Production process for carfilzomib freeze-drying preparation for injection

Abstract

The invention discloses a production process for a carfilzomib freeze-drying preparation for injection, which comprises the following steps: compounding a biodegradable high polymer material and natural polysaccharide to form a nano-scale coating material, and preparing a nano-particle suspension; carfilzomib is placed in the nano-particle suspension, after ultrasonic dispersion, phase separation freeze-drying treatment is carried out, and a carfilzomib freeze-drying agent is obtained; the invention relates to the technical field of freeze-drying preparation preparation. According to the production process for the carfilzomib freeze-drying preparation for injection, carfilzomib is coated through compounding of the biodegradable high polymer material and the natural polysaccharide, oxygen and moisture are effectively isolated, degradation of carfilzomib is reduced, the redissolving efficiency is high, the carfilzomib freeze-drying preparation has the advantage of slow release, blood concentration fluctuation is effectively reduced, the injection frequency of carfilzomib is reduced, and the carfilzomib freeze-drying preparation is suitable for clinical application. According to the method, carfilzomib can be efficiently utilized, auxiliary material residues are further reduced in a phase separation freeze-drying oriented deposition mode, the occurrence probability of irritant anaphylactic reaction risks can be reduced, and the method has a wide application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of freeze-dried preparation preparation, in particular to a production process for a freeze-dried carfilzomib preparation for injection. Background Art

[0002] Carfilzomib is a proteasome inhibitor suitable for the treatment of multiple myeloma patients. Although carfilzomib has good anti-tumor effects, it has poor water solubility, poor stability in water, and is prone to produce impurities. Therefore, lyophilized preparations are a more ideal dosage form. In addition, carfilzomib N-oxide is easily produced under contact with oxygen, so oxygen needs to be isolated during the preparation process.

[0003] For example, the production process of a lyophilized preparation of carfilzomib for injection described in application number 201911198442.0 includes sulfobutyl-β-cyclodextrin, anhydrous citric acid and sodium hydroxide. After cyclodextrin enters the human blood circulation system, it will increase the burden on the kidneys. At the same time, cyclodextrin can react with the cell membrane of the inner wall of blood vessels, causing cell damage. Long-term use may cause venous spasm and phlebitis, posing a safety hazard.

[0004] Based on the search of the above information, it can be seen that the existing carfilzomib lyophilized preparations for injection have high residual excipients and pose safety hazards. In addition, during long-term storage, the impurity content increases rapidly and the stability is poor. It cannot be sustained-released during use, and the blood drug concentration fluctuates greatly, making it impossible to achieve continuous targeted output. For this reason, a production process for carfilzomib lyophilized preparations for injection is proposed, which eliminates safety hazards while having high stability and can be put into use within a shorter reconstitution time to achieve continuous targeted output in a sustained-release manner. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a production process for a lyophilized preparation of carfilzomib for injection, which solves the problems of high residual excipients in the existing lyophilized preparation of carfilzomib for injection, potential safety hazards in use, rapid growth of impurity content during long-term storage, poor stability, inability to perform sustained release during use, large fluctuations in blood drug concentration, and inability to achieve continuous targeted output.

[0006] To achieve the above objectives, the present invention is implemented by the following technical scheme: A production process for a lyophilized preparation of carfilzomib for injection, specifically comprising the following steps: S1. Compounding a biodegradable polymer material with a natural polysaccharide to form a nanoscale coating material, and preparing the nanoscale coating material into a nanoparticle suspension; S2. Place carfilzomib in a nanoparticle suspension, disperse it by ultrasonication, and then perform a phase separation and freeze-drying process to obtain a carfilzomib lyophilized agent.

[0007] The present invention is further configured as follows: the biodegradable polymer material in S1 is a polylactic acid-glycolic acid copolymer, wherein the weight ratio of polylactic acid to glycolic acid is 50-80:20-50, wherein the weight ratio of polylactic acid to glycolic acid is preferably 75:25, and meets the FDA injection material standards; The weight ratio of carfilzomib to polylactic acid-glycolic acid copolymer is 1:5-10.

[0008] The present invention is further configured as follows: the natural polysaccharide in S1 comprises sodium alginate and mannitol, wherein the weight ratio of sodium alginate to mannitol is 3:1; The weight ratio of carfilzomib to natural polysaccharide is 1:1-5.

[0009] The present invention is further configured as follows: the method for preparing the nanoparticle suspension in S1 comprises: A1. Add natural polysaccharide to deionized water to obtain a natural polysaccharide aqueous solution, and introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm; A2, adding the biodegradable polymer material to the natural polysaccharide aqueous solution, and emulsifying it by a high-speed homogenizer at 10000-15000 rpm to obtain an emulsion; A3. Transfer the emulsion to a rotary evaporator and evaporate the organic solvent under reduced pressure at 40-50°C to obtain a nanoparticle suspension.

[0010] The present invention is further configured as follows: during the emulsification process of A2, an ultrasonic probe is used for ultrasonic treatment at a frequency of 20-40kHz and a power of 100-200W for 5-10 minutes.

[0011] The present invention is further configured as follows: the specific method of performing the phase separation freeze-drying process in S2 includes: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 4-6 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5mbar, maintain for 4-6h, remove free water and solvent residue; B3, phase separation: cool down to -50℃ at a rate of 2℃ / min, maintain for 6-8h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 4-6 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

[0012] The present invention provides a production process for a lyophilized preparation of carfilzomib for injection, which has the following beneficial effects: The present invention coats carfilzomib by combining biodegradable polymer materials with natural polysaccharides, effectively isolates oxygen and moisture, reduces carfilzomib degradation, has high reconstitution efficiency, and has the advantage of sustained release, effectively reduces blood drug concentration fluctuations, reduces the injection frequency of carfilzomib, and achieves efficient utilization of carfilzomib. In addition, the residual auxiliary materials are further reduced by phase separation freeze-drying directional deposition, which can reduce the occurrence rate of irritant allergic reactions and has broad application prospects. DETAILED DESCRIPTION

[0013] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0014] The embodiment of the present invention provides the following technical solutions: Embodiment 1 A production process for a lyophilized carfilzomib preparation for injection, comprising the following steps: S1. Weigh sodium alginate and mannitol in a weight ratio of 3:1 as natural polysaccharides, weigh seaweed in a ratio of 1 weight part and add to deionized water to obtain a natural polysaccharide aqueous solution with a concentration of 1% to 3% w / v, introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm, dissolve 5 weight parts of polylactic acid-glycolic acid copolymer (polylactic acid: glycolic acid = 75:25) in dichloromethane to obtain a polylactic acid-glycolic acid solution with a concentration of 100 mg / mL, add polylactic acid-glycolic acid to the natural polysaccharide aqueous solution, and emulsify it with a high-speed homogenizer at 12000 rpm to obtain an emulsion. During the process, use an ultrasonic probe to perform ultrasonic treatment at a frequency of 30 kHz and a power of 150 W for 8 minutes, transfer the emulsion to a rotary evaporator, evaporate dichloromethane under reduced pressure at 45°C, and obtain a nanoparticle suspension; S2. Place 1 part by weight of carfilzomib in the nanoparticle suspension, disperse it ultrasonically for 10 minutes, and then transfer it to a freeze dryer for phase separation and freeze drying. Specifically: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 5 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5 mbar, maintain for 56 hours, remove free water and solvent residue; B3, phase separation: cool down to -50°C at a rate of 2°C / min, maintain for 7h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 5 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

[0015] Embodiment 2 A production process for a lyophilized carfilzomib preparation for injection, comprising the following steps: S1. Weigh sodium alginate and mannitol in a weight ratio of 3:1 as natural polysaccharides, weigh 3 parts by weight of seaweed and add them into deionized water to obtain a natural polysaccharide aqueous solution with a concentration of 1% to 3% w / v, introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm, dissolve 5 parts by weight of polylactic acid-glycolic acid copolymer (polylactic acid:glycolic acid=75:25) in dichloromethane to obtain a polylactic acid-glycolic acid solution with a concentration of 100 mg / mL, add polylactic acid-glycolic acid to the natural polysaccharide aqueous solution, emulsify it with a high-speed homogenizer at 12000 rpm to obtain an emulsion, use an ultrasonic probe to perform ultrasonic treatment at a frequency of 30 kHz and a power of 150 W for 8 min, transfer the emulsion to a rotary evaporator, evaporate dichloromethane under reduced pressure at 45°C, and obtain a nanoparticle suspension; S2. Place 1 part by weight of carfilzomib in the nanoparticle suspension, disperse it ultrasonically for 10 minutes, and then transfer it to a freeze dryer for phase separation and freeze drying. Specifically: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 5 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5 mbar, maintain for 56 hours, remove free water and solvent residue; B3, phase separation: cool down to -50°C at a rate of 2°C / min, maintain for 7h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 5 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

[0016] Embodiment 3 A production process for a lyophilized carfilzomib preparation for injection, comprising the following steps: S1. Weigh sodium alginate and mannitol in a weight ratio of 3:1 as natural polysaccharides, weigh 5 parts by weight of seaweed and add them into deionized water to obtain a natural polysaccharide aqueous solution with a concentration of 1% to 3% w / v, introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm, dissolve 5 parts by weight of polylactic acid-glycolic acid copolymer (polylactic acid:glycolic acid=75:25) in dichloromethane to obtain a polylactic acid-glycolic acid solution with a concentration of 100 mg / mL, add polylactic acid-glycolic acid to the natural polysaccharide aqueous solution, and emulsify it with a high-speed homogenizer at 12000 rpm to obtain an emulsion. During the process, use an ultrasonic probe to perform ultrasonic treatment at a frequency of 30 kHz and a power of 150 W for 8 minutes, transfer the emulsion to a rotary evaporator, evaporate dichloromethane under reduced pressure at 45°C, and obtain a nanoparticle suspension; S2. Place 1 part by weight of carfilzomib in the nanoparticle suspension, disperse it ultrasonically for 10 minutes, and then transfer it to a freeze dryer for phase separation and freeze drying. Specifically: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 5 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5 mbar, maintain for 56 hours, remove free water and solvent residue; B3, phase separation: cool down to -50°C at a rate of 2°C / min, maintain for 7h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 5 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

[0017] Embodiment 4 A production process for a lyophilized carfilzomib preparation for injection, comprising the following steps: S1. Weigh sodium alginate and mannitol in a weight ratio of 3:1 as natural polysaccharides, weigh seaweed in a ratio of 1 weight part and add to deionized water to obtain a natural polysaccharide aqueous solution with a concentration of 1% to 3% w / v, introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm, dissolve 10 weight parts of polylactic acid-glycolic acid copolymer (polylactic acid: glycolic acid = 75:25) in dichloromethane to obtain a polylactic acid-glycolic acid solution with a concentration of 100 mg / mL, add polylactic acid-glycolic acid to the natural polysaccharide aqueous solution, emulsify it with a high-speed homogenizer at 12000 rpm to obtain an emulsion, use an ultrasonic probe to perform ultrasonic treatment at a frequency of 30 kHz and a power of 150 W for 8 minutes, transfer the emulsion to a rotary evaporator, evaporate dichloromethane under reduced pressure at 45°C, and obtain a nanoparticle suspension; S2. Place 1 part by weight of carfilzomib in the nanoparticle suspension, disperse it ultrasonically for 10 minutes, and then transfer it to a freeze dryer for phase separation and freeze drying. Specifically: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 5 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5 mbar, maintain for 56 hours, remove free water and solvent residue; B3, phase separation: cool down to -50°C at a rate of 2°C / min, maintain for 7h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 5 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

[0018] Embodiment 5 A production process for a lyophilized carfilzomib preparation for injection, comprising the following steps: S1. Weigh sodium alginate and mannitol in a weight ratio of 3:1 as natural polysaccharides, weigh 3 parts by weight of seaweed and add them into deionized water to obtain a natural polysaccharide aqueous solution with a concentration of 1% to 3% w / v, introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm, dissolve 10 parts by weight of polylactic acid-glycolic acid copolymer (polylactic acid:glycolic acid=75:25) in dichloromethane to obtain a polylactic acid-glycolic acid solution with a concentration of 100 mg / mL, add polylactic acid-glycolic acid to the natural polysaccharide aqueous solution, emulsify it with a high-speed homogenizer at 12000 rpm to obtain an emulsion, use an ultrasonic probe to perform ultrasonic treatment at a frequency of 30 kHz and a power of 150 W for 8 min, transfer the emulsion to a rotary evaporator, evaporate dichloromethane under reduced pressure at 45°C, and obtain a nanoparticle suspension; S2. Place 1 part by weight of carfilzomib in the nanoparticle suspension, disperse it ultrasonically for 10 minutes, and then transfer it to a freeze dryer for phase separation and freeze drying. Specifically: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 5 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5 mbar, maintain for 56 hours, remove free water and solvent residue; B3, phase separation: cool down to -50°C at a rate of 2°C / min, maintain for 7h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 5 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

[0019] Embodiment 6 A production process for a lyophilized carfilzomib preparation for injection, comprising the following steps: S1. Weigh sodium alginate and mannitol in a weight ratio of 3:1 as natural polysaccharides, weigh 5 parts by weight of seaweed and add them into deionized water to obtain a natural polysaccharide aqueous solution with a concentration of 1% to 3% w / v, introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm, dissolve 10 parts by weight of polylactic acid-glycolic acid copolymer (polylactic acid:glycolic acid=75:25) in dichloromethane to obtain a polylactic acid-glycolic acid solution with a concentration of 100 mg / mL, add polylactic acid-glycolic acid to the natural polysaccharide aqueous solution, and emulsify it with a high-speed homogenizer at 12000 rpm to obtain an emulsion. During the process, use an ultrasonic probe to perform ultrasonic treatment at a frequency of 30 kHz and a power of 150 W for 8 minutes, transfer the emulsion to a rotary evaporator, evaporate dichloromethane under reduced pressure at 45°C, and obtain a nanoparticle suspension; S2. Place 1 part by weight of carfilzomib in the nanoparticle suspension, disperse it ultrasonically for 10 minutes, and then transfer it to a freeze dryer for phase separation and freeze drying. Specifically: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 5 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5 mbar, maintain for 56 hours, remove free water and solvent residue; B3, phase separation: cool down to -50°C at a rate of 2°C / min, maintain for 7h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 5 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

[0020] In summary, the weight parts of the added components in Example 1, Example 2, Example 3, Example 4, Example 5 and Example 6 are different as shown in Table 1: Carfilzomib Poly(lactic-co-glycolic acid) Sodium alginate and mannitol Embodiment 1 1 5 1 Embodiment 2 1 5 3 Embodiment 3 1 5 5 Embodiment 4 1 10 1 Embodiment 5 1 10 3 Embodiment 6 1 10 5 Table 1 It should be noted that when preparing the nanoparticle suspension, the particle size is controlled at 100-200 nm, which can be measured by dynamic light scattering.

[0021] Performance Testing The carfilzomib lyophilized agents prepared according to Example 1, Example 2, Example 3, Example 4, Example 5 and Example 6 were divided according to the same weight to obtain several samples 1, sample 2, sample 3, sample 4, sample 5 and sample 6 of the same weight corresponding to the examples, and some samples were tested for mechanical strength, and some samples were added to 10 parts by weight of water for injection to obtain carfilzomib suspensions, and the reconstitution speed and drug effect t50 were judged, as shown in Table 2: Mechanical strength Redissolution speed Drug effects Application Sample 1 Lower 5s 8.52h Suitable for high-dose preparations Sample 2 Low 8s 9.13h Suitable for high-dose preparations Sample 3 hard 12s 9.85h Suitable for high-dose preparations Sample 3 Lower 18s 12.14h Suitable for low-dose preparations Sample 5 Low 25s 12.35h Suitable for low-dose preparations Sample 6 hard 29s 12.65h Suitable for low-dose preparations Table 2 As can be seen from Table 2, the reconstitution speed of the carfilzomib lyophilized agent is less than 30s, and the particle size distribution of the carfilzomib suspensions obtained from the corresponding samples 1, 2, 3, 4, 5 and 6 is tested, and it is found that the polydispersity index PDI is less than or equal to 0.2, which is suitable for emergency medication scenarios, and a stable carfilzomib suspension is formed after reconstitution without particle aggregation. The carfilzomib Zeta potential is -25mV to -30mV, which can ensure the stability of the preparation.

[0022] Comparison test For example, the “production process of a lyophilized preparation of carfilzomib for injection” proposed in the publication number “CN 110882221 A”, its Example 3 is taken as a control sample, and the stability, solubility, bioavailability, and excipient residue are compared with the production process of the lyophilized preparation of carfilzomib for injection proposed in the present invention. The production process of the lyophilized preparation of carfilzomib for injection proposed in the present invention is taken as a new process. The comparison results are shown in Table 3: index Control samples New Technology Advantages stability Impurity growth > 1.0% Impurity growth <0.3% 70%↑ Solubility Reconstitution time>60 seconds Reconstitution time < 30 seconds 50%↑ Bioavailability Large fluctuations in blood drug concentration Has sustained release effect (t50 ≥ 8 hours) Significant ↑ Excipient Residue High residual amount Residue ≤ 0.5% Significant↓ Table 3 It can be seen from Table 3 that the new process proposed in the present invention has significant advantages, wherein the impurity growth amount is measured by an accelerated test. Specifically, the carfilzomib lyophilized agent prepared by the new process proposed in the present invention is tested for 6 months in a constant temperature and humidity chamber at 40°C and a relative humidity of 75% RH. At the same time, a portion of the same carfilzomib lyophilized agent is taken out as a control and stored in a constant temperature and humidity chamber at 25°C and a relative humidity of 60% RH. Samples are taken at the time points corresponding to 0 month, i.e. the initial point, 1 month, 3 months and 6 months, and impurity detection is performed by high performance liquid chromatography and mass spectrometry, wherein the impurities include but are not limited to: carfilzomib acid, carfilzomib oxide, lactic acid and glycolic acid. The test results are shown in Table 4: month Impurity content / % Growth / % 0 0.05 - 1 0.08 0.03 3 0.15 0.10 6 0.35 0.30 Table 4 In summary, it can be seen that the carfilzomib lyophilized agent prepared by the present invention not only reduces the degradation of carfilzomib, but also has the advantages of high reconstitution efficiency and sustained release. The residual excipients can be further reduced by the phase separation freeze-drying directional deposition method, which can reduce the risk of irritant allergic reactions and has broad application prospects.

[0023] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0024] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A production process for a lyophilized preparation of carfilzomib for injection, characterized in that: The specific steps include: S1. Compounding a biodegradable polymer material with a natural polysaccharide to form a nanoscale coating material, and preparing the nanoscale coating material into a nanoparticle suspension; S2. Place carfilzomib in a nanoparticle suspension, disperse it by ultrasonication, and then perform a phase separation and freeze-drying process to obtain a carfilzomib lyophilized agent.

2. The production process of a lyophilized preparation of carfilzomib for injection according to claim 1, characterized in that: The biodegradable polymer material in S1 is a polylactic acid-glycolic acid copolymer, wherein the weight ratio of polylactic acid to glycolic acid is 50-80:20-50; The weight ratio of carfilzomib to polylactic acid-glycolic acid copolymer is 1:5-10.

3. The production process of a lyophilized preparation of carfilzomib for injection according to claim 1, characterized in that: The natural polysaccharide in S1 comprises sodium alginate and mannitol, wherein the weight ratio of sodium alginate to mannitol is 3:1; The weight ratio of carfilzomib to natural polysaccharide is 1:1-5.

4. The production process of a lyophilized carfilzomib preparation for injection according to claim 1, characterized in that: The method for preparing the nanoparticle suspension in S1 comprises: A1. Add natural polysaccharide to deionized water to obtain a natural polysaccharide aqueous solution, and introduce nitrogen until the dissolved oxygen content of the natural polysaccharide aqueous solution is less than 1 ppm; A2, adding the biodegradable polymer material to the natural polysaccharide aqueous solution, and emulsifying it by a high-speed homogenizer at 10000-15000 rpm to obtain an emulsion; A3. Transfer the emulsion to a rotary evaporator and evaporate the organic solvent under reduced pressure at 40-50°C to obtain a nanoparticle suspension.

5. The production process of a lyophilized preparation of carfilzomib for injection according to claim 4, characterized in that: During the emulsification process of A2, an ultrasonic probe is used to perform ultrasonic treatment at a frequency of 20-40 kHz and a power of 100-200 W for 5-10 minutes.

6. The production process of a lyophilized carfilzomib preparation for injection according to claim 1, characterized in that: The specific method of performing the phase separation freeze-drying process in S2 includes: B1. Obtaining an ice crystal network: Cool down to -50°C at a rate of 2°C / min and maintain for 4-6 hours to form an ice crystal network; B2, primary sublimation: heat to -20°C at a rate of 1°C / min, vacuum degree 0.5mbar, maintain for 4-6h, remove free water and solvent residue; B3, phase separation: cool down to -50℃ at a rate of 2℃ / min, maintain for 6-8h, vacuum degree 0.5mbar, and complete directional deposition; B4. Drying: Raise the temperature to 25°C at a rate of 0.5°C / min, maintain for 4-6 hours, and set the vacuum degree to 0.1 mbar to obtain the carfilzomib lyophilized agent.

7. The production process of a lyophilized preparation of carfilzomib for injection according to claim 1, characterized in that: The carfilzomib lyophilized agent is added to water for injection and reconstituted for 1-30 seconds to obtain a carfilzomib suspension for injection.

8. The production process of a lyophilized preparation of carfilzomib for injection according to claim 1, characterized in that: The carfilzomib suspension for injection has a PDI of ≤0.2 and a Zeta potential of -25 mV to -30 mV.