Mannitol injection and production method thereof

Abstract

The invention provides a mannitol injection and a production method thereof, which are characterized in that the dissolution and stability treatment of mannitol is improved, and the safety and effectiveness of a final product are enhanced. The preparation method comprises the following specific steps: firstly, mixing and dissolving mannitol and cyclodextrin according to a certain proportion, and forming a compound through a freeze-drying technology so as to improve the stability of a solution; then, adding a proper amount of electrolyte and an acid-base regulator to adjust the pH value so as to optimize physiological compatibility and reduce local stimulation; then, the purity and sterility of the solution are ensured through a double filtration system; and finally, high-temperature sterilization is adopted to ensure the sterility of the product. The series of processes not only improve the bioavailability of the mannitol injection, but also significantly reduce the complexity and risk caused by crystal precipitation, so that the product is more suitable for wide application in the medical field, such as treatment of encephaledema or reduction of intracranial pressure.

Description

Technical Field

[0001] The invention relates to the technical field of injections, in particular to a mannitol injection and a production method thereof. Background Art

[0002] As an effective osmotic diuretic, mannitol is widely used in medical fields such as the treatment of cerebral edema, reduction of intracranial pressure and intraocular pressure. Since the first use of mannitol injection in the mid-20th century, its production process and formulation have undergone many innovations. Early preparation methods mainly relied on simple solution preparation and heat sterilization technology. Although these methods can ensure basic efficacy, there is a large room for improvement in purity and stability. With the development of pharmaceutical preparation technology, especially the application of analytical techniques such as high performance liquid chromatography (HPLC), the purity detection and quality control level of mannitol injection have been significantly improved. At the same time, the introduction of microfiltration and ultrafiltration technology has greatly reduced the particles and impurities in the injection, and improved the purity and safety of the drug.

[0003] Although the prior art has made many advances in the preparation process of mannitol injection, there are still some significant technical problems to be solved. First, mannitol has the characteristics of high solubility, which causes it to easily precipitate crystals under high concentration conditions, thereby affecting the uniformity and efficacy of the drug. Although the existing filtration and purification technology can remove some impurities and particles, it is impossible to completely avoid the crystallization phenomenon caused by particles as crystal nuclei. Summary of the invention

[0004] Although the prior art has made many advances in the preparation process of mannitol injection, there are still some significant technical problems to be solved. First, mannitol has the characteristics of high solubility, which causes it to easily precipitate crystals under high concentration conditions, thereby affecting the uniformity and efficacy of the drug. Although the existing filtration and purification technology can remove some impurities and particles, it is impossible to completely avoid the crystallization phenomenon caused by particles as crystal nuclei.

[0005] The present application provides a method for producing mannitol injection, which adopts the following technical scheme:

[0006] S1. Add the pretreated mannitol to an appropriate amount of water for injection, heat it at a controlled temperature, and stir it until it is completely dissolved; S2. Add electrolytes to the solution completely dissolved in step S1, and then add an acid-base regulator to adjust the pH of the solution to 5.5 to 6.5; S3. Filter the pH-adjusted solution in step S2 through a filter of appropriate pore size to remove possible particulate impurities, and then sterilize the solution.

[0007] By adopting the above technical scheme, the mannitol after pretreatment improves the stability and bioavailability of the drug. The addition of electrolytes helps to adjust the osmotic pressure of the solution to make it closer to the osmotic pressure of the fluid in the human body, because if the osmotic pressure of the injection solution is too high or too low, it may cause cell damage or rupture, leading to pain or other complications. At the same time, proper electrolyte balance can promote cell absorption of drug components. Electrolytes such as sodium and potassium play a key role in cell function. Their proper concentration helps maintain the potential and permeability of the cell membrane, thereby affecting the transport and absorption of drugs. The purpose of adjusting the pH value to 5.5 to 6.5 by acid-base regulators is to create an environment that is relatively mild to human tissues. This pH range is usually consistent with the physiological pH value of the human body. Similar to the above, it can reduce local irritation during injection and relieve pain; filtering with a filter of appropriate pore size can remove particulate impurities in the solution, including incompletely dissolved solid particles, possible dust or impurities generated during the preparation process. If these particles are not removed, they may cause blood vessel blockage or local reactions during injection, increasing the risk of inflammation or infection. Sterilization is the process of removing or killing all microorganisms, including bacteria, viruses, fungi and spores. Sterilization of injection solutions is crucial because it ensures the sterility of the product when it is used by patients and prevents infection during use. Filtration and sterilization work together to ensure the safety and effectiveness of drugs, protect patients from unnecessary health risks, and maintain the quality and stability of drugs. These steps are a reflection of the extremely high requirements for drug safety in the pharmaceutical process, especially for injectable drugs, where sterility and purity are the most basic requirements.

[0008] As a preferred technical solution for the production method of mannitol injection, in step S1, the pretreatment comprises the following steps:

[0009] Cyclodextrin and mannitol are added to water for injection in a mass ratio of (1 to 9):1 and stirred until completely dissolved. The completely dissolved solution is pre-cooled and placed in a freeze dryer for freeze drying to obtain a mannitol-cyclodextrin complex powder.

[0010] By adopting the above technical solution, cyclodextrin and mannitol are mixed in a mass ratio of (4 to 10): 1. This ratio range allows cyclodextrin to effectively encapsulate mannitol molecules to form inclusion complexes. Cyclodextrins are cyclic macromolecules composed of multiple glucose units connected by α-1,4-glycosidic bonds. Their molecular structure presents a hollow cylindrical shape, which is hydrophilic on the outside and hydrophobic on the inside. This unique structure enables cyclodextrin to act as a "host" molecule and form stable inclusion complexes with other "guest" molecules through non-covalent interactions; mannitol molecules contain multiple hydroxyl groups (-OH). Although these hydroxyl groups are polar in themselves, the mannitol molecule as a whole can show a certain hydrophobicity, especially in its larger molecular structure. When mannitol approaches the internal cavity of cyclodextrin, the hydrophobic environment inside the cyclodextrin can interact with the hydrophobic part of the mannitol molecule. The hydrophobic effect helps to partially or completely insert mannitol into the cavity of cyclodextrin to form a stable inclusion complex. In addition to the hydrophobic effect, the interaction between mannitol and cyclodextrin also involves van der Waals force, which is a weak interaction between molecules, mainly involving dipole interactions and transient dipole interactions that exist even in non-polar molecules. In the process of mannitol and cyclodextrin forming inclusion complexes, these weak forces help to increase the attraction between molecules, thereby further stabilizing the structure of the complex. In summary, the combination of the internal cavity of cyclodextrin and mannitol molecules not only enhances the overall stability of the complex through physical embedding, but also through chemical hydrophobic effects and van der Waals forces. This stability helps to maintain the position of mannitol in the inclusion complex, thereby improving its release characteristics, solubility and stability in pharmaceutical applications. At the same time, the formation of this complex helps to physically isolate mannitol molecules, preventing them from moving freely and rearranging into a crystal structure, thereby effectively preventing the crystallization of mannitol.

[0011] As a preferred technical solution for the production method of mannitol injection, the precooling condition is 4° C. and the refrigeration time is 2-4 hours.

[0012] By adopting the above technical scheme, the pre-cooling treatment helps to evenly reduce the temperature of the solution to close to its freezing point. Such uniform cooling is necessary because it can make the subsequent freezing process more uniform and effective, avoid the formation of large ice crystals in the solution, and thus improve the quality of the final freeze-dried product; in freeze-drying, the formation of large ice crystals will lead to a decline in product quality, especially for biologically active substances (such as proteins, cells, etc.), large ice crystals may destroy their structure, pre-cooling makes the ice crystals in the solution form more slowly and evenly, thereby forming smaller ice crystals, which is beneficial to maintaining the integrity and stability of the mannitol-cyclodextrin complex; pre-cooling can make the temperature of the entire solution closer to the target freezing temperature, so that in the actual freezing step, the required temperature drop is smaller, and the ideal freezing state can be reached more quickly. This rapid freezing helps to reduce adverse chemical or physical changes that may occur during the freezing process.

[0013] As a preferred technical solution for the production method of mannitol injection, the specific process steps of freeze drying are as follows: quickly transfer the pre-cooled solution to the tray of the freeze dryer and quickly freeze it to -40°C to -80°C to form ice crystals; turn on the vacuum pump to reduce the pressure in the freeze dryer to 4 to 8 microtorr to promote the direct sublimation of ice crystals; slowly heat up to 25°C to convert solid water directly into gas; in order to remove residual bound water, additional drying is required at a temperature between 25°C and 40°C.

[0014] By adopting the above technical solution, the pre-cooled solution is quickly transferred to the tray of the freeze dryer and quickly frozen to -40℃ to -80℃. The purpose of this step is to quickly form ice crystals, thereby minimizing the migration of dissolved substances in the solution and the formation of large ice crystals; turn on the vacuum pump to reduce the pressure in the freeze dryer to 4 to 8 microtorr. The extremely low pressure environment helps the ice crystals to sublime directly. In this low-pressure environment, water ice can directly change from solid to gas without going through the liquid stage. Direct sublimation avoids the potential damage of liquid water to the structure of biological materials or compounds; gradually warming up from extremely low temperature to 25℃ is to control the sublimation rate of solid water and ensure that most of the water can be effectively removed. Slow heating can avoid physical stress caused by temperature changes and protect the structure of the material from being destroyed; the purpose of additional drying between 25℃ and 40℃ is to remove water in the material that is difficult to remove due to structural constraints.

[0015] As a preferred technical solution for the production of mannitol injection, the electrolyte includes one or more of calcium salt, sodium salt and magnesium salt, and the acid-base regulator is hydrochloric acid.

[0016] By adopting the above technical scheme, the coordinated use of hydrochloric acid and electrolytes plays a vital role in the cyclodextrin and mannitol inclusion compound injection. They not only play their own roles, but also enhance each other's effects and promote the drug together. Cyclodextrin, as a cyclic macromolecule, has an internal hydrophobic cavity that can encapsulate mannitol molecules. Hydrochloric acid enhances the molecular stability and solubility of cyclodextrin by adjusting the pH, so that cyclodextrin can more effectively encapsulate mannitol, thereby reducing the number of free mannitol molecules and reducing the risk of crystallization. In addition, hydrochloric acid changes the dissolution equilibrium of mannitol by lowering the pH value. Under acidic conditions, the solubility of mannitol may decrease, but due to the simultaneous presence of cyclodextrin encapsulation, excessive deposition and crystallization of mannitol can be prevented. Sodium salt, calcium salt and The addition of magnesium salts regulates the osmotic pressure of the solution, which is essential for maintaining the physiological compatibility of the injection solution. It also affects the dissolution and precipitation behavior of solutes (such as mannitol). The increased ionic strength can change the solubility of mannitol through the "salt effect". Usually, the addition of salts will reduce the solubility. In the presence of cyclodextrin, this effect helps to stabilize the complex of cyclodextrin and mannitol, reducing the possibility of free existence of mannitol molecules, thereby reducing crystallization; the non-covalent inclusion complex formed by cyclodextrin and mannitol shows higher stability in an acidic environment and under appropriate ionic strength conditions. The combined action of electrolytes and hydrochloric acid not only changes the chemical environment of mannitol, but also optimizes the structural performance of cyclodextrin, making the inclusion complex more stable.

[0017] As a preferred technical solution for the production method of mannitol injection, the specific steps of step S3 are: filtering the solution after adjusting the pH through two filters connected in series, the pore size of the front filter is larger than the pore size of the rear filter; adopting a high-temperature sterilization method: placing the filtered solution into a high-pressure sterilization pot, setting the temperature to generally 121° C., the pressure to approximately 15 pounds per square inch, and continuing for 15-20 minutes.

[0018] By adopting the above technical solution, the main purpose of using two filters with different pore sizes installed in series is to improve the filtration efficiency and ensure that a wider range of particles can be removed. The larger pore size filter will capture large particles and impurities, which helps prevent the smaller pore size filter from clogging prematurely. The smaller pore size filter can remove finer particles and provide a higher level of cleaning and purification. The filtered solution is sterilized by high pressure to completely eliminate microorganisms that may be present in the solution and ensure the sterility of the product. The combination of these two methods can maximize the safety and stability of the injection. Filtration provides physical purification to remove visible and microscopic impurities, while high temperature sterilization provides biological safety protection to ensure that the product is completely sterile.

[0019] The mannitol injection prepared by the production method of the present invention ensures extremely high purity and stability through fine double-stage filtration and high-pressure steam sterilization steps. The filtration process effectively removes suspended particles and microbial contaminants, while the high-pressure steam sterilization completely kills all possible microorganisms, including bacteria, viruses and spores with strong heat resistance. Such treatment ensures that mannitol injection remains stable during long-term storage and transportation, and will not cause a decrease in efficacy or safety problems due to microbial contamination; by precisely controlling the pH value and electrolyte concentration of the solution, the biocompatibility of mannitol injection has been significantly improved. The use of hydrochloric acid as an acid-base regulator helps adjust the pH value to close to the human physiological environment, reducing pain and local irritation during injection. At the same time, the addition of electrolytes helps adjust the osmotic pressure of the solution to avoid cell damage or discomfort caused by excessive or low osmotic pressure; the addition of cyclodextrin not only enhances the stability of mannitol, but also may improve its efficacy. Cyclodextrin can form inclusion complexes, which helps control the release rate of mannitol, allowing it to be more smoothly absorbed and distributed in the body, thereby possibly improving the therapeutic effect and reducing side effects. In addition, cyclodextrin itself has good biocompatibility and low toxicity, further ensuring the safety of the injection. DETAILED DESCRIPTION

[0020] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0021] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0022] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0023] Preparation example of cyclodextrin and mannitol inclusion compound

[0024] Preparation Examples 1 to 5

[0025] The following is an explanation using Preparation Example 1.

[0026] In this preparation example, the cyclodextrin and mannitol inclusion complex is prepared by the following method: cyclodextrin and mannitol are added to water for injection at a mass ratio of 1:1 and stirred until completely dissolved, and the completely dissolved solution is pre-cooled at 4°C for 3 hours, and the pre-cooled solution is quickly transferred to the tray of the freeze dryer and quickly frozen to -40°C to -80°C to form ice crystals; the vacuum pump is turned on to reduce the pressure in the freeze dryer to 6 microtorr to promote the direct sublimation of ice crystals; the temperature is slowly raised to 25°C to convert solid water directly into gas; in order to remove residual bound water, additional drying is required at a temperature between 30°C.

[0027] As shown in Table 1, the difference between Preparation Examples 1-5 is that the mass ratio between cyclodextrin and mannitol is M1:M2.

[0028] sample Preparation Example 1 Preparation Example 2 Preparation Example 3 Preparation Example 4 Preparation Example 5 M1:M2 1:1 3:1 5:1 7:1 9:1

[0029] Example

[0030] In the following examples and comparative examples, when the content of components other than water for injection in the solution changes or new components are added, the weight of the solution is still supplemented to 100% by water for injection.

[0031] Examples 1-5

[0032] The following description is given by taking Example 1 as an example.

[0033] Example 1

[0034] In this embodiment, the production method of mannitol injection comprises the following steps:

[0035] (1) Add 200 g of the pretreated mannitol prepared in Preparation Example 1 to 1000 ml of water for injection, heat at 60° C., and stir until completely dissolved at a stirring speed of 350 rpm / min;

[0036] (2) After the pretreated mannitol is completely dissolved, NaCl needs to be added to adjust the osmotic pressure of the solution, and HCl is used to accurately control the pH value of the solution to adjust the pH value of the solution to 6; wherein the amount of NaCl added accounts for 0.7 wt% of the total mass of the solution;

[0037] (3) Filter the pH-adjusted solution through two filters connected in series, with the pore size of the front filter being larger than that of the rear filter; adopt high-temperature sterilization method: place the filtered solution into a high-pressure sterilizer, set the temperature to usually 121°C, the pressure to about 15 pounds per square inch, and continue for 20 minutes.

[0038] As shown in Table 1, the difference between Examples 1-5 is that the amount of NaCl added to the total mass of the solution (hereinafter referred to as W1) is different.

[0039] Table 1 shows the NaCl addition amount as a percentage of the solution mass

[0040] sample Example 1 Example 2 Example 3 Example 4 Example 5 W1 / wt% 0.7 0.8 0.9 1.0 1.1

[0041] Examples 6-10

[0042] In this embodiment, the production method of mannitol injection comprises the following steps:

[0043] (1) Add 200 g of the pretreated mannitol prepared in Preparation Example 1 to 1000 ml of water for injection, heat at 60° C., and stir until completely dissolved at a stirring speed of 350 rpm / min;

[0044] (2) After the pretreated mannitol is completely dissolved, NaCl needs to be added to adjust the osmotic pressure of the solution, and HCl is used to accurately control the pH value of the solution to adjust the pH value of the solution to 6; wherein the amount of NaCl added accounts for 0.7 wt% of the total mass of the solution;

[0045] (3) Filter the pH-adjusted solution through two filters connected in series, with the pore size of the front filter being larger than that of the rear filter; adopt high-temperature sterilization method: place the filtered solution into a high-pressure sterilizer, set the temperature to usually 121°C, the pressure to about 15 pounds per square inch, and continue for 20 minutes.

[0046] As shown in Table 2, the difference between Examples 6-10 is that different preparation examples are used to prepare the cyclodextrin and mannitol inclusion complex.

[0047] Table 2 shows the preparation of cyclodextrin and mannitol inclusion complexes in different preparation examples

[0048] sample Example 6 Example 7 Example 8 Example 9 Example 10 Preparation Example Preparation Example 1 Preparation Example 2 Preparation Example 3 Preparation Example 4 Preparation Example 5

[0049] Comparative Example

[0050] Comparative Example 1

[0051] This comparative example provides a method for producing mannitol injection, comprising the following steps:

[0052] (1) Add 200 g of mannitol to 1000 ml of water for injection, heat at 60° C., and stir until completely dissolved at a stirring speed of 350 rpm / min;

[0053] (2) After the pretreated mannitol is completely dissolved, NaCl is added to adjust the osmotic pressure of the solution, and HCl is used to accurately control the pH value of the solution to adjust the pH value of the solution to 6; wherein the amount of NaCl added accounts for 0.7 wt% of the mass of the solution;

[0054] (3) Filter the pH-adjusted solution through two filters connected in series, with the pore size of the front filter being larger than that of the rear filter; adopt high-temperature sterilization method: place the filtered solution into a high-pressure sterilizer, set the temperature to usually 121°C, the pressure to about 15 pounds per square inch, and continue for 20 minutes.

[0055] Comparative Example 2

[0056] The difference between this comparative example and Example 1 is that the pretreated mannitol is not precooled.

[0057] Comparative Example 3

[0058] The difference between this comparative example and Example 1 is that after the pretreated mannitol is completely dissolved, HCl is directly added to control the pH value of the solution to 6.

[0059] Comparative Example 4

[0060] After the complete dissolution of the pretreated mannitol was completed, electrolytes were added to the completely dissolved solution, but HCl was not added to control the pH value of the solution.

[0061] Comparative Example 5

[0062] The difference between this comparative example and Example 1 is that step 2 is completely eliminated, electrolytes and acid-base regulators are not added, and step 3 is directly performed.

[0063] Performance Testing

[0064] The mannitol injection obtained in the examples and comparative examples of the present application was placed in a water bath at 25°C, 15°C, 0°C and -5°C for 6 weeks, and the precipitation of crystals was observed. The results are shown in Table 1 below.

[0065] Table 1

[0066]

[0067]

[0068] It can be seen from Examples 1 to 5 and Table 1 that according to the preparation method of the present application, mannitol is first pretreated and dissolved, electrolytes are added to the completely dissolved solution, and then an acid-base regulator is added to adjust the pH of the solution to 5.5 to 6.5. The prepared injection solution does not show crystallization at -10°C to 25°C.

[0069] It can be seen from Examples 6 to 10 and Table 1 that when the concentration of NaCl added to the volume of the solution is low, the prepared injection does not show crystallization at -10°C to 25°C. When the concentration of NaCl reaches 1.0wt%, crystallization occurs in the mannitol injection at -5°C and -10°C. This is mainly because increasing the ionic strength reduces the interaction between solvent molecules and non-electrolytes (such as mannitol) and reduces their solubility, which may cause mannitol to precipitate more easily to form crystals. This effect still exists even in the presence of cyclodextrin inclusion complexes.

[0070] It can be known that mannitol is pre-treated to form the inclusion compound of cyclodextrin and mannitol, and then is prepared into injection, and the injection has better stability than conventional mannitol injection without pretreatment, and crystallization phenomenon does not occur under normal temperature and low temperature conditions. The combination of the internal cavity of cyclodextrin and mannitol molecule is not only embedded by physics, but also strengthens the overall stability of the complex by chemical hydrophobic interaction and van der Waals force. This stability helps to keep the position of mannitol in the inclusion compound, thereby improving its release characteristics, solubility and stability in pharmaceutical applications, and at the same time, the formation of this complex helps to physically isolate the mannitol molecule, prevents it from freely moving and rearranging into a crystalline structure, thereby effectively preventing the crystallization phenomenon of mannitol.

[0071] It can be learned from Example 1, Comparative Example 2 and Table 1 that the injection prepared without pre-cooling treatment does not have crystallization phenomenon at room temperature, but crystallization phenomenon occurs under low temperature conditions. Under low temperature conditions, due to the large ice crystal formation and microparticles caused by the reduced solubility of mannitol, the solution entering the supersaturated state, non-uniform cooling as the influence of nucleus, mannitol is more likely to separate out and form crystals. Therefore, pre-cooling treatment can effectively improve the stability of solution, prevent crystallization phenomenon at low temperatures.

[0072] It can be seen from Example 1, Comparative Examples 3 to 5 and Table 1 that the injection of the cyclodextrin and mannitol inclusion complex prepared by adding electrolytes and adjusting the pH of the solution has high stability. Specifically, the injection does not show crystallization under -5°C and -10°C. The non-covalent inclusion complex formed by cyclodextrin and mannitol shows higher stability under acidic environment and appropriate ionic strength conditions. The combined action of electrolytes and hydrochloric acid not only changes the chemical environment of mannitol, but also optimizes the structural performance of cyclodextrin, making the inclusion complex more stable.

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for producing mannitol injection, characterized in that: The steps include: S1. Add the pretreated mannitol to an appropriate amount of water for injection, heat at a controlled temperature, and stir until completely dissolved; S2. Adding electrolyte to the completely dissolved solution in step S1, and then adding an acid-base regulator to adjust the pH of the solution to 5.5 to 6.5; S3. The pH-adjusted solution in step S2 is filtered through a filter of appropriate pore size to remove possible particulate impurities, and then the solution is sterilized.

2. The method for producing mannitol injection according to claim 1, characterized in that: In step S1, the preprocessing includes the following steps: Cyclodextrin and mannitol are added to water for injection in a mass ratio of (1 to 9):1 and stirred until completely dissolved. The completely dissolved solution is pre-cooled and placed in a freeze dryer for freeze drying to obtain a mannitol-cyclodextrin complex powder.

3. The method for producing mannitol injection according to claim 2, characterized in that: The precooling condition is 4° C. and the refrigeration time is 2-4 hours.

4. The method for producing mannitol injection according to claim 2, characterized in that: The specific process steps of the freeze drying are as follows: The pre-cooled solution was quickly transferred to a freeze dryer tray and rapidly frozen to -40°C to -80°C to form ice crystals; Turn on the vacuum pump to reduce the pressure in the freeze dryer to 4 to 8 microtorr to promote direct sublimation of ice crystals; Slowly raise the temperature to 25°C to convert solid water directly into gas; To remove residual bound water, additional drying at temperatures between 25°C and 40°C is required.

5. The method for producing mannitol injection according to claim 1, characterized in that: The electrolyte includes one or more of calcium salt, sodium salt and magnesium salt, and the acid-base regulator is hydrochloric acid.

6. The method for producing mannitol injection according to claim 1, characterized in that: The specific steps of step S3 are: The pH-adjusted solution is filtered through two filters connected in series, the pore size of the front filter is larger than the pore size of the rear filter; Use high temperature sterilization: Place the filtered solution into an autoclave, set the temperature to usually 121°C and the pressure to about 15 pounds per square inch for 15-20 minutes.

7. Mannitol injection prepared by the production method according to any one of claims 1 to 6.

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