JP2011006380A - EMULSIFIED COMPOSITION OF ω3 FATTY ACID - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an emulsified composition excellent in dispersibility, stability and absorbability, a production method therefor and a method of using the same.SOLUTION: The emulsified composition has an average emulsion droplet diameter of 2 μm or less and contains at least one selected from the group consisting of ω3 PUFA, pharmaceutically acceptable salts and esters thereof and at least one emulsifier selected from the group consisting of (a) lecithin and optionally a polyoxyethylene polyoxypropylene glycol, (b) a polyoxyethylene hydrogenated castor oil, and (c) a sucrose fatty acid ester.

Description

  The present invention provides an emulsified composition containing at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof, a method for producing the same, and a method for using the same.

  As the ω3 polyunsaturated fatty acid (hereinafter referred to as ω3PUFA), α-linolenic acid, icosapentoic acid (hereinafter referred to as EPA), docosahexaenoic acid (hereinafter referred to as DHA), and the like are known. ω3PUFA and its pharmaceutically acceptable salts and esters have various effects such as anti-arteriosclerosis, platelet aggregation-inhibition, blood lipid lowering, anti-inflammatory, anticancer, and central effects. It is blended in foods and is marketed as health foods or pharmaceuticals.

EPA ethyl ester (hereinafter referred to as EPA-E) is marketed in Japan as an oral treatment for ulcers associated with obstructive arteriosclerosis, improvement of pain and cooling, and hyperlipidemia (trade name Epadale, Mochida Pharmaceutical). When EPA-E is orally administered under fasting, the increase in plasma EPA concentration is lower than that when orally administered under fed conditions. It is thought that the absorption of EPA-E requires the secretion of bile acids and ingredients from food as a carrier. Therefore, Epadale is considered to be administered orally three times a day, immediately after each meal. (See Non-Patent Document 1).
Due to lifestyle changes in recent years, people who do not eat three times a day, patients who can eat only a small amount of food, and liquid foods (milk, heavy water, kuzuyu, egg, soup, fruit juice, oral nutrient) can be consumed How to take to patients, patients whose intestinal absorptivity has declined (the elderly, patients with bowel disease, after bowel surgery, patients with end-stage cancer, when taking lipase inhibitors) or patients who cannot take food such as after cerebral infarction, Or, compliance is a challenge.

  In addition, normal values appear on an empty stomach, but serum triglycerides (hereinafter referred to as TG) increase abnormally after meals, or there is a relationship between non-fasting hyperTGemia and coronary artery disease in which this condition persists. It has been attracting attention (see Non-Patent Document 2), and one of the causes is thought to be an increase in sterol regulatory element binding protein 1c (hereinafter referred to as SREBP1c). It has been reported that continuous oral administration of EPA-E prevents or ameliorates the lipotoxicity of pancreatic β cells caused by palmitic acid loading, and the action mechanism is via suppression of SREBP1c (non-patent literature). 3). However, there are no reports on the effectiveness of oral administration before meals (fasting).

  Apart from the above, application of emulsification has been proposed as a technique for stabilizing unsaturated fatty acids. For example, as an emulsified composition containing ω3PUFA, pharmaceutically acceptable salts and esters thereof, EPA-E was added with an emulsifier such as a phospholipid or a nonionic surfactant and an antioxidant such as vitamin E. A storage-stable emulsion (see Patent Document 1), an emulsified composition in which EPA and DHA-containing fish oil is dispersed and emulsified in soy milk (see Patent Document 2), or a polyglycerin fatty acid having a triglycerin content of 60% or more in polyglycerin An emulsified composition to which processing and storage stability are added and an emulsifier such as ester and polyoxyethylene sorbitan fatty acid ester is added, is gently absorbed after oral administration, and is maintained for a long time (see Patent Document 3) has been reported. ing.

  Ω3PUFA preparations that are rapidly absorbed even after pre-meal administration and suppress post-meal serum TG increase are desired, however, such as administration to patients who are not easily affected by meals and unable to take meals, before meals, before going to bed, etc. Even in the case of a preparation that can be administered orally on an empty stomach, or when taken on an empty stomach such as before meals or before going to bed, the blood EPA concentration rapidly increases, and its pharmacological action, for example, suppression of increase in serum TG after meal, There is no report yet about a drug product that is effective.

JP 60-123414 A Publication pamphlet of WO2002 / 037985 JP 2008-178341 A

Epadale S Pharmaceutical Interview Form, Mochida Pharmaceutical, March 2007 Japanese Arteriosclerosis Society edited "Arteriosclerotic disease prevention guidelines 2007 edition" Kyowa plan, April 25, 2007 Diabetes, 2008, 57, 9, p. 2382-2392

  The present invention provides an emulsified composition excellent in at least one of emulsifying dispersibility, emulsifying stability and absorptive, containing as an active ingredient at least one selected from the group consisting of ω3PUFA, pharmaceutically acceptable salts and esters thereof. It aims at providing the manufacturing method and its usage.

  As a result of intensive studies to solve the above problems, the present inventor has found that at least one selected from the group consisting of ω3PUFA, pharmaceutically acceptable salts and esters thereof, lecithin or optionally polyoxyethylene polyoxy By adding and emulsifying at least one emulsifier of propylene glycol, polyoxyethylene hydrogenated castor oil, and sucrose fatty acid ester, emulsification dispersibility, emulsification stability or absorbency, especially hungry, compared to existing ω3 PUFA emulsified compositions The present invention has been completed by finding an emulsified composition excellent in at least one of oral absorbability and absorption rate at the time. Examples of embodiments of the present invention are shown below.

(1) Contains at least one selected from the group consisting of ω3PUFA, pharmaceutically acceptable salts and esters thereof, and at least one emulsifier selected from the group consisting of the following (a), (b) and (c) An emulsified composition having an average emulsified droplet diameter of 2 μm or less:
(A) Lecithin and optionally polyoxyethylene polyoxypropylene glycol (b) polyoxyethylene hydrogenated castor oil (c) sucrose fatty acid ester.

(2) The emulsion composition according to (1), wherein the lecithin of (a) is at least one selected from the group consisting of soybean lecithin, enzyme-decomposed soybean lecithin, hydrogenated soybean lecithin and egg yolk lecithin.

(3) The polyoxyethylene polyoxypropylene glycol of (a) is polyoxyethylene (3) polyoxypropylene (17) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (42 ) Polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol , Polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol and polyoxyethylene (200) polyoxypropylene (70) glycol Emulsified composition according to any one of the at least one in which the selected from the group consisting Lumpur (1) or (2).

(4) The above (1) to (3), wherein the lecithin in (a) is soybean lecithin or enzyme-degraded soybean lecithin, and the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (105) polyoxypropylene (5) glycol. ).

(5) The polyoxyethylene hydrogenated castor oil of (b) is polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene ( 60) The emulsion composition according to any one of the above (1) to (4), which is at least one selected from the group consisting of hydrogenated castor oil and polyoxyethylene (100) hydrogenated castor oil.
(6) The emulsion composition according to any one of (1) to (5), wherein the polyoxyethylene hydrogenated castor oil of (b) is polyoxyethylene (60) hydrogenated castor oil.

(7) The sucrose fatty acid ester of (c) is at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose oleate and sucrose stearate The emulsified composition according to any one of (1) to (6) above.

(8) The emulsified composition according to any one of (1) to (7), wherein the emulsifier has a hydrophilic / lipophilic balance (hereinafter referred to as HLB) in the range of 10 to 18.
(9) The emulsified composition according to any one of (1) to (8), wherein the emulsifier has an HLB in the range of 12 to 16.

(10) The emulsified composition according to any one of (1) to (9) above, wherein the content of ω3PUFA, a pharmaceutically acceptable salt and ester thereof is in the range of 0.01 to 50% by mass.
(11) The emulsion composition according to any one of the above (1) to (10), wherein the content of ω3PUFA, a pharmaceutically acceptable salt and ester thereof is in the range of 0.1 to 30% by mass.
(12) The emulsified composition according to any one of (1) to (11) above, wherein the content of ω3PUFA, a pharmaceutically acceptable salt and ester thereof is 9% by mass or less.

(13) The emulsified composition according to any one of (1) to (12) above, wherein the content of the emulsifier is 5 to 100 parts by mass with respect to 100 parts by mass of ω3PUFA, pharmaceutically acceptable salts and esters thereof.
(14) The emulsified composition according to any one of (1) to (13) above, wherein the content of the emulsifier is 10 to 50 parts by mass with respect to 100 parts by mass of ω3PUFA, pharmaceutically acceptable salts and esters thereof.
(15) The emulsified composition according to the above (1) to (14), wherein the content of the emulsifier is 2% by mass or less.

(16) The emulsion composition according to any one of (1) to (15), wherein the average emulsion droplet diameter is 1.5 μm or less.
(17) The emulsion composition according to any one of (1) to (16), wherein an average emulsion droplet diameter in the emulsion composition is 0.3 μm or less.
(18) The emulsified composition according to any one of (1) to (17), wherein an average emulsified droplet diameter in the emulsified composition after storage for 6 months at 40 ° C. is 1.5 μm or less.
(19) The emulsified composition according to any one of (1) to (18), wherein an average emulsified droplet diameter in the emulsified composition after storage for 6 months at 40 ° C. is 0.3 μm or less.

(20) Correction to male beagle dogs by oral administration of ω3PUFA, an emulsified composition of 600 mg as a pharmaceutically acceptable salt and ester thereof under fasting conditions for 18 hours or more, and reducing the blood ω3PUFA concentration before administration The above (1) to (19), wherein the ω3PUFA blood concentration maximum value calculated in the above is 90 μg / mL or more and / or the area under the ω3PUFA blood concentration curve from 0 to 2 hours after administration is 100 μg / mL · hr or more. The emulsified composition according to any one of the above.
(21) Correction to male beagle dogs by oral administration of ω3PUFA, an emulsified composition of 600 mg as a pharmaceutically acceptable salt and ester thereof under fasting conditions for 18 hours or more, and reducing the blood ω3PUFA concentration before administration The above (1) to (19), wherein the ω3PUFA blood concentration maximum value calculated and performed is 80 μg / mL or more and / or the area under the ω3PUFA blood concentration curve from administration 0 to 2 hours is 90 μg / mL · hr or more. The emulsified composition according to any one of the above.

(22) Male cynomolgus monkeys were orally administered with ω3 PUFA, an emulsion composition of 45 mg / kg body weight as a pharmaceutically acceptable salt and ester thereof under fasting conditions for 12 hours or longer, and the blood ω3 PUFA concentration before administration was reduced. The maximum value of ω3PUFA blood concentration calculated with correction is 60 μg / mL or more and / or the area under the ω3PUFA blood concentration curve from 0 to 12 hours after administration is 450 μg / mL · hr or more (1) to ( The emulsified composition according to any one of 19).
(23) Male cynomolgus monkeys were orally administered with ω3PUFA, an emulsion composition of 45 mg / kg body weight as a pharmaceutically acceptable salt and ester thereof under fasting conditions for 12 hours or longer, and the blood ω3PUFA concentration before administration was reduced. The maximum value of ω3PUFA blood concentration calculated by correction is 50 μg / mL or more and / or the area under the ω3PUFA blood concentration curve from 0 to 12 hours after administration is 400 μg / mL · hr or more (1) to ( The emulsified composition according to any one of 19).

(24) ω3PUFA, ω3PUFA, calculated by administering ω3PUFA, an emulsified composition of 1800 mg as a pharmaceutically acceptable salt and ester thereof to a human before meals, and correcting the blood ω3PUFA concentration before administration. The emulsified composition according to any one of (1) to (19) above, wherein the maximum concentration is 50 μg / mL or more and / or the ω3PUFA blood concentration 2 hours after administration is 10 μg / mL or more.

(25) The emulsion composition according to any one of (1) to (24) above, which contains at least one selected from the group consisting of EPA, DHA, and pharmaceutically acceptable salts and esters thereof.
(26) The emulsified composition according to any one of (1) to (25) above, which contains EPA-E and / or DHA ethyl ester.
(27) The emulsified composition according to any one of (1) to (26), which contains EPA-E as an active ingredient.

(28) As the second active ingredient, polyemphosphatidylcholine, soybean oil unsaponifiable matter (soysterol), gamma oryzanol, riboflavin butyrate, sodium dextran sulfate sulfur 18, pantethine, elastase, pravastatin, simvastatin, atorvastatin, fluvastatin , Pitavastatin, rosuvastatin, cerivastatin, simfibrate, clofibrate, clinofibrate, bezafibrate, fenofibrate, orlistat, cetiristat, cholestyramine, colestimide, ezetimibe, vitamin C, vitamin E, tocopherol nicotinate, N-acetylcysteine, probucol, Irbesartan, olmesartan medoxomil, candesartan lexetil, telmisartan, ba Sultan, losartan potassium, alacepril, imidapril hydrochloride, enalapril maleate, captopril, quinapril hydrochloride, cilazapril hydrate, temocapril hydrochloride, delapril hydrochloride, trandolapril, benazepril hydrochloride, perindopril, lisinopril hydrate, Azelnidipine, amlodipine besilate, alanidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nifedipine, nimodipine, nitrendipine, nilvadipine, valnidipine hydrochloride, felodipine, benidipine, manidipine, torazoline, phentolamine, atenolol, metoprolol , Carvedilol, labetalol hydrochloride, clonidine, methyldopa, eplerenone, hydroc Lothiazide, furosemide, acarbose, voglibose, miglitol, gliclazide, glibenclamide, glimepiride, tolbutamide, nateglinide, mitiglinide, metformin hydrochloride, buformin hydrochloride, sitagliptin, vildagliptin, alogliptin, saxagliptin, pioglicezone hydrochloride, pioglicezone hydrochloride Liraglutide cilostazol, ticlopidine hydrochloride, alprostadil, limaprost, beraprost sodium, sarpogrelate hydrochloride, argatroban, naphthidrofuryl, isoxsuprine hydrochloride, batroxobin, dihydroergotoxine mesylate, trazoline hydrochloride, hepronicart, tetoyu extract, ursodeoxycholic acid , Chenodeoxycholic acid, bile powder, deoxycord Luric acid, cholic acid, bile extract, bear gall, cow yellow, dehydrocholic acid, biotin, cyanocobalamin, pantothenic acid, folic acid, thiamine, vitamin K, tyrosine, pyrodoxine, leucine, isoleucine, valine, calcium, iron, zinc, copper, Selected from the group consisting of magnesium, soy protein, chitosan, low molecular weight sodium alginate, dietary fiber derived from psyllium seed coat, phospholipid-bound soy peptide, plant sterol ester, plant stanol ester, diacylglycerol, globin proteolysate, and tea catechin The emulsified composition according to any one of (1) to (27), further containing at least one.
(29) The emulsion composition according to the above (28), wherein the second active ingredient is either tocopherol nicotinic acid ester or ursodeoxycholic acid.

(30) A medicament containing the emulsion composition according to any one of (1) to (29) above.
(31) From the group consisting of a dyslipidemic agent, a postprandial hyperTG disease agent, an anti-arteriosclerosis agent, a platelet aggregation inhibitor, a peripheral circulatory failure agent, an inflammatory disease agent, an anticancer agent and a central disease agent The medicament according to the above (30), which is at least one selected.

(32) At least one selected from the group consisting of ω3PUFA, pharmaceutically acceptable salts and esters thereof, and at least one emulsifier of the following (a), (b) and (c), and then high-pressure emulsification Or the manufacturing method of the emulsion composition characterized by stirring at high speed:
(A) Lecithin and optionally polyoxyethylene polyoxypropylene glycol (b) polyoxyethylene hydrogenated castor oil (c) sucrose fatty acid ester.

(33) At least one selected from the group consisting of ω3PUFA, pharmaceutically acceptable salts and esters thereof, and at least one emulsifier of the following (a), (b) and (c) are mixed and then average emulsified A method for producing an emulsified composition, wherein the droplet diameter is emulsified to 2 μm or less:
(A) Lecithin and optionally polyoxyethylene polyoxypropylene glycol (b) polyoxyethylene hydrogenated castor oil (c) sucrose fatty acid ester.

ω3 PUFA, at least one selected from the group consisting of pharmaceutically acceptable salts and esters thereof, from the group consisting of lecithin and optionally polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester Emulsification composition excellent in at least one of emulsifying dispersibility, emulsification stability or absorbability, particularly oral absorption and absorption rate on an empty stomach by adding at least one selected and emulsifying, its production method and its use Can be provided.
Compared to existing emulsified compositions, it is rapidly absorbed even in fasting oral administration, and is expected to exhibit preventive / improving or therapeutic effects on various diseases possessed by ω3 PUFA. Specifically, the efficacy is further improved by improving patient convenience and improving compliance by showing the effectiveness of administration at any time 1 to 3 times a day without restriction of the administration of 3 times a day immediately after meals. Can be combined with other drugs for administration other than administration immediately after meals, can be formulated, or can prevent postprandial serum TG increase by oral administration before meals, or can inhibit lipase by administration before going to bed It is expected to show clinical effects such as preventing essential fatty acid deficiency when taking the drug.

Of the ω3 PUFA and its pharmaceutically acceptable salts and esters, EPA-E is known as a highly safe active pharmaceutical ingredient, but very rarely nausea (0.21%), nausea (0.23%) Alternatively, side effects of stomach discomfort (0.23%) may occur. According to the present invention, it is possible to reduce the dose and / or frequency of administration of at least one selected from the group consisting of ω3PUFA, pharmaceutically acceptable salts and esters thereof, and to increase the compliance of medication by further reducing side effects. It is also expected to continue treatment in patients who have had to discontinue administration due to side effects.
In addition, for the improvement or treatment of chronic diseases such as dyslipidemia, the basic usage is to take continuously over a long period of time. However, according to the present invention, the improvement or treatment is performed with the smallest possible dose and number of administrations. Expected to be effective.

  In advanced countries such as Japan, the United States and Europe, complementary and alternative medicines are increasing, and special-purpose foods, health functional foods (specific health foods and nutritional functional foods) and health foods (supplements) are used. ω3PUFA, at least one selected from the group consisting of pharmaceutically acceptable salts and esters thereof, and at least selected from the group consisting of lecithin and polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester The emulsified composition containing any one of them can be provided as a health functional food for humans who require ω3 PUFA. For example, dyslipidemia, peripheral circulatory insufficiency, metabolic syndrome, or reserve humans can be prevented from progressing to further cardio-cerebral vascular events, limb peripheral ulcers, gangrene, etc., and quality of life can be maintained. .

The present invention is described in detail below.
The present invention relates to at least one selected from the group consisting of EPA, pharmaceutically acceptable salts and esters thereof, lecithin and optionally polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester. An emulsified composition containing at least one emulsifier, a method for producing the same, and a method for using the same.

  In the present invention, “ω3PUFA” is a fatty acid having a plurality of carbon-carbon double bonds in the molecule and the first double bond at the third position from the methyl group side. Representative examples include α-linolenic acid, EPA, DHA, icosatrienoic acid, stearidonic acid, icosatetraenoic acid, succinic acid, tetracosapentaenoic acid and nisic acid. In the present invention, the term “ω3 PUFAs” is used to mean not only ω3 PUFA but also pharmaceutically acceptable salts or esters thereof, unless otherwise specified.

  The ω3 PUFAs used in the present invention may be synthetic products, semi-synthetic products, natural products, or natural oils containing them. Here, the natural product means one extracted from a natural oil containing ω3 PUFAs by a known method, one obtained by crude purification, or one obtained by further highly purifying them. Semi-synthetic products include ω3 PUFAs produced by microorganisms and the like, and those obtained by subjecting the ω3 PUFAs or natural ω3 PUFAs to chemical treatment such as esterification and transesterification. In the present invention, ω3PUFAs can be used alone or in combination of two or more.

  In the present invention, EPA and DHA are preferred examples of the acid group of the ω3 PUFAs, and EPA is a more preferred example. Further, as pharmaceutically acceptable salts of ω3PUFA, inorganic bases such as sodium salts and potassium salts, organic bases such as benzylamine salts and diethylamine salts, salts with basic amino acids such as arginine salts and lysine salts, and ethyl as esters. Illustrative are alkyl esters such as esters and esters such as mono-, di- and TG. Preferably ethyl ester or TG ester is mentioned, and ethyl ester is mentioned as a more preferable example. That is, EPA-E, EPA TG ester, DHA ethyl ester (hereinafter referred to as DHA-E), and DHA TG ester are preferred examples, and EPA-E and DHA-E are more preferred examples. EPA-E is a more preferable example.

The purity of ω3 PUFAs is not particularly limited, but usually the content of ω3 PUFAs in the total fatty acids of the present composition is preferably 25% by mass or more, more preferably 45% by mass or more, more preferably 70% by mass or more, more Preferably it is 85 mass% or more, Most preferably, it is 96.5 mass% or more. EPA-E + DHA-E (EPA-E only, DHA-E only, or a total when both are included) having high purity, for example, EPA-E + DHA-E content ratio in ω3 PUFAs is 50% by mass or more Preferably, those having 60% by mass or more are more preferable, those having 90% by mass or more are more preferable, and those having 99% by mass or more are more preferable. That is, the present agent composition preferably has a high purity of ω3 PUFAs in all fatty acids, more preferably has a high EPA + DHA purity as an acid group of ω3 PUFAs, and more preferably has a high purity of EPA as an acid group. .
For example, when EPA-E and DHA-E are used, if the purity of the present composition of EPA as an acid group is as described above, the composition ratio of EPA-E / DHA-E and EPA-E + DHA- in all fatty acids The content ratio of E is not particularly limited, but as a preferred composition ratio, EPA-E / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, more preferably 1.2. That's it.
In addition, the composition of the present agent may contain polyunsaturated fatty acids other than ω3PUFAs such as linoleic acid, γ-linolenic acid, dihomo-γ-linolenic acid, and pharmaceutically acceptable salts or esters thereof. The arachidonic acid content is desired to be low, preferably less than 2% by mass, more preferably less than 1% by mass, and an embodiment that does not substantially contain arachidonic acid is particularly preferable.

  The content of ω3PUFAs in the emulsion composition of the present invention is not particularly limited, but is usually in the range of 0.01 to 50% by mass, preferably 0.1 to 30% by mass, typically 9% by mass or less, For example, it is 0.1 to 9% by mass, preferably 0.1 to 7% by mass, more preferably 0.5 to 5% by mass, and further preferably 1 to 3% by mass.

  The ω3 PUFAs used in the improvement or therapeutic agent of the present invention have less unfavorable impurities for cardiovascular events such as saturated fatty acids and arachidonic acid compared to fish oil or fish oil concentrates. It is possible to exert the effect without problems. In particular, in the case of the ethyl ester body, the oxidation stability is higher than that of fish oil or the like which is mainly a TG body, and a sufficiently stable composition can be obtained by adding a normal antioxidant.

In the present invention, commercially available products can be used as the ω3 PUFAs. For example, EPA-E is a high-purity EPA-E (96.5% by mass or more) -containing soft capsule (trade name Epadale: manufactured by Mochida Pharmaceutical Co., Ltd.) available as a therapeutic agent for ASO and hyperlipidemia in Japan. Can be used. In addition, a mixture of EPA-E and DHA-E is, for example, Lovaza (Lovaza®: GlaxoSmithKline: EPA-E of about 46.5 mass) marketed as a therapeutic agent for hyperTGemia in the United States. %, A soft capsule containing about 37.5% by mass of DHA-E) can also be used.
Refined fish oil can also be used as ω3 PUFAs. In addition, monoglycerides, diglycerides, TG derivatives, or combinations thereof of ω3PUFAs are also preferable embodiments. For example, Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPA4510TG, EPA4510TG, EPA4510TG, EPA4510TG , K85EE and K80EE (Pronova Biopharma, Lysaker, Norway) and other products containing various ω3 PUFAs are commercially available and can be obtained and used.

In the present invention, “lecithin” is one type of glycerophospholipid, and examples include soybean lecithin, enzyme-decomposed soybean lecithin, egg yolk lecithin, hydrogenated phospholipid, milk-derived phospholipid, lysolecithin, phosphatidylcholine, and phosphatidylserine. Preferably, soybean lecithin, enzyme-decomposed soybean lecithin and egg yolk lecithin are exemplified, and more preferably soybean lecithin. Moreover, one of these can be used alone or in combination of two or more. In the present invention, unless otherwise specified, lecithin is used in the meaning including all of the above glycerophospholipids.
Various products such as purified soybean lecithin (Nisshin Oilio), purified egg yolk lecithin (Asahi Kasei Pharma), egg yolk lecithin PL-100M (Cuppy) are commercially available, and these can also be obtained and used.

In the present invention, “polyoxyethylene polyoxypropylene glycol” is a compound obtained by polymerizing ethylene oxide to polypropylene glycol polymerized with propylene oxide.
Various compounds are commercially available depending on the average degree of polymerization of propylene oxide and ethylene oxide. For example, polyoxyethylene (3) polyoxypropylene (17) glycol (Adeka Pluronic L-31, Adeka), polyoxyethylene (20) Polyoxypropylene (20) glycol (Adeka Pluronic L-44, Adeka), Polyoxyethylene (42) Polyoxypropylene (67) Glycol (Adeka Pluronic P123, Adeka), Polyoxyethylene (54) Polyoxypropylene (39) Glycol (New Det PE-85, Sanyo Chemical Industries), Polyoxyethylene (105) Polyoxypropylene (5) Glycol (PEP101, Sanyo Chemical Industries), Polyoxyethylene (120) Polyoxypropylene (40) Glycol Adeka Pluronic F-87, Adeka), Polyoxyethylene (160) Polyoxypropylene (30) Glycol (Adeka Pluronic F-68, Adeka), Polyoxyethylene (196) Polyoxypropylene (67) Glycol (Lutrol F127, BASF) Japan) and polyoxyethylene (200) polyoxypropylene (70) glycol, preferably polyoxyethylene (105) polyoxypropylene (5) glycol. Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “polyoxyethylene polyoxypropylene glycol” is used in the meaning including all the above compounds unless otherwise specified.

  In the present invention, “polyoxyethylene hydrogenated castor oil” is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil. Various compounds are commercially available depending on the average degree of polymerization of ethylene oxide. For example, polyoxyethylene (20) hydrogenated castor oil (NIKKOL HCO-20, Nikko Chemicals), polyoxyethylene (40) hydrogenated castor oil (NIKKOL HCO- 40, Nikko Chemicals), polyoxyethylene (50) hydrogenated castor oil (NIKKOL HCO-50, Nikko Chemicals), polyoxyethylene (60) hydrogenated castor oil (NIKKOL HCO-60, Nikko Chemicals) and polyoxyethylene (100) Hardened castor oil (NIKKOL HCO-100, Nikko Chemicals) is exemplified, and polyoxyethylene (60) hardened castor oil is preferably exemplified. Moreover, one of these can be used alone or in combination of two or more. In the present invention, the term “polyoxyethylene hydrogenated castor oil” is used in the sense of including all of the above compounds unless otherwise specified.

  In the present invention, “sucrose fatty acid ester” is an ester of sucrose and a fatty acid. Various compounds are commercially available depending on the type of fatty acid to be esterified and the degree of esterification. For example, Surf Hope SE PHARMA J-1216 (Mitsubishi Chemical Foods) containing 95% lauric acid in the fatty acid, myristic acid in the fatty acid. Hope SE PHARMA J-1416 (Mitsubishi Chemical Foods) containing 95%, Surf Hope SE PHARMA J-1615 and J-1616 (Mitsubishi Chemical Foods) containing 70% palmitic acid in fatty acids, stearic acid in fatty acids SEPHARMA J-1811, J-1815 and J-1816 (Mitsubishi Chemical Foods), and Surfhope SE PHARMA J-1715 containing 70% oleic acid in the fatty acid are exemplified. Moreover, one of these can be used alone or in combination of two or more. In the present invention, sucrose fatty acid ester is used in the meaning including all of the above compounds.

The HLB of the emulsifier added to the emulsified composition of the present invention is preferably 10 to 18, and more preferably 12 to 16. When adding 2 or more types of emulsifiers, the HLB of the emulsifier added to the emulsion composition is determined as the mass average of each HLB. For example, when adding two types of emulsifiers A and B, the value obtained from the following formula is used as the HLB of the emulsifier added to the emulsified composition.
HLB = (W _A H _A + W _B H _B ) / (W _A + W _B )
W _A : Emulsifier A content (% by mass) in the emulsified composition
W _B : Emulsifier B content (% by mass) in the emulsion composition
H _A : HLB of emulsifier A in the emulsion composition
H _B : HLB of emulsifier B in the emulsion composition

The total content of lecithin, polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester to be added to the emulsified composition of the present invention is not particularly limited, but usually with respect to 100 parts by mass of ω3 PUFAs, It is 5 to 100 parts by mass, preferably 10 to 70 parts by mass, and more preferably 10 to 50 parts by mass.
Further, the content (total amount) of the emulsifier in the emulsified composition is preferably small, for example, 2% by mass or less is preferable.

  In the emulsified composition of the present invention containing the ω3 PUFAs and the emulsifier as described above, a preferred embodiment includes EPA-E and / or DHA-E, soy lecithin, enzyme-decomposed soy lecithin, hydrogenated soy lecithin or egg yolk lecithin. A combination of at least one selected from the group consisting of and optionally polyoxyethylene (105) polyoxypropylene (5) glycol, EPA-E and / or DHA-E, and polyoxyethylene (60) hydrogenated castor oil; Or a combination of EPA-E and / or DHA-E with sucrose fatty acid ester, and particularly preferred embodiments are EPA-E, soybean lecithin and polyoxyethylene (105) polyoxypropylene (5 ) Combination with glycol, or EPA-E and polyoxyethylene (60) is a combination of hydrogenated castor oil.

  In the present invention, the “average emulsified droplet diameter” is a value of a volume average diameter in an emulsified composition measured using a particle size distribution measuring apparatus (for example, Nanotorac, Nikkiso Co., Ltd.) using water as a dispersion medium. The average emulsified droplet diameter of the emulsified composition of the present invention is 2 μm or less, and is not particularly limited as long as it is in a range excellent in emulsification dispersibility, emulsification stability or absorbency, but usually the average emulsified droplet diameter is 1.5 μm or less, More preferably, it is 0.3 μm or less, and further preferably 0.2 μm or less. From the viewpoint of stability, a composition having an average emulsion droplet diameter of 2 μm or less, preferably 1.5 μm or less, more preferably 0.3 μm or less in an emulsified composition after preparation and storage at 40 ° C. for 6 months. Illustrated. Moreover, the composition in which the average emulsified droplet diameter in the emulsified composition after preparation and storage at 40 ° C. for 4 weeks is 1.5 μm or less, preferably 1 μm or less, more preferably 0.2 μm or less.

  The dosage and administration period of ω3PUFAs used in the emulsified composition of the present invention are set to an amount and a period sufficient to exhibit the intended effect, but the administration method, the number of administrations per day, the degree of symptoms, the body weight It can be increased or decreased as appropriate depending on the age.

  In the case of oral administration, for example, 0.1 to 5 g / day, preferably 0.2 to 3 g / day, more preferably 0.4 to 1.8 g / day, further preferably 0.6 to 0 as EPA-E. .9 g / day is administered in 1 to 3 divided doses, but the total amount may be divided into 1 or several doses as needed. Since the absorption of EPA-E is affected by meals, the administration time is preferably during or after meals, and administration after meals (within 30 minutes) is more preferred, but the emulsion composition of the present invention absorbs even when fasted. Because of its superior properties, when administered during meals, after meals, or at times other than immediately after meals, such as before meals, immediately before meals, and before going to bed, patients with reduced absorption in the intestinal tract (the elderly, patients with bowel disease, after bowel surgery, end stage The effect of the present invention can also be exhibited when administered to cancer patients or when taking lipase inhibitors) or when the dose is reduced.

  When the above dose is administered orally, the administration period can be arbitrarily set according to the target disease and the degree of symptoms. For example, if the target disease is dyslipidemia, it may be a biochemical marker related to dyslipidemia, improvement of disease state or therapeutic effect, metabolic syndrome, cardiac / cerebrovascular event, extremity ulcer, gangrene, etc. For example, lipid markers in plasma (total cholesterol (hereinafter referred to as Cho), TG, postprandial TG, low density lipoprotein Cho, high density lipoprotein Cho, ultra low density lipoprotein Cho, non-high density Specific gravity lipoprotein Cho, medium specific gravity lipoprotein Cho, ultra high density lipoprotein Cho, free fatty acid, phospholipid, chylomicron, ApoB, lipoprotein (a), remnant-like protein Cho, small high density low density lipoprotein Cho, etc.) Concentration of limbs, increased skin temperature around extremities that can be measured by thermography, extended walking distance, increased serum CPK What test values, or numbness, coldness, pain, pain at rest, itching, cyanosis, flare, frostbite, stiff neck, anemia, florid failure, improvement in symptoms such as itching and formication feeling is exemplified. The improvement or therapeutic effect may be monitored by biochemical / pathological or pathological parameters related to other dyslipidemia or peripheral blood circulation disorder. It is desirable to continue administration while abnormal values of biochemical indicators such as blood lipid levels and abnormal pathological conditions continue. In addition, for example, a mode of administration every other day, a mode of administration for 2 to 3 days per week, and a drug withdrawal period of about 1 day to 3 months, preferably about 1 week to 1 month may be provided depending on circumstances.

  Depending on the doctor's instructions, a dose lower than the recommended daily dose of ω3 PUFAs may be orally administered on the start day of administration, and then gradually increased to the maximum daily dose as a maintenance dose. . It is also possible to reduce the dose according to the patient's condition. It is more preferable to reduce the daily dose as much as possible from the viewpoint of reducing side effects and to administer once or twice a day from the viewpoint of compliance.

  The emulsification composition of the present invention may contain an emulsification aid, a preservative, a stabilizer, a surfactant, an antioxidant and the like. Examples of the emulsification aid include acid fatty acids having 12 to 22 carbon atoms such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid and myristic acid, or salts thereof. Examples of the stabilizer include phosphatidic acid, ascorbic acid, glycerin, cetanol and the like. Examples of the preservative include ethyl paraoxybenzoate and propyl paraoxybenzoate. Surfactants include sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxy A propylene alkyl ether etc. are illustrated. Antioxidants include butyrated hydroxytoluene, brechated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and α-tocopherol and other oil-soluble antioxidants and ascorbic acid and its derivatives, Examples are water-soluble antioxidants such as erythorbic acid and its derivatives, nitrite, citric acid and the like.

  In addition, generally used suitable carriers or media, coloring agents, flavoring agents, if necessary, sterilized water or vegetable oil, further harmless organic solvents or harmless solubilizers (eg glycerin, propylene glycol), emulsifiers, Suspending agents (eg Tween 80, gum arabic solution), tonicity agents, pH adjusters, stabilizers, flavoring agents, flavoring agents, preservatives, antioxidants, buffers, colorants, absorption enhancement An appropriate pharmaceutical preparation can be prepared by appropriately selecting and combining with additives such as an agent. As additives, for example, lactose, hydroxypropylcellulose, macrogol, tocopherol, hydrogenated oil, sucrose fatty acid ester, talc, dimethylpolysiloxane, carnauba wax, sodium desoxycholate and the like can be contained.

  In particular, ω3 PUFAs are highly unsaturated, and are susceptible to oxidation in emulsions containing water, and are particularly susceptible to oxidation by reducing the emulsion droplet size, so that they are water-soluble antioxidants and / or oil-soluble. It is desirable to contain an effective amount of an antioxidant as an antioxidant, and it is preferable to contain both a water-soluble antioxidant and an oil-soluble antioxidant. Examples of water-soluble antioxidants include ascorbic acid and its derivatives, erythorbic acid and its derivatives, nitrite, citric acid, etc., and oil-soluble antioxidants include butylated hydroxytoluene, breached hydroxyanisole, propyl gallate And propyl gallate, pharmaceutically acceptable quinone, astaxanthin and α-tocopherol. In addition, after the emulsion composition is prepared, it is preferable that the inside of the container be replaced with nitrogen and stored hermetically. The storage temperature is preferably room temperature, more preferably in a cool and dark place, and when frozen, there is a risk that the emulsification stability will deteriorate, so it is preferable to avoid frozen storage.

  The emulsified composition of the present invention is administered to a patient whether orally or intravenously or intraarterially, rectally or vaginally. For patients who can be taken orally, a simple oral liquid preparation is desirable, and dialysis is performed. It can also be administered to a patient or a patient having difficulty swallowing as a jelly agent gelatinized with gelatin or the like.

The emulsified composition of the present invention is prepared by mixing and dissolving ω3 PUFAs, emulsifiers, purified water, and other additives such as glycerin and antioxidants as necessary, for example, a high-pressure emulsification apparatus such as a manton gorin type homogenizer, and high-speed stirring. It can manufacture by emulsifying using a machine etc.
The emulsification conditions can be appropriately selected so that the average emulsified droplet diameter is 2 μm or less, preferably 1.5 μm or less, more preferably 0.3 μm or less, and even more preferably 0.2 μm or less. For example, a method of emulsifying at 15000 rpm using a high-speed stirrer (a foam-less mixer, manufactured by beautiful granules), or a method of high-pressure emulsification at 20000 PSI using a high-pressure emulsifier (DeBee 2000, manufactured by BEE International) can be mentioned.

  The emulsion composition of the present invention can also be used in combination with a second active ingredient. The second active ingredient can be arbitrarily selected according to the target disease and the degree of symptoms, and preferably does not diminish the effects of ω3 PUFAs, such as antihyperlipidemic drugs, antihypertensive drugs, antidiabetic drugs, Examples include antioxidants, blood flow improving agents, bile acid derivatives and the like.

  Among the therapeutic agents for hyperlipidemia, preferred second active ingredients include, for example, polyemphosphatidylcholine, soybean oil unsaponifiable matter (soysterol), gamma oryzanol, riboflavin butyrate, sodium dextran sulfate sulfur 18, pantethine, Examples include elastase. Also, statins such as pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, cerivastatin, fibrates such as simfibrate, clofibrate, clinofibrate, bezafibrate, fenofibrate, or lipolysis such as orlistat and cetiristat Enzyme inhibitors, resins such as cholestyramine and colestimide, tocopherol nicotinate, ezetimibe and the like can also be mentioned.

  Antihypertensive drugs include irbesartan, olmesartan medoxomil, candesartan lexetil, angiotensin II receptor antagonists such as telmisartan, valsartan, losartan potassium, alacepril, imidapril hydrochloride, enalapril maleate, captopril, quinapril hydrochloride, cilazapril hydration , Temocapril hydrochloride, delapril hydrochloride, trandolapril, benazepril hydrochloride, perindopril, angiotensin converting enzyme inhibitors such as lisinopril hydrate, azelnidipine, amlodipine besylate, alanidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride Salts such as salt, nifedipine, nimodipine, nitrendipine, nilvadipine, valnidipine hydrochloride, felodipine, benidipine, manidipine Α-receptor blockers such as cium antagonists, torazoline and phentolamine, beta-receptor blockers such as atenolol, metoprolol, acebutolol, propranolol, pindolol, carvedilol, labetalol hydrochloride, α-receptor stimulators such as clonidine, methyldopa And diuretics such as eplerenone, hydrochlorothiazide and furosemide.

  Antidiabetics include α-glucosidase inhibitors such as acarbose, voglibose and miglitol, sulfonylurea hypoglycemic agents such as gliclazide, glibenclamide, glimepiride and tolbutamide, fast-acting insulin secretagogues such as nateglinide and mitiglinide, metformin Biguanide hypoglycemic drugs such as hydrochloride, buformin hydrochloride, dipeptidylphosphatase 4 inhibitors such as sitagliptin, vildagliptin, alogliptin, saxagliptin, thiazolidine drugs such as pioglizone hydrochloride, rosiglitazone maleate, exenatide, Examples also include glucagon-like peptide 1 derivative drugs such as liraglutide.

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

  Examples of the blood flow improving agent include cilostazol, ticlopidine hydrochloride, alprostadil, limaprost, beraprost sodium, sarpogrelate hydrochloride, argatroban, naphthidrofuryl, isoxsuprine hydrochloride, batroxobin, dihydroergotoxine mesylate, trazoline hydrochloride, hepronicart, four Examples include natural water extract.

  Examples of bile acid derivatives include ursodeoxycholic acid, chenodeoxycholic acid, bile powder, deoxycholic acid, cholic acid, bile extract, bear gall, cow yellow, dehydrocholic acid, and the like. In addition, biotin (vitamin B7), cyanocobalamin (vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine (vitamin B1), vitamin A, vitamin D, vitamin K, tyrosine, pyrodoxine (vitamin B6), Preferred examples include branched chain amino acids such as leucine, isoleucine and valine, calcium, iron, zinc, copper and magnesium. In addition, certain health foods such as soy protein, chitosan, low molecular weight sodium alginate, dietary fiber derived from psyllium seed coat, phospholipid-bound soy peptide, plant sterol ester, plant stanol ester, diacylglycerol, globin proteolysate, tea catechin Ingredients of nutritional functional foods.

  The emulsified composition of the present invention is excellent in emulsification and dispersibility, excellent in emulsification stability, excellent in storage stability, so as to be able to express the pharmacological action of ω3 PUFAs, and has excellent absorbency, particularly fasting absorption and absorption rate. It is desirable to have at least one effect of a preparation that is excellent, convenient for patients, or excellent in compliance.

  The emulsified composition of the present invention is a therapeutic agent for various diseases of animals, particularly mammals, such as a therapeutic agent for dyslipidemia, a therapeutic agent for postprandial hyperTG, an anti-arteriosclerosis agent, a platelet aggregation inhibitor, a therapeutic agent for peripheral circulation failure, It can be used as a therapeutic agent for inflammatory diseases, an anticancer agent and a therapeutic agent for central diseases. In particular, it is effective for improvement or treatment of dyslipidemia and postprandial hyperTG, prevention of recurrence, or suppression of progression to metabolic syndrome, cardiac / cerebrovascular events, peripheral limb ulcers, gangrene, and the like. Mammals include, for example, domestic animals such as humans, cows, horses, and pigs, and domestic animals such as dogs, cats, rabbits, rats, and mice, and are preferably humans. In particular, improvement or treatment of dyslipidemia and postprandial hyperTG in patients with dyslipidemia, such as patients with metabolic syndrome who have increased blood lipids, developed insulin resistance, or have increased blood pressure It is expected to show an effect. Further, by reducing the dose and the number of daily administrations, it is possible to reduce the burden of the patient's medication and increase the compliance, thereby further improving or improving the therapeutic effect.

EXAMPLES Next, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.
Example 1
Concentrated glycerin 80.0 g and purified water 80.0 g were added to and mixed with 2.4 g of soybean lecithin, and 16.0 g of EPA-E was added to the mixture while stirring little by little (preparation solution A). Separately, 20.8 g of sodium erythorbate, 160.0 g of trehalose, and 2.4 g of polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in 1238.4 g of purified water (preparation solution B). Next, the preparation liquid B was added to the preparation liquid A little by little with stirring. This was emulsified at 15000 rpm using a high-speed stirrer (bubble-less mixer, manufactured by Beautiful Granules) to obtain an emulsion. Next, this emulsion was high-pressure emulsified at 20000 PSI using a high-pressure emulsifier (DeBee 2000, manufactured by BEE International) to obtain an emulsion composition. The prepared emulsified composition was purged with nitrogen in the container, sealed and stored at room temperature until evaluation was performed. Table 1 shows the formulation (% by mass) of the emulsion composition.

(Example 2)
4.8 g of polyoxyethylene (60) hydrogenated castor oil, 20.8 g of sodium erythorbate, 80.0 g of concentrated glycerin, 160.0 g of trehalose, and 1318.4 g of purified water were weighed and dissolved. To this was added 16.0 g of EPA-E. Thereafter, an emulsified composition was obtained by emulsification in the same manner as described in Example 1. The prepared composition was purged with nitrogen in the container, sealed and stored at room temperature until evaluation was performed. Table 2 shows the formulation (% by mass) of the composition.

(Example 3)
Concentrated glycerin 40.0 g and purified water 40.0 g were added to 2.4 g of enzymatically degraded soybean lecithin and mixed, and EPA-E 8.0 g was added to the mixture while stirring little by little (preparation solution A). Separately, 10.4 g of sodium erythorbate and 80.0 g of trehalose were dissolved in 619.2 g of purified water (preparation solution B). Next, the preparation liquid B was added to the preparation liquid A little by little with stirring. This was emulsified at 15000 rpm using a high-speed stirrer (bubble-less mixer, manufactured by beautiful granules) to obtain an emulsified composition. The prepared emulsified composition was purged with nitrogen in the container, sealed and stored at room temperature until evaluation was performed. Table 3 shows the formulation (mass%) of the emulsion composition.

Example 4
Sucrose fatty acid ester (Surf Hope SE PHARMA J-1816, Mitsubishi Chemical Foods) 3.84 g, Sucrose fatty acid ester (Surf Hope SE PHARMA J-1805, Mitsubishi Chemical Foods) 0.96 g, Sodium erythorbate 20.8 g, concentrated 80.0 g of glycerin, 160.0 g of trehalose, and 1318.4 g of purified water were weighed and dissolved by heating to 70 ° C. To this was added 16.0 g of EPA-E. Thereafter, an emulsified composition was obtained in the same manner as in the method described in Example 1. The prepared composition was purged with nitrogen in the container, sealed and stored at room temperature until evaluation was performed. Table 4 shows the formulation of the composition of Example 4.

(Example 5)
Concentrated glycerin 80.0 g and purified water 80.0 g were added to 2.4 g of soy lecithin and mixed, and a solution prepared by dissolving 5.3 g of tocopherol nicotinic acid ester in 16.0 g of EPA-E was added little by little while stirring. (Preparation solution A). Separately, 20.8 g of sodium erythorbate, 160.0 g of trehalose, and 2.4 g of polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in 1233.1 g of purified water (preparation solution B). Thereafter, an emulsified composition was obtained by emulsification in the same manner as described in Example 1. The prepared emulsified composition was purged with nitrogen in the container, sealed and stored at room temperature until evaluation was performed. Table 5 shows the formulation (mass%) of the emulsion composition.

(Comparative Example 1)
Polyoxyethylene (60) hydrogenated castor oil 2.4 g, sodium erythorbate 10.4 g, concentrated glycerin 40.0 g, trehalose 80.0 g, and purified water 659.2 g were weighed and dissolved. EPA-E8.0g was added to this, and it emulsified at 9000 rpm using the high-speed stirrer (bubbleless mixer, the product made from a beautiful grain), and obtained the emulsion composition. The prepared composition was purged with nitrogen in the container, sealed and stored at room temperature until evaluation was performed. Table 6 shows the formulation of the emulsion composition.

(Comparative Example 2)
4.8 g of polyoxyethylene (105) polyoxypropylene (5) glycol, 20.8 g of sodium erythorbate, 80.0 g of concentrated glycerin, 160.0 g of trehalose, and 1318.4 g of purified water were weighed and dissolved. To this was added 16.0 g of EPA-E. Thereafter, emulsification was carried out in the same manner as in the method described in Example 1 to obtain an emulsified composition. The prepared emulsified composition was purged with nitrogen in the container, sealed and stored at room temperature until evaluation was performed. Table 7 shows the formulation (mass%) of the emulsion composition.

(Experimental example 1)
Measurement of average emulsion droplet diameter Using a particle size distribution measuring device (Nanotorac, Nikkiso Co., Ltd.), water was used as a dispersion medium, and the average emulsion droplet diameter (volume average diameter) in the emulsion compositions of each Example and Comparative Example was measured. . Table 8 shows the measurement results of the average emulsion droplet diameter immediately after preparation.

  Table 9 shows the time-dependent changes in the average emulsion droplet diameter of Example 1 and Table 10 of Example 5.

  The change in the average emulsified droplet size during the storage period was slight, and was 0.3 μm or less even after storage at 40 ° C. for 6 months.

  The change in the average emulsified droplet diameter during the storage period was slight, and was 0.2 μm or less even after storage at 40 ° C. for 4 weeks.

(Experimental example 2)
Pharmacokinetics in Beagle Dogs The emulsion compositions of Examples and Comparative Examples were orally administered to male beagle dogs (34 to 55 months of age, body weight 11 to 17 kg, Kitayama Labes) under fasting conditions, and blood of EPA The change in concentration was evaluated. Each test animal was fasted for 18 hours or more before administration, and each animal was administered with an amount of the composition of 600 mg as EPA-E. Moreover, the EPA-E stock solution with which the capsule was filled was also administered as a control group. Blood samples were collected before administration, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours after administration, and after the plasma was collected and processed, the EPA concentration in the plasma was determined. Measured by LC / MS / MS. Table 11 shows the maximum blood concentration value (Cmax) calculated from the test results, the area under the blood concentration curve from 0 to 2 hours (AUC _0-2 ), and the blood concentration curve from 0 to 24 hours. The area (AUC _0-24 ) is indicated. In calculating each parameter, correction is performed by subtracting the blood EPA concentration before administration from the blood concentration.

In the animals administered with the emulsified composition of each Example, Cmax and AUC _0-2 values, which are parameters of absorption rate, were higher than those of the animals administered with the emulsified composition of the control group or the comparative example. In particular, AUC _{0-2, which} is a parameter for increasing blood concentration immediately after administration, is about 7.9 to 10.8 times that of the control group in the animals to which the composition of each example was administered. The dose was about 1.4 to 2.0 times that of the administered animal. Similarly, the Cmax value was about 5.6 to 8.3 times that of the control group, and about 1.4 times to about 2.1 times that of the animal administered with the comparative emulsion composition. On the other hand, the AUC _0-24 value, which is a parameter for the amount of absorption, was higher in animals administered with the emulsified composition of each Example than in the control group, but with animals administered with the emulsified composition of Comparative Example There was no significant difference. That is, when the emulsified composition of the example was administered, it was confirmed that EPA was absorbed promptly after oral administration, although there was not much difference in the amount of EPA absorbed up to 24 hours after oral administration compared to the comparative example. It was done. Therefore, even when the emulsion composition of the present invention is taken on an empty stomach such as before meals or before going to bed, the blood EPA concentration increases rapidly and more effectively, and its pharmacological action is exhibited quickly and more effectively. There is expected.

(Experimental example 3)
Pharmacokinetics in beagle dogs EPA-E and tocopherol nicotinate were orally administered to 4 male beagle dogs (approximately 18 months old, Kitayama Labes) in each group under fasting conditions, and blood concentrations of EPA and tocopherol nicotinate were The transition was evaluated. Each test animal was fasted at least 18 hours before administration, and each animal was administered with a composition in an amount of 600 mg as EPA-E and 200 mg as tocopherol nicotinate. An emulsion prepared according to Example 5 was administered to the emulsion administration group, and a composition in which EPA-E 1% and tocopherol nicotinate 0.33% were suspended in 5% gum arabic water was administered to the control group. Blood samples were collected before administration, 1, 2, 3, 4, 8 and 24 hours after administration, and after the plasma was collected and processed, the EPA concentration and tocopherol nicotinate concentration in the plasma were measured by LC / MS, respectively. / MS and LC / MS.
From each blood concentration, the maximum blood concentration (C _max ), the area under the blood concentration curve from 0 to 2 hours (AUC _0-2 ), and the area under the blood concentration curve from 0 to 24 hours (AUC) _0-24 ) was calculated. In calculating each parameter, correction is performed by subtracting the blood concentration before administration from the blood concentration.

In the emulsion administration group, for both EPA and tocopherol nicotinate, both C _max and AUC _0-2 which are parameters of absorption rate and AUC _0-24 which is a parameter of absorption amount were higher than those of the control group. Regarding EPA, AUC _{0-2, which} is a parameter for increasing blood concentration immediately after administration of the emulsion administration group, was about 6 times that of the control group, and similarly AUC _0-24 was about 2 times that of the control group. On the other hand, regarding tocopherol nicotinic acid ester, AUC _{0-2 of the} emulsion administration group was about 17 times that of the control group, and similarly AUC _0-24 was about 5 times that of the control group. The absorption of EPA and tocopherol nicotinate by administration of a fasted emulsion was almost the same as that obtained when UBERA N, which is an EPA-E stock solution or a tocopherol nicotinate preparation, was administered under feeding (Pharmacology and Treatment, 1980, 2: 410-414). Furthermore, the time to reach the maximum blood concentration (T _max ) of tocopherol nicotinic acid ester by administration of the emulsion under fasting was less than half compared to the case of administration of Übera N under feeding, and the absorption rate was fast.
That is, when EPA-E and tocopherol nicotinic acid ester were administered as an emulsion, it was confirmed that they were absorbed rapidly after oral administration and also a large amount of absorption compared with the control group. Therefore, the EPA-E and tocopherol nicotinate emulsion of the present invention rapidly and more increase the blood EPA concentration and tocopherol nicotinate concentration even when taken on an empty stomach such as before meals or before going to bed, and its pharmacological action It is expected and useful to exhibit this quickly and more effectively.

(Experimental example 4)
Pharmacokinetics in cynomolgus monkeys The emulsion composition of Example 1 was orally administered to male cynomolgus monkeys (2-5 years old, body weight 2.70-4.65 kg, Hamley) under fasting conditions, and the change in blood concentration of EPA was observed. evaluated. Each test animal was fasted for 12 hours or more before administration, and each animal was administered with an emulsified composition in an amount of 45 mg / kg as EPA-E. Moreover, the EPA-E stock solution with which the capsule was filled was also administered as a control group. Before and after administration, blood was collected at 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours, and after plasma was collected and processed, EPA in plasma was LC / MS / MS was measured. Table 12 shows the maximum blood concentration (Cmax) calculated from the test results, the area under the blood concentration curve from 0 to 12 hours (AUC _0-12 ), and the blood concentration curve from 0 to 72 hours. Area (AUC _0-72 ) is indicated. In calculating each parameter, correction is performed by subtracting the blood EPA concentration before administration from the blood concentration.

The animals to which the emulsified composition of Example 1 was administered showed an increase in all blood concentration parameters as compared with the control group, and Cmax and AUC _0-12 were particularly about 9 to 10 times higher. That is, when the emulsion composition of Example 1 was administered, it was confirmed that not only the absorption amount increased but also EPA was absorbed immediately after oral administration. Therefore, even when the emulsion composition of the present invention is taken on an empty stomach such as before meals or before going to bed, the blood EPA concentration increases rapidly and more effectively, and its pharmacological action is exhibited quickly and more effectively. There is expected.

(Experimental example 5)
Efficacy in fasting glucose tolerance model rats Male Sprague Dawley rats (10 weeks old, Charles River, Japan) are divided into 4 groups with 10 animals in each group so that there is no difference in body weight and serum TG value. The control group was olive oil filled in capsules, the EPA-E administration group was EPA-E stock solution filled in capsules, the example group was the emulsion composition of Example 1, and the comparative group was Comparative Example 2. The emulsified composition is orally administered. Each animal is fasted for at least 24 hours prior to administration, and each animal is administered with a composition in the amount of 100 mg / kg as olive oil or EPA-E. 30 minutes after administration, the glucose solution dissolved in physiological saline is orally loaded at a rate of 2 g / kg. Blood is collected from the tail vein over time, and the plasma TG concentration and free fatty acid concentration are measured using a commercially available measurement kit. For each index, the amount of change from the pre-sugar load value is calculated.
In the control group, the plasma TG concentration increased after glucose loading, and the EPA-E administration group did not show an inhibitory effect on this increase. In the Example group and the Comparative group, the increase in plasma TG concentration and free fatty acid concentration after glucose loading was suppressed, and the inhibitory effect of the Example group was superior to that of the Comparative group.
Therefore, the emulsion composition of the present invention is useful for improvement or treatment of postprandial hyperTG and postprandial hyperfree fatty acidemia by pre-meal administration.

(Formulation Example 1) Emulsion The emulsion composition obtained in Examples 1 to 4 is dispensed into glass bottles of 30 mL, 60 mL, or 90 mL, respectively, to obtain an emulsion containing 300 mg, 600 mg, or 900 mg as EPA-E per bottle. .

Formulation Example 2 Emulsion In Examples 1 to 5, ω3 PUFAs (Lovaza (registered trademark) (K85EE): about 90% ω3 PUFAs, about 84% EPA-E + DHA-E contained in place of EPA-E, EPA-E : DHA-E = about 1.2: 1) is used to obtain an emulsified composition in the same manner. 100 mL of this emulsified composition is dispensed into glass bottles to obtain an emulsion containing about 840 mg as EPA-E + DHA-E per bottle.

Formulation Example 3 Formulation Emulsion 100 mL of the emulsified composition obtained in Example 5 was dispensed into a glass bottle to obtain an emulsion containing 100 mg as EPA-E and 330 mg as tocopherol nicotinate ester per bottle.

(Formulation Example 4) Formulation Emulsion 1.6 g of ursodeoxycholic acid is further added to the preparation liquid A of Example 1, and an emulsified composition is obtained in the same manner as described in Example 1. This emulsified composition is dispensed into ampoules by 60 mL to obtain an emulsion containing 600 mg as EPA-E and 60 mg as ursodeoxycholic acid per ampoule.

The emulsified composition of the present invention is emulsified and dispersible by adding at least one of lecithin and polyoxyethylene polyoxypropylene glycol or polyoxyethylene hydrogenated castor oil to at least one selected from ω3 PUFAs and emulsifying it. In addition, it is possible to provide an emulsified composition excellent in either emulsion stability or absorbability, particularly oral absorption or absorption rate on an empty stomach, its production method and its use.
Compared to existing emulsified compositions, it is expected to be rapidly absorbed even in fasting oral administration and exhibit the preventive or therapeutic effects of ω3 PUFAs. Specifically, the efficacy is further enhanced by improving patient convenience and improving compliance by showing the effectiveness of administration once or twice a day without restriction of the administration of 3 times a day immediately after meals. Can be combined with other preparations for administration other than administration immediately after meals, or can be formulated, or can exhibit post-meal serum TG increase inhibitory effects by oral administration before meals, or can be administered before going to bed by a lipase inhibitor It can show clinical effects such as preventing essential fatty acid deficiency at the time of taking.

Claims (9)

at least one selected from the group consisting of ω3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof, and at least one emulsifier selected from the group consisting of the following (a), (b) and (c): An emulsion composition having an average emulsion droplet diameter of 2 μm or less:
(A) Lecithin and optionally polyoxyethylene polyoxypropylene glycol (b) polyoxyethylene hydrogenated castor oil (c) sucrose fatty acid ester.   The emulsified composition according to claim 1, wherein the lecithin is at least one selected from the group consisting of soybean lecithin, enzyme-decomposed soybean lecithin, hydrogenated soybean lecithin and egg yolk lecithin.   The polyoxyethylene polyoxypropylene glycol is polyoxyethylene (3) polyoxypropylene (17) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol , Polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) poly Group consisting of oxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol and polyoxyethylene (200) polyoxypropylene (70) glycol Emulsified composition according to claim 1 or 2 is at least one selected et.   The emulsion composition according to any one of claims 1 to 3, wherein the lecithin is soybean lecithin or enzymatically degraded soybean lecithin, and the polyoxyethylene polyoxypropylene glycol is polyoxyethylene (105) polyoxypropylene (5) glycol. .   The polyoxyethylene hydrogenated castor oil is polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil and polyoxyethylene The emulsified composition according to any one of claims 1 to 4, which is at least one selected from the group consisting of ethylene (100) hydrogenated castor oil.   The emulsified composition according to any one of claims 1 to 5, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene (60) hydrogenated castor oil.   The sucrose fatty acid ester is at least one selected from the group consisting of sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose oleate and sucrose stearate. The emulsified composition according to any one of 6.   The emulsified composition according to any one of claims 1 to 7, comprising at least one selected from the group consisting of icosapentoic acid, docosahexaenoic acid, and pharmaceutically acceptable salts and esters thereof.   The emulsified composition according to any one of claims 1 to 8, comprising ethyl icosapentate and / or ethyl docosahexaenoate.