Lattamoxef sodium freeze-dried powder for injection and preparation method thereof

Abstract

The invention discloses latamoxef sodium freeze-dried powder for injection and a preparation method of the latamoxef sodium freeze-dried powder, and belongs to the technical field of pharmaceutical preparations. The latamoxef sodium freeze-dried powder for injection disclosed by the invention comprises the following raw materials: 25-32% w / v of latamoxef sodium, 3.5-8% w / v of mannitol, 0.01-0.2% w / v of a pH regulator and 75-88% w / v of water for injection. The preparation method comprises the following steps: preparing latamoxef sodium, mannitol and part of water for injection into a solution, adding a pH regulator to regulate the pH value of the solution to 6.5-7.5, fixing the volume, filtering, filling, half plugging and pre-freezing, and then freeze-drying twice, re-pressing, plugging and capping. The latamoxef sodium for injection has good stability, solves the problems that latamoxef sodium for injection is easy to hydrolyze, unstable and unqualified in solution color in the prior art, can fully ensure the product quality and the safety and effectiveness in the clinical use process, remarkably shortens the freeze-drying period, saves energy consumption, and is beneficial to commercialized production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lyophilized powder of latamoxef sodium for injection and a preparation method thereof. Background Art

[0002] Latamoxefox sodium, molecular formula is C 20 H 18 N6Na2O9S, molecular weight is 564.44, chemical structure is as follows:

[0003] Latamoxefox sodium is a semi-synthetic oxycephalosporin β-lactam antibiotic. In order to enhance its antibacterial power against Gram-negative bacteria, its structure has been changed from the parent nucleus structure (7-aminopenicillanic acid, 7-ACA) of the classic β-lactam antibiotics, making it more effective in resisting β-lactamase than the classic β-lactam antibiotics. This product is mainly used for various infections caused by sensitive bacteria, such as sepsis, meningitis, respiratory system infections, digestive system infections, intra-abdominal infections, urinary system and reproductive system infections, skin and soft tissue infections, bone and joint infections and traumatic infections.

[0004] Latamoxef Sodium for injection was first developed by Shionogi Pharmaceutical Co., Ltd. and approved for marketing in Japan in 1982 with a marketing specification of 1.0. Currently, only the sterile lyophilized powder injection is available. The original formulation consists of the raw material Latamoxef Sodium (1g of Latamoxef) and the auxiliary material mannitol (150mg). Latamoxef Sodium is structurally unstable and is prone to hydrolysis impurities in aqueous solution and during the freeze-drying process. The color of the solution gradually turns yellow, which affects the safety and effectiveness of the drug in clinical use. At the same time, the solid content of this specification is relatively high, which makes the freeze-drying process development of this product more difficult, and is prone to problems such as long freeze-drying cycle, high energy consumption, and unqualified color and clarity of the freeze-dried product in commercial production.

[0005] The patent with publication number CN115737573A discloses a lyophilized powder of latamoxef sodium for injection and its preparation method, which uses aloe polysaccharide and mannitol as auxiliary agents for lyophilization of latamoxef sodium to inhibit the generation of free water and reduce the hydrolysis of latamoxef sodium caused by free water, thereby increasing the stability of latamoxef sodium. However, this method also has disadvantages: first, the aloe polysaccharide is extracted and separated from the aloe powder, and the extraction purity of the aloe polysaccharide must be guaranteed in this process, otherwise the introduction of other impurities will greatly increase the safety risk of the use of this product; secondly, the addition of aloe polysaccharide leads to an increase in the solid content and viscosity of the drug solution, further increasing the difficulty of freeze-drying process development of this product and extending the commercial production cycle.

[0006] Therefore, providing a lyophilized powder of latamoxef sodium for injection that is safe, effective, stable, and easy to commercialize has become an urgent problem to be solved by those skilled in the art. Summary of the invention

[0007] One of the purposes of the present invention is to provide a lyophilized powder of latamoxef sodium for injection, so as to solve the problems of long lyophilization cycle, high energy consumption and unqualified color and clarity of the product after lyophilization in the prior art, and to improve the stability and safety of the product.

[0008] The second object of the present invention is to provide a method for preparing the latamoxefox sodium lyophilized powder for injection.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] The latamoxef sodium lyophilized powder for injection provided by the invention comprises raw materials of 25-32% w / v latamoxef sodium, 3.5-8% w / v mannitol, 0.01-0.2% w / v pH regulator and 75-88% w / v water for injection.

[0011] In some embodiments of the present invention, the raw materials include: 27% w / v of latamoxef sodium, 3.5-8% w / v of mannitol, 0.01-0.2% w / v of pH regulator, and 86% w / v of water for injection.

[0012] In some embodiments of the present invention, the pH adjuster includes at least one of ethylenediamine, arginine, sodium hydroxide, phosphate buffer, and borate buffer.

[0013] In some embodiments of the present invention, before the freeze-drying operation, latamoxef sodium, mannitol and water for injection are prepared into a solution, and a pH adjuster is added to adjust the pH value of the solution to 6.5-7.5, specifically, the pH value of the solution is 7.0-7.5, more specifically, the pH value of the solution is greater than 7.0 and less than or equal to 7.5.

[0014] The stability of the latamoxef sodium lyophilized powder for injection is improved by optimizing the pH value in the present invention. The pH value of the solution adjusted by adding a pH adjuster is 6.5 to 7.5, such as 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5; specifically, the pH value of the solution is 7.0 to 7.5, and more specifically, the pH value of the solution is greater than 7.0 and less than or equal to 7.5.

[0015] The preparation method of the latamoxef sodium lyophilized powder for injection disclosed in the present invention comprises the following steps:

[0016] Step 1. Preparation of solution: prepare a solution by mixing latamoxef sodium, mannitol and part of water for injection;

[0017] Step 2. Adjusting the pH value: Adding a pH adjusting agent to the solution prepared in step 1 to adjust the pH value of the solution to 6.5 to 7.5, specifically, the pH value of the solution is 7.0 to 7.5, more specifically, the pH value of the solution is greater than 7.0 and less than or equal to 7.5.

[0018] Step 3. Make up the volume: After adjusting the pH value, add water for injection to make up the volume;

[0019] Step 4. Filtration and filling: Filter the fixed volume solution through a filter membrane, and then fill it into a vial and half-stopper it;

[0020] Step 5. Freeze-drying: pre-freeze the solution after filling, and then freeze-dry it twice;

[0021] The pre-freezing includes three stages: cooling, heating, and cooling. The first stage of pre-freezing is cooling to -50 to -40°C, the second stage of pre-freezing is heating to -26 to -18°C, and the third stage of pre-freezing is cooling to -50 to -40°C.

[0022] The primary drying includes two heating stages. The first stage of primary drying is heated to -18 to -10°C, and the second stage of primary drying is heated to 0 to 5°C.

[0023] The secondary drying temperature is raised to 35-45°C;

[0024] Step 6. After freeze-drying is completed, re-pressurize with nitrogen or inert gas, and then plug and cap. Preferably, re-pressurize to -0.04 MPa to -0.06 MPa.

[0025] In some embodiments of the present invention, in step 1, the amount of water for injection is 50-90% of the total amount; specifically, 60-80%, more specifically, 70%.

[0026] In some embodiments of the present invention, in step 4, the fixed volume solution is filtered using 0.45 μm and 2nd level 0.22 μm filter membranes.

[0027] In some embodiments of the present invention, in step 5, the cooling rate of the first stage of pre-freezing is 0.3-0.8°C / min, and the holding time is 2-4 hours; specifically, the first stage of pre-freezing is cooled to -45°C, the cooling rate is 0.35°C / min, and the holding time is 2 hours;

[0028] The cooling rate of the second stage of pre-freezing is 0.3-0.5°C / min, and the holding time is 1-3 hours; specifically, the second stage of pre-freezing is cooled to -22°C, the cooling rate is 0.5°C / min, and the holding time is 2 hours;

[0029] The cooling rate of the third stage of pre-freezing is 0.3-0.8°C / min, and the maintenance time is 1-2 hours; specifically, the third stage of pre-freezing is cooled to -45°C, the cooling rate is 0.5°C / min, and the maintenance time is 1 hour.

[0030] In some embodiments of the present invention, in step 5, the heating rate of the first stage of primary drying is 0.45-0.65°C / min, the holding time is 50-62 hours, and the vacuum degree is 0.10-0.25 mbar; specifically, the first stage of primary drying is heated to -14°C, the heating rate is 0.45°C / min, the holding time is 56 hours, and the vacuum degree is 0.18 mbar;

[0031] The heating rate of the second stage of primary drying is 0.45-0.65°C / min, the holding time is 2-4 hours, and the vacuum degree is 0.10-0.25 mbar; specifically, the temperature in the second stage of primary drying is raised to 0°C, the heating rate is 0.55°C / min, the holding time is 2 hours, and the vacuum degree is 0.18 mbar.

[0032] In some embodiments of the present invention, the heating rate of the secondary drying is 0.45 to 0.65°C / min, the holding time is 6 to 10 hours, and the vacuum degree is 0.08 to 0.12 mbar;

[0033] Preferably, the secondary drying is heated to 40° C., the heating rate is 0.55° C. / min, the maintenance time is 10 hours, and the vacuum degree is 0.10 mbar.

[0034] The "% w / v" mentioned in the present invention refers to the mass volume percentage. For example, "lamotoxef sodium 27% w / v" means that the content of laotoxef sodium in 100 ml of the solution is 27 g.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] The latamoxef sodium for injection of the present invention has good stability, solves the problems of easy hydrolysis, instability and unqualified solution color of latamoxef sodium for injection in the prior art, and can fully guarantee product quality and safety and effectiveness during clinical use. In addition, the method of the present invention effectively solves the problem of unqualified clarity of the product after freeze-drying, and can significantly shorten the freeze-drying cycle of the product, save energy consumption, and facilitate commercial production. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0038] The original preparation described in the examples of the present invention is latamoxef sodium for injection marketed in Japan by Shionogi Pharmaceutical Co., Ltd., with a specification of 1.0 g.

[0039] Example 1

[0040] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is as follows:

[0041] Latamoxef sodium 27w / v%, mannitol 3.8w / v%, sodium hydroxide 0.01-0.2%w / v, and water for injection about 86%w / v.

[0042] The preparation method is as follows:

[0043] S1. Take 70% of the prescribed amount of water for injection and place it in a container, and control the temperature of the water for injection to 0-15℃.

[0044] S2. Add the treated amount of mannitol and latamoxefox sodium to the water for injection and stir until completely dissolved;

[0045] S3. Add 1% w / v sodium hydroxide solution to adjust the pH value of the solution to 6.5;

[0046] S4. Add the remaining water for injection to make up the volume, stir evenly, and then filter through 0.45μm and 2nd level 0.22μm filter membranes. Maintain the liquid temperature at 0-15°C;

[0047] S5. Fill the filtered solution in step S4 into a vial and half-stopper it;

[0048] S6. Freeze-drying is performed according to the following freeze-drying process:

[0049] Table 1 Freeze-drying process of Example 1

[0050]

[0051] S7. Re-pressurize with nitrogen to -0.04MPa~-0.06MPa, then press the plug and roll the cap.

[0052] Example 2

[0053] This example discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation is as follows: 27% w / v latamoxef sodium, 5% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection; the preparation method is the same as that of Example 1.

[0054] Example 3

[0055] This example discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation is as follows: 27% w / v latamoxef sodium, 8% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection; the preparation method is the same as that of Example 1.

[0056] Example 4

[0057] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is the same as that of Example 1, which is: 27% w / v latamoxef sodium, 3.8% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection;

[0058] Compared with Example 1, the preparation method thereof is as follows: in step S3, the pH value of the solution is adjusted to 7.0, and the other conditions are the same.

[0059] Example 5

[0060] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is the same as that of Example 1, which is: 27% w / v latamoxef sodium, 3.8% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection;

[0061] Compared with Example 1, the preparation method thereof is as follows: in step S3, the pH value of the solution is adjusted to 7.5, and the other conditions are the same.

[0062] Example 6

[0063] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is the same as that of Example 2, namely: 27% w / v latamoxef sodium, 5% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection;

[0064] Compared with Example 2, the preparation method thereof is as follows: in step S3, the pH value of the solution is adjusted to 7.5, and the other conditions are the same.

[0065] Example 7

[0066] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is the same as that of Example 2, namely: 27% w / v latamoxef sodium, 5% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection;

[0067] Compared with Example 2, the preparation method thereof is as follows: in step S3, the pH value of the solution is adjusted to 7.2, and the other conditions are the same.

[0068] Example 8

[0069] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is the same as that of Example 1, which is: 27% w / v latamoxef sodium, 3.8% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection;

[0070] Compared with Example 1, the specific parameters of the freeze-drying process in step S6 are different, and the other conditions are the same. The freeze-drying process parameters of this embodiment are as follows:

[0071] Table 2 Freeze-drying process of Example 8

[0072]

[0073] Example 9

[0074] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is the same as that of Example 1, which is: 27% w / v latamoxef sodium, 3.8% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection;

[0075] Compared with Example 1, the specific parameters of the freeze-drying process in step S6 are different, and the other conditions are the same. The freeze-drying process parameters of this embodiment are as follows:

[0076] Table 3 Freeze-drying process of Example 9

[0077]

[0078] Example 10

[0079] This embodiment discloses a method for preparing the lyophilized powder of latamoxef sodium for injection of the present invention, and the formulation thereof is the same as that of Example 1, which is: 27% w / v latamoxef sodium, 3.8% w / v mannitol, 0.01-0.2% w / v sodium hydroxide, and about 86% w / v water for injection;

[0080] Compared with Example 1, the specific parameters of the freeze-drying process in step S6 are different, and the other conditions are the same. The freeze-drying process parameters of this embodiment are as follows:

[0081] Table 4 Freeze-drying process of Example 10

[0082]

[0083] Comparative Example 1

[0084] Compared with Example 1, the preparation formula of this comparative example does not contain pH adjuster pH sodium hydroxide; there is no step S3 in its preparation method, and the other conditions are the same.

[0085] Comparison document 2

[0086] Compared with Example 1, this comparative example has the same formulation, a different step S6 in the preparation method, and the other conditions are the same. The preparation method of this comparative example is as follows:

[0087] S1. Take 70% of the prescribed amount of water for injection and place it in a container, and control the temperature of the water for injection to 0-15℃.

[0088] S2. Add the treated amount of mannitol and latamoxefox sodium to the water for injection and stir until completely dissolved;

[0089] S3. Add 1% w / v sodium hydroxide solution to adjust the pH value of the solution to 6.5;

[0090] S4. Add the remaining water for injection to make up the volume, stir evenly, and then filter through 0.45μm and 2nd level 0.22μm filter membranes. Maintain the liquid temperature at 0-15°C;

[0091] S5. Fill the filtered solution in step S4 into a vial and half-stopper it;

[0092] S6. Freeze-drying is performed according to the following freeze-drying process:

[0093] Table 5 Freeze-drying process of comparative example 2

[0094]

[0095] S7. Re-pressurize with nitrogen to -0.04MPa~-0.06MPa, then press the plug and roll the cap.

[0096] Test Example 1

[0097] This test investigates the stability of the intermediate products of Examples 1 to 7 and Comparative Example 1, specifically as follows: Take samples of the intermediate products of Examples 1 to 7 and Comparative Example 1, place them under the same low temperature conditions (2 to 8°C) for 24 hours, and test the pH value, solution color and related substances at 0 hour and 24 hours, respectively. The test results are detailed in Table 6.

[0098] The intermediate product described in this test example refers to the solution whose pH value is adjusted before freeze-drying, that is, the sample prepared by steps S1-S4.

[0099] Detection methods for related substances: Detection shall be carried out in accordance with the detection methods for related substances in the quality standard of latamoxefox sodium for injection in the Chinese Pharmacopoeia (2020 edition, Part II).

[0100] Table 6 Stability results of intermediate products of Examples and Comparative Examples

[0101]

[0102]

[0103] As can be seen from Table 6, the stability of the intermediate product of latamoxef sodium for injection (aqueous solution before lyophilization) gradually increases with the increase of pH value and also increases with the increase of mannitol dosage; that is, the present invention optimizes the product prescription composition and adopts the method of increasing pH regulator and adjusting the dosage of mannitol to synergistically improve the stability of latamoxef sodium for injection.

[0104] Test Example 2

[0105] This test investigates the stability of the finished products of Examples 1 to 7 and Comparative Example 1, specifically as follows: Take samples of the finished products of Examples 1 to 7 and Comparative Example 1 respectively, place them under the same accelerated conditions (40°C / 75%RH), and investigate the changes in pH value, moisture, clarity and related substances under the conditions at different time periods. The investigation results are detailed in Table 7.

[0106] Relevant substances and clarity detection methods in this test example: The relevant substances and clarity detection methods in the quality standard of latamoxefox sodium for injection in the Chinese Pharmacopoeia (2020 edition, Part II) were used for detection.

[0107] Table 7 Accelerated stability test results of examples and comparative examples

[0108]

[0109]

[0110] It can be seen from Table 7 that all test items of the samples of Examples 1 to 7 meet the requirements, the hydrolyzed impurities in Comparative Example 1 are significantly higher than those in other cases, and some samples in Comparative Example 2 have unqualified clarity. It can be seen that the pH range of the present invention can significantly improve the stability of the preparation; the freeze-drying process of the present invention can effectively solve the problem of unqualified clarity of the preparation.

[0111] Test Example 3

[0112] This test example conducted a statistical investigation on the freeze-drying cycles of Examples 1 to 7 and Comparative Example 2. The results are shown in Table 8.

[0113] Table 8 Summary of freeze-drying cycles of Examples 1 to 6 and Comparative Example 2

[0114]

[0115] It can be seen from Table 8 that compared with Comparative Example 2, the primary drying maintenance time of the freeze-drying process of Examples 1 to 7 of the present invention is shortened by about 20%; the present invention can significantly shorten the freeze-drying process cycle of latamoxef sodium for injection, save energy consumption, and is conducive to the commercial production of this variety.

[0116] Test Example 4

[0117] This test example discloses a compatibility stability test of the lyophilized powder of latamoxef sodium for injection of the present invention, which is as follows:

[0118] The finished products and original preparations of Examples 4 to 7 were dissolved in sterile water for injection, 5% glucose injection, and 0.9% sodium chloride injection, respectively, to prepare 250 mg / ml solutions. To simulate the actual clinical use process, the prepared solutions were placed at room temperature for 12 hours, and the relevant substances of each solution at room temperature for 0 hours and 12 hours were measured. The test results are shown in Table 9.

[0119] Table 9 Compatibility stability test results

[0120]

[0121]

[0122] It can be seen from Table 9 that after the samples of Examples 4 to 7 were mixed with sterile water for injection, 5% glucose injection, and 0.9% sodium chloride injection, the hydrolyzed impurities and total impurities at 0 hours and 12 hours were lower than those of the original preparation. The results show that the present invention has better stability and fully guarantees the safety of the product during clinical use.

[0123] Finally, it should be noted that the above embodiments are only preferred embodiments of the present invention to illustrate the technical solution of the present invention, but not to limit it, and certainly not to limit the patent scope of the present invention. Any changes or modifications that are made to the main design concept and spirit of the present invention without any substantial meaning, and the technical problems they solve are still consistent with the present invention, should be included in the protection scope of the present invention; in addition, the direct or indirect application of the technical solution of the present invention in other related technical fields is also included in the patent protection scope of the present invention.

Claims

1. A lyophilized powder of latamoxef sodium for injection, It is characterized in that The raw materials include: 25-32% w / v of latamoxef sodium, 3.5-8% w / v of mannitol, 0.01-0.2% w / v of pH regulator, and 75-88% w / v of water for injection.

2. The lyophilized powder of latamoxef sodium for injection according to claim 1, It is characterized in that The raw materials include: 27% w / v of latamoxef sodium, 3.5-8% w / v of mannitol, 0.01-0.2% w / v of pH regulator and 86% w / v of water for injection.

3. A lyophilized powder of latamoxef sodium for injection according to claim 1 or 2, It is characterized in that The pH regulator includes at least one of ethylenediamine, arginine, sodium hydroxide, phosphate buffer and borate buffer.

4. A lyophilized powder of latamoxef sodium for injection according to claim 1 or 2, It is characterized in that Before freeze-drying, latamoxef sodium, mannitol and water for injection are prepared into a solution, and a pH adjuster is added to adjust the pH value of the solution to 6.5-7.5; specifically, the pH value of the solution is 7.0-7.5; more specifically, the pH value of the solution is greater than 7.0 and less than or equal to 7.

5.

5. A method for preparing a lyophilized powder of latamoxef sodium for injection according to any one of claims 1 to 4, It is characterized in that The steps include: Step 1. Preparation of solution: prepare a solution by mixing latamoxef sodium, mannitol and part of water for injection; Step 2. Adjusting the pH value: adding a pH adjusting agent to the solution prepared in step 1 to adjust the pH value of the solution to 6.5 to 7.5; specifically, the pH value of the solution is 7.0 to 7.5; more specifically, the pH value of the solution is greater than 7.0 and less than or equal to 7.5; Step 3. Make up the volume: After adjusting the pH value, add water for injection to make up the volume; Step 4. Filtration and filling: Filter the fixed volume solution through a filter membrane, and then fill it into a vial and half-stopper it; Step 5. Freeze-drying: pre-freeze the solution after filling, and then freeze-dry it twice; The pre-freezing includes three stages: cooling, heating, and cooling. The first stage of pre-freezing is cooling to -50 to -40°C, the second stage of pre-freezing is heating to -26 to -18°C, and the third stage of pre-freezing is cooling to -50 to -40°C. The primary drying includes two heating stages. The first stage of primary drying is heated to -18~-10℃, and the second stage of primary drying is heated to 0~5℃. The secondary drying temperature is raised to 35-45°C; Step 6. After freeze-drying is completed, re-pressurize with nitrogen or inert gas, and then plug and cap. Specifically, re-pressurize to -0.04 MPa to -0.06 MPa.

6. The preparation method according to claim 5, It is characterized in that In step 1, the amount of water for injection is 50-90% of the total amount; specifically, 60-80%, more specifically, 70%.

7. The preparation method according to claim 5, It is characterized in that In the step 4, the fixed volume solution is filtered using 0.45 μm and 2nd level 0.22 μm filter membranes.

8. The preparation method according to claim 5, It is characterized in that In step 5, the cooling rate of the first stage of pre-freezing is 0.3-0.8°C / min, and the holding time is 2-4 hours; specifically, the first stage of pre-freezing is cooled to -45°C, the cooling rate is 0.35°C / min, and the holding time is 2 hours; The cooling rate of the second stage of pre-freezing is 0.3-0.5°C / min, and the holding time is 1-3 hours; specifically, the second stage of pre-freezing is cooled to -22°C, the cooling rate is 0.5°C / min, and the holding time is 2 hours; The cooling rate of the third stage of pre-freezing is 0.3-0.8°C / min, and the maintenance time is 1-2 hours; specifically, the third stage of pre-freezing is cooled to -45°C, the cooling rate is 0.5°C / min, and the maintenance time is 1 hour.

9. The preparation method according to claim 5, It is characterized in that In step 5, the heating rate of the first stage of primary drying is 0.45-0.65°C / min, the holding time is 50-62 hours, and the vacuum degree is 0.10-0.25 mbar; specifically, the temperature in the first stage of primary drying is raised to -14°C, the heating rate is 0.45°C / min, the holding time is 56 hours, and the vacuum degree is 0.18 mbar; The heating rate of the second stage of primary drying is 0.45-0.65°C / min, the holding time is 2-4 hours, and the vacuum degree is 0.10-0.25 mbar; specifically, the temperature in the second stage of primary drying is raised to 0°C, the heating rate is 0.55°C / min, the holding time is 2 hours, and the vacuum degree is 0.18 mbar.

10. The preparation method according to claim 5, It is characterized in that The heating rate of secondary drying is 0.45-0.65°C / min, the holding time is 6-10 hours, and the vacuum degree is 0.08-0.12 mbar; Specifically, the secondary drying temperature was raised to 40° C., the heating rate was 0.55° C. / min, the maintenance time was 10 hours, and the vacuum degree was 0.10 mbar.

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