Aztreonam avibactam sodium lyophilized preparation for injection and preparation method thereof

Abstract

The invention discloses a freeze-dried preparation of aztreonam avibactam sodium for injection and a preparation method thereof, wherein the preparation method comprises freeze-drying an aqueous solution of aztreonam avibactam sodium, wherein the freeze-drying comprises sequentially pre-freeze-thaw, secondary freezing, sublimation drying and analytical drying; the pre-freeze-thaw comprises: cooling the aqueous solution of aztreonam avibactam sodium to ‑30-‑50° C., keeping for 2-6 hours, then heating to ‑10-0° C., keeping for 1-10 hours; the secondary freezing comprises: cooling to ‑30-‑50° C., keeping for 2-6 hours. In the present invention, the pre-freeze-thaw is firstly thawed and then re-frozen again during the freeze-drying process, so that the moisture content in the final freeze-dried product can be reduced to less than 1.0%, and the prepared freeze-dried preparation of aztreonam avibactam sodium for injection has low moisture and good stability.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a freeze-dried aztreonam avibactam sodium preparation for injection and a preparation method thereof. Background Art

[0002] Aztrenom is a monocyclic β-lactamase inhibitor that inhibits bacterial cell wall synthesis by blocking peptidoglycan cross-linking and has strong activity against sensitive Gram-negative bacteria. Avibactam is a diazabicyclic reversible β-lactamase inhibitor. Since avibactam itself does not have antibacterial activity, it needs to be combined with other antibiotics for clinical use.

[0003] Currently, there are very limited clinical treatments for Gram-bacterial infections that produce metallo-β-lactamases (MBL). Aztreonam is one of the few antibiotics that is not inactivated by MBL, but because the vast majority of MBL-producing bacteria also express serine-β-lactamases that inactivate aztreonam, the bactericidal effect of aztreonam when used alone is extremely limited. Avibactam can inhibit a variety of serine-β-lactamases, and the combined use of the two drugs can have a synergistic effect and is active against 80% of MBL isolates. Therefore, the development of a combination preparation of aztreonam and avibactam sodium can meet the clinical demand for effectively killing MBL-producing bacteria while its bactericidal effect is not inhibited.

[0004] Aztreonam and avibactam are not or almost not absorbed orally, but after intravenous or intramuscular injection, they can be rapidly and widely distributed in various tissues in the body, thereby achieving a therapeutic effect. In addition, the aqueous solutions of the two drugs have poor stability and cannot withstand hot pressure sterilization. Therefore, their preparations are suitable for development into powder injections or freeze-dried powder injections.

[0005] Currently, there is no combination of aztreonam and avibactam on the market.

[0006] Announcement number is that the Chinese patent literature of CN101579336B discloses a kind of preparation method of aztreonam for injection, and the method uses powder packing mode to prepare aztreonam for injection, but aztreonam and auxiliary material arginine all need to adopt aseptic process preparation, and cost is higher, and material needs to be mixed through long-time pulverizing (more than 2 hours).These operating procedures all can increase the time that aseptic material is exposed in the environment, greatly increase the microbial contamination risk of finished product, and environment, equipment, personnel requirements are extremely high, greatly increase production cost, and can't solve the problem that the re-dissolution time is slow.

[0007] A Chinese patent document with publication number CN101548956B discloses a freeze-dried microemulsion preparation of aztreonam, but the biodegradable polymer used therein is harmful to the human body and therefore cannot be used clinically.

[0008] The Chinese patent document with announcement number CN107789355B discloses a compound preparation containing piperacillin and avibactam, which confirms that the combined use of β-lactam antibiotics and β-lactamase inhibitors is more effective than single antibiotics. However, there is no in-depth research on the preparation method of the preparation, and the moisture content and stability of the finished product have not been tested, making it difficult to prove the feasibility of industrial production of the invention.

[0009] The ceftazidime avibactam sodium for injection currently used in clinical practice is produced using a sterile packaging process. The drug was once tried using a freeze-drying process, but the development of the freeze-dried preparation was discontinued because the crystal form of ceftazidime changed after freeze-drying, the stability became poor, and it could not meet the quality standard requirements.

[0010] Aztreonam avibactam sodium for injection can be obtained by aseptic subpackaging or lyophilization of powder. The process of aseptic subpackaging has higher requirements on material fluidity, especially because avibactam sodium has significant hygroscopicity when ambient humidity is above 60%RH, and is highly sensitive to moisture (requires less than 1.0%), and needs to be controlled at humidity 40%RH or even as low as 30%RH during production, to reduce the amount of moisture in the material absorption environment, which increases the difficulty of industrialized amplification production. In addition, aseptic subpackaging process, three materials are aztreonam, avibactam sodium, L-arginine and all need to be made into sterile powder, and aztreonam / L-arginine mixed powder also needs to be mixed and subpacked under aseptic conditions, and finally compound preparation also needs to be mixed or subpacked under aseptic conditions during subpackaging, wherein at least 5 production processes need to ensure aseptic, this undoubtedly increases the risk of the manufacturer to the management of sterile assurance level, and also significantly increases production cost. The freeze-drying process does not require sterility for all raw and auxiliary materials. During the production process, it only needs to be filtered and sterilized before freeze-drying. There is only one exposure step, and the sterility risk is significantly reduced. Therefore, the development of the freeze-drying process for aztreonam avibactam sodium injection is particularly urgent.

[0011] After years of research, it was found that since the material is sensitive to moisture, the moisture content is required to be below 1.0%, but conventional freeze-drying processes make it difficult to control the moisture content of the sample below 1.0%. Summary of the invention

[0012] The invention provides a freeze-dried aztreonam avibactam sodium preparation for injection and a preparation method thereof. The freeze-dried aztreonam avibactam sodium preparation for injection has low water content and good stability.

[0013] The technical solution of the present invention is as follows:

[0014] A method for preparing a freeze-dried preparation of aztreonam avibactam sodium for injection, comprising freeze-drying an aqueous solution of aztreonam avibactam sodium, wherein the freeze-drying comprises sequentially performing pre-freeze-thaw, secondary freezing, sublimation drying and analytical drying;

[0015] The pre-freeze-thaw process comprises: cooling the aqueous solution of aztreonam avibactam sodium to -30 to -50°C, maintaining the temperature for 2 to 6 hours, and then heating the aqueous solution to -10 to 0°C, maintaining the temperature for 1 to 10 hours;

[0016] The secondary freezing comprises: cooling to -30 to -50°C and maintaining for 2 to 6 hours.

[0017] Using conventional freeze-drying process, whether the pre-freezing process is rapid cooling or slow cooling, or changing the drying temperature and extending the drying time, the moisture content of the freeze-dried preparation of aztreonam avibactam sodium cannot be controlled below 1.0%. In the research and development process of the present invention, the inventor surprisingly found that the moisture content in the final freeze-dried product can be reduced to below 1.0% by pre-freezing and thawing and then refreezing in the freeze-drying process. This unexpected effect greatly reduces the moisture content in the freeze-dried product compared with the products of the previous conventional freeze-drying process. The reason may be that after the pre-freeze-thaw process, the crystal nuclei in the drug solution increase, so that the supercooling temperature in the secondary freezing process is higher, the product crystallization is more complete, the proportion of amorphous matter is reduced, thereby increasing the specific surface area of ​​the solid matter, and then increasing the freeze-drying rate and efficiency.

[0018] A large number of experiments have shown that the unconventional freeze-drying process of the present invention can significantly reduce the moisture content of the freeze-dried preparation while maintaining its structural integrity and high activity, making its quality more stable.

[0019] Preferably, during the pre-freeze-thaw process, the cooling rate is 0.2 to 1°C / min, and the heating rate is 0.2 to 1°C / min.

[0020] Further preferably, the pre-freeze-thaw comprises: pre-cooling the freeze dryer plate layer, adding the aztreonam avibactam sodium aqueous solution, cooling to -35 to -45°C at a rate of 0.5 to 1°C / min, maintaining for 3 to 4 hours, and then heating to -10 to 0°C at a rate of 0.2 to 1°C / min, and maintaining for 1 to 10 hours.

[0021] Preferably, during the secondary freezing process, the cooling rate is 0.2-1°C / min.

[0022] Preferably, the sublimation drying comprises: reducing the vacuum degree of the freeze dryer plate layer to 0.1-0.6 mbar within 5-30 minutes, and simultaneously raising the temperature of the freeze dryer plate layer to -15-15°C at a rate of 0.2-1°C / min, and maintaining it for 8-20 hours.

[0023] Further preferably, the sublimation drying comprises: reducing the vacuum degree of the freeze dryer plate layer to 0.2-0.5 mbar within 5-20 minutes, and simultaneously raising the temperature of the freeze dryer plate layer to -10-10°C at a rate of 0.3-0.8°C / min, and maintaining it for 10-20 hours.

[0024] Preferably, the analytical drying comprises: raising the temperature of the freeze dryer plate layer to 20-60° C. at a rate of 0.2-0.5° C. / min, and evacuating to 0-0.6 mbar for 10-24 hours.

[0025] Further preferably, the analytical drying comprises: reducing the vacuum degree of the freeze dryer plate layer to 0-0.4 mbar within 5-10 minutes, and at the same time increasing the temperature of the freeze dryer plate layer to 20-45°C at a rate of 0.3-0.8°C / min, and maintaining it for 10-18 hours.

[0026] The aztreonam avibactam sodium aqueous solution comprises aztreonam, avibactam sodium and auxiliary materials.

[0027] Preferably, in the freeze-dried preparation of aztreonam and avibactam sodium for injection, the weight ratio of aztreonam to avibactam sodium is 4 to 1:1.

[0028] The auxiliary materials include cosolvent and pH regulator.

[0029] Preferably, in the freeze-dried preparation of aztreonam avibactam sodium for injection, the weight ratio of aztreonam to the co-solvent is 1:0.7-0.9.

[0030] The cosolvent is L-arginine; the pH regulator includes at least one of hydrochloric acid, proline, lysine, glycine, arginine, sorbic acid, citric acid, sodium citrate, tartaric acid, glacial acetic acid, sodium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium hydroxide.

[0031] Preferably, in the aqueous solution of aztreonam avibactam sodium, the mass concentration of the solute is 12-40%.

[0032] Before freeze-drying, the solute concentration of the aqueous solution of aztreonam avibactam sodium has a certain influence on the performance of the freeze-dried preparation. An overly concentrated solution will make the drying layer too dense, resulting in insufficient sublimation channels and making it impossible for water to escape. An overly dilute solution will make it difficult to remove the bound water on the surface of the solid matter due to the low density of the drying layer and poor thermal conductivity. When the mass concentration of the solute in the solution is 12-40%, the moisture content of the obtained freeze-dried preparation is below 1.0%.

[0033] More preferably, the aztreonam avibactam sodium aqueous solution is placed in a vial for freeze-drying, and the volume of the aztreonam avibactam sodium aqueous solution is 3 to 12 ml.

[0034] Preferably, the pH of the aztreonam avibactam sodium aqueous solution is 4-8.

[0035] The preparation method of the aztreonam avibactam sodium aqueous solution comprises:

[0036] (A) adding the prescribed amount of aztreonam, avibactam sodium and cosolvent into a container containing part of the water for injection, stirring and dissolving;

[0037] (B) adding a pH adjuster to adjust the pH value of the solution;

[0038] (C) lowering the solution temperature to 2-8°C;

[0039] (D) Add water for injection to make up to the prescribed volume.

[0040] The present invention also provides a freeze-dried preparation of aztreonam avibactam sodium for injection prepared by the preparation method.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] The present invention provides a previously unreported aztreonam-avibactam sodium composite freeze-dried preparation, which has significantly improved antibacterial efficacy compared with single-prescription preparations, especially for MBL-producing Gram infections with limited clinical treatment methods.

[0043] At the same time, the freeze-drying process adopted in the present invention only requires a one-step sterilization and filtration process. Compared with the powder packaging process, it greatly reduces the risk of bacterial contamination during the production process and significantly improves the level of sterility assurance.

[0044] On the other hand, the present invention creatively adopts a freeze-drying process of secondary freeze-thawing, which solves the problem of low moisture that cannot be achieved by conventional freeze-drying processes, so that the final moisture content of the product reaches below 1.0%, significantly improves the stability of the product, and is conducive to the industrial scale-up production of the product. DETAILED DESCRIPTION

[0045] The present invention will be further described in detail below in conjunction with the examples. It should be pointed out that the examples described below are intended to facilitate the understanding of the present invention and do not have any limiting effect on the present invention.

[0046] Embodiment 1:

[0047] The composition of aztreonam avibactam sodium injection solution is shown in Table 1.

[0048] Table 1

[0049] Raw materials Unit dosage Aztreonam 2.0g L-Arginine 1.62g Avibactam sodium 0.667g (based on avibactam) Water for injection Add to 12mL

[0050] Embodiment 2:

[0051] The composition of aztreonam avibactam sodium injection solution is shown in Table 2.

[0052] Table 2

[0053] Raw materials Unit dosage Aztreonam 1.5g L-Arginine 1.215g Avibactam sodium 500.25mg (calculated as avibactam) Water for injection Add to 10mL

[0054] Embodiment 3:

[0055] The composition of aztreonam avibactam sodium injection solution is shown in Table 3.

[0056] Table 3

[0057]

[0058]

[0059] Embodiment 4:

[0060] The composition of aztreonam avibactam sodium injection solution is shown in Table 4.

[0061] Table 4

[0062] Raw materials Unit dosage Aztreonam 0.5g L-Arginine 405mg Avibactam sodium 167mg (as avibactam) Water for injection Add to 3mL

[0063] Embodiment 5:

[0064] The composition of aztreonam avibactam sodium injection solution is shown in Table 5.

[0065] Table 5

[0066] Raw materials Unit dosage Aztreonam 1.0g L-Arginine 0.78g Avibactam sodium 334mg (as avibactam) Water for injection Add to 15mL

[0067] Embodiment 6:

[0068] The composition of aztreonam avibactam sodium injection solution is shown in Table 6.

[0069] Table 6

[0070] Raw materials Unit dosage Aztreonam 0.5g L-Arginine 390mg Avibactam sodium 167mg (as avibactam) Water for injection Add to 7.5 mL

[0071] Embodiment 7:

[0072] The composition of aztreonam avibactam sodium injection solution is shown in Table 7.

[0073] Table 7

[0074]

[0075]

[0076] Embodiment 8:

[0077] The composition of aztreonam avibactam sodium injection solution is shown in Table 8.

[0078] Table 8

[0079] Raw materials Unit dosage Aztreonam 0.5g L-Arginine 390mg Avibactam sodium 167mg (as avibactam) Water for injection Add to 4 mL

[0080] The freeze-drying process of Examples 1 to 8 is as follows:

[0081] A. Plate precooling: The freeze dryer plate is precooled to 2-8℃ before loading;

[0082] B. Prefreezing: Cool the aztreonam avibactam sodium solution to -30--50°C at a rate of 0.2-1°C / min, and keep it for 2-6 hours; heat it to -10-0°C at a rate of 0.2-1°C / min, and keep it for 1-10 hours; cool it to -30--50°C at a rate of 0.2-1°C / min, and keep it for 2-6 hours;

[0083] C. Sublimation drying: reduce the vacuum degree to 0.1-0.6 mbar within 5-30 minutes, and at the same time increase the plate temperature to -15-15°C at a rate of 0.2-1°C / min, and maintain for 8-20 hours;

[0084] D. Desorption drying: Raise the temperature to 20-45°C at a rate of 0.2-0.5°C / min, and evacuate to 0-0.6 mbar for 10-24 hours.

[0085] The specific process parameters are shown in Table 9.

[0086] Table 9

[0087]

[0088] Comparative Example 1:

[0089] The composition of aztreonam avibactam sodium for powder injection is shown in Table 10.

[0090] Table 10

[0091] Raw materials Unit dosage Aztreonam 1.0g L-Arginine 800mg Avibactam sodium 334mg

[0092] Comparative Example 2:

[0093] The composition of aztreonam avibactam sodium for powder injection is shown in Table 11.

[0094] Table 11

[0095] Raw materials Unit dosage Aztreonam 1.0g L-Arginine 1.0g Avibactam sodium 334mg

[0096] Comparative Example 3:

[0097] The composition of aztreonam avibactam sodium for injection in powder form is shown in Table 12.

[0098] Table 12

[0099] Raw materials Unit dosage Aztreonam 1.0g L-Arginine 1.2g Avibactam sodium 334mg (as avibactam)

[0100] Comparative Example 4:

[0101] The composition of aztreonam avibactam sodium injection solution is shown in Table 13.

[0102] Table 13

[0103] Raw materials Unit dosage Aztreonam 1.5g L-Arginine 1.215g Avibactam sodium 500.25mg (calculated as avibactam) Water for injection Add to 10mL

[0104] The freeze-drying process is as follows:

[0105] A. Plate precooling: The freeze dryer plate is precooled to 2-8℃ before loading;

[0106] B. Prefreezing: Cool the aztreonam avibactam sodium solution to -30 to -50°C at a rate of 0.2 to 1°C / min and keep it for 2 to 6 hours;

[0107] C. Sublimation drying: reduce the vacuum degree to 0.1-0.6 mbar within 5-30 minutes, and at the same time increase the plate temperature to -15-15°C at a rate of 0.2-1°C / min, and maintain for 8-20 hours;

[0108] D. Desorption drying: Raise the temperature to 20-45°C at a rate of 0.2-0.5°C / min, and evacuate to 0-0.6 mbar for 10-24 hours.

[0109] The specific process parameters are shown in Table 14.

[0110] Table 14

[0111]

[0112] Comparative Example 5:

[0113] The composition of aztreonam avibactam sodium injection solution is shown in Table 15.

[0114] Table 15

[0115] Raw materials Unit dosage Aztreonam 2.0g L-Arginine 1.62g Avibactam sodium 0.667g (based on avibactam) Water for injection Add to 6mL

[0116] Comparative Example 6:

[0117] The composition of aztreonam avibactam sodium injection solution is shown in Table 16.

[0118] Table 16

[0119] Raw materials Unit dosage Aztreonam 2.0g L-Arginine 1.62g Avibactam sodium 0.667g (based on avibactam) Water for injection Add to 8mL

[0120] Comparative Example 7:

[0121] The composition of aztreonam avibactam sodium solution for injection is shown in Table 17.

[0122] Table 17

[0123]

[0124]

[0125] The freeze-drying process of Comparative Examples 5 to 7 is as follows:

[0126] A. Prefreezing: Cool the aztreonam avibactam sodium solution to -30--50°C at a rate of 0.2-1°C / min and keep it for 2-6 hours;

[0127] B. Sublimation drying: reduce the vacuum degree to 0.1-0.6 mbar within 5-30 minutes, and at the same time increase the plate temperature to -20-20°C at a rate of 0.2-1°C / min, and maintain for 8-20 hours;

[0128] C. Desorption and drying: Raise the temperature to 20-45°C at a rate of 0.2-0.5°C / min, and evacuate to 0-0.6 mbar for 10-24 hours.

[0129] The specific process parameters are shown in Table 18.

[0130] Table 18

[0131]

[0132] Comparative Example 8:

[0133] The composition of aztreonam avibactam sodium solution for injection is shown in Table 19.

[0134] Table 19

[0135] Raw materials Unit dosage Aztreonam 2.0g L-Arginine 1.62g Avibactam sodium 0.667g (based on avibactam) Water for injection Add to 12mL

[0136] Comparative Example 9:

[0137] The composition of aztreonam avibactam sodium injection solution is shown in Table 20.

[0138] Table 20

[0139]

[0140]

[0141] Comparative Example 10:

[0142] The composition of aztreonam avibactam sodium solution for injection is shown in Table 21.

[0143] Table 21

[0144] Raw materials Unit dosage Aztreonam 2.0g L-Arginine 1.62g Avibactam sodium 0.667g (based on avibactam) Water for injection Add to 20mL

[0145] The freeze-drying process of Comparative Examples 8 to 10 is as follows:

[0146] A. Plate precooling: The freeze dryer plate is precooled to 2-8℃ before loading;

[0147] B. Prefreezing: Cool the aztreonam avibactam sodium solution to -30 to -50°C at a rate of 0.2 to 1°C / min and keep it for 2 to 6 hours;

[0148] C. Sublimation drying: reduce the vacuum degree to 0.1-0.6 mbar within 5-30 minutes, and at the same time increase the plate temperature to -15-25°C at a rate of 0.2-1°C / min, and maintain for 8-20 hours;

[0149] D. Desorption drying: Raise the temperature to 20-45°C at a rate of 0.2-0.5°C / min, and evacuate to 0-0.6 mbar for 10-24 hours.

[0150] The specific process parameters are shown in Table 22.

[0151] Table 22

[0152]

[0153] Comparative Example 11:

[0154] The composition of aztreonam avibactam sodium injection solution is shown in Table 23.

[0155] Table 23

[0156]

[0157]

[0158] Comparative Example 12:

[0159] The composition of aztreonam avibactam sodium solution for injection is shown in Table 24.

[0160] Table 24

[0161] Raw materials Unit dosage Aztreonam 0.5g L-Arginine 390mg Avibactam sodium 167mg (as avibactam) Water for injection Add to 4 mL

[0162] The freeze-drying process of Comparative Examples 11 to 12 is as follows:

[0163] A. Plate precooling: The freeze dryer plate is precooled to 2-8℃ before loading;

[0164] B. Prefreezing: Cool the aztreonam avibactam sodium solution to -30 to -50°C at a rate of 0.2 to 1°C / min and keep it for 2 to 6 hours;

[0165] C. Sublimation drying: reduce the vacuum degree to 0.1-0.6 mbar within 5-30 minutes, and at the same time increase the plate temperature to -15-15°C at a rate of 0.2-1°C / min, and maintain for 8-20 hours;

[0166] D. Desorption drying: Raise the temperature to 20-45°C at a rate of 0.2-0.5°C / min, and evacuate to 0-0.6 mbar for 10-24 hours.

[0167] The specific process parameters are shown in Table 25.

[0168] Table 25

[0169]

[0170] The test results of the above embodiments and comparative examples are compared:

[0171] 1. Related substances

[0172] (1) Detection method of aztreonam-related substances: Check according to the analytical method listed in the Chinese Pharmacopoeia (202nd edition);

[0173] (2) Detection method of avibactam related substances:

[0174] Chromatographic column: porous graphite carbon column (Thermo Hypercarb, 100*4.6mm, 5μm);

[0175] Mobile phase: potassium dihydrogen phosphate / acetonitrile solution;

[0176] Detection wavelength: 195nm; flow rate: 1.5mL / min; column temperature 60℃; injection plate temperature: 8℃; injection volume: 10μL;

[0177] 2. Redissolution time

[0178] Add 10 mL of water to every 1 g of aztreonam, shake gently to dissolve, and record the dissolution time;

[0179] 3. pH value

[0180] Add 10 mL of water to every 1 g of aztreonam, shake gently to dissolve, and measure the pH value;

[0181] 4. Moisture

[0182] Determined by Karl Fischer method.

[0183] Test Example 1

[0184] The physical properties of the drugs prepared in the above embodiments and comparative examples are summarized in Table 26.

[0185] Table 26

[0186]

[0187]

[0188] Test Example 2:

[0189] The stability data of the drugs prepared in the above embodiments and comparative examples are shown in Table 27.

[0190] Table 27

[0191]

[0192]

[0193] The stability results in Table 2 show that the growth trend of related substances in the freeze-dried samples prepared by the present invention is similar to that in the powder packaging samples, indicating that the freeze-drying process of the present invention has no adverse effect on product quality. By adopting the freeze-drying process of the present invention, a freeze-dried preparation of aztreonam avibactam sodium for injection with good stability and low risk of contamination, which has not yet been reported in research and development, can be prepared.

[0194] The embodiments described above provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements and equivalent substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a freeze-dried preparation of aztreonam avibactam sodium for injection, characterized in that: The method comprises freeze-drying an aqueous solution of aztreonam avibactam sodium, wherein the freeze-drying comprises sequentially performing pre-freeze-thaw, secondary freezing, sublimation drying and analytical drying; The pre-freeze-thaw process comprises: cooling the aqueous solution of aztreonam avibactam sodium to -30 to -50°C, maintaining the temperature for 2 to 6 hours, and then heating the aqueous solution to -10 to 0°C, maintaining the temperature for 1 to 10 hours; during the pre-freeze-thaw process, the cooling rate is 0.2 to 1°C / min, and the heating rate is 0.2 to 1°C / min; The secondary freezing comprises: cooling to -30 to -50°C and maintaining for 2 to 6 hours; In the aztreonam avibactam sodium aqueous solution, the mass concentration of the solute is 12-40%.

2. The method for preparing the lyophilized preparation of aztreonam avibactam sodium for injection according to claim 1, wherein The pre-freeze-thaw process comprises: pre-cooling the freeze dryer plate layer, adding the aztreonam avibactam sodium aqueous solution, cooling to -35--45°C at a rate of 0.5-1°C / min, maintaining for 3-4 hours, and then heating to -10-0°C at a rate of 0.2-1°C / min, maintaining for 1-10 hours.

3. The method for preparing the lyophilized preparation of aztreonam avibactam sodium for injection according to claim 1, characterized in that: During the secondary freezing process, the cooling rate is 0.2-1°C / min.

4. The method for preparing the lyophilized preparation of aztreonam avibactam sodium for injection according to claim 1, wherein The sublimation drying comprises: reducing the vacuum degree of the freeze dryer plate layer to 0.1-0.6 mbar within 5-30 minutes, and simultaneously raising the temperature of the freeze dryer plate layer to -15-15°C at a rate of 0.2-1°C / min, and maintaining it for 8-20 hours.

5. The method for preparing the lyophilized preparation of aztreonam avibactam sodium for injection according to claim 1, characterized in that: The analytical drying comprises: raising the temperature of the freeze dryer plate layer to 20-60° C. at a rate of 0.2-0.5° C. / min, and evacuating to 0-0.6 mbar for 10-24 hours.

6. The method for preparing the lyophilized preparation of aztreonam avibactam sodium for injection according to claim 1, characterized in that: The aztreonam avibactam sodium aqueous solution comprises aztreonam, avibactam sodium and auxiliary materials.

7. The method for preparing the lyophilized preparation of aztreonam avibactam sodium for injection according to claim 1, characterized in that: In the freeze-dried preparation of aztreonam and avibactam sodium for injection, the weight ratio of aztreonam to avibactam sodium is 4-1:

1.

8. The method for preparing the lyophilized preparation of aztreonam avibactam sodium for injection according to claim 1, characterized in that: The auxiliary materials include a cosolvent and a pH regulator; the cosolvent is L-arginine.

9. A lyophilized preparation of aztreonam avibactam sodium for injection, characterized in that: The method is described in any one of claims 1 to 8.

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