JPH0228577B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel enteral nutritional preparation, specifically a protein source with a new composition that is particularly suitable as nutrition, supplementation, or therapeutic food for patients with liver diseases such as fulminant hepatitis and chronic hepatic encephalopathy. Relating to enteral nutritional preparations containing.

Various amino acids, including amino acid infusions, which are suitable for administering nutrients intravenously, have traditionally been used for nutritional management of patients in various fields, including liver disease patients, and in particular, to improve nutritional status through protein source supplementation. formulations are known. However, since all known amino acid preparations use amino acids as nitrogen compounds as protein sources, the osmotic pressure of the preparations themselves is too high. In addition, oral amino acid preparations similar to amino acid infusion formulations are currently being produced, but these also have high osmotic pressure and are irritating, and can often cause diarrhea in some patients. is observed, causing a significant decrease in therapeutic efficacy. Furthermore, known amino acid preparations have off-odor and bitter taste peculiar to amino acids, and there are still problems in oral administration.

The present inventors have discovered that, unlike the above-mentioned known amino acid infusions, it can be administered orally or enterally through a tube, and digestion and absorption occur physiologically, avoiding the occurrence of diarrhea due to high osmotic pressure. Various studies have been carried out with the aim of obtaining enteral nutritional preparations that are free from irritation and off-taste and odor, and which can sufficiently normalize the plasma amino acid balance, especially in patients with liver disease, by administering them as described above. As a result, nutritional preparations that utilize specific proteins and peptides as protein sources and have compositions in which they are combined with certain known essential and non-essential amino acids in specific ratios have excellent properties that meet the above objectives. The present invention has been completed based on this discovery.

That is, the present invention relates to an enteral nutritional preparation characterized by containing a nitrogen compound having the following composition as a protein source, based on the weight of the total nitrogen compound as a protein source.

Casein or its salts (as casein)
7.13-11.89% by weight Gelatin or its hydrolyzate (as pure peptide)
28.35-47.25 L-isoleucine 7.28-12.13 L-leucine 8.56-14.27 L-lysine 3.91-6.51 L-methionine 0.54-0.90 L-phenylalanine 0.14-0.23 L-threonine 3.19-5.31 L-tryptophan 0.56-0 .93 L-valine 6.41-10.69 L-alanine 0.92-1.54 L-arginine 3.82-6.37 L-cystine 0.25-0.42 In the above, the amounts of casein or its salt and gelatin or its hydrolyzate are expressed in terms of pure content as a protein source. It is determined by measuring the nitrogen content in the material used according to the Kjeldall method (for gelatin hydrolyzate,
The value of the above measurement x 6.25 is the pure peptide weight.
same as below).

As mentioned above, the enteral nutritional preparation of the present invention is based on the use of a specific ratio of a specific protein (casein), peptide (gelatin or its salt), and amino acids as a protein source. It can be used to improve the plasma amino acid balance of patients with liver disease, and because it allows the disassembly (digestion) and absorption in the intestines to proceed at an appropriate rate, it almost completely avoids the risk of diarrhea in patients receiving it, and also improves the plasma amino acid balance of patients with liver disease. Therefore, the nutritional condition improvement and therapeutic effects inherent to this type of preparation can be consistently and fully exerted. Furthermore, the preparation of the present invention has less bitterness and unpleasant odor derived from amino acids, and has a highly palatable taste, especially since it utilizes specific proteins and peptides. In addition, by using gelatin or its hydrolyzate, the preparation of the present invention has the advantage that it can be made into any form, from a liquid form with excellent preservability to a jelly form that matches the patient's preference, depending on the administration method. It also has

As the casein salt that can be used as one of the protein sources in the preparation of the present invention, any of the usual various salts that can increase the dispersibility and solubility of casein, such as sodium caseinate and calcium casein, can be used. Examples of the hydrolyzate of gelatin include peptides obtained by hydrolyzing gelatin in a conventional manner, for example, by hydrolysis with an acid or decomposition with a protease. If the average molecular weight of such peptides is usually in the range of about 200 to 100,000, any of them can be suitably used in the present invention. are preferred for the preparation of liquid formulations suitable for oral and intraluminal administration, and those of high molecular weight and gelatin are preferred for the preparation of jelly-like formulations suitable for oral administration. Furthermore, each amino acid constituting the nutritional preparation of the present invention is preferably a pure crystalline amino acid, but it does not have to be in a free form, for example, in the form of a normal salt such as hydrochloride or acetate, or in the form of a derivative thereof. But it can be used to your advantage.

The composition of the nitrogen compound used as the protein source in the nutritional preparation of the present invention was selected in consideration of the nutritional effect of the preparation and the correction of the imbalance in the plasma amino acid pattern of patients with liver disease, and is particularly suitable for patients with liver disease. It is characterized by a composition that can supply large amounts of the branched amino acids valine, leucine, and isoleucine, while hardly supplying aromatic amino acids such as phenylalanine. It can be played. If it deviates from the above range, it will be difficult to achieve the desired effect of the present invention, particularly the therapeutic effect based on normalization of plasma amino acid balance, and only the effect of protein supplementation will be obtained. Particularly preferable compositions of the protein source include the following ranges.

Casein or its salts (as casein)
8.56-10.46% by weight Gelatin or its hydrolyzate (as pure peptide)
34.02-41.58 L-isoleucine 7.76-11.65 L-leucine 9.14-13.70 L-lysine 4.16-6.25 L-methionine 0.57-0.87 L-phenylalanine 0.14-0.22 L-threonine 3.39-5.10 L-tryptophan 0.59-0 .89 L-valine 6.84-10.26 L-alanine 0.98-1.48 L-arginine 4.07-6.11 L-cystine 0.26-0.40 The nutritional preparation of the present invention is similar to known amino acid preparations, except that it uses a protein source consisting of the above-mentioned specific nitrogen compound. If necessary, various carbohydrates, lipids, electrolyte inorganic salts, vitamins, stabilizers, bactericides, etc. may be added or mixed, or they may be administered in combination with these. Specific examples of the carbohydrates include glucose, fructose, sucrose, maltose, dextrin, starch, and hydrogenated substances thereof, and specific examples of the lipids include rice oil, soybean oil, and the like. Among these, dextrin, maltose, etc. are particularly suitable as carbohydrates. The above-mentioned carbohydrates can be used together in an amount up to about 10 times the total weight of the protein source, and lipids can be used in an amount up to about 2 times the total weight of the protein source. Examples of electrolyte inorganic salts include sodium chloride, calcium chloride, magnesium sulfate, calcium glycerophosphate, sodium iron succinate citrate, and the like. It is preferable that these are used together in an amount of up to 0.05 times the total weight of the protein source as the total amount of electrolyte inorganic salts. Examples of vitamins include vitamin A, vitamin B ₁ nitrate, vitamin B ₂ , vitamin B ₆ hydrochloride, vitamin B ₁₂ , folic acid, vitamin C, vitamin D, vitamin E, calcium pantothenate, nicotinamide, choline phosphate, etc. These can be used together in an amount up to 0.002 times the total weight of the protein source as the total amount of vitamins. In addition, other additives such as stabilizers, bactericides, and preservatives include natural polysaccharides such as guar gum, pectin, locust bean gum, xanthan gum, tragacanth gum, and carrageenan as stabilizers, benzoic acid and its salts as preservatives, Examples include sorbic acid and its salts, propionic acid and its salts, dehydroacetic acid and its salts, salicylic acid, diphenyl, esters of parabenzoic acid, etc., and examples of disinfectants include hydrogen peroxide, hypochlorous acid, and its salts, etc. can.

When applying (administering) the nutritional preparation of the present invention thus obtained, it is usually diluted with water to an appropriate concentration according to a conventional method to form a solution or jelly. This is also subjected to treatments such as heat sterilization or pressure heat sterilization as necessary. The degree of dilution mentioned above can be determined arbitrarily, but usually when prepared in the form of a tube or oral nutritional solution, the resulting nutritional solution contains about 10 to 300 g/preferably about 20 to 100 g of total protein source. It is preferable to do so. The above nutritional solution is administered orally or directly into the stomach, duodenum or small intestine, and the jelly preparation is administered orally. The dosage can be determined as appropriate depending on the disease state of the patient, the intended treatment or nutritional improvement effect, etc., and is generally 1 Kcal/day per person.
It is desirable to administer about 1000 to 2500 ml in the form of a diluted solution. Furthermore, when using the enteral nutritional preparation of the present invention, the pH is usually 4-9, preferably 6-9.
8.5, and its osmotic pressure in the form of the above-mentioned diluted solution usually has a value of about 300 to 1500 mOsm/, preferably about 500 to 1000 mOsm/.

The preparation of the present invention can be used as a treatment food for the hepatitis convalescence period, chronic hepatitis or liver cirrhosis, especially for fulminant hepatitis,
It is suitable as a therapeutic agent or nutritional supplement for patients with liver diseases such as chronic hepatic encephalopathy.

Examples of the present invention are listed below.

Example 1 Sodium caseinate 10.563g (as casein) (9.51g) Gelatin hydrolyzate 42.000g (as pure peptide) (37.80g) L-isoleucine 9.705g L-leucine 11.419g L-lysine 5.209g L-methionine 0.723g L - Phenylalanine 0.181g L-threonine 4.248g L-tryptophan 0.743g L-valine 8.552g L-alanine 1.229g L-arginine 5.095g L-cystine 0.333g Total protein source (solid content) Total 100g In addition, as the above sodium caseinate After diluting skim milk powder with water, add acetic acid (other acids such as lactic acid and hydrochloric acid can also be used) to reach a pH of 4.6 to 4.7, which is the isoelectric point of casein.
This was precipitated and solubilized by adding sodium hydroxide. In addition, gelatin hydrolyzate is prepared by the following method and has an average molecular weight of 5000.
g/mol of peptide was used.

<Preparation of gelatin hydrolyzate> After crushing 1 kg of beef bone into approximately 8 x 8 (mm), 3-5%
After soaking in HCl for one week and removing the tertiary calcium phosphate in the bone as monocalcium phosphate, 0.2
Soaked in ~0.3% saturated lime water (PH13) for about 2 months,
Rinse with water to bring the pH back to about 7, then add hot water (50 to 100)
℃) several times to obtain about 100 g of extract.
This was enzymatically decomposed using protease at 50-70℃ for about 1 hour, filtered, and the liquid was passed through an ion-exchange resin column, sterilized with a plate heater at 120-130℃, and then heated in a drum at 140-160℃. Dry with a hair dryer for about 1 minute. Approximately 10 g of the desired peptide is thus obtained.

The nutritional preparation of the present invention is obtained by stirring and dissolving the above composition (100 g in total) in 350 ml of water. This has a PH of 8.2,
There is a calorific value of 1 Kcal per ml, and the osmotic pressure is
It was 925mOsm/.

<Sensory Test> The nutritional formulation of Example 1 was subjected to a sensory test by oral administration. As a control, a nutritional preparation consisting only of amino acids was used, in which the composition of Example 1 in which sodium caseinate and gelatin hydrolyzate were replaced with their constituent amino acids was stirred and dissolved in 35 ml of water. As a result, the control formulation had a bitter taste and acrid taste and an unpleasant odor, but the formulation of Example 1 had a pleasant taste with less bitterness and astringency.
There was no unpleasant odor.

Example 2 Sodium caseinate 1.215g (as casein) (1.09g) Gelatin hydrolyzate 4.830g (as pure peptide) (4.34g) L-isoleucine 1.116g L-leucine 1.313g L-lysine 0.599g L-methionine 0.083g L - Phenylalanine 0.021g L-threonine 0.489g L-tryptophan 0.085g L-valine 0.983g L-alanine 0.141g L-arginine 0.586g L-cystine 0.039g Dextrin 39.400g Maltose 39.400g Rice oil 9.700g total 100g casein Sodium and gelatin hydrolyzate are
The same one as in Example 1 was used.

The nutritional preparation of the present invention is obtained by mixing and dissolving each component in the amount of the above composition in 200 ml of water. This has a pH of 7.9, a calorific value of 1.6 Kcal per ml, and an osmotic pressure of
It was 807mOsm/. In addition, the above composition (powder 100
Mix and dissolve g) in 350ml of water to give 1Kcal per ml.
Obtain a nutritional preparation with a calorific value of It has a pH of 8.0 and an osmolality of 541 mOsm/.

Example 3 Sodium caseinate 1180mg (as casein) (1062mg) Gelatin hydrolyzate 4698mg (as pure peptide) (4228mg) L-isoleucine 1084mg L-leucine 1276mg L-lysine 582mg L-methionine 81mg L-phenylalanine 20mg L-threonine 476mg L-tryptophan 83mg L-valine 912mg L-alanine 137mg L-arginine 570mg L-cystine 37mg Dextrin 38281mg Maltose 38281mg Rice oil 9424mg Sodium chloride 955mg Potassium chloride 584mg Magnesium sulfate 411mg Calcium glycerophosphate 828 mg Sodium iron succinate citrate 25mg Vitamin A 150μg (500IU) Vitamin B ₁ nitrate 400μg Vitamin B ₂ 400μg Vitamin B ₆ hydrochloride 600μg Vitamin B ₁₂ 2μg Folic acid 120μg Vitamin C 20μg Vitamin D 1.25μg (50IU) Vitamin E 30mg Calcium pantothenate 3mg Nicotinic acid amide 4mg Sodium caseinate and Gelatin hydrolyzate is
The same material as in Example 1 was used.

Use each ingredient so that it has the above composition, and add it to water.
The nutritional preparation of the present invention is obtained by mixing and dissolving in 200 ml.
It has a pH of 8.1, a calorific value of 1.6 Kcal per ml, and an osmotic pressure of 921 mOsm/.

Further, the above composition is mixed and dissolved in 350 ml of water to obtain a nutritional preparation of the present invention having a calorific value of 1 Kcal per ml.
It has a pH of 8.1 and an osmolarity of 659 mOsm/.

Example 4 Sodium caseinate 10.563g (as casein) (9.51g) Gelatin 8.00g (as pure protein) (7.20g) Gelatin hydrolyzate 34.00g (as pure peptide) (30.60g) L-isoleucine 9.705g L-leucine 11.419 g L-lysine 5.209g L-methionine 0.723g L-phenylalanine 0.181g L-threonine 4.248g L-tryptophan 0.743g L-valine 8.552g L-alanine 1.229g L-arginine 5.095g L-cystine 0.333g Casein The sodium and gelatin hydrolyzate were the same as in Example 1, and the gelatin was obtained by crushing and defatting beef bones, leaching out impurity minerals with acid, boiling them, and soaking them in lime water to obtain keratin and elastin. After separating and removing mucoids, the product was washed with water, neutralized, filtered, and dried.

A jelly-like nutritional preparation of the present invention was obtained by mixing and dissolving the above composition (100 g in total) in 340 ml of water and cooling.

Example 5 Sodium caseinate 1.26g (as casein) (1.14g) Gelatin 4.00g (as pure protein) (3.60g) Gelatin hydrolyzate 0.83g (as pure peptide) (0.74g) L-isoleucine 1.116g L-leucine 1.313 g L-lysine 0.599g L-methionine 0.083g L-phenylalanine 0.021g L-threonine 0.489g L-tryptophan 0.085g L-valine 0.983g L-alanine 0.141g L-arginine 0.586g L-cystine 0.039g Dextrin 3 9.40 g (as carbohydrates) (38.22g) Maltose 39.40g (as carbohydrates) (37.04g) Rice oil 9.68g Sodium caseinate and gelatin hydrolyzate are as described in Example 1, gelatin as in Example 4, dextrin and maltose The same rice oil and rice oil as in Example 2 were used.

The above-mentioned components were added to 340 ml of water, heated and dissolved, and placed in a suitable container and allowed to cool to obtain a jelly-like nutritional preparation of the present invention.

Example 6 Sodium caseinate 1180mg (as casein) (1062mg) Gelatin 4000mg (as pure protein) (3600mg) Gelatin hydrolyzate 698mg (as pure peptide) (628mg) L-isoleucine 1084mg L-leucine 1276mg L-lysine 582mg L-methionine 81mg L-phenylalanine 20mg L-threonine 476mg L-tryptophan 83mg L-valine 912mg L-alanine 137mg L-arginine 570mg L-cystine 37mg Dextrin 38287mg (as carbohydrate) (38281mg) Rice oil 9424mg Sodium chloride 955mg Chloride Potassium 584mg硫酸マグネシウム 411mg グリセロリン酸カルシウム 828mg コハク酸クエン酸鉄ナトリウム 25mg ビタミンＡ 150μｇ（500IU） ビタミンB ₁硝酸塩 400μｇ ビタミンB ₂ 400μｇ ビタミンB ₆塩酸塩 600μｇへビタミンB ₁₂ 2μｇ 葉 酸 120μｇ ビタミンＣ 20μｇ ビタミンＤ 1.25μｇ（ 50 IU) Vitamin E 30 mg Calcium pantothenate 3 mg Nicotinic acid amide 4 mg Sodium caseinate and gelatin hydrolyzate were used as in Example 1, gelatin as in Example 4, and dextrin and rice oil as in Example 2. .

Each of the above components was added to 340 ml of water, dissolved by heating, and allowed to cool in a suitable container to obtain a jelly-like nutritional preparation of the present invention.

Claims (1)

[Scope of Claims] 1. An enteral nutritional preparation characterized by containing a nitrogen compound having the following composition as a protein source, based on the total weight of nitrogen compounds as a protein source. Casein or its salts (as casein)
7.13-11.89% by weight Gelatin or its hydrolyzate (as pure peptide)
28.35-47.25 L-isoleucine 7.28-12.13 L-leucine 8.56-14.27 L-lysine 3.91-6.51 L-methionine 0.54-0.90 L-phenylalanine 0.14-0.23 L-threonine 3.19-5.31 L-tryptophan 0.56-0 .93 L-valine 6.41-10.69 L-alanine 0.92-1.54 L-arginine 3.82-6.37 L-cystine 0.25-0.42