JPWO2010104023A1 - Peripheral intravenous infusion containing a sugar solution that contains vitamin B1 stably - Google Patents

Abstract

Peripheral intravenous administration in which vitamin B1 is stabilized by adding N-acetylcysteine to a sugar solution containing vitamin B1 in an infusion solution for peripheral vein administration in which a sugar solution and an amino acid solution are separately stored in a multi-chamber container Provide infusion.

Description

  The present invention relates to a peripheral intravenous administration infusion solution in which a sugar solution and an amino acid solution are separately stored in a multi-chamber container, and relates to a technique for stably blending vitamin B1 into the sugar solution.

In recent years, parenteral nutrition therapy has made remarkable progress, and infusions containing sugars, electrolytes, and amino acids have been widely used. However, vitamins and trace element deficiencies occur only by administration of sugars, electrolytes, and amino acids when oral nutritional supplementation is not possible and only the parenteral nutrition solution is relied upon. In addition, if a large amount of sugar load is applied without administering vitamin B1, a large abnormality is caused in sugar metabolism, which may cause lactic acidosis, which is a serious side effect. Therefore, it is widely practiced to add vitamin B1 to the sugar solution in advance.
Vitamin B1 is neutral to alkaline and unstable, and is decomposed by the presence of sulfite ions. Therefore, it is adjusted to be acidic and is added to the sugar solution side that does not contain sulfite ions.
Since the salt having a buffering property contained in the sugar solution prevents the stabilization of vitamin B1, the stability of vitamin B1 is reduced by setting the titrated acidity of the electrolyte contained in the sugar solution containing vitamin B1 to 1 or less. There is a report that it is increased (Patent Document 1). There is also a report that antioxidants such as ascorbic acid and L-cysteine increase the stability of vitamin B1 (Patent Document 2).
In addition, since the method of Patent Document 1 needs to reduce the buffering capacity of the sugar solution to the utmost limit, the electrolyte that can be blended is limited, pH adjustment is difficult, and the pH fluctuates with a slight decomposition of the blend. There is a problem in stability.

WO2004 / 103375 JP 2005-179200 A

  The subject of this invention exists in the point which mix | blends vitamin B1 stably with a sugar solution in the transfusion for peripheral venous administration which accommodated the sugar solution and the amino acid solution separately in the multi-chamber container.

By adding N-acetylcysteine to the sugar solution, it is possible to improve the stability of vitamin B1 formulated in the sugar solution even in a sugar solution containing a buffering salt and having a certain titratable acidity. Discovered and completed the present invention.
Accordingly, preferred embodiments of the present invention are as follows.
(1) An infusion for peripheral vein administration, wherein the sugar solution contains vitamin B1 and N-acetylcysteine in an infusion for peripheral vein administration in which a sugar solution and an amino acid solution are separately stored in a multi-chamber container.
(2) The infusion solution for peripheral vein administration according to (1), wherein the sugar solution contains 0.3 to 3.0 g / L of N-acetylcysteine.
(3) The infusion solution for peripheral vein administration according to (1) or (2), wherein the sugar solution contains at least one buffered salt selected from sodium lactate, sodium acetate, potassium glycerophosphate, and dipotassium phosphate.
(4) The infusion for peripheral vein administration according to any one of (1) to (3), wherein the sugar solution and the amino acid solution do not contain sulfite ions.

  Vitamin B1 can be stabilized by adding N-acetylcysteine to the sugar solution, and N-acetylcysteine added as a stabilizer can be used as an L-cysteine source. Although the stabilizing effect of vitamin B1 by L-cysteine is known (the above-mentioned patent document 2), L-cysteine added as an antioxidant decreases during storage of the infusion solution. It became clear that the content could not be guaranteed. On the other hand, when N-acetylcysteine is used as a stabilizer for vitamin B1, the decrease in the content of N-acetylcysteine is small, so that a stabilizing effect can be achieved and at the same time the content of N-acetylcysteine can be guaranteed. In addition, N-acetylcysteine works in the same manner as carboxylic acid, and makes the pH acidic, so that the amount of the pH regulator added to the sugar solution can be reduced.

  Hereinafter, the infusion for peripheral vein administration of the present invention will be described. The gist of the present invention is to stabilize vitamin B1 regardless of the titrated acidity of the sugar solution by containing N-acetylcysteine together with vitamin B1 in the sugar solution containing vitamin B1 and not containing sulfite ion. With regard to other points, conventionally known matters relating to peripheral infusion for peripheral intravenous administration can be applied.

<About sugar solution>
In the infusion solution for intravenous administration of the present invention, the sugar solution contains sugar, an electrolyte and vitamin B1 as basic components and does not contain a sulfite which inhibits the stabilization of vitamin B1. The sugar that can be used is not particularly limited as long as it is a sugar that is usually used for infusion. Examples of the reducing sugar include glucose, fructose, and maltose. Examples of the non-reducing sugar include trehalose, xylitol, sorbitol, and glycerin. Of the various sugars, glucose is preferably added from the viewpoint of nutritional effect. When glucose is used, glucose is used at a concentration of 35 to 150 g / L, preferably 70 to 130 g / L in the infusion after mixing with the amino acid solution.
The pH of the sugar solution is preferably pH 4.0 to 4.5 in order to stably mix vitamin B1.
The pH adjuster is not limited as long as it can be used as a pharmaceutical additive. In order to prevent chloric acidosis, it is preferable to use sulfuric acid not containing chloro or organic acids such as acetic acid, lactic acid, citric acid, succinic acid and malic acid, and one or more of these pH regulators are added. be able to.
Any known vitamin B1 can be used as the vitamin B1 contained in the sugar solution, and examples thereof include thiamine hydrochloride, thiamine nitrate, and fursultiamine. The amount of vitamin B1 is desirably blended at 0.7 to 3.5 mg / L in an infusion solution in which a sugar solution and an amino acid solution are mixed.
N-acetylcysteine for stabilizing vitamin B1 is preferably blended at a rate of 0.3 to 3.0 g / L. In this range, the blended N-acetylcysteine can be easily quantified by absorptiometry.
As the electrolyte, the same compounds as those used for general electrolyte infusion can be used, and examples thereof include sodium, potassium, magnesium, calcium, chloro, phosphorus, and the like, which are electrolytes essential for living bodies. Specifically, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium lactate, sodium citrate, sodium chloride, sodium sulfate, potassium chloride, potassium iodide, potassium dihydrogen phosphate, dihydrogen phosphate Potassium, potassium lactate, potassium citrate, potassium acetate, calcium lactate, sodium glycerophosphate, potassium glycerophosphate, calcium glycerophosphate, calcium gluconate, calcium chloride, magnesium chloride, magnesium acetate, zinc chloride, zinc sulfate, etc. can be used. May be a hydrate.
Sodium is preferably added as sodium lactate. The concentration of sodium in the infusion solution obtained by mixing the sugar solution and the amino acid solution is preferably 20 to 50 mEq / L.
Potassium is preferably added as potassium glycerophosphate or potassium chloride. Since potassium glycerophosphate serves as a phosphate source and does not cause a precipitation reaction with calcium salt and magnesium salt, it can be blended in the same solution as calcium salt and magnesium salt. The preferable potassium concentration in the infusion solution obtained by mixing the sugar solution and the amino acid solution is 10 to 30 mEq / L. The preferable concentration of phosphoric acid in the infusion solution obtained by mixing the sugar solution and the amino acid solution is 5 to 20 mmol / L.
Calcium chloride is suitable for calcium, and magnesium sulfate is suitable for magnesium. The preferable calcium and magnesium concentrations in the infusion solution in which the sugar solution and the amino acid solution are mixed are each 2 to 8 mEq / L.
Zinc is blended in the sugar liquid as zinc sulfate and zinc chloride. The preferable zinc concentration in the infusion solution obtained by mixing the sugar solution and the amino acid solution is 2.5 to 7.5 μmol / L.

<About amino acid solution>
The amino acid solution is a solution in which an amino acid containing at least essential amino acids is dissolved. In the infusion solution after mixing with the sugar solution, the amino acid is contained in a concentration of 10 to 70 g / L, preferably 15 to 45 g / L in terms of free amino acid. The The amino acid may be not only a free amino acid but also various salts, for example, metal salts such as sodium and potassium, salts with organic acids such as acetic acid, and salts with inorganic acids such as hydrochloric acid. Further, some of them may be acyl forms or peptides. In the present invention, since N-acetylcysteine is added to the sugar solution, L-cysteine can be omitted from the amino acid solution.
When a phosphorus compound other than glycerophosphate is blended, it is preferably separated from the calcium salt and the magnesium salt and blended in different liquids. Specifically, when calcium salt and magnesium salt are blended in a sugar solution, the phosphorus compound is blended in an amino acid solution. Other electrolytes are not particularly limited, and may be blended in either a sugar solution or an amino acid solution.

<About other ingredients>
It is well known to add sulfites, especially sodium hydrogen sulfite, to amino acid solutions as amino acid stabilizers. However, by using N-acetylcysteine in the sugar solution, the use of sodium bisulfite can be omitted when it is not necessary to use L-cysteine and N-acetylcysteine as amino acids. In addition, various vitamins, trace elements, and the like can be arbitrarily added to the sugar solution and the amino acid solution as necessary.

<About infusions that contain sugar solution and amino acid solution>
The sugar solution and the amino acid solution are mixed by breaking the partition that can be communicated by external pressure during use. The infusion in the present invention is for peripheral vein administration, and it is preferable that the pH is in the range of 6 to 7.5 and the titratable acidity is in the range of 5 to 10 so as not to cause phlebitis or vascular pain at the time of administration. The mixing ratio of the sugar solution and the amino acid solution is preferably 2-3: 1.

<About infusion containers>
Any known multi-chamber container configured to be able to communicate can be used. Of these, an infusion bag in which the partition wall is composed of an easily peelable seal is particularly preferable because the communication work is simple. Suitable materials for the infusion bag are, for example, polyolefins such as polyethylene, polypropylene and polybutene, ethylene / propylene copolymers, crosslinked ethylene / vinyl acetate copolymers, and laminates thereof.

<About outer packaging and iron-based oxygen absorbers>
An infusion bag filled with a sugar solution and an amino acid solution under nitrogen substitution is packaged with a gas-impermeable outer packaging material having a light shielding property together with an oxygen scavenger by a conventional method. Examples of the gas non-permeable outer packaging material having light shielding properties include aluminum foil and aluminum vapor deposition film which are generally used. When selecting transparent, gas-impermeable outer packaging materials such as polyethylene terephthalate, polyethylene naphthalate, ethylene / vinyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polyamide, alumina, silica, etc. It can be used by adding an ultraviolet cut layer.
As the oxygen scavenger, those containing iron compounds such as iron hydroxide, iron oxide and iron carbide as main components are used. Commercially available products include AGELESS (Mitsubishi Gas Chemical Co., Ltd.), Modulan (Nippon Kayaku Co., Ltd.), Secur (Nippon Soda Co., Ltd.) and the like.
The space between the infusion bag and the outer packaging container is preferably filled with an inert gas such as nitrogen.

上記処方の糖、電解質、ビタミンＢ１を注射用水に溶解し、ｐＨ調節剤として硫酸を用いてｐＨ４．３とした。この液３５０ｍＬをプラスチック製容器の各室に充填し、密封した後、窒素雰囲気下において高圧蒸気滅菌を行った。滅菌後、鉄系脱酸素剤（商品名「エージレスZA-200」）と共にアルミ箔をバリア層とするガス非透過性の外包装材（大日本印刷(株)製）に窒素ガス下で包装した。Examples are given below to illustrate the present invention, but are not intended to limit the present invention.
<Example 1>

The sugar, electrolyte and vitamin B1 of the above formulation were dissolved in water for injection and adjusted to pH 4.3 using sulfuric acid as a pH regulator. After 350 mL of this liquid was filled in each chamber of a plastic container and sealed, high-pressure steam sterilization was performed in a nitrogen atmosphere. After sterilization, it was packaged under nitrogen gas in a gas-impermeable outer packaging material (Dai Nippon Printing Co., Ltd.) with an aluminum foil as a barrier layer together with an iron-based oxygen scavenger (trade name “AGELESS ZA-200”) .

<Example 2>
A chemical solution was obtained in the same manner as in Example 1 except that N-acetylcysteine was changed to 0.29 g / L in the prescription.

<Comparative Example 1>
In the formulation, a drug solution was obtained in the same manner as in Example 1 except that N-acetylcysteine was excluded and 0.43 g / L of L-cysteine was added.

<Comparative example 2>
A chemical solution was obtained in the same manner as in Example 1 except that N-acetylcysteine was excluded from the formulation.

  Examples 1 and 2 and Comparative Examples 1 and 2 were stored at 25 ° C./60% RH and 40 ° C./75% RH. Vitamin B1 was measured by HPLC after 2 weeks, 4 weeks and 8 weeks. N-acetylcysteine and L-cysteine were quantified by a colorimetric method. Further, the absorbance was measured at an absorption wavelength of 430 nm in order to see the coloring tendency.

The measurement result regarding the residual amount of vitamin B1 is shown below. In the table, NAC represents N-acetylcysteine.

  As is clear from the above results, it was shown that vitamin B1 remained sufficiently when N-acetylcysteine was used (Examples 1 and 2) and when L-cysteine was used.

Next, the measurement result of the residual amount regarding N-acetylcysteine and L-cysteine is shown below.

  As is clear from the above results, when the contents of N-acetylcysteine and L-cysteine were compared, the content of L-cysteine was reduced by about 30% compared to the prescribed amount, while N-acetylcysteine was about 3%. It was a decrease of ~ 5%.

着色については、全ての液で認められなかった．Next, the measurement results of absorbance are shown below.

Coloring was not observed in all solutions.

Similar tests were performed using similar formulations.
<Example 3>

  The sugar solution was prepared by dissolving the above sugar, electrolyte, and vitamin B1 in water for injection and adjusting the pH to 4.5 using sulfuric acid as a pH regulator. The amino acid solution was adjusted to pH 6.8 by dissolving the above-described amino acid in water for injection and using sulfuric acid as a pH adjuster. Both solutions were aseptically filtered, filled with 350 mL of a sugar solution and 150 mL of an amino acid solution into each chamber of a plastic container partitioned by an easy peel seal, sealed, and then autoclaved under a nitrogen atmosphere. After cooling and drying, packaged under nitrogen gas in a gas-impermeable outer packaging material (Dai Nippon Printing Co., Ltd.) with an aluminum foil as a barrier layer together with an iron-based oxygen scavenger (trade name “AGELESS ZA-200”) did. The titratable acidity of the sugar solution was 20.

<Example 4>
A chemical solution was obtained in the same manner as in Example 3 except that N-acetylcysteine was changed to 1.17 g / L in the sugar solution formulation. The titratable acidity of the sugar solution was 21.

<Example 5>
A chemical solution was obtained in the same manner as in Example 3 except that N-acetylcysteine was changed to 2.93 g / L in the sugar solution formulation. The titratable acidity of the sugar solution was 21.

<Comparative Example 3>
A chemical solution was obtained in the same manner as in Example 3 except that N-acetylcysteine was excluded from the sugar solution formulation. The titrated acidity of the sugar solution was 20.

  Examples 3, 4, 5 and Comparative Example 3 were stored at room temperature. Two weeks later, two months later and four months later, vitamin B1 was quantified by HPLC. Further, N-acetylcysteine was quantified by a colorimetric method after 2 months and 4 months after storage.

The measurement result regarding the residual amount of vitamin B1 is shown below.

  As mentioned above, the stability of vitamin B1 was improved in the infusion solution formulated with N-acetylcysteine compared to the non-added solution.

The measurement results regarding the remaining amount of N-acetylcysteine are shown below.

  The N-acetylcysteine content was stable at 95% or more during the storage period compared to the prescribed amount.

Claims (4)

  An infusion for peripheral venous administration, wherein the saccharide solution contains vitamin B1 and N-acetylcysteine in an infusion for peripheral venous administration in which a sugar solution and an amino acid solution are separately stored in a multi-chamber container.   The infusion solution for peripheral vein administration according to claim 1, wherein the sugar solution contains 0.3 to 3.0 g / L of N-acetylcysteine.   The infusion solution for peripheral vein administration according to claim 1 or 2, wherein the sugar solution contains at least one buffered salt selected from sodium lactate, sodium acetate, potassium glycerophosphate and dipotassium phosphate.   The infusion solution for peripheral vein administration according to any one of claims 1 to 3, wherein the sugar solution and the amino acid solution do not contain sulfite ions.