WO2000056329A1 - Preventives/remedies for arteriosclerosis - Google Patents

Abstract

Preventives/remedies for arteriosclerosis containing, as the active ingredients, C20 monoenoic acids and/or derivatives thereof and C22 monoenoic acids and/or derivatives thereof, which preferably contain as the active ingredient a fat containing from 0.2 to 17 parts by weight of the C22 monoenoic acids and/or derivatives thereof per part by weight of the C20 monoenoic acids and/or derivatives thereof.

Description

 Description Arteriosclerosis prevention / treatment agent Technical field

 The present invention relates to a therapeutic agent for arteriosclerosis for the purpose of treating a patient who has developed arteriosclerosis by dietary therapy or the like, and for treating a risk factor of arteriosclerosis for preventing the owner from developing arteriosclerosis.

 More specifically, the present invention relates to a prophylactic and therapeutic agent for arteriosclerosis containing monoenoic acid having 20 carbon atoms and / or a derivative thereof, and monoenoic acid having 22 carbon atoms and Z or a derivative thereof as an active ingredient. . Background art

 Conventionally, to prevent arteriosclerosis, a type of lifestyle-related disease, the effects of diets rich in monounsaturated fatty acids (monoenoic acid), such as oleic acid, have been studied. Olive oil administration is known to reduce LDL-cholesterol, not HDL-cholesterol, reduce triglycerides, and ingest monounsaturated fatty acids (monoenoic acid) to prevent arteriosclerosis. It is known to be recommended (supervised by Ichiro Hara, "Nutrition and Diseases of Oils and Fats", No. 385, pp. 396, Koshobo, 1990).

 Also, for the prevention of atherosclerosis, a nutritional composition has been disclosed in which the proportion of oleic acid is increased by blending olive oil to approximate a Mediterranean diet (Japanese Unexamined Patent Publication No. Hei 5- No. 3049492).

However, these conventional techniques have the following disadvantages. As disclosed in the above prior art, it is known that the intake of monoenoic acid is recommended for preventing arteriosclerosis, and a nutritional composition containing monoenoic acid for preventing arteriosclerosis has been developed. . However, conventional nutritional compositions for preventing atherosclerosis mainly use oleic acid having 18 carbon atoms or partially palmitoleic acid having 16 carbon atoms derived from olive oil as monoenoic acid. Carbon which is monoenoic acid The use of a combination of monoenoic acid and / or a derivative thereof having the number of 20 and monoenoic acid and / or a derivative thereof having a carbon number of 22 and the use of these in a specific weight ratio have not been considered at all. Did not. Disclosure of the invention

 In view of the above prior art, the present inventors have found out the types and combinations of monoenoic acids having a high effect of preventing and treating arteriosclerosis and aiming to develop a therapeutic agent for preventing and treating arteriosclerosis. The test was performed on acids.

 As a result, as is clear from the results of the test examples described below, it is clear that monoenoic acid having 20 carbon atoms and a derivative thereof, or a derivative thereof, and monoenoic acid having 22 carbon atoms and Z or a derivative thereof can be used in combination. Compared to the case of using oleic acid having 18 carbon atoms or palmitoleic acid having 16 carbon atoms, which are relatively low-order monoenoic acids, the present inventors have found that the effect of preventing and treating arteriosclerosis is higher than that of using monooleic acid having 16 carbon atoms. Completed the invention.

 An object of the present invention is to provide a novel agent for preventing and treating arteriosclerosis.

 The present invention which solves the above-mentioned problems is a monoenoic acid having 20 carbon atoms and / or a derivative thereof, and an agent for preventing and treating arteriosclerosis containing a monoenoic acid having 22 carbon atoms and Z or a derivative thereof as an active ingredient. An oil or fat containing 0.2 to 17 parts by weight of monoenoic acid having 22 carbon atoms and Z or a derivative thereof with respect to 1 part by weight of monoenoic acid and / or a derivative thereof is used as an active ingredient. (Hereinafter referred to as Embodiment 1) is also a preferred embodiment. BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described in detail.

The monoenoic acid having 20 carbon atoms and / or a derivative thereof, and the monoenoic acid having 22 carbon atoms and / or a derivative thereof, which are the active ingredients of the agent for preventing and treating arteriosclerosis of the present invention, specifically have 20 carbon atoms. Gondonoic acid (gondouric acid), gadolinic acid, and icosenoic acid (eicosenoic acid) such as 5-icosenoic acid and Z or its derivatives, and eruconic acid (erucic acid) having 22 carbon atoms, cetrenic acid, and 5-docosene Docosenoic acid such as an acid and / or a derivative thereof. The monoenoic acid having 20 carbon atoms and the monoenoic acid having 22 carbon atoms, which are higher monoenoic acids used in the present invention, are not particularly limited as long as they are pharmaceutically or foodally acceptable. It is possible to use natural oils and fats with high monoenoic acid content, such as meadow hom oil, such as soybean liver oil, whale oil, cod liver oil, rapeseed oil, mustard oil, cabbage seed oil, jojoba oil, etc. It is also possible to extract and purify icosenoic acid or docosenoic acid from these natural fats and oils in a conventional manner, for example, by fractional distillation, crystallization, solvent extraction, urea clathration, or chromatography. It is possible. For convenience, commercially available gondioic acid or erucic acid (both of which are sigmanes: t) can be used.

 The monoenoic acid having 20 carbon atoms, which is a higher monoenoic acid used in the present invention, and a derivative of a monoenoic acid having 22 carbon atoms, a so-called higher monoenoic acid derivative, include salts of higher monoenoic acid, Derivatives such as esters are included. Specific examples include salts with alkali metals such as sodium and potassium, esters with lower aliphatic alcohols such as methanol and ethanol, and mono-, di-, and triglycerides.

 As shown in Embodiment 1 of the present invention, 0.2 to 17 parts by weight of a monoenoic acid having 22 carbon atoms and / or a derivative thereof is added to 1 part by weight of a monoenoic acid having 20 carbon atoms and / or a derivative thereof. As is clear from the results of the test examples described below, it is apparent that the fats and oils contained in the weight ratio (hereinafter sometimes referred to as a specific range of weight ratio) may be used as an active ingredient when the weight ratio is not within the specific range. In comparison, it is desirable because the effects of preventing and treating arteriosclerosis are high.

 The therapeutic agent for preventing or treating arteriosclerosis of the present invention can be administered to humans or animals by intravenous injection, oral administration, tube administration, and enteral administration, for example, depending on the administration method and the purpose of treatment. Various dosage forms, which are common pharmaceutical preparation forms, can be selected. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions, suspensions, etc.) and the like.

 In addition, the therapeutic agent for preventing or treating arteriosclerosis of the present invention can be orally supplied as a nutritional composition in the form of general food or drink for dietary therapy.

The effective dose of the therapeutic agent for preventing or treating arteriosclerosis of the present invention is the case of oral administration. The same applies to salary. ) From the test results using mice, the monoenoic acid having 20 carbon atoms and its derivative or the monoenoic acid having 22 carbon atoms and Z or its derivative

It was found to be 5-4 0 0 111 ₈ 7 weight 1 ^ g / 1 day the amount of the active ingredient consisting of (hereinafter, may be referred to as a premium monoenoic acids.) As standards.

Also, higher monoenoic acids as an active ingredient of the arteriosclerosis prophylactic treatment agent of the present invention, the results of acute toxicity test by oral administration using the mouse, extremely low toxicity, LD ₅₀ in 1 0 g / kg of body weight or more Yes, it can be used safely in humans or animals and with extremely few side effects.

 Furthermore, the therapeutic agent for preventing or treating arteriosclerosis of the present invention can be used in combination with other substances having an effect of preventing and treating arteriosclerosis, such as monoenoic acid and polyunsaturated fatty acids. In particular, it is desirable to contain a monoenoic acid having 24 carbon atoms and / or a derivative thereof from the viewpoint of synergistically enhancing the effects of preventing and treating arteriosclerosis.

 Further, the content of the monoenoic acid having 24 carbon atoms and Z or a derivative thereof is based on 1 part by weight of the monoenoic acid having 20 carbon atoms and / or a derivative thereof in the therapeutic agent for preventing or treating arteriosclerosis according to Embodiment 1 of the present invention. It is preferable to contain monoenoic acid having 24 carbon atoms and Z or a derivative thereof in a weight ratio of 0.1 to 10 parts by weight in order to further enhance the preventive and therapeutic effects of arteriosclerosis synergistically. That is, with respect to 1 part by weight of monoenoic acid having 20 carbon atoms and / or a derivative thereof, 0.2 to 17 parts by weight of monoenoic acid having 22 carbon atoms and Z or a derivative thereof, and monoene acid having 24 carbon atoms. An agent for preventing or treating arteriosclerosis containing an oil or fat as an active ingredient and containing 0.1 to 10 parts by weight of an acid and a derivative thereof or a derivative thereof is preferable because it further enhances the effect of preventing and treating arterial sclerosis.

 The monoenoic acid having 24 carbon atoms and / or a derivative thereof is, specifically, a tetracosenoic acid such as nervonic acid (ceracoleic acid, shark oil acid) having 24 carbon atoms and a derivative thereof.

 Next, the present invention will be described in detail with reference to test examples. In the present invention, the following test method was employed as a test method for preventing and treating arteriosclerosis. a) Serum collection method

SD rats (6-week-old female) were used as the basic diet shown in Table 1 and used in each test. The feed prepared by adding 0.2% was orally administered at a dose of 15 g per day and bred for 3 weeks, after which blood was collected and serum was separated. Ten SD rats were used for each sample group. Water was available ad libitum. table 1

b) Method for measuring serum cholesterol level

 The cholesterol level in the serum was measured by an enzyme method using a commercially available cholesterol E test (manufactured by Wako Pure Chemical Industries, Ltd.), and the average value of 10 SD rats in each sample group was calculated. c) Method for measuring high-density lipoprotein cholesterol (HDL cholesterol) in serum

HDL cholesterol in the serum was measured by precipitation and enzymatic method using a commercially available HDL cholesterol E test (manufactured by Wako Pure Chemical Industries, Ltd.). The average was calculated. d) Method for evaluating the preventive and therapeutic effects of arteriosclerosis From the serum cholesterol level (A) and HDL cholesterol level (B), the percentage (C) calculated by the following equation: If the percentage is low, the risk of arteriosclerosis is high, and if the percentage is high, the percentage is high. Since the risk of arteriosclerosis is low and can be used as an indicator of arteriosclerosis, the preventive and therapeutic effects of arteriosclerosis were evaluated based on the percentage.

 B / A X 1 0 0 = C Test example 1

 This test was performed to compare the present invention with the prior art, using the percentage of the HDL cholesterol value relative to the serum cholesterol value as an index.

(1) Sample preparation

 The following seven samples were prepared.

Sample 1: Higher monoenoic acid mixture comprising 1 part by weight of gondic acid which is a monoenoic acid having 20 carbon atoms and 1 part by weight of erucic acid which is a monoenoic acid having 22 carbon atoms of the present invention

Sample 2: Gondoic acid

Sample 3: L-acid

Sample 4: Prior art oleic acid having 18 carbon atoms

Sample 5: 16-carbon palmitoleic acid of the prior art

Sample 6: Monoenoic acid mixture consisting of 1 part by weight of oleic acid and 1 part by weight of erlic acid Sample 7: Monoenoic acid mixture consisting of 1 part by weight of oleic acid and 1 part by weight of gondic acid

 Gondoic acid, erucic acid, oleic acid, and palmitoleic acid were all commercially available products (manufactured by Sigma).

(2) Test method

The preventive and therapeutic effects of each sample on arteriosclerosis were tested by the test methods described above. (3) Test results

 The results of this test are shown in Table 2. As is clear from Table 2, the sample 1 of the higher monoenoic acid mixture of the present invention has a lower cholesterol level in serum than the sample 4 using oleic acid of the prior art and the sample 5 using palmitoleic acid. The percentage of HDL cholesterol to the HDL cholesterol level was high, indicating that it was excellent in preventing and treating arteriosclerosis.

 In addition, the higher monoenoic acid mixture sample 1 of the present invention has a higher HDL cholesterol percentage relative to the serum cholesterol value than the sample 2 using gondic acid alone and the sample 3 using erucic acid alone. Compared with Sample 6 which is a monoenoic acid mixture in which gondoic acid is replaced by oleic acid in Sample 1 and Sample 7 which is a monoenoic acid mixture in which erlic acid is replaced by oleic acid in Sample 1, Because of the high percentage of HDL cholesterol relative to cholesterol in serum, the prevention and treatment of arteriosclerosis requires the use of gondonic acid, a monocarbonic acid having 20 carbon atoms, and monoenoic acid, having 22 carbon atoms. The use of an erucic acid, which is an acid, in combination, ie, monoenoic acid having 20 carbon atoms and / or a derivative thereof, and monoenoic acid having 22 carbon atoms and Z or its It was found that the combined use of derivatives which are effective.

In addition, 20 g of carbonic acid, 5-icosenoic acid, or a derivative thereof, instead of gondic acid, or cetreic acid, 5 g-docosenoic acid of 22 carbon atoms, which is replaced with eric acid, or Tests using these derivatives gave almost similar results. The test was conducted by appropriately changing the weight ratio of monoenoic acid in Sample 1 within the range of 0.2 to 17 parts by weight of L-acid acid with respect to 1 part by weight of gondinoic acid, and almost the same results were obtained. Was. In addition, tests were performed by appropriately changing the weight ratio of monoenoic acid in Samples 6 and 7, and almost the same results were obtained. Blood コ Cholesteron in the stomach 1 ο Sample number

 Percentage of HDL cholesterol level (%)

 1 5 4

 2 3 1

 3 3 0

 4 2 6

 5 3 2

 6 3 3

 7 3 5 Test example 2

 In this test, the weight ratio of monoenoic acid and Ζ or a derivative thereof having 20 carbon atoms, and monoenoic acid and ノ or a derivative thereof having 22 carbon atoms was measured using the percentage of HDL cholesterol value relative to the cholesterol value in serum as an index. Went to find out.

(1) Sample preparation

 The following four samples were prepared.

Sample 8: Higher monoenoic acid mixture consisting of 1 part by weight of gondic acid, which is a monoenoic acid having 20 carbon atoms, and 0.1 part by weight of erucic acid, which is a monoenoic acid having 22 carbon atoms Sample 9: Monoene having 20 carbon atoms Higher monoenoic acid mixture consisting of 1 part by weight of gondic acid as an acid and 0.2 part by weight of erlic acid as a monoenoic acid having 22 carbons Sample 10: 1 part by weight of gondonic acid as a monoenoic acid having 20 carbons and Sample 11: 1 part by weight of gondonic acid, a monoenoic acid having 20 carbon atoms, and 1 part by weight of a monoenoic acid, which is a monoenoic acid having 22 carbon atoms. Higher monoenoic acid mixture consisting of 18 parts by weight of lactic acid

(2) Test method

The preventive and therapeutic effects of each sample on arteriosclerosis were tested by the test methods described above. (3) Test results

 The results of this test are shown in Table 3. As is evident from Table 3, the weight ratio of genoic acid, a monoenoic acid having 20 carbon atoms, to 1 part by weight of ernoic acid, a monoenoic acid having 22 carbon atoms, is 0.2 to 17 parts by weight. In order to prevent and treat arteriosclerosis more effectively, the ratio of HDL cholesterol to serum cholesterol is higher in the case of It has been found that it is desirable that the monoenoic acid having 22 carbon atoms and / or its derivative be in a weight ratio of 0.2 to 17 parts by weight to 1 part by weight of the derivative thereof.

 In addition, 20 carbon atoms of gadoleic acid, 5-icosenoic acid, or derivatives thereof, instead of gondic acid, or cetrenic acid, 5 -docosenoic acid of 22 carbon atoms, instead of erucic acid, or Tests using these derivatives gave almost similar results.

次に実施例を示して本発明を更に詳細に説明するが、 本発明は以下の実施例 限定されるものではない。 実施例

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples. Example

Example 1

Using a mixture of 150 g of gondonic acid (manufactured by Sigma) and 150 g of erucic acid (manufactured by Sigma) of a high monoenoic acid mixture, the mixture was added to a gelatin capsule of No. 1 of the Japanese Pharmacopoeia. Fill the capsule with 0 O mg each, and gelate the joint between the capsule cap and the body. Then, 900 capsules for preventing and treating arteriosclerosis were manufactured.

 Administration of 10 of the resulting forcepsels per day to in-house volunteers with risk factors for arteriosclerosis significantly improved the percentage of HDL cholesterol to serum cholesterol. Example 2

500 g of gondolic acid (manufactured by Sigma), lkg of erucic acid (manufactured by Sigma), and 1.5 kg of anhydrous ethanol (manufactured by Wako Pure Chemical Industries) were mixed to obtain a homogeneous solvent. Next, 8.5 kg of calcium carbonate (manufactured by Wako Pure Chemical Industries, Ltd.) is added to the mixed solution, the mixture is kneaded, and the mixture is dried at 40 ° C to remove ethanol. The obtained composition was directly tableted with a tableting machine (manufactured by Hata Iron and Steel Works) at a pressure of 3 tZm ² to obtain tablets having a diameter of 10 mm and a weight of 40 Omg.

 The surface of the tablet was coated by spraying with a homogeneous mixed solution of 8.5 kg of hydroxypropylmethylcellulose phthalate (Shin-Etsu Chemical Co., Ltd.) and 100 kg of acetone (Mitsui Petrochemical Co., Ltd.), and an arterial weight of 44 Omg was coated. 30,000 anti-sclerosis tablets were manufactured.

 Administration of 30 tablets per day to in-house volunteers with risk factors for atherosclerosis resulted in a marked improvement in the percentage of HDL cholesterol to serum cholesterol. Example 3

 Mustard oil (manufactured by Minohisa Inc., containing 14% of gondic acid and 21% of erucolic acid) 4.0 kg and 20 g of sorbitan fatty acid ester (manufactured by Kao Corporation, HLB 3.8) were added. Mix uniformly to form an oil phase. The oil phase is mixed with sodium caseinate [manufactured by New Zealand Dairy Board] 3.0 kg dissolved in 96 kg aqueous solution, and the mixed solution is stirred at 70 ° C for 5 minutes with a propeller stirrer. Preliminary emulsification was performed to prepare about 100 kg of a raw material solution.

Then, the raw material solution was heated to 60 ° C., homogenized with a homogenizer (manufactured by Sanmaru Machinery Co., Ltd.) in two stages (15 MPa and 5 MPa), and then subjected to an ultra-high temperature heat sterilizer (Morinaga Milk) Was sterilized at 135 ° C for 15 seconds to produce about 90 kg of synthetic milk for prevention and treatment of arteriosclerosis.

 The resulting synthetic milk was fed to an in-house volunteer with a risk factor for arteriosclerosis at a dose of 20 Om / day, resulting in a marked improvement in the percentage of HDL cholesterol to serum cholesterol. Example 4

 Casein [New Zealand Dairy Board] 4.2 kg, dextrin (manufactured by Sanmatsu Industries, Ltd. DE = 27) 14. O kg, and indigestible dextrin (Matsuya Chemical Industries 2. O kg was dispersed in 75.35 kg of tap water and dissolved, and 0.3 kg of the mineral mixture mixed with the compounding amount shown in Table 4 was added to form a water phase. . 0.03 kg of glycerin fatty acid ester (manufactured by Taiyo Chemical Co., Ltd.) is added to the aqueous phase as an emulsifier, and mustard oil (manufactured by Minohisa Inc., containing 14% of gondic acid and 21% of erucolic acid.) 4. O kg, and the mixture was pre-emulsified with a propeller stirrer at 70 ° C. for 5 minutes to prepare about 100 kg of a raw material solution. Subsequently, the raw material solution was homogenized using a high-pressure homogenizer (manufactured by APV Rannie) at a pressure of 30 MPa. After homogenization, 0.02 kg of vitamin mixture and 0.1 kg of vanilla flavor (manufactured by Saneigen F'F.I. Co.) were added to the obtained emulsion. The mixture was mixed and filled into retort bouches (manufactured by Toyo Seikan Co., Ltd.) in a volume of 200 ml each, and sealed, to produce 400 retort bouches containing nutrient threads. The filled retort bouch was sterilized at 125 ° C for 10 minutes using a retort sterilizer (manufactured by Hisaka Seisakusho) to produce 400 nutritional compositions for preventing and treating arteriosclerosis as a liquid food. did.

Use of the resulting liquid diet in in-house volunteers with atherosclerosis risk factors resulted in a significant improvement in the percentage of HDL cholesterol to serum cholesterol. Table 4

表 5

Table 5

産業上の利用可能性

Industrial applicability

 As described above in detail, the present invention relates to a therapeutic agent for preventing or treating arteriosclerosis comprising monoenoic acid having 20 carbon atoms and Z or a derivative thereof, and monoenoic acid having 22 carbon atoms and / or a derivative thereof as an active ingredient. The effects provided by the present invention are as follows.

 The agent for preventing or treating arteriosclerosis of the present invention is useful for treating patients suffering from arteriosclerosis causing hypertension, heart disease and the like by dietary therapy, and for preventing the onset of arteriosclerosis in those who have a risk factor for arteriosclerosis. Useful.

Claims

The scope of the claims 1. A preventive and therapeutic agent for arteriosclerosis comprising monoenoic acid having 20 carbon atoms and Z or a derivative thereof, and monoenoic acid having 22 carbon atoms and / or a derivative thereof as active ingredients. 2. An oil or fat containing a monoenoic acid having 22 carbon atoms and / or a derivative thereof in a weight ratio of 0.2 to 17 parts by weight with respect to 1 part by weight of monoenoic acid having 20 carbon atoms and Z or a derivative thereof. The agent for preventing or treating arteriosclerosis according to claim 1, which is an active ingredient. 3. The arteriosclerosis preventive agent according to claim 2, wherein the fat or oil contains 0.1 to 10 parts by weight of monoenoic acid having 24 carbon atoms and Z or a derivative thereof. 4. A dietary composition comprising monoenoic acid having 20 carbon atoms and / or a derivative thereof, and monoenoic acid having 22 carbon atoms and Z or a derivative thereof. 5. Claims containing a monoenoic acid having 22 carbon atoms and / or a derivative thereof in a weight ratio of 0.2 to 17 parts by weight per 1 part by weight of monoenoic acid having 20 carbon atoms and Z or a derivative thereof. A composition according to claim 4. 6. The composition according to claim 5, comprising 0.1 to 10 parts by weight of monoenoic acid having 24 carbon atoms and Z or a derivative thereof. 7. Use of a composition containing a monoenoic acid having 20 carbon atoms and Z or a derivative thereof, and a monoenoic acid having 22 carbon atoms and Z or a derivative thereof for the manufacture of a therapeutic agent for preventing or treating arteriosclerosis. 8. The weight ratio of the monoenoic acid having 22 carbon atoms and / or a derivative thereof to 0.2 to 17 parts by weight based on 1 part by weight of the monoenoic acid having 20 carbon atoms and Z or a derivative thereof. Use of the composition according to claim 7, which is contained in: 9. Use according to claim 8, wherein said composition contains 0.1 to 10 parts by weight of monoenoic acid having 24 carbon atoms and / or its derivatives. 10. A method for preventing and treating arteriosclerosis, comprising administering a composition containing monoenoic acid having 20 carbon atoms and Z or a derivative thereof, and monoenoic acid having 22 carbon atoms and Z or a derivative thereof. 1 1. The composition contains 0.2 to 17 parts by weight of monoenoic acid having 22 carbon atoms and Z or a derivative thereof to 1 part by weight of monoenoic acid having 20 carbon atoms and Z or a derivative thereof. 11. The method for preventing and treating arteriosclerosis according to claim 10. 12. The method for preventing and treating arteriosclerosis according to claim 11, wherein the composition contains 0.1 to 10 parts by weight of monoenoic acid having 24 carbon atoms and / or a derivative thereof.