TW201938143A - Self-emulsifying formulation and self-emulsifying composition of [omega]3 fatty acid exhibiting excellent self-emulsifying property, composition dispersing ability, emulsification stability and absorbability - Google Patents

Abstract

The present invention provides a self-emulsifying composition. When being defined to be 100% by mass as a whole, the self-emulsifying composition includes 70 to 90% by mass of at least one compound selected from the group consisting of [omega]3 polyunsaturated fatty acids and pharmaceutically acceptable salts and esters thereof; 0.5 to 6% by mass of water; 1 to 29% by mass of the polyoxyethyl sorbitan fatty acid ester serving as an emulsifier (optionally containing polyoxygen based sesame oil, except lecithin); and 3 to 40 parts by mass of lecithin based on 100 parts by mass of [omega]3 polyunsaturated fatty acid. The self-emulsifying composition is excellent in self-emulsifying property, composition dispersing ability, emulsification stability and absorbability, and is free from ethanol and polyol or only has ethanol and polyol added thereto at a reduced concentration. The self-emulsifying composition can be used for foods or pharmaceuticals.

Description

   Omega 3 fatty acid self-emulsifying preparation and self-emulsifying composition   

The present invention provides a self-emulsifying composition containing at least one selected from the group consisting of omega 3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof, a medicine thereof, and a method for producing the same.

The ω3 polyunsaturated fatty acid (hereinafter referred to as ω3PUFA) is known as α-linolenic acid, eicosapentaenoic acid (hereinafter referred to as EPA), docosahexaenoic acid (hereinafter referred to as DHA), and the like. ω3PUFA, its pharmaceutically acceptable salts and esters have been formulated in various foods because they exhibit various effects such as anti-arteriosclerosis, platelet aggregation inhibition, blood lipid reduction, anti-inflammatory, anti-cancer, and central effects. , Sold as health food or medicine.

EPA ethyl ester (hereinafter referred to as EPA-E) is sold in Japan as an oral treatment 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 administered orally under a hunger strike, the increase in plasma EPA concentration was lower than when it was administered orally after ingestion. It is considered that the absorption of EPA-E requires the secretion of bile acids or the components derived from food as a carrier. Therefore, the usage of EPADEL is to be administered orally immediately after a meal (see Non-Patent Document 1).

In recent years, people who have not eaten meals such as breakfast or patients who can eat only a small amount of meals can only take fluids (milk, rice soup, kudzu soup, eggs, soup, fruit juice, oral nutrition) Oral administration of patients, patients with low intestinal absorptivity (elderly people, patients with bowel disease, after bowel surgery, terminal cancer patients, when taking lipase inhibitors) or patients who cannot take meals after cerebral infarction, or follow Medication regulations have become one of the issues.

In addition, although it showed a normal value on fasting, serum triglyceride (hereinafter referred to as TG) showed an abnormal increase after meals, or the relationship between non-fasting hypertriglyceridemia and coronary artery disease was noticed as the state was delayed. And, it is expected that ω3PUFA preparations which can be quickly absorbed even after administration before meals and suppress the increase of serum TG after meals.

As a self-emulsifying formulation that does not contain water and is easy to disperse and self-emulsify when in contact with water, it has been reported that it contains the active ingredients of ω3PUFA and fenofibrate, and the self-emulsifying composition of ethanol and surfactant (See Patent Literature 1 and Non-Patent Literature 4).

Although these compositions contain ethanol for the purpose of improving the solubility of fenofibrate, when the ethanol is volatilized, the capsules may be deformed or mixed with air bubbles, the capsules may be deformed or cracked, and the capsule contents may become cloudy or separated. Concerns about degeneration. In addition, it is a preparation that cannot be taken or difficult to take by patients with alcohol (ethanol) intolerance.

In addition to ω3PUFA and a surfactant, a self-emulsifying composition containing ethanol or a polyhydric alcohol and capable of forming a dispersion having a small or very small average particle diameter when contacted with water has been reported (Patent Document 2).

As a self-emulsifying composition with low ethanol content, it has been reported that it contains omega 3 PUFA, an emulsifier with a balance of hydrophilic and lipophilicity (hereinafter referred to as HLB) of 10 or more, polyols such as lecithin, propylene glycol, or glycerin, and self-emulsifying properties, Oral absorptivity when fasting-A self-emulsifying composition with a good absorption rate (Patent Document 3).

A self-emulsifying composition that contains ω3PUFA ester and a surfactant and does not contain free ω3PUFA and is not affected by meals has been reported (Patent Document 4). The composition of EPA-E based on omega 3 PUFA esters has been reviewed.

It has been reported that when a co-solvent such as a polyhydric alcohol in the composition is encapsulated, it will migrate toward the capsule film and deform due to the denaturation of the composition or the softening of the capsule (Patent Document 5).

The self-emulsifying composition generally uses a large amount of emulsifier, and the total amount of liquid in the composition is also large, so it causes inflammation of the digestive tract or dissolves less physiologically active ingredients of the oil agent contained in each capsule (Patent Literature 6) Problems. Therefore, it is desirable that the emulsifier used in the composition is non-toxic or less toxic even if it is continuously administered, and the amount used is small.

In addition, from the viewpoint of taking property, in order to fix the amount of ω3PUFA in a single administration, when the components other than ω3PUFA in the self-emulsifying composition are increased, the dosage of the drug once taken will increase. Therefore, from the viewpoint of miniaturization of the formulation, it is also desirable to use a small amount of an emulsifier or an alcohol.

    [Prior technical literature]         [Patent Literature]    

[Patent Document 1] Japanese Special Table No. 2008-516890

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

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

[Patent Document 4] 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] "Artificial Sclerosis Prevention Guidelines 2007 Edition" compiled by the Japanese Society of Arteriosclerosis, Kyowa Planning, April 25, 2007

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

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

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

A preparation for reducing ethanol and polyol contained in the self-emulsifying composition is desired.

In addition, a formulation that reduces the emulsifier contained in the self-emulsifying composition is desired.

In addition, a preparation for increasing the content of ω3PUFA in a self-emulsifying composition is desired.

Further, a self-emulsifying composition having excellent drug compliance is desired.

In addition, when using a self-emulsifying composition as a pharmaceutical product, it is also assumed that it is stored in a cold zone, etc. Therefore, it is expected that the composition will not be turbid, separated, etc. when stored in a low-temperature or high-temperature environment other than room temperature, and the appearance is good Self-emulsifying composition.

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

In addition, it is desirable to provide a formulation that encapsulates the composition.

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

Therefore, an object of the present invention is to provide a self-emulsifying composition that improves at least one of these properties, and a formulation that encapsulates the composition.

In view of the above-mentioned problems, the present inventors have conducted an active review of components substituted for ethanol or polyol, and found that a specific amount of water is useful for improving the compatibility of the self-emulsifying composition.

In addition, it was found that the content of water in the composition is less than ethanol or polyhydric alcohol and may be 0.5 to 6% by mass, and the content of the emulsifier can be further reduced by the compatibility improvement effect of a small amount of water. Therefore, the content of ω3PUFA is high. Self-emulsifying composition.

Furthermore, it was found that the self-emulsifying composition excellent in at least one of the above problems can be obtained with the composition, and the present invention has been completed.

In addition, it was also found that the content of emulsifier can be made smaller, and the invention of ω3PUFA as a high-content self-emulsifying composition has been completed.

The composition of the present invention is a composition excellent in at least one or more of the above 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, a) 70 to 90% by mass is selected from the group consisting of ω3PUFA, which is pharmaceutically acceptable At least one compound in the group of salts and its esters, b) 0.5-6% by mass of water, c) 1-29% by mass of an emulsifier (except lecithin), preferably polyoxyethylene ethyl sorbate Emulsifiers of sugar alcohol anhydride fatty acid esters, d) 3 to 40 parts by mass of lecithin relative to 100 parts by mass of pharmaceutically acceptable salts of ω3 polyunsaturated fatty acids, their pharmaceutically acceptable esters, and e) ethanol and The polyhydric alcohol is 4% by mass or less of the total amount of the composition.

(1-2) A self-emulsifying composition characterized in that when the total amount of the self-emulsifying composition is 100% by mass, a) 70 to 90% by mass of ω3PUFA and a pharmaceutically acceptable salt thereof And at least one compound selected from the group formed by its esters, b) 0.5 to 6% by mass of water, c) 1 to 29% by mass of an emulsifier of polyoxyethylene sorbitan fatty acid ester, d) It is 3 to 40 parts by mass of lecithin with respect to 100 parts by mass of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts, and esters thereof, and e) ethanol has the aforementioned composition. 4 mass% or less of the total amount, and f) polyol is 4 mass% or less of the total amount of the aforementioned composition.

(1-3) The self-emulsifying composition according to (1-1) or (1-2), wherein the polyoxyethylene sorbitan fatty acid ester is at least one selected from the group consisting of : Polyoxyethyl monolaurate (20) sorbitan, polyoxyethyl monopalmitate (20) sorbitan, polyoxyethyl monostearate (20) sorbitan, Polyoxyethylene tristearate (20) sorbitan, Polyoxyethyl monostearate (20) sorbitan, Polyoxyethyl monooleate (20) sorbitan And trioleic acid polyoxyethyl (20) sorbitan.

(1-4) The self-emulsifying composition according to any one of (1-1) to (1-3), wherein the emulsifier further comprises polyoxyethylene hardened castor oil and / or polyoxyethylene Castor oil.

(1-5) The self-emulsifying composition according to any one of (1-1) to (1-4), wherein the emulsifier further comprises polyoxyethylene castor oil.

(1-6) The self-emulsifying composition according to any one of (1-1) to (1-5), wherein the polyhydric alcohol is propylene glycol or glycerol.

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

(1-8) The self-emulsifying composition according to any one of (1-1) to (1-6), wherein the composition does not contain more than 4% by mass of a polyol.

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

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

(1-11) The self-emulsifying composition according to any one of (1-1) to (1-8), wherein the composition does not contain more than 1% by mass of a 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 polyol.

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

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

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

(1-16) 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 according to any one of (1-1) to (1-16), wherein ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof are selected from EPA and DHA At least one of the group of pharmaceutically acceptable salts and the esters of these.

(1-18) The self-emulsifying composition according to any one of (1-1) to (1-17), wherein the ester of ω3PUFA is an ethyl ester or a triglyceride.

(1-19) The self-emulsifying composition according to any one of (1-1) to (1-18), wherein ω3PUFA, a pharmaceutically acceptable salt thereof, or an ester thereof is EPA-E or DHA Ethyl ester (hereinafter referred to as DHA-E).

(1-20) The self-emulsifying composition according to any one of (1-1) to (1-19), which contains a salt and ester selected from EPA, DHA, and pharmaceutically acceptable salts and esters thereof. At least one of the groups 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 according to any one of (1-1) to (1-22), wherein the lecithin is selected from the group consisting of soybean lecithin, enzyme-decomposed soybean lecithin, and hydrogenated soybean lecithin And at least one of the groups formed by egg yolk lecithin.

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

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

(1-26) The self-emulsifying composition according to any one of (1-1) to (1-25), wherein the appearance of the composition is clear when the composition is left to stand.

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

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

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

(1-30) The self-emulsifying composition according to any one of (1-1) to (1-29), wherein the composition has at least one of self-emulsifying property, composition dispersibility, and emulsifying stability. Those are good.

(1-31) The self-emulsifying composition according to any one of (1-1) to (1-30), wherein 10 μL of the composition is added dropwise to pure water at 37 ° C. or the first dissolution test of the Japanese Pharmacopoeia In 5 mL of the liquid, it was naturally emulsified only by dropping.

(1-32) The self-emulsifying composition according to any one of (1-1) to (1-31), wherein 10 μL of the composition is added dropwise to pure water at 37 ° C. or the Japanese Pharmacopoeia Dissolution Test Section 1 In 5 mL of the liquid, the composition was dispersed by stirring.

(1-33) The self-emulsifying composition according to any one of (1-1) to (1-32), wherein 10 μL of the composition is added dropwise to pure water at 37 ° C. or the first dissolution test of the Japanese Pharmacopoeia There was no oil separation in 5 mL of liquid.

(1-34) The self-emulsifying composition according to any one of (1-1) to (1-33), wherein the male Miguel dog is orally administered under the condition of hunger fasting for more than 18 hours and is selected from the group consisting of At least one compound in the group consisting of ω3PUFA, its pharmaceutically acceptable salts, and its esters is calculated as a self-emulsifying composition of 600 mg per dog, and is calculated by subtracting and correcting the ω3 concentration in the blood before administration. The highest plasma concentration of ω3PUFA (also known as the maximum blood concentration) is 50 μg / mL or more and / or the area under the blood concentration curve of ω3PUFA between 0 and 2 hours is 30 μg / mL or more. The highest ω3PUFA plasma is The area under the blood concentration curve of ω3PUFA with a medium concentration of 50 μg / mL or more and / or between 0 and 2 hours is 50 μg / mL or more. The highest plasma concentration of ω3PUFA is 60 μg / mL or more and / or 0 The area under the ω3PUFA blood concentration curve between 1 and 2 hours is 60 μg / mL‧hr or more, or the highest plasma concentration of ω3PUFA is 70 μg / mL or more and / or the ω3PUFA blood concentration curve between 0 and 2 hours The area is 70 μg / mL‧hr or more.

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

(1-36) The use of the self-emulsifying composition according to any one of (1-1) to (1-33), which is selected from omega 3 PUFA, a pharmaceutically acceptable salt thereof for humans before meals Orally administer the self-emulsifying composition according to any one of (1-1) to (1-33) in an amount of 1800 mg per person for at least one compound in the group formed by its and its esters, less before administration The highest ω3PUFA plasma concentration calculated by correcting the ω3 concentration in blood was 50 μg / mL or more and / or the ω3PUFA blood concentration was 10 μg / mL or more 2 hours after administration.

(1-37) The self-emulsifying composition according to any one of (1-1) to (1-33), which is selected from the group consisting of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof for humans before meals. At least one compound in the formed group was orally administered to the self-emulsifying composition described in any one of (1-1) to (1-33) in an amount of 1800 mg per person, and blood before administration was reduced The highest ω3PUFA plasma concentration calculated by correcting the middle ω3 concentration was 10 μg / mL or more and / or the area under the blood concentration curve of ω3PUFA between 0 and 72 hours was 250 μg / mL‧hr or more.

(1-38) The self-emulsifying composition according to any one of (1-1) to (1-37), in which the polyoxyethylene ethyl sorbitan fatty acid ester 100 is contained in the composition. The amount of polyoxyethylene castor oil is 120 parts by mass or less.

(1-39) 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 EPA-E, and b) 0.5 to 6% by mass. % Water, c) 1 to 29% by mass of an emulsifier of polyoxyethylene sorbitan fatty acid ester, d) 3 to 40 parts by mass of lecithin relative to 100 parts by mass of the aforementioned EPA-E, In addition, e) ethanol and / or polyhydric alcohol is 4% by mass or less of the total amount of the aforementioned composition.

(1-40) 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 EPA-E, and b) 0.5 to 6% by mass. % Water, c) 1 to 29% by mass of an emulsifier of polyoxyethylene sorbitan fatty acid ester, 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 aforementioned composition, and f) Polyol is 4% by mass or less of the total amount of the aforementioned 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 according to any one of (1-1) to (1-40), and is hard capsule And / or softly encapsulated.

(2-2) The encapsulated self-emulsifying preparation according to (2-1), wherein the hardness immediately after production is good.

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

(2-4) The encapsulated self-emulsifying preparation according to 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 according to 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 20 kgf or more.

(2-6) The encapsulated self-emulsifying preparation according to 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 storage.

(2-7) The preparation according to any one of (2-1) to (2-6), which is at least one selected from the group consisting of: dyslipidemia (hypercholesterolemia, high LDL) (Cholesterolemia, High Non-HDL Cholesterolemia, High VLDL Cholesterolemia, Low HDL Cholesterolemia, HyperTGemia, HyperApoBemia, HypoApoAIemia, etc.) Therapeutic agents , Anti-arteriosclerosis agents, platelet aggregation inhibitors, peripheral circulatory insufficiency agents, preventive agents for cardiovascular events, inflammatory diseases (non-alcoholic fatty liver disease (hereinafter referred to as NAFLD)), non-alcoholic fatty liver disease (hereinafter referred to as NASH), etc.), therapeutic agents, cognitive disorders (Alzheimer's syndrome, cerebrovascular cognitive disorders, mixed cognitive disorders, etc.) to inhibit ‧ therapeutic agents, anticancer agents and central diseases (depression, depression State, obsessive-compulsive disorder, social unrest, panic disorder, etc.).

A 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 ingredients 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 salts, and its esters, b) 0.5-6% by mass of water, and c) 1-29% by mass of polyoxyethylene ethyl sorbitol An emulsifier of an anhydride fatty acid ester, and d) 3 to 40 parts by mass based on 100 parts by mass of at least one compound selected from the group consisting of omega 3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof. Lecithin, and e) ethanol and / or polyhydric alcohol in the composition obtained above is mixed at 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 ingredients 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 salts, and its esters, b) 0.5-6% by mass of water, and c) 1-29% by mass of polyoxyethylene ethyl sorbitol An emulsifier of an anhydride fatty acid ester, and d) 3 to 40 parts by mass based on 100 parts by mass of at least one compound selected from the group consisting of omega 3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof. Lecithin, and in the composition obtained by the above mixing, e) ethanol is 4% by mass or less of the total amount of the foregoing composition, and f) polyol is 4% by mass or less of the total amount of the foregoing composition.

(3-3) The method for producing a self-emulsifying composition according to (3-1) or (3-2), which comprises heating a), b) and / or c) of the foregoing steps to 70 ° C The above and mixed steps.

The fourth aspect of the present invention is a medicine for a specific administration method of the self-emulsifying composition described below.

(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-organizing composition or the encapsulated self-emulsifying preparation, medicine or veterinary medicine as described.

(4-2) A preparation for the self-emulsifying composition produced by the production method described in any one of (3-1) to (3-3) orally when fasting or before bedtime. Or encapsulated self-emulsifying preparation, medicine or veterinary medicine.

(4-3) The preparation according to (4-1) or (4-2), which is at least one selected from the group consisting of: dyslipidemia (hypercholesterolemia, hyperLDL cholesterolemia) , High non-HDL cholesterolemia, high VLDL cholesterolemia, low HDL cholesterolemia, high TG bloodemia, high ApoB blood pressure, low ApoAI blood pressure, etc.) Therapeutics, post-prandial hyperTGemia, anti-arterial Sclerosing agents, platelet aggregation inhibitors, peripheral circulation insufficiency agents, preventive agents for cardiovascular events, therapeutic agents for inflammatory diseases (NAFLD, NASH, etc.), anticancer agents, and central diseases (depression, depression, obsessive-compulsive disorder) , Social anxiety disorder, panic disorder, etc.) preventive agents, therapeutic agents, and preventive agents.

(4-4) The preparation according to 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 according to any one of (4-1) to (4-4) above.

(4-6) A method for increasing the concentration of ω3PUFA in plasma by orally administering the preparation described in any one of (4-1) to (4-4) above.

A 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 the prevention, prevention and treatment of at least one disease selected from the group consisting of: dyslipidemia (hypercholesterolemia, hyperLDL cholesterolemia, hypernon-HDL cholesterolemia, hyperVLDL Cholesterolemia, low HDL cholesterolemia, hypertriglyceridemia, hyper-ApoBemia, hypo-ApoAIemia, etc.), post-prandial hypertriglyceridemia, anti-atherosclerosis, hyperplatelet aggregation, peripheral circulation insufficiency, cardiovascular events , Inflammatory diseases (NAFLD, NASH, etc.), cognitive diseases (Alzheimer's disease, cerebrovascular cognitive disease, mixed cognitive disease, etc.), cancer and central diseases (depression, depression, obsessive-compulsive disorder, etc.) Disorder, social disturbance disorder, panic disorder, etc.), characterized in that the patient is administered at least one autoemulsified composition selected from the group consisting of (1-1) to (1-40) and (2-1) to (2-7). Or encapsulated self-emulsifying preparation, medicine or veterinary medicine.

(5-2) The method according to the above (5-1), which is orally administered to the aforementioned self-emulsifying composition or encapsulated self-emulsifying preparation, medicine or veterinary medicine on an empty stomach or before bedtime .

(5-3) The method according to the above (5-1) or (5-2), wherein the self-emulsifying composition or the encapsulated self-emulsifying preparation, medicine or animal is administered 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 omega 3 PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof for a male Miguel dog under a hunger strike condition of 18 hours or more The amount of 600 mg per dog is orally administered to the aforementioned self-emulsifying composition of (1-1) to (1-40), (2-1) to (2-7), and the blood before administration is reduced The highest ω3PUFA plasma concentration calculated by correcting the middle ω3 concentration is 50 μg / mL or more and / or the area under the blood concentration curve of ω3PUFA between 0 and 2 hours is 30 μg / mL‧hr or more. The highest plasma concentration of ω3PUFA is The area under the blood concentration curve of ω3PUFA above 50 μg / mL and / or administered for 0 to 2 hours is 50 μg / mL‧hr or more, and the highest plasma concentration of ω3PUFA is above 60 μg / mL and / or administered for 0 to 2 hours The area under the blood concentration curve of ω3PUFA is 60 μg / mL or more, or the highest plasma concentration of ω3PUFA is 70 μg / mL or more and / or the area under the blood concentration curve of ω3PUFA between 0 and 2 hours is 70 μg. / mL‧hr or more.

(6-2) A self-emulsifying composition based on at least one compound selected from the group consisting of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof under fasting conditions of male cynomolgus monkeys for more than 12 hours It becomes the self-emulsifying composition of (1-1) to (1-40), (2-1) to (2-7) orally administered at 45 mg per 1 kg of body weight, and reduces omega 3 in blood before administration The maximum plasma concentration of ω3PUFA calculated by concentration correction is 50 μg / mL or more and / or the area under the blood concentration curve of ω3PUFA between 400 and 12 hours after administration is 400 μg / mL‧hr or more, or the maximum plasma concentration of ω3PUFA is 70 μg The area under the blood concentration curve of ω3PUFA above 500 / mL and / or administered between 0 and 12 hours was above 500 μg / mL‧hr.

(6-3) A self-emulsifying composition, which is orally administered to humans in an amount of 1800 mg per person based on at least one compound selected from the group consisting of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof. The above (1-1) to (1-40), (2-1) to (2-7) self-emulsifying composition was given, and the ω3 PUFA concentration in the blood before administration was subtracted and corrected to calculate the highest ω3PUFA plasma. The concentration of ω3PUFA in blood at a concentration of 50 μg / mL or more and / or 2 hours after the administration was 10 μg / mL or more.

(6-4) A self-emulsifying composition, which is orally administered to humans in an amount of 1800 mg per person based on at least one compound selected from the group consisting of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof. The above (1-1) to (1-40), (2-1) to (2-7) self-emulsifying composition was given, and the ω3 PUFA concentration in the blood before administration was subtracted and corrected to calculate the highest ω3PUFA plasma. The area under the blood concentration curve of ω3PUFA at a concentration of 10 μg / mL or more and / or between 0 and 72 hours was 250 μg / mL or more.

The self-emulsifying composition of the present invention contains a small amount of water instead of ethanol or a polyol in the composition, and the composition improves the compatibility of the composition, and can also use less emulsifier, so Excellent safety to animals (including humans). In addition, since the content of ω3PUFA is high, the emulsifier used is reduced, and the applicability is excellent.

In addition, the content of ethanol or polyhydric alcohol can be reduced due to the water contained in the composition, or the content of the alcohol or polyhydric alcohol can be eliminated, so that the softening of the capsule film can be prevented, and no deformation of the capsule can occur.

In addition, it is excellent in at least one of compatibility (appearance), self-emulsifying property, composition dispersibility, emulsification stability, and absorptivity, and can be quickly absorbed and suppressed after meal even if administered before meals or after taking low-fat foods. Increased serum TG, or prevent the lack of essential fatty acids when taking lipase inhibitors by administration before bedtime.

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

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

The present invention is explained in detail below.

The present invention is a total emulsification of at least one compound selected from the group consisting of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof 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 with respect to 100 parts by mass of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof, and not containing or adding a low concentration of ethanol or a polyol, Or an encapsulated self-emulsifying preparation with its content, its medicine, its preparation method and its use method.

In the present invention, "ω3PUFA" is a fatty acid having a plurality of carbon-carbon double bonds in the molecule and having a first double bond at the third position from the methyl side. Representative ones are exemplified by α-linolenic acid, EPA, DHA, eicosatrienoic acid, octacosatetraenoic acid, eicosatetraenoic acid, catfish acid, docosapentaenoic acid, and twenty-four Hexaenoic acid (nisinic acid) and the like. The terms "ω3PUFA", "EPAs", "DHAs" and "fatty acids" in the present invention are not only ω3PUFA, EPA, DHA, and fatty acids, but also include each of them unless otherwise specified. The use of pharmaceutically acceptable salts or esters.

The ω3PUFAs used in the present invention may be any of a synthetic product, a semi-synthetic product, or a natural product, and may also be in the form of a natural oil containing these. Here, the term "natural product" refers to those who extract, crudely purify, or make them more highly purified from natural oils containing ω3PUFAs by conventional methods. Semi-synthetic products also include ω3PUFAs produced by microorganisms, and chemical treatments such as esterification and transesterification of ω3PUFAs or natural ω3PUFAs. In the present invention, as the ω3PUFAs, one kind of these may be used alone, or two or more kinds may be used in combination.

In the present invention, ω3PUFAs and EPAs and DHAs are preferred, and more preferred examples are EPAs. In addition, pharmaceutically acceptable salts of ω3PUFA are exemplified by inorganic bases such as sodium salts and potassium salts, organic bases such as benzylamine salts and diethylamine salts, and basic amino acids such as spermine salts and lysine salts. Salts and alkyl esters such as ethyl esters or mono-, di-, and TG esters. Preferred examples include ethyl esters and TG esters, and more preferred examples include ethyl esters. That is, preferred examples are EPA-E, TG esters of EPA, DHA-E, and TG esters of DHA, more preferred examples are EPA-E and DHA-E, and even more preferred examples are EPA-E. .

The purity of the raw material ω3PUFAs used in the self-emulsifying composition of the present invention is not particularly limited, but it is usually based on the content of ω3PUFAs in the total fatty acids of the composition, which is preferably 50% by mass or more, more preferably It is 70% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and still more preferably 96.5% by mass or more, more preferably 98% by mass or more. EPA is preferably of high purity. For example, the content of EPA in ω3PUFA 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, and more preferably 98% by mass or more. That is, the composition of this agent is preferably the one with the highest purity of ω3PUFAs among all fatty acids, more preferably the one with high purity of EPA3 + DHAs of ω3PUFAs, and is preferably substantially free of DHA, or even contains For example, the purity of EPA is less than 1.0% by mass, preferably less than 0.5% by mass, and more preferably less than 0.2% by mass.

For example, when using EPA-E and DHA-E, if the purity of the EPA-E composition is as described 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 preferred composition ratio, EPA-E / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and even more preferably 1.2 or more.

In addition, the composition of this agent may also contain polyunsaturated fatty acids other than ω3PUFAs such as linoleic acid, γ-linolenic acid, dihomo-γ-linolenic acid, and their pharmaceutically acceptable salts or esters, but it is desirable Arachidonic acid and those whose pharmaceutically acceptable salt or ester content is less, preferably less than 2% by mass, more preferably less than 1% by mass, and more preferably substantially free of arachidonic acid or 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, and still more preferably 74 to 84% by mass. The ω3PUFAs may be one kind or a mixture of two or more kinds. When it is a mixture of two or more kinds, the total amount of the mixture is 70 to 90% by mass in the self-emulsifying composition.

The ω3PUFAs can be used in Japan as soft capsules (trade name: EPADEL: Mochida Pharmaceutical Co., Ltd.) containing high-purity EPA-E (96.5% by mass or more) available as an ASO and hyperlipidemia treatment in Japan, or in the United States. A soft capsule containing a high-purity EPA-E (trade name VASCEPA: AMARIN), which is available as a therapeutic agent for TG anemia. In addition, as a mixture of EPA-E and DHA-E, for example, Lovaza (registered trademark) (Glaxo Smith Kline, which is sold as a therapeutic agent for hypertriglyceridemia in the United States) (containing about 46.5 mass% of EPA-E and about 37.5 DHA-E) can be used. (% By mass of soft capsules) or LOTRIGA (registered trademark) sold in Japan (Takeda Pharmaceutical Industries: Soft capsules containing approximately 46.5% by mass of EPA-E and approximately 37.5% by mass of DHA-E). As a mixture of EPA and DHA, for example, Epanova (registered trademark) (AstraZeneca: a softener containing about 50 to 60% by mass of EPA free acid and about 15 to 25% by mass of DHA free acid) sold in the United States as a therapeutic agent for hyperTG. Capsules).

As omega 3 PUFAs, purified fish oil can also be used. In addition, ω3PUFA-based monoglycidyl ether, diglycidyl ether, TG derivative, or a combination of these are also one of the preferred aspects. For example, Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525, and E5015 (Yorkshire, Croda International PLC), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX7010EE, K85TG, K85EE, and 80EE (Norway, Lakers) , Pronova Biopharma) and other preparations containing omega 3 PUFAs have been sold, and these can also be obtained and used.

In the present invention, the "polyoxyethylene sorbitan fatty acid ester" is a polyoxyethyl ether of a fatty acid ester in which a part of hydroxyl groups of anhydrous sorbitol is fatty acid esterified. Various compounds are sold depending on the esterified fatty acid, exemplified by, for example, monolaurate polyoxyethylene (20) sorbitan (NIKKOL TL-10, Polysorbate 20, Tween20), monopalmitic acid polyoxyethylene Ethyl (20) sorbitan (NIKKOL TP-10V, Polysorbate 40, Tween 40), polystearenyl monostearate (20) sorbitan (NIKKOL TS-10MV, Polysorbate 60, Tween 60), 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. Preferred examples are polyoxyethyl monooleate (20) sorbitan, polyoxyethyl monooleate (20) sorbitan, polyoxyethyl trioleate (20) The sorbitan is more preferably exemplified by polyoxyethyl (20) sorbitan monooleate.

One of these may be used alone, or two or more of them may be used in combination. In the present invention, polyoxyethylene sorbitan fatty acid ester is used to include all the meanings of the compounds described above.

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 the total amount of the self-emulsifying composition is usually set to 100 mass In the case of%, it is 1 to 29% by mass, preferably 3 to 20% by mass, more preferably 5 to 15% by mass, and still more preferably 5 to 9% by mass.

In the present invention, "polyoxyethylene castor oil" is a compound obtained by addition polymerization of ethylene oxide to castor oil. Various compounds are sold according to the average addition mole number of ethylene oxide, and are exemplified by, for example, NIKKOL CO-3 (Nikko Chemical Co., Ltd.) having an average addition mole number of 3, and NIKKOL having an average addition mole number of 10. CO-10 (Nikko Chemicals Corporation), EMALEX C-20 (Japan Emulsifier Corporation) with an average addition mole number of 20, EMALEX C-30 (Japan Emulsifier Corporation) with an average addition mole number of 30, and the average addition Kolliphor EL (BASF) (Polyoxyl 35 castor oil) with a mole number of 35, EMALEX C-40 (Japanese emulsifier company) with an average added mole number of 40, and EMALEX C-50 with an average added mole number of 50 ( Japan Emulsifier Corporation), 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 polyoxyethylated castor oil in the present invention is used in a meaning including all the compounds as described above unless otherwise specified.

The content of polyoxyethylene castor oil in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effects of the present invention, but it is usually 1 when the total amount of the self-emulsifying composition is 100% by mass. To 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and even more preferably 5 to 9% by mass. In addition, the polyoxyethylene castor oil is preferably 150 parts by mass or less, more preferably 140 parts by mass or less, and more preferably 100 parts by mass of polyoxyethylene sorbitan fatty acid ester in the composition. It is contained in a proportion of 130 parts by mass or less, more preferably 120 parts by mass or less, still more preferably 110 parts by mass or less, and most preferably 100 parts by mass or less. In addition, the ratio of the amount of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil in the composition is preferably 100 parts by mass: 5 to 150 parts by mass, and more preferably 100 parts by mass: 10 to 140 parts by mass or less, preferably 100 parts by mass: 20 to 130 parts by mass, more preferably 30 to 120 parts by mass, even more preferably 100 parts by mass: 50 to 110 parts by mass, preferably 100 parts by mass: It is contained in a proportion of 80 to 120 parts by mass.

In the present invention, "polyoxyethylene hardened castor oil" is a compound obtained by addition polymerization of ethylene oxide to hardened castor oil obtained by hydrogenating castor oil. Various compounds are sold depending on the average degree of polymerization of ethylene oxide. Examples are polyoxyethylene (20) hardened castor oil (NIKKOL HCO-20, Nikko Chemical Co., Ltd.), and polyoxyethylene (40). ) Hardened Castor Oil (NIKKOL HCO-40, Nikko Chemicals), Polyoxyethylene (50) Hardened Castor Oil (NIKKOL HCO-50, Nikko Chemicals), Polyoxyethylene (60) Hardened Castor Oil (NIKKOL HCO-60, Nikko Chemical Co., Ltd.) and polyoxyethylene (100) hardened castor oil (NIKKOL HCO-100, Nikko Chemical Co.), preferably polyoxyethylene (60) hardened castor oil. In addition, one of these may be used alone, or two or more of them may be used in combination. The polyoxyethylene hardened castor oil in the present invention is used to include all the compounds as described above unless otherwise specified.

The content of the polyoxyethylene hardened castor oil in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effects of the present invention. Generally, when the total amount of the self-emulsifying composition is 100% by mass, 1 to 20% by mass, preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and even more preferably 5 to 9% by mass. In addition, the polyoxyethylene ethyl ester hardened castor oil is preferably 150 parts by mass or less, more preferably 140 parts by mass or less, more preferably 100 parts by mass of polyoxyethylene sorbitan fatty acid ester in the composition. 130 parts by mass or less, more preferably 120 parts by mass or less, still more preferably 110 parts by mass or less, and preferably 100 parts by mass or less are contained. In addition, the ratio of the amount of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil in the composition is preferably 100 parts by mass: 5 to 150 parts by mass, and more preferably 100 parts by mass: 10 to 140 parts by mass or less, more preferably 100 parts by mass: 20 to 130 parts by mass, more preferably 30 to 120 parts by mass, even more preferably 100 parts by mass: 50 to 110 parts by mass, preferably 100 parts by mass: It is contained in a proportion 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, and polyoxyethylene castor oil and / or polyoxyethylene hardened castor oil as emulsifiers. 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 an emulsifier other than polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as an emulsifier, but its content is used in emulsifying the composition. When the total amount of the agent is set to 100 parts by mass, it is 20 parts by mass or less, more preferably 10 parts by mass or less, still more preferably 5 parts by mass or less, and it is preferably not substantially contained. The emulsifier that can be contained is not particularly limited as long as it satisfies at least one of the aforementioned problems, and examples include sorbitan fatty acid esters, glycerol fatty acid esters, polyoxyethylene hardened castor oil, and propylene glycol fatty acid esters. , Saturated polyglycol glycidyl ether, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, polyethylene glycol fatty acid ester, tocopherol-polyethylene glycol-succinate (TPGS), etc. .

The total content of the emulsifier in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effects of the present invention. Generally, when the total amount of the self-emulsifying composition is 100% by mass, it is 1 to 29% by mass. It is preferably 3 to 27% by mass, more preferably 5 to 27% by mass, still more preferably 5 to 24% by mass, and still more preferably 10 to 20% by mass. Alternatively, it is preferably 8 to 27% by mass, and more preferably 10 to 27% by mass. In addition, it is 5 to 45 parts by mass, preferably 10 to 45 parts by mass, more preferably 15 to 35 parts by mass, and still more preferably 15 to 20 parts by mass based on 100 parts by mass of the ω3PUFAs.

The composition and medicine of the present invention contain a small amount of water. It is generally considered that the compatibility with the addition of water to a hydrophobic lipid-containing composition is deteriorated. Because the composition contains water, the compatibility of the composition is improved, and no polyol or ethanol is required. Therefore, the appearance is clear even if the polyol or ethanol is not contained, and no separation or turbidity of the composition occurs.

A small amount of water may be added during the preparation of the self-emulsifying composition, or the water in the gelatin film may be migrated to the self-emulsifying composition when it is encapsulated with a gelatin capsule or the like.

In addition, when no polyol or ethanol is contained, the capsule will not soften and deform when it is encapsulated, and alcohol-intolerant patients will not cause side effects due to ethanol.

When the total amount of the self-emulsifying composition is 100% by mass, water is preferably 0.5 to 6% by mass, more preferably 0.5 to 4% by mass, and even more preferably 0.5 to 3% by mass. It is preferably 1 to 3% by mass. Also, it is preferably from 0.5% by mass to 3% by mass, and more preferably from 0.5% by mass to 1.5% by mass.

In the present invention, "lecithin" is a kind of glycerophospholipid, and is exemplified by soybean lecithin, enzyme-degraded soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, hydrogenated phospholipid, milk-derived phospholipid, and hemolyzed egg. Phospholipids, choline phosphate and phosphatidylserine. Preferred examples are soybean lecithin, enzyme-degraded soybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin, and more preferred examples are soybean lecithin. One of these may be used alone, or two or more of them may be used in combination. Unless otherwise specified, the so-called lecithin in the present invention is used to include all the glycerophospholipids as described above. In the present invention, lecithin is not contained in the emulsifier (not included in the emulsifier constituting the element, and its amount is not added to the emulsifier content in the composition).

Commercially available products include purified soybean lecithin (Nissin OILLIO), purified egg yolk lecithin (Asahi Kasei PHAMA), and egg yolk lecithin PL-100M (KEWPIE). Soy lecithin has been marketed as, for example, BASIS LP-20B (Nissin Oil), Lipoid S45, S20 (LIPOID), etc. Enzyme-degraded lecithin has been sold as, for example, 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 it is preferably from 3 to 40 parts by mass, more preferably from 3 to 30 parts by mass, and even more from 100 parts by mass of ω3PUFAs. It is 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 3 to 15 parts by mass, more preferably 3 to 12 parts by mass, still more preferably 3 to 10 parts by mass, and most preferably 5 to 10 parts by mass.

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

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

In the present invention, the "polyol" is a polyol compound having a structure in which one or more hydroxyl groups are substituted on two or more carbon atoms of a chain aliphatic hydrocarbon or a cyclic aliphatic neck. Illustrated as, for example, ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butanediol, tetramethylene glycol, 1,3-butanediol, 2,3-butanediol, and pentamethylene Dihydric alcohols such as glycols, trihydric alcohols such as glycerol, trimethylolpropane, and hexamethylenetriol, diethylene glycol, dipropylene glycol, triethylene glycol, polyethylene glycol, poly Polyol polymers such as propylene glycol and polyglycerol are preferably propylene glycol or glycerol. Glycerol also contains concentrated glycerol. Unless otherwise specified, the polyol in the present invention is used to include all the polyol compounds as described above.

The content of the polyol added to the self-emulsifying composition of the present invention is preferably in a range that does not deform the capsule when the composition is filled in the capsule. For example, when the entire composition is 100% by mass, the composition preferably does not contain more than 4% by mass of a polyol. The polyhydric alcohol content in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, still more preferably 2% by mass or less, and even more preferably 1% by mass or less. It is preferably 0% by mass.

The ethanol contained in the self-emulsifying composition of the present invention is expected to be within a range that does not undergo quality change during capsule manufacturing steps or distribution and storage, and does not undergo denaturation of the capsule contents, and is expected to be calculated on a daily basis. Does not exceed the actual record of pharmaceutical use. For example, when the entire composition is 100% by mass, it is preferable that the composition does not contain more than 4% by mass of ethanol. The content of ethanol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, still more preferably 2% by mass or less, and still more preferably 1% by mass or less. It is preferably 0% by mass.

When the self-emulsifying composition contains ethanol and a polyol, when the entire composition is 100% by mass, the total content of the composition preferably does not contain more than 4% by mass of ethanol and a polyol. A preferred aspect is substantially free of ethanol and polyol. The total amount of ethanol and polyol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, still more preferably 2% by mass or less, and still more preferably 1% by mass or less. It is preferably 0% by mass or less.

The preferred ethanol concentration can be appropriately determined based on the ω3PUFA concentration and the daily dosage in the self-emulsifying composition. When 1800 mg per body is administered orally to the self-emulsifying composition of the present invention as ω3PUFA per day, for example, when the preparation of ω3PUFA is 75% by mass, if the ethanol is 0.135% by mass or less, it will not exceed the amount described in the Pharmacopoeia of Pharmaceutical Additives. The maximum daily usage is 3.26mg.

As described above, in the self-emulsifying composition of the present invention containing ω3PUFAs and emulsifiers, it is preferable to contain 1) EPA-E and / or DHA-E, 2) water, and 3) polyoxygen as an emulsifier. A combination of ethylene glycol sorbitan fatty acid ester and 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) polyoxygen is included. The emulsifier of ethyl sorbitol is 1 to 29% by mass (except lecithin), 4) The amount of lecithin is 3 to 40 parts by mass relative to 100 parts by mass of EPA-E and / or DHA-E. Another preferred form includes 1) EPA-E and / or DHA-E, 2) water, 3) polyoxyethylene sorbitan fatty acid ester as an emulsifier, 4) polyoxy castor oil, 5 ) A 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) polyoxygen is included. Ethyl sorbitol and polyoxy castor oil emulsifier (except lecithin) is 1 to 29% by mass, 4) 100 to mass parts of EPA-E and / or DHA-E, and lecithin is 3 to 40 Parts by mass. Another preferred aspect is to contain 1) at least one compound selected from the group consisting of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof, 2) water, and 3) a 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 100% by mass, 1) at least one compound selected from ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof is 70 to 90% by mass, and 2) water is 0.5 to 0.5%. 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 and 120 parts by mass of polyoxyethylene castor oil, 4) 100 parts by mass of at least one compound selected from the group consisting of ω3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof , Lecithin is 3 to 40 parts by mass of lecithin.

The self-emulsifying composition of the present invention can be enclosed in a capsule. The capsule may be selected from a hard capsule or a soft capsule, and is preferably a soft capsule. The shape of the soft capsule is not necessarily limited, but it is preferably a rotary pattern 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 examples thereof include gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hydroxypropyl methylcellulose, and hydroxyl group. Propyl cellulose and the like, and various conventional ingredients, but gelatin is preferred. There are no restrictions on gelatin. Conventional gelatins such as acid-treated gelatin, alkali-treated gelatin, amphoteric gelatin, and chemically modified gelatin can be used. One or more of these can be used. Preferred is acid-treated gelatin or alkali-treated gelatin. The source of gelatin is not necessarily limited, for example, beef bone, cow leather, pig bone, pig skin, fish scale, and fish skin, and preferably cow bone, cow leather, pig bone, and pig skin.

As "gelatin", ordinary users in the production of soft capsules are listed, for example, the 16th edition amends the medical gelatin (gelatin and purified gelatin) specified in the Japanese Pharmacopoeia. Gelatin can also be used in combination of two or more. The capsule film contains other plasticizers.

The "plasticizer" formulated in the capsule film is preferably a common user in the manufacture of soft capsules, such as glycerol (such as concentrated glycerol), ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol and other components Sugar alcohols such as alcohol, sorbitol, mannitol, and xylitol. These plasticizers may be used in combination of two or more kinds. Among them, glycerol and sorbitol are preferred. Moreover, a combination of glycerol and sorbitol is also preferably used. In this case, it is preferably used in a range of 1: 5 to 5: 1 by mass ratio of glycerol to sorbitol, and more preferably in a range of 1: 3 to 3: 1.

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

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

Furthermore, various additives generally used in capsule films, such as plasticizers such as amino acids, citric acid, glycerol, sorbitol, and trehalose, preservatives, colorants such as pigments and titanium oxide, and organic acids can be added as needed. .

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

The encapsulated self-emulsifying preparation using the self-emulsifying composition of the present invention as a content liquid is preferably good in hardness immediately after manufacture, and does not decrease in hardness after storage. Decreasing the hardness will not only deform the capsule, but also make it brittle and rupture the capsule, causing the content liquid to flow out, which is not good in quality. The presence or absence of softening of the capsule can be confirmed by measuring the hardness with a general durometer.

The hardness of the encapsulated self-emulsifying preparation of the present invention immediately after manufacture is 18 kgf or more, preferably 20 kgf or more, and more preferably 22 kgf or more. In addition, it is expected that the hardness of the sealed aluminum package will not be substantially reduced when stored at 40 ° C for 1 week compared with immediately after manufacture, or the hardness will not be reduced by more than 6kgf, and the hardness after storage at 40 ° C for 1 week will be 10kgf or more. It is preferably 15 kgf or more, and more preferably 20 kgf or more.

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

The dosage and period of administration of the ω3PUFAs used in the self-emulsifying composition of the present invention are sufficient amounts and periods to exhibit the effects of the object, but may be based on the method of administration, the number of administrations per day, the degree of symptoms, Weight, age, etc. are appropriately increased or decreased.

When administered orally, for example, 1 to 3 doses of EPA-E are 0.1 to 5 g / day for each body, preferably 0.2 to 3 g / day, more preferably 0.3 to 3 g / day, and even more preferably 0.5 ~ 3g / day, but you can also administer the total amount once or several times as needed. The number of administrations per day is preferably one administration per day, or two or three administrations per day. For 1 time / day administration, for example, when EPA-E contains 1g of soft capsules, 1 ~ 10 capsules, preferably 1 ~ 8 capsules, more preferably 1 ~ 6 capsules, and even better 1 ~ 4 Capsules, even better 1-3 capsules. In addition, a soft capsule containing 1g and a soft capsule containing 0.5g as EPA-E can be combined at 0.5g / time, 1.5g / time, 2.5g / time, 3.5g / time, 4.5g / time or 5.5g / time administration. The aforementioned 1-day dose or 1-time dose allows a difference of ± 5%. The absorption of EPA-E will affect the meal, so it is better to administer it during or after a meal, and it is better to administer it immediately after eating (within 30 minutes). However, the self-emulsifying composition of the present invention Absorptivity is still excellent on an empty stomach, so patients with low intestinal absorption energy during meals, after meals, or just after meals, such as when administered before, during, during, or before bedtime ( Elderly people, patients with bowel disease, patients with bowel surgery, patients with advanced cancer, or lipase inhibitors) can still exhibit the effects of the present invention when administered or when the dose is reduced.

The self-emulsifying composition of the present invention preferably has the characteristics of the time to reach the highest plasma concentration after oral administration and the ω3PUFA stock solution (referring to the same amount of ω3PUFAs as the self-emulsifying composition of the present invention, and does not contain emulsification). Compositions of agents, etc.) are equal or shorter. In addition, it is preferable that the highest plasma concentration is higher than the ω3PUFA stock solution. Further, it is preferable that the blood concentration after 2 hours of administration, the area under the blood curve after administration for 0 to 2 hours, and / or the area under the blood concentration curve for 0 to 72 hours are equal to or equal to the original liquid phase of ω3PUFA. 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 ω3PUFA, its concentration is high, and the blood concentration 2 hours after administration, 0 to 2 hours, and / or 0 Any area below the blood concentration curve at ~ 72 hours was higher than the ω3PUFA stock solution.

The above drug dynamics can be confirmed by animals such as dogs or monkeys, but it is preferably confirmed by human experiments.

In a drug dynamic test using a male Miguel dog, male miguel dogs were administered orally to a self-emulsifying composition at a dose of 600 mg per dog under the condition of hunger fasting for more than 18 hours, and the administration was reduced. The highest ω3PUFA plasma concentration calculated by correcting the ω3 concentration in the previous blood is, for example, preferably 50 μg / ml or more, more preferably 60 μg / ml or more, and even more preferably 70 μg / ml or more. And the area under the blood concentration curve of ω3PUFA administered between 0 and 2 hours is preferably 50 μg / ml‧hr or more, more preferably 60 μg / ml‧hr or more, and more preferably 70 μg / ml‧hr or more. In addition, the combination of the highest plasma concentration of ω3PUFA and the area under the blood concentration curve of ω3PUFA is preferably 50 μg / mL or more and 50 μg / ml‧hr or more, more preferably 60 μg / ml or more and 60 μg / ml‧hr or more, more preferably Above 70 μg / ml and above 70 μg / ml‧hr.

In a drug dynamic test using a male crab-eating macaque, male cynomolgus macaques were orally administered with an autoemulsifying composition at a weight of 45 mg per 1 kg in terms of ω3PUFA under the condition of hunger strike for more than 12 hours. The highest ω3PUFA concentration in blood calculated by correcting the ω3 concentration in blood is preferably 50 μg / ml or more, more preferably 70 μg / ml or more. And the area under the blood concentration curve of ω3PUFA administered between 0 and 12 hours is preferably 400 μg / ml‧hr or more, more preferably 500 μg / ml‧hr or more. In addition, the combination of the highest plasma concentration of ω3PUFA and the area under the blood concentration curve of ω3PUFA is preferably 50 μg / mL or more and 400 μg / ml‧hr or more, more preferably 70 μg / ml‧hr or more and 500 μg / ml‧hr or more.

In the drug dynamic test using humans, the oral self-emulsifying composition was administered to humans in an amount of 1800 mg per person before meals, immediately after meals, or after meals, reducing the amount before administration. The highest concentration of ω3PUFA in plasma calculated by correcting the ω3 concentration in blood is preferably 50 μg / mL or more, more preferably 100 μg / mL or more, still more preferably 150 μg / mL or more, still more preferably 200 μg / mL or more, and most preferably 300 μg / mL or more. Or preferably 10 to 1000 μg / mL, more preferably 20 to 500 μg / mL, still more preferably 40 to 300 μg / mL, still more preferably 50 to 150 μg / mL, and most preferably 50 to 100 μg / mL. And the area under the blood concentration curve of ω3PUFA administered between 0 and 72 hours is preferably more than 500 μg / ml‧hr, more preferably 1000 μg / ml‧hr or more, still more preferably 1500 μg / mL‧hr or more It is preferably 2000 μg / ml‧hr or more, and more preferably 3000 μg / ml‧hr or more. Or preferably 500 ~ 4500μg / ml‧hr, more preferably 600 ~ 3000μg / ml‧hr, still more preferably 700 ~ 2500μg / ml‧hr, and still more preferably 800 ~ 2000μg / ml‧hr, the best It is 1000 ~ 1500μg / ml‧hr. In addition, the arrival time of the highest plasma concentration is preferably 6 hours or less, more preferably 5 hours or less, still more preferably 3 hours or less, still more preferably 1 hour or less, and most preferably 0 hours or less. Alternatively, it is preferably 0.5 to 10 hours, more preferably 1 to 8 hours, still more preferably 1.5 to 7 hours, still more preferably 2 to 5 hours, and most preferably 2.5 to 4 hours. In addition, the disappearance half-life in plasma is preferably 10 hours or more, more preferably 20 hours or more, still more preferably 30 hours or more, even more preferably 40 hours or more, and most preferably 50 hours or more. Alternatively, it is preferably 0 to 150 hours, more preferably 10 to 120 hours, still more preferably 30 to 100 hours, still more preferably 25 to 75 hours, and most preferably 25 to 50 hours.

In a drug dynamic test using humans, for example, the amount of ω3PUFAs or EPAs before meals, immediately after meals, or EPAs is 3600 mg per person, and the self-emulsifying composition is orally administered to each person, and the administration is reduced. The highest concentration of ω3PUFA in the blood calculated by correcting the ω3 concentration in the previous blood is preferably 50 μg / mL or more, more preferably 100 μg / mL or more, more preferably 150 μg / mL or more, and still more preferably 200 μg / mL or more. It is preferably at least 300 μg / mL. Or preferably 10 to 1000 μg / mL, more preferably 20 to 500 μg / mL, still more preferably 50 to 400 μg / mL, even more preferably 100 to 300 μg / mL, and most preferably 150 to 200 μg / mL. And the area under the blood concentration curve of ω3PUFA administered from 0 to 72 hours is preferably 500 μg / ml‧hr or more, more preferably 1000 μg / ml‧hr or more, more preferably 1500 μg / mL‧hr or more, even more preferably Above 2000 μg / ml‧hr, preferably above 3000 μg / ml‧hr. Or preferably 500 ~ 5000μg / ml‧hr, more preferably 1000 ~ 4700μg / ml‧hr, more preferably 1500 ~ 4500μg / ml‧hr, even more preferably 2000 ~ 4000μg / ml‧hr, most preferably 2500 ~ 3500μg / ml‧hr. In addition, the maximum plasma concentration reaching time is preferably 6 hours or less, more preferably 5 hours or less, still more preferably 3 hours or less, still more preferably 1 hour or less, and most preferably 0 hours or less. Alternatively, it is preferably 0.5 to 10 hours, more preferably 1 to 8 hours, still more preferably 1.5 to 7 hours, still more preferably 2 to 6 hours, and most preferably 3 to 5 hours. In addition, the disappearance half-life in plasma is preferably 10 hours or more, more preferably 20 hours or more, still more preferably 30 hours or more, even more preferably 40 hours or more, and most preferably 50 hours or more. Alternatively, it is preferably 0 to 150 hours, more preferably 10 to 120 hours, still more preferably 30 to 100 hours, still more preferably 25 to 75 hours, and most preferably 25 to 50 hours.

When using a human-made drug dynamic test, in addition to the foregoing, the following numerical ranges can also be used. That is, for example, before meals, immediately after meals, or after meals, the amount of omega 3 PUFAs or EPAs is 1800 mg per person, and the self-emulsifying composition is orally administered. The omega 3 concentration in the blood before administration is subtracted and corrected. Although the maximum concentration of ω3PUFA in plasma is not particularly limited, it can be selected, for example, from 10 to 50, 50 to 100, 100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 350, 350 to 400, 400 ~ 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, 1 35 ~ 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, for example in When the self-emulsifying composition is administered in an amount of 3600 mg per person before meals, immediately after meals, or after meals, for example, 10 to 50, 50 to 100, 100 to 150, 150 to 200 can be selected. , 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 blood concentration curve of ω3PUFA from 0 to 72 hours is administered when the self-emulsifying composition is administered in an amount of 1800 mg per person in terms of ω3PUFA or EPA before, immediately after, or after meals. , Can choose 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 , 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 ~ 2150, 2100 ~ 2200, 2150 ~ 2250, 2200 ~ 2300, 2250 ~ 2350, 2300 ~ 2400, 2350 ~ 2450, 2400 ~ 2500, 2450 ~ 2550, 2500 ~ 2600, 2550 ~ 2650, 2600 ~ 2700, 2650 ~ 2750, 2700 ~ 2800, 2750 ~ 2850, 2800 ~ 2900, 2850 ~ 2950, 2900 ~ 3000, 2950 ~ 3050, 3000 ~ 3100, 3150 ~ 3250, 3200 ~ 3300, 3250 ~ 3350, 3300 ~ 3400, 3350 ~ 3450, 3400 ~ 3500, 3500 ~ 3600, 3600 ~ 3700, 3700 ~ 3800, 3800 ~ 3900, 3900 ~ 4000, 4000 ~ 4100, 4100 ~ 4200, 4200 ~ 4300, 4300 ~ 4400, 4400 ~ 4500μg / ml. hr, for example, when the self-emulsifying composition is administered in an amount of 3600 mg in terms of ω3PUFA or EPA before meals, immediately after meals, 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, 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 ~ 1 200, 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, 2250 ~ 2350, 2300 ~ 2400, 2350 ~ 2450, 2400 ~ 2500, 2450 ~ 2550, 2500 ~ 2600, 2550 ~ 2650, 2600 ~ 2700, 2650 ~ 2750, 2700 ~ 2800, 2750 ~ 2850, 2800 ~ 2900, 2850 ~ 2950, 2900 ~ 3000, 2950 ~ 3050, 3000 ~ 3100, 3150 ~ 3250, 3200 ~ 3300, 3250 ~ 3350, 3300 ~ 3400, 3350 ~ 3450, 3400 ~ 3500, 3500 ~ 3600, 3600 ~ 3700, 3700 ~ 3800, 3800 ~ 3900, 3900 ~ 4000, 4000 ~ 4100, 4100 ~ 4200, 4200 ~ 4300, 4300 ~ 4400, 4400 ~ 4500μg / ml. hr.

In addition, the maximum plasma concentration reaching time can be, for example, 0 to 2, when the self-emulsifying composition is administered in an amount of 1800 mg to 3600 mg per person in terms of ω3PUFA or EPA before meals, immediately after meals, or after meals. 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.

In addition, when the half-life of disappearance in plasma is, for example, ω3PUFAs or EPAs before administration, immediately after or after meals, the amount of 1800mg to 3600mg per person is administered to the self-emulsifying composition, for example, 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.

In the foregoing, the present invention may be specified by combining two or more selected from the maximum concentration of ω3PUFA plasma, the area under the ω3PUFA blood concentration curve from 0 to 72 hours after administration, the maximum plasma concentration arrival time, and the disappearance half-life in plasma.

The self-emulsifying composition of the present invention may also contain an emulsifying adjuvant, a stabilizing agent, a preservative, a surfactant, an antioxidant, and the like. Examples of the emulsifying adjuvant include fatty acids having a carbon number of 12 to 22 such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, and myristic acid, or their salts. Stabilizing agents are exemplified by phosphatidic acid, ascorbic acid, glycerol, cetyl alcohol, and the like. Preservatives are exemplified by ethyl parahydroxybenzoate, propyl paraoxybenzoate, and the like. Surfactants are exemplified by sucrose fatty acid esters, sorbitan fatty acid esters, glycerol fatty acid esters, polyoxyethylene ethyl sorbitan fatty acid esters, polyoxyethyl ethers, polyoxyethylene Ethyl fatty acid esters, polyoxyethylene alkylphenyl ethers, polyoxyethyl polyoxypropylene alkyl ethers, and the like. Antioxidants are exemplified by butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, quinone, astaxanthin, and alpha-fertility that are medically acceptable Oil-soluble antioxidants such as phenol.

In addition, it can be used with appropriate carriers or media generally used, colorants, flavoring agents, vegetable oils as needed, and harmless organic solvents or harmless dissolution aids, emulsifiers, suspending agents (such as Tween 80, gum arabic solution) Additives such as isotonicity agents, pH adjusters, stabilizers, flavoring agents, flavoring agents, preservatives, antioxidants, and absorption enhancers are appropriately selected and combined to prepare appropriate pharmaceutical preparations.

In particular, since ω3PUFAs are highly unsaturated, it is desirable to contain an effective amount of an oil-soluble antioxidant, such as selected from butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and gallic acid. At least one of propyl ester, quinone, astaxanthin, and α-tocopherol, which are pharmaceutically acceptable, is used as an antioxidant.

Since the self-emulsifying composition of the present invention is also used in medical applications, it is preferable that the self-emulsifying composition has good appearance, and has excellent self-emulsifying property, composition dispersibility, emulsification stability, and storage stability. The appearance of the self-emulsifying composition is not separated, turbid, cured, or precipitated, and is preferably clarified. When the appearance is poor, it is not good as medicine, and it may not have the originally required properties such as self-emulsifying property.

The storage temperature considers the possibility of disposing the self-emulsifying composition or the encapsulated preparations in a cold zone or a high temperature environment. It is better to clarify the appearance at low temperature and high temperature.

In the case of a self-emulsifying composition having excellent self-emulsifying properties, composition dispersibility, and emulsification stability, it disperses quickly when in contact with water, and forms a microemulsion with a moderate emulsifying droplet diameter. The absorption of oil such as EPA-E is related to the size of the emulsified droplet diameter. By measuring this, it can be predicted whether the absorption of the animal food is good.

In the present invention, the "average emulsified droplet diameter" is measured using a particle size distribution measuring device (for example, Nanotorac, manufactured by Nikkiso Co., Ltd.) using a standard measuring method (for example, Setzero time of 30 seconds, using water as a dispersion medium). Time 30 seconds, average of 3 times of measurement) The value of the volume average particle diameter in the emulsified composition measured. The average emulsified droplet diameter when the self-emulsifying composition of the present invention is dispersed in water or the like is not more than 2 μm, and there is no particular limitation as long as it is within the range of excellent emulsification dispersibility, emulsification stability, or absorptivity, but the average emulsified droplet is generally The diameter is exemplified as 1.5 μm or less, more preferably 1.0 μm or less, still more preferably 0.5 μm or less, and most preferably 0.3 μm or less.

The second effective ingredient may 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 disease and symptoms of the subject, and preferably does not reduce the effects of ω3PUFAs. Examples are, for example, hyperlipidemia treatment drugs, antihypertensive drugs, anti-diabetic drugs, antioxidants, blood flow improvers, bile acids Derivatives, NAFLD‧NASH therapeutic agents, inhibitors and therapeutic agents for cognitive disorders, etc.

Preferred second active ingredients are listed in the treatment of hyperlipidemia as, for example, polyenephosphatidylcholine, unsaponifiable soybean oil (soysterol), γ-diastatin, riboflavin butyrate , Dextran sodium sulfate sulfur 18, pantothenic acid, elastase. In addition, examples include pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, and rosafastat Statin of rosuvastatin, cerivastatin or simfibrate, clofibrate, clinofibrate, bezafibrate, phenofarate Fibrates of fenofibrate are pharmaceuticals, or lipolytic enzyme inhibitors such as Orlistat and cetilistat, such as colesyramine or colestiba Colestimide resin, ezetimibe and so on.

Antihypertensive drugs are listed such as irbesartan, olmesartan medoxomil, candesartan, telmisartan, valsartan, rosartan potassium (losartan potassium) angiotensin II receptor antagonists, such as alapril, imidapril hydrochloride, enalapril maleate, captopril ( captopril), quinapril hydrochloride, cilazapril hydrate, temocapril hydrochloride, delaprill hydrochloride, tolanpril (trandolapril), Bennapril and benazepril hydrochloride, perindopril, lisinopril hydrate hemagglutinin-converting enzyme inhibitors, such as azelnidipine ), Amlodipine besylate, aranidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, and nifedipine nifedipine), nimododipine, nitrendipine, Nilvadipine, barnidipine hydrochloride, fe1odipine, benidipine, such as manidipine calcium ion antagonists, such as tolazoline, Alpha receptor blockers of phentolamine, such as atenolol, metoprolol, acebutolol, propranolol, and pindolol Carvedilol, such as beta -blockers of labetalol hydrochloride, such as alpha receptor stimulants such as clonidine, methyldopa, etc. Diuretics of eplerenone, hydrochlorothiazide, and furosemide.

Anti-diabetic drugs are also listed as alpha -glucosidase inhibitors such as acarbose, voglibose, and miglitol, such as gliclazide, Glibenclamide, glimepiride, tolbutamide, sulfonylurea are hypoglycemic drugs, such as nateglinide, mitiglinide Insulin secretion-promoting drugs, such as metformin hydrochloride, buformin hydrochloride, biguanide-based hypoglycemic drugs, such as sitagliptin, vildagliptin, alogliptin alogliptin, linagliptin, teneligliptin, anagliptin, saxagliptin dipeptidyl phosphatase 4 inhibitors, such as pioglitazone hydrochloride ), Thiazolidine drugs such as rosiglitazone maleate, such as exenatide, liraglutide and other glucagon peptide 1 derivative drugs, such as Igg Ipragliflozin, dapagliflozin, Glenn net (luseogliflozin), net Torg column (tofogliflozin), canagliflozin (canagliflozin), ipamorelin column net (empagliflozin) of sodium glucose conjugated like hinder transport body 2.

Examples of the antioxidant include vitamins such as ascorbic acid (vitamin C), tocopherol (vitamin E), tocopherol nicotinate, N-acetylamylcysteine, and probucol.

Examples of blood flow improving agents include cilostazol, ticlopidine hydrochloride, alprostadil, limaprost, beraprost sodium, Sarpogrelate hydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride, batroxobin, dihydroergotoxin methane sulfonate (dihydroergotoxine mesilate), tolazoline hydrochloride, hepronicate, Siwutang extract and the like.

Bile acid derivatives are exemplified by, for example, ursodeoxycholic acid, chenodeoxycholic acid, bile powder, deoxycholic acid, bile acid, bile extract, bear bile, bezoar or Dehydrocholic acid and so on. As preferred examples, biotin (vitamin B7), cyanocobalamin (vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamin (vitamin B1), vitamin A, vitamin D, and vitamins are listed. K, tyrosine, pyridoxine (vitamin B6), leucine. Isoleucine. Valine acids and other branched chain amino acids, calcium, iron, ferrous, copper, magnesium. Also listed are soy protein, chitosan, low-molecular-weight sodium alginate, dietary fiber derived from psyllium seed coats, phospholipid-bound soybean peptides, plant sterol esters, plant stanol esters, dimethylglycerol, Ingredients for specific health foods or nutritional functional foods such as globulin protein breakdown products, tea catechins, etc.

NAFLD. The NASH therapeutic agents are listed as pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, and rishu Rosuvastatin, cerivastatin, statin, such as irbesartan, olmesartan medoxomil, candesartan, telmisartan (telmisartan), valsartan, losartan potassium, angiotensin II receptor antagonists, such as metformin hydrochloride, buformin hydrochloride Drugs, such as pioglitazone hydrochloride, rosiglitazone maleate, thiazolidine drugs, such as aspirin, ursodeoxycholic acid, chenodeoxycholic acid, obeticholic acid ( obeticholic acid) and the like.

Cognitive disorders are suppressed. Examples of therapeutic agents are acetylcholinesterase inhibitors such as donepezil hydrochloride, galanthamine hydrobromide, such as NMDA receptor inhibitors of memantine hydrochloride, aspen Antiplatelet agents such as Pilin, clopidogrel sulfate, cilostazol, ticlopidine hydrochloride, such as rivaroxaban, apixaban Factor Xa inhibitors and so on. In addition, the above-mentioned hyperlipidemia treatment drugs, antihypertensive drugs, anti-diabetic drugs, antioxidants, blood flow improvers and the like can also be suppressed as cognitive diseases. Use of therapeutic agents.

The self-emulsifying composition of the present invention is expected to exhibit the pharmacological effects of ω3PUFAs, and has excellent appearance, excellent self-emulsifiability, excellent composition dispersibility, excellent emulsification stability, storage stability (including low temperature, High temperature stability) excellent, absorbent, especially fasting absorption, excellent absorption speed, patient convenience, or at least one of the formulations excellent in compliance.

The self-emulsifying composition of the present invention can be used as a therapeutic agent for various diseases of animals, especially mammals, such as lipid disorders (hypercholesterolemia, hyperLDL cholesterolemia, hypernon-HDL cholesterolemia, hyperVLDL cholesterolemia). , Low HDL cholesterolemia, hypertriglyceridemia, hyperapoBemia, hypoapoAIemia, etc.) therapeutic agents, therapeutic agents for post-prandial hypertriglyceridemia, anti-arteriosclerosis agents, platelet aggregation inhibitors, peripheral circulation insufficiency agents , Preventive agents for cardiovascular event attacks, therapeutic agents for inflammatory diseases (NAFLD, NASH, etc.), cognitive disorders (cognition of Alzheimer's disease, cerebrovascular cognitive disorder, mixed cognitive disorders, etc.) Anticancer agents and therapeutic agents for central diseases (depression, depression, obsessive-compulsive disorder, social disturbance, panic disorder, etc.). In the treatment of the aforementioned diseases, the number of daily administrations of the self-emulsifying composition of the present invention is not limited, preferably once a day, or divided into two or three times a day, more preferably once a day Or 2 times, and more preferably 2 times a day.

Next, among the aforementioned diseases, suppression of lipid abnormality, improvement or treatment of post-prandial hypertriglyceridemia, recurrence prevention or metabolic syndrome, cardio-cerebrovascular events, ulcers or necrosis of peripheral limbs, etc. are particularly effective. Mammals include, for example, humans or livestock animals such as cattle, horses, and pigs, or domestic animals such as dogs, cats, rabbits, rats, and mice, and humans are preferred. In particular, it is expected to show improvement or treatment effect of lipid abnormality or post-prandial hypertriglyceridemia in patients with lipid abnormalities such as metabolic syndrome patients who have increased blood lipids, exhibited insulin resistance, or increased blood pressure.

    [Example]    

Next, examples and comparative examples are given to illustrate the present invention more specifically, but the present invention is not limited thereto.

Example 1

Measure 0.09 g of water, 0.53 g of polyoxyethylene (20) sorbitan oleate, 0.39 g of soy lecithin, 4.0 g of EPA-E, seal, mix while heating to about 70 ° C, and prepare from Body emulsified composition. The self-emulsifying composition was replaced with nitrogen, sealed, and stored at room temperature until evaluation was performed. Table 1 shows the formulation of the self-emulsifying composition.

Examples 2 to 11, Comparative Examples 1 to 2

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

Comparative Examples 3 to 4

The compositions of Comparative Examples 3 and 4 were prepared and stored in the same manner as in Example 1 in the composition ratios described in Table 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 having gelatin in 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 left to stand and evaluated for appearance after about 1 hour. When the compatibility is excellent and the composition is homogeneous, it is referred to as "clear", when it is separated, it is referred to as "separation", and when it is opaque, it is referred to as "haze".

Table 1 shows the test results.

Test Example 2 <Evaluation of self-emulsifying property>

For the self-emulsifying composition and the composition of the comparative example manufactured by the above-mentioned production method, 10 μL of each composition was dropped into 37 ° C pure water in the test tube and 5 mL of the first liquid of the Japanese Pharmacopoeia Dissolution Test. The bulk emulsifiability was evaluated. The case where emulsification was performed only by dropping was evaluated as good, and the case where natural emulsification was not achieved by dropping only was evaluated as bad. Next, after stirring gently under uniform conditions, the properties were evaluated. Regarding the dispersibility of the composition, it was evaluated as good when the composition was dispersed, and it was evaluated as poor when a part of the composition was not dispersed and remained in a block. Regarding emulsification stability, the case where oil separation did not occur was evaluated as good, and the case where oil separation occurred was evaluated as poor. In addition, the composition which was not evaluated as "clarified" in the evaluation of the appearance was considered to be unable to be properly evaluated due to uneven composition, and was not evaluated.

Table 1 shows the test results.

Test Example 3 <Evaluation of Emulsion Drop Diameter>

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

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

The "clear" or "hazy" composition of Test Example 1 was stored at 5 ° C or 40 ° C overnight (approximately 12 hours), and the appearance was evaluated. Compatibility is excellent. When the composition is uniform, it is evaluated as "clear", when it is separated, it is evaluated as "separated", and when it is opaque, it is evaluated as "haze".

Table 1 shows the test results.

Test example 5 <Drug dynamics of Miguel dogs>

6 male Miguel dogs (aged 2 to 6 years old, weighing 8 to 13 kg, 3 Marshall Miguel, 3 Nosan Miguel) were orally administered to the manufactured composition or capsule under hunger strike And evaluate the change in the blood concentration of EPA. In addition, each test animal has been on a hunger strike more than 18 hours before administration, and each animal is administered a composition of 600 mg in terms of EPA-E. Blood was collected before administration, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after administration, plasma was separated for processing, and the samples were separated by LC / MS / MS (liquid chromatography for mass analysis) The method of separating and measuring it) measuring the EPA concentration in plasma. In addition, EPA-E stock solution filled in capsules was also administered as a control group.

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

Test Example 6 <Drug Dynamics of Crab-eating Macaques>

Six crab-eating macaques (2 to 5 years old, weighing 2.70 to 4.65 kg, HAMRI) were orally administered to the manufactured composition or capsules under fasting conditions to evaluate the change in the blood concentration of EPA. In addition, each test animal had been on a hunger strike more than 12 hours before administration, and each animal was administered an EPA-E to obtain a self-emulsifying composition in an amount of 45 mg / kg. In addition, 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, plasma was separated for treatment, and EPA concentration 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 (AUC _0-12 ) between 0 and 12 hours, and the area under the blood concentration curve (AUC) between 0 and 72 hours _0-72 ). In addition, when each parameter is calculated, the EPA concentration in the blood before administration is subtracted from the concentration in each blood and corrected. The animals administered with the composition of Example 14 were compared with the control group, and it was confirmed that the blood concentration parameters such as Cmax and AUC _0-12 increased. That is, when the self-emulsifying composition of Example 14 was administered, it was confirmed that not only the amount of absorption increased but also that EPA was quickly absorbed after oral administration.

Test example 6-2 <Drug dynamics of humans (single administration test, administration of 1800 mg)

For humans (healthy adult men 20 to 40 years of age, weighing 55.0 to 77.0 kg, BMI 18.5 or higher and less than 25.0), 12 people were orally administered the present invention containing 80% by mass of EPA-E as a content under hunger strike. Capsules of the self-emulsifying composition were evaluated for changes in the blood concentration of EPA. Each person used a single oral administration of 200 mL of water in the morning on an empty stomach to give EPA-E a total of 1800 mg of self-emulsifying composition. 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 the blood was collected, it was ice-cold, centrifuged at 2000 × g for 10 minutes at 4 ° C, the plasma was separated, and frozen and stored below -20 ° C. The EPA concentration in the obtained plasma was measured by LC / MS / MS (method of separating a sample by liquid chromatography, separating and measuring it by mass analysis).

In addition, the same measurement was performed by orally administering capsules of the self-emulsifying composition of the present invention containing 80% by mass of EPA-E as a content under the conditions immediately after eating.

In addition, twelve humans (healthy adult men aged 20 to 40, body weight 55.0 to 77.0 kg, BMI 18.5 or higher and less than 25.0) were orally administered as a control group of EPA-E filled in capsules 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 applies hereinafter), and the same measurement was performed.

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

Test example 6-3 <Drug dynamics of humans (single administration test, 3600 mg administration)

The test was performed in the same manner as in Example 6-2, with the dosage of 3600 mg. Implemented on 6 humans. Table 3 shows the highest plasma concentration (Cmax) calculated from the test results, the plasma concentration (C ₂₄ ) 24 hours after administration, and the area under the blood concentration curve (AUC _0-72 ) between 0 and 72 hours. , The highest plasma concentration arrival time (Tmax), the disappearance half-life in plasma (t _1/2 ). In addition, when calculating each parameter, the EPA concentration in the blood before administration was subtracted from the concentration in each blood and corrected.

Test example 7 <appearance of capsule>

The soft capsules obtained in the examples were visually confirmed regarding the color, shape, and properties of the filling liquid after filling and drying were completed.

Defects were recognized in the case of discoloration in color, deformation or unevenness in the shape, turbidity or separation in the filling liquid, and abnormality was recorded in those who did not confirm.

Table 1 shows the test results. "-" In the following table means that the component was not added or was not measured.

Example 1 is a composition containing only polyoxyethylene sorbitan fatty acid ester as an emulsifier, and further containing a specific range of lecithin and water. As shown in Table 1, the composition has a good appearance. Excellent in self-emulsifying properties. From this result, it turns out that the composition containing lecithin has the effect of this invention even if the emulsifier is only a composition of polyoxyethylene sorbitan fatty acid ester.

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

Example 11 is a composition containing polyoxyethylene hardened castor oil as an emulsifier in the composition. As shown in Table 1, the composition has a good appearance and excellent self-emulsifying properties.

Comparative Example 1 is a composition containing no water in the composition, and the composition is separated. Further, Comparative Example 2 is a composition containing 8% by mass of water in the composition, and this composition is also separated in the same manner.

In the present invention, when the compatibility of the composition is improved, water or alcohol is not used, but water is used instead. In the absence of water, the composition is separated because it does not have sufficient compatibility. In addition, even if the amount of the water-containing formulation is too much relative to the composition, the separation is similar. Examples 1 to 6 in which water was 1 to 4% by mass were not separated. Therefore, it can be seen that a specific amount of water containing about 0.5 to 6% by mass is important for excellent appearance and the like.

Comparative Example 3 is a composition containing no polyhydric alcohol without water. The appearance of this composition was good, and excellent points such as self-emulsifiability were shared with Example 1 and the like.

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

Comparative Example 4 is a composition that contains polyoxyethylene castor oil as an emulsifier and does not contain polyoxyethylene sorbitan fatty acid ester, and the appearance of this composition becomes hazy.

Therefore, it can be seen that those containing polyoxyethylene sorbitan fatty acid ester as an emulsifier are important for excellent appearance.

Examples 1, 3, and 5 show the dynamic results when the self-emulsifying composition was administered to animals during a fast.

Animals administered these self-emulsifying compositions had significantly higher values of the absorption rate parameters Cmax and AUC _0-2 than animals administered the control group (when fasting). That is, when the self-emulsifying composition of Example was administered, it was confirmed that not only the amount of EPA absorption increased until 24 hours after oral administration, compared with the control group, and EPA was absorbed rapidly after oral administration.

Test Example 6-2 shows the parameters of the self-emulsifying composition of the present invention containing 80% by mass of EPA-E in 1800 mg and 1800 mg of EPA-E when EPA-E is administered to humans. Any one of the parameters of Cmax, _C24 , AUC _0-72 under hunger strike conditions, the composition of the example is about 10 times higher, confirming that EPA is quickly absorbed after oral administration. Test Example 6-3 shows the parameters of the aforementioned self-emulsifying composition with 3600 mg of EPA-E administered and 3600 mg of EPA-E, and it was confirmed that the same was quickly absorbed. In addition, it was confirmed that the self-emulsifying composition of the present invention is not easily affected by meals, and showed high EPA absorption regardless of the presence or absence of meals.

Accordingly, the EPA concentration in the blood when the self-emulsifying composition of the present invention is taken on a fasting period before meals or before bedtime is rapidly increased, and it can be expected to be used as a self-emulsification whose pharmacological action is rapid and more effective. Type preparation.

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

As shown in Table 4, the self-emulsifying composition and the composition of Comparative Example 2-3 were prepared and stored in the same manner as in Example 1. Table 4 shows the formulation of the self-emulsifying composition.

375 mg of the self-emulsifying composition was filled in Example 2-1 and 2-2 series by the rotary process method, and 441 mg of the self-emulsifying composition was filled in Comparative Example 2-3 series (both 300 mg in terms of EPA-E). ) Of soft gelatin capsules. In the self-emulsifying capsule preparation produced by this method, deformation of the capsule film was not confirmed.

Table 4 shows the composition of the content liquid.

Test example 8 <Capsule hardness>

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

Table 4 shows the results of each preparation at the initial stage and storage at 40 ° C for 1, 2, and 4 weeks. In addition, the initial stage refers to a preparation stored at room temperature before evaluation after production of the capsule. In addition, since each preparation was sealed in an aluminum package and stored at 40 ° C, 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 20 kgf or more. On the other hand, Comparative Example 2-3 of propylene glycol containing a polyhydric alcohol in a large amount of 8.3% by mass was lower in initial stage hardness compared to the Examples. After evaluating the hardness after storage at 40 ° C for 1 to 4 weeks in a sealed environment, Examples 2-1 and 2-2 showed almost no change. In contrast, Comparative Example 2-3 decreased the hardness to the initial level at 1 week. 57%, further decrease in hardness 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 absorptivity, and can be quickly absorbed and suppressed after meal even if administered before meals. Increased serum TG. It is useful as a special-purpose food, health functional food (specific health food and nutritional functional food), health food (supplement), or medicinal product prepared in various foods.

Since the self-emulsifying composition of the present invention has no added polyol or low added concentration, the risk of softening and deformation of the capsule due to the polyol during the distribution process or storage will not be low.

In addition, the composition has no denaturation or opacity when stored under low-temperature or high-temperature environments. Therefore, it has the quality that it can be stored in cold or high-temperature regions when used as medicine.

Claims (15)

    A self-emulsifying preparation comprising an encapsulated orally administered self-emulsifying preparation in which a self-emulsifying composition is held in a capsule as an internal solution; and the aforementioned self-emulsifying composition is composed of the self-emulsifying composition When the total amount of the substance is 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) 0.5-6% by mass of water, c) 1-29% by mass of an emulsifier of polyoxyethylene ethyl sorbitan fatty acid ester, d) pharmacologically based on ω3 polyunsaturated fatty acids Permissible salt and 100% by mass of at least one compound of the ester are 3 to 40 parts by mass of lecithin, and e) ethanol is 4% by mass or less of the total amount of the foregoing composition, and f) polyol is the total amount of the foregoing composition. The amount is less than 4% by mass.         The self-emulsifying preparation according to claim 1, which is used in at least one selected from the group consisting of foods, special-purpose foods, health functional foods, health foods, and pharmaceuticals.         The self-emulsifying preparation according to claim 2, which is used in pharmaceuticals.         The self-emulsifying preparation according to claim 1 or 2, wherein the capsule is a hard capsule and / or a soft capsule.         The self-emulsifying preparation according to claim 4, wherein the capsule film of the aforementioned soft capsule comprises gelatin.         The self-emulsifying preparation according to claim 1 or 2, wherein the emulsifier further comprises polyoxyethylene hardened castor oil and / or polyoxyethylene castor oil.         The self-emulsifying preparation according to claim 1 or 2, wherein the emulsifier comprises polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil.         The self-emulsifying preparation according to claim 1 or 2, wherein ethanol is 1% by mass or less of the total amount of the aforementioned composition.         The self-emulsifying preparation according to claim 1 or 2, wherein the polyol is 1% by mass or less of the total amount of the aforementioned composition.         A self-emulsifying preparation comprising an encapsulated orally administered self-emulsifying preparation in which a self-emulsifying composition is held in a capsule as an internal solution; and the aforementioned self-emulsifying composition is composed of the self-emulsifying composition When the total amount of the substance is 100% by mass, it contains: a) at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof, 70 to 90% by mass, b) 0.5 ~ 6 mass% water, c) 1 ~ 29 mass% polyoxyethylene sorbitan fatty acid ester and polyoxyethylene ethyl castor oil emulsifier, d) polyunsaturated with respect to ω3 Fatty acid, pharmaceutically acceptable salt thereof, and 100 parts by mass of its ester, 3 to 40 parts by mass of lecithin, and e) with respect to 100 parts by mass of the aforementioned polyoxyethylene sorbitan fatty acid ester, Polyoxyethylene castor oil is 120 parts by mass or less, f) ethanol is 4% by mass or less of the total composition, and g) polyol is 4% by mass or less of the total composition.         A self-emulsifying composition is a self-emulsifying composition administered orally, and when the total amount of the self-emulsifying composition is set to 100% by mass, it contains: a) 70 to 90% by mass selected from ω3 Polyunsaturated fatty acids, their pharmaceutically acceptable salts, and at least one compound in the group formed by their esters, b) 0.5-6% by mass of water, and c) 1-29% by mass of polyoxyethylene ethyl sorbide Emulsifiers of sugar alcohol anhydride fatty acid esters, d) 3 to 40 parts by mass of lecithin with respect to ω3 polyunsaturated fatty acids, their pharmaceutically acceptable salts, and 100 parts by mass of their esters; The total amount of the aforementioned composition is 4% by mass or less, and f) the polyol is not more than 4% by mass of the total amount of the aforementioned composition.         The self-emulsifying composition according to claim 11, which is used in at least one selected from the group consisting of food, special-purpose food, health functional food, health food, and pharmaceuticals.         The self-emulsifying composition according to claim 11 or 12, wherein the emulsifier further comprises polyoxyethylene hardened castor oil and / or polyoxyethylene castor oil.         The self-emulsifying composition according to claim 11 or 12, wherein ethanol is 1% by mass or less of the total amount of the aforementioned composition.         The self-emulsifying composition according to claim 11 or 12, wherein the polyol is 1% by mass or less of the total amount of the aforementioned composition.