JP2008088078A - Reducing agent of small dense low density lipoprotein in blood - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a reducing agent of a small dense low density lipoprotein (small dense LDL) in blood, capable of reducing the small dense LDL in the blood without reducing the low density lipoprotein (LDL). <P>SOLUTION: This reducing agent of the small dense LDL in the blood is provided by containing a 20-36C higher aliphatic alcohol as an active ingredient. This can be widely utilizable as a medicine or food useful for the prevention or improvement of arteriosclerosis or in a wider sense, for the improvement of metabolic syndrome. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a blood small dense low-density lipoprotein reducing agent. More specifically, the present invention relates to a blood small density low density lipoprotein lowering agent that lowers blood small density low density lipoprotein without reducing the total amount of low density lipoprotein (LDL). INDUSTRIAL APPLICABILITY The present invention is widely used as pharmaceuticals, foods, etc. useful for preventing or improving arteriosclerosis, and broadly improving metabolic syndrome.

Currently, cancer is the leading cause of death among Japanese. However, the total of the second largest heart disease and the third brain disease, which are vascular diseases, is approaching the first cancer. The biggest cause of these is that the metabolic symdome triggers arteriosclerosis.
This metabolic syndrome is a state in which two or more pathological conditions resulting from lifestyle such as obesity, hypertension, hyperlipidemia, and diabetes are combined. There is a consensus that obesity, in particular obesity with visceral fat accumulation (visceral fat-type obesity), is deeply involved in its development. The concept of “metabolic syndrome” was established for the purpose of providing an index for preventing cardiovascular diseases (myocardial infarction, angina pectoris, cerebral infarction, obstructive arteriosclerosis, etc.) due to arteriosclerosis. Arteriosclerosis is a symptom that is difficult to appear as a lesion if it does not progress to some extent, and metabolic syndrome is deeply involved in its onset.
In recent studies, in relation to metabolic syndrome, small dense low-density lipoprotein (hereinafter referred to as small dense LDL) in the LDL fraction in blood has a great influence on the onset of arterial effect. It has become clear. In patients with arterial disease, it has been reported that low-density lipoprotein (LDL) levels are normal but small-dense LDL is high, suggesting that qualitative abnormalities of LDL are strongly associated with arterial disease. (Non-Patent Document 1).

  Small dense LDL is LDL having a particle size of 25.5 nm or less. Such a small LDL is inferior in binding affinity with the LDL receptor and has a long residence time in the blood. This results in prolonged contact with vascular endothelial cells. Further, vitamin E and ubiquinol 10 for preventing oxidation, which should originally be possessed due to the miniaturization, are scarce and are very susceptible to oxidation by active oxygen. In addition, since the particle size is small, it easily penetrates into the arterial wall through the gaps of vascular endothelial cells. That is, small dense LDL is likely to be a precursor of oxidized LDL, which is a causative agent of arteriosclerosis, and is considered to be a strong arteriosclerosis-inducing substance that enters the blood vessel wall and promotes inflammation.

Since small dense LDL is a form of LDL, the use of statin drugs that inhibit the biosynthesis of cholesterol, which is a constituent component, can be considered to reduce this.
In a large-scale survey of double-blind statin drugs targeting 4000-9000 patients in 1994-98 (Non-Patent Documents 2-6), statin drugs were used for a long period of about 5 years. As a result of administration, the LDL-cholesterol level in blood, which is an index of the amount of LDL, decreased by 25-35%, the onset of myocardial infarction decreased by 23-34%, and the overall mortality rate decreased by 10-30%. Has been proven effective.
However, reducing the amount of LDL in the blood by such a method reduces the amount of total cholesterol in the blood, and its side effects are known.
First, a depression trend appears. For example, 195 men aged 65 years and older were scored for depression, and in the group with low and moderate blood total cholesterol levels, depression progressed 4 years later. In the high cholesterol group, there was a tendency to improve depression. (Non-patent document 7)
Next, there are some reports that cancer increases when the total cholesterol level in the blood decreases. The cell membrane of immune cells is also formed from cholesterol, and lymphocytes and macrophages such as killer T cells and NK cells are also said to be susceptible to cancer because of their functional decline. Specifically, as a result of analyzing domestic and foreign papers on cancer and cholesterol levels, it has been reported that the lower the LDL-cholesterol level, the higher the incidence and mortality of cancer (Non-patent Document 8).
Shinji Kiba et al., Journal of the Japanese Society of Cardiology, Vol. 36 No. 6 371-78 (2000) Scandinavian Simvastatin Survival Study Group, Lancet, 1994, 344, 1383-1389. Sacks FM et al., N Engl J Med, 1996, 335, 1001-1009. The Long-Term Intervention with Pravastatin in Ischiamatic Disease (LIPID) Study Group, N Engl J Med, 1988, 339, 1349-1357 Shepherd J et al., N Engl J Med, 1995, 333: 1301-1307. Downs, JR et al., JAMA, 1998, 279: 1615-1622. Shibata H et al., J Epideiol, 1999, Aug; 9 (4): 261-7. Yuko Tamakoshi et al., Journal of Japanese Society of Public Health vol. 41 no. 5 393-403.

Thus, when cholesterol biosynthesis inhibitors are used, the amount of LDL in the blood can be reduced, but there is a risk of side effects in long-term use.
Therefore, in order to prevent arteriosclerosis triggered by a metabolic symdome, it is necessary to reduce only the small-dense LDL level while maintaining the LDL level in the blood within a certain range and maintaining normal metabolism such as cholesterol. is important.
Therefore, at present, even in healthy people, in order to prevent and prevent the progression of metabolic syndrome, pharmaceuticals and foods that reduce LDL, which is a substance that causes arteriosclerosis, and improve LDL qualitatively are strong. It has been demanded.

As a result of intensive studies in view of the above problems, the present inventors have found that higher aliphatic alcohols having 20 to 36 carbon atoms can reduce small dense LDL without reducing the total amount of LDL in the blood, The present invention has been completed.
The present invention is a blood small-dense LDL lowering agent comprising a higher aliphatic alcohol having 20 to 36 carbon atoms as an active ingredient.

  According to the blood small dense LDL reducing agent containing the higher aliphatic alcohol of the present invention as an active ingredient, the small dense LDL can be reduced without reducing the total amount of LDL in the blood. Therefore, it can be used without worrying about side effects. It is effective in preventing or improving the formation of metabolic syndrome, particularly arteriosclerosis.

  The higher aliphatic alcohol used in the present invention is separated and purified from natural wax. The natural wax is not particularly limited as long as it is a natural wax having a higher aliphatic alcohol having 20 to 36 carbon atoms as a constituent component. Examples thereof include waxes derived from animals, plants, and microorganisms. Preferably, a wax having a high content of long-chain alcohol is used. These waxes include rice bran wax (rice wax), sugar cane wax, carnauba wax, candelilla wax, jojoba oil, tree wax, beeswax, beeswax, sperm whale oil, wool It is a wax of animal origin such as fat. At least one of these can be used, and rice bran wax (rice wax), sugar cane wax, carnauba wax, candelilla wax, jojoba oil, tree wax, beeswax, etc., containing a large amount of higher aliphatic alcohol (C20-36) Is particularly preferred.

  Furthermore, rice bran wax and sugar cane wax are particularly preferable because they can be obtained in large quantities and at low cost as residues after squeezing rice oil and residues during sugar production. Therefore, the higher aliphatic alcohol obtained in the present invention is obtained by decomposing the wax, and usually includes monovalent and divalent saturated alcohols having 20 to 36 carbon atoms. Specifically, for example, eicosanol (C20: indicates the number of carbon atoms; hereinafter the same), docosanol (C22), tetracosanol (C24), hexacosanol (C26), octacosanol (C28), nonacosanol (C29), Triacontanol (C30), melylsil alcohol (C31), dotriacontanol (C32), cellomerisyl alcohol (C33), tetratriacontanol (C34), heptatriacontanol (C35), hexatriacontanol (C36), eicosane 1,2-diol, docosan 1,2-diol, tetracosane 1,2-diol, docosan 1,3-diol, tricosane 1,3-diol, tetracosane 1,3-diol and the like.

  These can be purified and used as pure products, or they can be used in combination. Naturally derived higher alcohol mixtures are suitable for practice because they can be used in the present invention as they are. The composition of naturally derived higher alcohol mixtures is shown in the table below.

  Such higher aliphatic alcohol can be obtained by hydrolyzate of natural wax. The reaction method may be either a chemical reaction method using an alkali catalyst or the like, or a biochemical reaction method using an oil and fat hydrolase such as lipase. Examples of a general purification method for higher aliphatic alcohols that are decomposition products include extraction methods using organic solvents such as hexane, acetone, and ethanol, or food materials such as medium chain fatty acid triglycerides (MCT oil). . The extraction of the higher aliphatic alcohol according to the present invention may be any method. Further, the hydroxyl group in the higher aliphatic alcohol molecule is once modified with an ethyl group, a methyl group, and the like, and after separation by distillation, there is also a method of removing the modifying group. What was obtained by any method may be sufficient.

The blood small dense LDL reducing agent of the present invention comprises such a higher aliphatic alcohol as an active ingredient. The blood small dense LDL lowering agent of the present invention is preferably a pharmaceutical or a food or drink.
In the blood small dense LDL reducing agent of the present invention, the higher aliphatic alcohol is preferably in the form of a powder having an average particle size of 1 to 150 μm. When the average particle size exceeds 150 μm, the absorption efficiency by oral route becomes worse.

  Oral administration is preferred as the pharmaceutical. In the case of an oral administration agent, the form is not particularly limited, and examples thereof include solid preparations such as powders, granules, capsules, pills, tableted tablets, liquids such as liquids, suspensions, and emulsions. It is done. In addition to higher aliphatic alcohols, these pharmaceuticals are generally used according to the form of the pharmaceutical as necessary. Excipients, disintegrants, binders, lubricants, surfactants, alcohols, water, water-soluble Can be produced according to a conventional method by adding a functional polymer, a sweetener, a corrigent, a sour agent and the like.

  Examples of foods and drinks include health foods that provide specific functions to promote health. Specifically, cooking oils, tablets, granules, capsules, dressings, mayonnaise, synthetic creams, solubilized liquids, liquids, suspensions, emulsions and other liquids containing chocolates, Examples include confectionery such as fried snacks. Such foods and drinks can be produced according to a conventional method by adding food materials generally used according to the types of foods and drinks in addition to the above-mentioned higher alcohol aliphatic alcohols.

When the blood small dense LDL lowering agent of the present invention is used as a pharmaceutical, the content of the higher alcohol is preferably 30 to 90% by mass. When using as food and drink, 0.001-80 mass% is preferable.
The dosage should be 1 mg to 10 g, preferably 5 mg to 1 g divided into 1 to several times a day as a higher aliphatic alcohol per adult in order to effectively develop the effect of the higher fatty alcohol. Is preferred.

Hereinafter, the present invention will be described in more detail based on examples.
Example 1-1
Twenty healthy subjects were ingested with rice bran-derived higher alcohol having the composition shown in Table 2 at 20 mg / day for 4 weeks (28 days), and the effects of the blood small dense LDL reducing agent of the present invention were confirmed. The method of ingestion was to take 2 tablets of 200 mg tablets (5% by weight higher alcohol, 85% by weight lactose, 10% by weight cellulose; 10 mg higher alcohol per tablet) per day. The above subjects collected blood twice before and after the test, and measured the amount of small dense LDL in the blood.
The amount of small dense LDL is measured by separating multiple classes of lipoproteins using liquid chromatography equipped with a column with a resolution that depends on the particle size of the collected blood, and separating LDL with a particle size of around 23 nm. I drew it. This LDL fraction is a small dense LDL fraction. The obtained small dense LDL was measured with an ultraviolet-visible detector using a cholesterol quantification reagent, and the amount of cholesterol in the small dense LDL was quantified. (Refer to Japanese Patent Application No. 2004-264051, Arterioscler Thromb Vasc Biol. 25 578-584 2005). Tables 3 and 4 show the results.

Experiment 1-2
In Example 1-1, the amount of LDL (cholesterol amount) was measured by a direct method using an enzyme from the collected serum. The results are shown in Table 5.
In addition, the amount of apoprotein B was measured from the collected serum. In LDL, there is 1 mol of apoprotein B per particle, and 95% of apoprotein B in plasma is bound to LDL particles, so total apoprotein B in plasma is an indicator of the number of LDL particles in blood. Yeah. The amount of apoprotein B was quantified using an ELISA kit (Apo B Auto · N Daiichi) manufactured by Daiichi Chemicals. Table 6 shows the results.

From Tables 3 and 4, it became clear that the amount of small dense LDL in blood can be reduced by ingesting a blood small dense LDL reducing agent containing the higher alcohol of the present invention as an active ingredient. The number of subjects whose numerical value after the test decreased by 10% or more compared to before the test was 10 out of 20 subjects, which was 50% of the total.
On the other hand, from Tables 5 and 6, it was clarified that no change was observed in the amount of LDL in blood by ingesting a blood small-dense LDL lowering agent containing the higher alcohol of the present invention as an active ingredient. This is confirmed from the fact that no change is observed in the amount of LDL-cholesterol in the blood and the amount of apoprotein B which serves as an index of the amount of LDL.
From the above results, the blood small dense LDL lowering agent comprising the higher alcohol of the present invention as an active ingredient does not decrease the total amount of LDL in the blood, and brings about a qualitative change in LDL while maintaining this appropriately. It was found that only the amount of small dense LDL can be reduced.

Claims (1)

  A blood small dense low-density lipoprotein lowering agent comprising a higher aliphatic alcohol having 20 to 36 carbon atoms as an active ingredient.