A carbetocin injection and its preparation process

Abstract

This invention discloses a carbetocin injection solution and its preparation process. The raw materials for the carbetocin injection solution include at least carbetocin, methionine, disodium edetate, an antibacterial agent, a pH adjuster, and a solvent. The pH of the carbetocin injection solution is 4.0-4.5. The concentration of carbetocin is 50 μg / ml-80 μg / ml, the concentration of methionine is 10 mg / ml-20 mg / ml, the concentration of disodium edetate is 5 mg / ml-10 mg / ml, and the concentration of the antibacterial agent is 2 mg / ml-3 mg / ml. By controlling the concentrations of carbetocin, methionine, disodium edetate, and the antibacterial agent, and simultaneously adjusting the pH of the injection solution to 4.0-4.5, this invention eliminates the need for nitrogen purging during the preparation process, thereby enabling the prepared carbetocin injection solution to exhibit high antioxidant properties and stability, allowing for long-term storage at room temperature.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a carbetocin injection and its preparation process. Background Technology

[0002] Postpartum hemorrhage is defined as blood loss exceeding 500 ml within 24 hours after delivery. Its occurrence is mainly related to factors such as uterine atony and multiple pregnancies, with uterine atony being the primary cause. Oxytocin is a polypeptide hormone and a first-line drug for preventing and treating postpartum hemorrhage. It acts on uterine oxytocin receptors, effectively enhancing uterine contractions and preventing postpartum hemorrhage.

[0003] Carbetocin, molecular formula C 45 H 69 N 11 O 12 S, by binding to oxytocin receptors in uterine smooth muscle, induces rhythmic uterine contractions and increases uterine tone and contraction frequency, resulting in significant uterine contraction effects. It is characterized by rapid onset and long duration of action.

[0004] Carbetocin is generally available in the form of an injection. It requires a certain storage time from production to clinical use. However, the commonly available carbetocin injections generally suffer from poor stability and poor sterilization, which are not conducive to long-term storage. Its stability needs to be further improved. Summary of the Invention

[0005] The purpose of this invention is to provide a carbetocin injection solution and its preparation process, which can maintain high stability without the need for nitrogen filling and can be stored at room temperature for a long time.

[0006] To achieve the above objectives, a specific embodiment of the present invention provides the following technical solution:

[0007] A carbetocin injection solution, the raw materials of which include at least carbetocin, methionine, disodium edetate, antibacterial agent, pH adjuster and solvent, wherein the pH of the carbetocin injection solution is 4.0-4.5;

[0008] The concentration of carbetocin is 50 μg / ml-80 μg / ml, the concentration of methionine is 10 mg / ml-20 mg / ml, the concentration of disodium edetate is 5 mg / ml-10 mg / ml, and the concentration of the antibacterial agent is 2 mg / ml-3 mg / ml.

[0009] In one or more embodiments of the present invention, the antibacterial agent is selected from one or more of chlorobutanol, benzyl alcohol, and tert-butanol.

[0010] In one or more embodiments of the present invention, the pH adjuster is selected from one or both of acetic acid and succinic acid.

[0011] In one or more embodiments of the present invention, polyethylene glycol and catechin are also included. The amount of polyethylene glycol added is 5g-8g based on 1000ml of carbetocin injection, and the mass ratio of catechin to polyethylene glycol is 1:(3-5).

[0012] In one or more embodiments of the present invention, the polyethylene glycol comprises low molecular weight polyethylene glycol with a molecular weight of 600-1000 and high molecular weight polyethylene glycol with a molecular weight of 1500-2000, wherein the mass ratio of the low molecular weight polyethylene glycol to the high molecular weight polyethylene glycol is 1:(5-8).

[0013] In one or more embodiments of the present invention, trehalose is also included, with the amount of trehalose added being 3-5g per 1000ml of carbetocin injection.

[0014] In one or more embodiments of the present invention, chlorogenic acid is further included, wherein the mass ratio of chlorogenic acid to trehalose is 1:(3-5).

[0015] Another specific embodiment of the present invention provides the following technical solution:

[0016] A method for preparing carbetocin injection includes the following steps:

[0017] According to the formula, take part of the solvent, add methionine, disodium edetate and antibacterial agent, and mix well;

[0018] Add carbetocin, adjust the pH to 4.0-4.5 with a pH adjuster, and then add the remaining solvent to make up to the final volume to obtain the formulation;

[0019] The preparation is filtered, filled, and sterilized to obtain carbetocin injection.

[0020] In one or more embodiments of the present invention, the sterilization operation is as follows:

[0021] First, raise the temperature to 80℃-100℃ and hold for 10-15 minutes;

[0022] Reheat to 105℃-110℃ and hold for 5-10 minutes;

[0023] Reheat to 115℃-125℃ and hold for 15min-30min;

[0024] The temperature dropped to 60℃.

[0025] In one or more embodiments of the present invention, the cooling operation is as follows: first, the temperature is lowered to 110°C-112°C within 3-5 minutes; then, the temperature is lowered to 90°C-100°C within 3-5 minutes; and finally, the temperature is lowered to 60°C within 3-5 minutes.

[0026] Compared with the prior art, the present invention controls the concentrations of carbetocin, methionine, disodium edetate, and antibacterial agent, and adjusts the pH of the injection solution to 4.0-4.5. Nitrogen gas is not required during the preparation process, which enables the prepared carbetocin injection solution to have high antioxidant properties and stability and can be stored for a long time at room temperature. Detailed Implementation

[0027] To enable those skilled in the art to better understand the technical solutions in this disclosure, the technical solutions in the embodiments of this disclosure are described clearly and completely below. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. Based on the embodiments in this disclosure, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this disclosure.

[0028] One specific embodiment of the present invention provides a carbetocin injection solution, the raw materials of which include carbetocin, methionine, disodium edetate, antibacterial agent, pH adjuster and solvent. The concentration of carbetocin is 50μg / ml-80μg / ml, the concentration of methionine is 10mg / ml-20mg / ml, the concentration of disodium edetate is 5mg / ml-10mg / ml, the concentration of antibacterial agent is 2mg / ml-3mg / ml, and the pH of the carbetocin injection solution is 4.0-4.5.

[0029] Specifically, methionine, as an antioxidant, is preferentially oxidized in the system, thereby protecting the methionine residues (Met) in the carbetocin peptide chain. 4 It is not oxidized into sulfoxide impurities, ensuring the stability of the system. Disodium edetate can chelate metal ions and can bind Fe in the system. 2+ Cu 2+ It blocks the free radical oxidation chain reaction caused by the Fenton reaction. The antibacterial agent inhibits bacteria in the system, reducing the impact of bacteria on the system's stability.

[0030] In addition, the pH of carbetocin injection solution is adjusted to 4.0-4.5 using a pH adjuster. In this acidic environment, the pH adjuster can form a high ionic strength environment, which inhibits the aggregation caused by electrostatic attraction between carbetocin peptide molecules through charge shielding effect, thereby maintaining the uniformity and stability of carbetocin dispersion in the system.

[0031] Furthermore, by controlling the concentration of each raw material in the system, the stability of the system is improved, which helps to preserve it for a long time at room temperature.

[0032] Furthermore, the antibacterial agent is selected from one or more of chlorobutanol, benzyl alcohol, and tert-butanol, the pH adjuster is selected from one or two of acetic acid and succinic acid, and the solvent is water for injection.

[0033] Furthermore, it also includes polyethylene glycol and catechins. Based on 1000ml of carbetocin injection, the amount of polyethylene glycol added is 5g-8g, and the mass ratio of catechins to polyethylene glycol is 1:(3-5).

[0034] Specifically, catechins possess antibacterial and antioxidant properties, which can improve the stability of the system. Polyethylene glycol (PEG) helps dissolve and mix the various raw material components, ensuring their uniform dispersion within the system. Furthermore, the presence of phenolic hydroxyl groups and aromatic rings in the catechin structure gives PEG a high affinity for catechins. The hydrogen bonds and interactions formed between PEG and catechins in the system cause the PEG molecular chains to tend to "encapsulate" the catechins, which to some extent slows down the oxidative degradation of catechins. This allows methionine in the system to be preferentially oxidized, thus exerting an antioxidant effect, followed by the catechins' action to achieve the same effect. This, in turn, improves the stability of the injection solution and extends its shelf life.

[0035] Furthermore, polyethylene glycol includes low molecular weight polyethylene glycol with a molecular weight of 600-1000 and high molecular weight polyethylene glycol with a molecular weight of 1500-2000, with a mass ratio of low molecular weight polyethylene glycol to high molecular weight polyethylene glycol of 1:(5-8).

[0036] Specifically, lower molecular weight polyethylene glycols (PEGs) more easily contact and interact with catechins, promoting their dispersion in the system. Higher molecular weight PEGs, with their longer molecular chains, have a better effect of "encapsulating" catechins, thus improving their stability within the system and enabling them to exert their antioxidant effects, thereby enhancing the overall stability of the system. By using low-molecular-weight and high-molecular-weight PEGs in a specific mass ratio, a synergistic effect is achieved. This ensures that catechins are uniformly dispersed in the system to exert their antioxidant effects while also delaying their oxidative degradation, further improving the system's stability.

[0037] Furthermore, it also includes trehalose, with an addition of 3-5g per 1000ml of carbetocin injection.

[0038] Specifically, on the one hand, trehalose has a certain antioxidant effect and can assist methionine in achieving an antioxidant effect in the system; on the other hand, adding trehalose to the system helps maintain the structure of carbetocin and keep it stable in activity.

[0039] Furthermore, it also includes chlorogenic acid, with a mass ratio of chlorogenic acid to trehalose of 1:(3-5).

[0040] Specifically, this invention uses chlorogenic acid and trehalose in a certain proportion to achieve a synergistic effect, jointly maintaining the structure and activity of carbetocin.

[0041] Another specific embodiment of the present invention provides a method for preparing carbetocin injection, comprising the following steps 1-3.

[0042] Step 1: According to the formula, take part of the solvent, add methionine, disodium edetate and antibacterial agent, and mix well.

[0043] Specifically, according to the mixing ratio, take 80% of the volume of water for injection and dissolve methionine, disodium edetate, and the antibacterial agent.

[0044] Step 2: Add carbetocin, adjust the pH to 4.0-4.5 with a pH adjuster, and then add the remaining solvent to make up the volume to obtain the preparation.

[0045] Step 3: Filter, fill, and sterilize the preparation to obtain carbetocin injection.

[0046] Specifically, a conventional filter is used for filtration. The filter membrane can be polyethersulfone (PES) or polyvinylidene fluoride (PVDF), with a pore size of 0.22 μm. The filtered solution is filled into vials, partially stoppered, and then capped. The sterilization process is as follows: first, heat to 80℃-100℃ and hold for 10-15 minutes; then heat to 105℃-110℃ and hold for 5-10 minutes; then heat to 115℃-125℃ and hold for 15-30 minutes; then cool to 110℃-112℃ within 3-5 minutes; then cool to 90℃-100℃ within 3-5 minutes; finally, cool to 60℃ within 3-5 minutes.

[0047] Gradual heating ensures the stability of substances in the system and reduces the generation of impurities and bacteria. Simultaneously, gradient cooling further prevents the introduction of impurities, ensuring the purity and stability of the resulting injection solution.

[0048] The present invention will be further described in detail below with reference to specific embodiments.

[0049] Unless otherwise specified, all raw materials used in this invention are commercially available.

[0050] Example 1

[0051] A method for preparing carbetocin injection includes the following steps:

[0052] Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, and 2.5g of chlorobutanol, and stir to dissolve. Then divide 0.07g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0053] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0054] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 80°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0055] Example 2

[0056] A method for preparing carbetocin injection includes the following steps:

[0057] Step 1: Measure 800ml of water for injection, add 20g of methionine, 5g of disodium edetate, and 2.5g of chlorobutanol, and stir to dissolve. Then divide 0.07g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0058] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0059] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 90°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0060] Example 3

[0061] A method for preparing carbetocin injection includes the following steps:

[0062] Step 1: Measure 800ml of water for injection, add 20g of methionine, 10g of disodium edetate, and 2.5g of chlorobutanol, and stir to dissolve. Then divide 0.07g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0063] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0064] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 100°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0065] Example 4

[0066] A method for preparing carbetocin injection includes the following steps:

[0067] Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, and 2.5g of chlorobutanol, and stir to dissolve. Then divide 0.07g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.5 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0068] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0069] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 100°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0070] Example 5

[0071] A method for preparing carbetocin injection includes the following steps:

[0072] Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, and 2.5g of chlorobutanol, and stir to dissolve. Then divide 0.07g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with succinic acid, and add water for injection to a final volume of 1000ml.

[0073] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0074] Step 3: Place the sealed carbetocin preparation into a sterilizer, raise the temperature from 80°C to 100°C, maintain for 10 minutes, continue to raise the temperature to 120°C and maintain for 8 minutes, after which continue to raise the temperature to 123°C and sterilize for 6 minutes, then lower the temperature to 115°C within 3 minutes, then lower the temperature to 100°C within 3 minutes; finally, lower the temperature to 60°C within 5 minutes.

[0075] Example 6

[0076] A method for preparing carbetocin injection includes the following steps:

[0077] Step 1: Measure 800ml of water for injection, add 20g of methionine, 5g of disodium edetate, and 2g of chlorobutanol, and stir to dissolve. Then divide 0.05g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with succinic acid, and add water for injection to a final volume of 1000ml.

[0078] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0079] Step 3: Place the sealed carbetocin preparation into a sterilizer, raise the temperature from 80°C to 100°C, maintain for 10 minutes, continue to raise the temperature to 120°C and maintain for 8 minutes, after which continue to raise the temperature to 123°C and sterilize for 6 minutes, then lower the temperature to 112°C within 3 minutes, then lower the temperature to 95°C within 3 minutes; finally, lower the temperature to 60°C within 5 minutes.

[0080] Example 7

[0081] A method for preparing carbetocin injection includes the following steps:

[0082] Step 1: Measure 800ml of water for injection, add 20g of methionine, 5g of disodium edetate, and 3g of chlorobutanol, and stir to dissolve. Then divide 0.08g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with succinic acid, and add water for injection to a final volume of 1000ml.

[0083] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0084] Step 3: Place the sealed carbetocin preparation into a sterilizer, raise the temperature from 80°C to 100°C, maintain for 10 minutes, continue to raise the temperature to 120°C and maintain for 8 minutes, after which continue to raise the temperature to 123°C and sterilize for 6 minutes, then lower the temperature to 112°C within 3 minutes, then lower the temperature to 90°C within 3 minutes; finally, lower the temperature to 60°C within 5 minutes.

[0085] Example 8

[0086] A method for preparing carbetocin injection includes the following steps:

[0087] Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, 2.5g of chlorobutanol, and 5g of polyethylene glycol with a molecular weight of 600, and stir to dissolve. Then divide 0.07g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0088] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0089] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 80°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0090] Example 9

[0091] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, and 8 g of polyethylene glycol with a molecular weight of 1500 are added and stirred to dissolve. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0092] Example 10

[0093] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol with a molecular weight of 600, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:5. The mixture is stirred and dissolved. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0094] Example 11

[0095] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol with a molecular weight of 600, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:3. The mixture is stirred and dissolved. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0096] Example 12

[0097] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol with a molecular weight of 600, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:1, and the mixture is stirred to dissolve. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0098] Example 13

[0099] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 600 and polyethylene glycol with a molecular weight of 1500 in a mass ratio of 1:5. The mixture is stirred and dissolved. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0100] Example 14

[0101] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 1000 and polyethylene glycol with a molecular weight of 2000 in a mass ratio of 1:8. The mixture is stirred and dissolved. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0102] Example 15

[0103] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 1000 and polyethylene glycol with a molecular weight of 2000 in a mass ratio of 1:1. The mixture is stirred and dissolved. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0104] Example 16

[0105] The difference between this embodiment and Embodiment 8 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 1000 and polyethylene glycol with a molecular weight of 2000 in a mass ratio of 1:10. The mixture is stirred and dissolved. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0106] Example 17

[0107] A method for preparing carbetocin injection includes the following steps:

[0108] Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, 2.5g of chlorobutanol, 8g of polyethylene glycol, 3g of trehalose, and a certain amount of catechin. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 600 and polyethylene glycol with a molecular weight of 1500 in a mass ratio of 1:5. Stir to dissolve. Then divide 0.07g of carbetocin into three equal portions and add them to the solution in three separate additions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0109] Step 2: Filter the solution using a 0.22um filter. Pour the filtered solution into 10ml vials, partially stopper and crimp the cap.

[0110] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 80°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0111] Example 18

[0112] The difference between this embodiment and Embodiment 17 is that, in step one: 800 ml of water for injection is measured, and 10 g of methionine, 5 g of disodium edetate, 2.5 g of chlorobutanol, 8 g of polyethylene glycol, 5 g of trehalose, and a certain amount of catechin are added. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 600 and polyethylene glycol with a molecular weight of 1500 in a mass ratio of 1:5. The mixture is stirred and dissolved. Then, 0.07 g of carbetocin is divided into three equal portions and added to the solution in three separate additions. The pH is adjusted to 4.0 with glacial acetic acid, and water for injection is added to a final volume of 1000 ml.

[0113] Example 19

[0114] The difference between this embodiment and Embodiment 17 is as follows: Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, 2.5g of chlorobutanol, 8g of polyethylene glycol, 5g of trehalose, a certain amount of catechin, and a certain amount of chlorogenic acid. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 600 and polyethylene glycol with a molecular weight of 1500 in a mass ratio of 1:5. The mass ratio of chlorogenic acid to trehalose is 1:1. Stir to dissolve. Then, divide 0.07g of carbetocin into three equal parts and add them to the solution in three separate additions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0115] Example 20

[0116] The difference between this embodiment and Embodiment 17 is as follows: Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, 2.5g of chlorobutanol, 8g of polyethylene glycol, 5g of trehalose, a certain amount of catechin, and a certain amount of chlorogenic acid. The mass ratio of catechin to polyethylene glycol is 1:5, the mass ratio of chlorogenic acid to trehalose is 1:3, and the polyethylene glycol includes polyethylene glycol with a molecular weight of 600 and polyethylene glycol with a molecular weight of 1500 in a mass ratio of 1:5. Stir to dissolve. Then, divide 0.07g of carbetocin into three equal parts and add them to the solution in three separate portions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0117] Example 21

[0118] The difference between this embodiment and Embodiment 17 is as follows: Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, 2.5g of chlorobutanol, 8g of polyethylene glycol, 5g of trehalose, a certain amount of catechin, and a certain amount of chlorogenic acid. The mass ratio of catechin to polyethylene glycol is 1:5. The polyethylene glycol includes polyethylene glycol with a molecular weight of 600 and polyethylene glycol with a molecular weight of 1500 in a mass ratio of 1:5. The mass ratio of chlorogenic acid to trehalose is 1:5. Stir to dissolve. Then, divide 0.07g of carbetocin into three equal parts and add them to the solution in three separate portions. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0119] Comparative Example 1

[0120] A method for preparing carbetocin injection includes the following steps:

[0121] Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, and 2.5g of chlorobutanol, and stir to dissolve. Then, divide 0.07g of carbetocin into three equal portions and add them to the solution. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0122] Step 2: Perform two-stage filtration using a 0.45um filter and a 0.22um filter. The filtered solution is then bottled in 10ml vials, partially stoppered, and capped.

[0123] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 80°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0124] Comparative Example 2

[0125] A method for preparing carbetocin injection includes the following steps:

[0126] Step 1: Measure 800ml of water for injection, add 10g of methionine, 5g of disodium edetate, and 2.5g of chlorobutanol, and stir to dissolve. Then, divide 0.07g of carbetocin into three equal portions and add them to the solution. Adjust the pH to 4.0 with glacial acetic acid, and add water for injection to a final volume of 1000ml.

[0127] Step 2: Filter the solution using a 0.22um filter, pour the filtered solution into 10ml vials, fill with nitrogen, partially stopper and crimp the cap.

[0128] Step 3: Place the sealed carbetocin preparation into a sterilizer, heat to 80°C, maintain for 10 minutes, continue to heat to 110°C, maintain for 8 minutes, after the maintenance period, continue to heat to 123°C, sterilize for 15 minutes, and then cool to 60°C within 15 minutes.

[0129] The quality of the injection solutions in each embodiment and comparative example was compared, and the specific results are shown in Table 1.

[0130] Table 1 Comparison of injection solution mass in each embodiment and comparative example

[0131]

[0132] As can be seen from Table 1, the samples obtained in the embodiments of the present invention are basically the same in quality as the samples of Comparative Example 1 that have undergone multi-stage filtration and Comparative Example 2 that have undergone nitrogen-filled moist heat sterilization.

[0133] The samples in each embodiment were subjected to accelerated stability testing under the following conditions: temperature 40℃±2℃, RH 75%±5%. The test results are shown in Table 2.

[0134] Table 2. Accelerated stability results of the injection solutions in each example.

[0135]

[0136] As can be seen from Table 2, after 6 months of accelerated testing, the carbetocin injection in Example 1 showed almost no significant changes in terms of appearance, pH, chlorobutanol content, and related substances content, indicating that the carbetocin injection prepared by this invention has excellent stability.

[0137] As shown in Examples 8-12, using catechins and polyethylene glycol in a certain mass ratio can have a synergistic effect, thus improving the stability of the injection solution. Furthermore, as shown in Examples 13-16, using a combination of low-molecular-weight and high-molecular-weight polyethylene glycol can further improve the stability of the injection solution. This may be because, while ensuring that catechins are uniformly dispersed in the system to exert their antioxidant properties, it can also delay the oxidative degradation of catechins themselves, allowing them to exert their antioxidant effect for a longer period.

[0138] As demonstrated in Examples 17-21, the combined use of chlorogenic acid and trehalose resulted in superior stability of the injection solution. This may be because the hydroxyl groups in both trehalose and chlorogenic acid can interact with carbetocin, helping to maintain its structure and reducing its oxidation potential. The combined use of trehalose and chlorogenic acid exhibits a synergistic effect, significantly improving the stability of the injection solution.

[0139] It will be apparent to those skilled in the art that this disclosure is not limited to the details of the exemplary embodiments described above, and that this disclosure can be implemented in other specific forms without departing from the spirit or essential characteristics of this disclosure. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of this disclosure is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within this disclosure.

[0140] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A carbetocin injection solution, characterized in that, The raw materials at least include carbetocin, methionine, disodium edetate, bacteriostatic agent, pH regulator and solvent, the pH of the carbetocin injection is 4.0-4.5, and the solvent is water for injection; The concentration of the carbetocin is 70 μg / ml, the concentration of the methionine is 10 mg / ml, the concentration of the disodium edetate is 5 mg / ml, the bacteriostatic agent is chlorobutanol, and the concentration of the bacteriostatic agent is 2.5 mg / ml; The polyethylene glycol and catechin are further included, the addition amount of the polyethylene glycol is 8 g in 1000 ml of the carbetocin injection, and the mass ratio of the catechin to the polyethylene glycol is 1:

5. The polyethylene glycol is composed of small molecular weight polyethylene glycol with a molecular weight of 600 and large molecular weight polyethylene glycol with a molecular weight of 1500, and the mass ratio of the small molecular weight polyethylene glycol to the large molecular weight polyethylene glycol is 1:

5. The trehalose is further included, and the addition amount of the trehalose is 3-5 g in 1000 ml of the carbetocin injection. The chlorogenic acid is further included, and the mass ratio of the chlorogenic acid to the trehalose is 1:(3-5).

2. The carbetocin injection according to claim 1, characterized in that, The pH regulator is selected from one or both of acetic acid and succinic acid.

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