WO2016043251A1 - エイコサペンタエン酸アルキルエステルを含有する組成物及びその製造方法 - Google Patents
エイコサペンタエン酸アルキルエステルを含有する組成物及びその製造方法 Download PDFInfo
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C67/54—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
- C11B3/00—Refining fats or fatty oils
- C11B3/12—Refining fats or fatty oils by distillation
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
- C11C3/00—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom
- C11C3/04—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom by esterification of fats or fatty oils
- C11C3/10—Ester interchange
Definitions
- the present invention relates to a composition containing an eicosapentaenoic acid alkyl ester and a method for producing the same.
- Eicosapentaenoic acid (EPA; (5Z, 8Z, 11Z, 14Z, 17Z) -icosa- 5,8,11,14,17-pentaenoic acid; one of the ⁇ 3 fatty acids; ”Or“ EPA ”means this substance.) Is known as a component exhibiting an anti-arteriosclerosis action, a platelet aggregation inhibitory action, a blood lipid lowering action, and the like.
- Eicosapentaenoic acid ethyl ester (also described as “EPA-E” or “icosapentoic acid ethyl”), which is one of the esters of eicosapentaenoic acid, is sold as health food, switch OTC, pharmaceuticals, and the like.
- refined EPA-E contains a mixture of ethyl esters of fatty acids other than EPA derived from raw fish oil, impurities generated in the purification process, and the like.
- fatty acids other than EPA derived from raw fish oil include arachidonic acid and saturated fatty acids which are classified as ⁇ 6 fatty acids and are undesirable for cardiovascular events.
- impurities generated in the purification process fatty acids in which the five cis double bonds of EPA are partially isomerized to the trans form, which are caused by heat denaturation in the purification process, are known (for example, European Journal Lipid Science and Technology, 108 (2006) 589-597.
- an object of the present invention is to provide an eicosapentaenoic acid alkyl ester-containing composition having a reduced impurity content, a method for producing the same, and various uses of the eicosapentaenoic acid alkyl ester-containing composition.
- the present inventors have a structure very similar to that of ethyl eicosapentaenoate in the purification process of ethyl eicosapentaenoate, and impurities that are difficult to separate from ethyl eicosapentaenoate are produced.
- the present inventors have found that a composition containing eicosapentaenoic acid alkyl ester with high purity can be produced by reducing the content of impurities in the present invention, and the present invention has been completed.
- impurities examples include ethyl ester of arachidonic acid (C20: 4n-6) having the same carbon number as that of ethyl eicosapentaenoate, and other impurities (C20: 0, C20: 4n- 3, C20: 5n-3 (5,9,11,14,17), C18: 3n-3, C18: 4n-3, C19: 0, C19: 5n-3, C21: 5n-3, C22: 6n -3, each ethyl ester), the monotrans isomer of ethyl eicosapentaenoate, has been found by the inventors' research.
- aspects of the present invention include, but are not limited to, the following inventions.
- a monotrans form of an eicosapentaenoic acid alkyl ester containing 96 to 99 area% eicosapentaenoic acid alkyl ester and having an arachidonic acid alkyl ester content of 0.7 area% or less as measured by gas chromatography An eicosapentaenoic acid alkyl ester-containing composition wherein the content of is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less.
- the total content of the monotrans and ditrans isomers of the eicosapentaenoic acid alkyl ester is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less.
- Composition Composition.
- the total content of the eicosapentaenoic acid alkyl ester monotrans, ditrans, and tritrans isomers is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less.
- the total content of monotrans, ditrans, tritrans and tetratrans isomers of the eicosapentaenoic acid alkyl ester is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or The composition according to [1], which is 1.5 area% or less.
- GC-FID measurement conditions GC-FID measurement conditions
- GC 6890N (Agilent Technologies)
- Column DB-WAX (Agilent Technologies) 30 m x 0.25 mm ID, 0.25 ⁇ m film thickness
- Carrier gas helium, 0.5 mL / min
- Inlet 300 o C, 1 ⁇ L, Split (1: 100)
- Column temperature 200 ° C
- Constant temperature detector FID, 300 o C
- Make-up gas nitrogen 40mL / min.
- composition according to any one of [1] to [7], wherein the content of the arachidonic acid alkyl ester is 0.1 area% or less or 0.05 area% or less. [9] The content of the eicosatetraenoic acid alkyl ester is 0.7 area% or less, 0.5 area% or less, 0.4 area% or less, 0.3 area% or less, 0.2 area% or less, or 0.1 area% or less [1] [8] Any one of the compositions.
- composition according to any one of [1] to [11], wherein the eicosapentaenoic acid alkyl ester is ethyl eicosapentaenoate or methyl eicosapentaenoate.
- the content of n-nonadecanoic acid (C19: 0) alkyl ester is 0.1 area% or less, 0.07 area% or less, 0.05 area% or less, or 0.02 area% or less 1.
- the content of the arachidic acid (C20: 0) alkyl ester is 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 area% or less, or 0.02 area% or less, [1] to [13 ] Any one composition.
- [16] Content of icosa-5,9,11,14,17-pentaenoic acid (C20: 5n-3 (5,9,11,14,17)) alkyl ester is 0.2 area% or less, 0.15 area% or less
- the content of the henicosapentaenoic acid alkyl ester is 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 area% or less, 0.03 area% or less, or 0.02 area% or less [1] to [ 16] Any one composition.
- content of the eicosapentaenoic acid alkyl ester is 96 to 98 area%.
- a pharmaceutical composition comprising, as an active ingredient, the eicosapentaenoic acid alkyl ester-containing composition according to any one of [1] to [20].
- distillation is performed at a degree of vacuum of 0.2 Torr or less.
- a method for producing high-concentration ethyl eicosapentaenoate which is carried out by precision distillation at a temperature of 190 ° C. or lower in the tower, reduces ethyl arachidonic acid, and suppresses the formation of a trans isomer due to heat.
- a composition containing an eicosapentaenoic acid alkyl ester obtained by alkylating a feedstock oil containing eicosapentaenoic acid the degree of vacuum is 0.2 Torr or less, and the total tower is 190 ° C or less.
- a method for producing a high-concentration eicosapentaenoic acid alkyl ester-containing composition comprising performing precision distillation at a temperature and subjecting the composition after precision distillation to a concentration treatment using chromatography.
- the method according to [25] wherein the alkyl esterification is performed using a lower alcohol having 1 or 2 carbon atoms.
- the pharmaceutical composition is a therapeutic or prophylactic agent for at least one disease selected from the group consisting of arteriosclerosis, cerebral infarction, myocardial infarction, thrombosis, lifestyle-related diseases, allergies, inflammatory diseases, and cancer. Use [32].
- composition containing an eicosapentaenoic acid alkyl ester according to any one of [1] to [20] from arteriosclerosis, cerebral infarction, myocardial infarction, thrombosis, lifestyle-related disease, allergy, inflammatory disease, and cancer Use as an active ingredient of an agent for treating or preventing at least one disease selected from the group consisting of: [35]
- the pharmaceutical composition according to any one of [21] to [23] is selected from the group consisting of arteriosclerosis, cerebral infarction, myocardial infarction, thrombosis, lifestyle-related diseases, allergies, inflammatory diseases, and cancer.
- a method of preventing, treating or ameliorating a disease, comprising administering to a subject suffering from or at risk of suffering from at least one disease.
- the embodiments of the present invention include, but are not limited to, the following inventions.
- (1) When measured by gas chromatography, it contains 96 to 99 area% ethyl eicosapentaenoate, the content of ethyl arachidonic acid is 0.7 area% or less, and the content of the monotrans form of ethyl eicosapentaenoate Whose composition is 2.5 area% or less.
- composition according to (1) wherein the total content of monotrans form, ditrans form and tritrans form of ethyl eicosapentaenoate is 2.5 area% or less.
- composition according to (1) wherein the total content of monotrans, ditrans, tritrans and tetratrans forms of ethyl eicosapentaenoate is 2.5 area% or less.
- One of the double bonds at the 5-position, 14-position, and 17-position of ethyl eicosapentaenoate is trans-type, and the content of monotrans is 0.5 area% or less, respectively (1) to (4) Any composition.
- a composition in which the total content of substances appearing as a peak having a relative retention time of about 0.955, 1.027, 1.062, or 1.077 when the average retention time is 1 is 2.5 area% or less.
- (11) The content of icosa-5,9,11,14,17-pentaenoic acid (C20: 5n-3 (5,9,11,14,17)) ethyl ester is 0.2 area% or less, (1 ) To (10) any one of the compositions.
- a pharmaceutical composition comprising the composition according to any one of (1) to (12) as an active ingredient.
- the distillation process is performed at a vacuum degree of 0.2 Torr or less and a total tower of 190 ° C.
- a process for producing high-concentration ethyl eicosapentaenoate characterized by carrying out precision distillation at the following temperature to reduce ethyl arachidonic acid and suppress the formation of a trans isomer due to heat.
- the precision distillation is continuous precision distillation using two or more distillation columns.
- the chromatography step is a reverse phase chromatography step.
- Ethyl eicosapentaenoate is 96 area% or more, 96 to 99 area%, or 96 to 98 area%, and ethyl arachidonic acid is 0.7 area% or less, 0.5 area% or less, 0.4 area% or less, 0.3 area% or less , 0.2 area% or less, or 0.1 area% or less.
- the content of the monotrans form of arachidonic acid alkyl ester and eicosapentaenoic acid alkyl ester having a structure similar to that of eicosapentaenoic acid alkyl ester is reduced, and the composition contains eicosapentaenoic acid alkyl ester in high purity. It was found that can be manufactured.
- the composition according to an embodiment of the present invention can be manufactured on an industrial scale, and thus is advantageous in that it can be used as a health food, a pharmaceutical, or the like that requires safety and mass production. is there.
- the term “process” is not limited to an independent process, and is included in the term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. .
- the amount of each component in the composition means the total amount of the plurality of substances present in the composition unless there is a specific notice when there are a plurality of substances corresponding to each component in the composition. To do.
- a numerical range indicated by using “to” indicates a range including numerical values described before and after that as a minimum value and a maximum value, respectively.
- the terms “below” or “less than” in terms of percent include 0%, ie, “does not contain” unless otherwise stated, or include values not detectable by current means. Means range.
- oil or “oil / fat” as used herein refers not only to triglycerides but also includes triglycerides as the main component and includes other lipids such as diglycerides, monoglycerides, phospholipids, cholesterol, and free fatty acids. Includes crude oil. “Oil” or “fat” means a composition comprising these lipids.
- fatty acid includes not only free saturated or unsaturated fatty acids themselves, but also free saturated or unsaturated fatty acids, saturated or unsaturated fatty acid alcohol esters, triglycerides, diglycerides, monoglycerides, phospholipids, steryl esters and the like. Fatty acids as constituent units are also included and can be rephrased as constituent fatty acids.
- the form of a compound containing a fatty acid may be omitted. Examples of the form of the compound containing a fatty acid include a free fatty acid form, a fatty acid alcohol ester form, a glycerol ester form, a phospholipid form, and a steryl ester form.
- the compound containing the same fatty acid may be contained in a single form in the oil, or may be contained as a mixture of two or more forms.
- fatty acids When describing fatty acids, numerical representations may be used in which the number of carbon atoms, the number of double bonds, and the location of double bonds are simply expressed using numbers and alphabets, respectively.
- a saturated fatty acid having 20 carbon atoms is represented as “C20: 0”
- a monounsaturated fatty acid having 18 carbon atoms is represented as “C18: 1”, and the like
- arachidonic acid is represented as “C20: 4, n-6”.
- N- indicates the position of the double bond counted from the methyl terminus of the fatty acid.
- n-6 indicates that the position of the double bond is the sixth counted from the methyl terminus of the fatty acid. Show. This method is well known to those skilled in the art, and the fatty acid represented according to this method can be easily identified by those skilled in the art.
- crude oil means a mixture of the above-described lipids and extracted from a living organism.
- refined oil refers to a phospholipid by performing at least one oil and fat refining step selected from the group consisting of a degumming step, a deoxidizing step, a decoloring step, and a deodorizing step on the crude oil.
- purification process which removes substances other than target objects, such as a sterol, is meant.
- composition contains an eicosapentaenoic acid alkyl ester (hereinafter referred to as EPA alkyl ester) such as ethyl eicosapentaenoic acid (EPA-E) having the following content.
- EPA alkyl ester such as ethyl eicosapentaenoic acid (EPA-E) having the following content.
- EPA-E eicosapentaenoic acid alkyl ester
- impurities may be contained.
- the composition according to one embodiment of the present invention contains 96 to 99 area% of eicosapentaenoic acid alkyl ester and the content of arachidonic acid alkyl ester is 0.7 area% or less, as measured by gas chromatography. It is an eicosapentaenoic acid alkyl ester-containing composition in which the content of the monotrans form of the eicosapentaenoic acid alkyl ester is 2.5 area% or less.
- the composition in one embodiment of the present invention contains 96 to 99 area%, preferably 96 to 98 area% of EPA alkyl ester. Since the content of the EPA alkyl ester is 96 area% or more, it is preferably used when a high-purity EPA alkyl ester is required as in pharmaceutical use. Since the content of EPA alkyl ester is 99% by area or less, the yield of EPA alkyl ester in the concentration process can be maintained within a good range while containing EPA alkyl ester at a high concentration, and it should be considered industrially reasonable. Can do.
- the alkyl group in the EPA alkyl ester is an alkyl group derived from a lower alcohol generally used for fatty acid alkyl esterification.
- the alkyl group in the EPA alkyl ester is preferably an alkyl group having 1 or 2 carbon atoms, and examples thereof include a methyl group and an ethyl group.
- EPA alkyl esters include EPA ethyl (EPA-E) and EPA methyl (EPA-M).
- the isomers as impurities that can be contained in the composition according to an embodiment of the present invention include a monotrans isomer in which one of five cis isomer double bonds of the EPA alkyl ester is converted to a trans isomer. it can.
- the content of the monotrans isomer in the composition according to an embodiment of the present invention is 2.5 area% or less, and may be 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less. it can.
- the composition according to one embodiment of the present invention contains the EPA alkyl ester at a higher concentration, and the functionality of the EPA alkyl ester can be exhibited more effectively.
- isomers as other impurities include ditrans isomers in which two of the five cis double bonds of EPA alkyl ester are converted to trans isomers.
- the total content of the monotrans isomer and ditrans isomer in the composition according to one embodiment of the present invention is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less. can do.
- composition in one embodiment of the present invention contains EPA alkyl ester at a higher concentration, and the functionality of EPA alkyl ester is more effective. Can be demonstrated.
- Still other isomers as impurities include a tritrans form in which three of the five cis double bonds of the EPA alkyl ester are converted to a trans form.
- the composition in one embodiment of the present invention has a total content of these monotrans, ditrans and tritrans isomers of 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, Or it can be 1.5 area% or less.
- tetratrans isomer in which four of the five cis double bonds of the EPA-alkyl ester are converted into a trans isomer.
- the total content of these monotrans, ditrans, tritrans and tetratrans isomers is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 Area% or less, or 1.5 area% or less.
- the composition in one embodiment of the present invention is more It contains EPA alkyl ester at a high concentration, and the functionality of EPA alkyl ester can be exhibited more effectively.
- Examples of the isomer as an impurity in the composition according to the embodiment of the present invention include a monotrans isomer in which one of five cis-double bonds of EPA-E is converted into a trans isomer. .
- the content of this monotrans form that can be included in the composition in one embodiment of the present invention is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less. Can be.
- isomers as other impurities include ditrans isomers in which two of the five cis double bonds of EPA-E are converted to trans isomers.
- the total content of the monotrans and ditrans isomers that can be included in the composition in one embodiment of the present invention is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area % Or less.
- Still other isomers as impurities include, for example, a tritrans isomer in which three of the five cis double bonds of EPA-E are converted to a trans isomer.
- the total content of these monotrans, ditrans and tritrans isomers that can be included in the composition in one embodiment of the present invention is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area%. Or 1.5 area% or less.
- Still other isomers as impurities include, for example, a tetratrans form in which four of the five cis double bonds of EPA-E are converted to a trans form.
- the total content of these monotrans form, ditrans form, tritrans form and tetratrans form that can be contained in the composition in one embodiment of the present invention is 2.5 area% or less, 2.3 area% or less, and 2.0 area% or less. 1.8 area% or less, or 1.5 area% or less.
- the total content of the monotrans form, ditrans form, tritrans form and tetratrans form as described above may be 1.417 area% or more.
- the content of other fatty acids with different structures from EPA tends to be low depending on the content of these isomers. There is. If the composition contains more than a certain amount of these isomers, the content of other fatty acids that are difficult to separate from EPA, especially arachidonic acid alkyl esters, tends to be low, and tends to be difficult to separate from EPA alkyl esters in the composition. There is a tendency that the content balance with other fatty acid alkyl esters is better and the productivity is improved.
- the cis double bond of the EPA alkyl ester is converted into a trans form first when heat is applied during distillation, and di, tri, and tetra trans forms are formed when heat is further applied. Therefore, if the production of the monotrans form can be suppressed, the production of further trans forms can also be suppressed.
- EPA alkyl ester isomers When the entire column is distilled at a temperature of 190 ° C. or lower, EPA alkyl ester isomers may be formed.
- the isomers produced when the entire column is distilled at a temperature of 190 ° C. or less are the EPA-E 5th, 11th, 14th, 17th positions as shown in the Examples. This is a monotrans form in which any one of the double bonds is in a trans form.
- any one of the double bonds at the 5-position, the 14-position, and the 17-position of the EPA alkyl ester is a trans type, and the content of the monotrans form is 0.5 area each. % Area, 0.4 area% or less, 0.3 area% or less, 0.2 area% or less, or 0.1 area% or less.
- the double bond at the 11th position of the EPA alkyl ester is trans
- the content of the monotrans isomer is 1.0 area% or less, 0.9 area% or less, 0.8 area% or less, It can be 0.6 area% or less, 0.4 area% or less, 0.2 area% or less, or 0.1 area% or less.
- any one of the double bonds at the 5-position, the 14-position, and the 17-position of EPA-E is a trans type, It can be 0.5 area% or less, 0.4 area% or less, 0.3 area% or less, 0.2 area% or less, or 0.1 area% or less.
- the double bond at the 11th position of EPA-E is trans
- the content of monotrans is 1.0 area% or less, 0.9 area% or less, 0.8 area%
- it may be 0.6 area% or less, 0.4 area% or less, 0.2 area% or less, or 0.1 area% or less.
- the composition in one embodiment of the present invention contains a higher concentration of EPA alkyl ester, such as EPA-E.
- EPA alkyl esters such as EPA-E can be exhibited more effectively.
- the content of the trans isomer which has a low melting point and tends to become turbid or solidified at a low temperature, is lower, the composition tends to exhibit good handleability at a low temperature.
- area% refers to the peak of each component in a chart obtained by analyzing a composition using gas chromatography with a flame ionization detector (FID), and the Agilent ChemStation integration algorithm (revision) C.01.03 ([37], Agilent Technologies) is used to determine the peak area of each fatty acid, and the ratio of each peak area to the sum of the peak areas of the fatty acids indicates the content ratio of the peak component.
- FID flame ionization detector
- area% is almost synonymous with weight%.
- the compounds identified as the monotrans form of EPA-E are the peak retention times under the following gas chromatography measurement conditions, respectively, and the numerical values shown in Table 1 of Example 1 are used. Can be an indication.
- the relative retention time is a number obtained by dividing the actual retention time of each peak of gas chromatography measurement by the retention time of ethyl eicosapentaenoate. That is, it represents the relative retention time of each peak when the retention time of ethyl eicosapentaenoate is 1.
- the measurement value of the retention time of each peak varies somewhat depending on the measurement or the concentration of the component contained in the sample, but the variation is within ⁇ 0.01 when expressed in relative retention time.
- the term “about” as used for relative retention time is meant to include these ranges of variation.
- GC-FID measurement condition GC: 6890N (Agilent Technologies) Column: DB-WAX (Agilent Technologies) 30 m x 0.25 mm ID, 0.25 ⁇ m film thickness Carrier gas: helium, 0.5 mL / min Inlet: 300 o C, 1 ⁇ L, Split (1: 100) Column temperature: 200 °C constant temperature detector: FID, 300 o C Make-up gas: nitrogen 40mL / min.
- the total amount can be 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less.
- the total amount of can be 1.417 area% or more.
- examples of the impurity include saturated or unsaturated fatty acid alkyl esters having 18 or more carbon atoms such as arachidonic acid alkyl esters.
- Saturated or unsaturated fatty acid alkyl esters having 18 or more carbon atoms have a structure that is similar or very similar to EPA alkyl esters, and generally tend to be difficult to separate from EPA alkyl esters in distillation and chromatography processes. is there.
- An alkyl group in a saturated or unsaturated fatty acid alkyl ester having 18 or more carbon atoms is an alkyl group derived from a lower alcohol generally used for alkyl esterification of a fatty acid.
- the alkyl group in the saturated or unsaturated fatty acid alkyl ester having 18 or more carbon atoms is preferably an alkyl group having 1 or 2 carbon atoms, and specifically includes an ethyl group and a methyl group.
- examples of the saturated or unsaturated fatty acid alkyl ester having 18 or more carbon atoms include saturated or unsaturated fatty acid ethyl having 18 or more carbon atoms and saturated or unsaturated fatty acid methyl having 18 or more carbon atoms. The same applies to the alkyl group in the specific examples of the saturated or unsaturated fatty acid alkyl ester having 18 or more carbon atoms described below.
- an “arachidonic acid alkyl ester” (C20: 4n-6 alkyl ester, (5Z, 8Z, 11Z, 14Z) -5,8,11,14-icosatetraenoic acid alkyl ester)
- the content may be 0.7 area% or less, more preferably 0.5 area% or less, 0.4 area% or less, 0.3 area% or less, or 0.2 area% or less, more preferably 0.1 area% or less, or 0.05 area. % Or less.
- ethyl arachidonic acid (C20: 4n-6 ethyl ester, (5Z, 8Z, 11Z, 14Z) -5,8,11,14-ethyl icosatetraenoate)
- the content may be 0.7 area% or less, more preferably 0.5 area% or less, 0.4 area% or less, 0.3 area% or less, or 0.2 area% or less, more preferably 0.1 area% or less, or 0.05. Area% or more may be sufficient.
- an EPA alkyl ester such as EPA-E is reduced by reducing the content of arachidonic acid, which is a typical ⁇ 6 fatty acid, as much as possible. Can be effectively demonstrated.
- Examples of impurities other than the arachidonic acid alkyl ester contained in the composition according to one embodiment of the present invention include the following. These mainly have a structure similar to that of EPA alkyl esters, and are considered to be substances that are difficult to separate from EPA alkyl esters in the chromatography process. In the composition in each embodiment of the present invention, since the content of one or more of these impurities is low, the EPA alkyl ester can be contained in a high content.
- C20: 5n-3 (5,9,11,14,17) alkyl ester (icosa- 5,9,11,14,17-pentaenoic acid alkyl ester)
- the content may be 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.07 area% or less, 0.05 area% or less, or 0.02 area% or less.
- C20: 5n-3 (5,9,11,14,17) ethyl ester (icosa- 5,9,11,14,17-pentaenoic acid ethyl ester ) May be 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.07 area% or less, 0.05 area% or less, or 0.02 area% or less.
- C18: 3n-3 alkyl ester ( ⁇ -linolenic acid alkyl ester, (9Z, 12Z, 15Z) -9,12,15-octadecatrienoic acid alkyl ester)
- the content may be 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 area% or less, or 0.02 area% or less.
- “C18: 3n-3 ethyl ester” ethyl ⁇ -linolenate, (9Z, 12Z, 15Z) -9,12,15-ethyl octadecatrienoate
- the content may be 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 area% or less, or 0.02 area% or less.
- the composition includes “C18: 4n-3 alkyl ester” (stearidonic acid alkyl ester, (6Z, 9Z, 12Z, 15Z) -6,9,12,15-alkyl octadecatetraenoate.
- the content of the ester may be 0.4 area% or less, 0.3 area% or less, 0.2 area% or less, or 0.1 area% or less.
- “C18: 4n-3 ethyl ester” (ODTA-E, ethyl stearidate, (6Z, 9Z, 12Z, 15Z) -6,9,12,15-octa
- the content of ethyl decatetraenoate may be 0.4 area% or less, 0.3 area% or less, 0.2 area% or less, or 0.1 area% or less.
- C18: 4n-3 alkyl esters are known as functional ingredients
- compositions with a lower content of C18: 4n-3 alkyl esters such as C18: 4n-3 ethyl esters are added to the composition.
- the effects of additional features are weaker. For this reason, when using this composition as a functional composition based on an EPA alkyl ester, it is less necessary to consider other functions, and the handling of the composition is facilitated.
- the content of “C19: 5n-3 alkyl ester” is 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 It may be area% or less, 0.049 area% or less, or 0.02 area% or less.
- the content of “C19: 5n-3 ethyl ester” is 0.2 area% or less, 0.15 area% or less, 0.1 It may be area% or less, 0.05 area% or less, 0.049 area% or less, or 0.02 area% or less.
- compositions with a lower content of C19: 5n-3 alkyl esters, such as C19: 5n-3 ethyl esters, are added to the composition.
- the effects of additional features are weaker. For this reason, when using this composition as a functional composition based on an EPA alkyl ester, it is less necessary to consider other functions, and the handling of the composition is facilitated.
- the content of “C20: 4n-3 alkyl ester” (eicosatetraenoic acid alkyl ester) is 0.7 area% or less, 0.5 area% or less, 0.4 area% or less, 0.3 Area% or less, 0.2 area% or less, or 0.1 area% or less may be sufficient.
- the content of “C20: 4n-3 ethyl ester” (ETA-E, ethyl eicosatetraenoate) is 0.7 area% or less, 0.5 area% or less, 0.4 It may be area% or less, 0.3 area% or less, 0.2 area% or less, or 0.1 area% or less.
- compositions with a lower content of C20: 4n-3 alkyl esters, such as C20: 4n-3 ethyl esters, are added to the composition.
- the effects of additional features are weaker. For this reason, when using this composition as a functional composition based on an EPA alkyl ester, it is less necessary to consider other functions, and the handling of the composition is facilitated.
- the content of “C21: 5n-3 alkyl ester” (henicosapentaenoic acid alkyl ester) is 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 area%. Hereinafter, it may be 0.03 area% or less, or 0.02 area% or less.
- the content of “C21: 5n-3 ethyl ester” is 0.2 area% or less, 0.15 area% or less, 0.1 area%
- it may be 0.05 area% or less, 0.03 area% or less, or 0.02 area% or less.
- compositions with a lower content of C21: 5n-3 alkyl esters such as C21: 5n-3 ethyl esters are added to the composition.
- the effects of additional features are weaker. For this reason, when using this composition as a functional composition based on an EPA alkyl ester, it is less necessary to consider other functions, and the handling of the composition is facilitated.
- the fish oil contains a saturated fatty acid having 14 to 22 carbon atoms, but for cardiovascular use, it is preferable to avoid the intake of the saturated fatty acid.
- the total content of saturated fatty acid alkyl esters may be 0.5 area% or less, 0.3 area% or less, or 0.1 area% or less.
- the total content of ethyl esters of saturated fatty acids may be 0.5 area% or less, 0.3 area% or less, or 0.1 area% or less.
- the content of “C19: 0 alkyl ester” (n-nonadecanoic acid alkyl ester) among saturated fatty acids is 0.1 area% or less, 0.07 area% or less, 0.05 area% or less, Or 0.02 area% or less may be sufficient.
- the content of “C19: 0 ethyl ester” (ethyl n-nonadecanoate) is 0.1 area% or less, 0.07 area% or less, 0.05 area% or less, or 0.02 area. % Or less.
- the content of “C20: 0 alkyl ester” (arachidic acid alkyl ester) among the saturated fatty acids is 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 area. % Or less, or 0.02 area% or less.
- the content of “C20: 0 ethyl ester” (ethyl ethyl arachidate) is 0.2 area% or less, 0.15 area% or less, 0.1 area% or less, 0.05 area% or less, Or 0.02 area% or less may be sufficient.
- the composition according to one embodiment of the present invention may have a low content of fatty acids other than the EPA alkyl ester and the fatty acids described above.
- an EPA alkyl ester can be contained in a higher content, and when using this composition as a functional composition based on an EPA alkyl ester, the necessity to consider other functions can be reduced.
- Examples of the other fatty acid include alkyl esters of monounsaturated fatty acids (MUFA) having 20 or more carbon atoms.
- MUFA monounsaturated fatty acids
- the content of the MUFA alkyl ester is 0.05 area%. It may be the following.
- composition according to one embodiment of the present invention, “C20: 1n-11 ethyl ester” (ethyl galedate), “C20: 1n-9 ethyl ester (ethyl gondonoate),“ C22: 1n-11 ethyl ”
- the total content of MUFA ethyl, such as “ester” (ethyl cetrate) and “C22: 1n-9 ethyl ester” (ethyl erucate) may be 0.05 area% or less.
- the content of “C20: 3n-6 alkyl ester” may be 0.05 area% or less.
- the content of “C20: 3n-6 ethyl” may be 0.05 area% or less.
- a composition having a low content of n-6 fatty acids that may exert the opposite effect of EPA can exhibit a function based on the EPA alkyl ester.
- the content of “C22: 6n-3 alkyl ester” may be 0.1 area% or less, 0.05 area% or less, or 0.03 area% or less.
- the content of “C22: 6n-3 ethyl” is 0.1 area% or less, 0.05 area% or less, or 0.03 area% or less. It may be.
- compositions with a lower content of C22: 6n-3 alkyl esters, such as C22: 6n-3 ethyl esters, are added to the composition.
- the effects of additional features are weaker. For this reason, when using this composition as a functional composition based on an EPA alkyl ester, it is less necessary to consider other functions, and the handling of the composition is facilitated.
- One embodiment of the invention can include, for example, any of the following compositions that more effectively obtain the function of an EPA alkyl ester: (1) When measured by gas chromatography, it contains 96 to 99 area% of EPA alkyl ester such as EPA-E, and the content of alkyl arachidonic acid such as ethyl arachidonate is 0.1 area% or less, or 0.05 area% or less. Eicosapentaenoic acid alkyl ester such as EPA-E monotrans content is 2.5 area% or less, 2.3 area% or less, 2.0 area% or less, 1.8 area% or less, or 1.5 area% or less Ester-containing composition.
- EPA-E When measured under the following analysis conditions using gas chromatography, EPA-E is contained in 96 to 99 area%, and the ethyl arachidonic acid content is 0.1 area% or less, or 0.05 area% or less, When the average retention time of EPA-E is 1, the relative retention time is about 0.955, 1.027, 1.062, or 1.077. The total amount of substances that appear as peaks is 2.5 area% or less, 2.3 area% or less, 2.0 area%
- an eicosapentaenoic acid alkyl ester-containing composition that is 1.8 area% or less or 1.5 area% or less.
- EPA-E content is 96-99 area% and ethyl arachidonic acid content is 0.7 area% or less when measured by gas chromatography under the following analysis conditions, and the average retention of EPA-E
- the total amount of substances that appear as peaks with a relative retention time of about 0.955, 1.027, 1.062, or 1.077 when the time is 1 is 1.417 area% or more, 2.5 area% or less, 2.3 area% or less, 2.0 area % Eicosapentaenoic acid alkyl ester-containing composition that is not more than%, 1.8 area% or less, or 1.5 area% or less.
- the total content of substances appearing as a peak with a relative retention time of about 0.955, 1.027, 1.062 or 1.077 when the average retention time of EPA-E is 1 is 1.417% by area or more of the composition.
- the content of DGLA alkyl ester for example, DGLA ethyl
- the content of DGLA alkyl ester may be 0.05 area% or less, and instead of or in addition to the content of DGLA alkyl ester.
- the MUFA alkyl ester for example, the MUFA ethyl content may be 0.05 area% or less.
- compositions (1) to (8) may be a combination of at least one selected from the group consisting of: 0.7% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less eicosatetraenoic acid alkyl ester, such as ethyl eicosatetraenoate; 0.4 area% or less, 0.3 area% or less, 0.2 area% or less, or 0.1 area% or less of octadecatetraenoic acid alkyl ester, such as ethyl octadecatetraenoate; 0.2% or less, 0.15% or less, 0.1% or less, 0.05% or less, 0.049% or less, or 0.02% or less nonadecapentanoic acid alkyl ester, such as ethyl nonadecapentanoate; N-nonadecanoic acid (C)
- Another embodiment of the present invention provides an eicosapentaenoic acid alkyl ester containing 96 to 99 area% eicosapentaenoic acid alkyl ester and having an arachidonic acid alkylester content of 0.1 area% or less as measured by gas chromatography. Also included are ester-containing compositions. As mentioned above, eicosapentaenoic acid alkyl esters, such as EPA-E, tend to be difficult to separate in the purification process from arachidonic acid alkyl esters, such as ARA-E, that are similar in structure.
- the composition of the present embodiment contains the target eicosapentaenoic acid alkyl ester in a high content of 96 to 99% by area or more out of the two compounds that are difficult to separate, and is not intended.
- the content of arachidonic acid alkyl ester is as low as 0.1 area% or less. Therefore, in this composition, since the influence by an arachidonic acid alkyl ester is very low, this composition can be preferably used for the use for which a high content eicosapentaenoic acid alkyl ester is required.
- the content of the monotrans form of eicosapentaenoic acid alkyl ester is 10 area% or less, 5.0 area% or less, 3.0 area% or less, 2.5, area% or less, 2.0 area% or less, 1.8 area. % Or less, or 1.5 area% or less.
- a composition containing an eicosapentaenoic acid alkyl ester obtained by alkylating a feedstock containing eicosapentaenoic acid has a degree of vacuum of 0.2 Torr or less, and Including high-precision concentration, including performing precision distillation at a temperature of 190 ° C. or lower in all towers and subjecting the composition after precision distillation to a concentration treatment using chromatography, including other steps as necessary.
- a method for producing an icosapentaenoic acid alkyl ester-containing composition is included.
- the step of performing distillation may be simply referred to as a distillation step, and the step of performing chromatography may be simply referred to as a chromatography step.
- the distillation step and the chromatography step may be further collectively referred to as a purification step.
- fats or oils containing eicosapentaenoic acid as a constituent fatty acid, phospholipids, or the like can be used. It is known that eicosapentaenoic acid is contained in a large amount in microbial oils, marine animal oils, and the like. Specific examples of raw oils include fish such as sardines, tuna and bonito, marine animal oils of crustaceans such as krill, yeast such as Yarrowia, filamentous fungi such as Mortierella, algae such as Euglena, strameno Examples are oils derived from microorganisms that produce lipids, such as piles.
- oils derived from genetically modified microorganisms into which genes such as genetically modified mutant ⁇ 9 elongases have been introduced may be oils derived from genetically modified microorganisms into which genes such as genetically modified mutant ⁇ 9 elongases have been introduced.
- These microbial oils also have similar problems because they contain 20 carbon atoms such as arachidonic acid in addition to EPA.
- oil derived from genetically modified plants by oil seed plants such as Brassica species, sunflower, corn, cotton, flax, safflower, etc. into which a gene such as a mutant ⁇ 9 elongase has been introduced by recombinant technology can also be used as a raw material oil.
- Examples of the genetically modified vegetable oil and the genetically modified microbial oil include those described in WO2012 / 027698, WO2010 / 033753, and the like.
- fish oil contains EPA in the form of triglycerides in which three molecules of fatty acid are ester-bonded to one molecule of glycerol.
- Fish oil contains many types of fatty acids having 14 to 22 carbon atoms and 0 to 6 double bonds, so the concentration of EPA is limited. Therefore, the fatty acid bound to the triglyceride is reacted with a lower alcohol in the presence of a catalyst or an enzyme to form an alkyl ester, for example, it is reacted with ethanol to form an ethyl ester to separate the fatty acid from glycerin, and then EPA.
- the production method according to one aspect of the present invention may include preparing an EPA alkyl ester obtained by such an alkyl esterification, preparing a raw oil, and esterifying the raw oil with a lower alcohol. To obtain an EPA alkyl ester (hereinafter sometimes referred to as an esterification step).
- the raw material oil used in the alkyl esterification may be a crude oil or a refined oil.
- the crude oil may be an oil obtained from a marine product raw material or an oil obtained from a microbial raw material.
- any method may be used to obtain the crude oil from the marine product raw material, but in the case of fish oil, it is usually collected by the following method.
- Processed residues such as the head, skin, middle bone, and internal organs of fish generated from fish processing or marine processing are pulverized and boiled, and then pressed to separate into boiled juice (stick water) and compressed meal.
- the oil and fat obtained with the broth is separated from the broth by centrifugation to obtain a crude fish oil.
- crude oil of fish oil is subjected to a degumming step, a deoxidation step, a decolorization step using activated clay or activated carbon, a water washing step, a deodorizing step by steam distillation, etc. It is made into refined fish oil through a crude oil refining process that removes substances other than the target substance.
- this purified fish oil can also be used as a raw material.
- the fats and oils which are esterification process raw material oils are decomposed into lower alcohol esters by alcoholysis using lower alcohols.
- the lower alcohol include those generally used for alkyl esterification of fatty acids, for example, lower alcohols having 1 or 2 carbon atoms.
- Alcohol decomposition is a process in which a fatty alcohol is reacted with a lower alcohol such as ethanol and a catalyst or an enzyme to produce an ethyl ester from a fatty acid bonded to glycerin.
- a catalyst an alkali catalyst, an acid catalyst, or the like is used.
- Lipase is used as the enzyme.
- the reaction efficiency of alcoholysis of fatty acids is high, and a composition containing fatty acids mainly in the form of their alkyl esters is obtained after alcoholysis. Therefore, in the present specification, the fatty acid after the esterification step may be expressed by omitting that the fatty acid is an alkyl ester fatty acid unless otherwise specified. However, it is not completely excluded that fatty acids other than the alkyl ester form are included.
- the production of the composition in one embodiment of the present invention includes a purification step by a distillation step and a chromatography step using chromatography such as high performance liquid column chromatography (HPLC).
- HPLC high performance liquid column chromatography
- EPA-E and ethyl arachidonic acid have the same molecular structure, but the molecular weight is slightly different, so the difference in boiling point (EPA-E: 417 ° C / 760mmHg, ethyl arachidonic acid: 418.1 ° C / 760mmHg) It can be considered that it can be separated by distillation with higher accuracy. From this viewpoint, it is considered necessary to increase the number of stages and / or increase the reflux amount in order to increase the degree of separation.
- JP-A-5-222392 since the distillation described in JP-A-5-222392 is a method for collecting C20 fraction, EPA-E and ethyl arachidonic acid cannot be separated. Separation of EPA-E and ethyl arachidonic acid is possible to some extent in the subsequent purification process by HPLC, but in order to obtain high-purity EPA-E, the portion where EPA-E and ethyl arachidonic acid overlap must be cut. Therefore, the EPA-E recovery rate is greatly reduced. JP-A-5-222392 also shows that the EPA-E fraction is significantly cut from FIG.
- the entire tower temperature can be maintained at a vacuum degree of 0.2 Torr or lower and 190 ° C or lower by reducing the pressure resistance, selecting the type of vacuum pump, combining vacuum pumps, and the like.
- Examples of the decrease in pressure resistance include thickening the pipe and smoothing the angle of the pipe. Since the boiling point of a substance decreases as the pressure is lowered, distillation becomes possible at a lower temperature when a high vacuum (low pressure) is reached, and denaturation of the substance due to heat can be suppressed. On the other hand, when the boiling point is lowered, it becomes easier to evaporate and the amount of reflux can be increased.
- the precision distillation can be performed at a lower temperature and with a sufficient reflux amount.
- the amount of reflux separation accuracy in distillation is improved, and separation of substances having a boiling point close to that of EPA alkyl ester, such as arachidonic acid alkyl ester, is facilitated.
- the composition with higher content of EPA alkyl ester can be obtained from the viewpoint of balance between separation from other fatty acid alkyl ester such as arachidonic acid alkyl ester and suppression of generation of impurities by heat.
- precision distillation means that a part of the vapor generated under heating conditions is returned to the distillation column as a reflux liquid, and the vapor-liquid equilibrium between the vapor rising in the column and the liquid sample is used.
- This means a technique for accurately separating components see Japanese Patent Laid-Open Nos. 4-128250 and 5-222392).
- the “whole column” used for the pressure and temperature conditions in the distillation step means the conditions in all distillation columns that can be used in the distillation step. If there is a single distillation column used in the distillation process, it means that the conditions are in the single distillation column. If there are multiple distillation columns used in the distillation step, all the existing distillation columns are present. Means that the condition is
- the distillation step may be performed using a single distillation column, and can be continuous precision distillation using two or more, three or more, or four or more distillation columns.
- continuous precision distillation using two or more distillation towers it is more important to maintain the degree of vacuum.
- the vacuum degree of all the towers can be 0.2 Torr or less. If the degree of vacuum is further lowered, the temperature can be further lowered. From an industrial point of view, including the need to install higher performance equipment, the temperature is preferably 150 to 190 ° C, preferably 170 to 190 ° C.
- the chromatographic step by HPLC etc. following the distillation step reduces the content of non-target components by removing the non-target components in the composition obtained in the distillation step, etc., in the composition after precision distillation
- the chromatography used for the concentration treatment reverse phase column chromatography is suitable. If it is an adsorbent of a reverse phase distribution system as a stationary phase, it can be used without particular designation, and an ODS column using octadecylsilyl (ODS) is preferable.
- the EPA alkyl ester cut rate in HPLC is improved, the recovery rate is improved, and the content of EPA alkyl ester with a low content of impurities such as arachidonic acid alkyl ester is improved. Production on an industrial scale becomes possible.
- the content of impurities other than the arachidonic acid alkyl ester can also be reduced.
- the form of use of the composition in one embodiment of the present invention is not particularly limited, but is preferably an oral dosage form, and typically includes oral dosage forms such as granules, tablets, capsules, and liquids. can do.
- Uses of the composition of the present invention include, for example, foods and drinks (health foods, nutritional supplements, foods for specified health use, supplements, dairy products, soft drinks, pet foods and drinks, livestock feeds, etc.), pharmaceuticals, quasi drugs
- supplements and pharmaceuticals are preferable.
- the composition in one form of this invention can be used as a raw material or active ingredient of these food / beverage products, a pharmaceutical, and a quasi-drug, and can be preferably used in manufacture of these.
- compositions containing the above composition as an active ingredient.
- the content of the composition in the pharmaceutical composition is not particularly limited, but is preferably 25% by weight or more, more preferably 50% by weight or more, still more preferably 70% by weight or more, still more preferably 85% by weight or more, Especially preferably, it is 96 weight% or more, Most preferably, it is 98 weight% or more.
- the pharmaceutical composition can be used for treatment or prevention of diseases such as arteriosclerosis, cerebral infarction, myocardial infarction, thrombosis, hyperlipidemia and other lifestyle-related diseases, allergies, inflammatory diseases, cancer, etc. It is used as a therapeutic agent for obstructive arteriosclerosis, a therapeutic agent for hyperlipidemia, and the like.
- composition of one embodiment of the present invention since the content of impurities is reduced, the safety is extremely high, and a pharmaceutical preparation with a wide safety range can be prepared using this.
- high-purity EPA ethyl ester preparations such as high-purity EPA-E preparations whose daily dose of EPA-E is 3 times or more, preferably 5 or more times the normal dose, or daily administration of EPA-E
- a high purity EPA ethyl ester formulation, such as a high purity EPA-E formulation, in an amount of 6 g or more, preferably 10 g or more can be produced.
- diseases that cannot be expected to have therapeutic effects at normal doses such as hyperlipidemia can be safely treated.
- the pharmaceutical composition according to one aspect of the present invention can contain a pharmaceutically acceptable additive component in addition to the active ingredient.
- a pharmaceutical composition comprising such additive ingredients can comprise a pharmaceutically acceptable excipient.
- the pharmaceutical composition appropriately contains known antioxidants, coating agents, gelling agents, flavoring agents, flavoring agents, preservatives, antioxidants, emulsifiers, pH adjusting agents, buffering agents, coloring agents and the like. May be.
- the antioxidant for example, at least one selected from butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, gallic acid, pharmaceutically acceptable quinone, ascorbic acid esters such as ascorbyl palmitate, and tocopherols can be used. It is desirable to contain an effective amount as an oxidizing agent.
- the dosage form of the preparation varies depending on the combination form of the active ingredient and is not particularly limited, but an oral preparation is preferable, for example, tablet, film-coated tablet, capsule, microcapsule, granule, fine granule, powder, oral It can be used in the form of liquid preparations, syrups, jellies and inhalants.
- oral administration in capsules by encapsulating in capsules such as soft capsules or microcapsules is preferable.
- it may be orally administered as an enteric preparation or sustained release preparation, and it is also preferable to orally administer as a jelly agent to dialysis patients, patients who have difficulty swallowing and the like.
- the pharmaceutical composition in the present invention can be produced or formulated according to a conventional method.
- the pharmaceutical composition according to another embodiment of the present invention is selected from the group consisting of arteriosclerosis, cerebral infarction, myocardial infarction, thrombosis, lifestyle-related disease, allergy, inflammatory disease, and cancer.
- a method of preventing, treating or ameliorating a disease comprising administering to a subject suffering from or at risk of suffering from at least one selected disease.
- the administration form may be oral administration or topical administration.
- the dose may be any amount that is effective for treatment or prevention, and is appropriately set according to conditions such as the type of target disease, the degree of symptoms, the age, weight, and health status of the administration target.
- the composition in the case of an adult, is administered in an amount of 1 mg to 1 g / kg / day, preferably 5 mg to 300 mg / kg / day as an active ingredient, orally or parenterally, once a day or 2 to 2 It can be divided into four or more doses and administered at appropriate intervals.
- the therapeutic agent refers to a drug used for suppressing or alleviating the progression of such symptoms when symptoms due to the target disease are found.
- the preventive agent refers to a medicine used for pre-administration and suppression of the onset of symptoms caused by a target disease.
- these terms are used in combination depending on the time of use or symptoms during use, and are not interpreted in a limited way.
- an element with the indefinite article “a” or “an” does not exclude the possibility that one or more elements exist unless the context clearly indicates or connects.
- the indefinite article “a” or “an” usually means “at least one”.
- EPA-E is used as the EPA alkyl ester, but the present invention is not limited to this, and other EPA alkyl esters such as EPA-M may be used.
- Example 1 Preparation method> Fish oil ethyl ester prepared in a conventional manner (16% by area or more of EPA in fatty acid, acid value of 0.8 or less, POV of 30 or less), using a multistage distillation apparatus, the degree of vacuum of all towers is 0.2 Torr or less, and the temperature is 190 ° C. or less. Continuous precision distillation was carried out under the conditions described above to fractionate into the first fraction, main fraction and residue. The obtained main fraction was purified by high performance liquid column chromatography (HPLC) in which the column was packed with octadecylated silica gel of a reverse phase distribution system to obtain purified EPA-E.
- HPLC high performance liquid column chromatography
- GC-FID measurement condition GC: 6890N (Agilent Technologies)
- Carrier gas Helium, 0.5 mL / min (adjusted so that EPA-E elutes in about 30 minutes)
- Makeup gas nitrogen 40mL / min.
- isomers A to D using isomer samples produced by forced heating, confirmation of isomer composition by GC-FID, identification of double bond quantity by GC-MS of each peak, and NMR analysis of each peak was performed.
- isomers A to D are EPA-E isomers in which only one of the five double bonds of EPA-E is in the trans form at positions 14, 17, 5, and 11. It was confirmed. Since the peaks of isomer D and isomer E overlapped and could not be separated, the amount of isomer D was expressed as the total amount with isomer E.
- the vacuum degree of the entire column is set to 0.2 Torr or less and the temperature is set to 190 ° C. or less, whereby ethyl arachidonic acid, C20: 0 ethyl ester, C20: 4n-3 ethyl ester, C20: 5n-3 (5 , 9, 11, 14, 17) ethyl ester, C18: 3n-3 ethyl ester, C18: 4n-3 ethyl ester, C19: 0 ethyl ester, C19: 5n-3 ethyl ester, C21: 5n-3 ethyl ester, Impurities that were difficult to separate such as C22: 6n-3 ethyl ester were reduced, and at the same time, the trans isomer of EPA-E could be reduced. Moreover, in the obtained composition, MUFA ethyl ester and DHA ethyl ester were each 0.05 area% or
- ethyl eicosapentaenoate is contained in an amount of 96 to 99 area%, the content of ethyl arachidonic acid is 0.7 area% or less, and monoethyl eicosapentaenoate
- An eicosapentaenoic acid alkyl ester-containing composition having a trans isomer content of 2.5 area% or less was obtained.
- compositions containing an eicosapentaenoic acid alkyl ester, such as ethyl eicosapentaenoate, with a further reduced impurity content can be produced.
- the composition according to an embodiment of the present invention can be manufactured even on an industrial scale, and is advantageous in that it can be used as a raw material for health foods, pharmaceuticals, and the like that require mass production while having safety. It is.
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Abstract
Description
[1] ガスクロマトグラフィーにより測定した場合に、エイコサペンタエン酸アルキルエステルを96~99面積%含有し、アラキドン酸アルキルエステルの含有量が0.7面積%以下であり、エイコサペンタエン酸アルキルエステルのモノトランス体の含有量が2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下であるエイコサペンタエン酸アルキルエステル含有組成物。
[2] エイコサペンタエン酸アルキルエステルのモノトランス体及びジトランス体の含有量の合計が2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下である[1]の組成物。
[3] エイコサペンタエン酸アルキルエステルのモノトランス体、ジトランス体及びトリトランス体の含有量の合計が2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下である[1]の組成物。
[4] エイコサペンタエン酸アルキルエステルのモノトランス体、ジトランス体、トリトランス体及びテトラトランス体の含有量の合計が2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下である[1]の組成物。
[5] エイコサペンタエン酸アルキルエステルの5位、14位、及び17位の二重結合のうちのいずれか一つがトランス型である、モノトランス体の含有量がそれぞれ0.5面積%以下、0.4面積%以下、0.3面積%以下、0.2面積%以下、又は0.1面積%以下である[1]~[4]いずれか1の組成物。
[6] エイコサペンタエン酸アルキルエステルの11位の二重結合がトランス型である、モノトランス体の含有量が1.0面積%以下、0.9面積%以下、0.8面積%以下、0.6面積%以下、0.4面積%以下、0.2面積%以下、又は0.1面積%以下である[1]~[5]いずれか1の組成物。
[7] ガスクロマトグラフィーを用いて下記分析条件により測定した場合に、エイコサペンタエン酸エチルを96~99面積%含有し、アラキドン酸エチルの含有量が0.7面積%以下であり、エイコサペンタエン酸エチルの平均保持時間を1としたときの相対保持時間が約0.955、1.027、1.062又は1.077のピークとして現れる物質の含有量の合計量が2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下である組成物。
[ガスクロマトグラフィー分析条件:GC-FID測定条件]
GC: 6890N (Agilent Technologies)
カラム: DB-WAX (Agilent Technologies)
30 m x 0.25 mm ID, 0.25 μm film thickness
キャリアガス: ヘリウム, 0.5 mL/min
注入口: 300 oC, 1 μL, Split (1:100)
カラム温度:200℃恒温
検出器: FID, 300 oC
メークアップガス:窒素 40mL/min.
[8] アラキドン酸アルキルエステルの含有量が0.1面積%以下又は0.05面積%以下である[1]~[7]いずれか1の組成物。
[9] エイコサテトラエン酸アルキルエステルの含有量が、0.7面積%以下、0.5面積%以下、0.4面積%以下、0.3面積%以下、0.2面積%以下、又は0.1面積%以下である[1]~[8]いずれか1の組成物。
[10] オクタデカテトラエン酸アルキルエステルの含有量が、0.4面積%以下、0.3面積%以下、0.2面積%以下、又は0.1面積%以下である[1]~[9]いずれか1の組成物。
[11] ノナデカペンタエン酸アルキルエステルの含有量が、0.2面積%以下、0.15面積%以下、0.1面積%以下、0.05面積%以下、0.049面積%以下、又は0.02面積%以下である[1]~[10]いずれか1の組成物。
[12] エイコサペンタエン酸アルキルエステルが、エイコサペンタエン酸エチル又はエイコサペンタエン酸メチルである[1]~[11]いずれか1の組成物。
[13] n-ノナデカン酸(C19:0)アルキルエステルの含有量が0.1面積%以下、0.07面積%以下、0.05面積%以下、又は0.02面積%以下である、[1]~[12]いずれか1の組成物。
[14] アラキジン酸(C20:0)アルキルエステルの含有量が0.2面積%以下、0.15面積%以下、0.1面積%以下、0.05面積%以下、又は0.02面積%以下である、[1]~[13]いずれか1の組成物。
[15] 飽和脂肪酸のアルキルエステルの含有量が0.5面積%以下、0.3面積%以下、又は0.1面積%以下である[1]~[14]いずれか1の組成物。
[16] イコサ- 5,9,11,14,17-ペンタエン酸(C20:5n-3(5,9,11,14,17))アルキルエステルの含有量が0.2面積%以下、0.15面積%以下、0.1面積%以下、0.07面積%以下、0.05面積%以下、又は0.02面積%以下である、[1]~[15]いずれか1の組成物。
[17] ヘンイコサペンタエン酸アルキルエステルの含有量が、0.2面積%以下、0.15面積%以下、0.1面積%以下、0.05面積%以下、0.03面積%以下、又は0.02面積%以下である[1]~[16]いずれか1の組成物。
[18] エイコサペンタエン酸アルキルエステルの含有量が、96~98面積%である、[1]~[17]いずれか1の組成物。
[19] ジホモ-γ-リノレン酸アルキルエステルの含有量が、0.05面積%以下である、[1]~[18]いずれか1の組成物。
[20] 炭素数20以上の一価不飽和脂肪酸のアルキルエステルの含有量が、0.05面積%以下である、[1]~[19]いずれか1の組成物。
[21] [1]~[20]いずれか1のエイコサペンタエン酸アルキルエステル含有組成物を有効成分として含有する、医薬組成物。
[22] 更に、医薬的に許容可能な添加成分を含む[21]の医薬組成物。
[23] 動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患の治療又は予防剤である[21]又は[22]の医薬組成物。
[24] エイコサペンタエン酸を含有する原料油をエチルエステル化したのち、蒸留及びクロマトグラフィーを行うことによって、高濃度エイコサペンタエン酸エチルを製造する方法において、蒸留を、0.2 Torr以下の真空度及び全塔190℃以下の温度での精密蒸留を行うことにより行い、アラキドン酸エチルを低減させ、かつ、熱によるトランス体の生成を抑える、高濃度エイコサペンタエン酸エチルの製造方法。
[25] エイコサペンタエン酸を含有する原料油をアルキルエステル化することにより得られたエイコサペンタエン酸アルキルエステルを含有する組成物に対して、0.2 Torr以下の真空度、及び、全塔190℃以下の温度で、精密蒸留を行うこと、精密蒸留後の組成物に対してクロマトグラフィーを用いた濃縮処理を行うこと、を含む高濃度エイコサペンタエン酸アルキルエステル含有組成物の製造方法。
[26] アルキルエステル化が、炭素数1又は炭素数2の低級アルコールを用いて行われる[25]の方法。
[27] 精密蒸留及びクロマトグラフィーの実施により、[1]~[20]いずれか1のエイコサペンタエン酸アルキルエステル含有組成物が得られ得る[24]~[26]いずれか1の方法。
[28] 精密蒸留が、2塔以上の蒸留塔を用いた連続精密蒸留である[24]~[27]いずれか1の方法。
[29] クロマトグラフィーが、逆相クロマトグラフィーである[24]~[28]いずれか1の方法。
[30] 原料油が、水産物原料由来の油脂である[24]~[29]いずれか1の方法。
[31] [1]~[20]いずれか1のエイコサペンタエン酸アルキルエステル含有組成物の、食品の製造における使用。
[32] [1]~[20]いずれか1のエイコサペンタエン酸アルキルエステル含有組成物の、医薬組成物の製造における使用。
[33] 医薬組成物が、動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患の治療又は予防剤である[32]の使用。
[34] [1]~[20]いずれか1のエイコサペンタエン酸アルキルエステル含有組成物の、動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患の治療又は予防剤の有効成分としての使用。
[35] [21]~[23]いずれか1の医薬組成物を、動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患に罹患している又は罹患する危険性のある対象者に投与することを含む、疾患の予防、治療又は寛解方法。
(1)ガスクロマトグラフィーにより測定した場合に、エイコサペンタエン酸エチルを96~99面積%含有し、アラキドン酸エチルの含有量が0.7面積%以下であり、エイコサペンタエン酸エチルのモノトランス体の含有量が2.5面積%以下である組成物。
(2)エイコサペンタエン酸エチルのモノトランス体及びジトランス体の含有量の合計が2.5面積%以下である(1)の組成物。
(3)エイコサペンタエン酸エチルのモノトランス体、ジトランス体及びトリトランス体の含有量の合計が2.5面積%以下である(1)の組成物。
(4)エイコサペンタエン酸エチルのモノトランス体、ジトランス体、トリトランス体及びテトラトランス体の含有量の合計が2.5面積%以下である(1)の組成物。
(5)エイコサペンタエン酸エチルの5位、14位、17位の二重結合のうちのいずれか一つがトランス型である、モノトランス体の含有量がそれぞれ0.5面積%以下である(1)ないし(4)いずれかの組成物。
(6)エイコサペンタエン酸エチルの11位の二重結合がトランス型である、モノトランス体の含有量が1.0面積%以下である(1)ないし(5)いずれかの組成物。
(7)ガスクロマトグラフィーを用いて下記分析条件により測定した場合に、エイコサペンタエン酸エチルを96~99面積%含有し、アラキドン酸エチルの含有量が0.7面積%以下であり、エイコサペンタエン酸エチルの平均保持時間を1としたときの相対保持時間が約0.955、1.027、1.062又は1.077のピークとして現れる物質の含有量の合計量が2.5面積%以下である組成物。
[ガスクロマトグラフィー分析条件:GC-FID測定条件]
GC: 6890N (Agilent Technologies)
カラム: DB-WAX (Agilent Technologies)
30 m x 0.25 mm ID, 0.25 μm film thickness
キャリアガス: ヘリウム, 0.5 mL/min
注入口: 300℃, 1 μL, Split (1:100)
カラム温度:200℃恒温
検出器: FID, 300℃
メークアップガス:窒素40mL/min.
(8)n-ノナデカン酸(C19:0)エチルエステルの含有量が0.1面積%以下である、(1)ないし(7)いずれかの組成物。
(9)アラキジン酸(C20:0)エチルエステルの含有量が0.2面積%以下である、(1)ないし(8)いずれかの組成物。
(10)飽和脂肪酸のエチルエステルの含有量が0.5面積%以下である(1)ないし(9)いずれかの組成物。
(11)イコサ- 5,9,11,14,17-ペンタエン酸(C20:5n-3(5,9,11,14,17))エチルエステルの含有量が0.2面積%以下である、(1)ないし(10)いずれかの組成物。
(12)エイコサペンタエン酸エチルの含有量が、96~98面積%である、(1)ないし(11)いずれかの組成物。
(13)(1)ないし(12)いずれかの組成物を有効成分として含有する、医薬組成物。
(14)エイコサペンタエン酸含有する原料油をエチルエステル化したのち、蒸留工程及びクロマトグラフィー工程によって、エイコサペンタエン酸エチルを精製する方法おいて、蒸留工程を、真空度0.2Torr以下、全塔190℃以下の温度で精密蒸留を行うことにより行い、アラキドン酸エチルを低減させ、かつ、熱によるトランス体の生成を抑えることを特徴とする高濃度エイコサペンタエン酸エチルの製造方法。
(15)精密蒸留が、2塔以上の蒸留塔を用いた連続精密蒸留である(14)の方法。
(16)クロマトグラフィー工程が、逆相クロマトグラフィー工程である(14)又は(15)の方法。
(17)エイコサペンタエン酸エチルを96面積%以上、96~99面積%、または96~98面積%、及びアラキドン酸エチルを0.7面積%以下、0.5面積%以下、0.4面積%以下、0.3面積%以下、0.2面積%以下、または0.1面積%以下含有する組成物。
(18)ガスクロマトグラフィーにより上記分析条件により測定した場合のエイコサペンタエン酸エチルの平均保持時間を1としたときの相対保持時間が約0.955、1.027、又は1.062のピークとして現れる物質のそれぞれの含有量が0.5面積%以下、0.4面積%以下、0.3面積%以下、0.2面積%以下、または0.1面積%以下である(17)の組成物。
(19)ガスクロマトグラフィーにより上記分析条件により測定した場合のエイコサペンタエン酸エチルの平均保持時間を1としたときの相対保持時間が約1.077のピークとして現れる物質の含有量が1.0面積%以下、0.8面積%以下、0.6面積%以下、0.4面積%以下、0.3面積%以下、0.2面積%以下、または0.1面積%以下である(17)又は(18)の組成物。
(20)α-リノレン酸(C18:3n-3)エチルエステルの含有量が0.2面積%以下である(17)ないし(19)いずれかの組成物。
(21)エイコサペンタエン酸エチルを96~99面積%含有し、アラキドン酸エチルの含有量が0.2面積%以下、エイコサペンタエン酸エチルのモノトランス体、ジトランス体、トリトランス体及びテトラトランス体の含有量の合計が2.5面積%以下である組成物。
(22)さらに飽和脂肪酸のエチルエステルの含有量が0.5面積%以下である(21)の組成物。
(23)さらにイコサ- 5,9,11,14,17-ペンタエン酸(C20:5n-3(5,9,11,14,17))エチルエステルの含有量が0.2面積%以下である(21)又は(22)の組成物。
組成
本発明の一実施形態における組成物は、下記の含有量のエイコサペンタエン酸エチル(EPA-E)のようなエイコサペンタエン酸アルキルエステル(以下、EPAアルキルエステルと称する。)を含有し、下記の含有量の1種又は2種以上の後述するその他の成分、即ち、不純物を含有し得る。
GC: 6890N (Agilent Technologies)
カラム:DB-WAX (Agilent Technologies)
30 m x 0.25 mm ID, 0.25 μm film thickness
キャリアガス:ヘリウム, 0.5 mL/min
注入口:300 oC, 1 μL, Split (1:100)
カラム温度:200℃恒温
検出器:FID, 300 oC
メークアップガス:窒素 40mL/min.
(1) ガスクロマトグラフィーにより測定した場合に、EPAアルキルエステル例えばEPA-Eを96~99面積%含有し、アラキドン酸アルキル例えばアラキドン酸エチルの含有量が0.1面積%以下、又は0.05面積%以下であり、エイコサペンタエン酸アルキルエステル例えばEPA-Eのモノトランス体の含有量が2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下であるエイコサペンタエン酸アルキルエステル含有組成物。
(2) ガスクロマトグラフィーにより測定した場合に、EPAアルキルエステル例えばEPA-Eを96~99面積%含有し、アラキドン酸アルキル例えばアラキドン酸エチルの含有量が0.7面積%以下であり、エイコサペンタエン酸アルキルエステル例えばEPA-Eのモノトランス体の含有量が、1.417面積%以上、且つ2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下であるエイコサペンタエン酸アルキルエステル含有組成物。
(3) ガスクロマトグラフィーを用いて下記分析条件により測定した場合に、EPA-Eを96~99面積%含有し、アラキドン酸エチルの含有量が0.1面積%以下、又は0.05面積%以下であり、EPA-Eの平均保持時間を1としたときの相対保持時間が約0.955、1.027、1.062又は1.077のピークとして現れる物質の含有量の合計量が2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下であるエイコサペンタエン酸アルキルエステル含有組成物。
[ガスクロマトグラフィー分析条件:GC-FID測定条件]
GC: 6890N (Agilent Technologies)
カラム: DB-WAX (Agilent Technologies)
30 m x 0.25 mm ID, 0.25 μm film thickness
キャリアガス: ヘリウム, 0.5 mL/min
注入口: 300 oC, 1 μL, Split (1:100)
カラム温度:200℃恒温
検出器: FID, 300 oC
メークアップガス:窒素 40mL/min.
(4) ガスクロマトグラフィーを用いて下記分析条件により測定した場合に、EPA-Eを96~99面積%含有し、アラキドン酸エチルの含有量が0.7面積%以下であり、EPA-Eの平均保持時間を1としたときの相対保持時間が約0.955、1.027、1.062又は1.077のピークとして現れる物質の含有量の合計量が、1.417面積%以上、且つ2.5面積%以下、2.3面積%以下、2.0面積%以下、1.8面積%以下、又は1.5面積%以下であるエイコサペンタエン酸アルキルエステル含有組成物。
[ガスクロマトグラフィー分析条件:GC-FID測定条件]
GC: 6890N (Agilent Technologies)
カラム: DB-WAX (Agilent Technologies)
30 m x 0.25 mm ID, 0.25 μm film thickness
キャリアガス: ヘリウム, 0.5 mL/min
注入口: 300 oC, 1 μL, Split (1:100)
カラム温度:200℃恒温
検出器: FID, 300 oC
メークアップガス:窒素 40mL/min.
(5) 上記(1)の組成物において、エイコサペンタエン酸アルキルエステル例えばEPA-Eのモノトランス体の含有量が、1.417面積%以上である組成物。
(6) 上記(3)の組成物において、EPA-Eの平均保持時間を1としたときの相対保持時間が約0.955、1.027、1.062又は1.077のピークとして現れる物質の含有量の合計量が、1.417面積%以上である組成物。
(7) 上記(2)の組成物において、アラキドン酸エチルの含有量が0.1面積%以下、又は0.05面積%以下である組成物。
(8) 上記(4)の組成物において、アラキドン酸エチルの含有量が0.1面積%以下、又は0.05面積%以下の組成物。
0.7面積%以下、0.5面積%以下、0.4面積%以下、0.3面積%以下、0.2面積%以下、又は0.1面積%以下のエイコサテトラエン酸アルキルエステル、例えばエイコサテトラエン酸エチル;
0.4面積%以下、0.3面積%以下、0.2面積%以下、又は0.1面積%以下のオクタデカテトラエン酸アルキルエステル、例えばオクタデカテトラエン酸エチル;
0.2面積%以下、0.15面積%以下、0.1面積%以下、0.05面積%以下、0.049面積%以下、又は0.02面積%以下のノナデカペンタエン酸アルキルエステル、例えばノナデカペンタエン酸エチル;
0.1面積%以下、0.07面積%以下、0.05面積%以下、又は0.02面積%以下のn-ノナデカン酸(C19:0)アルキルエステル、例えばn-ノナデカン酸エチル;
0.2面積%以下、0.15面積%以下、0.1面積%以下、0.05面積%以下、又は0.02面積%以下のアラキジン酸(C20:0)アルキルエステル、例えばアラキジン酸エチル;
0.5面積%以下、0.3面積%以下、又は0.1面積%以下の飽和脂肪酸のアルキルエステル、例えば飽和脂肪酸エチル;
0.2面積%以下、0.15面積%以下、0.1面積%以下、0.07面積%以下、0.05面積%以下、又は0.02面積%以下のイコサ- 5,9,11,14,17-ペンタエン酸(C20:5n-3(5,9,11,14,17))アルキルエステル、例えばイコサ- 5,9,11,14,17-ペンタエン酸(C20:5n-3(5,9,11,14,17))エチル;
0.2面積%以下、0.15面積%以下、0.1面積%以下、0.05面積%以下、0.03面積%以下、又は0.02面積%以下のヘンイコサペンタエン酸アルキルエステル、例えばヘンイコサペンタエン酸エチル;
0.1面積%以下、0.05面積%以下、又は0.03面積%以下のドコサヘキサエン酸アルキルエステル、例えばドコサヘキサエン酸エチル;
0.2面積%以下、0.15面積%以下、0.1面積%以下、0.05面積%以下、又は0.02面積%以下のα-リノレン酸アルキルエステル、例えばα-リノレン酸エチル。
本発明の一実施形態は、エイコサペンタエン酸を含有する原料油をアルキルエステル化することにより得られたエイコサペンタエン酸アルキルエステルを含有する組成物に対して、0.2Torr以下の真空度、及び、全塔190℃以下の温度で、精密蒸留を行うこと、精密蒸留後の組成物に対してクロマトグラフィーを用いた濃縮処理を行うこと、を含み、必要に応じて他の工程を含む高濃度エイコサペンタエン酸アルキルエステル含有組成物の製造方法を含む。
アルキルエステル化で用いられる原料油は、粗油であってもよく、精製油であってもよい。粗油は、水産物原料から得られる油脂であっても、微生物原料から得られる油脂であってもよい。例えば、水産物原料から粗油を得る方法はいかなる方法でも構わないが、魚油の例では、通常、以下のような方法で採取される。魚全体又は水産加工から発生する魚の頭、皮、中骨、内臓等の加工残滓を粉砕して蒸煮した後、圧搾して煮汁(スティックウォーター)と圧搾ミールに分離する。煮汁とともに得られる油脂を煮汁から遠心分離により分離し、魚油粗油とする。
原料油である油脂を、低級アルコールを用いたアルコール分解により、低級アルコールエステルに分解する。低級アルコールとしては、脂肪酸のアルキルエステル化に一般的に用いられるもの、例えば、炭素数1又は炭素数2の低級アルコールが挙げられる。アルコール分解は油脂に、低級アルコール例えばエタノールと触媒又は酵素を加え反応させ、グリセリンに結合した脂肪酸からエチルエステルを生成させるものである。触媒としては、アルカリ触媒、酸触媒などを用いる。酵素としてはリパーゼが用いられる。
本発明の一実施形態における組成物の製造は、蒸留工程及び高速液体カラムクロマトグラフィー(HPLC)のようなクロマトグラフィーを用いたクロマトグラフィー工程による精製工程を含む。ここで、例えばEPA-Eとアラキドン酸エチルでは同様な分子構造を有するが、分子量がわずかに異なることから沸点の差(EPA-E;417℃/760mmHg、アラキドン酸エチル;418.1℃/760mmHg)を利用して精度を上げた蒸留で分離可能とも考えられる。この観点から分離度を上げるには段数の増加及び/又は、還流量を増やす必要があると考えられる。しかしながら、段数の増加は圧力抵抗の増加をもたらし蒸留温度を上げざるを得ない。同様に還流量の増加も蒸留温度を上げることになる。一方、EPAは熱により異性化することが知られている(European Journal of Lipid Science and Technology, 108 (2006) 589-597;JAOCS, 66 (1989) 1822-1830)。このことから、蒸留の精度を上げるためのさらなる加熱は異性化を引き起こし、異性体が増加してしまう。このように、EPA-Eの異性体を生成させず、あるいは生成量を少なく保ちながら、EPA-EのようなEPAアルキルエステルとアラキドン酸エチルのようなアラキドン酸アルキルエステルとを工業的に、すなわち歩留まりと純度を両立させて、分離することは極めて難しかった。
本発明の一実施形態における組成物の利用形態は、特に限定されないが、経口剤型であることが好ましく、典型的には、顆粒剤、錠剤、カプセル剤、液剤等の経口用製剤の形態とすることができる。本発明の組成物の用途には、例えば、飲食品(健康食品、栄養補助食品、特定保健用食品、サプリメント、乳製品、清涼飲料、ペット用飲食品、家畜飼料など)、医薬品、医薬部外品などが含まれ、特に、サプリメント、及び医薬品であることが好ましい。食品素材又は食品の他に、動物用の飼料用の添加成分として使用してもよい。従って、本発明の一形態における組成物は、これらの飲食品、医薬品、医薬部外品の素材又は有効成分として使用されることができ、これらの製造において、好ましく使用され得る。
本発明の別の実施形態は、上記組成物を有効成分として含有する医薬組成物を含む。医薬組成物中の上記組成物の含有量は、特に限定されないが、好ましくは25重量%以上、より好ましくは50重量%以上、更に好ましくは70重量%以上、より更に好ましくは85重量%以上、特に好ましくは96重量%以上、とりわけ好ましくは98重量%以上である。
<調製方法>
常法により調製した魚油エチルエステル(脂肪酸中EPA16面積%以上、酸価0.8以下、POV30以下)を、多段式蒸留装置を用いて、全塔の真空度0.2Torr以下、温度190℃以下の条件にて連続精密蒸留を行い、初留、主留、残留に分画した。得られた主留をカラムに逆相分配系のオクタデシル化シリカゲルを充填した高速液体カラムクロマトグラフィー(HPLC)にて精製し、精製EPA-Eを得た。
異なる原料を用いて精製EPA-Eを11ロット製造し、ガスクロマトグラフィー(GC)を用いて脂肪酸組成を分析した。各脂肪酸エチルエステルのピークの平均保持時間、相対保持時間、含有量の平均値、最高値、最低値(面積%)を表1に示した。表1の相対保持時間は、EPA-Eの平均保持時間を1とした場合のそれぞれのピークの平均保持時間である。
GC-FID測定条件
GC: 6890N (Agilent Technologies)
カラム: DB-WAX (Agilent Technologies)
30 m x 0.25 mm ID, 0.25 μm film thickness
キャリアガス:ヘリウム, 0.5 mL/min(EPA-Eが約30分で溶出するように調節する)
注入口:300 oC, 1 μL, Split (1:100)
カラム温度:200℃恒温
検出器:FID, 300 oC
メークアップガス:窒素 40mL/min.
精密蒸留において、全塔の真空度を0.2Torr以下、温度を190℃以下にすることによって、アラキドン酸エチル、C20:0エチルエステル、C20:4n-3エチルエステル、C20:5n-3(5,9,11,14,17)エチルエステル、C18:3n-3エチルエステル、C18:4n-3エチルエステル、C19:0エチルエステル、C19:5n-3エチルエステル、C21:5n-3エチルエステル、C22:6n-3エチルエステルなどの分離しにくい不純物を低減すると同時に、EPA-Eのトランス異性体も低減できた。また得られた組成物では、MUFAエチルエステル及びDHAエチルエステルはそれぞれ、0.05面積%以下であった。
Claims (35)
- ガスクロマトグラフィーにより測定した場合に、エイコサペンタエン酸アルキルエステルを96~99面積%含有し、アラキドン酸アルキルエステルの含有量が0.7面積%以下であり、エイコサペンタエン酸アルキルエステルのモノトランス体の含有量が2.5面積%以下であるエイコサペンタエン酸アルキルエステル含有組成物。
- エイコサペンタエン酸アルキルエステルのモノトランス体及びジトランス体の含有量の合計が2.5面積%以下である請求項1の組成物。
- エイコサペンタエン酸アルキルエステルのモノトランス体、ジトランス体及びトリトランス体の含有量の合計が2.5面積%以下である請求項1の組成物。
- エイコサペンタエン酸アルキルエステルのモノトランス体、ジトランス体、トリトランス体及びテトラトランス体の含有量の合計が2.5面積%以下である請求項1の組成物。
- エイコサペンタエン酸アルキルエステルの5位、14位、及び17位二重結合のうちのいずれか一つがトランス型である、モノトランス体の含有量がそれぞれ0.5面積%以下である請求項1~請求項4いずれか1項の組成物。
- エイコサペンタエン酸アルキルエステルの11位の二重結合がトランス型である、モノトランス体の含有量が1.0面積%以下である請求項1~請求項5いずれか1項の組成物。
- ガスクロマトグラフィーを用いて下記分析条件により測定した場合に、エイコサペンタエン酸エチルを96~99面積%含有し、アラキドン酸エチルの含有量が0.7面積%以下であり、エイコサペンタエン酸エチルの平均保持時間を1としたときの相対保持時間が約0.955、1.027、1.062又は1.077のピークとして現れる物質の含有量の合計量が2.5面積%以下である組成物。
[ガスクロマトグラフィー分析条件:GC-FID測定条件]
GC: 6890N (Agilent Technologies)
カラム: DB-WAX (Agilent Technologies)
30 m x 0.25 mm ID, 0.25 μm film thickness
キャリアガス: ヘリウム, 0.5 mL/min
注入口: 300 oC, 1 μL, Split (1:100)
カラム温度:200℃恒温
検出器: FID, 300 oC
メークアップガス:窒素 40mL/min. - アラキドン酸アルキルエステルの含有量が0.1面積%以下である請求項1~請求項7いずれか1項の組成物。
- エイコサテトラエン酸アルキルエステルの含有量が、0.7面積%以下である請求項1~請求項8いずれか1項の組成物。
- オクタデカテトラエン酸アルキルエステルの含有量が、0.4面積%以下である請求項1~請求項9いずれか1項の組成物。
- ノナデカペンタエン酸アルキルエステルの含有量が、0.2面積%以下である請求項1~請求項10いずれか1項の組成物。
- エイコサペンタエン酸アルキルエステルが、エイコサペンタエン酸エチル又はエイコサペンタエン酸メチルである請求項1~請求項11いずれか1項の組成物。
- n-ノナデカン酸(C19:0)アルキルエステルの含有量が0.1面積%以下である、請求項1~請求項12いずれか1項の組成物。
- アラキジン酸(C20:0)アルキルエステルの含有量が0.2面積%以下である、請求項1~請求項13いずれか1項の組成物。
- 飽和脂肪酸のアルキルエステルの含有量が0.5面積%以下である請求項1~請求項14いずれか1項の組成物。
- イコサ- 5,9,11,14,17-ペンタエン酸(C20:5n-3(5,9,11,14,17))アルキルエステルの含有量が0.2面積%以下である、請求項1~請求項15いずれか1項の組成物。
- ヘンイコサペンタエン酸アルキルエステルの含有量が、0.2面積%以下である請求項1~請求項16いずれか1項の組成物。
- エイコサペンタエン酸アルキルエステルの含有量が、96~98面積%である、請求項1~請求項17いずれか1項の組成物。
- ジホモ-γ-リノレン酸アルキルエステルの含有量が、0.05面積%以下である、請求項1~請求項18いずれか1項の組成物。
- 炭素数20以上の一価不飽和脂肪酸のアルキルエステルの含有量が、0.05面積%以下である、請求項1~請求項19いずれか1項の組成物。
- 請求項1~請求項20いずれか1項のエイコサペンタエン酸アルキルエステル含有組成物を有効成分として含有する、医薬組成物。
- 更に、医薬的に許容可能な添加成分を含む請求項21の医薬組成物。
- 動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患の治療又は予防剤である請求項21又は請求項22の医薬組成物。
- エイコサペンタエン酸を含有する原料油をエチルエステル化したのち、蒸留及びクロマトグラフィーを行うことによって、高濃度エイコサペンタエン酸エチルを製造する方法において、蒸留を、0.2 Torr以下の真空度及び全塔190℃以下の温度での精密蒸留を行うことにより行い、アラキドン酸エチルを低減させ、かつ、熱によるトランス体の生成を抑える、高濃度エイコサペンタエン酸エチルの製造方法。
- エイコサペンタエン酸を含有する原料油をアルキルエステル化することにより得られたエイコサペンタエン酸アルキルエステルを含有する組成物に対して、0.2 Torr以下の真空度、及び、全塔190℃以下の温度で、精密蒸留を行うこと、
精密蒸留後の組成物に対して、クロマトグラフィーを用いた濃縮処理を行うこと、
を含む高濃度エイコサペンタエン酸アルキルエステル含有組成物の製造方法。 - アルキルエステル化が、炭素数1又は炭素数2の低級アルコールを用いて行われる請求項25の方法。
- 精密蒸留及びクロマトグラフィーの実施により、請求項1~請求項20いずれか1項のエイコサペンタエン酸アルキルエステル含有組成物が得られる請求項24~請求項26いずれか1項の方法。
- 精密蒸留が、2塔以上の蒸留塔を用いた連続精密蒸留である請求項24~請求項27いずれか1項の方法。
- クロマトグラフィーが、逆相クロマトグラフィーである請求項24~請求項28いずれか1項の方法。
- 原料油が、水産物原料由来の油脂である請求項24~請求項29いずれか1項の方法。
- 請求項1~請求項20いずれか1項のエイコサペンタエン酸アルキルエステル含有組成物の、食品の製造における使用。
- 請求項1~請求項20いずれか1項のエイコサペンタエン酸アルキルエステル含有組成物の、医薬組成物の製造における使用。
- 医薬組成物が、動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患の治療又は予防剤である請求項32の使用。
- 請求項1~請求項20いずれか1項のエイコサペンタエン酸アルキルエステル含有組成物の、動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患の治療又は予防剤の有効成分としての使用。
- 請求項21~請求項23いずれか1項の医薬組成物を、動脈硬化、脳梗塞、心筋梗塞、血栓症、生活習慣病、アレルギー、炎症性疾患、及びがんからなる群より選択される少なくとも1つの疾患に罹患している又は罹患する危険性のある対象者に投与することを含む、疾患の予防、治療又は寛解方法。
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JP6953504B2 (ja) | 2021-10-27 |
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