WO2013072767A1

WO2013072767A1 - Compositions and preconcentrates comprising at least one salicylate and omega-3 fatty acid oil mixture

Info

Publication number: WO2013072767A1
Application number: PCT/IB2012/002850
Authority: WO
Inventors: Gunnar Berge; Preben Houlberg Olesen; Svein Olaf Hustvedt; Anette MÜLLERTZ; Jo Erik Johnsrud KLAVENESS
Original assignee: Pronova Biopharma Norge As
Priority date: 2011-11-18
Filing date: 2012-11-16
Publication date: 2013-05-23

Abstract

The present disclosure relates generally to compositions and preconcentrates comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or from about 25% to about 70% EPA and DHA, by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate. The present disclosure also relates to preconcentrates of the present disclosure in a form of a self-nanoemulsifying drug delivery system (SNEDDS), a self-microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS).

Description

COMPOSITIONS AND PRECONCENTRATES COMPRISING AT LEAST ONE SALICYLATE AND OMEGA-3 FATTY ACID OIL MIXTURE

[001] This application claims priority to U.S. Provisional Application Nos. 61/561,374, filed on November 18, 201 1, and 61/718,937, filed on October 26, 2012, which are incorporated herein by reference in their entirety.

[002] The present disclosure is generally directed to compositions and preconcentrates comprising a fatty acid oil mixture comprising at least 70% omega-3 fatty acids or derivatives thereof and aspirin (acetylsalicylic acid) or other salicylates suitable for oral administration, and methods of use thereof. The compositions and preconcentrates presently disclosed may be administered to a subject for therapeutic treatment and/or regulation of at least one health problem including, for example, irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, heart failure, and post myocardial infarction (Ml).

[003] In humans, cholesterol and triglycerides are part of lipoprotein complexes in the bloodstream and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) fractions. Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL, and released into the plasma. High levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (a membrane complex for LDL-C and VLDL-C) promote human atherosclerosis and decreased levels of HDL-C and its transport complex. Apolipoprotein A is also associated with the development of atherosclerosis. Furthermore, cardiovascular morbidity and mortality in humans can vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. In addition, research suggests that non-HDL cholesterol is an indicator of hypertriglyceridemia, vascular disease, atherosclerotic disease, and related conditions. In fact, NCEP ATP III specifies non-HDL cholesterol reduction as a treatment objective.

[004] Omega-3 fatty acids may regulate plasma lipid levels, cardiovascular and immune functions, insulin action, and neuronal development, and visual function. Marine oils, also commonly referred to as fish oils, are a source of omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and have been found to regulate lipid metabolism. Plant-based oils and microbial oils are also sources of omega-3 fatty acids. Omega-3 fatty acids may have beneficial effects on the risk factors for cardiovascular diseases, for example hypertension and hypertriglyceridemia, and on the coagulation factor VII phospholipid complex activity. Omega-3 fatty acids may also lower serum triglycerides, increase serum HDL cholesterol, lower systolic and diastolic blood pressure and/or pulse rate, and may lower the activity of the blood coagulation factor Vll-phospholipid complex. Further, omega-3 fatty acids are generally well-tolerated, without giving rise to severe side effects.

[005] Several formulations of omega-3 fatty acids have been developed. For example, one form of omega-3 fatty acid oil mixture is a concentrate of primary omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA, such as sold under the trademarks OMACOR® / LOVAZA™ / ZODIN® / SEACOR®. See, for example, U.S. Patent Nos. 5,502,077, 5,656,667, 5,698,594, and 7,732,488. In particular, each 1000 mg capsule of LOVAZA™ contains at least 90% omega-3 ethyl ester fatty acids (84% EPA/DHA): approximately 465 mg EPA ethyl ester and approximately 375 mg DHA ethyl ester.

[006] However, evidence suggests that long chain fatty acids and alcohols of up to at least C24 are reversibly interconverted. Enzyme systems exist in the liver, fibroblasts, and the brain that convert fatty alcohols to fatty acids. In some tissues, fatty acids can be reduced back to alcohols. The carboxylic acid functional group of fatty acid molecules targets binding, but this ionizable group may hinder the molecule from crossing the cell membranes, such as of the intestinal wall. As a result, carboxylic acid functional groups are often protected as esters. The ester is less polar than the carboxylic acid, and may more easily cross the fatty cell membranes. Once in the bloodstream, the ester can be hydrolyzed back to the free carboxylic acid by enzyme esterase in the blood. It may be possible that the plasma enzymes do not hydrolyze the ester fast enough, however, and that the conversion of ester to free carboxylic acid predominantly takes place in the liver. Ethyl esters of polyunsaturated fatty can also be hydrolyzed to free carboxylic acids in vivo.

[007] Aspirin and other salicylates have several drug effects, including analgesic, antipyretic, antithrombotic and anti-inflammatory activities. Aspirin belongs to the group non-steroid anti-inflammatory drugs (NSAIDs) and inhibits the enzyme cyclooxygenase (COX). This enzyme is responsible for formation of several important biological mediators from the fatty acid arachidonic acid. These mediators are called prostanoids and include prostaglandins, prostacyclin and thromboxane. There are two main isoforms of COX; COX-1 and COX-2. NSAIDs generally inhibit both COX-1 and COX-2, however, some relative new NSAIDs, the coxibs like for example celecoxib, inhibit selectively only COX-2.

[008] Aspirin and other salicylates include, in addition to acetylsalicylic acid, salicylic acid, salicylsalicylic acid (salsalate) and acetylsalicylsalicylic acid, pharmaceutically acceptable salts thereof such as for example sodium salts (acetylsalicylic acid sodium salt, salicylic acid sodium salt), salts with amines such as, for example, triethanolamine salt (trolamine acetylsalicylate, trolamine salicylate), salts with basic amino acids (such as, for example, lysine acetylsalicylate and lysine salicylate) and other salicylates such as, for example, salicylates described in Martindale: The Complete Drug Reference (36 Ed.) 2009 page 1.

[009] From the prior art different compositions comprising omega-3 oils and acetylsalicylic acid are known. EP 1 352 648 describes a pharmaceutical composition comprising acetylsalicylic acid in powder or crystal form and at least one oil of the so-called "omega-3" group, all enclosed in a soft elastic capsule. The omega-3 oil functions as an adjuvant and not as an active substance. This is also evident from the Examples where the actual amount of oil is low. The indication is prevention of thrombosis.

[010] However, WO2008/025819 considers that the stability of formulations of acetylsalicylic acid or its pharmaceutically acceptable derivatives in soft capsules, such as those described in EP 1 352 648, is not yet satisfactory. To solve this problem WO 2008/025819 provides formulations using a compound of the cyclodextrin class for stabilizing formulations of acetylsalicylic acid or its pharmaceutically acceptable derivatives against hydrolysis to salicylic acid, in soft capsules comprising an internal liquid or semi-liquid oil phase, containing the partly dissolved and partly suspended acetylsalicylic acid characterized in that the compound of the cyclodextrin class is suspended in the same internal oil phase and/or is present in the soft capsule shell. The oil phase comprises at least one omega-3 oil.

[01 1] WO 2008/068276 discloses a soft gelatin capsule comprising a shell of gelatinous material, said shell being in direct contact with a liquid or pasty lipophilic phase present within the capsule, in which the lipophilic phase comprises aspirin, characterized in that the internal lipophilic phase also comprises substances chosen from the group consisting of pharmaceutically acceptable solid polyhydroxylated organic compounds and water-soluble hygroscopic salts. The internal lipophilic phase comprises mixtures of polyunsaturated fatty acids or their esters with alcohol and the polyunsaturated fatty acid belong to the omega-3 and/or omega-6 series.

[012] WO 2002/089787 discloses pharmaceutical formulations for oral administration in which a fatty acid preparation containing more than 70% EPA or EPA derivative and less than 10% DHA or a DHA derivative and less than 10% linoleic acid or a linoleic acid derivative is combined in the same dosage form or same pack with an enzyme inhibitor selected from an inhibitor of COX-1 and/or COX-2, an inhibitor of LOX and an inhibitor of one or more of the FACL enzymes. The formulations can be used for the treatment of various diseases. No enabling examples for the preparation of these formulations are given. [013] DE10056351 discloses a pharmaceutical preparation comprising omega-3 fatty acids and other active substances; e.g, an anti-inflammatory cyclooxygenase II inhibitor, 5- lipoxygenase inhibitor or platelet aggregation inhibitor. The preparation can be used for the treatment of various diseases. No enabling examples for the preparation of these formulations are given.

[014] There remains a need in the art for compositions and/or methods to improve the prophylaxis and treatment of serious diseases like irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, heart failure, and post myocardial infarction.

[015] The present disclosure relates to a combined preparation providing the beneficial effects of both omega-3 fatty acids and salicylates. For example, when combining active substances, such as omega-3 fatty acids and salicylates, the solubility and the stability of each respective substances are considerations. The possible concerns related to stability of the drugs include chemical stability and physical stability. The chemical reactivity between substances generally increases when compounds are in solution; however, compounds might also react on the surface of solid materials. Another stability issue is the physical stability of the product. If drug substances are soluble in the formulation, one possible concern would be the physical stability, especially the potential for precipitation and uncontrolled crystal growth. The crystalline properties of drug substances often affect dissolution of the drug in the gastrointestinal system and thereby bioavailability.

[016] Esters such as EPA ethyl ester, DHA ethyl ester, and acetylsalicylic acid may to a certain extent be unstable and might undergo hydrolysis. For example, acetylsalicylic acid forms salicylic acid and acetic acid during hydrolysis. Furthermore, many omega-3 fatty acids, such as EPA and DHA, are polyunsaturated fatty acids. The double bonds in these molecules might undergo oxidation. In general, fixed dose combinations might result in unwanted oxidation of the double bonds in EPA and/or DHA.

[017] The present disclosure is directed to a composition comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, methyl or ethyl ester, phospholipid, and triglyceride; and at least one salicylate.

[018] The compositions according to the present disclosure primarily comprise the fatty acid oil mixture and the at least one salicylate. Accordingly, the fatty acid oil mixture comprises at least 70% by weight of the compositions, such as at least 75% by weigth, such as at least 80% by weigth, such as at least 85% by weigth, such as at least 90% by weigth , such as at least 95% by weigth, of the compositions depending on how the at least one salicylate is incorporated into the compositions. The at least one salicylate may be incorporated into the compositions in several ways as described below.

[019] The present disclosure is directed to a composition in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[020] The present disclosure is further directed to a composition in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said at least one salicylate is chosen from acetylsalicylic acid or salicylic acid and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[021] The present disclosure is further directed to a composition in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said at least one salicylate is chosen from pharmaceutically acceptable salts of acetylsalicylic acid or salicylic acid where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[022] The present disclosure is further directed to a composition in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said capsule is coated with a gastroresistant material and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[023] The present disclosure is further directed to a composition in a gelatin capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said gelatin capsule is coated with a gastroresistant material and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[024] The present disclosure is further directed to a composition in a gelatin capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said gelatin capsule is coated with a gastroresistant material, the at least one salicylate is chosen among acetylsalicylic acid and salicylic acid and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[025] The present disclosure is further directed to a composition in a gelatin capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said gelatin capsule is coated with a gastroresistant material, the at least one salicylate is chosen among pharmaceutically acceptable salts of acetylsalicylic acid and salicylic acid, and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[026] The present disclosure is further directed to a composition in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate where said at least one salicylate is coated with a gastroresistant material and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[027] In some embodiments the at least one salicylate may be encapsulated or partially encapsulated in the wall-forming material of the capsules.

[028] The present disclosure is also directed to preconcentrates comprising; a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant. [029] The present disclosure is also directed to preconcentrates in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[030] The present disclosure is also further directed to preconcentrates in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant where said capsule is coated with a gastroresistant material.

[031] The present disclosure is also further directed to preconcentrates in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant where said capsule is coated with a gastroresistant material and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[032] The present disclosure is also further directed to preconcentrates comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant where said at least one salicylate is coated with a gastroresistant material.

[033] The present disclosure is also further directed to preconcentrates in a capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant where said salicylate is coated with a gastroresistant material and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule.

[034] In some embodiments the at least one salicylate may be encapsulated or partially encapsulated in the wall-forming material of the capsules. [035] The present disclosure is also directed to a pharmaceutical preconcentrate comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate; and at least one surfactant.

[036] The present disclosure is also directed to a pharmaceutical preconcentrate comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate; and at least one surfactant chosen from polysorbates.

[037] The present disclosure is also further directed to a pharmaceutical preconcentrate in a capsule form comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate; and least one surfactant chosen from polysorbates where said capsules are coated with a gastroresistant material.

[038] The present disclosure is also further directed to a pharmaceutical preconcentrate comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate, and at least one surfactant chosen from polysorbates where said at least one salicylate is coated with a gastroresistant material.

[039] The present disclosure is also directed to a pharmaceutical preconcentrate comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate chosen from acetylsalicylic acid, salicylic acid, and pharmaceutically acceptable salts thereof, and at least one surfactant chosen among polysorbates. [040] The present disclosure is also directed to a pharmaceutical preconcentrate comprising: from about 65% to about 70% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 15% to about 20% by weight, relative to the weight of the preconcentrate, of at least one salicylate chosen from acetylsalicylic acid, salicylic acid, and pharmaceutically acceptable salts thereof; and at least one surfactant chosen among polysorbates.

[041] The present disclosure is also directed to a pharmaceutical preconcentrate comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate; and at least two surfactants.

[042] The present disclosure is also directed to a pharmaceutical preconcentrate in a gelatin capsule form comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate; and at least two surfactants, where said capsules are coated with a gastroresistant material.

[043] The present disclosure is also directed to a pharmaceutical preconcentrate comprising: from about 45% to about 55% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 1 % by weight, relative to the weight of the preconcentrate, of at least one salicylate; and at least two surfactants, where said at least one salicylate is coated with a gastroresistant material.

[044] The present disclosure is also directed to a preconcentrate in a gelatin capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form at least one salicylate; and at least one surfactant.

[045] The present disclosure is further directed to a preconcentrate comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the fatty acid oil mixture comprises from about 50% to about 60% EPA in free fatty acid form, by weight of the fatty acid oil mixture, and from about 15% to about 25% DHA in free fatty acid form, by weight of the fatty acid oil mixture; at least one salicylate; and at least one surfactant. The preconcentrate may be in capsule form, such as, e.g., gelatin capsules.

[046] The present disclosure is also directed to a pharmaceutical preconcentrate comprising: from about 60% to about 70% by weight, relative to the weight of the preconcentrate, of a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; at least one salicylate; and from about 30% to about 40% by weight, relative to the weight of the preconcentrate, of at least two surfactants.

[047] The present disclosure is also directed to a composition comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, and at least one salicylate, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[048] The present disclosure is also directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a preconcentrate, e.g. in a capsule form, comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, at least one salicylate, and at least one surfactant, and wherein the preconcentrate forms an emulsion in an aqueous solution.

[049] The present disclosure is also directed to a composition in a capsule form, e.g. a gelatin capsule, comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, and at least one salicylate where said capsule is coated with a gastroresistant material, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[050] The present disclosure is also directed to a composition comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, and at least one salicylate, where said at least one salicylate is coated with a gastroresistant material, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[051] The present disclosure is also directed to a composition in a gelatin capsule form comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, and at least one salicylate where said capsule is coated with a gastroresistant material and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[052] The present disclosure is also directed to a composition in a gelatin capsule form comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, and at least one salicylate where said salicylate is coated with a gastroresistant material and where said capsules comprise at least 200 mg EPA and DHA per capsule, such as at least 300 mg EPA and DHA per capsule, such as at least 400 mg EPA and DHA per capsule, such as at least 500 mg EPA and DHA per capsule, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[053] The present disclosure is also directed to a preconcentrate comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, at least one salicylate, and at least one surfactant, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[054] The present disclosure is also directed to a preconcentrate in a capsule form, e.g. a gelatin capsule, comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, at least one salicylate, and at least one surfactant where said capsules are coated with a gastroresistant material, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thromobosis cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[055] The present disclosure is also directed to a preconcentrate comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, at least one salicylate, and at least one surfactant where said at least one salicylate is coated with a gastroresistant material, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thromobosis cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[056] The present disclosure is also directed to a preconcentrate comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form, at least one salicylate and at least one surfactant, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[057] The present disclosure is also directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a preconcentrate in a gelatin capsule form comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, at least one salicylate, and at least one surfactant, and wherein the preconcentrate forms an emulsion in an aqueous solution, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[058] The present disclosure is also directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a preconcentrate comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form, at least one salicylate and at least one surfactant, and wherein the preconcentrate forms an emulsion in an aqueous solution, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[059] The present disclosure is also directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a preconcentrate comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride, at least one salicylate and at least one surfactant, and wherein the preconcentrate forms an emulsion in an aqueous solution, for the treatment of at least one health problem chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[060] The present disclosure is further directed to a composition comprising: a fatty acid oil mixture comprising from about 25% to about 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate.

[061] The present disclosure is also directed to a preconcentrate comprising: a fatty acid oil mixture comprising from about 25% to about 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant.

DESCRIPTION

[062] Particular aspects of the disclosure are described in greater detail below. The terms and definitions as used in the present application and as clarified herein are intended to represent the meaning within the present disclosure. The patent and scientific literature referred to herein and referenced above is hereby incorporated by reference. The terms and definitions provided herein control, if in conflict with terms and/or definitions incorporated by reference. The singular forms "a," "an," and "the" include plural reference unless the context dictates otherwise. The terms "approximately" and "about" mean to be nearly the same as a referenced number or value. As used herein, the terms "approximately" and "about" should be generally understood to encompass + 10% of a specified amount, frequency or value.

[063] The terms "administer," "administration" or "administering" as used herein refer to (1) providing, giving, dosing and/or prescribing by either a health practitioner or his authorized agent or under his direction a composition according to the disclosure, and (2) putting into, taking or consuming by the patient or person himself or herself, a composition according to the disclosure. [064] The present disclosure provides for compositions comprising a fatty acid oil mixture and at least one salicylate as well as at least one free fatty acid formulated as capsules, e.g., gelatin capsules, and tablets that may be coated. The compositions disclosed herein may comprise pharmaceutical compositions, food supplement compositions, medical products, non-medical products, and nutritional supplement compositions, for example.

[065] Also disclosed herein are preconcentrates comprising a fatty acid oil mixture, at least one salicylate and at least one surfactant. The preconcentrates of the present disclosure can produce dispersions of low or very low mean particle size when mixed with an aqueous medium. Such dispersions can be characterized as nanoemulsions, microemulsions, or emulsions. For example, upon delivery, the preconcentrates are thought to produce dispersions with gastric or other physiological fluids generating self-nanoemulsifying drug delivery systems (SNEDDS), self- microemulsifying drug delivery systems (SMEDDS), or self-emulsifying drug delivery systems (SEDDS). The preconcentrates disclosed herein may comprise pharmaceutical preconcentrates, food supplement preconcentrates, and nutritional supplement preconcentrates, for example.

FATTY ACID OIL MIXTURE

[066] Compositions and preconcentrates of the present disclosure comprise a fatty acid oil mixture. As used herein, the term "fatty acid oil mixture" includes fatty acids, such as unsaturated (e.g., monounsaturated, polyunsaturated) or saturated fatty acids, as well as pharmaceutically- acceptable esters, free acids, mono-, di- and triglycerides, derivatives, conjugates, precursors, salts, and mixtures thereof. The fatty acid oil mixture comprises eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In some embodiments the fatty oil mixture comprises EPA and DHA in a form chosen from free fatty acid, ethyl ester, phospholipid, and triglyceride. In addition to EPA and DHA, the fatty acid oil mixture may, in some embodiments, comprise one or more further fatty acids, such as omega-3 fatty acids other than EPA and DHA, in a form chosen, e.g., from free fatty acid, ethyl ester, and triglyceride.

[067] 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., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Patent No. 6,245,81 1, each hereby incorporated by reference), precursors, salts, and mixtures thereof. Examples of omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated, long- chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a-linolenic acid (ALA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e., stearidonic acid, STA); esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary and/or tertiary alcohol, such as, for example, fatty acid methyl esters and fatty acid ethyl esters. The omega-3 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and/or mixtures thereof according to the present disclosure can be used in their pure form and/or as a component of an oil, for example, as marine oil (e.g., fish oil and purified fish oil concentrates), algae oils, microbial oils and plant-based oils.

[068] As mentioned above, the fatty acid oil mixture of the present disclosure may further comprise at least one fatty acid other than EPA and DHA. Examples of such fatty acids include, but are not limited to, omega-3 fatty acids other than EPA and DHA and omega-6 fatty acids. For example, in some embodiments of the present disclosure, the fatty acid oil mixture comprises at least one fatty acid other than EPA and DHA chosen from a-linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DP A), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and stearidonic acid (STA), and mixtures thereof. In some embodiments, the at least one fatty acid other than EPA and DHA is chosen from linoleic acid, gamma-linolenic acid (GLA), arachidonic acid (AA), docosapentaenoic acid (i.e. osbond acid), and mixtures thereof. In some embodiments, the at least one fatty acid other than EPA and DHA comprises omega-9 fatty acids, such as oleic acid. In some embodiments, the at least one fatty acid other than EPA and DHA comprises sesame oil. In some embodiments, the at least one fatty acid other than EPA and DHA is in a form chosen from free fatty acid, ethyl ester, and triglyceride. In other embodiments, the at least one fatty acid other than EPA and DHA is in free acid form.

[069] Examples of further fatty acids, or mixtures thereof (fatty acid oil mixtures) encompassed by the present disclosure include, but are not limited to, the fatty acids defined in the European Pharmacopoeia Omega-3 Ethyl Esters 90 and purified marine oils, for example, the European Pharmacopoeia Omega-3 Acid Triglycerides, the European Pharmacopoeia Omega-3 acid Ethyl Esters 60, the European Pharmacopoeia Fish Oil Rich in Omega-3 Acids monograph, and/or for instance, the USP fish oil monograph.

[070] Commercial examples of omega-3 fatty acids suitable for the present disclosure comprising different fatty acid mixtures (e.g., that can be in the form of triglycerides (TG), ethyl esters (EE), free fatty acid form (FA) and/or as phospholipids) include, but are not limited to: Incromega™ omega-3 marine oil concentrates such as Incromega™ E1070, Incromega™ TG7010 SR, Incromega™ E7010 SR, Incromega™ TG6015, Incromega™ EPA500TG SR, Incromega™ E400200 SR, Incromega™ E4010, Incromega™ DHA700TG SR, Incromega™ DHA700E SR, Incromega™ DHA500TG SR, Incromega™ TG3322 SR, Incromega™ E3322 SR, Incromega™ TG3322, Incromega™ E3322, Incromega™ Trio TG/EE, Incromega™ F2250, Incromega™ F2628, Incromega™ E2251 , Incromega™ F2573, Incromega™ TG2162, Incromega™ TG2779, Incromega™ TG2928, Incromega™ TG3525, and Incromega™ E5015 (Croda International PLC, Yorkshire, England); EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX7010EE, EPAX5500EE, EPAX5500TG, EPAX5000EE, EPAX5000TG, EPAX6000EE, EPAX6000TG,

EPAX6000FA, EPAX6500EE, EPAX6500TG, EPAX4510TG, EPAX1050TG, EPAX205GTG, EPAX 7010TG, EPAX7010EE, EP AX6015TG/EE, EPAX4020TG, and EPAX4020EE (EPAX, formerly a wholly-owned subsidiary of Norwegian company Austevoll Seafood ASA, has been acquired by Trygg Pharma); MEG-3® EPA/DHA fish oil concentrates (Ocean Nutrition Canada); DHA FNO "Functional Nutritional Oil" and DHA CL "Clear Liquid" (Lonza); Superba™ Krill Oil (Aker); omega-3 products comprising DHA produced by Martek; Neptune krill oil (Neptune); cod- liver oil products and anti-reflux fish oil concentrate (TG) produced by Mollers; Lysi Omega-3 Fish oil; Seven Seas Triomega® Cod Liver Oil Blend (Seven Seas); Fri Flyt Omega-3 (Vesteralens); Pronova PURE™ products such as 10:70 EE/TG, 70: 10 EE/TG, 50:30, 500:200 EE/TG, 400:200 EE/TG, 360:240 EE TG, and 150:600 EE/TG; Epadel™ by Mochida; and Omthera products such as 44-55 mg/g EPA-FFA (Amarin; >97% EPA-EE) and 15-25 mg/g DHA-FFA.

[071] The fatty acid oil mixture according to the present disclosure may be derived from animal oils and/or non-animal oils. In some embodiments of the present disclosure, the fatty acid oil mixture is derived from at least one oil chosen from marine oil, algae oil, plant-based oil, and microbial oil. Marine oils include, for example, fish oil, krill oil, and lipid composition derived from fish. Plant-based oils include, for example, flaxseed oil, canola oil, mustard seed oil, and soybean oil.

[072] Microbial oils include, for example, products by Martek. In at least one embodiment of the present disclosure, the fatty acid oil mixture is derived from a marine oil, such as a fish oil. In at least one embodiment, the marine oil is a purified fish oil.

[073] In some embodiments of the present disclosure, the fatty acids, such as omega-3 fatty acids, of the fatty acid oil mixture are esterified, such as alkyl esters. The alkyl esters may include, but are not limited to, ethyl, methyl, propyl, and butyl esters, and mixtures thereof. In other embodiments, the fatty acids are chosen from mono-, di-, and triglycerides.

[074] In some embodiments, the fatty acid oil mixture is obtained by a transesterification of the body oil of a fat fish species coming from, for example, anchovy or tuna oil, and subsequent physico-chemical purification processes, including urea fractionation followed by molecular distillation. In some embodiments, the crude oil mixture may also be subjected to a stripping process for decreasing the amount of environmental pollutants and/or cholesterol before the transesterification.

[075] In another embodiment, the fatty acid oil mixture is obtained by using supercritical C02 extraction or chromatography techniques, for example, to up-concentrate primary EPA and DHA from fish oil concentrates. Commercial embodiments of fatty acids in triglyceride form encompassed by the present disclosure include, but are not limited to, K85TG (Pronova BioPharma Norge AS). Commercial embodiments of fatty acids in ethyl ester form encompassed by the present disclosure include, but are not limited to, K85EE (Pronova BioPharma Norge AS).

[076] In another embodiment, the fatty acid oil mixture is obtained by hydrolyzing a fatty acid oil mixture in ethyl ester form. Commercial embodiments of fatty acids in free acid form encompassed by the present disclosure include, but are not limited to, K85FA (Pronova BioPharma

Norge AS).

[077] In some embodiments of the present disclosure, at least one of the omega-3 fatty acids of the fatty acid oil mixture has a cis configuration. Examples include, but are not limited to, (all-Z)-9, 12, 15-octadecatrienoic acid (ALA), (all-Z)- 6,9, 12, 15-octadecatetraenoic acid (ST A), (all- Z)-l l ,14, 17-eicosatrienoic acid (ETE), (all-Z)-5,8,l l , 14, 17-eicosapentaenoic acid (EPA), (all-Z)- 4,7, 10, 13, 16, 19-docosahexaenoic acid (DHA), (all-Z)-8, l l , 14, 17-eicosatetraenoic acid (ETA), (all- Z)- 7, 10, 13, 16, 19-docosapentaenoic acid (DPA), (all-Z)-6,9, 12, 15, 19- heneicosapentaenoic acid (HP A); (all-Z)-5,8, l l , 14-eicosatetraenoic acid, (all-Z)- 4,7, 10, 13, 16-docosapentaenoic acid (osbond acid), (all-Z)-9, 12-octadecadienoic acid (linoleic acid), (all-Z)-5,8, l 1 , 14-eicosatetraenoic acid (AA), (all-Z)-6,9,12- octadecatrienoic acid (GLA); (Z)-9-octadecenoic acid (oleic acid), 13(Z)-docosenoic acid (erucic acid), (R-(Z))-12-hydroxy-9-octadecenoic acid (ricinoleic acid).

[078] In some embodiments of the present disclosure, the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 : 10 to about 10: 1 , from about 1 :8 to about 8: 1 , from about 1 :7 to about 7: 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: 1. In at least one embodiment, the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to about 2: 1. In at least one embodiment, the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 : 1 to about 2: 1. In at least one embodiment, the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to about 1 :3.

[079] In some embodiments of the present disclosure, the compositions comprise a fatty acid oil mixture in a form chosen from free fatty acid, ethyl ester, and triglyceride and at least one salicylate.

[080] In some embodiments of the present disclosure, the fatty acid oil mixture, together with the at least one salicylate, act as an active pharmaceutical ingredient (API), individually or in combination. In other embodiments, the at least one salicylate is the sole API. In some embodiments, the fatty acid oil mixture and the at least one salicylate are present in pharmaceutically-acceptable amounts. As used herein, the term "pharmaceutically-effective amount" means an amount sufficient to treat, e.g., reduce and/or alleviate the effects, symptoms, etc., at least one health problem in a subject in need thereof. [081] In compositions where the fatty acid oil mixture acts as an active pharmaceutical ingredient, for example, the fatty acid oil mixture may comprise at least 70% EPA and DHA by weight of the fatty acid oil mixture. For example, in one embodiment, the fatty acid oil mixture comprises at least 80% EPA and DHA by weight of the fatty acid oil mixture, such as at least 85%, at least 90%, or at least 95%, by weight of the fatty acid oil mixture. In some embodiments, the fatty acid oil mixture comprises about 80% EPA and DHA by weight of the fatty acid oil mixture, such as about 85%, about 90%, about 95%, or any number in between, by weight of the fatty acid oil mixture.

[082] For example, in some embodiments, the fatty acid oil mixture comprises from about 70% to about 95% EPA and DHA by weight of the fatty acid oil mixture, such as from about 70% to about 90%, from about 70% to about 88%, from about 70% to about 85%, from about 70% to about 80%, from about 80% to about 95%, from about 80% to about 90%, from about 80% to about 85%, from about 85% to about 95%, from about 85% to about 90%, and further for example, from about 90% to about 95% EPA and DHA, by weight of the fatty acid oil mixture, or any number in between. In at least one embodiment, the fatty acid oil mixture comprises from about 80% to about 85% EPA and DHA, by weight of the fatty acid oil mixture, such as from about 80% to about 88%, such as about 84% or 85%, by weight of the fatty acid oil mixture.

[083] In some embodiments, the fatty acid oil mixture comprises at least 95% of EPA or DHA, or EPA and DHA, by weight of the fatty acid oil mixture.

[084] In a further embodiment, the fatty acid oil mixture may comprise other omega-3 fatty acids. For example, the present disclosure encompasses at least 90% omega-3 fatty acids, by weight of the fatty acid oil mixture.

[085] In one embodiment, for example, the fatty acid oil mixture comprises from about 70% to about 88% EPA and DHA, by weight of the fatty acid oil mixture, wherein the fatty acid oil mixture comprises at least 90% of omega-3 fatty acids, by weight of the fatty acid oil mixture.

[086] In another embodiment, the fatty acid oil mixture comprises from about 70% to about 88% EPA and DHA, by weight of the fatty acid oil mixture, wherein the fatty acid oil mixture comprises at least 90% of omega-3 fatty acids, by weight of the fatty acid oil mixture, and wherein the fatty acid oil mixture comprises ot-linolenic acid (ALA).

[087] In one embodiment, the fatty acid oil mixture comprises from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, and further comprises docosapentaenoic acid (DP A).

[088] In another embodiment, the fatty acid oil mixture comprises from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, and further comprises from about 1% to about 4% (all-Z omega-3)-6,9, 12, 15, 18- heneicosapentaenoic acid (HP A), by weight of the fatty acid oil mixture. In another embodiment, the fatty acid oil mixture comprises from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture; and from 1% to about 4% fatty acids other than EPA and DHA, by weight of the fatty acid oil mixture, wherein the fatty acids other than EPA and DHA have C20, C21, or C22 carbon atoms.

[089] In one embodiment, the fatty acid oil mixture may comprise K85EE or AGP 103 (Pronova BioPharma Norge AS). In another embodiment, the fatty acid oil mixture may comprise K85TG (Pronova BioPharma Norge AS). In yet another embodiment, the fatty acid oil mixture may comprise K85FA (BioPharma Norge AS).

[090] In some embodiments of the present disclosure, the compositions provide for enhanced bioavailability, such as greater than about 40% increase in bioavailability, such as, about 80% increase, relative to OMACOR.

EPA AND DHA PRODUCTS

[091] In at least one embodiment, the fatty acid oil mixture comprises at least 70% EPA and DHA by weight of the fatty acid oil mixture, of which at least 95% is EPA. In another embodiment, the fatty acid oil mixture comprises at least 80% EPA and DHA by weight of the fatty acid oil mixture, of which at least 95% is EPA. In yet another embodiment, the fatty acid oil mixture comprises at least 90% EPA and DHA by weight of the fatty acid oil mixture, of which at least 95% is EPA.

[092] In another embodiment, the fatty acid oil mixture comprises at least 70% EPA and DHA by weight of the fatty acid oil mixture, of which at least 95% is DHA. For example, in one embodiment, the fatty acid oil mixture comprises at least 80% EPA and DHA by weight of the fatty acid oil mixture, of which at least 95% is DHA. In another embodiment, the fatty acid oil mixture comprises at least 90% EPA and DHA by weight of the fatty acid oil mixture, of which at least 95% is DHA.

[093] In said embodiments EPA and DHA are, as mentioned, in a form chosen from free fatty acid, ethyl ester, and triglyceride, or mixtures thereof. In some embodiments, the EPA and DHA may be chosen from phospholipid form as well.

[094] The amount of EPA and DHA ethyl ester in one dosage unit, e.g. in the form of a capsule, ranges, for example, from about 800 mg/g to about 880 mg/g of EPA ethyl ester and DHA ethyl ester, from about 430 mg/g to about 495 mg/g EPA ethyl ester and from about 350 mg/g to about 400 mg/g DHA ethyl ester.

AT LEAST ONE SALICYLATE

[095] The at least one salicylate may be incorporated into the compositions, preconcentrates, and capsules disclosed herein in several ways. For example, the at least one salicylate may be dissolved or suspended in the fatty acid oil mixture. In at least one embodiment, the at least one salicylate comprises "beads"— small particles agglomerated together—in the fatty acid oil mixture. In another embodiment, the at least one salicylate is encapsulated in tablets or capsules present in the fatty acid oil mixture which is itself contained in a capsule (sometimes called "cap-in-cap"). In yet another embodiment, the at least one salicylate comprises a dispersion of nanoparticles in the fatty acid oil mixture.

[096] As another way the at least one salicylate may be incorporated into the compositions, preconcentrates, and capsules disclosed herein, the at least one salicylate may be incorporated or partially incorporated into the wall of the capsule containing the fatty acid oil mixture.

[097] As yet another option, the at least one salicylate may be present in or on the coating of the capsule containing the fatty acid oil mixture. In one such embodiment, the at least one salicylate is sprayed onto the outside of the capsule containing the fatty acid oil mixture. In another such embodiment, the at least one salicylate is present between two coatings on the outside of the capsule containing the fatty acid oil mixture.

[098] The at least one salicylate may be chosen from, for example, aspirin and other salicylates, which include, in addition to acetylsalicylic acid and salicylic acid, pharmaceutically acceptable salts such as for example sodium salts (acetylsalicylic acid sodium salt, salicylic acid sodium salt), salts with amines like for example triethanolamine salt ( trolamine acetylsahcylate, trolamine salicylate), salts with basic amino acids like (lysine acetylsahcylate and lysine salicylate) and other salicylates such as salicylates described in Martindale: The Complete Drug Reference (36 Ed.) 2009 page 1. Still other salisylates include salicylsalicylic acid (salsalate) and acetylsalicylsalicylic acid.

[099] As noted above, the at least one salicylate may be dissolved in the oil, i.e. the fatty acid oil mixture, or suspended in the oil. In some embodiments the at least one salicylate is dissolved in the fatty acid oil mixture and the EPA and DHA are in free fatty acid form. In other embodiments the at least one salicylate is dissolved in the fatty acid oil mixture and the EPA and DHA are in ethyl ester form. One further aspect of the present disclosure relates to compositions where the at least one salicylate is partly dissolved in the oil.

[0100] The suspended at least one salicylate may be in the form of crystalline material or amorphous material. The particle size may vary over a wide range from nanoparticulate material to millimeter sized materials. The suspended at least one salicylate may be in the form of pure salicylate like acetylsalicylic acid, salicylic acid or pharmaceutically acceptable salts thereof. In another aspect of the present disclosure, the at least one salicylate is in the form of a granulated material that might comprise additional materials such as well-known pharmaceutical excipients, such as for example carbohydrates. In some embodiments the at least one salicylate is microencapsulated and contained in the fatty acid oil mixture and the EPA and DHA of the fatty acid oil mixture are in free fatty acid form. In other embodiments the at least one salicylate is microencapsulated and contained in the fatty acid oil mixture and the EPA and DHA of the fatty acid oil mixture are in ethyl ester form. The term "microencapsulated" means that the at least one salicylate is surrounded by a coating to give small capsules. The material inside the microcapsule, i.e. the at least one salicylate, is referred to as the core, whereas the coating is referred to as a shell, wall, or membrane. The coating may, e.g., comprise gastrointestinal material such as enteric material. The term microencapsulated used herein does also contemplate that the at least one salicylate is encapsulated or contained in the wall-forming material of the capsule containing the fatty acid oil mixture.

[0101] The compositions of the at least one salicylate and fatty acid oil mixture are according to the present disclosure substantially or free from water. If the composition is formulated in a gelatin capsule, the capsule may comprise some water, but the fatty acid oil mixture/salicylate mixture should for example contain less than 5% (w/w) water, for example less than 3% (w/w) water, such as less than 2% (w/w) water and such as less than 1% water. If the composition comprises some water, the water should for example be in a non-active form such as for example crystal-bond water.

[0102] In another embodiment the at least one salicylate may be partially or wholly contained in the wall-forming material of the capsule, i.e. the salicylate may be microencapsulated in the wall of the capsules containing the fatty acid oil mixture. In another embodiment all of the at least one salicylate may be microencapsulated in the wall of the capsules. In some embodiments the at least one salicylate is microencapsulated in the wall-forming material of the capsule, and the EPA and DHA of the fatty acid oil mixture are in free fatty acid form and contained in the cavity of the capsule. In still other embodiments the at least one salicylate is microencapsulated in the wall-forming material of the capsule, and the EPA and DHA of the fatty acid oil mixture are in ethyl ester form. In those embodiments, the EPA and DHA of the fatty acid oil mixture can be in a form chosen from free fatty acid form and ethyl ester form.

[0103] In some embodiments, the pharmaceutical composition comprises a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free fatty acid form; and where the at least one salicylate is dissolved in the fatty acid oil mixture. In some embodiments the pharmaceutical composition comprises a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid

(DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; and where the at least one salicylate is dissolved in the fatty acid oil mixture.

[0104] In other embodiments, the pharmaceutical composition comprises a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free fatty acid form; and where the at least one salicylate is microencapsulated and contained in the fatty acid oil mixture. In still other embodiments the pharmaceutical composition comprises a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; and where the at least one salicylate is microencapsulated and contained in the fatty acid oil mixture. The pharmaceutical compositions can be formulated as capsules.

[0105] The present disclosure is also directed to a pharmaceutical composition in a capsule form, e.g. a gelatin capsule, comprising a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free fatty acid form; and where the at least one salicylate is microencapsulated in the wall-forming material of the capsule. The present disclosure is also directed to a pharmaceutical composition in a capsule form, e.g. a gelatin capsule, comprising a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; and where the at least one salicylate is microencapsulated in the wall forming material of the capsule,

[0106] The amount of the at least one salicylate in one dosage unit, e.g. in the form of a capsule, ranges, for example, from about 30 to about 300 mg, such as from about 40 to a bout- 250 mg, such as from about 50 to about 200 mg, such as from about 75 to about 150 mg. In at least one embodiment, the amount of the at least one salicylate in one dosage unit is chosen from 75 mg, 100 mg, and 150 mg.

SURFACTANT / PRECONCENTRATE

[0107] The present disclosure also relates to omega-3/salicylate compositions in the form of a preconcentrate.

[0108] The present disclosure provides for a preconcentrate composition, wherein the term "preconcentrate" refers to a composition comprising at least a fatty acid oil mixture, at least one salicylate and at least one surfactant. In some embodiments, for example, the preconcentrate comprises a fatty acid oil mixture in a form chosen from free fatty acid, ethyl ester, and triglyceride, at least one salicylate, and at least one surfactant. In other embodiments, the preconcentrate comprises a fatty acid oil mixture in free acid form, at least one salicylate and at least one surfactant. In still other embodiments, the preconcentrate comprises a fatty acid oil mixture in ethyl ester form, a salicylate, and at least one surfactant.

[0109] A surfactant may, for example, lower the surface tension of a liquid or the surface tension between two liquids. For example, surfactants according to the present disclosure may lower the surface tension between the fatty acid oil mixture and an aqueous solution.

[01 10] Chemically speaking, surfactants are molecules with at least one hydrophilic part and at least one hydrophobic (i.e., lipophilic) part. Surfactant properties may be reflected in the hydrophilic-lipophilic balance (HLB) value of the surfactant, wherein the HLB value is a measure of the degree of hydrophilic versus lipophilic properties of a surfactant. The HLB value normally ranges from 0 to 20, where a HLB value of 0 represents high hydrophilic character, and a HLB of 20 represents high lipophilic character. Surfactants are often used in combination with other surfactants, wherein the HLB values are additive. The HLB value of surfactant mixtures may be calculated as follows:

HLBA (fraction of surfactant A) + HLBB (fraction of surfactant B) = HLBA+B mixture

[01 1 1 ] Surfactants are generally classified as ionic surfactants, e.g., anionic or cationic surfactants, and nonionic surfactants. If the surfactant contains two oppositely charged groups, the surfactant is named a zwitterionic surfactant. Other types of surfactants include, for example, phospholipids.

[01 12] In at least one embodiment of the present disclosure, the composition comprises at least one surfactant chosen from nonionic, anionic, cationic, zwitterionic surfactants, and mixtures thereof.

[0113] Non-limiting examples of nonionic surfactants suitable for the present disclosure are mentioned below.

[01 14] Pluronic(R) surfactants are nonionic copolymers composed of a central hydrophobic polymer (polyoxypropylene(poly(propylene oxide))) with a hydrophilic polymer (polyoxyethylene(poly(ethylene oxide))) on each side. Various commercially-available PLURONIC® products are listed in Table 1.

Table 1. Examples of PLURONIC® surfactants

PLUR0N1C®L-121 non-ionic 4400 1.0-7.0

PLURONIC®P-123 non-ionic 5800 7-9

PLURONIC®F-68 non-ionic 8400 more than 24

PLURONIC®F-108 non-ionic 14600 more than 24

[01 15] In at least one embodiment, the nonionic surfactants are chosen from nonionic copolymers composed of a central hydrophobic polymer (polyoxypropylene(poly(propylene oxide))) with a hydrophilic polymer of at least one of (polyoxyethylene(poly(ethylene oxide))), polyethylene ethers, sorbitan ethers, polyoxyethylene fatty acid esters, polyethylated castor oil, and mixtures thereof.

[01 16] BRIJ® are nonionic surfactants comprising polyethylene ethers. Various commercially-available BRIJ® products are listed in Table 2.

Table 2: Examples of BRIJ® surfactants

[01 17] SPAN® are nonionic surfactants comprising sorbitan esters. SPAN® is available from different sources including Aldrich. Various commercially-available SPAN® products are listed in Table 3.

Table 3: Examples of SPAN® surfactants

[01 18] TWEEN® (polysorbates) are nonionic surfactants comprising polyoxyethylene sorbitan esters. Various commercially-available TWEEN® products are listed in Table 4. Table 4: Examples of TWEEN® surfactants

[01 19] In at least one embodiment, the nonionic surfactants are chosen from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

[0120] MYRJ® are nonionic surfactants comprising polyoxyethylene fatty acid esters. Various commercially-available MYRJ® products are listed in Table 5.

Table 5: Examples of MYRJ® surfactants

[0121] CREMOPHOR® are nonionic surfactants. Various commercially-available CREMOPHOR® products are listed in Table 6.

Table 6: Examples of Cremophor(R) surfactants.

[0122] According to the present disclosure, other exemplary nonionic surfactants include, but are not limited to, diacetyl monoglycerides, diethylene glycol monopalmitostearate, ethylene glycol monopalmitostearate, glyceryl behenates, glyceryl distearates, glyceryl monolinoleates, glyceryl mono-oleates, glyceryl monostearates, macrogol cetostearyl ethers such as cetomacrogol 1000 and polyoxy 20 cetostearyl ether, macrogol 15 hydroxystearates, macrogol lauril ethers such as laureth 4 and lauromacrogol 400, macrogol monomethyl ethers, macrogol oleyl ethers such as polyoxyl 10 oleyl ether, macrogol stearates such as polyoxyl 40 stearate, menfegol, mono and diglycerides, nonoxinols such as nonoxinol-9, nonoxinol-10 and nonoxinol- 1 1 , octoxinols such as octoxinol 9 and oxtoxinol 10, polyoxamers such as polyoxalene, polyoxamer 188, polyoxamer 407, polyoxyl castor oils such as polyoxyl 35 castor oil, polyoxyl hydrogenated castor oils such as polyoxyl 40 hydrogenated castor oil, propylene glycol diacetates, propylene glycol laurates such as propylene glycol dilaurate and propylene glycol monolaurate. Further examples include propylene glycol monopalmitostearates, quillaia, sorbitan esters, sucrose esters, and mixtures thereof.

[0123] Anionic surfactants suitable for the present disclosure include, for example, salts of perfluorocarboxylic acids and perfluorosulphonic acid, alkyl sulphate salts such as sodium dodecyl sulphate and ammonium lauryl sulphate, sulphate ethers such as sodium lauryl ether sulphate, alkyl benzene sulphonate salts, and mixtures thereof.

[0124] Cationic surfactants suitable for the present disclosure include, for example, quaternary ammonium compounds such as benzalkonium chloride, cetylpyridinium chlorides, benzethonium chlorides, cetyl trimethylammonium bromides, other trimethylalkylammonium salts, and mixtures thereof.

[0125] Zwitterionic surfactants include, but are limited to, for example dodecyl betaines, coco amphoglycinates, cocamidopropyl betaines, and mixtures thereof.

[0126] In some embodiments of the present disclosure, the surfactant may comprise a phospholipid, derivative thereof, analogue thereof, or any mixture thereof. Such surfactants may, for example, be chosen from natural, synthetic, and semisynthetic phospholipids, derivatives thereof, analogues thereof, and mixtures thereof. Exemplary phospholipid surfactants include phosphatidylcholines with saturated, unsaturated and/or polyunsaturated lipids such as dioleoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, di- eicopentaenoyl(EPA)choline, didocosahexaenoyl(DHA)choline, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines and phosphatidylinositols. Other exemplary phospholipid surfactants include soybean lecithin, egg lecithin, diolelyl phosphatidylcholine, distearoyl phosphatidyl glycerol, PEG-ylated phospholipids, and dimyristoyl phosphatidylcholine.

[0127] Phospholipids may be "natural" or from a marine origin chosen from, e.g. phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinosytol. The fatty acid moiety may be chosen from 14:0, 16:0, 16:1 n-7, 18:0, 18: 1 n-9, 18: 1 n-7, 18:2 n-6, 18:3 n- 3, 18:4 n-3, 20:4 n-6, 20:5 n-3, 22:5 n-3 and 22:6 n-3, or any combinations thereof. In one embodiment, the fatty acid moiety is chosen from palmitic acid, EPA and DHA.

[0128] Other exemplary surfactants suitable for the present disclosure are listed in Table 7. Table 7: Other surfactants

Surfactant Surfactant Type HLB Value

Ethylene glycol distearate non-ionic 1.5

Glyceryl monostearate non-ionic 3.3

Propylene glycol monostearate non-ionic 3.4

Glyceryl monostearate non-ionic 3.8

Diethylene glycol monolaurate non-ionic 6.1

Acacia anionic 8.0

Cetrimonium bromide cationic 23.3

Cetylpyridinium chloride cationic 26.0

Polyoxamer 188 non-ionic 29.0

Sodium lauryl sulphate non-ionic 40

[0129] In some embodiments of the present disclosure, the at least one surfactant does not comprise LABRASOL, CREMOPHOR RH40, or the combination of CREMOPHOR and TWEEN- 80.

[0130] In some embodiments, the at least one surfactant has a hydrophilic-lipophilic balance (HLB) of less than about 10, such as less than about 9, or less than about 8.

[0131] In at least one embodiment, the at least one surfactant comprises for example from about 0.5% to about 40%, such as from about 10% to about 30%, such as from about 10% to about 25%, by weight relative to the total weight of the preconcentrate. In at least one embodiment, the at least one surfactant comprises about 20% by weight relative to the total weight of the preconcentrate.

[0132] The weight ratio of EPA and DHA to the at least one surfactant may range depending on the choice of surfactant(s), the EPA to DHA ratio, and the overall formulation. In some embodiments of the present disclosure, the weight ratio of EPA and DHA : surfactant ranges from about 10:5 to about 10:0.001 , from about 10:4 to about 10:0.005, from about 10:3 to about 10:0.01, from about 10:2 to about 0.015, from about 10:2 to about 10:0.02, or from about 10: 15 to about 10:0.03.

CO-SURFACTANT

[0133] In some embodiments, the preconcentrates of the present disclosure further comprise at least one co-surfactant. As used herein the term "co-surfactant" means a substance added to, e.g., the preconcentrate in combination with the at least one surfactant to positively affect, e.g., increase or enhance, emulsification and/or stability of the preconcentrate, for example to aid in forming an emulsion. In some embodiments, the at least one co-surfactant is hydrophilic.

[0134] Examples of co-surfactants suitable for the present disclosure include, but are not limited to, short chain alcohols comprising from 1 to 6 carbons (e.g., ethanol), benzyl alcohol, alkane diols and triols (e.g., propylene glycol, glycerol, polyethylene glycols such as PEG and PEG 400), glycol ethers such as tetraglycol and glycofurol (e.g., tetrahydrofurfuryl PEG ether), pyrrolidine derivatives such as N-methyl pyrrolidone (e.g., Pharmasolve(R)) and 2-pyrrolidone (e.g., Soluphor(R) P), bile salts, for example sodium deoxycholate, and mixtures thereof. Further examples include ethyl oleate.

[0135] In some embodiments, the at least one co-surfactant comprises from about 1 % to about 10%, by weight relative to the total weight of the preconcentrate.

SOLVENT

[0136] In some embodiments, the compositions and/or preconcentrates further comprise at least one solvent and/or co-solvent. Hydrophilic solvents suitable for the present disclosure include, but are not limited to, alcohols, including lower alcohols, water-miscible alcohols, such as absolute ethanol and/or glycerol, and glycols, for example glycols obtainable from an oxide such as ethylene oxide, such as 1,2-propylene glycol. Other non-limiting examples include polyols, such as polyalkylene glycol, e.g., poly(C2-3)alkylene glycol such as polyethylene glycol. Other non-limiting examples of solvents and/or co-solvents are benzyl alcohol, tetra glycol, and oleic acid. As mentioned above, oleic acid is also a free fatty acid and an omega-9 fatty acid.

[0137] In some embodiments of the present disclosure, the preconcentrate comprises at least one substance that acts both as a co-surfactant and a solvent, for example an alcohol such as ethanol. In other embodiments, the preconcentrate comprises at least one co-surfactant and at least one solvent that are different substances. For example, in some embodiments the preconcentrate comprises ethanol as the co-surfactant and glycerol as the solvent.

SUPERDISINTEGRANT

[0138] In some embodiments of the present disclosure, the compositions and/or preconcentrates may comprise at least one superdistintegrant.

[0139] Superdisintegrants may, for example, improve disintegrant efficiency resulting in decreased use levels in comparison to traditional disintegrants. Examples of superdisintegrants include, but are not limited to, crosscarmelose (a crosslinked cellulose), crospovidone (a crosslinked polymer), sodium starch glycolate (a crosslinked starch), and soy polysaccharides. Commercial examples of superdisintegrants include KOLLIDON® (BASF), POLYPLASDONE® XL (ISP), and AC-DI- SOL (FMC BioPolymer).

[0140] The compositions and/or preconcentrates may comprise from about 1 % to about 25% of at least one superdisintegrant by weight, such as from about 1 % to about 20% by weight, or from about 1 % to about 15% by weight of the composition and/or preconcentrate. In some embodiments, the compositions and/or preconcentrates comprising at least one superdisintegrant are in a granulated form. [0141] In some embodiments, the weight ratio of fatty acid oil mixture : superdisintegrant of the preconcentrate ranges from about 1 : 1 to about 10: 1, from about 1 : 1 to about 8: 1, from 1 : 1 to about 7: 1 , from 1 : 1 to about 6: 1 , from 1 : 1 to about 5:1, from 1 : 1 to about 4: 1, from 1 : 1 to about 3: 1, or from 1 : 1 to about 2: 1.

[0142] In some embodiments, the at least one superdisintegrant comprises from about 5% to about 55%, by weight relative to the total weight of the preconcentrate. For example, in some embodiments, the at least one superdisintegrant comprises from about 5% to about 35%, from about 10% to about 35%, from about 15% to about 35%, from about 15% to about 30%, or from about 20% to about 30%, by weight, relative to the total weight of the preconcentrate.

SNEDDS/SMEDDS/SEDDS

[0143] The preconcentrate of the present disclosure may be in a form of a self- nanoemulsifying drug delivery system (SNEDDS), a self-microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS), wherein the preconcentrate forms an emulsion in an aqueous solution.

[0144] Without being bound by theory, it is believed that the preconcentrate forms a SNEDDS, SMEDDS, and/or SEDDS upon contact with gastric and/or intestinal media in the body, wherein the preconcentrate forms an emulsion comprising micelle particles. The emulsion may, for example, provide for increased or improved stability of the fatty acids for uptake in the body and/or provide increased or improved surface area for absorption. SNEDDS/SMEDDS/SEDDS may thus provide for enhanced or improved hydrolysis, solubility, bioavailability, absorption, or any combinations thereof of fatty acids in vivo.

[0145] The SNEDDS/SMEDDS/SEDDS presently disclosed may form stable emulsions when dispersed in water having a particle size (i.e., particle diameter) ranging from about 5 nm to about 10 micrometer. For example, in some embodiments, the particle size ranges from about 5 nm to about 1 μηι , 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

[0146] The compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS presently disclosed may further comprise at least one non-active pharmaceutical ingredient, e.g., excipient. Non-active ingredients may solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and/or fashion active ingredients into an applicable and efficacious preparation, such that it may be safe, convenient, and/or otherwise acceptable for use. The at least one non-active ingredient may be chosen from, as non-limiting examples, colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, and xanthum gum. [0147] The compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS presently disclosed may further comprise at least one antioxidant. Examples of antioxidants suitable for the present disclosure include, but are not limited to, a-tocopherol (vitamin E), calcium disodium EDTA, alpha tocoferyl acetates, butylhydroxytoluenes (BHT), and butylhydroxyanisoles (BHA).

[0148] By way of example, in some embodiments the preconcentrates and/or SNEDDS/SMEDDS/SEDDS comprise a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; the fatty acid oil mixture further comprises oleic acid and at least one antioxidant; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate; and the at least one surfactant is polysorbate 20. In a further embodiment said antioxidant is BHA.

FORMS

[0149] The compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS presently disclosed may be in any form suitable for oral administration, e.g. pill, tablet, capsule, emulsion, suspension, granules, micro emulsion or micro tablet optionally included in a capsule or tablet. The different dosage forms may be coated. For example, the different dosage forms may be enteric coated.

[0150] In one embodiment the compositions, preconcentrates and/or SNEDDS/SMEDDS/SEDDS comprising EPA/DHA and at least one salicylate presently disclosed may be administered orally in the form of a capsule. The capsule form can be of any shape suitable for oral administration, such as spherical, oval, ellipsoidal, cube-shaped, regular, and/or irregular shaped. The dosage forms can be prepared according to processes known in the art and can include one or more additional pharmaceutically-acceptable excipients as discussed above.

[0151] In some embodiments of the present disclosure, the compositions and/or preconcentrates are in a capsule form. The capsule wall-forming material may comprise, for example, gelatin or polysaccharides other than alginate. In at least one embodiment, the capsule is a gelatin capsule. The capsules may be hard capsules or soft capsules.

[0152] The capsules and/or at least one salicylate of the present disclosure may comprise at least one coating. Such coatings can delay the release of the content from the capsule (e.g., release of the least one salicylate and/or EPA and/or DHA) for a predetermined period. For example, the at least one coating may allow the dosage form to pass through the stomach without being subjected to stomach acid or digestive juices to provide for delayed release of the at least one salicylate and/or EPA and/or DHA outside of the stomach. In some embodiments, the capsules release less than 30% of the total of the at least one salicylate in the stomach, such as less than 25%, less than 20%, less than 15%, or less than 10%. [0153] In some embodiments, the at least one coating is chosen from enteric coatings, sublayers, top-layers, and combinations thereof. The term "sub-layer" as used herein means a coating layer located between the capsule wall material (e.g., gelatin wall) and an enteric coating. The term "top-layer" as used herein means a coating layer over an enteric coating covering the capsule wall. The chemical composition of sub-layers and top-layers may vary depending upon the overall composition of the capsule. Typical materials for the sub-layers and top-layers presently disclosed include film-forming agents such as polysaccharides, for example hydroxypropyl methyl cellulose.

[0154] In embodiments of the present disclosure, the capsules and/or at least one salicylate comprise at least one enteric coating. In some embodiments, the capsules or at least one salicylate comprise at least one enteric coating and at least one top-layer over the at least one enteric coating. In other embodiments, the capsules and/or at least one salicylate comprise at least one enteric coating and at least one sub-layer between the capsule wall or the at least one salicylate surface and the at least one enteric coating. In still other embodiments, the capsules and/or the at least one salicylate comprise at least one enteric coating, at least one sub-layer between the capsule wall or the at least one salicylate surface, and at least one top-layer over the at least one enteric coating. In some embodiments, at least one of the sub-layer(s) and/or top-layer(s) comprises hydroxypropyl methyl cellulose.

[0155] In some embodiments, the at least one sub-layer comprises a sealant. Suitable sealants may comprise, for example, permeable or soluble agents such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, and xanthan gum. Other agents can be added to improve the processability of the sealant or barrier layer. Such agents include talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica, glycerol monostearate, magnesium trisilicate and magnesium stearate, or a mixture thereof. The sealant or barrier layer can be applied from solution (e.g., aqueous) or suspension using any known means, such as a fluidized bed coater (e.g., Wurster coating) or pan coating system. Suitable sealants or barriers include, for example, OP ADR Y® products such as OPADRY® II available from Colorcon.

[0156] In some embodiments, the at least one coating is pH-independent. Coatings with pH-independent profiles generally erode or dissolve away after a predetermined period, and the period is generally directly proportional to the thickness of the coating. In other embodiments, the at least one coating is pH- dependent. Coatings with pH-dependent profiles can generally maintain their integrity while in the acid pH of the stomach, but erode or dissolve upon entering the more basic upper intestine. In some embodiments, the at least one coating is insoluble at a pH below about 5 and soluble at a pH above about 6.

[0157] Examples of coating materials suitable for the present disclosure include, but are not limited to, gelatin, film-forming agents, polymers, and copolymers. Examples of polymers and copolymers include, but are not limited to, acrylate-based polymers and copolymers (e.g., methacrylic acid, copolymers between methacrylic acid and methyl methacrylate, copolymers between methacrylic acid and methyl acrylate, copolymers between metacrylic acid and ethyl methacrylate, and copolymers between metacrylic acid and ethyl acrylate) and polysaccharide and/or cellulose-based polymers and copolymers (e.g., cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and hydroxypropyl methyl cellulose acetate succinate). Others polymers include, for example, polyvinyl acetate phthalate. Additional materials suitable for the at least one coating include pharmaceutically acceptable acidic compounds that may not dissolve at the low pH in the stomach, but may dissolve at higher pH in the lower part of the gastrointestinal system.

[0158] Commerically-available examples of polymers suitable for the present disclosure include EUDRAGIT® products from Evonik. EUDRAGIT® polymers are polymeric lacquer substances based on acrylates and/or methacrylates, and may be pH-independent or pH-dependent.

[0159] For example, EUDRAGIT® RL and EUDRAGIT® RS are acrylic resins comprising copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. The ammonium groups are present as salts and give rise to permeability of the lacquer films. EUDRAGIT® RL and EUDRAGIT® RS are freely permeable (RL) and slightly permeable (RS), respectively, independent of pH. The polymers swell in water and digestive juices, in a pH-independent manner. In the swollen state, they are permeable to water and to dissolved active compounds. Specific examples include EUDRAGIT® RL 30D, EUDRAGIT® RL PO, EUDRAGIT® RL 100, EUDRAGIT® RL 12,5, EUDRAGIT® RS 30D, EUDRAGIT® RS PO, EUDRAGIT® RS 00, and EUDRAGIT® RS 12,5. Additional examples of pH- independent polymers include EUDRAGIT® E 100, EUDRAGIT® E 12,5, and EUDRAGIT® E PO. In at least one embodiment of the present disclosure, the at least one coating comprises EUDRAGIT® RS 30D.

[0160] Further, for example, EUDRAGIT® L and EUDRAGIT® S are anionic polymers synthesized from methacrylic acid and methacrylic acid methyl ester. They are insoluble in acids and pure water, and become soluble in neutral to weakly alkaline conditions. The permeability of EUDRAGIT® L and EUDRAGIT S is pH dependent. Above pH 5.0, the polymers become increasingly permeable. Specific examples include EUDRAGIT® LI 00-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S12,5, and EUDRAGIT® FS 30D. Additional examples of pH-dependent polymers include EUDRAGIT® El 00, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment of the present disclosure, the at least one coating comprises EUDRAGIT® LI 00-55.

[0161] The at least one coating may comprise at least one plasticizer. Plasticizers may, for example be used to improve the mechanical properties of pH-sensitive materials of the at least one coating. Suitable plasticizers include, but are not limited to, triethyl citrate, triacetin, polyethylene glycols, propylene glycol, phthalates, sorbitol and glycerin. The amount of plasticizer may vary depending upon the chemical composition of the at least one coating and the chemical composition and size of the capsule or tablet. In some embodiments, for example, the amount of plasticizer ranges from about 10% to about 60% by weight of the at least one coating.

[0162] The amount of coating material or thickness of the at least one coating may vary depending upon the chemical compositions and number of different coating layers, and chemical composition, size, and shape of the capsule or the tablet.

[0163] Generally speaking, the coating should be sufficient thick to prevent substantial release of the salicylate in the stomach, but also not contribute significantly to the capsule size. In some embodiments of the present disclosure, the thickness of the at least one coating ranges from about 10 microns to about 2 mm, such as from about 20 microns to about 1 mm. In some embodiments, the at least one coating comprises from about 1% to about 50% of the dry capsule wall-forming material (e.g., gelatin).

[0164] The capsules according to the present disclosure may be manufactured in low oxygen conditions to inhibit oxidation during the manufacturing process. The capsules may be prepared, for example, by direct encapsulation using standard methods known in the art. Examples of such methods include, but are not limited to, simple coacervation methods (see, e.g., ES 2009346, EP 0052510, and EP 0346879), complex coacervation methods (see, e.g., GB 1393805), double emulsion methods (see, e.g., U.S. 4,652,441), simple emulsion methods (see, e.g., U.S. 5,445,832), and solvent evaporation methods (see, e.g., GB 2209937). Those methods may, for example, provide for continuous processing and flexibility of batch size. The present disclosure further provides for coating pre-prepared capsules (e.g., gelatin capsules comprising a fatty acid oil mixture). The coating of pre-prepared capsules may be performed, for example, by spraying such as using spray drying techniques or spraying into a coating pan comprising preformed capsules, or by dipping capsules into coating solutions.

[0165] In some embodiments of the present 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, 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.

[0166] In some embodiments of the present disclosure, the compositions and/or preconcentrates comprise from about 300 mg to about 400 mg of DHA, such as about 375 mg. In some embodiment, the compositions and/or preconcentrates comprise from about 400 mg to about 500 mg of EPA, such as about 465 mg. In one embodiment, for example, the compositions and/or preconcentrates comprise about 375 mg of DHA and about 465 mg of EPA.

METHODS OR USES

[0167] The present disclosure further encompasses methods of treating and/or regulating at least one health problem in a subject in need thereof. The compositions and preconcentrates presently disclosed may be administered, e.g., in capsule form for drug delivery, to a subject for therapeutic treatment and/or regulation of at least one health problem including, for example, irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction. In some embodiments, the at least one health problem is chosen from mixed dyslipidemia, dyslipidemia, thrombosis, hypertriglyceridemia, hypercholesterolemia, heart failure, and post-myocardial infarction.

[0168] In one embodiment, the present disclosure provides for a method of treating at least one health problem in a subject in need thereof, comprising administering to the subject a composition in a capsule form, such as a gelatin capsule, comprising a pharmaceutically-effective amount of a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate; wherein the capsule and/or salicylate comprises at least one coating. In some embodiments, the method treats at least one of elevated triglyceride levels, non-HDL cholesterol levels, LDL cholesterol levels and/or VLDL cholesterol levels or thrombosis. For example, the method may reduce triglyceride levels from about 30% to about 80%, such as from about 40% to about 70%, from about 40% to about 60%, or from about 30% to about 50%, in a subject with elevated triglyceride levels.

[0169] In another embodiment, the present disclosure provides for a method of regulating at least one health problem in a subject in need thereof, comprising administering to the subject a composition in a gelatin capsule form comprising: a fatty acid oil mixture comprising from about 25% to about 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate; wherein the gelatin capsule or the at least one salicylate comprises at least one coating, and wherein the at least one health problem is chosen from irregular plasma lipid levels, thrombosis, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[0170] The present disclosure further provides for a method for enhancing at least one parameter chosen from stability, hydrolysis, solubility, bioavailability, absorption, and combinations thereof of at least one salicylate and/or EPA and/or DHA. The bioavailablity of the at least one salicylate and/or EPA and/or DHA may be increased, for example, by at least 40%, such as by about

80% or by at least 85%.

[0171] In one embodiment, the method for enhancing at least one parameter chosen from stability, hydrolysis, solubility, bioavailability, absorption, and combinations thereof of at least one salicylate and/or EPA and/or DHA comprises: combining a fatty acid oil mixture comprising EPA and DHA in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate in a gelatin capsule form, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0172] In another embodiment, the method for enhancing at least one parameter chosen from stability, hydrolysis, solubility, bioavailability, absorption, and combinations thereof of at least one salicylate and/or EPA and/or DHA comprises: combining a fatty acid oil mixture comprising EPA and DHA in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant in a gelatin capsule form, wherein the gelatin capsule or the at least one salicylate comprises at least one coating. In another embodiment, the method for enhancing at least one parameter chosen from stability, hydrolysis, solubility, bioavailability, absorption, and combinations thereof of salicylate and/or EPA and/or DHA comprises: combining a fatty acid oil mixture comprising EPA and DHA in free acid form and at least one salicylate in a gelatin capsule form, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0173] In yet another embodiment, the method for enhancing at least one parameter chosen from stability, hydrolysis, solubility, bioavailability, absorption, and combinations thereof of at least one salicylate and/or EPA and/or DHA comprises: combining a fatty acid oil mixture comprising EPA and DHA in a form chosen from free fatty acid, ethyl ester, and triglyceride, the at least one salicylate and at least one surfactant in a gelatin capsule form, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0174] The preconcentrates presently disclosed can form a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self- emulsifying drug delivery system (SEDDS) in an aqueous solution in the methods presently disclosed.

[0175] In some embodiments of the present disclosure, the compositions or preconcentrates may be administered to a subject in need thereof to treat and/or regulate at least one health problem.

[0176] In some embodiments, the preconcentrates of the present disclosure form a self- nanoemulsifying drug delivery system (SNEDDS), a self-microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS) in an aqueous solution. In some embodiments, the aqueous solution is gastric media and/or intestinal media. [0177] The total daily dosage of the fatty acid oil mixture may range from about 0.600 g to about 6.000 g. For example, in some embodiments, the total dosage of the fatty acid oil mixture ranges from about 0.800 g to about 4.000 g, from about 1.000 g to about 4.000 g, from about 0.5000 g to about 4.000 g, from about 0.250 g to about 2.000 g, from about 0.400 g to about 2.000 g, or from about 1.000 g to about 2.000 g. In one embodiment, the fatty acid oil mixture is chosen from K85EE and AGP 103 fatty acid oil compositions. In another embodiment, the fatty acid oil mixture comprises K85FA. The administration is oral intake of said capsules to a subject, such as a human. For example, the compositions and preconcentrates presently disclosed may be administered as capsules in from 1 to 10 dosages, such as from 1 to 4 times a day, such as once, twice, three times, or four times per day, and further for example, once, twice or three times per day.

FORMULATIONS

[0178] In some embodiments of the present disclosure, the preconcentrate is a preconcentrate in a gelatin capsule form comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and at least one surfactant, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0179] In one embodiment, the preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising at least 95% of EPA ethyl ester, DHA ethyl ester, or mixtures thereof, by weight of the fatty acid oil mixture; at least one salicylate chosen from acetylsalicylic acid, salicylic acid and pharmaceutically acceptable salts of acetylsalicylic acid and salicylic acid; and a least one surfactant chosen from the polysorbates, and mixtures thereof, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0180] In one embodiment the pharmaceutical preconcentrate comprises a fatty acid oil mixture comprising an amount chosen from at least 90% of EPA and DHA, at least 93% EPA in ethyl ester form, at least 93% DHA in ethyl ester form, at least 97% EPA in ethyl ester form, and at least 97% DHA in ethyl ester form by weight of the fatty acid oil mixture; at least one salicylate; and at least one surfactant. In another embodiment the preconcentrate comprises a fatty acid oil mixture comprising at least 93% EPA in ethyl ester form, by weight of the fatty acid oil mixture; at least one salicylate; and at least one surfactant. In yet another embodiment the preconcentrate comprises a fatty acid oil mixture comprising at least 93% DHA in ethyl ester form, by weight of the fatty acid oil mixture; at least one salicylate; and at least one surfactant. In one embodiment the preconcentrate comprises a fatty acid oil mixture comprising at least 97% EPA in ethyl ester form, by weight of the fatty acid oil mixture, and no DHA in ethyl ester form; at least one salicylate; and at least one surfactant. In another embodiment the preconcentrate comprises a fatty acid oil mixture comprising at least 97% DHA in ethyl ester form, by weight of the fatty acid oil mixture, and no EPA in ethyl ester form; at least one salicylate; and at least one surfactant. These pharmaceutical preconcentrates may be in capsule form, e.g. gelatin capsules.

[0181] In another embodiment, the pharmaceutical preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; at least one salicylate selected from acetylsalicylic acid and pharmaceutically acceptable salts thereof; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant constitutes less than 40%, by weight relative to the weight of the preconcentrate, and wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0182] In another embodiment, the pharmaceutical preconcentrate in a gelatin capsule or a tablet form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; at least one salicylate selected from acetylsalicylic acid and pharmaceutically acceptable salts of acetylsalicylic acid; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant constitutes less than 35%, by weight relative the weight of the preconcentrate, and wherein the gelatin capsule or the acetylsalicylic acid or salt thereof comprises at least one coating.

[0183] In another embodiment, the pharmaceutical preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; at least one acetylsalicylic acid or pharmaceutically acceptable salts thereof in an amount of 50-200 mg; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof, wherein the gelatin capsule or the acetylsalicylic acid or salt thereof comprises at least one coating. For example, the pharmaceutical preconcentrate may comprise K85EE as the fatty acid oil mixture, acetylsalicylic acid or lysine salt of acetylsalicylic acid, and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof.

[0184] In another embodiment, the pharmaceutical preconcentrate may comprise K85EE as the fatty acid oil mixture, acetylsalicylic acid, and at least one surfactant chosen from polysorbate 20 or polysorbate 80, wherein the weight ratio between [K85EE]:[Tween]:[acetylsalicylic acid] ranges from e.g. about 5:2:0.5 to 5:4:2. In a further embodiment, the weight ratio between [K85EE]:[Tween]: [acetylsalicylic acid] is about [4-5]:[3-4]:[l-1.5].

[0185] In some embodiments of the present disclosure, the preconcentrate is a preconcentrate in a gelatin capsule form comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free fatty acid form; at least one salicylate, such as acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof and at least one surfactant, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0186] In one embodiment, for example, the pharmaceutical preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; at least one salicylate such as acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0187] In one embodiment, the pharmaceutical preconcentrate in a gelatin capsule or a tablet form comprises; a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; at least one salicylate such as acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant constitutes less than 40%, by weight relative to the weight of the preconcentrate, and wherein the gelatin capsule, tablet or the at least one salicylate comprises at least one coating.

[0188] In another embodiment, for example, the pharmaceutical preconcentrate in a gelatin capsule or a tablet form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form, and oleic acid; at least one salicylate; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant constitutes less than 40%, by weight relative to the weight of the preconcentrate, and, wherein the gelatin capsule or the tablet comprises at least one coating.

[0189] In another embodiment, the pharmaceutical preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form, and at least one salicylate such as acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant constitutes less than 35%, by weight relative the weight of the preconcentrate, and, wherein the gelatin capsule comprises at least one coating.

[0190] In another embodiment, the preconcentrate in a gelatin capsule form comprises a K85FA fatty acid oil mixture, at least one salicylate such as acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof and at least one surfactant chosen from polysorbate 20 and polysorbate 80, wherein the gelatin capsule or the salicylate comprises at least one coating. [0191] In some embodiments of the present disclosure, the preconcentrate is a preconcentrate in a gelatin capsule form comprising a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate selected from acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof and at least one surfactant, wherein the gelatin capsule or salicylate comprises at least one coating.

[0192] In one embodiment, the pharmaceutical preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising at least 95% of EPA ethyl ester, DHA ethyl ester, or mixtures thereof, by weight of the fatty acid oil mixture; at least one salicylate selected from acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof and a least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0193] In another embodiment, the pharmaceutical preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; at least one salicylate selected from acetylsalicylic acid, salicylic acid, or the pharmaceutically acceptable salts thereof and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant constitutes less than 40%, by weight relative to the weight of the preconcentrate, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0194] In another embodiment, the pharmaceutical preconcentrate in a gelatin capsule form comprises: a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; at least one salicylate selected from acetylsalicylic acid, salicylic acid or the pharmaceutically acceptable salts thereof and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant constitutes less than 35%, by weight relative the weight of the preconcentrate, wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0195] In some embodiments, for example, the preconcentrate in a gelatin capsule form comprises K85EE as the fatty acid oil mixture, at least one salicylate selected from acetylsalicylic acid, salicylic acid or the pharmaceutically acceptable salts thereof and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof, wherein the gelatin capsule or the at least one salicylate comprises at least one coating. [0196] In another embodiment, the pharmaceutical preconcentrate in a gelatin capsule form comprises a fatty acid oil mixture comprising from about 80% to about 88% EPA and DHA, by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; at least one salicylate selected from acetylsalicylic acid, salicylic acid or the pharmaceutically acceptable salts thereof, at least one surfactant chosen from polysorbate 80; and at least one co-surfactant comprising ethanol, and wherein the gelatin capsule or the at least one salicylate comprises at least one coating.

[0197] In another embodiment the preconcentrate the fatty acid oil mixture comprises from about 80% to about 88% EPA and DHA, by weight of the fatty acid oil mixture; the EPA and DHA are in free acid form; the at least one surfactant comprises polysorbate 20 and macrogol 15 hydroxystearate; the at least one other fatty acid other than EPA and DHA comprises sesame oil; and the fatty acid oil mixture further comprises at least one antioxidant comprising butylhydroxyanisoles (BHA). In another embodiment the fatty acid oil mixture comprises about 84% or 85% EPA and DHA in free acid form, by weight of the fatty acid oil mixture.

[0198] In another embodiment the preconcentrate comprises: from about 45% to about 55% by weight, relative to the weight of preconcentrate, of a fatty acid mixture comprising about 84% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; and the fatty acid oil mixture further comprises from about 10% to about 15% by weight, relative to the preconcentrate, of oleic acid; the at least one surfactant comprises polysorbate 20 in an amount from about 30% to about 40% by weight, relative to the preconcentrate; and the faty acid oil mixture further comprises at least one antioxidant comprising BHA; and at least one salicylate. In another embodiment the fatty acid oil mixture comprises about 85% EPA and DHA in ethyl ester form, by weight of the fatty acid oil mixture.

[0199] As mentioned previously such preconcentrates may be in the form of capsules which may be coated with a gastroresistant material.

[0200] The at least one salicylate may be present for example in an amount of about 125 mg and the at least one salicylate may be dissolved or suspended in the oil mixture. Furthermore the at least one salicylate may be suspended in the oil mixture optionally coated with a gastroresistant material.

[0201] Alternatively the at least one salicylate is microencapsulated and contained in the wall-forming material of the the capsule. In still another embodiment the at last one salicylate is partly dissolved or suspended in the oil and partly microencapsulated in the wall-forming material of the capsule.

[0202] It should be noted that embodiments and features described in the context of the present disclosure also apply to the other parts of the present disclosure. Furthermore, individual features mentioned in different claims, may possibly be advantageously combined, and the mentioning of these features in different claims does not exclude that a combination of features is not possible and advantageous.

[0203] The following examples are intended to illustrate the present disclosure without, however, being limiting in nature. It is understood that the skilled artisan will envision additional embodiments consistent with the disclosure provided herein.

EXAMPLES

[0204] Fixed-dose products comprising acetylsahcylic acid and derivatives thereof in EPA/DHA ethyl ester (K85EE) were evaluated with regard to solubility and stability.

[0205] Acetylsahcylic acid:

is an ester regarded as an unstable drug substance due to its tendency to hydrolyze.

[0206] Salicylic acid:

is a strong acid (pKa 2.79) compared to acetylsahcylic acid (p a 3.8), but is more stable than acetylsahcylic acid.

EXAMPLE 1

Solubility experiments in K85EE

[0207] Chemicals:

- K85EE

- Acetylsahcylic acid (Sigma no. A5376)

- Salicylic acid (Aldrich no. 247588)

[0208] Acetylsahcylic acid (50 mg) was stirred with K85EE (5 ml) at room temperature, but it did not dissolve. The mixture was heated to 50°C; most of the crystals dissolved, but not completely. On cooling to room temperature, acetylsahcylic acid precipitated out. By dissolving 5 mg-portions in 5 ml K85EE, we determined that the solubility was 5 mg acetylsahcylic acid per ml K85EE at room temperature.

[0209] Salicylic acid (150 mg) was stirred with K85EE (5 ml) at room temperature. The compound dissolved completely in K85EE. More salicylic acid (50 mg) was added; it was partly dissolved after stirring overnight. The solubility of salicylic acid in K85EE at room temperature was at least 40 mg/ml.

EXAMPLE 2

Solubility experiments in K85EE with surfactants

[0210] Acetylsalicylic acid (50 mg) and CREMOPHOR EL (100 mg) were stirred with K85EE (5 ml) at room temperature, but it did not dissolve. The mixture was heated to 50 °C; most of the crystals dissolved, but not completely. On cooling to room temperature, acetylsalicylic acid precipitated out.

[0211] Acetylsalicylic acid (50 mg) and TWEEN 80 (100 mg) were stirred with K85EE (5 ml) at room temperature, but it did not dissolve. The mixture was heated to 50 °C; most of the crystals dissolved, but not completely. On cooling to room temperature, acetylsalicylic acid precipitated out.

EXAMPLE 3

Stability experiments in K85EE

Analytical methods:

[0212] The following GC method was used: Shimadzu GC-14A gas chromatograph with a 30-meter SPB-1 capillary column at 100 °C for 1 min then increasing at a rate of 10 °C/min to 250 °C using a flame-ionization detector. Two drops of the sample was dissolved in acetone (1.5 ml) and a 0.5 μΐ-sample was injected.

[0213] The following HPLC method was used: Agilent 1 100 series HPLC with a 4.5 x 250 mm Zorbax Extent-CT 8 5μ column eluted with methanol and 1% acetic acid in water (35:65) (isocratic) at 1.5 ml/min. A 100 μΐ-sample was shaken with hexane (2.0 ml) and water (1.0 ml). After the mixture separated, a 0.50ml aliquot of the aqueous layer was withdrawn and diluted with methanol (0.5 ml). A 5μ1^πιρ1ε of this solution was injected. Chromatograms were measured at 254, 230, and 280 nm

Materials:

[0214] Samples of K85EE, acetylsalicylic acid (Sigma no. A5376) and salicylic acid (Aldrich no. 247588) were used as controls.

[0215] All samples were stored in sealed vials at 37 °C in an incubator.

[0216] Samples of the acetylsalicylic acid (500 mg) in K85EE (5 ml) were stored as above. After 50 days storage at 37°, the samples were analyzed by HPLC.

[0217] Samples of acetic acid (500 mg) in K85EE (5ml), and salicylic acid (500 mg) in K85EE (5ml) were stored as above. After 25-30 days the samples were analyzed by GC and HPLC.

[0218] Additionally the following salts of acetylsalicylic acid and salicylic acid were prepared and tested using the same analytical methods: Sodium acetylsalicylate (prepared by mixing acetylsalicylic acid and sodium bicarbonate in water and freeze-drying the solution).

Sodium salicylate (Sigma #S2679)

Acetylsalicylic acid L-lysine salt (prepared by mixing acetylsalicylic acid and L-lysine in water and freeze-drying the solution).

Acetylsalicylic acid meglumine salt (prepared by mixing acetylsalicylic acid and N-methylglucosamine in water and freeze-drying the solution).

[0219] Samples of sodium acetylsalicylate, sodium salicylate, acetylsalicylic acid L-lysine salt, and acetylsalicylic acid meglumine salt for stability testing were prepared by suspending 100 mg of each compound in K85EE (1.0 ml) by shaking for 15 sec. The samples were stored at 37 °C for 22 days.

Results:

[0220] Acetylsalicylic acid in K85EE was quite stable after 50 days storage at 37°C. About 1-2% salicylic acid from hydrolysis of acetylsalicylic acid together with 15 and 13% of less polar impurities (salicylsalicylic acid and acetylsalicylsalicylic acid, respectively) were observed. EPA ethyl ester and DHA ethyl ester were, in presence of acetylsalicylic acid, stable after 50 days storage at 37°C.

[0221] No impurities were observed with salicylic acid in K85 after 35 days at 37°C. Acid- catalyzed hydrolysis of EPA ethyl ester and DHA ethyl ester was not observed after 29 days at 37°C in the presence of acetic acid or with salicylic acid.

[0222] For sodium acetylsalicylate, both salicylsalicylic acid and acetylsalicylsalicylic acid appeared after one day. After 28 days, about 66% acetylsalicylic acid remained while about 39% remained in the sodium salt mixture.

[0223] Sodium salicylate did not react or show any appreciable amount of impurities after 28 days at 37 °C.

[0224] L-Lysine and meglumine salts of acetylsalicylic acid exhibited over 40% salicylsalicylic acid after just one day at 37 °C. After 28 days, less than 2% acetylsalicylate remained.

Conclusions:

[0225] Both salicylic acid in K85EE, and the sodium salt of salicylic acid in K85EE appeared stable. Neither acetylsalicylic acid in K85EE nor various salts of acetylsalicylic acid in K85EE were stable. EXAMPLE 4: Preparation of suspensions for encapsulation

Preparation of sodium acetylsalicylate (^"Intermediate 1)

[0226] Acetylsalicylic acid (1.80 g; 10.0 mmol) was added to a solution of NaHC03 (0.84 g; 10.0 mmol) in water (10 ml). The mixture was swirled for 5 min. and then freeze-dried overnight to give 2.07 g (100%) white powder.

Example 4.1 Coated acetylsalicylic acid in EPA/DHA ethyl ester

[0227] Cellulose acetate phthalate (CAP) (270 mg, Fluka 22192) was dissolved in acetone (10 ml). The solution was cooled to -20 degrees centigrade. Solid acetylsalicylic acid (1.4 gram) was shaken with the cooled CAP solution for 10 seconds, and the solid acetylsalicylic acid was isolated and dried in vacuum. The CAP coated acetylsalicylic acid (100 mg) was mixed with EPA/DHA ethyl ester (860 mg, K85 EE) (Batch no. 2100107, Pronova, Sandefjord, Norway) using a 3M ESPE Capmix for 15 seconds. The suspension was ready for encapsulation in one soft gel capsule.

Example 4.2 Coated sodium salicylate in EPA/DHA ethyl ester

[0228] Cellulose acetate phthalate (CAP) (350 mg, Fluka 22192) was dissolved in acetone (5 ml). The solution was cooled to -20 degrees centigrade. Solid sodium salicylate (1.0 gram, S2679 from Aldrich) was shaken with the cooled CAP solution for 10 seconds, and the solid sodium salicylate was isolated and dried in vacuum. The CAP coated sodium salicylate (168 mg) was mixed with EPA/DHA ethyl ester (980 mg, K85 EE) (Batch no. 2100107, Pronova, Sandefjord, Norway) using a 3M ESPE Capmix for 15 seconds. The suspension was ready for encapsulation in one soft gel capsule.

Example 4.3 Coated sodium acetylsalicylate in EPA/DHA ethyl ester

[0229] Cellulose acetate phthalate (CAP) (350 mg, Fluka 22192) was dissolved in acetone (5 ml). The solution was cooled to -20 degrees centigrade. Solid sodium salicylate (Intermediate 1, 1.4 gram) was shaken with the cooled CAP solution for 10 seconds, and the solid sodium salicylate was isolated and dried in vacuum. The CAP coated sodium salicylate (94 mg) was mixed with EPA/DHA ethyl ester (590 mg, K85 EE) (Batch no. 2100107, Pronova, Sandefjord, Norway) using a 3M ESPE Capmix for 15 seconds. The suspension was ready for encapsulation in one soft gel capsule.

EXAMPLE 5: Preconcentrates

Example 5.1 SEDDS preconcentrates based on one surfactant

[0230] Preconcentrates were produced by mixing K85EE (500 mg or 750 mg), a surfactant, and in most cases, a solvent. The total mass of each SEDDS was 1000 mg. Excipients were weighed into 20 ml glass vials and mixed by shaking.

[0231] The solubility of acetylsalicylic acid (ASA) in the preconcentrates was determined by adding 300 mg ASA to 1 ml of each preconcentrate and agitating by end-over-end rotation at room temperature. After 72 hours, each preconcentrate was filtered (0.22 μιη). Subsequently, 100 μΐ of each preconcentrate was diluted with 900 μΐ acetonitrile and the ASA content quantified by HPLC (Dionex Ultimate 3000 system). Column: Phenomenex Luna CI 8 125mm, temperature 30°C. Eluent A: MilliQ water (20 mM formic acid) adjusted to pH 3 with ammonium hydroxide, Eluent B: Acetonitrile. Isocratic conditions: 25% B, flow: 0.8 ml/min, injection volume: 10 μΐ, detection: 256 nm, run time 15 minutes.

[0232] The ability of the preconcentrates to form emulsions in water was determined by adding 100 μΐ of preconcentrate to 2 ml MilliQ water (20 fold dilution) and agitating by shaking. Each vial was inspected immediately after mixing and again after a period of 4 hours with no agitation of the vials. The stability of the emulsions was evaluated by observing for signs of phase separation.

[0233] Particle size distribution of the emulsions formed from the preconcentrates was determined by dispersing 100 μΐ of each SEDDS in 2 ml MilliQ water and gentle agitation by shaking for approx. 30 seconds. Z-average measurements were completed using a Malvern ZetaSizer. Each emulsion was measured in triplicate.

[0234] The results are given in Tables 5.1 to 5.8 below.

Table 5.1 : SEDDS of K85EE (500 mg) and Tween 80

Table 5.2: Particle size of emulsions formed with SEDDS of K85EE (500 mg) and Tween 80

*SD = standard deviation Table 5.3: SEDDS of K85EE (500 mg) and Tween 20

Table 5.4: Particle size of emulsions formed with SEDDS of K85EE (500 mg) and Tween 20

Table 5.5: SEDDS of K85EE and Cremophor EL

Table 5.6: Particle size of emulsions formed with SEDDS of K85EE and Cremophor EL

Table 5.8: Particle size of emulsions formed with SEDDS of K85EE (500 mg) and Brij 97

The time for the SEDDS preconcentrates based on one surfactant to form emulsions was determined by adding 40 μΐ preconcentrate to 2 ml deionized water in 20 ml vials. Light agitation of the mixture was provided by means of a magnetic stirrer (100 RPM, magnet = 6mm, 0= 2mm). The time to full dispersion was visually determined. Generally, the dispersion time ranged from approximately 2 to 6 minutes for the majority of the pre-concentrates to form emulsions.

Example 5.2 SEDDS preconcentrates based on two surfactants

[0235] Preconcentrates were produced by mixing K85EE (500 mg), two surfactants and in most cases a solvent. The total mass of each SEDDS was 1000 mg. Excipients were weighed into 20 ml glass vials and mixed by shaking. Appearance of preconcentrates was evaluated after 24 and 48 hours.

[0236] The solubility of acetylsalicylic acid (ASA) in the preconcentrates, the ability of the SEDDS preconcentrates to form emulsions in water, and the particle size distribution of the preconcentrates were determined as described in Example 5.1.

[0237] The results are given in Tables 5.9 to 5.16 below.

[0238] Table 5.9 SEDDS of K85EE (500 mg), Tween 80 and one further surfactant

Table 5.10: Particle size and stability of emulsions formed with SEDDS of K85EE (500 mg) and

Tween 80 and one further surfactant

Table 5.1 1 SEDDS of K85EE (500mg), Tween 20 and one further surfactant Ex. Tween 20 Cremophor Brij 97 Oleic Appearance ASA solubility (mg) EL acid (mg ASA/1000 mg

(mg) SEDDS)

21-2-10 200 200 0 100 Turbid 43

21-2-11 200 0 200 100 clear 47

21-2-23 175 175 0 150 clear 38

21-2-24 175 0 175 150 clear -

Table 5.12: Particle size and stability of emulsions formed with SEDDS of K85EE (500 mg) and Tween 20 and one further surfactant

Table 5.13 SEDDS of K85EE (500 mg), Cremophor EL and Brij 97

Table 5.14: Particle size and stability of emulsions formed with SEDDS of K85EE (500 Cremophor EL and Brij 97

mg

SEDDS)-2-16 175 175 0 0 0 0 150 clear --2-17 175 0 175 0 150 0 0 clear 70-2-18 175 0 175 0 0 150 0 clear 68-2-19 175 0 175 0 0 0 150 clear --2-20 175 0 0 175 150 0 0 clear 73-2-21 175 0 0 175 0 150 0 clear 71-2-22 175 0 0 175 0 0 150 clear 36

Table 5.16: Particle size and stability of emulsions formed with SEDDS of K85EE (500 mg) and Tween 80 and one further surfactant

Claims

WHAT IS CLAIMED IS:

1. A composition comprising:

a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, triglyceride, and phospholipid; and

at least one salicylate.

2. The composition according to claim 1, wherein the fatty acid oil mixture comprises at least 90% omega-3 fatty acids, by weight of the fatty acid oil mixture.

3. The composition according to claim 2, wherein at least one of the omega-3 fatty acids has a cis configuration.

4. The composition according to claim 1, wherein the fatty acid oil mixture further comprises at least one other fatty acid other than EPA and DHA in a form chosen from free fatty acid, ethyl ester, and triglyceride.

5. The composition according to claim 4, wherein the at least one other fatty acid is chosen from -linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), stearidonic acid (ST A), and mixtures thereof.

6. The composition according to claim 4, wherein the at least one other fatty acid is chosen from linoleic acid, gamma-linolenic acid (GLA), arachidonic acid (AA), osbond acid, and mixtures thereof.

7. The composition according to claim 1, wherein the fatty acid oil mixture is derived from at least one oil chosen from marine oil, algae oil, plant-based oil, and microbial oil.

8. The composition according to claim 7, wherein the marine oil is a purified fish oil.

9. The composition according to claim 1, wherein the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :10 to 10: 1, from about 1 :8 to 8: 1, from about 1 :7 to about 7: 1, from about 1 :6 to 6: 1, from about 1 :5 to 5: 1 , from about 1 :4 to 4: 1, from about 1 :3 to 3 :1 , from about 1 :2 to 2: 1 , from about 1 : 1 to 2: 1 , or from about 1 :2 to 1 :3.

10. The composition according to claim 9, wherein the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to 2: 1.

1 1. The composition according to claim 9, wherein the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to 1 :3.

12. The composition according to claim 1, wherein the at least one salicylate is chosen from aspirin and other salicylates such as acetylsalicylic acid, salicylic acid, salicylsalicylic acid and acetylsalicylsalicylic acid, and pharmaceutically acceptable salts thereof.

13. The composition according to claim 1, wherein the at least one salicylate is dissolved or suspended in the oil mixture.

14. The composition according to claim 1, wherein the at least one salicylate is partly dissolved in the oil mixture.

15. The composition according to claim 1, wherein the at least one salicylate is in the form of crystalline material or amorphous material.

16. The composition according to claim 1, wherein the composition is in the form of a capsule.

17. The composition according to claim 16, wherein the composition is in the form of a gelatin capsule.

18. A composition comprising:

a fatty acid oil mixture comprising from about 25% to about 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and

at least one salicylate.

19. A preconcentrate comprising:

a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride;

at least one salicylate; and

at least one surfactant.

20. The preconcentrate according to claim 19, wherein the fatty acid oil mixture comprises at least 90% omega-3 fatty acids, by weight of the fatty acid oil mixture.

21. The preconcentrate according to claim 19, wherein at least one of the omega-3 fatty acids has a cis configuration.

22. The preconcentrate according to claim 19, wherein the fatty acid oil mixture further comprises at least one other fatty acid other than EPA and DHA in a form chosen from free fatty acid, ethyl ester, and triglyceride.

23. The preconcentrate according to claim 22, wherein the at least one other fatty acid is chosen from a-linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), stearidonic acid (STA), and mixtures thereof.

24. The preconcentrate according to claim 22, wherein the at least one other fatty acid is chosen from linoleic acid, gamma-linolenic acid (GLA), arachidonic acid (AA), osbond acid, and mixtures thereof.

25. The preconcentrate according to claim 19 , wherein the fatty acid oil mixture is derived from at least one oil chosen from marine oil, algae oil, plant-based oil, and microbial oil.

26. The preconcentrate according to claim 25, wherein the marine oil is a purified fish oil.

27. The preconcentrate according to claim 19, wherein the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 : 10 to 10: 1, from about 1 :8 to 8:1 , from about 1 :7 to about 7: 1, from about 1 :6 to 6: 1, from about 1 :5 to 5:1 , from about 1 :4 to 4: 1, from about 1 :3 to 3: 1 , from about 1 :2 to 2: 1 , from about 1 : 1 to 2: 1 , or from about 1 :2 to 1 :3.

28. The preconcentrate according to claim 27, wherein the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to 2: 1.

29. The preconcentrate according to claim 27, wherein the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to 1 :3.

30. The preconcentrate according to claim 19, wherein the fatty acid oil mixture comprises from about 50% to about 60% EPA in free fatty acid form, by weight of the fatty acid oil mixture, and from about 15% to about 25% DHA in free fatty acid form, by weight of the fatty acid oil mixture.

31. The preconcentrate according to claim 19, wherein the at least one salicylate is chosen from aspirin and other salicylates such as acetylsalicylic acid, salicylic acid,

salicylsalicylic acid and acetylsalicylsalicylic acid, and pharmaceutically acceptable salts thereof.

32. The preconcentrate according to claim 19, wherein the at least one salicylate is dissolved or suspended in the oil mixture.

33. The preconcentrate according to claim 19, wherein the at least one salicylate is partly dissolved in the oil mixture.

34. The preconcentrate according to claim 19, wherein the at least one salicylate is in the form of crystalline material or amorphous material.

35. The preconcentrate according to claim 19, wherein the at least one surfactant is chosen from anionic, nonionic, cationic, zwitterionic surfactants, and mixtures thereof.

36. The preconcentrate according to claim 35, wherein the anionic surfactants are chosen from salts of perfluorocarboxylic acids and perfluorosulphonic acid, alkyl sulphate salts, sulphate ethers, alkyl benzene sulphonate salts, and mixtures thereof.

37. The preconcentrate according to claim 35, wherein the nonionic surfactants are chosen from diacetyl monoglycerides, diethylene glycol monopalmitostearates, ethylene glycol monopalmitostearates, glyceryl behenates, glyceryl distearates, glyceryl monolinoleates, glyceryl mono-oleates, glyceryl monostearates, macrogol cetostearyl ethers, macrogol 15 hydroxystearates, macrogol lauril ethers, macrogol monomethyl ethers, macrogol oleyl ethers, macrogol stearates, menfegol, mono and diglycerides, nonoxinols, octoxinols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laurates, propylene glycol monopalmitostearates, quillaia, sorbitan esters, sucrose esters, and mixtures thereof.

38. The preconcentrate according to claim 35, wherein the nonionic surfactants are chosen from nonionic copolymers comprised of a central hydrophobic polymer of

polyoxypropylene(poly(propylene oxide)) with 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.

39. The preconcentrate according to claim 38, wherein the nonionic surfactants are chosen from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyethylene (10) oleyl ether, polyoxyethylated castor oils, and mixtures thereof.

40. The preconcentrate according to claim 35, wherein the cationic surfactants are chosen from quaternary ammonium compounds, cetylpyridinium chlorides, benzethonium chlorides, cetyl trimethylammonium bromides, and mixtures thereof.

41. The preconcentrate according to claim 35, wherein the zwitterionic surfactants are chosen from dodecyl betaines, coco amphoglycinates, cocamidopropyl betaines, and mixtures thereof.

42. The preconcentrate according to claim 19, wherein the at least one surfactant comprises a phospholipid, derivative thereof, analogue thereof, or any mixture thereof.

43. The preconcentrate according to claim 42, wherein the phospholipid, derivative thereof, or analogue thereof is chosen from natural, synthetic, semisynthetic phospholipids, and mixtures thereof.

44. The preconcentrate according to claim 43, wherein the phospholipid or derivative or analogue thereof is chosen from phosphatidylcholines, phosphatidylethanolamines,

phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, and mixtures thereof.

45. The preconcentrate according to claim 19, wherein the at least one surfactant comprises from about 0.5% to about 40%, from about 10% to about 30%, or from about 10% to about 25%, by weight relative to the total weight of the preconcentrate.

46. The preconcentrate according to claim 45, wherein the at least one surfactant comprises about 20%, by weight relative to the total weight of the preconcentrate.

47. The preconcentrate according to claim 19, further comprising at least one co- surfactant.

48. The preconcentrate according to claim 47, wherein the at least one co-surfactant is chosen from short chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile salts, polysorbates, polyoxyethylene (10) oleyl ether, polyoxyethylated castor oils, and mixtures thereof.

49. The preconcentrate according to claim 48, wherein the at least one co-surfactant comprises from about 1% to about 10%, by weight relative to the total weight of the preconcentrate.

50. The preconcentrate according to claim 19, wherein the preconcentrate further comprises at least one pharmaceutically acceptable solvent.

51. The preconcentrate according to claim 50, wherein the at least one pharmaceutically- acceptable solvent is chosen from lower alcohols and polyols.

52. The preconcentrate according to claim 19, further comprising at least one antioxidant.

53. The preconcentrate according to claim 20, wherein the fatty acid oil mixture is present in a pharmaceutically effective amount.

54. The preconcentrate according to claim 19, wherein the preconcentrate is in the form of a gelatin capsule.

55. A pharmaceutical preconcentrate comprising:

a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form;

from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate; and

at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof.

56. The preconcentrate according to claim 55, wherein the fatty acid oil mixture comprises about 84% EPA and DHA, by weight of the fatty acid oil mixture, and

the fatty acid oil mixture further comprises oleic acid and at least one antioxidant, and the at least one surfactant is polysorbate 20.

57. The preconcentrate according to claim 56, wherein the antioxidant is a

butylhydroxyanisole (BHA).

58. A pharmaceutical preconcentrate comprising:

a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; from about 10% to about 15% by weight, relative to the weight of the preconcentrate, of at least one salicylate;

at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; and at least one co-surfactant comprising ethanol.

59. A pharmaceutical preconcentrate comprising:

a fatty acid oil mixture comprising at least 90% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from fatty acid, ethyl ester, and triglyceride;

at least one salicylate; and

at least one surfactant

60. The preconcentrate according to claim 59, wherein the fatty acid oil mixture comprises at least 93% EPA in ethyl ester form, by weight of the fatty acid oil mixture.

61. The preconcentrate according to claim 59, wherein the fatty acid oil mixture comprises at least 93% DHA in ethyl ester form, by weight of the fatty acid oil mixture.

62. The preconcentrate according to claim 59, wherein the fatty acid oil mixture comprises at least 97% EPA in ethyl ester form, by weight of the fatty acid oil mixture, and no DHA in ethyl ester form.

63. The preconcentrate according to claim 59, wherein the fatty acid oil mixture comprises at least 97% DHA in ethyl ester form, by weight of the fatty acid oil mixture, and no EPA in ethyl ester form.

64. A self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a preconcentrate comprising:

a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride;

at least one surfactant;

wherein the preconcentrate forms an emulsion in an aqueous solution.

65. A method of treating at least one health problem in a subject in need thereof comprising administering to the subject a preconcentrate comprising:

a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; at least one salicylate; and

at least one surfactant;

wherein the at least one health problem is chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

66. The method according to claim 65, wherein the at least one health problem is chosen from mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, heart failure, and post myocardial infarction.

67. The method according to claim 66, wherein the at least one health problem is chosen from elevated triglyceride levels, non-HDL cholesterol levels, LDL cholesterol levels and/or VLDL cholesterol levels.

68. The method according to claim 65, wherein the preconcentrate is administered once, twice, or three times per day.

69. The method according to claim 65, wherein the preconcentrate forms a self- nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) in an aqueous solution.

70. A preconcentrate comprising:

a fatty acid oil mixture comprising from about 25% to about 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride;

at least one salicylate; and

at least one surfactant.

71. The preconcentrate according to claim 70, wherein the preconcentrate forms a self- nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) in an aqueous solution.

72. A method for enhancing at least one parameter chosen from hydrolysis, solubility, bioavailability, absorption, and combinations thereof of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) comprising combining:

a fatty acid oil mixture comprising EPA and DHA in a form chosen from free fatty acid, ethyl ester, and triglyceride; and

at least one salicylate in a gelatin capsule form,

wherein the gelatin capsule or the salicylate comprises at least one coating.

73. A pharmaceutical composition comprising:

a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride; and at least one salicylate.

74. The composition according to claim 73, wherein the at least one salicylate is dissolved in the fatty acid oil mixture and the EPA and DHA are in free fatty acid form.

75. The composition according to claim 73, wherein the at least one salicylate is dissolved in the fatty acid oil mixture and the EPA and DHA are in ethyl ester form.

76. The composition according to claim 73, wherein the at least one salicylate is microencapsulated and contained in the fatty acid oil mixture and the EPA and 1 ⁾1 1A are in free fatty acid form.

77. The composition according to claim 73, wherein the at least one salicylate is microencapsulated and contained in the fatty acid oil mixture and the EPA and DHA are in ethyl ester form.

78. The composition according to claim 73, wherein the composition is in the form of a capsule.

79. The composition according to claim 78, wherein the capsule comprises gelatin.

80. The composition according to claim 73, wherein the at least one salicylate is microencapsulated and contained in the wall-forming material of the capsule, and the EPA and DHA of the fatty acid oil mixture are in free fatty acid form.

81. The composition according to claim 73, wherein the at least one salicylate is microencapsulated and contained in the wall-forming material of the capsule, and the EPA and DHA of the fatty acid oil mixture are in ethyl ester form.

82. A preconcentrate comprising:

at least one salicylate; and

at least one surfactant

for the treatment of at least one health problem chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

83. A self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a preconcentrate comprising: a fatty acid oil mixture comprising at least 70% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from free fatty acid, ethyl ester, and triglyceride;

at least one salicylate; and

at least one surfactant;

wherein the preconcentrate forms an emulsion in an aqueous solution for the treatment of at least one health problem chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

84. The preconcentrate according to claim 22, wherein the fatty acid oil mixture comprises from about 80 to about 88% EPA and DHA, by weight of the fatty acid oil mixture; the EPA and DHA are in free acid form; the at least one surfactant comprises polysorbate 20 and macrogol 15 hydroxystearate; the at least one other fatty acid other than EPA and DHA comprises sesame oil; and the fatty acid oil mixture further comprises at least one antioxidant comprising butylhydroxyanisoles (BHA).

85. The preconcentrate according to claim 84, wherein the at least one salicylate is is chosen from acetylsalicylic acid, salicylic acid, and pharmaceutically acceptable salts thereof.

86. The preconcentrate according to claim 84, wherein the at least one salicylate comprises about 125 mg.

87. The preconcentrate according to claim 84, wherein the preconcentrate is in form of a capsule.

88. The preconcentrate according to claim 84, wherein the at least one salicylate is dissolved or suspended in the oil mixture.

89. The preconcentrate according to claim 88, wherein the at least one salicylate suspended in the oil mixture is coated with a gastroresistant material.

90. The preconcentrate according to claim 88, wherein the capsule is coated.

91. The preconcentrate according to claim 84, wherein the at least one salicylate is microencapsulated and contained in the wall-forming material of the the capsule.

92. The preconcentrate according to claim 84, wherein the at last one salicylate is partly dissolved or suspended in the oil and partly microencapsulated in the wall-forming material of the capsule.

93. A preconcentrate comprising: from about 45% to about 55% by weight, relative to the weight of preconcentrate, of a fatty acid mixture comprising from about 80 to about 88% EPA and DHA by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; and the fatty acid oil mixture further comprises from about 10% to about 15% by weight, relative to the preconcentrate, of oleic acid; the at least one surfactant comprises polysorbate 20 in an amount from about 30% to about 40% by weight, relative to the preconcentrate; and the faty acid oil mixture further comprises at least one antioxidant comprising BHA; and at least one salicylate.

94. The preconcentrate according to claim 93, wherein the at least one salicylate is is chosen from acetylsalicylic acid, salicylic acid, and pharmaceutically acceptable salts thereof.

95. The preconcentrate according to claim 93, wherein the at least one salicylate comprises about 125 mg.

96. The preconcentrate according to claim 93, wherein the preconcentrate is in form of a capsule.

97. The preconcentrate according to claim 93, wherein the at least one salicylate is dissolved or suspended in the oil mixture.

98. The preconcentrate according to claim 97, wherein the at least one salicylate suspended in the oil mixture is coated with a gastroresistant material.

99. The preconcentrate according to claim 97, wherein the capsule is coated.

100. The preconcentrate according to claim 93, wherein the at least one salicylate is microencapsulated and contained in the wall-forming material of the the capsule.

101. The preconcentrate according to claim 93, wherein the at last one salicylate is partly dissolved or suspended in the oil and partly microencapsulated in the wall-forming material of the capsule.

102. The preconcentrate according to claim 93, wherein the fatty acid oil mixture comprises about 84% EPA and DHA, by weight of the fatty acid oil mixture.