JP2599593B2 - Amino acid infusion for renal failure - Google Patents

Description

The present invention relates to a novel amino acid infusion for renal failure.

2. Description of the Related Art In recent years, studies on amino acid infusions essential for body protein synthesis have been actively conducted. In particular, attention has been paid to metabolic specificity in various disease states, and amino acid infusions for each disease state taking into account the specificity have been developed. It has been researched and developed. In particular,
In recent years, the importance of nutritional management has been increasingly recognized due to the development and spread of high-calorie infusion therapy, and the need for amino acid infusions adapted to various diseases, such as liver failure, renal failure, and cancer, has been raised. It has come.

For amino acid infusion for patients with renal disease, Rose et al., Which is already based on oral nutrition in Japan and the United States [W.
C. Rose et al., J. Biol. Chem., 223 , 107 (1956)], an amino acid infusion for renal failure based on the essential amino acid composition has been developed.
ndall Mc Gaw Laboratories) as "Amiyu" (registered trademark) and "NephrAmine" (registered trademark). Also, an amino acid infusion prescribed based on the blood aminogram kinetics of healthy subjects and dialysis patients has been proposed as a research stage (Japanese Patent Publication No. 61-1986).
323).

Problems to be Solved by the Invention However, conventionally known amino acid infusions are not yet sufficient for nutritional management, maintenance of nitrogen balance and improvement of subjective symptoms in patients with renal failure, and recently, conversely, hyperammonemia Adverse effects such as illness have been reported. In other words, in recent years, as the number of cases of surgery performed on patients with renal failure has increased, the number of cases in which nutritional management must be performed with high-calorie infusion therapy has increased. However, nutritional indicators such as nitrogen balance and self-objective symptoms do not always yield favorable results, but rather, with increasing doses, adverse effects such as hyperammonemia and even encephalopathy have been reported. .

Means for Solving the Problems In view of this situation, the present inventors have an ideal composition as an amino acid infusion for renal failure patients, and can correct the blood amino acid pattern of renal failure patients to normal values. In order to provide a new amino acid infusion that can be performed and does not induce adverse effects, intensive studies have been made. As a result, at least eight essential amino acids and L-tyrosine, L
-By combining histidine and L-arginine at optimal concentrations, the blood amino acid pattern and N-balance of patients with chronic and acute renal failure can be improved, and excellent nutritional management,
Reduction of BUN, improvement of self-objective symptoms, and even hyperammonemia induced by amino acid infusion for renal failure conventionally known,
It has been found that harmful effects such as fatty liver and encephalopathy can be eliminated, and an amino acid infusion for renal failure meeting the above-mentioned object can be obtained. The present invention has been completed based on this finding.

That is, the present invention relates to an amino acid transfusion for renal failure, comprising at least the following amino acids, and having the following molar composition in terms of free amino acids. L-amino acid composition range (mol /) leucine 0.0610-0.1372 isoleucine 0.0457-0.0991 valine 0.0512-0.1280 methionine 0.0101-0.0335 lysine 0.0205-0.0445 threonine 0.0084-0.0420 tryptophan 0.0049-0.0196 phenylalanine 0.0182-0.0363 tyrosine 0.0011-0.0055 histidine 0.0032-0.0258 arginine 0.0057-0.0344 The amino acid infusion of the present invention is required to have the above-mentioned amino acid composition, and further comprises at least one selected from L-cysteine (or L-cystine), L-serine, L-alanine and L-proline. Seeds can be formulated. In addition, the amino acid infusion of the present invention may optionally further contain non-essential amino acids other than the above amino acids, if necessary.

The amino acid infusion for renal failure of the present invention is based on the composition described above, and is based on the composition described above, and is incapable of ingesting nutrients orally due to trauma, surgery, or other causes in chronic and acute renal failure patients. Applying to difficult patients, supplementing the protein source can improve blood amino acid patterns and N-balance, thus providing superior nutritional management. Furthermore, the amino acid infusion of the present invention can exhibit effects such as reduction of BUN or improvement of subjective and objective symptoms. More specifically, the amino acid infusion of the present invention shortens the catabolic process of the living body, especially when administered to patients with chronic renal failure before or after surgery and patients who have entered acute renal failure due to trauma or surgical invasion. Or minimize the effects of surgical invasion, improve the patient's blood amino acid pattern and nitrogen balance to restore nutrition, improve BUN loss or improve subjective and objective symptoms, and hyperammonemia There is no danger of inducing adverse effects such as Furthermore, the amino acid infusion of the present invention is stable in terms of formulation.

Particularly preferred basic prescriptions and compositional characteristics of the amino acid infusion of the present invention for renal failure patients are as follows. L-amino acid composition range (mol /) leucine 0.0610-0.1372 isoleucine 0.0457-0.0991 valine 0.0512-0.1280 methionine 0.0101-0.0335 lysine 0.0205-0.0445 threonine 0.0084-0.0420 tryptophan 0.0049-0.0196 phenylalanine 0.0182-0.0363 tyrosine 0.0011-0.0055 histidine 0.0032-0.0258 arginine 0.0057 to 0.0344 (1) In the above composition range, the branched chain amino acids (L-leucine, L-isoleucine and L-valine) have 50 to 60 W / W% of the above 11 amino acids.

(2) Those having a weight ratio of L-lysine / L-arginine in the above composition range of 0.7 to 1.5.

(3) In the above composition range, L-phenylalanine / L-
Those having a weight ratio of tyrosine of 6.0 to 12.0.

In another preferred embodiment of the amino acid infusion of the present invention, L-cysteine (or L-cysteine) is added to the above basic composition.
-Cystine), L-serine, L-alanine and L-proline.

Furthermore, as another preferable embodiment, L-cysteine (or L-cystine), L-serine,
Examples of the formulation include at least two formulations selected from L-alanine, L-proline, L-aspartic acid, and L-glutamic acid.

The amino acid infusion of the present invention has a new composition and a compositional feature different from the conventionally known amino acid composition for renal insufficiency, so that it can be used in patients with chronic and acute renal insufficiency, especially in patients with chronic renal insufficiency. It can be used very effectively without inducing adverse effects in postoperative and postoperative or postoperative trauma patients with acute renal failure, and can achieve the desired excellent effects.

Each amino acid constituting the amino acid infusion of the present invention is preferably a pure crystalline amino acid, which is usually used in the form of a free amino acid, but need not be in a free form, and is a pharmacologically acceptable metal salt. For example, sodium salts, potassium salts and the like, mineral salts such as hydrochlorides, sulfates and the like,
It can also be used in the form of an organic acid salt, for example, acetate, lactate, malate or the like, or in the form of an ester which is hydrolyzed in vivo and converted into a free amino acid. Specific examples of the above salts and esters include, for example, L-lysine hydrochloride, L-lysine acetate, L-lysine malate, L-arginine hydrochloride, L-histidine hydrochloride-hydrate, L-lysine
Examples thereof include methionine methyl ester and L-methionine ethyl ester.

The amino acids may be partially or wholly used in the form of N-acyl derivatives, for example, N-acetyl-L-tyrosine, N-acetyl-L-tryptophan, N-acetyl-L-proline and the like. These derivatives can be used particularly effectively when the solubility is low in the free amino acid form and there is a risk of precipitation. They also have the advantage that they can advantageously suppress the browning phenomenon due to the Maillard reaction, which can be seen when a reducing sugar is added to the resulting amino acid preparation as required. Further, the above-mentioned amino acids are salts of two kinds of amino acids, for example, L-arginine-L-glutamate, L-lysine-L-aspartate, etc. or a dipeptide in which the same or different amino acids are peptide-bonded, for example, L-tyrosyl. -L-tyrosine, L
-Alanyl-L-tyrosine, L-arginyl-L-tyrosine and the like can also be used. Furthermore, L-methionine can be partially or entirely replaced with L-cystine or L-cysteine. When each amino acid is used in a form other than the above-mentioned free amino acids, the amount of these amino acids is determined so that the amount converted to the free amino acids falls within the above-mentioned specific range.

The amino acid infusion of the present invention is prepared in the form of a sterile aqueous solution in which the above-mentioned various forms of amino acids or derivatives thereof are mixed as free amino acids so as to be in the above-mentioned specific range, and is suitable for intravenous administration such as peripheral vein or central vein. Can be administered as an injection. The preparation method is not substantially different from ordinary amino acid infusion, and according to a conventional method, for example, typically the above-mentioned amino acid or its derivative is mixed and dissolved in distilled water for injection and the like, and if necessary, for example, sodium sulfite, sulfite Stabilizers such as sodium hydrogen, sodium pyrosulfite, sodium thiosulfate, etc., pH regulators such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, sodium hydroxide, and other known amino acid infusions It is carried out by adding various additives as described above and sterilizing the resulting aqueous solution by sterilization or heat sterilization. Thus, a pharmaceutically stable desired amino acid infusion can be easily prepared.

The amino acid infusion of the present invention prepared above is usually
The pH is adjusted to 3.0 to 8.0, preferably 4.0 to 7.5 and used. The amino acid concentration is not particularly different from ordinary amino acid infusion, and is generally about 2.0 to 12.0 W / V%, preferably,
It is preferable to be about 3.0 to 10.0 W / V%.

In addition, in the use and preparation of the amino acid infusion of the present invention, the use rate of the compounded amino acid is doubled, the synthesis of these amino acids into proteins in vivo is suppressed, or the consumption as an energy source is suppressed. For more ideal nutritional supplementation to patients, for example, glucose, fructose, xylitol, sorbitol, saccharides such as maltose can also be added and blended. Various components known to be able to be added to the infusion, such as lipids, vitamins, electrolytes, trace elements, etc., can be arbitrarily added and used as a so-called high-calorie infusion, and such a use form is more preferable. is there.

Examples of the lipids include soybean oil, cottonseed oil, sesame oil,
Egg yolk lecithin, soybean lecithin, vitamin A, vitamin B as vitamins, vitamin B _2, vitamin B _6, nicotinic acid, pantothenic acid, vitamin C, vitamin D, vitamin E, biotin, folic acid, etc., as an electrolyte Examples include sodium chloride, sodium acetate, potassium chloride, magnesium sulfate, magnesium chloride, calcium chloride, dipotassium phosphate, monosodium phosphate, and the like, and trace elements include iron, zinc, manganese, copper, iodine, cobalt, and the like. be able to.

The dose of the amino acid preparation of the present invention may be the same as that of a normal amino acid infusion, and generally, about 200 to 1000 ml per adult per day, the condition, nutritional state, age, It can be appropriately increased or decreased according to the weight or the like.

EXAMPLES Hereinafter, in order to further clarify the present invention, production examples of the amino acid infusion of the present invention will be described as examples, and then test examples will be described.

Example 1 L-amino acid g / leucine 14.00 isoleucine 9.00 valine 10.00 methionine 4.50 lysine acetate 6.91 (4.90 as lysine) threonine 2.80 tryptophan 2.40 phenylalanine 4.30 tyrosine 0.50 histidine 1.50 arginine 4.10 total free amino acid 58.00 each amino acid having the above composition The pure crystals were added to distilled water for injection and dissolved by stirring. Then, 0.3 g of sodium bisulfite was added as a stabilizer, and the pH was adjusted to about 7.0 using acetic acid as a pH adjuster. Next, the obtained amino acid aqueous solution was aseptically filtered and filled into an infusion container, and after nitrogen replacement, the container was sealed and sterilized in an autoclave at 105 ° C for 40 minutes to give an amino acid infusion solution of the present invention (total free amino acid concentration of 5.8%). W / V%).

Example 2 L-amino acid g / leucine 14.00 isoleucine 9.00 valine 10.00 methionine 3.00 lysine acetate 7.05 (5.00 as lysine) threonine 3.50 tryptophan 2.50 phenylalanine 4.50 tyrosine 0.50 histidine 2.50 arginine 4.50 cysteine 1.00 total free amino acids 60.00 Same as in Example 1. Thus, an amino acid infusion of the present invention having the above composition (total free amino acid concentration: 6.0 W / V%) was obtained.

Example 3 L-amino acid g / leucine 8.00 isoleucine 6.00 valine 6.00 methionine 3.50 lysine acetate 4.23 (3.00 as lysine) threonine 2.00 tryptophan 1.00 phenylalanine 4.00 tyrosine 0.50 histidine 2.00 arginine 40.00 total free amino acid 40.00 Same as in Example 1 An amino acid infusion of the present invention having a composition (total free amino acid concentration 4.0 W / V%) was obtained.

Example 4 L-amino acid g / leucine 18.00 isoleucine 9.00 valine 6.00 methionine 4.86 lysine acetate 7.48 (5.30 as lysine) threonine 3.02 tryptophan 2.59 phenylalanine 4.64 N-acetyl-tyrosine 0.67 (0.54 as tyrosine) histidine 1.62 arginine 4.43 total free amino acids 60.00 In the same manner as in Example 1, an amino acid infusion of the present invention having the above composition (total free amino acid concentration: 6.0 W / V%) was obtained.

Example 5 L-amino acid g / leucine 10.00 isoleucine 13.00 valine 10.00 methionine 5.00 lysine malate 12.46 (6.50 as lysine) threonine 4.00 tryptophan 2.00 phenylalanine 3.00 tyrosine 0.50 histidine 1.50 arginine 4.50 total free amino acid 60.00 malic acid as pH adjuster An amino acid infusion of the present invention having the above composition (total free amino acid concentration: 6.0 W / V%) was obtained in the same manner as in Example 1 except for using.

Example 6 L-amino acid g / leucine 14.00 isoleucine 9.00 valine 15.00 methionine 5.00 lysine acetate 8.46 (6.00 as lysine) threonine 5.00 tryptophan 4.00 phenylalanine 6.00 N-acetyl-tyrosine 1.23 (1.00 as tyrosine) histidine 4.00 arginine 6.00 total free amino acids 75.00 An amino acid infusion of the present invention having the above composition (total free amino acid concentration 7.5 W / V%) was obtained in the same manner as in Example 1.

Example 7 L-amino acid g / 2 leucine 14.00 isoleucine 9.00 valine 15.00 methionine 5.00 lysine acetate 8.46 (6.00 as lysine) threonine 5.00 tryptophan 4.00 phenylalanine 6.00 tyrosine 1.00 histidine 4.00 arginine 6.00 total free amino acid 75.00 In the same manner as in Example 1. An amino acid infusion of the present invention having the above composition (total free amino acid concentration: 3.75 W / V%) was obtained.

Example 8 L-amino acid g / leucine 14.00 isoleucine 9.00 valine 11.00 methionine 3.00 lysine acetate 7.05 (5.00 as lysine) threonine 3.50 tryptophan 2.50 phenylalanine 5.00 tyrosine 0.50 histidine 3.50 arginine 4.50 serine 2.50 alanine 2.50 proline 2.50 cysteine 1.00 total free amino acids 1.00 In the same manner as in Example 1, an amino acid infusion of the present invention having the above composition (total free amino acid concentration: 7.0 W / V%) was obtained.

Example 9 L-amino acid g / leucine 14.00 isoleucine 9.00 valine 10.00 methionine 3.00 lysine acetate 7.05 (5.00 as lysine) threonine 3.50 tryptophan 2.50 phenylalanine 5.00 tyrosine 0.50 histidine 3.50 arginine 4.50 serine 3.00 alanine 2.50 proline 3.00 cysteine 1.00 total amino acids 1.00 total free amino acids In the same manner as in Example 1, an amino acid infusion of the present invention having the above composition (total free amino acid concentration: 7.0 W / V%) was obtained.

Example 10 L-amino acid g / leucine 14.00 isoleucine 9.00 valine 7.00 methionine 4.50 lysine acetate 8.61 (6.10 as lysine) threonine 2.80 tryptophan 2.40 phenylalanine 4.30 tyrosine 0.50 histidine 1.50 arginine 4.10 total free amino acid 56.20 Same as in Example 1 An amino acid infusion of the present invention having a composition (total free amino acid concentration: 5.62 W / V%) was obtained.

Example 11 L-amino acid g / leucine 15.00 isoleucine 10.00 valine 7.00 methionine 4.50 lysine acetate 8.61 (6.10 as lysine) threonine 2.80 tryptophan 2.40 phenylalanine 4.30 tyrosine 0.50 histidine 1.50 arginine 4.10 total free amino acids 58.20 Same as in Example 1 An amino acid infusion of the present invention having a composition (total free amino acid concentration: 5.82 W / V%) was obtained.

Example 12 L-amino acid g / leucine 14.00 isoleucine 9.00 valine 10.00 methionine 3.00 lysine acetate 7.05 (5.00 as lysine) threonine 3.50 tryptophan 2.50 phenylalanine 5.00 tyrosine 0.50 histidine 3.50 arginine 4.50 serine 3.00 alanine 2.50 proline 3.00 cysteine 1.00 glutamic acid 1.00 glutamine Total free amino acid amount 72.00 An amino acid infusion of the present invention having the above composition (total free amino acid concentration 7.2 W / V%) was obtained in the same manner as in Example 1.

Test Example 11 1) Method for Producing Chronic Renal Failure (CRF) Rats A group of five Wistar male rats weighing about 200 g was used.

75% of one kidney was excised under Nembutal anesthesia, and one week later, the contralateral kidney was excised again under Nembutal anesthesia. Two weeks later, animals whose plasma creatinine was 1.5 mg / dl or more were subjected to the following experiments as CRF rats.

2) Experimental method CRF rats were anesthetized with Nembutal, and a silicone catheter was inserted and placed in the jugular vein. Thereafter, under fasting and water-fast conditions, the amino acid infusion of the present invention obtained in Example 1, a commercially available amino acid infusion of rose prescription ("Amiyu", manufactured by Morishita Pharmaceutical Co., Ltd.) (hereinafter referred to as "Comparative A") and Japanese Patent Publication No. Sho 61- Each mixture obtained by adding glucose, electrolyte, and vitamin to the amino acid infusion solution of Example 1 of 323 (hereinafter referred to as “Comparative B”) was added to each group.
CRF rats were administered via an intravenous catheter and subjected to one week of total parenteral nutrition (TPN). The daily composition of the mixture was 0.817 g / Kg nitrogen, 270 kcal / Kg calorie, and 270 ml / Kg water. The dose on the first day and the second day of the start of TPN was reduced to 50% and 75% of the daily dose, respectively.

Table 1 shows the amino acid infusion compositions used. In Table 1, the amino acid infusion compositions were all expressed in free form.

After the end of the 7-day TPN period, each group of rats was bled from the abdominal aorta under Nembutal anesthesia and the free amino acid concentration in plasma was measured.

Table 2 shows the results. In addition, a free-feeding group of the same age as a normal group and a free-feeding group of CRF rats as a renal failure group were respectively prepared, and the results of each of these groups are also shown in Table 2. The measured values shown in Table 2 are all average values.

As is apparent from Table 2, the branched chain amino acids (leucine, isoleucine and valine) induced by CRF
In the TPN group using the amino acid infusion of the present invention (the present invention group), the decrease in tryptophan and the decrease in tryptophan were all normalized, but in the group using the commercially available amino acid (comparative group A), methionine was reduced. , Lysine, threonine,
Histidine, glutamine, taurine, citrulline were increased and arginine was decreased. In the group using the amino acid infusion of Comparative B (Comparative B Group), an increase in valine, lysine, threonine, and tyrosine, and a decrease in histidine and methionine, a sulfur-containing amino acid, and cysteine were observed.

Test Example 2 1) Implementation method Six groups of CRF rats produced in the same manner as in Test Example 1 were anesthetized with Nembutal, and a silicone catheter was inserted and placed in the jugular vein. Thereafter, glucose, electrolytes, and vitamins were added to the amino acid infusion of the present invention obtained in Example 1 and a commercially available amino acid infusion for rose renal failure ("Amiyu", manufactured by Morishita Pharmaceutical Co., Ltd., Comparative A) obtained in Example 1 under fasting and fasting conditions. Each of the mixed solutions was administered through an intravenous catheter, and one week of total parenteral nutrition (TPN) was performed. The daily composition of the mixture is 0.817 g / Kg of nitrogen, 270 kcal / Kg of calories, and 270 ml / K of water.
g. The dose on the first day and the second day of the start of TPN was reduced to 50% and 75% of the daily dose, respectively.

Animals during the TPN period were maintained in metabolic cages, urine was collected daily, urinary nitrogen excretion was measured, and nitrogen balance was determined. Table 3 shows the results.

After the completion of the 7-day TPN period, blood was collected from the abdominal aorta under Nembutal anesthesia, a blood biochemical test was performed, and the liver was collected to measure the contents of glycogen, protein and triglyceride in the liver. Table 4 shows the results.

As is clear from Tables 3 and 4, the TPN using the amino acid infusion of the present invention (the present invention group) has a better nitrogen balance than the TPN using the amino acid infusion for renal failure in the market (Comparative Group A). Hematocrit, plasma total protein and albumin remained high, and BUN decreased. On the other hand, comparison A
In the group, hyperammonemia was present, and blood TG and NEFA decreased, and liver TG increased.

Test Example 3 Five Wistar male rats weighing about 250 g per group were used.

After an overnight fast, mercuric chloride 3mg / Kg under Nembutal anesthesia
Was administered subcutaneously to the back to produce acute renal failure (ARF) rats.

Immediately after the administration of mercuric chloride, a silicone catheter was inserted and placed in the jugular vein as in Test Example 2, and the amino acid infusion of the present invention obtained in Example 1 or a commercially available amino acid infusion for renal failure (“Amiyu”, manufactured by Morishita Pharmaceutical Co., Ltd. TPN was performed for 3 days with the mixture for TPN using A). These are referred to as the present invention group and comparative A group, respectively.

The daily composition of the mixture was 0.817 g / Kg of nitrogen, 270 kcal / Kg of calories, and 270 ml / Kg of water.
On day only the dose was reduced to 50%.

Table 5 shows the nitrogen balance obtained from the urinary nitrogen excretion for three days, and Table 6 shows the measurement results of blood ammonia, BUN and creatinine at the end of TPN. In Table 6,
The measured value in the normal rat group as a control is also shown.

From the above Tables 5 and 6, the amino acid infusion group of the present invention (the present invention group) was better maintained in nitrogen balance compared to the commercially available amino acid infusion group for renal failure (Comparative Group A),
It can be seen that the rise in BUN was suppressed. In addition, hyperammonemia was induced in the comparative group A.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Heizo Shingu 12-15 Inui, Sumiyoshi, Aizumi-cho, Itano-gun, Tokushima Prefecture (72) Inventor Naru Mukai 1-9, Marusu, Hiroshima-shi, Matsushige-cho, Itano-gun, Tokushima Prefecture (72) Inventor Toshio Ikeda 23-13 Yashita, Sasagino, Matsumo-cho, Itano-gun, Tokushima Prefecture (72) Inventor Kozo Asagi 841 Kizu, Fusyo-cho, Naruto-shi, Tokushima Prefecture (56) References JP-A-51-118839 (JP, A) 52-28946 (JP, A)

Claims (1)

(57) [Claims] 1. An amino acid transfusion for renal failure comprising at least the following amino acids and having the following molar composition in terms of free amino acids: L-amino acid composition range (mol /) leucine 0.0610-0.1372 isoleucine 0.0457-0.0991 valine 0.0512-0.1280 methionine 0.0101-0.0335 lysine 0.0205-0.0445 threonine 0.0084-0.0420 tryptophan 0.0049-0.0196 phenylalanine 0.0182-0.0363 tyrosine 0.0011-0.0055 histidine 0.0032-0.0258 arginine 0.0057-0.0344