A vercuronium bromide lyophilized agent for injection and its production process

Abstract

The application discloses a kind of vecuronium bromide freeze-dried agent for injection and its production process, by the following raw materials and weight parts composition: vecuronium bromide 3-5 parts, citric acid 0.21-1.35 parts, disodium hydrogen phosphate 7.9-9.3 parts, mannitol 10.5-13.2 parts, povidone K30 8.5-12.8 parts, wherein each unit preparation of drug is calculated with vecuronium bromide 3-5mg;By adding povidone K30, mannitol is dissolved to injection water first, then citric acid, disodium hydrogen phosphate is dissolved, then vecuronium bromide is added, complete injection water after adjusting pH to neutral, then use active carbon treatment with injection, after decarbonization filtration, filtrate is added to injection water to full amount, after dispensing, stage freeze-drying is obtained.The injection vecuronium bromide freeze-dried agent solution of the application is neutral, can reduce injection pain, and has good stability.

Description

Technical Field

[0001] This invention relates to a vecuronium bromide lyophilized agent for injection and its manufacturing process, belonging to the field of pharmaceutical technology. Background Technology

[0002] Vecuronium bromide, chemically known as 1-[3α,17β-diacetoxy-2-β(1-piperidinyl)-5α-androstane-16β-yl]-1-methylpiperidine bromide, is an adjunct to general anesthetics that promotes musculoskeletal relaxation. Currently available vecuronium bromide formulations are primarily injection solutions and lyophilized powder for injection. Vecuronium bromide injection solutions suffer from poor physical and chemical stability, leading to quality degradation and instability with prolonged storage. While existing lyophilized powder for injection improves the stability of the formulation, it requires the addition of a strong acid to increase solubility. The resulting acidic solution can severely irritate blood vessels, causing injection pain. Furthermore, studies have shown that intravenous injection pain is related to the pH of the injection solution; appropriately increasing the pH can help reduce injection pain.

[0003] Chinese patent CN201310489082.6 discloses a lyophilized powder injection of vecuronium bromide for injection and its preparation method. This lyophilized powder injection is made of vecuronium bromide, mannitol, lactose, trehalose, citric acid, and disodium hydrogen phosphate. However, it involves a large number of raw materials, resulting in high production costs. In addition, due to differences in individual constitutions, the use of lactose can cause severe lactose intolerance. Furthermore, the pH of the dissolved lyophilized powder injection is between 3.8 and 4.2, which can easily cause injection pain. CN201410102893.0 discloses a pharmaceutical composition for injection of vecuronium bromide and its preparation method. This pharmaceutical composition consists of vecuronium bromide, citric acid, and disodium hydrogen phosphate. Although it does not use amino acids or lactose, the pH of the dissolved pharmaceutical composition is also between 3.8 and 4.2, which can easily cause injection pain. Summary of the Invention

[0004] To address at least one problem existing in the prior art, the present invention provides an injectable vecuronium bromide lyophilized agent and its manufacturing process. This injectable vecuronium bromide lyophilized agent uses vecuronium bromide, citric acid, disodium hydrogen phosphate, mannitol, and povidone as raw materials, reducing the variety and cost of raw materials and avoiding lactose intolerance. Simultaneously, the lyophilized agent solution is neutral, which can reduce injection pain. Its manufacturing process ensures that the lyophilized agent has a full appearance, loose and porous texture, rapid reconstitution and clarification, while also improving the stability of the lyophilized agent.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: a vecuronium bromide lyophilized preparation for injection, composed of the following raw materials and parts by weight: 3-5 parts vecuronium bromide, 0.21-1.35 parts citric acid, 7.9-9.3 parts disodium hydrogen phosphate, 10.5-13.2 parts mannitol, and 8.5-12.8 parts povidone K30, wherein each unit of the preparation contains 3-5 mg of vecuronium bromide.

[0006] Preferably, the injectable vecuronium bromide lyophilized preparation is composed of the following raw materials and parts by weight: 4 parts vecuronium bromide, 0.7 parts citric acid, 8.7 parts disodium hydrogen phosphate, 12.5 parts mannitol, and 11.3 parts povidone K30, wherein each unit of the preparation contains 4 mg of vecuronium bromide.

[0007] Preferably, the injectable vecuronium bromide lyophilized preparation is composed of the following raw materials and parts by weight: 5 parts vecuronium bromide, 0.32 parts citric acid, 9.2 parts disodium hydrogen phosphate, 11.8 parts mannitol, and 12.2 parts povidone K30, wherein each unit of the preparation contains 5 mg of vecuronium bromide.

[0008] Preferably, the vecuronium bromide lyophilized agent for injection is produced through the following steps: In water for injection calculated based on 3-5 mg of vecuronium bromide per unit of formulation corresponding to 1 ml of water for injection, first add povidone K30 and mannitol to dissolve, then add citric acid and disodium hydrogen phosphate to dissolve, then add vecuronium bromide, and after replenishing the water for injection, adjust the pH to neutral, then treat with activated carbon for injection, then decarbonize and filter, add water for injection to the filtrate to the full volume, then dispense into 1 ml water for injection, and finally freeze-dry in stages; then package.

[0009] Preferably, the production process of the injectable vecuronium bromide lyophilized agent includes the following steps:

[0010] (1) The total volume of water for injection is calculated based on 3-5 mg of vecuronium bromide per unit of drug in the preparation, corresponding to 1 ml of water for injection;

[0011] (2) Take 80% water for injection, add povidone K30 and mannitol and stir until completely dissolved;

[0012] (3) Add citric acid and disodium hydrogen phosphate and stir until completely dissolved;

[0013] (4) Add vecuronium bromide and stir until completely dissolved, then add water for injection to the total volume and adjust the pH to neutral;

[0014] (5) Add 0.05% (w / w) of activated carbon for injection to the water for injection, stir for 25 min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume, mix well, and then dispense into vials according to 1 ml of water for injection.

[0015] (6) Then freeze-dry: First, rapidly cool down to 0℃ and hold for 0.5h, then slowly cool down to -45℃ and hold under vacuum of 5~8Pa for 2~3h, then gradually raise the temperature to -18℃ for the first stage of freeze-drying, then gradually raise the temperature to 0℃ for the second stage of freeze-drying, and then gradually raise the temperature to 20~25℃ for the third stage of freeze-drying to obtain vecuronium bromide lyophilized powder for injection;

[0016] (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

[0017] Preferably, in step (4), sodium hydroxide solution is used for pH adjustment.

[0018] Preferably, the pH value is 6.8 to 7.5.

[0019] Preferably, in step (6), the first stage freeze-drying conditions are: temperature -18℃, vacuum 18~20Pa, and time 3~4h.

[0020] Preferably, in step (6), the second stage freeze-drying conditions are: temperature 0℃, vacuum 30~32Pa, time 2~3h.

[0021] Preferably, in step (6), the conditions for the third stage freeze-drying process are: temperature 20~25℃, vacuum 40~42Pa, and time 1~2h.

[0022] Preferably, in step (6), the rapid cooling rate is 2~2.5℃ / min.

[0023] Preferably, in step (6), the rate of slow cooling is 2~2.5℃ / h.

[0024] Preferably, in step (6), the rate of gradual heating is 0.1~0.2℃ / min.

[0025] The beneficial effects of this invention are as follows: The vecuronium bromide lyophilized agent for injection of this invention uses vecuronium bromide, citric acid, disodium hydrogen phosphate, mannitol, and povidone as raw materials, avoiding lactose intolerance. Simultaneously, the lyophilized agent solution is neutral, which can reduce injection pain. The production process of the vecuronium bromide lyophilized agent for injection of this invention ensures that the lyophilized agent has a full appearance, loose and porous texture, rapid reconstitution and clarification, while improving the stability of the lyophilized agent. The vecuronium bromide lyophilized agent for injection of this invention reduces the types of raw materials and costs, making it more suitable for industrial production. Detailed Implementation

[0026] To provide a clearer and more complete description of the present invention, specific embodiments are described below, but these are not intended to limit the invention.

[0027] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0028] Example 1

[0029] A lyophilized vecuronium bromide injection is composed of the following raw materials and parts by weight: 3g vecuronium bromide, 1.35g citric acid, 7.9g disodium hydrogen phosphate, 10.5g mannitol, and 8.5g povidone K30, wherein each unit of the preparation contains 3mg of vecuronium bromide; its production process includes the following steps:

[0030] (1) The total volume of water for injection is calculated based on 3 mg of vecuronium bromide per unit of drug, corresponding to 1 ml of water for injection. The total volume of water for injection is 1000 ml.

[0031] (2) Take 800ml of water for injection, add 8.5g of povidone K30 and 10.5g of mannitol and stir until completely dissolved;

[0032] (3) Add 1.35g of citric acid and 7.9g of disodium hydrogen phosphate and stir until completely dissolved;

[0033] (4) Add vecuronium bromide and stir until completely dissolved. Add water for injection to a total volume of 1000 ml and adjust the pH to 7.0 using sodium hydroxide solution.

[0034] (5) Add 0.5g of activated carbon for injection to the water for injection, stir for 25min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume of 1000ml, mix well, and dispense into 2ml vials, 1ml per vial;

[0035] (6) Then freeze-dry: First, rapidly cool down to 0℃ at a rate of 2~2.5℃ / min and hold for 0.5h, then slowly cool down to -45℃ at a rate of 2~2.5℃ / h and hold under vacuum of 5Pa for 3h, then gradually heat up to -18℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum of 18Pa for 4h, then gradually heat up to 0℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum of 30Pa for 3h, then gradually heat up to 20~25℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum of 40Pa for 2h to obtain vecuronium bromide freeze-dried powder for injection, which is white, loose, and blocky, with a full appearance, smooth surface, and loose and porous texture;

[0036] (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

[0037] Example 2

[0038] A lyophilized vecuronium bromide injection is composed of the following raw materials and parts by weight: 4g vecuronium bromide, 0.76g citric acid, 8.6g disodium hydrogen phosphate, 11.8g mannitol, and 10.7g povidone K30, wherein each unit of the preparation contains 4mg of vecuronium bromide; its production process includes the following steps:

[0039] (1) The total volume of water for injection is calculated based on 4 mg of vecuronium bromide per unit of drug, corresponding to 1 ml of water for injection. The total volume of water for injection is 1000 ml.

[0040] (2) Take 800ml of water for injection, add 10.7g of povidone K30 and 11.8g of mannitol and stir until completely dissolved;

[0041] (3) Add 10.76g of citric acid and 8.6g of disodium hydrogen phosphate and stir until completely dissolved;

[0042] (4) Add vecuronium bromide and stir until completely dissolved. Add water for injection to a total volume of 1000 ml and adjust the pH to 7.2 using sodium hydroxide solution.

[0043] (5) Add 0.5g of activated carbon for injection to the water for injection, stir for 25min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume of 1000ml, mix well, and dispense into 2ml vials, 1ml per vial;

[0044] (6) Then freeze-dry: First, rapidly cool down to 0℃ at a rate of 2~2.5℃ / min and hold for 0.5h, then slowly cool down to -45℃ at a rate of 2~2.5℃ / h and hold under vacuum 7Pa for 2.5h, then gradually heat up to -18℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 19Pa for 3.5h, then gradually heat up to 0℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 31Pa for 2.5h, then gradually heat up to 20~25℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 41Pa for 1.5h to obtain vecuronium bromide freeze-dried powder for injection, which is white, loose, and blocky, with a full appearance, smooth surface, and loose and porous texture;

[0045] (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

[0046] Example 3

[0047] A lyophilized vecuronium bromide injection is composed of the following raw materials and parts by weight: 5g vecuronium bromide, 0.21g citric acid, 9.3g disodium hydrogen phosphate, 13.2g mannitol, and 12.8g povidone K30, wherein each unit of the preparation contains 5mg of vecuronium bromide; its production process includes the following steps:

[0048] (1) The total volume of water for injection is calculated based on 1 ml of water for injection for every 5 mg of vecuronium bromide per unit of the drug, and the total volume of water for injection is 1000 ml.

[0049] (2) Take 800ml of water for injection, add 12.8g of povidone K30 and 13.2g of mannitol and stir until completely dissolved;

[0050] (3) Add 0.21 mg citric acid and 9.3 g disodium hydrogen phosphate and stir until completely dissolved;

[0051] (4) Add vecuronium bromide and stir until completely dissolved. Add water for injection to a total volume of 1000 ml and adjust the pH to 6.8 using sodium hydroxide solution.

[0052] (5) Add 0.5g of activated carbon for injection to the water for injection, stir for 25min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume of 1000ml, mix well, and dispense into 2ml vials, 1ml per vial;

[0053] (6) Then freeze-dry: First, rapidly cool down to 0℃ at a rate of 2~2.5℃ / min and hold for 0.5h, then slowly cool down to -45℃ at a rate of 2~2.5℃ / h and hold under vacuum 8Pa for 2h, then gradually heat up to -18℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 20Pa for 3h, then gradually heat up to 0℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 32Pa for 2h, then gradually heat up to 20~25℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 42Pa for 1h to obtain vecuronium bromide freeze-dried powder for injection, which is white, loose, and lumpy, with a full appearance, smooth surface, and loose and porous texture;

[0054] (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

[0055] Example 4

[0056] A lyophilized vecuronium bromide injection is composed of the following raw materials and parts by weight: 5g vecuronium bromide, 0.45g citric acid, 8.9g disodium hydrogen phosphate, 10.5g mannitol, and 8.5g povidone K30, wherein each unit of the preparation contains 5mg of vecuronium bromide; its production process includes the following steps:

[0057] (1) The total volume of water for injection is calculated based on 1 ml of water for injection for every 5 mg of vecuronium bromide per unit of the drug, and the total volume of water for injection is 1000 ml.

[0058] (2) Take 800ml of water for injection, add 8.5g of povidone K30 and 10.5g of mannitol and stir until completely dissolved;

[0059] (3) Add 0.45g citric acid and 8.9g disodium hydrogen phosphate and stir until completely dissolved;

[0060] (4) Add vecuronium bromide and stir until completely dissolved. Add water for injection to a total volume of 1000 ml and adjust the pH to 7.5 using sodium hydroxide solution.

[0061] (5) Add 0.5g of activated carbon for injection to the water for injection, stir for 25min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume of 1000ml, mix well, and dispense into 2ml vials, 1ml per vial;

[0062] (6) Then freeze-dry: First, rapidly cool down to 0℃ at a rate of 2~2.5℃ / min and hold for 0.5h, then slowly cool down to -45℃ at a rate of 2~2.5℃ / h and hold under vacuum 6Pa for 2h, then gradually heat up to -18℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 18Pa for 3h, then gradually heat up to 0℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 30Pa for 2h, then gradually heat up to 20~25℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 40Pa for 1h to obtain vecuronium bromide freeze-dried powder for injection, which is white, loose, and blocky, with a full appearance, smooth surface, and loose and porous texture;

[0063] (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

[0064] Example 5

[0065] A lyophilized vecuronium bromide injection is composed of the following raw materials and parts by weight: 3g vecuronium bromide, 0.21g citric acid, 8.5g disodium hydrogen phosphate, 13.2g mannitol, and 12.8g povidone K30, wherein each unit of the preparation contains 3mg of vecuronium bromide; its production process includes the following steps:

[0066] (1) The total volume of water for injection is calculated based on 3 mg of vecuronium bromide per unit of drug, corresponding to 1 ml of water for injection. The total volume of water for injection is 1000 ml.

[0067] (2) Take 800ml of water for injection, add 2.8g of povidone K30 and 13.2g of mannitol and stir until completely dissolved;

[0068] (3) Add 0.21g of citric acid and 8.5g of disodium hydrogen phosphate and stir until completely dissolved;

[0069] (4) Add vecuronium bromide and stir until completely dissolved. Add water for injection to a total volume of 1000 ml and adjust the pH to 7.2 using sodium hydroxide solution.

[0070] (5) Add 0.5g of activated carbon for injection to the water for injection, stir for 25min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume of 1000ml, mix well, and dispense into 2ml vials, 1ml per vial;

[0071] (6) Then freeze-dry: First, rapidly cool down to 0℃ at a rate of 2~2.5℃ / min and hold for 0.5h, then slowly cool down to -45℃ at a rate of 2~2.5℃ / h and hold under vacuum of 5Pa for 3h, then gradually heat up to -18℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum of 19Pa for 4h, then gradually heat up to 0℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum of 32Pa for 2h, then gradually heat up to 20~25℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum of 42Pa for 1h to obtain vecuronium bromide freeze-dried powder for injection, which is white, loose, and blocky, with a full appearance, smooth surface, and loose and porous texture;

[0072] (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

[0073] Example 6

[0074] A lyophilized vecuronium bromide injection is composed of the following raw materials and parts by weight: 4g vecuronium bromide, 1.35g citric acid, 7.9g disodium hydrogen phosphate, 11.8g mannitol, and 10.4g povidone K30, wherein each unit of the preparation contains 4mg of vecuronium bromide; its production process includes the following steps:

[0075] (1) The total volume of water for injection is calculated based on 3 mg of vecuronium bromide per unit of drug, corresponding to 1 ml of water for injection. The total volume of water for injection is 1000 ml.

[0076] (2) Take 800ml of water for injection, add 10.4g of povidone K30 and 11.8g of mannitol and stir until completely dissolved;

[0077] (3) Add 1.35g of citric acid and 7.9g of disodium hydrogen phosphate and stir until completely dissolved;

[0078] (4) Add vecuronium bromide and stir until completely dissolved. Add water for injection to a total volume of 1000 ml and adjust the pH to 7.0 using sodium hydroxide solution.

[0079] (5) Add 0.5g of activated carbon for injection to the water for injection, stir for 25min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume of 1000ml, mix well, and dispense into 2ml vials, 1ml per vial;

[0080] (6) Then freeze-dry: First, rapidly cool down to 0℃ at a rate of 2~2.5℃ / min and hold for 0.5h, then slowly cool down to -45℃ at a rate of 2~2.5℃ / h and hold under vacuum 8Pa for 2.5h, then gradually heat up to -18℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 18Pa for 3.5h, then gradually heat up to 0℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 31Pa for 2h, then gradually heat up to 20~25℃ at a rate of 0.1~0.2℃ / min and freeze-dry under vacuum 41Pa for 1h to obtain vecuronium bromide freeze-dried powder for injection, which is white, loose, and blocky, with a full appearance, smooth surface, and loose and porous texture;

[0081] (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

[0082] Example 7

[0083] A lyophilized vecuronium bromide for injection is composed of the following raw materials and parts by weight: 4g vecuronium bromide, 0.7g citric acid, 8.7g disodium hydrogen phosphate, 12.5g mannitol, and 11.3g povidone K30, wherein each unit of the preparation contains 4mg of vecuronium bromide. Its production process is exactly the same as that in Example 2. This lyophilized vecuronium bromide powder for injection is white, loose, and lumpy, with a full appearance, smooth surface, and loose, porous texture.

[0084] Example 8

[0085] A lyophilized vecuronium bromide injection is composed of the following raw materials and parts by weight: 5g vecuronium bromide, 0.32g citric acid, 9.2g disodium hydrogen phosphate, 11.8g mannitol, and 12.2g povidone K30, wherein each unit of the preparation contains 5mg of vecuronium bromide. Its production process is exactly the same as that in Example 3. This lyophilized vecuronium bromide injection powder is white, loose, and lumpy, with a full appearance, smooth surface, and loose, porous texture.

[0086] Comparative Example 1

[0087] A vecuronium bromide lyophilized agent for injection is composed of the following raw materials and weight parts, which are exactly the same as those in Example 1. Its production process is partially the same as that in Example 1. The difference from Example 1 is that: (6) freeze-drying is performed again: the temperature is slowly lowered to -45°C at a rate of 2~2.5°C / h and then kept under vacuum of 5Pa for 3h. Then the temperature is gradually raised to -18°C at a rate of 0.1~0.2°C / min and then freeze-dryed under vacuum of 18Pa for 4h. Then the temperature is gradually raised to 0°C at a rate of 0.1~0.2°C / min and then freeze-dryed under vacuum of 30Pa for 3h. Then the temperature is gradually raised to 20~25°C at a rate of 0.1~0.2°C / min and then freeze-dryed under vacuum of 40Pa for 2h. The freeze-dried powder for injection of vecuronium bromide is obtained. It is white and loose in shape, with some parts full and some parts shrunken. The texture is loose and porous.

[0088] Comparative Example 2

[0089] A vecuronium bromide lyophilized agent for injection is composed of the following raw materials and weight parts, which are exactly the same as those in Example 1. Its production process is partly the same as that in Example 1. The difference from Example 1 is: (6) freeze-drying is performed again: the temperature is slowly lowered to -45°C at a rate of 2~2.5°C / h and then kept under vacuum of 5Pa for 3h. Then the temperature is gradually raised to -5°C at a rate of 0.1~0.2°C / min and then the first stage freeze-drying treatment is performed under vacuum of 25Pa for 4h. Then the temperature is gradually raised to 20~25°C at a rate of 0.1~0.2°C / min and then the second stage freeze-drying treatment is performed under vacuum of 40Pa for 2h. The vecuronium bromide lyophilized powder for injection is obtained. It is white and loose in shape, with some parts full and some parts shrunken. The texture is loose and porous.

[0090] Comparative Example 3

[0091] A lyophilized vecuronium bromide for injection is composed of the following raw materials and weight parts, which are the same as those in Example 1. Its production process is exactly the same as that in Example 1. The difference from Example 1 is that: mannitol 19g, and no povidone K30 is added; the lyophilized vecuronium bromide for injection is white, loose, and blocky, with a full appearance and a loose and porous texture.

[0092] Comparative Example 4

[0093] In Example 5 of CN201410102893.0, 3g of vecuronium bromide, 12g of citric acid, and 9g of disodium hydrogen phosphate were used, with a total volume of 1000ml of water for injection. The preparation process was as follows: 500ml of water for injection was added to a mixing tank, along with 12g of citric acid, 9g of disodium hydrogen phosphate, and 3g of vecuronium bromide. The mixture was heated to 50°C and stirred until dissolved. 0.1% (w / v) activated carbon for injection was added, stirred evenly, and kept warm for approximately 15 minutes for adsorption, stirring 2-3 times during this period. The mixture was then filtered to remove the activated carbon, and water for injection was added to the total volume, stirring evenly. After filtration and clarification, a semi-finished product inspection was performed. The pH value was adjusted using phosphoric acid solution or sodium hydroxide solution to control the pH at 3.9. The solution content was measured, and the solution was filled into vials. After passing the tests for fill volume uniformity and clarity, the product was freeze-dried, capped, sealed, and packaged. The freeze-dried powder for injection was white, loose, and lumpy in appearance, with a porous and loose texture.

[0094] Effect Example

[0095] 1. Stability evaluation: The samples of Examples 1 to 8 of the present invention and the samples of Comparative Examples 1 to 4 were placed at a temperature of 40°C and a relative humidity of 75% for 6 months for accelerated testing. The experimental results are shown in Table 1 below. The samples of Examples 1 to 8 of the present invention and the samples of Comparative Examples 1 to 4 were placed at a temperature of 25°C and a relative humidity of 60% for 24 months for long-term testing. The experimental results are shown in Table 2 below.

[0096] Table 1 Accelerated Testing

[0097]

[0098] Table 2 Long-term test

[0099]

[0100] As shown in Tables 1 and 2, through accelerated and long-term experiments, the content of Comparative Examples 1 to 4 decreased significantly while the content of related substances increased significantly, while the content and related substances of Examples 1 to 8 of the present invention did not change significantly, indicating that the product of the present invention has better stability. Compared with Comparative Example 3, the addition of povidone K30 in the present invention helps to improve the stability of the lyophilized vecuronium bromide injection product.

[0101] 2. Evaluation of Vascular Pain: Samples from Examples 1-8 and Comparative Examples 1-4 of this invention were administered to mice via the femoral artery. Vascular pain was appropriately evaluated by measuring electromyography (EMG). Each group of Examples 1-8 and Comparative Examples 1-4 consisted of 6 mice. After femoral artery administration, the EMG area was measured. The percentage of the EMG area obtained was calculated (referred to as the vascular pain index = EMG value of the calculated EMG peak area / calculated reference value; the smaller the vascular pain index value, the weaker the reduction in vascular pain). Based on the vascular pain index, the degree of vascular pain caused by the injectable vecuronium bromide lyophilized preparation was evaluated. The judgment criteria were: a vascular pain index greater than 60% indicated reduced vascular pain, suggesting a slight vascular stimulation effect; a vascular pain index less than 60% indicated more severe pain and a stronger vascular stimulation effect. The experimental results are shown in Table 3 below.

[0102] Table 3 Vascular pain

[0103]

[0104] As shown in Table 3, compared with Comparative Example 4, the vascular pain index of the vecuronium bromide lyophilized powder for injection in Examples 1-8 and Comparative Examples 1-3 was higher. This indicates that by preparing the vecuronium bromide lyophilized powder for injection using the raw materials of the present invention and controlling its pH to neutral, vascular pain was significantly reduced, and the vascular irritation effect was slight, which could significantly reduce the vascular pain generated during administration. Compared with Comparative Example 3, the vascular pain index of Examples 1-8 was greater than 60%. Povidone K30 is more helpful in maintaining the stability of the drug in the physiological pH environment of blood vessels and accelerating the dissolution of the drug, which can reduce the irritation of vecuronium bromide to blood vessels, thereby further reducing the vascular pain generated during administration. It was further found that Examples 7 and 8 of the present invention had a more significant effect on reducing vascular pain.

[0105] Finally, it should be noted that the above embodiments are only used to illustrate and not limit the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the present invention without departing from the spirit and scope of the present invention. Any modifications or partial substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A vecuronium bromide lyophilized agent for injection, characterized in that, It is composed of the following raw materials and parts by weight: 3-5 parts vecuronium bromide, 0.21-1.35 parts citric acid, 7.9-9.3 parts disodium hydrogen phosphate, 10.5-13.2 parts mannitol, and 8.5-12.8 parts povidone K30, wherein each unit of the preparation contains 3-5 mg of vecuronium bromide. The vecuronium bromide lyophilized concentrate for injection is produced through the following steps: In water for injection calculated based on 3-5 mg of vecuronium bromide per unit of formulation corresponding to 1 ml of water for injection, first add povidone K30 and mannitol to dissolve, then add citric acid and disodium hydrogen phosphate to dissolve, then add vecuronium bromide, and after replenishing the water for injection, adjust the pH to neutral, then treat with injectable activated carbon, then decarbonize and filter, add water for injection to the filtrate to the full volume, then dispense into 1 ml water for injection, and then freeze-dry in stages; package. The staged freeze-drying process involves: first, rapidly cooling to 0°C and holding for 0.5 hours; then slowly cooling to -45°C and holding under vacuum of 5-8 Pa for 2-3 hours; then gradually heating to -18°C for the first stage of freeze-drying; then gradually heating to 0°C for the second stage of freeze-drying; and finally gradually heating to 20-25°C for the third stage of freeze-drying to obtain vecuronium bromide lyophilized powder for injection. The rapid cooling rate is 2~2.5℃ / min; the slow cooling rate is 2~2.5℃ / h; and the gradual heating rate is 0.1~0.2℃ / min.

2. The vecuronium bromide lyophilized agent for injection according to claim 1, characterized in that, The injectable vecuronium bromide lyophilized preparation is composed of the following raw materials and parts by weight: 4 parts vecuronium bromide, 0.7 parts citric acid, 8.7 parts disodium hydrogen phosphate, 12.5 parts mannitol, and 11.3 parts povidone K30, wherein each unit of the preparation contains 4 mg of vecuronium bromide.

3. The vecuronium bromide lyophilized agent for injection according to claim 1, characterized in that, The injectable vecuronium bromide lyophilized preparation is composed of the following raw materials and parts by weight: 5 parts vecuronium bromide, 0.32 parts citric acid, 9.2 parts disodium hydrogen phosphate, 11.8 parts mannitol, and 12.2 parts povidone K30, wherein each unit of the preparation contains 5 mg of vecuronium bromide.

4. A production process for the injectable vecuronium bromide lyophilized agent according to any one of claims 1 to 3, characterized in that, Includes the following steps: (1) The total volume of water for injection is calculated based on 3-5 mg of vecuronium bromide per unit of drug in the preparation, corresponding to 1 ml of water for injection; (2) Take 80% water for injection, add povidone K30 and mannitol and stir until completely dissolved; (3) Add citric acid and disodium hydrogen phosphate and stir until completely dissolved; (4) Add vecuronium bromide and stir until completely dissolved, then add water for injection to the total volume and adjust the pH to neutral; (5) Add 0.05% (w / w) of activated carbon for injection to the water for injection, stir for 25 min, then decarbonize and filter, collect the filtrate and add water for injection to the total volume, mix well, and then dispense into vials according to 1 ml of water for injection. (6) Then freeze-dry: First, rapidly cool down to 0℃ and hold for 0.5h, then slowly cool down to -45℃ and hold under vacuum of 5~8Pa for 2~3h, then gradually raise the temperature to -18℃ for the first stage of freeze-drying, then gradually raise the temperature to 0℃ for the second stage of freeze-drying, and then gradually raise the temperature to 20~25℃ for the third stage of freeze-drying to obtain vecuronium bromide lyophilized powder for injection; (7) Add aluminum-plastic cap, sterilize, crimp cap, and store at room temperature.

5. The production process of the injectable vecuronium bromide lyophilized agent according to claim 4, characterized in that, The pH value is 6.8~7.

5.

6. The production process of the injectable vecuronium bromide lyophilized agent according to claim 4, characterized in that, In step (6), the first stage of freeze-drying conditions are: temperature -18℃, vacuum 18~20Pa, time 3~4h.

7. The production process of the injectable vecuronium bromide lyophilized agent according to claim 4, characterized in that, In step (6), the second stage of freeze-drying conditions are: temperature 0℃, vacuum 30~32Pa, time 2~3h.

8. The production process of the injectable vecuronium bromide lyophilized agent according to claim 4, characterized in that, In step (6), the conditions for the third stage of freeze drying are: temperature 20~25℃, vacuum 40~42Pa, and time 1~2h.

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