Glycerin fructose sodium chloride injection and preparation method thereof

Abstract

The application relates to the field of biological medicine, in particular to a glycerol fructose sodium chloride injection and a preparation method thereof. The glycerol fructose sodium chloride injection contains 80-120 g of glycerol, 40-60 g of fructose, 7-11 g of sodium chloride, 0.6-2.0 g of lecithin, 0.1-0.4 g of organic acid and injection water per 1000 mL. The lecithin is dispersed in the injection water at 50-60 DEG C first, then the glycerol, the sodium chloride and the organic acid are added, the fructose is added after the system is cooled to below 40 DEG C, finally the volume is fixed and the pH is adjusted to 4.0-4.5, and the two-stage filtration and wet heat sterilization are carried out to obtain the glycerol fructose sodium chloride injection. The compound of the lecithin and the organic acid can significantly inhibit the generation of the fructose degradation product 5-hydroxymethyl furfural.

Description

A glycerol fructose sodium chloride injection and its preparation method Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a glycerol fructose sodium chloride injection and its preparation method. Background Technology

[0002] Glycerol fructose sodium chloride injection is a widely used osmotic dehydrating agent in clinical practice, mainly used to reduce intracranial pressure and treat cerebral edema. The prescribed formula in the pharmacopoeia is: 100g glycerol, 50g fructose, and 9g sodium chloride, prepared with water for injection to a 1000mL formulation. However, the fructose component in this injection is unstable during high-temperature sterilization and storage, and is easily dehydrated and degraded to produce 5-hydroxymethylfurfural (5-HMF). 5-HMF has potential neurotoxicity and cytotoxicity in humans; therefore, the Chinese Pharmacopoeia has strict limits on its content. The test method is as follows: take 5.0mL of this product, add water to 20.0mL, shake well, and measure the absorbance at a wavelength of 284nm using ultraviolet-visible spectrophotometry (General Rule 0401). The absorbance should not exceed 0.80. Therefore, how to effectively control the formation of 5-HMF while ensuring the sterility of the product has long been a technical challenge in this field.

[0003] In existing technologies, methods such as adding stabilizers or optimizing processes are commonly used to suppress the formation of 5-HMF. For example:

[0004] Chinese invention patent CN105147724B discloses the use of polyethylene glycol-12-hydroxystearate as a stabilizer and citric acid to adjust the pH. While this method can inhibit 5-HMF, the specification also cites literature indicating that polyethylene glycol-12-hydroxystearate poses a significant risk of hemolysis or muscle damage, raising concerns about the safety of its injection administration.

[0005] Chinese invention patent CN112274533B proposes the use of polyethylene glycol-distearate phosphatidylethanolamine as a stabilizer to withstand sterilization levels of F0≥12. While this excipient offers improved safety, its synthesis process is complex and costly, and it is not a commonly included excipient in the pharmacopoeia, hindering its widespread promotion and application.

[0006] Chinese invention patent CN104666340B attempts to solve the stability problem through a low-temperature formulation and ultrafiltration process without additives. However, this method has extremely stringent requirements for production equipment and environmental control, which significantly increases production costs and makes it difficult to popularize in industrial production.

[0007] In summary, there is an urgent need in this field for a new technical solution to stably control the formation of 5-HMF in glycerol fructose sodium chloride injection, while the process should be simple, easy to implement, and suitable for large-scale industrial production. Summary of the Invention

[0008] To address the aforementioned technical problems, the present invention aims to provide a glycerol fructose sodium chloride injection and its preparation method. The injection, by employing a specific composite excipient system, can effectively inhibit the degradation of fructose during high-temperature sterilization and long-term storage, thereby preventing the formation of 5-hydroxymethylfurfural (5-HMF), while also possessing excellent biocompatibility and sterility assurance levels.

[0009] To achieve the above-mentioned technical effects, the present invention adopts the following technical solution:

[0010] First, the present invention provides a glycerol fructose sodium chloride injection solution, wherein each 1000 mL of the injection solution is composed of the following components: 80-120 g of glycerol; 40-60 g of fructose; 7-11 g of sodium chloride; 0.6-2.0 g of lecithin; 0.1-0.4 g of organic acid; and the balance being water for injection.

[0011] The organic acid is any one or more of L-malic acid, citric acid, or lactic acid.

[0012] Preferably, the mass ratio of lecithin to organic acid is 3-10:1.

[0013] More preferably, the mass ratio of lecithin to organic acid is 10:3;

[0014] More preferably, the lecithin is either soybean lecithin or egg yolk lecithin, and most preferably egg yolk lecithin.

[0015] In a preferred embodiment, each 1000 mL of injection solution consists of the following components: 100 g glycerol; 50 g fructose; 9 g sodium chloride; 1 g lecithin; 0.3 g L-malic acid; and the remainder is water for injection.

[0016] Furthermore, the present invention also provides a method for preparing the above-mentioned glycerol fructose sodium chloride injection, comprising the following steps:

[0017] (1) Dispersion: Add the prescribed amount of lecithin to water for injection at 50-60℃, stir and disperse evenly to obtain system A;

[0018] (2) Dissolution: In system A, add the prescribed amounts of glycerol, sodium chloride and organic acid in sequence, stir to dissolve, and obtain system B;

[0019] (3) Add fructose: Cool the temperature of system B to below 40°C, add the prescribed amount of fructose, stir to dissolve, and obtain system C;

[0020] (4) Volume adjustment: Add water for injection to system C to the total volume, and adjust the pH of the solution to 4.0-4.5;

[0021] (5) Sterilization and packaging: The drug solution is filtered, filled and sterilized to obtain the glycerol fructose sodium chloride injection solution.

[0022] Preferably, the filtration is a two-stage filtration using 0.45μm and 0.22μm microporous membranes.

[0023] Preferably, the sterilization is performed by moist heat sterilization at 121°C for 15 minutes.

[0024] Preferably, the pH adjuster is hydrochloric acid.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] The present invention provides a glycerol fructose sodium chloride injection, which uses a composite excipient system composed of lecithin and specific organic acids (especially L-malic acid) to effectively inhibit the degradation of fructose during high-temperature sterilization and long-term storage, and significantly reduce the formation of 5-hydroxymethylfurfural (5-HMF), thus ensuring the safety and efficacy of the product.

[0027] Furthermore, the preparation method of this invention does not require complex synthesis processes or demanding low-temperature ultrafiltration equipment. Stable product quality can be achieved through optimized feeding sequence and conventional sterilization conditions. The process conditions are mild, the steps are simple, and the requirements for production equipment are low, making it very suitable for large-scale industrial production.

[0028] Finally, the glycerol fructose sodium chloride injection provided by this invention uses widely available and inexpensive excipients, and the process route is mature. Compared with existing technologies that use expensive special excipients or complex processes, this invention has a significant cost advantage while ensuring the same or even better product quality. Detailed Implementation

[0029] The following embodiments are only used to illustrate the technical solutions of the present invention more clearly, and are therefore only examples and should not be used to limit the scope of protection of the present invention.

[0030] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some other embodiments, methods, means, apparatus, and steps well known to those skilled in the art have not been described in detail in order to highlight the spirit of the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Unless otherwise specified, all units used in this specification are International Standard Units (SI), and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors unavoidable in industrial production.

[0031] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the materials, reagents, or instruments used, unless otherwise specified by the manufacturer, are all commercially available; and the conditions not specified in the examples are all performed under conventional conditions or conditions recommended by the manufacturer. Furthermore, this invention does not limit the source of the raw materials used; unless otherwise specified, the raw materials used in this invention are all commercially available products commonly found in this technical field. Unless otherwise specified, the "ratio" referred to in the following examples refers to a ratio of mass in grams.

[0032] Example 1

[0033] The glycerol fructose sodium chloride injection solution of this embodiment is composed of the following components: 100g glycerol, 50g fructose, 9g sodium chloride, 1.0g soybean lecithin, 0.3g L-malic acid, and water for injection to a final volume of 1000mL.

[0034] Its preparation method includes the following steps:

[0035] (1) Dispersion: Take 70% of the prescribed amount of water for injection, heat it to 55°C, add the prescribed amount of soybean lecithin while stirring, and stir at a speed of 200 rpm for 15 minutes to make it fully dispersed and uniform, thus obtaining system A;

[0036] (2) Dissolution: Add the prescribed amounts of glycerol, sodium chloride and L-malic acid to system A in sequence, increase the stirring speed to 300 rpm and continue stirring for 20 minutes until all components are completely dissolved, and obtain a clear or opalescent system B;

[0037] (3) Add fructose: Cool system B to 35°C using a circulating water bath, add the prescribed amount of fructose, and stir at 300 rpm for 30 minutes to completely dissolve it, thus obtaining system C;

[0038] (4) Volume adjustment: Add water for injection to system C to a total volume of 1000 mL, and adjust the pH of the solution to 4.0 using 0.1 mol / L hydrochloric acid solution;

[0039] (5) Sterilization and packaging: The drug solution is filtered through 0.45μm and 0.22μm microporous membranes in sequence for two stages, filled into non-PVC soft bags, sterilized by moist heat at 121℃ for 15 minutes, and packaged after passing the light inspection.

[0040] Example 2

[0041] The glycerol fructose sodium chloride injection solution of this embodiment is composed of the following components: 100g glycerol, 50g fructose, 9g sodium chloride, 1.2g soybean lecithin, 0.2g L-malic acid, and water for injection to a final volume of 1000mL.

[0042] Its preparation method includes the following steps:

[0043] (1) Dispersion: Take 65% of the prescribed amount of water for injection, heat it to 50°C, add the prescribed amount of soybean lecithin while stirring, and stir at a speed of 180 rpm for 20 minutes to make it fully dispersed and uniform, to obtain system A;

[0044] (2) Dissolution: Add the prescribed amounts of glycerol, sodium chloride and L-malic acid to system A in sequence, increase the stirring speed to 280 rpm and continue stirring for 25 minutes until all components are completely dissolved to obtain system B;

[0045] (3) Adding fructose: Cool system B to 38°C using a circulating water bath, add the prescribed amount of fructose, and stir at 280 rpm for 35 minutes to completely dissolve it, thus obtaining system C;

[0046] (4) Volume adjustment: Add water for injection to system C to a total volume of 1000 mL, and adjust the pH of the solution to 4.0 using 0.1 mol / L hydrochloric acid solution;

[0047] (5) Sterilization and packaging: The drug solution is filtered through 0.45μm and 0.22μm microporous membranes in sequence for two stages, filled into non-PVC soft bags, sterilized by moist heat at 121℃ for 15 minutes, and packaged after passing the light inspection.

[0048] Example 3

[0049] The glycerol fructose sodium chloride injection solution of this embodiment is composed of the following components: 100g glycerol, 50g fructose, 9g sodium chloride, 0.8g egg yolk lecithin, 0.25g L-malic acid, and water for injection to a final volume of 1000mL.

[0050] Its preparation method includes the following steps:

[0051] (1) Dispersion: Take 75% of the prescribed amount of water for injection, heat it to 60°C, add the prescribed amount of egg yolk lecithin while stirring, and stir at a rate of 220 rpm for 18 minutes to make it fully dispersed and uniform, to obtain system A;

[0052] (2) Dissolution: Add the prescribed amounts of glycerol, sodium chloride and L-malic acid to system A in sequence, increase the stirring speed to 320 rpm and continue stirring for 22 minutes until all components are completely dissolved to obtain system B;

[0053] (3) Add fructose: Cool system B to 33°C using a circulating water bath, add the prescribed amount of fructose, and stir at 320 rpm for 28 minutes to completely dissolve it, thus obtaining system C;

[0054] (4) Volume adjustment: Add water for injection to system C to a total volume of 1000 mL, and adjust the pH of the solution to 4.0 using 0.1 mol / L hydrochloric acid solution;

[0055] (5) Sterilization and packaging: The drug solution is filtered through 0.45μm and 0.22μm microporous membranes in sequence for two stages, filled into non-PVC soft bags, sterilized by moist heat at 121℃ for 15 minutes, and packaged after passing the light inspection.

[0056] Comparative Example 1

[0057] The purpose of this comparative study is to investigate the effects of stabilizer absence, single-component use, substitution of different organic acids, and changes in the ratio on the formation of 5-HMF, as detailed below.

[0058] 1.1 Group Settings

[0059] Thirteen experimental groups were set up (examples and comparative examples 1-1 to 1-12), and the specific experimental design is shown in Table 1 below.

[0060] Table 1. Experimental Groups (Examples, Comparative Examples 1-1 to 1-12)

[0061]

[0062] *Note: In Comparative Examples 1-12, polyethylene glycol-12-hydroxystearate was used to replace soybean lecithin, at a dosage of 1.0 g / 1000 mL;

[0063] 1.2 Experimental methods and results analysis

[0064] Following the method described in Example 1, each experimental group prepared glycerol fructose sodium chloride injection using the same preparation method as in Example 1. The impurities in the prepared glycerol fructose sodium chloride injection were tested at the initial stage of preparation and after being stored at 40°C for 6 months. The experimental results of the influence of different excipient compositions on the content of 5-HMF impurities are shown in Table 2.

[0065] Table 2. Effect of different excipient compositions on the impurity content of 5-HMF (n=3)

[0066]

[0067] The above experimental results show that Example 1, which uses lecithin and L-malic acid in a mass ratio of 10:3, exhibits the best stability. Its 5-HMF absorbance values ​​at 0 and after accelerated testing are the lowest among all groups. Although Comparative Examples 1-12 have better impurity control at 0, they suffer from insufficient long-term stability.

[0068] Among them, Comparative Example 1-1 (blank control) contained no stabilizer, and its 5-HMF content was much higher than that of the other groups, proving that adding a stabilizer is the key to controlling impurity formation. The stabilizing effects of Comparative Example 1-2 (lecithin alone) and Comparative Example 1-3 (L-malic acid alone) were significantly inferior to those of Example 1, which used both, proving that a single component cannot achieve the ideal impurity control effect.

[0069] With a fixed ratio of lecithin and organic acids, replacing L-malic acid with other organic acids such as citric acid, lactic acid, D-malic acid, or tartaric acid (Comparative Examples 1-4 to 1-7) did not result in a stabilizing effect comparable to Example 1. This indicates that L-malic acid, due to its specific molecular structure, can effectively control impurities. When the mass ratio of lecithin to L-malic acid deviated from 10:3 (Comparative Examples 1-8 to 1-11), a noticeable decrease in product stability was observed regardless of whether the proportion of either component was increased or decreased, demonstrating that this specific ratio is key to achieving optimal technical results.

[0070] Comparative Example 2

[0071] The purpose of this comparative example is to observe the impact of the order of addition of each component and temperature control during the preparation process on the stability of the product, as detailed below.

[0072] 2.1 Group Settings

[0073] Five experimental groups were set up (Example 1, Comparative Examples 2-1 to 2-4). Except for the variables in Table 3, the preparation methods of each group were the same as in Example 1, and the remaining experimental conditions were kept consistent. Glycerol fructose sodium chloride injection was prepared in each group.

[0074] The group settings are shown in Table 3.

[0075] Table 3. Experimental group (Example 1, Comparative Examples 2-1 to 2-4) group settings

[0076]

[0077] *Note: In the order of adding ingredients, add ingredient 1 first, then ingredient 2, and finally ingredient 3;

[0078] 2.2 Experimental methods and results analysis

[0079] All experimental groups used the formulation of Example 1, only changing the order of adding ingredients or temperature parameters according to Table 3. The specific operating conditions were kept the same, including: lecithin dispersion temperature 55℃, stirring time 15 minutes; dissolution time of each component 20 minutes; fructose dissolution time 30 minutes; pH adjusted to 4.2; filtration and sterilization conditions were the same.

[0080] The impurities of the prepared glycerol fructose sodium chloride injection were detected in the initial stage of preparation and after being stored at 40℃ for 6 months. The experimental results of the effect of different preparation conditions on the control of 5-HMF impurities are shown in Table 4:

[0081] Table 4. Effect of different preparation conditions on impurity control of 5-HMF (n=3)

[0082]

[0083] The experimental results above show that the standard process (Example 1), by following the sequence of "lecithin first → L-malic acid then → fructose added at low temperature," ensures the preferential construction of the protective system and the gentle introduction of fructose, thus achieving optimal stability. When this sequence is changed, the protective effect decreases to varying degrees: adding L-malic acid first (Comparative Example 2-1) initially places the system in a low pH environment, which may affect the dispersion and functional integrity of lecithin, leading to a decrease in the protective effect; simultaneous addition (Comparative Example 2-2), while better than reversing the order, is still not as good as stepwise operation, indicating that stepwise addition is more conducive to the full interaction of the two excipients; and the most critical change in sequence—adding fructose first and then L-malic acid (Comparative Example 2-3)—leads to a significant deterioration in stability, indicating that fructose, without chemical protection, will trigger irreversible initial degradation upon contact with the solution. In addition, temperature control has also proven to be a crucial process parameter; even with the correct sequence, increasing the fructose addition temperature to 55°C (Comparative Example 2-4) still leads to a sharp increase in fructose degradation, with significant increases in both the 0°C and accelerated values. The experimental results show that a specific feeding sequence and low temperature control are essential process conditions for achieving impurity control.

[0084] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications and substitutions should be covered within the scope of the claims of the present invention. Technical aspects, shapes, and structures not described in detail in this invention are all well-known technologies.

Claims

1. A glycerol fructose sodium chloride injection solution, characterized in that, Each 1000 mL of injection solution consists of the following components Composition: 80-120g glycerol; 40-60g fructose; 7-11g sodium chloride; 0.6-2.0g lecithin; 0.1-0.4g organic acid; the remainder is water for injection; and the organic acid is L-malic acid; the lecithin is soybean lecithin, and the mass ratio of lecithin to organic acid is 10:3; and the glycerol fructose sodium chloride injection solution is prepared according to the following steps: (1) Dispersion: In water for injection at 50-60℃, add the prescribed amount of lecithin, stir and disperse. (1) Disperse evenly to obtain system A; (2) Dissolve: In system A, add the prescribed amount of glycerol, sodium chloride and organic acid in sequence, stir to dissolve, and obtain system B; (3) Add fructose: Lower the temperature of system B to below 40℃, add the prescribed amount of fructose, stir to dissolve, and obtain system C; (4) Adjust the volume: Add water for injection to system C to the full volume, and adjust the pH value of the drug solution to 4.0-4.5; (5) Sterilize and package: Filter, fill and sterilize the drug solution to obtain the glycerol fructose sodium chloride injection solution.

2. The glycerol fructose sodium chloride injection solution according to claim 1, characterized in that, The filtration in step (5) is a two-stage filtration using 0.45μm and 0.22μm microporous membranes.

3. The glycerol fructose sodium chloride injection solution according to claim 1, characterized in that, The sterilization in step (5) is wet heat sterilization at 121°C for 15 minutes.

4. The glycerol fructose sodium chloride injection solution according to claim 1, characterized in that, The pH adjuster in step (4) is hydrochloric acid.

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