JP2003055195A - Vitamin b1-formulated comprehensive transfusion for peripheral intravenous administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a peripheral intravenous administration comprehensive transfusion into which vitamin B1 is preliminarily formulated and which can retain the stability of the vitamin B1, has a pH value near to neutrality when used, and thereby hardly causes phlebitis. SOLUTION: This vitamin B1-formulated peripheral intravenous administration comprehensive transfusion is the one whose components are mixed when used, and are prepared by receiving a sugar solution not containing sulfite ion and containing vitamin B1 and a calcium salt and/or a phosphate in one of chambers divided by a separating method permitting the mutual communication of solutions and receiving an amino acid solution in the other chamber. Therein, the sugar solution has a pH value of 4.0 to 5.5 and a titration acidity of <=30, and the amino acid solution has a pH value of 6.5 to 8.5. When the sugar solution is mixed with the amino acid solution, the mixture has a pH value of 6.0 to 7.4 and a titration acidity of <=10.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a general infusion solution for peripheral intravenous administration in which vitamin B1 is preliminarily blended, and more specifically, the stability of vitamin B1 is maintained even if vitamin B1 is preliminarily blended. However, the present invention relates to a total infusion solution for peripheral intravenous administration containing vitamin B1 which can prevent phlebitis from occurring when the pH is close to neutral during use.

[0002]

2. Description of the Related Art Parenteral nutrition therapy and enteral nutrition therapy are widely used for nutritional management of patients, and these therapies have already become a part of daily medical care. In particular, nutritional management is performed by parenteral nutrition therapy for patients who have difficulty in oral nutrition. Parenteral nutrition therapy includes high calorie infusion (TPN) therapy using the central venous route and peripheral parenteral nutrition (PPN) therapy using the peripheral venous route. Since TPN therapy performs all nutritional supplementation by infusion, careful attention is paid to the type and amount of nutrients. When performing TPN therapy, if the period of nutritional management by TPN is relatively long, deficiency of trace elements and vitamins occurs, which is a problem.
In particular, since death cases due to vitamin B1 deficiency occurred in TPN therapy, now the Ministry of Health and Welfare has issued emergency safety information to ensure that vitamin B1 is administered. on the other hand,
Similar to TPN therapy, PPN therapy consumes vitamin B1 when the glucose administered intravenously is metabolized, and there is a risk of vitamin B1 deficiency unless vitamin B1 required for metabolism is administered. . In fact, PPN
Patients who are indicated for therapy are often malnourished and may have potential B vitamins even if deficiency is not observed macroscopically.
It has been reported that there are many cases of 1 deficiency. Therefore, in order to carry out safer PPN therapy, it is necessary to develop a total infusion solution for peripheral intravenous administration containing vitamin B1 in advance.

By the way, when PPN therapy is performed, the occurrence of phlebitis is an unavoidable problem. Therefore, it is necessary to consider delaying the occurrence of phlebitis or reducing the occurrence of phlebitis at a medical site where PPN therapy is performed. Phlebitis is considered to be one of the causes of the pH of the infusion agent, and it was necessary to make the pH of the infusion agent near neutral when performing PPN therapy in order to avoid phlebitis. on the other hand,
The stability of vitamin B1 is generally pH dependent. For example, the most representative thiamine hydrochloride among vitamin B1 is p
It is known that H2 is the most stable and becomes unstable as the pH increases. In addition, the 13th revised Japanese Pharmacopoeia commentary states that it is relatively stable at pH 2 to 4 in an aqueous solution. When vitamin B1 is mixed in advance with an infusion solution, it is preferable to lower the pH of the infusion solution in order to maintain the stability of vitamin B1.

As described above, in order to avoid phlebitis, it is necessary for the infusion solution for PPN therapy to have a pH close to neutral, but for stability of vitamin B1 p
It was necessary to lower H. That is, in the total infusion solution for peripheral intravenous administration, the optimum pH of the infusion agent for maintaining the stability of vitamin B1 and for preventing phlebitis from occurring.
Were contradictory. Therefore, even if vitamin B1 is preliminarily added to the general infusion for peripheral intravenous administration, the stability of vitamin B1 is maintained, and the pH is close to neutral during use, which makes it difficult to cause phlebitis. It was difficult to develop a total infusion solution for combined peripheral intravenous administration.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a total infusion solution for peripheral intravenous administration in which vitamin B1 is preliminarily blended, and the stability of vitamin B1 can be improved even if vitamin B1 is preliminarily blended. It is an object of the present invention to provide a comprehensive infusion solution for peripheral intravenous administration containing vitamin B1, which can be maintained and have a pH close to neutral at the time of use to prevent phlebitis from occurring.

[0006]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that a sugar solution and an amino acid solution are separately stored and vitamin B1 is added to the sugar solution. In the general infusion solution for peripheral intravenous administration containing vitamin B1 of mixed type, the sugar solution does not contain sulfite ion, and either or both of calcium salt and phosphate salt are added,
The pH of the sugar solution is 4.0 to 5.5, the titratable acidity is adjusted to 30 or less, the pH of the amino acid solution is adjusted to 6.5 to 8.5, and all the solutions are mixed. pH is 6.
If the titratable acidity is 10 or less at 0 to 7.4,
It was found that a stable infusion of vitamin B1 during storage and a pH close to neutrality when mixed during use give a comprehensive infusion solution for peripheral intravenous administration containing vitamin B1 that is unlikely to cause phlebitis. Based on this, the present invention has been completed.

That is, the present invention provides the following (1)-
It is shown in (6). (1) A sugar solution containing sugar is contained in one chamber of a container partitioned by an isolation means that can communicate with each other, and an amino acid solution containing amino acid is contained in the other chamber, and calcium salt and phosphate are contained in the sugar solution. A mixed-use type infusion solution in which either one is mixed with a sugar solution and the other is mixed with an amino acid solution, wherein the sugar solution does not contain sulfite ion and contains vitamin B1, and has a pH of 4. 0-5.5 and titratable acidity of 30
The amino acid solution is adjusted to have a pH of 6.5.
The pH is adjusted to 6.0 to 7.5 when the isolation means is in communication and all the liquids of the infusion solution are mixed.
A total infusion solution for peripheral intravenous administration containing vitamin B1 having a titratable acidity of 10 or less at 4. (2) The infusion solution for peripheral intravenous administration containing vitamin B1 according to the above (1), wherein the sugar is glucose. (3) The total infusion solution for peripheral intravenous administration containing vitamin B1 according to the above (1) or (2), wherein calcium salt and phosphate are separately mixed in a sugar solution and an amino acid solution. (4) The comprehensive infusion solution for peripheral intravenous administration containing vitamin B1 according to any of (1) to (3) above, wherein the vitamin B1 is at least one selected from thiamine and salts thereof.

(5) The composition after mixing all the liquids is as follows: glucose 3-10 w / v%, thiamine 0.4-40
mg / L, L-leucine 2.0-7.0 g / L, L-isoleucine 1.0-4.0 g / L, L-valine 0.7-
4.2 g / L, L-lysine 1.5 to 7.5 g / L, L-
Threonine 0.8-3.0 g / L, L-tryptophan 0.2-1.2 g / L, L-methionine 0.5-2.5
g / L, L-phenylalanine 1.0 to 4.0 g / L,
L-cysteine 0.1-0.7 g / L, L-tyrosine 0
~ 0.5 g / L, L-arginine 1.4-5.5 g /
L, L-histidine 0.8 to 2.7 g / L, L-alanine 1.0 to 4.2 g / L, L-proline 0.6 to 2.6
g / L, L-serine 0.3 to 1.7 g / L, aminoacetic acid
1.0-4.5 g / L, L-aspartic acid 0.1-
1.7 g / L, L-glutamic acid 0.1-3.0 g /
L, sodium 25-70 mEq / L, potassium 15-
50 mEq / L, calcium 3 to 15 mEq / L, magnesium 3 to 10 mEq / L, chlor 25 to 70 mEq
/ L, phosphorus 5 to 20 mmol / L, zinc 0 to 30 μmo
The total infusion solution for peripheral intravenous administration containing vitamin B1 according to any of (1) to (4) above, which is 1 / L. (6) The vitamin B1-containing peripheral intravenous administration synthetic preparation according to any one of (1) to (5) above, wherein the container is a gas-permeable container and is enclosed together with a deoxidizer in a gas-impermeable outer container. Infusion solution.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The general infusion solution for peripheral intravenous administration containing vitamin B1 of the present invention will be described in detail below. The total infusion solution for peripheral intravenous administration containing vitamin B1 of the present invention separately stores a sugar solution and an amino acid solution, the sugar solution does not contain sulfite ions, and contains either vitamin B1 or calcium salt and phosphate. A one-time-use mixed infusion type vitamin B1-containing total infusion solution for peripheral intravenous administration, in which the pH of the sugar solution is 4.0 to 5.5 and the titratable acidity is adjusted to 30 or less, The pH of the amino acid solution is 6.5 to 8.5
The pH is 6.0 to 7.4 and the titratable acidity is 10 or less when all the liquids are mixed.

As the vitamin B1 used in the present invention, any of those conventionally used can be used, and examples thereof include thiamine, fursultiamine, thiamine disulfide, cocarboxylase, prosultiamine, shicothiamine, thiamine monophosphate disulfide, Bisbentamine, benfotiamine, and the like, and salts thereof. Of these, thiamine and its salts are preferred.

Examples of the sugar used in the present invention include glucose, fructose, maltose, xylitol, sorbitol, glycerin, etc. These may be used alone or in combination of two or more. Of these, glucose is preferably used from the viewpoint of blood sugar control. The amount of sugar can be appropriately determined according to the purpose of use such as the route of administration, but the concentration after mixing the sugar solution and the amino acid solution is 3 to
It is preferable to mix in a concentration range of 10 w / v%. The sugar solution of the present invention may have a pH adjusting agent, if necessary, to a pH of 4.0 to 5.5, preferably a pH of 4.2 to 5.
Adjusted to 3. If the pH of the sugar solution is less than 4.0, it is difficult to adjust the pH when mixing the sugar solution and the amino acid solution to 6.0 or more, and if it exceeds 5.5, the solution is colored due to the decomposition of sugar. There is a high possibility that such quality deterioration will occur.
Further, the titratable acidity of the sugar solution needs to be 30 or less. When the titratable acidity of the sugar liquid exceeds 30, the pH tends to fall outside the pH range when the sugar liquid and the amino acid liquid are mixed.

The amino acid used in the present invention is not particularly limited as long as it is an amino acid used in the technical field of infusion solutions, and specifically, L-leucine, L-isoleucine, L-valine, L-lysine. , L-threonine, L-
Tryptophan, L-methionine, L-phenylalanine, L-cysteine, L-tyrosine, L-arginine,
L-histidine, L-alanine, L-proline, L-serine, aminoacetic acid, L-aspartic acid, L-glutamic acid and the like can be mentioned, and these amino acids are not only free amino acids but also various salts such as sodium and potassium. Or an acid salt of acetic acid or malic acid, a mineral acid salt of hydrochloric acid or sulfuric acid, or a part of amino acids may be used as a peptide. The blending amount of amino acid can be appropriately determined according to the purpose of use such as administration route, but the concentration after mixing the sugar solution and the amino acid solution is 2 to 10 w /
It is preferable to mix in a concentration range of v%.

The amino acid solution of the present invention may have a pH if necessary.
PH of 6.5-8.5, preferably p, using regulators
It is adjusted to H6.7-8.3. If the pH of the amino acid solution is less than 6.5, it will be difficult to adjust the pH when the sugar solution and the amino acid solution are mixed to 6.0 or more, and if it exceeds 8.5, amino acids such as L-cysteine will be generated. It becomes unstable and is not preferable. Further, sulfite salts such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, and sodium thiosulfate can be added to the amino acid solution of the present invention as a stabilizer.

As the electrolyte used in the present invention, the same compounds as those used in general electrolyte infusion can be used, and sodium, potassium, which are electrolytes essential to the living body,
Examples include magnesium, calcium, chlor, phosphorus and the like. Specifically, sodium hydrogen carbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium lactate, sodium citrate, sodium chloride, sodium sulfate, potassium chloride, potassium iodide, dihydrogen phosphate. Potassium hydrogen, dipotassium hydrogen phosphate, potassium lactate, potassium citrate, potassium acetate, calcium lactate, sodium glycerophosphate, potassium glycerophosphate, calcium glycerophosphate, calcium gluconate, calcium chloride, magnesium chloride, magnesium sulfate, magnesium acetate, chloride Zinc, zinc sulfate, iron sulfate, ferrous chloride, ferric chloride, iron gluconate, copper sulfate, manganese sulfate and the like can be used, and these may be hydrates. When the calcium salt and phosphate electrolytes are blended, if the pH of the solution is high, precipitation may occur due to both salts. Therefore, both salts should be blended in a low pH sugar solution or separated separately. It is preferable that the calcium salt is added to the amino acid solution when the calcium salt is added to the sugar solution, and the calcium salt is added to the amino acid solution when the phosphate salt is added to the sugar solution. preferable. Further, since magnesium salt may also form a precipitate with phosphate, it is preferable to mix it with the calcium salt in the same liquid.

The pH of the sugar solution and the amino acid solution can be adjusted as necessary. The pH adjusting agent used in the present invention is not limited as long as it can be used as a pharmaceutical additive. For example, citric acid, acetic acid, tartaric acid, carbonic acid, lactic acid, fumaric acid, propionic acid, boric acid, phosphoric acid,
Sulfuric acid and their compounds, adipic acid, hydrochloric acid, gluconic acid, succinic acid, potassium hydroxide, calcium hydroxide,
It is possible to mix one or more selected from sodium hydroxide, magnesium hydroxide, sodium hydrogen carbonate, maleic acid, malic acid and the like. The sugar solution and amino acid solution thus prepared are mixed before use. The pH when all the liquids are mixed is adjusted to 6.0 to 7.4, preferably pH 6.5 to 7.4. If the pH of the mixed solution is less than 6.0, phlebitis is likely to occur, and if it exceeds 7.4, the pH of blood is exceeded. The titratable acidity when all the liquids are mixed must be 10 or less. If the titratable acidity when all the liquids are mixed exceeds 10, the pH of the mixed liquid
Tends to be out of range. The drug solution of the total infusion solution for peripheral intravenous administration containing vitamin B1 of the present invention has been described above, but the present invention is not limited to these.
If necessary, water-soluble vitamins other than vitamin B1,
Fat-soluble vitamins, saccharides, amino acids, electrolyte components and additives may be added.

The container for accommodating the total infusion solution for peripheral intravenous administration containing vitamin B1 of the present invention is not particularly limited.
As the material of the container, polyethylene, polypropylene, polyvinyl chloride, which is usually used for medical containers, etc.
Examples thereof include crosslinked ethylene / vinyl acetate copolymers, ethylene / α-olefin copolymers, and blends and laminates of these polymers. Filling and storage in a container can be carried out by a conventional method, and examples thereof include a method in which each liquid is filled in an inert gas atmosphere, stoppered, and heat sterilized.
As the heat sterilization method, a known method such as high-pressure steam sterilization, hot water sterilization, hot water shower sterilization can be appropriately adopted.
The operating conditions of the sterilization method, such as the sterilizing time and the sterilizing temperature, can be the same as the ordinary operating conditions of this type of sterilization. Furthermore, the heat sterilization can be performed in an atmosphere of an inert gas such as nitrogen, if necessary.

Further, in order to surely prevent deterioration of the comprehensive infusion solution for peripheral intravenous administration containing vitamin B1 of the present invention such as oxidation, the container is packaged with an oxygen scavenger in an outer container that is substantially impermeable to oxygen. be able to. At this time, it is preferable to use a gas-permeable plastic as the material of the container for storing the infusion solution. As an oxygen absorber,
Various known materials can be used. For example, those containing iron compounds such as iron hydroxide, iron oxide and iron carbide as active ingredients can be used. Examples of commercially available products include Ageless (manufactured by Mitsubishi Gas Chemical Co., Inc.), Modulan (manufactured by Nippon Kayaku Co., Ltd.) and SECURE (manufactured by Nippon Soda Co., Ltd.).

As the material of the outer container which is suitable for packaging and is substantially impermeable to oxygen, film sheets of various commonly used materials can be used. For example, polyethylene terephthalate (PET), polyethylene naphthalate (PEN), ethylene / vinyl alcohol copolymer (EVOH), polyvinylidene chloride (PVD)
C), polyacrylonitrile, polyvinyl alcohol,
Examples thereof include polyamide, polyester, aluminum foil, aluminum vapor deposition film, aluminum oxide vapor deposition film, silicon oxide vapor deposition film, and multilayer film sheets containing at least one of these. The space inside the outer container is preferably filled with an inert gas such as nitrogen.
The thus obtained comprehensive infusion solution for peripheral intravenous administration containing vitamin B1 retains the stability of vitamin B1 even if vitamin B1 is preliminarily mixed, and when used, it is close to neutral p
By providing H, it is possible to provide a total infusion solution for peripheral intravenous administration containing vitamin B1, which can prevent phlebitis from occurring easily.

[0019]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these. (Example 1) Under a nitrogen stream, glucose 75 g / 700 m
L, sodium chloride 0.80 g / 700 mL, sodium lactate 2.29 g / 700 mL, calcium gluconate 1.12 g / 700 mL, magnesium sulfate 0.62 g
/ 700 mL, zinc sulfate 1.40 g / 700 mL and thiamine hydrochloride 2.3 mg / 700 mL are dissolved in distilled water for injection, and a small amount of glacial acetic acid is used as a pH adjuster to adjust the pH.
A sugar solution was prepared as 5.0. The titratable acidity of this sugar solution was 2. On the other hand, under nitrogen stream, 4.2 g of L-leucine
/ 300mL, L-isoleucine 2.4g / 300m
L, L-valine 2.4 g / 300 mL, lysine hydrochloride 3.
93 g / 300 mL, L-threonine 1.71 g / 30
0 mL, L-tryptophan 0.6 g / 300 mL, L
-Methionine 1.17 g / 300 mL, L-phenylalanine 2.1 g / 300 mL, L-cysteine 0.31
5 g / 300 mL, L-tyrosine 0.15 g / 300 m
L, L-arginine 3.15 g / 300 mL, L-histidine 1.5 g / 300 mL, L-alanine 2.4 g /
300 mL, L-proline 1.5 g / 300 mL, L-
Serine 0.9 g / 300 mL, aminoacetic acid 1.77 g /
300 mL, L-aspartic acid 0.3 g / 300 m
L, L-glutamic acid 0.3 g / 300 mL, dipotassium hydrogen phosphate 1.74 g / 300 mL and sodium bisulfite 90 mg / 300 mL were dissolved in distilled water for injection, and a small amount of glacial acetic acid was used as a pH adjuster to adjust the pH to 6. 9
As an amino acid solution was prepared. 350 mL of the sugar solution and 150 mL of the amino acid solution prepared as described above were filled in each chamber of a polyethylene two-chamber container and sealed, and then nitrogen gas was introduced to perform high-pressure steam sterilization treatment.
Furthermore, the container was enclosed in a gas-impermeable outer packaging material (aluminum vapor deposition film, manufactured by Dai Nippon Printing Co., Ltd.) together with two oxygen scavengers (Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.), and peripherally administered intravenously with B1. A total infusion solution 1 was obtained. The pH of the solution after mixing the sugar solution and the amino acid solution of the infusion solution was 6.
7, the titratable acidity was 8.

Comparative Example 1 In Example 1, sodium bisulfite was added to the amino acid solution at 60 mg / 30 instead of 90 mg / 300 mL of sodium bisulfite as the amino acid solution.
The same procedure as in Example 1 was repeated except that 0 mL and 30 mg / 700 mL of the sugar solution were separately mixed to obtain a total infusion solution for peripheral intravenous administration.

(Test Example 1) B prepared in each of the above Examples 1
The amounts of thiamine of 1 combined peripheral intravenous administration total infusion solution 1 and the peripheral intravenous administration total infusion solution 1 prepared in Comparative Example 1 were measured by liquid chromatography immediately after sterilization and after storage at room temperature for 7 days. The results are shown in Table 1. In addition, in Table 1, the ratio to the blending amount is shown in percentage.

[0022]

[Table 1]

From the results shown in Table 1, the total infusion solution for peripheral intravenous administration containing B1 of Example 1 contained thiamine at a high concentration immediately after sterilization and after being stored at room temperature for 7 days, but contained sulfite ion. The total infusion solution for peripheral intravenous administration of Comparative Example 1 showed a marked decrease in the amount of thiamine immediately after sterilization and after storage at room temperature for 7 days.

(Example 2) pH of sugar solution in Example 1
Except that the pH of the amino acid solution was set to 4.4 and the pH of the amino acid solution was set to 7.9 to obtain the total infusion solution 2 for peripheral intravenous administration containing B1 by repeating the same operation as in Example 1. The titratable acidity of this sugar solution was 15. The pH of the liquid after mixing the sugar liquid and the amino acid liquid of this infusion solution was 6.7, and the titratable acidity was 8.

Example 3 The pH of sugar solution in Example 1
Except that the pH of the amino acid solution was set to 4.2 and the pH of the amino acid solution was set to 8.2, and the same operation as in Example 1 was repeated to obtain a total infusion solution 3 for peripheral intravenous administration containing B1. The titratable acidity of this sugar solution was 25. The pH of the liquid after mixing the sugar liquid and the amino acid liquid of this infusion solution was 6.7, and the titratable acidity was 8.

(Example 4) 75 g of glucose under a nitrogen stream
/ 700mL, dipotassium hydrogen phosphate 1.74g / 70
A sugar solution was prepared by dissolving 0 mL of thiamine hydrochloride (2.3 mg / 700 mL) in distilled water for injection and adjusting the pH to 5.2 using a slight amount of glacial acetic acid as a pH adjuster. The titratable acidity of this sugar solution was 15. On the other hand, under a nitrogen stream, L-leucine 4.2 g / 300 mL, L-isoleucine 2.4 g
/ 300 mL, L-valine 2.4 g / 300 mL, lysine hydrochloride 3.93 g / 300 mL, L-threonine 1.7
1 g / 300 mL, L-tryptophan 0.6 g / 30
0 mL, L-methionine 1.17 g / 300 mL, L-
Phenylalanine 2.1 g / 300 mL, L-cysteine 0.315 g / 300 mL, L-tyrosine 0.15 g
/ 300mL, L-arginine 3.15g / 300m
L, L-histidine 1.5 g / 300 mL, L-alanine 2.4 g / 300 mL, L-proline 1.5 g / 30
0 mL, L-serine 0.9 g / 300 mL, aminoacetic acid 1.77 g / 300 mL, L-aspartic acid 0.3 g
/ 300mL, L-glutamic acid 0.3g / 300m
L, sodium chloride 0.80 g / 300 mL, sodium lactate 2.29 g / 300 mL, calcium gluconate 1.12 g / 300 mL, magnesium sulfate 0.62 g
/ 300 mL, zinc sulfate 1.40 g / 300 mL and sodium bisulfite 90 mg / 300 mL were dissolved in distilled water for injection, and a slight amount of glacial acetic acid was used as a pH adjuster to adjust the pH to 7.9 to prepare an amino acid solution. 350 mL of the sugar solution and 1 of the amino acid solution prepared as described above
50 mL of each was filled in each chamber of a polyethylene two-chamber container and sealed, and then nitrogen gas was introduced to perform high-pressure steam sterilization treatment. Furthermore, the container was enclosed in a gas-impermeable outer packaging material (aluminum vapor deposition film, manufactured by Dai Nippon Printing Co., Ltd.) together with two oxygen scavengers (Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.), and peripherally administered intravenously with B1. A total infusion solution 4 was obtained. The pH of the solution after mixing the sugar solution and the amino acid solution of this infusion solution was 6.7, and the titratable acidity was 8.

(Example 5) pH of sugar solution in Example 4
Except that the pH of the amino acid solution was set to 4.7 and the pH of the amino acid solution was set to 8.2, and the same operation as in Example 4 was repeated to obtain a total infusion solution 5 for peripheral intravenous administration containing B1. The titratable acidity of this sugar solution was 24. The pH of the liquid after mixing the sugar liquid and the amino acid liquid of this infusion solution was 6.7, and the titratable acidity was 8.

(Test Example 2) Immediately after the start of the storage of the B1-containing total infusion solution for peripheral venous administration 2-5 prepared in each of the above Examples 2-5, after storage at 60 ° C for 3 weeks and at 40 ° C for 12 weeks. After that, the amount of thiamine was measured by a liquid chromatography method, and the amount of L-cysteine was measured by a colorimetric method. Table 2 shows the results of the amount of thiamine and Table 3 shows the results of the amount of L-cysteine.
Shown in. In addition, in Tables 2 and 3, the ratio to the amount of thiamine and the amount of L-cysteine immediately after the start of storage is shown in percentage.

[0029]

[Table 2]

[0030]

[Table 3]

From the results of Tables 2 and 3, the total infusion solutions 2 to 5 for peripheral venous administration containing B1 of Examples 2 to 5 were treated at 60 ° C.
It contained thiamine and L-cysteine in high concentration even after being stored for a week and at 40 ° C. for 12 weeks.
It was also confirmed that no coloring was observed on the sugar liquid side and that sugar was not decomposed.

(Example 6) The same operation as in Example 4 was repeated except that the amino acid solution prepared in Example 5 was used to obtain a total infusion solution 6 for peripheral intravenous administration containing B1. P of the liquid after mixing the sugar solution and amino acid solution of this infusion
H was 7.3 and titratable acidity was 1.

[0033]

As described above, in the total infusion solution for peripheral intravenous administration containing B1 of the present invention, the sugar solution containing sugar is contained in one chamber of the container partitioned by the isolation means capable of communicating with others. An amino acid solution containing an amino acid is stored in the solution, and the calcium salt and the phosphate are both added to the sugar solution. One is a sugar solution and the other is an amino acid solution. The sugar solution does not contain sulfite ions, contains vitamin B1, and has a pH of 4.0 to 5.
5, the titratable acidity is adjusted to 30 or less, the pH of the amino acid solution is adjusted to 6.5 to 8.5, and the pH when all the solutions of the infusion solution are mixed by communicating the isolation means. Since it is a total infusion solution for peripheral intravenous administration containing vitamin B1 having a titratable acidity of 10 or less at 6.0 to 7.4, it is a general infusion solution for peripheral intravenous administration containing vitamin B1 in advance, but it is a vitamin for a long time. The stability of B1 can be maintained, and when the sugar solution and the amino acid solution are mixed at the time of use, the pH becomes close to neutral, so that phlebitis can be less likely to occur when administered. Further, according to the present invention, since the container containing the infusion solution is enclosed with the oxygen scavenger in the gas-impermeable outer packaging material, the sugar and amino acid of the infusion component are stably maintained for a long period of time.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 45/00 A61K 45/00 A61P 3/02 105 A61P 3/02 105 F term (reference) 4C076 AA12 BB17 CC22 DD26 DD80 FF11 4C084 AA23 AA27 BA44 CA59 MA02 MA17 MA66 NA10 NA14 ZA442 4C086 AA01 BC83 EA01 MA03 MA05 MA17 MA66 NA10 NA14 ZA44 4C206 AA01 FA53 JA57 JA58 MA03 MA05 MA37 MA86 ZA44

Claims (6)

[Claims] 1. A sugar solution containing a sugar is contained in one chamber of a container partitioned by an isolation means that can communicate with each other, and an amino acid solution containing an amino acid is contained in the other chamber. A mixed-use infusion solution in which either one is mixed with a sugar solution and the other is mixed with an amino acid solution, wherein the sugar solution does not contain sulfite ion and contains vitamin B1 and has a pH of The titratable acidity is adjusted to 30 or less at 4.0 to 5.5, the pH of the amino acid solution is adjusted to 6.5 to 8.5, and all the solutions of the infusion solution are made to communicate with the isolation means. PH when mixed with 6.0
A total infusion solution for peripheral intravenous administration containing vitamin B1, which has a titratable acidity of 10 or less at ˜7.4. 2. A total infusion solution for peripheral intravenous administration containing vitamin B1 according to claim 1, wherein the sugar is glucose. 3. A total infusion solution for peripheral intravenous administration containing vitamin B1 according to claim 1 or 2, wherein calcium salt and phosphate are separately mixed in the sugar solution and the amino acid solution. 4. The total infusion solution for peripheral intravenous administration containing vitamin B1 according to claim 1, wherein the vitamin B1 is one or more selected from thiamine and salts thereof. 5. The composition after mixing all the liquids is such that glucose is 3 to 10 w / v% and thiamine is 0.4 to 40 mg /
L, L-leucine 2.0 to 7.0 g / L, L-isoleucine 1.0 to 4.0 g / L, L-valine 0.7 to 4.2
g / L, L-lysine 1.5 to 7.5 g / L, L-threonine 0.8 to 3.0 g / L, L-tryptophan 0.2
~ 1.2 g / L, L-methionine 0.5-2.5 g /
L, L-phenylalanine 1.0 to 4.0 g / L, L-
Cysteine 0.1 to 0.7 g / L, L-tyrosine 0
0.5 g / L, L-arginine 1.4 to 5.5 g / L,
L-histidine 0.8 to 2.7 g / L, L-alanine 1.0 to 4.2 g / L, L-proline 0.6 to 2.6 g
/ L, L-serine 0.3 to 1.7 g / L, aminoacetic acid
1.0-4.5 g / L, L-aspartic acid 0.1-
1.7 g / L, L-glutamic acid 0.1-3.0 g /
L, sodium 25-70 mEq / L, potassium 15-
50 mEq / L, calcium 3 to 15 mEq / L, magnesium 3 to 10 mEq / L, chlor 25 to 70 mEq
/ L, phosphorus 5 to 20 mmol / L, zinc 0 to 30 μmo
The total infusion solution for peripheral intravenous administration containing vitamin B1 according to any one of claims 1 to 4, which is 1 / L. 6. The total infusion solution for peripheral intravenous administration containing vitamin B1 according to claim 1, wherein the container is a gas permeable container and is enclosed together with a deoxidizer in a gas impermeable outer container. Agent.