), wherein the internal contents have pH 7.5…8.5.

EFFECT: invention enables to obtain an encapsulated protein-containing product which is resistant to breakdown at low pH values and is impervious to pepsinolysis enzymes.

3 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly to a method for preparing a powder. The method involves the stages of providing at least one first ingredient that has a consistence of viscous fluid and that has an initial melting point within the temperature range of 15°C to 40°C, providing at least one second ingredient that has a melting point, particularly within the range above an ambient temperature up to 120°C, preparing a homogenous liquid mixture containing one first ingredient and one second ingredient by mixing and heating the mixture to a temperature or maintaining a temperature of the mixture within the range above the melting point. Supplying the liquid mixture to an irrigation hardening unit and extracting the powder prepared by irrigation hardening. In addition, the present invention refers to the method for preparing the solid dosage form containing the powder prepared by the method described above.

EFFECT: improvement of the method.

17 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: composition contains tacrolimus as an active substance in a therapeutically effective amount, a hydrophobic ingredient, a hydrophilic ingredient, an emulsifier and a stabiliser - disodium edentate and phenoxyethanol. As tacrolimus, the composition contains tacrolimus monohydrate. The composition contains phenoxyethanol in a combination with ethylhexyl glycerol in a ratio of 9:1. The composition is presented in the form of a semi-solid dosage form.

EFFECT: formulation is characterised by stability, uniform distribution of the active substance, usability and good pack extrusion.

6 cl, 2 tbl

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