JP2009155278A - Hyperhomocystemia improving agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition and food and drink effective in reducing homocysteine concentration in blood or suppressing an increase of the same. <P>SOLUTION: The hyperhomocystemia improving agent contains sesamines as active ingredients and is active for reducing the homocysteine concentration in blood or suppressing the increase of the same. The sesamines are ingredients originated from foods, have no adverse effects and can be safely ingested for a long period of time. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an agent for improving hyperhomocysteinemia, and more specifically, an agent for reducing blood homocysteine concentration containing sesamin as an active ingredient or suppressing increase in blood homocysteine concentration, and the like It relates to food and drink.

  Homocysteine is a kind of sulfur-containing amino acid derived from methionine, which is an intermediate product of the methionine metabolic pathway and is supplied from protein in the diet. In vivo, homocysteine is metabolized to methionine or cysteine, but when an abnormality occurs in the metabolic pathway, the concentration of homocysteine in the blood increases. It has been pointed out that an increase in blood homocysteine concentration is associated with the occurrence of diseases of the cardiovascular system, the cerebral vascular system and the peripheral venous system, and is also associated with an increased frequency of Alzheimer's dementia and depression. It has also been reported that aging of body tissues is promoted by the accumulation of homocysteine in the body. Therefore, in order to prevent or treat symptoms associated with aging and prevention or treatment of diseases that are said to be involved in these homocysteine, the amount of homocysteine in the body, that is, the concentration of homocysteine in the blood is reduced. Alternatively, it is considered important to suppress an increase in blood homocysteine concentration.

  As a treatment for symptoms with high blood homocysteine concentration (hyperhomocysteinemia), folic acid administration to facilitate homocysteine metabolism is the first treatment, and vitamin B6 and vitamin B12 are administered as the second treatment. (See Non-Patent Document 1).

  In addition, using daily food materials, etc., it may be possible to suppress or reduce the increase in blood homocysteine concentration. Examples of such food materials include raw coffee bean extract (Patent Document 1), A composition (Patent Document 2) containing a lily family plant such as garlic and onion or an extract thereof as an active ingredient, and a shiitake-derived eritadenine (Patent Document 3) as a homocysteine synthase inhibitor material have been proposed.

On the other hand, for sesamin, which is a physiologically active component of sesame, an arterial thickening inhibitory action (Non-patent Document 2) and a cholesterol lowering action (Patent Document 4) are known, but the blood homocysteine concentration is reduced, Alternatively, it has not been suggested or disclosed so far as an active ingredient that suppresses the increase.
JP 2006-16311 A US Pat. No. 6,129,918 JP 2006-121913 A Japanese Patent No. 3075360 Progress in Medicine, Vol.19 No.8, 1999 p. 49-54 Biol. Pharm. Bull. 21 (5) 469-473 (1998)

  As described above, Non-Patent Document 1 describes that homocysteine-lowering action can be obtained by administering an enzyme cofactor such as folic acid, vitamin B6, vitamin B12, etc. In order to expect this effect Had to take the above enzyme cofactor at a dose that greatly exceeded the daily nutritional requirements, and there was concern about side effects.

  An object of the present invention is to provide an active ingredient that is effective for lowering or suppressing the blood homocysteine concentration and that can be safely ingested without side effects.

  As a result of intensive studies to find an effective ingredient free from side effects derived from foods that lowers or suppresses the increase in blood homocysteine concentration, the present inventors have found that sesamin, which is a physiologically active ingredient of sesame, is found in blood. The present invention was completed by finding that it has an action of reducing the homocysteine concentration or suppressing the increase of blood homocysteine concentration.

That is, the present invention relates to the following contents.
1. A hyperhomocysteinemia improving agent containing sesamin as an active ingredient.
2. 2. Improvement of hyperhomocysteinemia according to 1 above, characterized by oral administration to a mammal deficient or deficient in any one or more of the vitamin B groups selected from the group consisting of folic acid, vitamin B6 and vitamin B12 Agent.
3. 2. The hyperhomocysteinemia improving agent according to 1 above, which suppresses an increase in blood homocysteine concentration induced by aging, smoking or drinking.
4). 4. The hyperhomocysteinemia improving agent according to any one of 1 to 3 above, which contains 1 to 200 mg of the sesamin per intake amount of the hyperhomocysteinemia improving agent per day for an adult.
5. 5. The hyperhomocysteinemia improving agent according to any one of 1 to 4 above, wherein the sesamin is sesamin, episesamin or a sesamin / episesamin mixture.
6). Food / beverage products containing the hyperhomocysteinemia improving agent in any one of said 1-5.
7). An anti-aging agent containing sesamin as an active ingredient.

  The hyperhomocysteinemia-improving agent of the present invention has a blood homocysteine concentration lowering action or an increase inhibiting action. Sesamin, which is an active ingredient, is a safe substance that has been ingested as a food and drink for many years, and it has been confirmed that it can be safely ingested over the medium and long term. The agent and food and drink are effective for the prevention, amelioration, and treatment of hyperhomocysteinemia and related diseases. In addition, by orally administering sesamin, it can be expected that not only the hyperhomocysteinemia improving effect of sesamin but also the physiological activity of sesamin known so far can be expected. Can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

(Hyperhomocysteinemia improving agent)
Homocysteine (hereinafter abbreviated as Hcy) is a metabolite produced in the process of conversion from methionine, which is a sulfur-containing amino acid, to cysteine. Homocysteine (reduced form) is rapidly oxidized in blood, and about 98% exists as protein-bound forms such as homocystin, homocysteine thiolactone, mixed disulfide, and albumin which are oxidized forms. In clinical tests and the like, the total homocysteine value is measured for both oxidized and reduced forms. In general, the normal value of the total Hcy concentration in the fasting is 5 to 15 μmol / L (preferably less than 6 μmol / L), and hyperhomocysteinemia is mild 15 to 30 μmol / L, moderate 30 to 100 μmol. / L, altitude> 100 μmol / L.

  The hyperhomocysteinemia-improving agent of the present invention exhibits a slightly higher value even in the above-mentioned patients with hyperhomocysteinemia (patients whose blood total Hcy concentration in the fasting exceeds 15 μmol / L) or normal values. It is preferably used for patients (patients whose fasting blood total Hcy concentration is 6 to 15 μmol / L). When the total Hcy concentration in blood exceeds 14 μmol / L, it has been reported that the risk of developing Alzheimer's dementia is doubled. Therefore, the hyperhomocysteinemia-improving agent of the present invention can be used as a preventive agent for Alzheimer's dementia. It can be said that it is useful.

Here, the subject (patient) to which the hyperhomocysteinemia improving agent of the present invention is administered is not only a human but also a mammal such as a domestic animal for work, a hound, a racehorse, a pet, and other animals.
The total blood Hcy concentration is a mutation of enzymes essential for Hcy metabolism (methylenetetrahydrofolate reductase, cystathionine synthase, methionine synthase), deficiency of vitamin B group (vitamin B6, vitamin B12, folate), decreased renal function, Aging, sex (male), malignant tumors (breast cancer, ovarian cancer, pancreatic cancer, acute leukemia, etc.), psoriasis, drugs (methotrexate, phenytoin, carbamazevin, niacin, theophylline, oral contraceptives, etc.), smoking and drinking It rises due to various causes. The agent for improving hyperhomocysteinemia as referred to in the present invention refers to an agent that suppresses the increase in the total blood Hcy concentration that increases due to these various causes or reduces the increased blood total Hcy concentration. .

  The hyperhomocysteinemia-improving agent of the present invention is effective in suppressing a blood Hcy concentration that rises mildly due to deficiency or deficiency of the vitamin B group, smoking, drinking, etc., and in particular, deficiency or deficiency of the vitamin B group. It is preferably used for mammals. Further, since the hyperhomocysteinemia improving agent of the present invention is expected to exert its effect even when used in combination with a drug, it is also useful for suppressing blood Hcy concentration increased by the above drug. . In middle-aged and elderly people, asymptomatic cerebral infarction (SBI) has been found in about 25% of people by MRI diagnosis even in the absence of subjective symptoms, and SBI and hyperhomocysteinemia are reported to be positively proportional. ing. The hyperhomocysteinemia-improving agent of the present invention can also be taken daily as a preventive or therapeutic agent for such age-related diseases or symptoms.

  The high homocysteine ameliorating agent and anti-aging agent of the present invention are not only the above-mentioned SBI, but also diseases related to hyperhomocysteinemia, such as dementia and degenerative degenerative diseases (Alzheimer-type dementia). , Progressive supranuclear palsy, Parkinson's disease, generalized Lewy body disease, Pick's disease, Huntington's chorea, dementia with ALS-like symptoms, cortical basal ganglia degenerative disease, etc., endocrine / metabolic toxic diseases (thyroid gland) Hypofunction, hypopituitarism, vitamin B12 / B1 deficiency, pellagra, brain lipidosis, mitochondrial encephalomyopathy, hepatic encephalopathy, pulmonary encephalopathy, dialysis encephalopathy, hypoxia, hypoglycemia, alcohol encephalopathy, drug addiction ), Infectious diseases (Creutzfeldt-Jakob disease, subacute sclerosing panencephalitis, progressive multifocal leukoencephalopathy, various encephalitis / meningitis, brain abscess, brain parasite, progressive paralysis, etc.) Diseases (primary / secondary brain tumors, meningeal carcinomatosis, etc.), traumatic diseases (chronic subdural hematoma, sequelae of head trauma, punchdrunk syndrome, etc.), normal pressure hydrocephalus, multiple sclerosis, neuro-betuit, Drugs, foods and drinks, foods for specified health use, quasi-drugs for prevention, treatment or improvement of sarcoidosis, Sjogren's syndrome, etc., osteoporosis, hallux valgus, digitosis, intelligence impairment, convulsions, lens dislocation, iris shaking, etc. Useful as.

  In addition, since it has been reported that aging of body tissues is promoted by accumulation of homocysteine in the body, the homocysteinemia improving agent of the present invention is an anti-cancer agent for preventing or improving aging of body tissues. It is also useful as an aging agent.

(Sesamin)
The high homocysteine improving agent and anti-aging agent of the present invention contain sesamin as an active ingredient. The sesamin of the present invention includes sesamin and its analogs. Examples of the sesamin analog include episesamin and dioxabicyclo [3.3.0] octane derivatives described in JP-A-4-9331. Specific examples of sesamin can include sesamin, sesaminol, episesaminol, sesamorin and the like. Among these, sesamin, episesamin or a mixture of sesamin and episesamin is preferable, and in particular, a mixture of sesamin and episesamin is a more preferable component. The sesamin used for this invention is not restrict | limited at all by the form, manufacturing method, etc. For example, when sesamin is selected as the sesamin, sesamin extracted from sesame oil by a known method (for example, the method described in JP-A-4-9331) (referred to as sesamin extract or concentrate) is usually used. Although it can also be used, commercially available sesame oil (liquid state) can also be used as it is. However, when sesame oil is used, the sesamin content is low (usually less than 1%), so when trying to add sesamin necessary to obtain the physiological effect of sesamin, the amount of the composition to be formulated per unit dose The volume can become too large, which can cause inconveniences. In particular, when formulated for oral administration, the dosage form (tablets, capsules, etc.) becomes too large, which causes problems in ingestion. Therefore, it is preferable to use a sesamin extract (or sesamin concentrate) from sesame oil from the viewpoint that the amount of intake may be small. In addition, since the flavor peculiar to sesame oil may be evaluated to be sensory unfavorable, the sesamin extract (or sesamin concentrate) may be made tasteless and odorless by a known means such as activated clay treatment.

    Thus, as sesamin, it is preferable to use a sesamin concentrate obtained by improving the concentration of sesamin by extraction and / or purification from a food-derived material such as sesame oil. The degree of concentration may be appropriately set depending on the type of sesamin used and the form of the composition to be blended. Usually, a sesamin concentrate concentrated so that the total amount of sesamin is 1% by weight or more is used. Is preferred. The total sesamin content in the sesamin concentrate is preferably 20% by weight or more, more preferably 50% by weight or more, still more preferably 70% by weight or more, and is concentrated (purified) to 90% by weight or more. Is optimal.

In addition, as long as the metabolite of sesamin shows the effect of this invention, it is a sesamin analog contained in the sesamin of this invention, and can be used for this invention.

(Food)
In the present invention, sesamin may be used as it is or in the form of a composition containing a pharmaceutically acceptable additive. This composition may decrease or increase blood homocysteine concentration. Compositions (including functional foods, health supplements, functional nutritional foods, special purpose foods, health foods such as foods for specified health use, supplements for animals), foods and drinks, animal feeds, etc. Or in an orally administered form. In the present invention, these are collectively called food and drink.

  The food or drink of the present invention can be formulated according to the purpose by a general method together with a pharmacologically acceptable carrier, diluent or excipient. Examples of diluents and carriers include liquid diluents such as water, ethanol, propylene glycol and glycerin, solid diluents and excipients such as glucose, sucrose, dextrin, cyclodextrin and gum arabic. In addition, emulsifiers, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, and the like that are generally used in formulation can be appropriately blended.

In order to enhance the homocysteine lowering action, vitamins such as folic acid, vitamin B6, and vitamin B12 may be added to the food and drink of the present invention.
Furthermore, other physiologically active ingredients such as minerals; vitamin E, vitamin C, vitamin A are used as necessary as long as the effects of sesamin are not impaired, that is, an undesirable interaction is not caused by blending with sesamin. Vitamins such as vitamin B and folic acid; nutritional ingredients; fragrances; other additives such as pigments can be mixed. Any of these additives commonly used for pharmaceuticals and foods and drinks can be used.

  The form of the food or drink of the present invention is not particularly limited. For example, it is a solid such as a powder, granule, or tablet; a liquid such as a solution, an emulsion, or a dispersion; or a paste It can be prepared in any form such as semi-solid. Specific dosage forms include powders, granules, fine granules, tablets, pills, troches, capsules (including soft capsules and heart capsules), chewable agents, solution agents, and the like.

  Moreover, it may be in a form prepared by adding and blending sesamin as an active ingredient to a conventional food and drink material, for example, beverages such as juice, milk, coffee beverage, tea beverage, liquid food such as soup, Any form such as pasty foods such as yogurt, semi-solid foods such as jelly and gummi, solid foods such as cookies and gums, and fat-containing foods such as dressings and mayonnaise may be used.

  The food / beverage product of the present invention contains sesamin as an active ingredient in an amount of preferably 0.001 to 5% by weight, more preferably 0.01 to 3% by weight, and still more preferably 0.05 to 1% by weight. Can be used as a form.

  The food / beverage products of the present invention are food / beverage products that can reduce or suppress the increase in blood homocysteine concentration. What is necessary is just to select suitably the dosage amount and dosage form of food-drinks (especially pharmaceutical composition) according to a subject, a disease state, its progress, and other conditions. For example, when sesamin is selected as the sesamin and is orally administered for the purpose of improving hyperhomocysteinemia in humans (adults), generally sesamin is 1 to 200 mg per day, preferably The dose may be continuously administered at a rate of about 20 to 100 mg, more preferably about 30 to 100 mg, about once or twice a day and 5 or more times a week.

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited thereto.
Example 1. Homocysteine lowering action of sesamin (1)
We examined the homocysteine-lowering effect of sesamin on rats that were made high homocysteine with a low vitamin diet. The specific test method is as follows.

Sprague Dawley male rats (9 weeks old) were purchased from CLEA Japan and acclimated in a test environment for 1 week, and animals that showed normal growth were used for the test. On the day before the start of the test, the rats were divided into 2 groups of 6 animals each, and both groups were prepared by partially modifying AIN-93G (vitamin B6, B12, the amount of folic acid was 1/5 of that of the normal diet. In 100g of feed, the compounding amount was vitamin B6 = 0.12 mg, vitamin B12 = 0.5 μg, folic acid = 0.04 mg: Oriental Yeast Co., Ltd.) for 2 days, and then the control group Dissolves olive oil at a dose of 3 ml / Kg, sesamin group (sesamin / episesamin mixture; sesamin: episesamin (weight ratio) = 5: 5) dissolved in olive oil at a dose of 100 mg / kg, And was administered orally. This administration was carried out at a rate of 5 times / week for 2 weeks, and after fasting overnight, blood was collected, and the amount of plasma homocysteine (total homocysteine concentration in blood) was measured. The amount of homocysteine was measured according to the method described in Kuo K et al. (1997) Clin. Chem. 43, 1653. Specifically, after blood collection, EDTA plasma was separated, the thiol group of homocysteine was reduced, and then deproteinized with acid. After neutralization, the sample was diluted with a buffer, fluorescently labeled, and analyzed by HPLC. For HPLC analysis, column: Develosil RP AQUEOUS-AR, fluorescence: Ex. 385 nm / Em. 515 nm, flow rate: 0.8 ml / min, buffer: 0.1 M KH ₂ PO ₄ (4% AcCN, pH 2.0) Was used.

  The result is shown in FIG. The homocysteine concentration was 7.16 μmol / L in the control group and 4.82 μmol / L in the sesamin 100 mg / Kg administration group, and the amount of homocysteine was significantly lower than the control group (significant level 1%). ). From this result, it became clear that sesamin has a homocysteine lowering action.

In addition, this experiment suggests that administration of sesamin is effective for patients who show a slightly high homocysteine concentration but a normal value.
Example 2 Homocysteine lowering action of sesamin (2)
Sprague Dawley male rats (9 weeks old) were purchased from CLEA Japan and acclimated in a test environment for 1 week, and animals that showed normal growth were used for the test. On the day before the start of the test, the rats were divided into two groups of 3 animals each, and both were bred for 2 weeks on the low vitamin diet used in Example 1, and then the control group was olive oil at a dose of 3 ml / Kg and the sesamin group. Sesamin (sesamin / episesamin mixture; sesamin: episesamin (weight ratio) = 5: 5) was dissolved in olive oil at a dose of 20 mg / Kg and orally administered using a sonde. This administration was performed at a rate of 5 times / week for 2 weeks, blood was collected after fasting overnight, and the amount of plasma homocysteine was measured.

The result is shown in FIG. No change in homocysteine amount was observed in the sesamin 20 mg / Kg administration group, and it was revealed that even when ingested sesamin at a low dose, no homocysteine lowering effect was shown.
Example 3 FIG. Formulation example
(Formulation Example 1) Granules Sesamin 3.0g
Tocopherol acetate 5.0g
Silica anhydride 20.0g
Corn starch 172.0g
After uniformly mixing the above powder, 100 ml of 10% hydroxypropylcellulose / ethanol solution was added, kneaded as usual, extruded and dried to obtain granules. This granule is taken 2g per day.
(Formulation Example 2) Capsule Gelatin 60.0%
Glycerin 30.0%
Methyl paraoxybenzoate 0.15%
Propyl paraoxybenzoate 0.51%
Appropriate amount of water The following composition was filled in a soft capsule skin made of the above-mentioned components by a conventional method to obtain about 360 mg of soft capsules per tablet.

Sesamin 10.0mg
Glycerin fatty acid ester 15.0mg
Beeswax 15.0mg
Wheat germ oil 250mg
This soft capsule is taken 360mg per day.
(Formulation example 3) Tablet sesamin 30g
252 g starch
Sucrose fatty acid ester 9.0g
9.0g of silicon oxide
These were mixed and tableted with a single-punch tableting machine to produce tablets with a diameter of 9 mm and a weight of 300 mg. This tablet is taken 2 tablets 600mg per day.
(Formulation example 4) Taste of drink agent: DL-sodium tartrate 0.1 g
0.009 g of succinic acid
Sweetness: 800g liquid sugar
Acidity: Citric acid 12g
Vitamins: Vitamin C 10g
Sesamin 1g
Vitamin E 30g
Cyclodextrin 5g
Fragrance 15mL
1g potassium chloride
Magnesium sulfate 0.5g
The above ingredients were blended and water was added to make 10 liters. About 200 mL of this drink is drunk.

  The composition, food / beverage product, and feed of the present invention exhibit an excellent homocysteine lowering action, particularly an action for improving hyperhomocysteinemia. Therefore, diseases that are said to involve homocysteine, such as arteriosclerosis, myocardial infarction, cerebral infarction, ischemic heart disease, circulatory dysfunction, peripheral vascular disorder, Alzheimer's disease, and other vascular-related symptoms It is expected to be useful for the prevention, amelioration or treatment.

It is a figure which shows the homocysteine reduction effect of sesamin 100mg / Kg intake. It is a figure which shows the homocysteine reduction effect of sesamin 20mg / Kg intake.

Claims (7)

A hyperhomocysteinemia improving agent containing sesamin as an active ingredient. The hyperhomocysteinemia according to claim 1, characterized by oral administration to a mammal deficient or deficient in any one or more of vitamin B groups selected from the group consisting of folic acid, vitamin B6 and vitamin B12 Improver. The agent for improving hyperhomocysteinemia according to claim 1, which suppresses an increase in blood homocysteine concentration induced by aging, smoking or drinking. The hyperhomocysteinemia improving agent according to any one of claims 1 to 3, comprising 1 to 200 mg of the sesamin per daily intake of the hyperhomocysteinemia improving agent. The agent for improving hyperhomocysteinemia according to any one of claims 1 to 4, wherein the sesamin is sesamin, episesamin or a sesamin / episesamin mixture. A food or drink comprising the hyperhomocysteinemia improving agent according to any one of claims 1 to 5. An anti-aging agent containing sesamin as an active ingredient.