JP2006062973A - LDL-C and Lp (a) reducing agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug for lowering both blood LDL cholesterol and lipoprotein (a).
A blood LDL cholesterol and lipoprotein (a) lowering agent containing diacylglycerol and plant sterols.
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Description

  The present invention relates to a reducing agent for both low density lipoprotein (LDL) cholesterol and lipoprotein (a) (hereinafter referred to as Lp (a)), which is particularly important as a risk factor for arteriosclerosis.

  Among lipoproteins, LDL has a role of transporting cholesterol from the liver to peripheral tissues, but when LDL becomes excessive, denatured LDL is generated. When denatured LDL is phagocytosed by macrophages, it differentiates into foam cells that accumulate a large amount of denatured cholesterol. It is believed that the foam cells eventually sink under the vascular endothelium, accumulate cholesterol, promote the proliferation of vascular smooth muscle, and form an arteriosclerotic lesion. Therefore, blood LDL cholesterol is important as a risk factor for arteriosclerosis, also called bad cholesterol.

On the other hand, Lp (a) is a LDL particle in which a glycoprotein called apolipoprotein (a) is disulfide-bonded, and is known to induce arteriosclerosis more than LDL. Lp (a) blood concentration Increases have been shown to increase the risk of heart disease and stroke. Therefore, it is desirable to keep the Lp (a) concentration in the blood as high as possible. However, especially in women who have reached menopause, menstrual periods are stopped due to the depletion of female hormones in the body, the number of LDL receptors decreases (decrease in the ability to collect LDL cholesterol), and the blood concentration of LDL cholesterol It is known that the blood concentration of Lp (a) is increased by 10 to 20%. With such rapid changes in the body, the prevalence of cardiovascular diseases increases significantly. Therefore, it is very important for postmenopausal women to manage both LDL cholesterol and Lp (a), which are extremely high risk factors, in preventing arteriosclerotic diseases. Become.
In general, when a drug that lowers cholesterol (for example, a statin drug or an ion exchange resin drug) or a food (such as a food containing a plant sterol) is used, inhibition of LDL cholesterol synthesis in the liver, promotion of recovery, Although it was possible to reduce the blood concentration of LDL cholesterol by suppressing absorption, it was difficult to reduce the blood concentration of Lp (a).

By the way, diacylglycerol is known to have actions such as suppression of weight gain, reduction of serum triglyceride, suppression of body fat accumulation, reduction of remnant-like lipoprotein, increase of HDL cholesterol, improvement of lipid metabolism in the small intestinal epithelium (Patent Documents 1 to 6). ing. In addition, it is known that when diacylglycerol and plant sterol are used in combination, blood cholesterol decreases (Patent Document 7). However, there are no reports on the effects on LDL cholesterol and Lp (a).
Japanese Unexamined Patent Publication No. 4-300826 Japanese Patent Laid-Open No. 4-300825 JP-A-10-176181 JP 2001-302509 A JP 2001-64170 A JP 2002-322052 A WO 99/48378 pamphlet

  Therefore, it is desired to develop a drug that can simultaneously reduce both LDL cholesterol and Lp (a), which are risk factors for arteriosclerosis, and the present invention aims to provide such a drug.

  Therefore, the present inventor, for a group of high-risk individuals with atherosclerosis who are both high in blood LDL cholesterol and Lp (a), simultaneously ingested diacylglycerol and plant sterols, and ingested only diacylglycerol. It has been found for the first time that both LDL cholesterol and Lp (a) are significantly reduced as compared with the case of the treatment. The improvement of both LDL cholesterol and Lp (a) in the present invention has been desired for many years especially for postmenopausal women and is extremely useful.

  That is, the present invention provides a blood LDL cholesterol and Lp (a) lowering agent containing diacylglycerol and plant sterols.

  According to the present invention, both LDL cholesterol in blood and Lp (a), which are important as risk factors for arteriosclerosis, can be reduced simultaneously. It is extremely useful for humans who have these two risk factors elevated at the same time, especially postmenopausal women.

  In the present invention, diacylglycerol and plant sterols may be ingested in combination, and each may be ingested as a separate composition, but it is preferably ingested as an oil and fat composition containing diacylglycerol and plant sterols. .

  The constituent fatty acid of diacylglycerol used in the present invention preferably has 8 to 24 carbon atoms, particularly 16 to 22 carbon atoms. The unsaturated fatty acid content in the total constituent fatty acids of diacylglycerol is preferably 80 to 100% by mass (hereinafter simply referred to as%), more preferably 85 to 100%, still more preferably 90 to 100%, and particularly preferably 93. -100%, most preferably 94-98%.

  Furthermore, from the viewpoint of further enhancing the effect of the present invention, (cis-type unsaturated fatty acid amount) / (trans-type unsaturated fatty acid amount + saturated fatty acid amount) is preferably 6 or more, more preferably 9-25, More preferably, it is 9-20. Further, the trans unsaturated fatty acid in diacylglycerol is particularly preferably 5% or less. The saturated fatty acid content is preferably 10% or less, particularly preferably 5% or less.

  Among the fatty acids constituting diacylglycerol, the content of oleic acid is 20 to 65%, preferably 25 to 60%, particularly 30 to 50%, especially 30 to 45%, in terms of appearance and fatty acid intake balance. Is desirable.

  Among the fatty acids constituting diacylglycerol, the content of linoleic acid is 15 to 65%, preferably 20 to 60%, particularly 30 to 55%, especially 35 to 50%, in terms of the balance of fatty acid intake. desirable. Furthermore, from the viewpoint of oxidation stability and physiological effects, the content weight ratio of linoleic acid / oleic acid is 0.01 to 2.0, preferably 0.1 to 1.8, particularly 0.3 to 1.7. It is desirable.

  Among fatty acids constituting diacylglycerol, the content of linolenic acid is less than 15%, preferably 0 to 13%, more preferably 1 to 10%, and particularly 2 to 9%. This is desirable. As linolenic acid, α-linolenic acid and γ-linolenic acid are known as isomers, and α-linolenic acid is preferable.

  Diacylglycerol includes 1,3-diacylglycerol and 1,2-diacylglycerol (2,3-diacylglycerol). More preferably, the mass ratio of 1,3-diacylglycerol to 1,2-diacylglycerol is 7: 3. The fact that 1,3-diacylglycerol in diacylglycerol is 50% or more of total diacylglycerol, further 55 to 100%, particularly 60 to 90% enhances the effect of the present invention and improves industrial productivity. It is preferable from the point.

  The diacylglycerol used in the present invention undergoes an esterification reaction by transesterifying, for example, fats and oils having a target constituent fatty acid and glycerin, or by allowing lipase to act on a mixture of the target constituent fatty acid or its ester and glycerin. Manufactured by performing. In order to prevent isomerization during the reaction, an esterification reaction using lipase is more preferable. Moreover, also in the esterification reaction using lipase, in order to prevent isomerization in the purification step after completion of the reaction, it is preferable to carry out the purification means under mild conditions so that fatty acid isomerization does not occur.

  Diacylglycerol is preferably used as an oil composition containing plant sterols and triglycerides. The oil and fat composition preferably contains 15 to 99.95% of diacylglycerol, more preferably 35 to 98.85%, still more preferably 60 to 94.8%, and particularly preferably 70 to 90% from the viewpoint of effects. It is preferably 94.7%, more preferably 80 to 94.55%.

  The triglyceride content in the oil or fat composition is preferably 0 to 84.95%, more preferably 1 to 64.85%, and still more preferably 5 to 39.8% from the viewpoint of effect, flavor and oxidation stability. In particular, the content is preferably 5 to 29.7%, more preferably 5 to 19.55%. As fatty acids constituting triglycerides, unsaturated fatty acids having 16 to 22 carbon atoms are preferably 80 to 100%, more preferably 85 to 100%, further 90 to 100%, and particularly 93 to 100% in terms of effect, flavor, and texture. %, Most preferably 94-98%. Further, from the viewpoint of oxidative stability, it is preferable to contain ω3 unsaturated fatty acid as a constituent fatty acid of triglyceride, preferably 0 to 40%, further 0 to 30%, particularly 0 to 20%, most preferably 0 to 15%. Good.

  The oil and fat composition may contain monoacylglycerol, and its content is 0 to 30% from the viewpoint of flavor and oxidation stability, preferably 0.1 to 10%, more preferably 0.1. It should be -5%, particularly preferably 0.1-2%, most preferably 0.1-1.5%. The constituent fatty acid of monoacylglycerol is preferably the same as diacylglycerol from the viewpoint of production.

The free fatty acid (salt) contained in the oil / fat composition should be reduced to 3.5% or less, preferably 0 to 2%, more preferably from the viewpoints of flavor, smoke prevention and industrial productivity. 0 to 1%, particularly preferably 0 to 0.5%, and most preferably 0.05 to 0.2%.
The content of fatty acids having 4 or more carbon-carbon double bonds in the total fatty acids constituting the oil and fat composition used in the present invention is 0 to 40%, preferably 0 to 20% in terms of oxidation stability. Further, it should be 0 to 10%, particularly 0 to 1%, and most preferably not substantially contained.

  Examples of the plant sterols used in the present invention include α-sitosterol, β-sitosterol, stigmasterol, campesterol, α-sitostanol, β-sitostanol, stigmasteranol, campestanol, and cycloartenol. And free esters such as these and esters such as fatty acid esters, ferulic acid esters and cinnamic acid esters. The plant sterol is preferably used by blending plant sterols in the oil or fat composition containing diacylglycerol. The content of plant sterols in the oil / fat composition is preferably 0.05 to 20%, more preferably 0.05 to 7%, still more preferably 0.1 to 5%, and particularly preferably 0. It is preferably 2 to 5%, more preferably 0.3 to 4.7%.

  In order to improve oxidation stability, it is preferable to add an antioxidant to the oil composition. Examples of antioxidants include butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), vitamin A, vitamin C, vitamin E, phospholipid, polyphenol, and tertiary butylhydroquinone (TBHQ). You may use it in combination. Said antioxidant is 0.005-0.2 mass part with respect to 100 mass parts of fats and oils composition, It is preferable to contain 0.04-0.1 mass part especially.

  It is preferable to add a crystallization inhibitor to the oil composition. Examples of the crystallization inhibitor used in the present invention include polyglycerin condensed ricinoleic acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and polyol fatty acid ester such as propylene glycol fatty acid ester. Can be mentioned. You may use these in combination of 2 or more type. The crystallization inhibitor is preferably contained in an amount of 0.02 to 0.5 parts by mass, particularly 0.05 to 0.2 parts by mass with respect to 100 parts by mass of the oil and fat composition.

  Examples of the administration form of the medicament of the present invention include oral preparations such as solid preparations such as powders, granules, capsules, pills and tablets, and liquids such as solutions, suspensions and emulsions. This orally administered agent is used in accordance with the form of the orally administered agent, in addition to the above oil and fat composition, respectively, excipients, disintegrants, binders, lubricants, surfactants, alcohols, water, water-soluble It can be produced by adding one or more of functional polymers, sweeteners, flavoring agents, acidulants and the like. When an oil or fat composition is used, its content in a pharmaceutical product for oral administration varies depending on the use and form of the pharmaceutical product, but is generally 0.1 to 100%, more preferably 1 to 80%, and particularly preferably 2 to 80%. .

  In the present invention, when diacylglycerol and plant sterols are consumed in the form of food, it may be an oil-and-fat processed food containing diacylglycerol and plant sterols. For example, health that promotes health by exerting a specific function It can be food, functional food, food for specified health use, food for the sick, etc. Specifically, capsules, tablets, granules, breads and cakes, cookies, pie, bars, bakery mixes and other bakery foods, French dressings and other dressings, mayonnaise and other oil-in-water emulsified foods, margarine and spreads, etc. Water-in-oil emulsified food, cream, chocolate, potato chips, ice cream, dessert and other confectionery, beverages, soup, sauce, coffee whitener, whipped cream, grilled meat sauce, peanut butter, flying shortening, baking shortening In addition to processed meat products, frozen foods, powdered foods, meal replacers, and the like, food materials such as cooking oil used for tempura, fried food, fried foods, and the like can be mentioned. Such a food can be produced by adding a commonly used food material according to the type of food in addition to the oil and fat composition. The content of the oil or fat composition in such foods varies depending on the type of food, but is generally 0.1 to 100%, more preferably 1 to 80%, and particularly preferably 2 to 80%.

  Hereinafter, the fat and oil processed food containing the diacylglycerol of the present invention and plant sterols will be described. In the present invention, the processed oil / fat food refers to a food processed by blending an oil / fat composition containing diacylglycerol and a plant sterol and other food ingredients. The raw material components used for processed oils and fats include the following.

(1) Edible fats and oils The edible fats and oils used for this invention will not be specifically limited if it is common edible fats and oils. For example, in addition to natural animal and vegetable fats and oils, processed fats and oils obtained by subjecting them to transesterification, hydrogenation, fractionation and the like can be mentioned. Preferably, vegetable oils such as soybean oil, rapeseed oil, cottonseed oil, rice bran oil, corn oil, sunflower oil, palm oil, palm kernel oil, coconut oil, and processed oils and fats thereof may be used.

(2) Emulsifier Any emulsifier generally used in foods is not particularly limited. Examples thereof include sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, lecithin and its degradation product, egg protein, soybean protein, milk protein, and various proteins obtained by separation or hydrolysis from these proteins, peptides and the like.

(3) Thickener If it is a thickener generally used for foodstuff, it will not specifically limit. Examples include xanthan gum, gellan gum, guar gum, carrageenan, pectin, tragacanth gum, polysaccharides such as various starches, and proteins such as gelatin and egg white.

(4) Various flavorings such as salt, sugar, vinegar, and seasoning (5) Various flavorings such as spices and flavors (6) Various colorants (7) Antioxidants such as tocopherols and natural antioxidant components

  Hereafter, the preferable formulation example of this invention is shown. However, the application of the present invention is not limited.

a) Acidic oil-in-water type processed foods / oil phase / water phase; 20/80 to 80/20 (preferably 30/70 to 70/30)
-Amount of diacylglycerol: 15% or more (preferably 40% or more, particularly 80% or more) with respect to fats and oils in the oil phase
-Amount of plant sterols; 0.05% or more based on fats and oils in the oil phase-Amount of emulsifier: 0.05-5%
・ PH: 2-6
The pH is adjusted with an organic acid such as vinegar or citric acid or a salt thereof, and a sour agent such as lemon juice. Using the above raw materials, acidic oil-in-water processed foods such as dressings and mayonnaise having an effect of lowering blood LDL cholesterol and Lp (a) can be prepared by conventional methods.

<Prescription Example> Mayonnaise Aqueous Salt 3.0 parts by mass Sugar 1.0
Seasoning (sodium glutamate) 0.5
Spice (Mustard powder) 0.3
Egg yolk 14
Vinegar (acidity 10%) 8
Thickener 0.5
Water 22.7
Oil phase fat composition (postscript DAG or PS / DAG) 50

b) Water-in-oil type plastic oil processed food / water phase / oil phase; 15/85 to 85/15 (preferably 20/80 to 50/50)
-Amount of diacylglycerol: 15% or more (preferably 40% or more, particularly 50% or more) with respect to fats and oils in the oil phase
-Amount of plant sterols: 0.05% or more based on fats and oils in the oil phase-Melting point of fats and oils in the oil phase: 20-50 ° C (preferably 20-40 ° C)
Using the above-mentioned raw materials, processed water-in-oil type plastic oil-and-fat foods such as margarine and spread having an effect of lowering blood LDL cholesterol and Lp (a) can be prepared by a conventional method.

<Prescription example> Spread oil phase fat * 69.3 mass parts lecithin 0.1
Monoacylglycerol 0.5
Flavor 0.1
Aqueous water 28.4
Nonfat dry milk 0.3
Salt 1.3
* Oil: Oil composition (PS / DAG described later); 70% / partially hardened palm oil (IV = 40); 30%, melting point 36 ° C.

c) Bakery food and fat content: 10-40%
-Amount of diacylglycerol: 15% or more (preferably 40% or more, particularly 50% or more) with respect to fats and oils in the oil phase
-Amount of plant sterols: 0.05% or more based on fats and oils in the oil phase-Wheat flour: 20-65%
・ Sugar: 5-30%
・ Whole eggs; 0-20%
・ Salt: 0.1-2%
・ Baking powder: 0 to 1%
Bakery foods such as shortbread (bar) and brioche having the effect of lowering blood LDL cholesterol and Lp (a) can be prepared by the conventional methods using the above-mentioned raw materials.

<Prescription example> Short bread (bar)
60 parts by weight of fat and oil composition (PS / DAG described later) 10
24.6 sugar
Salt 0.4
Whole egg 5

  When diacylglycerol and plant sterols are ingested by a high-risk population of arteriosclerosis with high blood LDL cholesterol and Lp (a) concentrations as shown in Examples below, the concentrations of both are significantly reduced.

  The intake amount of the diacylglycerol in the present invention is preferably divided into 1 to several times a day in the range of 0.1 to 25 g, particularly 0.1 to 20 g per adult. In addition, the intake of the plant sterols is preferably divided into one to several times a day in the range of 100 to 500 mg, particularly 200 to 400 mg per adult. The intake period is 1 week or longer, preferably 2 weeks or longer, more preferably 3 weeks or longer, 1 month or longer, especially 2 months or longer, most preferably 3 months or longer. Thus, in order for a subject with high blood LDL cholesterol and Lp (a) to ingest diacylglycerol and plant sterols for a long period of time, a food using the diacylglycerol and plant sterols in part or all of the triglyceride Is preferably prepared and ingested.

I) Subjects and methods:
1. Target:
The subjects were healthy postmenopausal women over 45 years old.

2. Test cooking oil:
In this test, cooking oil used at home is (1) diacylglycerol oil (comparative product, hereinafter referred to as DAG), (2) diacylglycerol oil containing 4% of plant sterols (PS) (product of the present invention). In the following, PS / DAG) was replaced with a blind, and used / ingested as before during the test period. The composition of each edible oil is shown in Tables 1 and 2.

3. Method:
A 4-week double blind randomized crossover comparative study was conducted on postmenopausal women (n = 14, age 45-62 years) with high cholesterol levels over 45 years old.
During the test period, subjects ingested the cooking oil used at home by blindly replacing one of the two test oils, (1) DAG, or (2) PS / DAG, and set the target intake per day. 10 g. The diet during the test period was instructed to be the same as before the test, and serum lipids were measured during that period. Blood collection was performed every 4 weeks on the same morning on an empty stomach, and body measurements were also taken on the same day.

4). Statistical analysis:
A statistically significant difference was determined to be significant when the risk rate was 5% or less using a paired t-test.

5. Serum test:
Serum lipid and biochemical blood tests were performed. The collected blood was rapidly centrifuged (1,500 × g) for 15 minutes under refrigeration (5 ° C.) to obtain serum and plasma. The analysis of inspection items was carried out by requesting SRL.

II) Results:
As a result of the blood test, a significant lowering effect of total cholesterol, LDL cholesterol, and Lp (a) was observed only during the PS / DAG intake period, and a significant difference was observed even when compared with DAG (Table 3). In addition, the amount of change in Lp (a) during the PS / DAG intake period has a strong negative correlation with the initial Lp (a) value (p <0.001), and the initial Lp (a) value is large. The decrease rate of Lp (a) was larger for the test subjects (FIG. 1).

  From the above, it can be seen that administration of diacylglycerol and plant sterols to humans with high LDL cholesterol and Lp (a) values, such as postmenopausal women, improves cholesterol and Lp (a).

It is a figure which shows the change of Lp (a) by PS / DAG ingestion.

Claims (4)

  A blood LDL cholesterol and lipoprotein (a) lowering agent containing diacylglycerol and plant sterols.   The blood LDL cholesterol and lipoprotein (a) lowering agent according to claim 1, comprising 15 to 99.95% by mass of diacylglycerol and 0.05 to 20% by mass of plant sterols.   The blood LDL cholesterol and lipoprotein (a) lowering agent according to claim 1 or 2, wherein the form is an oil or fat composition. The agent for lowering LDL cholesterol and lipoprotein (a) in blood according to claims 1 to 3, which is for postmenopausal women.

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