UA106608C2 - COMPOSITIONS INCLUDING OIL MIXTURE OF FATTY ACIDS AND SURFACE SUBSTANCES AND METHODS OF APPLICATION - Google Patents

Abstract

The invention relates to concentrates that include an oil mixture of fatty acids, which includes at least eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), where EPA and DHA are interrupted in the form selected from ethyl ester and triglyceride; and at least one non-ionic surfactant that does not contain a therapeutic agent other than an oily mixture of fatty acids. Concentrators are capable of forming a self-emulsifying drug delivery system (SNEDDS), a self-emulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS) in aqueous solution.

Description

IOO1| This application declares the priority of the temporary application 0.5. Mo. 61/158,613, filed on March 9, 2009, provisional application O.5. Mo. 61/242,630, filed on September 15, 2009, provisional application TSh.5.

Mo. 61/254,291, filed on October 23, 2009, and provisional application Sh.5. No. 61/254,293, filed Oct. 23, 2009, which are incorporated by reference in their entirety.

I002)| This description mainly relates to preconcentrates that include an oily mixture of fatty acids and at least one surfactant, and methods of their use. The fatty acid oil blend may include omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in ethyl ester or triglyceride form. Additionally, self-nanoemulsifying drug delivery systems (ZMEYUOYUO5), self-microemulsifying drug delivery systems (ZMEBOZ5) and self-emulsifying drug delivery systems (ZEYUO5) are described.

I0OO3| A preconcentrate described herein can be administered, for example, in capsule form to a subject for the therapeutic treatment and/or regulation of at least one health-related problem, which includes, for example, unstable plasma lipid levels, cardiovascular function - vascular system, immune functions, visual functions, insulin action, neuron development, hypertriglyceridemia, heart failure, and post-myocardial infarction (MI). This description additionally relates to a method of increasing hydrolysis, solubility, bioavailability, absorption, and/or any combination thereof.

I004) In humans, cholesterol and triglycerides are part of lipoprotein complexes in the bloodstream and can be separated by ultracentrifugation into high-density lipoprotein (HDL), medium-density lipoprotein (IM), low-density lipoprotein (LD), and very low-density lipoprotein (VL ). Cholesterol and triglycerides are synthesized in the liver, incorporated into MI, and released into the plasma. High levels of total cholesterol (total-C),

Both OG-C and apolipoprotein B (membrane complex for I 01-C and MI 0-C) provoke atherosclerosis in humans and decrease levels of NOI-C and its transport complex; apolipoprotein A is also associated with the development of atherosclerosis. In addition, cardiovascular morbidity and mortality in humans can also vary directly from the level of total-C and I01-C and indirectly from the level of NOI-C. In addition, the study found that non-NOI. cholesterol is an indicator of hypertriglyceridemia, vascular disorders, atherosclerotic disorders, and related conditions. In fact, MCER ATP I determines a decrease in the level of non-NOIGH. cholesterol as a treatment goal.

I0OO5)| Omega-3 fatty acids can regulate plasma lipid levels, cardiovascular and immune functions, insulin action, and neuron development and visual function. Marine oils, also called fish oils, have been found to be a source of omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and to regulate lipid metabolism.

Plant-based oils and microbial oils are also a source of omega-3 fatty acids. Omega-3 fatty acids may have beneficial effects on risk factors for cardiovascular disease, such as hypertension and hypertriglyceridemia, and on the coagulation index Mi! activity of the phospholipid complex. Omega-3 fatty acids can also lower serum triglycerides and increase NOI. cholesterol in the serum, reduce systolic and diastolic blood pressure and/or pulse rate, and can reduce the activity of the blood coagulation indicator MIiI-phospholipid complex. In addition, omega-3 fatty acids are usually well tolerated without causing serious side effects.

IOO6| Several formulations of omega-3 fatty acids have been developed. For example, one form of omega-3 fatty acid blend oil is a primary omega-3 long-chain, polyunsaturated fatty acid concentrate from fish oil containing ONA and EPA, sold under the brand name OtasogFf / | oma7gatM / 2odip? / Zeasog?). See, for example, US Patent Nos. 5,502,077, 5,656,667 and 5,698,594. In particular, each 1000 mg capsule of I oma7atM contains at least 90 95 ethyl ester of omega-3 fatty acids (84 95 EPA/ONA); about 465 mg of EPA ethyl ester and about 375 mg of ONA ethyl ester.

I007| In addition, for example, EPA/JUNA ethyl esters are also used in therapeutic drug delivery formulations. For example, US Patent No. 6,284,268 (Susiosrogipe Tpegareshisv tsa.) describes a self-emulsifying microemulsion or preconcentrate emulsion pharmaceutical composition comprising an omega-3 fatty acid oil and a poorly water-soluble therapeutic agent such as cyclosporine for oral administration. Claimed cyclosporins have additional or synergistic therapeutic effects with omega-3 fatty acid oil. Patent "268 describes the greater solubility and stability of cyclosporine compositions that include omega-3 fatty acid oils. UMO 99/29300 (KTR RIiagta) refers to self-emulsifying fenofibrate compositions based on a hydrophobic component selected from triglyceride, diglyceride, monoglycerides, free fatty acids and fatty acids and their derivatives.

I0O8) However, evidence suggests that long-chain fatty acids and alcohols up to at least C24 are non-reversibly converted. Enzyme systems found in the liver, fibroblasts, and brain convert fatty alcohols into fatty acids. In some tissues, fatty acids can be converted back to alcohols. The carboxylic acid functional group of fatty acid molecules is targeted for binding, but this ionizable group can prevent the molecule from crossing a cell membrane, such as the intestinal wall. As a result, the carboxylic acid functional groups are often protected as esters. The ester is less polar than the carboxylic acid and can more easily cross fatty cell membranes. Once in the bloodstream, the ester can be hydrolyzed back to the free carboxylic acid by the enzyme esterase in the blood. It may be that the plasma enzymes do not hydrolyze the ester fast enough, however, and the conversion of the ester to the free carboxylic acid mainly occurs in the liver. Polyunsaturated fatty acid ethyl esters can also be hydrolyzed to free carboxylic acids and mimo.

ИО0О9| Accordingly, there is a need in the art for compositions and/or methods that improve or enhance the solubilization, digestion, bioavailability, and/or absorption of omega-3 fatty acids while maintaining the ability to cross cell membranes.

IO101| It is to be understood that both the above general description and the following detailed description are illustrative and explanatory only and are not limiting of this description as indicated. 011) This description further relates to a pharmaceutical preconcentrate comprising: an oily fatty acid mixture comprising at least 75595 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the oily fatty acid mixture, wherein the EPA and DHA are in a form selected from ethyl ester and triglyceride; and at least one surfactant. 012) This description further relates to a pharmaceutical preconcentrate comprising: an oily fatty acid mixture comprising from about 80 95 to about 88 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the oily fatty acid mixture, where EPA and DHA are in the form of ethyl ester; and at least one surfactant selected from polysorbate 20, polysorbate 80 and mixtures thereof.

I0O13) This description further relates to a pharmaceutical preconcentrate comprising: an oily fatty acid mixture comprising from about 80 95 to about 88 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the oily fatty acid mixture, wherein EPA and DHA are in the form of ethyl ester; at least one surfactant selected from polysorbate 20, polysorbate 80 and their mixtures; and at least one co-surfactant which includes ethanol.

I014| This description further relates to a self-nanoemulsifying drug delivery system (ZMEBO5), a self-microemulsifying drug delivery system (ZMEBOZ5), or a self-emulsifying drug delivery system (ZEBO5), which include a pharmaceutical preconcentrate that contains: an oil mixture of fatty acids , which includes from about 80 95 to about 88 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DOH) by weight of the fatty acid oil mixture, wherein the EPA and DOH are in a form selected from an ethyl ester and a triglyceride; and at least one surfactant; where the preconcentrate forms an emulsion in an aqueous solution. 015) This description further relates to a method of treating at least one health-related problem in a subject in need thereof, comprising administering to the subject a pharmaceutical preconcentrate comprising: an oily mixture of fatty acids comprising at least 75 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the oily mixture of fatty acids, where the EPA and DHA are in a form selected from an ethyl ester and a triglyceride; and at least one surfactant; wherein at least one health-related problem is selected from unstable plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neuron development, heart failure, and post-myocardial infarction. 016) This description further relates to a preconcentrate dietary supplement or a preconcentrate dietary supplement comprising: an oily fatty acid blend comprising from about 25 95 to about 75 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the oily fatty acid blend , where EPA and ONA are in a form selected from ethyl ester and triglyceride; and at least one surfactant.

ЙО17| This disclosure further relates to a method of increasing at least one parameter selected from hydrolysis, solubility, bioavailability, absorption, and combinations thereof of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) comprising combining: an oily mixture of fatty acids comprising EPA and DHA in the form , selected from ethyl ester and triglyceride; and at least one surfactant; wherein the oily mixture of fatty acids and at least one surfactant form a preconcentrate.

ЙО18| This disclosure further relates to a method of treating at least one health-related problem in a subject in need thereof, which comprises administering to the subject a preconcentrate supplement comprising: an oily fatty acid mixture comprising from about 25 95 up to about 75 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form selected from an ethyl ester and a triglyceride; and at least one surfactant; wherein at least one health-related problem is selected from unstable plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neuron development, heart failure, and post-myocardial infarction.

ЙО19| This disclosure further relates to a dietary supplement or nutritional supplement preconcentrate comprising: an oily fatty acid blend that contains from about 25 95 to about 75 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the oily fatty acid blend, wherein the EPA and ONA are in a form selected from an ethyl ester and a triglyceride; and at least one surfactant to regulate at least one health-related problem selected from unstable plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neuron development, heart failure, and post-myocardial infarction.

BRIEF DESCRIPTION DRAWING

ИО20| Fig. 1 shows the disappearance of ERA-EE and ONA-EE and the appearance of ERA-BRA and ONA-BEA during lipolysis

That one).

IO21) Fig. 2 shows the percentage of recovery of ERAZHON at different time points for Otasog). (0221 Fig. C shows the percentage of lipolysis of EPA-EE, ONA-EE, and total K85EE at various time points for Otasog). (023) Fig. 4 shows the disappearance of ERA-EE and ONA-EE and the appearance of ERA-BA and ONA-BEA during lipolysis of preconcentrate A. (024) Fig. 5 shows the percentage of recovery of ERAZHON at different time points for preconcentrate A.

IO25) Fig. 6 shows the percentage of lipolysis of EPA-EE, ONA-EE and total K85EE at different time points for preconcentrate A. (026) FIG. 7 shows the disappearance of ERA-EE and ONA-EE and the appearance of ERA-BRA and ONA-BEA during lipolysis of preconcentrate B.

ИО27| Fig. 8 shows the percentage of recovery of ERAZHON at different time points for preconcentrate B.

IO28) Fig. 9 shows the percentage of lipolysis of ERA-EE, ONA-EE and total K85EE at different time points for preconcentrate B. 0291 FIG. 10 shows the disappearance of ERA-EE and ONA-EE and the appearance of ERA-ERA and ONA-EA during the lipolysis of preconcentrate C.

IOZOA Fig. 11 shows the percent recovery of ERAZHON at different time points for preconcentrate b.

IOZ31) Fig. 12 shows the percentage of lipolysis of EPA-EE, ONA-EE and total KV5EE at different time points for preconcentrate C.

IOZ321| Fig. 13 shows the disappearance of ERA-EE and ONA-EE and the appearance of ERA-ERA and ONA-EA during the lipolysis of preconcentrate 0.

ИОЗЗ| Fig. 14 shows the percentage of ERAZHON recovery at different time points for preconcentrate r.

ИО34| Fig. 15 shows the percentage of lipolysis of EPA-EE, ONA-EE, and total KV5OEE at various time points for preconcentrate 0.

IOZ5) Fig. 16 shows the disappearance of ERA-EE and ONA-EE and the appearance of ERA-ERA and ONA-EA during the lipolysis of preconcentrate E.

IOZb) Fig. 17 shows the percent recovery of ERAZHON at various time points for the preconcentrate

IS.

ИО37| Fig. 18 shows the percentage of lipolysis of EPA-EE, ONA-EE and total КВ5EE at different time points for preconcentrate E. description

IOZ38) Individual aspects of the description are described in more detail below. Terms and definitions as used in this application and as defined herein are intended to represent the content within the scope of this specification. Patent and scientific literature referenced herein and hereinafter are incorporated by reference. The following terms and definitions are explained if they conflict with terms and/or definitions incorporated by reference.

ИО39| The singular forms of the articles "a," "ap," and "pe" in the English text include plural references unless the context otherwise requires. 0401 The terms "near" and "approximately" mean nearly the same thing as the given figure or quantity. As used herein, the terms "about" and "about" are to be understood as including 95% of the stated amount, frequency, or magnitude.

I041| The terms "administer", "administer" or "administer" as used herein refer to (1) providing, administering, dosing and/or prescribing by or under the direction of any medical practitioner or his authorized representative a preconcentrate as described, and (2) administration, ingestion, or ingestion by the patient or subject of the preconcentrate as described. (042) This disclosure provides pharmaceutical and auxiliary preconcentrates that include an oily mixture of fatty acids and at least one surfactant, and methods of use thereof.

The preconcentrates of this description can produce dispersions with a low or very low average particle size when mixed with an aqueous medium. Such dispersions can be described as nanoemulsions, microemulsions, or emulsions. For example, upon delivery, preconcentrates can produce dispersions with gastric or other physiological fluids that form self-nanoemulsifying drug delivery systems (SDMDs), self-microemulsifying drug delivery systems (SDMDs), or self-emulsifying drug delivery systems. are emulsified (ZEYUOO5).

Fatty Acid Oil Blend 043) The compositions of this disclosure include at least one fatty acid oil blend comprising eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). As used herein, the term "oil mixture of fatty acids" includes fatty acids, such as unsaturated (eg, monounsaturated, polyunsaturated) or saturated fatty acids, such as pharmaceutically acceptable esters, free acids, mono-, di-, and triglycerides, derivatives, conjugates, precursors, salts and their mixtures. In at least one embodiment, the fatty acid oil mixture includes fatty acids, such as omega-3 fatty acids, in a form selected from an ethyl ester and a triglyceride. (044) The term "omega-3 fatty acids" includes natural and synthetic omega-3 fatty acids, as well as pharmaceutically acceptable esters, free acids, triglycerides, derivatives, conjugates (see, e.g., 7ioda et al., application issuing US Patent Publication Mo 2004/0254357, and Nogtobip et al., US Patent Mo 6,245,811, each incorporated herein by reference), precursors, salts and mixtures thereof. Examples of omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated acids, long-chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-linolenic acid (AHA), geneicosapentaenoic acid (HPA), docosapentaenoic acid (ODA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (ie, stearidonic acid, 5TA); esters of omega-3 fatty acids with glycerol, such as mono-, di- and triglycerides; and omega-3 fatty acid esters and a primary, secondary and/or tertiary alcohol, such as, for example, fatty acid methyl esters and fatty acid ethyl esters. Omega-3 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and/or mixtures thereof according to this description can be used in their pure form and/or as a component of an oil, for example as a marine oil (e.g. , fish oil concentrates and refined fish oil), algae oils, microbial oils and plant-based oils. 045) In some embodiments of this disclosure, the fatty acid oil mixture includes EPA and ONA.

In addition, for example, an oily blend of fatty acids includes EPA and ONA in a form selected from an ethyl ester and a triglyceride.

I046Y The oily mixture of fatty acids in this description may additionally include at least one fatty acid other than EPA and ONA. Examples of such fatty acids include, but are not limited to, omega-3 fatty acids other than EPA and ONA and omega-6 fatty acids. For example, in some embodiments of the present disclosure, the fatty acid oil mixture includes at least one fatty acid other than EPA and ONA selected from α-linolenic acid (AHA), geneicosapentaenoic acid (HPA), docosapentaenoic acid (ORA), eicosatetraenoic acid (ETA ), eicosatrienoic acid (ETE), and stearidonic acid (TA). In some embodiments, the at least one fatty acid other than EPA and ONA is selected from linoleic acid, gamma-linolenic acid (OA), arachidonic acid (AA), docosapentaenoic acid (ie, "o5ropa") and mixtures thereof. In some embodiments, the at least one fatty acid other than EPA and ONA is in a form selected from an ethyl ester and a triglyceride.

I047| Examples of additional fatty acids, or mixtures thereof (fatty acid oil blends) covered by this specification include, but are not limited to, fatty acids defined in the European

Pharmacopoeia Ethyl Esters 90 Omega-3 and purified oils of marine organisms, European Pharmacopoeia triglycerides of Omega-3 acids, European Pharmacopoeia ethyl esters 60 Omega-3 acids,

European Pharmacopoeia fish oil rich in Omega-3 acids (monograph), and/or, for example, OBR fish oil (monograph). 048) Commercial examples of fatty acid blend oils containing various fatty acids suitable for this description include, but are not limited to: Ipsgoteda "M omega-3 concentrates of oils from marine organisms, such as Ipsgoteda "m T37010 5K, Ipsgoteda "m E7010 5EK, Ipsgoteda " m. TO6015, Ipsgoteda "m

ERABOOTO 5EK, Ipsgoteda "m E400200 5K, Ipsgoteda m E4010, Ipsgoteda m ONA7OOTO 5K, Ipsgoteda "m

ONA7OOE 5, Ipsgoteda ONA5BOOTO ZK, Ipsgoteda T053322 ZK, Ipsgoteda E3322 5,

Ipsgotedatm TO3322, Ipsgoteda tm E3322, Ipsgotedatm To TO/EE (Consent of Ipiegpaiop! RI S, Yorkshire,

England); ERAKhbOOOBA, ERAKH5BO0OTO, ERAKH4510TO, ERAKH20O50TO, ERAKH7OTOEE, ERAKH5BOOEE,

ERAHBBOOTO, ERAHBOOOEE, ERAHBOOOTO, ERAHBbOOOEE, ERAHbOOOTO, ERAHbOOOBA, ERAHVBBOOEE,

ERAKHBBBOOTO, ERAKH4AB51OTO, ERAKHIOBOTO, ERAKH2gOBOTO, ERAKH 7010T0, ERAKH7OTOEE,

ЕРАХбО15ТОС/EE, ЕРАХ4020ТО, and ЕРАХ40О20EE (ЕРАХ is a branch that is fully owned by the Norwegian company A!yviemoiiY ZeatoYai AZBA); Otasomb / I Oomala"m / 7odip?b / bBeasogpb ready pharmaceutical product, KV5EE, and ASR 103 (Rgopoma VioRpagpta Mogde AB); MES-39 ERA/YUNA fish oil concentrates (Oseap Miigiop Canada); ONA EMO "Functional food oil" and ONA SI. "Sieg Hydcid" (Sop/a); krill oil Ziregbra m (AkKeg); omega-3 products include ONA produced by Magiek;

Meriipe krill oil (Meriipe); fish oil products and fish oil anti-reflux concentrate (To) produced by Maieg5; Guzi Omega-3 Fish oil; Zemep Zea5 TPiotedafb Sova I imeg OII Viepa (Zemep

Zeav); Egi GI Omega-3 (Uezieegaiepv); and Erade! (Mospida). These commercial embodiments offer various omega-3 fatty acids, combinations, and other components as a result of a transesterification process or preparation method to obtain omega-3 fatty acid(s) from various sources such as marine, algal , microbes, and plant-based sources.

I049) In some embodiments of the present disclosure, the fatty acid oil mixture includes at least one fatty acid derivative, such as an alpha-substituted omega-3 fatty acid derivative. At least one alpha-substituted omega-3 fatty acid derivative may be substituted, for example, on the second carbon atom of the omega-3 fatty acid functional group with at least one substituent selected from hydrogen, hydroxyl groups, alkyl groups such as C1-C3 alkyl groups, and alkyl groups. In one embodiment of this disclosure, the at least one alpha-substituted omega-3 fatty acid derivative is selected from mono-substituted and di-substituted fatty acids. In one embodiment, at least one alpha-substituted derivative of omega-3 fatty acids is selected from alpha-substituted C14-C24 alkenes having from 2 to b double bonds. In another embodiment, at least one alpha-substituted derivative of omega-3 fatty acids is selected from alpha-substituted C14-C24 alkenes, including from 5 to 6 double bonds in the si5 configuration.

ИО50| In some embodiments, the oily mixture of fatty acids includes EPA and/or ONA in the form of an alpha-substituted fatty acid derivative. For example, in one embodiment, the oily mixture of fatty acids includes EPA in the form of an alpha-substituted derivative. In another embodiment, the oily mixture of fatty acids includes ONA in the form of an alpha-substituted derivative. In yet another embodiment, the oily mixture of fatty acids includes EPA and ONA in the form of an alpha-substituted derivative.

I0O51| In some embodiments, the fatty acid oil blend includes EPA and EPA, and further includes at least one alpha-substituted omega-3 fatty acid derivative. For example, in some embodiments, the fatty acid oil mixture includes EPA and ONA, and at least one of the EPA and ONA is in the form of an alpha-substituted derivative.

I052| In another embodiment, the ERA and YA of the fatty acid oil mixture are at least one alpha-substituted derivative of omega-3 fatty acids.

ИО53| The fatty acid oil mixture according to this description may be derived from animal oils and/or non-animal oils. In some embodiments of this disclosure, the fatty acid oil blend is derived from at least one oil selected from marine oil, algae, plant-based oil, and microbial oil. Marine oils include, for example, fish oil, krill oil, and lipid compositions derived from fish. Vegetable-based oils include, for example, flaxseed oil, canola oil, mustard seed oil, and soybean oil. Microbial oils include, for example, Mapek products. In at least one embodiment of this description, the oily mixture of fatty acids is obtained from 3 oils of marine organisms, such as fish oil. In at least one embodiment, the marine organism oil is purified fish oil.

ИО54| In some embodiments of the present disclosure, the fatty acids, such as omega-3 fatty acids, fatty acid blends are esterified, such as alkyl esters, such as ethyl esters. In other embodiments, fatty acids are selected from mono-, di-, and triglycerides.

ЙО55| In some embodiments, the oily mixture of fatty acids is obtained by transesterification of the body oil of fatty fish species, which are derived from, for example, anchovy or tuna oil, and a subsequent physicochemical purification process, including urea fractionation followed by molecular distillation. In some embodiments, the crude oil mixture may also be subjected to a distillation process to reduce pollutants and/or cholesterol prior to transesterification.

ИО56) In another embodiment, the oily mixture of fatty acids is obtained using supercritical CO2 extraction techniques or chromatography, for example, for concentrating primary EPA and pHA from fish oil concentrates.

1057) In some embodiments of the present disclosure, at least one of the omega-3 fatty acids of the fatty acid oil mixture has an si5 configuration. Examples include, but are not limited to, (all-2)-9,12,15-octadecatrienoic acid (AHA), (all-2)-6,9,12,15-octadecatetraenoic acid (5TA), (all-2 )- 11,14,17-eicosatrienoic acid (ETE), (all-2)-5,68,11,14,17-eicosapentaenoic acid (EPA), (all-2)- 4,7,10,13, 16,19-docosahexaenoic acid (ONA), (all-2)-8,11,14,17-eicosatetraenoic acid (ETA), (all-2)-7,10,13,16,19-docosapentaenoic acid (ORA ), (all-27)-6,9,12,15,19-geneicosapentaenoic acid (HPA); (all-2)-5,8,11,14-eicosatetraenoic acid, (all-2)-4,7,10,13,16-docosapentaenoic acid ("Ozropa" acid), (all-27)-9, 12-octadecadienoic acid (linoleic acid), (all-2)-5,8,11,14-eicosatetraenoic acid (AA), (all-2)-6,9,12-octadecatrienoic acid (OA); (2)-9-octadecylenic acid (oleic acid), 13(2)-docosenic acid (erucic acid), (K-(2))-12-hydroxy-9-octadecylenic acid (ricinoleic acid).

IO58)| In some embodiments of this disclosure, the mass ratio of ERA:ONA of the fatty acid oil blend is in the range of from about 1:10 to about 10:1, from about 1:8 to about 8:1, from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2:11. In at least one embodiment, the EPA:ONA mass ratio of the fatty acid oil mixture is in the range of about 1:2 to about 2:1. In at least one embodiment, the EPA:NA mass ratio of the fatty acid oil mixture is in the range of about 1:1 to about 2:1. In at least one embodiment, the EPA:ONA mass ratio of the fatty acid oil mixture is in the range of about 1:2 to about 1:3.

Pharmaceutical drug

ИО59| In some embodiments of this disclosure, the oily mixture of fatty acids acts as an active pharmaceutical ingredient (API). For example, this disclosure provides a pharmaceutical composition comprising an oily mixture of fatty acids and at least one surfactant. In some embodiments, the oily mixture of fatty acids is present in a pharmaceutically acceptable amount. How is the term "pharmaceutically effective amount" used here? means an amount sufficient to treat, eg, reduce and/or alleviate the effects, symptoms, etc., of at least one health-related problem in a subject in need thereof. In at least several embodiments of this description, the fatty acid oil mixture does not contain an additional active agent.

106OY Oil mixture of fatty acids includes at least 75 95 ERA and ONA by weight of the oil mixture of fatty acids, where the preconcentrate is a pharmaceutical preconcentrate. In some embodiments, the fatty acid oil mixture comprises at least 80 95 EPA and ONA by weight of the fatty acid oil mixture, such as at least 85 95, at least 90 95, or at least 95 95 by weight of the fatty acid oil mixture. In some embodiments, the oily fatty acid mixture comprises about 80 95 EPA and ONA by weight of the oily fatty acid mixture, such as about 85 95, about 90 95, about 95 95, or any number in between by weight of the oily fatty acid mixture.

ИО61| For example, in some embodiments, the fatty acid oil blend comprises from about 75 96 to about 95 95 EPA and ONA by weight of the fatty acid oil blend, such as from about 75 95 to about 90 95, from about 75 95 to about 88 95, from about 75 95 to about 85 95, from about 75 95 to about 80 95, from about 80 95 to about 95 95, from about 80 95 to about 90 95, from about 80 95 to about 85 95, from about 85 95 to about 9595, from about 8595 to about 90 95, and further, for example, from about 9095 to about 95 95 ERA and ONA by weight of the fatty acid oil mixture, or any number in between. In at least one embodiment, the fatty acid blend oil comprises from about 80 95 to about 85 95 EPA and ONA by weight of the fatty acid blend oil, such as from about 80 95 to about 88 95, such as from about 84 95 by weight of the fatty acid blend oil .

I062| In some embodiments, the oil mixture of fatty acids includes at least 95 95 EPA or

ORNA, or ERA and ONA by weight of the oily mixture of fatty acids, where ERA and ONA are in the form of ethyl ester.

ИО63| In an additional embodiment, the fatty acid oil mixture may include other omega-3 fatty acids. For example, this description covers at least 90 95 omega-3 fatty acids by weight of the fatty acid oil mixture.

I064| In one embodiment, for example, the fatty acid oil mixture includes from about 7595 to about 8895 EPA and ONA by weight of the fatty acid oil mixture, where the EPA and ONA are in ethyl ester form; wherein the fatty acid oil mixture comprises at least 90 95 omega-3 fatty acids in ethyl ester form by weight of the fatty acid oil mixture.

I065| In another embodiment, the fatty acid oil mixture comprises from about 75 95 to about 88 95 EPA and ONA by weight of the fatty acid oil mixture, where the EPA and ONA are in ethyl ester form; wherein the fatty acid oil mixture comprises at least 90 96 omega-3 fatty acids in ethyl ester form by weight of the fatty acid oil mixture, and wherein the fatty acid oil mixture comprises α-linolenic acid (ALA).

ИО66| In one embodiment, the fatty acid oil mixture includes from about 80 95 to about 88 95 EPA and ONA by weight of the fatty acid oil mixture, where the EPA and ONA are in the ethyl ester form, and further includes docosapentaenoic acid (ORA) in the ethyl ester form.

ИО67| In another embodiment, the fatty acid blend oil comprises from about 80 95 to about 88 95 EPA and ONA by weight of the fatty acid oil blend, wherein the EPA and ONA are in the ethyl ester form, and further comprises from about 1 95 to about 4 95 (all -7 omega-3)-6,9,12,15,18-geneicosapentaenoic acid (HPA) in the form of ethyl ester by weight of the oily mixture of fatty acids.

ИО68| In another embodiment, the fatty acid oil mixture includes from about 80 95 to about 88 95 EPA and ONA by weight of the fatty acid oil mixture, where the EPA and ONA are in ethyl ester form; and from 1 96 to about 4 95 fatty acid ethyl esters other than

EPA and ONA by mass of fatty acid oil mixture, where fatty acid ethyl esters other than EPA and ONA have C20, C21, or C22 carbon atoms.

I0O69| In one embodiment, the oily mixture of fatty acids may include KV5EE or ACP 103 (Rgopoma VioRpapta Mogde A5). In another embodiment, the oily mixture of fatty acids may include

K85Ta (Rgopoma VioRpagta Mogde AB).

ERA and ONA products

IO70| In at least one embodiment, the oil mixture of fatty acids comprises at least 75 95

ERA and ONA by weight of the oily mixture of fatty acids, at least 95 95 of which is ERA. In another embodiment, the oily mixture of fatty acids includes at least 80 95 EPA and ONA by weight of the oily mixture of fatty acids, at least 95 95 of which is EPA. In yet another embodiment, the fatty acid oil mixture comprises at least 90 95 EPA and ONA by weight of the fatty acid oil mixture, at least 95 95 of which is EPA. 071) In another embodiment, the oil mixture of fatty acids includes at least 75,956 EPA and ONA by weight of the oil mixture of fatty acids, at least 95 95 of which is ONA. For example, in one embodiment, the fatty acid oil mixture includes at least 80 95 ERA and ONA by weight of the fatty acid oil mixture, at least 95 95 of which is ONA. In another embodiment, the fatty acid oil mixture includes at least 9095 EPA and ONA by weight of the fatty acid oil mixture, at least 95 95 of which is ONA.

Supplement

I072| This disclosure further provides a food additive or nutritional supplement comprising an oily fatty acid mixture and at least one surfactant, wherein the oily fatty acid mixture comprises less than 75 95 EPA and ONA by weight of the oily fatty acid mixture. In some embodiments, for example, the fatty acid oil mixture comprises less than 70 96 EPA and ONA by weight of the fatty acid oil mixture, such as less than 65 95, less than 60 95, less than 55 95, less than 95, less than 45 95 , less than 40 95, or even less than 35 95 by weight of the oil mixture of fatty ee

ИО73| In some embodiments, the fatty acid oil mixture comprises from about 25 95 to about 75 95 EPA and ONA by weight of the fatty acid oil mixture, such as from about 30 95 to about 75 95, from about 30 95 to about 70 95, from about 30 95 to about 65 95, from about 30 95 to about 55 95, from about 30 95 to about 50 95, from about 30 95 to about 45 95, from about 30 95 to about 40 95, and in addition, for example, from about 30 95 to about 35 95 ERA and ONA by weight of the fatty acid oil mixture. 074) In some embodiments of this disclosure, the fatty acids, such as omega-3 fatty acids, fatty acid blends are esterified, such as alkyl esters. Alkyl esters may include, but are not limited to, ethyl, methyl, propyl, and butyl esters and mixtures thereof. In other embodiments, fatty acids are selected from mono-, di-, and triglycerides. For example, an oil blend of fatty acids includes from about 25 95 to about 75 95 EPA and ONA by weight of the oil blend of fatty acids in a form selected from methyl ester, ethyl ester, and triglyceride.

Surfactant / Preconcentrate

I075| This specification further provides a preconcentrate composition. As used herein, the term "preconcentrate" refers to a composition comprising an oily mixture of fatty acids and at least one surfactant.

I076| A surfactant can, for example, reduce the surface tension of a liquid or the surface tension between two liquids. For example, surfactants according to this description can reduce the surface tension between an oily fatty acid mixture and an aqueous solution.

I077| In chemistry terms, surfactants are molecules with at least one hydrophilic part and at least one hydrophobic (ie, lipophilic) part. The properties of a surfactant can be reflected in the value of the hydrophilic-lipophilic balance (HIB) of the surfactant, where the value of the HIB is a measure of the degree of hydrophilicity compared to the lipophilic properties of the surfactant. The value of NI B is usually in the range from 0 to 20, where the value of NIV 0 represents high hydrophilic character, and NIV 20 represents high lipophilic character. Surfactants are often used in combination with other surfactants where the NIV values are complementary. Magnitudes

The NIV of surfactant mixtures can be calculated as defined below:

NI-Ba (fraction of surface-active substance A) « NI Bv (fraction of surface-active substance B) - and NI Vdzv mixture

I0O78)| Surfactants are generally classified as ionic surfactants, such as anionic or cationic surfactants, and nonionic surfactants.

If the surfactant contains two groups with opposite charges, the surfactant is called a zwitterionic surfactant. Other types of surfactants include, for example, phospholipids.

I0O79)| In at least one embodiment of this description, the preconcentrate includes at least one surfactant selected from nonionic, anionic, cationic, and zwitterionic surfactants.

I0O80| Non-limiting examples of nonionic surfactants suitable for this description are given below.

I081| RigopisF surfactants are non-ionic copolymers consisting of a central hydrophobic polymer (polyoxypropylene (poly(propylene oxide))) with a hydrophilic polymer -(polyoxyethylene (poly(ethylene oxide))) on each side. Various commercially available products

The results are shown in Table 1.

Table 1

Examples of surface-active substances Riigopist vysh (i v |uninnya mass (0) (082) You are nonionic surface-active substances that include polyethylene ethers.

Various commercially available HG products are listed in Table 2.

Table 2

Examples of surface-active substances Vgik 11100711 tType | 77717171 Compound///////////////// | VenerableV

I083| ZrapF are nonionic surfactants that include sorbitan esters. zZrapF is available from various sources, including AI. Various commercially available ZrapF products are listed in Table 3.

Table C

Examples of surfactants ZrapF

C 1017111111type 7 | 11111111 Compounds////////// | VenerableV

Zrapb20 | Neinna |sorbitan monolaurate/://.:.:/.О|////// 861

ZrapFf 85 Nonionic Sorbitantrioleate

ИО84| TmeepF (polysorbates) are nonionic surfactants that include polyoxyethylene sorbitan esters. The various commercially available TueepF products are listed in Table 4.

Table 4

Examples of surface-active substances TmeepF 11111011 type Compound Amount of NIV. polyoxyethylene (20

TmzheepFf 20 Nonionic and 20) 16.0 sorbitan monolaurate. polyoxyethylene (20

TmeepF 40 Neon ego) 15.6 sorbitan monopalmitate

TmeepF 60 Nonionic polyoxyethylene sorbitan monostearate

TmeepF 65 Nonionic polyoxyethylene sorbitan tristearate

TmeepF 80 Nonionic polyoxyethylene (20) sorbitan monooleate

TmeepFf 85 Nonionic polyoxyethylene sorban trioleate (085) Mugk are nonionic surfactants that include fatty acid esters of polyoxyethylene. Various commercially available Mug|F products are listed in Table 5.

Table 5

Examples of surfactants MugiF 11111011 type | Compound Value of NIV

Mugiv 45 Nonionic polyoxyethylene monostearate

Mugiv 49 Nonionic polyoxyethylene monostearate

Mugiv 52 Nonionic polyoxyethylene monostearate

Mugiv 53 Nonionic polyoxyethylene monostearate

ИО86| Stethorpogzh" are nonionic surface-active substances. The various commercially available Stethorpoge products are listed in Table 6.

Table 6

Examples of surface-active substances Stetorpoge 111110 type Compound Value NIV

Stetorpogo REI. Nonionic polyoxyethylated castor oil. hydrogenated polyoxyethylated

Stetorpoge VNAO Nonionic dr and 14-16 castor oil. hydrogenated polyoxyethylated

Stethorpog? VNbO Neionna Dr. 15-17 castor oil. hydrogenated polyoxyethylated

Stetorpoge KO Neiionna dr and 16.1 castor oil

ИО87| According to this description, other illustrative nonionic surfactants include, but are not limited to, diacetyl monoglycerides, diethylene glycol monopalmitostearate, ethylene glycol monopalmitostearate, glyceryl behenate, glyceryl distearate, glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, macrogolcetostearyl ether, such as cetomacrogol 1000, polycetosteroxy aryl ether20 macrogol 15 hydroxystearate, macrogol lauryl ethers such as laureth 4 and lauromacrogol 400, macrogol monomethyl ethers, macrohololeyl ethers such as polyoxyl 10 oleyl ether, macrogol stearates such as polyoxyl 40 stearate, menfegol, mono and diglycerides, nonoxynols such as nonoxynol- 9, nonoxynol-10 and nonoxynol-11, octoxynols such as octoxynol 9 and oxtoxinol 10, poloxamers such as poloxalene, poloxamer 188, poloxamer 407, polyoxyl castor oil such as polyoxyl 35 castor oil, polyoxyl hydrogenated castor oil such as polyoxyl 40 hydrogenated castor oil , propylene glycol diacetate, propylene glycol laureates such as propylene glycol dilaurate and propylene glycol monolaurate. Additional examples include propylene glycol monopalmitostearate, quillates, sorbitan esters, and sucrose esters. (088) Anionic surfactants suitable for this description include, for example, perfluorocarboxylic acid and perfluorosulfonic acid salts, alkyl sulfate salts such as sodium dodecyl sulfate and ammonium lauryl sulfate, sulfate ethers such as sodium sulfate lauryl ether, and alkylbenzene sulfonate salts.

ИО89| Cationic surfactants suitable for this description include, for example, quaternary ammonium compounds such as benzalkonium chloride, cetylpyridinium chlorides, benzethonium chlorides, and cetyl trimethylammonium bromides or other trimethylalkylammonium salts. 090 Zwitterionic surfactants include, but are not limited to, for example, dodecyl betaines, coconut oil amphoglycinates, and cocamidopropyl betaines.

ИО91| In some embodiments of this description, the surfactant may include a phospholipid, a derivative thereof, or an analog thereof. Such surfactants can, for example, be selected from natural, synthetic, and semi-synthetic phospholipids, their derivatives, and their analogs.

Phospholipids can be of "natural" or marine origin and are selected from, for example, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. The fatty acid group can be selected from 14:0, 16:0, 16: 1p-7, 18:0, 18:142-9, 18:1p-7, 18:2p-6, 18:3p-3, 18 :4p-3, 20:4p-6, 20:51-3, 22:51p-3 and 22:6p-3, or any of their combinations. In one embodiment, the fatty acid group is selected from palmitic acid, EPA, and ONA. Приклади поверхнево-активні речовини фосфоліпідів включають фосфатидилхоліни з насиченими, ненасиченими і/або поліненасиченими ліпідами, такі як диолеїлфосфатидилхолін, дипентадеканоїлфосфатидилхолін, дилауроїлфосфатидилхолін, диміристоїлфосфатидилхолін, дипальмітоїлфосфатидилухолін, дистеароїлфосфатидилухолін, діейкопентаеноїл(ЕРА)холін, дидокозагексаеноїл(ОНА)холін, фосфатидилетаноламіни, фосфатидилгліцерини, фосфатидилсерини та phosphatidylinositols Other examples of phospholipid surfactants include soy lecithin, egg lecithin, dioleoyl phosphatidylcholine, distearoyl phosphatidyl glycerol, PEG-ylated phospholipids, and dimyristoyl phosphatidylcholine. 0921 Other illustrative surfactants suitable for this specification are listed in Table 7.

Table 7

Other surfactants

Gum arabic 77777177 Anionic //// 17777777 80171

1093) In some embodiments of this disclosure, the at least one surfactant does not include I abgasoi, Stetorpog KEN4IO, or a combination of Stetorpog and Tuu"eep-80.

I094) In some embodiments, the at least one surfactant has a hydrophilic-lipophilic balance (HIB) of less than about 10, such as less than about 9, or less than about 8.

Common surfactant

I095) In some embodiments, the compositions of this disclosure further include at least one co-surfactant. As used herein, the term "co-surfactant" means a substance added to a preconcentrate in combination with at least one surfactant to produce an effect, such as increasing or enhancing, emulsifying and/or stabilizing the preconcentrate, such as to promote emulsion formation. In some embodiments, at least one co-surfactant is hydrophilic. In some embodiments, the at least one co-surfactant is not in the free acid form.

I0O96)| Examples of co-surfactants suitable for use herein include, but are not limited to, short chain alcohols containing from 1 to 6 carbon atoms (e.g., ethanol), benzyl alcohol, alkane diols and triols (e.g., propylene glycol, glycerin, polyethylene glycols, such as PEG and PEG 400), glycol ethers such as tetraglycol and glycofurol (e.g. tetrahydrofurfuryl PEG ether), pyrrolidine derivatives such as M-methyl pyrrolidine (e.g.

RPpaptaztoime?F) and 2-pyrrolidine (e.g. Boishrpog P), and salts of bile acids, e.g. sodium deoxycholate. Additionally, examples include ethyl oleate.

I097) In some embodiments, the at least one co-surfactant comprises from about 1 95 to about 10 95 by weight relative to the weight of the preconcentrate.

Solvent 098) In some embodiments of the composition according to this description, such as a preconcentrate, additionally includes at least one solvent. As used herein, the term "solvent" means a substance added to a preconcentrate to effect and/or change the consistency of the preconcentrate, such as in an aqueous solution. In some embodiments, the solvent is hydrophilic.

Hydrophilic solvents suitable for this description include, but are not limited to, alcohols, including water-soluble alcohols such as pure ethanol and/or glycerol, and glycols, for example glycols derived from an oxide such as ethylene oxide such as 1,2- propylene glycol. Other non-limiting examples include polyols such as polyalkylene glycol, for example poly(C2-3)alkylene glycol such as polyethylene glycol. In at least one embodiment, the at least one solvent is a pharmaceutically acceptable solvent. 099) In some embodiments of this disclosure, the preconcentrate includes at least one substance that acts as both a co-surfactant and a solvent, such as an alcohol such as ethanol. In other embodiments, the preconcentrate includes at least one co-surfactant and at least one solvent that have different substances. For example, in some embodiments, the preconcentrate includes ethanol as a co-surfactant and glycerin as a solvent.

ИО10О0| In some embodiments of the present disclosure, the preconcentrate is a pharmaceutical preconcentrate comprising an oleic fatty acid mixture containing at least 75 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the oleic fatty acid mixture, wherein the EPA and DHA are in the form selected from ethyl ester and triglyceride; and at least one surfactant.

ИО101) In one version of the embodiment, the pharmaceutical preconcentrate includes: an oily mixture of fatty acids containing at least 95 95 ethyl ester ERA, ethyl ester ONA, or their mixtures by weight of the oily mixture of fatty acids; and at least one surfactant selected from polysorbate 20, polysorbate 80, and mixtures thereof.

I0O102) In another embodiment, the pharmaceutical preconcentrate includes: an oily mixture of fatty acids containing from about 80 95 to about 8895 EPA and ONA by weight of the oily mixture of fatty acids, where ERA and INA are in the form of an ethyl ester; and at least one surfactant selected from polysorbate 20, polysorbate 80 and mixtures thereof; wherein at least one surfactant comprises less than 40% by weight relative to the weight of the preconcentrate.

I0O103) In another embodiment, the pharmaceutical preconcentrate includes: an oily mixture of fatty acids containing from about 80 95 to about 8895 EPA and ONA by weight of the oily mixture of fatty acids, where the EPA and ONA are in the form of an ethyl ester; and at least one surfactant selected from polysorbate 20, polysorbate 80 and mixtures thereof; wherein at least one surfactant comprises less than 3595 by weight relative to the weight of the preconcentrate.

I0104) In some embodiments, for example, the pharmaceutical preconcentrate includes KV5EE as an oily mixture of fatty acids, and at least one surfactant selected from polysorbate 20, polysorbate 80, and mixtures thereof.

IO105) In another embodiment, the pharmaceutical preconcentrate includes an oily mixture of fatty acids containing from about 80 95 to about 8895 EPA and ONA by weight of the oily mixture of fatty acids, where the EPA and ONA are in the form of an ethyl ester; at least one surfactant selected from polysorbate 80; and at least one co-surfactant comprises ethanol.

ИО106) In some embodiments, the preconcentrate is in the form of a gelatin capsule or placed in a tablet. 0107) In other embodiments, the preconcentrate is a preconcentrate food supplement or a preconcentrate food supplement that includes an oil mixture of fatty acids containing from about 25 95 to about 75 95 EPA and ONA by weight of the oil mixture of fatty acids, where the EPA and pHA are in a form selected from ethyl ester and triglyceride; and at least one surfactant.

ИО108) In some embodiments, the ratio of the oil mixture of fatty acids:total amount of surfactant ranges from about 1:11 to about 200:1, from about 1:1 to about 100:1, from about 1:11 to about 50: 1, from about 1:11 to about 10:1, from about 1:11 to about 8:1, from about 1:1 or 6:1 from about 1:1 to about 5:1, from about 1:1 to about 4:1, or from about 1:1 to about 3:1.

I0O109)| In some embodiments, the at least one surfactant comprises from about 0.595 to about 40,956 by weight relative to the total weight of the preconcentrate.

For example, in some embodiments, the at least one surfactant comprises from about 1 95 to about 35 95, from about 5 90 to about 35 95, from about 10 95 to about 35 95, from about 15 95 to about 35 95, from about 15 95 to about 30 95, or from about 20 95 to about 30 95 by weight, relative to the total weight of the preconcentrate.

In one embodiment, at least one surfactant comprises approximately 20 95% by weight of the total weight of the preconcentrate.

ЗМЕВОБ/ЗМЕ0ОБ/5ЕВО5 0110) The preconcentrate of this description can be in the form of a self-nanoemulsifying drug delivery system (ZMEYUUО5), a self-microemulsifying drug delivery system (ZMEOO5), or a self-emulsifying drug delivery system (ZEVO5), where the preconcentrate forms an emulsion in an aqueous solution. 0111) Without being limited by theory, it is believed that the preconcentrate forms ZMEVO5, 5ZMEOOZ5, and/or

ZEBO5 through contact with the intragastric and/or intraintestinal environment in the body, where the preconcentrate forms an emulsion that includes micelle particles. The emulsion may, for example, provide an increase or improvement in the stability of fatty acids for absorption in the body and/or provide an increase in surface area for absorption. ZMEOO5B/5ZMEOO5/5EBOZ may thus provide increased or improved hydrolysis, solubility, bioavailability, absorption, or any combination thereof with respect to fatty acids and mimo.

I0O112)| Commonly known compositions of ЗМЕООУ5Б/5ЗМЕООУ5З/5ЕБОЗ include "10 mg of drugs and 500 mg of surface-active substances/joint surface-active substances. The ZMEOOZ/5MEOO5Z/5EOO5 disclosed herein may have an inverse ratio, ie, the amount of oily fatty acid mixture containing the active pharmaceutical ingredient (API) is greater than the amount of surfactant. 0113! The 5MEVOZ/5MEOO5/5EOOOZ disclosed herein may include particles with a size (ie, particle diameter) ranging from about 5 nm to about 10 μm. For example, in some embodiments, the particle size ranges from about 5 nm to about 1 rt, such as from about 50 nm to about 750 nm, from about 100 nm to about 500 nm, or from about 150 nm to about 350 nm.

Excipients 0114) The compositions disclosed herein may further include at least one inactive pharmaceutical ingredient, such as an excipient. Inactive ingredients may dissolve, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and/or shape the active ingredients into suitable and effective medicaments that would be safe, convenient, and/or otherwise suitable for use. The at least one inactive ingredient may be selected from colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium sterilfumarate, talc, titanium dioxide, and xanthan gum. 0115) The compositions disclosed herein may further include at least one antioxidant. Examples of antioxidants suitable for this description include, but are not limited to, ca-ocopherol (vitamin EE), disodium calcium EOTA, alpha tocopheryl acetates, butylhydroxytoluenes (BHTs), and butylhydroxyanisoles (BHAs).

ИО116)| The compositions disclosed herein may further include at least one superdisintegrant. Super disintegrants can, for example, improve disintegrant efficiency resulting in lower levels used compared to traditional disintegrants.

Examples of superdisintegrants include, but are not limited to, croscarmellose (crosslinked cellulose), crospovidone (crosslinked polymer), sodium starch glycolate (crosslinked starch), and soybean polysaccharides. Commercial examples of superdisintegrants include

KopPaop( (VAZE), Roiuriazdaope( XI. (IZR), and As-0i-50I (EMO VioRoiuteg).

ИЙО117| In some embodiments of this disclosure, the composition includes from about 1 95 to about 25 95 of at least one superdisintegrant by weight of the composition, taco. such as from about 1 95 to about 20 95 by weight, or from about 1 95 to about 15 95 by weight of the composition. In some embodiments, the composition includes at least one superdisintegrant in tablet form. 0118) The compositions disclosed herein may be administered, for example, in the form of a capsule, tablet, or any other form of drug delivery. For example, the composition can be placed in a capsule, such as a gelatin capsule. In some embodiments, the preconcentrate is placed in a gelatin capsule. 0119) In some embodiments of this disclosure, the capsule fill content ranges from about 0.400 g to about 1.600 g. For example, in some embodiments, the capsule fill content ranges from about 0.400 g to about 1.300 g, from about 0.600 g to about 1.200 g, from about 0.600 g to about 0.800 g, from about 0.800 g to about 1.000 g, from about 1.000 g to about 1.200 g, or any amount in between. For example, in some embodiments, the capsule fill content is about 0.600 g, about 0.800 g, about 1.000 g, or about 1.200 g. 0120) The capsules disclosed herein may be produced under low oxygen conditions to inhibit oxidation during the process production Preparation of capsules and/or microcapsules according to this description can be carried out following any of the methods described in the literature. Examples of such methods include, but are not limited to, simple coacervation methods (see, e.g.,

E5 2009346, EP 0052510, and EP 0346879), complex methods of coacervation (see, for example, B 1393805), methods of double emulsification (see, for example, Sh.5. 4,652,441), simple emulsification methods (see, for example, Sh.5. 5,445,832), and methods of evaporating the solvent (see, for example, ZV 2209937). These methods can, for example, provide continuous processing and flexibility in the batch size of the drug.

Methods or uses

I0121| The present disclosure further encompasses methods of treating and/or regulating at least one health-related problem in a subject in need thereof. The compositions disclosed herein may be administered, e.g., in the form of a capsule, tablet, or any other form of drug delivery, to a subject for the therapeutic treatment and/or regulation of at least one health-related problem, including , for example, unstable plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neuronal development, heart failure, and post-myocardial infarction. In some embodiments, the at least one health-related problem is selected from mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, heart failure, and post-myocardial infarction.

I0122| In one embodiment, a method of treating at least one health-related problem in a subject in need thereof comprises administering to the subject a pharmaceutical preconcentrate that contains a pharmaceutically effective amount of an oily fatty acid mixture containing at least 75 9o of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DOH) by weight of the oily mixture of fatty acids, where EPA and DOH are in a form selected from ethyl ester and triglyceride; and at least one surfactant. In some embodiments, the method treats at least one of high triglyceride levels, non-HDL cholesterol levels, and HO levels. cholesterol and/or MI levels. cholesterol 0123) In another embodiment, a method of treating at least one health-related problem in a subject in need thereof comprises administering to the subject a preconcentrate supplement comprising: an oily mixture of fatty acids that contains from about 25 95 up to about 7595 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form selected from an ethyl ester and a triglyceride; and at least one surfactant; wherein at least one health-related problem is selected from unstable plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neuronal development, heart failure, and post-myocardial infarction.

I0124)| In some embodiments, the preconcentrate as a pharmaceutical preparation or food additive forms a self-nanoemulsifying drug delivery system (ZMEOO5), a self-microemulsifying drug delivery system (ZMEYUBO5), or a self-emulsifying drug delivery system (SEBOZ) in an aqueous solution In some embodiments, the aqueous solution is an intragastric and/or intraintestinal medium.

ИЙО125| The total daily dose of the fatty acid oil mixture can be in the range of about 0.600 g to about 6,000 g. For example, in some embodiments, the total daily dose of the fatty acid oil mixture is in the range of about 0.800 g to about 4,000 g, from about 1,000 g to about 4,000 g, or from about 1,000 g to about 2,000 g. In one embodiment, the fatty acid oil mixture is selected from K85EE and AOR 103 fatty acid oil compositions. 0126) The preconcentrates disclosed herein may be administered in 1 to 10 doses, such as 1 to 4 times per day, such as once, twice, three times, or four times per day, and in addition, e.g. once, twice or thrice a day. Administration may be oral or any other form of administration that provides a dose of fatty acids, such as omega-3 fatty acids, to the subject.

I0127| The following examples are intended to illustrate this disclosure without, however, limiting its spirit. It is understood that one skilled in the art will be able to develop additional embodiments within the scope of this description.

EXAMPLES

ИО128) Example 1: Compatibility of preconcentrates with solvents 0129) The compatibility of solvents and preconcentrates with a constant amount of КВ5EE and

Tmzheep-80. The preconcentrates described in Table 8 were prepared according to the schemes below, on a w/w basis. Preconcentrates are visually inspected after mixing and again after storage for 24 hours at room temperature. Under the heading preconcentrate, the term "pure" means a clear homogeneous mixture; the term "turbid" means a heterogeneous mixture in which some turbidity can be observed by visual inspection. The degree of turbidity was not determined.

Table 8

Compatibility of solvent and preconcentrates

KV5-EE Tmeep-80 96 95 ethanol 96 95 ethanol

MG MG MG to nnnnnn

КВ5-ЕЕ Тмееп-80 ПЕГ 300 ПЕГ 300 ннннн""н'ннІжІІЗООООТОЬООИТОТЛТОТООЗІЧХТТЬШОЬ6ЬШНШСТЬСЧСТТЬЇХОЬДТЦТОТОООЛОЛОЛЛОЛОЛОТОТОЛОЛОТЛОИТИТИТТНТИТНТИНТЦИНЬИНИОООТИ (мо) (мг) (мо) ор реконцентр 4001 о ЇЇ 777777771707777777171717171777171717171717171011111111111|177 чистий

400 | 110 | 77777556 .| ...юююююююююйм89824ююбжышый и | Clean/ 400 | 0 | 77777990. Clean neck

KV5-EE Tmeep-80 Triacetin Triacetin 400 | 110 | -.р/р/ю358 | 66 | Muddy 400 | 0 | ./7/7//790022ЮюЮБЙДМД.| 2 skirts 150 | УКаламутний шиюинншШ"ЬШІЇИЇВИВВВВВВВВТЛТЛТЛТЛТЛТЛОООТТИТ?ИЦИТИОТТ?ИТИТТЛОТИТОТОМІІЛООБІНЛТВІМБІІВВВВІТІЬВВВВВТИТТИО (мо) (мг) (мг) ор реконцентр 400 | пїй0 ЇЇ 77777786 7 | 77777717. | Осад/7/ шиюиннш"СШІІЮИГІИШІІПВВШТШИІІОІАОИСТ ВІЛІТЛІЛВОВВВИТЬНТЙИЙТНТШХШТШШІЯЙХЙИХИХВВТОТ реконцентрат

MG MG MG up to 400 | 100 | -.KMUY 373 | 68 | Muddy shushshnSHIBYUOOOVVVVVVVVVLTLVTSOIIKOII6VTVNIIIIIIITITIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

KV5-EE Tmeep-80 1-tetradecanol 97 95 1-tetradecanol 97 95 400 | 100 | .YUKYU/yu358 7 | 7777 7 66 2 4 | Precipitate! шиюшнншШСГПИ ЦВОВВЛ ООИМВТВИМИОЛОозЗВИОИЛОООЛЛТМОЛОВОЛОМИИИЛОООЛОВЛОЛЛИШЗВЛТЛОИВОТОВООТИТТЙТЙТЙТІІІІІІІІІІІІІІІІІ

KV5-EE Tmeep-80 glycerin glycerin shiyuinnIsh"ГШИЖlОИИОООЛОООВВ ОВОВОИОИТЛОЛИВОТТТТТЙЙЙТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТТХТХХХХ (mg) (mg) (mo) 9 reconcentr

KV5-EE Tmeep-80 1-docosanol 98 95 1-docosanol 98 95 400 | 700 | 96 777777 1777777171717811771111 77111 Osad///

ИО130И| Example 2: Lipolysis and solubilization

ИО131| Studies were conducted to analyze the extent of lipolysis (ie, hydrolysis) and solubilization for various preconcentrates containing K85EE and various free fatty acids and surfactants. Specifically, four experiments were designed to determine how the amount of surfactant affects the rate and extent of lipolysis and solubilization. Lipolysis was carried out on Z«MEOO5 compositions including K85EBE. 0132) Materials - bile acid pains: pig bile extract (Zidta); contains glycine and bovine conjugates of hyodeoxycholic acid and other salts of bile acids. - Pancreatic lipase, pig pancreas (bidta); contains many enzymes including amylase, trypsin, lipase, ribonuclease and protease. - Lecithin: Phospholipids (IP IROI 5 RS with PYRO!IU AC) - Trisma maleate (Zidta Alagisp) - Tzhsheep 20, of molecular biological quality (ArriiSpet Ragteiayu, Tmeep 80 (RiyKa) - a-Linoleic acid (Zidta 60 Pho), Oleic acid (Aiagisp 90 95) - KV5O-EE and KV5-BA 0133) Preconcentrates A-E were prepared as shown in Table 9.

Table 9

Pre-concentrates A-E reconcentrate Free fatty acid acid substance in | КВ5ЕЕ(400му) (|oleic acid(00 mg) Tmeep20(75м) 779 | КВОЕЕ(400му) (COBRA (00му) / Tmeеп20(300му БЖ 117 E | К85ЕФфЩО0мОо | 77 - о тмееп80(0б0му)

ИО134) General method of lipolysis 0135) Functional model of lipolysis of the liver, developed by 7apdeppego EI AI. (apdeprego, M.N. ei a!., shk. U. Riapt. zsi. 14, 237-244, 2001; 7apdeprega, M.N., ei a!., Eshig. U. Rpagt. zsi. 14 , 115-122, 2001), was used with minor modifications. Lipolysis was carried out in a 600 ml glass vessel with a thermostat and double walls in the presence of pig bile extract with the constant addition of calcium chloride. The source of lipase was porcine pancreatin and hydrolysis was followed by titration with sodium hydroxide solution (1.0 M) using a pH-stat (pH 6.5). The initial composition of the lipolysis medium is shown in Table 10.

Table 10

The initial composition of the lipolysis medium

IO136) The final volume in all experiments was 300 ml and the frequency of calcium dosing during the experiments was 0.045 mmol/min (0.09 ml/min). In all experiments, the amount of KV5-EE was added according to 5.58 mg/ml.

I0137| To enter the lipolysis course of KV5-EE by HPLC, crude samples were removed and oxidized with dilute hydrochloric acid. Concentrations of EPA-EE, ONA-EE, EPA-RA and ONA-

EA was determined three times by HPLC. The experiments were carried out on the S. Adiepi device

Tespoiodiye5 1200 series at column temperature ZF(C, mobile phase (A) water (0.1 95 acetic acid) and (B) Mesm (0.1 95 acetic acid), with a gradient: from 0 to 8 minutes, from 70 95 V to 100 95 V; 8 to minutes 100 95 V; 16 to 16 minutes: 10095 V to 70 95 V; 16 to 20 minutes: 70 95 V.

The flow rate was 0.5 mL/min, OM (F 210 nM, injection volume: 5 μL, and run time: 20 minutes.

I0138) Concentrations of EPA ethyl ester (EPA-EE), ONA ethyl ester (ONA-EE), EPA free acid (EPA-EA), and ONA free acid (ONA-ERA) were monitored over time and lipolysis percentages were calculated as shown in Tables 11 for comparison with Otasy)

Table 11

Lipolysis of ERA and Ethyl Ester ONA in comparison with Otasogyu eekeenyutnlinno | ope polyn enter pi: Z PO x: PO PO Z: POD KO CO 0 1777111111117855777111171 11111115 1771111171117155.ЖДЖДК

ИО139)| Fig. 1, 4, 7, 10, 3, and 16 graphically depict the disappearance of ERA-EE and ONA-EE and the appearance of ERA-RA and

RNA-RA during lipolysis of each respective tested sample. Control points from 2 minutes to 233 minutes were included in the graphs. In addition, linear regression lines were included.

IO140) Fig. 2, 5, 8, 11, 14, and 17 show the percent recovery of ERAZHON at various time points for each respective sample tested. Data are given as the sum of EPA-EE, ONA-EE, EPA-RBA, and pHA-RA and are expressed as a percentage of the theoretical amount of 5580 µg/ml.

ИО141| Fig. 3, 6, 9, 12, 15, and 18 graphically depict the percentage of lipolysis at various time points for

ERA-EE, ONA-EE and general KV5EE. Values are calculated relative to the total amount of EPA-EE and ONA-EE determined by HPLC after lipolysis for 2 minutes. 0142) Example 3: Emulsions in pure water 0143) The content of oil in one OMASOKO capsule includes ethyl ester ERA (465 mg), ethyl ester

ONA (375 mg) and alpha-tocopherol (4 mg) which were mixed in a scintillation vial with various surfactants as shown below in Table 12. Water (10 ml) was added at 37 degrees Celsius and the mixture was shaken for 15 seconds using a vortex mixer.

The mixture was examined after 1 minute and after 5 minutes. The visual emulsion homogeneity score was calculated as defined below: no emulsion - score 0, emulsion but not homogeneous emulsion - score 1, homogeneous emulsion - score 2.

I0144| After mixing, the mixture was also rotated in a roller mixer for 5 minutes.

The visual score of this rotation test was the same as the above.

Table 12

Emulsions in pure water 2. Calculation after | Account after

Quantity. . vortex | vortex |Account after

Surface-active surface: - substance(s) of the active mixer of the roller miller substance (mg) during the mixer minutes minutes 1

6 | in Viet2 77777777 lo Her 211111 | 2 8 |vyee2M 77777777 |711loo Her 2111112 | 2 9 |VvyeeZ 77777777 |71loo Her 2111112 | sh 2 21 |RishopsvR-b8. 777777777 | 7100 Her 077717177171110 11 32 Tsf|Alpinovakislotai | 100 | 1 1777770 HER 1 acids

Macrogolglycerin- 1,2-Dipalmitoyl-5p-glycerin ze nd 00 190 37 |/-Hexadevanol.//-/-//// | 100 | 17177770 10 39 |Macroyul4bo ///-/-/-/////|71100 HER 0777717771110 11 acids

Vgi)F 52/ Macrogolglycerol-

Macrogol 400/ Macrogol-

Sodium alginate salt

RiigopiseFe -68/Riigopist 0145) Example 4: Emulsions in artificial gastric juice 0146) Oil content in one capsule OMASOKF), includes ethyl ester ERA (465 mg), ethyl ester

ONA (375 mg) and alpha-tocopherol (4 mg) which were mixed in a scintillation vial with various surfactants as shown below in Table 13. The experimental setup in the examples below is the same as previously described except that , that artificial gastric juice, which does not contain pepsin, was used instead of water (European

Pharmacopoeia 6.0, page 274).

Table 13

Emulsions in artificial gastric juice

How many Accounts after | Account after number. . Vortex Vortex Account after

Surfactant(s)) surface-: - and mixer roller mixer substance) active. during 1 during 5 substance mixer (mg) minutes minutes |none////// Ї77770717 17111701 1110 1 0

Vg) in52

VgvovU

Richhopisei-64

TmeepF4o

Macrogolglycerol-595 Hydroxystearate 40 100 2 2 2

I0147| Example 5: Emulsions in artificial intestinal fluid 0148) Oil content in one capsule OMASOKF), includes ethyl ester ERA (465 mg), ethyl ester

ONA (375 mg) and alpha-tocopherol (4 mg) which were mixed in a scintillation vial with various surfactants as shown below in Table 14. The experimental setup in the examples below is the same as previously described except that , that an artificial intestinal fluid with a pH of 6.8 without pancreatic powder was used instead of water (European Pharmacopoeia 6.0, page 274).

Table 14

Emulsions in artificial intestinal fluid

How many Accounts after | Account after number. . Vortex Vortex Account after

Surfactant(s) | surface- : - and mixer roller mixer substance) active. within 1 within 5 substance mixer (mg) minutes minutes 56 |None////:/ / | 0 | 2 SW0 11 B south 0 |! 0

Vg) in52

VgvovU

Richgopisvi-64 60 |Tmeepe40

Macrogolglycerol-b1 Hydroxystearate 40 100 2 2 2 0149) Example 6: Microscopic examination of emulsions 0150) Emulsions from Example 52 (gastric juice) and Example 58 (intestinal fluid) were examined under a microscope after 24 hours of rotation. Both emulsions were found to be oil-in-water suspensions with no tendency to aggregate.

IO151) Example 7: Pharmaceutical compositions 0152) The following examples in Table 15 depict pharmaceutical compositions that can be prepared.

Table 15

Pharmaceutical compositions n K85EE or oil mixture Surface-active substance or ryklad Mo daRIOZ system of surface-active substances

TmeepF 20

Tmeepf 40

2681

ИЙО153| In one embodiment, the surfactant or combination of surfactants is selected from Tmeepft surfactants; TmeepFf 20, TzhmeepF 40, TueepF 60, Tzhueepe 65, Tmeepe 80 and Tmeeepf 85. 0154) In another embodiment, the surfactant is selected from a combination of Tmeepf surfactants and a surfactant selected from Stetrpog?), such as TmeepfF 20 and Stgetrpog EG. Moreover, in an additional embodiment, surface-active substances

TmeepFf 20 and 5oYshchoi H5 15 can be used together, as well as TjeepFf 20 and Tueepf 40.

ИО155)| The oily mixture of fatty acids of pharmaceutical preconcentrates, where the oily mixture of fatty acids is K85EE or the oily composition ASR-103, is presented in Table 16.

Table 16

Oil mixture of fatty acids for pharmaceutical preconcentrates

NOV DDT | mnetecheeni | reduction 1000 mg oily mixture of fatty acids Minimum value Maximum value

KVOEE

111 Total Omega3 EE | about 59096 (mass/mass)

EE - ethyl ester

ИО156) Example 8: Additional emulsions in artificial gastric juice and artificial intestinal fluid

I0157| Preconcentrates 1-23 were prepared from ERA/JUNA ethyl ester (1000 mg K8B5EE) and various surfactants and surfactant mixtures as shown in Table 17 below. Emulsions were prepared in both artificial gastric juice and artificial intestinal fluid as described in Examples 4 and 5. The results were the same for the emulsion in artificial gastric juice and artificial intestinal fluid and are presented in Table 17.

Table 17

Emulsions in artificial gastric juice and artificial intestinal fluid. Account 2. Account after y

Surface- Amount of vortex after Account active) surface- vortex mixer after substance(s) active during 1 mixer | roller substance (mg) during 5 | mixer minutes minutes 1712 | Setorpouyev | 80 2 Sh | 2 | 1 | 2 1.6 | Setorpouyev | 250 | 62 yush | 2 | 2 1.8 | Setorpouyev | 400 | 2 | 2 | 2 1.79 | Setorpouyev | 50 | 2 | 2 | 2 | Setorpouyev | 60 | 2 | 2 | 2 113 |Sebtorpouyev | 90 | 2 | 2 | 2 '-

Stetorny EI. 150 16 x 2 2 1

TmeepFf 60 100

Stetorny B. 40 17 Vgi 30 20 2 2 2

ZrapF 85 20

Stethornpogo EII-

Stetorny EI. (610) 19 R 2 1 2

TmeepFf 80 70

Macrogolglycerol acr 2 1 2

Hydroxystearate 40

Macrogolglycerol

Hydroxystearate 40 90 21 dv r 2 1 2

Zrapfb 20 zo

Polysorbate 20 50

Macrogolglycerol

Hydroxystearate 40 (610) 22 dr P 2 1 2

Vp) 93 Zo

Polysorbate 20 bo

Stetorny B. bo

RiIsgopisF E68 from 23. 2 2 2

Vp) 92U zo

Polysorbate 20 20

ИО158) Emulsions 4-15 prepared both in artificial gastric juice and in artificial intestinal fluid were homogeneous (milky consistency) during several hours of exposure. Emulsions 1-3 separated slightly after preparation (ie, after several hours of exposure). Microscopy of emulsions 1-15 showed that the average particle size is less than 100 micrometers. Treatment for homogenization (Shigakitah(IKA)) of emulsion 4 for 20 seconds resulted in a significant increase in the formation of small particles (x" 10 microns).

I0159| On the basis of the obtained preconcentrates, it is shown that 0.5 95 nonionic surfactant (ie, Stetorpog?)) can emulsify the ethyl ester of ERA/JUNA both in artificial gastric juice and in artificial intestinal fluid. In addition, the inclusion of more than one surfactant was found to stabilize the emulsion. In addition, the particle size may vary depending on the emulsification method.

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Claims (90)

1. A pharmaceutical preconcentrate comprising: an oily fatty acid mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form selected from an ethyl ester and a triglyceride ; 1 at least one nonionic surface-active substance, and the pharmaceutical preconcentrate does not contain a therapeutic agent other than the oily mixture of fatty acids. 2. The preconcentrate according to item I, at least 75% of which is an oily mixture of EPA and ONA fatty acids, and at least 95% of it is EPA. 3. The preconcentrate according to claim 1, at least 75% of which is an oily mixture of EPA and ONA fatty acids, and at least 95% of it is ONA. 4. The preconcentrate according to item I, in which the oily mixture of fatty acids includes at least 90 90 omega-3 fatty acids by weight of the oily mixture of fatty acids. 5. The preconcentrate according to claim 4, in which at least one of the omega-3 fatty acids has a sev configuration. 6. Preconcentrate according to claim 1, in which the oily mixture of fatty acids additionally contains at least one other fatty acid, other than EPA and JNA, selected from o-linolenic acid (AHA), geneicosapentaenoic acid (HPA), o-docosapentaenoic acid (PPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), stearidonic acid (5TA), linoleic acid, gamma-linolenic acid (SIA), arachidonic acid (AA), osbondic acid (O5ropd), oleic acid, ricinoleic acid, erucic acids and their mixtures. 7. The preconcentrate according to claim 1, in which the fatty acid oil mixture is obtained from at least one oil selected from marine organism oil, algal oil, plant-based oil and microbial oil. 8. Preconcentrate according to claim 7, in which the oil of marine organisms is purified fish oil. 9, The preconcentrate according to item I, in which the mass ratio of EPA to JNA of the oil mixture of fatty acids is in the range of from about 1:10 to 10:1, from about 1:8 to 8.1, from about 1:6 to 6:1, from about 1:5 to 5:1, from about 14 to 4.1, from about 1:3 to 311, from about 1:2 to 2:1, from about 1:1 to 2:1, or from about 1:2 to 1:3. 10. The preconcentrate according to item I, in which at least one nonionic surfactant is selected from diacetyl monoglycerides, diethylene glycol monopalmitostearates, ethylene glycol monopalmitostearates, glyceryl behenates, glyceryl distearates, glyceryl monolinoleates, glyceryl monooleates, glyceryl monostearates, macrogolcetostearyl ethers, macrogol-15-hydroxystearates, macrohollauryl ethers, macrogolmonomethyl ethers, macrogololeyl ethers, macrogolstearates, menfegol, mono- and diglycerides, nonoxynols, octoxynols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl oleyl propylene glycolated castor acetates , propylene glycol laurates, propylene glycol monopalmitostearate, quilaya, sorbitan esters, sucrose esters, and their mixtures, and nonionic copolymers consist of a central hydrophobic polymer of polyoxypropylene (poly(propylene oxide)) and a hydrophilic polymer of at least one of polyethylene (poly(ethylene oxide)), polyethylene ethers, sorbitan esters, polyoxyethylene fatty acid esters, polyethylated castor oil and their mixtures. 11. Preconcentrate according to claim 10, in which at least one nonionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and their mixtures. 12. The preconcentrate according to item I, in which at least one nonionic surfactant is from about 0.5 90 to about 40 90, from about 10 95 to about 30 96, or from about 10 90 to about 25 90 by weight relative to the total masses of preconcentrate. 13. The preconcentrate according to claim 12, in which at least one nonionic surfactant is about 20% by weight relative to the total weight of the preconcentrate. 14. The preconcentrate according to item I, which additionally includes at least one common surfactant selected from short-chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile acid salts, and their mixtures. 15. The preconcentrate of claim 14, wherein the at least one co-surfactant is from about 1 90 to about 10 90 by weight relative to the total weight of the preconcentrate. 16. The preconcentrate according to item I, in which the ratio of the oil mixture of fatty acids to the total amount of surfactant is in the range of from about 1:1 to about 200:1, from about 1:1 to about 100:1, from about 1 :1 to about 501, from about 1:1 to about 10:1, from about 1:1 to about 8:1, from about 1:1 to 6:1, from about 1:11 to about 5:1, from about 1:11 to about 4:1 or from about 1:1 to about 3.1. 17. The preconcentrate according to item I, which additionally contains at least one pharmaceutically acceptable solvent selected from lower alcohols and polyols. 18. Preconcentrate according to claim 1, which additionally contains at least one antioxidant. 19. Preconcentrate according to claim 18, in which at least one antioxidant is selected from butylhydroxyanisoles (BHA) and alpha-tocopherol. 20. The preconcentrate according to claim 1, in which the oily mixture of fatty acids is present in a pharmaceutically effective amount. 21. Preconcentrate according to claim 1, which is presented in the form of a gelatin capsule. 22. The preconcentrate of claim 21, wherein the capsule fill content ranges from about 0.400 g to about 1.300 g, from about 0.600 g to about 1.200 g, or from about 0.800 g to about 1.000 g. 23. The preconcentrate according to item I, in which at least one nonionic surfactant includes Stethorpog Ely, and the preconcentrate additionally includes at least one co-surfactant selected from short-chain alcohols. 24. The preconcentrate according to item I, for use in the treatment of at least one health-related problem selected from unstable plasma lipid levels, cardiovascular system functions, immune functions, visual functions, insulin action, neuron development, heart failure, post-myocardial infarction, mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, elevated levels of triglyceride, elevated levels of non-NOI, cholesterol, elevated levels of OA, cholesterol and/or elevated levels of MIDI, cholesterol. 25. A pharmaceutical preconcentrate comprising: an oily fatty acid mixture that contains from about 80,90 to about 88,905 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oily mixture, wherein the EPA and DHA are in the form of ethyl ester; and at least one nonionic surfactant selected from polysorbate 20, polysorbate 80 and mixtures thereof; and the pharmaceutical preconcentrate does not contain a therapeutic agent other than an oily mixture of fatty acids. 26. A pharmaceutical preconcentrate comprising: an oily fatty acid mixture that contains from about 80,90 to about 88,905 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in the form of ethyl ester; at least one nonionic surfactant selected from polysorbate 20, polysorbate 80 and their mixtures; 1 at least one co-surfactant, which includes ethanol, and the pharmaceutical preconcentrate does not contain a therapeutic agent other than the oily mixture of fatty acids. 27. A self-nanoemulsifying drug delivery system (SDM), a self-microemulsifying drug delivery system (SMEID5), or a self-emulsifying drug delivery system (SDMD) that includes a pharmaceutical preconcentrate containing: an oily mixture of fatty acids that includes from about 80 90 to about 88 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DOH) by weight of the fatty acid blend oil, wherein the EPA and DOH are in a form selected from an ethyl ester and a triglyceride; and at least one nonionic surfactant; wherein the preconcentrate forms an emulsion in an aqueous solution, and the pharmaceutical preconcentrate does not contain a therapeutic agent other than an oily mixture of fatty acids. 28. The system of claim 27, wherein the fatty acid oil mixture comprises at least 90 9o omega-3 fatty acids by weight of the fatty acid oil mixture. 29. The system of claim 28, wherein at least one of the omega-3 fatty acids has the following configuration. 30. The system according to claim 27, in which the oily mixture of fatty acids additionally includes at least one other fatty acid, other than EPA and ONA, selected from o-linolenic acid (AHA), geneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), eicosatetraenoic acid acid (ETA), eicosatrienoic acid (ETE), stearidonic acid (5TA), linoleic acid, gamma-linolenic acid (SI.A), arachidonic acid (AA), osbondic acid, oleic acid, ricinoleic acid, erucic acid and their mixtures . 31. The system of claim 27, wherein the fatty acid oil mixture is derived from at least one oil selected from marine organism oil, algal oil, plant-based oil, and microbial oil. 32. The system of claim 31, wherein the marine oil is purified fish oil. 33. The system of claim 27, wherein the mass ratio of EPA to ONA of the oily fatty acid mixture is in the range of from about 1:10 to 10:11, from about 1:8 to 8:1, from about 1:6 to 6:1 , from about 1:5 to 5:1, from about 14 to 4.1, from about 1:3 to 311, from about 1:2 to 2:1, from about 1:1 to 2:1, or from about 1:2 to 1:3. 34. Система за claim 27, у якій принаймні одна неіонна поверхнево-активна речовина вибрана з діацетилмоногліцеридів, діетиленглікольмонопальмітостеаратів, етиленглікольмонопальмітостеаратів, гліцерилбегенатів, гліцерилдистеаратів, гліцерилмонолінолеатів, гліцерилмоноолеатів, гліцерилмоностеаратів, макроголцетостеарилових етерів, макрогол-15-гідроксистеаратів, макроголлаурилових етерів, макроголмонометилових етерів, макрогололеїлових ethers, macroholstearates, menfegol, mono- and diglycerides, nonoxynols, octoxynols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laurates, propylene glycol monopalmitostearate, quilaya, sorbitan esters, esters, and sucrose and their mixtures copolymers consist of a central hydrophobic polymer of polyoxypropylene (poly(propylene oxide)) and a hydrophilic polymer of at least one of polyethylene (poly(ethylene oxide)), polyethylene ethers, sorbitan esters, polyoxyethylene fatty acid esters, polyethylated castor oil, and mixtures thereof. 35. The system according to claim 34, in which at least one nonionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof. 36. The system of claim 27, wherein the at least one nonionic surfactant is from about 0.5% to about 40,905, from about 10,905 to about 30,90 or from about 10,90 to about 25,95 by weight relative to the total weight preconcentrate 37. The system of claim 36, wherein the at least one nonionic surfactant is about 20 95 by weight relative to the total weight of the preconcentrate. 38. The system according to claim 27, in which the preconcentrate additionally includes at least one co-surfactant selected from short-chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile acid salts, and mixtures thereof. 39. The system of claim 38, wherein the at least one co-surfactant is from about 1 90 to about 10 95 by weight relative to the total weight of the preconcentrate. 40. The system of claim 27, wherein the mass ratio of the oil mixture of fatty acids to the total amount of surfactant is in the range of from about 1:1 to about 200:1, from about 1:1 to about 100:1, from about 1 :1 to about 50:1, from about 1:1 to about 10:1, from about 1:1 to about 8:1, from about 1:1 to 6:1, from about 1:11 to about 5:1 , from about 1:11 to about 4:1 or from about 1:1 to about 3.1. 41. The system of claim 27, wherein the preconcentrate further comprises at least one pharmaceutically acceptable solvent selected from lower alcohols and polyols. 42. The system of claim 27, wherein the preconcentrate further includes at least one antioxidant. 43. The system according to claim 42, in which at least one antioxidant is selected from butylhydroxyanisoles (BHA) and alpha-tocopherol. 44. The system of claim 27, wherein the oily mixture of fatty acids is present in a pharmaceutically effective amount. 45. The system according to claim 27, which is in the form of a gelatin capsule. 46. The system of claim 45, wherein the capsule fill content ranges from about 0.400 g to about 1.300 g, from about 0.600 g to about 1.200 g, or from about 0.800 g to about 1.000 g. 47. The system of claim 27, wherein the emulsion particle size ranges from about 150 nm to about 350 nm. 48. A method of treating at least one health-related problem in a subject in need thereof, comprising administering to the subject a pharmaceutical preconcentrate comprising: an oily fatty acid mixture comprising at least 75% eicosapentaenoic acid ( EPA) and docosahexaenoic acid (DHA) by weight of the oily mixture of fatty acids, where EPA and DHA are in a form selected from ethyl ester and triglyceride; and at least one nonionic surfactant; and at least one health-related problem selected from unstable plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neuron development, heart failure, post-myocardial infarction, mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, increased levels of triglyceride, increased levels of non-NOI, cholesterol, increased levels of I.O, cholesterol and/or increased levels of MI.O1, cholesterol; and the pharmaceutical preconcentrate does not contain a therapeutic agent other than an oily mixture of fatty acids. 49. The method of claim 48, wherein the at least one health problem is selected from elevated levels of triglyceride, elevated levels of non-NOI, cholesterol, elevated levels of 101, cholesterol 1/or elevated levels of MIP, cholesterol. 50. The method according to claim 48, in which the oil mixture of fatty acids includes at least 90 90 omega-3 fatty acids by weight of the oil mixture of fatty acids. 51. The method according to claim 50, in which at least one of the omega-3 fatty acids has the following configuration. 52. The method according to claim 48, in which the oily mixture of fatty acids additionally includes at least one other fatty acid, other than EPA and ONA, selected from o-linolenic acid (AHA), geneicosapentaenoic acid (HPA), docosapentaenoic acid (ORA), eicosatetraenoic acid acid (ETA), eicosatrienoic acid (ETE), stearidonic acid (5TA), from linoleic acid, gamma-linolenic acid (О1.А), arachidonic acid (AA), osbondic acid, oleic acid, ricinoleic acid, erucic acid and their mixtures 53. The method according to claim 48, in which the oily mixture of fatty acids is obtained from at least one oil selected from marine organism oil, algal oil, plant-based oil and microbial oil. 54. The method according to claim 53, in which the oil of marine organisms is purified fish oil. 55. The method of claim 48, wherein the mass ratio of EPA to ONA of the oily fatty acid mixture is in the range of from about 1:10 to 10:11, from about 1:8 to 81, from about 1:6 to 6:1, from about 1:5 to 5:1, about 14 to 4.1, about 1:3 to 311, about 1:2 to 2:1, about 1:1 to 2:1, or about 1:2 to 1 :3. 56. Спосіб за claim 48, у якому принаймні одну неіонну поверхнево-активну речовину вибирають З діацетилмоногліцеридів, діетиленглікольмонопальмітостеаратів, етиленглікольмонопальмітостеаратів, гліцерилбегенатів, гліцерилдистеаратів, гліцерилмонолінолеатів, гліцерилмоноолеатів, гліцерилмоностеаратів, макроголцетостеарилових етерів, макрогол-15-гідроксистеаратів, макроголлаурилових етерів, макроголмонометилових етерів, макрогололеїлових ethers, macroholstearates, menfegol, mono- and diglycerides, nonoxynols, octoxynols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laurates, propylene glycol monopalmitostearates, quilia and their esters, sorbitanose mixtures, and nonionic copolymers consist of a central hydrophobic polymer of polyoxypropylene (poly(propylene oxide)) and a hydrophilic polymer of at least one of polyethylene (poly (ethylene oxide)), polyethylene ethers, sorbitan esters, polyoxyethylene fatty acid esters, polyethylated castor oil and their mixtures. 57. The method according to claim 56, in which at least one nonionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and their mixtures. 58. The method according to claim 48, in which the preconcentrate additionally includes at least one common surfactant selected from short-chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile acid salts, and mixtures thereof. 59. The method according to claim 48, in which the preconcentrate additionally includes at least one antioxidant. 60. The method according to claim 48, in which the preconcentrate is in the form of a gelatin capsule. 61. The method of claim 60, wherein the capsule fill content ranges from about 0.400 g to about 1.300 g, from about 0.600 g to about 1.200 g, or from about 0.800 g to about 1.000 g. 62. The method according to claim 48, in which the preconcentrate is administered once, twice or three times a day. 63. The method according to n. 48, in which the preconcentrate forms a self-nanoemulsifiable drug delivery system (SDM5), a self-microemulsifiable drug delivery system (6MEPO5), or a self-emulsifying drug delivery system (ZE0ЮО5) in an aqueous solution. 64. A preconcentrate food or nutritional supplement comprising: an oily fatty acid mixture that includes from about 25 90 to about 75 96 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oily mixture, where EPA and DHA are in a form selected from ethyl ester and triglyceride; and at least one nonionic surfactant; and the preconcentrate of the food or nutritional supplement does not contain a therapeutic agent other than an oily mixture of fatty acids. 65. The preconcentrate according to claim 64, wherein the fatty acid oil mixture is from about 35 96 to about 75 95 EPA and ONA by weight of the fatty acid oil mixture, from about 40 96 to about 70 95 EPA and ONA by weight of the fatty acid oil mixture, from about 40 96 to about 65 95 EPA and ONA by weight of the oil mixture of fatty acids, from about 40 96 to about 60 905 EPA and ONA by weight of the oil mixture of fatty acids, from about 40 96 to about 55 95 ERA and UNA by weight of the oil mixture of fatty acids or from about 905 to about 5595 EPA and JNA by weight of the oil mixture of fatty acids. 66. The preconcentrate of claim 64, wherein the fatty acid oil mixture is derived from at least one oil selected from marine organism oil, algal oil, plant-based oil, and microbial oil. 67. Preconcentrate according to claim 66, in which the oil of marine organisms is purified fish oil. 68. The preconcentrate of claim 64, wherein the mass ratio of EPA to JNA of the fatty acid oil mixture is in the range of from about 1:10 to about 10:1, from about 1:8 to about 8:1, from about 1:6 to about 6:1, from about 1:5 to about 5.1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2. to about 2:1, from about 1:1 to about 2:1, or from about 1:2 to about 1:3. 69. Преконцентрат за claim 64, у якому принаймні одна неіонна поверхнево-активна речовина вибрана З діацетилмоногліцеридів, діетиленглікольмонопальмітостеаратів, етиленглікольмонопальмітостеаратів, гліцерилбегенатів, гліцерилдистеаратів, гліцерилмонолінолеатів, гліцерилмоноолеатів, гліцерилмоностеаратів, макроголцетостеарилових етерів, макрогол-15-гідроксистеаратів, макроголлаурилових етерів, макроголмонометилових етерів, макрогололеїлових ethers, macroholstearates, menfegol, mono- and diglycerides, nonoxynols, octoxynols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laurates, propylene glycol monopalmitostearates, quilia and their esters, sorbitanose mixtures and nonionic copolymers consist of a central hydrophobic polymer of polyoxypropylene (poly(propylene oxide)) and a hydrophilic polymer of at least one of polyethylene (poly(ethylene oxide)), polyethylene ethers, sorbitan esters, polyoxyethylene fatty acid esters, polyethylated castor oil and their mixtures. 70. The preconcentrate according to claim 69, in which at least one nonionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and their mixtures. 71. The preconcentrate according to claim 64, which additionally includes at least one common surfactant selected from short-chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile acid salts, and mixtures thereof. 72. Preconcentrate according to claim 64, which additionally includes at least one antioxidant. 73. The preconcentrate according to claim 64, in which the preconcentrate is in the form of a gelatin capsule. 74. The preconcentrate of claim 73, wherein the capsule fill content ranges from about 0.400 g to about 1.300 g, from about 0.600 g to about 1.200 g, or from about 0.800 g to about 1.000 g. 75. The preconcentrate according to claim 64, in which the preconcentrate ensures the formation of a self-nanoemulsifying drug delivery system (5MEYU5), a self-microemulsifying drug delivery system (5MEYUY5) or a self-emulsifying drug delivery system (SEDI) in an aqueous solution. 76. Preconcentrate food or nutritional supplement according to claim 64, in which at least one nonionic surfactant includes StethorpogFf EI, and the preconcentrate additionally includes at least one co-surfactant selected from short-chain alcohols. 77. The preconcentrate of a food or nutritional supplement according to claim 64, in which at least one nonionic surface-active substance includes polysorbate 20; the oily fatty acid mixture additionally includes at least one other fatty acid selected from oleic acid; and the preconcentrate further comprises at least one antioxidant. 78. Preconcentrate of a food or nutritional supplement according to claim 64, in which EPA and ONA are in the form of ethyl ester; and at least one nonionic surfactant selected from polysorbate 20, polysorbate 80, and mixtures thereof. 79. A method of increasing at least one parameter selected from hydrolysis, solubility, bioavailability, absorption, and combinations thereof of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which combines: an oily mixture of fatty acids that includes EPA and DHA in a form selected from ethyl ester and triglyceride; and at least one nonionic surfactant; and the oily mixture of fatty acids and at least one surfactant forms a preconcentrate, and the preconcentrate is either a therapeutic agent or is not a therapeutic agent; and, if the preconcentrate is a therapeutic agent, then said preconcentrate does not contain a therapeutic agent other than an oily mixture of fatty acids. 80. The method according to claim 79, in which the oily mixture of fatty acids consists of at least 75 90 eicosapentaenoic acid (EPA) and docosahexaenoic acid (ONA) by weight of the oily mixture of fatty acids. 81. The method according to claim 79, in which the oily mixture of fatty acids consists of from about 25 90 to about 75 9Uo of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DOH) by weight of the oily mixture of fatty acids. 82. Спосіб за claim 79, у якому принаймні одну неіонну поверхнево-активну речовину вибирають З діацетилмоногліцеридів, діетиленглікольмонопальмітостеаратів, етиленглікольмонопальмітостеаратів, гліцерилбегенатів, гліцерилдистеаратів, гліцерилмонолінолеатів, гліцерилмоноолеатів, гліцерилмоностеаратів, макроголцетостеарилових етерів, макрогол-15-гідроксистеаратів, макроголлаурилових етерів, макроголмонометилових етерів, макрогололеїлових ethers, macroholstearates, menfegol, mono- and diglycerides, nonoxynols, octoxynols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laurates, propylene glycol monopalmitostearates, quilia and their esters, sorbitanose mixtures, and nonionic epipolymers consist of a central hydrophobic polymer of polyoxypropylene (poly(propylene oxide)) and a hydrophilic polymer of at least one of polyethylene (pol and (ethylene oxide)), polyethylene ethers, sorbitan esters, polyoxyethylene fatty acid esters, polyethylated castor oil and their mixtures. 83. The method according to claim 82, in which at least one nonionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and their mixtures. 84. The method according to claim 79, in which the preconcentrate additionally includes at least one common surface-active substance selected from short-chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile acid salts, and mixtures thereof. 85. The method of claim 80, wherein the preconcentrate includes: an oily fatty acid mixture that includes from about 80,90 to about 88,956 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, where EPA and DHA are in a form selected from an ethyl ester and a triglyceride; 1 at least one nonionic surfactant selected from polysorbate 20, polysorbate 80 and their mixtures. 86. The method according to claim 80, in which the preconcentrate includes: an oily fatty acid mixture that includes from about 80 90 to about 88 95 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oily mixture, where EPA and DHA are in a form selected from an ethyl ester and a triglyceride; at least one nonionic surfactant selected from polysorbate 20, polysorbate 80 and their mixtures; 1 at least one common surfactant, which includes ethanol. 87. The method according to claim 79, in which the preconcentrate forms a self-nanoemulsifying drug delivery system (5MEYU5), a self-microemulsifying drug delivery system (5MEROB) or a self-emulsifying drug delivery system (BE) in an aqueous solution. 88. The method of claim 87, wherein the system comprises an emulsion with a particle size ranging from about 150 nm to about 350 nm. 89. A pharmaceutical preconcentrate comprising: an oily fatty acid mixture comprising at least 75 90 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oily mixture, wherein the EPA and DHA are in a form selected from an ethyl ester and a triglyceride ; at least one nonionic surfactant; at least one other fatty acid and at least one antioxidant, wherein the pharmaceutical preconcentrate does not contain a therapeutic agent other than the oily mixture of fatty acids. 90. The preconcentrate of claim 89, wherein the fatty acid oil mixture comprises about 84 96 EPA and ONA, by weight of the fatty acid oil mixture, wherein the EPA and ONA are in a form selected from an ethyl ester and a triglyceride; at least one nonionic surfactant includes polysorbate 20; at least one other fatty acid includes oleic acid; and at least one antioxidant comprises butylhydroxyanisoles (BHAs).