Compound sodium acetate fructose injection and preparation method thereof

Abstract

The invention relates to the field of injections, and particularly discloses a compound sodium acetate fructose injection and a preparation method thereof. The compound sodium acetate fructose injection comprises fructose, sodium chloride, potassium chloride, magnesium chloride, monopotassium phosphate, sodium acetate, citric acid and the balance of water. The preparation method comprises the following steps: preparing 50-90% of water, cooling to 30-60 DEG C, starting stirring, sequentially adding sodium chloride, potassium chloride, magnesium chloride, monopotassium phosphate and sodium acetate, stirring for 5-30 minutes, adding fructose, and stirring for 5-30 minutes to obtain a prepared solution; preparing a 50% (w / w) citric acid solution by using the residual water, adding the citric acid solution into the prepared solution, adjusting the pH value to 4.0-5.5, and stirring for 5-30 minutes to obtain a mixed solution; and filtering the mixed solution, filling, sterilizing at 121 DEG C for 8 minutes, and packaging. The compound sodium acetate fructose injection has the advantages of high stability and few impurities.

Description

Technical Field

[0001] The present application relates to the field of injections, and more specifically, to a compound sodium acetate fructose injection and a preparation method thereof. Background Art

[0002] In the modern medical field, postoperative conditions, burns, infections, and other conditions are often accompanied by significant changes in the patient's physical functions, among which insulin resistance is more common. Insulin resistance refers to the body's reduced sensitivity to insulin, resulting in a decrease in the effectiveness of insulin in promoting glucose uptake and utilization. In this state, the use of traditional glucose for fluid rehydration therapy faces many challenges.

[0003] For postoperative patients, surgical stress can trigger a series of neuroendocrine reactions, leading to an imbalance in hormone levels and increased insulin resistance. At this time, if glucose is simply infused, it will not only fail to provide energy effectively, but may also lead to abnormal increases in blood sugar levels, which in turn can cause a series of complications, such as hyperglycemic hyperosmolar state and increased risk of infection.

[0004] Burn patients suffer from large-area skin damage and are in a state of high metabolic stress, which can lead to insulin resistance. At the same time, burn patients lose a lot of body fluids. In addition to replenishing water to maintain circulating blood volume and internal environment stability, they also need appropriate energy substances to support high metabolic needs. However, the application of glucose in this case is limited and cannot meet the patient's needs for fluid replacement and energy supplementation. Fructose injection has great potential in dealing with insulin resistance-related situations. It can bypass the insulin-dependent glucose transport pathway to a certain extent and provide energy to the body.

[0005] However, the stability of fructose injection is greatly affected by pH value and temperature, which may lead to failure, deterioration, crystallization and other problems during storage. Impurities will also be introduced during the production process, which will not only affect the purity of the injection and pose a risk of adverse effects on the human body, but also accelerate the failure and deterioration of the injection during storage, thereby affecting the quality of the injection. Summary of the invention

[0006] In order to improve the stability and purity of fructose injection, the present application provides a compound sodium acetate fructose injection and a preparation method thereof.

[0007] In the first aspect, the present application provides a compound sodium acetate fructose injection using the following technical solution: A compound sodium acetate fructose injection, characterized in that the components include, by mass percentage, 1-10% fructose, 0.02922-0.29224% sodium chloride, 0.01044-0.10440% potassium chloride, 0.01017-0.10168% magnesium chloride, 0.02722-0.27220% potassium dihydrogen phosphate, 0.05443-0.54432% sodium acetate, 0.01-1.0% citric acid, and the rest is water.

[0008] By adopting the above technical solution, accurately defining the proportion of each component helps to accurately control the reaction conditions and the amount of raw materials used during the preparation process, and reduce impurities caused by improper raw material ratios. From the perspective of drug safety, strict formula design can reduce the risk of immune response caused by impurities. Due to the reduction of impurities, the probability of adverse reactions such as allergies caused by injections in patients under stress conditions such as surgery, burns, and infections is significantly reduced, and the burden on the body is reduced, which is conducive to the smooth progress of the patient's recovery process. The synergistic effect of each component reduces the possibility of changes in physical and chemical properties during storage and use, such as discoloration and precipitation, which can be effectively inhibited. This not only ensures the effectiveness of the drug, but also avoids adverse consequences such as vascular embolism and damage to liver and kidney function caused by the generation of particulate matter, improves the safety and reliability of the drug in clinical use, and enables it to better meet the clinical needs of rehydration and energy supplementation for patients with insulin resistance, and expands its application prospects in the medical field.

[0009] In the second aspect, the present application provides a method for preparing a compound sodium acetate fructose injection using the following technical solution: A method for preparing a compound sodium acetate fructose injection comprises the following steps: Prepare 50%-90% water, cool to 30-60°C, start stirring, add sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, sodium acetate, continue stirring for 5-30 minutes, then add fructose, stir for 5-30 minutes to obtain a preliminary solution; Add citric acid to the remaining amount of water and stir to prepare a 50% (w / w) citric acid solution; Add citric acid solution to the prepared solution and adjust the pH value of the solution to 4.0-5.5, and stir for 5-30 minutes to obtain a mixed solution; The mixed solution is filtered and then filled, sterilized at 121°C for 8 minutes, and packaged after sterilization.

[0010] By adopting the above technical scheme, sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, and sodium acetate are added in sequence at 30-60°C and stirred, so that these electrolytes can be fully dissolved and evenly dispersed in water, laying a good foundation for subsequent mixing with fructose. Low temperature is conducive to reducing the degradation or side reactions of certain components due to excessive temperature, ensuring the initial stability of the components. Subsequently, fructose is added and stirred, so that fructose can be evenly dissolved in the electrolyte solution to form a preparatory solution, avoiding precipitation due to excessive local fructose concentration, and further ensuring the uniformity and stability of the entire solution system. This gradual addition and stirring method helps to fully mix the components at the molecular level, improves the uniformity of the compound preparation, and is conducive to the stable control of product quality. After citric acid is prepared into a 50% (w / w) solution, it is added to the preparatory solution to adjust the pH value to 4.0-5.5. In this pH range, fructose and other electrolyte components can maintain a relatively stable chemical state, reduce the problems of component decomposition, oxidation or reaction with the container caused by excessively high or low pH, thereby extending the shelf life of the drug and maintaining its efficacy. After filtering, the mixed solution can effectively remove insoluble particles, impurities and possible residual undissolved substances in the solution, significantly improving the purity of the injection. This plays a key role in reducing the body's immune response caused by impurities and reducing the incidence of adverse drug reactions. Especially in dealing with postoperative, burn, infection and other situations where the patient's body is relatively fragile and the immune function is easily affected, high-purity injection can better ensure the patient's medication safety. Sterilization at 121°C can effectively kill microorganisms in the solution, including bacteria, spores and other pathogenic or corruptible microorganisms, ensuring the sterility of the injection during storage and use. This high-temperature sterilization process, while ensuring the sterilization effect, combined with the previous ingredient control and filtration steps, will not have a significant adverse effect on the active ingredients and stability of the drug, so that the product meets the sterility requirements and maintains its therapeutic efficacy, providing a strong guarantee for clinical safe drug use.

[0011] Optionally, the filter material comprises one of polyethersulfone or covalent organic framework membrane.

[0012] By adopting the above technical solution, polyethersulfone has good chemical stability and thermal stability, and its pore size can be precisely controlled within an appropriate range. In the filtration process of compound sodium acetate fructose injection, it can effectively intercept particulate impurities in the solution, such as incompletely dissolved drug particles, tiny dust introduced during the production process, etc., to ensure the clarity of the injection, thereby improving the purity and quality of the product. Polyethersulfone itself is less irritating to the human body, and will not release harmful substances when in contact with the injection, nor will it have adverse reactions with the components therein, which is crucial for injections that directly enter the human blood circulation. It can reduce the immune response and toxicity risks caused by the filter material and ensure the safety of patient medication. The covalent organic framework membrane has a regular and highly ordered pore structure. When filtering compound sodium acetate fructose injection, it can selectively intercept 5-HMF by virtue of the size screening effect, while having little effect on other effective ingredients in the injection. In the injection of the present application with a pH value of 4.0-5.5 and a system containing multiple salts, the covalent organic framework membrane can maintain a stable chemical structure and does not chemically react with the components in the injection, thereby ensuring that its own structure is not destroyed during the filtration process. It can perform a long-term and stable filtering effect on 5-HMF, avoid the introduction of new impurities, ensure the purity of the injection, and meet the strict requirements of drug production for safety and quality.

[0013] Optionally, the preparation method of the covalent organic framework membrane is: 1,3,5-tri(4-aminophenyl)benzene and 2,5-dihydroxyterephthalic acid are used as reactants in a molar ratio of 1:(1.25-1.35), 1,3,5-tri(4-aminophenyl)benzene is dissolved in an organic solvent to obtain an organic phase solution, and 2,5-dihydroxyterephthalic acid is dissolved in an aqueous solution containing acetic acid to obtain an aqueous phase solution, wherein the mass of acetic acid is 4-8% of the total mass of the reactants; In a reaction container, first pour the aqueous solution into the bottom of the container, then spread the organic solution on top of the aqueous solution, seal the reaction container, place it in a constant temperature environment of 50-60°C for reaction, and the reaction time is 35-40 hours to obtain a covalent organic framework membrane; After the reaction is completed, the covalent organic framework membrane is washed and dried, and the dried covalent organic framework membrane is heated to 130-140° C. under nitrogen protection and kept warm for 30-60 minutes.

[0014] By adopting the above technical scheme, by setting the molar ratio of 1,3,5-tri(4-aminophenyl)benzene and 2,5-dihydroxyterephthalic acid, the foundation is laid for the formation of pores of specific size. The reaction temperature is controlled at 50-60°C and the reaction time is set to 35-40h, which not only ensures that the polymerization reaction between the monomers is fully and orderly, but also avoids the disorder of the pore structure caused by excessive temperature or excessive time. The pores of the covalent organic framework membrane formed by the process of this application are uniform and regular, which is conducive to the selective filtration of 5-HMF precipitates. And the functional groups on the pore wall of the covalent organic framework membrane, such as amino groups and hydroxyl groups. The 5-HMF molecule contains functional groups such as aldehyde groups and furan rings, and the amino groups and other functional groups on the covalent organic framework membrane can form hydrogen bonds with the aldehyde groups of 5-HMF. At the same time, the benzene ring structure in the covalent organic framework membrane and the furan ring of 5-HMF produce π-π stacking. These weak interactions make 5-HMF more likely to be preferentially intercepted and adsorbed by the covalent organic framework membrane. The other liquid components have a weak interaction with the covalent organic framework membrane and can pass through the membrane smoothly. Heat treatment at 130-140℃ for 30-60min under nitrogen protection further enhances the mechanical properties of the membrane, making it more durable during the filtration process.

[0015] Optionally, the packaging material is a water-blocking composite material, which includes an inner layer film, a middle layer film and an outer layer film, the inner layer film includes an ethylene-propylene polymer film, the middle layer film includes an ethylene-vinyl alcohol copolymer film, and the outer layer film includes a homopolypropylene film.

[0016] By adopting the above technical scheme, this three-layer structure design enables each layer of film to play its own unique advantages and synergistically achieve an excellent water-blocking effect. The inner ethylene-propylene polymer film is first used as a layer in direct contact with the injection liquid, which plays a preliminary role in blocking the trace amount of water that may seep out from the inside; the middle ethylene-vinyl alcohol copolymer film, with its excellent water-blocking performance, constitutes the main water-blocking defense line, which can effectively prevent the water vapor in the external environment from penetrating into the inside; the outer homopolymer polypropylene film further strengthens the overall water-blocking barrier to prevent the external water vapor from invading the inside of the package from the outside. The three layers of film are closely combined to form an efficient water-blocking system, which greatly reduces the possibility of water entering or leaving the package, thereby ensuring that the compound sodium acetate fructose injection can always be in a relatively dry environment during storage and transportation, and maintain the stability and quality of the drug. The ethylene-vinyl alcohol copolymer film not only has outstanding water-blocking performance, but also has high chemical stability. During long-term storage, it can resist the influence of external environmental factors (such as temperature and humidity changes, etc.) on the drugs inside the package, and prevent the drugs from deteriorating and decomposing due to water penetration and possible chemical reactions. By effectively blocking water vapor, compound sodium acetate fructose injection can maintain a longer shelf life under specified storage conditions, reducing waste caused by expired drugs while also ensuring the quality and safety of clinical drug use.

[0017] Optionally, the ethylene-vinyl alcohol copolymer film is compounded with 5-10% nano-montmorillonite.

[0018] By adopting the above technical solution, nano-montmorillonite has a unique layered structure with a sheet thickness at the nanometer level. When it is evenly dispersed and compounded into the ethylene-vinyl alcohol copolymer film, these nano-level sheets will form an intricate barrier structure in the copolymer film. When water vapor molecules try to penetrate the film, they need to bypass these layers of montmorillonite sheets, which greatly increases the path length of water vapor diffusion, thereby effectively hindering the penetration of water vapor. The addition of nano-montmorillonite plays a role similar to that of reinforcing fiber. Its layered structure can interact with the ethylene-vinyl alcohol copolymer molecular chain. When the film is stretched, squeezed or punctured by external force, the montmorillonite sheet can bear part of the external force and disperse the stress concentration point, thereby improving the overall toughness and tensile and puncture resistance of the film. For example, when the package is collided, stacked, etc., the composite film is less likely to break or break, effectively protecting the medicines in the package.

[0019] Optionally, the mixed liquid is filtered using filter materials with pore sizes of 0.45 μm and 0.22 μm.

[0020] Optionally, the specific method for filtering the mixed liquid is: passing the mixed liquid once through a filter material with a pore size of 0.45 μm, and then passing it twice through a filter material with a pore size of 0.22 μm.

[0021] By adopting the above technical solution, the mixed solution is first passed through a filter material with a pore size of 0.45μm, which can effectively intercept and remove larger-sized particulate impurities in the mixed solution, such as incompletely dissolved drug particles, possible small amounts of fiber impurities, and some larger microorganisms. If these larger particles are not removed, they may affect the clarity and stability of the injection, and even induce immune reactions or other adverse reactions after entering the human body. Subsequently, the mixed solution after 0.45μm filtration is passed through a filter material with a pore size of 0.22μm twice to further finely filter smaller impurities. The pore size of 0.22μm can capture some smaller particles, bacterial spores, and some colloidal impurities that may remain. After such graded fine filtration, the purity of the injection can be greatly improved, ensuring that the compound sodium acetate fructose injection entering the human body contains almost no impurity particles that are harmful to the human body, thereby ensuring the safety and effectiveness of the patient's medication.

[0022] In summary, this application has the following beneficial effects: 1. Since the present application can reduce impurities, reduce the risk of immune response of the body, reduce the probability of adverse reactions in patients under stressful conditions such as surgery, and reduce the burden on the body by accurately limiting the proportion of ingredients, the synergistic effect of various ingredients can also reduce changes in physical and chemical properties, avoid adverse consequences, and improve the safety and reliability of clinical use. It can meet the fluid and energy replenishment needs of patients with insulin resistance and expand application prospects.

[0023] 2. In the method of the present application, it is preferred to first add a variety of electrolytes to part of the water at 30-0°C and stir to form a preliminary solution, which is conducive to uniform dispersion and stabilization of the ingredients, and then prepare citric acid into a 50% (w / w) solution and add it to the preliminary solution to adjust the pH to 4.0-5.5 to ensure the chemical stability of each component and the efficacy of the drug. The mixed solution is filtered to remove impurities and improve the purity to reduce the incidence of adverse reactions. Finally, it is sterilized at 121°C for 8 minutes to ensure sterility without affecting the effective ingredients and stability. The overall preparation process helps to fully mix and stabilize the ingredients, provide strong support for clinical safe drug use and ensure product quality.

[0024] 3. The covalent organic framework membrane preferably used in this application has a regular and highly ordered pore structure. When filtering the compound sodium acetate fructose injection, it can selectively intercept 5-HMF by virtue of the size screening effect, while having little effect on other effective ingredients in the injection. In the injection of this application with a pH value of 4.0-5.5 and a system containing a variety of salts, the covalent organic framework membrane can maintain a stable chemical structure and does not react chemically with the ingredients in the injection, ensuring that its own structure is not destroyed during the filtration process, and can play a long-term and stable filtering role on 5-HMF, avoiding the introduction of new impurities, ensuring the purity of the injection, and meeting the strict requirements of drug production for safety and quality. DETAILED DESCRIPTION

[0025] The present application is further described in detail below in conjunction with the examples. It is particularly noted that if no specific conditions are specified in the following examples, the experiments are carried out according to conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples can be obtained from common commercial sources.

[0026] Preparation Example 1 A method for preparing a covalent organic framework membrane: Material preparation 1,3,5-Tris(4-aminophenyl)benzene (TAPB): purity ≥98%, added amount 5mmol; 2,5-Dihydroxyterephthalic acid (DHBD): purity ≥98%, added amount 6.5mmol; Organic solvent: N,N-dimethylformamide, purity ≥99.9%, added amount 200mL; Acetic acid: purity ≥99.7%, the amount added is 6% of the total mass of the reactants (TAPB+DHBD); Deionized water, 200 mL; Nitrogen: purity ≥99.999%; Preparation steps Add TAPB to the organic solvent and stir with a magnetic stirrer until it is completely dissolved to obtain an organic phase solution;

[0027] DHBD and acetic acid were added into deionized water and stirred until completely dissolved to obtain an aqueous phase solution;

[0028] Pour the aqueous phase solution into the bottom of a sealed container, and slowly pour the organic phase solution along the bottle wall onto the aqueous phase solution to avoid mixing the two phases. Seal the container to ensure no gas leakage;

[0029] Place the sealed glass bottle in a thermostat, set the temperature to 55°C, and let it react for 38 hours. After the reaction is completed, open the container and take out the formed COF film;

[0030] Place the COF membrane in a centrifuge tube, add deionized water, centrifuge at 5000rpm for 5 minutes, and discard the supernatant. Repeat this step 3 times. Then wash it with an organic solvent twice to remove residual impurities. Place the washed COF membrane in a vacuum drying oven and dry it at 60°C for 12 hours to completely remove the solvent;

[0031] Place the dried COF film in a heating furnace and introduce nitrogen (flow rate: 50 mL / min) for protection. Heat to 135°C at a heating rate of 5°C / min and keep warm for 45 minutes. Cool naturally to room temperature and take out the COF film.

[0032] Preparation Example 2 A method for preparing a covalent organic framework membrane: The difference from Preparation Example 1 is that the amount of 2,5-dihydroxyterephthalic acid added is 6.25 mmol.

[0033] Preparation Example 3 A method for preparing a covalent organic framework membrane: The difference from Preparation Example 1 is that the amount of 2,5-dihydroxyterephthalic acid added is 6.75 mmol.

[0034] Preparation Example 4 A method for preparing a covalent organic framework membrane: The difference from Preparation Example 1 is that the amount of acetic acid added is 4% of the total mass of the reactants (TAPB+DHBD).

[0035] Preparation Example 5 A method for preparing a covalent organic framework membrane: The difference from Preparation Example 1 is that the amount of acetic acid added is 8% of the total mass of the reactants (TAPB+DHBD).

[0036] Preparation Example 6 A method for preparing a covalent organic framework membrane: The difference from Preparation Example 1 is that the dried COF membrane is not subjected to a heating furnace treatment.

[0037] Preparation Example 7 A method for preparing a water-blocking composite material: Raw material preparation Ethylene-propylene polymer: an ethylene-propylene polymer having an ethylene content of 45% (mass fraction) and a weight average molecular weight (Mw) of 150,000-250,000 is selected.

[0038] Ethylene-vinyl alcohol copolymer: Select ethylene-vinyl alcohol copolymer with an ethylene content of 30% (mass fraction) and an alcoholysis degree between 95% and 99%.

[0039] Homopolymer polypropylene: Homopolymer polypropylene with an isotacticity greater than 90% is used, and its melt flow rate (MFR) is in the range of 5-10g / 10min (230℃, 2.16kg).

[0040] Preparation of the inner membrane Add ethylene-propylene polymer particles to an internal mixer, set the temperature to 170°C, the speed to 50 rpm, and the mixing time to 10 minutes. During the mixing process, add antioxidant 1010, the addition amount is 0.2% of the polymer mass. The mixed material is extruded through a single screw extruder with a screw diameter of 40 mm and an aspect ratio (L / D) of 25. The extrusion temperature is set to 180°C and the extrusion pressure is 12 MPa. Use a T-die to extrude the material into a sheet to obtain an inner layer film with a thickness of 0.2-0.3 mm.

[0041] Preparation of middle membrane The ethylene-vinyl alcohol copolymer particles were dried in a vacuum oven at 80°C for 4 hours to reduce the moisture content to less than 0.5% (mass fraction). The dried ethylene-vinyl alcohol copolymer particles were added to a twin-screw extruder, the extruder temperature was set to 190°C, and the screw speed was 60rpm. The extruded material was blown into a film through a blow molding die, the blow ratio was 2, and the pulling speed was 4m / min, to obtain a middle layer film with a thickness of 0.1-0.15mm.

[0042] Preparation of outer membrane Melt extrusion Homopolymer polypropylene particles were added to a single screw extruder, the extruder temperature was controlled at 210°C, and the screw speed was 40 rpm. The molten homopolymer polypropylene was extruded into a film using a coat hanger die head, the die head temperature was 220°C, and the extrusion pressure was 18 MPa, to obtain an outer layer film with a thickness of 0.2-0.3 mm.

[0043] Film composite process The inner film, the middle film and the outer film are compounded by a dry compounding machine. In the compounding process, a two-component polyurethane adhesive is used, and the mass ratio of the main agent to the curing agent is 12:1. The adhesive is evenly coated on the surface of the film, and the amount of adhesive is 3g / m². The compounding pressure is 0.5MPa, the compounding temperature is 60℃, and after 24h of curing time, a water-blocking composite material is obtained.

[0044] The water-blocking composite material is cut and heat-sealed to obtain a composite water-blocking packaging bag, and one side of the inner film is located inside the water-blocking packaging bag.

[0045] Preparation Example 8 A method for preparing a water-blocking composite material: The difference from Preparation Example 7 is that the ethylene-vinyl alcohol copolymer particles are dried in a vacuum oven at 80°C for 4 hours to make their water content less than 0.5% (mass fraction). The dried ethylene-vinyl alcohol copolymer particles are added to a twin-screw extruder, and 8% of the mass of the ethylene-vinyl alcohol copolymer nano-montmorillonite is added, and the copolymer particles are heated to melt and stirred evenly. The extruder temperature is set to 190°C and the screw speed is 60rpm. The extruded material is blown into a film through a blow molding mold, the blow-up ratio is 2, and the pulling speed is 4m / min, to obtain a middle layer film with a thickness of 0.1-0.15mm.

[0046] Preparation Example 9 A method for preparing a water-blocking composite material: The difference from Preparation Example 8 is that 5% of nano-montmorillonite is compounded in the ethylene-vinyl alcohol copolymer film.

[0047] Preparation Example 10 A method for preparing a water-blocking composite material: The difference from Preparation Example 8 is that 10% of nano-montmorillonite is compounded in the ethylene-vinyl alcohol copolymer film.

[0048] Example 1 A preparation method of compound sodium acetate fructose injection: Raw material preparation Water for injection: Prepare in advance and ensure its quality meets the standards for water for injection.

[0049] Accurately weigh 0.15 g sodium chloride, 0.062 g potassium chloride, 0.055 g magnesium chloride, 0.14 g potassium dihydrogen phosphate, 0.325 g sodium acetate, 5 g fructose, and 0.25 g citric acid, all of which are analytical grade.

[0050] Solution preparation Add 60 g of water for injection into a clean mixing container that has been strictly cleaned and disinfected, and turn on the cooling device to reduce the water temperature to 45°C.

[0051] Start the stirrer and set the stirring frequency to 30 Hz. Under stirring, slowly add sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, and sodium acetate to the stirring container in sequence. After the addition is completed, continue stirring at the stirring frequency for 20 minutes to evenly disperse the salt substances in the solution. Then add fructose to the above solution and stir at a stirring frequency of 30 Hz for 20 minutes until the fructose is completely dissolved to obtain a preliminary mixed solution.

[0052] Take an appropriate amount of water for injection and slowly add citric acid into it while stirring manually to fully dissolve it to prepare a 50% citric acid solution (w / w).

[0053] Add the prepared citric acid solution to the main solution stirring container and adjust the pH value of the solution to 4.8. During the pH adjustment process, continue stirring and monitor the pH value changes in real time. After ensuring that the pH value is stable within the target range, continue stirring for 20 minutes to fully mix the solution.

[0054] Add water for injection to the stirring container until the total mass of the solution reaches 100 g, stir at a stirring frequency of 30 Hz for 20 min to ensure that the solution is uniform as a whole, and obtain the final mixed solution.

[0055] The mixed solution is first passed through a filter material with a pore size of 0.45 μm, and then passed through two filter materials with a pore size of 0.22 μm. The filter material is filtered using a 20-inch polyethersulfone filter element.

[0056] Filling and sterilization A five-layer co-extruded infusion bag was used for filling. The filtered solution was transported to the infusion bag through a filling pipe, and the filled infusion bag was placed in an autoclave and kept at 121°C for 8 minutes for wet heat sterilization. The sterilized mixed solution was packaged in a composite water-blocking packaging bag, and the water-blocking composite material was prepared by Preparation Example 7, and finally the finished product of the compound sodium acetate fructose injection was obtained.

[0057] Example 2 A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that 0.02922 g of sodium chloride, 0.01044 g of potassium chloride, 0.01017 g of magnesium chloride, 0.02722 g of potassium dihydrogen phosphate, 0.05443 g of sodium acetate, 1 g of fructose, and 0.01 g of citric acid are accurately weighed, all of which are analytically pure.

[0058] Example 3 A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that 0.29224 g of sodium chloride, 0.10440 g of potassium chloride, 0.10168 g of magnesium chloride, 0.27220 g of potassium dihydrogen phosphate, 0.54432 g of sodium acetate, 10 g of fructose, and 1.0 g of citric acid are accurately weighed, all of which are analytically pure.

[0059] Example 4 A method for preparing a compound sodium acetate fructose injection: The method is different from Example 1 in that the pH value of the solution is adjusted to 4.0.

[0060] Example 5 A method for preparing a compound sodium acetate fructose injection: The method is different from Example 1 in that the pH value of the solution is adjusted to 5.5.

[0061] Embodiment 6-10 A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the filter material uses a covalent organic framework membrane, which is prepared in sequence from Preparation Examples 1, 2, 3, 4, and 5.

[0062] Examples 11-13 A method for preparing a compound sodium acetate fructose injection: The method is different from Example 1 in that the water-blocking composite material is prepared in sequence from Preparation Examples 8, 9, and 10.

[0063] Embodiment 14 A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the pore size of the filter material is 0.45 μm.

[0064] Embodiment 15 A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the pore size of the filter material is 0.22 μm.

[0065] Example 16 A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the mixed solution is first passed through a filter material with a pore size of 0.45 μm, and then passed through a filter material with a pore size of 0.22 μm.

[0066] Comparative Example 1 A method for preparing a compound sodium acetate fructose injection: the difference from Example 1 is that the pH value of the solution is adjusted to 6.

[0067] Comparative Example 2 A method for preparing a compound sodium acetate fructose injection: the difference from Example 1 is that the pH value of the solution is adjusted to 7.

[0068] Comparative Example 3 A method for preparing a compound sodium acetate fructose injection: The method is different from Example 1 in that citric acid is directly added to the mixed solution, and a 50% (w / w) citric acid solution is not prepared.

[0069] Comparative Example 4 A method for preparing a compound sodium acetate fructose injection: The difference from Example 6 is that the filter material uses a covalent organic framework membrane, which is prepared by Preparation Example 6.

[0070] Comparative Example 5 A method for preparing a compound sodium acetate fructose injection: The method is different from Example 1 in that a medical PVC packaging bag is used instead of a composite water-blocking packaging bag.

[0071] Detection Methods The compound sodium acetate fructose injection prepared in the embodiment / comparative example was taken respectively, the product properties were observed, and the osmotic pressure, fructose content and 5-MHF content were tested. After the test, it was stored in a dark environment at room temperature of 25°C and humidity of 45%, and the above contents were retested at 1, 3 and 6 months respectively.

[0072] 40 patients with type I diabetes were enrolled in the clinical trial and randomly divided into two groups, A and B. Patients in group A received 1000 ml of compound sodium acetate fructose injection (prepared in Example 1) every day for 12 weeks; patients in group B received 1000 ml of normal saline every day for 12 weeks. Blood glucose and insulin levels of patients were tested in fasting state and 2 hours after meal one day before the start of treatment and one day after the end of treatment.

[0073] Table 1 Results of the first test

[0074] Table 2 Test results after 1 month storage

[0075] Table 3 Test results after 3-month storage

[0076] Table 4 Test results after 6 months storage

[0077] Table 5 Clinical trial results

[0078] Combining Examples 1, 4, 5 and Comparative Examples 1-2 and Tables 1-4, it can be seen that the initial pH values ​​of the injections of Examples 1, 4, and 5 are 4.8, 4.0, and 5.5, respectively. During storage, Comparative Examples 1-2 appear slightly yellow when stored for 6 months, indicating that too high a pH value may cause the solution color to change. The osmotic pressure of Examples 1, 4, and 5 is relatively stable and changes less during storage; the osmotic pressure of Comparative Examples 1-2 increases significantly over time, especially when stored for 6 months, Comparative Example 1 reaches 486.1, and Comparative Example 2 reaches 486.0, which is significantly higher than the examples, indicating that the pH value deviates from the appropriate range and aggravates the change in osmotic pressure. The sugar content of the examples changes relatively steadily, while the sugar content of the comparative examples increases significantly during storage, such as Comparative Example 1 reaching 126.3 when stored for 6 months, and Comparative Example 2 reaching 127.9. The amount of 5-HMF in the examples increased relatively slowly during storage, while the growth rate of the comparative examples was significantly faster. For example, the amount of 5-HMF in comparative example 1 reached 0.0320 after 6 months of storage, and that in comparative example 2 reached 0.0283, indicating that the pH value has a significant effect on the stability of the compound sodium acetate fructose injection, and a too high pH value will accelerate the generation of 5-HMF.

[0079] Combining Example 1 and Comparative Example 3 and Tables 1-4, it can be seen that Example 1 is to prepare citric acid into a 50% (w / w) solution and then add it, while Comparative Example 3 is to directly add citric acid to the mixed solution. Example 1 always remains a colorless and clear liquid, while Comparative Example 3 turns slightly yellow after being stored for 6 months, indicating that direct addition without preparing the citric acid solution may affect the stability of the solution. The osmotic pressure of Comparative Example 3 increased more than that of Example 1 during storage, reaching 484.2 after 6 months of storage, which is higher than 456.5 of Example 1, indicating that this operation may change the osmotic pressure of the solution. The sugar content of Comparative Example 3 increased significantly during storage, reaching 129.0 after 6 months of storage, which is higher than 107.0 of Example 1, affecting the stability of the sugar content. The amount of 5-HMF in Comparative Example 3 increased rapidly, reaching 0.0327 after 6 months of storage, which was much higher than 0.0106 in Example 1, indicating that not preparing the citric acid solution would increase the amount of 5-HMF generated in the injection and reduce the stability of the injection.

[0080] Combining Example 6 and Comparative Example 4 and Tables 1-4, it can be seen that Example 6 is a colorless clear liquid at each time point, and Comparative Example 4 becomes slightly yellow after 6 months of storage, indicating that different covalent organic framework membrane preparation processes have an effect on the appearance of the injection. The osmotic pressure of Example 6 is relatively stable, and Comparative Example 4 increases significantly during storage, reaching 485.8 after 6 months of storage, which is higher than 455.4 of Example 6, indicating that different preparation processes may cause different effects of covalent organic framework membranes on osmotic pressure. The sugar content of Example 6 changes relatively smoothly and is higher than that of Comparative Example 4 at each time point. The sugar content of Comparative Example 4 is 122.7 after 6 months of storage, which is lower than 109.4 of Example 6, indicating that covalent organic framework membranes with different processes have different effects on the stability of sugar content. The amount of 5-HMF in Example 6 increased slowly during storage, while that in Comparative Example 4 increased rapidly, reaching 0.0265 after 6 months of storage, which was higher than 0.0060 in Example 6. This indicates that the covalent organic framework membrane preparation process of Example 6 is more conducive to inhibiting the formation of 5-HMF and improving the stability of the injection.

[0081] Combining Example 1 and Comparative Example 5 and Tables 1-4, it can be seen that Example 1 uses a composite water-blocking packaging bag, and Comparative Example 5 uses a medical PVC packaging bag. Example 1 always maintains a colorless and clear liquid, while Comparative Example 5 turns slightly yellow after 6 months of storage, indicating that the packaging material has an effect on the appearance of the injection. The osmotic pressure of Comparative Example 5 increases more during storage than that of Example 1, reaching 485.2 after 6 months of storage, which is higher than 456.5 of Example 1, indicating that the composite water-blocking packaging bag may have more advantages in maintaining osmotic pressure stability. The sugar content of Comparative Example 5 increases rapidly during storage, reaching 124.6 after 6 months of storage, which is higher than 107.0 of Example 1, indicating that the composite water-blocking packaging bag maintains better stability of sugar content. The amount of 5-HMF in Comparative Example 5 increases significantly, reaching 0.0295 after 6 months of storage, which is higher than 0.0106 of Example 1, showing that the composite water-blocking packaging bag is superior to the medical PVC packaging bag in inhibiting the generation of 5-HMF, and is more beneficial to improving the stability of the injection.

[0082] It can be seen from Examples 1-3 and Tables 1-4 that within the scope of the components of the present application, the appearance of the product is always stable, and it can remain a colorless and clear liquid during storage. In terms of pH value, it can be initially stabilized in an appropriate range, and the change range is small during storage, which can maintain a relatively stable chemical environment, reduce chemical reactions that may be caused by pH fluctuations, and ensure the stability and effectiveness of the active ingredients of the drug. The osmotic pressure changes smoothly, which helps the injection to adapt to the osmotic pressure of the human cell environment in the body, ensure the normal absorption and effect of the drug, and avoid problems such as cell damage or poor drug absorption caused by abnormal osmotic pressure.

[0083] It can be seen from the combination of Example 1 and Example 6-10 and Table 1-4 that Example 1 and Example 6-10 maintain colorless clear liquid at each time point, indicating that the covalent organic framework membranes prepared by different processes can meet the requirements in terms of appearance as filter materials. The osmotic pressure of Example 6-10 is basically the same as that of Example 1 during storage, but the values ​​are slightly different, indicating that different covalent organic framework membrane preparation processes have a certain effect on the osmotic pressure, but the overall is relatively stable. The sugar content of Example 6-10 has a similar trend during storage as Example 1, but the sugar content of Example 6-9 is slightly higher than that of Example 1 at most time points, and Example 10 has a relatively large fluctuation, indicating that different preparation processes of covalent organic framework membranes have different degrees of influence on sugar content. The growth rate of the 5-HMF amount of Example 6-10 during storage is lower than that of Example 1, especially the 5-HMF amount of Example 10 is relatively low at each time point, indicating that the use of covalent organic framework membranes as filter materials may help reduce the amount of 5-HMF generated and improve the stability of the injection, and the effects of different processes are different.

[0084] Combining Example 1 and Examples 11-13 with Tables 1-4, it can be seen that after the nano-montmorillonite is compounded into the ethylene-vinyl alcohol copolymer film, these nano-scale sheets will form an intricate barrier structure in the copolymer film. When water vapor molecules try to pass through the film, they need to bypass these layers of montmorillonite sheets, which greatly increases the path length of water vapor diffusion, thereby effectively hindering the penetration of water vapor and enabling the injection solution to maintain long-term stability.

[0085] It can be seen from Example 1 and Examples 14-16 and Tables 1-4 that the mixed solution is first passed through a filter material with a pore size of 0.45 μm to intercept and remove undissolved drug particles, impurities, etc., to avoid affecting the clarity and stability of the injection and causing adverse reactions. It is then passed through a filter material with a pore size of 0.22 μm twice to finely filter smaller impurities and capture tiny particles. This graded fine filtration can improve the purity and stability of the injection and ensure the safety and effectiveness of the patient's medication.

[0086] It can be seen from Example 1, the clinical trial on patients with type I diabetes and Table 5 that the product prepared by the preparation method of compound sodium acetate fructose injection in Example 1 has better technical effects in lowering blood sugar and regulating insulin levels than normal saline in the treatment of patients with type I diabetes through clinical trials, and may provide a more favorable option for the treatment of patients with type I diabetes.

[0087] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A compound sodium acetate fructose injection, characterized in that: The components include, by mass percentage, 1-10% fructose, 0.02922-0.29224% sodium chloride, 0.01044-0.10440% potassium chloride, 0.01017-0.10168% magnesium chloride, 0.02722-0.27220% potassium dihydrogen phosphate, 0.05443-0.54432% sodium acetate, 0.01-1.0% citric acid, and the rest is water.

2. A method for preparing the compound sodium acetate fructose injection according to claim 1, characterized in that: The following steps are involved: Prepare 50%-90% water, cool to 30-60°C, start stirring, add sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, sodium acetate, continue stirring for 5-30 minutes, then add fructose, stir for 5-30 minutes to obtain a preliminary solution; Add citric acid to the remaining amount of water and stir to prepare a 50% (w / w) citric acid solution; Add citric acid solution to the prepared solution and adjust the pH value of the solution to 4.0-5.5, and stir for 5-30 minutes to obtain a mixed solution; The mixed solution is filtered and then filled, sterilized at 121°C for 8 minutes, and packaged after sterilization.

3. The method for preparing the compound sodium acetate fructose injection according to claim 2, characterized in that: The filter material includes one of polyethersulfone or covalent organic framework membrane.

4. The method for preparing the compound sodium acetate fructose injection according to claim 3, characterized in that: The preparation method of the covalent organic framework membrane: 1,3,5-tri(4-aminophenyl)benzene and 2,5-dihydroxyterephthalic acid are used as reactants in a molar ratio of 1:(1.25-1.35), 1,3,5-tri(4-aminophenyl)benzene is dissolved in an organic solvent to obtain an organic phase solution, and 2,5-dihydroxyterephthalic acid is dissolved in an aqueous solution containing acetic acid to obtain an aqueous phase solution, wherein the mass of acetic acid is 4-8% of the total mass of the reactants; In a reaction container, first pour the aqueous solution into the bottom of the container, then spread the organic solution on top of the aqueous solution, seal the reaction container, place it in a constant temperature environment of 50-60°C for reaction, and the reaction time is 35-40 hours to obtain a covalent organic framework membrane; After the reaction is completed, the covalent organic framework membrane is washed and dried, and the dried covalent organic framework membrane is heated to 130-140° C. under nitrogen protection and kept warm for 30-60 minutes.

5. The method for preparing the compound sodium acetate fructose injection according to claim 2, characterized in that: The packaging material is a water-blocking composite material, which includes an inner film, a middle film and an outer film. The inner film includes an ethylene-propylene polymer film, the middle film includes an ethylene-vinyl alcohol copolymer film, and the outer film includes a homopolymer polypropylene film.

6. The method for preparing the compound sodium acetate fructose injection according to claim 5, characterized in that: The ethylene-vinyl alcohol copolymer film is compounded with 5-10% of nano-montmorillonite.

7. The method for preparing the compound sodium acetate fructose injection according to claim 1, characterized in that: The mixed liquid is filtered using filter materials with pore sizes of 0.45 μm and 0.22 μm.

8. The method for preparing the compound sodium acetate fructose injection according to claim 7, characterized in that: The specific method of filtering the mixed liquid is: the mixed liquid first passes through a filter material with a pore size of 0.45 μm once, and then passes through a filter material with a pore size of 0.22 μm twice.

Images