CN107638386B - Kanamycin sulfate injection and preparation method thereof - Google Patents
Kanamycin sulfate injection and preparation method thereof Download PDFInfo
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- CN107638386B CN107638386B CN201711028918.7A CN201711028918A CN107638386B CN 107638386 B CN107638386 B CN 107638386B CN 201711028918 A CN201711028918 A CN 201711028918A CN 107638386 B CN107638386 B CN 107638386B
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Abstract
The invention provides a kanamycin sulfate injection and a preparation method thereof, wherein the preparation method of the kanamycin sulfate injection comprises the following steps: (1) dissolving sodium bisulfite in water for injection, and then filling nitrogen to prepare 20-40 wt% sodium sulfite aqueous solution; (2) adding kanamycin sulfate into a sodium sulfite aqueous solution, and stirring to obtain a mixture; (3) adding sulfuric acid into the mixture, and adjusting the pH value to 5.0-7.0; (4) adding sodium citrate, supplementing water for injection to 90% of the total preparation amount, and adjusting the pH value to 5.0-6.0; (5) adding water for injection to the total amount of the preparation, filtering and encapsulating; (6) sterilizing at 121 deg.C for 15 min. According to the invention, nitrogen is filled into the sodium bisulfite aqueous solution and the dissolving sequence of sodium bisulfite and kanamycin sulfate is adjusted, so that the risk of kanamycin sulfate oxidation is reduced, and the stability of the kanamycin sulfate injection is greatly improved.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to kanamycin sulfate injection and a preparation method thereof.
Background
Kanamycin sulfate is an aminoglycoside antibiotic, and kanamycin sulfate is easily degraded after injection is sterilized at high temperature, so that the solution becomes dark in color. Degradation is generally prevented by lowering the sterilization temperature (e.g., less than 110 ℃), but this practice reduces the sterility assurance levels of the injection and increases the risk of clinical use. Moreover, kanamycin injection is easy to discolor in the production and storage processes, the color of the product is not deeper than yellow or yellow-green No. 4 standard colorimetric solution specified by Chinese pharmacopoeia, and a plurality of processes designed by manufacturers cannot meet the requirements specified by the pharmacopoeia.
Chinese patent ZL201010606891.7 discloses a kanamycin sulfate injection, wherein an antioxidant, a metal ion complexing agent and a pH stabilizer are added, the sterilization temperature is increased from less than 110 ℃ to 115 ℃, and the sterilization is carried out for 30 minutes under the condition of 115 ℃. The sterilization at 115 ℃ for 30 minutes is carried out by the survival probability method, and the increase of the contamination level of the microorganisms or the increase of the heat resistance causes the failure of the objective of the sterilization process. Therefore, there is a need to develop a better method for preparing kanamycin sulfate injection.
Disclosure of Invention
The invention provides a kanamycin sulfate injection and a preparation method thereof, wherein a unique nitrogen replacement process is adopted in the preparation process of the kanamycin sulfate injection, so that the product is prevented from oxidative discoloration under the high-temperature condition, and the stability of the product is improved.
A preparation method of kanamycin sulfate injection comprises the following steps:
(1) dissolving sodium bisulfite into water for injection, and then filling nitrogen into the sodium bisulfite aqueous solution to prepare 20-40 wt% sodium bisulfite aqueous solution;
(2) adding kanamycin sulfate into the sodium bisulfite aqueous solution prepared in the step (1), and stirring to prepare a mixture;
(3) adding sulfuric acid into the mixture prepared in the step (1), stirring to prepare a mixed solution, and adjusting the pH value to 5.0-7.0;
(4) adding sodium citrate into the mixed solution prepared in the step (3), then supplementing water for injection to 90% of the total preparation amount, and adjusting the pH value to 5.0-6.0;
(5) adding water for injection to the total amount of the preparation, filtering and encapsulating;
(6) sterilizing at 121 deg.C for 15 min.
Preferably, in step (1) of the process of the present invention, the volume of the aqueous sodium bisulfite solution is 40% (v/v) of the total amount formulated.
Preferably, in step (3) of the process of the present invention, the concentration of sulfuric acid is 6 mol/L.
Preferably, in the step (5) of the method of the present invention, the temperature of the water for injection is 20 to 40 ℃.
Preferably, in step (5) of the process of the present invention, the potting is performed under nitrogen protection.
The invention also provides kanamycin sulfate injection prepared by the method.
The applicant of the present invention conducted intensive studies on the preparation steps of kanamycin sulfate injection, and found that the dissolution order of sodium bisulfite and kanamycin sulfate in the steps (1) and (2) is related to the product quality of the final kanamycin sulfate injection. The risk of kanamycin sulfate oxidation can be reduced by preparing an aqueous sodium bisulfite solution with nitrogen added, removing water oxides for injection (e.g., dissolved oxygen, etc.), and adding kanamycin sulfate.
In addition, when adding sulfuric acid, attention needs to be paid to diluting sulfuric acid in advance, otherwise, the stability of the liquid medicine is deteriorated and the content of related substances is increased due to overhigh local sulfuric acid concentration in the process of adding sulfuric acid. When the volume of the chemical solution is taken into consideration, the concentration of sulfuric acid is preferably 5.5 to 8.5mol/L, more preferably 6 mol/L.
According to the invention, through careful study, the addition sequence and the addition concentration of each auxiliary material are adjusted, so that the kanamycin sulfate injection product prepared by the invention can endure the sterilization condition of sterilization at 121 ℃ for 15 minutes, and the sterilization degree is higher than the residual probability method sterilization of sterilization at 115 ℃ for 30 minutes in Chinese patent ZL 201010606891.7. The invention can improve the sterilization temperature, ensure the over-sterilization of microorganisms, and repeatedly ensure the Sterility Assurance Level (SAL) of the sterilized articles to be less than or equal to 10-6。
Detailed Description
The present invention will be described in further detail below with reference to specific embodiments, and the present invention will be better understood from the following examples. However, it should be readily understood by those skilled in the art that the specific material ratios, process conditions and results thereof described in the examples are merely illustrative of the present invention and should not limit the scope of the invention covered by the claims.
Example 1
TABLE 1 kanamycin sulfate injection formulation of this example
(1) Dissolving sodium bisulfite with prescription amount in water for injection, and introducing nitrogen to obtain sodium bisulfite aqueous solution with volume of 40% of total amount;
(2) add the prescribed amount of kanamycin sulfate (as kanamycin C)18H36N4O11Metering), stirring to obtain a mixture;
(3) diluting the concentrated sulfuric acid solution of about 18mol/L to 6mol/L, adding the diluted sulfuric acid solution into the mixture prepared in the step (2), stirring, and measuring the pH value to be 5.0-7.0;
(4) adding sodium citrate with a prescription amount, supplementing water for injection to 90% of the total preparation amount, and adjusting the pH value to 5.0-6.0 by using a sulfuric acid solution;
(5) adding water for injection at 20-40 ℃ to the total preparation amount, filtering, and encapsulating under the protection of nitrogen;
(6) sterilizing at 121 deg.C for 15 min.
Example 2
Sample 1, sample 2 and sample 3 were prepared according to the method of example 1 of the present invention, and sample 1, sample 2 and sample 3 were subjected to stability test (examination conditions: 60 ℃ C. + -2 ℃ C.) and the results of the test are shown in Table 2.
As can be seen from the stability test results in table 2, samples 1, 2 and 3 prepared according to example 1 have no significant tendency of increasing or decreasing product properties, pH values, insoluble particles, solution colors, visible foreign substances, individual impurities and total impurities after stability test, and have good stability. The contents of the samples 1, 2 and 3 fluctuate within the range of +/-2%, and no obvious rising or falling trend exists; all the quality indexes meet the regulations of quality standards in the product expiration date.
Example 3
Kanamycin sulfate injection prepared under the condition of no nitrogen protection
TABLE 3 prescription of kanamycin sulfate injection of this example
(1) Dissolving sodium bisulfite with a prescription amount in water for injection to prepare a sodium bisulfite aqueous solution, wherein the volume of the sodium bisulfite aqueous solution is 40 percent of the total preparation amount;
(2) add the prescribed amount of kanamycin sulfate (as kanamycin C)18H36N4O11Metering), stirring to obtain a mixture;
(3) diluting a sulfuric acid solution of about 18mol/L to 6mol/L, adding the diluted sulfuric acid solution into the mixture prepared in the step (2), stirring, and measuring the pH value to be 5.0-7.0;
(4) adding sodium citrate with a prescription amount, then supplementing water for injection to about 90% of the total preparation amount, and adjusting the pH value to 5.0-6.0 by using a sulfuric acid solution;
(5) adding water for injection at 20-40 ℃ to the total preparation amount, filtering and encapsulating;
(6) sterilizing at 121 deg.C for 15 min.
Example 4
(1) Design of experiment
The pH range of kanamycin sulfate injection products is between 5.0 and 7.0, and experimental research is carried out on 3 gradients of 5.0, 6.0 and 7.0 designed on the pH. Preparing corresponding liquid medicine according to the preliminarily confirmed product prescription to meet the requirement that the pH value of the prescription is controlled within the range of 5.0-7.0, investigating the influence of different pH values on the stability of the preparation, and simultaneously dividing each group of test products into two parts before filling and sealing, wherein one part is filled with nitrogen, and the other part is not filled with nitrogen.
(2) Test results
The statistics of the test results of kanamycin sulfate injection under different pH conditions and nitrogen-filled conditions are shown in Table 4.
TABLE 4 Effect of different pH conditions and nitrogen-filling conditions on kanamycin sulfate injection color
Samples 4, 5, 6: prepared according to the method of the invention example 1.
Samples 7, 8, 9: prepared according to the method of the invention example 3.
And (4) experimental conclusion: in the process of preparing and filling the liquid medicine, when nitrogen charging protection is not adopted or the nitrogen charging protection effect is poor, the liquid medicine is easy to change color after the product is sterilized at the temperature of 121 ℃ for 15min, and the color of the liquid medicine is darker than that of a yellow or yellow-green No. 4 standard colorimetric liquid in the storage process and does not meet the standard regulation.
Example 5
TABLE 5 preparation of kanamycin sulfate injection solutions using high concentration sulfuric acid solution
(1) Dissolving sodium bisulfite with prescription amount in water for injection, and introducing nitrogen to obtain sodium bisulfite aqueous solution with volume of 40% of total amount;
(2) add the prescribed amount of kanamycin sulfate (as kanamycin C)18H36N4O11Metering), stirring to obtain a mixture;
(3) adding 18mol/L sulfuric acid solution into the mixture prepared in the step (2), stirring, and measuring the pH value to be 5.0-7.0;
(4) adding sodium citrate with a prescription amount, then supplementing water for injection to 90% of the total preparation amount, and adjusting the pH value to 5.0-6.0 by using a sulfuric acid solution;
(5) adding water for injection at 20-40 ℃ to the total preparation amount, filtering, and encapsulating under the protection of nitrogen;
(6) sterilizing at 121 deg.C for 15 min.
Example 6
Sample 1: prepared according to the method of the invention example 1
Sample 10: prepared according to the method of the invention example 5
TABLE 6 results and analysis of kanamycin sulfate injection solutions prepared with sulfuric acid of different concentrations
As a result: the product prepared by using 18mol/L concentrated sulfuric acid has larger difference in related substances with the product prepared by using 6mol/L sulfuric acid. According to the general preparation procedure, even if nitrogen protection is used in the preparation process, kanamycin sulfate is still easy to degrade, and related substances are easy to grow.
After the applicant examines other sulfuric acid concentrations, the excessive concentration can cause the substances in kanamycin sulfate to be easily increased; and too small concentration results in too large dilution factor and too large volume of sulfuric acid solution, which is not beneficial to production operation. From the viewpoint of product quality and operability of the actual process, the concentration of sulfuric acid may be between 5.5 and 8.5mol/L, preferably 6 mol/L.
Claims (5)
1. A preparation method of kanamycin sulfate injection is characterized by comprising the following steps:
(1) dissolving sodium bisulfite into water for injection, and then filling nitrogen into the sodium bisulfite aqueous solution to prepare 20-40 wt% sodium bisulfite aqueous solution;
(2) adding kanamycin sulfate into the sodium bisulfite aqueous solution prepared in the step (1), and stirring to prepare a mixture;
(3) adding sulfuric acid into the mixture prepared in the step (2), stirring to prepare a mixed solution, and adjusting the pH value to 5.0-7.0, wherein the concentration of the sulfuric acid is 5.5-8.5 mol/L;
(4) adding sodium citrate into the mixed solution prepared in the step (3), then supplementing water for injection to 90% of the total preparation amount, and adjusting the pH value to 5.0-6.0;
(5) adding water for injection to the total preparation amount, filtering, and encapsulating, wherein the encapsulation is carried out under the protection of nitrogen;
(6) sterilizing at 121 deg.C for 15 min.
2. The method according to claim 1, wherein in the step (1), the volume of the aqueous sodium hydrogen sulfite solution is 40 v% of the total amount formulated.
3. The production method according to claim 1, wherein in the step (3), the concentration of the sulfuric acid is 6 mol/L.
4. The method according to claim 1, wherein in the step (5), the temperature of the water for injection is 20 to 40 ℃.
5. A kanamycin sulfate injection prepared according to the method of any one of claims 1 to 4.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552118A (en) * | 2010-12-16 | 2012-07-11 | 四川科伦药物研究有限公司 | Kanamycin sulfate injection and preparation method thereof |
| CN105213300A (en) * | 2011-12-27 | 2016-01-06 | 四川科伦药物研究院有限公司 | A kind of amikacin sulfate injection and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552118A (en) * | 2010-12-16 | 2012-07-11 | 四川科伦药物研究有限公司 | Kanamycin sulfate injection and preparation method thereof |
| CN105213300A (en) * | 2011-12-27 | 2016-01-06 | 四川科伦药物研究院有限公司 | A kind of amikacin sulfate injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 硫酸卡那霉素注射剂变色问题探讨;章光文等;《医药工业》;19841231(第2期);第31-33页，第32页讨论 * |
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