JP5997887B2 - Oral administration - Google Patents

Description

  The present invention relates to an oral administration agent containing 1-alkyl ether type phospholipid as an active ingredient, and food and drink. The oral administration agent and food and drink of the present invention have good storage stability. According to the present invention, the amount of plasmalogen in a living body can be increased by ingestion.

Plasmalogen is a subclass of glycerophospholipid having a hydrocarbon chain with a vinyl ether bond at the sn-1 position and a fatty acid bonded at the sn-2 position, and is also referred to as an alkenylacyl phospholipid. In animals, it is relatively abundant in the brain, heart and spleen. The polar groups are mostly ethanolamine and choline, and it is known that the human at the sn-2 position is rich in polyunsaturated fatty acids such as arachidonic acid and docosahexaenoic acid.
The function of plasmalogens is still unclear, but in cases of peroxisomes with disorders in the plasmalogen synthesis site, peroxisomes, various symptoms such as mental retardation are observed. It is speculated that it plays an important role in maintaining the functions of cells and living bodies.
Even without this congenital abnormality, plasmalogens in blood or lymph decrease with age, brain plasmalogens decrease in Alzheimer's disease patients, and plasmalogens have LDL cholesterol levels. It is becoming clear that plasmalogens are related to diseases involving aging and oxidative stress, such as suppressing oxidation (Non-Patent Document 1 and Non-Patent Document 2).

In other words, it is thought that a decrease in plasmalogens in the body causes various diseases. Therefore, since increasing the amount of plasmalogens in a living body seems to be effective for the improvement and prevention of various diseases, a method for increasing plasmalogens in blood or lymph has been demanded.
In particular, since foods and drinks and oral medicines can be ingested continuously and easily, plasmalogen increasing agents that can increase the plasmalogen content in blood or lymph by ingestion have been proposed.

For example, alkylglycerol (Non-patent Document 3 and Patent Document 1) and plasmalogen-rich bovine brain phospholipid (Non-patent Document 4) are known to have an effect of increasing plasmalogens in vivo. Inositol (patent document 2), choline-type plasmalogen (patent document 3), linear monounsaturated fatty acid compound having 16 or more carbon atoms (patent document 4), and the like are disclosed.
However, the increase in plasmalogens due to ingestion of alkylglycerol, inositol, and straight-chain monounsaturated fatty acid compounds having 16 or more carbon atoms was as weak as about 1.5 times. In addition, ingestion of bovine brain phospholipid increases plasmalogen and choline-type plasmalogen several times, but these are poor in flavor and difficult to add in large quantities to foods and drinks. Therefore, the low storage stability of foods and drinks stored for a long time, particularly foods and drinks stored at room temperature, has been a problem.

US Pat. No. 6,177,476 JP 2007-51132 A JP 2009-269865 A JP 2009-062364 A

“Oleoscience 2002, (Japan) Volume 2, pages 27-36. “Oleoscience 2005, (Japan) Vol. 5, p.405-415. “Lipids”, 1991, (USA) Vol. 26, p. 166-169 “Lipids” 2003, (USA) vol. 38, p. 1227-1235

  Accordingly, the object of the present invention is to improve the amount of plasmalogens in the body in order to prevent or ameliorate diseases involving oxidative stress such as cancer, arteriosclerosis, Alzheimer's disease, etc. An object of the present invention is to provide an orally-administered agent that can be increased.

In the process of repeatedly studying the components constituting plasmalogen and its action, the present inventors have only studied the acyl moiety constituting plasmalogen and the base moiety bound to phosphoric acid, A prototype of a composition in which a part of its basic skeleton was modified instead of plasmalogen was compared and examined, and it was found that the above problem could be solved when the binding group at a specific site was modified. I found it.
That is, phospholipids can be divided into subclasses of diacyl phospholipids, alkenyl acyl phospholipids (plasmalogens), and 1-alkyl ether phospholipids (alkyl phospholipids). The diacyl phospholipid is a phospholipid having an ester bond at the sn-1 position and the sn-2 position. Plasmalogen is a phospholipid having a fatty acid residue having a vinyl ether bond at the sn-1 position and an acyl bond at the sn-2 position, and has ethanolamine or choline as a polar group. The 1-alkyl ether type phospholipid is a phospholipid having an ether bond and an alkyl group at the sn-1 position. Accordingly, diacyl phospholipids, plasmalogens, and 1-alkyl ether phospholipids have different basic skeletons.
Patent Document 3 or Non-Patent Document 4 discloses that plasmalogens in vivo are increased by bovine brain phospholipids rich in choline-type plasmalogen or plasmalogen among the phospholipids. On the other hand, the present inventors have found that plasmalogens increase in vivo by administering 1-alkyl ether type phospholipids whose basic skeleton is different from plasmalogens.
The present invention is based on the above-mentioned findings, and effectively increases plasmalogens in blood or lymph by using 1-alkyl ether type phospholipid as an active ingredient, preferably in the form of a pharmaceutical composition or food or drink. It is intended to provide an orally administrable agent.
Therefore, the present invention relates to an oral administration agent characterized by containing 1-alkyl ether type phospholipid as an active ingredient.
Moreover, this invention relates to the food-drinks characterized by including 1-alkyl ether type phospholipid as an active ingredient.

The oral administration agent of the present invention contains 1-alkyl ether type phospholipid as an active ingredient, has good flavor and storage stability, and can increase plasmalogen content in blood and lymph by ingestion. Is possible. Therefore, the oral administration agent of the present invention can be used as a plasmalogen increasing agent with good storage stability. Moreover, the pharmaceutical composition containing the orally administered agent of the present invention can effectively prevent or treat diseases that can be prevented or treated by increasing plasmalogens.
Furthermore, the food and drink according to the present invention contains a 1-alkyl ether type phospholipid, so that it has good flavor and storage stability, and increases the plasmalogen content in phospholipids in the living body, particularly in lymph and blood. It is possible. Therefore, it is useful for the prevention or treatment of diseases caused by a decrease or disappearance of plasmalogen content in blood or lymph by simply ingesting food and drink.

［式中、Ｒ^１は、炭素数１から２１の炭化水素基であり、Ｒ^２は、炭素数１〜２６の脂肪酸残基、または水素原子であり、Ｒ^３はコリン（−ＣＨ_２ＣＨ_２Ｎ（ＣＨ_３）_３）、エタノールアミン（−ＣＨ_２ＣＨ_２ＮＨ_２）、セリン（−ＣＨ_２−ＣＨ（ＮＨ_２）−ＣＯＯＨ）、グリセロール（−ＣＨ_２−ＣＨ（ＯＨ）−ＣＨ_２ＯＨ）、イノシトール（−ＣＨ−Ｃ_５Ｈ_５（ＯＨ）_５）、又は水素原子である］
で表される１−アルキルエーテル型リン脂質を有効成分として含む。
ここで、ｓｎ−１位がエステル結合であるリン脂質、例えば一般的なジアシル型リン脂質（すなわち「レシチン」）や、前記レシチンをホスホリパーゼ等で処理したリゾリン脂質を有効成分として用いた場合は本発明の効果は得られない。 [1] Oral administration agent (1-alkyl ether type phospholipid)
The oral administration agent of the present invention has the general formula (I)

[Wherein, R ¹ is a hydrocarbon group having 1 to 21 carbon atoms, R ² is a fatty acid residue having 1 to 26 carbon atoms, or a hydrogen atom, and R ³ is choline (—CH ₂ CH ₂ N (CH ₃ ) ₃ ), ethanolamine (—CH ₂ CH ₂ NH ₂ ), serine (—CH ₂ —CH (NH ₂ ) —COOH), glycerol (—CH ₂ —CH (OH) —CH ₂ OH) , Inositol (—CH—C ₅ H ₅ (OH) ₅ ), or a hydrogen atom]
The 1-alkyl ether type phospholipid represented by these is included as an active ingredient.
Here, when an active ingredient is a phospholipid having an ester bond at the sn-1 position, such as a general diacyl phospholipid (ie, “lecithin”), or a lysophospholipid obtained by treating the lecithin with phospholipase or the like as an active ingredient. The effect of the invention cannot be obtained.

The hydrocarbon group for R ¹ may be an alkyl group or an alkenyl group, and specific examples include a pentadecyl group, a heptadecyl group, and a heptadecyl group. In the present specification, the “sn-1 position fatty acid residue” means a fatty acid obtained by removing a carboxyl group (—COOH), and specifically, R ^{1 of} formula (1) and ether. This means “—CH ² —R ¹ ” containing carbon of the group, and is expressed as 16: 0, 18: 0, or 18: 1 (carbon number: unsaturated bond number).
Specific examples of the fatty acid residue of R ² include a palmitoyl group, an oleyl group, an arachidoyl group, and a docosahexaenoyl group. In the present specification, the “sn-2 position fatty acid residue” means a fatty acid minus —OH, and is 16: 0, 18: 1, 20: 4, or 22: 6 (carbon Number: number of unsaturated bonds). Moreover, in this specification, the sn-2 position acyl group means a group obtained by removing a hydrogen atom (—H) of a carboxyl group from a fatty acid.

  The 1-alkyl ether type phospholipid used in the oral administration agent of the present invention has good storage stability compared to plasmalogens conventionally used in the treatment of diseases or foods, and is also useful from this viewpoint. It is.

(Chemical synthesis of 1-alkyl ether type phospholipids)
The 1-alkyl ether type phospholipid that can be used in the present invention can be chemically synthesized by converting glycerin to 1-alkyl ether glycerol and performing esterification or phosphorylation. -Alkyl ether type phospholipids can also be used, but those extracted and purified from natural products are preferred from the viewpoint of availability and productivity.

(Production raw material of 1-alkyl ether type phospholipid)
Examples of natural products for extracting and separating the 1-alkyl ether type phospholipids include various animals, plants, microorganisms such as tuna and sardines that are generally known to have a high 1-alkyl ether type phospholipid content. Individuals such as fish such as scallops, oysters, mussels, craniopods such as octopus and squid, crustaceans such as shrimp, barnacles, krill and calanus, and poultry animals such as cows, pigs and chickens, The muscle tissue, fat tissue, nerve tissue such as brain, visceral tissue such as intestine, and eggs thereof can be used. In particular, in the present invention, it is a natural product having a high 1-alkyl ether type phospholipid content and an extremely low plasmalogen content, and further, the living body itself can be directly extracted without separating the tissue. In addition to being rich in resources and easy to obtain, and further containing astaxanthin, it is possible to obtain an orally-administered drug with good storage stability. It is particularly preferable to use it.

Here, in the natural product as the extraction source, the content of 1-alkyl ether type phospholipid in the total amount of 1-alkyl ether type phospholipid and plasmalogen (that is, ether type phospholipid amount) is 50% or more. It is preferable to use a natural product, more preferably 80% or more, and still more preferably 95% or more. The natural product preferably contains as little plasmalogen as possible, preferably the plasmalogen ratio in the ether type phospholipid is preferably 50% or less, more preferably 20% or less, still more preferably 5%. Use natural products that are:
Here, when a natural product containing both 1-alkyl ether type phospholipid and plasmalogen is used as the natural product as an extraction source, is the plasmalogen removed beforehand by a method such as weak acid solution treatment? Alternatively, in addition to the following fractionation / concentration / purification operations, an operation for removing the plasmalogen is preferably performed.

(Extraction method of 1-alkyl ether type phospholipid)
In the oral administration agent of the present invention, 1-alkyl ether type phospholipid-containing lipids extracted from these various animals, plants, and microorganisms by solvent extraction and the like, and if necessary, liquid extraction from the lipids. Use phospholipid fractions, phospholipid fractions separated by column chromatography, enzyme treatment, etc., concentrates enriched with 1-alkyl ether type phospholipids, and further purified 1-alkyl ether type phospholipids can do.

  Extraction methods from tissues such as various animals, plants and microorganisms include Folch method (Folch et al .: J. Biol. Chem., 226, 497-505, 1957), Bligh & Dyer method (Bligh et al. : Can. J. Biochem. Physiol., 37, 911-917, 1959), or a method using a mixed solvent using hexane or lower alcohol, which is a highly safe organic solvent (Hara et al .: Anal. Biochem. , 90 (1): 420-6,1978, JP-A-2005-179340), and a method using a mixed solvent of hexane and ethanol that is highly safe and has excellent interface separation in liquid-liquid extraction (JP-A 2009- 227765). Moreover, in order to improve extraction efficiency, what dehydrated the said animal tissue may be used.

  In addition, as the separation method, acetone precipitation method (supervised by Tamio Yamakawa: Biochemistry Experiment Course 3, Lipid Chemistry (Japan Biochemical Society), p.19-20, 1963, Tokyo Kagaku Dojin), column chromatography method ( James et al .: Lipids, 23, 1146-1149, 1988) can be used to remove triglycerides and partial glycerides and to separate and purify only the phospholipid fraction containing 1-alkyl ether type phospholipid.

  Furthermore, as the concentration method, diacyl-type phospholipids by weak alkali treatment (Hanahan et al .: J. Biol. Chem. 236, 59-60, 1961), or treatment with mammalian pancreatic lipase or microorganism-derived phospholipase A1. 1-alkyl ether type phospholipids can be concentrated using the method of degradation of (Woelk et al .: Z Physiol. Chem. 354, 1265-70, 1973).

  When the phospholipase A1 is used for concentration, specifically, the phospholipase A1, preferably Actinomadura sp., Is added to the 1-alkyl ether type phospholipid-containing lipid. The resulting phospholipase A1 is added, and a decomposition reaction is preferably performed with a small amount of diethyl ether and a weakly acidic buffer. The decomposition product is re-regenerated with a mixed solvent of a hydrophilic solvent and a hydrophobic solvent, for example, a hexane / ethanol mixed solvent. It can be obtained by extraction.

More specifically, 1 g of 1-alkyl ether type phospholipid-containing lipid is added with 0.1 to 2.0 U of phospholipase A1, and 2 to 20%, preferably 5 to 10% of acetate buffer pH 5.0 to 6.0. Then, the decomposition reaction is carried out at 30 to 60 ° C. with stirring for 2 to 100 hours. Mixing the reaction solution with a mixed solvent of hexane / ethanol / water, for example, hexane 65-90, ethanol 5-20, water 4-10, preferably hexane 75-85, ethanol 10-18, water 5-8 By adding a solvent and performing re-extraction, the 1-lysophospholipid produced by the phospholipase A1 reaction can be separated into the lower aqueous layer, and the 1-alkyl ether type phospholipid can be separated into the upper hexane layer. Here, the 1-alkyl ether type phospholipid can be concentrated by separating the upper hexane layer and removing hexane by a conventional method.
In addition, it is preferable to fractionate and remove neutral lipids represented by triglycerides before or after concentration of the 1-alkyl ether type phospholipid, preferably after. As a method for removing the neutral lipid, a known method such as an acetone precipitation method or column chromatography can be employed.

  Furthermore, it is possible to concentrate by the kind of Sn-3 base by silica gel chromatography. For example, a column packed with silica gel with hexane / ethanol mixed solvent, preferably 95: 5 to 60:40, is packed with 1-alkyl ether type phospholipid-containing lipid or 1-alkyl ether type phospholipid-containing phospholipid. Then, 2 to 8 times the column volume of the same solvent is passed to elute the neutral lipid, and then a hexane / ethanol mixed solvent, preferably 5:95 to 0: 100, or a mixed solvent of ethanol / water, Preferably, ethanolamine type or phosphatidic acid type can be fractionated by passing 100: 0 to 95: 5 in an amount of 6 to 15 times the column volume, followed by ethanol / water mixed solvent, preferably Choline type can be fractionated by passing 90:10 to 70:30 through 8 to 20 times the column volume.

The 1-alkyl ether type phospholipid content in the oral administration agent of the present invention is preferably 2 to 100%, more preferably 5 to 100%, and still more preferably 50 to 100%.
The oral administration agent of the present invention can also contain phospholipids other than 1-alkyl ether type phospholipids, such as diacyl phospholipids, sphingophospholipids, plasmalogens, etc., but 1-alkyl with respect to the total amount of phospholipids. The ratio of the ether type phospholipid is 5% or more, preferably 50% or more of the 1-alkyl ether type phospholipid. As described above, it is preferable to contain as little plasmalogen having low oxidative stability as possible, preferably the ratio of plasmalogen to the total amount of phospholipid is preferably 10% or less, more preferably 5% or less, still more preferably. Is 3% or less.

(Other ingredients)
The oral administration agent of the present invention can contain other components other than those described above. Examples of the other components include edible fats and oils, partial glycerides, complex lipids other than phospholipids, water, glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, glycerin organic acid fatty acid esters, and polyglycerin fatty acids. Emulsifiers such as ester, calcium stearoyl lactate, sodium stearoyl lactate, polyoxyethylene sorbitan fatty acid ester, locust bean gum, carrageenan, alginic acid, pectin, xanthan gum, crystalline cellulose, carboxymethylcellulose, methylcellulose, agar, glucomannan, gelatin, starch, Thickeners such as modified starch, salty agents such as salt and potassium chloride, acidulants such as acetic acid, lactic acid and gluconic acid, sugars and sugar alcohols, stevia Food materials such as sweeteners such as partame, coloring agents such as beta-carotene, caramel, and red bean pigment, antioxidants such as tocopherol and tea extract, flavoring agents, pH adjusters, food preservatives, or shelf life improvers There may be mentioned food additives. It is also possible to contain functional materials such as various vitamins, coenzyme Q, plant sterols, and milk butterflies.
The total content of these other components is preferably 80% by mass or less, more preferably 40% by mass or less, and still more preferably 20% by mass or less in the oral dosage form of the present invention.
The oral administration agent of the present invention can be blended and added to a wide variety of foods and beverages and pharmaceuticals, and its intake is, in the case of an adult, 1-alkyl ether phospholipid per day, preferably 100 mg to It is desirable to take 40 g, more preferably 200 mg to 20 g.
The oral administration agent of the present invention is usually used orally, but can be directly administered to the stomach or duodenum using a catheter or the like for absorption from the digestive tract.

The kind of plasmalogen that increases in vivo by the oral administration agent of the present invention is not particularly limited. Specific examples include choline type plasmalogen, phosphatidic acid type plasmalogen, and ethanol type plasmalogen.
Plasmalogens are increased in vivo by the oral administration agent of the present invention. In the present specification, “in vivo” is not particularly limited. Specific examples include body fluids such as blood (including plasma and serum), spinal fluid, urine, saliva, or tissue fluid, or tissues or organs, but plasmalogens are present in all tissues in the body. Since it is carried and the effect is acquired, it is preferable to increase in the blood.

(Target disease)
The oral administration agent of the present invention can prevent or ameliorate diseases involving oxidative stress such as cancer, arteriosclerosis, diabetes, and Alzheimer's disease.

[2] Food and drink The food and drink of the present invention contains 1-alkyl ether type phospholipid as an active ingredient. Moreover, the food-drinks of this invention can also contain the oral administration agent which contains the said 1-alkyl ether type phospholipid as an active ingredient.
The content of 1-alkyl ether type phospholipid in the food or drink of the present invention varies depending on the food or drink used, but in the case of an adult, it is 100 mg to 40 g, more preferably 200 mg to 1 day as 1-alkyl ether type phospholipid. What is necessary is just to be able to contain the oral administration agent of the quantity which can be ingested 20g in food and drink. Specifically, it is preferable that it is 0.1-100 mass% in food-drinks.
The food and drink in the present invention is not particularly limited, and seasonings such as miso, soy sauce, noodle soup, sauce, dashi, pasta sauce, dressing, mayonnaise, tomato ketchup, Worcester sauce, tonkatsu sauce, or sprinkle , Soups such as soup, soup, carrot, white sauce, tea sauce, or soup, soups such as miso soup, soup, consommé soup or potage soup, livestock such as yakiniku, ham or sausage Processed products, kamaboko, dried fish, salted fish, boiled fish, processed fish products such as delicacies, processed vegetables such as pickles, snacks such as potato chips or rice crackers, bakery foods such as bread, confectionery bread or cookies, boiled food, Cooking such as deep-fried food, grilled food, curry, stew, gratin, rice, rice porridge, or rice ball Products, pasta, udon, noodles such as ramen, processed foods such as margarine, shortening, fat spread or flavored fat spread, confectionery bakery materials such as flour paste, rice cake, bread mix powder, cake mix Powder, or mixed powder such as mixed powder for fried food, confectionery such as chocolate, candy, jelly, ice cream, or gum, Japanese confectionery such as bun or castella, coffee, coffee milk, tea, milk tea, soy milk, Drinks such as energy drinks, vegetable drinks, vinegar drinks, juices, colas, mineral water, or sports drinks, alcoholic drinks such as beer, wine, cocktails, or sours, milk or dairy products such as milk, yogurt, or cheese Is mentioned.

The food / beverage products containing 1-alkyl ether type phospholipid of this invention can be manufactured using the manufacturing method of well-known food / beverage products except containing 1-alkyl ether type phospholipid as a raw material.
By containing 1-alkyl ether type phospholipid, the food / beverage products of the present invention can increase the plasmalogen content in vivo, and can be used as a functional food or health food (including beverages). it can. It can also be given to animals as feed. The food / beverage product of the present invention preferably contains a 1-alkyl ether type phospholipid separated from, for example, animals, plants and microorganisms, preferably from krill.

[3] Pharmaceutical composition Since the pharmaceutical composition contains 1-alkyl ether type phospholipid as an active ingredient, it is possible to increase plasmalogens in blood or lymph. Oral administration agents containing the above 1-alkyl ether type phospholipid as an active ingredient can also be used.
The content of the orally administered agent of the present invention in the pharmaceutical composition varies depending on the pharmaceutical composition to be used, but in the case of an adult, it is taken as 100 mg to 40 g, more preferably 200 mg to 20 g per day as 1-alkyl ether type phospholipid. It suffices if the pharmaceutical composition can contain an amount of an orally administered agent that can be produced. Specifically, the amount of 1-alkyl ether type phospholipid in the pharmaceutical composition is preferably 0.1 to 100% by mass, preferably 0.5 to 99% by mass, and 1 to 80% by mass. Most preferably.
The pharmaceutical composition results from a decrease or disappearance of plasmalogen, with 1-alkyl ether phospholipids alone, or preferably with conventional carriers or diluents that are pharmaceutically or veterinarily acceptable. An effective amount can be administered to a subject in need of treatment and / or prevention of a disease [eg, animal, preferably mammal (particularly human)].
The pharmaceutical composition may also contain substances that can increase the concentration of plasmalogen. Examples of such substances include alkyl glycerol and inositol.

  The dosage form of the pharmaceutical composition is not particularly limited, and examples thereof include powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, or pills. Oral preparations are preferred.

Oral preparations include, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidene, crystalline cellulose, soybean lecithin, sucrose, fatty acid ester, talc, magnesium stearate , Polyethylene glycol, magnesium silicate, anhydrous silicic acid, or synthetic aluminum silicate excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, diluents, preservatives, colorants , Fragrances, flavoring agents, stabilizers, moisturizers, preservatives, antioxidants and the like can be used according to conventional methods.
The dosage when using the pharmaceutical composition of the present invention should be appropriately determined according to, for example, the type of active ingredient used, the type of illness, the patient's age, sex, body weight, degree of life, or administration method. It can be administered orally or directly into the gastrointestinal tract using a catheter or the like.
Furthermore, the dosage form is not limited to pharmaceuticals, and various forms such as functional foods and health foods (including beverages), or feeds can be given in the form of food and drink.

  The manufacturing method of the pharmaceutical composition containing the oral administration agent of this invention can be manufactured using the manufacturing method of a well-known pharmaceutical except the said 1-alkyl ether type phospholipid being included as an active ingredient.

  Plasmalogens inhibit the oxidation of LDL cholesterol. Since oxidation of LDL cholesterol induces arteriosclerosis, it is possible to prevent or treat arteriosclerosis by increasing plasmalogen. Furthermore, it is possible to prevent or treat myocardial infarction and cerebral infarction, which are based on arteriosclerosis. Furthermore, aging and oxidative stress are believed to be suppressed by plasmalogens. Diseases involving aging and oxidative stress include cancer, arteriosclerosis, diabetes, and Alzheimer's disease. Increasing plasmalogens can prevent or treat cancer, arteriosclerosis, diabetes, and Alzheimer's disease Is possible. Therefore, diseases caused by a decrease or disappearance of plasmalogen that can be prevented or treated by the oral administration agent, food and drink, or pharmaceutical composition according to the present invention include cancer, arteriosclerosis, diabetes, and Alzheimer's disease. be able to. It is also possible to suppress aging.

It is possible to increase plasmalogens in the living body, particularly in the lymph and blood, by administering the oral administration agent, food and drink, or pharmaceutical composition of the present invention into the living body, particularly by oral administration. That is, by administering the oral administration agent, food or drink, or pharmaceutical composition of the present invention containing a 1-alkyl ether type phospholipid as an active ingredient in vivo, particularly by oral administration, plasmalogens are increased in vivo. Can be provided.
As described above, the amount of ingestion when the food and drink or the pharmaceutical composition of the present invention is orally taken is 100 mg to 40 g, more preferably 200 mg to 20 g per day as 1-alkyl ether type phospholipid, for example, in the case of an adult. The amount of the oral administration agent can be contained in the pharmaceutical composition.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not restrict | limited at all by these Examples.

<1> Production of 1-alkyl ether type phospholipid-containing sample [Production Example 1]
A 1-alkyl ether type phospholipid-containing lipid was produced using krill.
216 L of a mixed solvent mixed with hexane: ethanol = 60: 40 was added to 60 kg (moisture content 87 mass%) of a frozen boiled krill kneaded product (krill CPM-MD, ADEKA Fine Foods), and the mixture was stirred for 10 minutes. Thereafter, the hexane layer, which is the upper layer of the filtrate obtained by suction filtration, was recovered as a lipid extract. Subsequently, the filtrate lower layer and the filtration residue were combined, 130 L of hexane was newly added thereto, and the mixture was stirred for 10 minutes to extract the lipid fraction, and the extract was similarly collected. Furthermore, the same operation is repeated once more for the filtrate lower layer and the filtration residue, and the collected extract is combined for a total of 3 times, and the mixed solvent is removed using an evaporator, and 1-alkyl ether type phospholipid is contained as a residue. A lipid of 2.2 kg of krill oil was obtained.
The obtained krill oil was measured for phospholipid content and 1-alkyl ether type phospholipid content in accordance with the following analysis method, and the results are shown in Table 1. Further, the content of the base type (choline type, ethanolamine type, phosphatidic acid type) in the phospholipid was also measured according to the following analytical method, and the results are also shown in Table 1.

[Production Example 2]
To 200 g of krill oil obtained in Production Example 1, 2.5 L of acetone was added and allowed to stand at 4 ° C. for 1 hour. The supernatant was removed, and 2.5 L of acetone was further added and treated in the same manner. The remaining precipitate was dried and neutral lipid was removed to obtain 87 g of krill oil phospholipid fraction, which is a phospholipid fraction containing 1-alkyl ether type phospholipid.
The obtained krill oil phospholipid fraction has the same phospholipid content, 1-alkyl ether type phospholipid content, and the type of base in the phospholipid (choline type, ethanolamine type, phosphatidic acid type) as in Production Example 1. The results are also shown in Table 1.

[Production Example 3]
LecitaseUltra (Novozymes) 100 kU suspended in 96 mL of diethyl ether and 205 mL of 0.2 M acetic acid buffer (pH 5.0) was added to 2000 g of krill oil obtained in Example 1, and the mixture was stirred at 40 ° C. for 70 hours. 18 L of hexane / ethanol / water (80: 14: 6) was added to the reaction solution, and after stirring and mixing for 10 minutes, the upper layer was collected. Subsequently, 14 L of hexane was newly added to the lower layer and stirred for 10 minutes, and the lipid fraction was similarly collected. Further, the same operation was repeated once again for the lower layer, and the extracted extracts for a total of 3 times were combined, and the mixed solvent was removed using an evaporator to obtain 1950 g of a residue.
About 200 g of residue, a glass column (100 cm × 3 cm) packed with 400 g of silica gel (Wakosil 200) suspended in 300 mL of a mixed solvent of hexane / ethanol = 80: 20 and suspended in a mixed solvent of hexane / ethanol = 80: 20 ). Neutral lipids were eluted by passing 4 L of a mixed solvent of hexane / ethanol = 80: 20, and then 8 L of ethanol was passed to elute ethanolamine phospholipids. Further, 11 L of a mixed solvent of ethanol / water = 80: 20 was passed through to elute the choline phospholipid.
The obtained eluate was concentrated with an evaporator to obtain 7.2 g of a krill oil choline phospholipid fraction in which 1-alkyl ether type phospholipid having a choline type base at the sn-3 position was concentrated as a residue. .
The obtained krill oil choline phospholipid fraction has the same phospholipid content, 1-alkyl ether type phospholipid content, and the type of base (choline type, ethanolamine type, phosphatidic acid type) in the phospholipid as in Production Example 1. The results are also shown in Table 1.

[Production Example 4]
To 14 g of the krill oil choline phospholipid fraction obtained in Production Example 3, diethyl ether 28 mL, 1 M calcium chloride solution 6 mL, acetate buffer (pH 6.0) 144 mL, ethanolamine chloride 20 g, Actinomadura sp. Origin phospholipase D1.2g (1200U, Meisei Sangyo) was added and stirred at 45 ° C for 40 hours. After adding 600 mL of hexane / ethanol (60:40) and stirring and mixing for 10 minutes, the upper layer was collected. Subsequently, 360 mL of hexane was newly added to the lower layer and stirred for 10 minutes, and the lipid fraction was similarly collected. Further, the same operation was repeated once again for the lower layer, and the extracted extracts for a total of 3 times were combined, and the mixed solvent was removed using an evaporator to obtain 11 g of a residue.
The residue dissolved in 300 mL of a mixed solvent of hexane / ethanol = 80: 20 is added to a glass column (100 cm × 3 cm) packed with 400 g of silica gel (Wakosil 200) suspended in a mixed solvent of hexane / ethanol = 80: 20. did. Neutral lipids were eluted by passing 4 L of a mixed solvent of hexane / ethanol = 80: 20, and then 8 L of ethanol was passed to elute ethanolamine-type phospholipids.
The obtained eluate was concentrated with an evaporator, and 10 g of krill oil ethanolamine phospholipid fraction in which 1-alkyl ether type phospholipid whose sn-3 base was ethanolamine type was concentrated was obtained as a residue. It was.
The obtained krill oil ethanolamine phospholipid fraction has the same phospholipid content, 1-alkyl ether type phospholipid content and type of base in the phospholipid (choline type, ethanolamine type, phosphatidic acid type) as in Production Example 1. The results are shown in Table 1.

[Production Example 5]
To 14 g of the krill oil choline phospholipid fraction obtained in Production Example 3, diethyl ether 28 mL, 1 M calcium chloride solution 6 mL, acetate buffer (pH 6.0) 144 mL, Actinomadura sp. Origin phospholipase D1.2g (1200U, Meisei Sangyo) was added and stirred at 45 ° C for 40 hours. After adding 600 mL of hexane / ethanol (60:40) and stirring and mixing for 10 minutes, the upper layer was collected. Subsequently, 360 mL of hexane was newly added to the lower layer and stirred for 10 minutes, and the lipid fraction was similarly collected. Further, the same operation was repeated once again for the lower layer, and the extracted extracts for a total of 3 times were combined, and the mixed solvent was removed using an evaporator to obtain 13 g of a residue.
The residue dissolved in 300 mL of a mixed solvent of hexane / ethanol = 80: 20 is added to a glass column (100 cm × 3 cm) packed with 400 g of silica gel (Wakosil 200) suspended in a mixed solvent of hexane / ethanol = 80: 20. did. Neutral lipids were eluted by passing 4 L of a mixed solvent of hexane / ethanol = 80: 20, and then 8 L of ethanol was passed to elute phosphatidic acid type phospholipids.
The obtained eluate was concentrated with an evaporator, and 12 g of a krill oil phosphatidic acid phospholipid fraction in which a 1-alkyl ether type phospholipid whose base at the sn-3 position is a phosphatidic acid type was concentrated was obtained as a residue. It was.
The obtained krill oil phosphatidic acid phospholipid fraction has the same phospholipid content, 1-alkyl ether type phospholipid content and type of base in the phospholipid (choline type, ethanolamine type, phosphatidic acid type) as in Production Example 1. The results are shown in Table 1.

<2> Animal test (feeding test)
[Examples 1-4, Comparative Examples 1-2]
Five-week-old male Wistar-ST rats were divided into 6 groups (6 animals per group), and were allowed to freely feed and water. The feed used was a refined feed according to AIN93G (basic feed: containing 7% soybean oil). The basic feed was changed every day, and drinking tap water was changed every 3 days. After feeding for 7 days under the above conditions, a feed using a mixed lipid of 1% krill oil phospholipid fraction obtained in Production Example 2 and 6% soybean oil instead of 7% soybean oil in the basic feed (Example 1) ), Feed using a mixed lipid of krill oil choline phospholipid fraction 1% obtained in Production Example 3 and soybean oil 6% (Example 2), krill oil ethanolamine phospholipid fraction obtained in Production Example 4 A feed using a mixed lipid of 1% and 6% soybean oil (Example 3), a feed using a mixed lipid of 1% krill oil phosphatidic acid phospholipid fraction obtained in Production Example 5 and 6% soybean oil ( Example 4), a basic feed (Comparative Example 1), and a feed (Comparative Example 2) using a mixed lipid of 1% egg yolk choline phospholipid, 1% fish oil and 5% soybean oil were fed and reared for 8 days. The egg yolk choline phospholipid contained 98% of diacyl choline phospholipid in the total lipid, and the 1-alkyl ether type phospholipid was 1% or less.
Table 2 shows the basic feed composition.
During the test period, there was no effect on the weight gain and food intake of the rats in each group.

After feeding for 8 days, blood was collected, lipids of the serum fraction were extracted, and the total plasmalogen content, choline-type plasmalogen content, and ethanolamine-type plasmalogen content in the serum were measured by LC-MS / MS. The results are shown in Table 3.
Table 4 shows the rate of increase when Comparative Example 1 (soybean oil only) is 1.

As can be seen from Table 3, the amount of total plasmalogen in the serum is a mixture of 1% krill oil phospholipid fraction obtained in Production Example 2 and 6% soybean oil with respect to the basic feed (Comparative Group 1). The feed (Example 1) used was 1.28 times, and the feed (Example 2) using a mixed lipid of the krill oil choline phospholipid fraction 1% and soybean oil 6% obtained in Production Example 3 was 1.87. The feed (test group 3) using the mixed lipid of krill oil ethanolamine phospholipid fraction 1% obtained in Production Example 4 and soybean oil 6% (Test Group 3) is 1.79 times, krill obtained in Production Example 5 The feed (Example 4) using the mixed lipid of 1% oil phosphatidic acid phospholipid fraction and 6% soybean oil was 2.09 times. However, the feed (Comparative Example 2) using a mixed lipid of 1% egg yolk choline phospholipid, 1% fish oil and 5% soybean oil was only 1.12 times.
From this result, it can be seen that the 1-alkyl ether type phospholipid has a function as a plasmalogen increasing agent even if the type of the base is changed. That is, since the base of a natural 1-alkyl ether type phospholipid is one of these three types, even a 1-alkyl ether type phospholipid other than krill oil has a function as a plasmalogen increasing agent. I understand that.

<3> Storage test [Production Example 6]
Lipids were extracted with a mixed solvent obtained by mixing 1.4 kg of lyophilized porcine brain with hexane: ethanol = 60: 40. The obtained crude lipid was dissolved in a mixed solvent (8: 2) mixed with hexane: ethanol = 80: 20 after solvent distillation, and mixed with a mixed solvent (8: 2) previously mixed with hexane: ethanol = 80: 20. It was applied to an equilibrated silica gel column (400 g). Subsequently, after neutral lipid was eluted with 4 L of a mixed solvent (8: 2) mixed with hexane: ethanol = 80: 20 on a silica gel column, it was eluted with 8 L of ethanol, and 24 g of a phospholipid fraction containing 54% plasmalogen was obtained. Obtained. In addition, 90% or more of the base type was ethanolamine type.

[Production Example 7]
Lipids were extracted with a mixed solvent prepared by mixing 3.6 kg of lyophilized bovine heart with hexane: ethanol = 60: 40. The obtained crude lipid was dissolved in a mixed solvent mixed with hexane: ethanol = 80: 20 after solvent distillation and applied to a silica gel column (400 g) equilibrated in advance with a mixed solvent mixed with hexane: ethanol = 80: 20. did. Subsequently, the neutral lipid was eluted with 4 L of a mixed solvent mixed with hexane: ethanol = 80: 20 on a silica gel column, then the ethanolamine-type glycerophospholipid was eluted with 8 L of ethanol, and further mixed with ethanol: water = 80: 20 Elution with 11 L of solvent gave 8.0 g of a phospholipid fraction containing 59% plasmalogen. In addition, 90% or more of the base type was choline type.
<2> Plasmalogen-containing phospholipid fraction 1 obtained in Production Example 6 instead of the feed of Examples 1 to 4 and the soybean oil 7% of the basic feed used in the animal test (feeding test) % And soy oil 6% mixed lipid feed (Comparative Example 3), plasmalogen-containing phospholipid fraction 1% obtained in Production Example 7 and soy oil 6% mixed fat feed (Comparative Example) 4) was prepared and the following storage stability test was conducted.

[Examples 5-8, Comparative Examples 3-4]
Each of the feeds was placed in a thermostatic bath at 30 ° C., the flavor was confirmed after 10 days, the degree of flavor deterioration was evaluated according to the following criteria, and the results are shown in Table 5.
(Evaluation criteria)
◎: Extremely good ○: Good △: Feeling oxidative degradation odor ×: Severe oxidative degradation odor

  From this result, it can be seen that the feed using 1-alkyl ether type phospholipid has good flavor stability, whereas the feed using plasmalogen has poor flavor stability. In addition, even if the kind of 1-alkyl ether type | mold phospholipid base changes, it turns out that flavor stability is similarly favorable. That is, since the base of the natural product 1-alkyl ether type phospholipid is any one of these three types, even if it is a 1-alkyl ether type phospholipid other than krill oil, it has good flavor stability. I understand.

  The oral administration agent and food and drink of the present invention can be used for preventing or ameliorating diseases involving oxidative stress such as school cancer, arteriosclerosis, diabetes, and Alzheimer's disease.

Claims (4)

  An orally-administered agent comprising 50 to 100% of 1-alkyl ether type phospholipid derived from krill as an active ingredient. The oral administration agent according to claim 1, which is for increasing plasmalogen . The oral administration agent according to claim 2, which is used for treatment or prevention of cancer, arteriosclerosis, diabetes, or Alzheimer's disease . A food and drink for increasing plasmalogens, comprising 50 to 100% of 1-alkyl ether type phospholipid derived from krill as an active ingredient.