CN112274484B - Process treatment method for improving stability of terbutaline sulfate atomized liquid - Google Patents
Process treatment method for improving stability of terbutaline sulfate atomized liquid Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a process treatment method for improving stability of terbutaline sulfate atomized liquid. The process treatment method effectively removes metal ions on the surface of the production equipment through passivating the production line equipment, ensures the stability of the product, synchronously ensures that the final packaging material does not influence the product through the optimized packaging material, does not need nitrogen filling protection in the production process, has low requirement on the production line, and saves the production cost.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a technological treatment method for improving stability of terbutaline sulfate atomized liquid and terbutaline sulfate atomized liquid obtained by the treatment method.
Background
Terbutaline sulfate, developed by astrazen and marketed in sweden in 1981, is a β 2 adrenoreceptor agonist that, by selectively exciting the β 2 receptor to dilate the bronchi, increases mucociliary clearance due to decreased obstructive pulmonary disease, thereby accelerating mucus secretion clearance. Has effects of relieving asthma, eliminating phlegm, and dilating bronchus. The traditional Chinese medicine composition is mainly used for relieving bronchospasm combined with bronchial asthma, chronic bronchitis, emphysema and other lung diseases in clinic. Mainly adopts atomization administration, and has the advantages of quick effect, good absorption, good curative effect, high bioavailability, etc.
The main component of terbutaline sulfate in the terbutaline sulfate atomized liquid is terbutaline sulfate with the chemical name of (+/-) alpha- [ (tert-butylamino) methyl ] -3, 5-dihydroxy benzyl alcohol sulfate (2:1) and the structural formula is
The measures that can be taken both from the prescription and from the process. Complexing agents or antioxidants can be added into the formula to improve the stability of the product, such as disodium edetate, sodium metabisulfite serving as an antioxidant and the like. However, since adding or changing any one ingredient to the formulation may bring unpredictable risks to patients, especially to products such as aerosol inhalation formulations, injections, etc., which have fast onset of action and high bioavailability, it is a more feasible and safer method to take measures in the process to ensure the stability of the formulation products.
At present, nitrogen is filled in a final packaging container and nitrogen is filled in a process to ensure the stability of products, such as: the original manufacturer of the terbutaline sulfate atomized liquid is Aslicon, the trade name of which is Borikoni, and the original manufacturer can detect the residual oxygen amount to find that the residual oxygen amount is 0.5 percent by purchasing a product sold in the market, so that the original manufacturer can be known to ensure the stability of the product by filling nitrogen into a final packaging container; for example, chinese patent CN110693861A discloses a terbutaline sulfate solution preparation for aerosol inhalation and a preparation method thereof, wherein the preparation method requires that positive pressure of nitrogen is maintained during the liquid preparation process, and the residual oxygen is less than 1 mg/L; for example, chinese patent CN108078918B discloses a treatment method for improving the stability of terbutaline sulfate injection, which requires the solution preparation and filling under the protection of nitrogen gas, although passivation equipment is used in the process to avoid metal ions.
At present, nitrogen filling is mainly adopted in the process to ensure the stability of the product, the nitrogen filling has higher requirements on a production line, the production operation requirements are higher, the production cost is high, and in order to solve the problems, the invention provides the sterile production process which does not need nitrogen filling and can ensure the stability of the terbutaline sulfate atomized liquid.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art and provide a process treatment method for improving the stability of terbutaline sulfate atomized liquid, metal ions on the surface of production equipment are effectively removed by passivating production line equipment, the stability of a product is ensured, meanwhile, the final packaging material is synchronously ensured not to influence the product by an optimized packaging material, nitrogen filling protection is not needed in the production process, the requirement on the production line is low, and the production cost is saved.
The technical scheme provided by the invention is as follows:
a process for improving the stability of terbutaline sulfate atomized liquid includes passivating the production equipment of terbutaline sulfate atomized liquid production line by metal chelating agent, and preparing liquid medicine by the passivated production equipment.
Further, the metal chelating agent is edetate disodium or edetate calcium sodium, and the concentration of the metal chelating agent is 0.01% -0.08%.
Further, the production equipment is cleaned and sterilized before or after passivation.
Furthermore, the time of the passivation treatment is 0.5-5 h.
Further, the step of preparing the liquid medicine comprises the following steps: weighing terbutaline sulfate, edetate disodium and sodium chloride according to the prescription amount; adding 20-70% of batch water for injection into the passivated solution preparation tank, adding ethylene diamine tetraacetic acid, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding the water for injection to 80-90% of the batch, stirring and dissolving, adding a hydrochloric acid solution, adjusting the pH value to 3.0-4.5, and adding the water for injection to the full batch.
Further, the cleaning step is as follows:
a. cleaning for the first time: cleaning the equipment with water for injection for more than 15min-60 min;
b. alkali washing: 1 to 8 percent of sodium hydroxide is used for cleaning for 0 to 5 hours;
c. water cleaning: washing with water for injection until the pH value of the washing water is in the range of 6.0-8.0;
d. acid washing: preparing a citric acid solution with the concentration of 8% -15% and cleaning for 0-10 h;
e. water cleaning: the equipment is washed with water for injection until the pH of the wash water is in the range of 6.0-8.0.
Further, after the preparation of the drug solution, the drug solution was filtered through a 0.45 μm filter and a 0.22 μm sterilizing filter.
Further, the edetate disodium solution is prepared by adopting water for injection, and the temperature of the water for injection is 10-80 ℃.
Furthermore, the liquid medicine is filtered and then filled in a plastic container.
Further, the temperature of passivation treatment is 25-70 ℃.
Furthermore, the concentration of the hydrochloric acid solution is 0.1-0.5 mol/L.
Furthermore, before passivation treatment, oil stains on the surface of production equipment are removed.
A process treatment method for improving the stability of terbutaline sulfate atomized liquid comprises the following steps:
1. disodium edetate is weighed and added with water for injection to prepare 0.04% disodium edetate solution, and the solution is used for passivating production equipment on a production line for 2 hours. And cleaning and sterilizing the equipment after passivation.
2. Weighing the terbutaline sulfate, edetate disodium and sodium chloride according to the prescription amount. Adding 30% of batch water for injection into the passivated solution preparation tank, adding ethylene diamine tetraacetic acid, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding water for injection to 80% of the batch amount, stirring and dissolving, adding a 0.1mol/L hydrochloric acid solution of a pH value regulator, regulating the pH value to 3.0-4.5, and adding water for injection to the whole batch amount.
3. The medicinal liquid is filtered by 0.45 μm filter and 0.22 μm bacteria-reducing filter.
4. And (6) filling.
In the step 1, the concentration of edetate disodium can be 0.01-0.08%, the temperature of water for injection can be 10-80 ℃, and the time of passivation treatment can be 0.5-5 h. Before or after step 1, the following steps can be preferably used for treating the equipment to remove oil stains and the like on the surface of the equipment:
a. cleaning for the first time: cleaning the equipment with water for injection for more than 15min-60 min;
b. alkali washing: 1 to 8 percent of sodium hydroxide is used for cleaning for 0 to 5 hours;
c. water cleaning: washing with water for injection until the pH value of the washing water is in the range of 6.0-8.0;
d. acid washing: preparing a citric acid solution with the concentration of 8% -15% and cleaning for 0-10 h;
e. water cleaning: the equipment is washed with water for injection until the pH of the wash water is in the range of 6.0-8.0.
After the passivation in the step 1 is finished, the equipment needs to be cleaned on line to remove the residual edetate disodium on the surface of the equipment, so that the produced product is not affected.
The terbutaline sulfate in the step 2 can be prepared by adopting a pre-dissolving mode and then put into a liquid preparation tank. If pre-dissolution is used, the concentration of the edetate disodium solution used for passivation needs to be increased accordingly.
The packaging material which is preferably made of plastic is filled in the step 4, so that the influence of metal ions in the packaging material can be avoided.
Advantageous effects
The process treatment method effectively removes metal ions on the surface of the production equipment through passivating the production line equipment, ensures the stability of the product, synchronously ensures that the final packaging material does not influence the product through the optimized packaging material, does not need nitrogen filling protection in the production process, has low requirement on the production line, and saves the production cost.
Detailed Description
Example 1
Prescription:
a process treatment method for improving the stability of terbutaline sulfate atomized liquid comprises the following steps:
1. cleaning the equipment until the pH value of the cleaning water is 6.0-8.0
2. Disodium edetate is weighed, injection water is added at 25 ℃ to prepare 0.02 percent disodium edetate solution, and the solution is used for passivating production equipment on a production line for 1h at the passivating temperature of 25 ℃.
3. Adding 30% of prescription dose of injection water into a passivated solution preparation tank at 40 ℃, adding edetate disodium, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding the injection water to 80% of the batch, stirring and dissolving, adding 0.1mol/L hydrochloric acid solution, adjusting the pH to 3.0-4.5, and adding the injection water to the full batch.
4. The medicinal liquid is filtered by 0.45 μm filter and 0.22 μm bacteria-reducing filter.
5. And (4) filling by adopting a plastic container.
Example 2
Prescription:
a process treatment method for improving the stability of terbutaline sulfate atomized liquid comprises the following steps:
1. disodium edetate is weighed, disodium edetate solution with the concentration of 0.04 percent is prepared at 70 ℃ for injection, and the solution is used for passivating production equipment on a production line, wherein the passivating time is 2 hours, and the passivating temperature is 70 ℃. After passivation, the equipment is cleaned until the pH of the cleaning water is 6.0-8.0.
2. Adding 30% of prescription dose of injection water into a passivated solution preparation tank at 40 ℃, adding edetate disodium, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding the injection water to 80% of the batch, stirring and dissolving, adding 0.1mol/L hydrochloric acid solution, adjusting the pH to 3.0-4.5, and adding the injection water to the full batch.
3. The medicinal liquid is filtered by 0.45 μm filter and 0.22 μm bacteria-reducing filter.
4. And (4) filling by adopting a plastic container.
Example 3
Prescription:
a process treatment method for improving the stability of terbutaline sulfate atomized liquid comprises the following steps:
cleaning production equipment for 1h by using 1.4% sodium hydroxide solution, and cleaning the production equipment by using injection water until the pH value of the cleaning water is 6.0-8.0; then cleaning the equipment with 11% citric acid solution for 2h, and cleaning with water for injection until the pH of the cleaning water is 6.0-8.0.
2. Disodium edetate is weighed, disodium edetate solution with the concentration of 0.02 percent is prepared by adding 70 ℃ for injection, and the solution is used for passivating production equipment on a production line, wherein the passivating time is 1h, and the passivating temperature is 70 ℃. After passivation, the equipment is cleaned until the pH of the cleaning water is 6.0-8.0.
3. Adding 30% of prescription dose of injection water into a passivated solution preparation tank at 40 ℃, adding edetate disodium, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding the injection water to 80% of the batch, stirring and dissolving, adding 0.1mol/L hydrochloric acid solution, adjusting the pH to 3.0-4.5, and adding the injection water to the full batch.
4. The medicinal liquid is filtered by 0.45 μm filter and 0.22 μm bacteria-reducing filter.
5. And (4) filling by adopting a plastic container.
Comparative example 1
Prescription:
the process comprises the following steps:
1. adding 30% of prescription dose of injection water into a liquid preparation tank at 40 ℃, adding edetate disodium, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding the injection water to 80% of the batch, stirring and dissolving, adding 0.1mol/L hydrochloric acid solution, adjusting the pH to 3.0-4.5, and adding the injection water to the whole batch.
2. The medicinal liquid is filtered by 0.45 μm filter and 0.22 μm bacteria-reducing filter.
3. And (4) filling by adopting a plastic container.
Comparative example 2
Prescription:
the process comprises the following steps:
cleaning production equipment for 1h by using 1.4% sodium hydroxide solution, and cleaning the production equipment by using injection water until the pH value of the cleaning water is 6.0-8.0; then cleaning the equipment with 11% citric acid solution for 2h, and cleaning with water for injection until the pH of the cleaning water is 6.0-8.0.
2. Adding 30% of prescription dose of injection water into a passivated solution preparation tank at 40 ℃, adding edetate disodium, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding the injection water to 80% of the batch, stirring and dissolving, adding 0.1mol/L hydrochloric acid solution, adjusting the pH to 3.0-4.5, and adding the injection water to the full batch.
3. The medicinal liquid is filtered by 0.45 μm filter and 0.22 μm bacteria-reducing filter.
4. And (4) filling by adopting a plastic container.
Sample detection:
the stability of the liquid medicine in a short time is examined after the liquid medicine is left for 72 hours before filling in example 1, example 2, example 3, comparative example 1 and comparative example 2, and the items including properties and impurities are examined. The results are detailed in table 1.
The sample in example 3 is placed under the accelerated condition for 6 months, the stability is inspected, and the inspection items comprise characters, pH, content and impurities. The results are detailed in table 2.
The detection method comprises the following steps:
the characteristics are as follows: visually, the solution should be colorless and transparent.
The pH value should be 3.0-4.5 (the general rule of the four kingdoms of the China pharmacopoeia 2020 edition 0631).
Terbutaline sulfate content: the chromatographic conditions are the same as impurities. 90.0 to 110.0 percent of terbutaline sulfate.
The impurity detection method comprises the following steps:
using a C18 column, taking 4.23g of sodium hexanesulfonate, adding 750mL of 0.05mol/L ammonium formate solution and 250mL of methanol, and uniformly mixing to obtain a mobile phase; the detection wavelength is 276 nm; and taking a sample for detection.
Limitation: the impurity B and the impurity C are not more than 0.2 percent, other single impurities are not more than 0.2 percent, and the total amount of the impurities is not more than 1.0 percent.
Stability in Table 172 h
Remarking: the unknown impurity content is neglected below 0.05%.
TABLE 2 accelerated 6 month stability
Remarking: the unknown impurity content is neglected below 0.05%.
As can be seen from the stability review data of the examples and comparative examples 72h of Table 1: the samples of examples 1, 2 and 3 were left for 72 hours, and almost no impurities were detected, while the comparative example was left for 72 hours, and the impurities reached 0.19%, which was close to the maximum limit of impurities, during which time the data was out of limit. The main difference between the examples and the comparative examples is the passivation process, such as: the difference between examples 1 and 2 in comparison with comparative example 1 is that examples 1 and 2 have one more passivation step before liquid preparation than comparative example 1; for another example: example 3 and comparative example 2 both used a pre-dispense rinse, and the same dispense, filter, and fill, with the only difference being that example 3 has one more passivation step. Therefore, the process treatment method for improving the stability of the terbutaline sulfate atomized liquid can reduce the impurity content from 0.19% or even higher to 0%, effectively control the impurities of the terbutaline sulfate in the production process, and ensure the stability of the product in the production process.
As can be seen from the data of the example shown in the table 2, the sample is placed for 6 months under the accelerated condition, and the properties, pH, content and impurities of the sample are basically not changed. Therefore, the process treatment method for improving the stability of the terbutaline sulfate atomized liquid can ensure the stability of the product for a long time.
Claims (8)
1. A process treatment method for improving the stability of terbutaline sulfate atomized liquid is characterized in that a metal chelating agent is adopted to passivate production equipment of a terbutaline sulfate atomized liquid production line, then passivated production equipment is adopted to prepare liquid medicine, and the liquid medicine is filled in a plastic container after being filtered; the metal chelating agent is edetate disodium or edetate calcium sodium; nitrogen charging protection is not needed in the production process; the concentration of the metal chelating agent is 0.01-0.08%; cleaning and sterilizing production equipment before or after passivation; the time of passivation treatment is 0.5-5 h; the edetate disodium solution is prepared by adopting water for injection, and the temperature of the water for injection is 10-80 ℃; the temperature of the passivation treatment is 25-70 ℃; the concentration of the hydrochloric acid solution is 0.1-0.5 mol/L;
the preparation method of the liquid medicine comprises the following steps: weighing terbutaline sulfate, edetate disodium and sodium chloride according to the prescription amount; adding 20-70% of batch injection water into the passivated liquid preparation tank, adding ethylene diamine tetraacetic acid, stirring and dissolving, adding terbutaline sulfate and sodium chloride, adding the injection water to 80-90% of the batch, stirring and dissolving, adding a hydrochloric acid solution, adjusting the pH to 3.0-4.5, and adding the injection water to the full batch;
the method for cleaning the equipment comprises the following steps:
a. cleaning for the first time: cleaning the equipment with water for injection for more than 15min-60 min;
b. alkali washing: 1 to 8 percent of sodium hydroxide is used for cleaning for 0 to 5 hours;
c. water cleaning: washing with water for injection until the pH value of the washing water is in the range of 6.0-8.0;
d. acid washing: preparing a citric acid solution with the concentration of 8% -15% and cleaning for 0-10 h;
e. water cleaning: the equipment is washed with water for injection until the pH of the wash water is in the range of 6.0-8.0.
2. The process for improving the stability of a terbutaline sulfate spray according to claim 1, wherein the liquid is filtered through a 0.45 μm filter and a 0.22 μm bacteria-reducing filter.
3. The process treatment method for improving the stability of terbutaline sulfate atomized liquid according to claim 1, wherein the metal chelating agent is edetate disodium.
4. The process treatment method for improving the stability of terbutaline sulfate atomized liquid according to claim 1, wherein the concentration of the metal chelating agent is 0.04%.
5. The process treatment method for improving the stability of terbutaline sulfate atomized liquid according to claim 1, characterized in that the passivation time is 2 h.
6. The process treatment method for improving the stability of terbutaline sulfate atomized liquid according to claim 1, wherein the concentration of hydrochloric acid is 0.1 mol/L.
7. The process treatment method for improving the stability of terbutaline sulfate atomized liquid according to claim 1, characterized in that the equipment is cleaned on line after passivation.
8. The process treatment method for improving the stability of terbutaline sulfate atomized liquid according to claim 1, characterized in that the temperature of passivation treatment is 70 ℃.
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| CN102145009B (en) * | 2010-12-29 | 2013-12-18 | 辰欣药业股份有限公司 | Octadeca compound amino acid injection and preparation method thereof |
| CN103463013B (en) * | 2013-09-22 | 2015-06-24 | 华仁药业股份有限公司 | Preparation process of high-concentration compound amino acid injection |
| CN103520096B (en) * | 2013-10-25 | 2015-02-25 | 成都晶博生物科技有限责任公司 | Process for producing terbutaline sulfate injection |
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| CN108078918B (en) * | 2017-12-28 | 2020-01-21 | 石药银湖制药有限公司 | Treatment method for improving stability of terbutaline sulfate injection |
| CN110693861A (en) * | 2018-07-09 | 2020-01-17 | 北京盈科瑞创新药物研究有限公司 | Terbutaline sulfate solution preparation for aerosol inhalation and preparation method thereof |
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