Isavuconazole sulfate injection and preparation method thereof

Abstract

The invention discloses an isavuconazole sulfate injection and a preparation method thereof, 2-butenal impurities in a product can be effectively controlled by controlling moisture in the product and a rubber plug, and the preparation method of the isavuconazole sulfate injection provided by the invention can shorten freeze-drying process time and improve freeze-drying efficiency.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to an isavuconazole sulfate injection and a preparation method thereof. Background Art

[0002] Isavuconazonium Sulfate is an antifungal drug. It is a new type of class II tricyclic candidate drug and can be rapidly converted into its active metabolite isavuconazole in vivo. This product is used to treat adult patients with invasive aspergillosis and invasive mucormycosis. Its chemical name is 1-{ (2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate, and its molecular structural formula is as follows:

[0003]

[0004] Isavuconazole sulfate for injection is a broad-spectrum antifungal drug developed by Astellas. It was approved by the FDA in 2015 and approved for marketing in China in 2022. Its indication is for the treatment of adult patients with invasive aspergillosis and invasive mucormycosis.

[0005] The prescription composition of the commercially available original research company's isavuconazole sulfate for injection is isavuconazole sulfate, mannitol, and sulfuric acid. Among them, isavuconazole sulfate is the active substance, mannitol is the excipient, and sulfuric acid is the pH regulator. However, the original research company did not disclose the specific preparation process. CN107661298B discloses an isavuconazole sulfate for injection and its preparation. During the freeze-drying process, the shelves need to be pre-cooled to -10°C in a freeze-dryer, and there is an annealing process step during the pre-freezing process (that is, when the product temperature drops below -40°C, keep it warm for 2 to 4 hours; then raise the shelf temperature to -25°C to -30°C, keep it warm for 1 to 2 hours, lower the shelf temperature below -40°C, keep it warm for 1 to 2 hours; raise the shelf temperature to -25 to -30°C, keep it warm for 1 to 2 hours; then lower the shelf temperature to -45°C, keep it warm for 2 to 4 hours). This patent mainly compares individual unknown impurities and total impurities, and does not study the key impurity 2-butenal in the product. At the same time, when the shelves are pre-cooled to -10°C, frost is likely to form in the freeze-dryer, and the freeze-dryer needs to be specially treated.

[0006] Chinese Patent CN107982221A discloses a lyophilized powder for injection of isavuconazole sulfate and its preparation method. Its lyophilization process is a conventional lyophilization process, and the primary sublimation drying temperature is -15 to 0 °C. The stability of the formulated product is also disclosed. Among them, the total impurities at 25 °C for 30 days increased from 1.32% on day 0 to 3.21%, and the total impurities in the long term for 1 year increased from 1.63% on day 0 to 2.99%. Moreover, the control of 2-butenal impurities was not studied.

[0007] Therefore, it is still necessary to provide a new solution to overcome the above disadvantages, making the prescription process of isavuconazole sulfate for injection simple, with qualified quality, and conducive to commercial production. Summary of the Invention

[0008] The purpose of the present invention is to provide a stable isavuconazole sulfate injection and its preparation method. The preparation method has a simple production process, stable product quality, and is suitable for commercial production.

[0009] The present invention provides an isavuconazole sulfate injection, including an injection bottle, a rubber stopper, and isavuconazole sulfate lyophilized powder encapsulated in the injection bottle. The moisture content of the rubber stopper is below 0.4% (such as 0.4%, 0.39%, 0.38%, 0.37%, 0.36%, 0.35%, 0.34%, 0.33%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%, 0.5% or any value and range during this period).

[0010] According to a specific embodiment of the present invention, the rubber stopper with a moisture content below 0.4% is obtained by drying a commercially available rubber stopper.

[0011] In a specific embodiment of the present invention, the rubber stopper with a moisture content below 0.4% is dried in a clean area oven for a commercially available rubber stopper (such as with a moisture content in the range of 0.6% - 0.7%). For example, after cumulative drying at 110 °C for 10 hours, the moisture content of the rubber stopper is 0.38%, or after cumulative drying at 115 °C for 8 hours, the moisture content of the rubber stopper is 0.37%. After drying, it is reserved for use within 48 hours.

[0012] According to a specific embodiment of the present invention, the moisture content of the isavuconazole sulfate lyophilized powder is below 0.4% (such as 0.4%, 0.39%, 0.38%, 0.37%, 0.36%, 0.35%, 0.34%, 0.33%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%, 0.5% or any value and range during this period).

[0013] According to a specific embodiment of the present invention, the isavuconazole sulfate lyophilized powder includes isavuconazole sulfate, an excipient, and a pH regulator.

[0014] The inventor found through research that when the moisture content of the rubber stopper in isavuconazole sulfate injection is controlled below 0.4%, the generation rate of product impurities in the stability experiment decreases. When the moisture content of the rubber stopper and the finished product in isavuconazole sulfate injection are both controlled below 0.4%, the total impurities and 2-butenal impurities in the product can be better controlled.

[0015] The present invention also provides a freeze-dried powder of isavuconazole sulfate, wherein the content of 2-butenal is ≤ 150 ppm.

[0016] According to a specific embodiment of the present invention, the weight ratio of isavuconazole sulfate to the excipient is 3-4:1.

[0017] According to a specific embodiment of the present invention, the excipient is mannitol.

[0018] According to a specific embodiment of the present invention, the pH regulator is sulfuric acid.

[0019] According to a specific embodiment of the present invention, the injection bottle is a middle-borosilicate controlled injection bottle.

[0020] According to a specific embodiment of the present invention, the rubber stopper is a rubber bottle stopper.

[0021] According to a specific embodiment of the present invention, every 1000 parts of isavuconazole sulfate injection are prepared and obtained by lyophilization according to the following ratio:

[0022] Ingredient Dosage Isavuconazole Sulfate 372.6g Mannitol 96g Sulfuric Acid Adjust the pH to 1.0 - 2.0 Make up the volume to with water for injection 3000L

[0023] On the other hand, the present invention provides a preparation method of the isavuconazole sulfate injection of the first aspect of the present invention, comprising the following steps:

[0024] a. Dissolve the excipient with 80%-85% of the prescribed amount of injection water;

[0025] b. At 2-10 °C, add the prescribed amount of isavuconazole sulfate to the solution in step a, and add dilute sulfuric acid to adjust the pH value to 1.0-2.0;

[0026] c. Make up the injection water to the prescribed amount;

[0027] d. After filtration, filling, semi-crimping with a rubber stopper with a moisture content below 0.4%, and then entering a freeze dryer for lyophilization;

[0028] e. After lyophilization, fully crimp the stopper, take out of the box and seal the lid.

[0029] According to a specific embodiment of the present invention, the concentration of the dilute sulfuric acid in step b is 1-2 mol / L.

[0030] According to a specific embodiment of the present invention, the concentration of isavuconazole sulfate in the solution obtained in step c is 124.2 mg / ml.

[0031] According to a specific embodiment of the present invention, in step d, filtration is carried out using a 0.22 μm polyethersulfone filter membrane.

[0032] According to a specific embodiment of the present invention, 3.24 ml is filled in step d.

[0033] According to a specific embodiment of the present invention, the bacterial endotoxin of the isavuconazole sulfate raw material drug used in the present invention is < 0.3 Eu / mg, the bacterial endotoxin of mannitol is < 2.5 Eu / g, and the bacterial endotoxin of the isavuconazole sulfate lyophilized powder is < 0.9 Eu / mg. The inventors have found through research that when the bacterial endotoxin in the raw and auxiliary materials is well controlled, there is no need to add activated carbon for adsorption and pyrogen removal during the preparation process, and the bacterial endotoxin of the prepared isavuconazole sulfate for injection still meets the quality requirements.

[0034] The inventors also provided a preparation method of an isavuconazole sulfate injection, including the processes of batching, freeze-drying, full plugging, out-of-box and capping. The freeze-drying includes the processes of pre-freezing stage, vacuum pumping, primary drying and secondary drying. The main purpose of the pre-freezing stage is to freeze the water in the material into ice; the main purpose of the primary drying is to remove the ice crystals formed by the water in the material through sublimation by raising the temperature; the main purpose of the secondary drying is to further raise the temperature to remove the remaining water in the material.

[0035] The inventors have found through research that in the pre-freezing stage, when the shelf temperature is pre-cooled to -10°C, serious frosting appears on the surface of the freeze-dryer, and the normal freeze-dryer cannot feed normally. The feeding of the freeze-dryer requires special equipment for treatment; the present invention adopts pre-freezing the shelf temperature to 10°C before feeding, which can effectively avoid the above problems.

[0036] According to a specific embodiment of the present invention, in the pre-freezing stage, it includes the process of heating from -40°C to about -15°C within 50 minutes and then maintaining the temperature at -15°C.

[0037] According to a specific embodiment of the present invention, the vacuum degree during the drying process is maintained at 20 Pa.

[0038] According to a specific embodiment of the present invention, in the primary drying, the temperature is directly raised from -15°C to 20°C within 1 hour, so as to improve the efficiency of the primary drying and shorten the time of the primary drying.

[0039] According to a specific embodiment of the present invention, the temperature of the secondary drying is controlled below 45°C. If the temperature is increased to 45°C or above, the impurity of 2-butenal in the product will increase significantly.

[0040] According to a specific embodiment of the present invention, the full plugging includes the following steps: after the freeze-drying is completed, the shelf temperature is cooled from 43°C to 20°C within 60 minutes, filled with nitrogen to repressurize to 800 mbar, plugged, and repressurized to atmospheric pressure.

[0041] According to a specific embodiment of the present invention, the pre-freezing includes the following steps: first, the shelf temperature is pre-cooled to 10°C, cooled from 10°C to -4°C within 30 minutes, and then kept at -4°C for 30 to 60 minutes; then the shelf temperature is cooled from -4°C to about -40°C within 90 minutes, and then kept at about -40°C for 120 to 180 minutes; finally, the shelf temperature is heated from about -40°C to -15°C within 50 minutes, and then kept at -15°C for 90 to 120 minutes;

[0042] According to a specific embodiment of the present invention, the vacuum pumping includes the following steps: turn on the vacuum pump and maintain the vacuum degree in the freeze-drying chamber at 20 Pa;

[0043] According to a specific embodiment of the present invention, the primary drying includes the following steps: the shelf temperature is heated from -15°C to 20°C within 1 hour for primary drying, and then kept at 20°C for 900 to 1100 minutes, and the vacuum degree is maintained at 20 Pa;

[0044] According to a specific embodiment of the present invention, the secondary drying includes the following steps: the shelf temperature is heated from 20°C to about 30°C within 20 minutes, and then kept at about 30°C for 360 to 420 minutes, and the vacuum degree is maintained at 20 Pa; the shelf temperature is heated from 30°C to 43°C within 26 minutes, and then kept at about 43°C for 240 to 300 minutes, and the vacuum degree is maintained at 20 Pa.

[0045] The main beneficial effects of the present invention:

[0046] 1) The isavuconazole sulfate injection provided by the present invention has stable product quality. By controlling the moisture in the product and the rubber stopper, the impurity of 2-butenal in the product can be effectively controlled.

[0047] 2) The preparation method of the isavuconazole sulfate injection provided by the present invention can shorten the freeze-drying process time and improve the freeze-drying efficiency. Specific embodiments

[0048] In order to understand the present invention more fully, the following specific examples are given, but the present invention is not limited to the following examples.

[0049] In this text, unless otherwise specified, % is the percentage of weight / weight (w / w).

[0050] Unless otherwise specified, any numerical value should be understood to be modified by the term "about" in all cases, indicating that such a value can vary within a certain range. When no range is recorded (such as the error range or the standard deviation of the average value given in a chart or data table), the term "about" should be understood to represent a larger range that includes the recorded value, as well as the range included by rounding to that number considering significant figures, and the range including plus or minus 10% of the recorded value.

[0051] The abbreviations used in this text and the specification are the conventional abbreviations in the art or as follows:

[0052] BAL4815: 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile;

[0053] A1: Accelerated one month (25 °C, 65% RH)

[0054] The detection conditions used in the present invention are as follows:

[0055] Chromatographic conditions for content and related substances: Octadecylsilane chemically bonded silica gel is used as the filler (Phenomenex AquaC18, 4.6 mm * 150 mm, 3 μm or a chromatographic column with equivalent efficiency); water - acetonitrile - trifluoroacetic acid (99:1:0.2) is used as mobile phase A, and acetonitrile - trifluoroacetic acid (100:0.1) is used as mobile phase B, with a flow rate of 1.5 ml per minute; the column temperature is 40 °C; the autosampler temperature is 4 °C; the detection wavelengths are 250 nm and 280 nm, and the injection volume is 20 μl.

[0056] Chromatographic conditions for 2-butenal: Octadecylsilane chemically bonded silica gel is used as the filler (Phenomenex Aqua C18, 4.6 mm * 150 mm, 3 μm or a chromatographic column with equivalent efficiency), water - acetonitrile - trifluoroacetic acid (99:1:0.2) is used as mobile phase A, and acetonitrile - trifluoroacetic acid (100:0.1) is used as mobile phase B, with a flow rate of 1.0 ml per minute; the column temperature is 40 °C; the autosampler temperature is 5 °C; the detection wavelength is 220 nm, and the injection volume is 10 μl.

[0057] Related substances are calculated by peak area normalization with the correction factor (the correction factor of BAL4815 is 0.71), and 2-butenal and content are calculated by the external standard method with peak area.

[0058] Finished product moisture detection method: Take 1 bottle of the product, and extract the content in the bottle with anhydrous methanol. Centrifuge and take the supernatant. Determine it according to the moisture determination method (General Chapter 0832, Method 1, 2020 Edition of Chinese Pharmacopoeia).

[0059] Closure moisture detection method: Cut the closure into pieces (3mm * 3mm) and put them into a weighing bottle. Place the weighing bottle in an oven at 105 °C and dry overnight until constant weight. Measure the loss on drying to obtain the moisture content.

[0060] For Comparative Example 1, the closures used were not dried before use, while the closures used in other examples and comparative examples were dried to a water content of less than 0.4% before use. After testing, the water content of the closures before and after freeze-drying remained basically unchanged, and the freeze-drying process did not affect the moisture of the closures.

[0061] In the present invention, "isavuconazole sulfate injection" refers to the packaged product. "Isavuconazole sulfate lyophilized powder" refers to the content of the product, also known as the finished product. "Isavuconazole sulfate" refers to the active pharmaceutical ingredient (API).

[0062] Example 1:

[0063] Drying of closures: Dry the commercially available closures (with a moisture content of 0.6% - 0.7%) in the clean area oven. After cumulative drying at 110 °C for 10 hours, the moisture content of the closures is 0.38%, or after cumulative drying at 115 °C for 8 hours, the moisture content of the closures is 0.37%. Keep them for use after drying, and use them within 48 hours.

[0064] Example 2:

[0065] Ingredient Dosage (g) Isavuconazole Sulfate 372.6 Mannitol 96 Adjust the pH with sulfuric acid 1.0～2.0 Make up the volume to with water for injection 3000L

[0066] Among them, the bacterial endotoxin of isavuconazole sulfate API is < 0.3 Eu / mg, and the bacterial endotoxin of mannitol is < 2.5 Eu / g.

[0067] The water content of the closures of the products in the examples was detected after freeze-drying.

[0068] Preparation method: Cool 80% of the prescribed amount of water for injection to 4 °C, add the auxiliary material mannitol and dissolve it; add the prescribed amount of isavuconazole sulfate to the above solution a, add 2 mol / L sulfuric acid to adjust the pH value to 1.0 - 2.0; make up the water for injection to the prescribed amount, stir and dissolve to make the concentration of isavuconazole sulfate 124.2 mg / ml; filter through a 0.22 μm polyethersulfone membrane, fill 3.24 ml, semi-plug the vial and then put it into the freeze-dryer for freeze-drying. After freeze-drying, fully plug the vial, take it out of the box and cap it. The moisture content of the product is 0.33%, and the moisture content of the closure is 0.38%.

[0069] The freeze-drying process and the steps after freeze-drying including fully plugging the vial, taking it out of the box include the following steps:

[0070] a. Pre-freezing: First, pre-cool the shelf temperature to 10°C, directly place the sample to be freeze-dried on the shelf, then cool from 10°C to -4°C within 30 minutes, and then hold at -4°C for 30 minutes; then cool the shelf temperature from -4°C to about -40°C within 90 minutes, and then hold at about -40°C for 120 minutes; finally, warm the shelf temperature from about -40°C to -15°C within 50 minutes, and then hold at -15°C for 90 minutes;

[0071] b. Vacuum pumping: Turn on the vacuum pump and maintain the vacuum degree in the freeze-drying chamber at 20 Pa;

[0072] c. Primary drying: Warm the shelf temperature from -15°C to 20°C within 1 hour for primary drying, then hold at 20°C for 900 minutes, and maintain the vacuum degree at 20 Pa;

[0073] d. Secondary drying: Warm the shelf temperature from 20°C to about 30°C within 20 minutes, then hold at about 30°C for 3600 minutes, and maintain the vacuum degree at 20 Pa; warm the shelf temperature from 30°C to 43°C within 26 minutes, then hold at about 43°C for 240 minutes, and maintain the vacuum degree at 20 Pa.

[0074] e. Full plugging, out of the chamber: Cool the shelf temperature from 43°C to 20°C within 60 minutes, refill with nitrogen to a pressure of 800 mbar for full plugging, then refill to atmospheric pressure and take out of the chamber (the endotoxin of isavuconazole lyophilized powder is less than 0.9 EU / mg).

[0075] Example 3:

[0076] Ingredient Dosage (g) Isavuconazole Sulfate 372.6 Mannitol 96 Adjust the pH with sulfuric acid 1.0～2.0 Make up the volume to with water for injection 3000L

[0077] The preparation method is as follows: Cool 80% of the amount of water for injection in the prescription to 10°C, add the excipient mannitol and dissolve; add the prescribed amount of isavuconazole sulfate to the above solution a, add 2 mol of sulfuric acid to adjust the pH value to 1.0 - 2.0; make up the water for injection to the prescribed amount, stir and dissolve to make the concentration of isavuconazole sulfate 124.2 mg / ml; filter through a 0.22 μm polyethersulfone filter membrane, fill 3.24 ml, semi-plug the vial, and then put it into the freeze-dryer for freeze-drying. After freeze-drying, fully plug the vial, take it out of the chamber and cap it. The water content of the product is 0.2%, and the water content of the rubber stopper is 0.38%.

[0078] The freeze-drying process and the full plugging and out of the chamber after freeze-drying include the following steps:

[0079] a. Pre-freezing: First, pre-cool the shelf temperature to 10°C, directly place the sample to be freeze-dried on the shelf, then cool from 10°C to -4°C within 30 minutes, and then hold at -4°C for 60 minutes; then cool the shelf temperature from -4°C to about -40°C within 90 minutes, and then hold at about -40°C for 180 minutes; finally, warm the shelf temperature from about -40°C to -15°C within 50 minutes, and then hold at -15°C for 120 minutes;

[0080] b. Vacuum pumping: Turn on the vacuum pump and maintain the vacuum degree in the freeze-drying chamber at 20 Pa;

[0081] c. Primary drying: Warm the shelf temperature from -15°C to 20°C within 1 hour for primary drying, then hold at 20°C for 1100 minutes, and maintain the vacuum degree at 20 Pa;

[0082] d. Secondary drying: Warm the shelf temperature from 20°C to about 30°C within 20 minutes, then hold at about 30°C for 420 minutes, and maintain the vacuum degree at 20 Pa; warm the shelf temperature from 30°C to 43°C within 26 minutes, then hold at about 43°C for 300 minutes, and maintain the vacuum degree at 20 Pa.

[0083] e. Full plugging, out of the box: Cool the shelf temperature from 43°C to 20°C within 60 minutes, fill with nitrogen to repressurize to 800 mbar, fully plug, repressurize to atmospheric pressure, and out of the box.

[0084] Comparative Example 1:

[0085]

[0086]

[0087] The preparation method is as follows: Cool 80% of the injection water in the prescription amount to 10°C, add the auxiliary material mannitol and dissolve; add the prescription amount of isavuconazole sulfate to the above solution a, add 2 mol of sulfuric acid to adjust the pH value to 1.0 - 2.0; make up the injection water to the prescription amount, stir and dissolve to make the concentration of isavuconazole sulfate 124.2 mg / ml; filter through a 0.22 μm polyethersulfone filter membrane, fill 3.24 ml, semi-plug and then enter the freeze-dryer for freeze-drying, and after freeze-drying, plug, out of the box and seal the lid. The water content of the product is detected to be 0.2%. The water content of the rubber stopper is 0.6%.

[0088] The freeze-drying process is the same as that in Example 2.

[0089] Comparative Example 2:

[0090] Repeat Example 3 of CN107661298B:

[0091] Ingredient Dosage / g Isavuconazole Sulfate 74.52g Mannitol 19.2g 5% Sulfuric Acid Aqueous Solution Adjust the pH value to 1.5 Water for Injection 600ml

[0092] Preparation process:

[0093] Take 74.52 g of isavuconazole sulfate, dissolve it in 480 ml of injection water at 4°C, add 19.2 g of mannitol and dissolve it. Slowly add dropwise 5% (w / v) sulfuric acid aqueous solution to adjust the pH value to 1.5, and make up the injection water to a volume of 600 ml. Subpackage under the laminar flow of Class A, 3 ml per vial, semi-corked, and freeze-dry using the following freeze-drying process:

[0094] Place the middle-borosilicate glass vials filled with 3 ml of the liquid medicine into the freeze-dryer with the shelf pre-cooled to -10°C; lower the temperature of the freeze-drying shelf at a rate of 30°C / h to below -40°C; when the temperature of the product drops below -40°C, keep it warm for 2 hours; raise the shelf temperature to -25 to -30°C and keep it warm for 1 hour; when the shelf temperature drops below -40°C, keep it warm for 1 hour; raise the shelf temperature to -25 to -30°C and keep it warm for 2 hours; then lower the shelf temperature to -45°C and keep it warm for 2 hours; start to evacuate, when the vacuum degree reaches below 10 Pa, start to heat up; raise the shelf temperature to -15°C at a rate of 6°C / h and keep it for 14 hours; raise the shelf temperature to 0°C at a rate of 8°C / h and keep it for 6 hours; raise the shelf temperature to 25°C at a rate of 12°C / h and keep it warm for 2 hours; raise the shelf temperature to 45°C at a rate of 15°C / h and keep it warm for 8 hours; control the vacuum degree at 50 Pa, stopper, break the vacuum, and discharge to obtain isavuconazole sulfate for injection. The water content of the product is detected to be 0.54%, and the water content of the rubber stopper is 0.37%.

[0095] Test Example 1:

[0096] The stability results of isavuconazole sulfate for injection obtained in Example 2 and Comparative Example 1 are shown in Table 1:

[0097] Table 1

[0098]

[0099] Note: Total impurities do not include BAL4815.

[0100] Test Example 2:

[0101] The stability results of isavuconazole sulfate for injection obtained in Example 2 and Comparative Example 2 are shown in Table 2:

[0102] Table 2

[0103]

[0104] Note: Total impurities do not include BAL4815.

[0105] An isavuconazole sulfate for injection and its preparation method proposed by the present invention have been described through examples. It is obvious to those skilled in the art that the isavuconazole sulfate for injection and its preparation method described herein can be modified or appropriately changed and combined without departing from the content, spirit and scope of the present invention to implement the technology of the present invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as being included in the spirit, scope and content of the present invention.

Claims

1. An isavuconazole sulfate injection, comprising an injection bottle, a rubber stopper, and isavuconazole sulfate lyophilized powder encapsulated in the injection bottle, characterized in that, the water content of the rubber stopper is below 0.4%.

2. The injection according to claim 1, characterized in that, the water content of the isavuconazole sulfate lyophilized powder is below 0.4%.

3. The injection according to claim 1, characterized in that, the isavuconazole sulfate lyophilized powder comprises isavuconazole sulfate, an excipient, and a pH regulator.

4. The injection according to claim 1, characterized in that, the content of 2-butenal in the isavuconazole sulfate lyophilized powder is not higher than 150 ppm.

5. The injection according to claim 3, characterized in that, the excipient is mannitol, and the weight ratio of the excipient to isavuconazole sulfate is 3-4:1; the pH regulator is sulfuric acid.

6. The injection according to claim 5, characterized in that, each 1000 parts of the isavuconazole sulfate injection is prepared in the following ratio and obtained by freeze-drying:

7. The preparation method of the injection according to any one of claims 1-6, characterized in that, it comprises the following steps: a. Dissolve the excipient with 80%-85% of the injection water in the prescription amount; b. At 2-10 °C, add the prescription amount of isavuconazole sulfate to the solution in step a, and add dilute sulfuric acid to adjust the pH value to 1.0-2.0; c. Make up the injection water to the prescription amount; d. After filtration, filling, and semi-pressing the rubber stopper with a water content below 0.4%, enter the freeze-dryer for freeze-drying; e. Full pressing of the stopper, taking out of the box, and capping.

8. The preparation method according to claim 7, characterized in that, the concentration of the dilute sulfuric acid in step b is 1-2 mol / L; the concentration of isavuconazole sulfate obtained in step c is 124.2 mg / ml; use a 0.22 μm polyethersulfone filter membrane for filtration in step d; fill 3.24 ml in step d.

9. A preparation method of an isavuconazole sulfate injection according to any one of claims 1-6, including the processes of batching, freeze-drying, full pressing of the stopper, taking out of the box, and capping, characterized in that, the freeze-drying includes the processes of pre-freezing stage, vacuum pumping, primary drying, and secondary drying; furthermore, in the pre-freezing stage, the shelf temperature is pre-frozen to 10 °C before feeding; furthermore, in the pre-freezing stage, it includes the process of heating from -40 °C to about -15 °C within 50 minutes, and then keeping the temperature at -15 °C; furthermore, the primary drying is carried out by directly raising the temperature from -15 °C to 20 °C within 1 hour; furthermore, the temperature of the secondary drying is controlled below 45 °C; the full pressing of the stopper comprises the following steps: after the freeze-drying is completed, the shelf temperature is cooled from 43 °C to 20 °C within 60 minutes, filled with nitrogen for re-pressurization to 800 mbar, pressed the rubber stopper tightly to the full pressing state, and re-pressurized to normal pressure.

10. The method according to claim 9, characterized in that: The pre-freezing includes the following steps: first, pre-cool the shelf temperature to 10°C, cool it from 10°C to -4°C within 30 minutes, and then keep it at -4°C for 30 to 60 minutes; then cool the shelf temperature from -4°C to about -40°C within 90 minutes, and then keep it at about -40°C for 120 to 180 minutes; finally, heat the shelf temperature from about -40°C to -15°C within 50 minutes, and then keep it at -15°C for 90 to 120 minutes; The vacuum pumping includes the following steps: turn on the vacuum pump and maintain the vacuum degree in the freeze-drying chamber at 20 Pa; The primary drying includes the following steps: heat the shelf temperature from -15°C to 20°C within 1 hour for primary drying, and then keep it at 20°C for 900 to 1100 minutes, with the vacuum degree maintained at 20 Pa; The secondary drying includes the following steps: heat the shelf temperature from 20°C to about 30°C within 20 minutes, and then keep it at about 30°C for 360 to 420 minutes, with the vacuum degree maintained at 20 Pa; heat the shelf temperature from 30°C to 43°C within 26 minutes, and then keep it at about 43°C for 240 to 300 minutes, with the vacuum degree maintained at 20 Pa.

11. The injection according to claim 6, wherein the bacterial endotoxin of the isavuconazole sulfate raw material drug is < 0.3 Eu / mg, the bacterial endotoxin of mannitol is < 2.5 Eu / g, and the bacterial endotoxin of the isavuconazole sulfate freeze-dried powder is < 0.9 Eu / mg.

12. The injection according to any one of claims 1 to 6, characterized in that the rubber stopper with moisture below 0.4% is obtained by drying the commercially available rubber stopper.

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