TWI788582B - SELF-EMULSIFYING FORMULATION AND SELF-EMULSIFYING COMPOSITION OF ω3 FATTY ACID - Google Patents

Abstract

The present invention provides a self-emulsifying composition, which contains 70-90% by mass of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts when the total amount of the self-emulsifying composition is 100% by mass. , and at least one compound in the group of esters thereof, 0.5-6% by mass of water, 1-29% by mass of polyoxyethylene sorbitan fatty acid ester as an emulsifier (optionally further containing polyoxygen base castor oil, except for lecithin) and a self-emulsifying composition of 3 to 40 parts by mass of lecithin relative to 100 parts by mass of ω3 polyunsaturated fatty acid, etc., its self-emulsifying property, composition dispersibility, emulsification stability Excellent performance and absorbency, and no ethanol and polyols are added, or the added concentration is low. The self-emulsifying composition can be used as food and medicine.

Description

Self-emulsifying preparation and self-emulsifying composition of ω3 fatty acid

The present invention provides a self-emulsifying composition containing at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof, its medicine, and its production method.

ω3 polyunsaturated fatty acids (hereinafter referred to as ω3 PUFA) include α-linolenic acid, eicosapentaenoic acid (hereinafter referred to as EPA), docosahexaenoic acid (hereinafter referred to as DHA), and the like. ω3 PUFA and its pharmaceutically acceptable salts and esters have been formulated in various foods due to their various effects such as anti-arteriosclerosis, inhibition of platelet aggregation, blood lipid reduction, anti-inflammation, anti-cancer, and central action. , marketed as health food or medicine.

EPA ethyl ester (hereinafter referred to as EPA-E) is sold in Japan as an oral treatment drug for the improvement of ulcers, pain and cold sensation associated with obstructive arteriosclerosis (hereinafter referred to as ASO) and hyperlipidemia (trade name EPADEL, Mochida Pharmaceutical). When EPA-E was orally administered under fasting conditions, the rise in plasma EPA concentration was lower than when EPA-E was orally administered after ingestion. This is considered to be due to the fact that the absorption of EPA-E requires the secretion of bile acids or ingredients from food as a carrier. Therefore, the usage of EPADEL is oral administration immediately after meals (see Non-Patent Document 1).

People who do not take breakfast and other meals due to the change of life style in recent years, or patients who can only take a small amount of meals, and those who can only take fluids (milk, rice soup, Ge soup, eggs, soup, fruit juice, oral nutrition) Patients, patients with low intestinal absorption capacity (elderly, patients with intestinal diseases, after intestinal surgery, terminal cancer patients, when taking lipase inhibitors) or patients who cannot take meals after cerebral infarction, etc., or observe Medication regulations became one of the topics.

In addition, although the normal value is shown on an empty stomach, the serum triglyceride (hereinafter referred to as TG) shows an abnormal increase after a meal, or the relationship between non-fasting hypertriglycerides and coronary artery patients is attracting attention. , and a ω3 PUFA preparation that can be rapidly absorbed even if it is administered before a meal and suppresses an increase in serum TG after a meal is desired.

As a self-emulsifying preparation that does not contain water itself and is easy to disperse and self-emulsify when it comes into contact with water, a self-emulsifying composition containing ω3 PUFA and active ingredients of fenofibrate, ethanol and a surfactant has been reported (see Patent Document 1 and Non-Patent Document 4).

Although these compositions contain ethanol for the purpose of increasing the solubility of fenofibrate, when the ethanol volatilizes, there will be capsule deformation or air bubbles, capsule deformation or cracking, etc. Quality changes, capsule contents become cloudy or separated, etc. Concerns about degeneration of nature. Furthermore, it is a preparation that cannot or is difficult to take for patients with alcohol (ethanol) intolerance.

A self-emulsifying composition containing ethanol or polyalcohol in addition to ω3 PUFA and a surfactant has been reported to form a dispersion with a small or very small average particle size when contacted with water (Patent Document 2).

As a self-emulsifying composition with a small ethanol content, it has been reported that ω3PUFA, an emulsifier with a hydrophilic-lipophilic balance (hereinafter referred to as HLB) of 10 or more, polyalcohols such as lecithin, propylene glycol, or glycerin, and self-emulsifying, Self-emulsifying composition with good oral absorbability and absorption speed on an empty stomach (Patent Document 3).

A self-emulsifying composition that contains ω3 PUFA ester and surfactant, does not contain ω3 PUFA free body, and is not affected by meals has been reported (Patent Document 4). The composition of EPA-E based on ω3 PUFA esters has been reviewed.

It has been reported that co-solvents such as polyols in the composition migrate toward the capsule membrane when encapsulated, and are deformed due to denaturation of the composition or softening of the capsule (Patent Document 5).

Self-emulsifying compositions generally use more emulsifiers, and the overall liquid volume of the composition is also large, so inflammation of the digestive tract occurs or the physiologically active ingredients of the oil dissolved in each capsule become less (patent literature 6) subject. Therefore, it is desired that the emulsifier used in the composition is non-toxic or less toxic even if it is administered continuously, and that the amount used is small.

In addition, from the viewpoint of dosability, in order to keep the amount of ω3 PUFA in one dose constant, when components other than ω3 PUFA in the self-emulsifying composition are increased, the dose of the drug in one dose will increase. Therefore, from the viewpoint of formulation miniaturization, it is also desirable to use less emulsifiers and alcohols.

[Prior Art Literature] [Patent Document]

[Patent Document 1] Japanese Patent Application No. 2008-516890

[Patent Document 2] Japanese Special Examination No. 2012-519728

[Patent Document 3] Specification of International Publication No. 2010/134614

[Patent Document 4] Specification of International Publication No. 2013/148136

[Patent Document 5] Japanese Patent Laid-Open No. 2011-12003

[Patent Document 6] Japanese Patent Laid-Open No. 2012-180337

[Non-patent literature]

[Non-Patent Document 1] EPADEL S Pharmaceuticals The Interview Form, Mochida Pharmaceutical, June 2012

[Non-Patent Document 2] "Guidelines for the Prevention of Arteriosclerotic Diseases 2007 Edition" compiled by the Japanese Society of Arteriosclerosis, Kyowa Project, April 25, 2007

[Non-Patent Document 3] Diabetes, Vol. 57, No. 9, 2382-2392, 2008

[Non-Patent Document 4] European Journal of Pharmaceutical Sciences, Volume 33, 351-360, 2008

[Non-Patent Document 5] "Dictionary of Pharmaceutical Additives 2007" compiled by the Japan Pharmaceutical Additives Association, July 25, 2007

A formulation that reduces the amount of ethanol and polyols contained in self-emulsifying compositions is desired.

Furthermore, a formulation that reduces the amount of emulsifier contained in self-emulsifying compositions is desired.

In addition, preparations that increase the content of ω3 PUFA in self-emulsifying compositions are desired.

Also, a self-emulsifying composition excellent in drug compliance is desired.

In addition, when using self-emulsifying compositions as pharmaceuticals, it is assumed that they will be stored in cold regions, etc., so it is expected that the composition will not be denatured such as cloudy or separated, and the appearance will be good when stored in a low-temperature or high-temperature environment other than room temperature. self-emulsifying composition.

In addition, it is desirable that the composition be a self-emulsifying composition with stable quality.

Also, it is desirable to provide a preparation in which the composition is encapsulated.

In addition, when the composition is encapsulated, a preparation that suppresses the softening of the capsule film and does not deform is desired.

Therefore, the object of the present invention is to provide a self-emulsifying composition with improved at least one of these properties, and a preparation for encapsulating the composition.

In view of the above problems, the inventors of the present invention actively examined components to replace ethanol or polyols, and found that a specific amount of water is useful for improving the compatibility of self-emulsifying compositions.

In addition, it was found that the water content in the composition is less than ethanol or polyols, but only 0.5-6% by mass, and the compatibility improvement effect of this small amount of water can further reduce the content of the emulsifier, so the high content of ω3PUFA self-emulsifying composition.

Furthermore, they discovered that a self-emulsifying composition excellent in at least one of the above-mentioned problems can be obtained with this composition, and thus completed the present invention.

In addition, it was also found that the content of emulsifier can be reduced to complete the invention of a self-emulsifying composition with a high content of ω3PUFA.

Furthermore, the composition of the present invention is a composition excellent in at least one of the above-mentioned problems.

That is, the first aspect of the present invention is the following self-emulsifying composition.

(1-1) A self-emulsifying composition characterized in that when the total amount of the self-emulsifying composition is 100% by mass, it contains a) 70 to 90% by mass of ω3 PUFA, which is pharmaceutically acceptable At least one compound in the group of salts and their esters, b) 0.5-6% by mass of water, c) 1-29% by mass of emulsifier (except lecithin), preferably polyoxyethylene sorbate An emulsifier of sugar-alcohol fatty acid ester, d) 3 to 40 parts by mass of lecithin relative to 100 parts by mass of ω3 polyunsaturated fatty acid, its pharmaceutically acceptable salt, and its ester, and e) ethanol and /or polyhydric alcohol is 4 mass % or less of the said composition whole quantity.

(1-2) A self-emulsifying composition characterized in that when the total amount of the self-emulsifying composition is 100% by mass, it contains a) 70 to 90% by mass of ω3 PUFA or a pharmaceutically acceptable salt thereof , and at least one compound selected from the group consisting of esters thereof, b) 0.5-6 mass % water, c) 1-29 mass % polyoxyethylene sorbitan fatty acid ester emulsifier, d) 3 to 40 parts by mass of lecithin relative to 100 parts by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, their pharmaceutically acceptable salts, and their esters, and e) ethanol is the aforementioned composition 4% by mass or less of the total amount of the composition, and f) polyhydric alcohol is less than 4% by mass of the total amount of the aforementioned composition.

(1-3) The self-emulsifying composition as described in (1-1) or (1-2), wherein the polyoxyethylene sorbitan fatty acid ester is at least one selected from the group consisting of the following : Polyoxyethylene(20) monolaurate, polyoxyethylene(20) sorbitan monopalmitate, polyoxyethylene(20) sorbitan monostearate, Tristearic acid polyoxyethylene (20) sorbitan, monoisostearic acid polyoxyethylene (20) sorbitan, monooleic acid polyoxyethylene (20) sorbitan and polyoxyethylene(20) sorbitan trioleate.

(1-4) The self-emulsifying composition described in any one of (1-1) to (1-3), wherein the emulsifier further contains polyoxyethylene hydrogenated castor oil and/or polyoxyethylene base castor oil.

(1-5) The self-emulsifying composition as described in any one of (1-1) to (1-4), wherein the emulsifier further contains polyoxyethylene castor oil.

(1-6) Self-milk as described in any one of (1-1) to (1-5) Chemical composition, wherein polyhydric alcohol is propylene glycol or glycerol.

(1-7) The self-emulsifying composition described in any one of (1-1) to (1-6), wherein the composition contains 0 to 4% by mass of polyhydric alcohol.

(1-8) The self-emulsifying composition described in any one of (1-1) to (1-6), wherein the composition does not contain more than 4% by mass of polyhydric alcohol.

(1-9) The self-emulsifying composition as described in any one of (1-1) to (1-8), wherein the polyhydric alcohol in the composition is 1% by mass or less.

(1-10) The self-emulsifying composition described in any one of (1-1) to (1-9), wherein the composition contains 0 to 1% by mass of polyhydric alcohol.

(1-11) The self-emulsifying composition described in any one of (1-1) to (1-8), wherein the composition does not contain more than 1% by mass of polyhydric alcohol.

(1-12) The self-emulsifying composition according to any one of (1-1) to (1-11), wherein the composition does not substantially contain a polyhydric alcohol.

(1-13) The self-emulsifying composition described in any one of (1-1) to (1-12), wherein ethanol in the composition is 4% by mass or less.

(1-14) The self-emulsifying composition described in any one of (1-1) to (1-12), wherein the composition contains 0 to 4% by mass of ethanol.

(1-15) The self-emulsifying composition described in any one of (1-1) to (1-12), wherein the composition does not contain more than 4% by mass of ethanol.

(1-16) The self-emulsifying composition according to any one of (1-1) to (1-15), wherein the composition does not substantially contain ethanol.

(1-17) The self-emulsifying composition described in any one of (1-1) to (1-16), wherein ω3PUFA, its pharmaceutically acceptable salt, and its ester are selected from EPA, DHA , such pharmaceutically acceptable salts, and such At least one of the group of esters.

(1-18) The self-emulsifying composition described in any one of (1-1) to (1-17), wherein the ester of ω3 PUFA is ethyl ester or triglyceride.

(1-19) The self-emulsifying composition according to any one of (1-1) to (1-18), wherein ω3 PUFA, its pharmaceutically acceptable salt, or its ester is EPA-E or DHA Ethyl ester (hereinafter referred to as DHA-E).

(1-20) The self-emulsifying composition described in any one of (1-1) to (1-19), which contains a compound selected from EPA, DHA, and pharmaceutically acceptable salts and esters thereof. At least one of the group is used as an active ingredient.

(1-21) The self-emulsifying composition according to any one of (1-1) to (1-20), which contains EPA-E and/or DHA-E as an active ingredient.

(1-22) The self-emulsifying composition according to any one of (1-1) to (1-21), which contains EPA-E as an active ingredient.

(1-23) The self-emulsifying composition described in any one of (1-1) to (1-22), wherein the lecithin is selected from soybean lecithin, enzymatically decomposed soybean lecithin, and hydrogenated soybean lecithin and at least one of the group consisting of egg yolk lecithin.

(1-24) The self-emulsifying composition as described in any one of (1-1) to (1-23), which is selected from polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester and The content of at least one emulsifier in the group consisting of polyoxyethylene polyoxypropylene glycol is less than 5% by mass of the total composition. Furthermore, the self-emulsifying composition described in any one of (1-1) to (1-23), wherein polyoxyethylene hydrogenated castor oil, polyoxyethylene glycol fatty acid ester and polyoxyethylene The content of each emulsifier in ethylpolyoxypropanol is less than 5% by mass of the total composition.

(1-25) The self-emulsifying composition described in any one of (1-1) to (1-24), wherein a) to d) are mixed in any order.

(1-26) The self-emulsifying composition as described in any one of (1-1) to (1-25), wherein the appearance of the composition is clear when the composition is left standing.

(1-27) The self-emulsifying composition as described in any one of (1-1) to (1-25), wherein the appearance of the composition is not separated or cloudy when the composition is left to stand.

(1-28) The self-emulsifying composition described in any one of (1-1) to (1-27), wherein the appearance of the composition when the composition is stored at 5°C or 40°C for 12 hours for clarification.

(1-29) The self-emulsifying composition described in any one of (1-1) to (1-28), wherein the appearance of the composition when the composition is stored at 5°C or 40°C for 12 hours Not separated or cloudy.

(1-30) The self-emulsifying composition described in any one of (1-1) to (1-29), wherein at least one of self-emulsifiability, composition dispersibility, and emulsification stability of the composition is good.

(1-31) The self-emulsifying composition described in any one of (1-1) to (1-30), wherein 10 μL of the composition is added dropwise to pure water at 37° C. or Japanese Pharmacopoeia Dissolution Test No. 1 In 5mL of solution, it is naturally emulsified only by adding it dropwise.

(1-32) The self-emulsifying composition described in any one of (1-1) to (1-31), wherein 10 μL of the composition is added dropwise to pure water at 37° C. or Japanese Pharmacopoeia Dissolution Test No. 1 In 5mL of solution, the composition is dispersed by stirring.

(1-33) The self-emulsifying composition described in any one of (1-1) to (1-32), wherein 10 μL of the composition is added dropwise to pure water at 37° C. or Japanese Pharmacopoeia Dissolution Test No. 1 In the liquid 5mL, there is no oil separation.

(1-34) The self-emulsifying composition as described in any one of (1-1) to (1-33), wherein male Beagle dogs are orally administered with the At least one compound in the group consisting of ω3 PUFA, its pharmaceutically acceptable salt, and its ester is calculated as a self-emulsified composition with an amount of 600 mg per dog, and it is calculated by subtracting the concentration of ω3 in the blood before administration. The highest plasma concentration of ω3PUFA (also known as the maximum blood concentration) is above 50 μg/mL and/or the area under the curve of the blood concentration of ω3PUFA between 0 and 2 hours after administration is above 30 μg/mL‧hr, the highest plasma concentration of ω3PUFA The medium concentration is above 50μg/mL and/or the area under the ω3PUFA blood concentration curve between 0 and 2 hours of administration is above 50μg/mL‧hr, the highest plasma concentration of ω3PUFA is above 60μg/mL and/or after administration of 0 The area under the ω3PUFA blood concentration curve between 2 hours and 60 μg/mL‧hr is above 60 μg/mL‧hr, or the highest plasma concentration of ω3PUFA is 70 μg/mL or above and/or the ω3PUFA blood concentration curve is under the ω3PUFA blood concentration curve between 0 and 2 hours The area is more than 70μg/mL‧hr.

(1-35) The self-emulsifying composition described in any one of the above (1-1) to (1-33), wherein male cynomolgus monkeys are starved for more than 12 hours and are selected from ω3PUFA, At least one compound in the group of pharmaceutically acceptable salts and esters thereof is 45 mg per 1 kg of body weight orally administered self-emulsified as described in any one of (1-1) to (1-33) For the composition, the highest plasma concentration of ω3PUFA calculated by subtracting the blood ω3 concentration before administration is 50 μg/mL or more and/or the area under the curve of ω3PUFA blood concentration between 0 and 12 hours after administration is 400 μg/mL ‧hr or more, or the highest plasma concentration of ω3PUFA is 70 μg/mL or more and/or the area under the curve of ω3PUFA blood concentration between 0 and 12 hours after administration is 500 μg/mL‧hr or more.

(1-36) Use of the self-emulsifying composition as described in any one of (1-1) to (1-33), which is selected from ω3 PUFA and its pharmaceutically acceptable salts before meals to humans Orally administer the self-emulsifying composition described in any one of (1-1) to (1-33) in an amount of 1800 mg per person at least one compound in the group formed by the ester and its ester, minus the amount before administration The highest plasma concentration of ω3 PUFA calculated by correcting the blood ω3 concentration is 50 μg/mL or more and/or the blood ω3 PUFA concentration 2 hours after administration is 10 μg/mL or more.

(1-37) The self-emulsifying composition according to any one of (1-1) to (1-33), which is selected from the group consisting of ω3 PUFA, pharmaceutically acceptable salts and esters thereof before meals to humans. At least one compound in the formed group is calculated as 1800 mg per person orally administered with the self-emulsifying composition described in any one of (1-1) to (1-33), minus the blood before administration The highest plasma concentration of ω3PUFA calculated by correcting the concentration of ω3 in the blood is above 10 μg/mL and/or the area under the curve of the blood concentration of ω3PUFA between 0 and 72 hours after administration is above 250 μg/mL‧hr.

(1-38) The self-emulsifying composition as described in any one of (1-1) to (1-37), wherein the polyoxyethylene sorbitan fatty acid ester in the composition is 100 Parts by mass, polyoxyethylene castor oil is 120 parts by mass or less.

(1-39) A self-emulsifying composition characterized by containing a) 70 to 90% by mass of EPA-E, b) 0.5 to 6% by mass, when the total amount of the self-emulsifying composition is 100% by mass % water, c) an emulsifier of 1-29 mass % polyoxyethylene sorbitan fatty acid ester, d) 3-40 parts by mass of lecithin relative to 100 parts by mass of the aforementioned EPA-E, And e) ethanol and/or polyols are 4% by mass or less of the total amount of the aforementioned composition.

(1-40) A self-emulsifying composition characterized by containing a) 70-90% by mass of EPA-E, b) 0.5-6% by mass when the total amount of the self-emulsifying composition is 100% by mass % of water, c) an emulsifier of polyoxyethylene sorbitan fatty acid ester of 1 to 29% by mass, d) 3 to 40 parts by mass of lecithin relative to 100 parts by mass of the aforementioned EPA-E, and e) ethanol is 4% by mass or less of the total amount of the composition, and f) polyol is 4% by mass or less of the total amount of the composition.

The second aspect of the present invention is the following encapsulated self-emulsifying preparation.

(2-1) A finely encapsulated self-emulsifying preparation, characterized in that the content liquid is the self-emulsifying composition as described in any one of (1-1) to (1-40), and it is encapsulated in a hard capsule and/or soft capsules.

(2-2) The encapsulated self-emulsifying preparation as described in (2-1), which has good hardness immediately after production.

(2-3) The encapsulated self-emulsifying preparation as described in (2-1) or (2-2), wherein the hardness immediately after production is 18 kgf or more.

(2-4) The encapsulated self-emulsifying preparation as described in any one of (2-1) to (2-3), wherein the preparation is injected into an aluminum package and sealed and stored at 40° C. for 1 week Compared with before storage, the hardness will not decrease by more than 6kgf.

(2-5) The encapsulated self-emulsifying preparation as described in any one of (2-1) to (2-4), wherein the preparation is injected into an aluminum package and sealed and stored at 40° C. for 1 week The hardness is above 20kgf.

(2-6) The encapsulated self-emulsifying preparation as described in any one of (2-1) to (2-5), wherein the preparation is injected into an aluminum package and sealed and stored at 40° C. for 1 week The hardness is more than 60% of the hardness before preservation.

(2-7) The preparation as described in any one of (2-1) to (2-6), which is at least one selected from the following group: dyslipidemia (hypercholesterolemia, high LDL Cholesterolemia, high non-HDL cholesterolemia, high VLDL cholesterolemia, low HDL cholesterolemia, hyperTGemia, hyperApoBemia, hypoApoAIemia, etc.) therapeutic agent, postprandial hyperTGemia therapeutic agent , anti-arteriosclerotic agents, platelet aggregation inhibitors, therapeutic agents for peripheral circulatory insufficiency, cardiovascular event prevention agents, inflammatory diseases (non-alcoholic fatty liver disease (hereinafter referred to as NAFLD), non-alcoholic fatty liver disease (hereinafter referred to as For NASH) etc.) therapeutic agent, dementia (Alzheimer's dementia, cerebrovascular dementia, mixed dementia, etc.) inhibitory therapeutic agent, anticancer agent and central disease (depression, melancholy) state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.) therapeutic agent.

The third aspect of the present invention is the following method for producing a self-emulsifying composition.

(3-1) A method for producing a self-emulsifying composition, characterized in that when the total amount of the self-emulsifying composition is 100% by mass, the following components are mixed in an arbitrary order: a) 70 to 90% by mass At least one compound selected from the group consisting of ω3PUFA, its pharmaceutically acceptable salt, and its ester, b) 0.5-6% by mass of water, c) 1-29% by mass of polyoxyethylene sorbitol An emulsifier of an anhydride fatty acid ester, and d) 3 to 40 parts by mass relative to 100 parts by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof phosphatidylcholine, and e) ethanol and/or polyhydric alcohol in the composition obtained above is mixed to be 4% by mass or less of the total composition.

(3-2) A method for producing a self-emulsifying composition characterized in that when the total amount of the self-emulsifying composition is 100% by mass, the following components are mixed in an arbitrary order: a) 70-90% by mass At least one compound selected from the group consisting of ω3PUFA, its pharmaceutically acceptable salt, and its ester, b) 0.5-6% by mass of water, c) 1-29% by mass of polyoxyethylene sorbitol An emulsifier of an anhydride fatty acid ester, and d) 3 to 40 parts by mass relative to 100 parts by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof lecithin, and in the composition obtained from the above mixing, e) ethanol is less than 4% by mass of the total amount of the aforementioned composition, and f) polyhydric alcohol is less than 4% by mass of the total amount of the aforementioned composition.

(3-3) The method for producing the self-emulsifying composition described in (3-1) or (3-2), comprising heating a), b) and/or c) of the aforementioned steps to 70°C The above and mixing steps.

The fourth aspect of the present invention is the medicine of the specific administration method of the following self-emulsifying composition.

(4-1) A preparation for orally administering any one of the aforementioned (1-1) to (1-40), (2-1) to (2-7) on an empty stomach or before bedtime The self-organized composition or encapsulated self-emulsifying preparation, medicine or veterinary medicine as described.

(4-2) A preparation for orally administering the self-emulsifying composition produced by the production method described in any one of the above (3-1) to (3-3) on an empty stomach or before going to bed Or encapsulated self-emulsifying preparations, medicines or veterinary medicines.

(4-3) The preparation described in (4-1) or (4-2), which is at least one selected from the group consisting of: dyslipidemia (hypercholesterolemia, hypercholesterolemia , high non-HDL cholesterol, high VLDL cholesterol, low HDL cholesterol, high TG blood, high ApoB blood, low ApoAI blood, etc.) therapeutic agent, postprandial hyper TG blood therapeutic agent, anti-arterial Sclerosing agents, platelet aggregation inhibitors, therapeutic agents for peripheral circulatory insufficiency, preventive agents for cardiovascular events, therapeutic agents for inflammatory diseases (NAFLD, NASH, etc.), anticancer agents, and central diseases (depression, depression, obsessive-compulsive , social anxiety disorder, panic disorder, etc.) preventive agent, therapeutic agent, progressive preventive agent.

(4-4) The preparation described in any one of (4-1) to (4-3) above, which is administered once a day.

(4-5) A method of administering and/or using the preparation described in any one of (4-1) to (4-4) above.

(4-6) A method for increasing the concentration of ω3 PUFA in plasma by orally administering the preparation described in any one of (4-1) to (4-4).

The fifth aspect of the present invention is a method for preventing, preventing and treating at least one disease selected from the following group.

(5-1) A method for preventing, preventing and treating at least one disease selected from the group consisting of: dyslipidemia (hypercholesterolemia, hypercholesterolemia, hyperlipidemia, non-HDL hypercholesterolemia, hyperlipidemia) Cholesterolemia, low HDL cholesterolemia, high TGemia, high ApoBemia, low ApoAIemia, etc.), postprandial hyperTGemia, anti-arteriosclerosis, increased platelet aggregation, peripheral circulatory insufficiency, cardiovascular events , inflammatory diseases (NAFLD, NASH, etc.), dementia (Alzheimer's dementia, cerebrovascular dementia, mixed dementia, etc.), cancer and central diseases (depression, depressive state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.), characterized by administering to the patient at least one self-emulsifying composition selected from the aforementioned (1-1) to (1-40), (2-1) to (2-7) or encapsulated self-emulsifying preparations, medicines or veterinary medicines.

(5-2) The method described in (5-1) above, which is to orally administer the aforementioned self-emulsifying composition or encapsulated self-emulsifying preparation, medicine or veterinary medicine on an empty stomach or before going to bed .

(5-3) The method described in (5-1) or (5-2) above, which is to administer the aforementioned self-emulsifying composition or encapsulated self-emulsifying preparation, pharmaceutical or veterinary drug once a day. medicine.

The sixth aspect of the present invention is the following self-emulsifying composition.

(6-1) A self-emulsifying composition comprising at least one compound selected from the group consisting of ω3 PUFA, its pharmaceutically acceptable salts and esters for male Beagle dogs under the condition of starvation for more than 18 hours The amount calculated as 600 mg per dog was orally administered to the aforementioned self-emulsified compositions (1-1) to (1-40), (2-1) to (2-7), and the blood before administration was subtracted The maximum plasma concentration of ω3PUFA calculated by correcting the concentration of ω3 in the blood is above 50 μg/mL and/or the area under the curve of the blood concentration of ω3PUFA between 0 and 2 hours after administration is above 30 μg/mL‧hr, the maximum concentration of ω3PUFA in plasma is 50μg/mL or more and/or the area under the ω3PUFA blood concentration curve between 0 and 2 hours of administration is 50μg/mL‧hr or more, and the highest plasma concentration of ω3PUFA is above 60μg/mL and/or 0 to 2 hours after administration The area under the ω3PUFA blood concentration curve between 60μg/mL‧hr or above, or the highest plasma concentration of ω3PUFA is above 70μg/mL and/or the area under the ω3PUFA blood concentration curve between 0 and 2 hours of administration is 70μg /mL‧hr or more.

(6-2) A self-emulsifying composition comprising at least one compound selected from the group consisting of ω3 PUFA, its pharmaceutically acceptable salts and esters thereof to male cynomolgus monkeys under fasting conditions for more than 12 hours Orally administer the self-emulsified composition of the aforementioned (1-1) to (1-40), (2-1) to (2-7) at 45 mg per 1 kg of body weight, and subtract the ω3 in the blood before administration The highest plasma concentration of ω3PUFA calculated by correcting the concentration is above 50μg/mL and/or the area under the curve of the blood concentration of ω3PUFA between 0 and 12 hours after administration is above 400μg/mL‧hr, or the maximum plasma concentration of ω3PUFA is 70μg /mL and/or the area under the ω3PUFA blood concentration curve between 0 and 12 hours after administration is 500μg/mL‧hr or more.

(6-3) A self-emulsifying composition comprising at least one compound selected from the group consisting of ω3 PUFA, its pharmaceutically acceptable salt, and its ester, which is orally administered to humans in an amount of 1800 mg per person before meals For the aforementioned self-emulsifying compositions (1-1) to (1-40), (2-1) to (2-7), the highest plasma concentration of ω3PUFA calculated by subtracting the blood ω3 concentration before administration was corrected The concentration is 50 μg/mL or more and/or the blood concentration of ω3 PUFA 2 hours after administration is 10 μg/mL or more.

(6-4) A self-emulsifying composition comprising at least one compound selected from the group consisting of ω3 PUFA, its pharmaceutically acceptable salt, and its ester, which is orally administered to humans in an amount of 1800 mg per person before meals For the aforementioned self-emulsifying compositions (1-1) to (1-40), (2-1) to (2-7), the highest plasma concentration of ω3PUFA calculated by subtracting the blood ω3 concentration before administration was corrected The concentration is above 10 μg/mL and/or the area under the curve of the blood concentration of ω3 PUFA between 0 and 72 hours after administration is above 250 μg/mL‧hr.

The self-emulsifying composition of the present invention contains a small amount of water instead of ethanol or polyalcohol, and the compatibility of the composition is improved by the composition, and the emulsifier used can be further reduced, so Excellent safety for animals (including humans). Furthermore, since the content of ω3 PUFA is high, the amount of emulsifiers used is reduced, and the ingestibility is excellent.

Furthermore, by reducing the content of ethanol or polyhydric alcohol due to water contained in the composition, or eliminating them, softening of the capsule film can be prevented, and capsule deformation does not occur.

In addition, it is excellent in at least one of compatibility (appearance), self-emulsification, composition dispersibility, emulsification stability, and absorbability. Even if it is administered before meals or after ingestion of low-fat food, it can still be rapidly absorbed and inhibits postprandial Serum TG increase, or the lack of essential fatty acids when taking lipase inhibitors can be prevented by administration before going to bed.

Furthermore, with the above composition, in addition to storage at room temperature, the composition does not separate or become cloudy even under low temperature (for example, 5° C.) or high temperature (for example, 40° C.) conditions, and has a good appearance.

The self-emulsifying composition of the present invention has at least one, preferably two or more of the above-mentioned preferred properties, more preferably all of them.

The present invention will be described in detail below.

In the present invention, the total amount of at least one compound selected from the group consisting of ω3PUFA, its pharmaceutically acceptable salt, and its ester is in the range of 70 to 90% by mass, and contains a specific emulsification in the range of 1 to 29% by mass. A self-emulsifying composition containing 3 to 40 parts by mass of lecithin relative to 100 parts by mass of ω3 PUFA, its pharmaceutically acceptable salt, and its ester, with no or low concentration of ethanol or polyol added, Or an encapsulated self-emulsifying preparation containing it as a content, its medicine, its preparation method and its use method.

In the present invention, the so-called "ω3 PUFA" is a fatty acid having multiple carbon-carbon double bonds in the molecule and the first double bond at the third position from the methyl side. Typical examples are α-linolenic acid, EPA, DHA, eicosatrienoic acid, stearidonic acid, eicosadonic acid, flounder acid, tetracosapentaenoic acid, and tetracosahexaenoic acid. Carbasexaenoic acid (nisinic acid), etc. The terms "ω3 PUFA", "EPAs", "DHAs" and "fatty acids" in the present invention are meant not only to refer to each ω3 PUFA, EPA, DHA and fatty acids, but also to include each of them, unless otherwise specified. Used in the meaning of pharmaceutically acceptable salts or esters, etc.

The ω3 PUFAs used in the present invention may be any of synthetic, semi-synthetic or natural products, and may also be in the form of natural oils containing them. Here, the so-called natural products refer to those extracted from natural oils containing ω3 PUFAs by conventional methods, crudely purified, or purified to a higher degree. Semi-synthetic products also include ω3 PUFAs produced by microorganisms, etc., and those ω3 PUFAs or natural ω3 PUFAs are subjected to chemical treatments such as esterification and transesterification. In the present invention, one of these ω3 PUFAs may be used alone, or two or more of them may be used in combination.

In the present invention, EPAs and DHAs are listed as preferable examples as ω3 PUFAs, and EPAs are listed as more preferable examples. In addition, pharmaceutically acceptable salts of ω3 PUFA are exemplified by inorganic bases such as sodium salts and potassium salts, organic bases such as benzylamine salts and diethylamine salts, arginine salts, lysine salts, etc., and basic amino acids. Salts and alkyl esters such as ethyl esters or mono-, di- and TG esters as esters. Preferable ones are ethyl esters or TG esters, and more preferred ones are ethyl esters. That is, preferred examples include EPA-E, TG ester of EPA, DHA-E, and TG ester of DHA, better examples include EPA-E and DHA-E, and even better examples include EPA-E .

The purity of the raw material ω3PUFAs used in the self-emulsifying composition of the present invention is not particularly limited, but usually based on the content of ω3PUFAs in all fatty acids in the composition, it is preferably at least 50% by mass, more preferably It is at least 70% by mass, more preferably at least 80% by mass, still more preferably at least 90% by mass, still more preferably at least 96.5% by mass, most preferably at least 98% by mass. High purity EPA is preferred. For example, the content ratio of EPA in ω3 PUFA is preferably 50% by mass or more, more preferably 60% by mass or more, and more preferably 70% by mass or more. It is 80% by mass or more, more preferably 90% by mass or more, most preferably 98% by mass or more. That is to say, the composition of this agent is preferably one with high purity of ω3 PUFA among all fatty acids, more preferably one with high purity of EPA + DHA of ω3 PUFA, and it is most preferable that it does not substantially contain DHA at all, or even if it contains Also, for example, the purity of EPA is less than 1.0% by mass, preferably less than 0.5% by mass, more preferably less than 0.2% by mass.

For example, when using EPA-E and DHA-E, if the purity of the composition of EPA-E is as above, the composition ratio of EPA-E/DHA-E and EPA-E+DHA-E in all fatty acids The content ratio is not particularly limited. As a preferable composition ratio, EPA-E/DHA-E is preferably at least 0.8, more preferably at least 1.0, and more preferably at least 1.2.

In addition, the composition of this agent may also contain polyunsaturated fatty acids other than ω3 PUFAs such as linoleic acid, γ-linolenic acid, and dihomo-γ-linolenic acid, and their pharmaceutically acceptable salts or esters. The content of arachidonic acid and their pharmaceutically acceptable salts or esters is relatively small, preferably less than 2% by mass, more preferably less than 1% by mass, and more preferably substantially free of arachidonic acid or The state of their pharmaceutically acceptable salts or esters.

The content of ω3PUFAs 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, still more preferably 74 to 84% by mass. One type of ω3 PUFA may be used, or a mixture of two or more types may be used. When it is a mixture of two or more types, the total amount of the mixture is 70 to 90% by mass of the self-emulsifying composition.

The ω3 PUFAs can be used as soft capsules containing high-purity EPA-E (more than 96.5% by mass) that are available in Japan as ASO and hyperlipidemia treatment drugs (trade name EPADEL: manufactured by Chida Pharmaceutical Co., Ltd.), or in the United States. Soft capsules containing high-purity EPA-E (trade name: VASCEPA: AMARIN) are available as TG blood medicine. Also, the mixture of EPA-E and DHA-E can be used, for example, Lovaza (registered trademark) (Glaxo Smith Kline: containing about 46.5% by mass of EPA-E and about 37.5% by weight of DHA-E) sold in the United States as a therapeutic agent for hyperTGemia. mass % soft capsules), or LOTRIGA (registered trademark) sold in Japan (Takeda Pharmaceutical Industry: soft capsules containing about 46.5 mass % of EPA-E and about 37.5 mass % of DHA-E). The mixture of EPA and DHA can be used, for example, Epanova (registered trademark) (AstraZeneca: a soft food containing about 50-60% by mass of EPA free acid and about 15-25% by mass of DHA free acid) sold in the United States as a therapeutic agent for hyperTGemia. capsules).

Purified fish oil can also be used as ω3 PUFAs. Also, monoglycidyl ethers, diglycidyl ethers, TG derivatives, or combinations thereof of ω3 PUFAs are also one of the preferred aspects.例如以Incromega F2250、F2628、E2251、F2573、TG2162、TG2779、TG2928、TG3525及E5015(英國，Yorkshire，Croda International PLC)、及EPAX6000FA、EPAX5000TG、EPAX4510TG、EPAX2050TG、EPAX7010EE、K85TG、K85EE及80EE(挪威，Lysaker , Pronova Biopharma) and other preparations containing ω3 PUFAs are already on the market, and they can also be obtained and used.

In the present invention, "polyoxyethylene sorbitan fatty acid ester" is a polyoxyethylene ether of a fatty acid ester obtained by esterifying a part of the hydroxyl group of anhydrous sorbitan with a fatty acid. Various compounds are sold depending on the esterified fatty acid, such as polyoxyethylene monolaurate (20) sorbitan (NIKKOL TL-10, Polysorbate 20, Tween 20), polyoxyethylene monopalmitate Ethyl (20) sorbitan (NIKKOL TP-10V, Polysorbate 40, Tween40), polyoxyethylene monostearate (20) sorbitan (NIKKOL TS-10MV, Polysorbate 60, Tween60), three Polyoxyethylene stearate (20) sorbitan (NIKKOL TS-30V, Polysorbate 65), polyoxyethylene monoisostearate (20) sorbitan (NIKKOL TI-10V), mono Polyoxyethylene Oleate (20) Sorbitan (NIKKOL TO-10MV, Polysorbate 80, Tween80), Polyoxyethylene Trioleate (20) Sorbitan (NIKKOL TO-30V, Polysorbate 85) etc., preferably exemplified by monooleic acid polyoxyethylene (20) sorbitan, monooleic acid polyoxyethylene (20) sorbitan, trioleic acid polyoxyethylene (20) Sorbitan is better exemplified by polyoxyethylene(20) sorbitan monooleate.

In addition, one of these may be used alone, or two or more of them may be used in combination. The so-called polyoxyethylene sorbitan fatty acid ester in the present invention is used in the meaning that includes all the above-mentioned compounds.

The content of the 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 usually the total amount of the self-emulsifying composition is 100% by mass %, it is 1 to 29 mass%, preferably 3 to 20 mass%, more preferably 5 to 15 mass%, more preferably 5 to 9 mass%.

In the present invention, "polyoxyethylene castor oil" is a compound in which ethylene oxide is added and polymerized on castor oil. Various compounds are sold according to the average added mole number of ethylene oxide, for example, NIKKOL CO-3 (Nikko Chemical Co., Ltd.) with an average added mole number of 3, and NIKKOL with an average added mole number of 10 CO-10 (Nikko Chemicals Co.), EMALEX C-20 (Japan Emulsifier Company) with an average added mole number of 20, EMALEX C-30 (Japan Emulsifier Company) with an average added mole number of 30, and an average added mole number Kolliphor EL (BASF) (Polyoxyl 35 castor oil) with a molar number of 35, EMALEX C-40 with an average molar number of 40 (Nippon Emulsifier Company) and EMALEX C-50 with an average molar number of 50 ( Japan Emulsifier Co., Ltd.), preferably Kolliphor EL. In addition, one of these may be used alone, or two or more of them may be used in combination. The so-called polyoxyethylene castor oil in the present invention is used in the meaning of including all the above-mentioned compounds unless otherwise specified. use.

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 usually when the total amount of the self-emulsifying composition is 100% by mass, it is 1 % to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, more preferably 5 to 9% by mass. And, with respect to 100 mass parts of polyoxyethylene sorbitan fatty acid esters in the composition, polyoxyethylene castor oil is preferably at most 150 mass parts, preferably at most 140 mass parts, more preferably at most It is contained in a ratio of not more than 130 parts by mass, more preferably not more than 120 parts by mass, still more preferably not more than 110 parts by mass, most preferably not more than 100 parts by mass. Moreover, the ratio of polyoxyethylene sorbitan fatty acid ester to polyoxyethylene castor oil in the composition is preferably 100 parts by mass: 5 to 150 parts by mass, preferably 100 parts by mass: 10 to 100 parts by mass. Less than 140 parts by mass, more preferably 100 parts by mass: less than 20 to 130 parts by mass, more preferably 30 to 120 parts by mass, more preferably 100 parts by mass: 50 to 110 parts by mass, most preferably 100 parts by mass: It is contained in a ratio of 80 to 120 parts by mass.

In the present invention, "polyoxyethylene hydrogenated castor oil" is a compound obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil obtained by hydrogenating castor oil. Various compounds are sold depending on the average degree of polymerization of ethylene oxide, exemplified by, for example, 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 Corporation) and Polyoxyethylene(100) hydrogenated castor oil (NIKKOL HCO-100, Nikko Chemicals Co., Ltd.), preferably polyoxyethylene(60) hydrogenated castor oil. In addition, one of these may be used alone, or two or more of them may be used in combination. The polyoxyethylene hydrogenated castor oil in the present invention is used in the meaning including all 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 usually when the total amount of the self-emulsifying composition is 100% by mass, it is 1 to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, more preferably 5 to 9% by mass. And, relative to 100 mass parts of polyoxyethylene sorbitan fatty acid esters in the composition, polyoxyethylene hydrogenated castor oil is preferably 150 mass parts or less, preferably 140 mass parts or less, more preferably 140 mass parts or less It is contained in a ratio of not more than 130 parts by mass, more preferably not more than 120 parts by mass, still more preferably not more than 110 parts by mass, most preferably not more than 100 parts by mass. Moreover, the ratio of polyoxyethylene sorbitan fatty acid ester to polyoxyethylene castor oil in the composition is preferably 100 parts by mass: 5 to 150 parts by mass, preferably 100 parts by mass: 10 to 100 parts by mass. Less than 140 parts by mass, more preferably 100 parts by mass: 20 to 130 parts by mass, more preferably 30 to 120 parts by mass, more preferably 100 parts by mass: 50 to 110 parts by mass, most preferably 100 parts by mass: It is contained in a ratio of 80 to 120 parts by mass.

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 aspects of the present invention contains polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and/or polyoxyethylene hydrogenated castor oil as an emulsifier. In addition, another preferred aspect 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 also contain emulsifiers other than polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers, but the content thereof is limited to the emulsifying agent used in the composition. When the total amount of the agent is 100 parts by mass, it is at most 20 parts by mass, more preferably at most 10 parts by mass, more preferably less than 5 parts by mass, and preferably not substantially contained. Furthermore, the emulsifier that can be contained is not particularly limited as long as it satisfies at least one of the aforementioned problems, and examples thereof include sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, propylene glycol fatty acid ester , saturated polyglycolized glycidyl ether, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, polyethylene glycol fatty acid ester, tocopherol-polyethylene glycol-succinate (TPGS), etc. .

The total content of emulsifiers 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 usually, when the total amount of the self-emulsifying composition is 100% by mass, it is 1 to 29% by mass, It is preferably from 3 to 27% by mass, more preferably from 5 to 27% by mass, still more preferably from 5 to 24% by mass, still more preferably from 10 to 20% by mass. Alternatively, it is preferably from 8 to 27 mass%, more preferably from 10 to 27 mass%. Moreover, it is 5-45 mass parts with respect to 100 mass parts of ω3 PUFAs, Preferably it is 10-45 mass parts, More preferably, it is 15-35 mass parts, More preferably, it is 15-20 mass parts.

The compositions and medicines of the present invention contain a small amount of water. It is generally believed that adding water compatibility to compositions containing hydrophobic lipids will make them worse. Since water is included in the composition, the compatibility of the composition becomes good, and polyol or ethanol is not required, so even without polyol or ethanol, the appearance is clear, and the composition does not separate or become cloudy.

A small amount of water can be added when the self-emulsifying composition is prepared, or the water in the gelatin film can migrate to the self-emulsifying composition when encapsulating with gelatin capsules or the like.

Moreover, when polyol or ethanol is not contained, the capsule will not soften or deform when encapsulated, and alcohol-intolerant patients will not cause side effects due to ethanol when taken.

When the total amount of the self-emulsified composition is 100% by mass, water is preferably from 0.5 to 6% by mass, more preferably from 0.5 to 4% by mass, and still more preferably from 0.5 to 3% by mass. Preferably it is 1 to 3% by mass. Moreover, it is preferably at least 0.5 mass % and less than 3 mass %, more preferably at least 0.5 mass % and less than 1.5 mass %.

In the present invention, "lecithin" is one type of glycerophospholipid, and examples include soybean lecithin, enzymatically decomposed soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, hydrogenated phospholipid, milk-derived phospholipid, lysed egg Phospholipids, Phosphocholine and Phosphatidylserine. Preferable examples include soybean lecithin, enzymatically decomposed soybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin, and more preferred examples are soybean lecithin. In addition, one of these may be used alone, or two or more of them may be used in combination. The so-called lecithin in the present invention is used in the meaning including all the above-mentioned glycerophospholipids unless otherwise specified. In the present invention, lecithin is not included in the emulsifier (it is not included in the emulsifier which constitutes the requirement, and the amount is not added to the emulsifier content in the composition).

Various products such as purified soybean lecithin (Nisshin OILLIO), purified egg yolk lecithin (Asahi Kasei PHAMA), and egg yolk lecithin PL-100M (KEWPIE) are commercially available. Soybean lecithin is commercially available such as BASIS LP-20B (Nissin Oil), Lipoid S45, S20 (LIPOID), etc. Enzyme-decomposed lecithin is commercially available such as BASIS LP-20E (Nissin Oil), Phospholipon Various products such as RLPC20 (LIPOID) can also be obtained and used.

The content of lecithin added to the self-emulsifying composition of the present invention is not particularly limited, but is preferably from 3 to 40 parts by mass, more preferably from 3 to 30 parts by mass, and more preferably with respect to 100 parts by mass of ω3 PUFAs 3 to 25 parts by mass, more preferably 3 to 20 parts by mass, 3.2 to 17 parts by mass, 3.5 to 15 parts by mass, and 3.7 to 17 parts by mass. Alternatively, it is preferably from 3 to 15 parts by mass, more preferably from 3 to 12 parts by mass, more preferably from 3 to 10 parts by mass, most preferably from 5 to 10 parts by mass.

When the total amount of the self-emulsifying composition is 100% by mass, lecithin is preferably 2.1 to 36% by mass, more preferably 2.1 to 20% by mass, more preferably 2.1 to 15% by mass, most preferably 2.1% by mass. ~10% by mass.

When the total content of the emulsifiers in the self-emulsifying composition is 100 parts by mass, the lecithin is preferably from 10 to 75 parts by mass, more preferably from 11 to 60 parts by mass, still more preferably from 20 to 55 parts by mass. Preferably it is 25 to 35 parts by mass. When the total content of polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition is 100 parts by mass, lecithin is preferably 10 to 150 parts by mass, more preferably 20 to 120 parts by mass, More preferably, it is 40 to 90 parts by mass. Preferably it is 50 to 70 parts by mass.

In the present invention, "polyol" refers to a polyol compound having a structure in which one hydroxyl group is substituted on each of two or more carbon atoms of a chain aliphatic hydrocarbon or a cyclic aliphatic neck. Examples are ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butanediol, tetramethylene glycol, 1,3-butanediol, 2,3-butanediol and pentamethylene Dihydric alcohols such as diol, trihydric alcohols such as glycerol, trimethylolpropane and 1,2,6-hexanetriol, diethylene glycol, dipropylene glycol, triethylene glycol, polyethylene glycol, poly Polyol polymers such as propylene glycol and polyglycerol, etc., are preferably propylene glycol or glycerin. Glycerin also includes concentrated glycerin. The polyol in the present invention is used in the sense of including all the above-mentioned polyol compounds unless otherwise specified.

The content of the polyhydric alcohol added to the self-emulsifying composition of the present invention is preferably within a range that does not deform the capsule when filling the composition into a capsule. For example, when the whole composition is 100% by mass, it is preferable not to contain more than 4% by mass of polyhydric alcohol in the composition. Moreover, the polyol content in the composition is preferably at most 4 mass %, more preferably at most 3 mass %, further preferably at most 2 mass %, still more preferably at most 1 mass %. Preferably it is 0% by mass.

The ethanol contained in the self-emulsifying composition of the present invention is expected to be within the range that does not cause quality changes during the encapsulation manufacturing process or distribution/storage, and does not cause denaturation of the capsule contents, and is desirably in the range of daily dosage Do not exceed the scope of the actual records of drug use. For example, when the whole composition is 100% by mass, it is preferable not to contain more than 4% by mass of ethanol in the composition. Furthermore, the ethanol content in the composition is preferably at most 4 mass %, more preferably at most 3 mass %, further preferably at most 2 mass %, still more preferably at most 1 mass %. Preferably it is 0% by mass.

In addition, when ethanol and polyols are contained in the self-emulsifying composition, when the whole composition is taken as 100% by mass, the total content of ethanol and polyols in the composition is preferably not more than 4% by mass. A preferred aspect is that ethanol and polyols are not substantially contained. In addition, the total amount of ethanol and polyol in the composition is preferably at most 4% by mass, more preferably at most 3% by mass, still more preferably at most 2% by mass, still more preferably at most 1% by mass. Preferably it is 0 mass % or less.

The preferred ethanol concentration can be appropriately determined according to the concentration of ω3PUFA in the self-emulsifying composition and the daily dosage. When the self-emulsifying composition of the present invention is orally administered per day in terms of ω3 PUFA at 1800 mg per body, for example, if ethanol is 0.135 mass % or less in a preparation with ω3 PUFA of 75 mass %, it will not exceed the value recorded in the Pharmacopoeia of Pharmaceutical Additives The maximum daily usage is 3.26mg.

In the above-mentioned self-emulsifying composition of the present invention containing ω3 PUFAs and emulsifiers, a preferred aspect is to contain 1) EPA-E and/or DHA-E, 2) water, and 3) polyoxygen as emulsifiers. Combination of ethylidene sorbitan fatty acid ester, 4) lecithin. When the total amount of the self-emulsifying composition is 100% by mass, 1) EPA-E and/or DHA-E is 70 to 90% by mass, 2) water is 0.5 to 6% by mass, and 3) polyoxyethylene is included The emulsifier of ethyl sorbitan is 1-29% by mass (except lecithin), and 4) 3-40 parts by mass of lecithin relative to 100 parts by mass of EPA-E and/or DHA-E. Another preferred state is to contain 1) EPA-E and/or DHA-E, 2) water, 3) polyoxyethylene sorbitan fatty acid ester as emulsifier, 4) polyoxygen castor oil, 5 ) combination of lecithin. When the total amount of the self-emulsifying composition is 100% by mass, 1) EPA-E and/or DHA-E is 70 to 90% by mass, 2) water is 0.5 to 6% by mass, and 3) polyoxyethylene is included The emulsifier of ethyl sorbitan and polyoxygenated castor oil (except lecithin) is 1~29% by mass, 4) relative to 100 parts by mass of EPA-E and/or DHA-E, the amount of lecithin is 3~40% parts by mass. Another preferred aspect is to contain 1) at least one compound selected from ω3 PUFA, its pharmaceutically acceptable salt, and its ester, 2) water, and 3) polyoxyethylene sorbitan fatty acid as an emulsifier A combination of esters and polyoxyethylene castor oil, 4) lecithin. When the total amount of the self-emulsifying composition is set as 100% by mass, 1) at least one compound selected from ω3PUFA, its pharmaceutically acceptable salt, and its ester is 70-90% by mass; 2) water is 0.5-90% by mass. 6% by mass, 3) Based on the emulsifier containing polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil, the emulsifier is 5 to 24% by mass, relative to polyoxyethylene 100 parts by mass of sorbitan fatty acid ester, 120 parts by mass or less of polyoxyethylene castor oil, 4) 100 parts by mass of at least one compound selected from ω3 PUFA, its pharmaceutically acceptable salt, and its ester , the lecithin is 3 to 40 parts by mass of lecithin.

The self-emulsifying composition of the present invention can be enclosed in capsules. Capsules can be selected from hard capsules or soft capsules, preferably soft capsules. The form of the soft capsule is not necessarily limited, but it is preferably a rotary-processed soft capsule or a seamless capsule.

In the soft capsule of the present invention, the composition of the capsule film is not necessarily limited, and the main components include, for example, gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hydroxypropylmethylcellulose, hydroxyl Propyl cellulose, etc., and various conventional ingredients, but gelatin is preferred. The 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. Acid-treated gelatin or alkali-treated gelatin is preferred. The source of gelatin is not necessarily limited, for example, bovine bone, bovine hide, pork bone, pig skin, fish scale, fish skin, preferably bovine bone, bovine hide, pork bone, and pig skin.

"Gelatin" is generally used in the production of soft capsules, for example, pharmaceutical gelatin (gelatin and purified gelatin) specified in the 16th edition of the revised Japanese Pharmacopoeia. Gelatin can also be used in combination of 2 or more types. The capsule film contains other plasticizers.

The "plasticizer" formulated in the capsule film is preferably commonly used in the manufacture of soft capsules, such as glycerin (such as concentrated glycerin), ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, etc. Sugar alcohols such as alcohol, sorbitol, mannitol, xylitol, etc. These plasticizers can also be used in combination of 2 or more types. Among them, glycerol and sorbitol are preferred. Furthermore, a combination of glycerol and sorbitol is also preferably used. In this case, the mass ratio of glycerol and sorbitol is preferably used in the range of 1:5 to 5:1, more preferably in the range of 1:3 to 3:1.

In the soft capsule of the present invention, especially in the seamless capsule, the capsule film liquid preferably contains gelatin and plasticizer in a weight ratio of 10:1~1:10, more preferably 10:1~1: 1 included.

The weight ratio of capsule film liquid to capsule contents is usually 10:1~1:10, preferably 3:1~1:10.

Furthermore, various additives commonly used in capsule films, such as amino acids, citric acid, glycerin, sorbitol, trehalose and other plasticizers, preservatives, pigments or coloring agents such as titanium oxide, organic acids, etc., may be added as needed. .

The composition for a capsule film can be produced by mixing and dissolving gelatin, a plasticizer, and various additives as necessary in water at normal temperature or under warming.

The self-emulsifying preparation encapsulated with the self-emulsifying composition of the present invention as the content liquid preferably has good hardness immediately after manufacture, and the hardness will not decrease after storage. Decreased hardness will not only deform the capsule, but will also become brittle and cause the capsule to rupture, causing the liquid in the capsule to flow out, so the quality is not good. Whether the capsule is softened or not can be confirmed by measuring the hardness with a general hardness tester.

The hardness immediately after manufacture of the encapsulated self-emulsifying preparation of the present invention is at least 18 kgf, preferably at least 20 kgf, more preferably at least 22 kgf. In addition, it is expected that when the sealed aluminum package is stored at 40°C for one week, the hardness will not decrease substantially, or the hardness will not decrease by more than 6kgf, and the hardness after storage at 40°C for one week will be more than 10kgf. It is preferably at least 15 kgf, more preferably at least 20 kgf.

Also, when the hardness immediately after production is 100%, the hardness when stored at 40° C. for one week in a sealed aluminum package is maintained at 60% or more, preferably 70% or more, more preferably 80% or more. Furthermore, it is better to maintain a hardness of more than 85%, and more preferably more than 90%.

The dose and period of administration of ω3 PUFAs used in the self-emulsifying composition of the present invention are sufficient doses and periods for exhibiting the desired effect, but may vary depending on the administration method, the frequency of administration per day, the degree of symptoms, Appropriate increase or decrease due to weight, age, etc.

In the case of oral administration, for example, EPA-E is administered in 1 to 3 times, and it is 0.1 to 5 g/day for each individual, preferably 0.2 to 3 g/day, more preferably 0.3 to 3 g/day, and more preferably 0.5~3g/day, but the total amount can also be administered once or in fractions as needed. The frequency of administration per day is preferably administered once a day, or divided into two or three times a day. For 1 time/day administration, for example, when using EPA-E as a soft capsule containing 1 g, 1~10 capsules can be administered, preferably 1~8 capsules, more preferably 1~6 capsules, and more preferably 1~4 capsules. capsules, preferably 1~3 capsules. In addition, soft capsules containing 1 g and soft capsules containing 0.5 g in terms of EPA-E can be combined at 0.5 g/time, 1.5 g/time, 2.5 g/time, 3.5 g/time, 4.5 g/time or 5.5g/time in the form of administration. The aforementioned 1-day dosage or 1-time dosage allows a difference of ±5%. Since the absorption of EPA-E will affect the meal, it is better to administer it during or after the meal, and it is better to administer it just after the meal (within 30 minutes), but the self-emulsifying composition of the present invention is The absorption is still excellent on an empty stomach, so patients with low intestinal absorption when administered during, after or immediately after meals, such as before meals, before meals, during meals, or before going to bed ( The effects of the present invention can still be exhibited when administered to elderly people, patients with intestinal diseases, after intestinal surgery, terminal cancer patients, or taking lipase inhibitors, or when the dose is reduced.

The self-emulsifying composition of the present invention is preferably characterized in that the time to reach the highest plasma concentration after oral administration is the same as that of the ω3PUFA stock solution (referring to the same amount of ω3PUFA as the self-emulsifying composition of the present invention, and does not contain emulsification The composition of the agent, etc.) is equal to or shorter than it. In addition, it preferably has the characteristic that the highest plasma concentration is higher than that of the stock solution of ω3 PUFA. In addition, it is preferable to have the characteristic that the blood concentration after administration for 2 hours, the area under the blood concentration curve for 0~2 hours after administration, and/or the area under the blood concentration curve for 0~72 hours are equal to or higher than that of the ω3 PUFA stock solution its high. The self-emulsifying composition of the present invention is more preferably characterized in that the time to reach the highest plasma concentration is shorter than that of ω3PUFA, and its concentration is high, and the blood concentration after administration 2 hours, administration 0~2 hours and/or 0 Anything below the area under the curve of blood concentration in ~72 hours is higher than that of ω3PUFA stock solution.

The dynamics of the above-mentioned drugs can be confirmed by animals such as dogs or monkeys, but it is better confirmed by human experiments.

In the drug kinetic test using male Beagle dogs, 600 mg of the self-emulsified composition was orally administered to male Beagle dogs in terms of ω3 PUFA per dog under fasting conditions for more than 18 hours, minus the dose The maximum plasma concentration of ω3 PUFA calculated by correcting the previous blood ω3 concentration is, for example, preferably at least 50 μg/ml, more preferably at least 60 μg/ml, still more preferably at least 70 μg/ml. The area under the curve of the blood concentration of ω3 PUFA between 0 and 2 hours after administration is preferably at least 50 μg/ml‧hr, more preferably at least 60 μg/ml‧hr, and more preferably at least 70 μg/ml‧hr. In addition, the combination of the highest plasma concentration of ω3PUFA and the area under the curve of ω3PUFA blood concentration is preferably at least 50 μg/mL and at least 50 μg/ml‧hr, more preferably at least 60 μg/ml and at least 60 μg/ml‧hr, more preferably Above 70μg/ml and above 70μg/ml‧hr.

In the drug kinetic test using male cynomolgus monkeys, the self-emulsifying composition was orally administered to male cynomolgus monkeys at a rate of 45 mg per 1 kg of body weight in terms of ω3 PUFAs under fasting conditions for more than 12 hours. The highest plasma concentration of ω3 PUFA calculated by correcting the blood ω3 concentration is preferably at least 50 μg/ml, more preferably at least 70 μg/ml. And the area under the curve of blood concentration of ω3 PUFA between 0 and 12 hours after administration is preferably at least 400 μg/ml‧hr, more preferably at least 500 μg/ml‧hr. In addition, the combination of the highest plasma concentration of ω3PUFA and the area under the curve of the blood concentration of ω3PUFA is preferably at least 50 μg/mL and at least 400 μg/ml‧hr, more preferably at least 70 μg/ml‧hr and above 500 μg/ml‧hr.

In the pharmacokinetic test using humans, the self-emulsifying composition was orally administered to humans at an amount of 1800 mg per person in terms of ω3 PUFAs or EPAs before meals, immediately after meals, or after meals, and the amount before the administration was subtracted. The highest plasma concentration of ω3 PUFA calculated by correcting the blood ω3 concentration is preferably at least 50 μg/mL, more preferably at least 100 μg/mL, more preferably at least 150 μg/mL, still more preferably at least 200 μg/mL, most preferably at least 50 μg/mL More than 300μg/mL. Or preferably 10-1000 μg/mL, more preferably 20-500 μg/mL, still more preferably 40-300 μg/mL, still more preferably 50-150 μg/mL, most preferably 50-100 μg/mL. And the area under the curve of the blood concentration of ω3 PUFA between 0 and 72 hours is preferably more than 500 μg/ml‧hr, more preferably more than 1000 μg/ml‧hr, more preferably more than 1500 μg/mL‧hr, and more Preferably at least 2000 μg/ml‧hr, most preferably at least 3000 μg/ml‧hr. Or preferably 500~4500μg/ml‧hr, more preferably 600~3000μg/ml‧hr, even more preferably 700~2500μg/ml‧hr, still more preferably 800~2000μg/ml‧hr, most preferably 1000~1500μg/ml‧hr. In addition, the maximum plasma concentration arrival time is preferably at most 6 hours, more preferably at most 5 hours, still more preferably at most 3 hours, still more preferably at most 1 hour, most preferably at most 0 hours. Or, it is preferably 0.5 to 10 hours, more preferably 1 to 8 hours, more preferably 1.5 to 7 hours, still more preferably 2 to 5 hours, most preferably 2.5 to 4 hours. In addition, the elimination half-life in plasma is preferably at least 10 hours, more preferably at least 20 hours, still more preferably at least 30 hours, still more preferably at least 40 hours, most preferably at least 50 hours. Or, it is preferably 0 to 150 hours, more preferably 10 to 120 hours, more preferably 30 to 100 hours, still more preferably 25 to 75 hours, most preferably 25 to 50 hours.

In the pharmacokinetic test using human beings, for example, the self-emulsifying composition is orally administered to each person in an amount of 3600 mg per person in terms of ω3 PUFAs or EPAs before, immediately after or after meals, minus the dose. The highest plasma concentration of ω3PUFA calculated by correcting the previous blood ω3 concentration is preferably above 50 μg/mL, more preferably above 100 μg/mL, more preferably above 150 μg/mL, still more preferably above 200 μg/mL, and most preferably It is preferably 300 μg/mL or more. Or preferably 10-1000 μg/mL, more preferably 20-500 μg/mL, still more preferably 50-400 μg/mL, still more preferably 100-300 μg/mL, most preferably 150-200 μg/mL. And the area under the curve of the blood concentration of ω3 PUFA administered for 0 to 72 hours is preferably at least 500 μg/ml‧hr, more preferably at least 1000 μg/ml‧hr, more preferably at least 1500 μg/mL‧hr, even more preferably Above 2000μg/ml‧hr, preferably above 3000μg/ml‧hr. Or preferably 500~5000μg/ml‧hr, more preferably 1000~4700μg/ml‧hr, more preferably 1500~4500μg/ml‧hr, more preferably 2000~4000μg/ml‧hr, most preferably 2500~3500μg/ml‧hr. Furthermore, the maximum plasma concentration arrival time is preferably at most 6 hours, more preferably at most 5 hours, still more preferably at most 3 hours, still more preferably at most 1 hour, most preferably at most 0 hours. Or, it is preferably 0.5 to 10 hours, more preferably 1 to 8 hours, more preferably 1.5 to 7 hours, still more preferably 2 to 6 hours, most preferably 3 to 5 hours. In addition, the elimination half-life in plasma is preferably at least 10 hours, more preferably at least 20 hours, still more preferably at least 30 hours, still more preferably at least 40 hours, most preferably at least 50 hours. Or, it is preferably 0 to 150 hours, more preferably 10 to 120 hours, more preferably 30 to 100 hours, still more preferably 25 to 75 hours, most preferably 25 to 50 hours.

When using the pharmacokinetic test conducted by human beings, the following numerical ranges can also be used in addition to the above. That is, for example, the self-emulsified composition is orally administered in an amount of 1800 mg per person in terms of ω3 PUFAs or EPAs before, immediately after or after a meal, and the blood ω3 concentration before administration is subtracted to correct and calculate Although the maximum concentration of ω3PUFA in plasma is not particularly limited, it can be selected, for example, 10~50, 50~100, 100~150, 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, 73~78, 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, 145~150, 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, such as before meals, just after meals or after meals When administering the self-emulsified composition in an amount of 3600 mg per person based on ω3 PUFAs or EPAs, for example, 10~50, 50~100, 100~150, 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, 73~78, 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, 145~150, 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.

In addition, the area under the curve of the blood concentration of ω3 PUFA from 0 to 72 hours after administration, for example, when the self-emulsifying composition is administered in an amount of 1800 mg per person in terms of ω3 PUFAs or EPAs before, immediately after or after meals , for example, 500~1500, 1000~2000, 1500~2500, 2000~3000, 2500~3500, 3000~4000, 500~1000, 750~1250, 1000~1500, 1250~1750, 1500~2000, 1750~ 2250, 2000~2500, 2250~2750, 2500~3000, 2750~3250, 3000~3500,, 3250~3750, 3500~4000, 3750~4250, 4000~4500, 4250~4750, 4500~5000, 500~700 . ~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 ~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 . ~1800, 1750~1850, 1800~1900, 1850~1950, 1900~2000, 1950~2050, 2000~2100, 2050~2150, 210 0~2200, 2150~2250, 2200~2300, 2250~2350, 2300~2400, 2350~2450, 2400~2500, 2450~2550, 2500~2600, 2550~2650, 2600~2700, 2650~2750, 2700~ 2800. 3500~3600, 3600~3700, 3700~3800, 3800~3900, 3900~4000, 4000~4100, 4100~4200, 4200~4300, 4300~4400, 4400~4500μg/ml. hr, when administering the self-emulsifying composition in an amount of 3600 mg in terms of ω3 PUFAs or EPAs, for example, before meals, immediately after meals, or after meals, for example, 500~1500, 1000~2000, 1500~2500, 2000~ 3000. 3000~3500, 3250~3750, 3500~4000, 3750~4250, 400~4500, 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, 800~900, 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, 2050~2100, 2100~2200, 2150~2250, 2200~2300, 225 0~2350, 2300~2400, 2350~2450, 2400~2500, 2450~2550, 2500~2600, 2550~2650, 2600~2700, 2650~2750, 2700~2800, 2750~2850, 2800~2900, 2850~ 2950. 3800~3900, 3900~4000, 4000~4100, 4100~4200, 4200~4300, 4300~4400, 4400~4500μg/ml. hr.

In addition, when the maximum plasma concentration reaching time is, for example, before meals, immediately after meals, or after meals, when the self-emulsifying composition is administered in an amount of 1800 mg to 3600 mg per person in terms of ω3 PUFAs or EPAs, it can be selected, for example, from 0 to 2, 1~3, 2~4, 3~5, 4~6, 5~7, 6~8, 7~9, 8~10, 0~1, 0.5~1.5, 1~2, 1.5~2.5, 2~ 3. 2.5~3.5, 3~4, 3.5~4.5, 4~5, 4.5~5.5, 5~6, 5.5~6.5, 6~7, 6.5~7.5, 7~8, 7.5~8.5, 8~9, 8.5~9.5, 9~10, 0~0.5, 0.3~0.8, 0.5~1, 0.8~1.3, 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.

Moreover, when the half-life in plasma is administered in an amount of 1800 mg to 3600 mg per person in terms of ω3 PUFAs or EPAs, for example, before meals, immediately after meals, or after meals, it can be selected from 0~50, 25~ 75, 50~100, 75~125, 100~150, 125~175, 150~200, 0~20, 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, 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, 90~10, 95~105, 100~110, 105~110, 110~120 hours.

As mentioned above, it is also possible to combine two or more selected from the maximum concentration of ω3 PUFA in plasma, the area under the curve of ω3 PUFA blood concentration from 0 to 72 hours after administration, the time to reach the maximum plasma concentration, and the half-life of disappearance in plasma to specify the present invention.

The self-emulsifying composition of the present invention may also contain emulsification aids, stabilizers, preservatives, surfactants, antioxidants, and the like. Examples of emulsification aids include stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, and other fatty acids with 12 to 22 carbon atoms, or their salts. The stabilizer is exemplified by phosphatidic acid, ascorbic acid, glycerol, cetyl alcohol, and the like. Preservatives are exemplified by ethyl p-hydroxybenzoate, propyl p-oxybenzoate, and the like. The surfactant is exemplified by sucrose fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene Ethyl fatty acid esters, polyoxyethylene alkylphenyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, etc. Antioxidants are exemplified by butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinones, astaxanthin, and α-tocopherol Oil-soluble antioxidants such as phenols.

In addition, it can be mixed with the appropriate carrier or medium, coloring agent, flavoring agent, vegetable oil if necessary, harmless organic solvent or harmless dissolution aid, emulsifier, suspending agent (such as Tween 80, gum arabic solution) , Isotonic agent, pH adjuster, stabilizer, flavoring agent, flavoring agent, preservative, antioxidant, absorption enhancer and other additives are properly selected and combined to prepare an appropriate pharmaceutical preparation.

In particular, since ω3 PUFAs are highly unsaturated, it is desirable to contain an effective amount of oil-soluble antioxidants, such as selected from butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, gallic acid At least one of propyl ester, quinone, astaxanthin, and α-tocopherol, which is acceptable as a medicine, is used as an antioxidant.

Since the self-emulsifying composition of the present invention is also used in medicine, it is preferable that it has a good appearance and is excellent in self-emulsifying property, composition dispersibility, emulsification stability and storage stability. The appearance of the self-emulsified composition is not separated, not cloudy, not solidified, not precipitated, and it is better to be clear. When the appearance is bad, it is not good as a medicine, and there is a possibility that it does not have the originally required performance such as self-emulsifying property.

The storage temperature considers the possibility of self-emulsifying compositions or such encapsulated preparations being handled in cold regions or high-temperature environments, and it is better to have a clear appearance at low temperature and high temperature.

In the case of a self-emulsifying composition excellent in self-emulsifying properties, composition dispersibility, and emulsification stability, it disperses rapidly when it comes into contact with water, and forms a microemulsion with an appropriate emulsified droplet diameter. The absorbability of oils such as EPA-E is related to the size of the emulsified droplet diameter. By measuring this, it can be predicted whether the absorbability of the drug administered to animal food is good.

In the present invention, the "average emulsified droplet diameter" uses a particle size distribution measuring device (for example, Nanotorac, manufactured by Nikkiso), uses water as a dispersion medium, and uses a standard measurement method (for example, set zero (Setzero) for 30 seconds, measure The value of the volume average particle diameter in the emulsified composition measured by the time of 30 seconds and the average of 3 measurements). When the self-emulsifying composition of the present invention is dispersed in water or the like, the average emulsified droplet diameter is not particularly limited as long as it is within the range of excellent emulsion dispersibility, emulsion stability, or absorbability, but the average emulsified droplet diameter is usually 2 μm or less. The diameter is, for example, 1.5 μm or less, more preferably 1.0 μm or less, still more preferably 0.5 μm or less, most preferably 0.3 μm or less.

A second active ingredient may also be used in combination in the self-emulsifying composition of the present invention. The second active ingredient can be arbitrarily selected according to the degree of the target disease and symptoms, preferably without weakening the effect of ω3PUFA, for example, drugs for treating hyperlipidemia, antihypertensive drugs, antidiabetic drugs, antioxidants, blood flow improving agents, bile acids Derivatives, NAFLD‧NASH therapeutic drugs, dementia inhibitors‧therapeutic agents, etc.

Preferred second active ingredients include, for example, polyenephosphatidylcholine, unsaponifiable soybean oil (soysterol), γ-vitamin, and riboflavin butyrate in drugs for treating hyperlipidemia. , Dextran Sulfate Sodium Sulfur 18, Pantothenic Acid, Elastase. Moreover, also enumerate such as pravastatin (pravastatin), simvastatin (simvastatin), atorvastatin (atorvastatin), fluvastatin (fluvastatin), pitavastatin (pitavastatin), rosufa history Statin (rosuvastatin), cerivastatin (statin) or such as simfibrate (simfibrate), clofibrate (clofibrate), clinofibrate (clinofibrate), bezafibrate (bezafibrate), if Fibrates of fenofibrate, or lipolytic enzyme inhibitors such as orlistat, cetilistat, colestyramine or colestide Blue (colestimide) resin, Vitoridine (ezetimibe), etc.

Antihypertensive drugs such as irbesartan, olmesartan medoxomil, candesartan, telmisartan, valsartan, rosartan potassium (losartan potassium) angiotensin II receptor antagonists, such as alacepril (alacepril), midapril (imidapril) hydrochloride, enalapril (enalapril) maleate, captopril ( captopril), quinapril hydrochloride, cilazapril hydrate, temocapril hydrochloride, delaprill hydrochloride, tolanpril (trandolapril), benazepril (benazepril) hydrochloride, perindopril (perindopril), lisinopril (lisinopril) hydrate hemokinin conversion enzyme inhibitors, such as azelnidipine (azelnidipine) ), amlodipine besylate, aranidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nifedipine ( nifedipine), nimodipine, nitrendipine, nilvadipine, barnidipine hydrochloride, felodipine, benidipine, such as manitipine Calcium antagonists of manidipine, such as tolazoline, α-receptor blockers of phentolamine, such as atenolol, metoprolol , acebutolol, propranolol, pindolol, carvedilol, beta -blockers such as labetalol hydrochloride, such as clonidine ( α- receptor stimulators such as clonidine, methyldopa, etc., such as eplerenone, hydrochlorothiazide, and furosemide, diuretics, etc.

Antidiabetic drugs, also exemplified as acarbose, voglibose, α -glucosidase inhibitors such as miglitol, such as gliclazide, glucosidase Glibenclamide, glimepiride, tolbutamide sulfonylurea hypoglycemic agents, such as nateglinide, mitiglinide quick-acting Insulin secretion promoting drugs, such as metformin hydrochloride, buformin hydrochloride, biguanide hypoglycemic drugs, such as sitagliptin, vildagliptin, alogliptin ( dipeptidyl phosphatase 4 inhibitors of alogliptin, linagliptin, teneligliptin, anagliptin, saxagliptin, such as pioglitazone hydrochloride ), thiazolidine-based drugs of rosiglitazone maleate, such as glucagon peptide 1 derivatives such as exenatide and liraglutide, such as Ig Sodium of ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin, canagliflozin, empagliflozin. Glucose Yoke delivery body 2 blocker etc.

Examples of antioxidants include vitamins such as ascorbic acid (vitamin C), tocopherol (vitamin E), and tocopheryl nicotinate, N-acetylcysteine, probucol, and the like.

Blood flow improving agents, such as cilostazol, ticlopidine hydrochloride, alprostadil, limaprost, beraprost sodium, Sarpogrelate hydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride, batroxobin, dihydroergotoxin methanesulfonate (dihydroergotoxine mesilate), tolazoline hydrochloride, hepronicate, Siwutang extract, etc.

Bile acid derivatives are exemplified by, for example, ursodeoxycholic acid, chenodeoxycholic acid, bile powder, deoxycholic acid, cholic acid, bile extract, bear bile, bezoar or dehydrocholic acid, etc. Furthermore, biotin (vitamin B7), cyanocobalamin (vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamin (vitamin B1), vitamin A, vitamin D, vitamin K, tyrosine, pyridoxine (vitamin B6), leucine. Isoleucine. Branched-chain amino acids such as valine, calcium, iron, ferrous iron, copper, and magnesium. Soy protein, chitosan (chitosan), low molecular weight sodium alginate, dietary fiber derived from psyllium seed coat, phospholipid-bound soybean peptide, phytosterol ester, phytostanol ester, diacylglycerol, Components of globulin proteolysis products, tea catechins, etc. of specific health food or nutritional functional food.

NAFLD. Therapeutic agents for NASH include the above-mentioned pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, and rosuvastatin. Statin drugs of rosuvastatin and cerivastatin, such as irbesartan, olmesartan medoxomil, candesartan, telmisartan (telmisartan), valsartan, losartan potassium (losartan potassium) angiotensin II receptor antagonists, such as metformin hydrochloride (metformin hydrochloride), buformin hydrochloride (buformin hydrochloride) biguanide hypoglycemic Drugs, such as pioglitazone hydrochloride, thiazolidine-based drugs of rosiglitazone maleate, such as aspirin, ursodeoxycholic acid, chenodeoxycholic acid, obeticholic acid ( farnesol X receptor (hereinafter referred to as FXR) ligands such as obeticholic acid).

Dementia suppressed. Therapeutic agents are exemplified by acetylcholinesterase inhibitors such as donepezil hydrochloride and galanthamine hydrobromide, NMDA receptor inhibitors such as memantine hydrochloride, aspen Antiplatelet agents such as pirin, clopidogrel sulfate, cilostazol, and ticlopidine hydrochloride, such as rivaroxaban and apixaban Factor Xa inhibitors, etc. In addition, the above-mentioned drugs for treating hyperlipidemia, antihypertensive drugs, antidiabetic drugs, antioxidants, and blood flow improving agents can also be used to suppress dementia. Therapeutics are used.

The self-emulsifying composition of the present invention is expected to have excellent appearance, excellent self-emulsifying property, excellent composition dispersibility, excellent emulsification stability, and storage stability (including low temperature, stability at high temperature), absorbability, especially absorbability and absorption speed when fasting, convenience for patients to take, or preparations with excellent compliance.

The self-emulsified composition of the present invention can be used as a therapeutic agent for various diseases of animals, especially mammals, such as lipid abnormalities (hypercholesterolemia, hypercholesterolemia, hypernon-HDL cholesterolemia, hyperVLDL cholesterolemia) , low HDL cholesterolemia, hyperTGemia, hyperApoBemia, hypoApoAIemia, etc.) therapeutic agents, postprandial hyperTGemia therapeutic agents, anti-arteriosclerotic agents, platelet aggregation inhibitors, peripheral circulatory insufficiency therapeutic agents , Cardiovascular event prevention agent, inflammatory disease (NAFLD, NASH, etc.) Anticancer agents and therapeutic agents for central diseases (depression, depressive state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.). In the treatment of the aforementioned diseases, the number of daily administration of the self-emulsifying composition of the present invention is not limited, preferably once a day, or divided into 2 or 3 times a day, more preferably once a day or 2 times, and more preferably 2 times a day.

Next, among the above-mentioned diseases, it is especially effective in the improvement or treatment of dyslipidemia, postprandial hyperTGemia, prevention of recurrence, metabolic syndrome, cardiovascular and cerebrovascular events, or peripheral ulcers or necrosis. Mammals include, for example, humans, livestock animals such as cows, horses, and pigs, or domestic animals such as dogs, cats, rabbits, rats, and mice, and are preferably humans. In particular, improvement or therapeutic effect of dyslipidemia or postprandial hyperTGemia in patients with dyslipidemia showing increased blood lipids such as metabolic syndrome, insulin resistance, or elevated blood pressure is expected.

[Example]

Next, although an Example and a comparative example are illustrated and this invention is demonstrated more concretely, this invention is not limited to these.

Example 1

Measure 0.09g of water, 0.53g of polyoxyethylene (20) sorbitan oleate, 0.39g of soybean lecithin, and 4.0g of EPA-E, seal them, mix them while heating to about 70°C, and prepare from Body emulsion 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.

Embodiment 2~11, comparative example 1~2

As with the composition ratios described in Table 1, the self-emulsifying compositions of Examples 2-8 and the compositions of Comparative Examples 1-2 were prepared and stored in the same manner as in Example 1. Table 1 shows the self-emulsifying composition and the formulation of the composition.

Comparative example 3~4

As with the composition ratios listed in Table 1, the compositions of Comparative Examples 3 and 4 were prepared and stored in the same manner as in Example 1. Table 1 shows the formulation of the composition.

The self-emulsifying composition produced by the aforementioned method and the composition of the comparative example were enclosed in soft capsules containing gelatin as the main component.

Test Example 1 <Evaluation of Appearance>

After the self-emulsifying composition and the composition of the comparative example were produced by the above-mentioned production method, they were allowed to stand still, and the appearance after about 1 hour was evaluated. When the compatibility is excellent and the composition is uniform, it is recorded as "clear", when it is separated, it is recorded as "separated", and when it is opaque, it is recorded as "cloudy".

Table 1 shows the test results.

Test Example 2 <Evaluation of self-emulsification>

For the self-emulsifying composition and the composition of the comparative example produced by the above-mentioned production method, 10 μL of each composition was added dropwise to 37 ° C pure water in the test tube and 5 mL of the first liquid of the Japanese Pharmacopoeia dissolution test. Body emulsification was evaluated. The case of emulsification by only dropping was evaluated as good, and the case where natural emulsification was not possible by only dropping was evaluated as poor. Next, after stirring lightly under uniform conditions, the properties were evaluated. Regarding the composition dispersibility, the evaluation was good when the composition was dispersed, and the evaluation was poor when a part of the composition was not dispersed and remained in lumps. Regarding the emulsification stability, the case where no oil separation occurred was evaluated as good, and the case where oil separation occurred was evaluated as poor. In addition, the composition that was not evaluated as "clear" in the evaluation of appearance was not considered to be properly evaluated due to the inhomogeneity of the composition, and was not evaluated.

Table 1 shows the test results.

Test Example 3 <Evaluation of emulsified droplet diameter>

Using about 1.5 mL of the emulsified composition obtained in Test Example 2 above, the average emulsified droplet diameter (volume average particle diameter) was measured using a particle size distribution measuring device (Nanotorac, manufactured by Nikkiso) using water as a dispersion medium.

Test Example 4 <appearance evaluation after storage under excessively severe conditions>

For the "clear" or "cloudy" composition of Test Example 1, after standing overnight (about 12 hours) at 5°C or 40°C, the appearance was evaluated. Compatibility is excellent, when the composition is uniform, it is evaluated as "clear", when separated, it is evaluated as "separated", and when it is opaque, it is evaluated as "cloudy".

Table 1 shows the test results.

Test Example 5 <Drug Dynamics of Beagle Dogs>

The composition or capsules were orally administered to 6 male Beagle dogs (age 2-6 years old, weight 8-13kg, 3 Marshall Beagle dogs, 3 Nosan Beagle dogs) under fasting conditions , and evaluate the transition of the blood concentration of EPA. In addition, each test animal was fasted for more than 18 hours before the administration, and each animal was administered the composition in an amount of 600 mg in terms of EPA-E. Before administration, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours after administration, blood was collected, the plasma was separated and processed, and LC/MS/MS (separated samples by liquid chromatography, analyzed by mass The method of separating and measuring it) Determination of EPA concentration in plasma. In addition, the EPA-E stock solution filled in capsules was also administered as a control group.

Table 1 shows the maximum plasma concentration (Cmax) calculated from the test results, the area under the blood concentration curve between 0 hours and 2 hours (AUC _0-2 ), and the blood concentration curve between 0 hours and 24 hours Area under (AUC _0-24 ). In addition, each parameter was corrected by subtracting the blood EPA concentration before administration from each blood concentration when calculating each parameter.

Test Example 6 <Drug Dynamics in Cynomolgus Monkeys>

Six cynomolgus macaques (2-5 years old, body weight 2.70-4.65kg, HAMRI) were orally administered the manufactured composition or capsules under fasting conditions, and the change of blood concentration of EPA was evaluated. In addition, each test animal was fasted 12 hours or more before the administration, and each animal was administered the self-emulsified composition in an amount of 45 mg/kg in terms of EPA-E. In addition, the EPA-E stock solution filled in capsules was also administered as a control group. Blood was collected before administration, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours after administration, the plasma was separated and processed, and the concentration of EPA in plasma was measured by LC/MS/MS. The highest plasma concentration (Cmax) calculated from the test results, the area under the blood concentration curve between 0 hours and 12 hours (AUC _0-12 ), the area under the blood concentration curve between 0 hours and 72 hours (AUC _0-72 ). In addition, each parameter was calculated by subtracting the blood EPA concentration before administration from each blood concentration for correction. Compared with the control group, animals administered the composition of Example 14 showed increases in blood concentration parameters such as Cmax and AUC _0-12 . That is, when the self-emulsified composition of Example 14 was administered, it was confirmed that not only the absorption amount increased, but also that EPA was rapidly absorbed after oral administration.

Test example 6-2 <human drug kinetics (single administration test, administration 1800mg)

Orally administered the present invention containing 80% by mass of EPA-E to 12 human beings (20-40 years old, healthy adult males with a body weight of 55.0-77.0kg and a BMI of 18.5 or more and less than 25.0) under hunger strike conditions The capsules of the self-emulsifying composition were used to evaluate the change of the blood concentration of EPA. Each person uses 200mL of water in the morning on an empty stomach, orally administers the self-emulsifying composition in an amount of 1800mg based on EPA-E. Blood was collected at 0, 5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 24, 48 and 72 hours after administration. Immediately after blood collection, it was ice-cooled, centrifuged at 2000×g for 10 minutes at 4°C, and the plasma was separated and stored frozen below -20°C. The concentration of EPA in the obtained plasma was measured by LC/MS/MS (a method of separating a sample by liquid chromatography, separating and measuring it by mass spectrometry).

Moreover, the capsule of the self-emulsifying composition of this invention containing 80 mass % of EPA-E as a content was also orally administered under the condition immediately after eating, and the same measurement was performed.

In addition, 12 humans (20-40 years old, healthy adult males with a body weight of 55.0-77.0kg, BMI of 18.5 or more and less than 25.0) were orally administered EPA-E filled in capsules as a control group under fasting conditions. Stock solution (refers to the same amount of EPA-E as the self-emulsifying composition of the present invention, and high-purity EPA-E (more than 96.5% by mass) without emulsifier, the same below), and the same measurement was carried out.

Table 2 shows the maximum plasma concentration (Cmax) calculated from the test results, the plasma concentration 24 hours after administration (C ₂₄ ), and the area under the blood concentration curve (AUC _0-72 ) between 0 hours and 72 hours , maximum plasma concentration arrival time (Tmax), plasma disappearance half-life (t _1/2 ). In addition, each parameter was corrected by subtracting the blood EPA concentration before administration from each blood concentration when calculating each parameter.

Test example 6-3 <human drug kinetics (single administration test, administration 3600mg)

The dosage in Test Example 6-2 was set to 3600 mg, and the same test was carried out. It was implemented on 6 human beings. Table 3 shows the maximum plasma concentration (Cmax) calculated from the test results, the plasma concentration 24 hours after administration (C ₂₄ ), and the area under the blood concentration curve (AUC _0-72 ) between 0 hours and 72 hours , maximum plasma concentration arrival time (Tmax), plasma disappearance half-life (t _1/2 ). In addition, each parameter was corrected by subtracting the blood EPA concentration before administration from each blood concentration when calculating each parameter.

Test Example 7 <Appearance of Capsule>

For each soft capsule obtained in the examples, the properties of filling, drying, capsule color, shape and filling liquid were visually confirmed.

Those with discoloration in color, deformation or unevenness in shape, turbidity or separation in the properties of the filling liquid were all recorded as defective, and those without any confirmation were recorded as normal.

Table 1 shows the test results. In the following tables, "-" indicates that the component was not added or was not measured.

Example 1 is a composition that only contains polyoxyethylene sorbitan fatty acid ester as an emulsifier, and then contains a specific range of lecithin and water in the composition. As shown in Table 1, the appearance of the composition is good. Excellent self-emulsifying properties, etc. From these results, it can be seen that even if the emulsifier is only polyoxyethylene sorbitan fatty acid ester in the lecithin-containing composition, the effect of the present invention is exhibited.

Examples 2 to 10 are compositions in which polyoxyethylene castor oil is further included as an emulsifier. For these, as shown in Table 1, the composition has good appearance and excellent self-emulsifying properties.

In Example 11, the composition further contained polyoxyethylene hydrogenated castor oil as an emulsifier, and as shown in Table 1, the composition had a good appearance and excellent self-emulsifying properties.

Comparative Example 1 is a composition in which water is not contained in the composition, and this composition is separated. In addition, Comparative Example 2 is a composition containing 8% by mass of water in the composition, and this composition is similarly separated.

In the present invention, water is used instead of ethanol or polyhydric alcohol for improving the compatibility of the composition. When there is no water, the components are not sufficiently compatible, so they are separated. Also, even if the formula containing water is too much in amount relative to the composition, it will also be separated in the same way. Examples 1 to 6 in which water is 1 to 4% by mass are not separated. Therefore, it can be seen that containing a specific amount of water of about 0.5 to 6% by mass is important for excellent appearance and the like.

Comparative Example 3 is a composition that does not contain water but contains polyhydric alcohols. The appearance of this composition is good, and it is excellent in self-emulsifying property, etc., and it is common to Example 1 etc. in common.

However, it separated when stored overnight at 40°C. Therefore, it can be seen that it is important to contain a specific amount of water of about 0.5 to 6% by mass for excellent appearance and the like.

In Comparative Example 4, the composition contained polyoxyethylene castor oil as an emulsifier and did not contain polyoxyethylene sorbitan fatty acid ester. The appearance of this composition became cloudy.

Therefore, it turns out that containing polyoxyethylene sorbitan fatty acid ester as an emulsifier is important for excellent appearance.

Examples 1, 3, and 5 show the dynamic results of administering the self-emulsifying composition to animals on hunger strike.

The parameters of absorption rate Cmax and AUC _0-2 were significantly higher in the animals administered with these self-emulsifying compositions than in the animals administered with the control group (during hunger strike). That is, it was confirmed that when the self-emulsifying composition of the example was administered, not only the amount of EPA absorption increased until 24 hours after oral administration, but EPA was rapidly absorbed after oral administration compared with the control group.

Test Example 6-2 shows the parameters of the self-emulsifying composition of the present invention containing 80% by mass of EPA-E when 1800 mg of EPA-E is administered to humans and when 1800 mg of EPA-E is administered. Any parameters of Cmax, C ₂₄ , and AUC _0-72 under fasting conditions were about 10 times higher than those of the Example composition, and it was confirmed that EPA was rapidly absorbed after oral administration. Test Example 6-3 shows the parameters of the self-emulsifying composition administered with 3600 mg of EPA-E and the administration of 3600 mg of EPA-E, and it was confirmed that it was absorbed rapidly as well. Furthermore, it was confirmed that the self-emulsifying composition of the present invention is not easily affected by meals, and shows high EPA absorbability regardless of the presence or absence of meals.

Accordingly, when the self-emulsifying composition of the present invention is taken on an empty stomach such as before meals or before going to bed, the concentration of EPA in the blood increases rapidly and further, and it can be expected to be used as a self-emulsifying self-emulsifying composition that exhibits its pharmacological effects quickly and more effectively. type preparations.

Self-emulsifying capsule preparations of Examples 2-1 and 2-2, capsule preparations of Comparative Example 2-3

The 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 described in Table 4. Table 4 shows the formulations of the self-emulsifying compositions.

The self-emulsifying composition was filled with 375 mg in Examples 2-1 and 2-2 respectively, and 441 mg of the self-emulsifying composition was filled in Comparative Example 2-3 (both 300 mg in terms of EPA-E) by the rotary process method. ) of soft gelatin capsules. In the self-emulsifying capsule preparation produced by this method, no deformation of the capsule film was confirmed.

Table 4 shows the composition of the content liquid.

Test Example 8 <Capsule Hardness>

Hardness was measured for each capsule preparation of Examples 2-1 and 2-2, and Comparative Example 2-3. The hardness of the formulations stored at 40°C for 1, 2, and 4 weeks at a relative humidity of 75% was also measured.

Table 4 shows the results of each preparation at the initial stage and when stored at 40° C. for 1, 2, and 4 weeks. In addition, the term "initial stage" refers to a preparation stored at room temperature before evaluation after production of capsules. In addition, each preparation was sealed in an aluminum package and stored at 40° C., so it was not affected by humidity.

Examples 2-1 and 2-2 are encapsulated preparations of the self-emulsifying composition of the present invention. These capsules have a hardness of 20kgf or more. On the other hand, in Comparative Example 2-3 containing 8.3% by mass of propylene glycol in a large amount of polyhydric alcohol, the hardness at the initial point was lower than that of the examples. After evaluating the hardness after storage at 40°C in a sealed environment for 1 to 4 weeks, there was almost no change in Examples 2-1 and 2-2. In contrast, the hardness of Comparative Example 2-3 decreased to the initial level after 1 week. 57%, and the hardness further decreased over time.

[Industrial availability]

The self-emulsifying composition of the present invention is excellent in at least one of compatibility (appearance), self-emulsifying property, composition dispersibility, emulsification stability, and absorbability. Serum TG increases. It is useful as special-purpose food, health function food (food for specific health use and nutrition function food) or health food (supplement) or medicine formulated in various foods.

Since the self-emulsifying composition of the present invention does not add polyol or the added concentration is low, it will not cause softening and deformation of the capsule due to polyol during circulation or storage, and the risk of quality change is low.

In addition, when stored in a low-temperature or high-temperature environment, the composition has no denaturation such as white turbidity or separation, so it has the quality of being able to be stored in cold or high-temperature regions when used as medicine.

Claims (14)

A self-emulsifying preparation for pharmaceuticals, which is an encapsulated self-emulsifying preparation for oral administration in which a self-emulsifying composition is held in a capsule as a content liquid; When the total amount of the self-emulsifying composition is 100% by mass, the body emulsion composition contains: a) 70-90% by mass of ω3 polyunsaturated fatty acids, their pharmaceutically acceptable salts, and their esters At least one compound of the formed group, b) 0.5-6 mass % of water, c) 1-29 mass % of polyoxyethylene sorbitan fatty acid ester emulsifier, d) relative to selected from 100 parts by mass of at least one compound of ω3 polyunsaturated fatty acid, its pharmaceutically acceptable salt, and its ester is 3-40 parts by mass of lecithin, and e) ethanol is 4 mass% or less of the total amount of the above-mentioned composition , f) The polyhydric alcohol is 4% by mass or less of the total amount of the aforementioned composition. The self-emulsifying preparation used in medicine according to claim 1, wherein the aforementioned capsules are hard capsules and/or soft capsules. The self-emulsifying preparation used in medicine according to claim 2, wherein the capsule film of the aforementioned soft capsule contains gelatin. The self-emulsifying preparation used in pharmaceuticals according to claim 1, wherein the emulsifier further includes polyoxyethylene hydrogenated castor oil and/or polyoxyethylene castor oil. The self-emulsifying preparation used in pharmaceuticals according to Claim 1, wherein ethanol is 1% by mass or less of the total amount of the aforementioned composition. The self-emulsifying preparation used in pharmaceuticals according to Claim 1, wherein the polyhydric alcohol is 1% by mass or less of the total amount of the aforementioned composition. A self-emulsifying preparation, which is an encapsulated self-emulsifying preparation for oral administration in which a self-emulsifying composition is held in a capsule as a content liquid; and the self-emulsifying composition is a self-emulsifying composition When the total amount of the substance is taken as 100% by mass, it contains: a) 70 to 90% by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof, b) 0.5 to 6 mass % of water, c) 1 to 29 mass % of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil emulsifier, d) polyunsaturated with respect to ω3 Fatty acids, their pharmaceutically acceptable salts, and 100 parts by mass of their esters are 3 to 40 parts by mass of lecithin, and e) relative to 100 parts by mass of the aforementioned polyoxyethylene sorbitan fatty acid ester, the Polyoxyethylene castor oil is 120 parts by mass or less, f) ethanol is 4 mass % or less of the total amount of the composition, and g) polyol is 4 mass % or less of the total amount of the composition. A self-emulsifying composition, which is an orally administered self-emulsifying composition, and when the total amount of the self-emulsifying composition is 100% by mass, it contains: a) 70 to 90% by mass of ω3 Polyunsaturated fatty acids, their At least one compound of a pharmaceutically acceptable salt and its ester group, b) 0.5-6% by mass of water, c) 1-29% by mass of polyoxyethylene sorbitan fatty acid ester The emulsifier, d) is 3-40 parts by mass of lecithin relative to 100 parts by mass of ω3 polyunsaturated fatty acid, its pharmaceutically acceptable salt, and its ester, and e) ethanol is the total amount of the above-mentioned composition 4% by mass or less, and f) polyhydric alcohol is 4% by mass or less of the total amount of the aforementioned composition. Such as the self-emulsifying composition of Claim 8, which is used in food or medicine. The self-emulsifying composition according to claim 8 or 9, wherein the aforementioned emulsifier further includes polyoxyethylene hydrogenated castor oil and/or polyoxyethylene castor oil. The self-emulsifying composition according to claim 8 or 9, wherein the aforementioned emulsifier includes polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil. The self-emulsifying composition according to claim 8 or 9, wherein ethanol is 1% by mass or less of the total amount of the composition. The self-emulsifying composition according to claim 8 or 9, wherein the polyhydric alcohol is 1% by mass or less of the total amount of the composition. A self-emulsifying composition, which is an orally administered self-emulsifying composition, and when the total amount of the self-emulsifying composition is 100% by mass, it contains: a) 70-90% by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, their pharmaceutically acceptable salts, and esters thereof, b) 0.5-6% by mass of water, c) 1 ~29% by mass of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil emulsifier, d) relative to ω3 polyunsaturated fatty acid, its pharmaceutically acceptable salt, and its ester 100 parts by mass is 3 to 40 parts by mass of lecithin, and e) ethanol is 4% by mass or less of the total amount of the aforementioned composition, f) polyol is less than 4% by mass of the total amount of the aforementioned composition, g) relative to The said polyoxyethylene sorbitan fatty acid ester is 100 mass parts, and the said polyoxyethylene castor oil is 120 mass parts or less.