CN113456598B - Sodium gluconate freeze-dried powder injection and preparation method thereof - Google Patents
Sodium gluconate freeze-dried powder injection and preparation method thereof Download PDFInfo
- Publication number
- CN113456598B CN113456598B CN202010253666.3A CN202010253666A CN113456598B CN 113456598 B CN113456598 B CN 113456598B CN 202010253666 A CN202010253666 A CN 202010253666A CN 113456598 B CN113456598 B CN 113456598B
- Authority
- CN
- China
- Prior art keywords
- freeze
- temperature
- shelf
- sodium
- drying
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002347 injection Methods 0.000 title claims abstract description 23
- 239000007924 injection Substances 0.000 title claims abstract description 23
- 239000000843 powder Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 13
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 title abstract description 7
- 239000000176 sodium gluconate Substances 0.000 title abstract description 7
- 229940005574 sodium gluconate Drugs 0.000 title abstract description 7
- 235000012207 sodium gluconate Nutrition 0.000 title abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000004108 freeze drying Methods 0.000 claims abstract description 37
- 238000003756 stirring Methods 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 24
- 239000011734 sodium Substances 0.000 claims abstract description 24
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 24
- 238000011049 filling Methods 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 239000000243 solution Substances 0.000 claims abstract description 17
- 239000008215 water for injection Substances 0.000 claims abstract description 17
- 229920002370 Sugammadex Polymers 0.000 claims abstract description 15
- WHRODDIHRRDWEW-VTHZAVIASA-N sugammadex Chemical compound O([C@@H]([C@@H]([C@H]1O)O)O[C@H]2[C@H](O)[C@H]([C@@H](O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O3)O[C@@H]2CSCCC(O)=O)O)[C@H](CSCCC(O)=O)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H]3[C@@H](CSCCC(O)=O)O1 WHRODDIHRRDWEW-VTHZAVIASA-N 0.000 claims abstract description 15
- 229960002257 sugammadex Drugs 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 10
- UNHKSXOTUHOTAB-UHFFFAOYSA-N sodium;sulfane Chemical compound [Na].S UNHKSXOTUHOTAB-UHFFFAOYSA-N 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 238000002474 experimental method Methods 0.000 claims description 32
- 238000010438 heat treatment Methods 0.000 claims description 31
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 18
- 229930195725 Mannitol Natural products 0.000 claims description 18
- 239000000594 mannitol Substances 0.000 claims description 18
- 235000010355 mannitol Nutrition 0.000 claims description 18
- 229930182555 Penicillin Natural products 0.000 claims description 17
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 17
- 229940049954 penicillin Drugs 0.000 claims description 17
- 239000003223 protective agent Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 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 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000000859 sublimation Methods 0.000 claims description 2
- 230000008022 sublimation Effects 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims 1
- 230000008014 freezing Effects 0.000 claims 1
- 238000012792 lyophilization process Methods 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 abstract description 6
- 239000001301 oxygen Substances 0.000 abstract description 6
- 230000001954 sterilising effect Effects 0.000 abstract description 5
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 5
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000011261 inert gas Substances 0.000 abstract description 3
- 239000002245 particle Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000005303 weighing Methods 0.000 description 28
- KSVSZLXDULFGDQ-UHFFFAOYSA-M sodium;4-aminobenzenesulfonate Chemical compound [Na+].NC1=CC=C(S([O-])(=O)=O)C=C1 KSVSZLXDULFGDQ-UHFFFAOYSA-M 0.000 description 16
- 238000007599 discharging Methods 0.000 description 14
- 230000002441 reversible effect Effects 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 4
- 230000002232 neuromuscular Effects 0.000 description 4
- 229960003682 rocuronium bromide Drugs 0.000 description 4
- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003158 myorelaxant agent Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 229960004298 vecuronium bromide Drugs 0.000 description 3
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 description 3
- 239000004115 Sodium Silicate Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 2
- 229910052911 sodium silicate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- -1 2-carboxyl ethyl Chemical group 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- NDDAQHROMJDMKS-XFYXLWKMSA-N [(2s,3s,5s,8r,9s,10s,13s,14s)-2-hydroxy-10,13-dimethyl-17-oxo-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-3-yl]azanium;chloride Chemical compound Cl.C1[C@H](N)[C@@H](O)C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 NDDAQHROMJDMKS-XFYXLWKMSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- KMGKABOMYQLLDJ-VKHHSAQNSA-F sugammadex sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O([C@@H]([C@@H]([C@H]1O)O)O[C@H]2[C@H](O)[C@H]([C@@H](O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O3)O[C@@H]2CSCCC([O-])=O)O)[C@H](CSCCC([O-])=O)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H]3[C@@H](CSCCC([O-])=O)O1 KMGKABOMYQLLDJ-VKHHSAQNSA-F 0.000 description 1
- 229940041622 sugammadex sodium Drugs 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- 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
- A61K47/26—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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Inorganic Chemistry (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a sodium gluconate freeze-dried powder injection and a preparation method thereof; the preparation method of the sodium sugammadex freeze-dried powder injection comprises the following steps: adding sodium sulfan into water for injection, and stirring to dissolve completely; adding the freeze-drying protection with the prescription amount into the solution, stirring until the solution is completely dissolved, adjusting the pH, stirring, filtering, filling, and freeze-drying to obtain the target; the method provides a sodium suger freeze-dried powder injection for injection, which solves the problems that the API is unstable as a ring-shaped molecular structure and a large amount of impurities are easy to generate after high-temperature sterilization; the freeze-drying is finished, and inert gas (nitrogen) is filled for protection, so that oxygen is effectively isolated, and the prepared sodium gluconate freeze-dried powder injection has fewer impurities and is more stable; the freeze-dried powder prepared by optimizing the freeze-drying process has the shortest re-dissolution time, and both clarity and insoluble particles meet the requirements, so that the freeze-dried powder has higher stability and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a sodium gluconate freeze-dried powder injection and a preparation method thereof.
Background
Sodium supreme (Sugammadex Sodium) was first developed by Organon Biosciences (the company of euganong), and in 2008, sodium supreme was first marketed in europe and then in japan, the united states, etc., respectively, and has been marketed in 75 countries.
Sodium supreme glucose, chemical name of 6-full deoxidized-6-full (2-carboxyl ethyl) thio-gamma-cyclodextrin sodium salt, is a modified gamma-cyclodextrin; is the first and only selective muscle relaxant (SRBA) which can block the relaxation effect by wrapping an amino steroid non-depolarizing muscle relaxant in a brand new and unique way, can quickly predictably reverse the relaxation of any strength caused by rocuronium bromide and vecuronium bromide, has smaller side effect, can lead the use of the muscle relaxant to be close to an ideal state, and has quicker and more predictably reverse neuromuscular blocking effect than the prior medicine. Is suitable for reversing the neuromuscular blocking effect caused by rocuronium bromide or vecuronium bromide, and can reverse (conventional reverse and immediate reverse) the neuromuscular blocking effect caused by adult rocuronium bromide or vecuronium bromide and the neuromuscular blocking effect caused by conventional reverse child and teenager rocuronium bromide. The chemical formula is as follows:
the research shows that oxygen is a protective agent for carbon-sulfur bonds in the high-temperature sterilization process, and the degradation impurity amount of RRT=2.04 generated by carbon-sulfur bonds after high-temperature sterilization of sodium gluconate injection under the aerobic condition is less; under the condition of no oxygen or lower oxygen concentration, the sodium sulmore injection is subjected to high-temperature sterilization, and the carbon-sulfur bond generates sulfhydryl groups to generate RRT=2.04, so that the degradation impurity amount is more and seriously exceeds the quality standard control range. In addition, sodium sulmore is sensitive to oxygen after being prepared into injection, and oxidation reaction is easy to occur in an aerobic solution environment to generate oxidation impurities of sulfone isomers RRT=0.45 and RRT=0.59 with the numbers of Org198958-2 and Org199425-1 respectively. Thus, it is very interesting to prepare a preparation with high stability which can be placed for a long period of time.
Aiming at the problems existing in the prior art, the invention aims to provide a quality-controllable sodium sugammadex preparation and a preparation method thereof, which mainly prepare the sodium sugammadex preparation into sterile freeze-dried powder injection, namely sodium sugammadex for injection. The research shows that mannitol is used as freeze-drying excipient, the grain diameter of the sodium silicate is controlled, a proper amount of pH regulator is added, the freeze-drying curve is optimized, the freeze-drying is finished, nitrogen is filled for protection, the quality of the prepared sodium silicate freeze-dried powder is far lower than that of a reference preparation, the clarity meets the requirement, and the quality is stable in the long-term storage process.
Disclosure of Invention
The invention aims to prepare a sodium sulfanilate powder injection, which solves the problems of preparation process and long-term storage stability of sodium sulfanilate.
The freeze-dried sodium sugammadex powder injection is characterized by comprising sodium sugammadex, a freeze-drying protective agent and a pH regulator.
Preferably, the lyoprotectant can be one or a combination of mannitol, lactose, dextran and povidone.
Preferably, the lyoprotectant is mannitol.
Preferably, the mass ratio of the sodium sugammadex to the lyoprotectant is 1:0.1 to 2.
Preferably, the mass ratio of the sodium sugammadex to the lyoprotectant is preferably 1:0.3 to 1, wherein further preferable is 1:0.65.
preferably, the pH regulator is selected from one or a combination of 0.1N hydrochloric acid solution, 0.1M tartaric acid solution, 0.1N acetic acid solution, 0.2M lactic acid solution and 0.1N malic acid solution.
Preferably, the pH regulator is preferably a 0.1N hydrochloric acid solution.
The specific preparation method of the invention comprises the following steps:
adding sodium sulfan into water for injection, and stirring to dissolve completely; adding a prescribed amount of freeze-drying protective agent into the solution, and stirring until the freeze-drying protective agent is completely dissolved; regulating pH with pH regulator, stirring, filtering, filling the filtrate into penicillin bottle, half-plugging, and freeze-drying in freeze-drying box.
Preferably, the pH adjustment range is 7.1 to 8.0.
The filling subsequent procedures are as follows:
filling the filtered filtrate into a penicillin bottle, half-plugging, and putting into a freeze-drying box; (1) prefreezing: placing the sample into a freeze dryer after the temperature of the plate layer is reduced to-40+/-5 ℃, vacuumizing and maintaining the pressure at 0.15+/-0.02 mbar, and preserving the temperature for 3-5 hours; (2) sublimation drying: maintaining vacuum of the freeze dryer, heating the shelf temperature to-30 to-20 ℃ at 0.5 ℃/h, and preserving heat for 4-6h; the temperature of the shelf is increased to-10 to 0 ℃ at 1.5 ℃/h, and simultaneously, vacuum is released to standard atmospheric pressure in the freeze dryer, and the temperature is kept for 6 to 8 hours; (3) analytical drying: vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 15-25 ℃ at 2 ℃/h, and preserving the temperature for 8-10h; the temperature of the shelf is raised to 50-60 ℃ at 5 ℃/h, and the temperature is kept for 8-10h; carrying out a pressure rise experiment for 2-4 hours under the ultimate vacuum, wherein the experiment is less than 0.1pa/min; (4) out of the box: and (5) restoring normal pressure by using nitrogen, pressing plugs, and taking out from the box.
Preferably, the filling volume of the sodium metagluconate aqueous solution is 5ml;
the invention has the technical advantages that:
1. the freeze-dried sodium sugammadex powder injection for injection is provided, and the dosage form solves the problems that the API is unstable as a ring-shaped molecular structure and a large amount of impurities are easy to generate after high-temperature sterilization; the freeze-drying is finished, and inert gas (nitrogen) is filled for protection, so that oxygen is effectively isolated, and the prepared sodium gluconate freeze-dried powder injection has fewer impurities and is more stable;
2. the freeze-dried powder prepared by optimizing the freeze-drying process has shorter re-dissolution time, high clarity, fewer insoluble particles and higher stability, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.50 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-25 ℃ at 0.5 ℃/h, and preserving heat for 5h; the temperature of the shelf is increased to-5 ℃ at 1.5 ℃/h, and simultaneously, the vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 6h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 20 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is raised to 55 ℃ at 5 ℃/h, and the shelf is kept for 8h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 2
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.47 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-45 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 5 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-20 ℃ at 0.5 ℃/h, and preserving heat for 6h; the temperature of the shelf is increased to-2 ℃ at 1.5 ℃/h, and simultaneously, the vacuum in the freeze dryer is released to the standard atmospheric pressure, and the temperature is kept for 6h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 15 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is increased to 60 ℃ at 5 ℃/h, and the temperature is kept for 6h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 3
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.51 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-42 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 4 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-30 ℃ at 0.5 ℃/h, and preserving heat for 5h; the temperature of the shelf is increased to-8 ℃ at 1.5 ℃/h, and simultaneously, the vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 7h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 25 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is increased to 50 ℃ at 5 ℃/h, and the shelf is kept for 8h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 4
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.48 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-15 ℃ at 0.5 ℃/h, and preserving heat for 4h; the temperature of the shelf is increased to-2 ℃ at 1.5 ℃/h, and simultaneously, the vacuum in the freeze dryer is released to the standard atmospheric pressure, and the temperature is kept for 6h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 20 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is increased to 60 ℃ at 5 ℃/h, and the temperature is kept for 6h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 5
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.82 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottle at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-42 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 5 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-30 ℃ at 0.5 ℃/h, and preserving heat for 6h; the temperature of the shelf is increased to-5 ℃ at 1.5 ℃/h, and simultaneously, the vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 6h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 18 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is raised to 55 ℃ at 5 ℃/h, and the shelf is kept for 7h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 6
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.88 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-43 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-20 ℃ at 0.5 ℃/h, and preserving heat for 4h; the temperature of the shelf is increased to 0 ℃ at 1.5 ℃/h, and simultaneously, the vacuum in the freeze dryer is released to the standard atmospheric pressure, and the temperature is kept for 8 hours; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 25 ℃ at 2.0 ℃/h, and preserving the temperature for 9 hours; the temperature of the shelf is increased to 60 ℃ at 5 ℃/h, and the temperature is kept for 6h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 7
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.26 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-30 ℃ at 0.5 ℃/h, and preserving heat for 4h; the temperature of the shelf is increased to-10 ℃ at 1.5 ℃/h, and simultaneously, the vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 6h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 15 ℃ at 2.0 ℃/h, and preserving the temperature for 10 hours; the temperature of the shelf is increased to 50 ℃ at 5 ℃/h, and the temperature is kept for 7h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 8
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.95 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottle at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-30 ℃ at 0.5 ℃/h, and preserving heat for 6h; the temperature of the shelf is increased to-10 ℃ at 1.5 ℃/h, and simultaneously, the vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 8h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 25 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is increased to 60 ℃ at 5 ℃/h, and the temperature is kept for 8h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 9
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.28 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-45 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-20 ℃ at 0.5 ℃/h, and preserving heat for 4h; the temperature of the shelf is increased to 0 ℃ at 1.5 ℃/h, and simultaneously, the vacuum in the freeze dryer is released to the standard atmospheric pressure, and the temperature is kept for 8 hours; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 25 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is raised to 55 ℃ at 5 ℃/h, and the shelf is kept for 7h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 10
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.42 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-25 ℃ at 0.5 ℃/h, and preserving heat for 5h; the temperature of the shelf is increased to-1 ℃ at 1.5 ℃/h, and simultaneously, the vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 7h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 15 ℃ at 2.0 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is raised to 55 ℃ at 5 ℃/h, and the shelf is kept for 8h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 11
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.12 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 5 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-20 ℃ at 0.5 ℃/h, and preserving heat for 6h; the temperature of the shelf is increased to-10 ℃ at 1.5 ℃/h, and simultaneously, the vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 8h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 25 ℃ at 2.0 ℃/h, and preserving the temperature for 10 hours; the temperature of the shelf is raised to 55 ℃ at 5 ℃/h, and the shelf is kept for 8h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 12
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.67 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-30 ℃ at 0.5 ℃/h, and preserving heat for 4h; raising the temperature of the shelf to-20 ℃ at 1.5 ℃/h, and preserving the temperature for 4 hours; raising the temperature of the shelf to-10 ℃ at 2.0 ℃/h, and preserving the temperature for 4 hours; the temperature of the shelf is increased to 0 ℃ at 2.5 ℃/h, and the temperature is kept for 4h; the temperature of the shelf is raised to 10 ℃ at 0.5 ℃/h, and the temperature is kept for 4h; the temperature of the shelf is increased to 25 ℃ at 5 ℃/h, and the shelf is kept for 3h; the temperature of the shelf is increased to 60 ℃ at 10 ℃/h, and the temperature is kept for 4h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging, capping and discharging.
Example 13
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.50 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-20 ℃ at 1 ℃/h, and preserving heat for 4h; the temperature of the shelf is increased to 0 ℃ at 1.5 ℃/h, and simultaneously, the vacuum in the freeze dryer is released to the standard atmospheric pressure, and the temperature is kept for 6h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 25 ℃ at 5 ℃/h, and preserving the temperature for 8 hours; the temperature of the shelf is increased to 60 ℃ at 10 ℃/h, and the temperature is kept for 6h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Example 14
Prescription of prescription
Accurately weighing 90% of the prescription amount of water for injection; weighing sodium sulfanilate and mannitol, slowly adding into injectable water, stirring to dissolve, adjusting pH to 7.70 with hydrochloric acid, stirring for about 5min, filtering, and filling the filtrate into penicillin bottles at a ratio of 5 ml/bottle, and half-plugging; the freeze dryer is cooled to-40 ℃ in advance, the filled sample is sent into a freeze drying box, the freeze dryer is vacuumized and maintained at 0.15+/-0.02 mbar, and the temperature is kept for 3 hours; maintaining vacuum of the freeze dryer, heating the shelf temperature to-15 ℃ at 0.5 ℃/h, and preserving heat for 4h; the temperature of the shelf is increased to-2 ℃ at 1 ℃/h, and simultaneously, vacuum is released to the standard atmospheric pressure in the freeze dryer, and the temperature is kept for 6h; vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 20 ℃ at 2 ℃/h, and preserving the temperature for 8 hours; raising the temperature of the shelf to 40 ℃ at 8 ℃/h, and preserving heat for 6h; and carrying out a pressure rise experiment for 2 hours under the condition that the experiment is less than 0.1pa/min, and finally recovering normal pressure by using nitrogen, plugging and discharging.
Verification embodiment
The samples prepared in examples and comparative examples were subjected to accelerated investigation at 40℃and the results are shown in the following table:
according to the effect of verification examples, the sodium suger sodium freeze-dried powder for injection prepared by the invention has short re-dissolution time, and both clarity and insoluble particles meet the requirements. In addition, the problem of unstable degradation of the API at high temperature is solved, the inert gas is filled for protection after freeze-drying is finished, the stability problem of the preparation in the storage process is effectively solved, and the method is suitable for industrial production.
Claims (3)
1. The freeze-dried sodium sugammadex powder injection is characterized by comprising sodium sugammadex, a freeze-drying protective agent and a pH regulator;
the freeze-drying protective agent is mannitol;
the mass ratio of the sodium sugammadex to the freeze-drying protective agent is 1:0.3 to 1;
the method for preparing the sodium sugammadex freeze-dried powder injection comprises the following steps of:
adding sodium sulfan into water for injection, and stirring to dissolve completely; adding a prescribed amount of freeze-drying protective agent into the solution, and stirring until the freeze-drying protective agent is completely dissolved; regulating pH with pH regulator, stirring, filtering, filling the filtrate into penicillin bottle, half-plugging, and freeze-drying in freeze-drying box; the pH adjusting range is 7.47-7.51;
the lyophilization process includes (1) pre-freezing: placing the sample into a freeze dryer after the temperature of the plate layer is reduced to-40 to-45 ℃, vacuumizing and maintaining 0.15+/-0.02 mbar, and preserving heat for 3-5 hours; (2) sublimation drying: maintaining vacuum of the freeze dryer, heating the shelf temperature to-30 to-20 ℃ at 0.5 ℃/h, and preserving heat for 4-6h; the temperature of the shelf is increased to-10 to 0 ℃ at 1.5 ℃/h, and simultaneously, vacuum is released to standard atmospheric pressure in the freeze dryer, and the temperature is kept for 6 to 8 hours; (3) analytical drying: vacuumizing in a freeze dryer, maintaining the pressure at 0.10+/-0.02 mbar, heating the shelf temperature to 15-25 ℃ at 2 ℃/h, and preserving the temperature for 8-10h; the temperature of the shelf is raised to 50-60 ℃ at 5 ℃/h, and the temperature is kept for 6-8h; carrying out a pressure rise experiment for 2-4 hours under the ultimate vacuum, wherein the experiment is less than 0.1pa/min; (4) out of the box: and (5) restoring normal pressure by using nitrogen, pressing plugs, and taking out from the box.
2. The freeze-dried sodium sugammadex powder injection according to claim 1, wherein the pH adjuster is one of a 0.1N hydrochloric acid solution, a 0.1M tartaric acid solution, a 0.1N acetic acid solution, a 0.2M lactic acid solution, a 0.1N malic acid solution, or a combination thereof.
3. The sodium sugammadex freeze-dried powder injection according to claim 1, wherein the pH regulator is a 0.1N hydrochloric acid solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010253666.3A CN113456598B (en) | 2020-03-31 | 2020-03-31 | Sodium gluconate freeze-dried powder injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010253666.3A CN113456598B (en) | 2020-03-31 | 2020-03-31 | Sodium gluconate freeze-dried powder injection and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113456598A CN113456598A (en) | 2021-10-01 |
| CN113456598B true CN113456598B (en) | 2024-04-02 |
Family
ID=77865785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010253666.3A Active CN113456598B (en) | 2020-03-31 | 2020-03-31 | Sodium gluconate freeze-dried powder injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113456598B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111714459B (en) * | 2020-06-18 | 2022-06-14 | 广州瑞尔医药科技有限公司 | Shugeng sodium gluconate powder injection and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103006586A (en) * | 2012-12-31 | 2013-04-03 | 山东新时代药业有限公司 | Epirubicin hydrochloride lyophilized injectable powder and preparation method thereof |
| CN107137359A (en) * | 2017-04-14 | 2017-09-08 | 鲁南制药集团股份有限公司 | A kind of injection azacitidine and preparation method thereof |
| WO2017163165A1 (en) * | 2016-03-22 | 2017-09-28 | Fresenius Kabi Anti-Infectives S.r.l. | An improved process for the preparation of sugammadex |
| CN110638751A (en) * | 2019-11-01 | 2020-01-03 | 上海键合医药科技有限公司 | Stable sugammadex sodium injection and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8158152B2 (en) * | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
-
2020
- 2020-03-31 CN CN202010253666.3A patent/CN113456598B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103006586A (en) * | 2012-12-31 | 2013-04-03 | 山东新时代药业有限公司 | Epirubicin hydrochloride lyophilized injectable powder and preparation method thereof |
| WO2017163165A1 (en) * | 2016-03-22 | 2017-09-28 | Fresenius Kabi Anti-Infectives S.r.l. | An improved process for the preparation of sugammadex |
| CN107137359A (en) * | 2017-04-14 | 2017-09-08 | 鲁南制药集团股份有限公司 | A kind of injection azacitidine and preparation method thereof |
| CN110638751A (en) * | 2019-11-01 | 2020-01-03 | 上海键合医药科技有限公司 | Stable sugammadex sodium injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 张超云，等.《药剂学》.辽宁大学出版社,2013,第234-235页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113456598A (en) | 2021-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113456598B (en) | Sodium gluconate freeze-dried powder injection and preparation method thereof | |
| US10617649B2 (en) | Preparation method of azacitidine for injection | |
| CN113350276A (en) | Preparation method and packaging method of octreotide acetate injection | |
| CN113101273A (en) | Omeprazole sodium for injection | |
| CN113197870B (en) | Mitomycin freeze-dried preparation for injection and preparation method thereof | |
| CN111904936B (en) | Famotidine freeze-dried powder injection | |
| CN109498564B (en) | Clindamycin phosphate solution and preparation method thereof | |
| CN114129523A (en) | Azacitidine freeze-dried preparation for injection | |
| CN109481459B (en) | Compound electrolyte glucose injection and preparation method thereof | |
| CN111110627B (en) | Amikacin sulfate injection and preparation method thereof | |
| CN108309944B (en) | Pantoprazole sodium for injection and preparation method thereof | |
| CN114159396A (en) | Espressol omeprazole sodium freeze-dried preparation for injection and preparation method thereof | |
| CN106619542B (en) | A method of improving bivalirudin medicine stability | |
| CN113041226B (en) | Preparation process of pantoprazole sodium for injection | |
| CN111643460A (en) | Pantoprazole sodium freeze-dried preparation, preparation method thereof and injection preparation prepared from pantoprazole sodium freeze-dried preparation | |
| CN110772487B (en) | Freeze-drying method of ethylenediamine diaceturate | |
| CN111297809B (en) | Azacitidine freeze-dried powder injection and preparation method thereof | |
| CN113750055B (en) | Acetazolamide sodium freeze-dried powder injection and preparation method and application thereof | |
| CN114191396B (en) | Omeprazole sodium for injection and preparation method thereof | |
| CN116421569B (en) | Parafaxib sodium pharmaceutical composition for injection and preparation method thereof | |
| CN113274359A (en) | Azithromycin freeze-dried powder for injection and production method thereof | |
| CN112641734B (en) | Idarubicin stock solution, idarubicin for injection and freeze-drying process thereof | |
| CN113908129B (en) | Rifampicin freeze-dried powder for injection and production method thereof | |
| CN113069420B (en) | Sodium ozagrel for injection and preparation method thereof | |
| CN113679677A (en) | Freeze-dried powder injection of blood hormone for animal and its preparing method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |