JPS63307822A - Amino acid transfusion solution for renal failure - Google Patents

Abstract

PURPOSE:To prepare an amino aid transfusion solution for renal failure by adding at least 8 essential amino acids, L-tyrosine, L-histidine and L-arginine in a certain concentration respectively. CONSTITUTION:The subject transfusion solution is prepared by using, as essential components, the amino acids in the proportion given in the table, further additionally at least one selected from L-cysteine or L-cystine, L-serine, L- alanine, and L-proline, in a usual manner. The transfusion solution has 2.0-12.0W/V% concentration and pH3.0-8.0. The dose is 200-1,000ml/day/ adult. The transfusion has an ideal amino acid composition to improve the blood amino acid pattern or N-balance in the patients with renal failure and relieve BUN reduction as well as objective and subjective symptoms. Moreover, it does not induce side-effects such as hyperammonemia, fatty liver or cerebropathy.

Description

[Detailed description of the invention] Rihigashijo Godankata! The present invention relates to a novel amino acid infusion for renal failure.

i-rice 12-and 1 plateRecently, research on amino acid infusions, which are essential for body protein synthesis, has been actively conducted, with a particular focus on the metabolic specificity of various pathological conditions. Amino acid infusions for different pathological conditions have been researched and developed. In particular, with the development and spread of high-calorie infusion therapy in recent years, the importance of nutritional management has become increasingly recognized, and the need for amino acid infusions adapted to pathological conditions of various diseases, such as liver failure, renal failure, and cancer, has become increasingly important. It's starting to get exposed.

Regarding amino acid infusions for renal disease patients, Rose et al. [W.
C. Rose et al., J. Biol.

Chem, 223, 107 (1956)], an amino acid infusion for renal failure has been developed that is similar to the essential amino acid composition of
ndall Mc Gaw 1-aborator
ies ) to “Amu” (registered trademark) and [NephrAmine J (registered trademark)
It is commercially available as. Furthermore, an amino acid infusion prescribed based on the dynamics of blood aminograms of healthy subjects and dialysis patients has also been proposed at the research stage (Japanese Patent Publication No. 61-3
23@).

1. However, conventionally known amino acid infusions are still not sufficient for nutritional management, maintenance of nitrogen balance, and improvement of subjective and objective symptoms in patients with renal failure. Adverse effects such as bloodemia have begun to be reported. In other words, as the number of surgeries performed on patients with renal failure has increased in recent years, there has been an increase in the number of cases in which nutritional management has to be carried out through high-calorie infusion therapy. However, favorable results are not necessarily obtained in terms of nutritional indicators such as nitrogen balance and subjective and objective symptoms.In fact, as the dosage increases, adverse effects such as hyperammonemia and even encephalopathy have been reported.

In view of the current situation in which it is difficult to determine the condition, the present inventors have developed an ideal composition for an amino acid infusion for patients with renal failure, and have found that it is possible to correct the amino acid pattern in the blood of patients with renal failure to normal values. We have conducted extensive research with the aim of providing a new amino acid infusion that is both effective and does not induce adverse effects. As a result, at least eight essential amino acids, L-tyrosine, L-
By combining histidine and L-arginine at optimal concentrations, it improves the blood amino acid pattern and N-balance of patients with chronic and acute renal failure, providing excellent nutritional management and B-arginine.
A decrease in UN, an improvement in subjective and objective symptoms, and a reduction in hyperammonemia induced by conventional amino acid infusions for renal failure.
It has been found that an amino acid infusion for renal failure can be obtained that can eliminate adverse effects such as fatty liver and encephalopathy and meets the above objectives. The present invention was completed based on this knowledge.

That is, the present invention contains at least the following amino acids,
The present invention relates to an amino acid infusion for renal failure, characterized in that the molar composition of free amino acids is as follows.

L-new U
0.0610-0.1372 isoleucine
0.0457-0.0991 Valine 0.0
512-0.1280 Methionine 0.0101
~0.0335 Lysine 0.0205~0.
0445 Threonine 0.0084-0.042
0 tryptophan 0.0049-0.0196 phenylalanine 0.0182-0.0363 tyrosine o, ooii-0.0055 histidine
0.0032-0.0258 Arginine 0
．． 0057-0.0344 The amino acid infusion of the present invention essentially has the above amino acid composition, and further contains L-cystine (or L-cystine), L-serine,
At least one selected from L-alanine and L-proline can be blended. Furthermore, the amino acid infusion of the present invention may further contain non-essential amino acids other than the above-mentioned amino acids as appropriate.

Based on the above-mentioned composition, the amino acid infusion for renal failure of the present invention can be used in patients with chronic and acute renal failure due to trauma,
It is suitable for patients who cannot or have difficulty taking nutritional sources orally due to surgery or other reasons, and it is possible to improve blood amino acid patterns and N-balance by supplementing protein sources, and thus it is an excellent drug. nutritional management can be carried out. Furthermore, the amino acid infusion of the present invention can have effects such as lowering BUN and improving symptoms of both self and others. More specifically, the amino acid infusion of the present invention can shorten the catabolic process of the living body by administering it to patients with chronic renal failure before or after surgery, or to patients who have entered a state of acute renal failure due to trauma or surgical intervention. It is possible to minimize the effects of surgical intervention, improve the patient's blood amino acid pattern and nitrogen balance, restore nutritional status, and improve BUN or subjective and objective symptoms, as well as reduce hyperammonemia. There is no risk of inducing adverse effects such as symptoms. Furthermore, the amino acid infusion of the present invention is stable in terms of formulation.

The basic formulation and compositional characteristics particularly preferred for patients with renal failure of the amino acid infusion of the present invention are as follows.

Difference (mol/Q leucine)
o, osio ~ 0.1372 isoleucine 0
．． 0457-0.0991 Valine 0.05
12-0.12130 Methionine 0.0101
~0.0335 Lysine 0.0205~0.
0445 Threonine 0.0084-0.042
0 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, branched chain amino acids (L-leucine, isoleucine and L-valine) account for 50 to 60 of the above 11 amino acids.
Those with W/W%.

(2) In the above composition range, the weight ratio of L-lysine/L-arginine is 0.7 to 1.5.

(3) L-phenylalanine/L in the above composition range
- The weight ratio of tyrosine is 6.0 to 12. Those with O.

In addition, in another preferred embodiment of the amino acid infusion of the present invention, in addition to the above basic composition, L-cysteine (or L-
Examples include formulations containing at least one selected from L-cystine, L-serine, L-alanine, and L-proline.

Furthermore, as another preferred embodiment, in addition to the above basic composition, L-cystine (or L-cystine), L-serine, L-cystine,
-alanine, L-proline, L-aspartic acid and L-
- A formulation containing at least two selected from glutamic acid can be mentioned.

The above amino acid infusion of the present invention has a new composition and compositional characteristics different from conventionally known amino acid compositions for renal failure, so that it can be used preoperatively and postoperatively in patients with chronic and acute renal failure, especially in patients with chronic renal failure. It can be used extremely effectively without inducing any adverse effects, and can produce the desired excellent effects for patients suffering from acute renal failure after surgery or trauma.

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 does not have to be in a free form, and can be used as a pharmacologically acceptable metal. Salts such as sodium salts, potassium salts, mineral salts such as hydrochlorides, sulfates, etc.
It can also be used in the form of organic acid salts, such as acetates, lactates, malates, etc., or in the form of esters that are hydrolyzed in vivo and converted into free amino acids. Specific examples of the above salts and esters include L-lysine hydrochloride, L-lysine acetate, L-lysine malate, L-arginine hydrochloride, L-histidine hydrochloride hydrate, L-methionine Examples include methyl ester and L-methionine ethyl ester.

Furthermore, part or all of the above amino acids may be used in the form of N-acyl derivatives, such as N-acetyl-L-tyrosine, N-acetyl-L-tryptophan, N-acetyl-L-proline, and the like.

These derivatives can be used particularly effectively when the free amino acid form has low solubility and there is a risk of forming a precipitate. They also have the advantage of advantageously suppressing the browning phenomenon caused by the Maillard reaction, which may occur when reducing sugar is added to the obtained aminoshun preparation, if necessary. Furthermore, the above amino acids are salts of two types of amino acids, such as arginine-L-glutamate, L-lysine-L-
Dipeptide forms in which aspartate, etc. or the same or different amino acids are peptide-bonded, such as L-tyrosyl-tyrosine, L-alanyl-L-tyrosine, and arginyl-tyrosine, can also be used. can. Furthermore, L-methionine is partially or entirely L-methionine.
- Cystine or L-cystine can also be substituted. In addition, when each amino acid is used in a form other than the above-mentioned free amino acid, the amount to be used shall be determined so that the amount converted to free amino acid 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 containing the above-mentioned various forms of amino acids or their derivatives as free amino acids within the specified ranges mentioned above, and is suitable for intravenous administration through peripheral veins or central veins. It can be administered as an injection. The preparation method is not substantially different from that of ordinary amino acid infusions, and typically involves mixing and dissolving the above-mentioned amino acids or derivatives thereof in distilled water for injection, etc., and adding, for example, sodium sulfite, as needed.
Stabilizers such as sodium bisulfite, sodium pyrosulfite, and sodium thiosulfate; pH regulators such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, and sodium hydroxide; and other substances known to be included in ordinary amino acid infusions. This is carried out by adding various additives listed above and sterilizing the resulting aqueous solution by sterile filtration or heat sterilization. In this way, a desired pharmaceutically stable amino acid infusion can be easily prepared.

The amino acid infusion of the present invention prepared above usually has a
H from 3.0 to 8. The O1 ratio is adjusted to 4.0 to 7.5 and used. The amino acid infusion is not particularly different from normal amino acid infusion, and is generally about 2.0 to 12.0 W/
It is good to set it to about V%, preferably about 3.0 to 10.0 W/V%.

In addition, for the use and preparation of the amino acid infusion of the present invention,
In order to double the utilization rate of formulated amino acids, assist in the synthesis of these amino acids into proteins in the body, or suppress consumption as an energy source to provide more ideal nutritional support to patients. Furthermore, for example, carbohydrates such as glucose, fructose, xylitol, sorbitol, and maltose can be added and blended, and in addition to these carbohydrates, various ingredients known to be added and blended in ordinary amino acid infusions, such as lipids, can be added. , vitamins, electrolytes, trace elements, etc. can be optionally added and blended and used as a so-called high-calorie infusion, and such a usage form is more suitable.

The above-mentioned lipids include, for example, soybean oil, cottonseed oil, sesame oil, egg yolk lecithin, soybean lecithin, etc., and the vitamins include vitamin A, vitamin B1, vitamin B2, vitamin B6,
Nicotinic acid, pantothenic acid, vitamin C, vitamin D,
Vitamin E1 biotin, folic acid, etc., electrolytes such as sodium chloride, sodium acetate, potassium chloride, magnesium sulfate, magnesium chloride, calcium chloride, dipotassium phosphate, sodium phosphate, etc., and trace elements such as iron, zinc, Manganese, copper, iodine, cobalt, etc. can be mentioned, respectively.

The dosage of the amino acid preparation of the present invention may be the same as that of ordinary amino acid infusions, and is generally about 200 to 10,100 O per adult per day, depending on the medical condition, nutritional status, and age of the patient to whom it is administered. , can be increased or decreased as appropriate depending on body weight, etc.

Main stream-1 Hereinafter, in order to further clarify the present invention, production examples of the amino acid infusion of the present invention will be given as examples, and then test examples will be given.

Example 1 Once 22 UNO I LLL Leucine 14.00 Isoleucine 9.00 Valine 10.00 Methionine 4.50 Lysine acetate 6.91 (as lysine 4.90> Threonine 2.80 Tryptophan 2.40 Phenylalanine 4.30 Tyrosine 0.50 Histidine 1.50 Alunine 4.10 Total free amine ti amount 58.00 Pure crystals of each amino acid in the above composition were added to distilled water for injection, stirred and dissolved, and sulfite was added as a stabilizer. 0.39 sodium hydrogen was added, and the pH was adjusted to approximately 7.0 using acetic acid as a pH adjuster.The obtained amino acid aqueous solution was then sterile filtered, filled into an infusion container, and after purging with nitrogen, the container was sealed. was sterilized at 79105°C in autoclay for 40 minutes to obtain an amino acid infusion of the present invention (total free amino acid concentration 5.8 W/V%).

Example 2 Amino acids 9/Q Leucine 14.00 Isoleucine 9.00 Valine 10.00 Methionine 3.00 Lysine acetate 7.05 (as lysine 5.00> Threonine 3.50 Tryptophan 2.50 Phenylalanine 4.50 Tyrosine 0.50 Histidine 2.50 Arginine 4.50 Cysteine 1.00 Total amount of free amino acids 60.00 Amino acid infusion of the present invention having the above composition as in Example 1 (total free amino M concentration 6.0 W/V% ) was obtained.

Example 3 [-Amino M'J/Q Leucine 8.00 Isoleucine 6.00 Valine 6.00 Methionine 3.50 Lysine acetate 4.23 (as lysine 3.00> Threonine 2.00 Tryptophan 1.00 Phenylalanine 4 .00 Tyrosine 0.50 Histidine 2.00 Alunine 4.00 Total amount of free amino acids 40.00 Amino acid infusion of the present invention having the above composition as in Example 1 (total free amino acids M11 degrees 4.0 W/V%) I got it.

Example 4 -Amino acids 'j/Q Leucine 18.00 Isoleucine 9.00 Valine 6.00 Methionine 4.86 Lysine acetate 7.48 (as lysine 5.30) Threonine 3.02 Tryptophan 2.59 Phenylalanine 4. 64 N-7 cetyl tyrosine 0.67 sine (as tyrosine 0.54> histidine 1.62 arsine 4.43 total free amino acid amount 60.00 The amino acid infusion of the present invention (total free amino acid) having the above composition was prepared in the same manner as in Example 1. An amino acid concentration of 6.0 W/V%) was obtained.

Example 5 -Ni2Yue 1 14 Main Leucine 10.00 Isoleucine 13.00 Valine 10.00 Methionine 5. OO Lysine malate 12.46 (as lysine 6.50> Threonine 4.00 Tryptophan 2.00 Phenylalanine 3.00 Tyrosine 0.50 Histidine 1.50 Alsine °4.50 Total free amine rti amount 60.00 I ) 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 that malic acid was used as the H adjuster.

Example 6 -Amino acids 'j/Q Leucine 14.00 Isoleucine 9.00 Valine 15.00 Methionine 5.00 Lysine acetate 8.46 (as lysine 6.00) Threonine 5.00 Tryptophan 4.00 Phenylalanine 6. 0O N-acetyl-tyro 1.23 sine (1.00 as tyrosine) Histidine 4.00 Al sine 6.00 Total amount of free amino acids 75.00 The amino acid infusion of the present invention having the above composition (total amount) was prepared in the same manner as in Example 1. A free amino acid concentration of 7.5 W/V%) was obtained.

Example 7 L-amino acid, LZ2'' - Leucine '14.00 Isoleucine 9.00 Valine 15.00 Methionine 5.00 Lysine acetate 8.46 (As lysine 6.00> Threonine 5.00 Tryptophan 4.OO Phenylalanine 6 .00 Tyrosine 1.00 Histidine 4.00 Arginine 6.OO Total amount of free amino acids 75.OO The amino acid infusion of the present invention having the above composition (total free amino M concentration 3.75 W/V%) was prepared in the same manner as in Example 1. Obtained.

Example 8 L-amino acid 9/Q Leucine 14.00 Isoleucine 9.00 Valine 11.00 Methionine 3.00 Lysine acetate 7.05 (as lysine 5.00> 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 Cisnine 1.00 Total amount of free amino acids 70.00 Amino acid infusion of the present invention having the above composition as in Example 1. (Total free amino acid concentration 7.0 W/V%) was obtained.

Example 9 Once euthanized [9/Q O leucine 4.00 isoleucine 9.00 valine 10.00 methionine 3.00 lysine acetate 7.05 (as lysine 5.00> 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 free amino M amount 70.00 The above composition was prepared in the same manner as in Example 1. An amino acid infusion of the present invention (total free amino Ha content 7.0 W/V%) was obtained.

Example 10 L-amino acid g/Q Leucine 14.00 Isoleucine 9.00 Valine 7.00 Methionine 4.50 Lysine acetate 8.61 (as lysine 6.10> Threonine 2.80 Tryptophan 2.40 Phenylalanine 4.30 Tyrosine 0.50 Histidine 1.50 Alnine 4.10 Total free amine Il amount 56.20 The amino acid infusion of the present invention having the above composition (total free amino IWA content 5.62 W/V%) was prepared in the same manner as in Example 1. Obtained.

Example 11 Shi-amino r! j, g/Q Leucine 15.00 Isoleucine 10.00 Valine 7.00 Methionine 4.50 Lysine acetate 8.61 (as lysine 6.10> Threonine 2.80 Tryptophan 2.40 Phenylalanine 4.30 Tyrosine 0.50 Histidine 1.50 Alnine 4.10 Total free amino acid amount 58.20 An amino acid infusion of the present invention having the above composition (total free amino M concentration 5.82 W/V%) was obtained in the same manner as in Example 1.

Example 12 Amino acids Bi/Q Leucine 14.00 Isoleucine 9.00 Valine 10.00 Methionine 3. OO Lysine acetate 7.05 (as lysine 5.00> 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 Aspartic acid 1.00 Lutamic acid 1.00 Total free amino acid M 72.00 The amino acid infusion of the present invention having the above composition (total free amino acid concentration 7.2 W/V%) was prepared in the same manner as in Example 1. Obtained.

Test Example 1 1) Chronic renal failure (CRF) rat production method Weight: approximately 200g
One group of 5 male Wistar rats was used.

75% of one kidney was removed under Nembutal anesthesia, and one week later, the opposite kidney was removed again under Nembutal anesthesia. Two weeks later, animals whose plasma creatinine was 1.5 mg/old or higher were used as CRF rats and subjected to the following experiment.

2) Experimental Method CRF rats were anesthetized with Nembutal, and a silicone catheter was inserted into the jugular vein. Amino acid infusion of the present invention obtained in [Examples] and a commercially available amino acid infusion for renal failure formulated with Rose ("Amicor", manufactured by Morishita Pharmaceutical Co., Ltd.)
Each group CRF Administered to rats via intravenous catheter, -
Weekly total parenteral nutrition (TPN) was administered. The daily dosage composition of the mixed solution is 0.817 SJ/Kg for nitrogen, 270 kcal/Ky for calorie content, and 270 mQ for water molecules fi.
/ was set as 'J'. The dosage at the 1st 28th day of TPN initiation was 50% and 75% of the previous administration on -days, respectively.
%.

Table 1 shows the composition of each amino acid infusion used. In addition, the first
In the table, all amino acid infusion compositions are expressed in free form.

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

The results are shown in Table 2. In addition, a same-week-old ad libitum feeding group as a normal group and an ad libitum feeding group of CRF rats as a renal failure group were created, and the results for each second class group are also listed in Table 2. . Furthermore, all the measured values shown in Table 2 are average values.

As is clear from Table 2, the branched chain amino acids (leucine, isoleucine and valine) induced by CRF
The decrease in methionine, the decrease in tryptophan, and the decrease in serine were all normalized in the TPN group using the amino acid infusion of the present invention (invention group), but in the group using commercially available amino acids (comparison group A), the decrease in methionine , lysine, threonine, histidine, glutamine, taurine, and citrulline, and a marked decrease in arginine. In the group using the amino acid infusion of Comparison B (Comparison Group 8), increases in valine, lysine, threonine, and tyrosine, and decreases in histidine and sulfur-containing amino acids methionine and cysteine were observed.

Test Example 2 1) Experimental Method A group of 6 CRF rats prepared in the same manner as in Test Example 1 was anesthetized with Nembutal, and a silicone catheter was inserted into the jugular vein and indwelled. Thereafter, glucose, electrolytes, and vitamins were added to the amino acid infusion of the present invention obtained in Example 1 and the commercially available amino acid infusion for renal failure prescribed by Rose ("Amu", manufactured by Nasashita Pharmaceutical Co., Ltd., Comparative A) under fasting and sugar water. Each of the mixed solutions was administered through an intravenous catheter, and total parenteral nutrition (TPN) was administered for one week.The daily dosage composition of the mixed solution was 10.817 g of nitrogen per day, 1270 kca of calories.
The water content was set to 9 and the water content to 270rrf2/Ks. Note that the doses for the first two days of TPN initiation were reduced to 50% and 75% of the above-mentioned daily doses, respectively.

During the TPN period, the animals were managed in metabolic cages, urine was collected every day, and urinary nitrogen excretion was measured to determine nitrogen balance. The results are shown in Table 3.

After the 7-day TPN period, blood was collected from the abdominal aorta under Nembutal anesthesia and blood biochemical tests were performed.The liver was also collected and the glycogen, protein, and triglyceride contents in the liver were measured.

The results are shown in Table 4.

As is clear from Tables 3 and 4 above, nitrogen balance was better in TPN using the amino acid infusion of the present invention (invention group) compared to TPN using commercially available amino acid infusion for renal failure (comparison group A). The hematocrit, plasma total protein, and albumin remained high, and the SUN decreased. On the other hand, comparison group A exhibited hyperammonemia, and blood TG and N
There was a marked decrease in EFA and increase in hepatic TO.

Test Example 3 One group of 5 male Wistar rats weighing 250 g was used.

After an overnight fast, mercuric chloride 31n' was administered under Nembutal anesthesia.
J/Kg was administered subcutaneously to the back to treat acute renal failure (8RF).
One rat was prepared.

Immediately after administering mercury chloride, a silicone catheter was inserted into the jugular vein in the same manner as in Test Example 2, and the amino acid infusion of the present invention obtained in Example 1 or the commercially available amino acid infusion for renal failure ("Amu", Nasinashia Pharmaceutical Co., Ltd.) was administered. TPN was carried out for 3 days using a mixed liquid mixture for TPN using Comparative A). These will be referred to as the present invention group and comparative group A, respectively.

The daily dosage composition of the mixed solution is nitrogen amount 0.817g/'J
, calorie content 270 kcal/Ng and water content 270
1m/! J, and the daily dose on the first day of starting TPN was 5.
reduced to 0%.

Table 5 shows the nitrogen balance determined from urinary nitrogen excretion for 3 days, and Table 6 shows the measurement results of blood ammonia, BUN, and creatinine amounts at the end of TPN. Table 6 also lists the measured values in a group of normal rats as a control.

From Tables 5 and 6 above, the group administered with the amino acid infusion of the present invention (the present invention group) maintained nitrogen balance better, and the BU
It can be seen that the increase in N was suppressed. In comparison group A, hyperammonemia was induced.

(that's all)

Claims (1)

[Claims] (1) An amino acid infusion for renal failure, which contains at least the following amino acids and has the following molar composition in terms of free amino acids. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼