Self-emulsifying composition of omega-3 fatty acids

Abstract

To provide a self-emulsifying composition that is excellent in self-emulsifying property, composition dispersibility, emulsion stability, and absorbability, is free from ethanol and polyhydric alcohols or only has such an alcohol added thereto at a reduced concentration, and is useful for foods and pharmaceuticals.SOLUTION: A self-emulsifying composition contains: 70 to 90% by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters; 0.5 to 6% by mass of water; 1 to 29% by mass of a polyoxyethylene sorbitan fatty acid ester as an emulsifier (optionally including a polyoxyl castor oil, and not including lecithin) in relation to 100 mass% of the total mass of the self-emulsifying composition; and lecithin in an amount of 3 to 40 parts by mass in relation to 100 parts by mass of ω3 polyunsaturated fatty acids and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention provides a self-emulsifying composition containing at least one selected from the group consisting of ω3 polyunsaturated fatty acids and pharma- ceutically acceptable salts and esters thereof, a pharmaceutical composition thereof, and a method for producing the same. [Background technology]

[0002] Known ω3 polyunsaturated fatty acids (hereinafter referred to as ω3PUFA) include α-linolenic acid, eicosapentaenoic acid (hereinafter referred to as EPA), docosahexaenoic acid (hereinafter referred to as DHA), etc. ω3PUFA and its pharma- ceutical acceptable salts and esters exhibit a variety of effects, such as anti-atherosclerotic effect, platelet aggregation inhibitory effect, blood lipid lowering effect, anti-inflammatory effect, anti-cancer effect, and central nervous system effect, and are therefore incorporated into various foods and are commercially available as health foods or medicines.

[0003] EPA ethyl ester (hereinafter referred to as EPA-E) is commercially available in Japan as an oral treatment for ulcers, pain, and coldness associated with arteriosclerosis obliterans, and for hyperlipidemia (trade name Epadel, Mochida Pharmaceutical). When EPA-E is orally administered under fasting conditions, the increase in plasma EPA concentration is lower than when it is orally administered under fed conditions. This is thought to be because the absorption of EPA-E requires the secretion of bile acids and components from food as carriers, and therefore the method of use of Epadel is to orally administer it immediately after a meal (see Non-Patent Document 1). Due to recent changes in lifestyle, one of the challenges is how to administer the drug and ensure compliance for patients who do not eat meals such as breakfast, patients who can only eat small amounts of food, patients who can only consume liquid foods (milk, gruel, kudzu soup, eggs, soup, fruit juice, oral nutrients), patients with reduced intestinal absorption (elderly people, patients with intestinal diseases, patients after intestinal surgery, patients with terminal cancer, patients taking lipase inhibitors), and patients who are unable to eat meals due to cerebral infarction, etc.

[0004] In addition, attention has been drawn to the relationship between non-fasting hypertriglyceridemia, in which serum triglycerides (TG) show normal values ​​when fasting but show an abnormal increase after meals or in which this condition persists, and coronary artery disease, and there is a demand for omega-3 PUFA preparations that are rapidly absorbed even when administered before meals and that suppress the increase in serum TG after meals.

[0005] A self-emulsifying composition containing the active ingredients ω-3 PUFA and fenofibrate, ethanol, and a surfactant has been reported as a self-emulsifying formulation that does not contain water itself and easily disperses and self-emulsifies when it comes into contact with water (see Patent Document 1 and Non-Patent Document 4). These compositions contain ethanol to improve the solubility of fenofibrate, but when the ethanol evaporates, there is concern that the capsule may become deformed or contain air bubbles, the capsule may become deformed or crack, or the capsule contents may become cloudy or separate, which may cause quality changes. In addition, these formulations are difficult or impossible to take for patients with alcohol (ethanol) intolerance.

[0006] A self-emulsifying composition has been reported that contains ethanol or a polyhydric alcohol in addition to ω-3 PUFA and a surfactant, and that can generate dispersions with small or very small average particle size when in contact with water (Patent Document 2).

[0007] A self-emulsifying composition with a low ethanol content (Patent Document 3) has been reported which contains ω3 PUFA, an emulsifier with a hydrophilic lipophilic balance (hereinafter referred to as HLB) of 10 or more, lecithin, and a polyhydric alcohol such as propylene glycol or glycerin, and which has good self-emulsifying properties and oral absorbability and absorption rate in fasting states.

[0008] It has been reported that when the composition is encapsulated, co-solvents such as polyhydric alcohols migrate into the capsule shell, causing denaturation of the composition and deformation due to softening of the capsule (Patent Document 4).

[0009] Self-emulsifying compositions generally use a large amount of emulsifier and have a large liquid volume as a whole, which can cause problems such as inflammation of the digestive tract and a decrease in the amount of physiologically active ingredients dissolved in the oil solution contained in each capsule (Patent Document 5). Therefore, it is desirable that the emulsifier used in the composition is non-toxic or has little toxicity even when administered continuously, and that the amount used is small. In terms of ease of administration, the amount of ω-3 PUFA to be administered at one time is fixed, so if the amount of ingredients other than ω-3 PUFA in the self-emulsifying composition increases, the amount of drug to be administered at one time increases accordingly. Therefore, from the viewpoint of miniaturization of the formulation, it is desirable to use a small amount of emulsifiers and alcohols. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Special table number 2008-516890 [Patent Document 2] Special table number 2012-519728 [Patent Document 3] International Publication No. 2010 / 134614 Brochure [Patent Document 4] Patent Publication No. 2011-12003 [Patent Document 5] Patent Publication No. 2012-180337 [Non-patent literature]

[0011] [Non-Patent Document 1] Epader S Pharmaceutical Interview Form, Mochida Pharmaceutical, June 2012 [Non-Patent Document 2] "Guidelines for the Prevention of Atherosclerotic Diseases 2007 Edition" edited by the Japan Atherosclerosis Society, Kyowa Kikaku, April 25, 2007 [Non-Patent Document 3] Diabetes, Volume 57, Issue 9, 2382-2392, 2008 [Non-Patent Document 4] European Journal of Pharmaceutical Sciences, Vol. 33, 351-360, 2008 [Non-Patent Document 5] "Dictionary of Pharmaceutical Additives 2007" edited by the Japan Pharmaceutical Additives Association, Yakuji Nipposha, July 25, 2007) Summary of the Invention [Problem to be solved by the invention]

[0012] There is a need for formulations that contain reduced ethanol and polyhydric alcohols in self-emulsifying compositions. There is also a need for formulations that contain reduced amounts of emulsifiers in self-emulsifying compositions. There is also a demand for preparations that have a high content of ω-3 PUFA in a self-emulsifying composition. There is also a demand for a self-emulsifying composition that is excellent in terms of drug compliance. In addition, when the self-emulsifying composition is used as a pharmaceutical, it is expected that it will be stored in cold regions, etc., and therefore there is a demand for a self-emulsifying composition that has a good appearance and does not denature, such as becoming cloudy or separating, when stored in low or high temperature environments in addition to room temperature. There is also a need for a self-emulsifying composition that has a stable quality of composition. It would also be desirable to provide a formulation in which the composition is encapsulated. In addition, there is a demand for a preparation in which, when the composition is encapsulated, the capsule shell is prevented from softening and is not deformed. It is an object of the present invention to provide a self-emulsifying composition that improves at least one of these properties, and a preparation in which the composition is encapsulated. [Means for solving the problem]

[0013] In view of the above problems, the present inventors have conducted extensive research into alternative components to ethanol and polyhydric alcohols, and have found that a specified amount of water is useful for improving the compatibility of a self-emulsifying composition. Furthermore, it was found that the content in the composition need only be 0.5 to 6 mass%, which is lower than that of ethanol or polyhydric alcohols, and that the emulsifier content can be further reduced due to the effect of improving compatibility with this small amount of water, resulting in a self-emulsifying composition with a high content of ω-3 PUFA. The inventors have also found that such a composition provides a self-emulsifying composition that excels in at least one of the above-mentioned problems, and have completed the present invention. They also discovered that it was possible to reduce the amount of emulsifier, and completed the invention of a self-emulsifying composition with a high ω-3 PUFA content. The composition of the present invention is a composition that excels in at least one of the above-mentioned objects.

[0014] That is, a first aspect of the present invention is the following self-emulsifying composition. (1-1) When the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90% by mass of at least one compound selected from the group consisting of ω-3 PUFA, pharma- ceutically acceptable salts thereof, and esters thereof; b) 0.5 to 6 mass% water, c) 1 to 29% by mass of an emulsifier (excluding lecithin), preferably a polyoxyethylene sorbitan fatty acid ester; d) 3 to 40 parts by weight of lecithin per 100 parts by weight of ω-3 polyunsaturated fatty acids, their pharma- ceutical acceptable salts, and their esters; Contains e) A self-emulsifying composition, characterized in that ethanol and / or polyhydric alcohol is contained in an amount of 4 mass% or less of the total amount of the composition. (1-2) When the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90% by mass of at least one compound selected from the group consisting of ω-3 PUFA, a pharma- ceutically acceptable salt thereof, and an ester thereof; b) 0.5 to 6 mass% water, c) 1 to 29% by mass of an emulsifier which is a polyoxyethylene sorbitan fatty acid ester; d) 3 to 40 parts by mass of lecithin per 100 parts by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharma- ceutically acceptable salts thereof, and esters thereof; Contains e) ethanol is 4% by mass or less of the total amount of the composition; f) A self-emulsifying composition, characterized in that the polyhydric alcohol is contained in an amount of 4 mass% or less of the total amount of the composition. (1-3) Polyoxyethylene sorbitan fatty acid ester, The self-emulsifying composition according to (1-1) or (1-2), which is at least one selected from the group consisting of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan monoisostearate, polyoxyethylene (20) sorbitan monooleate, and polyoxyethylene (20) sorbitan trioleate. (1-4) A self-emulsifying composition according to any one of (1-1) to (1-3), wherein the emulsifier further comprises polyoxyethylene hydrogenated castor oil and / or polyoxyethylene castor oil. (1-5) A self-emulsifying composition according to any one of (1-1) to (1-4), wherein the emulsifier further contains polyoxyethylene castor oil.

[0015] (1-6) A self-emulsifying composition according to any one of (1-1) to (1-5), wherein the polyhydric alcohol is propylene glycol or glycerin. (1-7) The self-emulsifying composition according to any one of (1-1) to (1-6), which contains 0 to 4% by mass of a polyhydric alcohol in the composition. (1-8) A self-emulsifying composition according to any one of (1-1) to (1-6), which does not contain more than 4 mass % of polyhydric alcohol in the composition. (1-9) A self-emulsifying composition according to any one of (1-1) to (1-8), in which the polyhydric alcohol content in the composition is 1% by mass or less. (1-10) The self-emulsifying composition according to any one of (1-1) to (1-9), which contains 0 to 1% by mass of a polyhydric alcohol in the composition. (1-11) A self-emulsifying composition according to any one of (1-1) to (1-8), which does not contain more than 1% by mass of polyhydric alcohol in the composition. (1-12) A self-emulsifying composition according to any one of (1-1) to (1-11), which is substantially free of polyhydric alcohol. (1-13) The self-emulsifying composition according to any one of (1-1) to (1-12), wherein the ethanol content in the composition is 4% by mass or less. (1-14) The self-emulsifying composition according to any one of (1-1) to (1-12), which contains 0 to 4% by mass of ethanol in the composition. (1-15) The self-emulsifying composition according to any one of (1-1) to (1-12), wherein the composition does not contain more than 4% by mass of ethanol. (1-16) A self-emulsifying composition according to any one of (1-1) to (1-15), which is substantially free of ethanol.

[0016] (1-17) A self-emulsifying composition described in any of (1-1) to (1-16), wherein the ω-3 PUFA, its pharma- ceutically acceptable salt, and its ester are at least one selected from the group consisting of EPA, DHA, their pharma- ceutically acceptable salts, and their esters. (1-18) A self-emulsifying composition according to any one of (1-1) to (1-17), wherein the ester of ω3 PUFA is an ethyl ester or a triglyceride ester. (1-19) A self-emulsifying composition according to any one of (1-1) to (1-18), wherein the ω-3 PUFA, a pharma- ceutically acceptable salt thereof, or an ester thereof is EPA-E or DHA ethyl ester (hereinafter referred to as DHA-E). (1-20) A self-emulsifying composition according to any one of (1-1) to (1-19), containing as an active ingredient at least one selected from the group consisting of EPA, DHA, and pharma-ceutically acceptable salts and esters thereof. (1-21) A self-emulsifying composition according to any one of (1-1) to (1-20) containing EPA-E and / or DHA-E as an active ingredient. (1-22) A self-emulsifying composition according to any one of (1-1) to (1-21), containing EPA-E as an active ingredient.

[0017] (1-23) The self-emulsifying composition according to any one of (1-1) to (1-22), wherein the lecithin is at least one selected from the group consisting of soybean lecithin, enzymatically hydrolyzed soybean lecithin, hydrogenated soybean lecithin and egg yolk lecithin. (1-24) A self-emulsifying composition according to any one of (1-1) to (1-23), in which the content of at least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol is less than 5% by mass of the total amount of the composition.Further, a self-emulsifying composition according to any one of (1-1) to (1-23), in which the content of each of the emulsifiers, polyoxyethylene hydrogenated castor oil, polyoxyethylene glycol fatty acid ester, and polyoxyethylene polyoxypropylene glycol, is each less than 5% by mass of the total amount of the composition.

[0018] (1-25) A self-emulsifying composition according to any one of (1-1) to (1-24), characterized in that a) to d) are mixed in any order.

[0019] (1-26) A self-emulsifying composition according to any one of (1-1) to (1-25), wherein the composition has a clear appearance when allowed to stand. (1-27) A self-emulsifying composition according to any one of (1-1) to (1-25), which has an appearance that is neither separated nor cloudy when the composition is allowed to stand. (1-28) A self-emulsifying composition according to any one of (1-1) to (1-27), wherein the composition has a clear appearance when stored for 12 hours in an environment of 5°C or 40°C. (1-29) A self-emulsifying composition according to any one of (1-1) to (1-28), wherein the composition has no separation or turbidity when stored for 12 hours in an environment of 5°C or 40°C. (1-30) A self-emulsifying composition according to any one of (1-1) to (1-29), which has good at least one of self-emulsifying property, composition dispersibility, and emulsion stability. (1-31) A self-emulsifying composition according to any one of (1-1) to (1-30), which is naturally emulsified when 10 μL of the composition is dropped into 5 mL of purified water or Japanese Pharmacopoeia dissolution test first fluid at 37° C. (1-32) The self-emulsifying composition according to any one of (1-1) to (1-31), in which 10 μL of the composition is dropped into 5 mL of purified water or Japanese Pharmacopoeia dissolution test first fluid at 37° C. and the composition is dispersed by stirring. (1-33) A self-emulsifying composition according to any one of (1-1) to (1-32), in which no oil separation occurs when 10 μL of the composition is dropped into 5 mL of purified water at 37° C. or JP Pharmacopoeia first fluid for dissolution test.

[0020] (1-34) A self-emulsifying composition containing 600 mg of at least one compound selected from the group consisting of ω3 PUFA, its pharma- ceutically acceptable salts, and its esters is orally administered to male beagle dogs under fasting conditions for 18 hours or more, and the maximum ω3 PUFA blood concentration calculated by subtracting the blood ω3 concentration before administration is 50 μg / mL or more and / or the area under the ω3 PUFA blood concentration curve from 0 to 2 hours after administration is 30 μg / mL·hr or more, and the maximum ω3 PUFA blood concentration is 50 μg / mL or more. A self-emulsifying composition described in any of (1-1) to (1-33), wherein the area under the ω3PUFA blood concentration curve from 0 to 2 hours after administration is 50 μg / mL·hr or more, the maximum ω3PUFA blood concentration is 60 μg / mL or more and / or the area under the ω3PUFA blood concentration curve from 0 to 2 hours after administration is 60 μg / mL·hr or more, or the maximum ω3PUFA blood concentration is 70 μg / mL or more and / or the area under the ω3PUFA blood concentration curve from 0 to 2 hours after administration is 70 μg / mL·hr or more. (1-35) The self-emulsifying composition according to any one of (1-1) to (1-33) above, which is orally administered to a male cynomolgus monkey under fasting conditions for 12 hours or more, in an amount of 45 mg per kg of body weight of at least one compound selected from the group consisting of ω3 PUFA, a pharma- ceutical acceptable salt thereof, and an ester thereof, and which, when corrected by subtracting the blood ω3 concentration before administration, results in a maximum ω3PUFA blood concentration of 50 μg / mL or more and / or an area under the ω3PUFA blood concentration curve from 0 to 12 hours after administration of 400 μg / mL·hr or more, or a maximum ω3PUFA blood concentration of 70 μg / mL or more and / or an area under the ω3PUFA blood concentration curve from 0 to 12 hours after administration of 500 μg / mL·hr or more. (1-36) Use of the self-emulsifying composition according to any one of (1-1) to (1-33), in which the self-emulsifying composition according to any one of (1-1) to (1-33) is orally administered to a human before a meal in an amount of 1800 mg of at least one compound selected from the group consisting of ω-3 PUFA, its pharma- ceutically acceptable salt, and its ester, and the maximum ω-3 PUFA blood concentration calculated by subtracting the blood ω-3 concentration before administration is 50 μg / mL or more and / or the ω-3 PUFA blood concentration 2 hours after administration is 10 μg / mL or more. (1-37) A self-emulsifying composition according to any one of (1-1) to (1-33), in which the self-emulsifying composition according to any one of (1-1) to (1-33) is orally administered to a human before a meal in an amount of 1,800 mg of at least one compound selected from the group consisting of ω-3 PUFA, a pharma- ceutically acceptable salt thereof, and an ester thereof, and the maximum ω-3 PUFA blood concentration calculated by subtracting the blood ω-3 concentration before administration is 10 μg / mL or more and / or the area under the ω-3 PUFA blood concentration curve from 0 to 72 hours after administration is 250 μg / mL·hr or more.

[0021] (1-38) A self-emulsifying composition according to any one of (1-1) to (1-37), in which the polyoxyethylene castor oil is contained in an amount of 120 parts by mass or less per 100 parts by mass of the polyoxyethylene sorbitan fatty acid ester in the composition. (1-39) When the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90 mass% EPA-E, b) 0.5 to 6% by mass of water c) 1 to 29% by mass of an emulsifier that is a polyoxyethylene sorbitan fatty acid ester d) 3 to 40 parts by weight of lecithin per 100 parts by weight of the EPA-E Contains e) ethanol and / or polyhydric alcohol is 4% by mass or less of the total amount of the composition; A self-emulsifying composition comprising: (1-40) When the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90 mass% EPA-E, b) 0.5 to 6 mass% water, c) 1 to 29% by mass of an emulsifier which is a polyoxyethylene sorbitan fatty acid ester; d) 3 to 40 parts by weight of lecithin per 100 parts by weight of the EPA-E Contains e) ethanol is 4% by mass or less of the total amount of the composition; f) polyhydric alcohol is 4% by mass or less of the total amount of the composition; A self-emulsifying composition comprising:

[0022] A second aspect of the present invention is an encapsulated self-emulsifying formulation comprising: (2-1) An encapsulated self-emulsifying preparation, the content of which is the self-emulsifying composition according to any one of (1-1) to (1-40) and which is encapsulated in a hard capsule and / or a soft capsule. (2-2) An encapsulated self-emulsifying preparation according to (2-1), which has good hardness immediately after production. (2-3) An encapsulated self-emulsifying preparation according to (2-1) or (2-2), having a hardness of 18 kgf or more immediately after production. (2-4) An encapsulated self-emulsifying preparation according to any one of (2-1) to (2-3), the hardness of which does not decrease by 6 kgf or more when the preparation is sealed in an aluminum package and stored at 40°C for one week compared to before storage. (2-5) An encapsulated self-emulsifying preparation according to any one of (2-1) to (2-4), which has a hardness of 20 kgf or more when the preparation is sealed in an aluminum package and stored at 40°C for one week. (2-6) An encapsulated self-emulsifying preparation according to any one of (2-1) to (2-5), wherein the hardness of the preparation when sealed in an aluminum package and stored at 40°C for one week is 60% or more of the hardness before storage. (2-7) The preparation according to (2-1), which is at least one selected from the group consisting of therapeutic agents for dyslipidemia (hypercholesterolemia, hyper LDL cholesterolemia, high non-HDL cholesterolemia, hyper VLDL cholesterolemia, hypo HDL cholesterolemia, hypertriglyceridemia, hyper ApoBemia, hypo ApoAIemia, etc.), therapeutic agents for postprandial hypertriglyceridemia, anti-arteriosclerotic agents, platelet aggregation inhibitors, therapeutic agents for peripheral circulatory failure, prophylactic agents for the onset of cardiovascular events, therapeutic agents for inflammatory diseases (non-alcoholic fatty liver disease (hereinafter referred to as NAFLD), non-alcoholic steatohepatitis (hereinafter referred to as NASH), etc.), agents for inhibiting / treating dementia (Alzheimer's dementia, vascular dementia, mixed dementia, etc.), anticancer agents, and therapeutic agents for central nervous system diseases (depression, depressive state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.).

[0023] A third aspect of the present invention is a method for producing a self-emulsifying composition as follows. (3-1) When the total amount of the self-emulsifying composition is 100% by mass a) 70 to 90% by weight of at least one compound selected from the group consisting of ω-3 PUFAs, pharma- ceutically acceptable salts thereof, and esters thereof; b) 0.5 to 6 mass% water, c) 1 to 29% by mass of an emulsifier which is a polyoxyethylene sorbitan fatty acid ester, and d) 3 to 40 parts by mass of lecithin per 100 parts by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharma- ceutically acceptable salts thereof, and esters thereof. in any order, and the resulting composition e) Ethanol and / or polyhydric alcohol is 4% by mass or less of the total amount of the composition A method for producing a self-emulsifying composition, comprising: (3-2) When the total amount of the self-emulsifying composition is 100% by mass a) 70 to 90% by weight of at least one compound selected from the group consisting of ω-3 PUFAs, pharma- ceutically acceptable salts thereof, and esters thereof; b) 0.5 to 6 mass% water, c) 1 to 29% by mass of an emulsifier which is a polyoxyethylene sorbitan fatty acid ester, and d) 3 to 40 parts by mass of lecithin per 100 parts by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharma- ceutically acceptable salts thereof, and esters thereof. in any order, and the resulting composition e) ethanol is 4% by mass or less of the total amount of the composition; f) polyhydric alcohol is 4% by mass or less of the total amount of the composition; A method for producing a self-emulsifying composition, comprising: (3-3) A method for producing the self-emulsifying composition according to (3-1) or (3-2), comprising the step of heating and mixing the steps a), b) and / or c) at 70°C or higher.

[0024] A fourth aspect of the present invention is a pharmaceutical composition comprising the self-emulsifying composition according to the specific method of administration described below. (4-1) A preparation for oral administration of the self-emulsifying composition, the encapsulated self-emulsifying preparation, the medicine or the veterinary drug according to any one of (1-1) to (1-40) and (2-1) to (2-7) above, on an empty stomach or before going to bed. (4-2) A preparation for oral administration of a self-emulsifying composition, an encapsulated self-emulsifying preparation, a medicine or a veterinary drug produced by the production method described in any one of (3-1) to (3-3) above, on an empty stomach or before going to bed. (4-3) The preparation according to (4-1) or (4-2), wherein the pharmaceutical agent is at least one selected from the group consisting of therapeutic agents for dyslipidemia (hypercholesterolemia, hyper LDL cholesterolemia, high non-HDL cholesterolemia, hyper VLDL cholesterolemia, hypo HDL cholesterolemia, hypertriglyceridemia, hyper ApoBemia, hypo ApoAIemia, etc.), therapeutic agents for postprandial hypertriglyceridemia, anti-arteriosclerotic agents, platelet aggregation inhibitors, therapeutic agents for peripheral circulatory failure, prophylactic agents for the onset of cardiovascular events, therapeutic agents for inflammatory diseases (NAFLD, NASH, etc.), anti-cancer agents, and prophylactic agents, therapeutic agents, or agents for preventing the progression of central nervous system diseases (depression, depressive state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.). (4-4) The formulation according to any one of (4-1) to (4-3) above, which is administered once a day. (4-5) A method for administering and / or using the formulation according to any one of (4-1) to (4-4) above. (4-6) A method for increasing plasma ω-3 PUFA concentration by oral administration according to any one of (4-1) to (4-4) above.

[0025] A fifth aspect of the present invention is a method for preventing, inhibiting the progression of, and treating at least one disease selected from the group consisting of the following: (5-1) A method for preventing, preventing the progression of, and treating at least one disease selected from the group consisting of dyslipidemia (hypercholesterolemia, hyper LDL cholesterolemia, hyper non-HDL cholesterolemia, hyper VLDL cholesterolemia, hypo HDL cholesterolemia, hypertriglyceridemia, hyper ApoBemia, hypo ApoAIemia, etc.), postprandial hypertriglyceridemia, anti-atherosclerosis, increased platelet aggregation, peripheral circulatory failure, onset of cardiovascular events, inflammatory diseases (NAFLD, NASH, etc.), dementia (Alzheimer's dementia, vascular dementia, mixed dementia, etc.), cancer, and central nervous system diseases (depression, depressive state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.), which comprises orally administering to a patient at least one self-emulsifying composition or encapsulated self-emulsifying preparation, medicine, or veterinary medicine selected from (1-1) to (1-40), (2-1) to (2-7), and (3-1) to (3-3). (5-2) The method according to (5-1) above, wherein the self-emulsifying composition or the encapsulated self-emulsifying preparation, medicine or veterinary drug is orally administered on an empty stomach or before going to bed. (5-3) The method according to (5-1) or (5-2) above, wherein the self-emulsifying composition or the encapsulated self-emulsifying preparation, pharmaceutical or veterinary drug is administered once a day.

[0026] A sixth aspect of the present invention is a self-emulsifying composition comprising: (6-1) Orally administer a self-emulsifying composition containing 600 mg of at least one compound selected from the group consisting of ω3 PUFA, its pharma- ceutically acceptable salts, and its esters to male beagle dogs under fasting conditions for 18 hours or more, and obtain a maximum ω3 PUFA blood concentration of 50 μg / mL or more and / or an area under the ω3 PUFA blood concentration curve from 0 to 2 hours after administration of 30 μg / mL hr or more, calculated by subtracting the blood ω3 concentration before administration. A self-emulsifying composition having an ω3PUFA blood concentration value of 50 μg / mL or more and / or an area under the ω3PUFA blood concentration curve from 0 to 2 hours after administration of 50 μg / mL·hr or more, a maximum ω3PUFA blood concentration value of 60 μg / mL or more and / or an area under the ω3PUFA blood concentration curve from 0 to 2 hours after administration of 60 μg / mL·hr or more, or a maximum ω3PUFA blood concentration value of 70 μg / mL or more and / or an area under the ω3PUFA blood concentration curve from 0 to 2 hours after administration of 70 μg / mL·hr or more. (6-2) A self-emulsifying composition which is orally administered to male cynomolgus monkeys under fasting conditions for 12 hours or more, the self-emulsifying composition being at least one compound selected from the group consisting of ω3 PUFA, its pharma- ceutical acceptable salts, and its esters, in an amount of 45 mg per kg of body weight, and which has, after subtracting the blood ω3 concentration prior to administration, a maximum ω3PUFA blood concentration of 50 μg / mL or more and / or an area under the ω3PUFA blood concentration curve from 0 to 12 hours after administration of 400 μg / mL·hr or more, or a maximum ω3PUFA blood concentration of 70 μg / mL or more and / or an area under the ω3PUFA blood concentration curve from 0 to 12 hours after administration of 500 μg / mL·hr or more. (6-3) A self-emulsifying composition in which a self-emulsifying composition containing 1,800 mg of at least one compound selected from the group consisting of ω-3 PUFA, its pharma- ceutically acceptable salt, and its ester is orally administered to a human before a meal, and the maximum ω-3 PUFA blood concentration calculated by subtracting the blood ω-3 concentration before administration is 50 μg / mL or more and / or the ω-3 PUFA blood concentration 2 hours after administration is 10 μg / mL or more. (6-4) A self-emulsifying composition in which 1,800 mg of at least one compound selected from the group consisting of ω-3 PUFA, its pharma- ceutically acceptable salt, and its ester is orally administered to a human before a meal, and the maximum ω-3 PUFA blood concentration calculated by subtracting the blood ω-3 concentration before administration is 10 μg / mL or more and / or the area under the ω-3 PUFA blood concentration curve from 0 to 72 hours after administration is 250 μg / mL·hr or more. Effect of the Invention

[0027] The self-emulsifying composition of the present invention contains a small amount of water in place of ethanol or polyhydric alcohol, and such a composition improves the compatibility of the composition and further reduces the amount of emulsifier used, making it safe for animals (including humans).In addition, since the content of ω3 PUFA is high, the amount of emulsifier used can be reduced, making it easy to take. Furthermore, by including water in the composition, the content of ethanol or polyhydric alcohol can be reduced or eliminated, thereby preventing the capsule shell from softening and causing deformation of the capsule. In addition, it has excellent at least one of compatibility (appearance), self-emulsifying properties, composition dispersibility, emulsion stability, and absorbency, and is rapidly absorbed even when administered before meals or after a low-fat meal, thereby suppressing an increase in serum TG after meals, or when administered before bedtime, it prevents essential fatty acid deficiency when taking a lipase inhibitor. Furthermore, due to the above-mentioned composition, the composition does not separate or become cloudy even when stored at room temperature or under low (eg, 5° C.) or high (eg, 40° C.) conditions, and the appearance is good. The self-emulsifying composition of the present invention has at least one, preferably two or more, of the above-mentioned preferable properties, and more preferably has all of the properties. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The present invention will be described in detail below. The present invention relates to a self-emulsifying composition which contains a total amount of at least one compound selected from the group consisting of ω-3 PUFA, its pharma- ceutically acceptable salt, and its ester in the range of 70 to 90% by mass, a specific emulsifier in the range of 1 to 29% by mass, and 3 to 40 parts by mass of lecithin per 100 parts by mass of ω-3 PUFA, its pharma- ceutically acceptable salt, and its ester, and which contains no added ethanol or polyhydric alcohol or has only a low concentration of added ethanol or polyhydric alcohol, as well as a self-emulsifying preparation encapsulated with the same as its contents, a pharmaceutical, a method for producing the same, and a method for using the same.

[0029] In the present invention, "ω3 PUFA" refers to a fatty acid having multiple carbon-carbon double bonds in the molecule, with the first double bond located at the third position counting from the methyl group. Representative examples include α-linolenic acid, EPA, DHA, eicosatrienoic acid, stearidonic acid, eicosatetraenoic acid, sardine acid, tetracosapentaenoic acid, and herring acid. In the present invention, the terms "ω3 PUFAs", "EPAs", "DHAs", and "fatty acids" are used to mean not only ω3 PUFA, EPA, DHA, and fatty acid, respectively, but also their respective pharma- ceutical acceptable salts or esters, unless otherwise specified.

[0030] The ω-3 PUFAs used in the present invention may be synthetic, semi-synthetic or natural products, or may be in the form of natural oils containing these. Here, the term "natural products" refers to those extracted by known methods from natural oils containing ω-3 PUFAs, those roughly refined, or those that have been further refined. Semi-synthetic products include ω-3 PUFAs produced by microorganisms, etc., and also include those that have been subjected to chemical treatments such as esterification and transesterification of said ω-3 PUFAs or natural ω-3 PUFAs. In the present invention, one of these products can be used alone as the ω-3 PUFAs, or two or more can be used in combination.

[0031] In the present invention, EPAs and DHAs are preferred examples of ω3PUFAs, and EPAs are more preferred.In addition, ω3PUFA pharmaceutically acceptable salts include inorganic bases such as sodium salt and potassium salt, organic bases such as benzylamine salt and diethylamine salt, salts with basic amino acids such as arginine salt and lysine salt, and esters such as alkyl esters such as ethyl ester, mono-, di- and TG esters.Preferably, ethyl ester or TG ester is used, and ethyl ester is more preferred.That is, preferred examples include EPA-E, EPA TG ester, DHA-E, and DHA TG ester, and more preferred examples include EPA-E and DHA-E, and EPA-E is more preferred.

[0032] The purity of the ω3PUFAs of the raw material used for the self-emulsifying composition of the present invention is not particularly limited, but usually, the content of ω3PUFAs in the total fatty acids of the composition is preferably 50% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, particularly preferably 96.5% by mass or more, and most preferably 98% by mass or more.EPA is preferably high purity, for example, the EPA content ratio in ω3PUFAs is preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, and particularly preferably 98% by mass or more. In other words, it is preferable that the composition of this agent has a high purity of ω-3 PUFAs among all fatty acids, and it is even more preferable that the purity of ω-3 PUFAs (EPA + DHA) is high, and it is most preferable that the composition contains substantially no DHA, or if it does contain DHA, the purity of EPA is, for example, less than 1.0% by mass, preferably less than 0.5% by mass, and more preferably less than 0.2% by mass. For example, when EPA-E and DHA-E are used, so long as the purity of the EPA-E composition is as described above, the composition ratio of EPA-E / DHA-E and the content ratio of EPA-E+DHA-E in the total fatty acids are not particularly limited, but the preferred composition ratio of EPA-E / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and even more preferably 1.2 or more. In addition, the composition of the present invention may contain polyunsaturated fatty acids other than ω3 PUFAs, such as linoleic acid, γ-linolenic acid, dihomo-γ-linolenic acid, and their pharma- ceutical acceptable salts or esters, but it is desirable that the content of arachidonic acid and its pharma- ceutical acceptable salts or esters is low, preferably less than 2% by mass, and more preferably less than 1% by mass, and particularly preferably an embodiment that is substantially free of arachidonic acid and its pharma- ceutical acceptable salts or esters.

[0033] The content of ω-3 PUFAs in the self-emulsifying composition of the present invention is 70 to 90% by mass, preferably 70 to 86% by mass, more preferably 72 to 85% by mass, and even more preferably 74 to 84% by mass. The ω-3 PUFAs may be one type or a mixture of two or more types. When a mixture of two or more types is used, the total amount of the mixture is 70 to 90% by mass in the self-emulsifying composition.

[0034] The ω3PUFAs can be used in Japan as a soft capsule containing high-purity EPA-E (96.5% by mass or more) available as an ASO and hyperlipidemia treatment drug (trade name Epader: manufactured by Mochida Pharmaceutical Co., Ltd.), or in the United States as a hypertriglyceridemia treatment drug (trade name VASCEPA: Amarin). In addition, a mixture of EPA-E and DHA-E can be used, for example, as a hypertriglyceridemia treatment drug, such as Lovaza (registered trademark: GlaxoSmithKline: soft capsule containing about 46.5% by mass of EPA-E and about 37.5% by mass of DHA-E) available in the United States (LOTRIGA (registered trademark): Takeda Pharmaceutical Co., Ltd.: soft capsule containing about 46.5% by mass of EPA-E and about 37.5% by mass of DHA-E). A mixture of EPA and DHA can be used, for example, as Epanova (registered trademark: AstraZeneca; soft capsules containing approximately 50-60% by mass of EPA free acid and approximately 15-25% by mass of DHA free acid), which is commercially available in the United States as a treatment for hypertriglyceridemia. As ω3 PUFAs, refined fish oil can also be used. In addition, monoglycerides, diglycerides, TG derivatives, or combinations thereof of ω3 PUFAs are also preferred embodiments. For example, products containing various ω3 PUFAs, such as Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX7010EE, K85TG, K85EE and K80EE (Pronova Biopharma, Lysaker, Norway), are commercially available, and these can also be obtained and used.

[0035] In the present invention, the "polyoxyethylene sorbitan fatty acid ester" is a polyoxyethylene ether of a fatty acid ester in which a portion of the hydroxyl groups of sorbitol anhydride is esterified with a fatty acid. Various compounds are commercially available depending on the fatty acid to be esterified, such as polyoxyethylene (20) sorbitan monolaurate (NIKKOL TL-10, polysorbate 20, Tween 20), polyoxyethylene (20) sorbitan monopalmitate (NIKKOL TP-10V, polysorbate 40, Tween 40), polyoxyethylene (20) sorbitan monostearate (NIKKOL TS-10MV, polysorbate 60, Tween 60), polyoxyethylene (20) sorbitan tristearate (NIKKOL TS-30V, polysorbate 65), polyoxyethylene (20) sorbitan monoisostearate (NIKKOL TI-10V), polyoxyethylene (20) sorbitan monooleate (NIKKOL TO-10MV, polysorbate 80, Tween 80), polyoxyethylene (20) sorbitan trioleate (NIKKOL Examples of the polyoxyethylene (20) sorbitan monooleate include polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan trioleate, and more preferably polyoxyethylene (20) sorbitan monooleate. In addition, one of these may be used alone, or two or more may be used in combination. In the present invention, the term "polyoxyethylene sorbitan fatty acid ester" is used to include all of the above-mentioned compounds. The content of polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effect of the present invention, but is usually 1 to 29% by mass, preferably 3 to 20% by mass, more preferably 5 to 15% by mass, and particularly preferably 5 to 9% by mass, when the total amount of the self-emulsifying composition is 100% by mass.

[0036] In the present invention, "polyoxyethylene castor oil" is a compound obtained by addition polymerization of ethylene oxide to castor oil. Various compounds are commercially available depending on the average number of moles of ethylene oxide added, such as NIKKOL CO-3 (Nikko Chemicals) with an average number of moles added of 3, NIKKOL CO-10 (Nikko Chemicals) with an average number of moles added of 10, EMALEX C-20 (Nippon Emulsion) with an average number of moles added of 20, EMALEX C-30 (Nippon Emulsion) with an average number of moles added of 30, Kolliphor EL (BASF) (polyoxyl 35 castor oil) with an average number of moles added of 35, EMALEX C-40 (Nippon Emulsion) with an average number of moles added of 40, and EMALEX C-50 (Nippon Emulsion) with an average number of moles added of 50, and preferably Kolliphor EL. In addition, one of these can be used alone, or two or more can be used in combination. In the present invention, the term "polyoxyethylene castor oil" is used to mean all of the above-mentioned compounds, unless otherwise specified. The content of polyoxyethylene castor oil in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effect of the present invention, but it is usually 1 to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and particularly preferably 5 to 9% by mass, when the total amount of the self-emulsifying composition is 100% by mass.In addition, it is suitable to include polyoxyethylene castor oil in a ratio of 150 parts by mass or less, preferably 140 parts by mass or less, more preferably 130 parts by mass or less, even more preferably 120 parts by mass or less, particularly preferably 110 parts by mass or less, and most preferably 100 parts by mass or less, relative to 100 parts by mass of polyoxyethylene sorbitan fatty acid ester in the composition. In addition, it is preferable that the ratio of polyoxyethylene sorbitan fatty acid ester to polyoxyethylene castor oil in the composition is 100 parts by mass:5 to 150 parts by mass, preferably 100 parts by mass:10 to 140 parts by mass or less, more preferably 100 parts by mass:20 to 130 parts by mass or less, even more preferably 30 to 120 parts by mass, particularly preferably 100 parts by mass:50 to 110 parts by mass, and most preferably 100 parts by mass:80 to 120 parts by mass.

[0037] In the present invention, "polyoxyethylene hydrogenated castor oil" is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil obtained by adding hydrogen to castor oil. Various compounds are commercially available depending on the average polymerization degree of ethylene oxide, and examples thereof include polyoxyethylene (20) hydrogenated castor oil (NIKKOL HCO-20, Nikko Chemicals), polyoxyethylene (40) hydrogenated castor oil (NIKKOL HCO-40, Nikko Chemicals), polyoxyethylene (50) hydrogenated castor oil (NIKKOL HCO-50, Nikko Chemicals), polyoxyethylene (60) hydrogenated castor oil (NIKKOL HCO-60, Nikko Chemicals) and polyoxyethylene (100) hydrogenated castor oil (NIKKOL HCO-100, Nikko Chemicals), and preferably polyoxyethylene (60) hydrogenated castor oil. In addition, one of these may be used alone, or two or more may be used in combination. In the present invention, the term "polyoxyethylene hydrogenated castor oil" is used to mean all of the above-mentioned compounds, unless otherwise specified. The content of polyoxyethylene hydrogenated castor oil in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effect of the present invention, but it is usually 1 to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and particularly preferably 5 to 9% by mass, when the total amount of the self-emulsifying composition is 100% by mass.In addition, it is suitable to include polyoxyethylene hydrogenated castor oil in a ratio of 150 parts by mass or less, preferably 140 parts by mass or less, more preferably 130 parts by mass or less, even more preferably 120 parts by mass or less, particularly preferably 110 parts by mass or less, and most preferably 100 parts by mass or less, relative to 100 parts by mass of polyoxyethylene sorbitan fatty acid ester in the composition. In addition, it is preferable that the ratio of polyoxyethylene sorbitan fatty acid ester to polyoxyethylene castor oil in the composition is 100 parts by mass:5 to 150 parts by mass, preferably 100 parts by mass:10 to 140 parts by mass or less, more preferably 100 parts by mass:20 to 130 parts by mass or less, even more preferably 30 to 120 parts by mass, particularly preferably 100 parts by mass:50 to 110 parts by mass, and most preferably 100 parts by mass:80 to 120 parts by mass.

[0038] The self-emulsifying composition of the present invention is characterized by containing at least polyoxyethylene sorbitan fatty acid ester as an emulsifier. One of the preferred embodiments of the present invention contains polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and / or polyoxyethylene hardened castor oil as emulsifiers. Another preferred embodiment of the present invention contains polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers. The self-emulsifying composition of the present invention may contain an emulsifier other than polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as an emulsifier, but the content is 20 parts by mass or less, more preferably 10 parts by mass or less, even more preferably less than 5 parts by mass, when the total amount of emulsifiers used in the composition is 100 parts by mass, and particularly preferably substantially free of emulsifiers. The emulsifier that can be further included is not particularly limited as long as it satisfies at least one of the above-mentioned objectives, and examples thereof include sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, propylene glycol fatty acid esters, saturated polyglycolized glycerides, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, polyethylene glycol fatty acid esters, tocopherol-polyethylene glycol-succinic acid ester (TPGS), and the like.

[0039] The total content of emulsifier in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effect of the present invention, but it is usually 1 to 29% by mass, preferably 3 to 27% by mass, more preferably 5 to 27% by mass, even more preferably 5 to 24% by mass, and particularly preferably 10 to 20% by mass, when the total amount of the self-emulsifying composition is 100% by mass. Alternatively, it is preferably 8 to 27% by mass, and more preferably 10 to 27% by mass. In addition, it is 5 to 45 parts by mass, preferably 10 to 45 parts by mass, more preferably 15 to 35 parts by mass, and particularly preferably 15 to 20 parts by mass, relative to 100 parts by mass of ω3PUFAs.

[0040] The composition and medicine of the present invention contain a small amount of water. It is generally believed that adding water to a composition containing hydrophobic lipids will result in poor compatibility. By including water in the composition, the compatibility of the composition is improved, and polyhydric alcohol or ethanol is not required, so that the appearance is clear even without polyhydric alcohol or ethanol, and the composition does not separate or become cloudy. A small amount of water may be added during preparation of the self-emulsifying composition, or the water in the gelatin shell may be transferred to the self-emulsifying composition when encapsulated in a gelatin capsule or the like. Furthermore, since the composition does not contain polyhydric alcohol or ethanol, the capsules will not soften or deform when encapsulated, and there will be no side effects from ethanol when the composition is administered to patients with alcohol intolerance. When the total amount of the self-emulsifying composition is taken as 100% by mass, the amount of water is preferably 0.5 to 6% by mass, more preferably 0.5 to 4% by mass, even more preferably 0.5 to 3% by mass, and most preferably 1 to 3% by mass. Alternatively, the amount of water is preferably 0.5% by mass or more and less than 3% by mass, and more preferably 0.5% by mass or more and less than 1.5% by mass.

[0041] In the present invention, "lecithin" refers to a type of glycerophospholipid, and examples thereof include soybean lecithin, enzymatically decomposed soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, hydrogenated phospholipid, milk-derived phospholipid, lysolecithin, phosphatidylcholine, and phosphatidylserine. Preferred examples include soybean lecithin, enzymatically decomposed soybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin, and more preferred examples include soybean lecithin. In addition, one of these may be used alone, or two or more may be used in combination. In the present invention, lecithin is used to mean all of the above-mentioned glycerophospholipids, unless otherwise specified. In the present invention, lecithin is not included in the emulsifier. Various products are commercially available, such as refined soybean lecithin (Nisshin Oillio), refined egg yolk lecithin (Asahi Kasei Pharma), egg yolk lecithin PL-100M (Kewpie). Various products, such as soybean lecithin (Basis LP-20B (Nisshin Oil Mills), Lipoid S45, S20 (Lipoid)) and enzyme-decomposed lecithin (Basis LP-20E (Nisshin Oil Mills) and Phospholipon RLPC20 (Lipoid)), are commercially available, and these can be obtained and used.

[0042] The content of lecithin added to the self-emulsifying composition of the present invention is not particularly limited, but is preferably 3 to 40 parts by mass, more preferably 3 to 30 parts by mass, even more preferably 3 to 25 parts by mass, particularly preferably 3 to 20 parts by mass, 3.2 to 17 parts by mass, 3.5 to 15 parts by mass, or 3.7 to 17 parts by mass, relative to 100 parts by mass of ω3 PUFAs. Alternatively, it is preferably 3 to 15 parts by mass, more preferably 3 to 12 parts by mass, and even more preferably 3 to 10 parts by mass. It is most preferably 5 to 10 parts by mass. When the total amount of the self-emulsifying composition is taken as 100% by mass, the content of lecithin is preferably 2.1 to 36% by mass, more preferably 2.1 to 20% by mass, further preferably 2.1 to 15% by mass, and most preferably 2.1 to 10% by mass. When the total content of the emulsifiers in the self-emulsifying composition is taken as 100 parts by mass, the amount of lecithin is preferably 10 to 75 parts by mass, more preferably 11 to 60 parts by mass, and even more preferably 20 to 55 parts by mass. Most preferably 25 to 35 parts by mass. When the total content of the polyoxyethylene sorbitan fatty acid esters in the self-emulsifying composition is taken as 100 parts by mass, the amount of lecithin is preferably 10 to 150 parts by mass, more preferably 20 to 120 parts by mass, and even more preferably 40 to 90 parts by mass. Most preferably 50 to 70 parts by mass.

[0043] In the present invention, the term "polyhydric alcohol" refers to a polyol compound having a structure in which two or more carbon atoms of a chain aliphatic hydrocarbon or a cyclic aliphatic hydrocarbon are substituted with one hydroxyl group each. Examples of the polyhydric alcohol include dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, and pentamethylene glycol; trihydric alcohols such as glycerin, trimethylolpropane, and 1,2,6-hexanetriol; polyhydric alcohol polymers such as diethylene glycol, dipropylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, and polyglycerin; and the like; preferably, propylene glycol or glycerin. Glycerin also includes concentrated glycerin. In the present invention, the term "polyhydric alcohol" refers to all of the above-mentioned polyol compounds unless otherwise specified.

[0044] The content of polyhydric alcohol added to the self-emulsifying composition of the present invention is preferably within a range that does not deform the capsule when the composition is filled into the capsule.For example, when the entire composition is 100% by mass, it is preferable that the composition does not contain more than 4% by mass of polyhydric alcohol.In addition, the content of polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, even more preferably 2% by mass or less, and particularly preferably 1% by mass or less.The most preferable is 0% by mass.

[0045] The ethanol contained in the self-emulsifying composition of the present invention is preferably in a range that does not cause quality changes during the encapsulation manufacturing process or during distribution and storage, and does not cause denaturation of the capsule contents, and is also preferably in a range that does not exceed the actual pharmaceutical use amount as a daily dosage. For example, when the entire composition is taken as 100% by mass, it is preferable that the composition does not contain more than 4% by mass of ethanol. In addition, the content of ethanol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, even more preferably 2% by mass or less, and particularly preferably 1% by mass or less. The most preferable is 0% by mass. In addition, when the self-emulsifying composition contains ethanol and polyhydric alcohol, it is preferable that the total content of ethanol and polyhydric alcohol in the composition does not exceed 4% by mass when the entire composition is taken as 100% by mass. In a preferred embodiment, the composition does not substantially contain ethanol and polyhydric alcohol. In addition, the total amount of ethanol and polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, even more preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferably, it is 0% by mass or less.

[0046] The preferred ethanol concentration can be appropriately determined according to the ω3PUFA concentration in the self-emulsifying composition and the daily dosage.When the self-emulsifying composition of the present invention is orally administered at 1800mg per day as ω3PUFA, for example, if the formulation contains 75% by mass of ω3PUFA, the ethanol content should be 0.135% by mass or less, and the daily maximum usage amount listed in the Pharmaceutical Additives Dictionary will not exceed 3.26mg.

[0047] In the self-emulsifying composition of the present invention containing the above-mentioned ω3 PUFAs and emulsifier, a preferred embodiment is a combination containing 1) EPA-E and / or DHA-E, 2) water, 3) polyoxyethylene sorbitan fatty acid ester as an emulsifier, and 4) lecithin. When the total amount of the self-emulsifying composition is taken as 100% by mass, 1) EPA-E and / or DHA-E is 70-90% by mass, 2) water is 0.5-6% by mass, 3) emulsifier containing polyoxyethylene sorbitan is 1-29% by mass (excluding lecithin), and 4) lecithin is 3-40 parts by mass per 100 parts by mass of EPA-E and / or DHA-E. Another preferred embodiment is a combination containing 1) EPA-E and / or DHA-E, 2) water, 3) polyoxyethylene sorbitan fatty acid ester as an emulsifier, and 4) polyoxyl castor oil, and 5) lecithin. When the total amount of the self-emulsifying composition is taken as 100% by mass, the composition contains 1) 70-90% by mass of EPA-E and / or DHA-E, 2) 0.5-6% by mass of water, 3) 1-29% by mass of an emulsifier (excluding lecithin) containing polyoxyethylene sorbitan and polyoxyl castor oil, and 4) 3-40 parts by mass of lecithin per 100 parts by mass of EPA-E and / or DHA-E. Another preferred embodiment is a combination containing 1) at least one compound selected from ω3 PUFA, a pharma- ceutically acceptable salt thereof, and an ester thereof, 2) water, 3) a polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers, and 4) lecithin. When the total amount of the self-emulsifying composition is taken as 100% by mass, the composition comprises: 1) 70 to 90% by mass of at least one compound selected from ω3 PUFA, a pharma- ceutically acceptable salt thereof, and an ester thereof; 2) 0.5 to 6% by mass of water; 3) 5 to 24% by mass of an emulsifier containing a polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil, with the emulsifier being 120 parts by mass or less per 100 parts by mass of the polyoxyethylene sorbitan fatty acid ester; and 4) 3 to 40 parts by mass of lecithin per 100 parts by mass of at least one compound selected from ω3 PUFA, a pharma-ceutically acceptable salt thereof, and an ester thereof.

[0048] The self-emulsifying composition of the present invention can be encapsulated in a capsule. The capsule can be a hard capsule or a soft capsule, and is preferably a soft capsule. The form of the soft capsule is not necessarily limited, but is preferably a rotary type soft capsule or a seamless capsule.

[0049] In the soft capsule of the present invention, the composition of the capsule shell is not necessarily limited, and the main components include, for example, gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hypromellose, hydroxypropyl cellulose, etc., and various known components, but preferably gelatin. Gelatin is not limited, and known gelatins such as acid-treated gelatin, alkali-treated gelatin, amphoteric gelatin, and chemically modified gelatin can be used, and one or more of these can be used. Preferably, it is acid-treated gelatin or alkali-treated gelatin. The origin of gelatin is not necessarily limited, but for example, it is cow bone, cowhide, pig bone, pig skin, fish scale, fish skin, preferably cow bone, cowhide, pig bone, and pig skin. "Gelatin" includes those commonly used in the manufacture of soft capsules, such as pharmaceutical gelatin (gelatin and purified gelatin) as specified in the 16th revised Japanese Pharmacopoeia. Two or more types of gelatin may be used in combination. The capsule shell may also contain other additives such as plasticizers. The "plasticizer" to be blended in the capsule shell is preferably one commonly used in the manufacture of soft capsules, such as polyhydric alcohols such as glycerin (e.g., concentrated glycerin), ethylene glycol, polyethylene glycol, propylene glycol, and polypropylene glycol, and sugar alcohols such as sorbitol, mannitol, and xylitol. Two or more of these plasticizers may be used in combination. Among them, glycerin and sorbitol are preferred. It is also preferred to use a combination of glycerin and sorbitol. In this case, the mass ratio of glycerin to sorbitol is preferably in the range of 1:5 to 5:1, and more preferably in the range of 1:3 to 3:1. In the soft capsule of the present invention, particularly in the seamless capsule, the capsule shell liquid contains gelatin and plasticizer in a weight ratio preferably in the range of 10:1 to 1:10, and more preferably in the range of 10:1 to 1:1. The weight ratio of the capsule shell liquid to the capsule contents is usually 10:1 to 1:10, and preferably 3:1 to 1:10. Furthermore, if necessary, various additives commonly used in capsule shells, such as plasticizers such as amino acids, citric acid, glycerin, sorbitol, and trehalose, preservatives, colorants such as pigments and titanium oxide, and organic acids, can be added.

[0050] The capsule shell composition can be produced by mixing and dissolving gelatin, a plasticizer, and, if necessary, various additives in water at room temperature or with heating.

[0051] The encapsulated self-emulsifying preparation containing the self-emulsifying composition of the present invention as the content liquid has a good hardness immediately after production, and it is preferable that the hardness does not decrease during storage. The decrease in hardness not only deforms the capsule, but also makes the capsule brittle, causing it to break and the content liquid to leak out, which is undesirable in terms of quality. The softening of the capsule can be confirmed by measuring the hardness with a general hardness meter. The encapsulated self-emulsifying preparation of the present invention has a hardness of 18 kgf or more immediately after production, preferably 20 kgf or more, more preferably 22 kgf or more. Furthermore, when stored in a sealed aluminum package at 40°C for one week, it is desirable that the hardness does not substantially decrease or does not decrease by 6 kgf or more compared to immediately after production, and the hardness after storage at 40°C for one week is 10 kgf or more, preferably 15 kgf or more, more preferably 20 kgf or more. In addition, when the hardness immediately after production is taken as 100%, the hardness is maintained at 60% or more, preferably 70% or more, more preferably 80% or more, further preferably 85% or more, and particularly preferably 90% or more when stored in a sealed aluminum package at 40°C for one week.

[0052] The dosage and administration period of the ω-3 PUFAs used in the self-emulsifying composition of the present invention are sufficient to produce the target effect, but can be increased or decreased as appropriate depending on the administration method, number of administrations per day, severity of symptoms, body weight, age, etc.

[0053] When orally administered, for example, 0.1 to 5 g / day, preferably 0.2 to 3 g / day, more preferably 0.3 to 3 g / day, and even more preferably 0.5 to 3 g / day of EPA-E is administered in one to three divided doses, but the total amount may be administered once or in several divided doses as necessary. The number of times of administration per day is preferably once a day, or twice or three times a day. When administered once a day, for example, in the case of a soft capsule containing 1 g of EPA-E, 1 to 10 capsules, preferably 1 to 8 capsules, more preferably 1 to 6 capsules, even more preferably 1 to 4 capsules, and even more preferably 1 to 3 capsules can be administered. In addition, a soft capsule containing 1 g of EPA-E and a soft capsule containing 0.5 g can be combined and administered at 0.5 g / time, 1.5 g / time, 2.5 g / time, 3.5 g / time, 4.5 g / time, or 5.5 g / time. Since the absorption of EPA-E is affected by food, it is preferable to administer it during or after a meal, and even more preferably immediately after a meal (within 30 minutes). However, since the self-emulsifying composition of the present invention has excellent absorbability even when administered on an empty stomach, the effects of the present invention can be achieved when the composition is administered at times other than during, after or immediately after a meal, for example, before meals, just before meals, between meals, or before bedtime, when administered to patients with reduced intestinal absorption ability (elderly people, patients with intestinal diseases, patients after intestinal surgery, patients with terminal cancer, and patients taking lipase inhibitors), or when the dosage is reduced.

[0054] The self-emulsifying composition of the present invention is preferably characterized in that the time to reach the maximum blood concentration after oral administration is equal to or shorter than that of an ω3PUFA stock solution. Alternatively, the maximum blood concentration is preferably higher than that of an ω3PUFA stock solution. In addition, the blood concentration 2 hours after administration, the area under the blood concentration curve 0-2 hours after administration, and / or the area under the blood concentration curve 0-72 hours after administration are preferably equal to or higher than that of an ω3PUFA stock solution. More preferably, the self-emulsifying composition of the present invention is characterized in that the time to reach the maximum blood concentration is shorter than that of an ω3PUFA, the concentration is higher, and the blood concentration 2 hours after administration, the area under the blood concentration curve 0-2 hours after administration, and / or the area under the blood concentration curve 0-72 hours after administration are all higher than that of an ω3PUFA stock solution. The above pharmacokinetics can be confirmed in animals such as dogs and monkeys, but are preferably confirmed by human studies.

[0055] In a pharmacokinetic study using male beagle dogs, a self-emulsifying composition equivalent to 600 mg of ω-3 PUFAs was orally administered to male beagle dogs under fasting conditions for 18 hours or more, and the maximum ω-3 PUFA blood concentration calculated by subtracting the blood ω-3 concentration before administration is, for example, preferably 50 μg / ml or more, more preferably 60 μg / ml or more, and particularly preferably 70 μg / ml or more. In addition, the area under the ω-3 PUFA blood concentration curve from 0 to 2 hours after administration is preferably 50 μg / ml·hr or more, more preferably 60 μg / ml·hr or more, and particularly preferably 70 μg / ml·hr or more. Furthermore, the combination of maximum ω3PUFA blood concentration and area under the ω3PUFA blood concentration curve is preferably 50 μg / ml or more and 50 μg / ml·hr or more, more preferably 60 μg / ml or more and 60 μg / ml·hr or more, and particularly preferably 70 μg / ml or more and 70 μg / ml·hr or more.

[0056] In a pharmacokinetic study using male cynomolgus monkeys, a self-emulsifying composition equivalent to 45 mg of ω3 PUFAs per kg of body weight was orally administered to male cynomolgus monkeys under fasting conditions for 12 hours or more, and the maximum ω3PUFA blood concentration calculated by subtracting the blood ω3 concentration before administration is preferably 50 μg / ml or more, more preferably 70 μg / ml. In addition, the area under the ω3PUFA blood concentration curve from 0 to 12 hours after administration is preferably 400 μg / ml·hr or more, more preferably 500 μg / ml. Furthermore, the combination of the maximum ω3PUFA blood concentration and the area under the ω3PUFA blood concentration curve is preferably 50 μg / ml or more and 400 μg / ml·hr or more, more preferably 70 μg / ml or more and 500 μg / ml·hr or more.

[0057] In a pharmacokinetic study using humans, a self-emulsifying composition equivalent to 1800 mg of ω3 PUFAs or EPAs is orally administered to humans before a meal, and the maximum ω3 PUFA blood concentration calculated by subtracting the blood ω3 concentration before administration is preferably 50 μg / mL or more, more preferably 100 μg / mL or more, particularly preferably 150 μg / mL or more, even more preferably 200 μg / mL or more, and most preferably 300 μg / mL or more. Alternatively, it is preferably 10 to 1000 μg / mL, more preferably 20 to 500 μg / mL, particularly preferably 40 to 300 μg / mL, even more preferably 50 to 150 μg / mL, and most preferably 50 to 100 μg / mL. In addition, the area under the ω3PUFA blood concentration curve from 0 to 72 hours after administration is preferably 500 μg / mL·hr or more, more preferably 1000 μg / mL·hr or more, particularly preferably 1500 μg / mL·hr or more, even more preferably 2000 μg / mL·hr or more, and most preferably 3000 μg / mL·hr or more. Alternatively, it is preferably 500 to 4500 μg / mL·hr, more preferably 600 to 3000 μg / mL·hr, particularly preferably 700 to 2500 μg / mL·hr, even more preferably 800 to 2000 μg / mL·hr, and most preferably 1000 to 1500 μg / mL·hr. In addition, the time to reach the maximum plasma concentration is preferably 6 hours or less, more preferably 5 hours or less, particularly preferably 3 hours or less, even more preferably 1 hour or less, and most preferably 0 hours or less. Alternatively, it is preferably 0.5 to 10 hours, more preferably 1 to 8 hours, particularly preferably 1.5 to 7 hours, even more preferably 2 to 5 hours, and most preferably 2.5 to 4 hours. The plasma elimination half-life is preferably 10 hours or more, more preferably 20 hours or more, particularly preferably 30 hours or more, even more preferably 40 hours or more, and most preferably 50 hours or more. Alternatively, it is preferably 0 to 150 hours, more preferably 10 to 120 hours, particularly preferably 30 to 100 hours, even more preferably 25 to 75 hours, and most preferably 25 to 50 hours.

[0058] In a pharmacokinetic study using humans, a self-emulsifying composition equivalent to 3600 mg of ω3 PUFAs or EPAs is orally administered to humans, for example, before, immediately after, or after a meal, and the maximum ω3 PUFA blood concentration calculated by subtracting the blood ω3 concentration before administration is preferably 50 μg / mL or more, more preferably 100 μg / mL or more, particularly preferably 150 μg / mL or more, even more preferably 200 μg / mL or more, and most preferably 300 μg / mL or more. Alternatively, it is preferably 10 to 1000 μg / mL, more preferably 20 to 500 μg / mL, particularly preferably 50 to 400 μg / mL, even more preferably 100 to 300 μg / mL, and most preferably 150 to 200 μg / mL. In addition, the area under the ω3PUFA blood concentration curve from 0 to 72 hours after administration is preferably 500 μg / mL·hr or more, more preferably 1000 μg / mL·hr or more, particularly preferably 1500 μg / mL·hr or more, even more preferably 2000 μg / mL·hr or more, and most preferably 3000 μg / mL·hr or more. Alternatively, 500 to 5000 μg / mL·hr is preferable, 1000 to 4700 μg / mL·hr is more preferable, 1500 to 4500 μg / mL·hr is particularly preferable, even more preferably 2000 to 4000 μg / mL·hr, and most preferably 2500 to 3500 μg / mL·hr. In addition, the time to reach the maximum plasma concentration is preferably 6 hours or less, more preferably 5 hours or less, particularly preferably 3 hours or less, even more preferably 1 hour or less, and most preferably 0 hours or less. Alternatively, it is preferably 0.5 to 10 hours, more preferably 1 to 8 hours, particularly preferably 1.5 to 7 hours, even more preferably 2 to 6 hours, and most preferably 3 to 5 hours. Also, the plasma elimination half-life is preferably 10 hours or more, more preferably 20 hours or more, particularly preferably 30 hours or more, even more preferably 40 hours or more, and most preferably 50 hours or more. Alternatively, it is preferably 0 to 150 hours, more preferably 10 to 120 hours, particularly preferably 30 to 100 hours, even more preferably 25 to 75 hours, and most preferably 25 to 50 hours.

[0059] In the case of a pharmacokinetic test using humans, the following numerical ranges may be used in addition to the above. That is, when a self-emulsifying composition with an amount of 1800 mg of EPAs is orally administered, for example, before a meal, immediately after a meal, or after a meal, and the maximum ω3PUFA plasma concentration calculated by subtracting the blood ω3 concentration before administration is not particularly limited, but may be, for example, 10 to 50, 50 to 100, 100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 350, 350 to 400, 400 to 450, 450 to 500, 500 to 600, 600 to 700, 700 to 800, 800 to 900, 900 to 1000, 10 to 30, 20 to 40, 30~50, 40~60, 50~70, 60~80, 70~90, 80~100, 90~110, 100~120, 110~130, 120~140, 130~150, 140~160, 150~170, 160~180, 170~190, 180~200, 190~210, 200~220, 220~240, 240~260, 260~280, 280~300, 10~20, 15~25, 20~30, 25~35, 30~40, 35~45, 40~50, 45~55, 50~55, 53~58, 55~60, 58~63, 60~65 , 63-68, 65-70, 68-73, 70-75, 73-78, 75-80, 78-83, 80-85, 83-88, 85-90, 88-93, 90-95, 93-98, 95-100, 98-103, 100-105, 103-108, 105-110, 108-113, 110-115, 113-118, 115-120, 118-123, 120-125, 123-128, 125-130, 128-133, 130-135, 133-138, 135-140, 138-143, 140-145, 143-148, 145 In the case where a self-emulsifying composition having an amount of 3600 mg of EPA is administered before, immediately after or after a meal, for example, the amount of EPA may be selected from the group consisting of 10 to 50, 50 to 100, 100 to 150, 150 to 160, 155 to 165, 160 to 170, 165 to 175, 170 to 180, 175 to 185, 180 to 190, 185 to 195, 190 to 200, 195 to 205, 200 to 210, 205 to 215, 210 to 220, 215 to 225, 220 to 230, 225 to 235, 230 to 240, 235 to 245, and 240 to 250 μg / ml.150~200, 200~250, 250~300, 300~350, 350~400, 400~450, 450~500, 500~600, 600~700, 700~800, 800~900, 900~1000, 10~30, 20~40, 30~50, 40~60, 50~70, 60~80, 70~90, 80~100, 90~110, 100~120, 110~130, 120~140, 130~150, 140~ 160, 150-170, 160-180, 170-190, 180-200, 190-210, 200-220, 220-240, 240-260, 260-280, 280-300, 10-20, 15-25, 20-30, 25-35, 30-40, 35-45, 40-50, 45-55, 50-55, 53-58, 55-60, 58-63, 60-65, 63-68, 65-70, 68-73, 70-75, 73-7 8, 75-80, 78-83, 80-85, 83-88, 85-90, 88-93, 90-95, 93-98, 95-100, 98-103, 100-105, 103-108, 105-110, 108-113, 110-115, 113-118, 115-120, 118-123, 120-125, 123-128, 125-130, 128-133, 130-135, 133-138, 135-140, 138-1 43, 140-145, 143-148, 145-150, 150-160, 155-165, 160-170, 165-175, 170-180, 175-185, 180-190, 185-195, 190-200, 195-205, 200-210, 205-215, 210-220, 215-225, 220-230, 225-235, 230-240, 235-245, 240-250μg / ml can be selected.

[0060] In addition, when a self-emulsifying composition in which the area under the ω-3 PUFA blood concentration curve from 0 to 72 hours after administration is an amount of 1800 mg in terms of EPAs is administered before, immediately after, or after a meal, the amount of EPAs is, for example, 500 to 1500, 1000 to 2000, 1500 to 2500, 2000 to 3000, 2500 to 3500, 3000 to 4000, 500 to 1000, 750 to 1250, 1000 to 1500, 1250 to 1750, 1500 to 2000, 1750 to 2250, 2000 to 2500, 2250 to 2750, 2500 to 3000, 2750 to 3250, 3000 to 350 0, 3250~3750, 3500~4000, 3750~4250, 4000~4500, 4250~4750, 4500~5000, 500~700, 600~800, 700~900, 800~1000, 900~1100, 1000~1200, 1100~1300, 1200~1400, 1300~1500, 1400~1600, 1500~1700, 1600~1800, 1700~1900, 1800~2000, 1900~2100, 2000~2200, 2100~2300, 2200~2400, 2300~2500, 2400~ 2600, 2500~2700, 2600~2800, 2700~2900, 2800~3000, 2900~3100, 3000~3200, 3100~3300, 3200~3400, 3300~3500, 3400~3600, 3500~3700, 3600~3800 , 3700~3900, 3800~4000, 3900~4100, 4000~4200, 4100~4300, 4200~4400, 4300~4500, 500~600, 550~650, 600~700, 650~750, 700~800, 750~850, 800~9 00, 850~950, 900~1000, 950~1050, 1000~1100, 1050~1150, 1100~1200, 1150~1250, 1200~1300, 1250~1350, 1300~1400, 1350~1450, 1400~1500, 1450~ 1550, 1500~1600, 1550~1650, 1600~1700, 1650~1750, 1700~1800, 1750~1850, 1800~1900, 1850~1950, 1900~2000, 1950~2050, 2000~2100, 2050~2150,2100~2200, 2150~2250, 2200~2300, 2250~2350, 2300~2400, 2350~2450, 2400~2500, 2450~2550, 2500~2600, 2550~2650, 2600~2700, 2650~2750, 2700 ~2800, 2750~2850, 2800~2900, 2850~2950, ​​2900~3000, 2950~3050, 3000~3100, 3150~3250, 3200~3300, 3250~3350, 3300~3400, 3350~3450, 3400~3500 , 3500 to 3600, 3600 to 3700, 3700 to 3800, 3800 to 3900, 3900 to 4000, 4000 to 4100, 4100 to 4200, 4200 to 4300, 4300 to 4400, 4400 to 4500 μg / mL·hr can be selected, and when a self-emulsifying composition containing 3600 mg of EPA is administered before, immediately after, or after a meal, for example, the ~1500, 1250~1750, 1500~2000, 1750~2250, 2000~2500, 2250~2750, 2500~3000, 2750~3250, 3000~3500, 3250~3750, 3500~4000, 3750~4250, 4000~450 0, 4250~4750, 4500~5000, 500~700, 600~800, 700~900, 800~1000, 900~1100, 1000~1200, 1100~1300, 1200~1400, 1300~1500, 1400~1600, 1500~1700, 1 600~1800, 1700~1900, 1800~2000, 1900~2100, 2000~2200, 2100~2300, 2200~2400, 2300~2500, 2400~2600, 2500~2700, 2600~2800, 2700~2900, 2800~ 3000, 2900~3100, 3000~3200, 3100~3300, 3200~3400, 3300~3500, 3400~3600, 3500~3700, 3600~3800, 3700~3900, 3800~4000, 3900~4100, 4000~4200,4100~4300, 4200~4400, 4300~4500, 500~600, 550~650, 600~700, 650~750, 700~800, 750~850, 800~900, 850~950, 900~1000, 950~1050, 1000~1100, 1050~1150, 1100~1200, 1150~1250, 1200~1300, 1250~1350, 13 00~1400, 1350~1450, 1400~1500, 1450~1550, 1500~1600, 1550~1650, 1600~1700, 1650~1750, 1700~1800, 1750~1850, 1800~1900, 1850~1950, 1900~2000, 1950~2050, 2000~2100, 2050~2150, 2100~2200, 2150~2 250, 2200~2300, 2250~2350, 2300~2400, 2350~2450, 2400~2500, 2450~2550, 2500~2600, 2550~2650, 2600~2700, 2650~2750, 2700~2800, 2750~2850, 2800~2900, 2850~2950, ​​2900~3000, 2950~3050, 3000~3100, You can select from 3150~3250, 3200~3300, 3250~3350, 3300~3400, 3350~3450, 3400~3500, 3500~3600, 3600~3700, 3700~3800, 3800~3900, 3900~4000, 4000~4100, 4100~4200, 4200~4300, 4300~4400, and 4400~4500μg / mL·hr.

[0061] In addition, when a self-emulsifying composition having an amount of 1800 mg to 3600 mg of EPAs is administered before, immediately after, or after a meal, the maximum plasma concentration reaching time is, for example, 0 to 2, 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, 6 to 8, 7 to 9, 8 to 10, 0 to 1, 0.5 to 1.5, 1 to 2, 1.5 to 2.5, 2 to 3, 2.5 to 3.5, 3 to 4, 3.5 to 4.5, 4 to 5, 4.5 to 5.5, 5 to 6, 5.5 to 6.5, 6 to 7, 6.5 to 7.5, 7 to 8, 7.5 to 8.5, 8 to 9, 8.5 to 9.5, 9 to 10, 0 to 0.5, 0.3 to 0.8, 0.5 to 1, 0.8 to 1. 3, 1~1.5, 1.3~1.8, 1.5~2, 1.8~2.3, 2~2.5, 2.3~2.8, 2.5~3, 2.8~3.3, 3~3.5, 3.3~3.8, 3.5~4, 3.8~4.3, 4~4.5, 4.3~4.8, 4.5~5, 4.8~5.3, 5~5.5, 5.3~5.8 , 5.5~6, 5.8~6.3, 6~6.5, 6.3~6.8, 6.5~7, 6.8~7.3, 7~7.5, 7.3~7.8, 7.5~8, 7.8~8.3, 8~8.5, 8.3~8.8, 8.5~9, 8.8~9.3, 9~9.5, 9.3~9.8, 9.5~10 hours are available.

[0062] In addition, when a self-emulsifying composition having a plasma elimination half-life of 1800 mg to 3600 mg of EPA is administered before, immediately after, or after a meal, the plasma elimination half-life may be, for example, 0 to 50, 25 to 75, 50 to 100, 75 to 125, 100 to 150, 125 to 175, 150 to 200, 0 to 20, 10 to 30, 20 to 40, 30 to 50, 40 to 60, 50 to 70, 60 to 80, 70 to 90, 80 to 100, 90 to 110 , 100~120, 110~130, 120~140, 130~150, 0~10, 5~15, 10~20, 15~25, 20~30, 25~35, 30~40, 35~45, 40~50, 45~55, 50~60, 55~65, 60~70, 65~75, 70~80, 75~85, 80~90, 85~95, 90~100, 95~105, 100~110, 105~115, 110~120 hours can be selected.

[0063] The present invention may be specified by combining two or more selected from the maximum ω-3 PUFA plasma concentration, the area under the ω-3 PUFA blood concentration curve from 0 to 72 hours after administration, the time to reach the maximum plasma concentration, and the plasma elimination half-life.

[0064] The self-emulsifying composition of the present invention may contain an emulsifying aid, a stabilizer, a preservative, a surfactant, an antioxidant, etc. Examples of the emulsifying aid include fatty acids having 12 to 22 carbon atoms, such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, and myristic acid, or salts thereof. Examples of the stabilizer include phosphatidic acid, ascorbic acid, glycerin, and cetanol. Examples of the preservative include ethyl paraoxybenzoate and propyl paraoxybenzoate. Examples of the surfactant include sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene alkyl phenyl ether, and polyoxyethylene polyoxypropylene alkyl ether. Examples of antioxidants include oil-soluble antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, pharma- ceutical acceptable quinones, astaxanthin, and alpha-tocopherol.

[0065] In addition, suitable pharmaceutical preparations can be prepared by appropriately selecting and combining additives such as commonly used suitable carriers or vehicles, colorants, flavorings, vegetable oils as necessary, harmless organic solvents or harmless solubilizing agents, emulsifiers, suspending agents (e.g., Tween 80, gum arabic solution), isotonicity agents, pH adjusters, stabilizers, flavorings, fragrances, preservatives, antioxidants, and absorption enhancers.

[0066] In particular, since ω-3 PUFAs are highly unsaturated, it is desirable to contain an effective amount of at least one antioxidant selected from the group consisting of oil-soluble antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, medicamentously acceptable quinones, astaxanthin, and α-tocopherol.

[0067] Since the self-emulsifying composition of the present invention is also used for medical purposes, it is preferable that the composition has a good appearance and is excellent in self-emulsifying property, composition dispersibility, emulsion stability and storage stability. The appearance of the self-emulsifying composition is preferably clear and does not separate, become cloudy, solidify or precipitate. If the appearance is poor, it is not preferable for use as a medicine and may not have the required performance such as self-emulsifying property. Regarding storage temperature, it is preferable that the appearance of the self-emulsifying composition and the encapsulated preparations thereof remain clear even at low and high temperatures, taking into consideration the possibility that the self-emulsifying composition and the encapsulated preparations thereof may be handled in cold or high temperature environments.

[0068] A self-emulsifying composition that has excellent self-emulsifying properties, composition dispersibility, and emulsion stability disperses quickly when it comes into contact with water, forming a microemulsion with an appropriate emulsion droplet size. The absorbency of oils such as EPA-E is related to the size of the emulsion droplet size, and by measuring this, it is possible to predict whether the absorbency will be good when administered to animals.

[0069] In the present invention, the "average emulsion droplet size" is the volume average diameter value in the emulsion composition measured by a particle size distribution measuring device (e.g., Nanotorac, manufactured by Nikkiso) using water as a dispersion medium and a standard measuring method (e.g., Setzero time 30 seconds, measuring time 30 seconds, average of three measurements). The average emulsion droplet size when the self-emulsifying composition of the present invention is dispersed in water or the like is 2 μm or less, and is not particularly limited as long as it is in a range that is excellent in emulsion dispersibility, emulsion stability or absorbency, but the average emulsion droplet size is usually 1.5 μm or less, more preferably 1.0 μm or less, even more preferably 0.5 μm or less, and most preferably 0.3 μm or less.

[0070] The self-emulsifying composition of the present invention can also be used in combination with a second active ingredient. The second active ingredient can be selected arbitrarily depending on the target disease and the severity of the symptoms, and is preferably one that does not weaken the effects of ω3 PUFAs, and examples of such second active ingredients include drugs for treating hyperlipidemia, antihypertensive drugs, antidiabetic drugs, antioxidants, blood flow improvers, bile acid derivatives, drugs for treating NAFLD / NASH, and drugs for inhibiting / treating the progression of dementia.

[0071] Preferred second active ingredients include, for example, polyenephosphatidylcholine, soybean oil unsaponifiable matter (soysterol), gamma oryzanol, riboflavin butyrate, dextran sulfate sodium sulfur-18, pantethine, and elastase, as well as statins such as pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and cerivastatin, fibrate drugs such as simfibrate, clofibrate, clinofibrate, bezafibrate, and fenofibrate, lipolytic enzyme inhibitors such as orlistat and cetilistat, resins such as cholestyramine and colestimide, and ezetimibe.

[0072] Antihypertensive drugs include angiotensin II receptor antagonists such as irbesartan, olmesartan medoxomil, candesartan lexetil, telmisartan, valsartan, and losartan potassium, angiotensin-converting enzyme inhibitors such as alacepril, imidapril hydrochloride, enalapril maleate, captopril, quinapril hydrochloride, cilazapril hydrate, temocapril hydrochloride, delapril hydrochloride, trandolapril, benazepril hydrochloride, perindopril, and lisinopril hydrate, azelnidipine, amlodipine besilate, aranidipine, and efoxalate. Examples of the drug include calcium antagonists such as nidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nifedipine, nimodipine, nitrendipine, nilvadipine, barnidipine hydrochloride, felodipine, benidipine, and manidipine, α-receptor blockers such as tolazoline and phentolamine, β-receptor blockers such as atenolol, metoprolol, acebutolol, propranolol, pindolol, carvedilol, and labetalol hydrochloride, α-receptor agonists such as clonidine and methyldopa, and diuretics such as eplerenone, hydrochlorothiazide, and furosemide.

[0073] Antidiabetic drugs include α-glucosidase inhibitors such as acarbose, voglibose, and miglitol, sulfonylurea hypoglycemic drugs such as gliclazide, glibenclamide, glimepiride, and tolbutamide, rapid-acting insulin secretion promoters such as nateglinide and mitiglinide, biguanide hypoglycemic drugs such as metformin hydrochloride and buformin hydrochloride, sitagliptin, vildagliptin, alogliptin, linagliptin, and tenegliptin. Other examples of anti-inflammatory drugs include dipeptidyl phosphatase 4 inhibitors such as saxagliptin, anagliptin, and saxagliptin; thiazolidinediones such as pioglizone hydrochloride and rosiglitazone maleate; glucagon-like peptide 1 derivatives such as exenatide and liraglutide; and sodium-glucose cotransporter 2 inhibitors such as ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin, canagliflozin, and empagliflozin.

[0074] Examples of antioxidants include vitamins such as ascorbic acid (vitamin C), tocopherol (vitamin E), and tocopherol nicotinate, as well as N-acetylcysteine ​​and probucol.

[0075] Examples of blood flow improvers include cilostazol, ticlopidine hydrochloride, alprostadil, limaprost, beraprost sodium, sarpogrelate hydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride, batroxobin, dihydroergotoxine mesylate, tolazoline hydrochloride, hepronicate, and Shimotsuto extract.

[0076] Examples of bile acid derivatives include ursodeoxycholic acid, chenodeoxycholic acid, bile powder, deoxycholic acid, cholic acid, bile extract, bear bile, bovine gall bladder, and dehydrocholic acid. In addition, preferred examples include biotin (vitamin B7), cyanocobalamin (vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine (vitamin B1), vitamin A, vitamin D, vitamin K, tyrosine, pyrodoxine (vitamin B6), branched-chain amino acids such as leucine, isoleucine, and valine, calcium, iron, zinc, copper, and magnesium. In addition, ingredients of foods for specified health uses and foods with nutritional functions, such as soy protein, chitosan, low-molecular-weight sodium alginate, dietary fiber derived from psyllium seed coat, phospholipid-bound soybean peptides, plant sterol esters, plant stanol esters, diacylglycerol, globin proteolysate, and tea catechins, are included.

[0077] Examples of therapeutic agents for NAFLD and NASH include statin drugs such as the above-mentioned pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and cerivastatin; angiotensin II receptor antagonists such as irbesartan, olmesartan medoxomil, candesartan lexetil, telmisartan, valsartan, and losartan potassium; biguanide hypoglycemic drugs such as metformin hydrochloride and buformin hydrochloride; thiazolidinediones such as pioglizone hydrochloride and rosiglitazone maleate; and farnesoid X receptor (hereinafter referred to as FXR) ligands such as aspirin, ursodeoxycholic acid, chenodeoxycholic acid, and obelicholic acid.

[0078] Examples of dementia progression inhibitors and therapeutic agents include acetylcholinesterase inhibitors such as donepezil hydrochloride and galantamine hydrobromide, NMDA receptor inhibitors such as memantine hydrochloride, antiplatelet agents such as aspirin, clopidogrel sulfate, cilostazol and ticlopidine hydrochloride, and factor Xa inhibitors such as rivaroxaban and apixaban. In addition, the above-mentioned hyperlipidemic drugs, antihypertensive drugs, antidiabetic drugs, antioxidants, blood flow improving agents, etc. can also be used as dementia inhibitors and therapeutic agents.

[0079] It is desirable for the self-emulsifying composition of the present invention to have at least one of the following effects, so that the pharmacological action of ω-3 PUFAs can be expressed: excellent appearance, excellent self-emulsifying ability, excellent composition dispersibility, excellent emulsion stability, excellent storage stability (including stability at low and high temperatures), excellent absorbability, particularly absorbability and absorption rate in the fasted state, and excellent convenience for patients to take the composition or excellent compliance.

[0080] The self-emulsifying composition of the present invention can be used as a therapeutic agent for various diseases of animals, particularly mammals, for example, a therapeutic agent for dyslipidemia (hypercholesterolemia, hyper LDL cholesterolemia, hyper non-HDL cholesterolemia, hyper VLDL cholesterolemia, hypo HDL cholesterolemia, hypertriglyceridemia, hyper ApoBemia, hypo ApoAIemia, etc.), a therapeutic agent for postprandial hypertriglyceridemia, an anti-arteriosclerotic agent, a platelet aggregation inhibitor, a therapeutic agent for peripheral circulatory failure, a preventive agent for the onset of cardiovascular events, a therapeutic agent for inflammatory diseases (NAFLD, NASH, etc.), a therapeutic agent for suppressing or treating dementia (Alzheimer's dementia, cerebrovascular dementia, mixed dementia, etc.), an anti-cancer agent, and a therapeutic agent for central diseases (depression, depressive state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.). In the treatment of the above diseases, the number of times of administration of the self-emulsifying composition of the present invention per day is not particularly limited, but it is preferably administered once a day, or divided into two or three times a day, more preferably administered once or twice a day, and particularly preferably administered once a day. Among the above diseases, the compound is particularly effective in improving or treating dyslipidemia and postprandial hypertriglyceridemia, preventing recurrence, or inhibiting progression to metabolic syndrome, cardiovascular and cerebrovascular events, peripheral ulcers, gangrene, etc. Mammals include, for example, humans, livestock animals such as cows, horses, and pigs, and household animals such as dogs, cats, rabbits, rats, and mice, and is preferably humans. In particular, the compound is expected to show an improving or therapeutic effect on dyslipidemia and postprandial hypertriglyceridemia in dyslipidemia patients, such as metabolic syndrome patients, who have increased blood lipids, developed insulin resistance, or have elevated blood pressure. EXAMPLES

[0081] Next, the present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to these.

[0082] Example 1 0.09g of water, 0.53g of polyoxyethylene (20) sorbitan oleate, 0.39g of soybean lecithin, and 4.0g of EPA-E were weighed out, sealed, and mixed while heating to about 70°C to prepare a self-emulsifying composition. The self-emulsifying composition was replaced with nitrogen, sealed, and stored at room temperature until evaluation. Table 1 shows the formulation of the self-emulsifying composition.

[0083] Examples 2 to 11, Comparative Examples 1 to 2 The self-emulsifying compositions of Examples 2 to 8 and the compositions of Comparative Examples 1 and 2 were prepared and stored in the same manner as in Example 1 so as to have the composition ratios shown in Table 1. Table 1 shows the formulations of the self-emulsifying compositions and compositions.

[0084] Comparative Examples 3 to 4 The composition of Comparative Example 3 was prepared and stored in the same manner as in Example 1 so as to have the composition ratio shown in Table 1. Table 1 shows the formulation of the composition.

[0085] The self-emulsifying compositions prepared by the above-mentioned method and the comparative composition were encapsulated in soft capsules containing gelatin as the main component.

[0086] Test Example 1 <Appearance Evaluation> After the self-emulsifying composition and the comparative composition were produced by the above-mentioned production method, they were left to stand and the appearance was evaluated after about 1 hour. If the composition had excellent compatibility and was homogeneous, it was rated as "clear," if it was separated, it was rated as "separated," and if it was opaque, it was rated as "cloudy." The test results are shown in Table 1.

[0087] Test Example 2 <Evaluation of self-emulsifying property> For the self-emulsifying compositions and the comparative compositions produced by the above-mentioned manufacturing method, 10 μL of each composition was dropped into 5 mL of purified water at 37° C. and the first solution of the Japanese Pharmacopoeia dissolution test in a test tube, and the self-emulsifying properties were evaluated. If the composition emulsified by dropping only, it was considered to be good, and if the composition did not emulsify naturally by dropping only, it was considered to be bad. Then, after lightly stirring under uniform conditions, the properties were evaluated. For the composition dispersibility, if the composition was dispersed, it was considered to be good, and if a part of the composition did not disperse and remained as a lump, it was considered to be bad. For the emulsion stability, if there was no separation of oil, it was considered to be good, and if there was separation of oil, it was considered to be bad. In addition, compositions that were not "clear" in the appearance evaluation were not evaluated because the composition was not uniform and the evaluation was considered to be inappropriate. The test results are shown in Table 1.

[0088] Test Example 3 <Evaluation of emulsion droplet size> About 1.5 mL of the emulsion composition obtained in Test Example 2 above was used to measure the average emulsion droplet size (volume average size) with a particle size distribution measuring device (Nanotorac, manufactured by Nikkiso Co., Ltd.) using water as a dispersion medium.

[0089] Test Example 4 <Evaluation of appearance after storage under harsh conditions> Compositions that were "clear" or "cloudy" in Test Example 1 were left to stand overnight (about 12 hours) at 5° C. or 40° C. and then evaluated for appearance. A composition that was highly compatible and homogeneous was rated as "clear," a composition that was separated was rated as "separated," and a composition that was opaque was rated as "cloudy." The test results are shown in Table 1.

[0090] Test Example 5 <Pharmacokinetics in Beagle Dogs> The prepared compositions or capsules were orally administered to six male beagle dogs (2-6 years old, body weight 8-13 kg, 3 Marshallese beagles, 3 Northern beagles) under fasting conditions, and the transition of EPA blood concentration was evaluated. Each subject animal was fasted for 18 hours or more before administration, and each animal was administered with the composition in an amount equivalent to 600 mg of EPA-E. Blood was collected before administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours after administration, and the plasma was separated and processed, and the EPA concentration in the plasma was measured by LC / MS / MS (a method in which a sample is separated by liquid chromatography, and then separated and measured by mass spectrometry). In addition, EPA-E stock solution filled in a capsule was also administered as a control group. Table 1 shows the maximum blood concentration (Cmax) and the area under the blood concentration curve (AUC 0-2 ), area under the blood concentration curve from 0 to 24 hours (AUC 0-24 In addition, when calculating each parameter, correction was made by subtracting the blood EPA concentration before administration from each blood concentration.

[0091] Test Example 6 <Pharmacokinetics in cynomolgus monkeys> The composition of Example 14 is orally administered to six cynomolgus monkeys (2-5 years old, body weight 2.70-4.65 kg, Hamley) under fasting conditions, and the change in blood concentration of EPA is evaluated. Each subject animal is fasted for at least 12 hours before administration, and each animal is administered with the self-emulsifying composition in an amount equivalent to 45 mg / kg of EPA-E. In addition, a control group is administered with EPA-E stock solution filled in a capsule. Blood is collected before administration and 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours after administration, and the plasma is separated and processed, after which the EPA in the plasma is measured by LC / MS / MS. From the test results, the maximum blood concentration (Cmax), the area under the blood concentration curve from 0 to 12 hours (AUC 0-12 ), area under the blood concentration curve from 0 to 72 hours (AUC 0-72 When calculating each parameter, a correction is made by subtracting the blood EPA concentration before administration from each blood concentration. The animals administered the composition of Example 14 had significantly lower Cmax and AUC0-12 In other words, when the self-emulsifying composition of Example 14 was administered, not only was the amount absorbed increased, but it was also confirmed that EPA was rapidly absorbed after oral administration.

[0092] Test Example 7 <Appearance of capsules> After filling and drying, the soft capsules obtained in the Examples were visually inspected for color, shape and properties of the filling liquid. Those that showed discoloration in color, those that showed distortion or dents in shape, and those that showed turbidity or separation in the filling liquid were rated as defective, and those that showed none of these were rated as normal. The test results are shown in Table 1. In the table below, "-" indicates that the corresponding component was not added or was not measured.

[0093] [Table 1]

[0094] In Example 1, the composition contains only polyoxyethylene sorbitan fatty acid ester as an emulsifier, and further contains lecithin and water in specific ranges, but the composition has a good appearance and excellent self-emulsifying properties, as shown in Table 1. These results show that the effect of the present invention can be achieved even in a composition containing lecithin and containing only polyoxyethylene sorbitan fatty acid ester as an emulsifier.

[0095] In Examples 2 to 10, the composition further contained polyoxyethylene castor oil as an emulsifier, and these compositions also had good appearances as shown in Table 1, and were excellent in self-emulsifying properties.

[0096] Example 11 is a composition further containing polyoxyethylene hydrogenated castor oil as an emulsifier, and these compositions also had good appearances as shown in Table 1 and were excellent in self-emulsifying properties, etc.

[0097] In Comparative Example 1, the composition did not contain water, but separation occurred in this composition, and in Comparative Example 2, the composition contained 8 mass % of water, but separation also occurred in this composition. In the present invention, water was used, without containing ethanol or polyhydric alcohol, in order to improve the compatibility of the composition. When water was not contained, the composition did not have sufficient compatibility and separated. In addition, even in the case of a formulation containing water, separation also occurred if the amount of water was too large relative to the composition. Separation did not occur in Examples 1 to 6, in which the water content was 1 to 4 mass %. This shows that it is important to contain a specific amount of water, about 0.5 to 6 mass %, in order to achieve excellent appearance, etc.

[0098] Comparative Example 3 is a composition that does not contain water but contains a polyhydric alcohol. This composition has a good appearance and is similar to Example 1 in that it has excellent self-emulsifying properties. However, separation occurred when stored overnight at 40° C. This shows that the inclusion of a specific amount of water, about 0.5 to 6 mass %, is important for achieving excellent appearance, etc.

[0099] Comparative Example 4 was a composition containing polyoxyethylene castor oil as an emulsifier but not containing polyoxyethylene sorbitan fatty acid ester, and this composition had a cloudy appearance. This shows that the inclusion of polyoxyethylene sorbitan fatty acid ester as an emulsifier is important for achieving excellent appearance.

[0100] Examples 1, 3 and 5 show the kinetic results of administering a self-emulsifying composition to fasted animals. The absorption rate parameters Cmax and AUC were significantly higher in animals administered these self-emulsifying compositions than in animals administered the control group (fasted state). 0-2The value was significantly high. That is, when the self-emulsifying composition of the embodiment is administered, not only is the EPA absorption amount increased up to 24 hours after oral administration compared to the control group, but it was confirmed that EPA is absorbed especially quickly after oral administration. Therefore, it is expected that the self-emulsifying composition of the present invention can be used as a self-emulsifying preparation that can rapidly and more rapidly increase blood EPA concentration and rapidly and more effectively exert its pharmacological action even when administered on an empty stomach such as before meals or before going to bed.

[0101] Self-emulsifying capsule preparations of Examples 2-1 and 2-2, and capsule preparation of Comparative Example 2-3 A self-emulsifying composition and the compositions of Comparative Examples 2-3 were prepared and stored in the same manner as in Example 1 so as to have the compositions shown in Table 2. Table 2 shows the formulations of the self-emulsifying compositions. Soft gelatin capsules were produced by filling this self-emulsifying composition in an amount of 375 mg for Examples 2-1 and 2-2, and 441 mg for Comparative Example 2-3 (each amount being 300 mg as EPA-E) using a rotary method. No deformation of the capsule shell was observed in the self-emulsifying capsule preparations produced by this method. Table 2 shows the composition of the liquid.

[0102] Test Example 8 <Capsule hardness> The hardness of each capsule formulation of Examples 2-1 and 2-2 and Comparative Example 2-3 was measured. In addition, the hardness of the formulations stored at 40°C and 75% relative humidity for 1, 2, and 4 weeks was similarly measured. The results of each formulation stored initially and at 40°C for 1, 2, and 4 weeks are shown in Table 2. Note that "initial" refers to the formulations stored at room temperature after capsule production until evaluation. In addition, each formulation was sealed in an aluminum package and stored at 40°C, so it was not affected by humidity.

[0103] [Table 2]

[0104] Examples 2-1 and 2-2 are preparations in which the self-emulsifying composition of the present invention is encapsulated. These capsules had a hardness of 20 kgf or more. On the other hand, Comparative Example 2-3, which contains a large amount of propylene glycol, a polyhydric alcohol, at 8.3 mass%, already had a low hardness at an early stage compared to the Examples. When the hardness was evaluated after storage at 40°C for 1 to 4 weeks in a sealed environment, Examples 2-1 and 2-2 showed almost no change, while Comparative Example 2-3 showed a hardness reduction to 57% of the initial hardness in 1 week, and further reduced over time. [Industrial Applicability]

[0105] The self-emulsifying composition of the present invention is excellent in at least one of compatibility (appearance), self-emulsifying property, composition dispersibility, emulsion stability, and absorbability, and is rapidly absorbed even when administered before meals, suppressing an increase in serum TG after meals. It is useful as a food for special dietary uses, a food with health claims (foods for specified health uses and foods with nutrient functions), a health food (supplement), or a medicine, when incorporated into various foods. Since the self-emulsifying composition of the present invention does not contain polyhydric alcohol or contains polyhydric alcohol in a low concentration, capsule softening and deformation caused by polyhydric alcohol during distribution and storage do not occur, and the risk of quality changes is low. Furthermore, since the composition does not denature, such as becoming cloudy or separating, even when stored in a low- or high-temperature environment, it has a quality that allows it to be stored in cold or high-temperature regions when used as a medicine.

Claims

1. When the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90% by weight of at least one compound selected from the group consisting of icosapentaenoic acid, its pharma- ceutically acceptable salts, and its esters; b) 0.5 to 6% by weight of water; c) 1 to 29% by mass of an emulsifier selected from the following emulsifiers i) and ii): i) polyoxyethylene sorbitan fatty acid esters, ii) at least one emulsifier selected from polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil; d) 3 to 25 parts by weight of lecithin per 100 parts by weight of icosapentaenoic acid, its pharma- ceutically acceptable salts, and its esters; Contains e) ethanol is 4% by mass or less of the total amount of the composition; f) A self-emulsifying composition, characterized in that the polyhydric alcohol is contained in an amount of 4 mass% or less of the total amount of the composition.

2. 2. The self-emulsifying composition of claim 1, wherein the emulsifier comprises a polyoxyethylene sorbitan fatty acid ester and a polyoxyethylene castor oil.

3. 3. The self-emulsifying composition according to claim 1 or 2, wherein the polyhydric alcohol is propylene glycol or glycerin.

4. The self-emulsifying composition according to claim 1 , wherein the content of ethanol is 1% by mass or less of the total amount of the composition.

5. 5. The self-emulsifying composition according to claim 1, wherein the polyhydric alcohol is contained in an amount of 1% by mass or less of the total amount of the composition.

6. When the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90% by weight of at least one compound selected from the group consisting of icosapentaenoic acid, its pharma- ceutically acceptable salts, and its esters; b) 0.5 to 6% by weight of water; c) 5 to 24% by weight of an emulsifier which is a polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil; d) containing 3 to 25 parts by mass of lecithin per 100 parts by mass of icosapentaenoic acid, its pharma- ceutical acceptable salts, and its esters; e) the polyoxyethylene castor oil is 120 parts by mass or less per 100 parts by mass of the polyoxyethylene sorbitan fatty acid ester; f) ethanol is 4% by mass or less of the total amount of the composition; 6. The self-emulsifying composition according to claim 1, wherein the content of g) polyhydric alcohol is 4% by mass or less of the total amount of the composition.

7. When the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90% by weight of at least one compound selected from the group consisting of icosapentaenoic acid, its pharma- ceutically acceptable salts, and its esters; b) 0.5 to 6% by weight of water; c) 1 to 29% by mass of an emulsifier selected from the following emulsifiers i) and ii): i) polyoxyethylene sorbitan fatty acid esters, ii) at least one emulsifier selected from polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil; d) containing 3 to 25 parts by mass of lecithin per 100 parts by mass of at least one compound selected from icosapentaenoic acid, a pharma- ceutically acceptable salt thereof, and an ester thereof; e) An encapsulated self-emulsifying preparation, which contains a self-emulsifying composition in an amount of 4% by mass or less of the total amount of the composition, as an internal solution in a capsule, A self-emulsifying formulation that is encapsulated in a hard and / or soft capsule.

8. The encapsulated self-emulsifying formulation of claim 7, wherein the capsule shell of the soft capsule comprises gelatin.

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