CN116942605A - Carbazochrome sodium sulfonate injection and preparation method thereof - Google Patents
Carbazochrome sodium sulfonate injection and preparation method thereof Download PDFInfo
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- CN116942605A CN116942605A CN202311053237.1A CN202311053237A CN116942605A CN 116942605 A CN116942605 A CN 116942605A CN 202311053237 A CN202311053237 A CN 202311053237A CN 116942605 A CN116942605 A CN 116942605A
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- sodium sulfonate
- carbazochrome
- concentration
- sodium
- carbazochrome sodium
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- 229960004353 carbazochrome sodium sulfonate Drugs 0.000 title claims abstract description 73
- 238000002347 injection Methods 0.000 title claims abstract description 49
- 239000007924 injection Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- HLFCZZKCHVSOAP-WXIWBVQFSA-M sodium;(5e)-5-(carbamoylhydrazinylidene)-1-methyl-6-oxo-2,3-dihydroindole-2-sulfonate Chemical compound [Na+].NC(=O)N\N=C/1C(=O)C=C2N(C)C(S([O-])(=O)=O)CC2=C\1 HLFCZZKCHVSOAP-WXIWBVQFSA-M 0.000 title claims abstract 17
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 20
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 19
- 239000008139 complexing agent Substances 0.000 claims abstract description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 76
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 38
- 238000001914 filtration Methods 0.000 claims description 38
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 34
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 32
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 26
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 25
- 230000001954 sterilising effect Effects 0.000 claims description 24
- 229960004106 citric acid Drugs 0.000 claims description 21
- 239000008215 water for injection Substances 0.000 claims description 19
- 238000011049 filling Methods 0.000 claims description 15
- 238000004659 sterilization and disinfection Methods 0.000 claims description 14
- 229960004543 anhydrous citric acid Drugs 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- 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 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- RHPXYIKALIRNFA-UHFFFAOYSA-L disodium;2-[carboxylatomethyl(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CC([O-])=O RHPXYIKALIRNFA-UHFFFAOYSA-L 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- FEJQDYXPAQVBCA-UHFFFAOYSA-J tetrasodium;ethane-1,2-diamine;tetraacetate Chemical compound [Na+].[Na+].[Na+].[Na+].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.NCCN FEJQDYXPAQVBCA-UHFFFAOYSA-J 0.000 claims description 2
- HLFCZZKCHVSOAP-DAMYXMBDSA-M sodium;(5z)-5-(carbamoylhydrazinylidene)-1-methyl-6-oxo-2,3-dihydroindole-2-sulfonate Chemical compound [Na+].NC(=O)N/N=C/1C(=O)C=C2N(C)C(S([O-])(=O)=O)CC2=C\1 HLFCZZKCHVSOAP-DAMYXMBDSA-M 0.000 description 57
- 229960001484 edetic acid Drugs 0.000 description 30
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 11
- 239000002994 raw material Substances 0.000 description 10
- 238000007789 sealing Methods 0.000 description 10
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 8
- 239000000600 sorbitol Substances 0.000 description 8
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000009467 reduction Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 description 3
- 235000019800 disodium phosphate Nutrition 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- XSXCZNVKFKNLPR-SDQBBNPISA-N carbazochrome Chemical class NC(=O)N/N=C/1C(=O)C=C2N(C)CC(O)C2=C\1 XSXCZNVKFKNLPR-SDQBBNPISA-N 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- KFDNQUWMBLVQNB-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;sodium Chemical compound [Na].[Na].[Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KFDNQUWMBLVQNB-UHFFFAOYSA-N 0.000 description 1
- CEGPKOIWQYWDNX-UHFFFAOYSA-N 2-[bis(carboxymethyl)amino]acetic acid;sodium Chemical compound [Na].[Na].OC(=O)CN(CC(O)=O)CC(O)=O CEGPKOIWQYWDNX-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229960002631 carbazochrome Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000008155 medical solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000002792 vascular Effects 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- 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)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application relates to a carbazochrome sodium sulfonate injection and a preparation method thereof, which consists of carbazochrome sodium sulfonate, a pH regulator, an antioxidant and a complexing agent, wherein the pH value is 5.7-6.1.
Description
Technical Field
The application relates to the technical field of pharmaceutical preparations, in particular to a carbazochrome sodium sulfonate injection and a preparation method thereof.
Background
Chemical name of carbazochrome sodium sulfonate: 1-methyl-6-oxo-2, 3,5, 6-tetrahydroindole-5-semicarbazone-2-sodium sulfonate, molecular formula C 10 H 11 N 4 NaO 5 S·3H 2 O has the structural formula shown in formula I:
the carbazochrome sodium sulfonate is a vascular hemostat, and is mainly used for bleeding of diseases of urinary system, upper digestive tract, respiratory tract and obstetrics and gynecology, and also can be used for traumatic and surgical bleeding.
The carbazochrome sodium sulfonate is a carbazochrome derivative, and sodium sulfonate groups are introduced into the molecular structure, so that the defect that the carbazochrome is small in solubility and must be dissolved by salicylic acid is overcome, and the hemostatic effect is obvious. The carbazochrome sodium sulfonate can strengthen the elasticity of capillary vessels, reduce the permeability of the capillary vessels, promote the retraction effect of broken ends of the capillary vessels, stabilize acidic mucopolysaccharide in the capillary vessels and surrounding tissues, obviously shorten the bleeding time, do not influence the coagulation/fibrinolysis system, and is an effective hemostatic for bleeding caused by capillary vessel injury. The carbazochrome sodium sulfonate does not contain salicylic acid groups, so that the problem of hemolysis is avoided, and the hematopoietic function is not influenced; the water solubility is good, and the effect is rapid; the toxicity is low, the kidney-simulating effect is avoided, and the fluctuation of blood pressure and heart rate is avoided; does not affect the coagulation mechanism, has quick response, lasting effect and wide application range.
The existing carbazochrome sodium sulfonate injection has the following defects: the prior art has a plurality of auxiliary materials of the carbazochrome sodium sulfonate injection, and the carbazochrome sodium sulfonate injection has the physical and chemical changes, such as deepening color, generating degradation products and the like, which are slightly soluble in water, easily soluble in hot water and easily affected by oxygen and temperature in long-term storage.
Disclosure of Invention
Problems to be solved by the application
The application researches the prescription composition with better stability of the liquid medicine, and the reference preparation, namely, the carbazochrome sodium sulfonate injection (Adona) has 5 compositions of anhydrous disodium hydrogen phosphate, citric acid, sorbitol, propylene glycol and sodium bisulphite, and researches find that the sodium bisulphite is reduced in the stability influence process of the sorbitol and the propylene glycol, and the faster the antioxidant is consumed, the quality stability of the product is not facilitated.
The application screens a more stable PH range, thereby reducing the quality risk of carbazochrome sodium sulfonate injection.
Solution for solving the problem
The application relieves the problem of deepening of the color of the current reference in the process of setting out influencing factors, and produces more stable carbazochrome sodium sulfonate injection.
The application relates to a carbazochrome sodium sulfonate injection which comprises the following components of carbazochrome sodium sulfonate, a pH regulator, an antioxidant and a complexing agent, wherein the pH value is 5.7-6.1.
Preferably, the pH regulator is any two or more of hydrochloric acid, tartaric acid, sodium hydroxide, potassium hydroxide, anhydrous disodium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, sodium bicarbonate and sodium carbonate.
Preferably, the pH regulator is citric acid or anhydrous disodium hydrogen phosphate.
Preferably, the pH adjuster concentration: the concentration of citric acid is 0.25-1.0g/L, and the concentration of anhydrous disodium hydrogen phosphate is 0.5-1.5g/L; preferably, the concentration of citric acid is 0.3-0.8g/L, and the concentration of anhydrous disodium hydrogen phosphate is 0.65-1.3g/L; more preferably, the concentration of citric acid is 0.45g/L, and the concentration of anhydrous disodium hydrogen phosphate is 0.8g/L.
Preferably, the concentration of the carbazochrome sodium sulfonate is 5-20g/L, preferably 5-10g/L, and more preferably 5g/L.
Preferably, the antioxidant is any one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite and sodium thiosulfate; sodium bisulphite is preferred.
Preferably, the antioxidant concentration is 0.02-0.1g/L, preferably 0.04-0.08g/L, more preferably 0.07g/L.
Preferably, the complexing agent is any one or more of ethylenediamine tetraacetic acid, ethylenediamine tetraacetic acid disodium salt, ethylenediamine tetraacetic acid tetrasodium salt and nitrilotriacetic acid disodium salt; ethylene Diamine Tetraacetic Acid (EDTA) is preferred.
Preferably, the complexing agent concentration is in the range of 0.2 to 0.8g/L, preferably 0.2 to 0.6g/L, more preferably 0.2g/L.
The application provides a preparation method of the carbazochrome sodium sulfonate injection, which comprises the following steps:
1) Dissolving citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and ethylenediamine tetraacetic acid (EDTA) in 90% of water for injection, stirring, and mixing well;
2) Adding carbazochrome sodium sulfonate and stirring;
3) Adding the rest water, and filtering to obtain the carbazochrome sodium sulfonate injection.
Preferably, the pH value is adjusted to 5.7-6.1 by citric acid or anhydrous disodium hydrogen phosphate after the step (2).
Preferably, the filter cartridge specification for filtration is 0.22-0.45 μm.
Preferably, the temperature of the water is below 40 ℃.
Preferably, the filtration is performed by aseptic filtration using a non-terminal sterilization mode.
Preferably, the filtering is followed by filling, and the filling is performed in a nitrogen-free manner.
ADVANTAGEOUS EFFECTS OF INVENTION
The carbazochrome sodium sulfonate injection disclosed by the application reduces the use of auxiliary materials, relieves the consumption of antioxidants in the injection, improves the quality stability of products, reduces the quality risk of the carbazochrome sodium sulfonate injection by using a stable PH range, solves the problem of deepening of colors, and produces the carbazochrome sodium sulfonate injection with less impurities and more stability.
Drawings
FIG. 1 is a line graph showing the effect of sorbitol and propylene glycol on the reduction of antioxidant content in an injection in test example 1 of the present application;
FIG. 2 is a line graph showing the effect of different pH values on the decrease in antioxidant content in the injection solution in test example 2 of the present application.
Detailed Description
In order to make the technical scheme and the beneficial effects of the application more obvious and understandable, the following detailed description is given by way of example. Wherein the drawings are not necessarily to scale, and wherein local features may be exaggerated or reduced to more clearly show details of the local features; unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
The carbazochrome sodium sulfonate injection consists of carbazochrome sodium sulfonate, pH regulator, antioxidant and complexing agent with pH value of 5.7-6.1.
In certain embodiments, the pH adjuster is any two or more of hydrochloric acid, tartaric acid, sodium hydroxide, potassium hydroxide, anhydrous disodium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, sodium bicarbonate, and sodium carbonate.
In certain embodiments, the pH adjuster is citric acid and anhydrous disodium hydrogen phosphate.
In certain embodiments, the pH adjustor is at a citric acid concentration of 0.25 to 1.0g/L.
In certain embodiments, the pH adjustor is at a citric acid concentration of 0.3 to 0.8g/L.
In certain embodiments, the pH adjustor is at a citric acid concentration of 0.45g/L;
in certain embodiments, the pH adjustor anhydrous disodium phosphate concentration is 0.5 to 1.5g/L.
In certain embodiments, the pH adjustor anhydrous disodium phosphate concentration is 0.65 to 1.3g/L.
In certain embodiments, the pH adjustor anhydrous disodium phosphate concentration is 0.8g/L.
In certain embodiments, the concentration of carbazochrome sodium sulfonate is 5-20g/L.
In certain embodiments, the concentration of carbazochrome sodium sulfonate is 5-10g/L.
In certain embodiments, the concentration of carbazochrome sodium sulfonate is 5g/L.
In certain embodiments, the antioxidant is any one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite and sodium thiosulfate.
In certain embodiments, the antioxidant is sodium bisulfite.
In certain embodiments, the antioxidant concentration is from 0.02 to 0.1g/L.
In certain embodiments, the antioxidant concentration is 0.04-0.8g/L.
In certain embodiments, the antioxidant concentration is 0.07g/L.
In certain embodiments, the sodium bisulfite concentration is from 0.02 to 0.1g/L.
In certain embodiments, the sodium bisulfite concentration is 0.04 to 0.8g/L.
In certain embodiments, the sodium bisulfite concentration is 0.07g/L.
In certain embodiments, the complexing agent is any one or more of ethylenediamine tetraacetic acid, disodium ethylenediamine tetraacetic acid, tetrasodium ethylenediamine tetraacetic acid, disodium nitrilotriacetic acid.
In certain embodiments, the complexing agent is ethylenediamine tetraacetic acid (EDTA).
In certain embodiments, the complexing agent concentration is from 0.2 to 0.8g/L.
In certain embodiments, the complexing agent concentration is from 0.2 to 0.6g/L.
In certain embodiments, the complexing agent concentration is 0.2g/L.
In certain embodiments, the ethylenediamine tetraacetic acid (EDTA) concentration is from 0.2 to 0.8g/L.
In certain embodiments, the ethylenediamine tetraacetic acid (EDTA) concentration is from 0.2 to 0.6g/L.
In certain embodiments, the ethylenediamine tetraacetic acid (EDTA) concentration is 0.2g/L.
The application provides a preparation method of the carbazochrome sodium sulfonate injection, which comprises the following steps:
1) Dissolving citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and ethylenediamine tetraacetic acid (EDTA) in 90% of water for injection, stirring, and mixing well;
2) Adding carbazochrome sodium sulfonate and stirring;
3) Adding the rest water, and filtering to obtain the carbazochrome sodium sulfonate injection.
In certain embodiments, the PH is adjusted to 5.7-6.1 with citric acid or anhydrous disodium hydrogen phosphate after step (2).
In certain embodiments, the filter cartridge size for filtration is 0.22 to 0.45 μm.
In certain embodiments, the filter cartridge size for filtration is 0.22 μm.
In certain embodiments, the filter cartridge size for filtration is 0.45 μm. In certain embodiments, the temperature of the water is less than 40 ℃.
In certain embodiments, the filtration is performed by aseptic filtration using a non-terminal sterilization mode.
In certain embodiments, the filtration is followed by filling, which is performed without nitrogen.
Example 1
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
dissolving the citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA with the prescribed amount in 90% of water for injection (less than 40 ℃), and stirring for 5min;
1) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
2) Adding the rest water for injection to constant volume, and filtering with one-stage 0.45 μm and two-stage 0.22 μm;
3) Filling and sealing;
4) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 1
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving sorbitol, citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA in the amount of the prescription in 90% of water for injection (less than 40 ℃), and stirring for 8min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adding the rest water for injection to constant volume, and filtering with one-stage 0.45 μm and two-stage 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 2
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving propylene glycol, citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA in the amount of the prescription in 90% of water for injection (less than 40 ℃), and stirring for 8min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adding the rest water for injection to constant volume, and filtering with one-stage 0.45 μm and two-stage 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 3
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving sorbitol, propylene glycol, citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA in the amount of the prescription in 90% of water for injection (less than 40 ℃), and stirring for 10min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adding the rest water for injection to constant volume, and filtering with one-stage 0.45 μm and two-stage 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 4
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving citric acid, anhydrous disodium hydrogen phosphate and sodium bisulphite in the prescribed amount in 90% water for injection (less than 40 ℃) and stirring for 5min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adding the rest water for injection to constant volume, and filtering with one-stage 0.45 μm and two-stage 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Example 1
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving the citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA with the prescribed amount in 90% of water for injection (less than 40 ℃), and stirring for 5min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adding the rest water for injection to constant volume, filtering with one-stage 0.45 μm and two-stage 0.22 μm, and filtering to obtain filtrate with pH of 5.9;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 5
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving the citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA with the prescribed amount in 90% of water for injection (less than 40 ℃), and stirring for 5min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adjusting pH to about 5.7 with 0.1mol/l citric acid solution, adding the rest injectable water to constant volume, and filtering with one stage of 0.45 μm and two stages of 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 6
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving the citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA with the prescribed amount in 90% of water for injection (less than 40 ℃), and stirring for 5min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adjusting pH to about 5.5 with 0.1mol/l citric acid solution, adding the rest injectable water to constant volume, and filtering with one stage of 0.45 μm and two stages of 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 7
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving the citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA with the prescribed amount in 90% of water for injection (less than 40 ℃), and stirring for 5min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adjusting pH to about 6.1 with 0.1mol/l anhydrous disodium hydrogen phosphate solution, adding the rest injectable water to constant volume, and filtering with one stage of 0.45 μm and two stages of 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Comparative example 8
The prescription of the carbazochrome sodium sulfonate injection is as follows:
the preparation process comprises the following steps:
1) Dissolving the citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and EDTA with the prescribed amount in 90% of water for injection (less than 40 ℃), and stirring for 5min;
2) Adding carbazochrome sodium sulfonate raw material after the step 1) is dissolved uniformly, and stirring for 10min;
3) Adjusting pH to about 6.3 with 0.1mol/l anhydrous disodium hydrogen phosphate solution, adding the rest injectable water to constant volume, and filtering with one stage of 0.45 μm and two stages of 0.22 μm;
4) Filling and sealing;
5) And (5) sterilizing and filtering in a non-terminal sterilization mode.
Test example 1
Investigation conditions: and (3) storing for 5 days, 10 days and 30 days at a high temperature of 40 ℃, and examining the influence of sorbitol and propylene glycol on the reduction of the antioxidant in the carbazochrome sodium sulfonate injection by taking the content of sodium bisulphite as an index. The data are shown in Table 1, and the spectrum is shown in FIG. 1.
TABLE 1 influence of sorbitol and propylene glycol on antioxidant degradation in medical solutions
Results: the sodium bisulphite of the example 1 has the smallest amplitude reduction, the sodium bisulphite of the comparative example 1 has no obvious difference from the sodium bisulphite of the comparative example 2, the sodium bisulphite of the comparative example 3 has the largest amplitude reduction, sorbitol and propylene glycol are not added in the prescription, and the content change of the sodium bisulphite is the smallest, thus indicating that the stability of the application is better.
Test example 2
Investigation conditions: and (3) storing for 30 days at a high temperature of 60 ℃, and examining the influence of EDTA on the quality of the carbazochrome sodium sulfonate injection by taking the properties, the content and related substances as indexes. The results are shown in Table 2.
TABLE 2 influence of EDTA on quality of Carbazochrome sodium sulfonate injection
Results: EDTA added to the recipe had no obvious effect on the content, but was significantly better for the properties and related substances than for the recipe without EDTA, compared to day 0 and day 30. It is stated that the addition of EDTA to the formulation is beneficial to slow the darkening and related growth of color during stability of carbazochrome sodium sulfonate.
The detection method of the related substances comprises the following steps of
Chromatographic conditions: octadecylsilane chemically bonded silica is used as a packing material (Shim-pack GIST C18-AQ, 4.6mm. Times.250 mm,5 μm or column with equivalent performance); performing gradient elution by taking 0.05mol/L ammonium dihydrogen phosphate solution (pH value is adjusted to 3.8 by phosphoric acid) as a mobile phase A and methanol as a mobile phase B according to the following table; the detection wavelength is 220nm; the column temperature is 30 ℃; the sample volume was 10. Mu.l.
Test example 3
Investigation conditions: and (3) storing for 5 days, 10 days and 30 days at a high temperature of 40 ℃, and examining the influence of different pH values on the reduction of the antioxidant in the carbazochrome sodium sulfonate injection by taking the content of sodium bisulphite as an index.
The preparation process was the same as in example 1 except that the pH was varied, the data are shown in Table 3, and the profile is shown in FIG. 2.
TABLE 3 influence of different pH values on quality of Carbazochrome sodium sulfonate injection
Results: further research shows that when the pH is in the range of 5.5-6.5, the sodium bisulphite has smaller and stable amplitude reduction and is more beneficial to the quality stability of the injection when the pH is in the range of 5.7-6.1 compared with the pH in the range of 0 days, 5 days, 10 days and 30 days.
It should be understood that the above examples are illustrative and are not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes may be made in the above embodiments without departing from the scope of the disclosure. Likewise, the individual features of the above embodiments can also be combined arbitrarily to form further embodiments of the application which may not be explicitly described. Therefore, the above examples merely represent several embodiments of the present application and do not limit the scope of protection of the patent of the present application.
Claims (10)
1. The carbazochrome sodium sulfonate injection is characterized by comprising the following components of carbazochrome sodium sulfonate, a pH regulator, an antioxidant and a complexing agent, wherein the pH value is 5.7-6.1.
2. The carbazochrome sodium sulfonate injection according to claim 1, wherein the pH regulator is any two or more of hydrochloric acid, tartaric acid, sodium hydroxide, potassium hydroxide, anhydrous disodium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, sodium bicarbonate and sodium carbonate; preferably citric acid and anhydrous disodium hydrogen phosphate;
preferably, the pH adjuster concentration: the concentration of citric acid is 0.25-1.0g/L, and the concentration of anhydrous disodium hydrogen phosphate is 0.5-1.5g/L; preferably, the concentration of citric acid is 0.3-0.8g/L, and the concentration of anhydrous disodium hydrogen phosphate is 0.65-1.3g/L; more preferably, the concentration of citric acid is 0.45g/L, and the concentration of anhydrous disodium hydrogen phosphate is 0.8g/L.
3. The carbazochrome sodium sulfonate injection according to claim 1, wherein the concentration of carbazochrome sodium sulfonate is 5-20g/L, preferably 5-10g/L, more preferably 5g/L;
preferably, the antioxidant is any one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite and sodium thiosulfate; sodium bisulphite is preferred;
preferably, the antioxidant concentration is 0.02-0.1g/L, preferably 0.04-0.08g/L, more preferably 0.07g/L.
4. The carbazochrome sodium sulfonate injection according to claim 1, wherein the complexing agent is any one or more of ethylenediamine tetraacetic acid, ethylenediamine tetraacetic acid disodium salt, ethylenediamine tetraacetic acid tetrasodium salt and nitrilotriacetic acid disodium salt; preferably ethylenediamine tetraacetic acid (EDTA);
preferably, the complexing agent concentration is in the range of 0.2 to 0.8g/L, preferably 0.2 to 0.6g/L, more preferably 0.2g/L.
5. A process for the preparation of the carbazochrome sodium sulfonate injection according to any one of claims 1 to 4, comprising the steps of:
1) Dissolving citric acid, anhydrous disodium hydrogen phosphate, sodium bisulphite and ethylenediamine tetraacetic acid (EDTA) in 90% of water for injection, stirring, and mixing well;
2) Adding carbazochrome sodium sulfonate and stirring;
3) Adding the rest water, and filtering to obtain the carbazochrome sodium sulfonate injection.
6. The method for preparing carbazochrome sodium sulfonate injection according to claim 5, wherein the PH value is adjusted to 5.7-6.1 by citric acid or anhydrous disodium hydrogen phosphate after the step (2).
7. The method for preparing carbazochrome sodium sulfonate injection according to claim 5, wherein the specification of the filter element for filtering is 0.22-0.45 μm.
8. The method for preparing carbazochrome sodium sulfonate injection according to claim 5, wherein the temperature of the water is lower than 40 ℃.
9. The method for preparing carbazochrome sodium sulfonate injection according to claim 5, wherein the filtering adopts a non-terminal sterilization mode for sterilization and filtration.
10. The method for preparing carbazochrome sodium sulfonate injection according to claim 5, wherein the filtering is followed by filling, and the filling is performed in a nitrogen-free manner.
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