WO2015008848A1 - ω3脂肪酸の自己乳化組成物 - Google Patents
ω3脂肪酸の自己乳化組成物 Download PDFInfo
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- WO2015008848A1 WO2015008848A1 PCT/JP2014/069114 JP2014069114W WO2015008848A1 WO 2015008848 A1 WO2015008848 A1 WO 2015008848A1 JP 2014069114 W JP2014069114 W JP 2014069114W WO 2015008848 A1 WO2015008848 A1 WO 2015008848A1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Definitions
- the present invention provides a self-emulsifying composition containing at least one selected from the group consisting of ⁇ 3 polyunsaturated fatty acids, pharmaceutically acceptable salts and esters thereof, pharmaceuticals thereof, and methods of manufacturing the same.
- ⁇ 3PUFA polyunsaturated fatty acid
- EPA icosapentoic acid
- DHA docosahexaenoic acid
- ⁇ 3PUFA 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-E EPA ethyl ester
- Japan an oral treatment for improving ulcers associated with obstructive arteriosclerosis, pain and cold sensation, and hyperlipidemia (trade name Epadale, Mochida Pharmaceutical).
- Epadale a pharmaceutically administered under fasting
- the increase in plasma EPA concentration is lower than that when orally administered under fed conditions. This is thought to be because bile acid secretion and ingredients from food are necessary as a carrier for absorption of EPA-E. Therefore, Epadale is said to be administered orally immediately after meals (non-patented). Reference 1). People who do not eat breakfast, etc.
- TG serum triglycerides
- These compositions contain ethanol for the purpose of improving the solubility of fenofibrate, but when ethanol volatilizes, the capsule deforms and contains bubbles, changes in quality such as capsule deformation and cracking, and cloudiness of the capsule contents. There is a concern about degeneration such as separation.
- a self-emulsifying composition that contains ethanol and polyhydric alcohol in addition to ⁇ 3 PUFA and a surfactant and can produce a dispersion having a small or very small average particle diameter when contacted with water has been reported (Patent Document 2). .
- a self-emulsifying composition with low ethanol content it contains ⁇ 3 PUFA, hydrophilic / lipophilic balance (hereinafter referred to as HLB) 10 or more emulsifiers, lecithin, polyhydric alcohols such as propylene glycol and glycerin, self-emulsifying, hungry
- HLB hydrophilic / lipophilic balance
- emulsifiers lecithin
- polyhydric alcohols such as propylene glycol and glycerin
- Patent Document 4 It has been reported that when a co-solvent such as polyhydric alcohol in the composition is encapsulated, it shifts to the capsule film and causes deformation due to modification of the composition or softening of the capsule.
- Self-emulsifying compositions generally use more emulsifiers, and the amount of liquid in the entire composition is large, resulting in less inflammation of the gastrointestinal tract and physiologically active ingredients dissolved in the oil contained in one capsule (Patent Document) 5) Problems arise. Therefore, it is desirable that the emulsifier used in the composition has no or little toxicity even when continuously administered, and the amount used is small. Further, from the viewpoint of ingestion, the amount of ⁇ 3 PUFA to be taken at a time is determined. Therefore, when the amount of ingredients other than ⁇ 3 PUFA in the self-emulsifying composition increases, the amount of the medicine to be taken at once increases. Therefore, it is desirable that the amount of emulsifier and alcohol used is small from the viewpoint of miniaturization of the preparation.
- a preparation in which ethanol and polyhydric alcohol contained in the self-emulsifying composition are reduced is desired.
- the formulation which reduced the emulsifier contained in a self-emulsification composition is desired.
- a preparation having a high content of ⁇ 3PUFA in the self-emulsifying composition is desired.
- a self-emulsifying composition excellent in medication compliance is desired.
- the self-emulsifying composition is used as a pharmaceutical product, it is assumed that the composition is stored in a cold region or the like, so that when the composition is stored in a low temperature or high temperature environment in addition to room temperature, the composition is not clouded or denatured, such as separation. Self-emulsifying compositions with good appearance are desired.
- a self-emulsifying composition having a stable quality is desired.
- provision of the formulation which encapsulated the composition is desired.
- the present inventors have conducted extensive studies on components that replace ethanol and polyhydric alcohol, and as a result, have found that a predetermined amount of water is useful for improving the compatibility of the self-emulsifying composition.
- the content in the composition may be 0.5 to 6% by mass, which is smaller than that of ethanol or polyhydric alcohol, and the content of emulsifier can be further reduced by the effect of improving the compatibility of this small amount of water. It was found to be a self-emulsifying composition of content. And it discovered that the self-emulsification composition excellent in at least 1 of the said subject was obtained with this composition, and completed this invention.
- the inventors have found that the content of emulsifier can be further reduced, and completed the invention of a self-emulsifying composition having a high content of ⁇ 3 PUFA. And the composition of this invention is a composition excellent in at least 1 or more of the said subject.
- the first aspect of the present invention is the following self-emulsifying composition.
- (1-1) When the total amount of the self-emulsifying composition is 100% by mass, a) at least one compound selected from the group consisting of 70-90% by weight of ⁇ 3 PUFA, pharmaceutically acceptable salts thereof, and esters thereof; b) 0.5-6% by weight of water, c) 1 to 29% by weight of an emulsifier (except lecithin), preferably an emulsifier which is a polyoxyethylene sorbitan fatty acid ester, d) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of ⁇ 3 polyunsaturated fatty acid, its pharmaceutically acceptable salt, and its ester, Containing e) Self-emulsifying composition, wherein ethanol and / or polyhydric alcohol is 4% by mass or less of the total amount of the composition.
- the total amount of the self-emulsifying composition is 100% by mass, a) at least one compound selected from the group consisting of 70-90% by weight of ⁇ 3 PUFA, pharmaceutically acceptable salts thereof, and esters thereof; b) 0.5-6% by weight of water, c) an emulsifier which is 1 to 29% by weight of polyoxyethylene sorbitan fatty acid ester, d) 3 to 40 parts by weight of lecithin with respect to 100 parts by weight of at least one compound selected from the group consisting of ⁇ 3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof; Containing e) 4% by mass or less of ethanol based on the total amount of the composition, f) A self-emulsifying composition, wherein the polyhydric alcohol is 4% by mass or less of the total amount of the composition.
- Polyoxyethylene sorbitan fatty acid ester is Polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene monoisostearate ( 20) At least one selected from the group consisting of sorbitan, polyoxyethylene monooleate (20) sorbitan and polyoxyethylene trioleate (20) sorbitan, described in (1-1) or (1-2) Self-emulsifying composition.
- (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 glycerin.
- (1-7) The self-emulsifying composition according to any one of (1-1) to (1-6), wherein 0 to 4% by mass of a polyhydric alcohol is contained in the composition.
- (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 polyhydric alcohol.
- (1-9) The self-emulsifying composition according to any one of (1-1) to (1-8), wherein the polyhydric alcohol in the composition is 1% by mass or less.
- (1-17) at least one selected from the group consisting of ⁇ 3 PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof, EPA, DHA, a pharmaceutically acceptable salt thereof, and an ester thereof
- (1-18) The self-emulsifying composition according to any one of (1-1) to (1-17), wherein the ester of ⁇ 3PUFA is an ethyl ester or a triglyceride ester.
- (1-19) ⁇ 3PUFA, a pharmaceutically acceptable salt thereof, or an ester thereof is EPA-E or DHA ethyl ester (hereinafter referred to as DHA-E) (1-1) to (1-18)
- DHA-E DHA ethyl ester
- (1-20) Any one of (1-1) to (1-19) containing as an active ingredient at least one selected from the group consisting of EPA, DHA, pharmaceutically acceptable salts and esters thereof The self-emulsifying composition described in 1.
- the lecithin is at least one selected from the group consisting of soybean lecithin, enzyme-degraded soybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin (1-1) to (1-22)
- the self-emulsifying composition as described.
- the content of at least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester and polyoxyethylene polyoxypropylene glycol is less than 5% by mass of the total amount of the composition ( The self-emulsifying composition according to any one of 1-1) to (1-23).
- each emulsifier of polyoxyethylene hydrogenated castor oil, polyoxyethylene glycol fatty acid ester and polyoxyethylene polyoxypropylene glycol is less than 5% by mass of the total amount of the composition, respectively (1-1) to (1- 23)
- composition (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 allowed 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 allowed to stand. (1-28) The self-emulsification according to any one of (1-1) to (1-27), wherein the appearance of the composition is clear when the composition is stored at 5 ° C. or 40 ° C. for 12 hours. Composition. (1-29) The composition according to any one of (1-1) to (1-28), wherein the appearance of the composition is not separated or turbid when the composition is stored at 5 ° C. or 40 ° C.
- Self-emulsifying composition (1-30) The self-emulsifying composition according to any one of (1-1) to (1-29), wherein the composition is good in at least one of self-emulsifying property, composition dispersibility, and emulsion stability.
- (1-31) 10 ⁇ L of the composition is added dropwise to purified water at 37 ° C. or 5 mL of the first solution of JP elution test, and emulsified spontaneously just by adding the solution to any one of (1-1) to (1-30) The self-emulsifying composition as described.
- the area under the ⁇ 3PUFA blood concentration curve was calculated by correcting the blood ⁇ 3 concentration before administration and performing corrections by subtracting the blood ⁇ 3 concentration before administration from 50 ⁇ g / mL and / or from 0 to 2 hours after administration.
- ⁇ 3PUFA blood concentration maximum value is 50 ⁇ g / mL or more, and / or the area under the ⁇ 3PUFA blood concentration curve from administration to 0 to 2 hours is 50 ⁇ g / mL ⁇ hr or more, ⁇ 3PUFA blood concentration maximum value Is 60 ⁇ g / mL ⁇ hr or more and / or the area under the ⁇ 3PUFA blood concentration curve from 0 to 2 hours after administration is 60 ⁇ g / mL ⁇ hr or less (1-1) to (1) to (1) to (1) to (1) to (1) or (1) to (1) to (1) to (1) the maximum ⁇ 3PUFA blood concentration is 70 ⁇ g / mL or more and / or the area under the ⁇ 3PUFA blood concentration curve from administration to 2 hours is 70 ⁇ g / mL ⁇ hr or more 33)
- the self-emulsifying composition as described in any one of 33).
- Male cynomolgus monkey is 45 mg per kg body weight as at least one compound selected from the group consisting of ⁇ 3 PUFA, its pharmaceutically acceptable salt, and its ester under fasting conditions for 12 hours or longer (1- The maximum ⁇ 3PUFA blood concentration calculated by orally administering the self-emulsifying composition according to any one of 1) to (1-33) and reducing the blood ⁇ 3 concentration before administration was 50 ⁇ g / mL.
- the area under the ⁇ 3 PUFA blood concentration curve from 0 to 12 hours after administration is 400 ⁇ g / mL ⁇ hr or more, or the ⁇ 3 PUFA blood concentration maximum value is 70 ⁇ g / mL or more and / or ⁇ 3 PUFA blood from 0 to 12 hours after administration
- (1-36) Any one of (1-1) to (1-33) in an amount of 1800 mg as at least one compound selected from the group consisting of ⁇ 3PUFA, pharmaceutically acceptable salts and esters thereof in humans
- the ⁇ 3PUFA maximum blood concentration was 50 ⁇ g / mL or more and / or 2 hours after administration, which was calculated by orally administering the self-emulsifying composition according to any one of the above before a meal and performing correction by reducing the blood ⁇ 3 concentration before administration.
- the amount of 1800 mg of (1-1) to (1-33) as at least one compound selected from the group consisting of ⁇ 3PUFA, pharmaceutically acceptable salts thereof, and esters thereof in humans The self-emulsifying composition according to any one of the above was orally administered before a meal, and the ⁇ 3 PUFA blood concentration maximum value calculated by performing correction by reducing the blood ⁇ 3 concentration before administration was 10 ⁇ g / mL or more and / or from administration 0
- a self-emulsifying composition characterized in that (1-40) When the total amount of the self-emulsifying composition is 100% by mass, a) 70-90% by weight of EPA-E, b) 0.5-6% by weight of water, c) 1-29% by weight of polyoxyethylene sorbitan fatty acid ester emulsifier d) containing 3-40 parts by weight of lecithin with respect to 100 parts by weight of EPA-E And e) ethanol and / or polyhydric alcohol is 4% by mass or less of the total amount of the composition, A self-emulsifying composition, characterized in that (1-40) When the total amount of the self-emulsifying composition is 100% by mass, a) 70-90% by weight of EPA-E, b) 0.5-6% by weight of water, c) an emulsifier which is 1 to 29% by weight of polyoxyethylene sorbitan fatty acid ester, d) containing 3 to 40 parts by weight of lecithin with respect to 100 parts by
- the second aspect of the present invention is the following encapsulated self-emulsifying preparation.
- (2-1) The self-emulsifying composition according to any one of (1-1) to (1-40), wherein the content liquid is encapsulated in hard capsules and / or soft capsules.
- (2-2) The encapsulated self-emulsifying preparation according to (2-1) having good hardness immediately after production.
- (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) Encapsulation according to (2-1) to (2-3), when the preparation is sealed in aluminum packaging and stored at 40 ° C.
- Dyslipidemia hypercholesterolemia, hyper-LDL-cholesterolemia, hyper-non-HDL-cholesterolemia, hyper-VLDL-cholesterolemia, hypo-HDL-cholesterolemia, hyper-TG, hyper-ApoB, low ApoAIemia, etc.
- therapeutic agent postprandial hyperTGemia therapeutic agent, anti-arteriosclerotic agent, platelet aggregation inhibitor, peripheral circulation failure therapeutic agent, cardiovascular event onset preventive agent, inflammatory disease (non-alcoholic fatty liver Treatment of diseases (hereinafter referred to as NAFLD), non-alcoholic steatohepatitis (hereinafter referred to as NASH), dementia (Alzheimer type dementia, cerebrovascular dementia, mixed type dementia, etc.) progression inhibition -It is at least one selected from the group consisting of therapeutic agents, anticancer agents and therapeutic agents for central diseases (mania, mania, obsessive compulsive disorder, social anxiety disorder, panic disorder, etc.) (2- The formulation
- the third aspect of the present invention is the following method for producing a self-emulsifying composition.
- (3-1) When the total amount of the self-emulsifying composition is 100% by mass a) At least one selected from the group consisting of 70 to 90% by mass of ⁇ 3 PUFA, pharmaceutically acceptable salts thereof, and esters thereof Compound, b) 0.5-6% by weight of water, c) an emulsifier that is 1 to 29% by weight of polyoxyethylene sorbitan fatty acid ester, and d) at least one selected from the group consisting of ⁇ 3 polyunsaturated fatty acids, pharmaceutically acceptable salts thereof, and esters thereof 3 to 40 parts by mass of lecithin is mixed in an arbitrary order with respect to 100 parts by mass of the compound, and e) ethanol and / or polyhydric alcohol in the obtained composition is 4% by mass or less of the total amount of the composition.
- a fourth aspect of the present invention is a medicament for a specific administration method of the following self-emulsifying composition.
- (4-2) Fasting the self-emulsifying composition or the encapsulated self-emulsifying preparation, the medicine or the veterinary medicine produced by the production method according to any one of (3-1) to (3-3) Or a preparation for oral administration before going to bed.
- Drug is dyslipidemia (hypercholesterolemia, hyper-LDL cholesterolemia, hyper-non-HDL cholesterolemia, hyper-VLDL cholesterolemia, hypoHDL-cholesterolemia, hyperTGemia, hyper ApoBemia , Hypo ApoAI blood, etc.) therapeutic agent, postprandial hyperTG therapeutic agent, anti-arteriosclerotic agent, platelet aggregation inhibitor, peripheral circulation failure therapeutic agent, cardiovascular event onset preventive agent, inflammatory disease (NAFLD, NASH, Etc.) At least one selected from the group consisting of a therapeutic agent, an anticancer agent, and a central disease (mania, mania, obsessive compulsive disorder, social anxiety disorder, panic disorder, etc.) preventive agent, therapeutic agent, progression inhibitor A preparation according to (4-1) or (4-2).
- the fifth aspect of the present invention is a method for the prevention, progression prevention and treatment of at least one disease selected from the following group.
- At least one self-emulsifying selected from the above (1-1) to (1-40), (2-1) to (2-7), (3-1) to (3-3) A dyslipidemia (hypercholesterolemia, hyper-LDL cholesterolemia, hyper-non-HDL cholesterolemia, hypertension, characterized by orally administering a composition or encapsulated self-emulsifying preparation, pharmaceutical or veterinary medicine to a patient VLDL cholesterolemia, low HDL cholesterolemia, hyperTGemia, hyperApoBemia, hypoApoAIemia, etc.), postprandial hyperTGemia, anti-arteriosclerosis, increased platelet aggregation, peripheral circulatory failure, cardiovascular event Onset, inflammatory diseases (NAFLD, NASH, etc.), dementia (Alzheimer-type dementia, cerebrovascular dementia, mixed dementia, etc.), cancer and central diseases (mania, mania, obsessive-compulsive disorder)
- the sixth aspect of the present invention is the following self-emulsifying composition.
- (6-1) Self-emulsifying composition in an amount of 600 mg as at least one compound selected from the group consisting of ⁇ 3PUFA, its pharmaceutically acceptable salt, and its ester under fasting conditions for 18 hours or more in male beagle dogs Under the ⁇ 3PUFA blood concentration curve, the maximum value of ⁇ 3PUFA blood concentration was 50 ⁇ g / mL or more and / or 0 to 2 hours after administration, calculated by correcting the blood ⁇ 3 concentration before administration.
- the area under the ⁇ 3PUFA blood concentration curve is 50 ⁇ g / mL ⁇ hr or more, and / or the ⁇ 3PUFA blood concentration maximum value is 50 ⁇ g / mL or more and / or 0 to 2 hours after administration.
- the area under the ⁇ 3 PUFA blood concentration curve is 60 ⁇ g / mL ⁇ hr or more when the value is 60 ⁇ g / mL or more and / or from 0 to 2 hours after administration.
- the self-emulsifying composition having an upper or ⁇ 3 PUFA blood concentration maximum value of 70 ⁇ g / mL or more and / or an area under the ⁇ 3 PUFA blood concentration curve from 0 to 2 hours after administration of 70 ⁇ g / mL ⁇ hr or more.
- (6-2) A self-emulsifying composition in which male cynomolgus monkey is 45 mg per kg body weight as at least one compound selected from the group consisting of ⁇ 3 PUFA, pharmaceutically acceptable salts thereof, and esters thereof under fasting conditions for 12 hours or more.
- the maximum value of ⁇ 3PUFA blood concentration was 50 ⁇ g / mL or more and / or 0 to 12 hours after administration, which was calculated by correcting the blood ⁇ 3 concentration before administration.
- Self-emulsifying composition with an area of 400 ⁇ g / mL ⁇ hr or more, or a maximum ⁇ 3 PUFA blood concentration of 70 ⁇ g / mL or more and / or an area under the ⁇ 3 PUFA blood concentration curve from 0 to 12 hours of administration of 500 ⁇ g / mL ⁇ hr or more object.
- a self-emulsifying composition in an amount of 1800 mg as at least one compound selected from the group consisting of ⁇ 3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof is orally administered to a human before meals and administered Self-emulsifying composition having a maximum ⁇ 3PUFA blood concentration of 50 ⁇ g / mL or more and / or a ⁇ 3PUFA blood concentration of 10 ⁇ g / mL or more 2 hours after administration, calculated by correcting the previous blood ⁇ 3 concentration. .
- a self-emulsifying composition in an amount of 1800 mg as at least one compound selected from the group consisting of ⁇ 3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof is orally administered to a human before meals and administered.
- the maximum value of ⁇ 3PUFA blood concentration calculated by correcting the previous blood ⁇ 3 concentration was 10 ⁇ g / mL or more and / or the area under the ⁇ 3PUFA blood concentration curve from 0 to 72 hours after administration was 250 ⁇ g / mL ⁇ hr.
- the self-emulsifying composition of the present invention contains a small amount of water in the composition instead of ethanol or polyhydric alcohol, and this composition improves the compatibility of the composition and further reduces the amount of emulsifier used. Excellent safety for animals (including humans). Moreover, since ⁇ 3PUFA has a high content, the amount of emulsifier used can be reduced, and the dosage is excellent. Since the composition can contain water, the content of ethanol or polyhydric alcohol can be reduced or not contained, so that the capsule film is prevented from being softened and the capsule is not deformed.
- the self-emulsifying composition of the present invention comprises at least one, preferably two or more, and more preferably all of the above preferred properties.
- the total amount of at least one compound selected from the group consisting of ⁇ 3 PUFA, a pharmaceutically acceptable salt thereof and an ester thereof is in the range of 70 to 90% by mass, and the specific emulsifier is 1 to 29% by mass. %, 3 to 40 parts by mass of lecithin with respect to 100 parts by mass of ⁇ 3 PUFA, pharmaceutically acceptable salt and ester thereof, ethanol or polyhydric alcohol not added or low concentration
- ⁇ 3PUFA 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 ⁇ -linolenic acid, EPA, DHA, eicosatrienoic acid, stearidonic acid, eicosatetraenoic acid, succinic acid, tetracosapentaenoic acid, and nisic acid.
- ⁇ 3 PUFAs EPAs
- DHAs fatty acids
- ⁇ 3 PUFAs used in the present invention may be synthetic, semi-synthetic or natural products, and may be in the form of natural oils containing them.
- the natural product means one extracted from a natural oil containing ⁇ 3 PUFAs by a known method, one that has been roughly purified, or one that has been further refined.
- Semi-synthetic products include ⁇ 3 PUFAs produced by microorganisms and the like, and those obtained by subjecting the ⁇ 3 PUFAs or natural ⁇ 3 PUFAs to chemical treatment such as esterification and transesterification.
- ⁇ 3PUFAs can be used alone or in combination of two or more.
- ⁇ 3 PUFAs include EPAs and DHAs, and more preferred examples include EPAs.
- pharmaceutically acceptable salts of ⁇ 3PUFA 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.
- alkyl esters such as esters and esters such as mono-, di- and TG.
- 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-E, and DHA TG ester are preferred examples, EPA-E and DHA-E are further preferred examples, and EPA-E is a more preferred example.
- the purity of the raw material ⁇ 3PUFAs used in the self-emulsifying composition of the present invention is not particularly limited, but usually the content of ⁇ 3PUFAs in the total fatty acids of the composition is preferably 50% by mass or more, more preferably 70% by mass. % Or more, more preferably 80% by mass or more, more preferably 90% by mass or more, particularly preferably 96.5% by mass or more, and most preferably 98% by mass or more.
- the EPA has a high purity, for example, the EPA content ratio in the ⁇ 3 PUFA is preferably 50% by mass or more, more preferably 60% by mass or more, further preferably 70% by mass or more, and further 80% by mass.
- the composition of the present agent preferably has a high purity of ⁇ 3PUFAs in all fatty acids, more preferably has a high purity of EPAs + DHAs that are ⁇ 3PUFAs, and substantially does not contain DHA at all. Even so, for example, the purity of EPA is most preferably less than 1.0% by weight, preferably less than 0.5% by weight, more preferably less than 0.2% by weight.
- EPA-E and DHA-E are used, if the purity of the composition of EPA-E is as described above, the composition ratio of EPA-E / DHA-E and EPA-E + DHA-E in all fatty acids
- EPA-E / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, more preferably 1.2 or more.
- the composition of the present agent may contain polyunsaturated fatty acids other than ⁇ 3PUFAs such as linoleic acid, ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid, and pharmaceutically acceptable salts or esters thereof.
- Arachidonic acid and their pharmaceutically acceptable salt or ester content is desired to be low, preferably less than 2% by weight, more preferably less than 1% by weight, arachidonic acid and their pharmaceutically acceptable salts Or the aspect which does not contain ester substantially is especially preferable.
- the content of ⁇ 3 PUFAs in the self-emulsifying composition of the present invention is 70 to 90% by mass, preferably 70 to 86% by mass, more preferably 72 to 85% by mass, and more preferably 74 to 84% by mass.
- One type of ⁇ 3 PUFAs may be used, or a mixture of two or more types may be used. In the case of two or more kinds of mixtures, the total amount of the mixture is 70 to 90% by mass in the self-emulsifying composition.
- These ⁇ 3 PUFAs are soft capsules containing high-purity EPA-E (96.5% by mass or more) available as a therapeutic agent for ASO and hyperlipidemia in Japan (trade name Epadale: Mochida Pharmaceutical Co., Ltd.) Can be used as a high-purity EPA-E-containing soft capsule (trade name VASCEPA: amarin) available as a therapeutic agent for hyperTGemia.
- EPA-E and DHA-E can be used, for example, as a therapeutic agent for hyperTGemia in Lovaza (Lovaza (registered trademark): GlaxoSmithKline: EPA-E approximately 46.5).
- Soft capsules containing about 37.5% by mass of DHA-E) and Rotriga (registered trademark) marketed in Japan LOTRIGA (registered trademark): Takeda Pharmaceutical: EPA-E about 46.5% by mass , A soft capsule containing about 37.5% by mass of DHA-E) can also be used.
- a mixture of EPA and DHA is, for example, an Epanova (Epanova (registered trademark): Astra Xeneca: EPA free acid about 50 to 60% by mass, DHA free acid about 15%) marketed in the United States as a therapeutic agent for hyperTG.
- Soft capsules containing up to 25% by weight can also be used.
- Refined fish oil can also be used as ⁇ 3 PUFAs.
- monoglycerides, diglycerides, TG derivatives, or combinations thereof of ⁇ 3PUFAs are also preferable embodiments.
- Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yale, England)
- EPAX6000FA EPAX5000TG
- EPAX4510TG, EPA4510TG, EPA4510TG, EPA4510TG, EPA4510TG, EPA4510TG, K85EE and K80EE Pronova Biopharma, Lysaker, Norway
- other products containing various ⁇ 3 PUFAs are commercially available and can be obtained and used.
- polyoxyethylene sorbitan fatty acid ester is a polyoxyethylene ether of a fatty acid ester in which a part of hydroxyl groups of anhydrous sorbitol is esterified with a fatty acid.
- Various compounds are commercially available depending on the fatty acid to be esterified.
- polyoxyethylene (20) sorbitan monolaurate NIKKOL TL-10, polysorbate 20, Tween 20
- polyoxyethylene (20) sorbitan monopalmitate NIKKOL TP
- polysorbate 40 Tween 40
- polyoxyethylene (20) sorbitan monostearate NIKKOL TS-10MV
- polysorbate 60 Tween 60
- polyoxyethylene sorbitan tristearate
- polysorbate 65 Polyoxyethylene (20) sorbitan monoisostearate (NIKKOL TI-10V)
- polyoxyethylene (20) sorbitan monooleate NIK
- sorbitan trioleate NIKKOL TO-30V, polysorbate 85), etc.
- preferably polyoxyethylene (20) sorbitan monooleate, mono Examples include polyoxyethylene (20) sorbitan oleate and polyoxyethylene (20) sorbitan triole
- polyoxyethylene sorbitan fatty acid ester is used in the sense of including all of the above compounds.
- the content of the polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effects of the present invention, but usually 1 to 29 masses when the total amount of the self-emulsifying composition is 100 mass%. %, Preferably 3 to 20% by mass, more preferably 5 to 15% by mass, particularly preferably 5 to 9% by mass.
- polyoxyethylene castor oil is a compound obtained by addition polymerization of ethylene oxide to castor oil.
- Various compounds are commercially available depending on the average number of moles of ethylene oxide added.
- NIKKOL CO-3 Nikko Chemicals
- NIKKOL CO-10 Nikko Chemicals
- EMALEX C-20 Japanese emulsion
- EMALEX C-30 Japanese emulsion
- Kolliphor EL BASF
- polyoxyl 35 castor oil with an average added mole number of 35
- EMALEX C-40 Japanese emulsion
- EMALEX C-50 Japanese e emulsion
- Kolliphor EL is preferable.
- polyoxyethylene castor oil is used in the sense of including all the above compounds unless otherwise specified.
- the content of polyoxyethylene castor oil in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effects of the present invention. It is preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and particularly preferably 5 to 9% by mass.
- polyoxyethylene castor oil is 150 parts by mass or less, preferably 140 parts by mass or less, more preferably 130 parts by mass or less, further preferably 120 parts by mass with respect to 100 parts by mass of the polyoxyethylene sorbitan fatty acid ester in the composition.
- the amount ratio of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil in the composition is 100 parts by mass: 5 to 150 parts by mass, preferably 100 parts by mass: 10 to 140 parts by mass or less, more preferably 100 parts by mass.
- polyoxyethylene hydrogenated castor oil is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil obtained by adding hydrogen to castor oil.
- Various compounds are commercially available depending on the average degree of polymerization of ethylene oxide.
- NIKKOL HCO-100, Nikko Chemicals polyoxyethylene (60) hydrogenated castor oil is preferable.
- one of these can be used alone or in combination of two or more.
- polyoxyethylene hydrogenated castor oil is used in the sense of including all of the above compounds unless otherwise specified.
- the content of polyoxyethylene hydrogenated castor oil in the self-emulsifying composition of the present invention is not particularly limited as long as it has the effects of the present invention, but usually 1 to 20 masses when the total amount of the self-emulsifying composition is 100 mass%. %, Preferably 2 to 15% by mass, more preferably 3 to 10% by mass, and particularly preferably 5 to 9% by mass.
- polyoxyethylene hydrogenated castor oil is 150 parts by mass or less, preferably 140 parts by mass or less, more preferably 130 parts by mass or less, and still more preferably 120 parts by mass with respect to 100 parts by mass of the polyoxyethylene sorbitan fatty acid ester in the composition. It is suitable to contain at a ratio of not more than 110 parts by weight, particularly preferably not more than 110 parts by weight, most preferably not more than 100 parts by weight.
- the amount ratio of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil in the composition is 100 parts by mass: 5 to 150 parts by mass, preferably 100 parts by mass: 10 to 140 parts by mass or less, more preferably 100 parts by mass. Parts: 20 to 130 parts by mass, more preferably 30 to 120 parts by mass, particularly preferably 100 parts by mass: 50 to 110 parts by mass, and most preferably 100 parts by mass: 80 to 120 parts by mass. Is preferred.
- the self-emulsifying composition of the present invention is characterized by containing at least a polyoxyethylene sorbitan fatty acid ester as an emulsifier.
- a polyoxyethylene sorbitan fatty acid ester as an emulsifier.
- One of the preferable embodiments of the present invention includes polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil and / or polyoxyethylene hydrogenated castor oil as emulsifiers.
- Another preferred embodiment of the present invention includes polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers.
- the self-emulsifying composition of the present invention may contain an emulsifier other than polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as an emulsifier, but the content thereof is 100 parts by mass of the total amount of emulsifier used in the composition. Sometimes it is 20 parts by weight or less, more preferably 10 parts by weight or less, still more preferably less than 5 parts by weight, and particularly preferably substantially free. Further, the emulsifier that can be contained is not particularly limited as long as at least one of the above problems is satisfied.
- sorbitan fatty acid ester for example, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, propylene glycol fatty acid ester, saturated polyglycolized glyceride, polyoxy And ethylene polyoxypropylene glycol, sucrose fatty acid ester, polyethylene glycol fatty acid ester, tocopherol-polyethylene glycol-succinic acid ester (TPGS), and the like.
- TPGS tocopherol-polyethylene glycol-succinic acid ester
- 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, but is usually 1 to 29% by mass when the total amount of the self-emulsifying composition is 100% by mass,
- the amount is preferably 3 to 27% by mass, more preferably 5 to 27% by mass, still more preferably 5 to 24% by mass, and particularly preferably 10 to 20% by mass.
- 8 to 27 mass% is preferable, and 10 to 27 mass% is more preferable.
- it is 5 to 45 parts by mass, preferably 10 to 45 parts by mass, more preferably 15 to 35 parts by mass, and particularly preferably 15 to 20 parts by mass with respect to 100 parts by mass of the ⁇ 3 PUFAs.
- compositions and medicaments of the present invention contain a small amount of water.
- water By including water in the composition, the compatibility of the composition is improved, and no polyhydric alcohol or ethanol is required. Therefore, the appearance is clear even if polyhydric alcohol or ethanol is not included, and the composition is separated or clouded. Does not occur.
- a small amount of water may be added during the preparation of the self-emulsifying composition, and the water in the gelatin film may be transferred to the self-emulsifying composition when encapsulated in a gelatin capsule or the like.
- Water is preferably 0.5 to 6% by mass, more preferably 0.5 to 4% by mass, even more preferably 0.5 to 3% by mass, when the total amount of the self-emulsifying composition is 100% by mass. . Most preferably, it is 1 to 3% by mass. Or 0.5 to 3 mass% is preferable, and 0.5 to 1.5 mass% is more preferable.
- lecithin is one of glycerophospholipids, and examples include soybean lecithin, enzyme-degraded soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, hydrogenated phospholipid, milk-derived phospholipid, lysolecithin, phosphatidylcholine, and phosphatidylserine. Is done.
- soybean lecithin, enzyme-decomposed soybean lecithin, hydrogenated soybean lecithin and egg yolk lecithin are exemplified, and soybean lecithin is more preferred.
- soybean lecithin is more preferred.
- one of these can be used alone or in combination of two or more.
- lecithin is used in the meaning including all of the above glycerophospholipids. In the present invention, lecithin is not included in the emulsifier.
- Various products such as purified soybean lecithin (Nisshin Oilio), purified egg yolk lecithin (Asahi Kasei Pharma), egg yolk lecithin PL-100M (Kupie) are commercially available.
- Soy lecithin is, for example, Basis LP-20B (Nisshin Oil), Lipoid S45, S20 (lipoid), and enzymatically decomposed lecithin is various, such as Basis LP-20E (Nisshin Oil), Phospholipon RLPC20 (lipoid). Products are commercially available and can be obtained and used.
- the content of lecithin added to the self-emulsifying composition of the present invention is not particularly limited, but is preferably 3 to 40 parts by weight, more preferably 3 to 30 parts by weight, and more preferably 3 to 25 parts by weight with respect to 100 parts by weight of ⁇ 3 PUFAs.
- 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 are particularly preferable.
- Or 3-15 mass parts is preferable, 3-12 mass parts is more preferable, and 3-10 mass parts is further more preferable. Most preferred is 5 to 10 parts by mass.
- Lecithin is preferably 2.1 to 36% by mass, more preferably 2.1 to 20% by mass, and even more preferably 2.1 to 15% by mass, when the total amount of the self-emulsifying composition is 100% by mass. . Most preferably, the content is 2.1 to 10% by mass. 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, when the total content of emulsifiers in the self-emulsifying composition is 100 parts by mass. Most preferred is 25 to 35 parts by mass.
- Lecithin is preferably 10 to 150 parts by weight, more preferably 20 to 120 parts by weight, and more preferably 40 to 90 parts by weight, when the total content of polyoxyethylene sorbitan fatty acid ester in the self-emulsifying composition is 100 parts by weight. Further preferred. Most preferred is 50 to 70 parts by mass.
- the “polyhydric alcohol” is a polyol compound having a structure in which one or more hydroxy groups are substituted for two or more carbon atoms of a chain aliphatic hydrocarbon or a cyclic aliphatic hydrocarbon.
- dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol and pentamethylene glycol, glycerin, trimethyl
- dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol and pentamethylene glycol, glycerin, trimethyl
- polyhydric alcohol polymers such as diethylene glycol, dipropylene glycol triethylene glycol, polyethylene glycol, polypropylene glycol, and polyglycerin.
- Glycerin also includes concentrated glycerin.
- the polyhydric alcohol is used in the meaning including all the polyol compounds as described above unless otherwise specified.
- the content of the polyhydric alcohol 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.
- the composition does not contain more than 4% by mass of polyhydric alcohol.
- the content of the polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by weight.
- the ethanol contained in the self-emulsifying composition of the present invention preferably has a range that does not cause a change in quality during the encapsulation production process, distribution and storage, and does not cause a denaturation of the capsule contents.
- a range that does not exceed the record of drug use is desirable.
- the entire composition is 100% by mass, it is preferable not to contain more than 4% by mass of ethanol in the composition.
- the content of ethanol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by weight.
- ethanol and a polyhydric alcohol when contained in the self-emulsifying composition, when the total composition is 100% by mass, the total content of the composition does not include ethanol and polyhydric alcohol more than 4% by mass. It is preferable.
- a preferred embodiment is substantially free of ethanol and polyhydric alcohol.
- the total amount of ethanol and polyhydric alcohol in the composition is preferably 4% by mass or less, more preferably 3% by mass or less, further preferably 2% by mass or less, and particularly preferably 1% by mass or less. Most preferred is 0% by mass or less.
- a preferable ethanol concentration can be appropriately determined according to the ⁇ 3 PUFA concentration in the self-emulsifying composition and the daily dose.
- the self-emulsifying composition of the present invention is orally administered at 1800 mg / day as ⁇ 3PUFA, for example, when the ⁇ 3PUFA is a preparation of 75% by mass, if the ethanol is 0.135% by mass or less, The maximum usage amount of 3.26 mg will not be exceeded.
- preferred embodiments are 1) EPA-E and / or DHA-E, 2) water, 3) polyoxyethylene sorbitan fatty acid ester as an emulsifier 4) A combination containing lecithin.
- 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, 3) polyoxyethylene sorbitan 4)
- the amount of lecithin is 3 to 40 parts by weight with respect to 100 parts by weight of EPA-E and / or DHA-E.
- Another preferred embodiment is a combination comprising 1) EPA-E and / or DHA-E, 2) water, 3) polyoxyethylene sorbitan fatty acid ester as emulsifier, and 4) polyoxyl castor oil, 5) lecithin.
- 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, 3) polyoxyethylene sorbitan And 1 to 29% by mass of an emulsifier containing polyoxyl castor oil (excluding lecithin), 4) 3 to 40 parts by mass of lecithin with respect to 100 parts by mass of EPA-E and / or DHA-E.
- Another preferred embodiment is 1) at least one compound selected from ⁇ 3 PUFA, its pharmaceutically acceptable salt, and its ester, 2) water, 3) polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil as emulsifier 4) A combination containing lecithin.
- the total amount of the self-emulsifying composition is 100% by mass, 1) 70 to 90% by mass of at least one compound selected from ⁇ 3PUFA, a pharmaceutically acceptable salt thereof, and an ester thereof, and 2) 0 of water 5-6 mass%, 3) an emulsifier comprising polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil, the emulsifier being 5-24 mass%, based on 100 mass parts of polyoxyethylene sorbitan fatty acid ester
- Lecithin is 3 to 40 parts by mass of lecithin with respect to 100 parts by mass of at least one compound selected from polyoxyethylene castor oil of 120 parts by mass or less, 4) ⁇ 3 PUFA, pharmaceutically acceptable salts thereof, and esters thereof .
- the self-emulsifying composition of the present invention can be encapsulated.
- a hard capsule or a soft capsule can be selected, and a soft capsule is preferable.
- the form of the soft capsule is not necessarily limited, but is preferably a rotary soft capsule or a seamless capsule.
- the composition of the capsule film is not necessarily limited.
- main components include gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hypromellose, hydroxypropylcellulose, and various known components.
- gelatin is preferable.
- the gelatin is not limited, and known gelatins such as acid-treated gelatin, alkali-treated gelatin, amphoteric gelatin, and chemically modified gelatin can be used, and one or more of these can be used. Preferred is acid-treated gelatin or alkali-treated gelatin.
- gelatin Although the origin of gelatin is not necessarily limited, for example, cow bone, cow skin, pig bone, pig skin, fish scale, fish skin, preferably cow bone, cow skin, pig bone, pig skin.
- examples of “gelatin” include those normally used in the manufacture of soft capsules, for example, pharmaceutical gelatin (gelatin and purified gelatin) defined by the 16th revision Japanese Pharmacopoeia. Two or more types of gelatin may be used in combination.
- the capsule film may contain a plasticizer and the like.
- plasticizer to be blended in the capsule film
- polyhydric alcohols such as glycerin (eg, concentrated glycerin), ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, etc.
- Sugar alcohols such as sorbitol, mannitol, and xylitol are preferred.
- plasticizers may be used in combination of two or more. Of these, glycerin and sorbitol are preferable. It is also preferable to use a combination of glycerin and sorbitol.
- the mass ratio of glycerin and sorbitol is preferably used in the range of 1: 5 to 5: 1, and more preferably in the range of 1: 3 to 3: 1.
- the capsule film solution preferably contains gelatin and a plasticizer in a weight ratio of 10: 1 to 1:10. It is more preferable to contain in the range of: 1.
- the weight ratio of the capsule film solution to the capsule contents is usually 10: 1 to 1:10, preferably 3: 1 to 1:10.
- plasticizers such as amino acids, citric acid, glycerin, sorbitol, trehalose, preservatives, coloring agents such as pigments and titanium oxide, organic acids, etc. Can be added.
- composition for capsule film can be produced by mixing and dissolving gelatin and a plasticizer and, if necessary, various additives in water at room temperature or under heating.
- the encapsulated self-emulsifying preparation containing the self-emulsifying composition of the present invention as a content liquid has good hardness immediately after production, and it is preferable that the hardness does not decrease by storage. The decrease in hardness not only deforms the capsule but also becomes brittle, so the capsule breaks and the content liquid flows out, which is not preferable in terms of quality. The presence or absence of softening of the capsule can be confirmed by measuring the hardness with a general hardness meter.
- the encapsulated self-emulsifying preparation of the present invention has a hardness immediately after production of 18 kgf or more, preferably 20 kgf or more, more preferably 22 kgf or more.
- the hardness does not substantially decrease when stored in a sealed aluminum package at 40 ° C. for one week, or that the hardness does not decrease more than 6 kgf, and the hardness after storage at 40 ° C. for one week. Is 10 kgf or more, preferably 15 kgf or more, more preferably 20 kgf or more. Further, when the hardness immediately after production is 100%, the hardness when stored in a sealed aluminum package at 40 ° C. for 1 week is maintained at 60% or more, preferably 70% or more, more preferably 80% or more. More preferably, the hardness of 85% or more, particularly preferably 90% or more is maintained.
- the dosage and administration period of the ⁇ 3 PUFAs used in the self-emulsifying 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 dosage can be adjusted according to weight, age, etc.
- EPA-E is 0.1 to 5 g / day, preferably 0.2 to 3 g / day, more preferably 0.3 to 3 g / day, and further preferably 0.5 to 3 g / day. Is administered in 1 to 3 divided doses, but the total amount may be administered in one or several divided doses as necessary.
- the number of administrations per day is preferably administered once a day, or divided into two or three times a day.
- a soft capsule containing 1 g as EPA-E 1 to 10 capsules, preferably 1 to 8 capsules, more preferably 1 to 6 capsules, still more preferably 1-4 capsules can be administered, more preferably 1-3 capsules.
- a soft capsule containing 1 g as EPA-E and a soft capsule containing 0.5 g were combined to give 0.5 g / time, 1.5 g / time, 2.5 g / time, 3.5 g / It can also be administered at a dose of 4.5 g / dose or 5.5 g / dose.
- the administration time is preferably during or after meals, and administration after meals (within 30 minutes) is more preferred, but the self-emulsifying composition of the present invention can be used even on an empty stomach.
- patients with reduced absorption capacity in the intestinal tract when administered before, during or after meals, before meals, between meals, and before going to bed e.g. elderly, enteric patients, intestines
- the effects of the present invention can also be exhibited when administered to patients with terminal cancer after surgery, taking a lipase inhibitor), or when the dose is reduced.
- the self-emulsifying composition of the present invention preferably has a feature that the time until it reaches the maximum blood concentration after oral administration is equal to or shorter than that of the ⁇ 3 PUFA stock solution. Alternatively, it is preferable that the maximum value of blood concentration is higher than that of the ⁇ 3 PUFA stock solution. Further, the blood concentration at 2 hours after administration, the area under the blood curve at 0 to 2 hours after administration, and / or the area under the blood concentration curve at 0 to 72 hours are characterized by being equal to or higher than the ⁇ 3 PUFA stock solution. It is preferable.
- the time to reach the maximum blood concentration is shorter than that of ⁇ 3PUFA, the concentration is high, and the blood concentration after 2 hours of administration, 0 to 2 hours of administration and / or What has the characteristic that all below the area under the blood concentration curve of 0 to 72 hours is higher than the ⁇ 3 PUFA stock solution is preferable.
- the above pharmacokinetics can be confirmed in animals such as dogs and monkeys, but is preferably confirmed by human tests.
- a self-emulsifying composition of 600 mg as ⁇ 3 PUFAs was orally administered to male beagle dogs under fasting conditions for 18 hours or longer, and correction was performed by reducing the blood ⁇ 3 concentration before administration.
- the maximum value of ⁇ 3PUFA blood concentration calculated as described above is preferably 50 ⁇ g / ml or more, more preferably 60 ⁇ g / ml or more, and particularly preferably 70 ⁇ g / ml or more.
- the area under the ⁇ 3PUFA blood concentration curve from 0 to 2 hours after administration is preferably 50 ⁇ g / ml ⁇ hr or more, more preferably 60 ⁇ g / ml ⁇ hr or more, and particularly preferably 70 ⁇ g / ml ⁇ hr or more.
- the combination of the maximum value of ⁇ 3PUFA blood concentration and the area under the ⁇ 3PUFA blood concentration curve is preferably 50 ⁇ g / ml or more and 50 ⁇ g / ml ⁇ hr or more, more preferably 60 ⁇ g / ml or more and 60 ⁇ g / ml ⁇ hr or more, 70 ⁇ g. / Ml or more and 70 ⁇ g / ml ⁇ hr or more are particularly preferable.
- a self-emulsifying composition of 45 mg / kg body weight as ⁇ 3 PUFAs to male cynomolgus monkeys under fasting conditions for 12 hours or more, and reducing the blood ⁇ 3 concentration before administration.
- the ⁇ 3PUFA blood concentration maximum value calculated by performing the measurement is preferably 50 ⁇ g / ml or more, and more preferably 70 ⁇ g / ml.
- the area under the ⁇ 3 PUFA blood concentration curve from 0 to 12 hours after administration is preferably 400 ⁇ g / ml ⁇ hr or more, more preferably 500 ⁇ g / ml.
- the combination of the maximum value of ⁇ 3PUFA blood concentration and the area under the ⁇ 3PUFA blood concentration curve is preferably 50 ⁇ g / ml or more and 400 ⁇ g / ml ⁇ hr or more, more preferably 70 ⁇ g / ml or more and 500 ⁇ g / ml ⁇ hr or more.
- a self-emulsifying composition having an amount of 1800 mg as ⁇ 3 PUFAs or EPAs was orally administered to a human before meals, and the correction was made by reducing the blood ⁇ 3 concentration before administration.
- the maximum value of ⁇ 3PUFA blood concentration is preferably 50 ⁇ g / mL or more, more preferably 100 ⁇ g / mL or more, particularly preferably 150 ⁇ g / mL or more, further preferably 200 ⁇ g / mL or more, and most preferably 300 ⁇ g / mL or more.
- the area under the ⁇ 3 PUFA blood concentration curve from 0 to 72 hours after administration is preferably 500 ⁇ g / mL ⁇ hr or more, more preferably 1000 ⁇ g / mL ⁇ hr or more, particularly preferably 1500 ⁇ g / mL ⁇ hr or more, and 2000 ⁇ g / mL ⁇ hr.
- hr or more is more preferable, and most preferably 3000 ⁇ g / mL ⁇ hr or more.
- 500 to 4500 ⁇ g / mL ⁇ hr is preferable, 600 to 3000 ⁇ g / mL ⁇ hr is more preferable, 700 to 2500 ⁇ g / mL ⁇ hr is particularly preferable, 800 to 2000 ⁇ g / mL ⁇ hr is further preferable, and most preferably 1000 to 1500 ⁇ g. / ML ⁇ hr.
- the maximum plasma concentration reaching time is preferably 6 hours or less, more preferably 5 hours or less, particularly preferably 3 hours or less, further preferably 1 hour or less, and most preferably 0 hour or less.
- the elimination half-life in plasma is preferably 10 hours or more, more preferably 20 hours or more, particularly preferably 30 hours or more, further preferably 40 hours or more, and most preferably 50 hours or more.
- it is preferably 0 to 150 hours, more preferably 10 to 120 hours, particularly preferably 30 to 100 hours, further preferably 25 to 75 hours, and most preferably 25 to 50 hours.
- a self-emulsifying composition in an amount of 3600 mg as ⁇ 3 PUFAs or EPAs was orally administered to humans, for example, before meals, immediately after meals or after meals, and the blood ⁇ 3 concentration before administration was reduced.
- the ⁇ 3PUFA blood concentration maximum value calculated after correction is preferably 50 ⁇ g / mL or more, more preferably 100 ⁇ g / mL or more, particularly preferably 150 ⁇ g / mL or more, further preferably 200 ⁇ g / mL or more, most preferably 300 ⁇ g / mL. More than mL.
- the area under the ⁇ 3PUFA blood concentration curve from 0 to 72 hours after administration is preferably 500 ⁇ g / mL ⁇ hr or more, more preferably 1000 ⁇ g / mL ⁇ hr or more, particularly preferably 1500 ⁇ g / mL ⁇ hr or more, 2000 ⁇ g / mL ⁇ hr.
- the above is more preferable, and most preferable is 3000 ⁇ g / mL ⁇ hr or more.
- 500 to 5000 ⁇ g / mL ⁇ hr is preferable, 1000 to 4700 ⁇ g / mL ⁇ hr is more preferable, 1500 to 4500 ⁇ g / mL ⁇ hr is particularly preferable, 2000 to 4000 ⁇ g / mL ⁇ hr is further preferable, and most preferably 2500 to 3500 ⁇ g. / ML ⁇ hr.
- the maximum plasma concentration arrival time is preferably 6 hours or less, more preferably 5 hours or less, particularly preferably 3 hours or less, further preferably 1 hour or less, and most preferably 0 hour or less.
- the elimination half-life in plasma is preferably 10 hours or more, more preferably 20 hours or more, particularly preferably 30 hours or more, further preferably 40 hours or more, and most preferably 50 hours or more.
- it is preferably 0 to 150 hours, more preferably 10 to 120 hours, particularly preferably 30 to 100 hours, further preferably 25 to 75 hours, and most preferably 25 to 50 hours.
- a self-emulsifying composition having an amount of 1800 mg as EPA, for example, orally administered before, immediately after, or after a meal, and corrected by reducing the blood ⁇ 3 concentration before administration.
- the maximum value is not particularly limited, for example, 10 to 50, 50 to 100, 100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 350, 350 to 400, 400 to 450, 450 to 500, 500 to 600, 600 to 700, 700 to 800, 800 to 900, 900 to 1000, 10 to 30, 20 to 40, 30 to 50, 40 to 60, 50 to 70, 60 to 80, 70 to 90, 80 to 100, 90-110, 100-120, 110-130, 120-140, 130-150, 140-160, 150-170, 16 0 to 180, 170 to 190, 180 to 200, 190 to 210, 200 to 220, 220 to 240, 240 to 260, 260 to 280, 280 to 300, 10 to 20, 15 to 25, 20 to 30, 25 to 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 to 75, 73 to 78
- the self-emulsifying composition in which the area under the ⁇ 3PUFA blood concentration curve from 0 to 72 hours after administration is 1800 mg as EPA is administered before, immediately after, or after a meal, for example, 500-1500, 1000 -2000, 1500-2500, 2000-3000, 2500-3500, 3000-4000, 500-1000, 750-1250, 1000-1500, 1250-1750, 1500-2000, 1750-2250, 2000-2500, 2250-2750 2500-3000, 2750-3250, 3000-3500, 3250-3750, 3500-4000, 3750-4250, 4000-4500, 4250-4750, 4500-5000, 500-700, 600-800, 700-90 800 to 1000, 900 to 1100, 1000 to 1200, 1100 to 1300, 1200 to 1400, 1300 to 1500, 1400 to 1600, 1500 to 1700, 1600 to 1800, 1700 to 1900, 1800 to 2000, 1900 to 2100, 2000 ⁇ 2200, 2100-2300, 2200-2400, 2300-2500, 2400-2
- the self-emulsifying composition whose maximum plasma concentration reaching time is 1800 mg to 3600 mg as EPAs is administered, for example, before, immediately after, or after a meal, for example, 0 to 2, 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, 6 to 8, 7 to 9, 8 to 10, 0 to 1, 0.5 to 1.5, 1 to 2, 1.5 to 2.5, 2 to 3, 2.5 to 3.5, 3 to 4, 3.5 to 4.5, 4 to 5, 4.5 to 5.5, 5 to 6, 5.5 to 6.5, 6 to 7, 6.5-7.5, 7-8, 7.5-8.5, 8-9, 8.5-9.5, 9-10, 0-0.5, 0.3-0.
- a self-emulsifying composition having an elimination half-life in plasma of 1800 mg to 3600 mg as EPA is administered before, immediately after, or after a meal, for example, 0 to 50, 25 to 75, 50 to 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, 90-100, 95 105,100 ⁇ 110,105 ⁇ 115,110 to 120 hours can be selected.
- the present invention may be specified by combining two or more selected from the maximum value of ⁇ 3PUFA plasma concentration, the area under the ⁇ 3PUFA blood concentration curve from 0 to 72 hours after administration, the maximum plasma concentration arrival time, and the elimination half-life in plasma. good.
- the self-emulsifying composition of the present invention may contain an emulsification aid, a stabilizer, a preservative, a surfactant, an antioxidant and the like.
- the emulsification aid include fatty acids having 12 to 22 carbon atoms such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, or salts thereof.
- the stabilizer include phosphatidic acid, ascorbic acid, glycerin, cetanol and the like.
- the preservative include ethyl paraoxybenzoate and propyl paraoxybenzoate.
- Surfactants include sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxy A propylene alkyl ether etc. are illustrated.
- the antioxidant include oil-soluble antioxidants such as butylated hydroxytoluene, breached hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and ⁇ -tocopherol.
- suitable carriers or media coloring agents, flavoring agents, vegetable oils as necessary, harmless organic solvents or harmless solubilizers, emulsifiers, suspending agents (for example, Tween 80, Arabic Rubber solutions), isotonic agents, pH adjusters, stabilizers, flavoring agents, flavoring agents, preservatives, antioxidants, absorption promoters, etc.can be prepared.
- oil-soluble antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinones, astaxanthins and ⁇ -tocopherols It is desirable to contain an effective amount of at least one selected from the above as an antioxidant.
- the self-emulsifying composition of the present invention is also used for pharmaceutical use, it is preferable that the appearance is good and the self-emulsifying property, the composition dispersibility, the emulsion stability and the storage stability are excellent. It is preferable that the self-emulsifying composition does not separate, does not become turbid, does not solidify, does not precipitate, and is clear in appearance. If the appearance is poor, it is not preferable as a medicine, and there is a possibility that it does not have originally required performance such as self-emulsification. In consideration of the possibility that the self-emulsifying composition and these encapsulated preparations are handled in a cold region or a high temperature environment, the storage temperature is preferably clear in appearance even at low and high temperatures.
- a self-emulsifying composition excellent in self-emulsifying property, composition dispersibility, and emulsion stability when it comes into contact with water, it disperses quickly and forms a microemulsion having an appropriate emulsion droplet size.
- the absorbability of oil such as EPA-E is related to the size of the emulsion droplet diameter, and by measuring this, it can be predicted whether the absorbability when administered to animals is good.
- the “average emulsified droplet size” is a standard measurement method (for example, a Setzero time of 30 seconds and a measurement time of 30 seconds) using a particle size distribution measuring apparatus (for example, Nanotorac, manufactured by Nikkiso) using water as a dispersion medium. It is the value of the volume average diameter in the emulsified composition measured by the average of 3 seconds).
- the average emulsified droplet diameter is 2 ⁇ m or less, and is not particularly limited as long as it is in a range excellent in emulsifying dispersibility, emulsification stability, or absorbency, but usually the average
- the emulsified droplet diameter is 1.5 ⁇ m or less, more preferably 1.0 ⁇ m or less, still more preferably 0.5 ⁇ m or less, and most preferably 0.3 ⁇ m or less.
- the second active ingredient can be used in combination with the self-emulsifying composition of the present invention.
- 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 ⁇ 3 PUFAs, such as antihyperlipidemic drugs, antihypertensive drugs, antidiabetic drugs, Examples include antioxidants, blood flow improving agents, bile acid derivatives, NAFLD / NASH therapeutic agents, dementia progression inhibitory / therapeutic agents, and the like.
- 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.
- 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, and ezetimibe are also included.
- 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 colestimid
- 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 hydrochloride, nicardipine hydrochloride Such as salt, nifedipine,
- Antidiabetic drugs include ⁇ -glucosidase inhibitors such as acarbose, voglibose and miglitol, sulfonylurea hypoglycemic drugs 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, linagliptin, tenegliptin, anagliptin, saxagliptin, pioglycone hydrochloride, rosiglitazone maleate Thiazolidine drugs, glucagon-like peptide 1 derivatives such as exenatide and liraglutide, ipra
- antioxidants examples include vitamins such as ascorbic acid (vitamin C), tocopherol (vitamin E), 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.
- bile acid derivatives examples include ursodeoxycholic acid, chenodeoxycholic acid, bile powder, deoxycholic acid, cholic acid, bile extract, bear gall, cow yellow, dehydrocholic acid, and the like.
- biotin vitamin B7
- cyanocobalamin vitamin B12
- pantothenic acid vitamin B5
- folic acid vitamin B9
- thiamine vitamin B1
- vitamin A vitamin D
- vitamin K vitamin K
- tyrosine pyrodoxine
- Preferred examples include branched chain amino acids such as leucine, isoleucine and valine, calcium, iron, zinc, copper and magnesium.
- certain health foods such as soy protein, chitosan, low molecular 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.
- NAFLD / NASH therapeutic agents include statin drugs such as pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, cerivastatin, irbesartan, olmesartan medoxomil, candesartan lexetyl, telmisartan, valsartan, losartan potassium, etc.
- statin drugs such as pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, cerivastatin, irbesartan, olmesartan medoxomil, candesartan lexetyl, telmisartan, valsartan, losartan potassium, etc.
- biguanide antihyperglycemic drugs such as metformin hydrochloride and buformin hydrochloride
- thiazolidine drugs such as pioglizone hydrochloride and rosiglitazone maleate
- aspirin ursodeoxycholic acid, chenodeoxycholic acid, obelicholic acid
- FXR farnesoid X receptor
- Dementia progression inhibitors / agents include: donepezil hydrochloride, acetylcholinesterase inhibitors such as galantamine hydrobromide, NMDA receptor inhibitors such as memantine hydrochloride, aspirin, clopidogrel sulfate, cilostazol, ticlopidine hydrochloride
- Antiplatelet agents such as salts, factor Xa inhibitors such as rivaroxaban, apixaban, and the like.
- the above-mentioned antihyperlipidemic agents, antihypertensive agents, antidiabetic agents, antioxidants, blood flow improving agents, etc. can also be used as dementia suppression / treatment agents.
- the self-emulsifying composition of the present invention has excellent appearance, excellent self-emulsifying property, excellent composition dispersibility, excellent emulsification stability, storage stability (low temperature, high temperature) so that the pharmacological action of ⁇ 3 PUFAs can be expressed. It is desirable to have at least one effect of a formulation excellent in absorption, especially in fasting absorption and absorption speed, convenient for patients to take, or excellent in compliance. .
- the self-emulsifying composition of the present invention is a therapeutic agent for various diseases of animals, particularly mammals, such as dyslipidemia (hypercholesterolemia, high LDL cholesterolemia, high non-HDL cholesterolemia, high VLDL cholesterolemia, low HDL cholesterolemia, hyperTGemia, hyperApoBemia, hypoApoAIemia, etc.) therapeutic agent, postprandial hyperTGemia therapeutic agent, anti-arteriosclerotic agent, platelet aggregation inhibitor, peripheral circulation failure therapeutic agent, heart Prevention of vascular events, treatment for inflammatory diseases (NAFLD, NASH, etc.), dementia (Alzheimer-type dementia, cerebrovascular dementia, mixed dementia, etc.) progression inhibitor / treatment agent, anticancer agent and central It can be used as a therapeutic agent for diseases (manic, manic state, obsessive-compulsive disorder, social anxiety disorder, panic disorder, etc.).
- dyslipidemia hypercholesterolemia, high LDL cholesterolemia, high non-HDL cholesterolemia, high VLDL cholesterolemia
- the number of daily administrations of the self-emulsifying composition of the present invention is not particularly limited, but it is preferable to administer once a day, or twice or three times a day. Administration once or twice a day is more preferred, and administration once a day is particularly preferred. Of the above-mentioned diseases, it is particularly effective in improving or treating dyslipidemia, postprandial hyperTGemia, preventing recurrence, or suppressing 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.
- domestic animals such as humans, cows, horses, and pigs
- domestic animals such as dogs, cats, rabbits, rats, and mice
- 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.
- Example 1 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 are weighed, sealed and mixed while heating to about 70 ° C. An emulsified composition was prepared. The self-emulsifying composition was sealed with nitrogen and stored at room temperature until evaluation was performed. Table 1 shows the formulation of the self-emulsifying composition.
- Examples 2-11, Comparative Examples 1-2 The self-emulsifying compositions of Examples 2-8 and the compositions of Comparative Examples 1-2 were prepared and stored in the same manner as in Example 1 so that the composition ratios shown in Table 1 were obtained.
- Table 1 shows the self-emulsifying composition and the formulation of the composition.
- Comparative Examples 3-4 The composition of Comparative Example 3 was prepared and stored in the same manner as in Example 1 so that the composition ratio shown in Table 1 was obtained. Table 1 shows the formulation of the composition.
- the self-emulsifying composition produced by the above-described method and the composition of the comparative example were encapsulated in a soft capsule having gelatin as a main component.
- Test Example 1 ⁇ Appearance Evaluation> The self-emulsifying composition and the composition of the comparative example were produced by the above production method, and then allowed to stand, and the appearance was evaluated after about 1 hour. When the composition was excellent in compatibility and the composition was uniform, it was “clear”, “separated” when separated, and “cloudy” when opaque. Table 1 shows the test results.
- Test Example 2 ⁇ Evaluation of self-emulsification> About self-emulsification composition manufactured by said manufacturing method and the composition of a comparative example, 10 microliters of each composition is dripped at 5 mL of purified water of 37 degreeC in a test tube, and a 1st dissolution test first liquid, and self-emulsification. Sexuality was evaluated. The case where it emulsified just by dripping was made favorable, and the case where it was not emulsified naturally only by dripping was made bad. Next, after lightly stirring under uniform conditions, the properties were evaluated.
- composition dispersibility the case where the composition was dispersed was regarded as good, and the case where a part of the composition remained as a lump without being dispersed was regarded as poor.
- emulsion stability the case where there was no oil separation was judged good, and the case where there was oil separation was judged bad.
- the composition that was not “clear” in the evaluation of the external appearance was not evaluated because the composition was not uniform, and was not evaluated. Table 1 shows the test results.
- Test Example 3 ⁇ Evaluation of emulsion droplet size> Using about 1.5 mL of the emulsified composition obtained in Test Example 2 above, using a particle size distribution measuring device (Nanotorac, Nikkiso), water is used as a dispersion medium, and the average emulsion droplet size (volume average diameter) is measured. did.
- a particle size distribution measuring device Nanotorac, Nikkiso
- Test Example 4 ⁇ Evaluation of appearance after storage under severe conditions> The composition that was “clear” or “cloudy” in Test Example 1 was allowed to stand at 5 ° C. or 40 ° C. and stored overnight (about 12 hours), and then the appearance was evaluated. When the composition was excellent in compatibility and the composition was uniform, it was “clear”, “separated” when separated, and “cloudy” when opaque. Table 1 shows the test results.
- Test Example 5 ⁇ Pharmacokinetics in Beagle Dog>
- the prepared composition or capsule was orally administered to 6 male beagle dogs (2-6 years old, body weight 8-13 kg, 3 Marshall beagle, 3 Northam beagle) under fasting conditions, and the blood concentration of EPA changed Evaluated.
- each test animal was fasted for 18 hours or more before administration, and each animal was administered with a composition in an amount of 600 mg as EPA-E.
- blood is collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours, and after the plasma is collected and processed, the EPA concentration in the plasma is measured.
- Test Example 6 ⁇ Pharmacokinetics in Cynomolgus Monkey>
- the composition of Example 14 is orally administered to 6 cynomolgus monkeys (2-5 years old, body weight 2.70-4.65 kg, Hamley) under fasting conditions, and the change in blood concentration of EPA is evaluated.
- Each test animal is fasted for at least 12 hours before administration, and each animal is administered with a self-emulsifying composition in an amount of 45 mg / kg as EPA-E.
- EPA-E stock solution filled in capsules is administered. 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 / Measured with MS.
- Test Example 7 ⁇ Appearance of capsule> About each soft capsule obtained by the Example, after completion
- Example 1 is a composition containing only polyoxyethylene sorbitan fatty acid ester as an emulsifier in the composition and further containing a specific range of lecithin and water, but the appearance of the composition is good as shown in Table 1, and self-emulsifying Etc. From this result, it can be seen that the composition containing lecithin has the effect of the present invention even when the emulsifier is composed only of polyoxyethylene sorbitan fatty acid ester.
- Examples 2 to 10 are compositions containing polyoxyethylene castor oil as an emulsifier in the composition, but these also have good appearance of the composition as shown in Table 1 and are excellent in self-emulsifying properties and the like. .
- Example 11 is a composition further containing polyoxyethylene hydrogenated castor oil as an emulsifier in the composition, but these also had a good appearance of the composition as shown in Table 1 and were excellent in self-emulsifying properties and the like.
- the comparative example 1 is a composition which does not contain water in a composition, it isolate
- the comparative example 2 is a composition which contains 8 mass% of water in a composition, it isolate
- the present invention does not contain ethanol or polyhydric alcohol and uses water in order to improve the compatibility of the composition. When water was not included, the composition was not sufficiently compatible and thus separated. Moreover, even if it was the prescription containing water, even if the quantity was too much with respect to a composition, it isolate
- Comparative Example 3 does not contain water and has a composition containing polyhydric alcohol. This composition was common in Example 1 and the like in that the appearance was good and the self-emulsifying property was excellent. However, it separated when stored at 40 ° C. overnight. From this, it can be seen that it is important to include a specific amount of water of about 0.5 to 6% by mass because the appearance is excellent.
- Comparative Example 4 was a composition containing polyoxyethylene castor oil as an emulsifier in the composition and not containing polyoxyethylene sorbitan fatty acid ester, but with such a composition, the appearance became cloudy. From this, it can be seen that containing a polyoxyethylene sorbitan fatty acid ester as an emulsifier is important because of its excellent appearance.
- Examples 1, 3, and 5 show the kinetic results when a self-emulsifying composition was administered to a fasted animal.
- the animals that received these self-emulsifying compositions had significantly higher Cmax and AUC 0-2 values, parameters of absorption rate, than animals that received the control group (fasted). That is, when the self-emulsifying composition of the example was administered, it was confirmed that not only the amount of EPA absorbed up to 24 hours after oral administration was increased compared to the control group, but also EPA was absorbed particularly immediately after oral administration. It was done.
- the self-emulsifying 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 demonstrated quickly and more effectively. It is expected that it can be used as a self-emulsifying preparation.
- Self-emulsifying capsule preparations of Examples 2-1 and 2-2 and capsule preparation of Comparative Example 2-3 Self-emulsifying compositions and comparative examples were prepared in the same manner as in Example 1 so that the compositions shown in Table 2 were obtained. 2-3 compositions were prepared and stored. Table 2 shows the formulation of the self-emulsifying composition. Soft gelatin capsules filled with 375 mg of this self-emulsifying composition for Examples 2-1 and 2-2 and 441 mg for Comparative Example 2-3 (both 300 mg as EPA-E) were produced by the rotary method. . The self-emulsifying capsule preparation produced by this method showed no deformation of the capsule film. Table 2 shows the composition of the content liquid.
- Test Example 8 ⁇ Capsule hardness> The hardness of each capsule formulation of Examples 2-1 and 2-2 and Comparative Example 2-3 was measured. Moreover, the hardness was similarly measured about the formulation stored at 40 degreeC relative humidity 75% for 1, 2, and 4 weeks. Table 2 shows the results when each preparation was initially stored at 40 ° C. for 1, 2, and 4 weeks. The initial term refers to a preparation stored at room temperature until the evaluation after the capsule is produced. Moreover, since each formulation was sealed in aluminum packaging and stored at 40 ° C., it was not affected by humidity.
- Examples 2-1 and 2-2 are preparations in which the self-emulsifying composition of the present invention is encapsulated. These capsules had a hardness of 20 kgf or more.
- Examples 2-1 and 2-2 showed almost no change, whereas Comparative Example 2-3 was 57% of the initial value in 1 week. The hardness decreased to a point and further decreased over time.
- the self-emulsifying composition of the present invention is excellent in at least one of compatibility (appearance), self-emulsifying property, composition dispersibility, emulsion stability, and absorbability, and is rapidly absorbed even after pre-meal administration and increases serum TG after meal. Suppress. It is blended in various foods, and is useful as a special-purpose food, a health functional food (a food for specified health use and a nutritional functional food), a health food (supplement), or a pharmaceutical product. Since the self-emulsifying composition of the present invention does not contain polyhydric alcohol or has a low concentration, capsule softening and deformation caused by polyhydric alcohol during distribution and storage do not occur and the risk of quality change is low. Further, since the composition is not denatured such as cloudiness or separation even when stored in a low temperature or high temperature environment, it has a quality that can be stored in cold or high temperature areas when used as a medicine.
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Abstract
Description
近年のライフスタイルの変化に伴い朝食等の食事を摂らない人や、少量の食事しか摂取できない患者、流動食(牛乳、重湯、葛湯、卵、スープ、果汁、経口栄養剤)しか摂取できない患者、腸管での吸収能が低下した患者(高齢者、腸疾患患者、腸手術後、末期癌患者、リパーゼ阻害剤服用時)あるいは脳梗塞後など食事摂取不可能な患者等への服用法、あるいは服薬コンプライアンスの遵守が課題の一つとなっている。
これらの組成物はフェノフィブラートの溶解性の向上を目的としてエタノールを含有するが、エタノールが揮発すると、カプセルの変形や気泡の混入、カプセルの変形やクラック発生等の品質変化、カプセル内容物の白濁や分離等の変性が懸念される。また、アルコール(エタノール)不耐性の患者にとって服用できないあるいは服用しづらい製剤である。
また服用性の観点では、一度に服用するω3PUFAの量は定められているため、自己乳化組成物のω3PUFA以外の成分が増えるとその分一度に服用する薬剤の量が増えてしまう。そのため、製剤の小型化の観点からも乳化剤やアルコール類の使用量は少ないことが望ましい。
また、自己乳化組成物中に含有させる乳化剤を減らした製剤が望まれている。
また、自己乳化組成物中のω3PUFAを高含量化した製剤が望まれている。
また、服薬コンプライアンスに優れる自己乳化組成物が望まれている。
また、自己乳化組成物を医薬品として用いる場合に寒冷地等での保管も想定されるため、室温に加え低温又は高温環境下で保存した場合に、組成物が白濁、分離等の変性のない、外観が良好な自己乳化組成物が望まれている。
また、組成物が安定な品質を有する自己乳化組成物が望まれている。
また、組成物をカプセル化した製剤の提供が望まれている。
また、組成物をカプセル化した場合に、カプセル皮膜の軟化を抑制し、変形しない製剤が望まれている。
そして、これらの性質の少なくとも1つを改善する自己乳化組成物、およびその組成物をカプセル化した製剤を提供することが本発明の課題である。
また、組成物中の含量もエタノールや多価アルコールよりも少ない0.5~6質量%で良く、この少量の水の相溶性改善の効果により乳化剤の含量をさらに少なく出来ることから、ω3PUFAが高含量の自己乳化組成物となることを見出した。
そして、かかる組成物では上記課題の少なくとも1つに優れる自己乳化組成物が得られることを見出し、本発明を完成させた。
また、乳化剤の含量をより少なく出来ることも見出し、ω3PUFAが高含量の自己乳化組成物の発明を完成させた。
そして、本発明の組成物は上記課題の少なくとも1つ以上に優れる組成物である。
(1-1)自己乳化組成物の全量を100質量%としたとき、
a)70~90質量%のω3PUFA、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物、
b)0.5~6質量%の水、
c)1~29質量%の乳化剤(ただしレシチンを除く)、好ましくはポリオキシエチレンソルビタン脂肪酸エステルである乳化剤、
d)ω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステル100質量部に対して、3ないし40質量部のレシチン、
を含有し、
e)エタノールおよび/または多価アルコールが前記組成物全量の4質量%以下、であることを特徴とする自己乳化組成物。
(1-2)自己乳化組成物の全量を100質量%としたとき、
a)70~90質量%のω3PUFA、その製薬学上許容しうる塩、および、そのエステルからなる群から選択される少なくとも1つの化合物、
b)0.5~6質量%の水、
c)1~29質量%のポリオキシエチレンソルビタン脂肪酸エステルである乳化剤、
d)ω3多価不飽和脂肪酸、その製薬学上許容しうる塩、および、そのエステルからなる群から選択される少なくとも1つの化合物100質量部に対して、3~40質量部のレシチン、
を含有し、
e)エタノールが前記組成物全量の4質量%以下、
f)多価アルコールが前記組成物全量の4質量%以下、であることを特徴とする自己乳化組成物。
(1-3)ポリオキシエチレンソルビタン脂肪酸エステルが、
モノラウリン酸ポリオキシエチレン(20)ソルビタン、モノパルミチン酸ポリオキシエチレン(20)ソルビタン、モノステアリン酸ポリオキシエチレン(20)ソルビタン、トリステアリン酸ポリオキシエチレン(20)ソルビタン、モノイソステアリン酸ポリオキシエチレン(20)ソルビタン、モノオレイン酸ポリオキシエチレン(20)ソルビタンおよびトリオレイン酸ポリオキシエチレン(20)ソルビタンからなる群から選択される少なくとも1つである(1-1)または(1-2)に記載の自己乳化組成物。
(1-4)乳化剤がさらにポリオキシエチレン硬化ヒマシ油および/またはポリオキシエチレンヒマシ油を含む(1-1)ないし(1-3)に記載の自己乳化組成物。
(1-5)乳化剤がさらにポリオキシエチレンヒマシ油を含む(1-1)ないし(1-4)に記載の自己乳化組成物。
(1-7)組成物中に0~4質量%の多価アルコールを含む(1-1)ないし(1-6)のいずれかに記載の自己乳化組成物。
(1-8)組成物中に4質量%より多い多価アルコールを含まない(1-1)ないし(1-6)のいずれかに記載の自己乳化組成物。
(1-9)組成物中の多価アルコールが1質量%以下である(1-1)ないし(1-8)のいずれかに記載の自己乳化組成物。
(1-10)組成物中に0~1質量%の多価アルコールを含む(1-1)ないし(1-9)のいずれかに記載の自己乳化組成物。
(1-11)組成物中に1質量%より多い多価アルコールを含まない(1-1)ないし(1-8)のいずれかに記載の自己乳化組成物。
(1-12)組成物中に多価アルコールを実質的に含有しない(1-1)ないし(1-11)のいずれかに記載の自己乳化組成物。
(1-13)組成物中のエタノールが4質量%以下である(1-1)ないし(1-12)のいずれかに記載の自己乳化組成物。
(1-14)組成物中に0~4質量%のエタノールを含む(1-1)ないし(1-12)のいずれかに記載の自己乳化組成物。
(1-15)組成物中に4質量%より多いエタノールを含まない(1-1)ないし(1-12)のいずれかに記載の自己乳化組成物。
(1-16)組成物中にエタノールを実質的に含有しない(1-1)ないし(1-15)のいずれかに記載の自己乳化組成物。
(1-18)ω3PUFAのエステルがエチルエステルまたはトリグリセリドエステルである(1-1)ないし(1-17)のいずれかに記載の自己乳化組成物。
(1-19)ω3PUFA、その製薬学上許容しうる塩、または、そのエステルがEPA-EまたはDHAエチルエステル(以下、DHA-Eと記す)である(1-1)ないし(1-18)のいずれかに記載の自己乳化組成物。
(1-20)EPA、DHA、これらの製薬学上許容しうる塩およびエステルからなる群から選択される少なくとも1つを有効成分として含有する(1-1)ないし(1-19)のいずれかに記載の自己乳化組成物。
(1-21)EPA-Eおよび/またはDHA-Eを有効成分として含有する(1-1)ないし(1-20)のいずれかに記載の自己乳化組成物。
(1-22)EPA-Eを有効成分として含有する(1-1)ないし(1-21)のいずれかに記載の自己乳化組成物。
(1-24)ポリオキシエチレン硬化ヒマシ油、ポリエチレングリコール脂肪酸エステルおよびポリオキシエチレンポリオキシプロピレングリコールからなる群から選択される少なくとも1つの乳化剤の含量が組成物の全量の5質量%未満である(1-1)ないし(1-23)のいずれかに記載の自己乳化組成物。さらにはポリオキシエチレン硬化ヒマシ油、ポリオキシエチレングリコール脂肪酸エステルおよびポリオキシエチレンポリオキシプロピレングリコールの各乳化剤の含量がそれぞれ組成物の全量の5質量%未満である(1-1)ないし(1-23)のいずれかに記載の自己乳化組成物。
(1-27)組成物を静置した時に組成物の外観が分離または濁りのない(1-1)ないし(1-25)のいずれかに記載の自己乳化組成物。
(1-28)組成物を5℃あるいは40℃の環境下で12時間保存した時の組成物の外観が澄明である(1-1)ないし(1-27)のいずれかに記載の自己乳化組成物。
(1-29)組成物を5℃あるいは40℃の環境下で12時間保存した時の組成物の外観が分離または濁りのない(1-1)ないし(1-28)のいずれかに記載の自己乳化組成物。
(1-30)組成物が自己乳化性、組成物分散性、乳化安定性の少なくとも1つが良好である(1-1)ないし(1-29)のいずれかに記載の自己乳化組成物。
(1-31)組成物10μLを37℃の精製水または日局溶出試験第1液5mLに滴下し、滴下しただけで自然に乳化する(1-1)ないし(1-30)のいずれかに記載の自己乳化組成物。
(1-32)組成物10μLを37℃の精製水または日局溶出試験第1液5mLに滴下し、撹拌により組成物が分散する(1-1)ないし(1-31)のいずれかに記載の自己乳化組成物。
(1-33)組成物10μLを37℃の精製水または日局溶出試験第1液5mLに滴下し、油の分離が無い(1-1)ないし(1-32)のいずれかに記載の自己乳化組成物。
(1-35)雄性カニクイザルに12時間以上絶食条件下でω3PUFA、その製薬学上許容しうる塩、および、そのエステルからなる群から選ばれる少なくとも1つの化合物として体重1kgあたり45mgとなる(1-1)ないし(1-33)のいずれかに記載の自己乳化組成物を経口投与し、投与前の血中ω3濃度を減じた補正を行なって算出した、ω3PUFA血中濃度最大値が50μg/mL以上および/または投与0から12時間までのω3PUFA血中濃度曲線下面積が400μg/mL・hr以上、またはω3PUFA血中濃度最大値が70μg/mL以上および/または投与0から12時間までのω3PUFA血中濃度曲線下面積が500μg/mL・hr以上である上記(1-1)ないし(1-33)のいずれかに記載の自己乳化組成物。
(1-36)ヒトにω3PUFA、その製薬学上許容しうる塩およびそのエステルからなる群から選択される少なくとも1つの化合物として1800mgの量となる(1-1)ないし(1-33)のいずれかに記載の自己乳化組成物を食前に経口投与し、投与前の血中ω3濃度を減じた補正を行なって算出した、ω3PUFA血中濃度最大値が50μg/mL以上および/または投与2時間後のω3PUFA血中濃度が10μg/mL以上である(1-1)ないし(1-33)のいずれかに記載の自己乳化組成物の用途。
(1-37)ヒトにω3PUFA、その製薬学上許容しうる塩、および、そのエステルからなる群から選ばれる少なくとも1つの化合物として1800mgの量となる(1-1)ないし(1-33)のいずれかに記載の自己乳化組成物を食前に経口投与し、投与前の血中ω3濃度を減じた補正を行なって算出した、ω3PUFA血中濃度最大値が10μg/mL以上および/または投与0から72時間までのω3PUFA血中濃度曲線下面積が250μg/mL・hr以上である(1-1)ないし(1-33)のいずれかに記載の自己乳化組成物。
(1-39)自己乳化組成物の全量を100質量%としたとき、
a)70~90質量%のEPA-E、
b)0.5~6質量%の水
c)1~29質量%のポリオキシエチレンソルビタン脂肪酸エステルである乳化剤
d)前記EPA-E 100質量部に対して、3ないし40質量部のレシチン
を含有し、
e)エタノールおよび/または多価アルコールが前記組成物の全量の4質量%以下、
であることを特徴とする自己乳化組成物。
(1-40)自己乳化組成物の全量を100質量%としたとき、
a)70~90質量%のEPA-E、
b)0.5~6質量%の水、
c)1~29質量%のポリオキシエチレンソルビタン脂肪酸エステルである乳化剤、
d)前記EPA-E 100質量部に対して、3ないし40質量部のレシチン
を含有し、
e)エタノールが前記組成物全量の4質量%以下、
f)多価アルコールが前記組成物の全量の4質量%以下、
であることを特徴とする自己乳化組成物。
(2-1)内容液が(1-1)ないし(1-40)のいずれかに記載の自己乳化組成物であって、硬カプセルおよび/または軟カプセルでカプセル化されていることを特徴とするカプセル化された自己乳化製剤。
(2-2)製造直後の硬度が良好な(2-1)に記載のカプセル化された自己乳化製剤。
(2-3)製造直後の硬度が18kgf以上である(2-1)または(2-2)に記載のカプセル化された自己乳化製剤。
(2-4)製剤をアルミ包装に入れて密封し40℃で1週間保管した時に保管前と比較して硬度が6kgf以上低下しない(2-1)ないし(2-3)に記載のカプセル化された自己乳化製剤。
(2-5)製剤をアルミ包装に入れて密封し40℃で1週間保管した時に硬度が20kgf以上である(2-1)ないし(2-4)のいずれかに記載のカプセル化された自己乳化製剤。
(2-6)製剤をアルミ包装に入れて密封し40℃で1週間保管した時の硬度が保管前の硬度の60%以上である(2-1)ないし(2-5)のいずれかに記載のカプセル化された自己乳化製剤。
(2-7)脂質異常症(高コレステロール血症、高LDLコレステロール血症、高非HDLコレステロール血症、高VLDLコレステロール血症、低HDLコレステロール血症、高TG血症、高ApoB血症、低ApoAI血症、等)治療剤、食後高TG血症治療剤、抗動脈硬化剤、血小板凝集抑制剤、末梢循環不全治療剤、心血管イベント発症予防剤、炎症性疾患(非アルコール性脂肪性肝疾患(以下、NAFLDと記す)、非アルコール性脂肪肝炎(以下、NASHと記す)、等)治療剤、認知症(アルツハイマー型認知症、脳血管性認知症、混合型認知症、等)進行抑制・治療剤、抗癌剤および中枢性疾患(欝病、欝状態、強迫性障害、社会不安障害、パニック障害、等)治療剤からなる群から選択される少なくとも1つである(2-1)に記載の製剤。
(3-1)自己乳化組成物の全量を100質量%としたとき
a)70ないし90質量%のω3PUFA、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物、
b)0.5~6質量%の水、
c)1~29質量%のポリオキシエチレンソルビタン脂肪酸エステルである乳化剤、および
d)ω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物100質量部に対して、3ないし40質量部のレシチン
を任意の順序で混合し、得られる組成物中の
e)エタノールおよび/または多価アルコールが組成物全量の4質量%以下
とすることを特徴とする自己乳化組成物の製造方法。
(3-2)自己乳化組成物の全量を100質量%としたとき
a)70ないし90質量%のω3PUFA、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物、
b)0.5~6質量%の水、
c)1~29質量%のポリオキシエチレンソルビタン脂肪酸エステルである乳化剤、および
d)ω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物100質量部に対して、3ないし40質量部のレシチン
を任意の順序で混合し、得られる組成物中の
e)エタノールが前記組成物全量の4質量%以下、
f)多価アルコールが前記組成物全量の4質量%以下、
とすることを特徴とする自己乳化組成物の製造方法。
(3-3)前記工程のa)、b)および/またはc)を70℃以上に加温して混合する工程を含む、(3-1)または(3-2)に記載の自己乳化組成物の製造方法。
(4-1)前記(1-1)ないし(1-40)、(2-1)ないし(2-7)、のいずれかに記載の自己乳化組成物またはカプセル化された自己乳化製剤、医薬または獣医薬を、空腹時または就寝前に経口投与するための製剤。
(4-2)前記(3-1)ないし(3-3)、のいずれかに記載の製造方法で製造した自己乳化組成物またはカプセル化された自己乳化製剤、医薬または獣医薬を、空腹時または就寝前に経口投与するための製剤。
(4-3)医薬が脂質異常症(高コレステロール血症、高LDLコレステロール血症、高非HDLコレステロール血症、高VLDLコレステロール血症、低HDLコレステロール血症、高TG血症、高ApoB血症、低ApoAI血症、等)治療剤、食後高TG血症治療剤、抗動脈硬化剤、血小板凝集抑制剤、末梢循環不全治療剤、心血管イベント発症予防剤、炎症性疾患(NAFLD、NASH、等)治療剤、抗癌剤および中枢性疾患(欝病、欝状態、強迫性障害、社会不安障害、パニック障害、等)予防剤、治療剤、進行防止剤からなる群から選択される少なくとも1つである(4-1)または(4-2)に記載の製剤。
(4-4)1日1回投与する前記(4-1)ないし(4-3)に記載の製剤。(4-5)前記(4-1)ないし(4-4)に記載の製剤の投薬および/または使用方法。
(4-6)前記(4-1)ないし(4-4)に記載の経口投与により血漿中のω3PUFA濃度を上げる方法。
(5-1)前記(1-1)ないし(1-40)、(2-1)ないし(2-7)、(3-1)ないし(3-3)から選択される少なくとも1つの自己乳化組成物またはカプセル化された自己乳化製剤、医薬または獣医薬を患者に経口投与することを特徴とする、脂質異常症(高コレステロール血症、高LDLコレステロール血症、高非HDLコレステロール血症、高VLDLコレステロール血症、低HDLコレステロール血症、高TG血症、高ApoB血症、低ApoAI血症、等)、食後高TG血症、抗動脈硬化、血小板凝集亢進、末梢循環不全、心血管イベント発症、炎症性疾患(NAFLD、NASH、等)、認知症(アルツハイマー型認知症、脳血管性認知症、混合型認知症、等)、癌および中枢性疾患(欝病、欝状態、強迫性障害、社会不安障害、パニック障害、等)からなる群から選ばれる少なくとも1つの疾患の予防、進行防止および治療方法である。
(5-2)前記自己乳化組成物またはカプセル化された自己乳化製剤、医薬または獣医薬を、空腹時または就寝前に経口投与する前記(5-1)に記載の方法。
(5-3)前記自己乳化組成物またはカプセル化された自己乳化製剤、医薬または獣医薬を、1日1回投与する前記(5-1)または(5-2)に記載の方法。
(6-1)雄性ビーグル犬に18時間以上絶食条件下でω3PUFA、その製薬学上許容しうる塩、および、そのエステルからなる群から選ばれる少なくとも1つの化合物として600mgの量となる自己乳化組成物を経口投与し、投与前の血中ω3濃度を減じた補正を行なって算出した、ω3PUFA血中濃度最大値が50μg/mL以上および/または投与0から2時間までのω3PUFA血中濃度曲線下面積が30μg/mL・hr以上、ω3PUFA血中濃度最大値が50μg/mL以上および/または投与0から2時間までのω3PUFA血中濃度曲線下面積が50μg/mL・hr以上、ω3PUFA血中濃度最大値が60μg/mL以上および/または投与0から2時間までのω3PUFA血中濃度曲線下面積が60μg/mL・hr以上、またはω3PUFA血中濃度最大値が70μg/mL以上および/または投与0から2時間までのω3PUFA血中濃度曲線下面積が70μg/mL・hr以上、とする自己乳化組成物。
(6-2)雄性カニクイザルに12時間以上絶食条件下でω3PUFA、その製薬学上許容しうる塩、および、そのエステルからなる群から選ばれる少なくとも1つの化合物として体重1kgあたり45mgとなる自己乳化組成物を経口投与し、投与前の血中ω3濃度を減じた補正を行なって算出した、ω3PUFA血中濃度最大値が50μg/mL以上および/または投与0から12時間までのω3PUFA血中濃度曲線下面積が400μg/mL・hr以上、またはω3PUFA血中濃度最大値が70μg/mL以上および/または投与0から12時間までのω3PUFA血中濃度曲線下面積が500μg/mL・hr以上である自己乳化組成物。
(6-3)ヒトにω3PUFA、その製薬学上許容しうる塩、および、そのエステルからなる群から選ばれる少なくとも1つの化合物として1800mgの量となる自己乳化組成物を食前に経口投与し、投与前の血中ω3濃度を減じた補正を行なって算出した、ω3PUFA血中濃度最大値が50μg/mL以上および/または投与2時間後のω3PUFA血中濃度が10μg/mL以上である自己乳化組成物。
(6-4)ヒトにω3PUFA、その製薬学上許容しうる塩、および、そのエステルからなる群から選ばれる少なくとも1つの化合物として1800mgの量となる自己乳化組成物を食前に経口投与し、投与前の血中ω3濃度を減じた補正を行なって算出した、ω3PUFA血中濃度最大値が10μg/mL以上および/または投与0から72時間までのω3PUFA血中濃度曲線下面積が250μg/mL・hr以上である自己乳化組成物。
そして、組成物中に水を含むことでエタノールや多価アルコールの含量を低くする、あるいはこれらを含まないと出来るため、カプセル皮膜の軟化を防止し、カプセルの変形が生じない。
また、相溶性(外観)、自己乳化性、組成物分散性、乳化安定性および吸収性の少なくとも1つに優れ、食前投与や低脂肪食摂取後の投与でも速やかに吸収されて食後の血清TG増加を抑制する、あるいは就寝前投与によりリパーゼ阻害剤服用時の必須脂肪酸欠乏を予防する。
さらに、上述の組成により、室温での保存に加え、低温(例えば5℃)や高温(例えば40℃)の条件下でも組成物が分離、白濁することなく、外観が良好である。
本発明の自己乳化組成物は上記の好ましい性質を少なくとも1つ以上、好ましくは2つ以上備え、さらに好ましくは全ての性質を備える。
本発明は、ω3PUFA、その製薬学上許容しうる塩およびそのエステルからなる群から選択される少なくとも1つの化合物の合計量が70ないし90質量%の範囲であり、特定の乳化剤を1ないし29質量%の範囲で含有し、ω3PUFA、その製薬学上許容しうる塩およびそのエステル100質量部に対して3ないし40質量部のレシチンを含有し、エタノールや多価アルコールが非添加または添加濃度が低い自己乳化組成物やそれを内容物としてカプセル化された自己乳化製剤、その医薬、その製法およびその使用方法である。
例えば、EPA-EとDHA-Eを用いる場合、EPA-Eの本剤組成物の純度が上記であれば、EPA-E/DHA-Eの組成比および全脂肪酸類中のEPA-E+DHA-Eの含量比は特に問わないが、好ましい組成比として、EPA-E/DHA-Eは、0.8以上であることが好ましく、更に好ましくは、1.0以上、より好ましくは、1.2以上である。
また、本剤組成物はリノール酸、γリノレン酸、ジホモ-γ-リノレン酸などのω3PUFA類以外の多価不飽和脂肪酸、それらの製薬学上許容される塩またはエステルを含んでいても良いが、アラキドン酸およびそれらの製薬学上許容される塩またはエステル含量は少ないことが望まれ、2質量%未満が好ましく、1質量%未満がさらに好ましく、アラキドン酸およびそれらの製薬学上許容される塩またはエステルを実質的に含まない態様がとくに好ましい。
ω3PUFA類として、精製魚油も使用できる。また、ω3PUFA類のモノグリセリド、ジグリセリド、TG誘導体またはこれらの組合せなども好ましい態様の一つである。例えばインクロメガ(lncromega)F2250、F2628、E2251、F2573、TG2162、TG2779、TG2928、TG3525およびE5015(クローダ インターナショナル ピーエルシー (Croda International PLC, Yorkshire, England))、および EPAX6000FA、EPAX5000TG、EPAX4510TG、EPAX2050TG、EPAX7010EE、K85TG、K85EEおよびK80EE(プロノバ バイオファーマ(Pronova Biopharma, Lysaker, Norway) )などの種々のω3PUFA類を含有する製品が市販されており、これらを入手して使用することもできる。
また、これらのうちの1種を単独で、あるいは2種以上を組み合わせて用いることもできる。本発明においてポリオキシエチレンソルビタン脂肪酸エステルとは上記のような化合物をすべて含む意味で用いられる。
本発明の自己乳化組成物におけるポリオキシエチレンソルビタン脂肪酸エステルの含量は本発明の効果を有すれば特に限定されないが、通常、自己乳化組成物の全量を100質量%としたとき、1ないし29質量%であり、好ましくは3ないし20質量%、より好ましくは5ないし15質量%、とりわけ好ましくは5ないし9質量%である。
本発明の自己乳化組成物におけるポリオキシエチレンヒマシ油の含量は本発明の効果を有すれば特に限定されないが、通常、自己乳化組成物の全量を100質量%としたとき、1ないし20質量%であり、好ましくは2ないし15質量%、より好ましくは3ないし10質量%、とりわけ好ましくは5ないし9質量%である。また、組成物中のポリオキシエチレンソルビタン脂肪酸エステル100質量部に対し、ポリオキシエチレンヒマシ油が150質量部以下、好ましくは140質量部以下、より好ましくは130質量部以下、さらに好ましくは120質量部以下、とりわけ好ましくは110質量部以下、最も好ましくは100質量部以下となる割合で含ませることが好適である。また、組成物中のポリオキシエチレンソルビタン脂肪酸エステルとポリオキシエチレンヒマシ油の量比が100質量部:5ないし150質量部、好ましくは100質量部:10ないし140質量部以下、より好ましくは100質量部:20~130質量部以下、さらに好ましくは30~120質量部、とりわけ好ましくは100質量部:50ないし110質量部、最も好ましくは100質量部:80ないし120質量部となる割合で含ませることが好適である。
本発明の自己乳化組成物におけるポリオキシエチレン硬化ヒマシ油の含量は本発明の効果を有すれば特に限定されないが、通常、自己乳化組成物の全量を100質量%としたとき、1ないし20質量%であり、好ましくは2ないし15質量%、より好ましくは3ないし10質量%、とりわけ好ましくは5ないし9質量%である。また、組成物中のポリオキシエチレンソルビタン脂肪酸エステル100質量部に対し、ポリオキシエチレン硬化ヒマシ油が150質量部以下、好ましくは140質量部以下、より好ましくは130質量部以下、さらに好ましくは120質量部以下、とりわけ好ましくは110質量部以下、最も好ましくは100質量部以下となる割合で含ませることが好適である。また、組成物中のポリオキシエチレンソルビタン脂肪酸エステルとポリオキシエチレンヒマシ油の量比が100質量部:5ないし150質量部、好ましくは100質量部:10ないし140質量部以下、より好ましくは100質量部:20ないし130質量部以下、さらに好ましくは30ないし120質量部、とりわけ好ましくは100質量部:50ないし110質量部、最も好ましくは100質量部:80ないし120質量部となる割合で含ませることが好適である。
少量の水は、自己乳化組成物の調製時に加えてもよく、ゼラチンカプセル等にカプセル化した時にゼラチン皮膜中の水分が自己乳化組成物に移行してもよい。
また、多価アルコールやエタノールを含まないと、カプセル化した場合にカプセルが軟化、変形せず、アルコール不耐性患者の服用時にエタノールによる副作用もない。
水は自己乳化組成物の全量を100質量%としたとき、0.5~6質量%であることが好ましく、0.5~4質量%がより好ましく、0.5~3質量%がさらに好ましい。最も好ましくは1~3質量%である。または、0.5質量%以上3質量%未満が好ましく、0.5質量%以上1.5質量%未満がより好ましい。
精製大豆レシチン(日清オイリオ)、精製卵黄レシチン(旭化成ファーマ)、卵黄レシチンPL-100M(キューピー)などの種々の製品が市販されている。大豆レシチンは、例えば、ベイシスLP-20B(日清製油)、Lipoid S45、S20(リポイド)などが、酵素分解レシチンは例えばベイシスLP-20E(日清製油)、Phospholipon RLPC20(リポイド)などの種々の製品が市販されており、これらを入手して使用することもできる。
レシチンは自己乳化組成物の全量を100質量%としたとき、2.1~36質量%であることが好ましく、2.1~20質量%がより好ましく、2.1~15質量%がさらに好ましい。最も好ましくは2.1~10質量%である。
レシチンは自己乳化組成物における乳化剤の合計含量を100質量部としたとき、10~75質量部であることが好ましく、11~60質量部がより好ましく、20~55質量部がさらに好ましい。最も好ましくは25~35質量部である。 レシチンは自己乳化組成物におけるポリオキシエチレンソルビタン脂肪酸エステルの合計含量を100質量部としたとき、10~150質量部であることが好ましく、20~120質量部がより好ましく、40~90質量部がさらに好ましい。最も好ましくは50~70質量部である。
また、自己乳化組成物にエタノールと多価アルコールが含まれる場合には、組成物全体を100質量%としたとき、組成物中に合計含量として4質量%より多いエタノール及び多価アルコールを含まないことが好ましい。好ましい態様としてはエタノール及び多価アルコールを実質的に含まない。また、組成中のエタノール及び多価アルコールの合計量が4質量%以下が好ましく、3質量%以下がより好ましく、2質量%以下がさらに好ましく、1質量%以下がとりわけ好ましい。最も好ましいのは0質量%以下である。
「ゼラチン」としては、軟カプセル剤の製造において通常使用されるもの、例えば、第16改正日本薬局方で規定される医薬用ゼラチン(ゼラチンおよび精製ゼラチン)が挙げられる。ゼラチンは、2種以上を組合せて用いてもよい。カプセル皮膜はその他に可塑剤等を含有しうる。
カプセル皮膜に配合する「可塑剤」としては、軟カプセル剤の製造において通常使用されるもの、例えば、グリセリン(例、濃グリセリン)、エチレングリコール、ポリエチレングリコール、プロピレングリコール、ポリプロピレングリコール等の多価アルコール、ソルビトール、マンニトール、キシリトール等の糖アルコールなどが好ましい。これらの可塑剤は、2種以上を組合せて用いてもよい。中でも、グリセリン、ソルビトールが好ましい。また、グリセリンとソルビトールとの組み合わせを使用することも好ましい。この場合、グリセリンとソルビトールとの質量比を、1:5~5:1の範囲で使用することが好ましく、1:3~3:1の範囲で使用することがより好ましい。
本発明の軟カプセル剤、特にシームレスカプセルにおいて、カプセル皮膜液は、ゼラチンと可塑剤とを、その重量比において、10:1~1:10の範囲で含有することが好ましく、10:1~1:1の範囲で含有することがより好ましい。
カプセル皮膜液とカプセル内容物との重量比は、通常10:1~1:10で、好ましくは3:1~1:10である。
さらに、必要に応じて、カプセル皮膜に一般に用いられる各種添加剤、例えば、アミノ酸、クエン酸、グリセリン、ソルビトール、トレハロース、等の可塑剤、防腐剤、色素や酸化チタン等の着色剤、有機酸等を添加することができる。
本発明のカプセル化された自己乳化製剤は、製造直後の硬度が18kgf以上、好ましくは20kgf以上、より好ましくは22kgf以上である。また、密封されたアルミ包装で40℃1週間保管した場合に製造直後と比較して硬度が実質的に低下しない、あるいは硬度が6kgf以上低下しないことが望ましく、40℃1週間の保管後の硬度が10kgf以上、好ましくは15kgf以上、より好ましくは20kgf以上である。
また、製造直後の硬度を100%とした時、密封されたアルミ包装で40℃1週間保管した場合の硬度が60%以上、好ましくは70%以上、より好ましくは80%以上維持される。さらに好ましくは85%以上、とりわけ好ましくは90%以上の硬度が維持される。
上記の薬物動態は、イヌやサル等の動物で確認することができるが、好ましくは、ヒトでの試験により確認される。
保存温度は、自己乳化組成物やこれらのカプセル化された製剤が寒冷地や高温環境で扱われる可能性を考慮し、低温・高温時にも外観が澄明であることが好ましい。
また、前記疾患のうち、特に、脂質異常症、食後高TG血症の改善または治療、再発予防あるいはメタボリックシンドロームや心・脳血管イベントや四肢末梢潰瘍や壊疽などへの進行抑制に有効である。哺乳動物とは、例えば、ヒトやウシ、ウマ、ブタなどの家畜動物やイヌ、ネコ、ウサギ、ラット、マウスなどの家庭用動物等があげられ、好ましくはヒトである。特に、メタボリックシンドローム患者など、血中脂質が増加している、インスリン抵抗性を発現している、あるいは血圧が上昇している脂質異常症患者において脂質異常症や食後高TG血症の改善または治療効果を示すことが期待される。
水0.09g、ポリオキシエチレン(20)ソルビタンオレイン酸エステル0.53g、大豆レシチン0.39g、EPA-E 4.0gを量り取り、密封し、約70℃に加温しながら混合し、自己乳化組成物を調製した。自己乳化組成物は窒素置換して密封し、評価を実施するまで室温にて保存した。表1に自己乳化組成物の処方を示す。
表1に記載の組成比となる様に、実施例1と同様の方法で実施例2~8の自己乳化組成物および比較例1~2の組成物を調製及び保存した。表1に自己乳化組成物および組成物の処方を示す。
表1に記載の組成比となる様に、実施例1と同様の方法で比較例3の組成物を調製および保存した。表1に組成物の処方を示す。
上記の製造方法にて自己乳化組成物および比較例の組成物を製造後、静置し、約1時間後外観を評価した。相溶性に優れ、組成物が均一となっている場合には「澄明」、分離している場合には「分離」、不透明である場合には「曇り」とした。
表1に試験結果を示す。
上記の製造方法にて製造した自己乳化組成物および比較例の組成物について、試験管内の37℃の精製水および日局溶出試験第1液、各5mLに各組成物を10μL滴下し、自己乳化性について評価した。滴下しただけで乳化した場合を良好とし、滴下しただけでは自然に乳化しなかった場合を不良とした。次いで、均一条件にて軽く撹拌した後、その性状を評価した。組成物分散性について、組成物が分散した場合を良好とし、組成物の一部が分散しないで塊として残った場合を不良とした。乳化安定性について、油の分離がなかった場合を良好とし、油の分離があった場合を不良とした。なお、外観の評価で「澄明」でなかった組成物は、組成が均一でないことから評価は妥当でないと考えられ、評価を行わなかった。
表1に試験結果を示す。
上記試験例2で得られた乳化組成物約1.5mLを用いて、粒度分布測定装置(Nanotorac、日機装製)により、分散媒として水を使用し、平均乳化滴径(体積平均径)を測定した。
試験例1にて「澄明」または「曇り」であった組成物について、5℃あるいは40℃で静置して一晩(約12時間)保管後、外観を評価した。相溶性に優れ、組成物が均一となっている場合には「澄明」、分離している場合には「分離」、不透明である場合には「曇り」とした。
表1に試験結果を示す。
製造した組成物あるいはカプセルを各々雄性ビーグル犬(2~6年齢、体重8~13kg、マーシャルビーグル3例、ノーサンビーグル3例)6例に絶食条件下で経口投与し、EPAの血中濃度の推移を評価した。なお、各被験動物は投与の18時間以上前より絶食とし、各動物にはEPA-Eとして600mgとなる量の組成物を投与した。投与前、投与後0.5、1、1.5、2、3、4、6、8および24時間に採血を行い、血漿を分取して処理を行った後、血漿中のEPA濃度をLC/MS/MS(サンプルを液体クロマトグラフィーで分離し、それを質量分析で分離して測定する方法)により測定した。また、対照群としてカプセルに充填したEPA-E原液も投与した。
表1には試験結果より算出した血中濃度最大値(Cmax)、0時間から2時間までの血中濃度曲線下面積(AUC0-2)、0時間から24時間までの血中濃度曲線下面積(AUC0-24)を示す。なお、各パラメーターの算出の際には各血中濃度より投与前の血中EPA濃度を減じた補正を行っている。
実施例14の組成物をカニクイザル(2~5歳、体重2.70~4.65Kg、ハムリー)6例に絶食条件下で経口投与し、EPAの血中濃度の推移を評価する。なお、各被験動物は投与の12時間以上前より絶食とし、各動物にはEPA-Eとして45mg/kgとなる量の自己乳化組成物を投与する。また、対照群としてカプセルに充填したEPA-E原液を投与する。投与前、投与後1、2、4、6、8、10、12、24、48および72時間に採血を行い、血漿を分取して処理を行った後、血漿中のEPAをLC/MS/MSにより測定する。試験結果より血中濃度最大値(Cmax)、0時間から12時間までの血中濃度曲線下面積(AUC0-12)、0時間から72時間までの血中濃度曲線下面積(AUC0-72)を算出する。なお、各パラメーターの算出の際には各血中濃度より投与前の血中EPA濃度を減じた補正を行なう。
実施例14の組成物を投与した動物は、対照群と比較して、CmaxおよびAUC0-12等の血中濃度パラメーターの上昇を認める。すなわち、実施例14の自己乳化組成物を投与した場合、吸収量が増加するのみならず、経口投与後速やかにEPAが吸収されることが確認される。
実施例で得られた各軟カプセルについて、充てん、乾燥終了後、カプセルの色、形状および充てん液の性状について目視にて確認した。
色については変色が認められるもの、形状については歪みや凹み等が認められるもの、充てん液の性状については濁りや分離等が認められるものをそれぞれ不良とし、いずれも認められないものを正常とした。
表1に試験結果を示す。下記表中「―」の記載は、該当成分を添加せず、または測定せずを示す。
本発明は組成物の相溶性を良好にするためにエタノールや多価アルコールを含まず、水を使用した。水を含まない場合には組成物が相溶性を充分に有しないため分離した。また、水を含む処方であってもその量が組成物に対して多すぎても同様に分離した。水が1ないし4質量%の実施例1~6では分離しなかった。これより、0.5ないし6質量%程度の特定の量の水を含むことが外観等に優れるために重要であると分かる。
しかしながら、40℃で一晩保管すると分離した。これより、0.5ないし6質量%程度の特定の量の水を含むことが外観等に優れるために重要であると分かる。
これより乳化剤としてポリオキシエチレンソルビタン脂肪酸エステルを含有することが外観に優れるために重要であると分かる。
これらの自己乳化組成物を投与した動物では対照群(絶食時)を投与した動物よりも吸収速度のパラメーターであるCmaxおよびAUC0-2値が著しく高かった。すなわち、実施例の自己乳化組成物を投与した場合、対照群に比べて経口投与24時間後までのEPA吸収量が増加するのみならず、特に経口投与後速やかにEPAが吸収されることが確認された。従って、本発明の自己乳化組成物は、食前や就寝前などの空腹時に服用した場合でも血中EPA濃度が速やかに、かつより上昇し、その薬理作用を速やかに、かつより効果的に発揮する自己乳化型製剤として使用し得ることが期待される。
表2に記載の組成となる様に、実施例1と同様の方法で自己乳化組成物および比較例2-3の組成物を調製し保存した。表2に自己乳化組成物の処方を示す。
この自己乳化組成物を実施例2-1および2-2については375mg、比較例2-3については441mg(いずれも、EPA-Eとして300mg)それぞれ充てんしたソフトゼラチンカプセルを、ロータリー法により製造した。本法により製造した自己乳化型カプセル製剤は、カプセル皮膜の変形等は認められなかった。
表2に内容液の組成を示す。
実施例2-1および2-2、比較例2-3の各カプセル製剤について、硬度を測定した。また、40℃相対湿度75%で1、2、4週間保管した製剤について、同様に硬度を測定した。
各製剤を初期、40℃ 1、2、4週間保管した場合の結果を表2に示す。なお、初期とはカプセルの製造後、評価するまで室温で保管した製剤をいう。また、各製剤はアルミ包装に密封して40℃に保管したため、湿度の影響は受けていない。
本発明の自己乳化組成物は、多価アルコール非添加または添加濃度が低いため、流通過程や保存中における多価アルコールが原因のカプセル軟化、変形が起こらず、品質変化のリスクが低い。
また、低温又は高温環境下の保存でも組成物が白濁、分離等の変性のないことから、医薬として用いられる場合に寒冷地や高温地での保管可能な品質を有する。
Claims (9)
- 自己乳化組成物の全量を100質量%としたとき、
a)70~90質量%のω3PUFA、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物、
b)0.5~6質量%の水
c)1~29質量%のポリオキシエチレンソルビタン脂肪酸エステルである乳化剤
d)ω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステル100質量部に対して、3~25質量部のレシチン、
を含有し、
e)エタノールが前記組成物全量の4質量%以下、
f)多価アルコールが前記組成物全量の4質量%以下、であることを特徴とする自己乳化組成物。 - 前記乳化剤がさらにポリオキシエチレン硬化ヒマシ油および/またはポリオキシエチレンヒマシ油を含む請求項1に記載の自己乳化組成物。
- 前記乳化剤がポリオキシエチレンソルビタン脂肪酸エステルおよびポリオキシエチレンヒマシ油を含む請求項1に記載の自己乳化組成物。
- 前記多価アルコールがプロピレングリコールまたはグリセリンである請求項1ないし3のいずれか1項に記載の自己乳化組成物。
- エタノールが前記組成物全量の1質量%以下である請求項1ないし4のいずれか1項に記載の自己乳化組成物。
- 多価アルコールが前記組成物全量の1質量%以下である請求項1ないし5のいずれか1項に記載の自己乳化組成物。
- 自己乳化組成物の全量を100質量%としたとき、
a)70ないし90質量%のω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物、
b)0.5~6質量%の水、
c)5~24質量%のポリオキシエチレンソルビタン脂肪酸エステルおよびポリオキシエチレンヒマシ油である乳化剤、
d)ω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステル100質量部に対して、3~40質量部のレシチンを含有し、
e)前記ポリオキシエチレンソルビタン脂肪酸エステル100質量部に対して前記ポリオキシエチレンヒマシ油が120質量部以下、
f)エタノールが前記組成物全量の4質量%以下、
g)多価アルコールが前記組成物全量の4質量%以下、であることを特徴とする請求項1ないし6のいずれか1項に記載の自己乳化組成物。 - 自己乳化組成物の全量を100質量%としたとき、
a)70~90質量%のω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステルからなる群から選択される少なくとも1つの化合物、
b)0.5~6質量%の水、
c)1~29質量%のポリオキシエチレンソルビタン脂肪酸エステルである乳化剤、
d)ω3多価不飽和脂肪酸、その製薬学上許容しうる塩、およびそのエステルから選択される少なくとも1つの化合物100質量部に対して、3~40質量部のレシチンを含有し、
e)エタノールおよび/または多価アルコールが組成物全量の4質量%以下、である自己乳化組成物を内溶液としてカプセル中に保持するカプセル化された自己乳化製剤であって、
硬カプセルおよび/または軟カプセルでカプセル化されている自己乳化製剤。 - 前記軟カプセルのカプセル皮膜がゼラチンを含むことを特徴とする請求項8に記載のカプセル化された自己乳化製剤。
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JPWO2016117621A1 (ja) * | 2015-01-21 | 2017-10-26 | 持田製薬株式会社 | ω3脂肪酸の自己乳化組成物 |
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Also Published As
Publication number | Publication date |
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PH12016500100B1 (en) | 2016-04-18 |
CN111888343A (zh) | 2020-11-06 |
ES2841344T3 (es) | 2021-07-08 |
JP2022062147A (ja) | 2022-04-19 |
US20210128510A1 (en) | 2021-05-06 |
SG11201600337PA (en) | 2016-02-26 |
EP3023099B1 (en) | 2020-09-30 |
KR102275447B1 (ko) | 2021-07-08 |
SG10201800243XA (en) | 2018-02-27 |
CN105530927A (zh) | 2016-04-27 |
PH12016500100A1 (en) | 2016-04-18 |
CN110840874A (zh) | 2020-02-28 |
US20160158184A1 (en) | 2016-06-09 |
CA2918330A1 (en) | 2015-01-22 |
JPWO2015008848A1 (ja) | 2017-03-02 |
JP2020011958A (ja) | 2020-01-23 |
KR20160032120A (ko) | 2016-03-23 |
EP3023099A4 (en) | 2017-01-04 |
EP3023099A1 (en) | 2016-05-25 |
JP2024028839A (ja) | 2024-03-05 |
EP3763364A1 (en) | 2021-01-13 |
CA2918330C (en) | 2022-08-30 |
MY187003A (en) | 2021-08-26 |
HK1222551A1 (zh) | 2017-07-07 |
CN111939125A (zh) | 2020-11-17 |
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