Compound sodium acetate fructose injection and preparation method thereof

Abstract

The application relates to the field of injection solutions, and particularly discloses a compound sodium acetate fructose injection solution and a preparation method thereof. The compound sodium acetate fructose injection solution comprises fructose, sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, sodium acetate and citric acid, and the rest is water; the preparation method is as follows: 50%-90% water is prepared and cooled to 30-60 DEG C, sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate and sodium acetate are sequentially added after stirring, and then the stirring is continued for 5-30 min; fructose is added and stirred for 5-30 min to obtain a prepared solution; 50% (w / w) citric acid solution is prepared by using the remaining water, the prepared solution is added into the citric acid solution, and the pH value is adjusted to 4.0-5.5; the stirring is continued for 5-30 min to obtain a mixed solution; the mixed solution is filtered, filled, sterilized at 121 DEG C for 8 min, and then packaged. The compound sodium acetate fructose injection solution has the advantages of high stability and few impurities.

Description

TECHNICAL FIELD

[0001] The application relates to the field of injection solutions, in particular to a compound sodium acetate fructose injection solution and a preparation method thereof. BACKGROUND

[0002] In the modern medical field, postoperative, burn, infection and other conditions are often accompanied by significant changes in the patient's physical function, among which insulin resistance is relatively common. Insulin resistance refers to the decrease in the sensitivity of the body 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 replacement therapy faces many challenges.

[0003] For postoperative patients, surgical stress can trigger a series of neuroendocrine reactions, causing an imbalance in hormone levels in the body and exacerbating insulin resistance. At this time, if only glucose is input, due to the limited uptake and utilization of glucose by cells, not only can energy not be effectively provided, but also blood glucose levels can abnormally increase, thereby triggering a series of complications, such as hyperglycemic hyperosmolar state, increased risk of infection, etc.

[0004] Burn patients, due to large-area skin damage, are in a high metabolic stress state, and also have insulin resistance. At the same time, the body fluid of burn patients is lost in large quantities, and in addition to the need to supplement water to maintain circulating blood volume and internal environment stability, appropriate energy substances are also needed to support the high metabolic demand. The application of glucose in this case is limited and cannot meet the patient's fluid replacement and energy supplement needs. Fructose injection has great potential in dealing with insulin resistance-related conditions, as it can bypass the insulin-dependent glucose transport pathway to some extent and provide energy to the body.

[0005] However, the stability of fructose injection is greatly affected by pH value and temperature, which can cause failure, deterioration, crystallization and other problems during storage. In addition, impurities can be introduced during production, which not only affects the purity of the injection and poses a risk to the human body, but also accelerates the failure and deterioration of the injection during storage, thereby affecting the quality of the injection. SUMMARY

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

[0007] In a first aspect, the application provides a compound sodium acetate fructose injection solution, which adopts the following technical scheme:

[0008] The compound sodium acetate fructose injection is characterized in that the components include fructose 1-10%, sodium chloride 0.02922-0.29224%, potassium chloride 0.01044-0.10440%, magnesium chloride 0.01017-0.10168%, potassium dihydrogen phosphate 0.02722-0.27220%, sodium acetate 0.05443-0.54432%, and citric acid 0.01-1.0% by mass percentage, and the rest is water.

[0009] By adopting the technical scheme, accurate limitation of the proportion of each component helps to accurately control the reaction conditions and the amount of raw materials in the preparation process, and reduces impurities caused by improper raw material ratio. From the perspective of drug safety, strict formula design can reduce the risk of immune response of the body caused by impurities. Due to the reduction of impurities, the probability of adverse reactions such as allergy caused by injection in the postoperative, burn, infection and other stress states of patients is significantly reduced, the physical burden is reduced, and the smooth progress of the patient's rehabilitation process is conducive. The mutual 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 the adverse consequences of vascular embolism, damage to liver and kidney function and other adverse consequences caused by the generation of particulate matter, improves the safety and reliability of the drug in clinical use, and makes it better meet the needs of clinical fluid and energy supplementation for patients with insulin resistance, and expands its application prospects in the medical field.

[0010] In a second aspect, the application provides a preparation method of the compound sodium acetate fructose injection, which adopts the following technical scheme:

[0011] The preparation method of the compound sodium acetate fructose injection comprises the following steps:

[0012] Prepare 50%-90% water, cool to 30-60℃, start stirring, add sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, and sodium acetate, continue stirring for 5-30min, then add fructose, stir for 5-30min, and obtain a prepared solution;

[0013] Add citric acid to the remaining amount of water and stir to prepare a 50%(w / w) citric acid solution;

[0014] Add the citric acid solution to the prepared solution and adjust the pH value of the solution to 4.0-5.5, stir for 5-30min, and obtain a mixed solution; the mixed solution is filled through a filter material, sterilized at 121℃ for 8min, and packaged after sterilization.

[0015] By employing the above technical solution, adding sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, and sodium acetate sequentially at 30-60℃ with stirring ensures that these electrolytes are fully dissolved and uniformly dispersed in water, laying a good foundation for subsequent mixing with fructose. Low temperature helps reduce degradation or side reactions that may occur due to excessively high temperatures, ensuring the initial stability of the components. Subsequent addition and stirring of fructose allows it to dissolve uniformly in the electrolyte solution, forming a preparative solution and preventing localized high fructose concentrations that could lead to precipitation, further ensuring the homogeneity and stability of the entire solution system. This step-by-step addition and stirring method helps the components mix thoroughly at the molecular level, improving the uniformity of the compound preparation and facilitating stable control of product quality. After preparing a 50% (w / w) solution of citric acid, it is added to the preparative solution to adjust the pH to 4.0-5.5. Within this pH range, fructose and other electrolyte components maintain a relatively stable chemical state, reducing problems such as component decomposition, oxidation, or reactions with the container caused by excessively high or low pH levels, thereby extending the shelf life of the drug and maintaining its efficacy. The mixture undergoes filtration, effectively removing insoluble particles, impurities, and any remaining undissolved substances, significantly improving the purity of the injection. This plays a crucial role in reducing immune responses triggered by impurities and lowering the incidence of adverse drug reactions, especially in patients with weakened immune systems, such as those recovering from surgery, burns, or infections. High-purity injections better ensure patient safety. Sterilization at 121°C effectively kills microorganisms in the solution, including bacteria, spores, and other pathogenic or putrefactive microorganisms, ensuring the sterility of the injection during storage and use. This high-temperature sterilization process, combined with the preceding component control and filtration steps, ensures that the effective components and stability of the drug are not significantly affected, allowing the product to meet sterility requirements while maintaining its therapeutic efficacy, providing strong assurance for safe clinical use.

[0016] Optionally, the filter material includes one of polyethersulfone or covalent organic framework membrane.

[0017] By employing the above-mentioned technical solutions, polyethersulfone exhibits excellent chemical and thermal stability, and its pore size can be precisely controlled within a suitable range. During the filtration process of compound sodium acetate fructose injection, it can effectively intercept particulate impurities in the solution, such as incompletely dissolved drug particles and fine dust introduced during production, ensuring the clarity of the injection and thus improving product purity and quality. Polyethersulfone itself has low irritation to the human body, does not release harmful substances upon contact with the injection, and does not react adversely with its components. This is crucial for injections that directly enter the human bloodstream, reducing the risk of immune reactions and toxicity caused by the filter material and ensuring patient safety. The covalent organic framework membrane has a regular and highly ordered pore structure. When filtering compound sodium acetate fructose injection, it can selectively retain 5-HMF through size sieving effect, while having minimal impact on other active ingredients in the injection. In the application's injection solutions with pH values ​​of 4.0-5.5 and systems containing multiple salts, the covalent organic framework membrane maintains a stable chemical structure and does not react chemically with the components in the injection solution. This ensures that its own structure is not damaged during the filtration process, allowing it to stably perform its filtration function for 5-HMF over a long period of time. It also avoids the introduction of new impurities, ensuring the purity of the injection solution and meeting the stringent safety and quality requirements of pharmaceutical production.

[0018] Optionally, the method for preparing the covalent organic framework membrane is as follows:

[0019] 1,3,5-Tris(4-aminophenyl)benzene and 2,5-dihydroxyterephthalic acid were used as reactants in a molar ratio of 1:(1.25-1.35). 1,3,5-Tris(4-aminophenyl)benzene was dissolved in an organic solvent to obtain an organic phase solution, and 2,5-dihydroxyterephthalic acid was dissolved in an aqueous solution containing acetic acid to obtain an aqueous phase solution. The mass of acetic acid was 4-8% of the total mass of the reactants.

[0020] In the reaction vessel, the aqueous phase solution is first poured into the bottom of the vessel, and then the organic phase solution is spread on top of the aqueous phase solution. The reaction vessel is sealed and placed in a constant temperature environment of 50-60℃ for static reaction for 35-40 hours to obtain a covalent organic framework membrane. After the reaction is completed, the covalent organic framework membrane is washed and dried. The dried covalent organic framework membrane is heated to 130-140℃ under nitrogen protection and held at that temperature for 30-60 minutes.

[0021] By adopting the above technical solution and setting the molar ratio of 1,3,5-tris(4-aminophenyl)benzene and 2,5-dihydroxyterephthalic acid, a foundation is laid for forming pores of a specific size. Controlling the reaction temperature at 50-60℃ and the reaction time at 35-40h ensures both sufficient and orderly polymerization of the monomers and avoids pore structure disorder caused by excessively high temperatures or prolonged times. The covalent organic framework membrane formed by this process has uniform and regular pores, which is beneficial for the selective filtration of 5-HMF precipitates. Furthermore, the functional groups on the pore walls of the covalent organic framework membrane, such as amino and hydroxyl groups, are crucial. Since 5-HMF molecules contain aldehyde and furan ring functional groups, the amino groups on the covalent organic framework membrane can form hydrogen bonds with the aldehyde groups of 5-HMF. Simultaneously, π-π stacking interactions occur between the benzene ring structure in the covalent organic framework membrane and the furan ring of 5-HMF. These weak interactions make 5-HMF more readily retained and adsorbed by the covalent organic framework membrane. Other liquid components interact very weakly with the covalent organic framework membrane and can pass through the membrane layer smoothly. Heat treatment at 130-140℃ for 30-60 minutes under nitrogen protection further enhances the membrane's mechanical properties, making it more durable during filtration.

[0022] Optionally, 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.

[0023] By adopting the above technical solution, this three-layer structure design allows each membrane layer to leverage its unique advantages, synergistically achieving excellent water-blocking performance. The inner ethylene-propylene polymer membrane, acting as the layer in direct contact with the injection solution, provides initial protection against trace amounts of moisture that may seep out from the inside. The middle ethylene-vinyl alcohol copolymer membrane, with its excellent water-blocking properties, forms the main water-blocking barrier, effectively preventing moisture from the external environment from penetrating the packaging. The outer homopolymer polypropylene membrane further strengthens the overall water-blocking barrier, preventing external moisture from intruding into the packaging. The three membranes are tightly bonded together, forming a highly efficient water-blocking system that significantly reduces the possibility of moisture entering or leaving the packaging, thereby ensuring that the compound sodium acetate fructose injection solution remains in a relatively dry environment during storage and transportation, maintaining the stability and quality of the drug. The ethylene-vinyl alcohol copolymer membrane not only has outstanding water-blocking performance but also high chemical stability. During long-term storage, it can resist the influence of external environmental factors (such as changes in temperature and humidity) on the drug inside the packaging, preventing deterioration or decomposition of the drug due to moisture penetration and possible accompanying chemical reactions. By effectively blocking moisture, the compound sodium acetate fructose injection can maintain a longer shelf life under the specified storage conditions, reducing waste caused by drug expiration and ensuring the quality and safety of clinical medication.

[0024] Optionally, the ethylene-vinyl alcohol copolymer film contains 5-10% nano-montmorillonite.

[0025] By employing the above-mentioned technical solution, nano-montmorillonite possesses a unique layered structure with sheet thicknesses at the nanometer level. When uniformly dispersed and composited into an ethylene-vinyl alcohol copolymer membrane, these nano-scale sheets form an intricate barrier structure within the copolymer membrane. Water vapor molecules attempting to permeate the membrane must bypass these stacked montmorillonite sheets, significantly increasing the path length for water vapor diffusion and effectively hindering its penetration. The addition of nano-montmorillonite acts similarly to reinforcing fibers. Its layered structure interacts with the molecular chains of the ethylene-vinyl alcohol copolymer. When the membrane is subjected to external forces such as stretching, compression, or puncture, the montmorillonite sheets can bear a portion of the external force, dispersing stress concentration points and thus improving the overall toughness and tensile and puncture resistance of the membrane. For example, when packaging is subjected to collisions or stacking, the composite membrane is less prone to breakage or damage, effectively protecting the medicine inside the packaging.

[0026] Optionally, the mixture filtration uses filter materials with pore sizes of 0.45 μm and 0.22 μm.

[0027] Optionally, the specific method for filtering the mixture is as follows: the mixture 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 twice.

[0028] By employing the above technical solution, the mixture is first passed through a filter material with a pore size of 0.45 μm, which effectively intercepts and removes larger particulate impurities such as incompletely dissolved drug particles, possible small amounts of fibrous impurities, and some larger microorganisms. If these larger particles are not removed, they may affect the clarity and stability of the injection solution, and may even trigger immune responses or other adverse reactions after entering the human body. Subsequently, the mixture after 0.45 μm filtration is passed twice more through filter materials with a pore size of 0.22 μm for further fine filtration of smaller impurities. The 0.22 μm pore size can capture even smaller particles, bacterial spores, and any remaining colloidal impurities. This multi-stage fine filtration significantly improves the purity of the injection solution, ensuring that the compound sodium acetate fructose injection solution entering the human body is virtually free of harmful particulate impurities, thereby guaranteeing the safety and efficacy of the medication for patients.

[0029] In summary, this application has the following beneficial effects:

[0030] 1. Because this application precisely defines the proportion of components, it can reduce impurities, lower the risk of immune response, reduce the probability of adverse reactions in patients under postoperative and other stress conditions, reduce the burden on the body, and the synergistic effect of each component can also reduce changes in physicochemical properties, avoid adverse consequences, improve the safety and reliability of clinical use, meet the fluid and energy replenishment needs of insulin-resistant patients, and expand application prospects.

[0031] 2. In the method of this application, it is preferable to first add multiple electrolytes to a portion of water at 30-0℃ and stir to form a preparative solution, which is conducive to the uniform dispersion and stability of the components. Then, citric acid is prepared into a 50% (w / w) solution and added to the preparative solution to adjust the pH to 4.0-5.5, ensuring the chemical stability of each component and the efficacy of the drug. The mixture is filtered to remove impurities and improve purity to reduce the incidence of adverse reactions. Finally, it is sterilized at 121℃ for 8 minutes to ensure sterility without affecting the active ingredients and stability. The overall preparation process helps to fully mix and stabilize the components, providing strong support for safe clinical use and ensuring product quality.

[0032] 3. This application preferably uses a covalent organic framework membrane with a regular and highly ordered pore structure. When filtering compound sodium acetate fructose injection, it can selectively retain 5-HMF through size sieving effect, while having minimal impact on other active ingredients in the injection. In systems with pH values ​​of 4.0-5.5 and containing multiple salts, the covalent organic framework membrane maintains a stable chemical structure and does not react chemically with the components in the injection. This ensures that its own structure is not damaged during filtration, allowing it to stably filter 5-HMF over a long period, avoiding the introduction of new impurities, ensuring the purity of the injection, and meeting the stringent safety and quality requirements of pharmaceutical production. Detailed Implementation

[0033] The following detailed description of this application is provided in conjunction with the embodiments. It should be noted that: unless otherwise specified, the conditions in the following embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following embodiments are all from commercially available sources.

[0034] Preparation Example 1

[0035] A method for preparing a covalent organic framework membrane:

[0036] Material preparation

[0037] 1,3,5-Tris(4-aminophenyl)benzene (TAPB): Purity ≥98%, addition amount 5 mmol;

[0038] 2,5-Dihydroxyterephthalic acid (DHBD): Purity ≥98%, Addition amount 6.5 mmol;

[0039] Organic solvent: N,N-dimethylformamide, purity ≥99.9%, addition amount 200mL;

[0040] Acetic acid: purity ≥99.7%, added at 6% of the total mass of reactants (TAPB+DHBD);

[0041] Deionized water, 200mL;

[0042] Nitrogen: Purity ≥ 99.999%;

[0043] Preparation steps

[0044] Add TAPB to an organic solvent and stir with a magnetic stirrer until completely dissolved to obtain an organic phase solution.

[0045] Add DHBD and acetic acid to deionized water and stir until completely dissolved to obtain an aqueous solution.

[0046] Pour the aqueous solution into the bottom of the sealed container, and slowly pour the organic solution along the bottle wall onto the aqueous solution to avoid mixing the two phases. Seal the container to ensure there is no gas leakage.

[0047] Place the sealed glass bottle in a constant temperature incubator, set the temperature to 55℃, and allow the reaction to proceed for 38 hours. After the reaction is complete, open the container and remove the formed COF membrane.

[0048] Place the COF membrane in a centrifuge tube, add deionized water, and centrifuge at 5000 rpm for 5 minutes. Discard the supernatant. Repeat this step 3 times. Then wash twice with an organic solvent to remove residual impurities. Place the washed COF membrane in a vacuum drying oven and dry at 60°C for 12 hours to completely remove the solvent.

[0049] The dried COF membrane was placed in a heating furnace and protected with nitrogen gas (flow rate: 50 mL / min). It was heated to 135 °C at a rate of 5 °C / min and held at that temperature for 45 minutes. After naturally cooling to room temperature, the COF membrane was removed.

[0050] Preparation Example 2

[0051] 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.

[0052] Preparation Example 3

[0053] 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.

[0054] Preparation Example 4

[0055] 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).

[0056] Preparation Example 5

[0057] 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).

[0058] Preparation Example 6

[0059] 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 furnace treatment.

[0060] Preparation Example 7

[0061] A method for preparing a water-blocking composite material:

[0062] Raw material preparation

[0063] Ethylene-propylene polymer: An ethylene-propylene polymer with an ethylene content of 45% (mass fraction) and a weight-average molecular weight (Mw) between 150,000 and 250,000 is selected.

[0064] Ethylene-vinyl alcohol copolymer: Select ethylene-vinyl alcohol copolymers with an ethylene content of 30% (mass fraction) and a degree of alcoholysis between 95% and 99%.

[0065] Homopolymer polypropylene: Homopolymer polypropylene with isotacticity greater than 90% is used, and its melt flow rate (MFR) is in the range of 5-10 g / 10 min (230℃, 2.16 kg).

[0066] Preparation of inner membrane

[0067] Ethylene-propylene polymer granules were added to a Banbury mixer, and the temperature was set at 170℃, the speed at 50 rpm, and the mixing time at 10 min. During the mixing process, antioxidant 1010 was added at a rate of 0.2% of the polymer mass. The mixed material was then extruded through a single-screw extruder with a screw diameter of 40 mm and a length-to-diameter ratio (L / D) of 25. The extrusion temperature was set at 180℃, and the extrusion pressure was 12 MPa. A T-die was used to extrude the material into sheets, resulting in an inner layer film with a thickness of 0.2-0.3 mm.

[0068] Preparation of the middle layer membrane

[0069] Ethylene-vinyl alcohol copolymer granules were dried in a vacuum oven at 80°C for 4 hours until their moisture content was below 0.5% (mass fraction). The dried ethylene-vinyl alcohol copolymer granules were then fed into a twin-screw extruder, with the extruder temperature set to 190°C and the screw speed at 60 rpm. The extruded material was blow-molded into a film through a blow molding die at a blow-up ratio of 2 and a traction speed of 4 m / min, resulting in a middle layer film with a thickness of 0.1-0.15 mm.

[0070] Preparation of outer membrane

[0071] Melt extrusion

[0072] Homopolymer polypropylene granules were added to a single-screw extruder, with the extruder temperature controlled at 210℃ and the screw speed at 40 rpm. The molten homopolymer polypropylene was extruded into a film using a coat hanger die, with the die temperature at 220℃ and the extrusion pressure at 18 MPa, resulting in an outer film with a thickness of 0.2-0.3 mm.

[0073] Membrane composite process

[0074] The inner, middle, and outer membranes are laminated using a dry laminator. A two-component polyurethane adhesive is used during the lamination process, with a main component to curing agent mass ratio of 12:1. The adhesive is evenly coated onto the membrane surface at a coating amount of 3 g / m². 2 The composite pressure was 0.5 MPa, the composite temperature was 60℃, and the curing time was 24 hours to obtain the water-blocking composite material.

[0075] A composite water-blocking packaging bag is prepared by cutting and heat-sealing the water-blocking composite material, with one side of the inner film located inside the water-blocking packaging bag.

[0076] Preparation Example 8

[0077] A method for preparing a water-blocking composite material: The method differs from Preparation Example 7 in that ethylene-vinyl alcohol copolymer particles are dried in a vacuum oven at 80°C for 4 hours to reduce their moisture content to below 0.5% (mass fraction). The dried ethylene-vinyl alcohol copolymer particles are added to a twin-screw extruder, along with 8% (by mass) of nano-montmorillonite from the ethylene-vinyl alcohol copolymer. The mixture is heated to melt the copolymer particles and stirred until homogeneous. The extruder temperature is set to 190°C, and the screw speed is 60 rpm. The extruded material is blow-molded into a film using a blow molding die, with a blow-up ratio of 2 and a traction speed of 4 m / min, resulting in a middle layer film with a thickness of 0.1-0.15 mm.

[0078] Preparation Example 9

[0079] A method for preparing a water-blocking composite material: the difference from preparation example 8 is that 5% nano-montmorillonite is incorporated into the ethylene-vinyl alcohol copolymer film.

[0080] Preparation Example 10

[0081] A method for preparing a water-blocking composite material: the difference from preparation example 8 is that 10% nano-montmorillonite is incorporated into the ethylene-vinyl alcohol copolymer film.

[0082] Example

[0083] Example 1

[0084] A method for preparing compound sodium acetate fructose injection:

[0085] Raw material preparation

[0086] Water for injection: Prepared in advance and ensured that its quality meets the standards for water for injection.

[0087] Accurately weigh 0.15g of sodium chloride, 0.062g of potassium chloride, 0.055g of magnesium chloride, 0.14g of potassium dihydrogen phosphate, 0.325g of sodium acetate, 5g of fructose, and 0.25g of citric acid, all of which are of analytical grade.

[0088] Solution preparation

[0089] Add 60g of water for injection into a clean mixing container that has undergone rigorous cleaning and disinfection, and turn on the cooling device to lower the water temperature to 45℃.

[0090] Turn on the stirrer and set the stirring frequency to 30 Hz. While stirring, slowly add sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, and sodium acetate to the mixing container in sequence. After all additions are complete, continue stirring at the same frequency for 20 minutes to ensure the salts are evenly dispersed in the solution. Next, add fructose to the solution and stir at 30 Hz for 20 minutes, again until the fructose is completely dissolved, resulting in a preliminary mixed solution.

[0091] Take an appropriate amount of water for injection, slowly add citric acid to it while stirring manually to ensure it is fully dissolved, and prepare a 50% citric acid solution (w / w).

[0092] Add the prepared citric acid solution to the main solution mixing container and adjust the pH of the solution to 4.8. During the pH adjustment process, continue stirring and monitor the pH change in real time. After ensuring that the pH value is stable within the target range, continue stirring for 20 minutes to ensure that the solution is fully mixed.

[0093] Add water for injection to the mixing container until the total mass of the solution reaches 100g. Stir at a stirring frequency of 30Hz for 20 minutes to ensure that the solution is uniform and consistent, thus obtaining the final mixed solution.

[0094] The mixed solution was first passed through a filter material with a pore size of 0.45 μm, and then through two filter materials with a pore size of 0.22 μm. The filter materials were 20-inch polyethersulfone filter cartridges.

[0095] Filling and sterilization

[0096] The filling operation was performed using five-layer co-extruded infusion bags. The filtered solution was conveyed into the infusion bags through filling pipes, and the filled infusion bags were placed in an autoclave for moist heat sterilization at 121°C for 8 minutes. The sterilized mixed solution was then packaged in composite water-resistant packaging bags. The water-resistant composite material was prepared in Preparation Example 7, ultimately yielding the finished compound sodium acetate fructose injection solution.

[0097] Example 2

[0098] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that 0.02922g of sodium chloride, 0.01044g of potassium chloride, 0.01017g of magnesium chloride, 0.02722g of potassium dihydrogen phosphate, 0.05443g of sodium acetate, 1g of fructose, and 0.01g of citric acid are accurately weighed, all of which are of analytical grade.

[0099] Example 3

[0100] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that 0.29224g of sodium chloride, 0.10440g of potassium chloride, 0.10168g of magnesium chloride, 0.27220g of potassium dihydrogen phosphate, 0.54432g of sodium acetate, 10g of fructose, and 1.0g of citric acid are accurately weighed, all of which are of analytical grade.

[0101] Example 4

[0102] 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 4.0.

[0103] Example 5

[0104] 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 5.5.

[0105] Examples 6-10

[0106] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the filter material is a covalent organic framework membrane, which is prepared sequentially by Examples 1, 2, 3, 4, and 5.

[0107] Examples 11-13

[0108] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the water-blocking composite material is prepared sequentially from Preparation Examples 8, 9, and 10.

[0109] Example 14

[0110] 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.

[0111] Example 15

[0112] 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.

[0113] Example 16

[0114] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the mixture is first passed through a filter material with a pore size of 0.45 μm, and then through a filter material with a pore size of 0.22 μm.

[0115] Comparative Example

[0116] Comparative Example 1

[0117] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the pH of the solution is adjusted to 6.

[0118] Comparative Example 2

[0119] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that the pH of the solution is adjusted to 7.

[0120] Comparative Example 3

[0121] A method for preparing a compound sodium acetate fructose injection: The difference from Example 1 is that citric acid is directly added to the mixed solution, without preparing a 50% (w / w) citric acid solution.

[0122] Comparative Example 4

[0123] A method for preparing a compound sodium acetate fructose injection: The difference from Example 6 is that the filter material is a covalent organic framework membrane, which was prepared by Example 6.

[0124] Comparative Example 5

[0125] A method for preparing compound sodium acetate fructose injection: The difference from Example 1 is that a medical PVC packaging bag is used instead of a composite water-resistant packaging bag.

[0126] Performance testing

[0127] Detection methods

[0128] Take the compound sodium acetate fructose injection solutions prepared in the examples / comparative examples, observe the product properties, and then test the osmotic pressure, fructose content, and 5-MHF content. After the tests are completed, store them in a dark environment at room temperature (25°C) and humidity (45%), and repeat the above tests at 1, 3, and 6 months.

[0129] Forty patients with type 1 diabetes were enrolled in a clinical trial. Patients were randomly assigned to either group A or group B. Group A received 1000 ml of compound sodium acetate fructose injection (prepared in Example 1) daily for 12 weeks; group B received 1000 ml of normal saline daily for 12 weeks. Fasting blood glucose and insulin levels were measured one day before treatment began and one day after treatment ended, both at 2 hours postprandial.

[0130] Table 1 Results of the first test

[0131]

[0132]

[0133] Table 2. Test results after 1 month of storage.

[0134] Appearance Osmotic pressure Sugar content / % 5-HMF / % Example 1 Colorless, clear liquid 453.1 103.9 0.0068 Example 2 Colorless, clear liquid 452.8 104.2 0.0068 Example 3 Colorless, clear liquid 453.4 104.7 0.0063 Example 4 Colorless, clear liquid 453.4 103.2 0.0058 Example 5 Colorless, clear liquid 453.4 103.1 0.0070 Example 6 Colorless, clear liquid 453.4 106.4 0.0034 Example 7 Colorless, clear liquid 453.2 106.0 0.0037 Example 8 Colorless, clear liquid 453.1 105.8 0.0039 Example 9 Colorless, clear liquid 453.2 105.9 0.0038 Example 10 Colorless, clear liquid 453.0 105.7 0.0041 Example 11 Colorless, clear liquid 452.2 102.4 0.0043 Example 12 Colorless, clear liquid 451.6 105.2 0.0038 Example 13 Colorless, clear liquid 454.0 104.9 0.0045 Example 14 Colorless, clear liquid 453.8 103.5 0.0066 Example 15 Colorless, clear liquid 452.6 102.8 0.0072 Example 16 Colorless, clear liquid 454.6 106.2 0.0057 Comparative Example 1 Colorless, clear liquid 463.7 105.7 0.0097 Comparative Example 2 Colorless, clear liquid 463.8 107.8 0.0077 Comparative Example 3 Colorless, clear liquid 462.2 108.9 0.0106 Comparative Example 4 Colorless, clear liquid 463.2 104.7 0.0098 Comparative Example 5 Colorless, clear liquid 463.0 105.0 0.0082

[0135] Table 3. Test results after 3 months of storage.

[0136]

[0137]

[0138] Table 4. Test results stored for 6 months

[0139]

[0140]

[0141] Table 5 Clinical trial results

[0142]

[0143] Combining Examples 1, 4, and 5 with Comparative Examples 1-2 and Table 1-4, it can be seen that the initial pH values ​​of the injection solutions in Examples 1, 4, and 5 were 4.8, 4.0, and 5.5, respectively. During storage, Comparative Examples 1-2 turned slightly yellow after 6 months, indicating that excessively high pH values ​​may cause color changes in the solution. The osmotic pressure of Examples 1, 4, and 5 was relatively stable, with minimal changes during storage; however, the osmotic pressure of Comparative Examples 1-2 increased significantly over time, especially after 6 months of storage, reaching 486.1 for Comparative Example 1 and 486.0 for Comparative Example 2, significantly higher than the Examples, indicating that pH deviations from the suitable range exacerbate osmotic pressure changes. The sugar content of the Examples remained relatively stable, while the sugar content of the Comparative Examples increased significantly during storage, with Comparative Example 1 reaching 126.3% and Comparative Example 2 reaching 127.9% after 6 months of storage. The 5-HMF levels in the examples increased relatively slowly during storage, while the levels in the comparative examples increased significantly faster. For instance, the 5-HMF level in Comparative Example 1 reached 0.0320 after 6 months of storage, and in Comparative Example 2 it reached 0.0283. This indicates that pH value has a significant impact on the stability of the compound sodium acetate fructose injection solution; excessively high pH values ​​accelerate the formation of 5-HMF.

[0144] Combining Example 1 and Comparative Example 3 with Tables 1-4, it can be seen that in Example 1, citric acid was added after being prepared as a 50% (w / w) solution, while in Comparative Example 3, citric acid was added directly to the mixed solution. Example 1 remained a colorless and clear liquid throughout, while Comparative Example 3 turned slightly yellow after 6 months of storage, indicating that adding citric acid directly without preparing a solution may affect solution stability. The osmotic pressure of Comparative Example 3 increased more significantly during storage than that of Example 1, reaching 484.2 after 6 months, higher than 456.5 in Example 1, indicating that this operation may have altered the osmotic pressure. The sugar content of Comparative Example 3 increased significantly during storage, reaching 129.0 after 6 months, higher than 107.0 in 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. This indicates 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.

[0145] Combining Example 6 and Comparative Example 4 with Tables 1-4, it can be seen that Example 6 was a colorless and clear liquid at all time points, while Comparative Example 4 turned slightly yellow after 6 months of storage, indicating that different covalent organic framework membrane preparation processes affect the appearance of the injection solution. The osmotic pressure of Example 6 was relatively stable, while that of Comparative Example 4 increased significantly during storage, reaching 485.8 after 6 months, higher than Example 6's 455.4, indicating that different preparation processes may lead to different effects of covalent organic framework membranes on osmotic pressure. The sugar content of Example 6 changed relatively smoothly and was higher than that of Comparative Example 4 at all time points. The sugar content of Comparative Example 4 was 122.7 after 6 months of storage, lower than Example 6's 109.4, indicating that covalent organic framework membranes prepared using different processes have different effects on sugar content stability. The amount of 5-HMF in Example 6 increased slowly during storage, while that in Comparative Example 4 increased more 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 solution.

[0146] Combining Example 1 and Comparative Example 5 with Tables 1-4, it can be seen that Example 1 used a composite water-resistant packaging bag, while Comparative Example 5 used a medical PVC packaging bag. Example 1 remained a colorless and clear liquid throughout, while Comparative Example 5 turned slightly yellow after 6 months of storage, indicating that the packaging material affects the appearance of the injection solution. The osmotic pressure of Comparative Example 5 increased more significantly during storage than that of Example 1, reaching 485.2 after 6 months, higher than 456.5 in Example 1, suggesting that the composite water-resistant packaging bag may be more advantageous in maintaining stable osmotic pressure. The sugar content of Comparative Example 5 increased more rapidly during storage, reaching 124.6 after 6 months, higher than 107.0 in Example 1, indicating that the composite water-resistant packaging bag better maintains the stability of sugar content. The 5-HMF content of Comparative Example 5 increased significantly, reaching 0.0295 after 6 months of storage, higher than 0.0106 in Example 1, showing that the composite water-resistant packaging bag is superior to the medical PVC packaging bag in inhibiting 5-HMF formation, which is more beneficial for improving the stability of the injection solution.

[0147] As can be seen from Examples 1-3 and Tables 1-4, within the component range of this application, the appearance of the prepared product remains consistently stable. It maintains its colorless and clear liquid state during storage. Regarding pH, it initially remains stable within a suitable range with minimal fluctuations during storage, maintaining a relatively stable chemical environment and reducing potential chemical reactions caused by pH fluctuations, thus ensuring the stability and efficacy of the active pharmaceutical ingredient. Stable osmotic pressure changes help the injection solution match the osmotic pressure of the human cellular environment, ensuring normal drug absorption and efficacy, while avoiding cell damage or poor drug absorption caused by abnormal osmotic pressure.

[0148] Combining Examples 1 and 6-10 with Tables 1-4, it can be seen that Examples 1 and 6-10 maintained a colorless and clear liquid at all time points, indicating that the covalent organic framework membranes prepared by different processes can meet the appearance requirements as filter materials. The osmotic pressure of Examples 6-10 showed a similar trend to Example 1 during storage, but with slight differences in value, indicating that different covalent organic framework membrane preparation processes have some influence on osmotic pressure, but the overall trend is relatively stable. The sugar content of Examples 6-10 showed a similar trend to Example 1 during storage, but the sugar content of Examples 6-9 was slightly higher than that of Example 1 at most time points, while Example 10 showed relatively larger fluctuations, indicating that different covalent organic framework membrane preparation processes have different degrees of influence on sugar content. The 5-HMF content of Examples 6-10 increased at a lower rate than that of Example 1 during storage, especially the 5-HMF content of Example 10, which was relatively low at all time points, indicating that using covalent organic framework membranes as filter materials may help reduce the generation of 5-HMF and improve the stability of the injection solution, and that the effects of different processes vary.

[0149] As can be seen from Examples 1 and 11-13, and Tables 1-4, after nano-montmorillonite is incorporated into the ethylene-vinyl alcohol copolymer membrane, these nanoscale sheets form an intricate barrier structure within the copolymer membrane. When water vapor molecules attempt to permeate the membrane, they must bypass these stacked montmorillonite sheets, significantly increasing the path length for water vapor diffusion. This effectively hinders water vapor penetration, enabling the injection solution to maintain long-term stability.

[0150] As can be seen from Examples 1 and 14-16 and Tables 1-4, passing the mixture through a filter material with a pore size of 0.45 μm first can intercept and remove undissolved drug particles and impurities, thus avoiding affecting the clarity and stability of the injection and causing adverse reactions. Then, passing it through two filters with a pore size of 0.22 μm can further filter smaller impurities and capture tiny particles. This graded fine filtration can improve the purity and stability of the injection, ensuring the safety and effectiveness of medication for patients.

[0151] As can be seen from Example 1, the clinical trial of patients with type 1 diabetes, and Table 5, the product prepared by the method of compound sodium acetate fructose injection in Example 1, as shown in the clinical trial, has better technical effects in lowering blood glucose and regulating insulin levels compared with normal saline when treating patients with type 1 diabetes, and may provide a more favorable option for the treatment of patients with type 1 diabetes.

[0152] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A compound sodium acetate fructose injection solution, characterized in that, The components, by mass percentage, include fructose 1-10%, sodium chloride 0.02922-0.29224%, potassium chloride 0.01044-0.10440%, magnesium chloride 0.01017-0.10168%, potassium dihydrogen phosphate 0.02722-0.27220%, sodium acetate 0.05443-0.54432%, citric acid 0.01-1.0%, and the remainder is water; The compound sodium acetate fructose injection solution is prepared by the following method: Prepare 50%-90% water, cool to 30-60℃, start stirring, add sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, and sodium acetate, continue stirring for 5-30 minutes, then add fructose, stir for 5-30 minutes to obtain a preparative solution; add citric acid to the remaining water and stir to prepare a 50% w / w citric acid solution; Add the citric acid solution to the prepared solution and adjust the pH of the solution to 4.0-5.5, stir for 5-30 minutes to obtain a mixture; pass the mixture through a filter material and fill it into a container, sterilize it at 121°C for 8 minutes, and then package it after sterilization. The mixture is filtered using filter materials with pore sizes of 0.45 μm and 0.22 μm; the filter material includes either polyethersulfone or a covalent organic framework membrane; the covalent organic framework membrane is prepared by the following method: 1,3,5-tris(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-tris(4-aminophenyl)benzene is dissolved in an organic solvent to obtain an organic phase solution; 2,5-dihydroxyterephthalic acid is dissolved in... An aqueous phase solution is obtained by reacting acetic acid in an aqueous solution, with the mass of acetic acid being 4-8% of the total mass of the reactants. In a reaction vessel, the aqueous phase solution is first poured to the bottom of the vessel, and then the organic phase solution is spread on top of the aqueous phase solution. The reaction vessel is sealed and placed in a constant temperature environment of 50-60℃ for static reaction for 35-40 hours to obtain a covalent organic framework membrane. After the reaction is completed, the covalent organic framework membrane is washed and dried. The dried covalent organic framework membrane is then heated to 130-140℃ under nitrogen protection and held at that temperature for 30-60 minutes.

2. A method for preparing the compound sodium acetate fructose injection according to claim 1, characterized in that: Includes the following steps: Prepare 50%-90% water, cool to 30-60℃, start stirring, add sodium chloride, potassium chloride, magnesium chloride, potassium dihydrogen phosphate, and sodium acetate, continue stirring for 5-30 minutes, then add fructose and stir for 5-30 minutes to obtain the prepared solution. Add citric acid to the remaining water and stir to prepare a 50% w / w citric acid solution; Add citric acid solution to the prepared solution and adjust the pH of the solution to 4.0-5.

5. Stir for 5-30 minutes to obtain a mixed solution. The mixture is passed through a filter material and then filled into containers. It is then sterilized at 121°C for 8 minutes and packaged after sterilization.

3. The preparation method of 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 preparation method of compound sodium acetate fructose injection according to claim 3, characterized in that: The preparation method of the covalent organic framework membrane: 1,3,5-Tris(4-aminophenyl)benzene and 2,5-dihydroxyterephthalic acid were used as reactants in a molar ratio of 1:(1.25-1.35). 1,3,5-Tris(4-aminophenyl)benzene was dissolved in an organic solvent to obtain an organic phase solution, and 2,5-dihydroxyterephthalic acid was dissolved in an aqueous solution containing acetic acid to obtain an aqueous phase solution. The mass of acetic acid was 4-8% of the total mass of the reactants. In the reaction vessel, the aqueous phase solution is first poured into the bottom of the vessel, and then the organic phase solution is spread on top of the aqueous phase solution. The reaction vessel is sealed and placed in a constant temperature environment of 50-60℃ for static reaction. The reaction time is 35-40h to obtain a covalent organic framework membrane. After the reaction was completed, the covalent organic framework membrane was washed and dried. The dried covalent organic framework membrane was then heated to 130-140℃ under nitrogen protection and held for 30-60 minutes.

5. The preparation method of 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 preparation method of compound sodium acetate fructose injection according to claim 5, characterized in that: The ethylene-vinyl alcohol copolymer film contains 5-10% nano-montmorillonite.

7. The preparation method of compound sodium acetate fructose injection according to claim 2, characterized in that: The filter material used for filtering the mixture has a pore size of 0.45 μm and 0.22 μm.

8. The preparation method of compound sodium acetate fructose injection according to claim 7, characterized in that: The specific method for filtering the mixture is as follows: the mixture 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 twice.

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