JP2005053872A - Sugar electrolyte maintenance transfusion solution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sugar electrolyte maintenance infusion solution which maintains a suitable electrolyte balance, titratable acidity and pH and is pharmaceutically stable.
A sugar electrolyte maintenance infusion solution having a composition in the following range, containing glycerophosphate as a phosphorus source, adjusted to pH 5.0 to 6.0 with citric acid, and having a titratable acidity of 15 or less It is.
Glucose 2.5-7.5% (W / V)
Na ⁺ 25-50 mEq / L
K ⁺ 15-30 mEq / L
Ca ²⁺ 3-7 mEq / L
Mg ²⁺ 2-7 mEq / L
Cl ^- 20-30 mEq / L
CH ₃ COO ^- 15-25 mEq / L
P 2.5-10 mmol / L
[Selection figure] None

Description

  The present invention relates to a sugar electrolyte maintenance infusion solution in which glucose and an electrolyte are blended in a well-balanced manner.

The maintenance infusion is an infusion for the purpose of maintaining the balance between water and electrolyte and supplying the minimum amount of energy for patients who have difficulty in ingestion and do not require correction of body fluid balance (Non-patent Document 1).
Therefore, the maintenance infusion solution must contain an electrolyte and an energy source necessary for life support in its water content, and of course, it is required not to cause acidosis or alkalosis by its administration.

As mentioned above, it is necessary to mix glucose and electrolyte in a balanced manner in the maintenance infusion, but depending on the case, the chloride ion becomes high, there is a concern about high chloroacidosis, or unnecessary ions such as sulfate ion You may have to choose the salt that is produced.
Even if the electrolyte can be blended in a well-balanced manner, the titration acidity becomes high, or heat sterilization may cause precipitation of calcium phosphate, etc. May not be perfect in terms of
Furthermore, if the stability is to be improved, the pH must be kept away from the physiological range.

  In order to solve such problems, an infusion preparation containing a good balance of grapes and electrolytes in a well-balanced manner has been described, such as no coloring by heat sterilization and no precipitation, and the following patents have been described (Patent below) Documents 1 and 2) require further stabilization.

JP 59-16818 JP-A-6-172191 Clinical Nursing, 13, 2047 (1987)

  An object of the present invention is to provide a glycoelectrolyte maintenance infusion solution that maintains a suitable electrolyte balance, titratable acidity, pH, and is pharmaceutically stable.

The glycoelectrolyte maintenance infusion solution of the present invention for solving the above problems has a composition in the following range, glycerophosphate is blended as a phosphorus supply source, adjusted to pH 5.0 to 6.0 with citric acid, And titration acidity is 15 or less, It is characterized by the above-mentioned.
Glucose 2.5-7.5% (W / V)
Na ⁺ 25-50 mEq / L
K ⁺ 15-30 mEq / L
Ca ²⁺ 3-7 mEq / L
Mg ²⁺ 2-7 mEq / L
Cl ^- 20-30 mEq / L
CH ₃ COO ^- 15-25 mEq / L
P 2.5-10 mmol / L

  In the sugar electrolyte maintenance infusion of the present invention, it is preferable that the acetic acid supply source is shared with at least a part of the sodium supply source, and the phosphorus supply source is shared with at least a part of the potassium supply source. Moreover, it is preferable that the remainder of a sodium supply source is sodium chloride, and the remainder of a potassium supply source is potassium chloride. The magnesium supply source is preferably magnesium chloride, and calcium gluconate is preferably blended as the calcium supply source.

Moreover, as a sugar electrolyte maintenance infusion, it is more preferable to have the composition of the following range.
Glucose 3.5-7% (W / V)
Na ⁺ 30-40 mEq / L
K ⁺ 17-25 mEq / L
Ca ²⁺ 4-6 mEq / L
Mg ²⁺ 2-5 mEq / L
Cl ^- 25-30 mEq / L
CH ₃ COO ^- 17-23 mEq / L
P 3-8 mmol / L

  Moreover, it is preferable that the above-described sugar electrolyte maintenance infusion is heat-sterilized.

  According to the sugar electrolyte maintenance infusion solution of the present invention, there are effects that a suitable electrolyte balance, titratable acidity and pH can be maintained, and the pharmaceutical electrolyte can be stably supplied.

  Hereinafter, the sugar electrolyte maintenance infusion of the present invention will be described in detail. The maintenance infusion solution of the present invention has a composition in the range described below for glucose and each electrolyte. This maintenance infusion is preferably adjusted for pH and titrated acidity so that the patient does not experience vascular pain. This maintenance infusion is adjusted to pH with citric acid, and the pH is in the range of 5.0 to 6.0, preferably 5.2 to 5.8. The titratable acidity is 15 or less, preferably 3 to 14, more preferably 3 to 10.

<Glucose>
Glucose is used at a concentration of 2.5-7.5% (W / V), preferably 3.5-7% (W / V). As a solvent for the glucose solution, distilled water for injection is usually used.
Furthermore, in addition to glucose, an appropriate amount of one or more reducing sugars such as fructose and maltose, or non-reducing sugars such as sorbitol and glycerin may be blended as necessary.

<Electrolyte>
(A) Sodium Examples of sodium sources include sodium salts such as sodium chloride, sodium acetate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium lactate. Of these, sodium acetate is preferable because it also serves as a source of acetic acid. Sodium chloride is preferably used as the remainder of the sodium source. However, when chloride is used for potassium or magnesium, high chloric acidosis is not generated. It is preferable to limit to the limit. The blending concentration of sodium is 25 to 50 mEq / L, preferably 30 to 40 mEq / L.

(B) Potassium As the potassium supply source, the same compounds as those used in general electrolyte infusion can be used, for example, potassium chloride, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, Examples include potassium glycerophosphate and potassium lactate. Of these, potassium glycerophosphate is preferable because it also serves as a phosphorus supply source. These potassium sources may be in hydrate form. As the remainder of the potassium source, potassium chloride is preferably used. However, in order not to cause hyperchloric acidosis, the amount used is preferably minimized. The compounding concentration of potassium is 15 to 30 mEq / L, preferably 17 to 25 mEq / L.

(C) Calcium Calcium gluconate is preferably used as the calcium supply source in order to prevent precipitation due to reaction with phosphate. In addition, calcium chloride, which is a strong electrolyte, can be used as another calcium supply source, but it is preferable to suppress the use in order not to cause hyperchloric acidosis. The calcium concentration is 3 to 7 mEq / L, preferably 4 to 6 mEq / L.

(D) Magnesium As the magnesium supply source, it is preferable to use magnesium chloride. Moreover, magnesium sulfate, magnesium acetate, etc. are illustrated as another supply source. The compounding concentration of magnesium is 2 to 7 mEq / L, preferably 2 to 5 mEq / L.

(E) Phosphorus As the phosphorus supply source, glycerophosphate such as potassium glycerophosphate and sodium glycerophosphate is blended. The compounding concentration of phosphorus is 2.5 to 10 mmol / L, preferably 3 to 8 mmol / L.

(F) Other electrolytes Examples of the supply source of chlorine and acetic acid include chlorides and acetates with the respective electrolytes described above. The blending concentration of chlorine is 20 to 30 mEq / L, preferably 25 to 30 mEq / L. The blending concentration of acetic acid is 15 to 25 mEq / L, preferably 17 to 23 mEq / L.

<Additives, compounding agents>
Additives such as stabilizers can be added to the maintenance infusion of the present invention as needed. Examples of such additives include sulfites such as sodium bisulfite which are typical as stabilizers. In addition, other maintenance drugs such as various vitamins, trace elements (minerals) and the like can be optionally added to the maintenance infusion solution of the present invention.

<Infusion container>
As a container for storing the maintenance infusion solution of the present invention, a plastic infusion bag widely used for medical purposes can be used. As the material of the infusion bag, various gas permeable plastics commonly used in medical containers, such as polyethylene, polypropylene, polyvinyl chloride, crosslinked ethylene / vinyl acetate copolymer, ethylene / α-olefin copolymer And flexible plastics such as blends and laminates of these polymers.

  Filling and storing the infusion solution according to the present invention into an infusion bag can be performed according to a conventional method. For example, each component is dissolved in an injection solution, filtered through a filter as necessary, and sealed after filling the infusion bag. And heat sterilization. Here, the heat sterilization can employ known methods such as high-pressure steam sterilization and hot water shower sterilization, and can be performed in an inert gas atmosphere such as carbon dioxide and nitrogen as necessary.

  Further, the maintenance infusion contained in the infusion bag is preferably packaged with an oxygen barrier outer packaging bag together with an oxygen scavenger in order to reliably prevent alteration, oxidation and the like. Moreover, inert gas filling packaging etc. can also be performed as needed.

  As a material of the gas impermeable outer container suitable for the packaging, films, sheets and the like of various materials that are generally used can be used. Specific examples thereof include an ethylene / vinyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polyamide, polyester and the like, or a film or sheet made of a material containing at least one of these.

  As the oxygen scavenger, various known materials such as those containing iron compounds such as iron hydroxide, iron oxide and iron carbide as active ingredients, and those using low molecular phenol and activated carbon may be used. it can. Typical commercial product names include “Ageless” (Mitsubishi Gas Chemical Co., Ltd.), “Modulan” (Nippon Kayaku Co., Ltd.), “Sequel” (Nihon Soda Co., Ltd.), and “Tamotsu” (Oji Chemical). Etc.).

  Hereinafter, although an example and a comparative example are given and explained in detail, the present invention is not limited to the following examples.

[Adjustment of maintenance infusion]
Water for injection 500 g glucose, 8.77 g sodium chloride, 7.46 g potassium chloride, 11.21 g calcium gluconate monohydrate, 3.05 g magnesium chloride hexahydrate, sodium acetate trihydrate 27. 22 g and 24.83 g of a 50% potassium glycerophosphate aqueous solution were sequentially added and dissolved in water for injection. After adjusting the pH to 5.0 with citric acid, water for injection was added to make a total volume of 10 liters. A maintenance infusion was prepared.
Glucose 5% (W / V)
Na ⁺ 35 mEq / L
K ⁺ 20 mEq / L
Ca ²⁺ 5 mEq / L
Mg ²⁺ 3 mEq / L
Cl ^- 28 mEq / L
CH ₃ COO ^- 20 mEq / L
P 5 mmol / L
This infusion solution was filtered through a 0.22 μm membrane filter, filled in 500 ml each into a polyethylene infusion bag, and sealed with a stopper attached. Then, high-pressure steam sterilization was performed at 106 ° C. for 40 minutes to obtain a final product. The titrated acidity of this infusion was about 13.2.

  In Example 1, a maintenance infusion was obtained in the same manner as in Example 1 except that the pH was adjusted to 5.5 with citric acid. The titratable acidity of this infusion was about 6.8.

  In Example 1, a maintenance infusion was obtained in the same manner as in Example 1 except that the pH was adjusted to 6.0 with citric acid. The titratable acidity of this infusion was about 3.9.

[Comparative Example 1]
In Example 1, a maintenance infusion was obtained in the same manner as in Example 1 except that the pH was adjusted to 4.5 with citric acid. The titratable acidity of this infusion was about 20.4.

[Comparative Example 2]
In Example 1, a maintenance infusion was obtained in the same manner as in Example 1 except that the pH was adjusted to 6.5 with citric acid. The titratable acidity of this infusion was about 2.7.

[Comparative Example 3]
In Example 1, a maintenance infusion was performed in the same manner as in Example 1 except that 6.8 g of potassium dihydrogen phosphate was used instead of the 50% aqueous potassium glycerophosphate solution and the pH was adjusted to 5.5 with citric acid. Obtained.

[Stability test]
The maintenance infusion solutions of Examples 1 to 3 and Comparative Examples 1 to 3 were stored at 60 ° C. (75% RH) for 1 week and examined for changes with time.
In addition, about coloring, an external appearance and a color difference ((DELTA) b) were measured, coloring presence was set to x and nothing was set to (circle). A color difference of less than 1.0 was marked as ◯ and 1.0 or more was marked as x. For 5-hydroxymethylfurfurals (5-HMFs), which are glucose oxides, the absorbance at 284 nm at 2.5% equivalent (2-fold dilution) was measured. Those less than 0.2 were rated as x. About fructose, it measured by the liquid chromatography method, 5.0% or more was set as x, and less than 5.0% was set as (circle). With respect to the presence or absence of precipitation, visual observation was performed.
Moreover, about titration acidity, the thing below 15 was set to (circle), 15 or more was set to x.
The results of Examples and Comparative Examples are shown in Table 1 and Table 2, respectively.

  From the results shown in Tables 1 and 2, the maintenance infusions of Examples 1 to 3 were stable in terms of formulation, with no change in appearance and purity even after storage for 1 week, compared to the maintenance infusions of Comparative Examples 1 to 3. It can be seen that it is maintained.

Water for injection 35kg glucose, 740g sodium chloride, 839g potassium chloride, 899g calcium gluconate monohydrate, 199g magnesium chloride hexahydrate, 2339g sodium acetate trihydrate and 1489g 50% aqueous potassium glycerophosphate solution After sequentially adding and dissolving, and adjusting the pH to 5.5 with citric acid, water for injection was added to bring the total volume to 1000 liters, and a maintenance infusion solution having the following composition was prepared.
Glucose 3.5% (W / V)
Na ⁺ 30 mEq / L
K ⁺ 17 mEq / L
Ca ²⁺ 4 mEq / L
Mg ²⁺ 2 mEq / L
Cl ^- 26 mEq / L
CH ₃ COO ^- 17 mEq / L
P 3 mmol / L
This infusion solution was filtered through a 0.22 μm membrane filter, filled in 500 ml each into a polyethylene infusion bag, and sealed with a stopper attached. Then, high-pressure steam sterilization was performed at 106 ° C. for 40 minutes to obtain a final product. The titratable acidity of this infusion was about 5.2.

Water for injection: 70 kg glucose, 958 g sodium chloride, 671 g potassium chloride, 1347 g calcium gluconate monohydrate, 509 g magnesium chloride hexahydrate, 3181 g sodium acetate trihydrate and 3959 g 50% aqueous potassium glycerophosphate solution After sequentially adding and dissolving, and adjusting the pH to 5.5 with citric acid, water for injection was added to bring the total volume to 1000 liters, and a maintenance infusion solution having the following composition was prepared.
Glucose 7% (W / V)
Na ⁺ 40 mEq / L
K ⁺ 25 mEq / L
Ca ²⁺ 6 mEq / L
Mg ²⁺ 5 mEq / L
Cl ^- 30 mEq / L
CH ₃ COO ^- 23 mEq / L
P 8 mmol / L
This infusion solution was filtered through a 0.22 μm membrane filter, filled in 500 ml each into a polyethylene infusion bag, and sealed with a stopper attached. Then, high-pressure steam sterilization was performed at 106 ° C. for 40 minutes to obtain a final product. The titratable acidity of this infusion was about 9.6.

  The maintenance infusions of Examples 4 and 5 also showed the same temporal stability as the maintenance infusions of Examples 1 to 3 above.

Claims (7)

Maintaining a sugar electrolyte characterized by having a composition in the following range, blended with glycerophosphate as a phosphorus source, adjusted to pH 5.0 to 6.0 with citric acid, and titrated acidity of 15 or less Infusion.
Glucose 2.5-7.5% (W / V)
Na ⁺ 25-50 mEq / L
K ⁺ 15-30 mEq / L
Ca ²⁺ 3-7 mEq / L
Mg ²⁺ 2-7 mEq / L
Cl ^- 20-30 mEq / L
CH ₃ COO ^- 15-25 mEq / L
P 2.5-10 mmol / L   The sugar electrolyte maintenance infusion according to claim 1, wherein the acetic acid source is shared with at least a part of the sodium source, and the phosphorus source is shared with at least a part of the potassium source.   The sugar electrolyte maintenance infusion according to claim 2, wherein the remainder of the sodium source is sodium chloride and the remainder of the potassium source is potassium chloride.   The sugar electrolyte maintenance infusion according to any one of claims 1 to 3, wherein the magnesium supply source is magnesium chloride.   The sugar electrolyte maintenance infusion according to any one of claims 1 to 4, wherein calcium gluconate is blended as the calcium supply source. The sugar electrolyte maintenance infusion in any one of Claims 1-5 which has a composition of the following range.
Glucose 3.5-7% (W / V)
Na ⁺ 30-40 mEq / L
K ⁺ 17-25 mEq / L
Ca ²⁺ 4-6 mEq / L
Mg ²⁺ 2-5 mEq / L
Cl ^- 25-30 mEq / L
CH ₃ COO ^- 17-23 mEq / L
P 3-8 mmol / L The sugar electrolyte maintenance infusion according to any one of claims 1 to 6, which is heat-sterilized.