JP2002068998A - Composition for preventing occurrence of fatty liver accompanied by transintestine nutrition and intraveneous nutrition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a composition having preventing effect on fatty liver generated by long-term intake of a compositional nutrient agent and TPN. SOLUTION: It is found that a phospholipid derived from cow milk has a preventing effect on the crises of the fatty liver.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a composition having an effect of preventing the development of fatty liver caused by oral and enteral nutrition and parenteral nutrition, an oral and enteral nutritional preparation containing an effective amount of the composition, and It relates to parenteral nutrition, the oral and enteral nutrition and the use of the composition for the production of parenteral nutrition.

[0002]

BACKGROUND OF THE INVENTION Enteral nutrition and parenteral nutrition are widely used as two of the most basic clinical nutritional therapies in modern medicine. Enteral nutrition is indicated for patients who are unable or difficult to take orally but have enough intestinal area to absorb the necessary calories and nutrients of the nutrient being administered, and are usually inserted orally or nasally. This is a method of injecting nutrients from a tube, gastrostomy, or jejunostomy, and is rarely indicated for oral administration. Enteral nutrition is closer to oral intake and more physiological than parenteral nutrition described below,
Parenteral nutrition, described below, is required for intestinal insufficiency in which the digestive function is not sufficient after massive intestinal resection or intractable diarrhea. Enteral nutrition is broadly divided into artificial concentrated liquid diet and natural concentrated liquid diet. The former is divided into elemental diet (ED) and digestive nutrition (low resident diet: LRD). It is a semi-digestive nutritional supplement. In component nutrients, the nitrogen source is composed of only crystalline amino acids, sugars, lipids,
It contains all the nutrients necessary for living organisms, such as electrolytes, vitamins, and trace elements, and is composed of only chemically identifiable substances. All components are almost completely water-soluble. Component nutrients do not require digestion, all components are absorbed in the upper gastrointestinal tract, leaving no residue.

[0003] On the other hand, parenteral nutrition is a therapeutic means applied to various diseases requiring parenteral nutritional supplementation. The most commonly used central parenteral nutrition is hypertonic sugars and amino acids as main components. High calorie infusion (total parenteral nut)
rition: TPN) is a method of continuous infusion of a catheter placed in the central vein below the clavicle for a long time.

[0004] Enteral nutrition using component nutrients and central parenteral nutrition using TPN are excellent clinical nutritional treatments.
On the other hand, component nutrients and TPN contain a high concentration of carbohydrate (generally glucose) as a calorie source, and may cause various complications due to long-term administration or excessive administration. These complications include intestinal atrophy, bile abnormalities, fat accumulation in the liver, abnormal activation of the reticuloendothelial tissue system, increased protein catabolism, and the like. In particular, liver damage that occurs in patients undergoing TPN has been well known for a long time,
Typical pathological conditions include fatty liver, which is common in adult cases, and cholestasis, which is common in pediatric cases.

To prevent fat accumulation in the liver by performing enteral nutrition, a 6-unsaturated essential fatty acid composition (Japanese Patent Laid-Open No.
1) and high-purity whey (whey) protein (Patent No. 2,94
4,008) is said to be effective.

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a composition having an effect of preventing component complications and various complications caused by TPN administration, in particular, fatty liver. It is another object of the present invention to provide oral and enteral nutrition and parenteral nutrition containing an effective amount of the composition. Still another object of the present invention is to provide a method of using the composition for producing the oral / enteral nutrition and parenteral nutrition.

[0007]

DISCLOSURE OF THE INVENTION The present inventors have previously shown that when milk-derived phospholipids are administered to hyperlipidemic rats induced by a high cholesterol diet, they can lower blood cholesterol and triglycerides. It has been found to have an effect of improving lipid metabolism, such as suppressing cholesterol accumulation in the liver (Japanese Patent Application No. 2000-94334). Therefore, it is further considered that milk-derived phospholipids may also have an effect of preventing the occurrence of various complications caused by the long-term administration of the above component nutrients and TPN, particularly the development of fatty liver. ^R
(Protein nutrient, Ajinomoto)
Oral ingestion of a low-nutrition model rat to which a phospholipid derived from milk was added revealed that the neutral fat in the liver was significantly reduced as compared to the control group. That is,
It has been found that the addition of milk-derived phospholipids to component nutrients and high calorie infusion (TPN) can be expected to prevent the development of fatty liver.

That is, the present invention relates to (1) an enteral nutrition agent containing an effective amount of a phospholipid having an action of preventing the development of fatty liver associated with enteral nutrition, and (2) an enteral nutrition is a component nutrition method. An enteral nutritional supplement of (1),
(3) an intravenous nutritional supplement containing an effective amount of a phospholipid having an effect of preventing the development of fatty liver associated with parenteral nutrition; (4) an intravenous nutritional supplement according to (3) wherein parenteral nutrition is high-calorie infusion therapy; 5) The phospholipid is derived from mammalian milk (1)
Enteral nutritional supplement, (6) parenteral nutritional supplement of (3), wherein the phospholipid is derived from mammalian milk, (7) enteral nutritional supplement of (5), wherein the mammal is bovine, (8) mammal (6) parenteral nutrition, wherein (5) is a bovine, (9) enteral nutritional supplement, wherein the phospholipid contains phosphatidylcholine, phosphatidylethanolamine and sphingomyelin as main components, (10) phosphatidylcholine, wherein the phospholipid is phosphatidylcholine (6) an intravenous nutritional supplement containing phosphatidylethanolamine and sphingomyelin as main components, (11) a phospholipid mixture or a fraction thereof for the production of an enteral nutritional supplement without the development of fatty liver. use,
(12) Use of the phospholipid of (11) in which the enteral nutrition is a component nutrition, (13) Use of the phospholipid for production of a parenteral nutrition without the development of fatty liver, (14) Parenteral nutrition (13) Use of phospholipid which is a high calorie infusion preparation, (15) Use of phospholipid which is derived from mammalian milk, (16) Use of phospholipid which is derived from mammalian milk Use of the phospholipid of (13),
7) Use of the phospholipid of (15), wherein the mammal is bovine; (18) Use of the phospholipid of (16), wherein the mammal is bovine; (19) use of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin wherein the phospholipid is bovine (17) Use of a phospholipid containing (17) a phosphatidylcholine,
Phosphatidylethanolamine, and the use of the phospholipid (18) containing sphingomyelin as a main component.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Phospholipids are major lipids constituting a biological membrane system, and their constituents include glycerophospholipids having a glycerol skeleton (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol) and sphingosine. Are classified as sphingolipids (sphingomyelin) having a skeleton of. As used herein, the term "phospholipid" also includes fractions of these phospholipids.

[0010] Most lipids in milk are dispersed in the form of fat globules. The film covering the fat globules is the milk fat globule film (Mi
It is called lk Fat Globular Membrane (MFGM) and forms an interface between fat and water. Phospholipids are localized only in MFGM and not in core lipids. It is also present in skim milk membrane fractions separated from MFGM. The phospholipid content in milk is between 0.3 and 0.4 g per liter of milk, which corresponds to 1% of the total lipids. Its composition is: phosphatidylcholine 34.5%, phosphatidylethanolamine 31.8%, sphingomyelin 25.2%, phosphatidylserine 3.1%, phosphatidylinositol 4.
At 7%, it is characterized by a high proportion of sphingomyelin, with the choline phosphate material accounting for 52-60% of the total. [(Kanno Choue-Emon, “Milk Encyclopedia”, Yamauchi Kunio, Yokoyama Kenkichi eds., P41, Asakura Shoten Co., Ltd. (199
2)].

The phospholipid used for the purpose of the present invention is preferably a phospholipid derived from mammals, and is preferably a phospholipid derived from mammals, including all nutrients and phospholipids having a preventive action against fatty liver development associated with TPN. Is preferred. The phospholipids derived from milk can be prepared from buttermilk produced as a by-product during butter production, whey produced as a by-product during cheese production, or skim milk using a known method [“Lipid Chemistry (Biochemical Experiment Course 3)”,
The Biochemical Society of Japan, p23, Tokyo Kagaku Dojin, 1974; “Lipid II
Phospholipid (Lecturer on Experimental Chemistry 4) ”, edited by The Biochemical Society of Japan, p
7, Tokyo Chemical Dojin, 1991], and can be obtained by solvent extraction or fractionation of the extract by various chromatography. For example, butterram (Bu), a by-product of producing butter oil from cream or butter,
tter Serum) as a solvent acetone-insoluble fraction. Bater sam is also used in the market milk market and is available (for example, manufactured by Belgian Corman). Batathram contains a milk fat globule membrane in which phospholipids are localized, and is suitable as a raw material for phospholipid extraction.

In order to separate phospholipids from butterram, the property that phospholipids are insoluble in acetone is used. The acetone-soluble fraction containing neutral lipids is removed by acetone extraction multiple times to obtain an acetone-insoluble fraction enriched in phospholipids. The acetone-insoluble fraction is concentrated under reduced pressure to remove acetone. The concentrate is sterilized and freeze-dried.
The dried product is pulverized to obtain a milk-derived phospholipid concentrate.
An example of the composition of the phospholipid fraction thus obtained contains 85% (% by weight) of phospholipid, and its main composition is 40% phosphatidylcholine, 7% phosphatidylethanolamine, and 20% sphingomyelin. is there.
This phospholipid composition can vary depending on the milk used as a raw material and the fractionation method used.

According to the present invention, phospholipids derived from mammalian milk other than cow's milk, egg yolk, and soybean phospholipids (lecithin) also have an effect of suppressing fat accumulation in the liver. Such phospholipids are also encompassed by the present invention, as they can be readily conceived and the effect can be easily ascertained by a person skilled in the art by experiment. Here, “lecithin” chemically means phosphatidylcholine, and a mixture of four kinds of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid and other phospholipids is usually called lecithin. The preventive action of milk-derived phospholipids on fatty liver development is phosphatidylcholine, its main component,
The effect of a mixture of various phospholipids such as phosphatidylethanolamine and sphingomyelin is also considered.These phospholipids are fractionated, and the preventive effect of each phospholipid alone is examined. Setting the optimal combination of lipids
It is possible for those skilled in the art. Therefore, such a combination is also included in the present invention.

The above phospholipid can be used as it is in the present invention as a lipid mixture, and the lipid mixture is further subjected to a solvent method or a column method [“Lipid Chemistry (Biochemical Experiment Course 3)”, edited by The Biochemical Society of Japan. , p23, Tokyo Chemical
1974; “Lipid II Phospholipids (New Chemistry Experiment Course 4)”, edited by The Biochemical Society of Japan, p7, Tokyo Kagaku Dojin, 1991]. Can be used in the present invention as long as it has the preventive action of Therefore, such fractions are also included in the present invention. For the phospholipid fractionation, for example, adsorption chromatography and ion exchange chromatography are used. Examples of the adsorbent include silicic acid, florisil (magnesium silicate), and alumina, and examples of the ion exchanger include DEAE (diethylaminoethyl) -cellulose and TEAE (triethylaminoethyl) -cellulose. Used.

As described above, the phospholipid fractions may be used alone or in combination. For example, the composition of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin is considered to be one of the preferred combinations where the composition is similar or similar to the phospholipid composition of milk from mammals.

The present invention is to prevent the development of fatty liver associated with enteral nutrition and parenteral nutrition, and to add an effective amount of the phospholipid to an enteral nutritional or parenteral nutritional supplement at the time of administration, or It is characterized by being given together with these. Here, the enteral nutritional supplement of the present invention includes oral administration as an administration route. The concept of the additive of the present invention is:
It means that it can be modified at the time of use without fundamental changes in the composition of the enteral or parenteral nutrition. The present invention also provides a method for producing an enteral nutrition or parenteral nutrition for preventing the development of fatty liver, comprising the steps of: It is characterized by being produced as an enteral nutrition or parenteral nutrition together with an agent or carrier.

The phospholipid of the present invention can be expected to further enhance lipid metabolism in the liver when used in combination with other substances. For example, a combination with at least one 6-unsaturated fatty acid can be expected to further enhance hepatic lipid metabolism. Examples of such unsaturated fatty acids include essential fatty acids such as n-6 series γ-linolenic acid or dihomo-γ-linolenic acid, or n-3 series octadecatetraenoic acid, eicosapentaenoic acid (EPA). ) Or essential fatty acids such as docosahexaenoic acid (DHA). When combined, the fatty acid may be used as it is, or a salt such as sodium, potassium or ammonium, or an ester such as methyl ester or ethyl ester. Also,
Fats and oils containing these fatty acids are also included. An appropriate mixing ratio of the phospholipid and the 6-unsaturated fatty acid can be easily determined by a person skilled in the art by experiment.

The effective dose of the phospholipid of the present invention is 0.1 to 100 mg / kg of body weight / day, preferably 1 to 50 mg / body weight.
It can be estimated as kg / day, most preferably 10-40 mg / kg body weight / day, but should be determined by clinical trial results. The amount of the phospholipid fraction of the present invention added to the enteral nutrient (particularly nutrient) or TPN is 0.01 to 20%, preferably 0.5 to 10%, more preferably 0.5 to 10% of their dry weight. Add in the range of 0.5-2%.

[0019]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Test Examples and Examples, but the present invention is not limited to these Test Examples and Examples.

Example 1: Preparation of a milk-derived phospholipid concentrate Crude fat (phospholipid content: about 45% by weight) obtained by extracting ethanol containing hydrate from butterram is suspended in acetone, and the acetone-soluble fraction of the supernatant is suspended. The fraction (primarily containing neutral fats) was removed by suction to obtain an acetone-insoluble fraction (primarily containing phospholipids). After performing the acetone treatment four times, the acetone-insoluble fraction was dispersed in water, and most of the acetone was removed using a vacuum concentrator. Next, the dispersion was subjected to batch sterilization in a tank and then freeze-dried. The dried product was pulverized and used for the test. The composition of the dried product is phospholipid 85
%, The main component of which is phosphatidylcholine 4
0.9%, phosphatidylethanolamine 7.0%,
Sphingomyelin was 20.2%.

Example 2 Inhibition of Liver Lipid Accumulation by Milk-Derived Phospholipid Concentrate Materials and Methods Male Sprague-Dawley (SD-IGS) rats (6 weeks old) (Charles River Japan) were prepared from commercially available solid feed ( (CRF-1, Oriental Yeast Co., Ltd.) for one week, and then freely fed a protein-free diet (Table 1) (Oriental Yeast Co., Ltd.) and water for 2 weeks. The undernutrition model rats were divided into three groups (six per group) and subjected to experiments so that the average body weights were equal.

[0022]

[Table 1]

The protein-free diet and Elental ^R [Ajinomoto] a were mixed 1: 1 (weight ratio) to prepare a 50% Elental mixed feed. Example 1 was added to this mixed feed.
Three test groups were set: a group to which 1% by weight of the phospholipid prepared in the above was added, a group to which 5% was added, and a control group to which no phospholipid was added. For 7 days (during the test period), the test feed and water were freely available. During the test period, there was no difference in feed and water intake between the test groups.

On the 7th day, the rats were laparotomized under ether anesthesia, the blood was collected from the abdominal aorta and centrifuged to obtain serum. Necropsy was performed for various tests. During the test period, the intake of the test feed, body weight fluctuation, and liver wet weight at necropsy were measured. The total lipid content of the liver was determined by extracting lipids according to the method of Folch et al. And quantifying the lipid components by eartroscan. Serum lactate, blood glucose, total lipids, total cholesterol, neutral fat, GOT, and GPT were measured.

As a result , no significant difference was observed between the three groups, however, the increase in body weight was higher in the group added with 5% milk-derived phospholipid than in the group not added with phospholipid (control group). (Table 2).

[0026]

[Table 2]

The liver weight / body weight ratio was 1 compared to the control group.
No significant difference was observed in the group added with 5% milk-derived phospholipids, but the ratio was significant (p <
0.05) (FIG. 1). The degree of this decrease was close to the liver weight / weight ratio of normal rats. In the control group, the liver was enlarged and macroscopically, the liver was white and had a clear fatty liver-like appearance. On the other hand, in the group added with 1% milk-derived phospholipid, the liver size and color tone tended to be improved as compared with the control group. In the 5% milk-derived phospholipids-added group, both the size and color tone of the liver were close to normal liver.

The blood biochemical test values are as follows. The blood glucose level was abnormally decreased in the control group, whereas the group with added milk-derived phospholipids showed a tendency to recover, and the 5% milk-derived phospholipids significantly increased as compared to the control group (FIG. 2). ). This returned to normal rat values. Total lipids are 1
The group containing 5% milk-derived phospholipids had a tendency to decrease, although there was no significant difference, compared to the control group, and the group containing 5% milk-derived phospholipids significantly decreased (p <0.05) (FIG. 3). There was no difference in total cholesterol in the group added with 1% milk-derived phospholipids, but in the group added with 5% milk-derived phospholipids, there was no significant difference, but a decreasing tendency was observed (FIG. 4). Neutral fat is 1
In both the group added with 5% milk-derived phospholipids and the group added with 5% milk-derived phospholipids, the values decreased to the same degree (p <0.05) (FIG. 5). Lactic acid (Figure 6), GOT (Figure 7), and GPT (Figure 8)
No difference was observed between the control group and the 1% milk-derived phospholipid-added group and the 5% milk-derived phospholipid-added group. Liver biochemical test values are as follows. Neutral fat was not significantly different in the 1% milk-derived phospholipid-added group compared to the control group, but significantly decreased (p <0.05) in the 5% milk-derived phospholipid-added group (FIG. 9-a). Cholesterol was significantly higher in both the 1% milk-derived phospholipid-added group and the 5% milk-derived phospholipid-added group than in the control group (p <0.0
5) (Fig. 9-b).

[0029]

EFFECT OF THE INVENTION Fatty liver may be caused by overdose or long-term administration of a component nutrient or high-calorie infusion. Prevention of the development of fatty liver can be expected by adding an effective amount or by giving it together with a component nutrient or a high-calorie infusion.

[0030]

[Brief description of the drawings]

FIG. 1 shows a protein-free diet containing 50% (% by weight) of Elental ^R , a component nutrient, and a diet obtained by adding 1% or 5% (% by weight) of milk-derived phospholipids to this diet. It is a figure which shows the liver weight / body weight ratio on the 7th day after freely ingesting. Each bar represents the mean ± standard error (n = 6). *: P <0.05 (Dunnett test)

FIG. 2 is a view showing a blood glucose level among blood biochemical test values on the 7th day. Each bar represents the mean ± standard error (n = 6). *: P <0.05 (Dunnett test)

FIG. 3 is a view showing total lipids among blood biochemical test values on the 7th day. Each bar represents the mean ± standard error (n = 6). *: P <0.05 (Dunnett test)

FIG. 4 is a view showing total cholesterol among blood biochemical test values on the 7th day. Each bar represents the mean ± standard error (n = 6). *: P <0.05 (Dunnett test)

FIG. 5 is a view showing neutral fat among blood biochemical test values on the 7th day. Each bar represents the mean ± standard error (n = 6). *: P <0.05 (Dunnett test)

FIG. 6 is a diagram showing a lactate value among blood biochemical test values on the 7th day. Each bar represents the mean ± standard error (n = 6). *: P <0.05 (Dunnett test)

[FIG. 7] Among blood biochemical test values on the 7th day
It is a figure showing GOT. Each bar represents the mean ± standard error (n
= 6). *: P <0.05 (Dunnett test)

FIG. 8: Blood biochemical test values on the 7th day
It is a figure showing GPT. Each bar represents the mean ± standard error (n
= 6). *: P <0.05 (Dunnett test)

FIG. 9 is a graph showing neutral fat (FIG. 9-a) and liver cholesterol (FIG. 9-b) in liver biochemical test values on the 7th day. Each bar represents the mean ± standard error (n = 6). *: P <0.05 (Fisher-PLSD test)

Continued on the front page (72) Inventor Hisae Kume 540 Narita, Odawara City, Kanagawa Prefecture Meiji Dairy Products Co., Ltd. ZA75 ZC33

Claims (20)

[Claims] 1. An enteral nutritional supplement containing an effective amount of a phospholipid having an effect of preventing the development of fatty liver associated with enteral nutrition. 2. The enteral nutrition method is a component nutrition method.
Enteral nutrition as described. 3. An intravenous nutritional preparation containing an effective amount of a phospholipid having an effect of preventing the development of fatty liver associated with parenteral nutrition. 4. The parenteral nutrition according to claim 3, wherein the parenteral nutrition is high-calorie infusion therapy. 5. The enteral nutrition according to claim 1, wherein the phospholipid is derived from mammalian milk. 6. The parenteral nutrition according to claim 3, wherein the phospholipid is derived from mammalian milk. 7. The enteral nutrition according to claim 5, wherein the mammal is a cow. 8. The parenteral nutrition according to claim 6, wherein the mammal is a cow. 9. The enteral nutrition according to claim 5, wherein the phospholipid contains phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin as main components. 10. The parenteral nutritional preparation according to claim 6, wherein the phospholipid contains phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin as main components. 11. Use of a phospholipid mixture or a fraction thereof for the production of an enteral nutrient without the development of fatty liver. 12. The use of the phospholipid according to claim 11, wherein the enteral nutritional supplement is a component nutritional supplement. 13. Use of a phospholipid for the manufacture of a parenteral nutrition without the development of fatty liver. 14. The use of the phospholipid according to claim 13, wherein the parenteral nutrition is a high-calorie infusion preparation. 15. The use of the phospholipid according to claim 11, wherein the phospholipid is derived from mammalian milk. 16. The use of the phospholipid according to claim 13, wherein the phospholipid is derived from mammalian milk. 17. The use of the phospholipid according to claim 15, wherein the mammal is a bovine. 18. The use of the phospholipid according to claim 16, wherein the mammal is a bovine. 19. The use of the phospholipid according to claim 17, wherein the phospholipid contains phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin as main components. 20. Use of the phospholipid according to claim 18, wherein the phospholipid contains phosphatidylcholine, phosphatidylethanolamine and sphingomyelin as main components.