CN112891332A - Bumetanide injection and preparation method thereof - Google Patents
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Abstract
The invention relates to the technical field of medicine technology, in particular to a bumetanide injection which comprises the following components: bumetanide; sodium hydroxide; water for injection. The bumetanide injection provided by the invention ensures stable dissolution of bumetanide, does not introduce other substances, has low allergenicity and is safer in clinical application. The invention also relates to a preparation method of the bumetanide injection, which comprises the following steps: (1) weighing bumetanide; (2) adding 90% of injection water into bumetanide, adding sodium hydroxide solution under stirring, and adjusting the pH value of the mixed solution to 7.0-8.0 after the addition; (3) supplementing the rest of the water for injection; (4) fine filtering, and reserving filtrate for later use; (5) filling the filtrate and rolling a cover. The preparation method provided by the invention is simple to operate, the operations such as filtering off by activated carbon are not set, the content of the main drug is ensured, the stability of bumetanide in the process is high, and the prepared bumetanide injection has excellent comprehensive performance.
Description
Technical Field
The invention relates to the technical field of medicine technology, in particular to a bumetanide injection and a preparation method thereof.
Background
Bumetanide is a derivative of m-aminobenzenesulfonamide, belongs to a powerful diuretic, has the action parts, action mechanisms and action characteristics similar to those of furosemide and ethacrynic acid clinically, is mainly used for treating liver diseases, heart failure, kidney diseases and the like, and has the characteristics of high efficiency, quick effect, short effect and low toxicity. The diuretic action mechanism of bumetanide is related to the inhibition of the activity of Na-K-ATPase, which is mainly realized by inhibiting the loop branch-rising thick segment from reacting on Cl-Active reabsorption of (3) and Na+The passive reabsorption of the drug influences the concentration and dilution process of urine to play a role in diuresis, and the bumetanide can also act on the proximal convoluted tubule and also has the function of renal vasodilation.
The bumetanide is prepared into tablets, freeze-dried powder injection, injection and other formulations in clinical application, wherein the injection is very widely applied by virtue of excellent comprehensive performance. In the preparation of the bumetanide injection, because bumetanide is insoluble in water, in order to fully dissolve the bumetanide raw drug in the water for injection, the bumetanide powder is usually dissolved by an alkaline solution, and then buffer salt is added to adjust the pH value of the solution to 6.5-8.5; meanwhile, the subsequent preparation process also comprises the operations of activated carbon decoloration, detoxification, fine filtration and sterilization and the like; the preparation processes are complicated to operate, and the addition of the buffer solution and the excessive alkaline solution can cause uncontrollable quality defects of the prepared bumetanide injection in subsequent clinical application.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a bumetanide injection, which simplifies the components of the bumetanide injection, enhances the comprehensive performance thereof, and improves the safety and convenience thereof in clinical application.
In order to achieve the aim, the invention provides a bumetanide injection which comprises the following components: bumetanide; sodium hydroxide; water for injection.
Further, the bumetanide injection consists of the following components: bumetanide is less than or equal to 0.5 g; proper amount of sodium hydroxide solution; supplementing the injection water to 1000 ml; the pH value of the bumetanide injection is 7.0-8.0.
Further, the specification of the bumetanide injection is 2 ml: 0.5mg, consisting of the following components: bumetanide 0.25 g; proper amount of 3 percent sodium hydroxide solution; supplementing the injection water to 1000 ml; the pH value of the bumetanide injection is 7.0-8.0.
Further, the feeding molar ratio of the bumetanide to the sodium hydroxide is 1 (1.1-1.04).
Further, the feeding molar ratio of the bumetanide to the sodium hydroxide is 1: 1.05.
Further, the water for injection is pyrogen-free water.
In view of the above problems, another object of the present invention is to provide a method for preparing bumetanide injection.
A preparation method of bumetanide injection specifically comprises the following steps: (1) weighing bumetanide; (2) adding 90% of injection water into bumetanide, adding sodium hydroxide solution under stirring, and dissolving to obtain mixed solution with pH value of 7.0-8.0; (3) supplementing the rest of the water for injection; (4) fine filtering, and reserving filtrate for later use; (5) filling the filtrate and rolling a cover.
Further, the method also comprises the following steps: and (3) carrying out ultrasonic treatment on the mixed solution of bumetanide and sodium hydroxide for 10-15 minutes.
Further, the temperature of the water for injection in the step (2) is 2-8 ℃.
Further, the sodium hydroxide solution is a 3% sodium hydroxide solution; the feeding molar ratio of the sodium hydroxide to the bumetanide in the bumetanide injection (1.04-1.1) is as follows: 1.
the invention has the beneficial effects that:
1. the bumetanide injection consists of bumetanide, sodium hydroxide and pyrogen-free water for injection, the preparation process is stable, and other substances such as buffer salt for adjusting the pH value are not introduced, compared with the existing bumetanide injection, the bumetanide injection has simple components, improved comprehensive performance, greatly weakened allergenicity and safer and more convenient clinical application;
2. the invention enables bumetanide to be stably dissolved by adjusting the adding proportion of bumetanide and sodium hydroxide in the system and further limiting the pH value of the bumetanide injection, and does not need to add buffer salt to adjust back the pH value of the solution, and meanwhile, the finished bumetanide injection can stably keep a dissolved state and is not easy to deteriorate within the range of setting the pH value to be 7.0-8.0;
3. according to the invention, the temperature (2-8 ℃) of water for injection is limited, and ultrasonic treatment is carried out on the mixed solution of bumetanide and sodium hydroxide, so that the bumetanide is dissolved rapidly and has higher stability, the comprehensive performance of the finished bumetanide injection is improved, and the bumetanide injection is safer in clinical application;
4. the bumetanide injection has the advantages of small dose and high stability, the injection is colorless clear liquid, the injection water for burdening is pyrogen-free water (without toxin in the injection), the decoloring and detoxifying operations such as activated carbon adsorption and the like are not needed in the preparation process, the process is simplified, the content of the main drug is ensured, and the practicability of the bumetanide injection is further improved.
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
FIG. 1 is a schematic flow chart of the preparation process of bumetanide injection.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Raw material preparation
Bumetanide, produced by Hainan chemical combination pharmaceutical industry, Inc.;
the water for injection is pyrogen-free water;
3% sodium hydroxide solution, which is prepared by sodium hydroxide and water for injection after sterile and nontoxic detection.
Examples
The quality standard pH value of the bumetanide injection in the current pharmacopoeia requires 6.5-8.5, and the pH value is set to be in the range of 7.0-8.0 in the invention.
Example 1
(1) Accurately weighing 0.25g of bumetanide;
(2) adding injection water with the temperature of 8 ℃ into bumetanide, wherein the amount of the injection water is 90 percent of the total preparation amount; precisely adding 0.95ml of 3% sodium hydroxide solution according to the molar ratio of 1:1.04 of bumetanide to sodium hydroxide under stirring, carrying out ultrasonic treatment on the mixed liquid medicine for 15min, and continuously stirring the mixed liquid medicine for 20min after the treatment is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Example 2
(1) Accurately weighing 0.25g of bumetanide;
(2) adding injection water with the temperature of 6 ℃ into bumetanide, wherein the amount of the injection water is 90 percent of the total preparation amount; precisely adding 0.96ml of 3% sodium hydroxide solution according to the molar ratio of 1:1.05 of bumetanide to sodium hydroxide under stirring, carrying out ultrasonic treatment on the mixed liquid medicine for 13min, and continuously stirring the mixed liquid medicine for 20min after the treatment is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Example 3
(1) Accurately weighing 0.25g of bumetanide;
(2) adding water for injection at 2 ℃ into bumetanide, wherein the amount of the water for injection is 90 percent of the total preparation amount; precisely adding 1.005ml of 3% sodium hydroxide solution according to the molar ratio of 1:1.10 of bumetanide to sodium hydroxide under stirring, carrying out ultrasonic treatment on the mixed liquid medicine for 10min, and continuously stirring the mixed liquid medicine for 20min after the treatment is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Example 4
(1) Accurately weighing 0.25g of bumetanide;
(2) adding 90% of injection water into bumetanide, precisely adding 0.96ml of 3% sodium hydroxide solution according to the molar ratio of bumetanide to sodium hydroxide of 1:1.05 under the stirring state, and continuously stirring for 55min after the addition is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Example 5
(1) Accurately weighing 0.5g of bumetanide;
(2) adding injection water with the temperature of 6 ℃ into bumetanide, wherein the amount of the injection water is 90 percent of the total preparation amount; precisely adding 1.152ml of 3% sodium hydroxide solution according to the molar ratio of 1:1.05 of bumetanide to sodium hydroxide under stirring, carrying out ultrasonic treatment on the mixed liquid medicine for 13min, and continuously stirring the mixed liquid medicine for 30min after the treatment is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 1mg for later use.
Comparative example
Comparative example 1
(1) Accurately weighing 0.25g of bumetanide;
(2) adding 90% of injection water into bumetanide, precisely adding 0.915ml of 3% sodium hydroxide solution according to the 1:1 molar ratio of bumetanide to sodium hydroxide under the stirring state, and continuously stirring for 1.5h after the addition is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Comparative example 2
(1) Accurately weighing 0.25g of bumetanide;
(2) adding 90% of injection water into bumetanide, precisely adding 0.94ml of 3% sodium hydroxide solution according to the molar ratio of bumetanide to sodium hydroxide of 1:1.025 under the stirring state, and continuously stirring for 1.5h after the addition is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Comparative example 3
(1) Accurately weighing 0.25g of bumetanide;
(2) adding injection water with the temperature of 8 ℃ into bumetanide, wherein the amount of the injection water is 90 percent of the total preparation amount; precisely adding 0.94ml of 3% sodium hydroxide solution according to the molar ratio of 1:1.025 of bumetanide to sodium hydroxide under stirring, carrying out ultrasonic treatment on the mixed liquid medicine for 15min, and continuously stirring the mixed liquid medicine for 20min after the treatment is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Comparative example 4
(1) Accurately weighing 0.25g of bumetanide;
(2) adding 90% of injection water into bumetanide, precisely adding 1.05ml of 3% sodium hydroxide solution according to the molar ratio of bumetanide to sodium hydroxide of 1:1.15 under the stirring state, and continuously stirring for 45min after the addition is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine just after the 3 percent sodium hydroxide solution is added and the stirring is finished, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Comparative example 5
(1) Accurately weighing 0.25g of bumetanide;
(2) adding 90% of injection water into bumetanide, precisely adding 1.1ml of 3% sodium hydroxide solution according to the molar ratio of bumetanide to sodium hydroxide of 1:1.2 under the stirring state, and continuously stirring for 45min after the addition is finished; observing the dissolution state of bumetanide, monitoring the pH value of the liquid medicine, and recording the pH value in the table 1;
(3) adding the rest water for injection to make up to 1000 ml;
(4) redundant filtration is carried out on the solution by using 2 lines of PES material sterilizing filters with the diameter of 0.22 mu m, and filtrate is reserved;
(5) the above filtration was performed at 2 ml: subpackaging with 0.5mg for use.
Comparative example 6
The specification of the bumetanide injection is 2 ml: 0.5mg, manufactured by Yongkang pharmaceutical Co., Ltd, Beijing.
Comparative example 7
The specification of the bumetanide injection is 2 ml: 0.5mg, manufactured by Guilin south drug, Inc.
Comparative example 8
The specification of the bumetanide injection is 2 ml: 0.5mg, manufactured by Ningbo Dahong Ying liquor GmbH.
Inspection and characterization
The content of the related substances of the bumetanide injection prepared in the examples 1 to 5 and the comparative examples 1 to 5 was measured by high performance liquid chromatography (general rule 0512), and the measurement results are recorded in the following table 1:
TABLE 1 dissolution of bumetanide injection, pH value and measurement results of related substances
TABLE 2 bumetanide
According to the pharmacopoeia, it can be known that bumetanide is insoluble in water, and can be dissolved in water after being reacted with sodium hydroxide to generate bumetanide sodium salt, the chemical structural formula of bumetanide is shown in the table 2, the bumetanide is a molecule with a benzoic acid group, and the bumetanide sodium salt can be completely reacted to generate the bumetanide sodium salt under the condition that the theoretical proportion of the bumetanide and the sodium hydroxide is 1:1 mol ratio.
By comparing the data of examples 1 to 5 and comparative examples 1 to 5 with Table 1, it can be seen that:
in the actual production, when the feeding molar ratio of bumetanide to sodium hydroxide is 1:1, the reaction is not complete, the solution is turbid, and a large amount of bumetanide cannot be dissolved.
After the feed molar ratio of bumetanide to sodium hydroxide is adjusted to 1:1.025, bumetanide still cannot be completely dissolved. On the basis, the ultrasonic treatment is carried out on the mixed solution of the components, the dissolution condition is improved, but the bumetanide is not completely dissolved, and the pH value of the solution is not in the set range.
When the feeding molar ratio of the bumetanide to the sodium hydroxide is (1:1.1) - (1:1.04), the bumetanide can be completely dissolved, and the solution is clear; and when the bumetanide and the sodium hydroxide are just mixed, the pH value of the solution is between 8 and 9, the pH value of the solution after the dissolution is between 7 and 8, the bumetanide has better stability in the preparation process and after the preparation, and the content of related substances in the finished bumetanide injection is lower. Especially, when the feeding molar ratio of bumetanide to sodium hydroxide in example 2 and example 4 is 1:1.05, the pH values of the solution are 7.67 and 7.63, which are close to the intermediate value of 7.5, and the solution is the best choice in the actual production.
When the feeding molar ratio of the bumetanide to the sodium hydroxide is 1:1.15 or more (the sodium hydroxide ratio is increased), the pH value before dissolution is high, and the pH value before dissolution exceeds the control requirement of 8.0, so the feeding molar ratio of 1:1.15 or more (the sodium hydroxide ratio is increased) is not suitable for the actual production of the bumetanide injection.
(II) investigation of the amount of activated carbon
The active carbon is commonly used in the preparation process of the bumetanide injection in the prior art and is used for decoloring and removing endotoxin in the solution. Five parts of the bumetanide injection prepared in the examples 2, 4 and 5 are respectively numbered as 1-5, 6-10 and 11-15, one part of the bumetanide injection is respectively arranged for each group to be used as a blank solution, and 0.05 percent, 0.1 percent, 0.15 percent and 0.2 percent (w/v) of activated carbon are respectively added into the other four parts of the bumetanide injection, the bumetanide injection is stirred for 15min at room temperature and is respectively stirred for 0.22 mu m, the content of the bumetanide is measured (according to high performance liquid chromatography, general rule 0512), the clarity and the bacterial endotoxin (general rule 0512), and the test results are shown in the table 3.
Table 3 examination results of the amount of activated carbon
The data in table 3 show that the activated carbon has an adsorption effect on the main drug, which results in the decrease of the content of the main drug, and the addition and removal processes require strict operations, which increases the processing difficulty. The results of the examples 2, 4 and 5 show that the preparation method of the bumetanide injection is simple in process, the prepared bumetanide injection is small in amount, and after proportioning and preparation, the content, the clarity and the bacterial endotoxin of the liquid medicine in the finished bumetanide injection meet the requirements no matter the liquid medicine is directly stirred and dissolved or dissolved after ultrasonic treatment, and the operations of decoloring, detoxifying and the like are not required to be added with active carbon.
(III) comparison of prescription Components
The components of examples 1 to 5 and comparative examples 6, 7 and 8 were analyzed, and the statistics of the analysis results are shown in table 4.
TABLE 4 ingredient analysis Table
In the actual production of bumetanide injection, the reaction speed of bumetanide and sodium hydroxide is slow, and the addition of alkali is usually excessive when the sodium hydroxide is gradually added until the bumetanide is completely dissolved. Therefore, manufacturers often add buffer salt in the prescription to adjust back the pH value so as to ensure the stability of the medicine in the storage and transportation process; although the preparation process accelerates the production speed, other substances are introduced, and the related substances are easily increased, so that the finished bumetanide injection has uncontrollable quality defects.
Clinical applications have proved that the content of the related substances and the addition of non-medicinal substances are important influencing factors for the sensitization of the medicines. The preparation process is simple, the stability of bumetanide in the process is high, and compared with products in comparative examples 6, 7 and 8, the prepared bumetanide injection does not introduce other substances and has better comprehensive performance.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (10)
1. The bumetanide injection is characterized by comprising the following components:
bumetanide;
sodium hydroxide;
water for injection.
2. The bumetanide injection according to claim 1, which consists of the following components:
bumetanide is less than or equal to 0.5 g;
proper amount of sodium hydroxide solution;
supplementing the injection water to 1000 ml;
the pH value of the bumetanide injection is 7.0-8.0.
3. The bumetanide injection according to claim 2, wherein the specification of the bumetanide injection is 2 ml: 0.5mg, consisting of the following components:
bumetanide 0.25 g;
proper amount of 3 percent sodium hydroxide solution;
supplementing the injection water to 1000 ml;
the pH value of the bumetanide injection is 7.0-8.0.
4. The bumetanide injection according to claims 1 to 3, wherein the feed molar ratio of bumetanide to sodium hydroxide is 1 (1.1 to 1.04).
5. The bumetanide injection according to claim 4, wherein the charge molar ratio of bumetanide to sodium hydroxide is 1: 1.05.
6. The bumetanide injection according to claim 1, wherein the water for injection is pyrogen-free water.
7. A method for preparing bumetanide injection, which is used for preparing the bumetanide injection of any one of claims 1 to 6, and comprises the following steps:
(1) weighing bumetanide;
(2) adding 90% of injection water into bumetanide, adding sodium hydroxide solution under stirring, and dissolving to obtain mixed solution with pH value of 7.0-8.0;
(3) supplementing the rest of the water for injection;
(4) fine filtering, and reserving filtrate for later use;
(5) filling the filtrate and rolling a cover.
8. The method of claim 7, further comprising: and (3) carrying out ultrasonic treatment on the mixed solution of bumetanide and sodium hydroxide for 10-15 minutes.
9. The method of claim 8, wherein the temperature of the water for injection in step (2) is 2-8 ℃.
10. The method for preparing bumetanide injection according to claim 7, wherein the sodium hydroxide solution is a 3% strength aqueous sodium hydroxide solution; the feeding molar ratio of the sodium hydroxide to the bumetanide in the bumetanide injection is (1.04-1.1): 1.
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| CN115487141A (en) * | 2022-09-30 | 2022-12-20 | 浙江和沐康医药科技有限公司 | Bumetanide injection composition and preparation method thereof |
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| CN101591276A (en) * | 2009-05-21 | 2009-12-02 | 苏州立新制药有限公司 | A kind of preparation method of bumetanide |
| CN103520122A (en) * | 2013-10-25 | 2014-01-22 | 海南通用康力制药有限公司 | Bumetanide freeze-dried powder preparation for injection and preparation method thereof |
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| CN101591276A (en) * | 2009-05-21 | 2009-12-02 | 苏州立新制药有限公司 | A kind of preparation method of bumetanide |
| CN103520122A (en) * | 2013-10-25 | 2014-01-22 | 海南通用康力制药有限公司 | Bumetanide freeze-dried powder preparation for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115487141A (en) * | 2022-09-30 | 2022-12-20 | 浙江和沐康医药科技有限公司 | Bumetanide injection composition and preparation method thereof |
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