CN117679360A - Salbutamol sulfate injection and preparation method thereof - Google Patents
Salbutamol sulfate injection and preparation method thereof Download PDFInfo
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- CN117679360A CN117679360A CN202211076775.8A CN202211076775A CN117679360A CN 117679360 A CN117679360 A CN 117679360A CN 202211076775 A CN202211076775 A CN 202211076775A CN 117679360 A CN117679360 A CN 117679360A
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- nitrogen
- injection
- salbutamol sulfate
- salbutamol
- charging
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- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 238000002347 injection Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 336
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 183
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 50
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 48
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000001301 oxygen Substances 0.000 claims abstract description 38
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000008215 water for injection Substances 0.000 claims abstract description 32
- 239000000243 solution Substances 0.000 claims abstract description 27
- 239000011780 sodium chloride Substances 0.000 claims abstract description 24
- 230000001954 sterilising effect Effects 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 238000007789 sealing Methods 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000005303 weighing Methods 0.000 claims abstract description 12
- 239000003708 ampul Substances 0.000 claims abstract description 3
- 239000012982 microporous membrane Substances 0.000 claims abstract description 3
- 238000005491 wire drawing Methods 0.000 claims description 12
- 239000002158 endotoxin Substances 0.000 claims description 8
- 229910001873 dinitrogen Inorganic materials 0.000 claims 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 8
- 238000009472 formulation Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 32
- 239000012535 impurity Substances 0.000 description 14
- 238000004659 sterilization and disinfection Methods 0.000 description 11
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 10
- 239000012528 membrane Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229960002052 salbutamol Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- -1 salbutamol aldehyde Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a salbutamol sulfate injection and a preparation method thereof, wherein each ml of the formulation contains 0.6mg of salbutamol sulfate, 8.89mg of sodium chloride, sulfuric acid and water for injection, wherein the pH value of the injection is 3.0-3.7, the salbutamol sulfate injection is packaged in an ampoule, and the headspace oxygen content is controlled below 3%. The preparation process comprises the following steps: 1. weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); 2. adding the sodium chloride and salbutamol sulfate with the prescribed amount, stirring and dissolving; 3. adjusting the pH value of the solution to 3.0-3.7 by sulfuric acid; 4. constant volume to the prescribed dosage with water for injection (temperature is less than or equal to 30 ℃); 5. filtering with 0.22 μm microporous membrane, filling, introducing nitrogen, and sealing; 6. sterilizing at 121deg.C for 15 min. The salbutamol sulfate injection prepared by the process has stable quality and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to salbutamol sulfate injection and a preparation method thereof.
Background
Salbutamol sulphate (Salbutamol Sulfate) having the chemical name 4-hydroxy-alpha' - [ (tert-butylamino) methyl ] -1, 3-benzenedimethanol sulphate and having the following molecular structural formula:
salbutamol sulphate injection (trade name:) Specification 1ml:0.5mg (equivalent to salbutamol sulphate 0.6 mg) was approved for sale in the uk by the original manufacturer Glaxo Wellcome UK Ltd, 9 earliest 2000. The indications are as follows: is suitable for adult and teenagers, provides short-acting (4-6 hours) bronchiectasis, and can rapidly attack (within 5 minutes) when reversible airway obstruction occurs, and is used for relieving severe bronchospasm. The specification of the original salbutamol sulfate injection 1ml to 0.5mg (equivalent to salbutamol sulfate 0.6 mg) is not sold on the market in China, and the specification of the salbutamol sulfate injection on the market in China at present is 1ml:0.4mg (corresponding to salbutamol sulphate 0.48 mg).
US patent 6451289 discloses an albuterol injection comprising albuterol or a pharmaceutically acceptable salt thereof, sodium chloride and water; the pH of the formulation was about 4. Packaging it in special oxygen-permeable plastic container, and keeping the product stable for 12 months under the condition of containing salbutamol aldehyde less than 0.08% (weight) and dissolved oxygen less than 1 ppm. The concrete preparation method is that nitrogen is blown through a hollow cylinder made of oxygen-permeable plastic, and the hollow cylinder is molded into an oxygen-permeable container, so that an atmosphere with reduced oxygen is at least partially closed, but in actual production, control of the oxygen content is difficult to achieve.
Therefore, a new solution is still necessary at present, so that the prescription process of the salbutamol sulfate injection is simple to operate, the product quality is stable, and the commercial production is facilitated.
Disclosure of Invention
The invention aims to provide a stable salbutamol sulfate preparation and a preparation method thereof, which have the advantages of simple production process and stable product quality and are suitable for commercial production.
The invention provides a salbutamol sulfate injection, wherein each 1ml of the injection contains 0.6mg of salbutamol sulfate and 8.89mg of sodium chloride, the pH value of the injection is 3.0-3.7, the salbutamol sulfate injection is packaged in an ampoule, and the headspace oxygen content of the salbutamol sulfate injection is controlled below 3%.
In some embodiments, the headspace oxygen content of the salbutamol sulphate injection is controlled below 1.5%.
According to the invention, bacterial endotoxin of salbutamol sulfate bulk drug is less than 2.2Eu/mg, bacterial endotoxin of sodium chloride is less than 5Eu/g, and bacterial endotoxin of salbutamol sulfate injection finished product is less than 200Eu/mg, when bacterial endotoxin in the bulk drug is well controlled, active carbon is not required to be added in the preparation process for adsorption and pyrogen removal steps, and the produced bacterial endotoxin of salbutamol sulfate injection still meets the quality requirement.
The invention also provides a preparation method of the salbutamol sulfate injection, which comprises the following steps:
a. weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃);
b. adding the sodium chloride and salbutamol sulfate with the prescribed amount, stirring and dissolving;
c. adjusting the pH value of the solution by sulfuric acid;
d. constant volume to the prescribed dosage with water for injection (temperature is less than or equal to 30 ℃);
e. filtering with 0.22 μm microporous membrane, filling, introducing nitrogen, and sealing;
f. sterilizing at 121deg.C for 15 min.
The inventor finds that the pH value of the filled salbutamol sulfate solution has an ascending trend after the sterilization process, the pH value influences the stability of the product, and the oxygen content of the product after filling also has a significant influence on the stability of the product. When the pH value of salbutamol sulfate liquid after liquid preparation is controlled to be 3.0-3.7, and the headspace oxygen content of the finished salbutamol sulfate injection after filling is controlled to be below 3%, the stability of the salbutamol sulfate injection in the shelf life can be ensured, the total impurities of the finished salbutamol sulfate injection at the high temperature of 60 ℃ for 30 days are not more than 1.0%, and the liquid color is unchanged.
When the pH value of salbutamol sulfate solution in the liquid preparation process is 3.4, and the product is not filled with nitrogen (the oxygen content is about 20%), the total impurities are increased from 0.15% in 0 days to 5.54% in 30 days at the high temperature of 60 ℃, and meanwhile, the color of the solution is changed from colorless to light yellow; when the pH value of salbutamol sulfate solution in the liquid preparation process is 4.0, filling nitrogen (the oxygen content is about 1%), raising the pH value of the sterilized solution to 5.0, raising the total impurity content to 0.54% after sterilization for 0 days, raising the pH value to 5.8 at a high temperature of 60 ℃ for 30 days, and raising the total impurity content to 2.49%; when the pH value of salbutamol sulfate solution in the liquid preparation process is 4.5, the product is filled with nitrogen (the oxygen content is about 1%), the pH value of the sterilized solution is raised to 5.2, meanwhile, the total impurities in the sterilized solution are raised to 0.52% after 0 days, the pH value is raised to 6.0 after 30 days at a high temperature of 60 ℃, and the total impurities are raised to 3.62%.
When the product is filled with nitrogen (oxygen content is about 20%) and placed at 60 ℃, the total impurities increase from 0.15% in 0 day to 5.54% in 30 days, and the color of the solution changes from colorless to light yellow; the total impurities of the sample with the headspace oxygen content controlled at 5% are increased from 0.05% in 0 days to 2.7% in 30 days at the high temperature of 60 ℃; the total impurities of the sample with the headspace oxygen content controlled below 3% are increased from 0.05% in 0 days to 0.84% in 30 days at the high temperature of 60 ℃; the total impurities of the sample with the headspace oxygen content controlled below 1.5% increased from 0.05% for 0 day to 0.53% for 30 days at high temperature 60 ℃.
The nitrogen charging method can effectively control the oxygen content in the finished product to be below 3.0 percent and has stable oxygen content, wherein the nitrogen charging process comprises four nitrogen charging steps of front nitrogen charging, rear nitrogen charging, nitrogen charging in the preheating section and nitrogen charging in the wire drawing section. Wherein the flow of nitrogen in the front nitrogen charging is 8-10L/min, the flow of nitrogen in the rear nitrogen charging is 5-8L/min, the flow of nitrogen in the preheating section is 5-8L/min, and the flow of nitrogen in the wire drawing section is 8-10L/min.
The invention has the main beneficial effects that:
1) The salbutamol sulfate injection product provided by the invention has the advantages that the pH value and the oxygen content after filling are controlled in the process, so that the product quality is stable, the stability of the salbutamol sulfate injection in the shelf life can be ensured, and the medication safety of patients is ensured.
2) According to the preparation method of salbutamol sulfate injection provided by the invention, the steps of adsorption and pyrogen removal by adding activated carbon are not needed, the sterility level of the product can be ensured, and meanwhile, the impurity stability of the product is greatly improved, so that the commercial production is facilitated.
3) The preparation method of salbutamol sulfate injection provided by the invention comprises a nitrogen charging step, is simple and easy to control, has stable oxygen content, and is suitable for commercial production.
Detailed Description
The following specific examples are given for a more complete understanding of the present invention, but the present invention is not limited to the following examples.
Example 1:
| composition of the components | Dosage (g) |
| Salbutamol sulfate | 0.6 |
| Sodium chloride | 8.89 |
| Sulfuric acid | Proper amount of |
| The volume of the water for injection is fixed to | 1004.8 |
The preparation method comprises the following steps:
a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 3.0 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content of the headspace is controlled to be 1.0%), adjusting a nitrogen filling flowmeter and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle at the front nitrogen filling nitrogen flow of 10L/min: about 3.5cm; and the flow of nitrogen and nitrogen is 8L/min, and the position of the nitrogen filling needle is fixed to the top end height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of the preheating section is 8L/min, and the position of the nitrogen charging needle is fixed to the top height of the nitrogen charging needle: about 3.5cm; the nitrogen flow rate of nitrogen filling in the wire drawing section is 10L/min, and the position of the nitrogen filling needle is fixed to the top height of the nitrogen filling needle: about 3.5cm; and (5) sealing in a melting way. f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Example 2:
the preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 3.4 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content is controlled to be 1.0%), adjusting a flowmeter for filling nitrogen and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and the nitrogen flow rate of the previous nitrogen filling is 10L/min, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle: about 3.5cm; and the flow of nitrogen and nitrogen is 8/min, and the position of the nitrogen filling needle is fixed to the top end height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of the preheating section is 8L/min, and the position of the nitrogen charging needle is fixed to the top height of the nitrogen charging needle: about 3.5cm; the nitrogen flow rate of nitrogen filling in the wire drawing section is 10L/min, and the position of the nitrogen filling needle is fixed to the top height of the nitrogen filling needle: about 3.5cm, and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Example 3:
| composition of the components | Dosage (g) |
| Salbutamol sulfate | 0.6 |
| Sodium chloride | 8.89 |
| Sulfuric acid | Proper amount of |
| The volume of the water for injection is fixed to | 1004.8 |
The preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 3.7 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content of the headspace is controlled to be 1.0%), adjusting a nitrogen filling flowmeter and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle at the front nitrogen filling nitrogen flow of 10L/min: about 3.5cm; and the flow of nitrogen and nitrogen is 8/min, and the position of the nitrogen filling needle is fixed to the top end height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of the preheating section is 8L/min, and the position of the nitrogen charging needle is fixed to the top height of the nitrogen charging needle: about 3.5cm; the nitrogen flow rate of nitrogen filling in the wire drawing section is 10L/min, and the position of the nitrogen filling needle is fixed to the top height of the nitrogen filling needle: about 3.5cm, and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Example 4:
the preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 3.4 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content of the headspace is controlled to be 3.0%), adjusting a nitrogen filling flowmeter and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle at the front nitrogen filling nitrogen flow of 8L/min: about 3.5cm; and (3) after-filling nitrogen flow is 5L/min, fixing the position of the nitrogen filling needle to the top end height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of nitrogen filling in the preheating section is 5L/min, and the position of the nitrogen filling needle is fixed to the top height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of the nitrogen filled in the wire drawing section is 8L/min, and the position of the nitrogen filled needle is fixed to the top height of the nitrogen filled needle: about 3.5cm, and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Example 5:
| composition of the components | Dosage (g) |
| Salbutamol sulfate | 0.6 |
| Sodium chloride | 8.89 |
| Sulfuric acid | Proper amount of |
| The volume of the water for injection is fixed to | 1004.8 |
The preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 3.4 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content of the headspace is controlled to be 1.5%), adjusting a nitrogen filling flowmeter and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle at the front nitrogen filling nitrogen flow of 9L/min: about 3.5cm; and the flow rate of nitrogen filled with nitrogen is 6.5L/min, and the position of the nitrogen filled needle is fixed to the top height of the nitrogen filled needle: about 3.5cm; the nitrogen flow rate of the preheating section is 6.5L/min, and the position of the nitrogen charging needle is fixed to the top height of the nitrogen charging needle: about 3.5cm; the nitrogen flow rate of the nitrogen filled in the wire drawing section is 9L/min, and the position of the nitrogen filled needle is fixed to the top height of the nitrogen filled needle: about 3.5cm, and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Comparative example 1:
the preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 4.0 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content of the headspace is controlled to be 1.0%), adjusting a nitrogen filling flowmeter and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle at the front nitrogen filling nitrogen flow of 10L/min: about 3.5cm; and the flow of nitrogen and nitrogen is 8/min, and the position of the nitrogen filling needle is fixed to the top end height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of the preheating section is 8L/min, and the position of the nitrogen charging needle is fixed to the top height of the nitrogen charging needle: about 3.5cm; the nitrogen flow rate of nitrogen filling in the wire drawing section is 10L/min, and the position of the nitrogen filling needle is fixed to the top height of the nitrogen filling needle: about 3.5cm, and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Comparative example 2:
| composition of the components | Dosage (g) |
| Salbutamol sulfate | 0.6 |
| Sodium chloride | 8.89 |
| Sulfuric acid | Proper amount of |
| The volume of the water for injection is fixed to | 1004.8 |
The preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 4.5 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content of the headspace is controlled to be 1.0%), adjusting a nitrogen filling flowmeter and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle at the front nitrogen filling nitrogen flow of 10L/min: about 3.5cm; and the flow of nitrogen and nitrogen is 8L/min, and the position of the nitrogen filling needle is fixed to the top end height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of the preheating section is 8L/min, and the position of the nitrogen charging needle is fixed to the top height of the nitrogen charging needle: about 3.5cm; the nitrogen flow rate of nitrogen filling in the wire drawing section is 10L/min, and the position of the nitrogen filling needle is fixed to the top height of the nitrogen filling needle: about 3.5cm, and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Comparative example 3:
| composition of the components | Dosage (g) |
| Salbutamol sulfate | 0.6 |
| Sodium chloride | 8.89 |
| Sulfuric acid | Proper amount of |
| The volume of the water for injection is fixed to | 1004.8 |
The preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 3.4 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling nitrogen (the oxygen content of the headspace is controlled to be 5.0%), adjusting a nitrogen filling flowmeter and fixing the position of a nitrogen filling needle to the height of the top end of the nitrogen filling needle, and fixing the position of the nitrogen filling needle to the height of the top end of the nitrogen filling needle at the front nitrogen filling nitrogen flow of 6L/min: about 3.5cm; and (3) after the nitrogen filling flow is 3/min, fixing the position of the nitrogen filling needle to the top end height of the nitrogen filling needle: about 3.5cm; the nitrogen flow rate of the preheating section is 3L/min, and the position of the nitrogen charging needle is fixed to the top height of the nitrogen charging needle: about 3.5cm; the nitrogen flow rate of the nitrogen filled in the wire drawing section is 6L/min, and the position of the nitrogen filled needle is fixed to the top height of the nitrogen filled needle: about 3.5cm, and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
Comparative example 4:
| composition of the components | Dosage (g) |
| Salbutamol sulfate | 0.6 |
| Sodium chloride | 8.89 |
| Sulfuric acid | Proper amount of |
| The volume of the water for injection is fixed to | 1004.8 |
The preparation method comprises the following steps: a, weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃); b, adding the sodium chloride and salbutamol sulfate with the prescribed amount, and stirring and dissolving; c, adjusting the pH value of the solution to 3.4 by sulfuric acid; d, fixing the volume to the prescribed dosage by using water for injection (the temperature is less than or equal to 30 ℃); e, filtering by a microporous filter membrane with the thickness of 0.22 mu m, filling (the headspace oxygen content is about 20.0 percent), and sealing; f, sterilizing by adopting a sterilization process at 121 ℃ for 15 min.
(1) Effects of different pH values adjusted by sulfuric acid on salbutamol sulfate injection obtained in example 1, example 2, example 3, comparative example 1 and comparative example 2.
The detection method comprises the following steps:
according to the analysis method of salbutamol sulfate injection carried by British pharmacopoeia, the prepared sample is placed at a high temperature of 60 ℃ to examine stability, and related substances are detected by adopting a high performance liquid phase method, and the results of the related substances are shown in Table 1:
TABLE 1 influence of different pH values on salbutamol sulphate injection
From the results of Table 1, it can be seen that when the pH of the salbutamol sulfate solution is adjusted to 3.0-3.7 by sulfuric acid, the final pH at 60℃for 30 days is still within the target pH range of 3.0-4.5; when the pH value of the salbutamol sulfate solution is regulated to 4.0 and 4.5 by sulfuric acid, the pH value of the salbutamol sulfate injection for 0 day is 5.0 and 5.2, and the pH value exceeds the target pH value range. From the results of the related substances, the stability at 60℃tends to decrease as the pH of the salbutamol sulfate solution is adjusted with sulfuric acid. And the pH value and the stability data are combined, the pH value of the salbutamol sulfate solution is regulated to 3.0-3.7 by sulfuric acid, and when the oxygen content is controlled to be 1%, the stability of the salbutamol sulfate injection can be ensured.
(2) Effects of different headspace oxygen contents obtained in example 2, example 4, example 5, comparative example 3, comparative example 4 on salbutamol sulphate injection. The detection method comprises the following steps:
according to the analysis method of salbutamol sulfate injection carried by British pharmacopoeia, the prepared sample is placed at a high temperature of 60 ℃ to examine stability, and related substances are detected by adopting a high performance liquid phase method, and the results of the related substances are shown in Table 2:
TABLE 2 influence of different headspace oxygen contents on salbutamol sulphate injection
Remarks: and represents a colorless clear liquid; report limit rl=0.05%, n.d represents undetected.
As can be seen from the results in table 2, the headspace nitrogen-free sample (oxygen content about 20%) increased from 0.15% for 0 days to 5.54% for 30 days at high temperature 60 ℃ while the color of the solution changed from colorless to pale yellow; the total impurities of the sample with the headspace oxygen content controlled at 5% are increased from 0.05% in 0 days to 2.7% in 30 days at the high temperature of 60 ℃; the total impurities of the sample with the headspace oxygen content controlled below 3% are increased from 0.05% in 0 days to 0.84% in 30 days at the high temperature of 60 ℃; the total impurities of the sample with the headspace oxygen content controlled below 1.5% increased from 0.05% for 0 day to 0.5.3% for 30 days at high temperature 60 ℃. When the pH value is controlled to be 3.0-3.7, the headspace oxygen content is controlled to be below 3%, so that the stability of the salbutamol sulfate injection can be ensured.
The salbutamol sulfate injection and the preparation method thereof provided by the invention have been described by way of example, and it is obvious that the relevant technical personnel can change or appropriately modify and combine the salbutamol sulfate injection and the preparation method thereof described herein without departing from the content, spirit and scope of the invention, so as to realize the technology of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the spirit, scope and content of the invention.
Claims (8)
1. The salbutamol sulfate injection comprises salbutamol sulfate 0.6mg, sodium chloride 8.89mg, sulfuric acid and water for injection per 1ml, and is characterized in that the pH value of the injection is 3.0-3.7, the salbutamol sulfate injection is packaged in an ampoule, and the headspace oxygen content is controlled below 3%.
2. The salbutamol sulphate injection as claimed in claim 1, wherein the salbutamol sulphate drug substance has a bacterial endotoxin of < 2.2Eu/mg and sodium chloride has a bacterial endotoxin of < 5Eu/g.
3. Salbutamol sulphate injection according to claim 1, wherein bacterial endotoxin of the salbutamol sulphate injection product is < 200Eu/mg.
4. The salbutamol sulphate injection as claimed in claim 4 wherein the salbutamol sulphate injection is packaged in an ampoules with a headspace oxygen content of less than 1.5%.
5. A method for preparing salbutamol sulphate injection as claimed in claim 1, comprising the steps of:
a. weighing water for injection with the prescription amount of 95 percent (the temperature is less than or equal to 30 ℃);
b. adding the sodium chloride and salbutamol sulfate with the prescribed amount, stirring and dissolving;
c. adjusting the pH value of the solution by sulfuric acid;
d. constant volume to the prescribed dosage with water for injection (temperature is less than or equal to 30 ℃);
e. filtering with 0.22 μm microporous membrane, filling, introducing nitrogen, and sealing;
f. sterilizing at 121deg.C for 15 min.
6. The method of claim 5, wherein the nitrogen charging process comprises four nitrogen charging steps of pre-charging nitrogen, post-charging nitrogen, preheating section charging nitrogen and wire drawing section charging nitrogen.
7. The preparation method according to claim 6, wherein the flow rate of nitrogen gas of the front nitrogen charge is 8-10L/min and the flow rate of nitrogen gas of the rear nitrogen charge is 5-8L/min.
8. The preparation method according to claim 6, wherein the nitrogen flow rate of the preheating section is 5-8L/min, and the nitrogen flow rate of the wire drawing section is 8-10L/min.
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