Mannitol injection and production method thereof

Abstract

The present application provides a mannitol injection and its production method, the key lies in improving the solubility and stability of mannitol, and enhancing the safety and effectiveness of the final product. The specific steps include: first, mannitol is mixed with cyclodextrin in a certain proportion to form a complex through freeze-drying technology, thereby improving the stability of the solution; then, adding appropriate amount of electrolyte and acid-base regulator to adjust the pH value, to optimize the physiological compatibility and reduce local irritation; then, through the double filtration system to ensure the purity and sterility of the solution; finally, using high temperature sterilization to ensure the sterility of the product. This series of processes not only improves the bioavailability of mannitol injection, but also significantly reduces the complexity and risk caused by crystal precipitation, making the product more suitable for wide application in the medical field, such as treating cerebral edema or reducing intracranial pressure.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of injection solutions, and in particular to a mannitol injection solution and a production method thereof. BACKGROUND

[0002] Mannitol, as an effective osmotic diuretic, is widely used in medical fields such as treating cerebral edema, reducing intracranial pressure and intraocular pressure. Since the mid-20th century, mannitol injection solution has been first used, and its production process and formula have undergone many innovations. The early preparation method mainly relies on simple solution preparation and heat sterilization technology, although these methods can ensure the basic efficacy, but there is a lot of 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 solution has been significantly improved. At the same time, the introduction of microfiltration and ultrafiltration technology greatly reduces the particles and impurities in the injection solution, improving the purity and safety of the drug.

[0003] Although the existing technology has made many progress in the preparation process of mannitol injection solution, there are still some significant technical problems to be solved. First, mannitol has the characteristics of high solubility, which leads to the precipitation of crystals under high concentration conditions, thereby affecting the uniformity and efficacy of the drug. Although the existing filtration and purification technology can remove part of the impurities and particles, it cannot completely avoid the crystallization phenomenon caused by particles as crystal nuclei. SUMMARY

[0004] Although the existing technology has made many progress in the preparation process of mannitol injection solution, there are still some significant technical problems to be solved. First, mannitol has the characteristics of high solubility, which leads to the precipitation of crystals under high concentration conditions, thereby affecting the uniformity and efficacy of the drug. Although the existing filtration and purification technology can remove part of the impurities and particles, it cannot completely avoid the crystallization phenomenon caused by particles as crystal nuclei.

[0005] The present application provides a production method of mannitol injection solution, which adopts the following technical scheme:

[0006] S1. The pretreated mannitol is added to an appropriate amount of water for injection, heated under controlled temperature, and stirred until completely dissolved; S2. Add electrolyte to the completely dissolved solution in step S1, and then add acid-base adjusting agent to adjust the PH of the solution to 5.5-6.5; S3. The solution after adjusting PH in step S2 is filtered through a filter with a suitable pore size to remove possible particulate impurities, and then the solution is sterilized.

[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, making it closer to the osmotic pressure of the body fluid, because if the osmotic pressure of the injection solution is too high or too low, it may cause damage or rupture of cells, leading to pain or other complications, at the same time, proper electrolyte balance can promote the absorption of drug ingredients by cells, electrolytes such as sodium and potassium play a key role in cell function, and their proper concentration helps to 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 the acid-base regulator is to create a relatively mild environment for human tissues, this pH range is usually close to the physiological pH value of the human body, which can reduce the local irritability during injection and reduce the pain; filtering with a filter with a suitable pore size can remove particulate impurities in the solution, including incompletely dissolved solid particles, possible dust or impurities generated during preparation, if these particles are not removed, they may cause blood vessel blockage or local reaction during injection, increasing the risk of inflammation or infection, sterilization is a process of removing or killing all microorganisms, including bacteria, viruses, fungi and spores, sterilizing the injection solution is essential because it ensures the sterility of the product when used by patients, preventing infection during use, filtering and sterilization process work together to ensure the safety and effectiveness of the drug, protect patients from unnecessary health risks, while maintaining the quality and stability of the drug. These steps are a manifestation of the extremely high requirements for drug safety in the pharmaceutical process, especially for injectable drugs, sterility and purity are the most basic requirements.

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

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

[0010] By adopting the above technical scheme, the cyclodextrin and mannitol are mixed according to the mass ratio (4 to 10):1, and this ratio range allows the cyclodextrin to effectively wrap the mannitol molecules to form inclusion compounds. Cyclodextrin is a cyclic macromolecule formed by connecting multiple glucose units through α-1, 4-glycosidic bonds, and its molecular structure presents a hollow cylindrical shape, which is more hydrophilic on the outside and more hydrophobic on the inside. This unique structure allows cyclodextrin to act as a "host" molecule and form stable inclusion compounds with other "guest" molecules through non-covalent interactions; the mannitol molecule contains multiple hydroxyl groups (-OH), which are polar in themselves, but the mannitol molecule as a whole can exhibit certain hydrophobicity, especially in its larger molecular structure. When mannitol approaches the internal cavity of cyclodextrin, the hydrophobic environment in the interior of cyclodextrin can interact with the hydrophobic part of the mannitol molecule, which helps to insert the mannitol partially or completely into the cavity of cyclodextrin to form a stable inclusion compound. In addition to hydrophobic interaction, the interaction between mannitol and cyclodextrin also involves van der Waals force, which is a weak intermolecular interaction mainly involving dipole interaction and transient dipole interaction that exists even in nonpolar molecules. In the process of forming inclusion compounds between mannitol and cyclodextrin, these weak forces help to increase the attraction between molecules, thereby further stabilizing the complex structure. In summary, the combination of the internal cavity of cyclodextrin and the mannitol molecule not only physically inserts, but also chemically enhances the overall stability of the complex through hydrophobic interaction and van der Waals force. This stability helps to maintain the position of mannitol in the inclusion compound, 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 freely moving and rearranging into a crystalline structure, thereby effectively preventing the crystallization of mannitol.

[0011] As a preferred technical scheme of the production method of the mannitol injection, the pre-cooling 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 uniformly reduce the temperature of the solution to close to its freezing point, and such uniform cooling is necessary because it can make the subsequent freezing process more uniform and effective, avoiding the formation of large ice crystals in the solution, thereby improving the quality of the final freeze-dried product; in freeze-drying, the formation of large ice crystals can lead to a decrease in product quality, especially for biologically active substances (such as proteins, cells, etc.), large ice crystals can destroy their structure, pre-cooling makes the formation of ice crystals in the solution slower and more uniform, 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 faster, and such rapid freezing helps to reduce the adverse chemical or physical changes that may occur during freezing.

[0013] As a preferred technical scheme of the production method of the mannitol injection, the specific process steps of the freeze-drying are as follows: the pre-cooled solution is quickly transferred to the tray of the freeze-dryer, rapidly frozen to -40℃ to -80℃ to form ice crystals; the vacuum pump is started, and the pressure in the freeze-dryer is reduced to 4 to 8 microtorr to promote the direct sublimation of ice crystals; slowly warm up to 25℃ to directly convert solid water into gaseous state; additional drying is required at a temperature of 25℃ to 40℃ to remove residual bound water.

[0014] By adopting the above technical scheme, the pre-cooled solution is quickly transferred to the tray of the freeze-dryer, rapidly 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; the vacuum pump is started, and the pressure in the freeze-dryer is reduced to 4 to 8 microtorr, which helps the ice crystals to directly sublimate in a very low pressure environment. In such a low pressure environment, water ice can directly change from solid state to gaseous state without going through the liquid state, and direct sublimation avoids the potential damage of liquid water to the structure of biological materials or compounds; gradually warming up from the extremely low temperature to 25℃ aims to control the sublimation speed of solid water, ensuring that most of the water can be effectively removed, and slow warming can avoid physical stress caused by temperature changes, protecting the structure of the substance from being damaged; additional drying between 25℃ and 40℃ aims to remove water that is difficult to remove due to structural constraints in the material.

[0015] As a preferred technical scheme of the production method of the 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 synergistic use of hydrochloric acid and electrolytes plays a crucial role in the cyclodextrin and mannitol inclusion complex injection, not only does each play its role, but also enhances the effect of each other, and promotes the drug together; cyclodextrin, as a cyclic macromolecule, has an internal hydrophobic cavity that can encapsulate mannitol molecules, hydrochloric acid adjusts the pH, enhances the molecular stability and solubility of cyclodextrin, and makes cyclodextrin more effectively encapsulate mannitol, thereby reducing the number of free mannitol molecules and reducing the risk of crystallization. In addition, by reducing the pH value, the solubility balance of mannitol is changed, and under acidic conditions, the solubility of mannitol may decrease, but due to the presence of cyclodextrin encapsulation, it can prevent excessive deposition and crystallization of mannitol; the addition of sodium salt, calcium salt and magnesium salt adjusts the osmotic pressure of the solution, which is crucial for maintaining the physiological compatibility of the injection, and also affects the dissolution and precipitation behavior of the solute (such as mannitol), the increased ionic strength can change the solubility of mannitol through the "salt effect", and the addition of salts usually reduces the solubility, in the presence of cyclodextrin, this effect helps to stabilize the complex of cyclodextrin and mannitol, reducing the possibility of free mannitol molecules, thereby reducing crystallization; the non-covalent bond inclusion complex formed by cyclodextrin and mannitol shows higher stability under acidic conditions and appropriate ionic strength, the combined effect 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 scheme of the production method of the 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 that of the rear filter; using high temperature sterilization method: placing the filtered solution into an autoclave, setting the temperature to 121℃, the pressure to about 15 pounds per square inch, and maintaining for 15-20 minutes.

[0018] By adopting the above technical scheme, the main purpose of using two filters with different pore sizes connected in series is to improve the filtering efficiency and ensure that more extensive size particles can be removed, the larger pore size filter can capture large particles and impurities, which helps to prevent the smaller pore size filter from being clogged too early, and the smaller pore size filter can remove finer particles, providing higher levels of cleaning and purification. The filtered solution is treated by autoclaving, which can completely eliminate microorganisms that may exist in the solution and ensure the sterility of the product. The combination of the 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 assurance to ensure complete sterility of the product.

[0019] The mannitol injection prepared by the production method has high purity and stability, the suspended particles and microbial contaminants are effectively removed in the filtering process, and the high-pressure steam sterilization completely kills all possible microorganisms, including bacteria, viruses and extremely heat-resistant spores. Such treatment ensures that the mannitol injection remains stable during long-term storage and transportation, and does not cause drug efficacy decline or safety problems due to microbial contamination; by accurately controlling the pH value and electrolyte concentration of the solution, the biocompatibility of the mannitol injection is significantly improved, the use of hydrochloric acid as an acid-base regulator helps to adjust the pH value to be close to the human physiological environment, reducing the pain and local irritation during injection, at the same time, the addition of electrolytes helps to adjust the osmotic pressure of the solution, avoiding cell damage or discomfort caused by too high or too low osmotic pressure; the addition of cyclodextrin not only enhances the stability of mannitol, but also may improve its efficacy, cyclodextrin can form inclusion compounds, which helps to control the release rate of mannitol, making it 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 purposes, features and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application will be described in detail below with reference to the embodiments of the specification.

[0021] In the following description, many specific details are set forth in order to provide a thorough understanding of the present application, but the present application can also be implemented in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the concept of the present application, therefore the present application is not limited to the specific embodiments disclosed below.

[0022] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an independent or alternative embodiment that excludes other embodiments.

[0023] Preparation example of cyclodextrin and mannitol inclusion compound

[0024] Preparation examples 1 to 5

[0025] The following will be illustrated by taking preparation example 1 as an example.

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

[0027] As shown in Table 1, the difference between Preparation Examples 1-5 is the mass ratio between cyclodextrin and mannitol, 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 in the solution changes or new components are added, the weight of the solution is made up to 100% by water for injection.

[0031] Examples 1-5

[0032] The following is illustrated by Example 1.

[0033] Example 1

[0034] In this example, the production method of mannitol injection includes the following steps:

[0035] (1) 200g of pre-processed mannitol prepared in Preparation Example 1 is added to 1000ml of water for injection, heated at a controlled temperature of 60°C, and stirred until completely dissolved, with a stirring speed of 350rpm / min;

[0036] (2) After the complete dissolution of the pre-processed mannitol, NaCl is added to adjust the osmotic pressure of the solution, and HCl is used to accurately control the pH value of the solution, adjusting the pH value of the solution to 6; wherein the amount of NaCl added is 0.7wt% of the total mass of the solution;

[0037] (3) The solution after adjusting the pH is filtered through two filters connected in series, with the pore size of the front filter being larger than that of the rear filter; high temperature sterilization method: the filtered solution is placed in an autoclave, with the temperature usually set at 121°C and the pressure at about 15 pounds per square inch, for 20 minutes.

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

[0039] Table 1 is the amount of NaCl added accounting for the mass of the solution

[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 the mannitol injection solution includes the following steps:

[0043] (1) 200g of the pretreated mannitol prepared in Preparation Example 1 is added to 1000ml of water for injection, heated at a controlled temperature of 60°C, and stirred until completely dissolved, with a stirring speed of 350rpm / min;

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

[0045] (3) The solution after adjusting the pH is filtered through two filters connected in series, the pore size of the front filter is larger than that of the rear filter; high temperature sterilization method is adopted: the filtered solution is placed in an autoclave, the temperature is usually set to 121°C, the pressure is about 15 pounds per square inch, and the duration is 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 is the preparation of cyclodextrin and mannitol inclusion complex by 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 production method of a mannitol injection solution, including the following steps:

[0052] (1) 200g of mannitol is added to 1000ml of water for injection, heated at a controlled temperature of 60°C, and stirred until completely dissolved, with a stirring speed of 350rpm / min;

[0053] (2) After the complete dissolution of the pretreated mannitol, NaCl is added to adjust the osmotic pressure of the solution, and HCl is used to accurately control the pH value of the solution, and the pH value of the solution is adjusted to 6; wherein the mass fraction of NaCl added is 0.7wt% of the mass of the solution;

[0054] (3) The solution after adjusting the pH value is filtered through two filters connected in series, the pore size of the front filter is larger than that of the rear filter; high temperature sterilization method is adopted: the filtered solution is placed in a high pressure sterilization pot, the temperature is usually set to 121℃, the pressure is about 15 pounds per square inch, and the duration is 20 minutes.

[0055] Comparative Example 2

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

[0057] Comparative Example 3

[0058] The difference between this comparative example and Example 1 is that after the complete dissolution of the pretreated mannitol, 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, an electrolyte is added to the completely dissolved solution, but no HCl is 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 cancelled, no electrolyte and acid-base regulator is added, and step 3 is directly performed.

[0063] Performance test

[0064] The mannitol injection obtained in the examples and comparative examples of the present application is respectively placed in a 25℃, 15℃, 0℃ water bath and a-5℃ environment for observation for 6 weeks, and the crystallization is observed, and the results are shown in Table 1.

[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, the mannitol is first pretreated and dissolved, then an electrolyte is 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, and the prepared injection does not appear crystallization phenomenon at-10℃ to 25℃.

[0069] It can be seen from Examples 6 to 10 and Table 1 that when the concentration of NaCl added is low, the prepared injection solution does not appear to be crystallized at -10°C to 25°C, and when the concentration of NaCl reaches 1.0wt%, the mannitol injection solution appears to be crystallized at -5°C and -10°C. The main reason is that increasing the ionic strength reduces the interaction between solvent molecules and non-electrolytes (such as mannitol), which reduces the solubility of mannitol, which can lead to mannitol more easily forming crystals, even in the presence of cyclodextrin inclusion complexes. This effect still exists.

[0070] It can be seen from Example 1, Comparative Example 1 and Table 1 that the mannitol is pretreated to form a cyclodextrin and mannitol inclusion complex, and then prepared into an injection solution. The stability of the injection solution is better than that of the conventional mannitol injection solution without pretreatment, and no crystallization phenomenon occurs at room temperature and low temperature conditions. The combination of the internal cavity of cyclodextrin and the mannitol molecule not only physically embeds, but also enhances the overall stability of the complex through chemical hydrophobic interaction and van der Waals force. 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 freely moving and rearranging into a crystal structure, thereby effectively preventing the crystallization of mannitol.

[0071] It can be seen from Example 1, Comparative Example 2 and Table 1 that the injection solution prepared without precooling treatment does not appear to be crystallized at room temperature, but does appear to be crystallized at low temperature. At low temperature, the solubility of mannitol decreases, the solution enters a supersaturated state, large ice crystals form due to non-uniform cooling, and microparticles act as crystal nuclei, which can cause mannitol to more easily form crystals. Therefore, precooling treatment can effectively improve the stability of the solution and prevent crystallization at low temperature.

[0072] It can be seen from Example 1, Comparative Examples 3 to 5 and Table 1 that by adding electrolytes and adjusting the pH of the solution, the prepared injection solution of cyclodextrin and mannitol inclusion complex has very high stability, specifically, the injection solution does not appear to be crystallized at -5°C and -10°C. The non-covalent bond inclusion complex formed by cyclodextrin and mannitol shows higher stability under acidic conditions 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 merely describes the preferred embodiments of the present application and is not used to limit the present application, and although the present application is described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments, or equivalently replace some technical features thereof. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

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 solution after adjusting the pH in step S2 is filtered through a filter of appropriate pore size to remove possible particulate impurities, and then the solution is sterilized; In step S1, the preprocessing includes the following steps: Add cyclodextrin and mannitol in a mass ratio of 1 to 5:1 to water for injection and stir until completely dissolved, pre-cool the completely dissolved solution, and place the pre-cooled solution in a freeze dryer for freeze drying to obtain a mannitol-cyclodextrin complex powder; The pre-cooling condition is 4°C and the refrigeration time is 2-4 hours; Wherein, the electrolyte is selected from one or more of calcium salt, sodium salt and magnesium salt.

2. The production method of mannitol injection according to claim 1, 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 quickly 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℃ to convert solid water directly into gaseous state; To remove residual bound water, additional drying at temperatures between 25°C and 40°C is required.

3. The production method of mannitol injection according to claim 1, characterized in that, The acidity and alkalinity regulator is hydrochloric acid.

4. The production method of 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, with the pore size of the front filter being larger than that 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 15 pounds per square inch for 15-20 minutes.

5. The mannitol injection prepared by the production method according to any one of claims 1 to 4.

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