CN114533759A - Sodium potassium magnesium calcium glucose injection composition and preparation method thereof - Google Patents

Abstract

The invention relates to a sodium potassium magnesium calcium glucose injection composition and a preparation method thereof. The invention particularly relates to a sodium potassium magnesium calcium glucose injection prepared from sodium chloride, potassium chloride, magnesium chloride, calcium gluconate, sodium citrate, sodium acetate and anhydrous glucose as raw materials and a preparation method thereof. The sodium potassium magnesium calcium glucose injection is a large-capacity injection with terminal sterilization, is safe and stable, and meets the requirements of medicinal preparations. The injection contains various ions with molar concentration, osmotic pressure and pH value close to those of human extracellular fluid, and can be used for supplementing extracellular fluid and correcting metabolic acidosis when circulating blood volume and interstitial fluid are reduced.

Description

Sodium potassium magnesium calcium glucose injection composition and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a sodium potassium magnesium calcium glucose injection pharmaceutical composition and a preparation method thereof.

Background

In the body composition, water accounts for about 60% of the body weight. The body fluid balance has important effect on human body, and can maintain the homeostasis of human body. Clinically, various wounds, operations and various diseases can cause the imbalance of body fluid balance, and serious imbalance of body fluid balance can cause the dysfunction of body tissues and organs and systems, even shock and death. Thus, a crystal solution is produced.

The extracellular fluid supplementary solution clinically used at present comprises: normal saline, ringer's solution, lactated ringer's solution (both sugar-containing and sugar-free), acetified ringer's solution (both sugar-containing and sugar-free), sodium bicarbonate ringer's solution, and the like. In normal saline and ringer's solution, such electrolytes cause acidosis when infused rapidly in large amounts due to the high concentration of chloride ions. Currently, the clinical use of the electrolyte injection is lactic acid ringer's solution, but the electrolyte injection contains more lactic acid (the concentration of lactate can reach 28mEq/L), the lactic acid value in blood can be increased when a large amount of the electrolyte injection is transfused, and the lactic acid is mainly metabolized in the liver, so that the lactic acid metabolic disorder can be caused when the liver has low function, and the hyperlactacidosis can be caused. Ringer's acetate solution has emerged with sodium acetate as the alkalizing agent instead of sodium lactate. Acetic acid is not only metabolized in the liver, but acetic acid is distributed in almost all tissues of the body, starting from skeletal muscle. The latest generation of ringer's solution is the ringer's injection of sodium bicarbonate, which uses sodium bicarbonate as the source of bicarbonate instead of sodium acetate and sodium lactate. However, the sodium ion concentration (130mEq/L) in lactated ringer's solution, aceturated ringer's solution and sodium bicarbonate ringer's solution is lower than that in plasma, and therefore, such electrolytes are likely to cause hyponatremia during infusion.

Compared with the conventional fluid infusion, the sodium potassium magnesium calcium glucose injection has obvious clinical treatment advantages, has the advantages that the molar concentration (Na +140mEq/L, Mg2+2mEq/L), osmotic pressure and pH value of various ions are approximate to those of the components of human plasma electrolytes, does not increase the burden of liver and kidney metabolism, can be used for treating the reduction of tissue fluid caused by factors such as shock, operation, trauma, scald, heavy bleeding and the like due to the reduction of circulating blood volume, and is used for supplementing and adjusting extracellular fluid. As the concentration of chloride ions in human plasma is lower than that of sodium ions, compared with isotonic normal saline, Na +/Cl-in the sodium-potassium-magnesium-calcium-glucose injection is closer to the physiological ratio, and the hyperchloremic metabolic acidosis and hyponatremia can be avoided when a large amount of fluid is supplemented. The product contains magnesium ion, and can avoid hypomagnesemia which may occur during rapid administration. In addition, 1% of glucose can inhibit hypoglycemia and fat metabolism decomposition in vivo, and is beneficial to metabolic balance of blood sugar and fat without causing hyperglycemia and urine sugar excretion.

A commonly used reference preparation of sodium potassium magnesium calcium glucose Injection is "Physio 140 Injection" from tsukamur pharmaceutical corporation of japan, and the patent of "ZL 200710059911.1 compound sodium acetate electrolyte Injection and its preparation method" of the product discloses a preparation method of the compound sodium acetate electrolyte Injection. The product has pH of 6.0-6.1, and sterilization condition of 110 deg.C for 40 min. Calculated F sterilized at 110 ℃ for 40min₀The value is only 3.18, which does not meet the requirement of terminal sterilization process for injection in China, has poor sterility guarantee effect, can not effectively kill microbes, heat sources and the like, and has very high potential safety hazard. . In addition, the effect of the preparation process on the degradation of glucose in the product is not described in this patent. Patent "CN201510042510. X preparation method of sodium potassium magnesium calcium glucose injection"Comparative example 3 discloses a preparation method of a sodium potassium magnesium calcium glucose injection, wherein the pH value of the product is 6.0, the sterilization process is sterilization at 121 ℃ for 12min, the glucose content in the obtained product is 89.1%, and the content of the impurity 5-hydroxymethylfurfural is as high as 0.162%. Therefore, when the pH value of the product is 6.0, after the product is sterilized at the high temperature of 121 ℃ for 12min, which meets the sterilization requirements of the injection in China, the glucose degradation impurities are greatly increased, and the use risk of the product is improved.

Therefore, the field generally recognizes that in order to obtain the sodium potassium magnesium calcium glucose injection meeting the sterilization requirements of China, the stability of glucose in the injection can be ensured only when the pH value of the sodium potassium magnesium calcium glucose injection subjected to the terminal sterilization process is 4.0-5.5, so that the pH values of like products on the market are listed.

Disclosure of Invention

The invention provides a sodium potassium magnesium calcium glucose injection composition and a preparation method thereof, the injection contains sodium chloride, potassium chloride, calcium gluconate, magnesium chloride, sodium acetate, sodium citrate and glucose, the injection is prepared by terminal sterilization, the obtained sodium potassium magnesium calcium glucose injection has high sterility guarantee level, and the molar concentration, osmotic pressure and pH value of various ions contained in the injection are close to those of human plasma electrolyte, so that the injection composition can be used for extracellular fluid supplementation and metabolic acidosis correction when the circulating blood volume and interstitial fluid are reduced.

In embodiments, the injection is prepared by terminal sterilization, F₀The value range is selected from 8 < F0 ≦ 27, preferably 10 ≦ F0 ≦ 27, more preferably 12 ≦ F0 ≦ 25.

In embodiments, the injection has a pH of 5.5 to 7.0, preferably a pH of 5.9 to 6.2, and more preferably a pH of 6.0.

In the invention F₀The value is that the bacillus stearothermophilus is taken as a microorganism indicator, different sterilization temperatures and time are converted into the time (minutes) equivalent to the moist heat sterilization at 121 ℃ with the same sterilization efficiency, when F₀When the value is more than 8, it is confirmed that a reliable sterilization effect is achieved. The calculation formula is as follows:

the invention provides a sodium potassium magnesium calcium glucose injection composition, which is prepared from 250ml of injection and 500ml of injection according to the following weight ratio:

according to the sodium potassium magnesium calcium glucose injection composition and the preparation method thereof, provided by the invention, a terminal sterilization process is adopted, so that the sterilization effect can be further improved, and the sterility of the sodium potassium magnesium calcium glucose injection is ensured.

In embodiments, the terminal sterilization process is an overkill method or a survival probability method.

In an embodiment, the terminal sterilization process adopts a sterilization temperature of 121 ℃ and a sterilization time of 6-8 minutes, and preferably a sterilization time of 8 minutes.

The applicant researches and discovers that the stability of the glucose solution is related to both the temperature and the pH value of the solution, and under the weak acid or alkaline condition, the glucose is easy to degrade to generate 5-hydroxymethylfurfural and fructose. When the sterilization temperature is too high or the sterilization time is too long, the degradation of glucose in the solution can also be caused. The injection and the preparation method thereof overcome the technical bias in the prior art, when the pH value of the product is 5.5-7.0, the product is sterilized at the high temperature of 121 ℃ for 6-8 minutes, the obtained final product has high sterility guarantee level, the stability of glucose in the solution is good, the content of degraded impurity 5-hydroxymethylfurfural is extremely low, only a small amount of fructose harmless to human bodies is generated, the injection meets the relevant process and quality requirements of the injection in China, and the injection is suitable for industrial large-scale production and application.

The injection and the preparation method thereof can simultaneously give consideration to the stability of glucose and the sterility guarantee level of the injection, and can also enable the pH value of the injection to be closer to the pH value of human plasma, thereby reducing the irritation to blood vessels and reducing the occurrence of anaphylactic reaction.

Under the conditions of the pH value and terminal sterilization, the content of glucose tends to decrease after sterilization, and the glucose can be degraded into fructose after sterilization, but the fructose is still at a lower level and is far less than the use limit of the fructose.

The preparation method of the sodium potassium magnesium calcium glucose injection provided by the invention comprises the following steps: 1) dissolving calcium gluconate, sodium chloride, potassium chloride, magnesium chloride, sodium citrate, sodium acetate and anhydrous glucose in water for injection; 2) regulating the pH value of the liquid medicine by using hydrochloric acid; 3) filtering, and packaging in a composite membrane bag; 4) and (5) terminal sterilization.

Further, the preparation method comprises the following steps:

1) the preparation method comprises the following steps of preparing the calcium gluconate injection by adopting a stainless steel preparation tank with a stirring paddle, adding about 25 percent of injection water by weight, adding the calcium gluconate according to the prescription amount, and stirring to dissolve the calcium gluconate;

2) adding water for injection into the preparation tank to about 90% of the total weight, cooling to 50-60 deg.C, adding other raw materials (sodium chloride, potassium chloride, magnesium chloride, sodium citrate, sodium acetate, and anhydrous glucose), stirring and dissolving;

3) adding water for injection into the preparation tank to about 99% of the total weight, adjusting the pH value of the liquid medicine with 2mol/L hydrochloric acid while adding acid, and stirring and mixing uniformly. Finally adding water for injection to full volume, and stirring and mixing uniformly;

4) cooling the medicinal liquid to 40 deg.C, filtering, pre-filtering with 5 parallel polyethersulfone filters of 0.45 μm, circulating in the pipeline with 5 parallel polyethersulfone sterilizing filters of 0.2 μm for 15min, and filtering the intermediate medicinal liquid;

5) filling the liquid medicine into 250ml or 500ml composite membrane bags, and sterilizing in a water bath sterilization cabinet to obtain the sodium potassium magnesium calcium glucose injection.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Example 1: preparation of sodium potassium magnesium calcium glucose injection (250 ml/bag, 21000 bags)

TABLE 1 formulation composition and dosage of Na-K-Mg-Ca-glucose injection (250 ml/bag, 21000 bags)

Name of material	Each bag is composed of	21000 batch prescription
			Sodium chloride	1.593g	33.453Kg
Potassium chloride	0.075g	1.575Kg
			Magnesium chloride	0.051g	1.071Kg
Calcium gluconate	0.168g	3.528Kg
			Citric acid sodium salt	0.147g	3.087Kg
Sodium acetate	0.851g	17.871Kg
			Anhydrous glucose	2.500g	52.500Kg
Hydrochloric acid	Proper amount of	Proper amount of
			Water for injection	Adding to 250ml	To 5250L

The preparation method comprises the following steps:

1) the preparation method comprises the following steps of preparing the calcium gluconate injection by adopting a stainless steel preparation tank with a stirring paddle, adding about 25 percent of injection water by weight, adding the calcium gluconate according to the prescription amount, and stirring to dissolve the calcium gluconate;

2) adding water for injection into the preparation tank to about 90% of the total weight, cooling to 50-60 deg.C, adding other raw materials (sodium chloride, potassium chloride, magnesium chloride, sodium citrate, sodium acetate, and anhydrous glucose), stirring and dissolving;

3) adding water for injection into the preparation tank to about 99% of the total weight, adjusting the pH value of the liquid medicine with 2mol/L hydrochloric acid while adding acid, and stirring and mixing uniformly. Finally adding water for injection to full volume, and stirring and mixing uniformly;

4) cooling the medicinal liquid to 40 deg.C, filtering, pre-filtering the medicinal liquid with 5 parallel polyethersulfone filters of 0.45 μm, circulating in the pipeline for 15min with 5 parallel polyethersulfone filters of 0.2 μm, and filtering the intermediate medicinal liquid;

5) filling the liquid medicine into 250ml or 500ml composite membrane bags, and sterilizing in a water bath sterilization cabinet to obtain the sodium potassium magnesium calcium glucose injection.

Example 2: preparation of sodium potassium magnesium calcium glucose injection (500 ml/bag, 15000 bag)

TABLE 2 prescription composition and dosage of Na-K-Mg-Ca glucose injection (500 ml/bag, 15000 bags)

A sodium potassium magnesium calcium glucose injection was prepared in the same manner as in example 1, except that: there is a difference in the amount of prescription for the two specifications due to rounding off the carry.

Example 3: study on pH value of sodium-potassium-magnesium-calcium glucose injection

TABLE 3 pH value screening results

Note: "+" indicates absorbance measurements.

As is clear from the results in Table 3, the glucose content in the sterilized drug solution was almost unchanged at pH values of 5.0 and 5.5 by using sterilization conditions of 15min at 121 ℃ and 12min at 121 ℃. When the pH value exceeds 5.5, the glucose content in the sterilized liquid medicine is gradually reduced along with the increase of the pH value, and the generation amount of fructose which is an impurity for degradation is gradually increased.

The results of the solutions sterilized at 121 ℃ for 8min are shown in Table 4.

Table 4 results of further investigation of pH

Note: 1) "+" indicates absorbance measurements; 2) the batch of liquid medicine is sterilized at 121 ℃ for 8 min.

From the results in Table 4, it can be seen that:

1) within the pH value range of 5.9-6.2, the degradation degree of glucose in the sterilized liquid medicine is gradually increased along with the increase of the pH value.

2) Within the pH value range of 5.9-6.2, along with the increase of the pH value, the glucose content in the sterilized liquid medicine is gradually reduced, and the generation amount of 5-hydroxymethylfurfural is also gradually increased.

3) No fructose was detected before sterilization at a pH of 5.9 to 6.2, and the amount of fructose produced after sterilization increased as the pH of the sample increased.

Example 4: study on sodium potassium magnesium calcium glucose injection sterilization process

TABLE 5 Sterilization conditions screening results

Note: "+" indicates absorbance measurements.

From the results in Table 5, it is understood that the self-made preparation was sterilized at a temperature of 121 ℃ for various times, and as the sterilization time was prolonged, the degree of degradation of glucose in the sterilized drug solution was gradually increased and the amount of fructose produced was increased. By comparing the sterilization effects at 121 ℃ and 115 ℃, it can be seen that the same F is achieved₀When the value is high, the content of the glucose is reduced by less than 115 ℃ when the sterilization is carried out at 121 ℃, which indicates that the sterilization process at high temperature and short time is more favorable for maintaining the stability of the glucose.

According to the data, the upper limit of the dosage of the fructose in an FDA inactive component database (FDA IIG limit) is 5% (w/v), the content of glucose in the liquid medicine with the pH value of 6.0 is about 93-95%, and the content of the degradation product fructose is about 0.05-0.06% (w/v), which is far less than the use limit of the fructose.

During the production verification period, sterilization F for sterilizing multiple batches of products at 121 ℃ for 8min is counted₀The values, results are shown in Table 6.

TABLE 6 Sterilization F of the products₀Value of

The results in the table show that F sterilized at 121 ℃ for 8min is used in the actual production process₀The value is more than 12, the requirement of over-killing is met, the sterility can be ensured, and the safety of the injection is ensured.

Example 5: sodium potassium magnesium calcium glucose injection sterilization F₀Determination of a value

To investigate F which the product can tolerate₀The liquid medicine is prepared according to the prescription, and the change of related indexes before and after different sterilization processes is inspected. (sterilization at 115 ℃ for 32min, sterilization at 121 ℃ for 8min, sterilization at 121 ℃ for 15min, sterilization at 121 ℃ for 20min, sterilization at 121 ℃ for 25min, and sterilization at 121 ℃ for 30min) the results of the investigation are shown in Table 7.

TABLE 7F₀Value screening results

Note: "+" indicates absorbance measurements.

As can be seen from the results in Table 7,

1) sterilizing the medicinal liquid with pH of 6.0 at 121 deg.C for different times, and F₀The value is gradually increased, and the degradation degree of glucose in the sterilized liquid medicine is gradually increased, and the production amount of fructose is increased.

2) Comparison of the sterilization effects at 121 ℃ and 115 ℃ shows that the same F is achieved₀When the value is high, the content of glucose is reduced by less than 115 ℃ when sterilization is carried out at 121 ℃.

In order to better ensure the product quality and reduce the variation range of various indexes after sterilization, F of the product needs to be added₀The value range is controlled to be 8-27 (F is more than 8)₀≤27)。

Example 6: study of Special safety

1. Rabbit hemolytic and vascular irritation test

New Zealand rabbits were selected for red blood cells for hemolytic assays. The results show that under the experimental conditions, the test sample has no obvious in vitro hemolysis and coagulation-causing effect on rabbit blood erythrocytes.

Observing whether the intravenous drip of the ear edge vein of the test sample has stimulating effect on the ear edge vein of the New Zealand rabbit and the surrounding tissues by using a visual morphological and histopathological method. The results show that the volume of the drug administration is 10mL/kg, the rate of the drug administration is 1050mL/h, the drug administration is carried out 1 time per day for 7 days continuously, and no irritation effect of the test product on the ear vein and surrounding tissues of the New Zealand rabbit is found at 72h after the last drug administration and at the end of the recovery period.

2. Active systemic anaphylaxis test in guinea pigs

Carrying out intraperitoneal injection on Hartley guinea pigs for 3 times every other day continuously to give a sodium potassium magnesium calcium glucose injection test sample, wherein the sensitization volume is 0.5 mL/mouse; 2-fold sensitizing dose is respectively injected into the vein on 14 days and 21 days after the last sensitization for excitation, and the excitation volume is 1.0 mL/mouse. The results show that the guinea pigs tested were negative for active systemic anaphylaxis under the conditions of this test.

3. Passive skin allergy test in rats

SD rats are injected with 0.5mL of sodium potassium magnesium calcium glucose injection sample and 1.0mL of mixed emulsion of 0.5mL of adjuvant every 3 consecutive days, and blood is taken 10 days after the last sensitization to prepare antiserum. The sensitizing serum is diluted according to the original solution and the ratio of 1:2, 1:4 and 1:8, 0.1mL of sensitizing serum with each concentration is injected into the skin of the back of a rat for passive sensitization, and the sensitizing serum is injected into the vein after 24 hours and is excited by the antigen with the same sensitizing dose. The result shows that no positive result is found in the anaphylactic reaction of the test article under the test condition.

Claims (9)

1. A sodium potassium magnesium calcium glucose injection comprises sodium chloride, potassium chloride, calcium gluconate, magnesium chloride, sodium acetate, sodium citrate and glucose, and is characterized in that the injection is prepared by terminal sterilization, and F is₀The value range is selected from 8 < F₀27 or less, preferably 10 or less F₀27 or less, more preferably 12 or less F₀Less than or equal to 25; the pH value of the injection is 5.5-7.0, preferably 5.9-6.2, and more preferably 6.0.

2. The injection of claim 1, wherein each 250ml of the injection comprisesComprises the following steps: 1.593g of sodium chloride (NaCl), 0.075g of potassium chloride (KCl) and calcium gluconate (C)₁₂H₂₂CaO₁₄·H₂O)0.168g, magnesium chloride (MgCl)₂·6H₂O)0.051g, sodium acetate (C)₂H₃NaO₂·3H₂O)0.851g, sodium citrate (C)₆H₅Na₃O₇·2H₂O)0.147g, Anhydrous glucose (C)₆H₁₂O₆)2.500g。

3. The injection according to claim 1 or 2, wherein the terminal sterilization process is performed at 121 ℃ for 6-8 minutes, preferably 8 minutes.

4. A process for preparing an injection according to any one of claims 1 to 3, comprising: 1) dissolving calcium gluconate, sodium chloride, potassium chloride, magnesium chloride, sodium citrate, sodium acetate and anhydrous glucose in water for injection; 2) regulating the pH value of the liquid medicine by using hydrochloric acid; 3) filtering, and packaging in a composite membrane bag; 4) and (5) terminal sterilization.

5. The preparation method according to claim 4, wherein the terminal sterilization process is performed at 121 ℃ for 6-8 minutes, preferably 8 minutes.

6. The method of claim 4, wherein F is the terminal sterilization process₀The value range is selected from 8 < F₀27 or less, preferably 10 or less F₀27 or less, more preferably 12 or less F₀≤25。

7. The method according to claim 4, wherein the pH of the solution is adjusted to 5.5 to 7.0, preferably 5.9 to 6.2, more preferably 6.0 with hydrochloric acid.

8. The method of any one of claims 4 to 7, comprising:

1) the preparation method comprises the following steps of preparing the calcium gluconate injection by adopting a stainless steel preparation tank with a stirring paddle, adding about 25 percent of injection water by weight, adding the calcium gluconate according to the prescription amount, and stirring to dissolve the calcium gluconate;

2) supplementing water for injection to the preparation tank to about 90% of the total weight, cooling to 50-60 ℃, adding sodium chloride, potassium chloride, magnesium chloride, sodium citrate, sodium acetate and anhydrous glucose, and stirring for dissolving;

3) adding water for injection into the preparation tank to about 99% of the total weight, adjusting pH with 2mol/L hydrochloric acid while adding acid, stirring, mixing, adding water for injection to full dose, and stirring;

4) cooling the medicinal liquid to 40 deg.C, filtering, pre-filtering with 5 parallel polyethersulfone filters of 0.45 μm, circulating in the pipeline with 5 parallel polyethersulfone sterilizing filters of 0.2 μm for 15min, and filtering the intermediate medicinal liquid;

5) filling the liquid medicine into a composite membrane bag, and sterilizing by a water bath sterilization cabinet to obtain the sodium potassium magnesium calcium glucose injection.

9. A method of preparing an injection according to any one of claims 1 to 3, comprising:

1) the preparation method comprises the following steps of preparing the calcium gluconate injection by adopting a stainless steel preparation tank with a stirring paddle, adding about 25 percent of injection water by weight, adding the calcium gluconate according to the prescription amount, and stirring to dissolve the calcium gluconate;

2) adding water for injection into the preparation tank to about 90% of the total weight, cooling to 50-60 ℃, adding sodium chloride, potassium chloride, magnesium chloride, sodium citrate, sodium acetate and anhydrous glucose, and stirring for dissolving;

3) adding water for injection into the preparation tank to about 99% of the total weight, adjusting pH with 2mol/L hydrochloric acid while adding acid, stirring, mixing, adding water for injection to full dose, and stirring;

4) cooling the medicinal liquid to 40 deg.C, filtering, pre-filtering with 5 parallel polyethersulfone filters of 0.45 μm, circulating in the pipeline with 5 parallel polyethersulfone sterilizing filters of 0.2 μm for 15min, and filtering the intermediate medicinal liquid;

5) filling the liquid medicine into a composite membrane bag, and sterilizing by a water bath sterilization cabinet to obtain the sodium potassium magnesium calcium glucose injection.