Zhengqing Fengtongning injection composition

Abstract

The invention provides an optimized composition of raw material medicines and auxiliary materials of Zhengqingfengtongning injection, which is prepared from 25 parts by weight of sinomenine hydrochloride, 0.1-0.4 part by weight of EDTA-2Na (disodium edetate) and 1000 parts by volume of water by a conventional method. Research results prove that edetate disodium has a remarkable effect of inhibiting damage of an oxidizing agent to sinomenine hydrochloride, the total impurity amount is controlled to be 1% or below, and new impurities cannot be generated.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine and relates to a Zhengqing Fengtongning injection composition. Background Art

[0002] Zhengqing Fengtongning Injection is a preparation with sinomenine hydrochloride as the drug ingredient. The impurity detection and control of injection preparations must start from the raw materials and excipients. Sinomenine hydrochloride is a monomer compound extracted from the medicinal material of Sinomenine. The preparations made with it as the raw material include Zhengqing Fengtongning Injection, Zhengqing Fengtongning Sustained-Release Tablets, and Zhengqing Fengtongning Tablets. There is no detection of relevant substances (impurities) in the existing quality standards. In 2021, an analytical method for detecting impurities in sinomenine hydrochloride was developed and established in accordance with the quality standards for chemical drugs. It was found that the main impurity of sinomenine hydrochloride is bisinomenine. Summary of the invention

[0003] The purpose of the present invention is to optimize the process of raw materials and excipients of Zhengqing Fengtongning injection, and the present invention is achieved through the following technical scheme.

[0004] 25 parts by weight of sinomenine hydrochloride, 0.1-0.4 parts by weight of EDTA-2Na (disodium edetate), 1000 parts by volume of water, and a conventional method for preparing an injection. Preferably, 25 parts by weight of sinomenine hydrochloride and 0.3 parts by weight of EDTA-2Na (disodium edetate) are used. The relationship between the volume part and the weight part described in the present invention is the relationship between ml and g.

[0005] The research results of the present invention prove that the aqueous solution of sinomenine hydrochloride is unstable under high temperature oxidation conditions and will be greatly degraded. It is necessary to add appropriate excipients to stabilize it and prevent it from degrading. Sodium bisulfite can partially inhibit the degradation of sinomenine hydrochloride under high temperature and oxidation conditions, but the effect is limited and new impurities will be generated; after sodium bisulfite and disodium edetate are added at the same time, the number of impurities and the total impurity content will increase. Disodium edetate has the effect of significantly inhibiting the destruction of sinomenine hydrochloride by oxidants, and the total impurity content is controlled below 1%, and no new impurities will be generated. The present invention preferably uses disodium edetate as an excipient for sinomenine hydrochloride injection.

[0006] Experimental Example 1: Screening of Zhengqing Fengtongning prescriptions 1Original prescription

[0007] Process: Add in order according to the above prescription, stir evenly, filter, seal, and heat at 100℃ for 30 minutes.

[0008] 1.1 Compatibility study of raw materials and excipients According to the above process, sinomenine hydrochloride and sodium bisulfite, disodium edetate refluxed at 100℃, 0H, 2H; 1% hydrogen peroxide solution refluxed at 100℃ for 0, 2H; 1% hydrogen peroxide solution refluxed at 45℃ for 0min, 2H; related substances were investigated. The results are as follows: 1.1.1 Effect of excipients on sinomenine hydrochloride under high temperature conditions Table 1. Results of impurities of sinomenine hydrochloride by auxiliary materials at high temperature 100℃

[0009] The results from the above table show that: 1. After the aqueous solution of sinomenine hydrochloride without auxiliary materials was heated at 100°C for two hours, three impurities appeared and the total impurity content increased by 16%.

[0010] 2. When sinomenine hydrochloride was added to sodium bisulfite solution, there were 3 impurities before heating, and the total impurities were 7.63%; after heating at 100°C for two hours, there were 6 impurities, and the total impurities were 2.61%; 3. When sinomenine hydrochloride was added to the disodium edetate solution, the number of impurities was 1 before heating, and the total impurity content was 0.17%; after heating at 100°C for two hours, the number of impurities was 2, and the total impurity content was 0.25%.

[0011] 4. When sinomenine hydrochloride was added to the prescribed amount of sodium bisulfite and EDTA aqueous solution, the number of impurities was 2 without heating, and the total impurity content was 0.96%; after heating at 100°C for two hours, the number of impurities was 3, and the total impurity content was 0.69%.

[0012] 1.1.2 Effects of excipients and sinomenine hydrochloride under oxidation (1% hydrogen peroxide solution) and high temperature conditions Table 2. Results of excipients on the impurities of sinomenine hydrochloride under high temperature conditions of oxidation (1% hydrogen peroxide solution)

[0013] The results in the table above show that under 100°C oxidation conditions: 1. The solution of sinomenine hydrochloride is unstable and will degrade significantly; 2. When sodium bisulfite was added alone, the impurities of sinomenine hydrochloride at 0 hours were 6 and the total impurities were 22.04%; after heating at 100°C for two hours, the impurities were 9 and the total impurities were 49.94%.

[0014] 3. When only disodium edetate was added, there were 3 impurities in sinomenine hydrochloride at 0 hours, and the total impurities were less than 1%. There was no obvious change in the number of impurities and the total impurities before and after heating.

[0015] 4. Sodium bisulfite and disodium edetate were added at the same time. The impurities of sinomenine hydrochloride at 0 hours were 7 and the total impurities were 9.46%; after heating at 100°C for two hours, the impurities were 7 and the total impurity content was 7.2%.

[0016] The above results show that disodium edetate can significantly inhibit the production of impurities in sinomenine hydrochloride under high temperature (100°C) and oxidative conditions, while sodium bisulfite has no inhibitory effect.

[0017] 1.1.3 Effect of excipients on sinomenine hydrochloride at 45°C under oxidative conditions (1% hydrogen peroxide solution) Table 3. Results of excipients on sinomenine hydrochloride impurities at 45°C under oxidation conditions (1% hydrogen peroxide solution)

[0018] The results in the table above show that: at 45°C under oxidative conditions 1. The destructiveness of sinomenine hydrochloride is less than that at 100°C; 2. After adding sodium bisulfite, the impurities of sinomenine hydrochloride were 7 and the total impurities were 23.0%; after heating for two hours, the impurities were 7 and the total impurities were 16.1%.

[0019] 3. After adding disodium edetate, sinomenine hydrochloride will only produce two impurities, and the total impurity content is reduced to less than 1%. There is no obvious change in the total impurities before and after heating.

[0020] 4. After adding sodium bisulfite and disodium edetate, the impurities of sinomenine hydrochloride were 6 and the total impurities were 6.12%; after heating for two hours, the impurities were 6 and the total impurities were 4.89%.

[0021] 1.2 Compatibility experiment summary: 2. Screening of the amount of EDTA added 2.1 Take an appropriate amount of water for injection, heat it, add EDTA (0.03%, 0.02%, 0.01%, 0), 10g of sinomenine hydrochloride, stir to dissolve, measure the pH value, heat to reflux at 100℃, and cool.

[0022] 2.2 Take an appropriate amount of water for injection, heat it, add EDTA (0.03%, 0.02%, 0.01%, 0), 10g of sinomenine hydrochloride, dissolve it, adjust the pH value to about 3, heat it to reflux at 100℃, and cool it.

[0023] 2.4 Experimental Results

[0024] The results in the above table show that: (1) All three EDTA concentrations can significantly reduce the number of impurities and total impurity content of sinomenine hydrochloride.

[0025] (2) Under the same EDTA concentration, the number and content of impurities in the solution with pH = 3 were lower than those in the solution without pH adjustment (pH 4.2).

[0026] (3) Under the same pH conditions, the impurity content of the solutions with three excipient concentrations was not much different, and the impurity content of the solution without excipients was significantly higher than that of the solution with excipients.

[0027] 3. Conclusion of prescription screening experiment 1. Prescription composition: Raw materials: sinomenine hydrochloride, auxiliary materials: disodium edetate. 2. Prescription quantity: The amount of disodium edetate added is 0.03%. The mechanism of EDTA protecting sinomenine hydrochloride may be to complex the metal ions in the solution, so that the metal ions cannot catalyze the oxidation of sinomenine hydrochloride. Considering the metal ions brought by the pipeline in the actual production process, an excess of EDTA is added to complex the metal ions brought by the pipeline. 3. The pH of the solution is adjusted to 3.0. DETAILED DESCRIPTION Embodiment 1:

[0028] 25g of Sinomenine hydrochloride, 0.3 of disodium edetate, and 1000ml of water. Add in the above prescription in order, stir evenly, filter, seal, and heat at 100℃ for 30 minutes to obtain the product. Example 2

[0029] 25 g of sinomenine hydrochloride, 0.2 g of EDTA-2Na (edetate disodium), and 1000 ml of water are prepared into an injection by conventional methods. Example 3

[0030] 25g of Sinomenine hydrochloride, 0.1g of EDTA-2Na (edetate disodium), 1000ml of water. Add in the above prescription in order, stir evenly, filter, seal, and heat at 100℃ for 30 minutes to obtain the product.

Claims

1. A Zhengqing Fengtongning injection composition, characterized in that The composition is: 25 parts by weight of Sinomenine hydrochloride, 0.1-0.4 parts by weight of EDTA-2Na (disodium edetate), and 1000 parts by volume of water.

2. The Zhengqing Fengtongning injection composition according to claim 1, characterized in that The composition is: 25 parts by weight of Sinomenine hydrochloride, 0.3 parts by weight of EDTA-2Na (disodium edetate), and 1000 parts by volume of water.

3. The Zhengqing Fengtongning injection composition according to claim 1, characterized in that The composition is: 25 parts by weight of Sinomenine hydrochloride, 0.2 parts by weight of EDTA-2Na (disodium edetate), and 1000 parts by volume of water.

4. The method for preparing the Zhengqing Fengtongning injection composition according to any one of claims 1 to 3, characterized in that The method is: Add sinomenine hydrochloride, EDTA-2Na (edetate disodium), and water in the order given above, stir evenly, filter, seal, and heat at 100°C for 30 minutes to obtain the product.

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