WO2012032414A2

WO2012032414A2 - Compositions comprising a fatty acid oil mixture, a surfactant, and a statin

Info

Publication number: WO2012032414A2
Application number: PCT/IB2011/002727
Authority: WO
Inventors: Svein Olaf Hustvedt; Preben Houlberg Olesen; Gunnar Berge; Jo Erik Johnsrud Klaveness
Original assignee: Pronova Biopharma Norge As
Priority date: 2010-09-08
Filing date: 2011-09-08
Publication date: 2012-03-15
Also published as: AR082930A1; WO2012032414A3

Abstract

Preconcentrates comprising a fatty acid oil mixture, at least one surfactant, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof, and uses thereof are disclosed. The preconcentrates may be capable of forming a self-nanoemulsifying drug delivery system (SNEDDS), a self- microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery systems (SEDDS) in an aqueous solution.

Description

COMPOSITIONS COMPRISING A FATTY ACID OIL MIXTURE,

A SURFACTANT, AND A STATIN

[001 ] This application claims priority to U.S. Provisional Application

No. 61/381 ,070, filed on September 8, 2010, which is incorporated herein by reference in its entirety.

[002] The present disclosure relates generally to preconcentrates comprising a fatty acid oil mixture, at least one surfactant, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof, and methods of use thereof. The fatty acid oil mixture may comprise omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in ethyl ester or triglyceride form. Further disclosed are self-nanoemulsifying drug delivery systems (SNEDDS), self-microemulsifying drug delivery systems (SMEDDS) and self- emulsifying drug delivery systems (SEDDS).

[003] The preconcentrates presently disclosed may be administered, e.g., in capsule, caplet, or tablet form, to a subject for therapeutic treatment of at least one health problem including, for example, irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, heart failure, and post myocardial infarction (Ml). The present disclosure further relates to a method of increasing hydrolysis, solubility, bioavailability, absorption, and/or any combination thereof.

[004] 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. Conditions characterized by abnormally high blood cholesterol and/or lipid values include hypercholesterolemia, hyperlipidemia (hyperlipoproteinemia), hypertriglyceridemia, and mixed dyslipidemia. High levels of total cholesterol (total- C), LDL-C, and apolipoprotein B (a membrane complex for LDL-C and VLDL-C) may promote human atherosclerosis. Decreased levels of HDL-C and its transport complex, apolipoprotein A, are also associated with the development of

atherosclerosis. 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, the NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) report specifies non-HDL cholesterol reduction as a treatment objective.

[005] 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), which 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.

[006] 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 trademark Omacor® / Lovaza™ / Zodin® / Seacor®. See, e.g., U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594. 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.

[007] 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.

[008] The biosynthesis of cholesterol by human liver cells is a multistep process starting with acetyl-CoA. In the early part of this process, hydroxymethyl- glutaryl-CoA (HMG-CoA) is reduced forming R-mevalonic acid. This process is catalyzed by the enzyme HMG-CoA reductase. Several compounds inhibit this enzyme and thereby inhibit the biosynthesis of cholesterol (see FIG 1 ). These inhibitors are named statins or HMG-CoA reductase inhibitors, and are frequently used as drugs for reduction of plasma cholesterol. Examples of statins include atorvastatin, cerivastatin, fluvastatin, itavastatin, lovastatin, mevastatin, rosuvastatin, simvastatin, pravastatin, and pitavastatin. The chemical formulae for various statins are shown in FIG 2.

[009] Atorvastatin and atorvastatin-like drugs, and processes of preparation, compositions, and uses thereof are described, for example, in U.S. Patent Nos. US 4,681 ,893, US 5,969, 156, US 6,262,092, US 6,486, 182, US 6,528,660, US

6,600,051 , US 6,605,636, US 6,605,727, US 6,613,916, US 6,646, 133, US

6.730,797, US 6,737,430, US 6,750,353, US 6,835,742, US 6,867,306, US

6,891 ,047, US 6,992, 194, US 7,030, 151 , US 7,074,818, US 7,074,940, US

7, 1 12,604, US 7, 122,681 , US 7, 129,265, US 7,144,916, US 7,151 , 183, US

7, 161 ,012, US 7, 186,848, US 7, 189,861 , US 7, 193,090, US 7,256,212, US

7,342,120, US 7,361 ,772, US 7,41 1 ,075, US 7,414, 141 , US 7,429,613,

US7,456,297, US 7,468,444, US 7,488,750, US 7,501 ,450, US 7,538, 136, US 7,615,647, US 7,645,888, US 7,655,692, US 7,674,923, US 7,732,623, US

7,745,480 and US 7,772,273.

[010] Simvastatin and simvastatin-like drugs, and processes of preparation, compositions, and uses thereof are described, for example, in U.S. Patent Nos. US 4,444,784; US 5,393,893, US 5,763,646, US 5,763,653 , US 6, 100,407, US

6,252,091 , US 6,271 ,398, US 6,307,066, US 6,331 ,641 , US 6,384,238, US

6,506,929, US 6,521 ,762, US 6,541 ,51 1 , US 6,573,385, US 6,573,392, US 6,576,775, US 6,603,022, US 6,686,481 , US 6,696,086, US 6,797,831 , US

6,825,362, US 6,833,461 , US 6,984,399, US 6,995,277, US 7,205,415, US

7,528,265, US 7,678,928 and US 7,700,339.

[01 1] Pravastatin and pravastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in U.S. Patent Nos. US 4,346,227; US 4,857,522, US 5,047,549, US 5,140,012, US 5,155,229, US

5, 180,589, 5,260,305; US 5, 180,589, US 5,260,305, US 5,942,423, US 6,204,032, US 6,274,360, US 6,306,629, US 6,566,120, US 6,682,913, US 6,696,599, US 6,716,615, US 6,740,775, US 6,750,366, US 6,790,984, US 6,905,851 , US

6,936,731 , US 6,967,218, US 7,001 ,019, US 7,056,710, US 7,078,558, US

7, 189,558, US 7,223,590, US 7,262,218, US 7,425,644, US 7,582,464 and US 7,642,286.

[012] Fluvastatin and fluvastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in U.S. Patent Nos. US 6,858,643, US 7,241 ,800, US 7,368,468, US 7,368,581 , US 7,414, 140, US

7,432,380, US 7,662,848 and US 7,687,642.

[013] Lovastatin and lovastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in U.S. Patent Nos. US 4,866, 186, US 5,082,650, US 5,409,820, US 5,595,734, US 5,712, 130, US

5,763,646, US 6, 197,560, US 6,472,542, US 6,500,651 , US 6,521 ,762, US

6,696,086, US 6,984,399, US 7,052,886 and US 7,566,792.

[014] Rosuvastatin and rosuvastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in U.S. Patent Nos. US 6,858,618, US 7, 161 ,004, US 7, 179,916, US 7,244,844, US

7,396,927, US 7,51 1 , 140, US 7,566,782, US 7,582,759, US 7,612,203, US

7,692,008, US 7,692,009, US 7,672,010, US 7,741 ,482 and US 7,777,034.

[015] Cerivastatin and cerivastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in U.S. Patent No.

6,51 1 ,985.

[016] Itavastatin and itavastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in Saito et al.,

Atherosclerosis, 151 : 1 , 154 (July 2000); Teramoto et al., Atherosclerosis, 151 : 1 , 53 (July 2000); Kithhara et al., Atheriosclerosis, 151 :1 , 295 (2000), and further publications in the same issue.

[017] Mevastatin and meavastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in U.S. Patent Nos. US 6,384,238, US 6,531 ,507, US 6,583,295, US 6,695,969, US 6,806,290, US

6,838,566, US 7,078,558, US 7,141 ,602 and US 7,582,464.

[018] Pitavastatin and pitavastatin-like drugs, and processes of preparation, composition, and uses thereof, are described, for example, in U.S. Patent Nos. US 6,777,552, US 7,238,826, US 7,241 ,800, US 7,301 ,046, US 7,459,447, US

5,598,233 and US 7,776,881.

[019] Statins may be used in the form of salts; specific examples include calcium salts of atorvastatin, itavastatin, rosuvastatin, and pitavastatin; and sodium salts of pravastatin and fluvastatin. Statins may also be in lactone form, such as simvastatin, mevastatin, and lovastatin. Further, statins may exist in various crystalline forms and/or in amorphous form. For example, atorvastatin calcium salt can exist in an amorphous form or in different crystalline forms. See, e.g. , WO 97/3958, WO 97/3959, WO 01/36384, WO 02/41834, WO 02/43732, WO 02/51804, and WO 02/57229. Processes for the preparation of amorphous atorvastatin calcium are described, for example, in WO 97/3960, WO 00/71 1 16, WO 01/28999, WO 01/42209, WO 02/57228, and WO 02/59087.

[020] The oral bioavailability of statins is generally low: atorvastatin (20%), simvastatin (less than 5%), pravastatin (18%) and rosuvastatin (20%). Active drug substances in an amorphous form may be better soluble and dissolve more rapidly than in a crystalline form. Atorvastatin calcium in amorphous form is claimed to have higher bioavailability than crystalline forms of the same salt.

[021 ] The half-life of statins may vary over a wide range, e.g., pravastatin (about 0.8 hours), simvastatin (about 2-3 hours), atorvastatin (about 20 hours) and rosuvastatin (about 20 hours). The daily clinical dose of various statins may also vary, e.g., atorvastatin (10-80 mg), cerivastatin (0.2-0.3 mg), fluvastatin (20-80 mg), lovastatin (20-80 mg), pravastatin ( 0-40 mg), and simvastatin (5-80 mg).

[022] Further, statins may be unstable. For example, atorvastatin calcium is susceptible to heat, light, oxygen, moisture, and low pH. At low pH, atorvastatin calcium is converted from the carboxylic acid form to the lactone form, and in presence of oxygen various oxidation products are formed. Problems associated with stability issues in solid drug formulations have been addressed. See, e.g. , U.S. Patent Nos. US 7,772,273 (LifeCyclePharma), US 6,680,341 (LEK), US 6,531 ,505 (LEK), US 2010/0178338 (Ranbaxy); and U.S. Patent Application Publication Nos. US 2009/0264487 (LEK) and US 2009/0247603 (Orbus Pharma).

[023] Administration of one active agent and/or diet modification may not be sufficient to reach a patient's target cholesterol and/or lipid levels. There remains a need in the art for compositions and/or methods to better regulate abnormal plasma lipid values in subjects in need of such treatment. Such compositions must also be sufficiently stable for pharmaceutical use and provide for sufficient solubilization, digestion, bioavailability and/or absorption of omega-3 fatty acids in vivo, while maintaining the ability to cross cell membranes.

[024] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure, as claimed.

[025] The present disclosure is further directed to a pharmaceutical preconcentrate comprising: a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

[026] The present disclosure is further directed to 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; at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof chosen from atorvastatin, simvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

[027] The present disclosure is further directed to 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; at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; at least one co-surfactant comprising ethanol; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof chosen from atorvastatin, simvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

[028] The present disclosure is further directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system

(SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising 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 a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the preconcentrate forms an emulsion in an aqueous solution.

[029] The present disclosure is further directed to a method of treating at least one health problem in a subject in need thereof comprising administering to the subject a pharmaceutical preconcentrate comprising: a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the at least one health problem is chosen from irregular plasma lipid levels (e.g., hypertriglyceridemia, hypercholesterolemia, and/or mixed dyslipidemia), cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.

[030] The present disclosure is further directed to 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 ethyl ester and triglyceride; at least one surfactant and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the fatty acid oil mixture, the at least one surfactant, and the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof form a preconcentrate.

[031] The present disclosure is further directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system

(SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a pharmaceutical preconcentrate comprising: a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the preconcentrate forms an emulsion in an aqueous solution for the treatment of at least one health problem chosen from mixed dyslipidemia, dyslipidemia,

hypertriglyceridemia, and hypercholesterolemia.

BRIEF DESCRIPTION OF THE DRAWINGS

[032] FIG 1 shows biosynthesis of cholesterol and a mechanism of action of statins (Jo Klaveness, Compendium in Medicinal Chemistry, Oslo, Norway (2009)).

[033] FIG 2 shows the chemical formulae of simvastatin, lovastatin, pravastatin, fluvastatin, and atorvastatin.

[034] FIG 3 shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of Omacor® .

[035] FIG 4 shows the percent recovery of EPA + DHA at different time- points for Omacor®.

[036] FIG 5 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for Omacor®.

[037] FIG 6 shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of preconcentrate A.

[038] FIG 7 shows the percent recovery of EPA + DHA at different time- points for preconcentrate A.

[039] FIG 8 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate A. [040] FIG 9 shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of preconcentrate B.

[041] FIG 10 shows the percent recovery of EPA + DHA at different time- points for preconcentrate B.

[042] FIG 1 1 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate B.

[043] FIG 12 shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of preconcentrate C.

[044] FIG 13 shows the percent recovery of EPA + DHA at different time- points for preconcentrate C.

[045] FIG 14 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate C.

[046] FIG 15 shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of preconcentrate D.

[047] FIG 16 shows the percent recovery of EPA + DHA at different time- points for preconcentrate D.

[048] FIG 17 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate D.

[049] FIG 18 shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of preconcentrate E.

[050] FIG 19 shows the percent recovery of EPA + DHA at different time- points for preconcentrate E.

[051 ] FIG 20 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate E.

DESCRIPTION

[052] 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 is hereby incorporated by reference. The terms and definitions provided herein control, if in conflict with terms and/or definitions incorporated by reference.

[053] The singular forms "a," "an," and "the" include plural reference unless the context dictates otherwise. [054] 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.

[055] 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 preconcentrate according to the disclosure, and (2) putting into, taking or consuming by the patient or person himself or herself, a preconcentrate according to the disclosure.

[056] The present disclosure provides for pharmaceutical preconcentrates comprising a fatty acid oil mixture, at least one surfactant, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof, and methods of use thereof. 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, microemuisions, 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).

Fatty acid oil mixture

[057] Compositions of the present disclosure comprise at least one fatty acid oil mixture comprising eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 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. In at least one embodiment, the fatty acid oil mixture comprises fatty acids, such as omega-3 fatty acids, in a form chosen from ethyl ester and triglyceride.

[058] 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.

[059] In some embodiments of the present disclosure, the fatty acid oil mixture comprises EPA and DHA. Further for example, the fatty acid oil mixture comprises EPA and DHA in a form chosen from ethyl ester and triglyceride.

[060] 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 (HPA), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and stearidonic acid (STA). 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 is in a form chosen from ethyl ester and triglyceride.

[061 ] 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 Pharamacopoeia Omega-3 Ethyl Esters 90 or the USP omega-3 EE Monograph. Commercial embodiments provide for various omega-3 fatty acids, combinations, and other components as a result of the transesterification process or method of preparation in order to obtain the omega-3 fatty acid(s) from various sources, such as marine, algae, microbial, and plant-based sources.

[062] 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.

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.

[063] 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, such as ethyl ester. In other embodiments, the fatty acids are chosen from mono-, di-, and triglycerides.

[064] 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.

[065] 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.

[066] 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 (STA), (all-Z)-1 1 , 14, 17-eicosatrienoic acid (ETE), (all-Z)-5,8, 1 1 , 14, 17-eicosapentaenoic acid (EPA), (all-Z)-4,7, 10,13,16, 19- docosahexaenoic acid (DHA), (all-Z)-8, 1 1 ,14, 17-eicosatetraenoic acid (ETA), (all-Z)- 7,10, 13,16, 19-docosapentaenoic acid (DPA), (all-Z)-6,9, 12,15, 19- heneicosapentaenoic acid (HPA); (all-Z)-5,8, 1 1 , 14-eicosatetraenoic acid, (all-Z)- 4,7, 10, 13, 16-docosapentaenoic acid (osbond acid), (all-Z)-9, 12-octadecadienoic acid (linoieic acid), (all-Z)-5,8,1 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).

[067] 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 :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.

Statin

[068] The compositions presently disclosed comprise at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. As used herein, the term "statin" includes statins, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and complexes thereof. Any regulatory approved statin may be suitable for the preconcentrates and/or SNEDDS/SMEDDS/SEDDS presently disclosed. Examples include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, itavastatin, lovastatin, mevastatin, rosuvastatin, simvastatin, pravastatin, and pitavastatin.

[069] Statins according to the present disclosure may be used in the free acid form or in the form of a pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. Typical salts of statins suitable for the present disclosure include, for example, ammonia salts, L-arginine salts, benethamine salts, benzathine salts, calcium salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2- (diethylamino)-ethanol salts, ethanolamine salts, ethylenediamine salts, N-methyl- glucamine salts, hydravamine salts, 1 H-imidazole salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)-morpholine salts, piperazine salts, potassium salts, 1 -(2- hydroxyethyl)-pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, zinc salts, and meglumin salts. Statins according to the present disclosure may also be in lactone form, for example simvastatin, mevastatin, and/or lovastatin.

Complexes according to the present disclosure include, for example, complexes comprising a statin and at least one of meglumin CD, meglumin beta-CD, calcium CD, calcium beta-CD, crysmeb, beta cyclodextrin, and kleptose. In some

embodiments, the statin complex may be crystallized.

[070] In some embodiments of the present disclosure, the at least one statin is chosen from atorvastatin, cerivastatin, fluvastatin, itavastatin, lovastatin, mevastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof. For example, in some embodiments, the at least one statin is chosen from simvastatin, atorvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof. In at least one embodiment, the at least one statin is chosen from atorvastatin, for example atorvastatin calcium, rosuvastatin, such as

rosuvastatin calcium, and simvastatin.

[071 ] Commercial embodiments of statins encompassed by the present disclosure include, but are not limited to, Lipitor® (atorvastatin), Lescol® (fluvastatin), Mevacor® (lovastatin), Crestor® (rosuvastatin), Zocor® (simvastatin), Pravachol® (pravastatin), and Livalo® (pitavastatin), or regulatory approved generics thereof.

[072] The statins or pharmaceutically acceptable hydrates, solvates, and complexes thereof according to the present disclosure may be amorphous or in crystalline form. In at least one embodiment, the at least one statin or

pharmaceutically acceptable hydrate, solvate, or complex thereof is in amorphous form.

[073] The amount of the at least one statin in the preconcentrates presently disclosed may range from about 0.1 mg to about 100 mg, such as from about 5 mg to about 80 mg, from about 10 mg to about 80 mg, or from about 10 mg to about 40 mg. In at least one embodiment, the at least one statin is chosen from atorvastatin, such as atorvastatin calcium, rosuvastatin, such as rosuvastatin calcium, and simvastatin, in an amount ranging from about 10 mg to about 80 mg.

[074] In some embodiments of the present disclosure, the fatty acid oil mixture acts as an active pharmaceutical ingredient (API), i.e., the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof and the fatty acid oil mixture both act as APIs. For example, the present disclosure provides for a pharmaceutical preconcentrate comprising a fatty acid oil mixture, at least one surfactant, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. In some embodiments, the fatty acid oil mixture is present in a pharmaceutically-acceptable amount. 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. In at least some embodiments of the present disclosure, the pharmaceutical preconcentrate comprises a fatty acid oil mixture, at least one surfactant, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof, wherein the fatty acid oil mixture and the statin are the sole active agents in the preconcentrate.

[075] In the pharmaceutical preconcentrates presently disclosed, the fatty acid oil mixture may comprise at least 75% EPA and DHA by weight of the fatty acid oil mixture. In some embodiments, 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.

[076] For example, in some embodiments, the fatty acid oil mixture comprises from about 75% to about 95% EPA and DHA by weight of the fatty acid oil mixture, such as from about 75% to about 90%, from about 75% to about 88%, from about 75% to about 85%, from about 75% 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 88% EPA and DHA, by weight of the fatty acid oil mixture, such as from about 80% to about 85%, such as about 84%, by weight of the fatty acid oil mixture.

[077] 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, wherein the EPA and DHA are in ethyl ester form. [078] 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.

[079] In one embodiment, for example, the fatty acid oil mixture comprises from about 75% to about 88% EPA and DHA, by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; wherein the fatty acid oil mixture comprises at least 90% of omega-3 fatty acids in ethyl ester form, by weight of the fatty acid oil mixture.

[080] In another embodiment, the fatty acid oil mixture comprises from about 75% to about 88% EPA and DHA, by weight of the fatty acid oil mixture, wherein the EPA and DHA are in ethyl ester form; wherein the fatty acid oil mixture comprises at least 90% of omega-3 fatty acids in ethyl ester form, by weight of the fatty acid oil mixture, and wherein the fatty acid oil mixture comprises a-linolenic acid (ALA).

[081 ] 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, wherein the EPA and DHA are in ethyl ester form, and further comprises docosapentaenoic acid (DPA) in ethyl ester form.

[082] 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, wherein the EPA and DHA are in ethyl ester form, and further comprises from about 1 % to about 4% (all-Z omega-3)-6,9, 12, 15, 8-heneicosapentaenoic acid (HPA) in ethyl ester form, by weight of the fatty acid oil mixture.

[083] 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, wherein the EPA and DHA are in ethyl ester form; and from 1 % to about 4% fatty acid ethyl esters other than EPA and DHA, by weight of the fatty acid oil mixture, wherein the fatty acid ethyl esters other than EPA and DHA have C₂o, C₂i , or C₂₂ carbon atoms.

[084] 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). EPA and DHA products

[085] In at least one embodiment, the fatty acid oil mixture comprises at least 75% 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.

[086] In another embodiment, the fatty acid oil mixture comprises at least 75% 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.

Surfactant / Preconcentrate

[087] The present disclosure further provides for a preconcentrate composition. As used herein, the term "preconcentrate" refers to a composition comprising at least the combination of a fatty acid oil mixture and at least one surfactant. In some embodiments, for example, the preconcentrate comprises a fatty acid oil mixture, at least one surfactant, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

[088] 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.

[089] 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:

HLB_A (fraction of surfactant A) + HLB_B (fraction of surfactant B) = HLB_A+B mixture

[090] 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.

[091 ] In at least one embodiment of the present disclosure, the

preconcentrate comprises at least one surfactant chosen from nonionic, anionic, cationic, and zwitterionic surfactants.

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

[093] Pluronic® 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.

[094] Brij® are nonionic surfactants comprising polyethylene ethers.

Various commercially-available Brij® products are listed in Table 2. Table 2: Examples of Brij® surfactants.

[095] 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.

[096] 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.

[097] 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.

[098] Cremophor® are nonionic surfactants. Various commercially-available Cremophor® products are listed in Table 6. Table 6: Examples of Cremophor® surfactants.

[099] According to the present disclosure, other exemplary nonionic surfactants include, but are not limited to, diacetyl monoglycerides, diethylene glycol monopalmitostearate, ethylene glycol monopalmitostearate, glyceryl behenate, glyceryl distearate, glyceryl monolinoleate, glyceryl mono-oleate, glyceryl monostearate, macrogol cetostearyl ether such as cetomacrogol 1000 and polyoxy 20 cetostearyl ether, macrogol 15 hydroxystearate, 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 poiyoxalene, polyoxamer 188, polyoxamer 407, polyoxyl castor oil such as polyoxyl 35 castor oil, polyoxyl hydrogenated castor oil such as polyoxyl 40 hydrogenated castor oil, propylene glycol diacetate, propylene glycol laurates such as propylene glycol dilaurate and propylene glycol monolaurate. Further examples include propylene glycol monopalmitostearate, quillaia, sorbitan esters, and sucrose esters.

[0100] 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, and alkyl benzene sulphonate salts.

[0101 ] Cationic surfactants suitable for the present disclosure include, for example, quaternary ammonium compounds such as benzalkonium chloride, cetylpyridinium chlorides, benzethonium chlorides, and cetyl trimethylammonium bromides or other trimethylalkylammonium salts.

[0102] Zwitterionic surfactants include, but are limited to, for example dodecyl betaines, coco amphoglycinates and cocamidopropyl betaines.

[0103] In some embodiments of the present disclosure, the surfactant may comprise a phospholipid, derivative thereof, or analogue thereof. Such surfactants may, for example, be chosen from natural, synthetic, and semisynthetic

phospholipids, derivatives thereof, and analogues thereof. 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, 18:2n- 6, 18:3n-3, 18:4n-3, 20:4n-6, 20:5n-3, 22:5n-3 and 22:6n-3, or any combinations thereof. In one embodiment, the fatty acid moiety is chosen from palmitic acid, EPA and DHA. Exemplary phospholipids 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.

[0104] Other exemplary surfactants suitable for the present disclosure are listed in Table 7.

Table 7: Other surfactants

Surfactant Type HBL Value

Ethylene glycol distearate Nonionic 1.5

Glyceryl monostearate Nonionic 3.3

Propylene glycol monostearate Nonionic 3.4

Glyceryl monostearate Nonionic 3.8

Diethylene glycol monolaurate Nonionic 6.1

Acacia Anionic 8.0 Cetrimonium bromide Cationic 23.3

Cetylpyridinium chloride Cationic 26.0

Polyoxamer 188 Nonionic 29.0

Sodium lauryl sulphate Anionic 40

[0105] 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.ln 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.

Additional Oils

[0106] In some embodiments, preconcentrates of the present disclosure further comprise at least one additional oil, such as medium chain triglyceride (MCT) oil and long chain triglycerides (LCT) oil, including sesame oil. Further examples can include ethyl oleate.

Co-surfactant

[0107] In some embodiments, preconcentrates of the present disclosure further comprise at least one co-surfactant. As used herein the term "co-surfactant" means a substance added to the preconcentrate in combination with the at least one surfactant to 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 hydrophiiic. In some embodiments, the at least one co-surfactant is not in free acid form.

[0108] 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®) and 2-pyrrolidone (e.g., Soluphor® P), and bile salts, for example sodium deoxycholate.

[0109] In some embodiments, the at least one co-surfactant comprises from about 1 % to about 0%, by weight relative to the weight of the preconcentrate. Solvent

[01 10] In some embodiments, compositions according to the present disclosure, such as the preconcentrate, further comprises at least one solvent. As used herein, the term "solvent" means a substance added to the preconcentrate to affect and/or alter the consistency of the preconcentrate, for example in an aqueous solution. In some embodiments, the solvent is hydrophilic. Hydrophilic solvents suitable for the present disclosure include, but are not limited to, alcohols, including 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. In at least one embodiment, the at least one solvent is a pharmaceutically-acceptable solvent.

[01 1 1 ] 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.

[01 12] In some embodiments of the present disclosure, the preconcentrate is a pharmaceutical preconcentrate comprising a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

[01 13] In one embodiment, the pharmaceutical preconcentrate 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 surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof chosen from atorvastatin, simvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

[01 14] In another embodiment, the pharmaceutical preconcentrate 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 surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof and at least one statin chosen from atorvastatin, rosuvastatin, simvastatin, and a pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the at least one surfactant comprises less than 40%, by weight relative to the weight of the preconcentrate.

[01 15] In another embodiment, the pharmaceutical preconcentrate 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 surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; and at least one statin chosen from atorvastatin , rosuvastatin, simvastatin, and a pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the at least one surfactant comprises less than 35%, by weight relative the weight of the preconcentrate.

[01 16] In some embodiments, for example, the pharmaceutical

preconcentrate comprises K85EE as the fatty acid oil mixture; at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; and at least one statin chosen from atorvastatin, rosuvastatin, simvastatin, and a pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

[01 17] In some embodiments, the preconcentrate is in the form of a gelatin capsule or loaded into a tablet.

[01 18] In some embodiments, the weight ratio of fatty acid oil mixture:total surfactant of the preconcentrate ranges from about 1 :1 to about 200:1 , from about 1 : 1 to about 100: 1 , from about 1 : 1 to about 50: 1 , from about 1 : 1 to about 10: 1 , from about 1 : 1 to about 8:1 , from about 1.1 to 6: 1 from about 1 : 1 to about 5:1 , from about 1 : 1 to about 4:1 , or from about 1 : 1 to about 3: 1.

[01 19] In some embodiments, the at least one surfactant comprises from about 0.5% to about 40%, by weight relative to the total weight of the preconcentrate. For example, in some embodiments, the at least one surfactant comprises from about 1 % to about 35%, 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. In one embodiment, the at least one surfactant comprises about 20%, by weight relative to the total weight of the preconcentrate.

[0120] In one embodiment, the pharmaceutical preconcentrate comprises K85EE and at least one surfactant chosen from Tween-20 and Tween-80 in a fixed dose combination with atorvastatin (Lipitor®).

[0121 ] In another embodiment, the pharmaceutical preconcentrate comprises K85EE and Tween-20 in a fixed dose combination with atorvastatin (Lipitor®).

SNEDDS/SMEDDS/SEDDS

[0122] 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.

[0123] 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 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.

[0124] Generally, known SNEDDS/SMEDDS/SEDDS formulations comprise -10 mg of a drug and -500 mg of surfactants/co-surfactants. The

SNEDDS/SMEDDS/SEDDS presently disclosed may have the opposite relationship, i.e., the amount of API (e.g., the fatty acid oil mixture and the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof) is greater than the amount of surfactant.

[0125] The SNEDDS/SMEDDS/SEDDS presently disclosed may comprise a particle size (i.e., particle diameter) ranging from about 5 nm to about 10 μιη. For example, in some embodiments, the particle size ranges from about 5 nm to about 1 μιη, 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

[0126] The compositions 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. Examples of excipients include, but are not limited to, carriers, fillers, extenders, binders, humectants, disintegrating agents (e.g., disintegrants and/or

superdisintegrants), solution-retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, coloring agents, buffering agents, chelating agents, dispersing agents, basic substances, and preservatives. Excipients may have more than one role or function, or may be classified in more than one group; classifications are descriptive only and are not intended to be limiting. In some embodiments, the excipient may be chosen from colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, and xanthum gum.

[0127] In some embodiments, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one chelating agent. Examples of suitable chelating agents include, but are not limited to, aminopolycarboxylic acids such as EDTA and DTPA or pharmaceutically acceptable salts thereof including disodium EDTA and sodium calcium DTPA, and citric acid and pharmaceutically acceptable salts thereof. The at least one chelating agent may comprise from about 0.001 % to about 10% by weight, such as from about 0.005% to about 5% by weight, or from about 0.01 % to about 3% by weight .

[0128] In some embodiments, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one basic substance. Examples of suitable basic substances include, but are not limited to, any pharmaceutically acceptable basic material such as L-arginine, benethamine, benzathine, basic calcium salts, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydravamine, 1 H-imidazole, L-lysine, basic magnesium salts, 4-(2-hydroxyethyl)- morpholine, piperazine, basic potassium salts, 1 -(2-hydroxyethyl)-pyrrolidine, basic sodium salts, triethanolamine, tromethamine, basic zinc salts, and other organic pharmaceutically acceptable bases.

[0129] In some embodiments, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one buffering agent. Examples of suitable basic substances include, but are not limited to, any pharmaceutically acceptable buffering material such as pharmaceutically acceptable salts of inorganic acids, salts of organic acids, and salts of organic bases. Examples of salts of pharmaceutically acceptable inorganic acids include salts with phosphoric acid such as sodium or potassium phosphate or hydrogen phosphate, dibasic sodium phosphate, sodium, potassium, magnesium or calcium carbonate or hydrogen carbonate, sulphate, or mixtures thereof. Examples for salts of organic acids include potassium or sodium salts of acetic acid, citric acid, lactic acid, ascorbic acid, fatty acids like for eample EPA/DHA salts, maleic acid, benzoic acid, lauryl sulphuric acid.

[0130] The compositions presently disclosed may further comprise at least one antioxidant. Examples of antioxidants suitable for the present disclosure include, but are not limited to, cx-tocopherol (vitamin E), calcium disodium EDTA, alpha tocoferyl acetates, butylhydroxytoluenes (BHT), and butylhydroxyanisoles (BHA). Other examples of antioxidants include ascorbic acid and pharmaceutically acceptable salts thereof such as sodium ascorbate, pharmaceutically acceptable esters of ascorbic acid including fatty acid ester conjugates, propyl gallate, citric acid and pharmaceutically acceptable salts thereof, malic acid and pharmaceutically acceptable salts thereof, and sulfite salts such as sodium sulfite and mixtures thereof.

[0131 ] The preconcentrates and/or SNEDDS/SMEDDS/SEDDS presently disclosed may comprise from about 0.001 % to about 10% by weight of at least one antioxidant with respect to the total weight of the composition and/or preconcentrate, such as from about 0.005% to about 5% by weight, or from about 0.01 % to about 3% by weight.

[0132] In some embodiments, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one antioxidant and at least one excipient. In one embodiment, for example, the preconcentrates and/or SNEDDS/SMEDDS/SEDDS comprise a mixture of at least three compounds chosen from antioxidants, basic substances, chelating agents, and buffering agents. In one embodiment, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS comprise at least one antioxidant and at least one excipient chosen from chelating agents, bufferent agents, and basic materials. In one embodiment, the preconcentrates and/or SNEDDS/SMEDDS/SEDDS comprise at least one chelating agent, at least one basic material, and at least one buffering agent. In another embodiment, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS comprise at least one chelating agent and at least one basic material. In yet another embodiment, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS comprise at least one chelating agent and at least one buffering agent. All of the aforementioned preconcentrates may be sufficiently stable for pharmaceutical use. For example, the preconcentrates and/or

SNEDDS/SMEDDS/SEDDS presently disclosed may have a shelf-life of at least 2 years, e.g., no more than 2% degradation of statin and no more than 5% degradation of EPA/DHA ethyl ester over a period of 12 months according to ICH (International Conference on Harmonization) Guidelines (i.e., temperature, humidity).

[0133] The preconcentrates presently disclosed may further comprise at least one superdistintegrant. 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).

[0134] In some embodiments of the present disclosure, the preconcentrate comprises from about 1 % to about 25% of at least one superdisintegrant by weight of the preconcentrate, such as from about 1 % to about 20% by weight, or from about 1 % to about 15% by weight of the preconcentrate. In some embodiments, the preconcentrates comprising at least one superdisintegrant are in a tablet form.

[0135] In further embodiments of the present disclosure, the pharmaceutical preconcentrate comprises a fatty acid oil mixture, at least one surfactant chosen from Tween-20 and Tween-80, at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof, and at least one antioxidant. For example, the fatty acid oil mixture is present in an amount ranging from about 45% to about 70% by weight, such as from about 45% to about 55% by weight, relative to the weight of the preconcentrate and/or composition; the at least one surfactant is present in an amount ranging from about 0.5% to about 40% by weight, such as from about 10% to about 30%, such as from about 10% to about 25%, such as about 20% by weight, relative to the weight of the preconcentrate and/or composition;; and the at least one antioxidant is present in an amount ranging from about 0.001 % to about 10% by weight, such as from about 0.005% to about 5%, such as from about 0.01 % to about 3% by weight, relative to the weight of the preconcentrate and/or composition.

Further for example, the pharmaceutical preconcentrate comprises about 50% K85- EE; about 38% Tween-20, about 13% oleic acid, about 0.03% BHA, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

[0 36] In other embodiments of the present disclosure, the pharmaceutical preconcentrate comprises a fatty acid oil mixture, at least one surfactant chosen from Tween-20 and Tween-80, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. For example, the fatty acid oil mixture is present in an amount ranging from about 45% to about 70% by weight, such as from about 45% to about 55% by weight, relative to the weight of the preconcentrate and/or composition; and the at least one surfactant is present in an amount ranging from about 0.5% to about 40% by weight, such as from about 10% to about 30%, such as from about 10% to about 25%, such as about 20% by weight, relative to the weight of the preconcentrate and/or composition. Further for example, the pharmaceutical preconcentrate comprises about 400 mg K85-EE, about 300 mg Tween-20, about 100 mg K85-FA, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

Formulations

[0137] The preconcentrates presently disclosed may be administered, e.g., in capsule, caplet, tablet or any other forms suitable for drug delivery.

[0 38] In some embodiments, for example, the preconcentrates are loaded into a tablet. When the dosage form is in the form of tablets, the tablets may be, for example, disintegrating tablets, fast dissolving tablets, effervescent tablets, fast melt tablets, and/or mini-tablets. Tablet formulations are described, for example, in patent publication WO 2006/000229. [0139] Further, the dosage 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.

[0140] The preconcentrates presently disclosed may be encapsulated, such as in a gelatin capsule. In some embodiments, the preconcentrates presently disclosed comprise microcapsules encapsulated with a material chosen from cyclodextrin, and gelatin. Examples of cyclodextrins include, but are not limited to, substituted and unsubstituted cyclodextrins, e.g., alpha-cyclodextrin, beta- cyclodextrin, gamma-cyclodextrin, alkylated cyclodextrins such as methylated cyclodextrins and 2-hydroxypropyl-cyclodextrins. In at least one embodiment, the compositions and/or preconcentrates are polymer-free.

[0141] In one embodiment, the preconcentrate comprises a capsule comprising two compartments, wherein a first compartment comprises at least a first API (e.g., fatty acid oil mixture), and a second compartment comprises at least a second API (e.g., statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof). In one embodiment, the first API comprises a fatty acid oil mixture comprising EPA and DHA, and the second API comprises atorvastatin calcium. For example, the preconcentrate presently disclosed may comprise a two compartment capsule, wherein a first compartment comprises a fatty acid oil mixture and at least one surfactant, and a second compartment comprises at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

[0142] The two compartment capsule may comprise two compartments adjacent to each other, or may comprise one compartment inside a second compartment. Examples of two compartment capsules include, but are not limited to, a DuoCap™ capsule delivery system (Encap Drug Delivery).

[0143] The DuoCap™ is a single oral dosage unit that comprises a capsule- in-a-capsule. The inner and outer capsules may contain the same active agent providing multiple release profiles from the dosage unit, for example the outer capsule comprises an immediate release formulation and the inner capsule comprises a controlled release formulation. In addition to modifying the release profiles, it is also possible to formulate the inner and outer capsules to target release at different areas of the Gl tract (small intestine or colon). Alternatively, the two compartment capsule may comprise different active agents for use in combination therapies, or for actives that may be incompatible in a single capsule.

[0144] In one embodiment of the present disclosure, the capsule comprises an inner compartment (e.g., inner capsule) comprising a fatty acid oil mixture and an outer compartment (e.g., outer capsule) comprising at least one statin or

pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. For example, the capsule may comprise an inner capsule comprising a fatty acid oil mixture and at least one surfactant, and an outer capsule comprising at least one statin chosen from atorvastatin, rosuvastatin, simvastatin, and a pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. In other embodiments, the capsule comprises an inner capsule comprising atorvastain or a pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; and the outer capsule comprises a fatty acid mixture and at least one surfactant. In some embodiments, the compartment comprising the fatty acid oil mixture is formulated in a form chosen from liquid, semisolid, powder and pellet form. Moreover, the two compartment capsule can further be coated with at least one enteric coating or with Encap's colonic delivery system, ENCODE™.

[0145] In some embodiments, the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is dissolved in the fatty acid oil mixture with no crystal formation of statin before administration. In other

embodiments, the preconcentrates comprise an emulsion or suspension, such as a nanoemulsion or a microemulsion, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is suspended in the fatty acid oil mixture with little to no statin dissolved in the oil.

[0146] Further, in some embodiments, the preconcentrates comprise an emulsion comprising microcapsules of at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. For example, in at least one embodiment of the present disclosure, the preconcentrate comprises statin microcapsules suspended in a combination of a fatty acid oil mixture and at least one surfactant. The statin microcapsules may be encapsulated, for example, in a material chosen from cyclodextrin and alginate. The preconcentrates comprising the statin microcapsules may be encapsulated in a material that may be the same or different from that of the statin microcapsules. For example, in some embodiments, the compositions and/or preconcentrates comprise gelatin capsules that comprise statin microcapsules, wherein the at least one statin is encapsulated in a material chosen from cyclodextrin and alginate.

[0147] In other embodiments, the preconcentrates comprise an encapsulated fatty acid oil mixture wherein the capsule shell wall, such as a gelatin shell, comprises at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof, such as atorvastatin, rosuvastatin, simvastatin, or a

pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. The statin may be added to the encapsulation material during preparation of the capsule shell, or may also be spray-dried onto the outside of a prepared capsule shell.

[0148] The present disclosure also provides for one or more enteric coating layer(s) formed from gastro-resistant materials, such as pH-dependent and/or pH- independent polymers. 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. Coatings with pH-dependent profiles, on the other hand, can generally maintain their integrity while in the acid pH of the stomach, but erode or dissolve upon entering the more basic upper intestine. Such coatings generally serve the purpose of delaying the release of a drug for a predetermined period. For example, such coatings can allow the dosage form to pass through the stomach without being substantially subjected to stomach acid or digestive juices for delayed release outside of the stomach.

[0149] Examples of enteric coating materials include, but are not limited to, acrylic and cellulosic polymers and copolymers, e.g., methacrylic acid, copolymers between methacrylic acid and methyl methacrylate or methyl acrylate, copolymers between metacrylic acid and ethyl methacrylate or ethyl acrylate, polysaccharides like cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, and polyvinyl acetate phthalate. Additional useful enteric coating materials include pharmaceutically acceptable acidic compounds that may not dissolve at the low pH in the stomach, but at higher pH in the lower part of the gastrointestinal system.

[0150] The enteric coating material may comprise one or more plasticizer(s) to improve the mechanical properties of pH-sensitive material(s). Typical plasticizers include triethyl citrate, triacetin, polyethylene glycols, propylene glycol, phthalates, sorbitol and glycerin. The amount of plasticizer suitable for enteric coating according to the present disclosure may vary depending upon the chemical composition of the enteric coating, the chemical nature of the encapsulating material(s), and the size and the shape of the capsules. In some embodiments, for example, the plasticizer for capsules comprising EPA and DHA ethyl esters comprises from about 10% to about 60% by weight of the enteric coating material.

[0151 ] In some embodiments, the preconcentrates comprise one or more sub-layer(s) between the capsule shell and an enteric coating and/or one or more top-layer(s) and/or top-layer(s) over the enteric coating. The chemical composition of sub-layers and top-layers may vary depending upon the overall composition of the capsule. Typical sub-layers and top-layers comprise one or more film-forming agent(s) such as polysaccharides, e.g., hydroxypropyl methyl cellulose.

[0152] 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.

[0153] The capsules presently disclosed may be manufactured in low oxygen conditions to inhibit oxidation during the manufacturing process. Preparation of capsules and/or microcapsules in accordance with the present disclosure may be carried out following any of the methods described in the literature. Examples of such methods include, but are not limited to, simple coacervation methods (see, e.g., 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.

[0154] In other embodiments, the preconcentrates are loaded into a tablet, wherein the tablet is coated by at least one of a film coating, a sub-layer, and an enteric coating. Suitable sub-layer and enteric coating materials are described above. Suitable coating materials for the film coating include, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol, sodium

carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, gelatin, methacrylic acid copolymer, polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, and zein.

Methods or Uses

[0155] The present disclosure further encompasses methods of treating at least one health problem in a subject in need thereof. The compositions presently disclosed may be administered, e.g., in capsule, caplet, tablet or any other drug delivery forms, such as the formulations described above, to a subject for therapeutic treatment of at least one health problem including, for example, irregular plasma lipid levels, 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, hypertriglyceridemia, and hypercholesterolemia.

[0156] In one embodiment, there is a method of treating at least one health problem in a subject in need thereof, comprising administering to the subject a pharmaceutical preconcentrate comprising a pharmaceutically-effective amount of a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof. 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.

[0157] In some embodiments, the pharmaceutical preconcentrate forms 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. [0158] The present disclosure further provides for a method for treating at least one health problem while 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 wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride, at least one surfactant, and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the fatty acid oil mixture, the at least one surfactant, and the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof form a preconcentrate. In addition, the preconcentrate 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. The bioavailablity may be increased.

[0159] 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, 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.

[0160] The preconcentrates presently disclosed may be administered 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. The administration may be oral or any other form of administration that provides a dosage of fatty acids, e.g., omega-3 fatty acids and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof, to a subject.

[0161 ] 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

[0162] Example 1 : Compatibility of Preconcentrates with Solvents

[0163] The compatibility of solvents and a preconcentrate having a fixed amount of K85EE and Tween-80 were evaluated. The preconcentrates described in Table 8 were prepared according to the schemes below on a weight to weight basis. The preconcentrates were visually inspected after mixing and again after being stored for 24 hours at room temperature. Under the Preconcentrate heading, a "clear" designation represents a transparent homogenous mixture; a "turbid" designation represents a nonhomogenous mixture, where some turbidity can be observed by visual inspection. The degree of turbidity was not determined.

Table 8: Compatibility of Solvent and Preconcentrates.

[0164] Example 2: Lipolysis and Solubilization

[0165] Studies were done to analyze the rate of lipolysis (i.e., hydrolysis) and solubilization for different preconcentrates comprising K85EE and different free fatty acids and surfactants. Specifically, four experiments were designed to determine how the amount of surfactant influences the rate and extent of lipolysis and solubilization. The lipolysis was conducted on SMEDDS formulations comprising K85EE.

[0166] Materials

■ Bile salts: Porcine Bile extract (Sigma); contains glycine and taurine

conjugates of hyodeoxycholic acid and other bile salts.

■ Pancreatic lipase, Porcine pancreas (Sigma); contains many enzymes, including amylase, trypsin, lipase, ribonuclease and protease.

- Lechitin: Phospholipids (LIPOID S PC from LIPOID AG)

^■ Trizma maleate (Sigma Aldrich)

■ Tween 20, Molecular Biology Grade (AppliChem Darmstadt), Tween 80 (Fluka)

- a-Linoleic acid (Sigma 60%), Oleic acid (Aldrich 90%)

■ K85-EE and K85-FA

[0167] Preconcentrates A-E were prepared as summarized in Table 9.

Table 9: Preconcentrates A-E.

c K85EE (500 mg) linoleic acid (100 Tween 80 (200 mg) mg)

D K85EE (400 mg) K85FA (100 mg) Tween 20 (300 mg)

E K85EE (400 mg) — Tween 80 (100 mg)

[0168] Lipolysis general procedure

[0169] The in vitro dynamic lipolysis model developed by Zangenberg et al. (Zangenberg, N.H. et al., Eur. J. Pharm. Sci. 14, 237-244, 2001 ; Zangenberg, N.H., et al., Eur. J. Pharm. Sci. 14, 1 15-122, 2001) was used with slight modifications. The lipolysis was conducted in a thermostated 600 ml jacketed glass vessel in the presence of porcine bile extract, with continuous addition calcium chloride. The lipase source was porcine pancreatin and the hydrolysis was followed by titration with sodium hydroxide solution (1.0 N) using a pH stat (pH 6.5). The initial composition of the lipolysis media is shown in Table 0.

Table 10: Initial composition of lipolysis media.

[0170] The final volume in all experiments was 300 ml and the calcium dispensing rate during the experiments was 0.045 mmol/min (0.09 ml/min). In all experiments, the amount of K85-EE added corresponds to 5.58 mg/ml.

[0171 ] To determine the course of K85-EE lipolysis by HPLC, crude samples were withdrawn and acidified with dilute hydrochloric acid. The concentrations of EPA-EE, DHA-EE, EPA-FA and DHA-FA were determined by HPLC in triplicate. Experiments were performed with LC Agilent Technologies 1200 series at a column temperature of 30°C, mobile phase (A) water (0.1 % acetic acid) and (B) MeCN (0.1 % acetic acid), with gradient: 0 to 8 minutes, from 70% B to 100% B; 8 to 15 minutes, 100 % B; 16 to 16 minutes: from 100 % B to 70% B, 16 to 20 minutes: 70% B. The flow rate was 0.5 ml/min, UV @ 210 nM, injection volume: 5 pl. and run time: 20 minutes. [0172] Concentrations of EPA ethyl ester (EPA-EE), DHA ethyl ester (DHA- EE), EPA free acid (EPA-FA), and DHA free acid (DHA-FA) were monitored over time and the rate of lipolysis calculated as shown in Table 1 1 for comparison with Omacor®.

Table 1 1 : Lipolysis of EPA and DHA ethyl ester in comparison to Omacor®.

[0173] FIGs 3, 6, 9, 12, 15, and 18 graphically illustrate the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of each respective sample examined. Sample points from 2 minutes to 233 minutes were included in the graphs. In addition, linear regression lines have been included.

[0174] FIGs 4, 7, 10, 13, 16, and 19 provide the percent recover of EPA + DHA at different time-points for each respective sample examined. Data are given as the sum of EPA-EE, DHA-EE, EPA-FA, and DHA-FA and given as a percentage of theoretical amount 5580 μg/ml.

[0175] FIGs 5, 8, 1 1 , 14, 17, and 20 graphically illustrate the percent lipolysis at different time points for EPA-EE, DHA-EE and total K85EE. Values are calculated relative to the total amount of EPA-EE and DHA-EE determined by HPLC after lipolysis for 2 minutes.

[0176] Example 3: Emulsions in pure water

[0177] The oil content in one capsule OMACOR®, comprising EPA ethyl ester (465 mg), DHA ethyl ester (375 mg) and alpha-tochopherol (4 mg) were mixed in a scintillation vial with various surfactants as shown below in Table 12. Water (10 ml) was added at 37 degrees centigrade and the mixture was shaken for 15 seconds using a Vortex mixer. The mixture was observed after 1 minute and after 5 minutes. The visual score for emulsion homogeneity was scored as follows: No emulsion = score 0, emulsion but not homogeneous emulsion= score 1 , homogenous emulsion = score 2.

[0178] The mixture was after mixing also rolled in a roller mixer for 5 minutes. The visual score for this roller test was the same as above.

Table 12: Emulsions in pure water.

Reference Surfactant(s) Amount of Score Score Score

No. Surfactant After After Roller

(mg) Vortex for Vortex 5 Mixer

1 minute minutes

1 None 0 0 0 0

2 Brij® 30 100 2 2 2

3 Brij® 35 100 2 1 2

4 Brij® 52 100 2 2 2

5 Brij® 58 100 2 1 2

6 Brij® 72 100 2 1 2

7 Brij® 78 100 2 1 2

8 Brij® 92V 100 2 2 2

9 Brij® 93 100 2 2 2

10 Brij® 96V 100 2 2 2

11 Brij® 97 100 2 2 2

12 Brij® 98 100 2 1 2

13 Brij® 700 100 1 1 2

14 Brij® S-10 100 1 1 2

15 Pluronic® L-31 100 1 1 2

16 Pluronic® L-35 100 1 1 2

17 Pluronic® L-81 100 2 2 2

18 Pluronic® L-64 100 2 2 2

19 Pluronic® L-121 100 2 2 2

20 Pluronic® P-123 100 1 1 2

21 Pluronic® F-68 100 0 0 1

22 Pluronic® F-108 100 0 0 1

23 Span® 20 100 2 2 2

24 Span® 60 100 0 0 1

25 Span® 65 100 0 0 0

26 Span® 80 100 1 1 2

27 Span® 85 100 0 0 1

28 Tween® 20 00 2 1 2

29 Tween® 40 100 2 1 2 30 Tween® 60 100 2 1 2

31 Tween® 80 100 2 1 2

32 Alginic Acid 100 1 0 1

33 Alginic Acid 100 2 1 1 sodium salt

34 Macrogolglycerol- 100 2 2 2 hydroxystearate 40

35 Sodium lauryl 100 1 1 2 sulphate

36 1 ,2-Dipalmitoyl-sn- 100 0 0 0 glycerol

ethanolamine

37 1-Hexadecanol 100 1 0 0

38 1 ,2-Dipalmitoy-sn 100 2 1 1

39 Macrogol 400 100 0 0 1

40 Myristic acid 100 1 1 1 sodium salt

41 Brij® 52/ 30/20 2 2 2

Macrogolglycerol- hydroxystearate 40

42 Brij®62/Pluronic®L 30/50 2 2 2

64

43 Span® 40/90 2 2 2

20/Pluronic® L64

44 Macrogol 400/ 120/60 2 2 2

Macrogolglycerol- hydroxystearate 40

45 Tween®20/Span® 60/60 2 2 2

20

46 Tween®20/Span® 90/90/60 2 2 2

20/Macrogol 400

47 Span®20/Tween® 70/100/40 2 2 2

20/Brij®97

48 Alginic acid sodium 1 10/60 2 2 2 salt/Span®60

49 Pluronic®F- 20/180/20 2 2 2

68/Pluronic®

L64/Span®60

[0179] Example 4: Emulsions in Artificial Gastric Juice

[0180] The oil content in one capsule OMACOR®, comprising EPA ethyl ester (465 mg), DHA ethyl ester (375 mg) and alpha-tochopherol (4 mg) were mixed in a scintillation vial with various surfactants as shown below in Table 13. The experimental set up in the examples below is the same as described previously except that that artificial gastric juice without pepsin (European Pharmacopeia 6.0, page 274) was used instead of water.

Table 13: Emulsions in artificial gastric juice

[0181 ] Example 5: Emulsions in Simulated Intestinal fluid

[0182] The oil content in one capsule OMACOR®, comprising EPA ethyl ester (465 mg), DHA ethyl ester (375 mg) and alpha-tochopherol (4 mg) were mixed in a scintillation vial with various surfactants as shown below in Table 14. The experimental set up in the examples below is the same as described previously except that that simulated intestinal fluid pH 6.8 without pancreas powder (European Pharmacopeia 6.0, page 274) was used instead of water.

Table 14: Emulsions in simulated intestinal fluid.

[0183] Example 6: Microscopic Examination of Emulsions

[0184] Emulsions from Example 52 (gastric juice) and Example 58 (intestinal fluid) were examined under the microscope after 24 hours rolling. Both emulsions were found to be suspensions of oil in water with no tendency to aggregation.

[0185] Example 7: Pharmaceutical Formulations

[0186] The following examples in Table 15 illustrate pharmaceutical formulations comprising omega-3 fatty acids that can be prepared.

Table 15: Pharmaceutical Formulations

[0187] In an embodiment, the surfactant or combination of surfactants is chosen from Tween® surfactants; Tween® 20, Tween® 40, Tween® 60, Tween® 65, Tween® 80 and Tween® 85.

[0188] In another embodiment, the surfactant is chosen from a combination of a Tween® surfactants and a surfactant chosen from Cremophor®, for instance Tween® 20 and Cremophor EL. Moreover, in a further embodiment, a Tween® 20 and Solutol HS 15 surfactant can be used together as well as Tween® 20 and Tween® 40.

[0189] Fatty acid oil mixtures of pharmaceutical preconcentrates, wherein the fatty acid oil mixture is a K85EE or AGP-103 oil composition are presented in Table 16.

Table 16: Fatty acid oil mixture for pharmaceutical preconcentrates.

Fatty acid oil mixture:

linimum Value Maximum Value 1000 mg K85EE fatty acid oil mixture EPAEE + DHAEE 800 mg/g 880 mg/g

EPA EE 430 mg/g 495 mg/g

DHA EE 347 mg/g 403 mg/g

Total omega-3 EE

>90% (w/w)

EE = ethyl ester

[0190] Example 8: Additional Emulsions in Artificial Gastric Juice and Simulated Intestinal Fluid

[0191 ] Preconcentrates 1-23 were prepared with EPA/DHA ethyl ester (1000 mg K85EE) and various surfactants and surfactant mixtures as shown in Table 17 below. Emulsions were prepared in both gastric juice and simulated intestinal fluid as described in Examples 4 and 5. Results were the same for emulsions in artificial gastric juice and simulated intestinal fluid, and appear in Table 17.

Table 17: Emulsions in artificial gastric juice and simulated intestinal fluid.

Cremophor® EL 40

17 Brij® 30 20 2 2 2

Span® 85 20

18 Cremophor® EL 5 2 1 2

Cremophor® EL 60

19 2 1 2

Tween® 80 70

Macrogolglycerol

20 Hydroxystearate 60 2 1 2

40

Macrogolglycerol

Hydroxystearate

90

21 40 2 1 2

30

Span® 20

50

Polysorbate 20

Macrogolglycerol

Hydroxystearate

60

22 40 2 1 2

30

Brij® 93

60

Polysorbate 20

Cremophor® EL 60

Pluronic® F68 30

23 2 2 2

Brij® 92V 30

Polysorbate 20 20

[0192] Emulsions 4-15 prepared in both artificial gastric juice and simulated intestinal fluid were homogenous (milky) for several hours when standing .

Emulsions 1 -3 separated somewhat after preparation (i.e., after several hours of standing). Microscopy of Emulsions 1-15 showed that the average particle size was less than 100 micrometers. Homogenization treatment (UltraRurrax(IKA)) of Emulsion 4 for 20 seconds resulted in a substantial increase of formation of small particles (< 10 microns).

[0193] Based on the preconcentrates prepared, a 0.5% non-ionic surfactant (e.g., Cremophor®) can emulsify EPA/DHA ethyl ester in both artificial gastric juice and simulated intestinal fluid. In addition, including more than one surfactant appears to stabilize the emulsion. Further, the particle size can vary depending upon the emulsification method. [0194] Example 9: Additional Preconcentrate Compositions

[0195] Preconcentrates can be prepared comprising atorvastatin and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof in omega-3 fatty acid compositions, preconcentrates, and/or

SNEDDS/SMEDDS/SEDDS (e.g., self-emulsifying EPA and DHA compositions), wherein atorvastatin is either not soluble in the EPA and DHA oil composition, or soluble but without crystallizing in the mixed oil composition.

Table 18: Examples of API combinations according to the present disclosure.

[0196] Example 10: Formulations comprising atorvastatin

[0197] The following atorvastatin salts, hydrates, and cyclodextrin (CD) complexes were prepared for testing in compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS according to the present disclosure:

[0198] Sample 1 : Amorphous atorvastatin calcium

[0199] Sample 2: Atorvastatin meglumin salt

[0200] Sample 3: Atorvastatin meglumin CD complex [0201 ] Sample 4: Atorvastatin calcium CD complex

[0202] Sample 5: Atorvastatin calcium trihydrate

[0203] Sample 6: Atorvastatin calcium

[0204] The following atorvastatin formulations were also prepared for testing in preconcentrates and/or SNEDDS/SMEDDS/SEDDS according to the present disclosure.

[0205] Sample 1 : Atorvastatin calcium amorphous. (Drug Discovery Laboratory AS, No)

[0206] Sample 2: Atorvastatin meglumin salt (Drug Discovery Laboratories AS, No), batch 010-85.

[0207] Sample 3 : Atorvastatine meglumin beta-CD complex (Drug Dicovery Laboratories AS, No).

[0208] Sample 4: Atorvastatine calcium beta-CD complex (Drug Discovery Laboratories AS, No)

[0209] Sample 5: Atorvastatin free acid, batch EXP-10-AB7860-1

[0210] Sample 6: Atorvastatine- crysmeb complex crystallized: BF-10- AB7862-CA-1.

[021 1 ] Sample 7: Atorvastatine -beta cyclodextrin complex crystallized: BF- 0-AB7862-BA-1.

[0212] Sample 8: Atorvastatine-kleptose complex crystallized: BF-10- AB7862-KA-1 :

[0213] Sample 9: Atorvastatine- crysmeb complex: BF-10-AB7857-CA-B.

[0214] Sample 10: Atorvastatine -beta cyclodextrin complex: BF-10-AB7857- BA-B.

[0215] Sample 1 1 : Atorvastatine-kleptose complex: BF- 0-AB7862-KA-B [0216] Sample 12: Atorvastatine- crysmeb complex crystallized BF- 0- AB7862-CA-

[0217] Sample 13: Atorvastatine -beta cyclodextrin complex crystallized 2BF-10-AB7862-BA-2

[0218] Sample 14: Atorvastatine-kleptose complex crystallised: BF-10- AB7862-KA-2

[0219] Sample 14: Atorvastatine-kleptose complex crystallised: BF-10- AB7862-KA-2 [0220] Cyclodextrin complexes of atorvastatine calcium trihydrate were prepared by evaporating a solution of a mixture of atorvastatine and the appropriate cyclodextrin. The purity of salts, free acids and cyclodextrin complexes to be included in later solubility and stability studies was determined by HPLC.

[0221 ] Example 11 : Additional Preconcentrate Compositions

[0222] The following additional preconcentrate compositions were prepared and evaluated visually, which are summarized in Table 19. To these preconcentrate compositions, a statin may be added, such as, for example, atorvastatin,

rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof.

[0223] Under the Preconcentrate heading, a "homogeneous" designation represents that a homogenous mixture was formed. The "%" in the "% K85-FA" heading represents the weight percentage of K85-FA in the preconcentrate composition.

Table 9: Examples of additional preconcentrate compositions.

[0224] Preconcentrates can be prepared comprising atorvastatin, rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof in omega-3 fatty acid compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS (e.g., self-emulsifying EPA and DHA compositions), wherein the atorvastatin, rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof are either not soluble in the EPA and DHA oil composition, or soluble but without crystallizing in the mixed oil composition.

[0225] Example 12: Additional Preconcentrate Compositions

[0226] The following additional preconcentrate compositions were prepared and evaluated visually, which are summarized in Tables 20-29. To these

preconcentrate compositions, a statin may be added, such as, for example, atorvastatin, rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof.

[0227] Under the Preconcentrate heading, a "homogeneous" designation represents that a homogenous mixture was formed, and a "turbid" designation represents that a nonhomogeneous mixture was formed, where some turbidity can be observed by visual inspection. The degree of turbidity was not determined.

[0228] The "%" in the "% K85-EE" heading represents the weight percentage of K85-EE in the preconcentrate composition.

Table 20: Examples of additional preconcentrate compositions, comprising

Tween 20 and/or 80.

450 550 3000 75 turbida 450 550 250 20 homogeneousb 450 550 500 33 homogeneousc 450 550 750 43 homogeneouse 450 550 1000 50 homogeneousf 450 550 1500 60 homogeneous

400 600 3000 75 turbida 400 600 250 20 homogeneousb 400 600 500 33 homogeneousc 400 600 750 43 homogeneouse 400 600 1000 50 homogeneousf 400 600 1500 60 homogeneous

350 650 3000 75 turbida 350 650 250 20 homogeneousb 350 650 500 33 homogeneousc 350 650 750 43 homogeneousd 350 650 1000 50 homogeneousf 350 650 1500 60 homogeneous

200 800 3000 75 turbida 200 800 250 20 homogeneousb 200 800 500 33 homogeneousc 200 800 750 43 homogeneouse 200 800 1000 50 homogeneousf 200 800 1500 60 homogeneous

100 900 3000 75 turbida 100 900 250 20 homogeneousb 100 900 500 33 homogeneousc 100 900 750 43 homogeneouse 100 900 1000 50 homogeneousf 100 900 1500 60 homogeneous

50 950 3000 75 homogeneousa 50 950 250 20 homogeneousb 50 950 500 33 homogeneousc 50 950 750 43 homogeneouse 50 950 1000 50 homogeneous 7f 50 950 1500 60 homogeneous

8 0 1000 3000 75 homogeneous

8a 0 1000 250 20 homogeneous

8b 0 000 500 33 homogeneous

8c 0 1000 750 43 homogeneous

8d 0 1000 1000 50 homogeneous

8f 0 1000 1500 60 homogeneous

Table 21 : Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and benzyl alcohol as a co-surfactant.

43f 450 450 50 800 46 homogeneous

Table 22: Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and benzyl alcohol and Solutol HS 15.

Table 23: Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and tetraglycol as a co-surfactant.

100t 450 450 100 800 44 homogeneous

100u 450 450 75 800 45 homogeneous

100v 450 450 50 800 46 homogeneous

Table 24: Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and oleic acid.

Ref. No. Tween 20 Tween 80 Oleic K85-EE % K85- Preconcentrate

(mg) (mg) acid (mg) (mg) EE

101 450 450 100 1200 55 homogeneous

101 a 450 450 75 1000 51 homogeneous

101 b 450 450 50 1000 51 homogeneous

101 c 400 500 100 1^'100 52 homogeneous

101 d 350 550 100 1 100 52 homogeneous

101 e 300 600 100 1100 52 homogeneous

101f 200 700 100 1100 52 homogeneous

101 g 100 800 100 1 100 52 homogeneous

101 h 300 300 400 825 45 homogeneous 01 i 450 450 100 900 47 homogeneous

101j 500 400 100 900 47 homogeneous

101 k 550 350 100 900 47 homogeneous

1011 600 300 100 900 47 homogeneous

101 m 700 200 100 900 47 homogeneous

101 n 700 200 75 1000 51 homogeneous

101 o 700 200 50 1000 51 homogeneous

101 p 450 450 100 675 40 homogeneous

101 q 450 450 100 700 41 homogeneous

101 r 450 450 75 700 42 homogeneous

101 s 450 450 50 700 42 homogeneous

101t 450 450 100 800 44 homogeneous

101 u 450 450 75 800 45 homogeneous

101 v 450 450 50 800 46 homogeneous

Table 25: Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and K85-FA.

Ref. No. Tween 20 Tween 80 K85-FA K85-EE % K85- Preconcentrate (mg) (mg) (mg) (mg) EE

102 450 450 100 1200 55 homogeneous

102a 450 450 75 1000 51 homogeneous

102b 450 450 50 1000 51 homogeneous

102c 400 500 100 1 100 52 homogeneous

102d 350 550 100 1 100 52 homogeneous

102e 300 600 100 1100 52 homogeneous

102f 200 700 100 1100 52 homogeneous

102g 100 800 100 1 100 52 homogeneous

102h 300 300 400 825 45 homogeneous

102i 450 450 100 900 47 homogeneous 02j 500 400 100 900 47 homogeneous

102k 550 350 100 900 47 homogeneous

1021 600 300 100 900 47 homogeneous

102m 700 200 100 900 47 homogeneous

102n 700 200 75 1000 51 homogeneous

102o 700 200 50 1000 51 homogeneous

102p 450 450 100 675 40 homogeneous

102q 450 450 100 700 41 homogeneous

102r 450 450 75 700 42 homogeneous

102s 450 450 50 700 42 homogeneous

102t 450 450 100 800 44 homogeneous

102u 450 450 75 800 45 homogeneous

102v 450 450 50 800 46 homogeneous

Table 26: Examples of additional preconcentrate compositions, comprising different solvents/co-surfactants. The abbreviation "DR" represents "dispersion rate."

103d 0 400 75 400 46 homogeneous fast

103e 435 0 75 400 44 turbid -

103f 300 0 100 400 50 turbid -

103g 0 400 100 400 44 homogeneous fast

103h 435 0 100 400 43 turbid -

Ref. Tween Tween 1-tetra- K85-EE % K85- Preconcentrate DR No. 20 (mg) 80 (mg) decanol (mg) EE

(mg)

104 300 0 50 400 53 turbid -

104a 0 400 50 400 47 turbid -

104b 435 0 50 400 45 turbid -

104c 300 0 75 400 52 turbid -

104d 0 400 75 400 46 turbid -

104e 435 0 75 400 44 turbid -

104f 300 0 100 400 50 turbid -

104g 0 400 100 400 44 turbid -

104h 435 0 100 400 43 turbid -

Ref. Tween Tween Benzyl K85-EE % K85- Preconcentrate DR No. 20 (mg) 80 (mg) alcohol (mg) EE

(mg)

105 300 0 50 400 53 turbid -

105a 0 400 50 400 47 homogeneous -

105b 435 0 50 400 45 homogeneous -

105c 300 0 75 400 52 turbid -

105d 0 400 75 400 46 homogeneous -

105e 435 0 75 400 44 homogeneous -

105f 300 0 100 400 50 homogeneous -

105g 0 400 100 400 44 homogeneous -

105h 435 0 100 400 43 homogeneous -

Ref. Tween Tween Triacetin K85-EE % K85- Preconcentrate DR No. 20 (mg) 80 (mg) (mg) (mg) EE

106 300 0 50 400 53 turbid - 106a 0 400 50 400 47 homogeneous fast

106b 435 0 50 400 45 homogeneous fast

106c 300 0 75 400 52 turbid -

106d 0 400 75 400 46 homogeneous fast

106e 435 0 75 400 44 homogeneous fast

106f 300 0 100 400 50 turbid -

106g 0 400 100 400 44 homogeneous fast

106h 435 0 100 400 43 homogeneous fast

Ref. Tween Tween Ethanol K85-EE % K85- Preconcentrate DR No. 20 (mg) 80 (mg) (mg) (mg) EE

107 300 0 50 400 53 turbid -

107a 0 400 50 400 47 homogeneous fast

107b 435 0 50 400 45 homogeneous fast

107c 300 0 75 400 52 turbid -

107d 0 400 75 400 46 homogeneous fast

107e 435 0 75 400 44 homogeneous fast

107f 300 0 100 400 50 turbid -

107g 0 400 100 400 44 homogeneous fast

107h 435 0 100 400 43 homogeneous fast

Ref. Tween Tween Tetra- K85-EE % K85- Preconcentrate DR No. 20 (mg) 80 (mg) glycol (mg) EE

(mg)

108 300 0 50 400 53 turbid -

108a 0 400 50 400 47 homogeneous fast

108b 435 0 50 400 45 homogeneous fast

108c 300 0 75 400 52 turbid -

108d 0 400 75 400 46 homogeneous fast

108e 435 0 75 400 44 homogeneous fast

108f 300 0 100 400 50 turbid -

108g 0 400 100 400 44 homogeneous fast

108h 435 0 100 400 43 homogeneous fast Table 27: Examples of additional preconcentrate compositions, comprising Cremophor EL.

24b 100 900 0 1300 57 homogeneous

1 1 900 0 100 3000 75 turbid

11 a 900 0 100 1300 57 turbid

11 b 900 0 100 1 100 52 turbid

12 700 0 300 3000 75 turbid

12a 700 0 300 1 100 52 turbid

12b 700 0 300 1300 57 turbid

13 500 0 500 3000 75 turbid

14 400 0 600 3000 75 turbid

14a 400 0 600 1 100 52 homogeneous

14b 400 0 600 1300 57 homogeneous

15 300 0 700 3000 75 turbid

16 200 0 800 3000 75 turbid

17 100 0 900 3000 75 turbid

Table 28: Examples of additional preconcentrate compositions, comprising Cremophor RH40.

1101 400 0 100 600 55 turbid

Table 29: Examples of additional preconcentrate compositions, comprising Solutol HS 15.

Ref. No. Solutol HS Tween 80 Tween 20 K85-EE % K85- Preconcentrate

15 (mg) (mg) (mg) (mg) EE

111 400 0 0 400 50 turbid

111a 400 0 0 500 56 turbid

111b 400 0 0 600 60 turbid

111c 300 100 0 400 50 turbid

111d 200 0 400 50 turbid

111e 300 100 0 500 56 turbid

11 f 300 100 0 600 60 turbid

111g 100 300 0 400 50 homogeneous

111 h 50 350 0 400 50 homogeneous

111i 300 0 100 400 50 turbid

111j 200 0 200 400 50 turbid

Ref. No. Solutol HS Benzyl Tetra- K85-EE % K85- Preconcentrate

15 (mg) alcohol glycol (mg) EE

(mg) (mg)

111k 400 100 0 400 44 homogeneous

1111 400 0 100 400 44 homogeneous

111m 400 100 0 500 50 homogeneous

111n 400 0 100 500 50 homogeneous

111o 400 100 0 600 55 homogeneous

111 p 400 0 100 600 55 homogeneous

[0229] Preconcentrates can be prepared comprising atorvastatin,

rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof in omega-3 fatty acid compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS (e.g., self-emulsifying EPA and DHA compositions), wherein the atorvastatin, rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof are either not soluble in the EPA and DHA oil composition, or soluble but without crystallizing in the mixed oil composition.

[0230] Example 13: Statin Solubility in Preconcentrates

[0231] The solubility of 3 different stains in 4 different formulations was evaluated. The following materials and equipment were used:

HPLC: Dionex Ultimate 3000

Column: Phenomenex luna 5μ C18(2) 100A

125x4.0mm (batch no.: 00E-4252-D0)

Atorvastatin calcium trihydrate: AvaChem Scientific (Lot. no: AF803) Simvastatin: Toronto Research Chemicals (8-ABY-

98-1)

Rosuvastatin calcium: Sequoia Research Pruducts (control no:

040101 13265r)

Acetonitrile: HiperSolv Isocratic grade

Acetic acid: Glacial 100 %

K85-EE: batch no. 2100033

Tween 20: lot. no. 5N004 74

Tween 80: lot. no. 143321 1 51209P03

Tetraglycol: lot. no. BCBC1357

Benzyl alcohol: lot. no. S010409

Cremophor: lot. no. 35-2026

[0232] Four preconcentrate compositions were prepared according to Table 30 below.

[0233] Procedure for making the four formulations

[0234] Approximately 1000 mg of preconcentrate composition 1 in Table 30 was added to three Eppendorf tubes (n = 2). To the first tube, 30 mg/gram atorvastatin calcium trihydrate was added. To the second tube, 30 mg/gram rosuvastatin calcium was added. To the third tube, 100 mg/gram simvastatin was added. The tubes were then incubated in an end-over-end rotator for 48 hours. [0235] After 48 hours of incubation, the samples were centrifuged at 15.000 rpm for 10 min. A sample of approximately 200 mg was withdrawn from each tube. Each sample was added to an Eppendorf tube containing 1000 μΙ 2-propanol/MeCN (25/75). This solution was further diluted 100 μΙ + 900 μΙ 2-propanol/MeCN (25/75), followed by analysis by HPLC. An identical procedure was followed for

preconcentrate compositions 2-4 in Table 30.

[0236] The following HPLC parameters were used:

Injection volume 5 μΙ

Column temp.: 30°C

Detection (UV): 254 nm

Flow rate: 0.5 ml

Used column: Phenomenex luna 5μ C 8(2) 100A

125x4.0mm (batch no.: 00E-4252-D0)

Solvents:

1 ml acetic acid added to 1000 ml with milli Q

water

B: 1 ml acetic acid added to 1000 ml with

MeCN

HPLC Gradient:

[0237] By looking at the area, one can determine the solubilityy of the statin in the preconcentrate composition. For example, the atorvastatin calcium trihydrate exhibited the following HPLC results summarized in Table 31. From the data, the solubility of the statins in mg per gram of formulation was calculated. The rosuvastatin calcium and simvastatin exhibited the HPLC results summarized in Tables 32 and 33.

Results for Atorvastatin Calcum Trih drate

1 14 2816.9 173.5 13.84

3 187 4630.2 174.5 22.59 29.19 9.33

286 7070.3 169 35.79

4 61 1506.9 176.5 7.26 7.45 0.27

58 1443.3 162.5 7.64

Table 33. Results for Simvastatin

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical preconcentrate comprising:

a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride;

at least one surfactant; and

at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

2. The preconcentrate according to claim 1 , wherein of the at least 75% EPA and DHA of the fatty acid oil mixture, at least 95% is EPA.

3. The preconcentrate according to claim 1 , wherein of the at least 75% EPA and DHA of the fatty acid oil mixture, at least 95% is DHA.

4. The preconcentrate 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.

5. The preconcentrate according to claim 4, wherein at least one of the omega-3 fatty acids has a c/^'s configuration.

6. The preconcentrate 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 ethyl ester and triglyceride.

7. The preconcentrate according to claim 6, wherein the at least one other fatty acid is chosen from a-linolenic acid (ALA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), stearidonic acid (STA), and mixtures thereof.

8. The preconcentrate according to claim 6, 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.

9. The preconcentrate according to claim 1 1 , wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is chosen from atorvastatin, cerivastatin, fluvastatin , itavastatin, lovastatin, mevastatin, rosuvastatin, simvastatin, pravastatin, pravastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

10. ■ The preconcentrate according to claim 9, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is chosen from simvastatin, atorvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

1 1. The preconcentrate according to claim 10, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof comprises atorvastatin or a calcium salt of atorvastatin.

12. The preconcentrate according to claim 1 1 , wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is present in an amount ranging from about 10 mg to about 80 mg.

13. The preconcentrate 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.

14. The preconcentrate according to claim 13, wherein the marine oil is a purified fish oil.

15. The preconcentrate according to claim , wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1 : 10 to 10: 1 , from about 1 :8 to 8:1 , from about 1 :6 to 6:1 , from about 1 :5 to 5: 1 , from about 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.

16. The preconcentrate according to claim 15, wherein the EPA.DHA weight ratio of the fatty acid oil mixture ranges from about 1 :2 to 2: 1.

17. The preconcentrate according to claim 16, wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1.2 to 1.3.

18. The preconcentrate according to claim 1 , wherein the at least one surfactant is chosen from anionic, nonionic, cationic, zwitterionic surfactants, and mixtures thereof.

19. The preconcentrate according to claim 18, 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.

20. The preconcentrate according to claim 18, 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 ethesr, macrogol 15 hydroxystearates, macrogol lauril ethers, macrogol monomethyl ethers, macrogol oleyl ethers, macrogol stearas, menfegol, mono and diglycerides, nonoxinols, octoxinols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laureates, propylene glycol monopalmitostearates, quillaia, sorbitan esters, sucrose esters, and mixtures thereof.

21. The preconcentrate according to claim 18, 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.

22. The preconcentrate according to claim 21 , wherein the nonionic surfactants are chosen from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

23. The preconcentrate according to claim 18, wherein the cationic surfactants are chosen from quaternary ammonium compounds, cetylpyridinium chlorides, benzethonium chlorides, cetyl trimethylammonium bromides, and mixtures thereof.

24. The preconcentrate according to claim 18, wherein the zwitterionic surfactants are chosen from dodecyl betaines, coco amphoglycinates,

cocamidopropyl betaines, and mixtures thereof.

25. The preconcentrate according to claim 1 , wherein the at least one surfactant is a phospholipid, derivative thereof, analogue thereof, or any mixture thereof.

26. The preconcentrate according to claim 25, wherein the phospholipid, derivative thereof, or analogue thereof is chosen from natural, synthetic,

semisynthetic phospholipids, and mixtures thereof.

27. The preconcentrate according to claim 26, wherein the phospholipid or derivative or analogue thereof is chosen from phosphatidylcholines,

phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, and mixtures thereof.

28. The preconcentrate according to claim 1 , 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.

29. The preconcentrate according to claim 28, wherein the at least one surfactant comprises about 20%, by weight relative to the total weight of the preconcentrate.

30. The preconcentrate according to claim 1 , further comprising at least one co-surfactant.

31. The preconcentrate according to claim 30, wherein the at least one co- surfactant is chosen from short chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile salts, and mixtures thereof.

32. The preconcentrate according to claim 30, wherein the at least one co- surfactant comprises from about 1 % to about 10%, by weight relative to the total weight of the preconcentrate.

33. The preconcentrate according to claim 1 , wherein the ratio of fatty acid oil mixture:total surfactant ranges from about 1 : 1 to about 200:1 , from about 1 : 1 to about 100: 1 , from about : 1 to about 50: , from about 1 : 1 to about 10: 1 , from about 1 : 1 to about 8: 1 , from about 1.1 to 6: 1 from about 1 : 1 to about 5:1 , from about 1 : 1 to about 4: 1 , or from about 1 : 1 to about 3: 1.

34. The preconcentrate according to claim 1 , wherein the preconcentrate further comprises at least one pharmaceutically-acceptable solvent.

35. The preconcentrate according to claim 34, wherein the at least one pharmaceutically-acceptable solvent is chosen from lower alcohols and polyols.

36. The preconcentrate according to claim 1 , further comprising at least one antioxidant.

37. The preconcentrate according to claim 1 , further comprising at least one antioxidant, at least one chelating agent, at least one basic material, and at least one buffering agent.

38. The preconcentrate according to claim 1 , wherein the fatty acid oil mixture is present in a pharmaceutically-effective amount.

39. The preconcentrate according to claim 1 , wherein the preconcentrate is in the form of a gelatin capsule.

40. The preconcentrate according to claim 39, wherein the capsule comprises at least one enteric coating.

41. The preconcentrate according to claim 1 , wherein the preconcentrate is loaded into a tablet.

42. The preconcentrate according to claim 41 , wherein the tablet is coated by at least one of a film coating, a sub-layer, and an enteric coating.

43. The preconcentrate according to claim 39, wherein the capsule fill content ranges from about 0.400 g to about 1.300 g.

44. The preconcentrate according to claim 43, wherein the capsule fill content ranges from about 0.600 g to about 1.200 g.

45. The preconcentrate according to claim 44, wherein the capsule fill content ranges from about 0.800 g to about 1.000 g.

46. 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;

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

at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof chosen from atorvastatin, simvastatin, rosuvastatin, and

pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

47. A pharmaceutical preconcentrate comprising:

a fatty acid oil mixture comprising from about 80% to about 88%

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

at least one co-surfactant comprising ethanol; and

pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

48. A self-nanoemulsifying drug delivery system (SNEDDS), self- microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising 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 a form chosen from ethyl ester and triglyceride;

at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof;

wherein the preconcentrate forms an emulsion in an aqueous solution.

49. The system according to claim 48, wherein the fatty acid oil mixture comprises at least 90% omega-3 fatty acids, by weight of the fatty acid oil mixture.

50. The system according to claim 49, wherein at least one of the omega-3 fatty acids has a cis configuration.

51. The system according to claim 48, wherein the fatty acid oil mixture further comprises at least one other fatty acid other than EPA and DHA in a form chosen from ethyl ester and triglyceride.

52. The system according to claim 51 , wherein the at least one other fatty acid is chosen from a-linolenic acid (ALA), heneicosapentaenoic acid (HPA),

docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), stearidonic acid (STA), and mixtures thereof.

53. The system according to claim 51 , 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.

54. The system according to claim 48, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is chosen from atorvastatin, cerivastatin, fluvastatin , itavastatin, lovastatin, mevastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

55. The system according to claim 54, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is chosen from simvastatin, atorvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

56. The system according to claim 55, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof comprises atorvastatin or a calcium salt of atorvastatin.

57. The system according to claim 48, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is present in an amount ranging from about 10 mg to about 80 mg.

58. The system according to claim 48, 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.

59. The system according to claim 58, wherein the marine oil is a purified fish oil.

60. The system according to claim 48, wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1 : 10 to 10:1 , from about 1 :8 to 8:1 , from about 1 :6 to 6: 1 , from about 1 :5 to 5:1 , from about 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.

61. The system according to claim 60, wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1 :2 to 2:1.

62. The system according to claim 61 , wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1.2 to 1.3.

63. The system according to claim 48, wherein the at least one surfactant is chosen from anionic, nonionic, cationic, zwitterionic surfactants, and mixtures thereof.

64. The system according to claim 63, 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.

65. The system according to claim 63, 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 ethesr, macrogol 15 hydroxystearates, macrogol lauril ethers, macrogol monomethyl ethers, macrogol oleyl ethers, macrogol stearas, menfegol, mono and diglycerides, nonoxinols, octoxinols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laureates, propylene glycol monopalmitostearates, quillaia, sorbitan esters, sucrose esters, and mixtures thereof.

66. The system according to claim 63, 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,

67. The system according to claim 66, wherein the nonionic surfactants are chosen from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

68. The system according to claim 63, wherein the cationic surfactants are chosen from quaternary ammonium compounds, cetylpyridinium chlorides, benzethonium chlorides, cetyl trimethylammonium bromides, and mixtures thereof.

69. The system according to claim 63, wherein the zwitterionic surfactants are chosen from dodecyl betaines, coco amphoglycinates, cocamidopropyl betaines, and mixtures thereof.

70. The system according to claim 48, wherein the at least one surfactant is a phospholipid, derivative thereof, analogue thereof, or any mixture thereof.

71. The system according to claim 70, wherein the phospholipid, derivative thereof, or analogue thereof is chosen from natural, synthetic, semisynthetic phospholipids, and mixtures thereof.

72. The system according to claim 71 , wherein the phospholipid or derivative or analogue thereof is chosen from phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerois, phosphatidylserines, phosphatidylinositols, and mixtures thereof.

73. The system according to claim 48, 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 system.

74. The system according to claim 73, wherein the at least one surfactant comprises about 20%, by weight relative to the total weight of the preconcentrate.

75. The system according to claim 48, wherein the preconcentrate further comprises at least one co-surfactant.

76. The system according to claim 75, wherein the at least one co-surfactant is chosen from short chain alcohols, glycol ethers, pyrrolidine derivatives, 2-pyrrolidone, bile salts, and mixtures thereof.

77. The system according to claim 75, wherein the at least one co-surfactant comprises from about 1 % to about 10%, by weight relative to the total weight of the preconcentrate.

78. The system according to claim 48, wherein the ratio of fatty acid oil mixture:total surfactant ranges from about 1 : 1 to about 200: 1 , from about 1 : 1 to about 100: 1 , from about 1 : 1 to about 50: 1 , from about 1 : 1 to about 10: 1 , from about 1 : 1 to about 8: 1 , from about 1.1 to 6: 1 from about 1 : 1 to about 5:1 , from about 1 : to about 4: 1 , or from about 1 : 1 to about 3: 1.

79. The system according to claim 48, wherein the preconcentrate further comprises at least one pharmaceutically-acceptable solvent.

80. The system according to claim 79, wherein the at least one

pharmaceutically-acceptable solvent is chosen from lower alcohols and polyols.

81. The system according to claim 48, wherein the preconcentrate further comprises at least one antioxidant.

82. The system according to claim 48, further comprising at least one antioxidant, at least one chelating agent, at least one basic material, and at least one buffering agent.

83. The system according to claim 48, wherein the fatty acid oil mixture is present in a pharmaceutically-effective amount.

84. The system according to claim 48, wherein the system is in the form of a gelatin capsule.

85. The system according to claim 84, wherein the capsule comprises at least one enteric coating.

86. The system according to claim 48, wherein the preconcentrate is loaded into a tablet.

87. The system according to claim 86, wherein the tablet is coated by at least one of a film coating, a sub-layer, and an enteric coating.

88. The system according to claim 84, wherein the capsule fill content ranges from about 0.400 g to about 1.300 g.

89. The system according to claim 88, wherein the capsule fill content ranges from about 0.600 g to about 1.200 g.

90. The system according to claim 89, wherein the capsule fill content ranges from about 0.800 g to about 1.000 g.

91. The system according to claim 48, wherein the particle size of the emulsion ranges from about 150 nm to about 350 nm.

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

a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and

at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof;

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.

93. The method according to claim 92, wherein the at least one health problem is chosen from mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia.

94. The method according to claim 93, 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.

95. The method according to claim 92, wherein the fatty acid oil mixture comprises at least 90% omega-3 fatty acids, by weight of the fatty acid oil mixture.

96. The method according to claim 95, wherein at least one of the omega-3 fatty acids has a c/^'s configuration.

97. The method according to claim 92, wherein the fatty acid oil mixture further comprises at least one other fatty acid other than EPA and DHA in a form chosen from ethyl ester and triglyceride.

98. The method according to claim 97, wherein the at least one other fatty acid is chosen from a-linolenic acid (ALA), heneicosapentaenoic acid (HPA),

99. The method according to claim 97, 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.

100. The method according to claim 92, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is chosen from atorvastatin, cerivastatin, fluvastatin , itavastatin, lovastatin, mevastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

101 . The method according to claim 100, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof is chosen from simvastatin, atorvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.

102. The method according to claim 101 , wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof comprises atorvastatin or a calcium salt of atorvastatin.

103. The method according to claim 92, 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.

104. The method according to claim 103, wherein the marine oil is a purified fish oil.

105. The method according to claim 92, wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1 : 10 to 10:1 , from about 1 :8 to 8:1 , from about 1 :6 to 6: 1 , from about 1 :5 to 5:1 , from about 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.

106. The method according to claim 105, wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1 :2 to 2: 1 .

107. The method according to claim 106, wherein the EPA:DHA weight ratio of the fatty acid oil mixture ranges from about 1.2 to 1 .3.

108. The method according to claim 92, wherein the at least one surfactant is chosen from anionic, nonionic, cationic, zwitterionic surfactants, and mixtures thereof.

109. The method according to claim 108, 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.

1 10. The method according to claim 108, 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 ethesr, macrogol 15 hydroxystearates, macrogol lauril ethers, macrogol monomethyl ethers, macrogol oleyl ethers, macrogol stearas, menfegol, mono and diglycerides, nonoxinols, octoxinols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laureates, propylene glycol monopalmitostearates, quillaia, sorbitan esters, sucrose esters, and mixtures thereof.

1 1 1. The method according to claim 108, 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,

1 12. The method according to claim 11 1 , wherein the nonionic surfactants are chosen from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

1 13. The method according to claim 108, wherein the cationic surfactants are chosen from quaternary ammonium compounds, cetylpyridinium chlorides, benzethonium chlorides, cetyl trimethylammonium bromides, and mixtures thereof.

1 14. The method according to claim 108, wherein the zwitterionic surfactants are chosen from dodecyl betaines, coco amphoglycinates, cocamidopropyl betaines, and mixtures thereof.

1 15. The method according to claim 92, wherein the at least one surfactant is a phospholipid, derivative thereof, analogue thereof, or any mixture thereof.

1 16. The method according to claim 115, wherein the phospholipid, derivative thereof, or analogue thereof is chosen from natural, synthetic, semisynthetic phospholipids, and mixtures thereof.

1 17. The method according to claim 1 16, wherein the phospholipid or derivative or analogue thereof is chosen from phosphatidylcholines,

phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines,

phosphatidylinositols, and mixtures thereof.

1 18. The method according to claim 92, wherein the preconcentrate further comprises at least one co-surfactant.

1 19. The method according to claim 118, wherein the at least one co-surfactant is chosen from short chain alcohols, glycol ethers, pyrrolidine derivatives, 2- pyrrolidone, bile salts, and mixtures thereof.

120. The method according to claim 92, wherein the preconcentrate further comprises at least one antioxidant.

121. The method according to claim 92, wherein the preconcentrate further comprises at least one antioxidant, at least one chelating agent, at least one basic material, and at least one buffering agent.

122. The method according to claim 92, wherein the preconcentrate further comprises at least one superdisintegrant, and wherein the preconcentrate is loaded into a tablet.

123. The method according to claim 122, wherein the at least one

superdisintegrant is chosen from crosscarmelose, crospovidone, and sodium starch glycolate.

124. The method according to claim 122, wherein the tablet is coated by at least one of a film coating, a sub-layer, and an enteric coating.

125. The method according to claim 122, wherein the at least one

superdisintegrant comprises from about 1 % to about 20%, by weight relative to the total weight of the preconcentrate.

126. The method according to claim 92, wherein the preconcentrate is in the form of a gelatin capsule.

127. The method according to claim 126, wherein the capsule comprises at least one enteric coating.

128. The method according to claim 126, wherein the capsule fill content ranges from about 0.400 g to about 1.300 g.

129. The method according to claim 128, wherein the capsule fill content ranges from about 0.600 g to about 1.200 g.

130. The method according to claim 129, wherein the capsule fill content ranges from about 0.800 g to about 1.000 g.

131. The method according to claim 92, wherein the preconcentrate is administered once, twice, or three times per day.

132. The method according to claim 92, 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.

133. 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 ethyl ester and triglyceride;

at least one surfactant; and

wherein the fatty acid oil mixture, the at least one surfactant, and the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof form a preconcentrate.

134. The method according to claim 133, wherein the fatty acid oil mixture comprises at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture.

135. The method according to claim 133, wherein the at least one surfactant is chosen from anionic, nonionic, cationic, zwitterionic surfactants, and mixtures thereof.

136. The method according to claim 135, 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.

137. The method according to claim 135, 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 ethesr, macrogol 15 hydroxystearates, macrogol lauril ethers, macrogol monomethyl ethers, macrogol oleyl ethers, macrogol stearas, menfegol, mono and diglycerides, nonoxinols, octoxinols, polyoxamers, polyoxamer 188, polyoxamer 407, polyoxyl castor oils, polyoxyl hydrogenated castor oils, propylene glycol diacetates, propylene glycol laureates, propylene glycol monopalmitostearates, quillaia, sorbitan esters, sucrose esters, and mixtures thereof.

138. The method according to claim 135, 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,

139. The method according to claim 138, wherein the nonionic surfactants are chosen from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

140. The method according to claim 135, wherein the cationic surfactants are chosen from quaternary ammonium compounds, cetylpyridinium chlorides, benzethonium chlorides, cetyl trimethylammonium bromides, and mixtures thereof.

141 . The method according to claim 135, wherein the zwitterionic surfactants are chosen from dodecyl betaines, coco amphoglycinates, cocamidopropyl betaines, and mixtures thereof.

142. The method according to claim 133, wherein the at least one surfactant is a phospholipid, derivative thereof, analogue thereof, or any mixture thereof.

143. The method according to claim 142, wherein the phospholipid, derivative thereof, or analogue thereof is chosen from natural, synthetic, semisynthetic phospholipids, and mixtures thereof.

144. The method according to claim 143, wherein the phospholipid or derivative or analogue thereof is chosen from phosphatidylcholines,

phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines,

phosphatidylinositols, and mixtures thereof.

145. The method according to claim 133, wherein the preconcentrate further comprises at least one co-surfactant.

146. The method according to claim 145, wherein the at least one co-surfactant is chosen from short chain alcohols, glycol ethers, pyrrolidine derivatives, 2- pyrrolidone, bile salts, and mixtures thereof.

147. The method according to claim 134, wherein the preconcentrate 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 a form chosen from ethyl ester and triglyceride;

at least one statin chosen from atorvastatin, rosuvastatin, simvastatin, and a pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

148. The method according to claim 134, wherein the preconcentrate comprises: a fatty acid oil mixture comprising from about 80% to about 88%

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

at least one co-surfactant comprising ethanol; and

149. The method according to claim 133, 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.

150. The method according to claim 149, wherein the system comprises an emulsion with a particle size ranging from about 150 nm to about 350 nm.

151. A pharmaceutical preconcentrate comprising a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; for the treatment of at least one health problem chosen from mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia.

152. A self-nanoemulsifying drug delivery system (SNEDDS), self- microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising a pharmaceutical preconcentrate comprising: a fatty acid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) and

docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in a form chosen from ethyl ester and triglyceride; at least one surfactant; and at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof; wherein the preconcentrate forms an emulsion in an aqueous solution for the treatment of at least one health problem chosen from mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia.

153. The preconcentrate according to claim 39, wherein the capsule comprises two compartments, a first compartment comprising the fatty acid oil mixture and a second compartment comprising the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

154. The preconcentrate according to claim 153, wherein the first compartment comprising the fatty acid oil mixture further comprises the at least one surfactant.

155. The preconcentrate according to claim 39, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof comprises microcapsules suspended in the fatty acid oil mixture.

156. The preconcentrate according to claim 155, wherein the microcapsules are encapsulated in a material chosen from cyclodextrin and alginate.

157. The preconcentrate according to claim 39, wherein the gelatin capsule comprises a gelatin shell comprising the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.

158. The preconcentrate according to claim 39, wherein the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof forms an outer layer on the gelatin capsule.