CN118217230A - Stable sodium thiosulfate high-capacity injection and preparation method thereof - Google Patents
Stable sodium thiosulfate high-capacity injection and preparation method thereof Download PDFInfo
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- CN118217230A CN118217230A CN202211651782.6A CN202211651782A CN118217230A CN 118217230 A CN118217230 A CN 118217230A CN 202211651782 A CN202211651782 A CN 202211651782A CN 118217230 A CN118217230 A CN 118217230A
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- injection
- sodium thiosulfate
- sodium
- water
- chloride
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 title claims abstract description 49
- 235000019345 sodium thiosulphate Nutrition 0.000 title claims abstract description 49
- 238000002347 injection Methods 0.000 title claims abstract description 45
- 239000007924 injection Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 229940090044 injection Drugs 0.000 claims abstract description 44
- 239000008215 water for injection Substances 0.000 claims abstract description 36
- 239000007788 liquid Substances 0.000 claims abstract description 34
- 229940035976 sodium thiosulfate injection Drugs 0.000 claims abstract description 25
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000004327 boric acid Substances 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 78
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 31
- 239000001301 oxygen Substances 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 238000011049 filling Methods 0.000 claims description 29
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 230000001954 sterilising effect Effects 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 26
- 238000004659 sterilization and disinfection Methods 0.000 claims description 22
- 239000001103 potassium chloride Substances 0.000 claims description 14
- 235000011164 potassium chloride Nutrition 0.000 claims description 14
- 230000004888 barrier function Effects 0.000 claims description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 239000006179 pH buffering agent Substances 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 239000001569 carbon dioxide Substances 0.000 claims description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 150000003841 chloride salts Chemical class 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 238000005538 encapsulation Methods 0.000 claims description 3
- 239000006174 pH buffer Substances 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000008351 acetate buffer Substances 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- 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 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 239000001433 sodium tartrate Substances 0.000 claims description 2
- 229960002167 sodium tartrate Drugs 0.000 claims description 2
- 235000011004 sodium tartrates Nutrition 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 28
- 208000005374 Poisoning Diseases 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 231100000572 poisoning Toxicity 0.000 abstract description 5
- 230000000607 poisoning effect Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 25
- 239000000523 sample Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- 230000008569 process Effects 0.000 description 16
- 239000002245 particle Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000011521 glass Substances 0.000 description 12
- 239000004033 plastic Substances 0.000 description 10
- 239000005388 borosilicate glass Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 239000003963 antioxidant agent Substances 0.000 description 8
- 230000003078 antioxidant effect Effects 0.000 description 8
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000012423 maintenance Methods 0.000 description 5
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 5
- 229960000907 methylthioninium chloride Drugs 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000005022 packaging material Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- -1 polypropylene Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 208000029039 cyanide poisoning Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 229940046892 lead acetate Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- NYQDCVLCJXRDSK-UHFFFAOYSA-N Bromofos Chemical compound COP(=S)(OC)OC1=CC(Cl)=C(Br)C=C1Cl NYQDCVLCJXRDSK-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 208000019872 Drug Eruptions Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 241000519995 Stachys sylvatica Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000130764 Tinea Species 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 238000004544 sputter deposition Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 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
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds 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
- A61K47/02—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
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- 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
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/14—Ectoparasiticides, e.g. scabicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a stable sodium thiosulfate high-capacity injection and a preparation method thereof. The specification of the injection is 50-200 mL, the injection contains 10-70 g of sodium thiosulfate, 150-1000 mg of chloride, 100-600 mg of boric acid, a proper amount of pH regulator and a proper amount of water for injection, and the pH value of the injection is 7.5-8.4. The sodium thiosulfate injection disclosed by the invention has the advantages that the stability is high, the medicament containing amount is large, the specification is large, only 1 bottle of liquid medicine is needed each time, the risk of puncture and chip falling is reduced, the sodium thiosulfate injection can be directly used without being prepared by nurses, the burden of nurses is reduced, the first aid of a poisoning patient is facilitated, and meanwhile, the secondary pollution during liquid preparation is avoided; the invention has simple preparation process, conventional package and convenient operation, and can realize large-scale industrial production.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a stable sodium thiosulfate high-capacity injection and a preparation method thereof.
Background
The sodium thiosulfate injection is an aqueous solution obtained by mixing sodium thiosulfate with an injection liquid. Sodium thiosulfate injection, which is currently marketed, is used as an antidote for treating cyanide poisoning, as well as arsenic, mercury, lead, bismuth, iodine poisoning. In addition, the traditional Chinese medicine composition is also used for treating skin pruritus, chronic dermatitis, chronic urticaria, drug eruptions, scabies, tinea and the like, and has wide clinical application.
The sodium thiosulfate injection has large clinical dosage, for example, the sodium thiosulfate injection is applied to cyanide poisoning of adults, and is slowly and statically injected for 12.5-25 g, and half or full dose can be repeated after 1 hour if necessary. The standard dosage approved to be marketed at present is smaller, for example, 0.32g of powder for injection and 10ml of water for injection: 0.5g;20ml:1g, etc., and a plurality of products are required to be dissolved or mixed by adding a diluent in clinical use, so that the operation steps are complicated, the precious administration rescuing time is delayed, and the first aid of a poisoning patient is not facilitated. Compared with small injection, in order to facilitate clinical administration and prevent secondary pollution during dosage, it is necessary to directly use large-capacity sodium thiosulfate injection.
In addition, the aqueous solution of sodium thiosulfate is unstable and easy to oxidize, and is easy to degrade after high-temperature sterilization, insoluble particles are increased in the preparation and storage processes of the product, so that small white lumps or precipitates can appear, the problem of visible foreign matters exists, and certain potential safety hazards exist. The prior art avoids oxidation by adding an antioxidant, but the injection is added with an antioxidant with conventional concentration, such as sodium sulfite and the like, which can generate allergic reaction in human bodies, sometimes generate serious side effects, and can have life-threatening complications for asthmatics sensitive to sulfite. Therefore, development of a large-capacity sodium thiosulfate injection with good stability is a target pursued in the field.
Patent CN114848597A develops a powder-liquid separation process by a non-terminal sterilization process, and the sodium thiosulfate injection is packaged by a ready-to-use double-chamber bag. However, before clinical use, the technical scheme needs to be prepared at present, is inconvenient to operate and delay in time, is a large-capacity non-terminal sterilization injection, has low sterility assurance level, and is difficult to obtain approval according to the existing evaluation technical requirements of the national drug administration.
Patent CN 112805014A mentions a sodium thiosulfate formulation for injection sterilized at 121 ℃ for 0.5h in a glass bottle package, and the patent does not give the detection results of each quality index after 121 ℃ for 0.5h, and cannot prove the stability; and the formulation is sterilized at 121 ℃ for 0.5h, the pH value of the liquid medicine is 8.6-8.8, the glass bottle package is very easy to corrode, and the formulation is very likely to be unstable during preparation and long-term storage, the insoluble particles are increased, visible foreign matters appear, and potential safety hazards exist like glass package samples on the market.
The existing sodium thiosulfate injection still has the problems of low safety, low stability and poor quality, and the preparation of the sodium thiosulfate high-capacity injection with low impurity content, high stability and high safety is a technical problem which needs to be solved by the force of technicians in the field.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a stable sodium thiosulfate high-capacity injection and a preparation method thereof, and the product has few insoluble particles, no visible foreign matters and high safety in the preparation and storage processes; the injection can be directly used without secondary preparation, does not contain an antioxidant, has good sterilization stability, ensures high sterile level, meets the requirement of drug registration regulations on quality, and is suitable for industrial production.
In order to achieve the above purpose, the present invention provides the following technical solutions:
A stable sodium thiosulfate high-capacity injection contains 10-70 g of sodium thiosulfate, 150-1000 mg of chloride, 100-600 mg of pH buffering agent, a proper amount of pH regulator and a proper amount of water for injection, and the pH value is 7.5-8.4, and the injection is prepared into 50-200 mL.
Furthermore, the injection does not contain an antioxidant.
In a preferred embodiment of the present invention, the sodium thiosulfate high-capacity injection comprises 12.5g of sodium thiosulfate, 220mg of chloride, 140mg of pH buffering agent, a proper amount of pH regulator and a proper amount of water for injection, wherein the pH value is 7.5-8.4, and the total amount of the injection is 50mL.
In a preferred scheme of the invention, the sodium thiosulfate high-capacity injection comprises 25g of sodium thiosulfate, 440mg of chloride, 280mg of pH buffering agent, a proper amount of pH regulator and a proper amount of water for injection, wherein the pH value is 7.5-8.4, and the total injection is prepared into 100mL.
In a preferred embodiment of the present invention, the sodium thiosulfate high-capacity injection comprises 50g of sodium thiosulfate, 880mg of chloride, 560mg of pH buffer, a proper amount of pH regulator and a proper amount of water for injection, wherein the pH value is 7.5-8.4, and the injection is prepared into 200mL.
The high-dose sodium thiosulfate high-capacity injection provided by the invention has the concentration of about 25% (w/w), the volume specification of 50mL, 100mL and 200mL, and can repeat half or full dose after 1 hour if necessary, thereby being more in line with clinical dosage, only needing 1 bottle of liquid medicine each time, avoiding complicated preparation and dissolution process, reducing the risk of puncture falling scraps, being beneficial to emergency treatment of poisoning patients, and avoiding pollution caused by secondary preparation.
In a preferred embodiment of the invention, the chloride salt is selected from sodium chloride or potassium chloride, preferably potassium chloride;
the pH buffer is at least one selected from acetate buffer, phosphate buffer, boric acid and sodium hydroxide buffer, preferably boric acid or sodium hydroxide buffer.
In a preferred embodiment of the present invention, the pH adjustor is selected from one of sodium hydroxide, sodium bicarbonate, sodium citrate, sodium tartrate, and sodium acetate, preferably sodium hydroxide.
The invention also provides a preparation method of the sodium thiosulfate high-capacity injection, which comprises the following steps:
(1) Boiling water for injection, and blowing inert gas into a liquid preparation tank to enable the dissolved oxygen of the water for injection to be within 0.5 ppm;
(2) Cooling to 30-60 deg.c, adding pH buffering agent and chloride salt, dissolving, regulating pH value to 7.8-8.7 with pH regulator, and adding sodium thiosulfate;
(3) And (3) after the pH value is adjusted to 7.5-8.4 by using a pH regulator, the volume is fixed by using water for injection, and the water for injection is obtained through filtration, encapsulation and high-temperature damp-heat sterilization.
The invention boils the water for injection, which can reduce the oxygen content in the solution to improve the stability of the product. The pH value of the injection is 7.5-8.4, and the glass bottle package is not easy to erode in the pH value range, so that the stability in the long-term storage process is ensured.
In a preferred embodiment of the present invention, the inert gas is selected from nitrogen, argon, helium or carbon dioxide.
In a preferred embodiment of the invention, a filter cartridge of 0.45 μm and 0.22 μm is used in sequence for filtration.
In a preferred scheme of the invention, the specific method for encapsulating is as follows: filling the mixture into a transfusion bag or a transfusion bottle, adding an outer bag with a high barrier air function, filling nitrogen into the top space to control residual oxygen to be within 0-5%, and sealing in a melting way;
Further, the Gao Wenshi heat sterilization conditions are: under the condition that the high-capacity injection is feasible at 121 ℃ for 8-30 min, the invention firstly kills the injection excessively at 121 ℃ for 12min.
The inner packaging material of the infusion bag or the infusion bottle is a plastic infusion bag or a polymer plastic bottle, and is further a three-layer co-extrusion infusion bag or other polymer plastic bottles made of polypropylene; the "other" means a polymer other than polypropylene.
The outer bag with the high air-blocking function is a composite film bag or an aluminum plastic film bag, and the outer bag material of the composite film bag is at least one selected from PET, PA, CPP, PE.
In order to reduce the contact between the sodium thiosulfate injection and the air and improve the stability of the sodium thiosulfate injection, the inner packaging bag and the outer bag are vacuum-packed.
Compared with the prior art, the invention has the beneficial effects that:
1. the sodium thiosulfate injection provided by the invention has the advantages that the dosage is large, the specification is large, only 1 bottle of liquid medicine is needed each time, the risk of puncture and chip falling is reduced, the injection can be directly used without being prepared by nurses, the burden of nurses is lightened, and the injection is beneficial to emergency treatment of poisoning patients; and simultaneously, the pollution generated by secondary preparation is avoided.
2. The sodium thiosulfate injection adopts a proper oxygen control process, and a sulfite antioxidant is not added, so that anaphylactic reaction and side effects brought by sulfite to a human body are avoided, and the quality and safety of the product are improved; meanwhile, unexpected effects are obtained, and the sulfide level of the sterilized product is greatly reduced; the plastic package is used, so that the problems of increased insoluble particles and easy generation of small white blocks in the preparation process and the long-term placement process of the product are avoided, the clinical medication safety of the product is ensured, and the accelerated test proves that the quality indexes of sodium thiosulfate content, sodium sulfate content, elemental sulfur content, sulfide and the like are not greatly different after the product is placed for 6 months at 40 ℃ and all meet the regulations.
3. The sodium thiosulfate injection adopts a terminal sterilization process, and the sterility assurance level is high.
4. The sodium thiosulfate injection disclosed by the invention is simple in preparation process, conventional in package and convenient to operate, meets the requirements of drug registration regulations, and can realize large-scale industrial production.
Detailed Description
The invention will be further described by the following examples for the purpose of more clearly and specifically describing the object of the invention. The following examples are only for specific illustration of the implementation method of the present invention and do not limit the protection scope of the present invention.
Example 1
The prescription of the sodium thiosulfate injection of the invention is as follows:
| The components | Dosage of |
| Sodium thiosulfate | 12.5g |
| Potassium chloride | 220mg |
| Boric acid | 140mg |
| Sodium hydroxide | Proper amount of |
| Water for injection | 50mL |
The preparation process comprises the following steps:
Adding water for injection with 90% of the total water content of the prescription into a liquid preparation tank, heating and boiling for 10min, vacuumizing the head space, filling nitrogen for 3 times, and then filling nitrogen for maintenance, wherein the dissolved oxygen is controlled to be less than or equal to 0.5ppm. Cooling to 30-60 ℃, adding the prescribed amount of potassium chloride and boric acid, stirring and dissolving, adjusting the pH value to 7.8-8.7 by sodium hydroxide, and then adding sodium thiosulfate for dissolving. And regulating the pH value to 7.5-8.4 by using sodium hydroxide, and adding a small amount of water for injection to fix the volume. The liquid medicine is filtered by a 0.45 mu m filter core and a 0.22 mu m filter core, is filled in a polypropylene three-layer co-extrusion transfusion bag, and is sealed by filling nitrogen into the top space to control residual oxygen within 0-5 percent. An outer bag with high oxygen and carbon dioxide barrier function is additionally arranged, and the wet heat sterilization is carried out for 12min at 121 ℃.
Example 2
The prescription of the sodium thiosulfate injection of the invention is as follows:
| The components | Dosage of |
| Sodium thiosulfate | 25.0g |
| Potassium chloride | 440mg |
| Boric acid | 280mg |
| Sodium hydroxide | Proper amount of |
| Water for injection | 100mL |
The preparation process comprises the following steps:
Adding water for injection with 90% of the total water content of the prescription into a liquid preparation tank, heating and boiling for 10min, vacuumizing the head space, filling nitrogen for 3 times, and then filling nitrogen for maintenance, wherein the dissolved oxygen is controlled to be less than or equal to 0.5ppm. Cooling to 30-60 ℃, adding the prescribed amount of potassium chloride and boric acid, stirring and dissolving, adjusting the pH value to 7.8-8.7 by sodium hydroxide, and then adding sodium thiosulfate for dissolving. And regulating the pH value to 7.5-8.4 by using sodium hydroxide, and adding a small amount of water for injection to fix the volume. Filtering the liquid medicine by a 0.45 mu m filter core and a 0.22 mu m filter core, filling the liquid medicine into a polymer plastic bottle, filling nitrogen into the headspace to control residual oxygen to be within 0-5%, and sealing by a plug. An outer bag with high oxygen and carbon dioxide barrier function is additionally arranged, and the wet heat sterilization is carried out for 12min at 121 ℃.
Example 3
The prescription of the sodium thiosulfate injection of the invention is as follows:
| The components | Dosage of |
| Sodium thiosulfate | 50.0g |
| Potassium chloride | 880mg |
| Boric acid | 560mg |
| Sodium hydroxide | Proper amount of |
| Water for injection | 200ml |
The preparation process comprises the following steps:
Adding water for injection with 90% of the total water content of the prescription into a liquid preparation tank, heating and boiling for 10min, vacuumizing the head space, filling nitrogen for 3 times, and then filling nitrogen for maintenance, wherein the dissolved oxygen is controlled to be less than or equal to 0.5ppm. Cooling to 30-60 ℃, adding the prescribed amount of potassium chloride and boric acid, stirring and dissolving, adjusting the pH value to 7.8-8.7 by sodium hydroxide, and then adding sodium thiosulfate for dissolving. And regulating the pH value to 7.5-8.4 by using sodium hydroxide, and adding a small amount of water for injection to fix the volume. Filtering the liquid medicine by a 0.45 mu m filter core and a 0.22 mu m filter core, filling the liquid medicine into a polymer plastic bottle, filling nitrogen into the headspace to control residual oxygen to be within 0-5%, and sealing by a plug. An outer bag with high oxygen and carbon dioxide barrier function is additionally arranged, and the wet heat sterilization is carried out for 12min at 121 ℃.
Test example 1 sodium thiosulfate injection sample detection
The invention relates to a key quality index detection method, which is characterized by the following experimental examples:
(1) Determination of sodium thiosulfate content: precisely measuring the proper amount of the product (about equivalent to 0.5g of sodium thiosulfate), adding 20ml of water and 2ml of acetone, standing for 5 minutes, adding 2ml of dilute acetic acid and 2ml of starch indicator liquid, and titrating with iodine titration solution (0.05 mol/L) until the solution shows a continuous blue color. Each 1ml of iodine titration solution (0.05 mol/L) corresponds to 24.82mg of Na 2S2O3·5H2 O.
(2) And (3) measuring the sulfate content: taking 0.50g of the product, placing the product into a 50ml measuring flask, adding water for dissolving and diluting to a scale, precisely measuring 5ml, dropwise adding iodine titration solution (0.05 mol/L) until the solution is light yellow, adding 0.5ml of 10% hydrochloric acid solution, adding 1 drop of sodium thiosulfate titration solution (0.2 mol/L) to fade the yellow of the solution, diluting the solution to 25ml with water, and performing legal inspection (Chinese pharmacopoeia 2020 edition four general rule 0802), wherein the solution cannot be deeper (0.2%) compared with a control solution prepared from 5.0ml of standard potassium sulfate solution.
(3) Sulfide content determination: taking 2.5g of the product, adding 20ml of water to dissolve, adding 0.3ml of lead acetate solution (taking 5g of lead acetate and 15g of sodium hydroxide, adding 80ml of water to dissolve, diluting with water to 100 ml), shaking uniformly, standing for 2 minutes, and not making the product deeper than a control solution prepared from 2.5ml of standard sodium sulfide solution.
(4) Sulfur content determination: the measurement is carried out by high performance liquid chromatography (China pharmacopoeia 2020 edition, four-part rule 0512).
Taking 10ml of sample solution, precisely adding 20ml of ethyl acetate, shaking, standing to separate layers, and taking ethyl acetate layer.
The reference substance solution is taken to be a proper amount of sulfur reference substance, precisely weighed, dissolved and diluted by ethyl acetate to prepare a solution containing about 5 mug in each 1ml, precisely measured to be 2.5ml, precisely added with 2.5ml of water, shaken for 1 minute, stood for layering, and the ethyl acetate layer is separated.
The chromatographic conditions used octadecylsilane chemically bonded silica as the filler (4.6 mm. Times.100 mm, or column with equivalent performance), methanol as the mobile phase, and the flow rate was 0.8ml per minute; the column temperature is 30 ℃; the detection wavelength is 240nm; sample volume 10. Mu.l; the temperature of the sample pan was 4 ℃.
The measuring method precisely measures the solution of the sample and the solution of the reference substance, respectively injects the solution into a liquid chromatograph, and records the chromatograms.
(5) Methylene blue staining test method: preparing 0.5% (w/w) methylene blue aqueous solution, pouring out the sample solution, carefully pouring in water and pouring out again (taking care not to rinse) until the sample solution is cleaned, then adding 5ml of 0.5% methylene blue solution into each of the sample solutions by a pipette, standing for 20min, pouring out again (taking care not to rinse) by carefully pouring in water, and repeating for ten times until the blue color on the inner surface of the glass is not changed. The wall built-up of methylene blue on the inner surface of the glass was observed visually.
(6) The scanning electron microscope observation test method comprises the following steps: pouring out the liquid medicine in the sample, cutting the bottle body (the part contacted with the solution) to prepare a rectangular sample with the side length of about 5mm, cleaning the inner surface of the glass bottle by pure water, airing, preparing the blank sample by the same method as an empty bottle without the medicine packaged, performing metal spraying treatment, observing the appearance of the inner surface by using a tungsten wire emission scanning electron microscope, and photographing and recording. Instrument scanning electron microscope: phenom-world ProX scanning electron microscope; metal spraying instrument: the ion sputtering instrument of Zhongke KYKY SBC-12.
(7) The elemental impurity detection test method comprises the following steps: taking 1 bottle of the injection, precisely measuring 2.5mL of the liquid medicine, adding the liquid medicine into a 25mL volumetric flask, fixing the volume to the scale by using 1% nitric acid, and detecting by adopting ICP-MS. Inductively coupled plasma mass spectrometer: PERKINELMER NEXION 350D.
(8) Insoluble particles and visible foreign matter: insoluble particle detection is described in "Chinese pharmacopoeia" (2020 edition) insoluble particle examination method (general rule 0903); visible foreign matter detection refers to the Chinese pharmacopoeia (2020 edition) -visible foreign matter inspection method (general rule 0904).
1. Screening experiment of oxygen control process
Sample 1: the preparation process comprises the following steps of: adding water for injection with 90% of the total water content of the prescription into a liquid preparation tank, heating and boiling for 10min, vacuumizing the head space, filling nitrogen for 3 times, and then filling nitrogen for maintenance, wherein the dissolved oxygen is controlled to be less than or equal to 0.5ppm. Cooling to 30-60 ℃, adding the prescribed amount of potassium chloride, boric acid and sodium sulfite, stirring and dissolving, adjusting the pH value to 7.8-8.7 by sodium hydroxide, and then adding sodium thiosulfate for dissolving. And regulating the pH value to 7.5-8.4 by using sodium hydroxide, and adding a small amount of water for injection to fix the volume. Filtering the liquid medicine by a 0.45 mu m filter core and a 0.22 mu m filter core, filling the liquid medicine in a borosilicate glass bottle, filling nitrogen into the headspace to control residual oxygen to be within 0-5%, and plugging and capping. Sterilizing with heat and humidity at 121deg.C for 12min.
Sample 2: according to the prescription of the example 1, the preparation process comprises the following steps: adding water for injection with 90% of the total water content of the prescription into a liquid preparation tank, cooling to 30-60 ℃, adding potassium chloride and boric acid with the prescribed amount, stirring and dissolving, adjusting the pH value to 7.8-8.7 by sodium hydroxide, and then adding sodium thiosulfate for dissolving. And regulating the pH value to 7.5-8.4 by using sodium hydroxide, and adding a small amount of water for injection to fix the volume. The liquid medicine is filtered by a 0.45 mu m filter core and a 0.22 mu m filter core, filled in a borosilicate glass bottle, and plugged and capped. Sterilizing with heat and humidity at 121deg.C for 12min.
Samples 3, 4, 5: adding water for injection with 90% of the total water in the prescription into the liquid preparation tank, filling nitrogen for 10-30 min, vacuumizing the headspace, filling nitrogen for 3 times, maintaining the nitrogen, and controlling the dissolved oxygen to be less than or equal to 0.5ppm. Cooling to 30-60 ℃, adding the prescribed amount of potassium chloride and boric acid, stirring and dissolving, adjusting the pH value to 7.8-8.7 by sodium hydroxide, and then adding sodium thiosulfate for dissolving. And regulating the pH value to 7.5-8.4 by using sodium hydroxide, and adding a small amount of water for injection to fix the volume. The liquid medicine is filtered by a 0.45 mu m filter core and a 0.22 mu m filter core, and is filled in a borosilicate glass bottle, and the residual oxygen is respectively controlled to be 10.0%, 5.0% and 1.0% by filling nitrogen in the headspace, and the samples respectively correspond to samples 3, 4 and 5, and a plug is covered by rolling. Sterilizing with heat and humidity at 121deg.C for 12min.
And 6, adding water for injection with 90% of the total water content of the prescription into a liquid preparation tank, heating and boiling for 10-30 min, vacuumizing and filling nitrogen into the head space for 3 times, and filling nitrogen for maintenance, wherein the dissolved oxygen is controlled to be less than or equal to 0.5ppm. Cooling to 30-60 ℃, adding the prescribed amount of potassium chloride and boric acid, stirring and dissolving, adjusting the pH value to 7.8-8.7 by sodium hydroxide, and then adding sodium thiosulfate for dissolving. And regulating the pH value to 7.5-8.4 by using sodium hydroxide, and adding a small amount of water for injection to fix the volume. Filtering the liquid medicine by a 0.45 mu m filter core and a 0.22 mu m filter core, filling the liquid medicine in a borosilicate glass bottle, filling nitrogen into the headspace to control residual oxygen to be within 0-5%, and plugging and capping. Sterilizing with heat and humidity at 121deg.C for 12min.
And (3) screening the samples subjected to sterilization by the different oxygen control processes, examining the detection indexes below, and examining and comparing the results as follows.
TABLE 1 screening test results of different oxygen control technologies
From the above results, it is clear that the sodium sulfite as an antioxidant is added to sample 1, the prescription components are increased, the toxic and side effects possibly caused by adding the antioxidant with the conventional concentration to the injection cannot be avoided, and the patients with asthma sensitive to sulfite may have life-threatening complications.
Sulfide is a strong neurotoxin and has strong irritation to mucous membrane. The conventional oxygen control process researches of the samples 2, 3, 4 and 5 with different levels of oxygen control and nitrogen filling are carried out, and the results show that the sample 2 has no oxygen control, the sodium thiosulfate content can be reduced, the sulfide of the samples with different nitrogen filling and oxygen control can not be qualified, and the two cannot be taken into consideration. Through a great deal of experimental study, the inventor unexpectedly discovers that better results can be obtained by controlling the dissolved oxygen according to the boiling control of the sample 6 and the nitrogen filling of the headspace at a certain level. Therefore, the invention preferably adopts the steps of boiling the liquid medicine to remove oxygen and charging nitrogen to control the headspace oxygen to be about 0 to 5 percent.
2. Stability investigation under different sterilization conditions
Screening study (100 mL specification) is carried out according to the prescription process of sample 6, and the sample is tested 0 days after sterilization and the sample is accelerated for 3 months at 40 ℃. The detection indexes of sodium thiosulfate content, related substance content, sulfide content and the like of samples under different sterilization conditions for 0 days have no obvious difference from those of non-sterilized samples, and are qualified. However, the sample accelerated at 40 ℃ for 6 months showed a difference between insoluble particles and visible foreign matters, and the accelerated test results were as follows:
TABLE 2 examination of different sterilization conditions
The result shows that under different sterilization conditions of the glass bottle package, insoluble particles are increased in the accelerated placing process, and visible foreign matters appear, so that the product is disqualified. The longer and more severe the high temperature sterilization conditions, the more insoluble particles increase and the poorer the product quality.
3. Screening and comparing experiment for different packing materials
The inner packaging material adopts borosilicate glass bottle, plastic bottle (with barrier outer bag), transfusion soft bag (with barrier outer bag), and the liquid medicine is prepared according to the prescription process of sample 6 in test example 1, 100mL of the inner packaging material is filled, and each bottle is subjected to heat sterilization at 121 ℃ for 12 min. A sample-retaining investigation was carried out with reference to a sodium thiosulfate injection (borosilicate glass ampoule) sample (indicated by sample 7 in the table) in patent CN114848597 a.
The key quality index related to the pharmaceutical quality index and the package compatibility of the sample accelerated for 6 months at 40 ℃ is detected, and the results are shown in the following table:
TABLE 3 results of pharmaceutical Critical quality index study on different package samples
TABLE 4 Experimental results of compatibility of different samples
In the aspect of key indexes of pharmaceutical research, after accelerating for 6 months at 40 ℃, the content of sodium thiosulfate in the commercial glass ampoule packaged sodium thiosulfate injection is obviously reduced, the content of sulfur simple substances, sodium sulfate and other impurities are obviously increased, insoluble particles are increased, and visible foreign matters appear.
After the process is adopted, compared with borosilicate glass packaging samples, plastic bottles (with a barrier outer bag) and transfusion soft bags (with a barrier outer bag) are used for packaging sterilized samples, after the samples are placed for 6 months at the accelerated temperature of 40 ℃, the quality indexes of sodium thiosulfate content, sodium sulfate content, elemental sulfur content, sulfide and the like are not greatly different, and all meet the regulations; it was surprisingly found that the plastic packaged sterilized samples were not only significantly better than borosilicate glass sterilized samples in terms of insoluble particles, but also did not exhibit small white spots and the like as visible foreign matter, and the product quality was significantly better than glass bottles and glass ampoule packaged sterilized samples.
Regarding relevant key indexes of package material compatibility research, commercial glass ampoule packages and borosilicate glass packages are used for sterilizing samples, the inner surface of the package material has blue wall hanging phenomenon after being dyed with methylene blue, the inner surface is not smooth or has obvious corrosion phenomenon when observed by an electron microscope, and the elemental impurities Si and Al are also at very high level, so that potential safety hazards exist. The plastic bottle (with the barrier outer bag) and the transfusion soft bag (with the barrier outer bag) are adopted to package the sterilization sample, so that various indexes are normal, and the compatibility of the packaging materials is good.
In conclusion, the sodium thiosulfate high-capacity injection product provided by the invention has few insoluble particles, no visible foreign matters and high safety in the preparation and storage processes; the injection can be directly used without being prepared by nurses, does not contain an antioxidant, has good sterilization stability, high sterility assurance level and very good clinical application prospect.
Finally, it should be noted that the foregoing description is only an example of the present application, and is merely for illustrating the technical solution of the present application, not for limiting the present application. Various modifications and variations of the present application will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the application are to be included in the scope of the claims of the present application.
Claims (10)
1. The stable sodium thiosulfate high-capacity injection is characterized by comprising 10-70 g of sodium thiosulfate, 150-1000 mg of chloride, 100-600 mg of pH buffering agent, a proper amount of pH regulator and a proper amount of water for injection, wherein the pH value is 7.5-8.4, and the injection is prepared into 50-200 mL.
2. The high-capacity sodium thiosulfate injection according to claim 1, wherein the injection contains 12.5g of sodium thiosulfate, 220mg of chloride, 140mg of pH buffering agent, an appropriate amount of pH regulator and an appropriate amount of water for injection, and the pH value is 7.5-8.4, and the total amount of the injection is 50mL.
3. The high-capacity sodium thiosulfate injection according to claim 1, wherein the injection contains 25g of sodium thiosulfate, 440mg of chloride, 280mg of pH buffering agent, an appropriate amount of pH regulator and an appropriate amount of water for injection, and has a pH value of 7.5-8.4, and is prepared to be 100mL.
4. The high-capacity sodium thiosulfate injection according to claim 1, wherein the injection contains 50g of sodium thiosulfate, 880mg of chloride, 560mg of pH buffering agent, an appropriate amount of pH regulator and an appropriate amount of water for injection, and has a pH value of 7.5-8.4, and is prepared into 200mL.
5. The high volume injection of sodium thiosulfate of any one of claims 1 to 4, wherein the chloride salt is selected from sodium chloride or potassium chloride, preferably potassium chloride;
the pH buffer is at least one selected from acetate buffer, phosphate buffer, boric acid and sodium hydroxide buffer, preferably boric acid or sodium hydroxide buffer.
6. The high volume injection of sodium thiosulfate of any one of claims 1 to4, wherein the pH modifier is selected from one of sodium hydroxide, sodium bicarbonate, sodium citrate, sodium tartrate, sodium acetate, preferably sodium hydroxide.
7. The method for preparing the sodium thiosulfate high-capacity injection as claimed in any one of claims 1 to 6, which is characterized by comprising the following steps:
(1) Boiling water for injection, and blowing inert gas into a liquid preparation tank to enable the dissolved oxygen of the water for injection to be within 0.5 ppm;
(2) Cooling to 30-60 deg.c, adding pH buffering agent and chloride salt, dissolving, regulating pH value to 7.8-8.7 with pH regulator, and adding sodium thiosulfate;
(3) And (3) after the pH value is adjusted to 7.5-8.4 by using a pH regulator, the volume is fixed by using water for injection, and the water for injection is obtained through filtration, encapsulation and high-temperature damp-heat sterilization.
8. The method of claim 7, wherein the inert gas is selected from nitrogen, argon, helium, or carbon dioxide.
9. The method of claim 7, wherein the filtration is performed sequentially with 0.45 μm and 0.22 μm cartridges.
10. The preparation method according to claim 7, wherein the specific method of encapsulation is as follows: filling the mixture into a transfusion bag or a transfusion bottle, adding an outer bag with a high barrier air function, filling nitrogen into the top space to control residual oxygen to be within 0-5%, and sealing in a melting way;
Further, the Gao Wenshi heat sterilization conditions are: 121 ℃, 8-30 min, and further 121 ℃ for 12min.
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