Preparation method of bumetanib injection

Abstract

The invention discloses a preparation method of a bumetanib injection, and belongs to the technical field of medicines. The method comprises the following steps: (1) preparing materials, namely respectively weighing bumetanib, xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate and benzoic anhydride modified polyoxyethylated castor oil according to prescription amounts for later use; (2) preparing a solution: weighing water for injection, adding xylitol, sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate dihydrate according to the prescription dosage in a stirring state, stirring and dissolving, then adding benzoic anhydride modified polyoxyethylated castor oil and bumetanib according to the prescription dosage, and stirring until the materials are completely dissolved; and (3) fixing the volume: supplementing the water for injection to the total amount of the prescription, and uniformly stirring and mixing. According to the bumetanib injection disclosed by the invention, the polyoxyethylated castor oil is modified by benzoic anhydride, so that the dissolution rate of bumetanib is effectively improved, and meanwhile, the high-temperature and illumination stability of the bumetanib injection is remarkably enhanced.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a preparation method of a bumetanide injection. BACKGROUND

[0002] Bumetanide is a derivative of m-aminobenzenesulfonamide and belongs to a strong diuretic. The injection thereof is widely used in clinical treatment of edematous diseases and hypertension. The preparation method of the bumetanide injection has been disclosed in the prior art. The bumetanide itself has poor water solubility and needs to be effectively dissolved under a slightly alkaline condition. However, the dissolution efficiency thereof under the slightly alkaline condition still needs to be improved. In the traditional method, it often takes 1 hour or even more to completely dissolve the bumetanide, which greatly prolongs the production cycle. Even with the aid of conventional auxiliary dissolution means, it is difficult to effectively improve the dissolution efficiency. For example, the Chinese patent application with the application number 202211706215.6 discloses a bumetanide injection formula and a preparation process thereof. It can be seen from the application document that even with the aid of ultrasonic assistance, it takes about 45 minutes to effectively dissolve the bumetanide.

[0003] In addition, the bumetanide is unstable under the conditions of light and high temperature. The sulfonamide group (-SO2NH2), aromatic ring and amino group in the structure of the bumetanide are prone to hydrolysis, oxidation or photodegradation under the conditions of light and high temperature, thereby producing specific impurities. For example, under the light condition, the S-N bond of the sulfonamide group is broken, and at the same time, the substitution group on the aromatic ring may be rearranged, thereby producing impurities. This poses great challenges to the bumetanide injection in the storage and transportation processes, and strict control of the environmental conditions is required, which increases the cost and management difficulty.

[0004] Therefore, it is of great practical significance to develop a preparation method capable of effectively improving the dissolution rate and stability of the bumetanide. SUMMARY

[0005] In view of the deficiencies of the prior art, the purpose of the present application is to provide a preparation method of a bumetanide injection.

[0006] The technical scheme of the present application mainly includes the following contents: A preparation method of a bumetanide injection, comprising the following steps: ① Dosing: respectively take the prescription amount of bumetanide, xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate and benzoic anhydride modified polyoxyethylene castor oil, and reserve them; ② Liquid preparation: take the injection water, and under the stirring state, add the prescription amount of xylitol, sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate dihydrate to be dissolved by stirring, and then add the prescription amount of benzoic anhydride modified polyoxyethylene castor oil and bumetanide to be stirred until completely dissolved; ③Constant volume: add water for injection to the full amount of the prescription, and stir to mix evenly.

[0007] Preferably, the amount of water in step 2 is 80% of the total volume.

[0008] Preferably, in step 2, the temperature of the water for injection is 40-50°C.

[0009] Preferably, each 4000ml of bumetanide injection contains 2g of bumetanide, 45-55g of xylitol, 0.35-0.45g of sodium dihydrogen phosphate dihydrate, 1.05-1.2g of disodium hydrogen phosphate dihydrate, and 1.0-1.5g of benzoic anhydride modified polyoxyethylene castor oil.

[0010] Preferably, the preparation method of the benzoic anhydride modified polyoxyethylene castor oil comprises the following steps: Mix the polyoxyethylene castor oil with anhydrous dichloromethane to prepare a polyoxyethylene castor oil solution with a concentration of 20-30% w / v, slowly add a mixture of benzoic anhydride and triethylamine under nitrogen protection, stir for at least 4h after the addition is complete, add water after the reaction is complete, stir and mix, and take the organic phase after standing and layering; wash the organic phase with water until it is neutral, and finally add anhydrous sodium sulfate to dry the organic phase, and filter to remove the sodium sulfate; remove the dichloromethane from the dried organic phase under reduced pressure, filter, and then sterilize by dry heat to finally obtain the benzoic anhydride modified polyoxyethylene castor oil.

[0011] Preferably, the molar ratio of polyoxyethylene castor oil hydroxyl, benzoic anhydride, and triethylamine is 1:1.2-1.5:1.5-1.8.

[0012] Preferably, the molar ratio of polyoxyethylene castor oil hydroxyl, benzoic anhydride, and triethylamine is 1:1.2:1.5.

[0013] The benzoic anhydride modified polyoxyethylene castor oil is used to improve the stability of bumetanide.

[0014] Preferably, the stability is high-temperature stability and / or light stability.

[0015] The beneficial effects of the present application are: Bumetanide is difficult to dissolve in water, but it is soluble in weak alkaline solution, but the dissolution efficiency is low, and the stability of bumetanide under alkaline conditions will be poor, and the stability will be further reduced under high temperature and light conditions, and a large amount of impurities will be produced. The product formula is optimized, sodium hydroxide used in the traditional prescription is removed, and the dissolution of bumetanide is ensured by controlling the ratio of sodium dihydrogen phosphate and disodium hydrogen phosphate and controlling the pH of the liquid medicine. The pH of the buffer system composed of sodium dihydrogen phosphate and disodium hydrogen phosphate is relatively stable, which avoids the problem caused by the sudden change of pH caused by directly adding sodium hydroxide in the traditional formula. In addition, the dissolution rate of bumetanide and the high temperature and light stability of bumetanide injection are effectively improved by adding modified polyoxyethylene castor oil.

[0016] The bumetanide injection prepared by the present application meets the "bumetanide injection" standard in the second part of Chinese Pharmacopoeia 2020 edition, the product quality is reliable, the stability is good, and it is beneficial to the storage, transportation and clinical application of the medicine. DETAILED DESCRIPTION

[0017] In order to better understand the technical content of the present application, the present application will be further described below in combination with specific examples.

[0018] Example 1: Modification of polyoxyethylene castor oil Raw materials: injection grade polyoxyethylene (35) castor oil (moisture ≤0.1%), benzoic anhydride, triethylamine, anhydrous dichloromethane. According to the molar ratio of 1:1.2:1.5, polyoxyethylene castor oil hydroxyl, benzoic anhydride and triethylamine are fed.

[0019] The polyoxyethylene castor oil is mixed with anhydrous dichloromethane to prepare a polyoxyethylene castor oil solution with a concentration of 20%-30% w / v. Under the protection of nitrogen, the mixed solution of benzoic anhydride and triethylamine is slowly added dropwise, and after the addition is completed, stirring is carried out for 4h. After the reaction is completed, water (2 times the volume of the reaction solution) is added, stirring is carried out for 30min, and after standing and layering, the organic phase is taken; the organic phase is washed with water until it is neutral (pH 6.5-7.5), and finally anhydrous sodium sulfate is added to dry the organic phase, and the sodium sulfate is removed by filtration.

[0020] The dried organic phase is distilled under reduced pressure (40℃) to remove dichloromethane, and the residual solvent content is controlled to be ≤0.006% v / v. The product is filtered through a 0.22μm microporous filter, and then subjected to dry heat sterilization (121℃ / 2h), to finally obtain modified polyoxyethylene castor oil.

[0021] Example 2: Modification of polyoxyethylene castor oil Raw materials: injection grade polyoxyethylene (35) castor oil (moisture ≤0.1%), benzoic anhydride, triethylamine, anhydrous dichloromethane. Polyoxyethylene castor oil hydroxyl, benzoic anhydride, and triethylamine were added in a molar ratio of 1:1.5:1.8.

[0022] Polyoxyethylene castor oil was mixed with anhydrous dichloromethane to prepare a polyoxyethylene castor oil solution with a concentration of 20%-30% w / v. Under nitrogen protection, the mixture of benzoic anhydride and triethylamine was slowly added dropwise. After the addition was completed, stirring was carried out for 4 hours. After the reaction was completed, water was added (volume was 2 times the volume of the reaction solution), stirring was carried out for 30 minutes, and after standing and layering, the organic phase was taken. The organic phase was washed with water until it was neutral (pH 6.5-7.5), and finally anhydrous sodium sulfate was added to dry the organic phase, and the sodium sulfate was removed by filtration.

[0023] The dried organic phase was distilled under reduced pressure (40°C) to remove dichloromethane, and the residual solvent content was controlled to be ≤0.006% v / v. The product was filtered through a 0.22 μm microporous filter, then subjected to dry heat sterilization (121°C / 2h), and finally the modified polyoxyethylene castor oil was obtained.

[0024] Example 3 Preparation of bumetanide injection Prescription 1

[0025] Prescription analysis: 1) Bumetanide: main drug, has pharmacological effect 2) Xylitol: osmotic pressure regulator 3) Sodium phosphate monobasic dihydrate / sodium phosphate dibasic dihydrate: buffer system, pH regulator 4) Modified polyoxyethylene castor oil: cosolvent, stabilizer 5) Water for injection: solvent for raw and auxiliary materials.

[0026] Preparation method: ① Dosing: respectively weigh the prescription amount of bumetanide (dry and pure), xylitol, sodium phosphate monobasic dihydrate, sodium phosphate dibasic dihydrate, and modified polyoxyethylene castor oil, and reserve for use; ② Liquid preparation: Weigh a certain amount of water for injection (about 80% of the total volume, temperature 40°C~50°C), and under stirring, add the prescription amount of xylitol, sodium phosphate monobasic dihydrate, and sodium phosphate dibasic dihydrate, and stir to dissolve (about 10 min). Then add the prescription amount of modified polyoxyethylene castor oil and bumetanide, and stir until all are dissolved (observed that the total dissolution time is about 30 min). ③ Volume setting: add water for injection to the full amount (weight method volume setting, relative density 1.0163, -20°C volume setting), and stir to mix evenly (5 min). IV. Filtration: The medicinal liquid was filtered through a 0.22 μm polyether sulfone filter; V. Filling: Brown medium borosilicate glass ampoule, 1 ml:0.5 mg specification loading is 1.00 ml~1.10 ml, 4 ml:2 mg specification loading 4.00 ml~4.25 ml; VI. Sterilization: 121 ℃ flow through steam sterilization for 15 min, after sterilization, spray cooling to room temperature (rapid cooling); VII. Leak detection, lamp inspection; packaging, warehousing.

[0027] The product is detected according to the provisions of "Bumetanide Injection" in the second part of "Chinese Pharmacopoeia" 2020 edition, and the detection results of each index meet the standard, and the product is qualified.

[0028] Example 4 Preparation of Bumetanide Injection Prescription 2

[0029] The preparation method refers to Example 3.

[0030] Preparation method: I. Dosing: The prescription amount of bumetanide (dry and pure), xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, and modified polyoxyethylene castor oil were weighed and prepared; II. Liquid preparation: A certain amount of water for injection (about 80% of the total volume, temperature 40~50℃) was weighed, and the prescription amount of xylitol, sodium dihydrogen phosphate dihydrate, and disodium hydrogen phosphate dihydrate was added under stirring and dissolved (about 10 min). Then the prescription amount of modified polyoxyethylene castor oil and bumetanide was added and stirred until completely dissolved (observed, the total dissolution time was about 25 min); III. Volume setting: Add water for injection to the full amount (weight method volume setting, relative density 1.0163, -20℃ volume setting), and mix evenly (5 min); IV. Filtration: The medicinal liquid was filtered through a 0.22 μm polyether sulfone filter; V. Filling: Brown medium borosilicate glass ampoule, 1 ml:0.5 mg specification loading is 1.00 ml~1.10 ml, 4 ml:2 mg specification loading 4.00 ml~4.25 ml; VI. Sterilization: 121 ℃ flow through steam sterilization for 15 min, after sterilization, spray cooling to room temperature (rapid cooling); VII. Leak detection, lamp inspection; packaging, warehousing.

[0031] The product is detected according to the provisions of "Bumetanide Injection" in the second part of "Chinese Pharmacopoeia" 2020 edition, and the detection results of each index meet the standard, and the product is qualified.

[0032] Preparation of bumetanide injection Formulation 3

[0033] The preparation method is reference example 3.

[0034] Preparation method: ①Dosing: respectively take the prescription amount of bumetanide (dry and pure), xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, and reserve; ②Liquid preparation: Take a certain amount of water for injection (about 80% of the total volume, temperature 40~50℃), add the prescription amount of xylitol, sodium dihydrogen phosphate dihydrate, and disodium hydrogen phosphate dihydrate under stirring state, and stir to dissolve (about 10min), then add the prescription amount of bumetanide, and stir to dissolve (about 1h); ③Constant volume: add water for injection to the full amount (constant volume by weight, relative density 1.0163, constant volume at-20℃), and stir to mix evenly (stirring time 20min±5min); ④Filtration: the liquid medicine is filtered through a 0.22μm polyether sulfone filter; ⑤Filling and sealing: brown borosilicate glass ampoule, 4ml:2mg specification, 4.00ml~4.25ml; ⑥Sterilization: 121℃ flow steam sterilization for 15min, and after sterilization, spray cooling to room temperature (rapid cooling); ⑦Leak detection, lamp inspection; packaging, warehousing.

[0035] The product is detected according to "bumetanide injection" in Chinese Pharmacopoeia 2020 edition part two, and the detection results of each index meet the standard, and the product is qualified.

[0036] Preparation of bumetanide injection Formulation 4

[0037] The preparation method is reference example 3.

[0038] Preparation method: ①Dosing: respectively take the prescription amount of bumetanide (dry and pure), xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, and polyoxyethylene castor oil, and reserve; ②Liquid preparation: Take a certain amount of water for injection (about 80% of the total volume, temperature 40~50℃), under the condition of stirring, add the prescription amount of xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, stir and dissolve (about 10 min), then add the prescription amount of polyoxyethylene castor oil, bumetanide, stir until completely dissolved (observed, the total dissolution time is about 45 min); ③Constant volume: add water for injection to the full amount (constant volume by weight, relative density 1.0163, constant volume at -20℃), stir and mix evenly (10 min); ④Filter: the liquid medicine is filtered through a 0.22 μm polyether sulfone filter; ⑤Filling and sealing: brown borosilicate glass ampoule, 1ml:0.5mg specification loading 1.00ml~1.10ml, 4ml:2mg specification loading 4.00ml~4.25ml; ⑥Sterilization: 121℃ flow steam sterilization for 15min, after sterilization, spray cooling to room temperature (rapid cooling); ⑦Leak detection, lamp inspection; packaging, warehousing.

[0039] The product is detected according to "Bumetanide Injection" in Chinese Pharmacopoeia 2020 edition II, and the detection results of each index meet the standard, and the product is qualified.

[0040] Experiment 1 High temperature, light stability experiment Take each example, comparative product and commercially available sample, respectively, under light 4000±200lx and high temperature 60±1℃ (light sample is placed in transparent borosilicate glass ampoule, high temperature sample is placed in brown borosilicate glass ampoule), respectively, on the 5th, 10th day, high temperature sample is extended to 30 days, according to the detection conditions of related substances in "Bumetanide Injection" in Chinese Pharmacopoeia 2020 edition II (high performance liquid chromatography), detect the maximum single impurity and total impurity. Each group of 5 samples, 2 parallel experiments for each group, take the average value. The results are shown in Table 1.

[0041] Table 1

[0042] From the experimental results in Table 1 above, the dissolution time of each example and comparative example, it can be seen that the application effectively improves the dissolution rate and stability of bumetanide by modifying polyoxyethylene castor oil with benzoic anhydride. Compared with Comparative Example 1 and Comparative Example 2, the dissolution time of Example 3 and Example 4 is shortened to within 30 minutes, which greatly improves the dissolution efficiency.

[0043] In addition, the modified adjuvant also significantly enhances the high temperature and light stability of the bumetanide injection, especially solves the key problem that bumetanide is very unstable under light conditions. Under high temperature or light conditions, the sulfonamide group S-N bond of bumetanide is easy to hydrolyze, the aromatic ring substituent is easy to rearrange, and the impurities of the conventional preparation increase rapidly under high temperature or light. By adding the modified adjuvant, the degradation of bumetanide is inhibited, and the high temperature stability of the bumetanide injection is effectively improved.

[0044] According to the above experimental data, compared with Comparative Example 1, the dissolution time of Example 3 and Example 4 is shortened by 50%-58%, and the total impurities after light irradiation for 10 days are reduced by 33.8%-36.6%; compared with Comparative Example 2, the dissolution time is shortened by 33.3%-44.4%, and the total impurities after light irradiation for 10 days are reduced by 31.8%-31.9%; compared with the commercially available sample, the total impurities after high temperature for 30 days are reduced by 55.6%, and the total impurities after light irradiation for 10 days are reduced by 50%-52.1%. It can be seen that by structural design and process optimization of benzoic anhydride modified polyoxyethylene castor oil, the dissolution rate and high temperature and light stability of bumetanide are simultaneously improved for the first time. The above only describes some embodiments of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall fall within the protection scope of the present application.

Claims

1. A method for preparing a bumetanide injection solution, characterized by, It comprises the following steps: ①Ingredients: respectively take the prescription amount of bumetanide, xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, benzoic anhydride modified polyoxyethylene castor oil, for standby; ②Liquid preparation: take the injection water, under the stirring state, add the prescription amount of xylitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, stirring and dissolving, then add the prescription amount of benzoic anhydride modified polyoxyethylene castor oil and bumetanide, stirring until all dissolved; ③Constant volume: add injection water to the full amount of prescription, stirring and mixing evenly.

2. The production method according to claim 1, characterized by, The water amount in step ② is 80% of the total volume.

3. The production method according to claim 1, characterized by, In step ②, the temperature of the injection water is 40℃-50℃.

4. The method of claim 1, wherein, Each 4000ml of bumetanide injection contains 2g of bumetanide, 45-55g of xylitol, 0.35-0.45g of sodium dihydrogen phosphate dihydrate, 1.05-1.2g of disodium hydrogen phosphate dihydrate, and 1.0-1.5g of benzoic anhydride modified polyoxyethylene castor oil.

5. The preparation method according to claim 1, characterized in that, The preparation method of the benzoic anhydride modified polyoxyethylene castor oil comprises the following steps: Mix the polyoxyethylene castor oil with anhydrous dichloromethane to prepare a polyoxyethylene castor oil solution with a concentration of 20%-30% w / v, slowly add the mixture of benzoic anhydride and triethylamine under nitrogen protection, stir for at least 4h after the addition is completed, add water after the reaction is completed, stir and mix, take the organic phase after standing and separating; wash the organic phase with water until it is neutral, finally add anhydrous sodium sulfate to dry the organic phase, filter to remove sodium sulfate; remove dichloromethane from the dried organic phase under reduced pressure, filter, then sterilize by dry heat, and finally obtain benzoic anhydride modified polyoxyethylene castor oil.

6. The production method according to claim 5, characterized by, The molar ratio of polyoxyethylene castor oil hydroxyl, benzoic anhydride, and triethylamine is 1:1.2-1.5:1.5-1.

8.

7. The preparation method of claim 5, further characterized in that the molar ratio of polyoxyethylene castor oil hydroxyl, benzoic anhydride, and triethylamine is 1:1.2:1.

5.

8. A benzoic anhydride-modified polyoxyethylene castor oil, characterized by, The preparation method of benzoic anhydride modified polyoxyethylene castor oil is as claimed in claim 5.

9. The use of benzoic anhydride modified polyoxyethylene castor oil of claim 8 in improving the stability of bumetanide.

10. Use according to claim 9, characterized in that, The stability is high temperature stability and / or light stability.

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