JPH06211653A - Diarrhea-preventive medicine containing omega-3 series fatty acid-containing fat as active agent - Google Patents

Abstract

PURPOSE:To provide a safe medicine/preventive having no side effect, capable of preventing diarrhea which may occur as a result of administering a perintestinal nutriment after surgery. CONSTITUTION:Perilla oil or purified fish oil rich in fatty acid(s) of omega-3 series such as alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid is administered either before or in combination with the administration of a nutriment to raise the ratio of omega-3 to omega-6 to suppress the production of prostaglandins which stimulate the peristaltic movement of the intestinal canal to suppress the moving rate in the digestive tract, thus preventing the development of or curing diarrhea. The oil may be administered either singly or in combination with other substance(s).

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to a preventive and / or therapeutic agent for diarrhea caused by enteral nutrition.

[0002]

2. Description of the Related Art There are two types of nutritional supplementation after surgery: parenteral nutrition and enteral nutrition. Enteral nutrition is widely used because it has fewer serious side effects and is easier to administer than parenteral nutrition. However, enteral nutrition, when applied immediately after surgery, especially after surgery on the digestive tract,
Occasionally, severe diarrhea was caused, and there was an unavoidable case of having to switch to parenteral nutrition. After surgery, the effects are large, and as a result, the body protein metabolism of patients is strongly catabolic. In order to address this tendency to assimilation at an early stage, it is said that high calorie nutritional supplementation is preferred after surgery, and it is general to supplement high calorie by enteral nutrition or parenteral nutrition. However, it is necessary to pay attention to the occurrence of diarrhea when performing high-calorie supplementation by enteral nutrition, and in particular, fat supplementation is contraindicated because it induces diarrhea, and it is necessary to only supply essential fatty acids. It has been.

However, the low supply of fat requires administration of a large amount of nutritional composition for high calorie administration, which may cause diarrhea. Currently, even with enteral nutrition, the administration of fat is not contraindicated, and an appropriate amount should be carefully administered while observing the patient's condition, and in the unlikely event that fat administration causes severe diarrhea, A guideline for promptly switching to low-fat component nutritional supplements or parenteral nutrition has been established. For the development of mild diarrhea, treatment with administration of lactic acid bacteria preparations, albumin tannate, bismuth salt, etc. is performed.
It has not been known so far that the ω-3 fatty acid or the fat containing the same provided by the present invention is effective in preventing or treating diarrhea.

[0004]

DISCLOSURE OF THE INVENTION The present invention aims to prevent and treat the occurrence of diarrhea caused by enteral nutrition by administering fatty acids or oils and fats. The ω-3 fatty acid used in the present invention is converted into various prostaglandins by a metabolic pathway different from the conventionally known essential fatty acids such as linoleic acid and arachidonic acid fatty acids. Examples of ω-3 fatty acids include α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). As fats and oils containing these fatty acids, α-
Perilla oil (perilla oil) as fats and oils containing linoleic acid
Examples include flaxseed oil, tung oil, soybean oil, rapeseed oil, and the like.
In addition, examples of oils and fats containing EPA and DHA include fish oil.

As described above, the metabolism of ω-6 type fatty acids such as linoleic acid and arachidonic acid is well known as the metabolism of unsaturated fatty acids. Recently, the metabolism of ω-3 fatty acids, which are completely different from these metabolisms, has become known. In the metabolism of these fatty acids in animals, it has become clear that ω-3 fatty acids and ω-6 fatty acids antagonize each other (Shiro Watanabe et al., Proteins / Nucleic Acids / Enzymes, Vol.36, 584 ─ 588, 1991
Year) . In particular, it is said that the ratio of ω-3 / ω-6 in the diet may affect chronic diseases. It is metabolized into various prostaglandins by metabolism in the body and regulates various functions of the body.

[0006] The fats that have been mainly mixed and used in enteral nutritional supplements to date are vegetable oils and fats containing a high concentration of so-called ω-6 type fatty acids having a high linoleic acid content, especially soybean oil, safflower oil, and rapeseed oil. Was the main focus. Linoleic acid contained in these fats is metabolized from arachidonic acid to prostaglandin E ₂ . In the gastrointestinal tract, prostaglandins produced from ω-6 fatty acids are known to stimulate the peristaltic movement of the gastrointestinal tract and water leakage into the gastrointestinal tract. For example, when prostaglandin E ₂ is administered intravenously or into the small intestine of humans, intestinal peristalsis is enhanced and water and electrolytes accumulate in the intestinal tract, resulting in diarrhea (edited by Aya Kobayashi et al., Lecture Prostaglandin. 4 Digestive system and substance metabolism, p. 162, Tokyo Kagaku Dojin, 1987), which are known to cause this symptom. On the other hand, prostaglandins produced from ω-3 fatty acids such as α-linolenic acid act antagonistically against these diarrhea-causing effects.
It is known that the ω-3 fatty acid metabolizing enzyme and the ω-6 fatty acid metabolizing enzyme are the same, and both fatty acids have a competitive relationship (Shiro Watanabe et al., Protein Nucleic Acid Enzyme, Vol. 36, Five
84-588, 1991). Therefore, by adjusting the fatty acid ratio of ω-3 / ω-6, it becomes possible to regulate the biological reaction derived from prostaglandins. Up to now, it has been confirmed from the above-mentioned literature that one of the causes of diarrhea is prostaglandin, but by controlling this metabolism, no preventive treatment for diarrhea has been attempted by anyone. This is because it is difficult to clarify the quantitative relationship and there is no appropriate evaluation model. In such a situation, as described below, the present inventors first created an appropriate evaluation model for the occurrence of diarrhea associated with enteral nutrition, and used this model to prevent the above-mentioned prostaglandin-related diarrhea prevention. Succeeded in controlling. Therefore, an object of the present invention is to provide a preventive and therapeutic agent for diarrhea caused by enteral nutrition.

[0007]

The present invention enables prevention or treatment of diarrhea which occurs when an enteral nutritional supplement is administered. Examples of fats and oils containing ω-3 fatty acids used for diarrhea prevention treatment include perilla oil (perilla oil) containing α-linolenic acid, flaxseed oil, rapeseed oil and soybean oil. Incidentally, perilla oil is an oil conventionally extracted from perilla and is also called perilla seed oil. Also EPA and DH
Examples of fats and oils containing A include fish oil and the like. Table 1 shows the contents of ω-3 fatty acids in the fatty acids of these fats and oils.
(Extracted from 1971, edited by Maruzen, edited by Oil Chemistry Association, 2nd revised edition, Oil and Fat Chemistry Handbook).

[0008]

[Table 1]

These oils and fats can be used alone or in admixture with other oils and fats in order to adjust the amount of fatty acids. Furthermore, the present invention is a hydrolyzed triglyceride ω-3
The system fatty acid may be a single fatty acid, a fatty acid ester, or a salt. These fats and fatty acids are administered at a ratio of 0.1-10, particularly preferably 0.2-4, in terms of ω-3 fatty acids, relative to the ω-6 fatty acid content present in the enteral nutritional supplement. To do. If this ratio is large, the ω-6 fatty acid tends to be insufficient, and if this ratio is too small, the desired preventive and therapeutic effects on diarrhea cannot be achieved.
Furthermore, the dose ratio can be appropriately changed depending on the symptoms of the patient. For example, when the symptom of diarrhea is severe, by increasing this ratio, diarrhea can be suppressed, and then this ratio can be gradually decreased to approach the ratio of the patient's normal diet.

For administration of ω-3 fatty acids, usual routes for administration of pharmaceuticals can be adopted. For example, omega-3 fatty acids and salts thereof can be administered in capsules, tablets, or intravenously, and if fats and oils containing a high concentration of omega-3 fatty acids are administered, capsules can be used. Agent, emulsion, tablet,
Examples thereof include oral administration such as a method of mixing with an enteral nutritional agent, or drip infusion with a fat infusion. In general, perilla oil containing α-linoleic acid, which is one of the ω-3 fatty acids, and fats containing eicosapentaenoic acid, can be directly administered without the need for formulation. Further, it is a simple administration method to mix it with an enteral nutritional supplement. Alternatively, these oils and fats may be orally administered immediately before the administration of the enteral nutritional supplement.

In formulating, any excipients, emulsifiers, and stabilizers usually used in formulating can be used, and particularly those having no action of oxidizing or degrading ω-3 fatty acid. Anything can be used.
Examples thereof include sugars such as lactose, sucrose, dextrin, proteins such as casein and sodium casein, and antioxidants for encapsulation in gelatin capsules.
In administration, as described above, after measuring the ω-6 fatty acid content in the enteral nutritional drug to be administered to patients in need of treatment or prevention, the formulation containing the component of the present invention is administered. ,
Normally, when α-linolenic acid is administered, a preferable effect can be obtained by administering 400 mg to 30 g per patient per day. The same applies to other ω-3 fatty acids. This ω-3 fatty acid is a component that is present in ordinary edible oils and fats, and has no problems of toxicity and side effects.

The present invention will be described in more detail with reference to Examples and Experimental Examples.

Example 1 This example shows an example of a formulation using perilla oil containing α-linolenic acid. (1) Perilla oil (containing 68% α-linolenic acid) 450 g, α-
5 g of tocopherol was mixed, and 0.1 ml of this mixed solution was filled in a gelatin soft capsule by a conventional method to produce a capsule. (2) Perilla oil 500g, egg yolk lecithin 60g, glycerin 125g
, And after mixing with a homomixer, add purified water to bring the total volume to 5 l.
Then, the mixture was emulsified using an emulsifying machine, dispensed in 10 ml aliquots, and then sterilized.

[0013]

Example 2 In this example, an example of a formulation using purified fish oil containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is shown. (1) 450 g of refined fish oil (containing EPA12.6% and DHA12.6%),
5 g of α-tocopherol was mixed, and 0.1 ml of this mixed solution was filled in a gelatin soft capsule by a conventional method to produce a capsule. (2) Purified fish oil 500g, egg yolk lecithin 60g, glycerin 1
After adding 25 g and mixing with a homomixer, purified water was added to bring the total amount to 5 l, and the mixture was emulsified using an emulsifying machine, dispensed in 10 ml aliquots and sterilized.

[0014]

[Experimental Example 1] In this Experimental Example, the diarrhea-preventing therapeutic effect of α-linolenic acid, which is a typical fatty acid of the ω-3 series, will be described. (1) Animal model for diarrhea generation SD male rats with an average body weight of 220 g were subjected to small intestine resection and indwelling with a duodenal catheter to prepare a diarrhea generation model. As a specific procedure, a rat anesthetized with Nembutal is subjected to a midline abdominal incision, and after ligation of the mesenteric blood vessels at the surgical site,
A small intestine of about 45 cm was excised from the 15 cm anal side of the small intestine ligament to the 10 cm oral side of the ileocecal region, and the residual intestine was sutured by end-to-end anastomosis. Then, a polyvinyl chloride catheter was inserted from the bulge of the stomach and the tip was placed in the duodenum. This animal was used as a diarrhea generation model by administration of enteral nutritional supplements.

(2) Administration Enteral nutritional agent, administration agent The compositions shown in Table 2 below were administered to the above animal model through an indwelling catheter. The dose is the afternoon of the treatment
From 10 o'clock to 9 o'clock in the morning, the administration rate was 1 ml / hour, and from the next day, from 10 pm to 9 o'clock in the morning, the administration rate was 3 ml / hour.

[0016]

[Table 2]

(3) Occurrence of Diarrhea Symptoms and Inhibitory Effect From the first day after surgery, the feces were observed and evaluated with the naked eye every morning according to the following criteria. The mud-like stool and watery stool were judged to be diarrhea. Ordinary stool: Stool that retains its shape and does not adhere to the stool appearance observation net under the cage. Soft stool: The shape of the feces is maintained, but the stool appearance observation net under the cage has a trace of adhesion, or the shape of the feces is not maintained, but it passes even when observed from the back side of the stool appearance observation net. Flights not done. Mud stool: A stool that does not retain the shape of feces and can be seen passing from the back side of the stool appearance observation net. Aqueous stool: A stool that does not maintain the shape of feces and that has passed through the cage net and adhered to the urine collection funnel or is mixed with urine. According to the above criteria, the fecal characteristics of the animal model of diarrhea of 12 animals per group from the 1st to the 5th day after surgery are summarized in Fig. 1.
It was shown to. It was revealed that diarrhea was less likely to occur in the group to which ω-3 fatty acid was administered, and that the ratio of ω-3 / ω-6 of 0.1 or more was effective in preventing diarrhea.

(4) Transit time in the digestive tract The residence time in the digestive tract greatly affects the occurrence of diarrhea. It can also be used as an index of intestinal movement. Therefore, the time for food to stay in the digestive tract was measured as the transit time for the digestive tract. Carmine red was mixed with a 0.22% suspension of nutrients at the beginning of the administration of nutrients on the first day after surgery, and the fecal condition was observed every hour thereafter, and red feces were excreted. Was measured as the residence time in the digestive tract. The measurement results are shown in Table 3.

[0019]

[Table 3]

(6) Prostaglandin amount in blood Blood was collected at the time of the above dissection, and the amount of prostaglandin in blood was measured by a radioimmunoassay method. The measurement results are shown in Fig. 2. As a result, PGE ₂ involved in the peristaltic movement of prostaglandins in blood is ω-3 / ω
It was found that the -6 ratio decreased above 0.1.

(7) Retention of water in the intestinal tract The water retention in the intestinal tract of the group to which the nutritional supplement was administered was measured in the same manner as in (2). The measurement results are shown in Table 4 below.

[0022]

[Table 4]

From the above results, the increase of ω-3 / ω-6 ratio reduces the occurrence of diarrhea. This is because the prostaglandins involved in the movement of the intestinal tract are decreased, the peristalsis of the intestinal tract is suppressed, and the retention time in the digestive tract is shortened,
It was found that the invasion of water into the intestine was suppressed and the intestinal content was decreased.

[0024]

[Experimental Example 2] In this Experimental Example, the effect of eicosapentaenoic acid, which is an ω-3 fatty acid, on diarrhea prevention treatment will be described. 4.7% protein, 1.7% lipid (rice bran oil),
Basic nutritional supplement consisting of 16.2% sugar and 0.7% ash (ω-3 / ω
-6 ratio 0.04), and 100 ml of this nutrient to purified fish oil (EPA
A nutritional supplement (ω-3 / ω-6 ratio 0.32) was prepared by adding 0.4 g of ω-3 fatty acid containing 45%. This nutritional supplement
Fifteen normal rats in each group were allowed to freely ingest, and the fecal properties from the next day were observed. 15 patients in the basic nutrition only group,
Although diarrhea occurred in all cases, no diarrhea was observed in any of the 15 cases in the refined fish oil supplemented nutritional group. It was confirmed that the agent of the present invention is effective in preventing diarrhea.

[0025]

[Experimental example 3] In this experimental example, ω-3 fatty acids are used.
Explain the diarrhea prevention treatment effect of DHA. Protein 4.7
%, Lipid 1.7% (palm oil), sugar 16.2%, ash 0.7%
A basic nutrient consisting of (ω-3 / ω-6 ratio 0.03), and 100 ml of this nutrient refined fish oil (DHA 12.6%, EPA 9.5%)
A nutritional supplement (ω-3 / ω-6 ratio 0.97) containing 0.7 g was prepared. Each group of 10 normal rats was allowed to freely ingest this nutrient, and the fecal properties from the next day were observed. Diarrhea symptoms occurred in 10 cases and all cases in the group of basal nutrition only, but diarrhea symptoms were not observed in all cases of the group supplemented with refined fish oil. It was confirmed that the agent of the present invention is effective in preventing diarrhea.

[0026]

INDUSTRIAL APPLICABILITY The present invention provides a preventive and therapeutic agent for diarrhea caused by enteral nutrition. In addition, the present invention provides a safe and low-cost preventive / therapeutic agent, since components derived from fats and oils ingested as food and fats and oils themselves can be used.

[Brief description of drawings]

FIG. 1 shows the results of summarizing fecal characteristics from 1 day to 5 days after surgery of 12 animal models of diarrhea per group. PO in the figure
D represents the number of days after administration of the preventive / therapeutic agent of the present invention. The numerical value at the top of the graph shows the number of rats in each administration group.

FIG. 2 shows the results of measuring the amount of prostaglandins in blood according to a radioimmunoassay method.

Claims (3)

[Claims] 1. A therapeutic agent for preventing diarrhea accompanying enteral nutrition, which comprises an oil or fat containing an ω-3 series fatty acid as an active ingredient. 2. The therapeutic agent for diarrhea according to claim 1, wherein the ω-3 series fatty acid is one or more fatty acids selected from the group consisting of α-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. 3. A therapeutic agent for preventing diarrhea according to claim 1, wherein the oil / fat containing an ω-3 series fatty acid is perilla oil and / or fish oil. [0001]