WO2012032414A2 - Compositions comprenant un mélange d'huile constituée d'acides gras, un tensioactif et une statine - Google Patents

Compositions comprenant un mélange d'huile constituée d'acides gras, un tensioactif et une statine Download PDF

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WO2012032414A2
WO2012032414A2 PCT/IB2011/002727 IB2011002727W WO2012032414A2 WO 2012032414 A2 WO2012032414 A2 WO 2012032414A2 IB 2011002727 W IB2011002727 W IB 2011002727W WO 2012032414 A2 WO2012032414 A2 WO 2012032414A2
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preconcentrate
chosen
fatty acid
oil mixture
epa
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WO2012032414A3 (fr
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Svein Olaf Hustvedt
Preben Houlberg Olesen
Gunnar Berge
Jo Erik Johnsrud Klaveness
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Pronova Biopharma Norge As
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • 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.
  • omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in ethyl ester or triglyceride form.
  • SNEDDS self-nanoemulsifying drug delivery systems
  • SMEDDS self-microemulsifying drug delivery systems
  • SEDDS self- emulsifying drug delivery systems
  • 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.
  • 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.
  • HDL high- density lipoprotein
  • IDL intermediate-density lipoprotein
  • LDL low-density lipoprotein
  • VLDL very-low-density lipoprotein
  • 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.
  • Total- C total cholesterol
  • LDL-C LDL-C
  • apolipoprotein B a membrane complex for LDL-C and VLDL-C
  • apolipoprotein A a membrane complex for LDL-C and VLDL-C
  • 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.
  • non-HDL cholesterol is an indicator of hypertriglyceridemia, vascular disease, atherosclerotic disease, and related conditions.
  • NCEP ATP III National Cholesterol Education Program Adult Treatment Panel III
  • 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.
  • 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® / LovazaTM / Zodin® / Seacor®. See, e.g., U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594.
  • each 1000 mg capsule of LovazaTM 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.
  • 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.
  • polyunsaturated fatty can also be hydrolyzed to free carboxylic acids in vivo.
  • HMG-CoA hydroxymethyl- glutaryl-CoA
  • R-mevalonic acid hydroxymethyl- glutaryl-CoA
  • HMG-CoA reductase hydroxymethyl- glutaryl-CoA reductase
  • statins or HMG-CoA reductase inhibitors are frequently used as drugs for reduction of plasma cholesterol.
  • statins examples include atorvastatin, cerivastatin, fluvastatin, itavastatin, lovastatin, mevastatin, rosuvastatin, simvastatin, pravastatin, and pitavastatin.
  • the chemical formulae for various statins are shown in FIG 2.
  • Atorvastatin and atorvastatin-like drugs 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
  • 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
  • Atherosclerosis, 151 : 1 , 154 July 2000
  • Teramoto et al. Atherosclerosis, 151 : 1 , 53
  • Kithhara et al. Atheriosclerosis, 151 :1 , 295 (2000), and further publications in the same issue.
  • 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.
  • statins may exist in various crystalline forms and/or in amorphous form.
  • 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.
  • statins 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.
  • 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).
  • statins may be unstable.
  • 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).
  • compositions and/or methods to better regulate abnormal plasma lipid values in subjects in need of such treatment 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.
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the present disclosure is further directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system
  • SNEDDS self-nanoemulsifying drug delivery system
  • SMEDDS self-emulsifying drug delivery system
  • SEDDS self-emulsifying drug delivery system
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahex
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the present disclosure is further directed to a self-nanoemulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system
  • SNEDDS self-nanoemulsifying drug delivery system
  • SMEDDS self-emulsifying drug delivery system
  • SEDDS self-emulsifying drug delivery system
  • 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.
  • FIG 1 shows biosynthesis of cholesterol and a mechanism of action of statins (Jo Klaveness, Compendium in Medicinal Chemistry, Oslo, Norway (2009)).
  • FIG 2 shows the chemical formulae of simvastatin, lovastatin, pravastatin, fluvastatin, and atorvastatin.
  • FIG 3 shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of Omacor® .
  • FIG 4 shows the percent recovery of EPA + DHA at different time- points for Omacor®.
  • FIG 5 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for Omacor®.
  • 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.
  • FIG 7 shows the percent recovery of EPA + DHA at different time- points for preconcentrate A.
  • FIG 8 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate A.
  • 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.
  • FIG 10 shows the percent recovery of EPA + DHA at different time- points for preconcentrate B.
  • FIG 1 1 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate B.
  • 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.
  • FIG 13 shows the percent recovery of EPA + DHA at different time- points for preconcentrate C.
  • FIG 14 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate C.
  • 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.
  • FIG 16 shows the percent recovery of EPA + DHA at different time- points for preconcentrate D.
  • FIG 17 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate D.
  • 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.
  • FIG 19 shows the percent recovery of EPA + DHA at different time- points for preconcentrate E.
  • FIG 20 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for preconcentrate E.
  • administer refers 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.
  • 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.
  • the preconcentrates upon delivery, 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).
  • SNEDDS self- nanoemulsifying drug delivery systems
  • SMEDDS self-microemulsifying drug delivery systems
  • SEDDS self emulsifying drug delivery systems
  • compositions of the present disclosure comprise at least one fatty acid oil mixture comprising eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the term "fatty acid oil mixture” includes fatty acids, such as unsaturated (e.g., monounsaturated, polyunsaturated) or saturated fatty acids, as well as pharmaceutically-acceptable esters, free acids, mono-, di- and triglycerides, derivatives, conjugates, precursors, salts, and mixtures thereof.
  • the fatty acid oil mixture comprises fatty acids, such as omega-3 fatty acids, in a form chosen from ethyl ester and triglyceride.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • marine oil e.g., fish oil and purified fish oil concentrates
  • algae oils e.g., microbial oils and plant-based oils.
  • 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.
  • the fatty acid oil mixture of the present disclosure may further comprise at least one fatty acid other than EPA and DHA.
  • fatty acids include, but are not limited to, omega-3 fatty acids other than EPA and DHA and omega-6 fatty acids.
  • 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).
  • ALA -linolenic acid
  • HPA heneicosapentaenoic acid
  • DPA docosapentaenoic acid
  • ETA eicosatetraenoic acid
  • ETE eicosatrienoic acid
  • STA stearidonic acid
  • 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.
  • the at least one fatty acid other than EPA and DHA is in a form chosen from ethyl ester and triglyceride.
  • 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.
  • the fatty acid oil mixture according to the present disclosure may be derived from animal oils and/or non-animal oils.
  • 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.
  • the fatty acid oil mixture is derived from a marine oil, such as a fish oil.
  • the marine oil is a purified fish oil.
  • 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.
  • the fatty acids are chosen from mono-, di-, and triglycerides.
  • 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.
  • 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.
  • the fatty acid oil mixture is obtained by using supercritical C0 2 extraction or chromatography techniques, for example to up- concentrate primary EPA and DHA from fish oil concentrates.
  • 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- hene
  • 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.
  • the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to about 2:1.
  • the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 : 1 to about 2:1.
  • the weight ratio of EPA:DHA of the fatty acid oil mixture ranges from about 1 :2 to about 1 :3.
  • compositions presently disclosed comprise at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.
  • 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.
  • 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,
  • 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.
  • a statin 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.
  • statin complex may be crystallized.
  • 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.
  • the at least one statin is chosen from simvastatin, atorvastatin, rosuvastatin, and pharmaceutically acceptable salts, hydrates, solvates, and complexes thereof.
  • the at least one statin is chosen from atorvastatin, for example atorvastatin calcium, rosuvastatin, such as
  • 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.
  • statins or pharmaceutically acceptable hydrates, solvates, and complexes thereof according to the present disclosure may be amorphous or in crystalline form.
  • 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.
  • 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.
  • 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.
  • API active pharmaceutical ingredient
  • 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.
  • the fatty acid oil mixture is present in a pharmaceutically-acceptable amount.
  • the term “API) active pharmaceutical ingredient
  • 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.
  • the fatty acid oil mixture may comprise at least 75% EPA and DHA by weight of the fatty acid oil mixture.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the fatty acid oil mixture may comprise other omega-3 fatty acids.
  • the present disclosure encompasses at least 90% omega-3 fatty acids, by weight of the fatty acid oil mixture.
  • 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.
  • 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).
  • EPA and DHA are in ethyl ester form
  • omega-3 fatty acids in ethyl ester form
  • ALA a-linolenic acid
  • 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.
  • DPA docosapentaenoic acid
  • 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.
  • HPA 8-heneicosapentaenoic acid
  • 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 C 2 o, C 2 i , or C 22 carbon atoms.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure further provides for a preconcentrate composition.
  • preconcentrate refers to a composition comprising at least the combination of a fatty acid oil mixture and at least one surfactant.
  • 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.
  • a surfactant may, for example, lower the surface tension of a liquid or the surface tension between two liquids.
  • surfactants according to the present disclosure may lower the surface tension between the fatty acid oil mixture and an aqueous solution.
  • 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.
  • HLB hydrophilic-lipophilic balance
  • 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:
  • 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.
  • preconcentrate comprises at least one surfactant chosen from nonionic, anionic, cationic, and zwitterionic surfactants.
  • Non-limiting examples of nonionic surfactants suitable for the present disclosure are mentioned below.
  • 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.
  • a central hydrophobic polymer polyoxypropylene(poly(propylene oxide))
  • a hydrophilic polymer polyoxyethylene(poly " (ethylene oxide)
  • Brij® are nonionic surfactants comprising polyethylene ethers.
  • 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.
  • Tween® polysorbates
  • Tween® are nonionic surfactants comprising polyoxyethylene sorbitan esters.
  • Various commercially-available Tween® products are listed in Table 4.
  • Myrj® are nonionic surfactants comprising polyoxyethylene fatty acid esters. Various commercially-available Myrj® products are listed in Table 5.
  • Cremophor® are nonionic surfactants. Various commercially-available Cremophor® products are listed in Table 6. Table 6: Examples of Cremophor® surfactants.
  • 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
  • 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.
  • 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.
  • Zwitterionic surfactants include, but are limited to, for example dodecyl betaines, coco amphoglycinates and cocamidopropyl betaines.
  • the surfactant may comprise a phospholipid, derivative thereof, or analogue thereof.
  • Such surfactants may, for example, be chosen from natural, synthetic, and semisynthetic
  • 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.
  • 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
  • dipalmitoylphosphatidylcholine dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, di- eicopentaenoyl(EPA)choline, didocosahexaenoyl(DHA)choline,
  • phospholipid surfactants include soybean lecithin, egg lecithin, diolelyl phosphatidylcholine, distearoyl phosphatidyl glycerol, PEG-ylated phospholipids, and dimyristoyl phosphatidylcholine.
  • 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.
  • HLB hydrophilic-lipophilic balance
  • 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.
  • MCT medium chain triglyceride
  • LCT long chain triglycerides
  • preconcentrates of the present disclosure further comprise at least one co-surfactant.
  • 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.
  • the at least one co-surfactant is hydrophiiic. In some embodiments, the at least one co-surfactant is not in free acid form.
  • 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.
  • short chain alcohols comprising from 1 to 6 carbons
  • benzyl alcohol alkane diols and triols
  • alkane diols and triols e.g., propylene glycol, glycerol, poly
  • the at least one co-surfactant comprises from about 1 % to about 0%, by weight relative to the weight of the preconcentrate.
  • compositions according to the present disclosure further comprises at least one solvent.
  • solvent means a substance added to the preconcentrate to affect and/or alter the consistency of the preconcentrate, for example in an aqueous solution.
  • 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.
  • the at least one solvent is a pharmaceutically-acceptable solvent.
  • the preconcentrate comprises at least one substance that acts both as a co-surfactant and a solvent, for example an alcohol such as ethanol.
  • the preconcentrate comprises at least one co-surfactant and at least one solvent that are different substances.
  • the preconcentrate comprises ethanol as the co-surfactant and glycerol as the solvent.
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • 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.
  • 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.
  • 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.
  • the pharmaceutically acceptable salt 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.
  • the preconcentrate is in the form of a gelatin capsule or loaded into a tablet.
  • 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.
  • the at least one surfactant comprises from about 0.5% to about 40%, by weight relative to the total weight of the preconcentrate.
  • 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.
  • the at least one surfactant comprises about 20%, by weight relative to the total weight of the preconcentrate.
  • 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®).
  • the pharmaceutical preconcentrate comprises K85EE and Tween-20 in a fixed dose combination with atorvastatin (Lipitor®).
  • 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.
  • SNEDDS self-nanoemulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • SEDDS self emulsifying drug delivery system
  • 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.
  • known SNEDDS/SMEDDS/SEDDS formulations comprise -10 mg of a drug and -500 mg of surfactants/co-surfactants.
  • 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.
  • API e.g., the fatty acid oil mixture and the at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof
  • the SNEDDS/SMEDDS/SEDDS presently disclosed may comprise a particle size (i.e., particle diameter) ranging from about 5 nm to about 10 ⁇ .
  • the particle size ranges from about 5 nm to about 1 ⁇ , 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.
  • 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
  • excipients include, but are not limited to, carriers, fillers, extenders, binders, humectants, disintegrating agents (e.g., disintegrants and/or
  • 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.
  • 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.
  • SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one chelating agent.
  • 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 .
  • SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one basic substance.
  • 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.
  • any pharmaceutically acceptable basic material such as L-arginine, benethamine, benzathine, basic calcium salts, choline, deanol, diethanolamine, dieth
  • SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one buffering agent.
  • 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.
  • 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.
  • 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.
  • compositions presently disclosed may further comprise at least one antioxidant.
  • 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).
  • 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.
  • 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.
  • SNEDDS/SMEDDS/SEDDS presently disclosed further comprise at least one antioxidant and at least one excipient.
  • 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.
  • SNEDDS/SMEDDS/SEDDS comprise at least one antioxidant and at least one excipient chosen from chelating agents, bufferent agents, and basic materials.
  • the preconcentrates and/or SNEDDS/SMEDDS/SEDDS comprise at least one chelating agent, at least one basic material, and at least one buffering agent.
  • SNEDDS/SMEDDS/SEDDS comprise at least one chelating agent and at least one basic material.
  • 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).
  • ICH International Conference on Harmonization
  • 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).
  • 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.
  • the preconcentrates comprising at least one superdisintegrant are in a tablet form.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • preconcentrates presently disclosed may be administered, e.g., in capsule, caplet, tablet or any other forms suitable for drug delivery.
  • the preconcentrates are loaded into a tablet.
  • 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.
  • 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.
  • the preconcentrates presently disclosed may be encapsulated, such as in a gelatin capsule.
  • the preconcentrates presently disclosed comprise microcapsules encapsulated with a material chosen from cyclodextrin, and gelatin.
  • 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.
  • the compositions and/or preconcentrates are polymer-free.
  • 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).
  • the first API comprises a fatty acid oil mixture comprising EPA and DHA
  • the second API comprises atorvastatin calcium.
  • 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.
  • 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 DuoCapTM capsule delivery system (Encap Drug Delivery).
  • the DuoCapTM 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.
  • the inner and outer capsules may target release at different areas of the Gl tract (small intestine or colon).
  • 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.
  • 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
  • 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.
  • 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.
  • the compartment comprising the fatty acid oil mixture is formulated in a form chosen from liquid, semisolid, powder and pellet form.
  • the two compartment capsule can further be coated with at least one enteric coating or with Encap's colonic delivery system, ENCODETM.
  • 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.
  • 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.
  • the preconcentrates comprise an emulsion comprising microcapsules of at least one statin or pharmaceutically acceptable salt, hydrate, solvate, or complex thereof.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 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.
  • 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.
  • the enteric coating material may comprise one or more plasticizer(s) to improve the mechanical properties of pH-sensitive material(s).
  • 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.
  • the plasticizer for capsules comprising EPA and DHA ethyl esters comprises from about 10% to about 60% by weight of the enteric coating material.
  • 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.
  • the capsule fill content ranges from about 0.400 g to about 1 .600 g.
  • 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.
  • the capsule fill content is about 0.600 g, about 0.800 g, about 1.000 g, or about 1.200 g.
  • 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.
  • 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.
  • a film coating e.g., methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol, sodium
  • 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.
  • the at least one health problem is chosen from mixed dyslipidemia, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia.
  • 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.
  • the method treats at least one of elevated triglyceride levels, non-HDL cholesterol levels, LDL cholesterol levels and/or VLDL cholesterol levels.
  • 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.
  • SNEDDS self-nanoemulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • SEDDS self-emulsifying drug delivery system
  • the aqueous solution is gastric media and/or intestinal media.
  • 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.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • 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.
  • SNEDDS self-nanoemulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • SEDDS self-emulsifying drug delivery system
  • the total daily dosage of the fatty acid oil mixture may range from about 0.600 g to about 6.000 g.
  • 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.
  • the fatty acid oil mixture is chosen from K85EE and AGP 103 fatty acid oil compositions.
  • 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.
  • Example 1 Compatibility of Preconcentrates with Solvents
  • Table 8 Compatibility of Solvent and Preconcentrates.
  • ⁇ Bile salts Porcine Bile extract (Sigma); contains glycine and taurine
  • Pancreatic lipase Porcine pancreas (Sigma); contains many enzymes, including amylase, trypsin, lipase, ribonuclease and protease.
  • Table 1 1 Lipolysis of EPA and DHA ethyl ester in comparison to Omacor®.
  • 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.
  • 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 ⁇ g/ml.
  • 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.
  • Example 3 Emulsions in pure water
  • 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.
  • Table 12 Emulsions in pure water.
  • Example 4 Emulsions in Artificial Gastric Juice
  • 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.
  • Example 5 Emulsions in Simulated Intestinal fluid
  • 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.
  • Example 52 gastric juice
  • Example 58 intestinal fluid
  • the surfactant or combination of surfactants is chosen from Tween® surfactants; Tween® 20, Tween® 40, Tween® 60, Tween® 65, Tween® 80 and Tween® 85.
  • the surfactant is chosen from a combination of a Tween® surfactants and a surfactant chosen from Cremophor®, for instance Tween® 20 and Cremophor EL.
  • a Tween® 20 and Solutol HS 15 surfactant can be used together as well as Tween® 20 and Tween® 40.
  • 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.
  • Example 8 Additional Emulsions in Artificial Gastric Juice and Simulated Intestinal Fluid
  • 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.
  • 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).
  • a 0.5% non-ionic surfactant e.g., Cremophor®
  • Cremophor® can emulsify EPA/DHA ethyl ester in both artificial gastric juice and simulated intestinal fluid.
  • including more than one surfactant appears to stabilize the emulsion.
  • the particle size can vary depending upon the emulsification method.
  • 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
  • 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.
  • Example 10 Formulations comprising atorvastatin
  • Sample 3 Atorvastatin meglumin CD complex
  • Sample 4 Atorvastatin calcium CD complex
  • Sample 1 Atorvastatin calcium amorphous. (Drug Discovery Laboratory AS, No)
  • Sample 2 Atorvastatin meglumin salt (Drug Discovery Laboratories AS, No), batch 010-85.
  • Sample 3 Atorvastatine meglumin beta-CD complex (Drug Dicovery Laboratories AS, No).
  • Sample 4 Atorvastatine calcium beta-CD complex (Drug Discovery Laboratories AS, No)
  • Sample 5 Atorvastatin free acid, batch EXP-10-AB7860-1
  • Sample 6 Atorvastatine- crysmeb complex crystallized: BF-10- AB7862-CA-1.
  • Sample 7 Atorvastatine -beta cyclodextrin complex crystallized: BF- 0-AB7862-BA-1.
  • Sample 8 Atorvastatine-kleptose complex crystallized: BF-10- AB7862-KA-1 :
  • Sample 9 Atorvastatine- crysmeb complex: BF-10-AB7857-CA-B.
  • Sample 10 Atorvastatine -beta cyclodextrin complex: BF-10-AB7857- BA-B.
  • Sample 1 1 Atorvastatine-kleptose complex: BF- 0-AB7862-KA-B
  • Sample 12 Atorvastatine- crysmeb complex crystallized BF- 0- AB7862-CA-
  • Sample 13 Atorvastatine -beta cyclodextrin complex crystallized 2BF-10-AB7862-BA-2
  • Sample 14 Atorvastatine-kleptose complex crystallised: BF-10- AB7862-KA-2
  • Sample 14 Atorvastatine-kleptose complex crystallised: BF-10- AB7862-KA-2
  • 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.
  • statin such as, for example, atorvastatin
  • rosuvastatin rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof.
  • 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.
  • SNEDDS/SMEDDS/SEDDS e.g., self-emulsifying EPA and DHA compositions
  • a statin may be added, such as, for example, atorvastatin, rosuvastatin, simvastatin, and pharmaceutically acceptable salts, hydrates, solvates, or complexes thereof.
  • a "homogeneous” designation represents that a homogenous mixture was formed
  • 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.
  • Tween 20 and/or 80 are examples of Tween 20 and/or 80.
  • Table 21 Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and benzyl alcohol as a co-surfactant.
  • 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.
  • Table 24 Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and oleic acid.
  • Table 25 Examples of additional preconcentrate compositions, comprising Tween 20 and 80, and K85-FA.
  • Table 26 Examples of additional preconcentrate compositions, comprising different solvents/co-surfactants.
  • the abbreviation “DR” represents "dispersion rate.”
  • Table 28 Examples of additional preconcentrate compositions, comprising Cremophor RH40.
  • Table 29 Examples of additional preconcentrate compositions, comprising Solutol HS 15.
  • Preconcentrates can be prepared comprising atorvastatin,
  • SNEDDS/SMEDDS/SEDDS e.g., self-emulsifying EPA and DHA compositions
  • Atorvastatin calcium trihydrate AvaChem Scientific (Lot. no: AF803) Simvastatin: Toronto Research Chemicals (8-ABY-
  • Rosuvastatin calcium Sequoia Research Pruducts (control no:
  • statins in the preconcentrate composition By looking at the area, one can determine the solubilityy of the statin in the preconcentrate composition.
  • 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.

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Abstract

L'invention concerne des préconcentrats comprenant un mélange d'huile constituée d'acides gras, au moins un tensioactif et au moins une statine ou un sel pharmaceutiquement acceptable, un hydrate, un solvate ou un complexe de celle-ci, ainsi que les utilisations de ces préconcentrats. Les préconcentrats peuvent former un système d'administration de médicament auto-nanoémulsifiant (SNEDDS), un système d'administration de médicament microémulsifiant (SMEDDS) ou des systèmes d'administration de médicament auto-émulsifiants (SEDDS) dans une solution aqueuse.
PCT/IB2011/002727 2010-09-08 2011-09-08 Compositions comprenant un mélange d'huile constituée d'acides gras, un tensioactif et une statine WO2012032414A2 (fr)

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WO2015066176A1 (fr) * 2013-10-30 2015-05-07 Banner Life Sciences, LLC Capsules entériques molles comprenant des acides gras polyinsaturés
WO2015142307A1 (fr) 2014-03-21 2015-09-24 T.C. Ege Universitesi Système vecteur de médicament auto-micro/nanoémulsifiant destiné à l'administration par voie orale de rosuvastatine
WO2015185240A1 (fr) * 2014-06-04 2015-12-10 Sigma-Tau Industrire Farmaceutiche Riunite S.P.A. Compositions contenant de la simvastatine dans des acides gras polyinsaturés oméga-3
WO2016057915A1 (fr) * 2014-10-10 2016-04-14 Sancilio & Company, Inc. Compositions d'acides gras et d'esters d'acides gras auto-micellisantes, ainsi que leur utilisation dans le traitement d'états pathologiques
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