Classifications

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Definitions

• the present disclosure relates generally to preconcentrates comprising a fatty acid oil mixture and at least one surfactant, 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 free fatty acid form.
• omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in free fatty acid 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 form, to a subject for therapeutic treatment and/or regulation of at least one health problem including, for example, irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, hypertriglyceridemia, 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
• total-C total-C
• LDL-C low-density lipoprotein
• apolipoprotein B a membrane complex for LDL-C and VLDL-C
• apolipoprotein A is 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.
• non-HDL cholesterol is an indicator of hypertriglyceridemia, vascular disease, atherosclerotic disease, and related conditions.
• NCEP ATP III specifies non-HDL cholesterol reduction as a treatment objective.
• 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), 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 VII- 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, for example, 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.
• EPA/DHA ethyl esters have also been used in compositions for delivery of therapeutic drugs.
• U.S. Patent No. 6,284,268 (Cyclosporine Therapeutics Ltd.) describes a self-emulsifying microemulsion or emulsion preconcentrate pharmaceutical compositions containing an omega-3 fatty acid oil and poorly water soluble therapeutic agent such as cyclosporine for oral administration. Cyclosporines are claimed to have additive or synergistic therapeutic effects with omega- 3 fatty acid oil.
• the '268 patent discloses greater solubility and stability of cyclosporine formulations comprising omega-3 fatty acid oils.
• WO 99/29300 (RTP Pharma) relates to self-emulsifying fenofibrate formulations based on a hydrophobic component selected from triglyceride, diglyceride, monoglycerides, free fatty acids and fatty acids and derivatives thereof.
• 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.
• compositions and/or methods that improve or enhance 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 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 free acid form; and at least one surfactant.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the present disclosure is also 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 free acid form; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the present disclosure also provides for 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 free acid form; and at least one surfactant; 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
• a pharmaceutical preconcentrate comprising: a fatty acid oil mixture comprising from about 80% to about 88% eicosapentaenoic acid (
• the present disclosure is 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 free acid form; and at least one surfactant; wherein the at least one health problem is chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the present disclosure also provides for a food supplement preconcentrate or nutritional supplement preconcentrate comprising: a fatty acid oil mixture comprising from about 25% to about 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; and at least one surfactant.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the present disclosure still further provides for 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 free acid form; and at least one surfactant; wherein the fatty acid oil mixture and the at least one surfactant form a preconcentrate.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the present disclosure also provides for 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 free acid form; and at least one surfactant for the treatment of at least one health problem chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the present disclosure additional is 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 free acid form; and at least one surfactant; wherein the preconcentrate forms an emulsion in an aqueous solution for the treatment of at least one health problem chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.
• SNEDDS self-nanoemulsifying drug delivery system
• SMEDDS self-microemulsifying drug delivery system
• SEDDS self-emulsifying drug
• the present disclosure is further directed to a method of regulating at least one health problem in a subject in need thereof comprising administering to the subject a food supplement preconcentrate or nutritional supplement preconcentrate comprising: a fatty acid oil mixture comprising from about 25% to about 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; and at least one surfactant; wherein the at least one health problem is chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the present disclosure is also further directed to a food supplement or nutritional supplement preconcentrate comprising: a fatty acid oil mixture comprising from about 25% to about 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; and at least one surfactant for the regulation of at least one health problem chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• 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 and supplement preconcentrates comprising a fatty acid oil mixture and at least one surfactant, 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, microemulsions, 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 free acid form.
• 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. 6,245,811, 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), ⁇ -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.
• 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 free acid form.
• free fatty acids may enhance lipolysis of fatty acids in the body, e.g., the interconversion of fatty acid esters and/or triglycerides to the free fatty acid form for efficient uptake.
• a fatty acid oil mixture comprising free fatty acids may, for example, provide for enhanced hydrolysis, solubility, bioavailability, absorption, or any combinations thereof of fatty acids in vivo
• 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 ⁇ -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.
• fatty acids include, but are not limited to, oleic acid, ricinoleic acid, erucic acid, and mixtures thereof.
• the at least one other fatty acid other than EPA and DHA is a polyunsaturated fatty acid.
• the at least one fatty acid other than EPA and DHA is in a form chosen from ethyl ester, triglyceride, and free acid.
• the at least one other fatty acid other than EPA and DHA is chosen from oleic acid, ricinoleic acid, linoleic acid, and erucic acid. In one embodiment, the at least one other fatty acid comprises oleic acid or linoleic acid.
• Examples of further fatty acids, or mixtures thereof encompassed by the present disclosure include, but are not limited to, the fatty acids defined in the European Pharamacopoeia Omega-3 Ethyl Esters 90 and purified marine oils, the European Pharamacopoeia Omega-3 Acid Triglycerides, the European Pharamacopoeia Omega-3 acid Ethyl Esters 60, the European Pharmacopoeia Fish Oil Rich in Omega-3 Acids monograph, and/or for instance the USP fish oil monograph.
• fatty acid oil mixtures comprising different fatty acids include, but are not limited to: IncromegaTM omega-3 marine oil concentrates such as IncromegaTM TG7010 SR, IncromegaTM E7010 SR, IncromegaTM TG6015, IncromegaTM EPA500TG SR, IncromegaTM E400200 SR, IncromegaTM E4010, IncromegaTM DHA700TG SR, IncromegaTM DHA700E SR, IncromegaTM DHA500TG SR, IncromegaTM TG3322 SR, IncromegaTM E3322 SR, IncromegaTM Trio TG/EE (Croda International PLC, Yorkshire, England); EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX7010EE, EPAX5500EE, EPAX5500TG, EPAX5000EE, EPAX5000TG, EPAX6000EE
• the fatty acid oil mixture comprises at least one fatty acid derivative, such as an alpha-substituted omega-3 fatty acid derivative.
• the at least one alpha substituted omega-3 fatty acid derivative may be substituted, for example, at the second carbon atom from the functional group of the omega-3 fatty acid with at least one substituent chosen from hydrogen, hydroxyl groups, alkyl groups, such as Ci-C 3 alkyl groups, and alkoxy groups.
• the at least one alpha-substituted omega-3 fatty acid derivative is chosen from mono-substituted and di-substituted fatty acids. In one embodiment, the at least one alpha substituted omega-3 fatty acid derivative is chosen from alpha-substituted C 14 -C 24 alkenes having 2 to 6 double bonds. In another embodiment, the at least one alpha-substituted omega-3 fatty acid derivative is chosen from alpha-substituted C 14 -C 24 alkenes having 5 or 6 double bonds in cis configuration.
• the fatty acid oil mixture comprises EPA and/or DHA in a form of an alpha-substituted fatty acid derivative.
• the fatty acid oil mixture comprises EPA in a form of an alpha-substituted derivative.
• the fatty acid oil mixture comprises DHA in a form of an alpha-substituted derivative.
• the fatty acid oil mixture comprises EPA and DHA in a form of an alpha-substituted derivative.
• the fatty acid oil mixture comprises EPA and DHA, and further comprises at least one alpha-substituted omega-3 fatty acid derivative.
• the fatty acid oil mixture comprises EPA and DHA, and at least one of EPA and DHA in a form of an alpha-substituted derivative.
• the EPA and DHA of the fatty acid oil mixture is at least one alpha-substituted omega-3 fatty acid derivative.
• 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 fatty acids of the fatty acid oil mixture
• the fatty acids are chosen from mono-, di-, and triglycerides.
• the fatty acids are 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 acids are obtained by using supercritical CO 2 extraction or chromatography techniques, for example to up-concentrate primary EPA and DHA from fish oil concentrates.
• the fatty acid oil mixture in free acid form is a K85FA fatty acid oil mixture obtained by hydrolyzing a K85EE fatty acid oil mixture.
• 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)-11 ,14,17-eicosatrienoic acid (ETE), (all-Z)- 5,8,11 ,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-8,11,14,17-eicosatetraenoic acid (ETA), (all-Z)-7,10,13,16,19- docosapentaenoic acid (DPA), (all-Z)-6,9,12,15,19- docosapentaeno
• 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.
• the fatty acid oil mixture acts as an active pharmaceutical ingredient (API).
• the present disclosure provides for a pharmaceutical composition comprising a fatty acid oil mixture and at least one surfactant.
• the fatty acid oil mixture is present in a pharmaceutically-acceptable amount.
• 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.
• the fatty acid oil mixture does not comprise an additional active agent.
• the fatty acid oil mixture comprises 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.
• 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 85% EPA and DHA, by weight of the fatty acid oil mixture, such as from about 80% to about 88%, 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 free acid 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 free acid form; wherein the fatty acid oil mixture comprises at least 90% omega-3 fatty acids in free acid 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 free acid form; wherein the fatty acid oil mixture comprises at least 90% of omega-3 fatty acids in free acid form, by weight of the fatty acid oil mixture, and wherein the fatty acid oil mixture comprises ⁇ -linolenic acid (ALA) in free acid form.
• 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 free acid form, and further comprises docosapentaenoic acid (DPA) in free acid 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 free acid form, and further comprises from about 1% to about 4% (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid (HPA) in free acid form, by weight of the fatty acid oil mixture.
• HPA all-Z omega-3-6,9,12,15,18-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 free acid form; and from 1% to about 4% fatty acids other than EPA and DHA, by weight of the fatty acid oil mixture, wherein the fatty acids other than EPA and DHA have C 20 , C 21 , or C 22 carbon atoms.
• the fatty acid oil mixture may comprise K85FA (Pronova BioPharma Norge AS).
• the present disclosure further provides for a food supplement preconcentrate or a nutritional supplement preconcentrate comprising a fatty acid oil mixture and at least one surfactant, wherein the fatty acid oil mixture comprises less than 75% EPA and DHA by weight of the fatty acid oil mixture.
• the fatty acid oil mixture comprises less than 70% EPA and DHA by weight of the fatty acid oil mixture, such as less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, or even less than 35% by weight of the fatty acid oil mixture.
• the fatty acid oil mixture comprises from about 25% to about 75% EPA and DHA by weight of the fatty acid oil mixture, such as from about 30% to about 75%, from about 30% to about 70%, from about 30% to about 65%, from about 30% to about 55%, from about 30% to about 50%, from about 30% to about 45%, from about 30% to about 40%, and further for example, from about 30% to about 35% EPA and DHA, by weight of the fatty acid oil mixture.
• the fatty acids, such as omega-3 fatty acids, of the fatty acid oil mixture are esterified, such as alkyl esters.
• the alkyl esters may include, but are not limited to, ethyl, methyl, propyl, and butyl esters, and mixtures thereof.
• the fatty acids are chosen from mono-, di-, and triglycerides.
• the fatty acid oil mixture comprises from about 25% to about 75% EPA and DHA by weight of the fatty acid oil mixture in a form chosen from methyl ester, ethyl ester, and triglyceride.
• preconcentrate composition refers to a composition comprising a fatty acid oil mixture and at least one surfactant.
• 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.
• the 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.
• Various commercially- available Pluronic® products are listed in Table 1.
• Brij® are nonionic surfactants comprising polyethylene ethers.
• Various commercially-available Brij® products are listed in Table 2.
• 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® 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.
• 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.
• 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, 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.
• 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.
• phosphatidylcholines with saturated, unsaturated and/or polyunsaturated lipids such as dioleoylphosphatidylcholine, dipentadecanoyl
• exemplary 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.
• 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
• compositions of the present disclosure further comprise at least one co-surfactant.
• co-surfactant means a substance added to, e.g., 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 hydrophilic.
• 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. Further examples include ethyl oleate.
• short chain alcohols comprising from 1 to 6 carbons
• benzyl alcohol alkane diols and triols
• alkane diols and triols e.g., prop
• the at least one co-surfactant comprises from about 1 % to about 10%, 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 free fatty acid form; and at least one surfactant.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• 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 free acid form; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures 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 free acid form; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures 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 free acid form, and oleic acid; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures 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 free acid form, and ⁇ -linoleic acid; and at least one surfactant chosen from polysorbate 20, polysorbate 80, and mixtures thereof; wherein the at least one surfactant comprises less than 35%, by weight relative the weight of the preconcentrate.
• the pharmaceutical pre-concentrate comprises a K85FA fatty acid oil mixture and at least one surfactant chosen from polysorbate 20 and polysorbate 80.
• the preconcentrate is a food supplement preconcentrate or nutritional supplement preconcentrate comprising a fatty acid oil mixture comprising from about 25% to about 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; and at least one surfactant.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• 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 5% to about 40%, by weight relative to the total weight of the preconcentrate.
• the at least one surfactant comprises from about 5% to about 35%, from about 10% to about 35%, from about 15% to about 35%, from about 15% to about 30%, or from about 20% to about 30%, by weight, relative to the total weight of the preconcentrate.
• the at least one surfactant comprises about 20%, by weight relative to the total weight of the preconcentrate.
• 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 fatty acid oil mixture comprising the active pharmaceutical ingredient (API) is greater than the amount of surfactant.
• the SNEDDS/SMEDDS/SEDDS presently disclosed may comprise a particle size (i.e., particle diameter) ranging from about 5 nm to about 10 ⁇ m.
• the particle size ranges from about 5 nm to about 1 ⁇ m, 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.
• the preconcentrates and/or SNEDDS/SMEDDS/SEDDS presently disclosed may further comprise at least one non-active pharmaceutical ingredient, e.g., excipient.
• Non-active ingredients may solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and/or fashion active ingredients into an applicable and efficacious preparation, such that it may be safe, convenient, and/or otherwise acceptable for use.
• the at least one non-active ingredient may be chosen from colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, and xanthum gum.
• the preconcentrates and/or SNEDDS/SMEDDS/SEDDS presently disclosed may further comprise at least one antioxidant.
• antioxidants suitable for the present disclosure include, but are not limited to, ⁇ -tocopherol (vitamin E), calcium disodium EDTA, alpha tocoferyl acetates, butylhydroxytoluenes (BHT), and butylhydroxyanisoles (BHA).
• compositions 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.
• 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-SoI (FMC BioPolymer).
• the composition comprises from about 1% to about 25% of at least one superdisintegrant by weight of the composition, such as from about 1% to about 20% by weight, or from about 1% to about 15% by weight of the composition.
• the compositions comprising at least one superdisintegrant are in a tablet form.
• compositions presently disclosed may be administered, e.g., in capsule, tablet or any other drug delivery forms.
• the composition may be encapsulated, such as in a gelatin capsule.
• the preconcentrate is encapsulated in a gelatin capsule.
• 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 1.20O 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 present disclosure further encompasses methods of treating and/or regulating at least one health problem in a subject in need thereof.
• the compositions presently disclosed may be administered, e.g., in capsule, tablet or any other drug delivery forms, to a subject for therapeutic treatment and/or regulation 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, hypercholesterolemia, heart failure, and post-myocardial infarction.
• 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 free acid form; and at least one surfactant.
• the method treats at least one of elevated triglyceride levels, non-HDL cholesterol levels, LDL cholesterol levels and/or VLDL cholesterol levels.
• a method of regulating at least one health problem in a subject in need thereof comprising administering to the subject administering to the subject a food supplement preconcentrate or nutritional supplement preconcentrate comprising: a fatty acid oil mixture comprising from about 25% to about 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHA are in free acid form; and at least one surfactant; wherein the at least one health problem is chosen from irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, heart failure, and post myocardial infarction.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the 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.
• the aqueous solution is gastric media and/or intestinal media.
• 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 AGP103 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, to a subject.
• EPA fatty acid (465 mg), DHA fatty acid (375 mg) and alpha-tochopherol (4 mg) are mixed in a scintillation vial with various surfactants as shown below in Table 8.
• Water (10 ml ) is added at 37 degrees centigrade and the mixture is shaken for 15 seconds using a Vortex mixer. The mixture is observed after 1 minute and after 5 minutes.
• the mixture is, after mixing, also rolled in a roller mixer for 5 minutes.
• the visual score for this roller test is the same as above.
• Table 8 Emulsions in pure water.
• Examples 50-55 Emulsions in artificial gastric iuice
• EPA fatty acid (465 mg) and DHA fatty acid (375 mg) and alpha- tochopherol (4 mg) are mixed in a scintillation vial with various surfactants as shown below in Table 9.
• 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) is used instead of water.
• Table 9 Emulsions in artificial gastric juice.
• EPA fatty acid (465 mg), DHA fatty acid (375 mg) and alpha-tochopherol (4 mg) are mixed in a scintillation vial with various surfactants as shown below in Table 10.
• 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) is used instead of water.
• Table 10 Emulsions in simulated intestinal fluid.
• Examples 62-63 Microscopic Examination of Emulsions
• Emulsions from Example 52 (gastric juice) and Example 58 (intestinal fluid) are examined under the microscope after 24 hours rolling.
• the surfactant is chosen from among Tween® surfactants, such as 20, 40, 60, 80, and 85.
• a composition according to the disclosure can include at least one surfactant chosen from Tween® 20 and 40.
• composition 1 A SEDDS composition
• a pharmaceutical composition was prepared by mixing the following components: Fatty acid oil mixture a) EPA-FA in an amount of 5.5 g and DHA-FA in an amount of 4.5 g (achieving approximately the EPA: DHA ratio in a K85EE or FA fatty acid mixture); b) a second fatty acid mixture in EE form: ethyl oleate: Fluka 75100, 137044 50308P14 in an amount of 5.0 g; and as the surfactant c): Tween® 20, Molecular Biology Grade, AppliChem Darmstadt, A4974.0250 lot 5N004174 in an amount of 10.0 g.
• a transparent homogenous solution was obtained.
• the density of the formulation was determined to be 1.03 g/ml.
• Tween® 80 instead of Tween® 20.
• mixed fatty acids EPA-FA (110mg) + DHA-FA (90 mg), ethyl oleate (100mg) and Tween 80 (200mg).
• EPA-FA 110mg
• DHA-FA 90 mg
• ethyl oleate 100mg
• Tween 80 200mg

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