JP3643879B2 - Electrolyte infusion composition - Google Patents

Description

【０００９】
本発明の電解質輸液組成物は種々の方法により調製することができ、例えば、各々の成分を秤量し、対応する量の注射用水に溶解した後、塩酸を用いてｐＨを５．０〜７．５、好ましくは５．５〜７．０に調整することにより調製することができる。
また、本発明の電解質輸液組成物は加熱滅菌することができ、加熱滅菌は、例えば、当該輸液をガラス容器やプラスチック（例えば、ポリプロピレン、ポリエチレン、エチレン−酢酸ビニル共重合体、ポリ塩化ビニル等）容器（例えば、バック、ボトル等）に充填し、密封した後、滅菌工程に付すことにより行われる。滅菌工程は常法に準じて行うことができ、例えば、高圧蒸気滅菌、熱水浸漬滅菌、熱水シャワー滅菌等の方法により行うことができる。
本発明の電解質輸液組成物は、単独で若しくは必要に応じて他のアミノ酸、脂肪乳剤等の輸液、薬剤等と混合されて患者に非経口的に投与される。
【００１０】
【実施例】
本発明をより詳細に説明するために、以下に実施例を挙げるが、本発明はこれらによってなんら限定されるものではない。
実施例１
常温の注射用水９００ｍｌにブドウ糖１０．００ｇ、塩化ナトリウム６．３７ｇ、塩化カリウム０．３０ｇ、グルコン酸カルシウム０．６７ｇ、塩化マグネシウム０．２０ｇ、無水酢酸ナトリウム２．０５ｇ、クエン酸ナトリウム０．５９ｇを順次添加し、溶解した。１Ｎ塩酸でｐＨを６．０に調整した後、更に注射用水を加え全量を１０００ｍｌにした。０．４５μｍのメンブランフィルターを用いて濾過し、５００ｍｌのＰＥバッグ（ポリエチレン製ソフトバッグ）に２５０ｍｌづつ分注した。１１５℃にて３０分間、熱水静置滅菌を行い輸液組成物を得た。
上記組成物の１リットル中の各成分組成を下記に示す。
ナトリウム １４０．０ mEq/l
カリウム ４．０ 〃
カルシウム ３．０ 〃
マグネシウム ２．０ 〃
クロール １１５．０ 〃
酢酸 ２５．０ 〃
ブドウ糖 １０．０ ｇ
本輸液組成物の安定性を７０℃６日間及び４０℃３ヵ月間で検討した。その結果、ｐＨの低下や着色は起こらず、また沈殿物の生成も認められず、本輸液組成物が極めて安定なものであることが判明した。
【００１１】
実験例１
ウサギ脱血ショックモデルにおける血液ｐＨ回復機能試験
一夜絶食した日本白色雄性ウサギ（体重２．４１±０．１４ｋｇ）より前血の約３０％量の血液を無麻酔下に一時に採取し、脱血ショックモデルとした。モデル作成後、速やかに耳辺縁静脈より試験輸液の投与を行った。試験輸液としては、本発明輸液（実施例１で調製した輸液）及び市販リンゲル液（日本薬局方）を用い、６０ｍｌ／ｋｇ／ｈｒの投与速度にて１時間の持続投与とした。血液ｐＨの測定は、脱血直前、輸液投与開始３０分後、輸液投与終了時、輸液投与終了１時間後及び３時間後の計５回行った。
その結果（平均値±標準偏差）を図１に示す。図１に示されるように、血液ｐＨは脱血ショックにより有意に低下した。リンゲル液投与によっては、その後も持続的に低値を示したが、本発明輸液の投与では投与直後より投与前値への回復が認められ、投与終了１時間後及び３時間後の時点においては、リンゲル液投与群に対して有意な高値を示した。このように、本発明の輸液によれば、血液ｐＨの速やかな回復を図ることができることが明らかになった。
【００１２】
【発明の効果】
本発明の電解質輸液組成物は、細胞外液組成に類似した電解質組成であり、アルカリ化剤として用いる酢酸は肝臓のみならず全身の筋肉中で効率良く代謝、利用される。その血液アルカリ化能は迅速且つ良好であり、循環血液量低下によるアシドーシス惹起の際には、急速注入により速やかな血液ｐＨの是正が期待できる。従って、本発明の電解質輸液組成物は、急性出血、熱傷、手術時等の細胞外液欠乏の是正を目的として使用される緊急輸液製剤として好適に用いることができ、特に肝不全、循環不全の患者にも大量急速注入することができるという利点を有する。また、製剤的に安定であるので長期の保存が可能である。更に糖質を含有するので、適度な栄養補給を図りながら輸液注入を行なうことができる。
【図面の簡単な説明】
【図１】本発明輸液及び市販リンゲル液を投与したウサギ脱血ショックモデルにおける血液ｐＨの経時的変化を示す図である。[0001]
[Industrial application fields]
The present invention relates to an electrolyte infusion composition. More specifically, the present invention relates to an electrolyte infusion composition containing a specific amount of electrolyte and carbohydrate, which is useful as an emergency infusion preparation.
[0002]
[Prior art]
The emergency infusion preparation is a preparation similar to the extracellular fluid used to correct the state where the blood flow cannot maintain the cellular activity of tissues and organs normally.
Various preparations have been developed so far, such as preparations in which the electrolyte has a specific mixing ratio, preparations using lactic acid as an alkalizing agent, preparations added with glucose as an energy source, and the like.
[0003]
[Problems to be solved by the invention]
The extracellular fluid contains bicarbonate ions as a major component (approximately 27 mEq / l for healthy external fluids), and in order to improve metabolic acidosis, electrolyte infusions contain either bicarbonate or in vivo It is necessary to add a substance (so-called alkalizing agent) that is metabolized in order to produce bicarbonate ions. For treatment of severe acidosis, an infusion solution containing bicarbonate itself may be administered, but in general, formulation of bicarbonate together with other electrolyte components etc. is in terms of stability etc. Because of the difficulty, lactate that is metabolized in the liver to produce bicarbonate ions is usually used as an alkalizing agent.
However, in the preparation using lactate as an alkalizing agent, lactic acid is metabolized mainly in the liver, and since the alkalizing action is slow, lactic acidosis occurs when lactic acid metabolism in the liver is reduced. Can not be administered at the time of severe liver disease patients or hemorrhagic shock. In addition, electrolyte infusion preparations containing glucose at high concentrations have problems such as the risk of hyperglycemia during surgery.
As described above, a satisfactory formulation has not yet emerged as an emergency infusion formulation, and development of a better formulation is desired.
The present invention has been made to solve the above-described problems of the prior art, and provides an electrolyte infusion composition that can effectively replenish electrolyte and water, is stable in terms of formulation, and is useful as an emergency infusion formulation. For the purpose.
[0004]
[Means for Solving the Problems]
The electrolyte infusion composition of the present invention made to overcome the above problems contains an electrolyte and a saccharide within the following range,
Sodium 112.0-168.0 mEq / l
Potassium 3.2 to 4.8 mEq / l
Calcium 2.4-3.6 mEq / l
Magnesium 1.6-2.4 mEq / l
Crawl 92.0-138.0 mEq / l
Acetic acid 20.0-30.0 mEq / l
Carbohydrate 0.8 ~ 1.2 w / v%
The pH is adjusted to 5.0 to 7.5 with hydrochloric acid.
[0005]
In the electrolyte infusion composition of the present invention, sodium chloride, sodium acetate, sodium citrate, etc. as sodium sources, potassium chloride, potassium aspartate, etc. as potassium sources, calcium gluconate, asparagine as calcium sources Calcium acid, calcium chloride, and the like can be used as the magnesium source, such as magnesium chloride, and sodium chloride, potassium chloride, magnesium chloride, and the like as the chlore source. They can also be used as hydrates.
[0006]
The electrolyte infusion composition of the present invention uses acetic acid as an alkalizing agent. Unlike lactic acid, acetic acid is efficiently metabolized not only in the liver but also in the muscles of the whole body. Therefore, acetic acid has the advantage that it can be administered even in patients with severe liver disease or bleeding shock. Acetic acid can be used in any form of free acid, salt (for example, sodium salt and the like), and hydrate.
[0007]
Examples of the saccharide used in the electrolyte infusion composition of the present invention include glucose, fructose, maltose, sorbitol, xylitol, glycerin and the like, and glucose, which is the safest saccharide source, is preferably used. Various effects such as an osmotic pressure adjusting action can be expected by incorporating a saccharide.
Moreover, the pH of the electrolyte infusion composition of the present invention is adjusted to 5.0 to 7.5 with hydrochloric acid. Therefore, problems such as vascular pain and phlebitis can be avoided even in the case of rapid mass administration.
[0008]
The preferable composition range of the electrolyte infusion composition of the present invention is as follows, and the electrolyte composition has a composition similar to the extracellular fluid.

[0009]
The electrolyte infusion composition of the present invention can be prepared by various methods. For example, each component is weighed and dissolved in a corresponding amount of water for injection, and then the pH is adjusted to 5.0-7. It can be prepared by adjusting to 5, preferably 5.5 to 7.0.
In addition, the electrolyte infusion composition of the present invention can be heat sterilized, and heat sterilization can be performed by, for example, injecting the infusion liquid into a glass container or plastic (for example, polypropylene, polyethylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, etc.). It is performed by filling a container (for example, bag, bottle, etc.), sealing, and then subjecting it to a sterilization process. The sterilization step can be performed according to a conventional method, for example, by a method such as high-pressure steam sterilization, hot water immersion sterilization, hot water shower sterilization.
The electrolyte infusion composition of the present invention is administered parenterally to a patient alone or mixed with other amino acid, fat emulsion and other infusion solutions, drugs and the like as necessary.
[0010]
【Example】
In order to describe the present invention in more detail, examples are given below, but the present invention is not limited to these examples.
Example 1
In 900 ml of water for injection at room temperature, 10.00 g of glucose, 6.37 g of sodium chloride, 0.30 g of potassium chloride, 0.67 g of calcium gluconate, 0.20 g of magnesium chloride, 2.05 g of anhydrous sodium acetate, and 0.59 g of sodium citrate Sequentially added and dissolved. After adjusting the pH to 6.0 with 1N hydrochloric acid, water for injection was further added to bring the total volume to 1000 ml. Filtration was performed using a 0.45 μm membrane filter, and 250 ml each was dispensed into a 500 ml PE bag (polyethylene soft bag). Sterilization was performed at 115 ° C. for 30 minutes to obtain an infusion composition.
The composition of each component in 1 liter of the above composition is shown below.
Sodium 140.0 mEq / l
Potassium 4.0 〃
Calcium 3.0 〃
Magnesium 2.0 〃
Crawl 115.0 〃
Acetic acid 25.0 〃
Glucose 10.0 g
The stability of the infusion composition was examined at 70 ° C. for 6 days and 40 ° C. for 3 months. As a result, no decrease in pH or coloration occurred, and no precipitate was observed, indicating that the infusion composition was extremely stable.
[0011]
Experimental example 1
Blood pH recovery function test in a rabbit blood removal shock model About 30% of the blood from the pre-blooded Japanese white male rabbit (weight 2.41 ± 0.14 kg) fasted overnight was collected at once without anesthesia The blood removal shock model was used. After the model was created, the test infusion was immediately administered from the marginal vein. As the test infusion, the infusion of the present invention (infusion prepared in Example 1) and the commercially available Ringer's solution (Japanese Pharmacopoeia) were used, and the administration was continued for 1 hour at an administration rate of 60 ml / kg / hr. Blood pH was measured 5 times, immediately before blood removal, 30 minutes after the start of infusion administration, at the end of infusion administration, 1 hour after the end of infusion administration, and 3 hours later.
The results (average value ± standard deviation) are shown in FIG. As shown in FIG. 1, blood pH was significantly reduced by blood removal shock. Depending on the Ringer's solution administration, it continuously showed a low value, but in the administration of the infusion of the present invention, recovery to the pre-administration value was observed immediately after administration, and at the time point 1 hour and 3 hours after the end of administration, The value was significantly higher than that of the Ringer's solution administration group. As described above, according to the infusion solution of the present invention, it was revealed that blood pH can be promptly recovered.
[0012]
【The invention's effect】
The electrolyte infusion composition of the present invention has an electrolyte composition similar to the extracellular fluid composition, and acetic acid used as an alkalizing agent is efficiently metabolized and utilized not only in the liver but also in the muscles of the whole body. The blood alkalinizing ability is rapid and good, and when acidosis is caused by a decrease in circulating blood volume, rapid correction of blood pH can be expected by rapid injection. Therefore, the electrolyte infusion composition of the present invention can be suitably used as an emergency infusion preparation used for the purpose of correcting the deficiency of extracellular fluid during acute bleeding, burns, surgery, etc., particularly for liver failure and circulatory failure. The patient also has the advantage that it can be rapidly infused in large quantities. In addition, since it is stable in terms of formulation, it can be stored for a long time. Furthermore, since it contains saccharides, infusion can be performed while achieving proper nutrition.
[Brief description of the drawings]
FIG. 1 is a graph showing changes in blood pH over time in a rabbit blood removal shock model administered with the transfusion of the present invention and a commercially available Ringer's solution.

Claims (1)

Contains electrolytes and carbohydrates in the following ranges,
Sodium 112.0-168.0 mEq / l
Potassium 3.2 to 4.8 mEq / l
Calcium 2.4-3.6 mEq / l
Magnesium 1.6-2.4 mEq / l
Crawl 92.0-138.0 mEq / l
Acetic acid 20.0-30.0 mEq / l
Carbohydrate 0.8 ~ 1.2 w / v%
An electrolyte infusion composition, wherein the pH is adjusted to 5.0 to 7.5 with hydrochloric acid.

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