Cetrorelix acetate freeze-dried preparation and preparation method thereof

Abstract

The invention discloses a cetrorelix acetate freeze-dried preparation and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the preparation method comprises the following steps: dissolving cetrorelix acetate and then freeze-drying; the freeze-drying process comprises the following stages: S1, a pre-cooling stage; s2, a pre-freezing stage; s3, a sublimation drying stage; s4, a desorption drying stage; ice crystal nucleation is induced in the pre-cooling stage, so that the product is completely frozen at the pre-freezing temperature, in addition, the desorption drying temperature is increased, the water and impurity levels of the freeze-dried product are reduced, the freeze-drying time is shortened, and the product quality is improved. The product obtained by the technology disclosed by the invention is controllable in key quality attributes such as character, acidity, solution clarity, related substances and the like in a storage process, and is relatively good in stability; the product freeze-drying process time is short, the energy consumption in the production process is reduced, and the production cost is reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a lyophilized cetrorex acetate formulation and its preparation method. Background Technology

[0002] Cetrorelix acetate is a gonadotropin-releasing hormone (GnRH) antagonist. It inhibits the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by competitively binding to pituitary cell membrane receptors with endogenous GnRH, thereby controlling ovarian stimulation, preventing premature ovulation, and aiding in oocyte retrieval and assisted reproductive technology treatments to facilitate conception. After treatment, the antagonistic effect of cetrorelix acetate is completely reversible, and its clinical safety is high. Therefore, cetrorelix acetate has excellent clinical application prospects.

[0003] Patent application CN1112019A discloses a method for preparing cetrorex lyophilized products, including dissolving cetrorex acetate in 30% (v / v) acetic acid and transferring it to half the total volume of water for injection, adding mannitol, and diluting with water for injection to a solution containing 3% acetic acid; filtering with a 0.2 μm filter membrane and dispensing into suitable injection vials; transferring the half-stopped injection vials containing the solution to a lyophilizer and lyophilizing according to a drying program of plate temperature rising from -40℃ to 40℃. The applicant, through repeated experiments, found that the product prepared by this process has poor chemical stability, and under accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%), the deamidated cetrorex impurity (D-21739) increases rapidly.

[0004] Patent application CN112933210A discloses a method for preparing a cetrorex lyophilized pharmaceutical composition, including a method for preparing a final acetic acid concentration of 0%–0.3% (v / v) in the pharmaceutical solution and a filtration method using low-temperature filtration (0–15°C); patent application CN102423484A discloses a "stepwise cooling" pre-freezing process; and patent application CN112807418A discloses a cooling-heating-re-cooling process. Pre-freezing processes: Patent application CN114712315A discloses a pre-freezing process that adds an "annealing (heating-cooling)" step after freezing; patent application CN113616775A discloses a freeze-drying process that controls the cooling rate (0.1~1.5℃ / min) and the vacuum degree of the first drying stage; and patent application CN117883393A discloses a freeze-drying process that divides pre-freezing, sublimation drying, and re-drying into two stages. It is believed that the above patent applications can improve product stability, but the preparation cycle of the drug solution and the freeze-drying cycle are both relatively long, mainly due to the long dissolution time of cetrorex acetate and the long pre-freezing time.

[0005] The formulation and lyophilization process both affect the stability of lyophilized formulations. Therefore, it is necessary to conduct in-depth research on the formulation information and lyophilization process of cetrorex acetate lyophilized formulations, and develop a preparation method with good physicochemical stability and a relatively short lyophilization cycle to solve the problems existing in the current technology and facilitate commercial production. Summary of the Invention

[0006] The purpose of this invention is to provide a cetrorex acetate lyophilized formulation and its preparation method. By inducing ice crystal nucleation during the pre-cooling stage, the product is completely frozen at the pre-freezing temperature. Furthermore, increasing the desorption drying temperature not only reduces the moisture and impurity levels after lyophilization but also shortens the lyophilization time. The product obtained by this invention exhibits controllable key quality attributes such as appearance, acidity, solution clarity, and related substances during storage, demonstrating good stability. The short lyophilization process reduces energy consumption and lowers production costs.

[0007] The objective of this invention can be achieved through the following technical solutions: The first aspect of this invention provides a method for preparing a lyophilized formulation of cetrorex acetate, comprising the following steps: dissolving cetrorex acetate and then lyophilizing it; the lyophilization process includes the following stages: S1. Pre-cooling stage: either vacuum the air first and then cool down, or cool down first and then vacuum the air. S2. Pre-freezing stage: Reduce the temperature of the plate to -40 to -30℃ at a rate of 1.0 to 2.0℃ / min, and keep it warm for 60 to 300 min; S3, Sublimation Drying Stage: Raise the plate temperature to -20 to -5℃ at a rate of 1.0 to 2.0℃ / min, hold for 400 to 900 min, and maintain a vacuum of 0.1 to 0.5 mbar; S4. Desorption and drying stage: The plate temperature is raised to 35-45℃ at a rate of 0.1-1.0℃ / min, and the holding time is 60-600min. The vacuum degree is 0.1-0.5mbar.

[0008] In some possible implementations, vacuuming is performed first, followed by cooling: first, the chamber pressure is evacuated to 0.1 to 0.5 bar, and then the plate temperature is reduced to -5 to -15°C at a rate of ≤2.0°C / min, with a holding time of ≥60 min; Preferably, the chamber pressure is first evacuated to 0.1 to 0.3 bar, and then the temperature of the plate layer is reduced to -15 to -10°C at a rate of 1.0 to 2.0°C / min, with a holding time of 60 to 120 min.

[0009] In some possible implementations, the temperature is lowered first and then the vacuum is evacuated: the plate temperature is lowered to -15 to -5℃ at a rate of ≤2.0℃ / min, and then the chamber pressure is evacuated to 0.1 to 0.5 bar, with a holding time of ≥60min; Preferably, the plate temperature is first reduced to -15 to -10℃ at a rate of 1.0 to 2.0℃ / min, then evacuated to a chamber pressure of 0.1 to 0.3 bar, and the heat preservation time is 60 to 120 min.

[0010] In some possible implementations, S2, the pre-freezing stage: the plate temperature is reduced to -37 to -34℃ at a rate of 1.0 to 1.5℃ / min, and the holding time is 100 to 200 min.

[0011] In some possible implementations, S3, the sublimation drying stage: the plate temperature is raised to -15 to -10℃ at a rate of 1.0 to 1.5℃ / min, the holding time is 500 to 600 min, and the vacuum degree is 0.1 to 0.3 mbar.

[0012] In some possible implementations, S4, the desorption and drying stage: the plate temperature is raised to 40-45℃ at a rate of 0.2-0.5℃ / min, the holding time is 100-400min, and the vacuum degree is 0.1-0.3mbar.

[0013] In some possible implementations, the dissolution of cetrorex acetate includes the following steps: Cetrorexate acetate is dissolved in an aqueous acetic acid solution and then added to an aqueous mannitol solution. The volume concentration of the aqueous acetic acid solution is 20%–50% (v / v), and the concentration of the aqueous mannitol solution is 55–65 mg / mL. The volume ratio of the aqueous acetic acid solution to the aqueous mannitol solution is 1:5 to 1:15. By dissolving cetrorexate acetate in the aqueous acetic acid solution, the cetrorexate is rapidly dissolved before being added to the aqueous mannitol solution, thus shortening the preparation time of the drug solution.

[0014] In some possible implementations, preferably, the volume concentration of the acetic acid aqueous solution is 20% to 40% (v / v); the volume ratio of the acetic acid aqueous solution to the mannitol aqueous solution is 1:5 to 1:14; More preferably, the volume concentration of the acetic acid aqueous solution is 30% to 40% (v / v); the volume ratio of the acetic acid aqueous solution to the mannitol aqueous solution is 1:9 to 1:12.

[0015] In some possible implementations, the freeze-drying process includes the following stages: S1. Pre-cooling stage: First, evacuate the chamber to a pressure of 0.3 bar, then lower the temperature of the board to -10°C at a rate of 1.0°C / min, and keep it warm for 60 minutes; or first, lower the temperature of the board to -10°C at a rate of 1.0°C / min, then evacuate the chamber to a pressure of 0.3 bar, and keep it warm for 60 minutes. S2. Pre-freezing stage: Reduce the temperature of the plate to -35℃ at a rate of 1.0℃ / min, and keep it warm for 120min; S3, Sublimation Drying Stage: The plate temperature is raised to -14℃ at a rate of 1.0℃ / min, and the holding time is 600min, with a vacuum degree of 0.15mbar; S4. Desorption and drying stage: The plate temperature is raised to 45℃ at a rate of 0.5℃ / min, and the holding time is 200min. The vacuum degree is 0.3mbar.

[0016] A second aspect of the present invention provides a lyophilized formulation of cetrorex acetate, which is prepared by the above-described preparation method.

[0017] The beneficial effects of this invention are: This invention utilizes induced ice crystal nucleation in the pre-cooling stage to obtain a stable pharmaceutical composition, which facilitates complete freezing of the product during the pre-freezing stage, resulting in a product that meets specifications and exhibits good stability. The chamber pressure, cooling rate, pre-cooling temperature, and holding time are optimized. Furthermore, after the above pre-cooling treatment, a higher temperature can be selected for drying in the analytical drying stage, which not only does not affect product quality but also shortens drying time and reduces production costs. Attached Figure Description

[0018] The invention will now be further described with reference to the accompanying drawings.

[0019] Figure 1 This is the zero-time related matter spectrum of cetrorex acetate for injection according to Example 1 of the present invention; Figure 2 This is the zero-time related matter spectrum of cetrorex acetate for injection, Comparative Example 1 of this invention; Figure 3 This is the related material spectrum of cetrorex acetate for injection in Example 1 of the present invention at 40°C for 30 days; Figure 4 This is the related material spectrum of Comparative Example 1 of the present invention, cetrorex acetate for injection, at 40°C for 30 days. Detailed Implementation

[0020] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0021] The following is a detailed description of a cetrorex acetate lyophilized formulation and its preparation method according to an embodiment of this application.

[0022] The following is a detailed description with reference to specific examples.

[0023] Example 1: Step 1: Preparation of cetrorex acetate solution containing mannitol and acetic acid Weigh 54.8 g of mannitol and dissolve it in water for injection to obtain 900 mL of mannitol aqueous solution. Separately, accurately weigh 0.2828 g of cetrorex acetate and dissolve it in 100 mL of 30% acetic acid aqueous solution to obtain cetrorex acetate acetic acid solution. Add the cetrorex acetate acetic acid solution to the above mannitol aqueous solution and mix well to obtain a cetrorex acetate solution containing mannitol and acetic acid (hereinafter referred to as "the solution"). The solution is sterilized by filtration through a 0.2 μm filter, dispensed into 2 mL control bottles, and partially stoppered, with a volume of 1.0 mL.

[0024] Step 2: Freeze-drying process 1) Pre-cooling stage: First, evacuate the chamber to a pressure of 0.3 bar, and then reduce the plate temperature from the feed temperature of 4℃ to -10℃ at a rate of 1.0℃ / min, with a holding time of 60min; 2) Pre-freezing stage: The temperature of the plate layer is reduced to -35℃ at a rate of 1.0℃ / min, and the holding time is 120min; 3) Sublimation drying stage: The plate temperature is raised to -14℃ at a rate of 1.0℃ / min, and the holding time is 600min, with a vacuum degree of 0.15mbar; 4) Drying stage: The plate temperature is raised to 45℃ at 0.5℃ / min, and the holding time is 200min, with a vacuum degree of 0.3mbar; cetrorex acetate for injection is obtained.

[0025] The freeze-drying time is approximately 19.3 hours.

[0026] Example 2 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0027] Step 2: Freeze-drying process 1) Pre-cooling stage: First, evacuate the chamber to a pressure of 0.1 bar, then reduce the plate temperature from the feed temperature of 4℃ to -15℃ at a rate of 1.0℃ / min, and keep it warm for 60 minutes; 2) Pre-freezing stage: The temperature of the plate layer is reduced to -37℃ at a rate of 1.0℃ / min, and the holding time is 100min; 3) Sublimation drying stage: The plate temperature is raised to -15℃ at a rate of 1.0℃ / min, and the holding time is 600min, with a vacuum degree of 0.1mbar; 4) Drying stage: The plate temperature is raised to 45℃ at 0.5℃ / min, and the holding time is 200min, with a vacuum degree of 0.3mbar; cetrorex acetate for injection is obtained.

[0028] The freeze-drying time is approximately 19.1 hours.

[0029] Example 3 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0030] Step 2: Freeze-drying process 1) Pre-cooling stage: First, reduce the plate temperature from the feed temperature of 4℃ to -10℃ at a rate of 2.0℃ / min, then evacuate the chamber to a pressure of 0.3 bar and keep it warm for 120 minutes; 2) Pre-freezing stage: The temperature of the plate layer is reduced to -37℃ at a rate of 1.0℃ / min, and the holding time is 100min; 3) Sublimation drying stage: The plate temperature is raised to -10℃ at a rate of 1.0℃ / min, and the holding time is 500min, with a vacuum degree of 0.1mbar; 4) Drying stage: The plate temperature is raised to 40℃ at 0.5℃ / min, and the holding time is 400min, with a vacuum degree of 0.1mbar; cetrorex acetate for injection is obtained.

[0031] The freeze-drying time is approximately 21.4 hours.

[0032] Example 4 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0033] Step 2: Freeze-drying process 1) Pre-cooling stage: First, evacuate the chamber to a pressure of 0.1 bar, then reduce the plate temperature from the feed temperature of 4℃ to -15℃ at a rate of 2.0℃ / min, and keep it warm for 120 minutes; 2) Pre-freezing stage: The temperature of the plate layer is reduced to -34℃ at a rate of 1.5℃ / min, and the holding time is 200min; 3) Sublimation drying stage: The plate temperature is raised to -15℃ at a rate of 1.5℃ / min, and the holding time is 500min, with a vacuum degree of 0.3mbar; 4) Drying stage: The plate temperature is raised to 40℃ at 0.2℃ / min, held for 100min, and the vacuum degree is 0.1mbar; cetrorex acetate for injection is obtained.

[0034] The freeze-drying time is approximately 20.5 hours.

[0035] Example 5 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0036] Step 2: Freeze-drying process 1) Pre-cooling stage: First, reduce the plate temperature from the feed temperature of 4℃ to -10℃ at a rate of 1.0℃ / min, then evacuate the chamber to a pressure of 0.3 bar and keep it warm for 60 minutes; 2) Pre-freezing stage: The temperature of the plate layer is reduced to -35℃ at a rate of 1.5℃ / min, and the holding time is 120min; 3) Sublimation drying stage: The plate temperature is raised to -14℃ at a rate of 1.0℃ / min, and the holding time is 600min, with a vacuum degree of 0.15mbar; 4) Drying stage: The plate temperature is raised to 45℃ at 0.5℃ / min, and the holding time is 200min, with a vacuum degree of 0.3mbar; cetrorex acetate for injection is obtained.

[0037] The freeze-drying time is approximately 19.2 hours.

[0038] Example 6 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0039] Step 2: Freeze-drying process 1) Pre-cooling stage: First, reduce the plate temperature from the feed temperature of 4℃ to -15℃ at a rate of 2.0℃ / min, then evacuate the chamber to a pressure of 0.1 bar and keep it warm for 120 minutes; 2) Pre-freezing stage: The temperature of the plate layer is reduced to -34℃ at a rate of 1.5℃ / min, and the holding time is 200min; 3) Sublimation drying stage: The plate temperature is raised to -10℃ at a rate of 1.5℃ / min, and the holding time is 500min, with a vacuum degree of 0.3mbar; 4) Drying stage: The plate temperature is raised to 40℃ at 0.2℃ / min, held for 100min, and the vacuum degree is 0.1mbar; cetrorex acetate for injection is obtained.

[0040] The freeze-drying time is approximately 20.2 hours.

[0041] Comparative Example 1 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0042] Step 2: Freeze-drying process 1) Pre-freezing stage: The plate temperature is reduced from the feed temperature of 4℃ to -35℃ at a rate of 1.0℃ / min, and the holding time is 120min; 2) Sublimation drying stage: The plate temperature is raised to -14℃ at a rate of 1.0℃ / min, and the holding time is 600min, with a vacuum degree of 0.15mbar; 3) Drying stage: The plate temperature is raised to 45℃ at 0.5℃ / min and held for 200min under a vacuum of 0.3mbar to obtain cetrorex acetate for injection.

[0043] The freeze-drying time is approximately 18.3 hours.

[0044] Comparative Example 2 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0045] Step 2: Freeze-drying process 1) Pre-freezing stage: The plate temperature is reduced from the feed temperature of 4℃ to -35℃ at a rate of 1.0℃ / min, and the holding time is 120min; 2) Sublimation drying stage: The plate temperature is raised to -14℃ at a rate of 1.0℃ / min, and the holding time is 900min, with a vacuum degree of 0.15mbar; 3) Drying stage: The plate temperature is raised to 25℃ at 0.5℃ / min and held for 900min under a vacuum of 0.3mbar to obtain cetrorex acetate for injection.

[0046] The freeze-drying time is approximately 34.3 hours.

[0047] Comparative Example 3 The preparation, filtration, and dispensing of the liquid medicine are the same as the first step in Example 1.

[0048] Step 2: Freeze-drying process 1) Pre-cooling stage: The plate temperature is reduced from the feed temperature of 4℃ to -10℃ at a rate of 1.0℃ / min, and the holding time is 60min; 2) Pre-freezing stage: The temperature of the plate layer is reduced to -35℃ at a rate of 1.0℃ / min, and the holding time is 120min; 3) Sublimation drying stage: The plate temperature is raised to -14℃ at a rate of 1.0℃ / min, and the holding time is 600min, with a vacuum degree of 0.15mbar; 4) Drying stage: The plate temperature is raised to 45℃ at 0.5℃ / min, and the holding time is 200min, with a vacuum degree of 0.3mbar; cetrorex acetate for injection is obtained.

[0049] The freeze-drying time is approximately 19.3 hours.

[0050] The products from Examples 1-6 and Comparative Examples 1-3 were packaged and placed together with the reference formulation Cetrotiede in a stability test chamber at 40℃±2℃ for investigation. Samples were taken at 0, 5, 10, and 30 days, and the test results are shown in Table 1. Table 1

[0051] Example 1: Related substances chromatogram of cetrorelix acetate for injection on day 0 (as shown in the image) Figure 1 As shown; the related substances chromatogram of cetrorex acetate for injection in Comparative Example 1 after 0 days is as follows. Figure 2 As shown; Example 1: Related material spectrum of cetrorex acetate for injection at 40°C for 30 days. Figure 3As shown; the related material spectrum of cetrorex acetate for injection in Comparative Example 1 at 40℃ for 30 days is shown below. Figure 4 As shown. From Figure 1 and Figure 2 It can be seen that there was essentially no difference in the levels of various impurities between the injectable cetrorexate prepared in Example 1 and Comparative Example 1 on day 0; from Figure 3 and Figure 4 It can be seen that the number and content of impurities in the injectable cetrorex acetate prepared in Example 1 are significantly less than those in Comparative Example 1 under the condition of 40℃ for 30 days. Moreover, the degraded impurity cetrorex acetate prepared in Comparative Example 1 increases rapidly under the condition of 40℃ for 30 days.

[0052] Examples 1-6 are cetrorex acetate formulations prepared according to the freeze-drying process of the present invention. The overall freeze-drying process running time ranges from 19.1 to 21.4 hours. High-temperature test results show that the increased levels of deamidated cetrorex (degraded impurities) and total impurities in the prepared products are minimal, which is beneficial for commercial scale-up production. Comparative Example 1 is a freeze-drying process of Example 1 without the pre-cooling stage. The moisture content of the prepared product is higher than that of Examples 1-6. High-temperature test results show that the increased levels of deamidated cetrorex and total impurities in the prepared product are significant, presumably due to the higher desorption drying temperature and shorter sublimation and desorption drying times. Comparative Example 2 is based on Comparative Example 1, with a lower desorption drying temperature and longer sublimation and desorption drying times. Although the increased levels of deamidated cetrorex and total impurities in the prepared product are less than in Comparative Example 1, the overall freeze-drying process running time is extended to 34.3 hours. Comparative Example 3 is Example 1 with the vacuuming process removed during the pre-cooling stage. The pre-cooling process was retained but ice crystals were not induced. The high-temperature test results showed that the stability of the product was better than that of Comparative Example 1, but still worse than that of Example 1. This indicates that the induction of ice crystals during the pre-cooling process is beneficial to improving the stability of the product.

[0053] Example 1 represents the optimal freeze-drying process of this application. High-temperature test results show that the properties, acidity, turbidity, and moisture content of the obtained product all meet the import registration standards of the reference preparation. The increase values ​​of deamidated cetrorex and total impurities after 30 days compared to 0 days were 0.06% and 0.25%, respectively, while the increase values ​​of deamidated cetrorex and total impurities of the reference preparation were 0.13% and 0.58%, respectively. The results indicate that the products of Example 1 have good stability.

[0054] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0055] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a lyophilized formulation of cetrorex acetate, characterized in that, The process includes the following steps: dissolving cetrorex acetate and then lyophilizing it; the lyophilization process includes the following stages: S1. Pre-cooling stage: either vacuum the air first and then cool down, or cool down first and then vacuum the air. S2. Pre-freezing stage: Reduce the temperature of the plate to -40 to -30℃ at a rate of 1.0 to 2.0℃ / min, and keep it warm for 60 to 300 min; S3, Sublimation Drying Stage: Raise the plate temperature to -20 to -5℃ at a rate of 1.0 to 2.0℃ / min, hold for 400 to 900 min, and maintain a vacuum of 0.1 to 0.5 mbar; S4. Desorption and drying stage: The plate temperature is raised to 35-45℃ at a rate of 0.1-1.0℃ / min, and the holding time is 60-600min. The vacuum degree is 0.1-0.5mbar.

2. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, Vacuuming followed by cooling: First, evacuate the chamber to a pressure of 0.1 to 0.5 bar, then lower the temperature of the plate layer to -5 to -15°C at a rate of ≤2.0°C / min, and maintain the temperature for ≥60 minutes.

3. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, Cool down first, then vacuum: First, reduce the temperature of the plate to -15 to -5℃ at a rate of ≤2.0℃ / min, then evacuate the chamber to a pressure of 0.1 to 0.5 bar, and keep it warm for ≥60 minutes.

4. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, S2. Pre-freezing stage: Reduce the temperature of the plate to -37 to -34℃ at a rate of 1.0 to 1.5℃ / min, and keep it warm for 100 to 200 minutes.

5. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, S3, Sublimation Drying Stage: Raise the plate temperature to -15 to -10℃ at a rate of 1.0 to 1.5℃ / min, hold for 500 to 600 minutes, and maintain a vacuum of 0.1 to 0.3 mbar.

6. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, S4. Desorption and drying stage: Raise the plate temperature to 40-45℃ at 0.2-0.5℃ / min, hold for 100-400min, and maintain a vacuum of 0.1-0.3mbar.

7. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, The dissolution of cetrorex acetate includes the following steps: Cetrilac acetate is dissolved in an aqueous acetic acid solution and then added to an aqueous mannitol solution; the volume concentration of the aqueous acetic acid solution is 20%–50%; the concentration of the aqueous mannitol solution is 55–65 mg / mL; the volume ratio of the aqueous acetic acid solution to the aqueous mannitol solution in the solution is 1:5 to 1:

15.

8. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, The volume concentration of the acetic acid aqueous solution is 20% to 40%; the volume ratio of the acetic acid aqueous solution to the mannitol aqueous solution is 1:5 to 1:

14.

9. The method for preparing a lyophilized formulation of cetrorex acetate according to claim 1, characterized in that, The freeze-drying process includes the following stages: S1. Pre-cooling stage: First, evacuate the chamber to a pressure of 0.3 bar, then lower the temperature of the board to -10°C at a rate of 1.0°C / min, and keep it warm for 60 minutes; or first, lower the temperature of the board to -10°C at a rate of 1.0°C / min, then evacuate the chamber to a pressure of 0.3 bar, and keep it warm for 60 minutes. S2. Pre-freezing stage: Reduce the temperature of the plate to -35℃ at a rate of 1.0℃ / min, and keep it warm for 120min; S3, Sublimation Drying Stage: The plate temperature is raised to -14℃ at a rate of 1.0℃ / min, and the holding time is 600min, with a vacuum degree of 0.15mbar; S4. Desorption and drying stage: The plate temperature is raised to 45℃ at a rate of 0.5℃ / min, and the holding time is 200min. The vacuum degree is 0.3mbar.

10. A lyophilized formulation of cetrorex acetate, characterized in that, Prepared by the preparation method according to any one of claims 1-9.

Images