CN113456598A - Shugeng sodium gluconate freeze-dried powder injection and preparation method thereof - Google Patents
Shugeng sodium gluconate freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN113456598A CN113456598A CN202010253666.3A CN202010253666A CN113456598A CN 113456598 A CN113456598 A CN 113456598A CN 202010253666 A CN202010253666 A CN 202010253666A CN 113456598 A CN113456598 A CN 113456598A
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- sugammadex sodium
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- 238000002347 injection Methods 0.000 title claims abstract description 38
- 239000007924 injection Substances 0.000 title claims abstract description 38
- 239000000843 powder Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 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 description 2
- 239000000176 sodium gluconate Substances 0.000 title description 2
- 229940005574 sodium gluconate Drugs 0.000 title description 2
- 235000012207 sodium gluconate Nutrition 0.000 title description 2
- 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 claims abstract description 52
- 229940041622 sugammadex sodium Drugs 0.000 claims abstract description 52
- 238000004108 freeze drying Methods 0.000 claims abstract description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 239000008215 water for injection Substances 0.000 claims abstract description 17
- 239000000243 solution Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- -1 sodium dimercaptoglucose Chemical compound 0.000 claims abstract description 6
- 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
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 30
- 229930195725 Mannitol Natural products 0.000 claims description 30
- 239000000594 mannitol Substances 0.000 claims description 30
- 235000010355 mannitol Nutrition 0.000 claims description 30
- 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
- 238000003825 pressing Methods 0.000 claims description 16
- 239000003223 protective agent Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000008176 lyophilized powder Substances 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
- 229920002370 Sugammadex Polymers 0.000 claims description 3
- 229960002257 sugammadex Drugs 0.000 claims description 3
- 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 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 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 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 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 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-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
- 238000007599 discharging Methods 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 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 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 229940069328 povidone Drugs 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
- 125000006239 protecting group Chemical group 0.000 claims 2
- 238000012792 lyophilization process Methods 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 238000010979 pH adjustment Methods 0.000 claims 1
- 238000011049 filling Methods 0.000 abstract description 19
- 239000012535 impurity Substances 0.000 abstract description 8
- 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
- 239000002245 particle Substances 0.000 abstract description 4
- 230000001954 sterilising effect Effects 0.000 abstract description 4
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 4
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 3
- 229940079593 drug Drugs 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
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 238000005457 optimization Methods 0.000 abstract 1
- 238000005303 weighing Methods 0.000 description 28
- 229940090044 injection Drugs 0.000 description 24
- 238000001816 cooling Methods 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 14
- 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 description 4
- 230000000694 effects 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
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 206010029315 Neuromuscular blockade Diseases 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
- 206010021118 Hypotonia Diseases 0.000 description 2
- 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 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000002999 depolarising effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000036640 muscle relaxation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 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
- 230000002232 neuromuscular Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940041637 sugammadex injection Drugs 0.000 description 1
- 150000003457 sulfones Chemical class 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (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 sugammadex sodium freeze-dried powder injection and a preparation method thereof; the preparation method of the sugammadex sodium freeze-dried powder injection comprises the following steps: adding the prescription of the sodium dimercaptoglucose into water for injection, and stirring until the sodium dimercaptoglucose is completely dissolved; adding the formula amount of freeze-drying protection base into the solution, stirring until the freeze-drying protection base is completely dissolved, adjusting the pH value, stirring, filtering, filling, and freeze-drying to obtain the target; the method provides the sugammadex sodium freeze-dried powder injection for injection, and solves the problems that API as a cyclic molecular structure is unstable, and a large amount of impurities are easily generated through high-temperature sterilization; inert gas (nitrogen) is filled for protection after freeze-drying is finished, so that oxygen is effectively isolated, and the prepared sugammadex sodium freeze-dried powder injection has fewer impurities and is more stable; through the optimization of the freeze-drying process, the prepared freeze-dried powder has the shortest redissolution time, higher stability and higher suitability for industrial production, and both clarity and insoluble particles meet the requirements.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a sugammadex sodium freeze-dried powder injection and a preparation method thereof.
Background
Sugammadex Sodium was first developed by organic Biosciences (ogagatans) in 2008, and was first marketed in europe and subsequently in japan, usa, etc., respectively, and is now marketed in 75 countries.
Sugammadex sodium, chemically named 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt, is modified gamma-cyclodextrin; the single-component amino steroid non-depolarizing muscle relaxant is the first and only selective muscle relaxation antagonist (SRBA), blocks the relaxation effect by wrapping the amino steroid non-depolarizing muscle relaxant through a brand-new and only way, can quickly and predictably reverse the muscle relaxation of any intensity caused by rocuronium bromide and vecuronium bromide, has small side effect, can enable the use of the muscle relaxant to be close to an ideal state, and has quicker and more predictable effects of reversing the neuromuscular blocking effect than the existing drugs. The method is suitable for reversing the neuromuscular blockade caused by rocuronium bromide or vecuronium bromide, reversing (normally reversing and immediately reversing) the neuromuscular blockade caused by adult rocuronium bromide or vecuronium bromide and normally reversing the neuromuscular blockade caused by rocuronium bromide in children and juveniles. The chemical formula is as follows:
researches find that oxygen is a protective agent for carbon-sulfur bonds in the high-temperature sterilization process, and the quantity of degradation impurities generated by the generation of sulfydryl by the carbon-sulfur bonds after the sugammadex injection is subjected to high-temperature sterilization under the aerobic condition is less than that of RRT (RRT 2.04); under the condition of no oxygen or low oxygen concentration, the sugammadex sodium injection is sterilized at high temperature, and then generates sulfydryl through carbon-sulfur bonds to generate more degradation impurities with RRT 2.04, which seriously exceeds the quality standard control range. In addition, after the sugammadex sodium is prepared into an injection, the sugammadex sodium is sensitive to oxygen, and oxidation reaction is easily carried out in an aerobic solution environment to generate oxidation impurities with the mark Org198958-2 and Org199425-1 of sulfone isomers RRT 0.45 and RRT 0.59 respectively. Therefore, it is very useful to prepare a formulation having high stability which can be stored for a long period of time.
Aiming at the problems in the prior art, the invention aims to provide a quality-controllable sugammadex sodium preparation and a preparation method thereof, and the preparation method is mainly used for preparing the quality-controllable sugammadex sodium preparation into a sterile freeze-dried powder injection, namely the sugammadex sodium for injection. Researches show that mannitol is used as a freeze-drying excipient, the particle size of sugammadex is controlled, a proper amount of pH regulator is added, a freeze-drying curve is optimized, nitrogen gas is filled for protection after freeze-drying is finished, various impurities in the quality of the prepared sugammadex freeze-dried powder are far lower than those 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 sugammadex sodium powder injection, and solves the problems of the preparation process and long-term storage stability of sugammadex sodium.
The sugammadex sodium freeze-dried powder injection is characterized by comprising sugammadex sodium, a freeze-drying protective agent and a pH regulator.
Preferably, the lyoprotectant can be one of mannitol, lactose, dextran, povidone or their combination.
Preferably, the lyoprotectant is mannitol.
Preferably, the mass ratio of the sugammadex sodium to the lyoprotectant is 1: 0.1 to 2.
Preferably, the mass ratio of the sugammadex sodium to the lyoprotectant is 1: 0.3 to 1, and more preferably 1: 0.65.
preferably, the pH regulator is selected from 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.
Preferably, the pH regulator is 0.1N hydrochloric acid solution.
The preparation method comprises the following steps:
adding the prescription of the sodium dimercaptoglucose into water for injection, and stirring until the sodium dimercaptoglucose is completely dissolved; adding a prescription amount of freeze-drying protective agent into the solution, and stirring until the freeze-drying protective agent is completely dissolved; adjusting pH with pH regulator, stirring, filtering, filling filtrate into penicillin bottle, half plugging, and lyophilizing.
Preferably, the pH adjusting range is 7.1-8.0.
Further the filling subsequent process comprises:
filling the filtered filtrate into a penicillin bottle, half plugging, and putting into a freeze-drying box; (1) pre-freezing: cooling the temperature of the plate layer to-40 +/-5 ℃, putting the sample into the plate layer, vacuumizing the freeze dryer, maintaining the vacuum pressure at 0.15 +/-0.02 mbar, and preserving the heat for 3-5 hours; (2) sublimation drying: the freeze dryer maintains vacuum, the temperature of the shelf is increased to-30 to-20 ℃ at the speed of 0.5 ℃/h, and the temperature is kept for 4 to 6 h; the temperature of the shelf is increased to-10-0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in a freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6-8 h; (3) and (3) resolving and drying: vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15-25 ℃ at the speed of 2 ℃/h, and preserving the heat for 8-10 h; raising the temperature of the shelf to 50-60 ℃ at the speed of 5 ℃/h, and preserving the heat for 8-10 h; then limiting the vacuum for 2-4h, and carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1 pa/min; (4) discharging: recovering normal pressure with nitrogen, pressing plug, and taking out.
Preferably, the filling volume of the sugammadex sodium aqueous solution is 5 ml;
the technical advantages of the invention are as follows:
1. the preparation formulation solves the problems that API as a cyclic molecular structure is unstable and a large amount of impurities are easily generated by high-temperature sterilization; inert gas (nitrogen) is filled for protection after freeze-drying is finished, so that oxygen is effectively isolated, and the prepared sugammadex sodium freeze-dried powder injection has fewer impurities and is more stable;
2. by optimizing the freeze-drying process, the prepared freeze-dried powder has shorter redissolution 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 properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until dissolving, adjusting the pH value to 7.50 with hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-25 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 5 h; the temperature of the shelf is raised to-5 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 20 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 2
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until dissolving, adjusting the pH value to 7.47 with hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-45 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 5 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-2 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 3
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.51 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-42 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 4 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 5 h; the temperature of the shelf is raised to-8 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 7 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 50 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 4
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.48 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-15 deg.C at a rate of 0.5 deg.C/h, and maintaining for 4 h; the temperature of the shelf is raised to-2 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 20 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 5
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.82 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-42 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 5 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-5 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 18 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 7 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 6
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.88 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-43 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 9 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 7
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sulgamide sodium and mannitol in a prescription amount, slowly adding into water for injection, stirring until the sulgamide sodium and the mannitol are dissolved, adjusting the pH value to 7.26 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to-10 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 10 h; the temperature of the shelf is raised to 50 ℃ at the speed of 5 ℃/h, and the temperature is kept for 7 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 8
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sulgamide sodium and mannitol in a prescription amount, slowly adding into water for injection, stirring until the sulgamide sodium and the mannitol are dissolved, adjusting the pH value to 7.95 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-10 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 60 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 9
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.28 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-45 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 7 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 10
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.42 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-25 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 5 h; the temperature of the shelf is raised to-1 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 7 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 11
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.12 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 5 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 6 h; the temperature of the shelf is raised to-10 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 8 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 2.0 ℃/h, and preserving the heat for 10 h; the temperature of the shelf is raised to 55 ℃ at the speed of 5 ℃/h, and the temperature is kept for 8 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 12
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.67 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-30 ℃ at the temperature of 0.5 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to-20 ℃ at the speed of 1.5 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to-10 ℃ at the speed of 2.0 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 2.5 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to 10 ℃ at the speed of 0.5 ℃/h, and the temperature is kept for 4 h; the temperature of the shelf is raised to 25 ℃ at the speed of 5 ℃/h, and the temperature is kept for 3 h; the temperature of the shelf is increased to 60 ℃ at the speed of 10 ℃/h, and the temperature is kept for 4 h; and finally, carrying out ultimate vacuum for 2 hours, carrying out a pressure rise experiment, wherein the experiment needs to meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, pressing a plug, rolling a cover, and taking out of the box.
Example 13
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until dissolving, adjusting the pH value to 7.50 with hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-20 ℃ at the temperature of 1 ℃/h, and preserving heat for 4 h; the temperature of the shelf is raised to 0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 25 ℃ at the speed of 5 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is increased to 60 ℃ at the speed of 10 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Example 14
Prescription
Accurately weighing 90% of injection water according to the prescription amount; weighing sugammadex sodium and mannitol according to the prescription amount, slowly adding into water for injection, stirring until the sugammadex sodium and the mannitol are dissolved, adjusting the pH value to 7.70 by hydrochloric acid, stirring for about 5min, filtering, filling the filtered filtrate into a penicillin bottle according to 5 ml/bottle, and half plugging; cooling to-40 deg.C in advance, feeding the filled sample into a freeze drying box, vacuumizing in the freeze drying machine, maintaining at 0.15 + -0.02 mbar, and maintaining for 3 hr; maintaining vacuum in the freeze dryer, heating the shelf to-15 deg.C at a rate of 0.5 deg.C/h, and maintaining for 4 h; the temperature of the shelf is raised to-2 ℃ at the speed of 1 ℃/h, meanwhile, the vacuum is released in the freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6 h; vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 20 ℃ at the speed of 2 ℃/h, and preserving the heat for 8 h; the temperature of the shelf is raised to 40 ℃ at the speed of 8 ℃/h, and the temperature is kept for 6 h; and finally, carrying out ultimate vacuum for 2h, carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1pa/min, recovering the normal pressure by using nitrogen, carrying out plug pressing, and taking out of the box.
Verification examples
The samples prepared in the examples and comparative examples were subjected to accelerated examination at 40 ℃ and the results are shown in the following table:
according to the effect of the verification example, the lyophilized powder for injection prepared by the invention has short reconstitution time, and both clarity and insoluble particles meet the requirements. In addition, the problem that API is not stably degraded under high temperature is solved, 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 (10)
1. The sugammadex sodium freeze-dried powder injection is characterized by comprising sugammadex sodium, a freeze-drying protective agent and a pH regulator.
2. The sugammadex sodium lyophilized powder for injection according to claim 1, wherein the lyoprotectant is one or a combination of mannitol, lactose, dextran, and povidone.
3. The lyophilized powder for injection of sugammadex sodium according to claim 1, wherein the lyoprotectant is preferably mannitol.
4. The sugammadex sodium lyophilized powder for injection of claim 1, wherein the mass ratio of sugammadex sodium to lyophilized protecting groups is 1: 0.1 to 2.
5. The sugammadex sodium lyophilized powder for injection according to claim 1, wherein the mass ratio of sugammadex sodium to lyophilized protecting groups is preferably 1: 0.3 to 1.
6. The sugammadex sodium lyophilized powder for injection of claim 1, wherein the pH modifier is one of 0.1N hydrochloric acid solution, 0.1M tartaric acid solution, 0.1N acetic acid solution, 0.2M lactic acid solution, 0.1N malic acid solution or a combination thereof.
7. The lyophilized sugammadex powder for injection according to claim 1, wherein the pH regulator is preferably a 0.1N hydrochloric acid solution.
8. A method for preparing the sugammadex sodium freeze-dried powder injection of claim 1, which is characterized by comprising the following steps:
adding the prescription of the sodium dimercaptoglucose into water for injection, and stirring until the sodium dimercaptoglucose is completely dissolved; adding a prescription amount of freeze-drying protective agent into the solution, and stirring until the freeze-drying protective agent is completely dissolved; adjusting pH with pH regulator, stirring, filtering, bottling the filtrate in penicillin bottle, half plugging, and freeze drying in freeze drying box.
9. The method of claim 8, wherein the pH adjustment range is 7.1 to 8.0.
10. The method of claim 8, wherein the lyophilization process comprises (1) pre-freezing: after the temperature of the plate layer is reduced to-40 to-45 ℃, putting a sample into the plate layer, vacuumizing the plate layer in a freeze dryer, maintaining the vacuum pressure at 0.15 +/-0.02 mbar, and preserving the heat for 3-5 hours; (2) sublimation drying: the freeze dryer maintains vacuum, the temperature of the shelf is increased to-30 to-20 ℃ at the speed of 0.5 ℃/h, and the temperature is kept for 4 to 6 h; the temperature of the shelf is increased to-10-0 ℃ at the speed of 1.5 ℃/h, and meanwhile, the vacuum is released in a freeze dryer to the standard atmospheric pressure, and the temperature is kept for 6-8 h; (3) and (3) resolving and drying: vacuumizing in a freeze dryer, maintaining the vacuum pressure at 0.10 +/-0.02 mbar, raising the temperature of a shelf to 15-25 ℃ at the speed of 2 ℃/h, and preserving the heat for 8-10 h; raising the temperature of the shelf to 50-60 ℃ at the speed of 5 ℃/h, and preserving the heat for 6-8 h; then limiting the vacuum for 2-4h, and carrying out a pressure rise experiment, wherein the experiment should meet the requirement of less than 0.1 pa/min; (4) discharging: recovering normal pressure with nitrogen, pressing plug, and taking out.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111714459A (en) * | 2020-06-18 | 2020-09-29 | 广州瑞尔医药科技有限公司 | Shugeng sodium gluconate powder injection and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070116729A1 (en) * | 2005-11-18 | 2007-05-24 | Palepu Nageswara R | Lyophilization process and products obtained thereby |
| 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 |
-
2020
- 2020-03-31 CN CN202010253666.3A patent/CN113456598B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070116729A1 (en) * | 2005-11-18 | 2007-05-24 | Palepu Nageswara R | Lyophilization process and products obtained thereby |
| 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, pages: 234 - 235 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111714459A (en) * | 2020-06-18 | 2020-09-29 | 广州瑞尔医药科技有限公司 | Shugeng sodium gluconate powder injection and preparation method thereof |
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