JPH04300828A - Preventive or therapeutic agent for fatty liver - Google Patents

Abstract

PURPOSE:To obtain a preventive or therapeutic agent for fatty liver, containing a diglyceride as an active ingredient and having action on prevention of a rise in lipid concentration in the liver and high safety. CONSTITUTION:A preventive or therapeutic agent for fatty liver containing a diglyceride, e.g. a compound expressed by the formula (two of R<1> to R<3> are acyl derived from a 12-22C saturated fatty acid or unsaturated fatty acid and the rest is H), preferably a compound having an acyl group derived from a 16-20C unsaturated fatty acid as an active ingredient. The aforementioned diglyceride is obtained by transesterification of, e.g. a mixture of fats and oils (e.g. rapeseed oil) with glycerol in the presence of an alkali (earth) metallic hydroxide or reacting a lipase with a mixture of a fatty acid or its ester with the glycerol and conducting esterifying reaction.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preventive or therapeutic agent for fatty liver, and more particularly to a highly safe preventive or therapeutic agent for fatty liver that has the effect of preventing an increase in hepatic lipid concentration.

0002

[Prior Art and Problems to be Solved by the Invention] Fatty liver refers to a state in which a large amount of lipid accumulates within liver cells, and since it is one of the causes of chronic hepatitis, liver cirrhosis, etc., its prevention and treatment are is extremely important. Causes of fatty liver include excessive intake of alcohol, overnutrition, side effects of drugs,
In addition to diabetes, malnutrition can also be cited. If the cause is overnutrition, one possible treatment would be to reduce the intake of carbohydrates, lipids, etc. However, on the other hand, if the intake of lipids is reduced too much, the synthesis of endogenous lipids in the liver will increase, leading to fatty liver disease. It is said that it occurs. As described above, it is difficult to control nutrition in the treatment of fatty liver, and the development of simple preventive or therapeutic means has been eagerly awaited.

0003

[Means for Solving the Problems] Under these circumstances, the present inventors have made extensive studies to solve the above problems, and have found that diglyceride, even at a large dose, at least prevents an increase in liver lipid concentration and is safe. The present invention was completed based on the discovery that it has high properties.

That is, the present invention provides a preventive or therapeutic agent for fatty liver containing diglyceride as an active ingredient.

[0005] As the diglyceride used in the fatty liver preventive or therapeutic agent of the present invention, for example, the following general formula (1) is used.

0
006]

[Chemical 2]

[0007] [In the formula, two of R1, R2 and R3 represent an acyl group derived from a saturated or unsaturated fatty acid having 12 to 22 carbon atoms, and the remainder represents a hydrogen atom.] One or more types may be mentioned. Examples of such saturated or unsaturated fatty acids include stearic acid, oleic acid, linoleic acid, linolenic acid, dihomo-γ-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and the like. More preferably, it is a diglyceride having an acyl group derived from an unsaturated fatty acid having 16 to 20 carbon atoms.

[0008] The method for producing such diglycerides is not particularly limited, but for example, a mixture of oil and fat and glycerin is transesterified in the presence of an alkali metal and/or alkaline earth metal hydroxide, or a fatty acid or a fatty acid ester is transesterified. It is produced by applying lipase to a mixture of glycerin and glycerin to perform an esterification reaction. To give a specific example of the transesterification reaction, 30 to 1 part of purified glycerin is added to a mixture of 100 parts of linoleic acid-rich triglyceride and 100 parts of linolenic acid-rich triglyceride.
00 parts (preferably about 50 parts) and C as a catalyst.
0.2 part of a(OH)2 is added, and stirring is continued at 230° C. for 30 minutes under reduced pressure in a nitrogen stream to carry out a random transesterification reaction. After cooling, deglycerol is removed, and monoglycerides are removed by thin film molecular distillation. Diglyceride with a concentration of 85% is obtained as a distillation residue. The linoleic acid-rich triglycerides used in this production include safflower oil, soybean oil,
Examples include corn oil, but safflower oil is particularly preferred. Examples of triglycerides with high linolenic acid content include linseed oil, perilla oil, corn goby oil, and eno oil, with linseed oil being particularly preferred.

[0009] To give a specific example of an esterification reaction using lipase, in a mixture in which 1.5 moles or more of fatty acid or fatty acid ester is added to 1 mole of glycerin, lipase is added to 1 g of fatty acid or fatty acid ester at 200%
~1000 units were added, and stirring was continued at 40°C for 21 hours to carry out the esterification reaction. After filtering off the lipase from the reaction product, unreacted fatty acids or fatty acid esters and monoglycerides are removed by molecular distillation to obtain diglycerides. The fatty acid to be used may be selected depending on the desired diglyceride. Furthermore, as the fatty acid ester, esters with lower alcohols having 1 to 3 carbon atoms are preferable. Examples of the lower alcohol having 1 to 3 carbon atoms include methanol, ethanol, propanol, and isopropanol. These fatty acids or fatty acid esters can be used alone or in combination of two or more. Furthermore, examples of the lipase include immobilized or intracellular 1,3-position selective lipase. Immobilization 1
, 3-position selective lipase can be obtained by immobilizing 1,3-position selective lipase by a known method. Known methods for immobilization are described, for example, in "Immobilized Enzymes" edited by Ichiro Chibata, published by Kodansha, pages 9-85 and "Immobilized Biocatalysts" edited by Ichiro Chibata, published by Kodansha, pages 12-101. However, a method of fixing with an ion exchange resin is exemplified as a preferred method. The 1,3-position selective lipase used for immobilization includes lipases derived from microorganisms such as Rhizopus, Aspergillus, and Mucor;
There are pancreatic lipases, etc. For example, Rhizopus delemer (R
Rhizopus delemar), Rhizopus japonicus, Aspergillus niger (Aspergillus nt.
ger), Mucorjav
anicus), Mucor Mihai (Mucor
Lipases originating from A. miehei) can be used. Commercially available immobilized 1,3-position selective lipases include Novo Industries A. S. Company product name “
Lipozyme 3A" is available. Intracellular 1,3-position selective lipase is a 1,3-position selective lipase adsorbed or bound to microbial cells, and a commercially available product is the product name "Olipase" manufactured by Osaka Bacteria Research Institute. . Among these, it is particularly preferable to use lipase immobilized with an ion exchange resin. The diglyceride content in the obtained crude diglyceride product can be increased by distillation or silicic acid column chromatography.

[0010] The acute oral toxicity of these diglycerides in rats is 10 g/kg body weight or more, and they are highly safe.

[0011] The fatty liver preventive or therapeutic agent of the present invention can be administered orally;
It can be administered by any parenteral method, and dosage forms for oral administration include, for example, tablets, capsules, powders, granules, and syrups. Examples include injections and enteral preparations. Conventional excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used in their preparation.

Excipients include glucose, lactose, etc., disintegrants include starch, sodium alginate, etc., lubricants include magnesium stearate, paraffin sulfate, talc, etc., and binders include dimethyl cellulose, gelatin, polyvinyl, etc. Pyrrolidone and the like are used. The usual dosage for adults is 1 g of diglyceride per day.
~70g, but can be increased or decreased depending on age, symptoms, etc. Furthermore, diglyceride can be administered by blending it into dietary ingredients and nutritional supplements. In this case, it is preferable to replace 50% by weight or more of normal triglyceride with diglyceride.

[0013]

EXAMPLES Next, the present invention will be further explained with reference to Examples, but the present invention is not limited thereto.

Reference Example 1 Production of diglyceride: 125 g of glycerin in 375 g of rapeseed oil (iodine value 168)
0.1% by weight of calcium hydroxide was added to the total system, and stirring was continued at 230° C. for 30 minutes in a nitrogen atmosphere to carry out Langueum transesterification reaction. After cooling, the reaction product was transferred to a separatory funnel, separated into layers, and the lower layer was removed. Furthermore, 500 ml of 10% citric acid aqueous solution was added and stirred, and after standing to separate, the upper layer was dehydrated and filtered to obtain a crude diglyceride having a fatty acid composition of rapeseed oil. Furthermore, the crude rapeseed oil fatty acid composition diglyceride was passed through a thin film molecular distillation vessel under conditions of 190° C. and 0.01 mmHg to obtain 165 g of a reaction product containing diglyceride suitable for the present invention. The fatty acid composition and molecular species contained in the obtained reaction product are shown in Tables 1 and 2.
are shown respectively. In addition, these tables also show the analysis results for rapeseed oil as triglyceride.

[0015]

[Table 1]

[0016]

[Table 2]

Example 1 Three male Wistar rats were fed with a diet having the composition shown in Table 3.
The animals were kept for a week, and the lipid concentration in the liver was measured. The results are shown in Table 4.

[0018]

[Table 3]

[0019]

[Table 4]

As a result, normal lipids (triglycerides)
When administered, hepatic lipid concentrations increased at least and at most doses. On the other hand, when diglyceride was administered, the lipid concentration in the liver was lower than when normal lipids were administered, regardless of whether the dose was small or high, indicating that diglyceride had a preventive effect on fatty liver.

Example 2 Tablet: Soft capsule composition Gelatin

70.0% glycerin

22.
9% Methyl paraoxybenzoate

0.15% Propyl paraoxybenzoate

0.15% water


Appropriate amount total

The product of Reference Example 1 in a soft capsule shell consisting of 100% of the above ingredients 5
00 mg (containing 395 mg as diglyceride) was filled in a conventional manner to produce soft capsules.

[0022]

Effects of the Invention According to the preventive or therapeutic agent for fatty liver of the present invention, the lipid concentration in the liver can be safely and easily lowered, and fatty liver can be effectively prevented or treated.

Claims (2)

[Claims] 1. A preventive or therapeutic agent for fatty liver containing diglyceride as an active ingredient. [Claim 2] The diglyceride has the following general formula (1) [
A claim is a compound represented by the formula [wherein, two of R1, R2 and R3 represent acyl groups derived from saturated fatty acids or unsaturated fatty acids having 12 to 22 carbon atoms, and the remainder represent hydrogen atoms] Item 1. The agent for preventing or treating fatty liver according to item 1.