CN117298042A - Amikacin sulfate injection and preparation method thereof - Google Patents
Amikacin sulfate injection and preparation method thereof Download PDFInfo
- Publication number
- CN117298042A CN117298042A CN202311367393.5A CN202311367393A CN117298042A CN 117298042 A CN117298042 A CN 117298042A CN 202311367393 A CN202311367393 A CN 202311367393A CN 117298042 A CN117298042 A CN 117298042A
- Authority
- CN
- China
- Prior art keywords
- injection
- equal
- nitrogen
- filling
- amikacin sulfate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002347 injection Methods 0.000 title claims abstract description 59
- 239000007924 injection Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 54
- YWMSSKBMOFPBDM-UHFFFAOYSA-N 4-carbamoylbenzenesulfonyl chloride Chemical compound NC(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 YWMSSKBMOFPBDM-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960001656 amikacin sulfate Drugs 0.000 title claims abstract description 40
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 52
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 52
- 239000001301 oxygen Substances 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 39
- 230000008569 process Effects 0.000 claims abstract description 32
- 230000001954 sterilising effect Effects 0.000 claims abstract description 32
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 29
- 239000007951 isotonicity adjuster Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000008215 water for injection Substances 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 74
- 239000007788 liquid Substances 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 238000011049 filling Methods 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- 239000003963 antioxidant agent Substances 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 230000003078 antioxidant effect Effects 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 11
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000007789 sealing Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 230000001276 controlling effect Effects 0.000 claims description 4
- 238000006392 deoxygenation reaction Methods 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 4
- 235000011164 potassium chloride Nutrition 0.000 claims description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 16
- 230000036512 infertility Effects 0.000 abstract description 9
- 229940090044 injection Drugs 0.000 description 42
- 238000009472 formulation Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 239000000126 substance Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000001509 sodium citrate Substances 0.000 description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 229940027572 amikacin injection Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000000227 grinding Methods 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960003415 propylparaben Drugs 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 3
- 239000000022 bacteriostatic agent Substances 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- 229960002216 methylparaben Drugs 0.000 description 3
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- -1 organic acid salts Chemical class 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FRKGSNOMLIYPSH-VKHMYHEASA-N (3s)-3-hydroxypyrrolidin-2-one Chemical compound O[C@H]1CCNC1=O FRKGSNOMLIYPSH-VKHMYHEASA-N 0.000 description 1
- 206010060968 Arthritis infective Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 208000031729 Bacteremia Diseases 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010014666 Endocarditis bacterial Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000289690 Xenarthra Species 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 208000009361 bacterial endocarditis Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000003066 decision tree Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000007119 infective endocarditis Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000004383 yellowing Methods 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
- A61K9/08—Solutions
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides amikacin sulfate injection and a preparation method thereof, wherein the injection comprises amikacin sulfate, an isotonic agent, a pH regulator and the balance of water for injection, the pH is controlled to be 4.5-5.5, and the residual oxygen content is controlled to be less than or equal to 1%. The method adopts the strict control of residual oxygen and terminal sterilization process, improves the stability of amikacin sulfate greatly while improving the sterility assurance level, reduces the impurity content and obviously improves the safety of amikacin sulfate injection.
Description
Technical Field
The application belongs to the technical field of chemical medicines, and in particular relates to amikacin sulfate injection and a preparation method thereof.
Background
Amikacin sulfate injection belongs to aminoglycoside antibiotics, and is used for treating severe infections caused by sensitive gram-negative bacilli such as pseudomonas aeruginosa, other pseudomonas, escherichia coli, proteus, klebsiella and the like and staphylococcus, such as bacteremia or septicemia, bacterial endocarditis, lower respiratory tract infection, bone joint infection, biliary tract infection and the like. Because the product is stable to most aminoglycoside passivating enzymes, the product is also used for treating serious infection caused by gram-negative bacillus to kanamycin, gentamicin or tobramycin drug-resistant strains, and has wide clinical application.
The product (hereinafter referred to as original grinding enterprise) is developed and marketed for the first time in 1976 by Japanese medical Co, and the prescription of the original grinding enterprise comprises amikacin sulfate, sodium bisulphite serving as an antioxidant, sodium citrate serving as an antioxidant synergist, methylparaben serving as a bacteriostatic agent and propyl hydroxybenzoate, wherein the pH range is 6.0-7.5, and the product has various problems at present. Firstly, due to the unstable chemical structure of the raw materials and the possible reaction between the raw materials and auxiliary materials, the product has obvious rising trend of degrading the impurity (S) -3-hydroxy-2-pyrrolidone in the long-term storage process, especially under the high temperature condition; secondly, the product contains a bacteriostatic agent of methylparaben (easy to cause cancer) and propylparaben (having skin irritation) which are harmful to human bodies; finally, the product adopts a filtration sterilization process with lower sterility assurance level, the decision tree requirement is selected according to the sterilization process issued by EMA, and the terminal sterilization process with higher sterility assurance level is preferably adopted on the premise that the product quality is not greatly affected.
The amikacin sulfate injection formulas in the prior art can be summarized into the following categories:
in order to improve the stability of the product, sodium citrate is added into the product of an original grinding enterprise as an antioxidant synergist, and the sodium citrate is matched with sodium bisulphite serving as an antioxidant to ensure that oxidative damage is reduced in the storage process of the product, however, impurities in the storage process of the prepared product are still increased, the product can only select a sterilization and filtration process with low sterility assurance level because of being unable to withstand high temperature, and meanwhile, in order to improve the antibacterial performance, bacteriostats, namely methylparaben and propylparaben which have certain harm to human bodies are forced to be added.
The invention patent with publication number of CN111110627A discloses an amikacin sulfate injection and a preparation method thereof, wherein the formulation comprises amikacin sulfate, a pH buffer, an antioxidant and a pH regulator, terminal sterilization is adopted, and the adopted antioxidants such as sodium metabisulfite, sodium sulfite, sodium bisulphite and sodium thiosulfate have certain side effects on human bodies, if the control is not good, adverse effects can be caused on the bodies, especially the liver function still has risks, and particularly the injection product needs to be paid attention to.
The invention patent with publication number of CN101584658A discloses a preparation method of amikacin sulfate injection, wherein only disodium edentate and lactic acid are added to auxiliary materials in the prescription, terminal sterilization is adopted, active carbon is used in the preparation, and because of the diversity of raw materials and production processes of the active carbon, uncertainty of an activation mechanism and limitation of quality control, the active carbon is used for introducing element impurities into the injection, mixing with microparticle impurities and adsorbing main medicine to influence the stable content of the main medicine, the amikacin sulfate injection is prepared according to the method described by the active carbon, and the obtained product has obvious yellowing after sterilization and does not meet the requirements of product quality standards.
The invention patent with publication number of CN115282116B discloses an amikacin injection and a preparation method thereof, wherein the amikacin injection consists of amikacin sulfate, an isotonic agent, an antioxidant and a pH regulator, sodium chloride serving as the isotonic agent is subjected to special alkalization treatment, wherein the special alkalization treatment is carried out by using sodium hydroxide to dissolve and adding active carbon, heating to 60-80 ℃ and treating for 30-60min, on one hand, the amikacin injection also uses the antioxidants of sodium bisulfite, sodium metabisulfite, sodium thiosulfate and the like, and on the other hand, the amikacin injection also uses the active carbon, and has a certain safety risk on the product quality risk.
For amikacin sulfate injection, in the prior art products including raw grinding and the like, organic acid salts such as sodium citrate, sodium acetate and the like are used as antioxidant synergists or buffer salts, and as the acids are natural metabolites, the acids possibly have interference effects on the biochemical reaction process, and meanwhile, the acids are easy to interact with other organic components and organic auxiliary materials, so that more impurities can be generated.
Aiming at the problems that in the prior art, impurities are more, the stability is low, the product quality and the safety cannot be ensured due to auxiliary materials, processes and the like, the prescription of amikacin sulfate injection and the preparation process thereof are considered to be necessary to be further optimized. The inventor of the application surprisingly discovers that for amikacin sulfate injection products, the residual oxygen content is controlled to be less than or equal to 1 percent in the preparation process, the products can still maintain very stable level under the condition of no antioxidant, the impurity content has no obvious change compared with the initial comparison under the terminal sterilization and accelerated experiment conditions, the product stability is excellent, and the problems of the existing amikacin sulfate injection in the aspects of quality stability and safety are well solved.
Disclosure of Invention
Aiming at the defects existing in the prior art, the application provides a novel amikacin sulfate injection and a preparation method thereof, wherein sodium chloride is adopted as an isotonic agent, the pH of liquid medicine is strictly controlled within the range of 4.5-5.5, the residual oxygen is controlled to be less than or equal to 1%, an antioxidant is not required to be added, and after the injection is sterilized at a terminal, impurities in the injection can be reduced to the greatest extent, the quality and safety of the liquid medicine are improved, and the medication risk is reduced.
The technical scheme of the application is as follows:
provided is amikacin sulfate injection, which comprises: amikacin sulfate, an isotonic agent, a proper amount of pH regulator and the balance of water for injection; the pH of the injection is 4.5-5.5; the residual oxygen content of the injection is less than or equal to 1 percent.
Further, the injection comprises the following components in percentage by mass and volume: 100mg/ml amikacin sulfate, 1-10mg/ml isotonic agent, a proper amount of pH regulator (regulating the pH of injection to 4.5-5.5) and the balance of water for injection; the residual oxygen content of the injection is less than or equal to 1 percent.
In some embodiments, the isotonic agent is sodium chloride or potassium chloride, preferably sodium chloride.
In some embodiments, the pH adjustor is dilute sulfuric acid, with a dilute sulfuric acid concentration of 1mol/L.
The application also provides a preparation method of amikacin sulfate injection, which comprises the following steps:
a. filling nitrogen into the liquid preparation tank and the pipeline, and adding water for injection into the liquid preparation tank;
b. adding an isotonic agent and amikacin sulfate into a liquid preparation tank according to a proportion, and stirring for dissolution;
c. adding a pH regulator into the solution obtained in the step b, and regulating the pH value to 4.5-5.5;
d. c, fixing the volume of the solution obtained in the step c, and stirring to obtain a liquid medicine;
e. d, sterilizing and filtering the liquid medicine obtained in the step d;
f. filling nitrogen into the liquid medicine obtained by filtering in the step e, controlling the filling speed to be 300-400 counts/min, and filling
The flow rates of the front and the rear nitrogen are 8L/min-12L/min, the purity of the nitrogen is more than or equal to 99.99 percent, and the residual oxygen is less than or equal to 1 percent;
g. performing terminal sterilization on the liquid medicine obtained after the filling and sealing in the step f to obtain the injection product;
and c, filling nitrogen in the whole process in the operation process of the steps a to e, wherein the nitrogen filling flow of the liquid preparation tank is 12L/min-20L/min, the purity of the nitrogen is more than or equal to 99.99%, and the dissolved oxygen in the liquid preparation tank is controlled to be less than or equal to 0.5ppm.
Optionally, during the whole nitrogen filling process in the steps a to e, the solution in the liquid preparation tank is subjected to ultrasonic deoxidation treatment, and the dissolved oxygen in the liquid preparation tank is further controlled to be less than or equal to 0.3ppm, and the residual oxygen filling amount is further controlled to be less than or equal to 0.8%; further can control the dissolved oxygen in the liquid preparation tank to be less than or equal to 0.1ppm and the residual oxygen filling amount to be less than or equal to 0.6 percent. In some embodiments, the operating parameters of the ultrasound deoxygenation process are: the frequency is 30-80kHz, preferably 50kHz.
In some embodiments, the ultrasonic deoxygenation treatment is operated in a continuous mode or an intermittent mode, wherein the continuous mode is the same as the nitrogen charging time, and the intermittent mode is operated for 1/6 of the nitrogen charging time, and the intermittent mode is suspended for 1/40 of the nitrogen charging time until the nitrogen charging is completed.
In some embodiments, the terminal sterilization temperature of step g above is 121 ℃ or 115 ℃, the sterilization time is 8min-30min, preferably the sterilization temperature is 121 ℃, the sterilization time is 12min-15min.
Compared with the prior art, the beneficial effect of this application lies in:
(1) The amikacin sulfate injection does not contain an antioxidant, has high stability and extremely low impurity content, and greatly improves the safety of amikacin sulfate injection.
(2) The injection prescription adopts sodium chloride as an isotonic agent and inorganic acid as a pH regulator, so that organic acid salts such as sodium citrate are avoided, the possibility of impurities generated by interaction between organic auxiliary materials and active organic molecules is eliminated, and the product quality is improved; and sodium chloride does not need to use sodium hydroxide and active carbon for alkalization treatment, so that the generation of impurities is reduced from the source, and the stability of the product is improved.
(3) The injection is filled with nitrogen through the liquid preparation and filling and sealing processes in the preparation process, and the ultrasonic deoxidation treatment technology in the liquid preparation process greatly reduces the oxygen content in the injection, and can slow down the oxidative degradation of raw materials, so that the stability of the product is improved.
(4) In the preparation process of the injection, the pH is controlled within the range of 4.5-5.5 suitable for the stability of the active ingredients, so that the increase of impurities in the storage process of the liquid medicine is controlled, and the stability of the product is improved.
(5) The injection adopts a terminal sterilization process, so that the higher sterility assurance level of the product is ensured, the medication risk is reduced, and meanwhile, the prescription does not contain a bacteriostatic agent harmful to human bodies due to the adoption of the terminal sterilization process, thereby improving the safety of the medicine.
In summary, the impurity level in the preparation and storage processes of the product is reduced together through the regulation of the prescription, the control of the residual oxygen amount, the strict control of the pH of the liquid medicine and the terminal sterilization process, and meanwhile, the sterility assurance level and the safety of the medicine are greatly improved.
Detailed Description
The present application is further illustrated by the following specific examples. It should be understood that: the examples of the present application are merely illustrative of the present application and are not limiting of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The raw materials of specific origin are not noted in the following examples, and are generally commercially available conventional products. The technical scheme obtained by simply improving the application or adopting conventional means or components to perform equivalent substitution on the basis of the technical scheme belongs to the protection scope of the application.
Comparative example 1: comparative example 1 was prepared with the formulation A
TABLE 1 information on the original formulation A
Comparative example 2: preparation of formulation B as comparative example 2
Formulation B was prepared according to amikacin injection formulation and method of preparation disclosed in example 3 of publication No. CN 115282116B.
Example 1: amikacin sulfate injection preparation component optimization (shown in table 2)
Table 2 amikacin sulfate injection formulations formulas 1-4
| Sample name | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| Amikacin sulfate (mg/ml) | 100 | 100 | 100 | 100 |
| Sodium chloride (mg/ml) | 1 | 4.5 | 10 | / |
| Potassium chloride (mg/ml) | / | / | / | 4.5 |
| 1mol/L dilute sulfuric acid | pH is adjusted to 5.0 | pH is adjusted to 5.0 | pH is adjusted to 5.0 | pH is adjusted to 5.0 |
| Water for injection | Constant volume to 1000mL | Constant volume to 1000mL | Constant volume to 1000mL | Constant volume to 1000mL |
The method for preparing the injection of the prescription 1-4 comprises the following steps:
a. filling nitrogen into the liquid preparation tank and the pipeline, and adding water for injection into the liquid preparation tank;
b. adding isotonic agent (sodium chloride or potassium chloride) and amikacin sulfate into a liquid preparation tank according to the prescription amount, stirring and dissolving;
c. adding a pH regulator (1 mol/L dilute sulfuric acid) into the solution obtained in the step b, and regulating the pH value to each prescription set value;
d. c, fixing the volume of the solution obtained in the step c, and stirring to obtain a liquid medicine;
e. d, sterilizing and filtering the liquid medicine obtained in the step d;
f. filling nitrogen into the liquid medicine obtained by filtering in the step e, and filling and sealing, wherein the filling and sealing speed is controlled to be 300-400 counts/min, the nitrogen flow is 8-12L/min (preferably 10L/min) before and after filling, and the purity of the nitrogen is more than or equal to 99.99%, so that the residual oxygen content is less than or equal to 1%;
g. performing terminal sterilization (121 ℃ for 12-15 min) on the liquid medicine obtained after the encapsulation in the step f to obtain amikacin sulfate injection products corresponding to the prescriptions 1-4; and c, filling nitrogen in the whole process in the operation process of the steps a to e, wherein the nitrogen filling flow of the liquid preparation tank is 12L/min-20L/min (preferably 15L/min), the purity of the nitrogen is more than or equal to 99.99%, and the dissolved oxygen in the liquid preparation tank is controlled to be less than or equal to 0.5ppm.
The amikacin sulfate injections prepared in the prescriptions 1 to 4 were compared with comparative example 1 (original preparation a), wherein in order to verify the change of the related substances after the sterilization of the original preparation a, a parallel comparison group was set, i.e., the other original preparation a was subjected to terminal sterilization (121 ℃ C., 12min to 15 min) after the pot sealing. The final test results are shown in table 3:
TABLE 3 optimization results of amikacin sulfate injection formulation components
As can be seen from table 3, after the primary formulation a (sterile filtration) is subjected to terminal sterilization, the relevant substances are significantly increased, and after the adjustment of the prescription process, the prescriptions 1-4 adopt terminal sterilization with higher sterility assurance level than the primary formulation a (sterile filtration), so that the safety is higher, and meanwhile, the relevant substances are significantly reduced, wherein the relevant substances of the prescription 2 are lower and the osmotic molar concentration is basically consistent with that of the primary formulation a (sterile filtration); compared with the preparation B, the injection products prepared by the prescriptions 1-4 have no difference in sterility assurance level, but the related substances are obviously reduced, and the preparation process is simpler (no alkalization treatment operation) and has a prescription with proper osmotic pressure. In view of the above, the recipe and process of recipe 2 are intended to be preferred.
Example 2: investigation of the pH Range
In order to verify the effect of the pH range on the stability of the injection, the present application was based on prescription 2 and the preparation method thereof in example 1, and prescriptions 5 to 10 were respectively set, wherein prescriptions 5 to 10 were substantially the same as prescription 2, except that the pH values were different, and the specific differences and results are shown in table 4:
table 4 results of investigation of pH ranges
As can be seen from Table 4, the pH of the product has a great influence on the substances concerned, and the meta-acid or meta-base substances have an increasing tendency, so that the pH of the product is set to a range of 4.5 to 5.5, preferably 4.7 to 5.3, most preferably 5.0.
Example 3: investigation of residual oxygen and dissolved oxygen
The application finds that the oxygen content is a primary factor influencing the stability of the product, reduces the oxygen content in the injection, and can greatly improve the stability of amikacin sulfate injection. The residual oxygen amount refers to the oxygen content in the air at the upper part of the bottle after the injection is packaged, the dissolved oxygen amount refers to the oxygen content dissolved in the liquid medicine, and the residual oxygen amount and the dissolved oxygen amount affect the stability of the injection together. The present example is given as prescription 11, prescription 12, and blank comparative example, respectively.
Prescription 11: the formula is basically the same as the raw and auxiliary materials of the formula 2 (dissolved oxygen amount 0.5ppm, residual oxygen amount 1.0%) in the embodiment 1 in proportion and the preparation method, and the difference is that: and c, filling nitrogen in the whole process in the operation process in the step a to the step e, and simultaneously connecting an ultrasonic transducer (the model is HS-CP 50K) on the outer wall of the liquid preparation tank, and carrying out ultrasonic deoxidation treatment on the solution in the liquid preparation tank by utilizing ultrasonic waves emitted by the ultrasonic transducer. The frequency of the ultrasonic wave can be selected to be 30-80kHz, 50kHz is preferred in the embodiment, the working mode is continuous, and the working time is equal to the nitrogen charging time. The dissolved oxygen content can be controlled to be 0.3ppm, and the residual oxygen content can be controlled to be 0.8%.
Prescription 12: the recipe is substantially the same as recipe 12 except that the ultrasonic operation mode is intermittent operation, i.e., 1/40 of the nitrogen filling time is paused for every 1/6 of the nitrogen filling time until the nitrogen filling is completed. Dissolved oxygen can be controlled to be 0.1ppm, and residual oxygen is controlled to be 0.6%.
Blank comparative example: the comparative example is basically the same as the raw and auxiliary materials of the prescription 2 in the example 1 in proportion and the preparation method, except that: and c, in the whole process of the operation of the steps a to f, nitrogen is not filled, and the dissolved oxygen amount is 6.0ppm and the residual oxygen amount is 20.9 percent. The differences of the related substances after sterilization of the products prepared by the prescription 2, the prescription 11 and the prescription 12 are examined respectively, and the results are shown in Table 5.
TABLE 5 examination results of residual oxygen amount and dissolved oxygen amount
The result shows that different residual oxygen and dissolved oxygen have larger influence on related substances of the product, when the oxygen content is smaller, the related substances of the product are fewer, the product can control the residual oxygen to be 0.6% at the minimum and control the dissolved oxygen to be 0.1ppm by assisting in introducing nitrogen and deoxidizing through an ultrasonic deoxidizing technology, and the oxidation of raw materials and the increase of impurities are further slowed down, so that the stability of the product is improved.
Example 4: investigation of product stability comparison
The stability of the formulations prepared by the original grinding formulation A, the formulation B, the formulation 2 and the formulation 12 are respectively compared as experimental examples, the stability is compared and examined, and the stability results of the accelerated test (40 ℃ and 75% RH) are shown in Table 6.
Table 6 results of investigation of product stability comparisons
The test results prove that: when sodium citrate, methyl hydroxybenzoate and propyl hydroxybenzoate are removed from the prescription, and sodium chloride is used instead, the residual oxygen content is controlled to be less than or equal to 1%, and the pH of the product is strictly controlled to be in the range of 4.5-5.5, the stability of the pharmaceutical preparation in the transportation and storage processes can be ensured. The impurity level of the product can be further reduced by precisely controlling the pH, the residual oxygen and the dissolved oxygen in the preparation process of the product. In addition, the terminal sterilization process can ensure the higher sterility assurance level of the product, reduce the medication risk and improve the safety of the medicine.
The above embodiments are only for illustrating the technical solutions of the present application and not for limiting the same, and although the present application has been described in detail with reference to examples, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solutions of the present application without departing from the scope of the technical solutions of the present application, and all the modifications or equivalent are included in the scope of the claims of the present application.
Claims (9)
1. Amikacin sulfate injection, characterized in that the injection comprises: amikacin sulfate, an isotonic agent, an antioxidant, a pH regulator and the balance of water for injection; the pH of the injection is 4.5-5.5; the residual oxygen content of the injection is less than or equal to 1 percent.
2. The injection according to claim 1, wherein the injection comprises, in terms of mass to volume ratio: 100mg/ml amikacin sulfate, 1-10mg/ml isotonic agent and a proper amount of pH regulator are used for regulating the pH of the injection to 4.5-5.5, and the balance is water for injection; the residual oxygen content of the injection is less than or equal to 1 percent.
3. Injection according to claim 1 or 2, characterized in that the isotonic agent is sodium chloride or potassium chloride, preferably sodium chloride.
4. The injection according to claim 1 or 2, wherein the pH adjuster is dilute sulfuric acid, and the concentration of the dilute sulfuric acid is 1mol/L.
5. A process for the preparation of amikacin sulfate injection as claimed in any of claims 1 to 4, comprising the steps of:
a. filling nitrogen into the liquid preparation tank and the pipeline, and then adding the water for injection into the liquid preparation tank;
b. adding the isotonic agent and amikacin sulfate into the liquid preparation tank according to the proportion, and stirring for dissolution;
c. adding the solution obtained in the step b into the pH regulator, and regulating the pH value to 4.5-5.5;
d. c, fixing the volume of the solution obtained in the step c, and stirring to obtain a liquid medicine;
e. d, sterilizing and filtering the liquid medicine obtained in the step d;
f. filling nitrogen into the liquid medicine obtained by filtering in the step e, controlling the filling speed to be 300-400 counts/min, and controlling the nitrogen flow to be 8-12L/min before and after filling, wherein the nitrogen purity is more than or equal to 99.99%, so that the residual oxygen content is less than or equal to 1%;
g. performing terminal sterilization on the liquid medicine obtained after the filling and sealing in the step f to obtain the injection product;
and c, filling nitrogen in the whole process in the operation process of the steps a to e, wherein the nitrogen filling flow of the liquid preparation tank is 12L/min-20L/min, the purity of the nitrogen is more than or equal to 99.99%, and the dissolved oxygen in the liquid preparation tank is controlled to be less than or equal to 0.5ppm.
6. The preparation method of claim 5, wherein the step a to the step e are carried out ultrasonic deoxidation treatment on the solution in the liquid preparation tank while nitrogen is filled in the whole process in the operation process, so that the dissolved oxygen in the liquid preparation tank is further controlled to be less than or equal to 0.3ppm, and the residual oxygen content in filling is further controlled to be less than or equal to 0.8%; furthermore, the dissolved oxygen in the liquid preparation tank can be controlled to be less than or equal to 0.1ppm, and the residual oxygen filling amount is controlled to be less than or equal to 0.6%.
7. The method according to claim 6, wherein the working parameters of the ultrasonic deoxygenation treatment are: the frequency is 30-80kHz, preferably 50kHz.
8. The method according to claim 7, wherein the ultrasonic deoxygenation treatment is performed in a continuous mode or an intermittent mode, the continuous mode is performed for the same time as the nitrogen charging time, and the intermittent mode is performed for 1/6 of the time per operation, and the 1/40 of the time is stopped until the nitrogen charging is completed.
9. The method of any one of claims 5-8, wherein the terminal sterilization temperature in step g is 121 ℃ or 115 ℃, the sterilization time is 8min-30min, preferably the sterilization temperature is 121 ℃, and the sterilization time is 12min-15min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311367393.5A CN117298042A (en) | 2023-10-21 | 2023-10-21 | Amikacin sulfate injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311367393.5A CN117298042A (en) | 2023-10-21 | 2023-10-21 | Amikacin sulfate injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117298042A true CN117298042A (en) | 2023-12-29 |
Family
ID=89260243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311367393.5A Pending CN117298042A (en) | 2023-10-21 | 2023-10-21 | Amikacin sulfate injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117298042A (en) |
-
2023
- 2023-10-21 CN CN202311367393.5A patent/CN117298042A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108566954A (en) | A kind of disinfectant and its preparation method and application | |
| CN101080230A (en) | Treatment and control of severe infections including cystic fibrosis | |
| CN103126978A (en) | Preparing method for ambroxol hydrochloride injection | |
| NO339109B1 (en) | Preservative composition for ophthalmic use | |
| CN116036130A (en) | Antibacterial composite material combining Chinese and western medicine and preparation method and application thereof | |
| CN117298042A (en) | Amikacin sulfate injection and preparation method thereof | |
| CN111110627B (en) | Amikacin sulfate injection and preparation method thereof | |
| CN104644551A (en) | Hydroxyfasudil-containing pharmaceutical composition for injection | |
| CN103073562A (en) | Method for refining cefamandole nafate, cefamandole nafate and application thereof | |
| CN110403905A (en) | A kind of control method that vitamin C injection is anti-oxidation | |
| CN113730348B (en) | Dexamethasone sodium phosphate injection and preparation method thereof | |
| CN103951732B (en) | A kind of antibacterial peptide | |
| CN112089693B (en) | Penicillin composition for injection and preparation method thereof | |
| CN113633610A (en) | Methotrexate injection and preparation method thereof | |
| CN115369061A (en) | Selective helicobacter pylori culture medium and preparation method thereof | |
| CN116265010A (en) | Medicinal composition containing diquafosol sodium and preparation method thereof | |
| CN114306228A (en) | Diquafosol sodium eye drops and preparation method thereof | |
| CN100402033C (en) | Fleroxacin injection and its preparing method | |
| CN1742718A (en) | Method for preparing rifamicina injecta | |
| CN111264555A (en) | Hydrogen peroxide disinfectant and preparation method and application thereof | |
| CN111888377A (en) | Antibacterial electrolyte flushing fluid for surgical operation and preparation method thereof | |
| CN110876718A (en) | Tranexamic acid injection and preparation method thereof | |
| CN105796603A (en) | Antibacterial peptide gel and preparation method thereof | |
| CN115721605B (en) | Atropine sulfate liquid preparation and preparation method thereof | |
| CN115607656B (en) | Application of chitosan enzyme and composite gel thereof in preparation of products for preventing or treating skin diseases caused by malassezia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |