JPH04300827A - Preventive or therapeutic agent for diarrhea - Google Patents

Abstract

PURPOSE:To obtain a preventive or therapeutic agent for diarrhea, containing a diglyceride as an active ingredient, having inhibitory action on bile acid secretion and effective against not only primary diarrhea but also secondary diarrhea in which grave primary diseases exist. CONSTITUTION:A preventive or therapeutic agent for diarrhea 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. The above-mentioned pharmaceutical is useful for preventing diarrhea caused by especially ingestion of lipids and has high safety.

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 diarrhea, and more particularly to a medicament for suppressing the secretion of bile acids and preventing the occurrence of diarrhea.

0002

2. Description of the Related Art Diarrhea includes primary diarrhea caused by pathogens, food, water, etc.; and secondary diarrhea that occurs after suffering from various diseases. Primary diarrhea can be prevented or treated by removing the causative agent, but secondary diarrhea is often not cured until the causative disease is treated. Particularly in post-operative patients, when the digestive and absorption functions have not recovered, bile secretion is promoted by intake of fat, etc., resulting in diarrhea. Diarrhea associated with such fat intake is an alarming situation in that if fat intake or administration is discontinued, there will be a shortage of energy intake, which will delay the healing of the underlying disease, and that fat intake will cause diarrhea. becomes.

0003

SUMMARY OF THE INVENTION An object of the present invention is to provide a preventive or therapeutic agent for diarrhea that is effective not only for primary diarrhea but also for secondary diarrhea caused by a serious underlying disease.

0004

[Means for Solving the Problems] The present inventors have conducted intensive research to solve the problems and have found that diglycerides do not promote the secretion of bile acids like triglycerides, and can prevent diarrhea, especially diarrhea caused by fat intake. The inventors have also discovered that the present invention is useful as a therapeutic agent, and have completed the present invention.

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

[0006] As the diglyceride used in the diarrhea preventive or therapeutic agent of the present invention, for example, the following general formula (1) is used.

00
07]

[Case 2]

[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.

The method for producing such diglycerides is not particularly limited, but for example, a mixture of oil and fat and glycerin may be transesterified in the presence of an alkali metal and/or alkaline earth metal hydroxide, or a fatty acid or fatty acid ester may be 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 100 parts (preferably about 50 parts) of purified glycerin is blended into a mixture of 100 parts of linoleic acid-rich triglyceride and 100 parts of linolenic acid-rich triglyceride, and Ca ( O
0.2 part of H)2 was added and the mixture was heated to
℃ and continued stirring for 30 minutes to perform random transesterification. 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. Examples of the linoleic acid-rich triglyceride used in this production include safflower oil, soybean oil, and corn oil, with safflower oil being particularly preferred. Examples of triglycerides with high linolenic acid content include linseed oil, perilla oil, cane oil, and eno oil, with linseed oil being particularly preferred.

[0010] To give a specific example of the 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 at a rate of 200 to 1 g of fatty acid or fatty acid ester.
Add 10,000 units and continue stirring 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
The -position selective lipase can be obtained by immobilizing the 1,3-position selective lipase by a known method. Known methods for immobilization include, for example, "Immobilized Enzymes" edited by Ichiro Chibata,
Although described in "Immobilized Biocatalyst" edited by Ichiro Chibata, published by Kodansha, pages 9-85, published by Kodansha, pages 12-101, a method of immobilization using an ion exchange resin is exemplified as a preferred method. Examples of 1,3-position selective lipases used for immobilization include lipases derived from microorganisms such as Rhizopus, Aspergillus, and Mucor, pancreatic lipase, and the like. For example, Rhizopus delemer (Rhiz
opus delemar), Rhizopus japonicus, Rhizopus niveus, Aspergillus ni
ger), Mucor j.
avanicus), Muco
Lipases originating from, for example, R. miehei) can be used. Commercially available immobilized 1,3-position selective lipases include Novo Industries A. S. There is a product name "Lipozyme 3A" manufactured by the company. Inside the bacterial body 1,3
The -position selective lipase is a 1,3-position selective lipase adsorbed or bound to microbial cells, and commercially available products include:
There is a product name "Olipase" manufactured by Osaka Bacteriological 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 a distillation method, a silicic acid column chromatography method, or the like.

[0011] The oral acute toxicity of these diglycerides in rats is 10 g/kg body weight or more, and they are highly safe.

The preventive or therapeutic agent for diarrhea of the present invention can be administered either orally or parenterally, and dosage forms for oral administration include, for example, tablets, capsules, powders, granules, and syrups. Examples of dosage forms for parenteral administration include injections and enteral preparations. These preparations require the usual excipients, disintegrants, binders, lubricants,
Dyes, diluents, etc. are used.

Excipients include glucose, lactose, etc.; disintegrants include starch, sodium alginate, etc.
Magnesium stearate, paraffin sulfate, talc, etc. are used as lubricants, and dimethylcellulose, gelatin, polyvinylpyrrolidone, etc. are used as binders. The usual dosage for adults is 1 diglyceride per day.
The amount can be increased or decreased depending on age, symptoms, etc. In addition, in the present invention, normal dietary ingredients,
It can also be administered by replacing triglycerides with diglycerides in nutritional supplements. In this case, it is desirable that 50% by weight or more of the lipid is diglyceride.

[0014]

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 Rapeseed oil (
125 g of glycerin was blended with 375 g of iodine value 168), 0.1% by weight of calcium hydroxide was added to the entire system, and the mixture was continuously stirred at 230°C for 30 minutes in a nitrogen atmosphere to perform a random transesterification reaction. Ta. After cooling, the reaction product was transferred to a separatory funnel, separated into layers, and the lower layer was removed. Further, 500 ml of a 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 rapeseed oil fatty acid composition diglyceride. 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, respectively. These tables also show the analysis results for rapeseed oil as triglyceride.

[0016]

[Table 1]

[0017]

[Table 2]

Example 1 (Experimental method) Wistar male rats (7 rats per group) were Mealfeeded once a day for one hour with the composition shown in Table 1.
ing method for 2 weeks.

[0019]

[Table 3]

On the last day of rearing, bile was collected from the common bile duct one hour after feeding, and the flow rate and bile acid content were measured. (Results) Table 4 shows the results obtained.

[0021]

[Table 4]

Table 4 shows that both the bile flow rate and bile acid content were significantly lower in diglyceride than in triglyceride. Furthermore, no occurrence of diarrhea was observed in the diglyceride-administered group.

Example 2 Soft capsule shell composition gelatin
70.0% glycerin

22.9% Methyl paraoxybenzoate
0.15% Propyl paraoxybenzoate 0.15%
water
Dosage meter

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

[0024]

EFFECTS OF THE INVENTION The agent for preventing or treating diarrhea of the present invention has a bile acid secretion suppressing effect, is particularly useful for preventing diarrhea associated with fat intake, and is highly safe.

Claims (3)

[Claims] Claim 1: A preventive or therapeutic agent for diarrhea containing diglyceride as an active ingredient. [Claim 2] The diglyceride has the following general formula (1) [
A claim that the compound is a compound represented by the formula [wherein, two of R1, R2 and R3 represent an acyl group derived from a saturated fatty acid or an unsaturated fatty acid having 12 to 22 carbon atoms, and the remainder represents a hydrogen atom] Item 1. The agent for preventing or treating diarrhea. 3. A bile acid secretion inhibitor containing diglyceride as an active ingredient.