CN116350581B - Preparation method of acetylcysteine injection - Google Patents
Preparation method of acetylcysteine injection Download PDFInfo
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- CN116350581B CN116350581B CN202310255748.5A CN202310255748A CN116350581B CN 116350581 B CN116350581 B CN 116350581B CN 202310255748 A CN202310255748 A CN 202310255748A CN 116350581 B CN116350581 B CN 116350581B
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- acetylcysteine
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- 229940021715 acetylcysteine injection Drugs 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 238000011049 filling Methods 0.000 claims abstract description 61
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 54
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims abstract description 43
- 229960004308 acetylcysteine Drugs 0.000 claims abstract description 42
- 230000001954 sterilising effect Effects 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 26
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000007788 liquid Substances 0.000 claims abstract description 22
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 21
- 239000004695 Polyether sulfone Substances 0.000 claims abstract description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000001301 oxygen Substances 0.000 claims abstract description 19
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 19
- 229920006393 polyether sulfone Polymers 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 8
- 239000007924 injection Substances 0.000 claims abstract description 8
- 229940090044 injection Drugs 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000004659 sterilization and disinfection Methods 0.000 claims description 25
- 238000001514 detection method Methods 0.000 claims description 21
- 239000008215 water for injection Substances 0.000 claims description 15
- 239000011148 porous material Substances 0.000 claims description 12
- -1 polytetrafluoroethylene Polymers 0.000 claims description 7
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 7
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 7
- 239000012535 impurity Substances 0.000 abstract description 14
- 238000012360 testing method Methods 0.000 abstract description 7
- 238000004806 packaging method and process Methods 0.000 abstract description 5
- 238000007789 sealing Methods 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 4
- 238000011835 investigation Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 230000001502 supplementing effect Effects 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 12
- 239000003708 ampul Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000007689 inspection Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 241000289690 Xenarthra Species 0.000 description 2
- 238000009924 canning Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- YTPQSLLEROSACP-YUMQZZPRSA-N (2R)-2-acetamido-3-[[(2R)-2-acetamido-2-carboxyethyl]disulfanyl]propanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CSSC[C@@H](C(O)=O)NC(C)=O YTPQSLLEROSACP-YUMQZZPRSA-N 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 229960003486 acetylcysteine sodium Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- HSPYGHDTVQJUDE-LURJTMIESA-N dacisteine Chemical compound CC(=O)N[C@H](C(O)=O)CSC(C)=O HSPYGHDTVQJUDE-LURJTMIESA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, and in particular discloses an acetylcysteine injection and a preparation method thereof. Adding injection water with the total volume of 40% -70% and prescription amount of edetate disodium into a preparation tank, uniformly mixing to obtain edetate disodium solution, adding prescription amount of acetylcysteine, stirring and dissolving, regulating pH to 6.8-7.2, supplementing injection water to the total volume of preparation to obtain acetylcysteine liquid medicine, filtering by a multi-stage polyethersulfone filter element with sequentially reduced aperture, filling nitrogen, controlling the residual oxygen content of the headspace in a canned container after filling to be less than 3%, sealing, sterilizing, lamp detecting, detecting leakage and packaging to obtain the acetylcysteine injection. The impurity content of the acetylcysteine injection prepared by the method is obviously reduced, the storage stability of the acetylcysteine injection is obviously improved, and the impurity content is not obviously increased in a stability investigation test.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an acetylcysteine injection and a preparation method thereof.
Background
The acetylcysteine injection is an amino acid medicine, and is mainly used for early treatment of liver failure patients on the basis of comprehensive treatment, so that bilirubin can be reduced, and prothrombin activity can be improved; acetylcysteine belongs to reduced glutathione in pharmacological action, and also belongs to an in vivo oxygen free radical scavenger, and has a relation with liver protection effect and in vivo glutathione level maintenance.
At present, the existing preparation process of the acetylcysteine injection comprises the steps of preparing a NaOH solution with a certain concentration as a solution A, dissolving acetylcysteine and edetate disodium to prepare a solution B with a certain concentration, fixing the volume, adjusting the pH, filtering, sterilizing and then filling to obtain the acetylcysteine injection. The complex preparation steps of the existing acetylcysteine injection can cause degradation of acetylcysteine raw materials in the preparation process, so that the prepared acetylcysteine injection has high impurity content and various types, and the impurity growth is obvious in the storage process. Therefore, the development of the acetylcysteine injection with low impurity content and high storage stability has very important significance for improving the medication safety of patients.
Disclosure of Invention
In view of the above, the invention provides an acetylcysteine injection and a preparation method thereof. The invention effectively reduces the content of related substances, improves the product quality of the acetylcysteine injection by determining the lining material of the preparation tank, controlling the temperature of the water for injection and changing the filling condition, and has very important significance for improving the medication safety of patients.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a preparation method of acetylcysteine injection comprises the following steps:
step a, adding injection water with the total volume of 40-70% into a preparation tank with polytetrafluoroethylene lining, filling nitrogen to exhaust air in the preparation tank, adding the prescription amount of disodium edetate at 40-65 ℃ and uniformly mixing to obtain disodium edetate solution;
step b, adding the prescribed amount of acetylcysteine into the edetate disodium solution, stirring and dissolving, adjusting the pH value to 6.8-7.2, and adding water for injection at the temperature of 40-65 ℃ until the total amount is prepared to obtain acetylcysteine liquid medicine;
and c, introducing nitrogen into the acetylcysteine liquid medicine until the content of dissolved oxygen is lower than 3ppm, filtering by a multistage polyethersulfone filter element with sequentially reduced pore diameters, filling nitrogen, controlling the residual oxygen content of the headspace in a canned container after filling to be lower than 3%, and sterilizing to obtain the acetylcysteine injection.
Compared with the prior art, the preparation method of the acetylcysteine injection provided by the invention has the advantages that the specific preparation tank is selected, so that the increase of impurity content in the preparation process of the liquid medicine can be avoided, the degradation of acetylcysteine can be avoided, the pH value of the liquid medicine is stabilized, and the stability of the product quality is improved; the dissolution rate of the raw materials is further improved by controlling the temperature of the water for injection, the preparation time is shortened, and the oxidation of the raw materials in the preparation process of the acetylcysteine injection can be further avoided, so that the content of related substances and impurities is greatly reduced, the defect that impurities and insoluble particles are introduced when activated carbon is added to remove a heat source in the traditional process is avoided by matching with a multi-stage polyethersulfone filter core filtering method, and the safety of the product is improved; the specific pH value can avoid the degradation of acetylcysteine, thereby reducing the content of related substances; the oxidation of the acetylcysteine can be further avoided by limiting the dissolved oxygen concentration of the acetylcysteine liquid medicine to be less than 3ppm, so that the content of the acetylcysteine is improved, and the content of related substances is reduced; by limiting the residual oxygen content of the headspace in the filling container to be less than 3%, the influence of oxygen on the stability of the acetylcysteine can be effectively avoided, the stability of the acetylcysteine injection is improved, and the product quality of the acetylcysteine injection product is ensured.
The invention effectively reduces the content of related substances, improves the product quality of the acetylcysteine injection by determining the material of the preparation tank, controlling the temperature of the water for injection and changing the filling condition, and has very important significance for improving the medication safety of patients.
Preferably, in the step c, the multi-stage filter element is a two-stage polyethersulfone filter element, wherein the pore diameter of the first-stage polyethersulfone filter element is 0.45 μm, and the pore diameter of the second-stage polyethersulfone filter element is 0.2 μm.
The invention adopts the multistage polyethersulfone filter core with specific aperture to filter in sequence, which not only can ensure that the bacterial and endotoxin contents of the product are qualified, but also can ensure that the particles and visible foreign matters of the product are qualified, and active carbon is not adopted in the production process, thereby reducing the pollution to a clean area of production, reducing the environmental protection pressure, reducing the impurities and insoluble particles possibly introduced by the active carbon, and being beneficial to further improving the effectiveness, the safety and the stability of the product quality.
Preferably, in the step c, the specific steps of nitrogen filling are as follows: filling nitrogen into the filling container to discharge air in the filling container, filling the filtered acetylcysteine liquid medicine, and filling nitrogen after filling, so that the residual oxygen content of the headspace in the filling container is less than 3%.
By limiting the residual oxygen content of the headspace in the filling container to be less than 3%, the influence of oxygen on the acetylcysteine can be effectively avoided, and the stability of the acetylcysteine injection is improved.
Preferably, in the step c, when filling nitrogen, the filling temperature is 20-40 ℃, the filling speed is 60-90 bottles/min, and the filling pressure is 0.1-0.5 MPa.
The optimized canning temperature can avoid the oxidation of acetylcysteine caused by high temperature, reduce the content of related substances and ensure the drug effect; the preferable nitrogen filling pressure and filling speed can ensure that the residual oxygen content in the headspace is less than 3 percent.
Preferably, in step c, the method further comprises a leak detection step after sterilization, wherein the leak detection adopts a high-voltage discharge leak detection method, and the leak detection conditions are as follows: the discharge voltage is 16KV-20KV, and the threshold value is less than or equal to 5.
The traditional color water leakage detection method is too dependent on subjective judgment of people, and has the risk of misjudgment.
Preferably, in the step c, the sterilization method adopts terminal sterilization, the sterilization temperature is 121 ℃, and the standard sterilization time is: f (F) 0 The value > 12.
The acetylcysteine injection prepared by the prior art adopts a non-terminal sterilization method or a residual probability method in terminal sterilization, and the sterility assurance level of the product is low; the invention adopts an overkill method of terminal sterilization, improves the impurity level of the product and improves the sterility assurance level of the product.
The invention also provides an acetylcysteine injection, which is prepared by the preparation method of the acetylcysteine injection.
Preferably, each 1mL of acetylcysteine injection comprises: 1mg-5mg of edetate disodium and 200mg of acetylcysteine, and the pH value is 6.8-7.2.
The acetylcysteine injection with obviously reduced impurity types and contents prepared by the invention obviously improves the storage stability of the acetylcysteine injection, has insignificant increase of impurity contents in stability investigation tests, improves the production efficiency, reduces the production cost, is convenient for realizing industrial production, and has wide application prospect.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
In order to better illustrate the present invention, the following examples are provided for further illustration.
Example 1
The embodiment provides an acetylcysteine injection, the prescription dosage is as follows:
edetate disodium 1g
Acetylcysteine 200g
Water for injection to 1000mL
pH 6.8。
The embodiment also provides a preparation method of the acetylcysteine injection, which comprises the following specific steps:
step a, adding injection water with the total volume of 40% of the total volume of the preparation tank with polytetrafluoroethylene lining, filling nitrogen gas to clean air in the preparation tank, and uniformly mixing the edetate disodium with the prescription amount at 40 ℃ to obtain an edetate disodium solution;
step b, adding the prescription amount of acetylcysteine into the edetate disodium solution, stirring and dissolving, adding sodium hydroxide to adjust the pH value to 6.8, and adding water for injection at 40 ℃ until the total amount is prepared to obtain acetylcysteine liquid medicine;
step c, filtering the acetylcysteine liquid medicine sequentially through a polyether sulfone filter core with the pore diameter of 0.45 mu m and a polyether sulfone filter core with the pore diameter of 0.2 mu m; filling nitrogen into a 25mL ampoule at a pressure of 0.1MPa to discharge air in the ampoule, filling acetylcysteine liquid medicine at a speed of 60 pieces/min, filling at a temperature of 20 ℃, filling nitrogen at a pressure of 0.1MPa until the residual oxygen content in the headspace is less than 3%, and sealing; adopting a terminal sterilization method, setting the sterilization temperature to 121 ℃ and sterilizing at a standard sterilization time F0 value of more than 12; controlling the illuminance to be 1000lx for lamp inspection; setting the voltage of the high-voltage discharge leakage detector to be 16KV, and carrying out leakage detection, wherein the threshold value is less than or equal to 5; packaging after the leak detection is qualified to obtain the acetylcysteine injection.
Example 2
The embodiment provides an acetylcysteine injection, the prescription dosage is as follows:
edetate disodium 5g
Acetylcysteine 200g
Water for injection to 1000mL
pH 7.2。
The embodiment also provides a preparation method of the acetylcysteine injection, which comprises the following specific steps:
step a, adding injection water with the total volume of 70% of the total volume of the preparation tank with polytetrafluoroethylene lining, filling nitrogen gas to clean air in the preparation tank, and uniformly mixing the edetate disodium with the prescription amount at 65 ℃ to obtain an edetate disodium solution;
step b, adding the prescription amount of acetylcysteine into the edetate disodium solution, stirring and dissolving, adding sodium hydroxide to adjust the pH value to 7.2, and adding water for injection at 65 ℃ until the total amount is prepared to obtain acetylcysteine liquid medicine;
step c, filtering the acetylcysteine liquid medicine sequentially through a polyether sulfone filter core with the pore diameter of 0.45 mu m and a polyether sulfone filter core with the pore diameter of 0.2 mu m; filling nitrogen into a 25mL ampoule at a pressure of 0.5MPa to discharge air in the ampoule, filling acetylcysteine liquid medicine at a speed of 90 pieces/min, filling at a temperature of 40 ℃, filling nitrogen at a pressure of 0.3MPa after filling until the residual oxygen content in the headspace is less than 3%, and sealing; adopting a terminal sterilization method, setting the sterilization temperature to 121 ℃ and sterilizing at a standard sterilization time F0 value of more than 12; controlling the illuminance to be 1000lx for lamp inspection; setting the voltage of the high-voltage discharge leakage detector to 18KV, and carrying out leakage detection, wherein the threshold value is less than or equal to 5; packaging after the leak detection is qualified to obtain the acetylcysteine injection.
Example 3
The embodiment provides an acetylcysteine injection, the prescription dosage is as follows:
edetate disodium 3g
Acetylcysteine 200g
Water for injection to 1000mL
pH 7.0。
The embodiment also provides a preparation method of the acetylcysteine injection, which comprises the following specific steps:
step a, adding water for injection with the total volume of 60% of the total volume of the preparation tank with polytetrafluoroethylene lining, filling nitrogen gas to clean air in the preparation tank, and uniformly mixing the disodium edentate with the prescription amount at 50 ℃ to obtain disodium edentate solution;
step b, adding the prescription amount of acetylcysteine into the edetate disodium solution, stirring and dissolving, adding sodium hydroxide to adjust the pH value to 7.0, and adding water for injection at 50 ℃ until the total amount is prepared to obtain acetylcysteine liquid medicine;
step c, filtering the acetylcysteine liquid medicine sequentially through a polyether sulfone filter core with the pore diameter of 0.45 mu m and a polyether sulfone filter core with the pore diameter of 0.2 mu m; filling nitrogen into a 25mL ampoule at a pressure of 0.3MPa to discharge air in the ampoule, filling acetylcysteine liquid medicine at a speed of 70 pieces/min, filling at a temperature of 30 ℃, filling nitrogen at a pressure of 0.3MPa after filling until the residual oxygen content in the headspace is less than 3%, and sealing; adopting a terminal sterilization method, setting the sterilization temperature to 121 ℃ and sterilizing at a standard sterilization time F0 value of more than 12; controlling the illuminance to be 1000lx for lamp inspection; setting the voltage of the high-voltage discharge leakage detector to be 20KV, and carrying out leakage detection, wherein the threshold value is less than or equal to 5; packaging after the leak detection is qualified to obtain the acetylcysteine injection.
Comparative example 1
The present comparative example provides an acetylcysteine injection, which has the same formulation and preparation method as in example 1, except that the temperature of the water for injection in step a and step b was controlled to 75 ℃, and the other operations were the same as in example 1.
Comparative example 2
The formulation and preparation method of the acetylcysteine injection were the same as those of example 1, except that the preparation tank lined with polytetrafluoroethylene was replaced with a preparation tank made of 316L stainless steel, and the other operations were the same as those of example 1.
Comparative example 3
The formulation and preparation method of the acetylcysteine injection were the same as those of example 1, except that the canning speed was changed to 120 pieces/min, the headspace residual oxygen amount was 5.3%, and the other operations were the same as in example 1.
Comparative example 4
The comparative example provides an acetylcysteine injection, the prescription dosage is as follows:
edetate disodium 1g
Acetylcysteine 200g
Water for injection to 1000mL
pH 7.5。
The comparative example also provides a preparation method of the acetylcysteine injection, which comprises the following specific steps:
step a, adding injection water with the total volume of 40% of the total volume of the preparation tank lined with polytetrafluoroethylene, filling nitrogen gas to clean air in the preparation tank, and uniformly mixing the edetate disodium with the prescription amount at 40 ℃ to obtain an edetate disodium solution;
step b, adding the prescription amount of acetylcysteine into the edetate disodium solution, stirring and dissolving, adding sodium hydroxide to adjust the pH value to 7.5, and adding water for injection at 40 ℃ until the total amount is prepared to obtain acetylcysteine liquid medicine;
step c, filtering the acetylcysteine liquid medicine sequentially through a polyether sulfone filter core with the pore diameter of 0.45 mu m and a polyether sulfone filter core with the pore diameter of 0.2 mu m; filling nitrogen into a 25mL ampoule at a pressure of 0.1MPa to discharge air in the ampoule, filling acetylcysteine liquid medicine at a speed of 60 pieces/min, filling at a temperature of 20 ℃, filling nitrogen at a pressure of 0.1MPa until the residual oxygen content in the headspace is less than 3%, and sealing; adopting a terminal sterilization method, setting the sterilization temperature to 121 ℃ and sterilizing at a standard sterilization time F0 value of more than 12; controlling the illuminance to be 1000lx for lamp inspection; setting the voltage of the high-voltage discharge leakage detector to be 16KV, and carrying out leakage detection, wherein the threshold value is less than or equal to 5; packaging after the leak detection is qualified to obtain the acetylcysteine injection.
Quality inspection
The detection method of the related substances comprises the following steps:
chromatographic column: a C18 column;
mobile phase: 0.01mol/L phosphate buffer-methanol (95:5);
detection wavelength: 210nm;
sample injection amount: 20. Mu.L;
flow rate: 1.5 mL/min;
column temperature: 20 ℃.
Wherein, the peak time of cystine is 5-6min, the peak time of N, N' -diacetyl cystine is 10-11min, and the peak time of N, S-diacetyl cysteine is 13-15min.
Other detection projects except related substances, quality detection and stability tests are carried out on acetylcysteine injection products prepared in examples 1-3 and comparative examples 1-4 according to Chinese pharmacopoeia (2010 edition), wherein the conditions of light treatment are as follows: 4500lx, conditions of high temperature treatment are: the results are shown in tables 1-3 at 60 ℃.
Table 1 test results of examples 1-3
Table 2 comparative examples 1-2 test results
TABLE 3 comparative examples 3-4 test results
As can be seen from the above test data, compared with comparative examples 1 to 4, the acetylcysteine injection prepared in examples 1 to 3 of the present invention has lower impurity content and higher stability, and the increase of impurity content in the test process of 15 days under light and 30 days at high temperature is obviously lower than that of comparative examples 1 to 4, which proves that the acetylcysteine injection prepared in the examples of the present invention has better stability and safety, thereby being more favorable for improving the safety of clinical application.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (3)
1. The preparation method of the acetylcysteine injection is characterized by comprising the following steps:
step a, adding injection water with the total volume of 40-70% into a preparation tank with polytetrafluoroethylene lining, filling nitrogen to exhaust air in the preparation tank, adding the prescription amount of disodium edetate at 40-65 ℃ and uniformly mixing to obtain disodium edetate solution;
step b, adding the prescribed amount of acetylcysteine into the edetate disodium solution, stirring and dissolving, adjusting the pH value to 6.8-7.2, and adding water for injection at the temperature of 40-65 ℃ until the total amount is prepared to obtain acetylcysteine liquid medicine;
step c, introducing nitrogen into the acetylcysteine liquid medicine until the content of dissolved oxygen is lower than 3ppm, filtering by a multistage polyethersulfone filter element with sequentially reduced pore diameters, filling nitrogen, controlling the residual oxygen content of the headspace in a canned container after filling to be lower than 3%, and sterilizing to obtain the acetylcysteine injection;
in the step c, the multi-stage filter element is a two-stage polyether sulfone filter element, wherein the aperture of the first-stage polyether sulfone filter element is 0.45 mu m, and the aperture of the second-stage polyether sulfone filter element is 0.2 mu m;
in the step c, when filling nitrogen, the filling temperature is 20-40 ℃, the filling speed is 60-90 bottles/min, and the nitrogen filling pressure is 0.1-0.5 MPa;
in the step c, the sterilization method adopts terminal sterilization, the sterilization temperature is 121 ℃, and the standard sterilization time is as follows: f (F) 0 A value > 12;
each 1mL of acetylcysteine injection comprises: 1mg-5mg of edetate disodium and 200mg of acetylcysteine, and the pH value is 6.8-7.2.
2. The method for preparing acetylcysteine injection according to claim 1, wherein in the step c, the specific steps of filling nitrogen are as follows: filling nitrogen into the filling container to discharge air in the filling container, filling the filtered acetylcysteine liquid medicine, and filling nitrogen after filling, so that the residual oxygen content of the headspace in the filling container is less than 3%.
3. The method for preparing acetylcysteine injection according to claim 1, wherein in step c, the method further comprises a step of leak detection after sterilization, wherein the leak detection adopts a high-voltage discharge leak detection method, and the leak detection conditions are as follows: the discharge voltage is 16KV-20KV, and the threshold value is less than or equal to 5.
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