阅读说明：本技术 一种舒更葡糖钠冻干粉针剂及其制备方法 (Shugeng sodium gluconate freeze-dried powder injection and preparation method thereof ) 是由 贾俊伟 冯中 刘忠 于 2020-03-31 设计创作，主要内容包括：本发明涉及医药技术技术领域,具体涉及一种舒更葡糖钠冻干粉针剂及其制备方法；所述舒更葡糖钠冻干粉针剂制备方法包括：处方量舒更葡糖钠加入注射用水中,搅拌至完全溶解；加入处方量的冻干保护基于上述溶液中,搅拌至完全溶解,调节pH,搅拌,过滤,灌装后冷冻干燥即得目标；该方法提供了一种注射用舒更葡糖钠冻干粉针剂,解决了API作为环状分子结构不稳定,经高温灭菌易产生大量杂质的难题；冻干结束充惰性气体(氮气)进行保护,有效的隔绝了氧气,制得的舒更葡糖钠冻干粉针杂质更少,更加稳定；通过冻干工艺的优化,制得冻干粉复溶时间最短,澄明度和不溶性微粒均符合要求,稳定性更高,适合工业化生产。(The invention relates to the technical field of medicines, in particular to a sugammadex sodium freeze-dried powder injection and a preparation method thereof; the preparation method of the sugammadex sodium freeze-dried powder injection comprises the following steps: adding the prescription of the sodium dimercaptoglucose into water for injection, and stirring until the sodium dimercaptoglucose is completely dissolved; adding the formula amount of freeze-drying protection base into the solution, stirring until the freeze-drying protection base is completely dissolved, adjusting the pH value, stirring, filtering, filling, and freeze-drying to obtain the target; the method provides the sugammadex sodium freeze-dried powder injection for injection, and solves the problems that API as a cyclic molecular structure is unstable, and a large amount of impurities are easily generated through high-temperature sterilization; inert gas (nitrogen) is filled for protection after freeze-drying is finished, so that oxygen is effectively isolated, and the prepared sugammadex sodium freeze-dried powder injection has fewer impurities and is more stable; through the optimization of the freeze-drying process, the prepared freeze-dried powder has the shortest redissolution time, higher stability and higher suitability for industrial production, and both clarity and insoluble particles meet the requirements.)

1. The sugammadex sodium freeze-dried powder injection is characterized by comprising sugammadex sodium, a freeze-drying protective agent and a pH regulator.

2. The sugammadex sodium lyophilized powder for injection according to claim 1, wherein the lyoprotectant is one or a combination of mannitol, lactose, dextran, and povidone.

3. The lyophilized powder for injection of sugammadex sodium according to claim 1, wherein the lyoprotectant is preferably mannitol.

4. The sugammadex sodium lyophilized powder for injection of claim 1, wherein the mass ratio of sugammadex sodium to lyophilized protecting groups is 1: 0.1 to 2.

5. The sugammadex sodium lyophilized powder for injection according to claim 1, wherein the mass ratio of sugammadex sodium to lyophilized protecting groups is preferably 1: 0.3 to 1.

6. The sugammadex sodium lyophilized powder for injection of claim 1, wherein the pH modifier is one of 0.1N hydrochloric acid solution, 0.1M tartaric acid solution, 0.1N acetic acid solution, 0.2M lactic acid solution, 0.1N malic acid solution or a combination thereof.

7. The lyophilized sugammadex powder for injection according to claim 1, wherein the pH regulator is preferably a 0.1N hydrochloric acid solution.

8. A method for preparing the sugammadex sodium freeze-dried powder injection of claim 1, which is characterized by comprising the following steps:

adding the prescription of the sodium dimercaptoglucose into water for injection, and stirring until the sodium dimercaptoglucose is completely dissolved; adding a prescription amount of freeze-drying protective agent into the solution, and stirring until the freeze-drying protective agent is completely dissolved; adjusting pH with pH regulator, stirring, filtering, bottling the filtrate in penicillin bottle, half plugging, and freeze drying in freeze drying box.

9. The method of claim 8, wherein the pH adjustment range is 7.1 to 8.0.

10. The method of claim 8, wherein the lyophilization process comprises (1) pre-freezing: after the temperature of the plate layer is reduced to-40 to-45 ℃, putting a sample into the plate layer, vacuumizing the plate layer in a freeze dryer, maintaining the vacuum pressure at 0.15 +/-0.02 mbar, and preserving the heat for 3-5 hours; (2) sublimation drying: the freeze dryer maintains vacuum, the temperature of the shelf is increased to-30 to-20 ℃ at the speed of 0.5 ℃/h, and the temperature is kept for 4 to 6 h; the temperature of the shelf is increased to-10-0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in a freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6-8 h; (3) and (3) resolving and drying: vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15-25 ℃ at the speed of 2 ℃/h, and preserving the heat for 8-10 h; raising the temperature of the shelf to 50-60 ℃ at the speed of 5 ℃/h, and preserving the heat for 6-8 h; then limiting the vacuum for 2-4h, and carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1 pa/min; (4) discharging: recovering normal pressure with nitrogen, pressing plug, and taking out.

Technical Field

The invention relates to the technical field of medicines, and in particular relates to a sugammadex sodium freeze-dried powder injection and a preparation method thereof.

Background

Sugammadex Sodium was first developed by organic Biosciences (ogagatans) in 2008, and was first marketed in europe and subsequently in japan, usa, etc., respectively, and is now marketed in 75 countries.

Sugammadex sodium, chemically named 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt, is modified gamma-cyclodextrin; the single-component amino steroid non-depolarizing muscle relaxant is the first and only selective muscle relaxation antagonist (SRBA), blocks the relaxation effect by wrapping the amino steroid non-depolarizing muscle relaxant through a brand-new and only way, can quickly and predictably reverse the muscle relaxation of any intensity caused by rocuronium bromide and vecuronium bromide, has small side effect, can enable the use of the muscle relaxant to be close to an ideal state, and has quicker and more predictable effects of reversing the neuromuscular blocking effect than the existing drugs. The method is suitable for reversing the neuromuscular blockade caused by rocuronium bromide or vecuronium bromide, reversing (normally reversing and immediately reversing) the neuromuscular blockade caused by adult rocuronium bromide or vecuronium bromide and normally reversing the neuromuscular blockade caused by rocuronium bromide in children and juveniles. The chemical formula is as follows:

researches find that oxygen is a protective agent for carbon-sulfur bonds in the high-temperature sterilization process, and the quantity of degradation impurities generated by the generation of sulfydryl by the carbon-sulfur bonds after the sugammadex injection is subjected to high-temperature sterilization under the aerobic condition is less than that of RRT (RRT 2.04); under the condition of no oxygen or low oxygen concentration, the sugammadex sodium injection is sterilized at high temperature, and then generates sulfydryl through carbon-sulfur bonds to generate more degradation impurities with RRT 2.04, which seriously exceeds the quality standard control range. In addition, after the sugammadex sodium is prepared into an injection, the sugammadex sodium is sensitive to oxygen, and oxidation reaction is easily carried out in an aerobic solution environment to generate oxidation impurities with the mark Org198958-2 and Org199425-1 of sulfone isomers RRT 0.45 and RRT 0.59 respectively. Therefore, it is very useful to prepare a formulation having high stability which can be stored for a long period of time.

Aiming at the problems in the prior art, the invention aims to provide a quality-controllable sugammadex sodium preparation and a preparation method thereof, and the preparation method is mainly used for preparing the quality-controllable sugammadex sodium preparation into a sterile freeze-dried powder injection, namely the sugammadex sodium for injection. Researches show that mannitol is used as a freeze-drying excipient, the particle size of sugammadex is controlled, a proper amount of pH regulator is added, a freeze-drying curve is optimized, nitrogen gas is filled for protection after freeze-drying is finished, various impurities in the quality of the prepared sugammadex freeze-dried powder are far lower than those of a reference preparation, the clarity meets the requirement, and the quality is stable in the long-term storage process.

Disclosure of Invention

The invention aims to prepare a sugammadex sodium powder injection, and solves the problems of the preparation process and long-term storage stability of sugammadex sodium.

The sugammadex sodium freeze-dried powder injection is characterized by comprising sugammadex sodium, a freeze-drying protective agent and a pH regulator.

Preferably, the lyoprotectant can be one of mannitol, lactose, dextran, povidone or their combination.

Preferably, the lyoprotectant is mannitol.

Preferably, the mass ratio of the sugammadex sodium to the lyoprotectant is 1: 0.1 to 2.

Preferably, the mass ratio of the sugammadex sodium to the lyoprotectant is 1: 0.3 to 1, and more preferably 1: 0.65.

preferably, the pH regulator is selected from one of a 0.1N hydrochloric acid solution, a 0.1M tartaric acid solution, a 0.1N acetic acid solution, a 0.2M lactic acid solution, a 0.1N malic acid solution, or a combination thereof.

Preferably, the pH regulator is 0.1N hydrochloric acid solution.

The preparation method comprises the following steps:

adding the prescription of the sodium dimercaptoglucose into water for injection, and stirring until the sodium dimercaptoglucose is completely dissolved; adding a prescription amount of freeze-drying protective agent into the solution, and stirring until the freeze-drying protective agent is completely dissolved; adjusting pH with pH regulator, stirring, filtering, filling filtrate into penicillin bottle, half plugging, and lyophilizing.

Preferably, the pH adjusting range is 7.1-8.0.

Further the filling subsequent process comprises:

filling the filtered filtrate into a penicillin bottle, half plugging, and putting into a freeze-drying box; (1) pre-freezing: cooling the temperature of the plate layer to-40 +/-5 ℃, putting the sample into the plate layer, vacuumizing the freeze dryer, maintaining the vacuum pressure at 0.15 +/-0.02 mbar, and preserving the heat for 3-5 hours; (2) sublimation drying: the freeze dryer maintains vacuum, the temperature of the shelf is increased to-30 to-20 ℃ at the speed of 0.5 ℃/h, and the temperature is kept for 4 to 6 h; the temperature of the shelf is increased to-10-0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in a freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6-8 h; (3) and (3) resolving and drying: vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15-25 ℃ at the speed of 2 ℃/h, and preserving the heat for 8-10 h; raising the temperature of the shelf to 50-60 ℃ at the speed of 5 ℃/h, and preserving the heat for 8-10 h; then limiting the vacuum for 2-4h, and carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1 pa/min; (4) discharging: recovering normal pressure with nitrogen, pressing plug, and taking out.

Preferably, the filling volume of the sugammadex sodium aqueous solution is 5 ml;

the technical advantages of the invention are as follows:

1. the preparation formulation solves the problems that API as a cyclic molecular structure is unstable and a large amount of impurities are easily generated by high-temperature sterilization; inert gas (nitrogen) is filled for protection after freeze-drying is finished, so that oxygen is effectively isolated, and the prepared sugammadex sodium freeze-dried powder injection has fewer impurities and is more stable;

2. by optimizing the freeze-drying process, the prepared freeze-dried powder has shorter redissolution time, high clarity, fewer insoluble particles and higher stability, and is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.

Example 1

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until dissolving, adjusting the pH value to 7.50 with hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-25 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 5 h; the temperature of the shelf is raised to-5 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 20 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 2

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until dissolving, adjusting the pH value to 7.47 with hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-45 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 5 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-2 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 3

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.51 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-42 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 4 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 5 h; the temperature of the shelf is raised to-8 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 7 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 50 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 4

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.48 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-15 deg.C at a rate of 0.5 deg.C/h, and maintaining for 4 h; the temperature of the shelf is raised to-2 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 20 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 5

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.82 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-42 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 5 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-5 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 18 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 7 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 6

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.88 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-43 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 9 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 7

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sulgamide sodium and mannitol in a prescription amount, slowly adding into water for injection, stirring until the sulgamide sodium and the mannitol are dissolved, adjusting the pH value to 7.26 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to-10 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 10 h; the temperature of the shelf is raised to 50 ℃ at the speed of 5 ℃/h, and the temperature is kept for 7 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 8

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sulgamide sodium and mannitol in a prescription amount, slowly adding into water for injection, stirring until the sulgamide sodium and the mannitol are dissolved, adjusting the pH value to 7.95 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-10 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 9

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.28 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-45 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 7 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 10

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.42 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-25 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 5 h; the temperature of the shelf is raised to-1 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 7 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 11

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.12 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 5 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-10 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 10 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 12

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.67 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to-20 ℃ at the speed of 1.5 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to-10 ℃ at the speed of 2.0 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 2.5 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to 10 ℃ at the speed of 0.5 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to 25 ℃ at the speed of 5 ℃/h, and the temperature is kept for 3 h; the temperature of the shelf is increased to 60 ℃ at the speed of 10 ℃/h, and the temperature is kept for 4 h; and finally, carrying out ultimate vacuum for 2 hours, carrying out a pressure rise experiment, wherein the experiment needs to meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, pressing a plug, rolling a cover, and taking out of the box.

Example 13

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until dissolving, adjusting the pH value to 7.50 with hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 1 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 5 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is increased to 60 ℃ at the speed of 10 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Example 14

Prescription

Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.70 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-15 deg.C at a rate of 0.5 deg.C/h, and maintaining for 4 h; the temperature of the shelf is raised to-2 ℃ at the speed of 1 ℃/h, meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 20 ℃ at the speed of 2 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 40 ℃ at the speed of 8 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.

Verification examples

The samples prepared in the examples and comparative examples were subjected to accelerated examination at 40 ℃ and the results are shown in the following table:

according to the effect of the verification example, the lyophilized powder for injection prepared by the invention has short reconstitution time, and both clarity and insoluble particles meet the requirements. In addition, the problem that API is not stably degraded under high temperature is solved, inert gas is filled for protection after freeze-drying is finished, the stability problem of the preparation in the storage process is effectively solved, and the method is suitable for industrial production.