Isavuconazole sulfate freeze-dried preparation for injection and preparation method of isavuconazole sulfate freeze-dried preparation

Abstract

The invention discloses an isavuconazole sulfate freeze-dried preparation for injection. The isavuconazole sulfate freeze-dried preparation comprises isavuconazole sulfate, a freeze-drying protective additive and a pH regulator, wherein the freeze-drying protective agent is mannitol and lactose; the pH regulator is sulfuric acid. According to the technical scheme, mannitol and lactose are selected as binary freeze-drying protective agents for ensuring stable product quality, a sample prepared after freeze-drying is a white block, the water content is low, a solution is clear after redissolution, and the acidity, the redissolution time and the like are all within the limit range of quality requirements. Related substances of the prepared isavuconazole sulfate for injection are not obviously increased under the condition of 25 DEG C, the isavuconazole sulfate for injection can be stored and transported under the condition of 25 DEG C, the quality stability of the product is obviously improved compared with that of an original product, the prepared product is low in impurity level and good in stability, and meanwhile the safety and effectiveness of medication are guaranteed.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a lyophilized isavuconazole sulfate preparation for injection and a preparation method thereof. Background Art

[0002] Isavuconazole sulfate is a water-soluble prodrug form of isavuconazole and a new triazole antifungal drug used to treat adult patients with invasive aspergillosis and invasive mucormycosis. Isavuconazole blocks the synthesis of ergosterol, a key component of fungal cell membranes, by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-α-demethylase. This leads to the accumulation of methylated sterol precursors and the loss of ergosterol in the cell membrane, thereby weakening the structure and function of the fungal cell membrane and achieving the purpose of antifungal treatment.

[0003] Isavuconazonium sulfate, whose English name is Isavuconazonium sulfate, has a chemical name of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate, and has the structural formula: Isavuconazole sulfate for injection was jointly developed by Japan's Astellas Pharmaceuticals and Switzerland's Basilea Pharmaceuticals. It was first approved for marketing in the United States in March 2015 by Astellas Pharma US, Inc. It was approved for marketing in the European Union in October of the same year. It will be imported and marketed in China in 2022 under the trade name Kangxinbo®.

[0004] The review report of the isavuconazole sulfate injection marketed in the EU shows that isavuconazole sulfate is very easy to degrade under high temperature conditions. Literature reports that the degradation impurity of isavuconazole sulfate is isavuconazole. The sterile lyophilized powder injection of isavuconazole sulfate currently marketed in China and abroad uses mannitol as a lyophilization protective agent and sulfuric acid as a pH regulator. Due to poor stability, the final preparation needs to be stored at 2-8°C.

[0005] The Chinese patent with publication number CN107982221A provides a lyophilized powder injection of isavuconazolium sulfate for injection and its preparation method. The powder injection uses mannitol as a lyophilization protective agent and sulfuric acid as a pH regulator, and the lyophilized preparation is prepared by freeze drying. The prepared sample was placed at 25°C for 30 days. Compared with 0 days, the maximum single impurity increased by 1.1% and the total impurities increased by 1.89%. The amount of related substances increased significantly, and the stability was poor.

[0006] The Chinese patent with publication number CN116898814A provides a lyophilized powder injection of isavuconazole sulfate for injection and its preparation method. The powder injection is composed of isavuconazole sulfate for injection, mannitol, sulfuric acid, and water for injection, wherein the distribution ratio of each component is 3.4~3.9mg of isavuconazole sulfate, 95~100mg of mannitol, an appropriate amount of sulfuric acid, and water for injection is added to 3ml. The patent optimizes the lyophilization curve of isavuconazole sulfate for injection, and prepares a lyophilized product with low moisture and significantly improved stability compared with the original research. However, the preparation was placed at 25°C for 3 months, and compared with 0 days, the maximum unknown single impurity increased by 0.03%, and the total impurity increased by 0.32%. The amount of related substances increased significantly, and the stability was poor.

[0007] In summary, due to poor product stability, isavuconazole sulfate for injection needs to be stored for a long time at 2-8°C. Compared with storage at 25°C, it needs to be stored and transported under more stringent conditions, which greatly increases the drug cost for patients. In order to solve this problem, it is necessary to improve the stability of the product so that it can be stored and transported at 25°C. Summary of the invention

[0008] The main purpose of the present invention is to provide a lyophilized preparation of isavuconazole sulfate for injection and a preparation method thereof, aiming to solve the technical problem that the existing lyophilized preparation of isavuconazole sulfate for injection has poor stability when stored and transported at 25°C.

[0009] To achieve the above object, the present invention provides a lyophilized preparation of isavuconazole sulfate for injection, which comprises isavuconazole sulfate, a lyophilization protective agent and a pH regulator; Wherein, the freeze-drying protective agent is mannitol and lactose; and the pH adjusting agent is sulfuric acid.

[0010] Optionally, the mass ratio of isavuconazole sulfate to mannitol and lactose is 7.76:(1-2):(1-2.5).

[0011] The present invention also proposes a method for preparing the above-mentioned isavuconazole sulfate lyophilized preparation, which comprises the following steps: S10. Dissolve the lyophilized protective agent and isavuconazole sulfate in water for injection; S20, add pH adjuster to adjust pH value to 1.0-1.6, and add water for injection to prepare batch; S30, filtering the prepared drug solution through a 0.22 μm PES microporous filter membrane to obtain a filtrate; S40, filling the filtrate into the injection bottle according to the prescribed filling amount; S50, half-stoppering, freeze drying, nitrogen filling and re-pressing, stoppering, unpacking, and capping to obtain the isavuconazole sulfate freeze-dried powder injection product.

[0012] Optionally, the weight of the water for injection is 60% to 80% of the prescribed amount, and the temperature is 2 to 8°C.

[0013] Optionally, the pH adjuster is sulfuric acid with a mass percentage of 5% to 10%.

[0014] Optionally, in step S50, freeze drying comprises the following steps: S501, placing the tube bottle containing the filtrate on a partition pre-cooled to 0-5°C in a freeze-drying chamber, then lowering the temperature of the partition and maintaining a constant temperature, then raising the temperature of the partition and maintaining a constant temperature, and then lowering the temperature of the partition and maintaining a constant temperature; S502, after the medicine is frozen, the whole system is evacuated, the plate temperature is raised and kept warm; S503, raising the plate temperature again and keeping it warm.

[0015] Optionally, in step S501, the plate temperature is frozen to -45°C and kept at -45°C for 1 to 2 hours, then the plate temperature is raised to -10°C and kept at -10°C for 2 to 3 hours, then the plate temperature is frozen to -45°C and kept at -45°C for 1 to 2 hours.

[0016] Optionally, in step S502, the vacuum degree is not higher than 20Pa.

[0017] Optionally, in step S502, the plate temperature is raised to 10°C-20°C and kept warm for 6-8 hours.

[0018] Optionally, raise the plate temperature to 50°C and keep it there for 3-4 hours.

[0019] In the technical scheme of the present invention, mannitol and lactose are selected as binary freeze-drying protective agents to ensure stable product quality. The sample obtained after freeze-drying is a white block with low water content, clear solution after reconstitution, and the acidity and reconstitution time are within the limit range of quality requirements. The isavuconazole sulfate for injection prepared by the present invention has no significant increase in related substances under 25°C, can be stored and transported under 25°C, and the quality stability of the product is significantly improved compared with the original research. The obtained product has a low impurity level and good stability, while also ensuring the safety and effectiveness of the medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.

[0021] Figure 1It is a schematic flow chart of an embodiment of a method for preparing a lyophilized isavuconazole sulfate preparation for injection provided by the present invention; Figure 2 The figure is a graph showing the change in the content of the impurity isavuconazole in each embodiment of the isavuconazole sulfate lyophilized preparation for injection provided by the present invention from 1 to 12 months; Figure 3 The figure is a graph showing the change in the content of total impurities in each embodiment of the isavuconazole sulfate lyophilized preparation for injection provided by the present invention from 1 to 12 months.

[0022] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0023] To make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them.

[0024] It should be noted that, in the embodiments, those without specifying specific conditions are carried out according to normal conditions or conditions recommended by the manufacturer. Those without specifying the manufacturer of reagents or instruments used are conventional products that can be purchased commercially. In addition, the meaning of "and / or" appearing in the full text includes three parallel schemes, and "A and / or B" is taken as an example, including schemes A, B, or A and B that meet the same time. In addition, the technical schemes between the various embodiments can be combined with each other, but must be based on the ability of ordinary technicians in the field to achieve. When the combination of the technical schemes is contradictory or cannot be achieved, it should be considered that the combination of such technical schemes does not exist, and is not within the scope of protection required by the present invention. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work, all belong to the scope of protection of the present invention.

[0025] Currently, the prescription of isavuconazole sulfate sterile lyophilized powder injection products marketed domestically and overseas uses mannitol as a lyophilization protectant and sulfuric acid as a pH adjuster. Due to poor stability, the final preparation needs to be stored at 2-8°C.

[0026] In view of this, the present invention proposes a lyophilized preparation of isavuconazole sulfate for injection. By studying the lyophilized protectant in the lyophilized preparation, as well as the single lyophilized protectant and the binary lyophilized protectant, a lyophilized protectant that can ensure the storage and transportation of the product at 25°C is found. The lyophilized preparation includes isavuconazole sulfate, a lyophilized protectant and a pH regulator; wherein the lyophilized protectant is mannitol and lactose; and the pH regulator is sulfuric acid. In this embodiment, the mass ratio of isavuconazole sulfate to mannitol and lactose is 7.76: (1-2): (1-2.5).

[0027] The present invention also provides a method for preparing the above-mentioned isavuconazole sulfate lyophilized preparation, combining Figure 1 A schematic flow chart of an embodiment of a method for preparing a low-volatility alcohol ether silicone oil component is provided, which includes the following steps.

[0028] Step S10, preparing a pharmaceutical solution: dissolving the lyophilization protective agent and isavuconazole sulfate in water for injection.

[0029] During specific implementation, first add 60% to 80% by weight of water for injection for preliminary dissolution, and the water temperature is 2 to 8°C to ensure stability during dissolution.

[0030] Step S20, adjusting the pH value: adding a pH adjusting agent to adjust the pH value to 1.0-1.6, and adding water for injection to prepare the batch size.

[0031] In a specific implementation, the pH adjuster is sulfuric acid with a mass percentage of 5% to 10%.

[0032] Step S30, filtration: the prepared drug solution is filtered through a 0.22 μm PES microporous filter membrane to obtain a filtrate.

[0033] Step S40, filling: filling the filtrate into a borosilicate glass controlled injection bottle according to the specified filling volume (3.0 ml / bottle).

[0034] Step S50, half-stoppering, freeze drying, nitrogen filling and re-pressing, stoppering, unpacking, and capping to obtain the isavuconazole sulfate lyophilized powder injection product.

[0035] Among them, in one embodiment of the present invention, in the freeze-drying procedure in step S50, the technicians in this field use an annealing process according to the equipment adjustment, which can remove residual moisture and ensure the dryness of the product; reduce shrinkage and deformation, ensure the stability of the product shape and structure; improve the physical and chemical stability of the product, and extend the shelf life of the product. Specifically, it includes the following steps.

[0036] Step S501, pre-freezing: placing the tube bottle containing the filtrate on a partition pre-cooled to 0-5°C in a freeze-drying chamber, then cooling the plate temperature to -45°C, keeping it at a constant temperature of -45°C for 1-2 hours, heating the plate temperature to -10°C, keeping it at a constant temperature of -10°C for 2-3 hours; freezing the plate temperature to -45°C, keeping it at a constant temperature of -45°C for 1-2 hours.

[0037] Step S502, primary drying: After the medicine is frozen, the entire system is evacuated, the vacuum degree is not higher than 20Pa, the plate temperature is raised to 10℃~20℃, and kept warm for 6~8 hours.

[0038] Step S503, secondary drying: raise the plate temperature to 50°C and keep it warm for 3-4 hours.

[0039] In this embodiment, a reasonable freeze-drying procedure is set according to the reaction activity of isavuconazole sulfate, and an annealing process is adopted. First, the critical temperature and residence time, which are factors affecting the annealing effect, are set. The annealing temperature set in this embodiment ensures the dryness of the product while ensuring the stability of the product; secondly, the higher the vacuum degree, the faster the water sublimation rate, the better the dehydration effect, but it will cause deformation of the product. In this embodiment, it is set to within 20Pa, and the shape of the product changes very little.

[0040] In the technical scheme of the present invention, by studying and comparing the stability of the products, the products prepared according to the original research prescription were placed at 25°C for 12 months, and the related substances increased significantly, exceeding the limit range, indicating that the products prepared by the original research prescription are not suitable for long-term storage and transportation at 25°C; products with single lyophilized protective agents lactose, trehalose, sucrose, and glycine were prepared and placed at 25°C for 12 months. It was found that the products containing a single lyophilized protective agent lactose had a low increase in related substances compared with 0 days, and the stability was better than that of the original research prescription products. The stability of other single lyophilized protective agent products was not as good as that of the original research prescription products; products containing binary lyophilized protective agents of mannitol and lactose in different proportions were prepared, and it was found that the products under a certain proportion were placed at 25°C for 12 months, and the related substances did not increase significantly compared with 0 days, and the stability was better than that of the products prepared by the single lyophilized protective agent lactose. This shows that the use of a certain proportion of binary lyophilized protective agents mannitol and lactose can prepare isavuconazole sulfate for injection with good stability after storage at 25°C.

[0041] The present invention obtains a binary freeze-drying protective agent that can ensure the stability of product quality by studying freeze-drying protective agents such as mannitol, lactose, trehalose, sucrose, and glycine, and determines that mannitol and lactose are the most preferred. The sample obtained after freeze-drying is a white block with low water content, clear solution after reconstitution, and acidity and reconstitution time are within the limit range of quality requirements. The product obtained by the original prescription and the product of the present invention are compared and studied. The results show that the original prescription product is stored at 25°C, and the related substances increase significantly, which is not suitable for storage at 25°C; the isavuconazole sulfate for injection prepared by the present invention has no significant increase in related substances at 25°C, and can be stored and transported at 25°C, indicating that the quality stability of the product is significantly improved compared with the original research. The obtained product has a low impurity level and good stability, and also ensures the safety and effectiveness of the medication. The preparation method of the present invention is used to prepare isavuconazole sulfate for injection, which has a safe formula, can be stored and transported at 25°C, and is suitable for industrial production.

[0042] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to explain the present invention, and are not used to limit the present invention.

[0043] Table 1-Specific prescription table of Examples 1 to 9: .

[0044] *: Example 1 is an original research prescription. Example 1

[0045] Add mannitol and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 2

[0046] Add lactose and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 3

[0047] Add trehalose and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 4

[0048] Add sucrose and isavuconazole sulfate to 210ml of injection water at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add injection water to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 5

[0049] Add glycine and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 6

[0050] Add mannitol, lactose and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 7

[0051] Add mannitol, lactose and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 8

[0052] Add mannitol, lactose and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product. Example 9

[0053] Add mannitol, lactose and isavuconazole sulfate to 210ml of water for injection at 2-8℃ and stir to dissolve. After dissolution, measure the pH value, adjust the pH value to 1.0-1.6 with 5%-10% (g / g) sulfuric acid, and add water for injection to 300ml. Filter the prepared solution through a 0.22μm microporous filter membrane to obtain a filtrate; fill the filtrate into a borosilicate glass tube injection bottle at 3.0ml / bottle, half-stopper, freeze-dry, stopper, and cap to obtain the finished product.

[0054] The specific freeze-drying conditions of each embodiment are shown in the following table.

[0055] Table 2 - Freeze-drying conditions of Examples 1 to 9:

[0056] The freeze-dried products of Examples 2 to 9 and the freeze-dried product of the original formula (Example 1) were placed under (25°C ± 2°C, RH 60% ± 5%) for 12 months, and samples were taken at 0, 3, 6, and 12 months to test their properties, acidity, solution clarity, water content, reconstitution time, related substances and content. The experimental results are shown in Table 3 below.

[0057] Table 3-Summary of stability results (experimental data stored at 25℃±2℃, RH60%±5% for 12 months): .

[0058] See also Figure 2 and Figure 3 , and combined with the above data, it is shown that the main indicators of the 0-day finished products prepared according to Examples 1 to 9, such as properties, acidity, water content, re-dissolution time, solution clarity, related substances, and content, all meet the quality standard requirements. After the products of Examples 2 to 9 and the original prescription product (Example 1) were placed at 25°C ± 2°C and relative humidity of 60% ± 5% for 12 months, the properties, acidity, solution clarity, re-dissolution time, and water content of Examples 2 to 9 and the original prescription product (Example 1) did not change significantly; the isavuconazole and total impurities of the original prescription product (Example 1) and Examples 3-5 increased significantly, and the impurity level exceeded the quality standard limit; the isavuconazole and total impurities of the products of Examples 2, 6, 7, and 8 increased slightly, and were all within the standard limit; the isavuconazole and total impurities of Example 9 did not increase significantly, and the impurity level was the lowest.

[0059] In summary, the test data in Table 3 prove that the isavuconazole sulfate lyophilized powder for injection obtained by the prescription and preparation method studied in Example 9 has low levels of related substances and good stability.

[0060] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0061] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims.

Claims

1. A lyophilized preparation of isavuconazole sulfate for injection, characterized in that: Including isavuconazole sulfate, a lyoprotectant, and a pH adjuster; Wherein, the freeze-drying protective agent is mannitol and lactose; and the pH adjusting agent is sulfuric acid.

2. The isavuconazole sulfate lyophilized preparation for injection according to claim 1, characterized in that: The mass ratio of isavuconazole sulfate to mannitol and lactose is 7.76:(1-2):(1-2.5).

3. A method for preparing the isavuconazole sulfate lyophilized preparation according to any one of claims 1 to 2, characterized in that: The following steps are involved: S10. Dissolve the lyophilized protective agent and isavuconazole sulfate in water for injection; S20, add pH adjuster to adjust pH value to 1.0-1.6, and add water for injection to prepare batch; S30, filtering the prepared drug solution through a 0.22 μm PES microporous filter membrane to obtain a filtrate; S40, filling the filtrate into the injection bottle according to the prescribed filling amount; S50, half-stoppering, freeze drying, nitrogen filling and re-pressing, stoppering, unpacking, and capping to obtain the isavuconazole sulfate freeze-dried powder injection product.

4. The method for preparing the isavuconazole sulfate lyophilized preparation according to claim 3, characterized in that: The weight of the water for injection is 60% to 80% of the prescribed amount, and the temperature is 2 to 8°C.

5. The method for preparing the isavuconazole sulfate lyophilized preparation according to claim 3, characterized in that: The pH regulator is sulfuric acid with a mass percentage of 5% to 10%.

6. The method for preparing the isavuconazole sulfate lyophilized preparation according to claim 3, characterized in that: In step S50, freeze drying comprises the following steps: S501, placing the tube bottle containing the filtrate on a partition pre-cooled to 0-5°C in a freeze-drying chamber, then lowering the temperature of the partition and maintaining a constant temperature, then raising the temperature of the partition and maintaining a constant temperature, and then lowering the temperature of the partition and maintaining a constant temperature; S502, after the medicine is frozen, the whole system is evacuated, the plate temperature is raised and kept warm; S503, raising the plate temperature again and keeping it warm.

7. The method for preparing the isavuconazole sulfate lyophilized preparation according to claim 6, characterized in that: In step S501, the plate temperature is frozen to -45°C and kept at -45°C for 1 to 2 hours, then the plate temperature is raised to -10°C and kept at -10°C for 2 to 3 hours, then the plate temperature is frozen to -45°C and kept at -45°C for 1 to 2 hours.

8. The method for preparing the isavuconazole sulfate lyophilized preparation according to claim 6, characterized in that: In step S502, the vacuum degree is not higher than 20Pa.

9. The method for preparing the isavuconazole sulfate lyophilized preparation according to claim 6, characterized in that: In step S502, the plate temperature is raised to 10°C to 20°C and kept warm for 6 to 8 hours.

10. The method for preparing the isavuconazole sulfate lyophilized preparation according to claim 6, characterized in that: Raise the plate temperature to 50°C and keep it warm for 3 to 4 hours.

Images