CN111374942B - Steroid muscle relaxant injection and preparation method thereof - Google Patents
Steroid muscle relaxant injection and preparation method thereof Download PDFInfo
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- CN111374942B CN111374942B CN201811644166.1A CN201811644166A CN111374942B CN 111374942 B CN111374942 B CN 111374942B CN 201811644166 A CN201811644166 A CN 201811644166A CN 111374942 B CN111374942 B CN 111374942B
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- 238000002347 injection Methods 0.000 title claims abstract description 52
- 239000007924 injection Substances 0.000 title claims abstract description 52
- 239000003158 myorelaxant agent Substances 0.000 title claims abstract description 19
- 150000003431 steroids Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 37
- 239000000243 solution Substances 0.000 claims abstract description 95
- 239000007853 buffer solution Substances 0.000 claims abstract description 74
- 230000003204 osmotic effect Effects 0.000 claims abstract description 26
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims abstract description 24
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 claims abstract description 23
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000000872 buffer Substances 0.000 claims abstract description 7
- 229960003682 rocuronium bromide Drugs 0.000 claims description 60
- 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 claims description 60
- 238000003756 stirring Methods 0.000 claims description 56
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 38
- 230000001954 sterilising effect Effects 0.000 claims description 28
- 238000001914 filtration Methods 0.000 claims description 27
- 238000011049 filling Methods 0.000 claims description 23
- 239000011780 sodium chloride Substances 0.000 claims description 19
- 238000003825 pressing Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000008362 succinate buffer Substances 0.000 claims description 7
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 claims description 6
- 239000008351 acetate buffer Substances 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- 229940095064 tartrate Drugs 0.000 claims description 5
- 239000007979 citrate buffer Substances 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 12
- 238000003860 storage Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000008215 water for injection Substances 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 239000003381 stabilizer Substances 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000007731 hot pressing Methods 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical group OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229950006191 gluconic acid Drugs 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- -1 organic acid salt Chemical class 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 125000004964 sulfoalkyl group Chemical group 0.000 description 2
- DWHMPBALQYTJFJ-DKWTVANSSA-N (2s)-2-aminobutanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CC(O)=O DWHMPBALQYTJFJ-DKWTVANSSA-N 0.000 description 1
- QLAJNZSPVITUCQ-UHFFFAOYSA-N 1,3,2-dioxathietane 2,2-dioxide Chemical compound O=S1(=O)OCO1 QLAJNZSPVITUCQ-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 150000007522 mineralic acids Chemical group 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 238000001782 photodegradation Methods 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- PQRHBEQNPCVBSM-UHFFFAOYSA-M potassium;2-carboxybenzoate;hydrochloride Chemical compound Cl.[K+].OC(=O)C1=CC=CC=C1C([O-])=O PQRHBEQNPCVBSM-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 229950004777 sodium calcium edetate Drugs 0.000 description 1
- LLVQEXSQFBTIRD-UHFFFAOYSA-M sodium;2,3,4-trihydroxy-4-oxobutanoate;hydrate Chemical compound O.[Na+].OC(=O)C(O)C(O)C([O-])=O LLVQEXSQFBTIRD-UHFFFAOYSA-M 0.000 description 1
- IGHGOYDCVRUTSU-UHFFFAOYSA-M sodium;2-hydroxypropane-1,2,3-tricarboxylic acid;hydroxide Chemical compound [OH-].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O IGHGOYDCVRUTSU-UHFFFAOYSA-M 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicinal preparations, and particularly provides a steroid muscle relaxant injection which comprises active ingredients, a buffer solution, a pH regulator, an osmotic pressure regulator and polyethylene glycol 1000 vitamin E succinate, wherein two buffer systems are adopted in the preparation process to control the change of the pH value of the solution. The invention selects proper prescription components and preparation method, and avoids the increase of related substances in the production and storage process of the injection to the maximum extent. The steroid muscle relaxant injection prepared by the invention has stable and uniform quality, excellent safety and compliance, green and economic preparation process and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a steroid muscle relaxant injection and a preparation method thereof.
Background
Rocuronium Bromide (Rocuronium Bromide) is a widely used steroid non-depolarizing muscle relaxant with rapid onset of action and moderate potency, and is used clinically as an adjuvant for conventional endotracheal intubation for general anesthesia. Contains propenyl on the active quaternary nitrogen atom, and has the following molecular structure:
rocuronium bromide is unstable to alkali, heat and other conditions in water, and the accelerated degradation reaction comprises hydrolysis, thermal degradation, photodegradation and oxidative degradation. The pH value of the original preparation Aikosong (Emeron) is 3.8-4.2, the storage period is 2 years at the temperature of 2-8 ℃, and the storage period is 60 days at the temperature of 25 ℃. The rocuronium bromide injection is affected by sterilization temperature and time, solution pH value, storage time, light, metal ions and other factors in the preparation process, so that according to the stipulations of European pharmacopoeia and Chinese pharmacopoeia 2015 edition, related substances A, B, C, D, E, F, G, H and unknown impurities of the injection are checked, the stipulation limit of total impurities is less than 2.0%, the limit of impurity C is less than 1.5%, other single impurities are less than 0.1%, and other unknown impurities are less than 0.5%. The related substances and structural changes of rocuronium bromide are shown in the following table:
the presence of impurities, even in small amounts, can affect the effectiveness and safety of pharmaceutical products, and therefore impurity analysis has become an important component of the research of drug development processes. Various regulatory agencies, such as the international harmonization for drug registration technology (ICH) and the Food and Drug Administration (FDA), recommend reporting impurities that exceed allowable limits. The ICH impurity guidelines state that all degradation products formed by pharmaceutical products are characterized at levels greater than or equal to 0.1%.
WO2008/065142 discloses the addition of sulfoalkyl ether- β -cyclodextrin derivatives or pharmaceutically acceptable salts thereof to an aqueous solution containing rocuronium bromide to stabilize rocuronium bromide. To reduce injection pain, the pH should be in the range of 3.5-7.5, preferably 4-5. It has been reported that sulfoalkyl ether- β -cyclodextrin derivatives or pharmaceutically acceptable salts thereof may cause renal dysfunction.
CN201310410100.7 discloses a stable rocuronium bromide injection formulation and its preparation method, wherein the stabilizer is selected from phosphate buffer or citrate buffer, and the pH range is preferably 3.0-5.0. The pH regulator is selected from inorganic acid, organic acid, and/or inorganic base. The osmotic pressure regulator is preferably sodium chloride. The preparation method comprises adding stabilizer and osmotic pressure regulator into water for injection, adding rocuronium bromide, adjusting pH to 3.0-5.0 with appropriate pH regulator, adding active carbon, quantifying, filtering, sterilizing, bottling, pressing, and capping. The rocuronium bromide injection prepared by the method is stored at normal temperature, and the impurity content changes rapidly.
CN201210364536.2 discloses a preparation method of rocuronium bromide injection, which comprises the steps of dissolving 25 ℃ water for injection with a prescribed amount of sodium acetate, adjusting the pH value to 3.8-4.2 with glacial acetic acid, adding a prescribed amount of rocuronium bromide bulk drug to dissolve, adjusting the pH value to 3.8-4.2 with glacial acetic acid, adding sodium chloride to adjust the solution to be isotonic, filtering and sterilizing, filling, corking, capping, and sterilizing at 115 ℃ for 35min under hot pressure. The injection obtained by the method is placed for 10 days, and the related substances reach 2.85%.
CN200910177540.6 discloses a stable rocuronium bromide injection for intravenous administration, wherein a buffer system adopts citrate or acetate with pH value of 3.8-4.0, and adopts sodium calcium edetate or disodium edetate as a stabilizer. The preparation process comprises the steps of dissolving the citric acid with the prescription amount by adding the water for injection with the prescription amount of more than 80 percent, adding the sodium hydroxide to adjust the pH value to be within 4.0, sequentially adding the stabilizer and the raw material medicine, stirring and dissolving, adjusting the pH value to be 3.8-4.0, performing an activated carbon process, quantifying, filling, plugging, capping, and performing hot-pressing sterilization at 115 ℃ for 30 min. The prepared injection has the advantage of rapid increase of impurity content in the storage process.
CN201480076036.6 discloses a rocuronium bromide preparation with excellent stability, wherein the buffer solution is selected from citric acid-sodium hydroxide buffer solution, tartaric acid-sodium hydroxide buffer solution, potassium hydrogen phthalate-hydrochloric acid buffer solution, glycine-hydrochloric acid buffer solution, etc., preferably 0.1M glycine-hydrochloric acid buffer solution, the pH value of the preparation is adjusted to be below 3.5, too low pH has large irritation to human body, if stored for 6 months under the condition of controlling pH to be 4.0, the impurity C reaches 5.46%, and how to ensure the stability of rocuronium bromide when the pH is raised to reduce irritation is not reported.
CN201210501837.5 discloses an injection containing rocuronium bromide, which maintains the pH value of a system to be 4.0-5.0 through 1% -5% acetate buffer solution, improves the stability of a main drug, and is sterilized by hot pressing at 121 ℃ for 15min, although the generation of impurity C is reduced to a certain extent, the impurity content is increased rapidly in the long-term storage process.
CN201610061810.7 discloses a preparation method of rocuronium bromide injection of muscle relaxant, which comprises the steps of dissolving sorbitol, ammonium methosulfate and ammonium acetate in the prescribed amount with water for injection, then carrying out an activated carbon process, keeping the temperature of filtrate at 85-90 ℃ for 5-15min, adding rocuronium bromide raw material, adjusting the pH value to 6.0-6.5 with glacial acetic acid, carrying out filtration sterilization, filling nitrogen into liquid medicine, filling the liquid medicine into a brown ampoule bottle, and carrying out autoclaving at 121 ℃ for 10-20min, wherein the content of impurity C in the prepared rocuronium bromide injection is obviously increased in the long-term storage process.
CN201380042469.5 discloses a stable aqueous composition of rocuronium bromide, excipient is selected from D-gluconic acid, lactone of gluconic acid or mixture thereof, buffer is selected from buffer based on citrate and acetate, preferably pH value is 3.8-4.0, which can not solve the problem of stability of rocuronium bromide injection.
CN200910075875.7 discloses a preparation method of rocuronium bromide injection, which comprises cooling water for injection to room temperature, adding acetic acid-sodium acetate buffer solution, and mixing well. Dissolving the sodium chloride and rocuronium bromide according to the prescription amount, adjusting the pH value to 4.0 by using 1mol/L acetic acid solution, performing activated carbon process, filtering and sterilizing, filling, pressing and capping, and performing hot-pressing sterilization at 121 ℃ for 20min to obtain the injection with poor stability and excessive impurity content.
The rocuronium bromide varieties reported in the literature and on the market at present mainly adopt water injection, and the rocuronium bromide is found to be unstable and extremely easy to hydrolyze in practical application, so that the rocuronium bromide is required to be stored at 2-8 ℃. The content of related substances of the existing rocuronium bromide injection is obviously increased along with the prolonging of time in the storage and transportation processes. Therefore, in order to improve the medication safety and the drug stability and reduce the condition requirement of drug storage, new rocuronium bromide injection must be further developed.
Disclosure of Invention
Based on the defects and research and development difficulties in the prior art, in order to avoid increase of related substances in the injection production and storage processes to the maximum extent, the inventor provides a formula of rocuronium bromide injection, selects a proper buffer solution, and then adds polyethylene glycol 1000 vitamin E succinate as a stabilizer, so that the stability of the rocuronium bromide injection can be remarkably improved, and the generation of related substances is reduced.
The amino acid-hydrochloric acid buffer solution and the organic acid salt buffer solution are used in combination, so that the generation of insoluble particles can be reduced, the vascular irritation reaction and the injection pain can be effectively relieved, and the generation of related substances can be reduced. The polyethylene glycol 1000 vitamin E succinate has larger molecular volume and molecular surface area, the molecular structure comprises a long polyethylene glycol chain and a lipophilic vitamin E group, and the polyethylene glycol 1000 vitamin E succinate can be used as a stabilizer in rocuronium bromide injection to provide stronger steric hindrance and potential steric hindrance and better prevent the nucleophilic attack of an affinity group with high electronegativity of hydroxide ions on rocuronium bromide unstable groups. And the buffer solution of the two buffer systems and the polyethylene glycol 1000 vitamin E succinate are combined, so that the generation of related substances, particularly impurity C, is reduced to a greater extent, the stability of the rocuronium bromide injection is improved, and the administration safety and the compliance are more excellent.
The injection is realized by the following scheme:
a steroid muscle relaxant injection comprises rocuronium bromide, buffer solution, pH regulator, osmotic pressure regulator, and polyethylene glycol 1000 vitamin E succinate.
The buffer solution is an amino acid-hydrochloric acid buffer solution.
Preferably, the buffer solution is one of glycine-hydrochloric acid and alanine-hydrochloric acid.
The pH regulator is one of acetate buffer solution, citrate buffer solution, mesylate buffer solution, tartrate buffer solution and succinate buffer solution.
Preferably, the pH regulator is one of tartrate buffer and succinate buffer.
The osmotic pressure regulator is sodium chloride.
The pH value of the steroid muscle relaxant injection is 3.5-5.0.
The steroid muscle relaxant injection comprises the following specific components in percentage by weight:
the invention also provides a preparation method of the steroid muscle relaxant injection, which specifically comprises the following steps:
(a) preparing a buffer solution with a certain pH value, and measuring the buffer solution with a prescribed amount for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of pH regulator into the solution obtained in the step (c) to regulate the pH value;
(e) adding an osmotic pressure regulator into the solution obtained in the step (d) to regulate the osmotic pressure, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, and packaging.
Preferably, the steroid muscle relaxant injection is prepared by the following steps:
(a) preparing a buffer solution with the pH value of 3.0-4.0, and measuring the buffer solution with the amount according to the prescription for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of pH regulator into the solution obtained in the step (c), and regulating the pH value to 3.5-5.0;
(e) adding an osmotic pressure regulator into the solution obtained in the step (d) to regulate the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
The invention selects proper prescription components and a preparation method, avoids the increase of related substances in the production and storage processes of the injection to the maximum extent, and the prepared rocuronium bromide injection has stable and uniform quality, excellent safety and compliance, green and economic preparation process 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 given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
1) Prescription
2) Preparation process
(a) Preparing a glycine-hydrochloric acid buffer solution with the pH value of 3.5, measuring the buffer solution with the prescription amount, and uniformly mixing for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of succinate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 4.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing, and capping.
Example 2
1) Prescription
2) Preparation process
(a) Preparing alanine-hydrochloric acid buffer solution with the pH value of 3.5, measuring the buffer solution with the prescription amount, and uniformly mixing for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of tartrate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 4.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Example 3
1) Prescription
2) Preparation process
(a) Preparing a proline-hydrochloric acid buffer solution with the pH value of 4.0, and measuring the buffer solution with the amount according to the prescription for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of acetate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 5.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Example 4
1) Prescription
2) Preparation process
(a) Preparing a histidine-hydrochloric acid buffer solution with the pH value of 3.0, and measuring the buffer solution with the prescription amount for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of citrate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 3.5;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Example 5
1) Prescription
2) Preparation process
(a) Preparing arginine-hydrochloric acid with the pH value of 4.0, and measuring a prescription amount of buffer solution for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of a mesylate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 5.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Example 6
1) Prescription
2) Preparation process
(a) Preparing lysine-hydrochloric acid with the pH value of 5.0, and measuring a prescription amount of buffer solution for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of phosphate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 6.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Example 7
1) Prescription
2) Preparation process
(a) Preparing a succinate buffer solution with a pH value of 4.0, and measuring a prescription amount of the buffer solution for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of succinic acid into the solution obtained in the step (c), and adjusting the pH value to 4.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing, and capping.
Example 8
1) Prescription
2) Preparation process
(a) Preparing an aspartic acid-hydrochloric acid buffer solution with the pH value of 3.5, and measuring the buffer solution with the prescription amount for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of citrate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 4.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing, and capping.
Example 9
1) Prescription
2) Preparation process
(a) Preparing a lysine-hydrochloric acid buffer solution with the pH value of 3.5, and measuring the buffer solution with the prescription amount for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of acetate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 4.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Example 10
1) Prescription
2) Preparation process
(a) Preparing an acetate buffer solution with the pH value of 3.5, and measuring the buffer solution with the prescription amount for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of phthalate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 4.0;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Comparative example 1
1) Prescription
2) Preparation process
Precisely measuring a citric acid-sodium citrate buffer solution with the pH value of 3.8, adding a proper amount of water for injection, and uniformly mixing; adding sodium chloride, stirring or shaking to dissolve completely; adding rocuronium bromide, stirring or shaking to completely dissolve, and adjusting pH to 4.0 with 1mol/L citric acid or 1mol/L sodium hydroxide; then adding 0.05% (w/v) of active carbon for injection, stirring for 30min at room temperature, and coarsely filtering; quantifying, filtering and sterilizing by a 0.22 mu m microporous filter membrane; filling, wherein each bottle is 2.5ml or 5ml, pressing a rubber plug completely, and rolling a cover; sterilizing at 121 deg.C under hot pressure for 20 min; and (5) inspecting, printing, packaging and storing in a refrigerator at 2-8 ℃.
Comparative example 2
1) Prescription
2) The preparation method comprises the following steps:
(a) taking sorbitol, methionine and ammonium acetate according to the prescription amount, adding water for injection, stirring for dissolving, then adding 3g of active carbon for injection, stirring for adsorbing for 30min, decarburizing and filtering to obtain filtrate;
(b) heating the filtrate to 87 ℃, preserving the heat for 10min, adding 10g rocuronium bromide, stirring for dissolving, adding glacial acetic acid to ensure that the pH value is 6.3, and uniformly stirring;
(c) filtering with microporous membrane with average pore diameter of 0.22 μm, filling nitrogen into the medicinal liquid, bottling in brown ampoule, sterilizing in 121 deg.C water bath for 15min, testing with lamp, packaging, and storing.
Comparative example 3
1) Prescription
2) The preparation method comprises the following steps:
(a) taking povidone, adding water for injection, dissolving completely, adding 2/3 wt% of L-aspartic acid, dissolving completely, filtering with 0.22 μm filter element, and filtering to obtain filtrate;
(b) adding rocuronium bromide raw material into the standby filtrate, completely dissolving, adding the residual L-aspartic acid, and adding water for injection to 5000ml to obtain a solution;
(c) filtering the solution in step b with 0.22 μm filter core, bottling, and sterilizing at 121 deg.C for 30min to obtain 1000 injection.
Comparative example 4
1) Prescription
2) The preparation method comprises the following steps:
measuring 850g of water for injection cooled to below 25 ℃, aerating with nitrogen, cooling the solution to 8-12 ℃, adjusting the pH to 2.9-3.1 with glacial acetic acid to obtain a solution A, adding rocuronium bromide in the solution A in the formula amount, stirring and dissolving to obtain a solution B, adding sodium acetate and sodium chloride in the formula amount into the solution B, adjusting the pH of the solution B to 2.9-3.1 with glacial acetic acid, supplementing 1000.0g of water for injection, adjusting the pH of the solution B to 3.9-4.1 with glacial acetic acid or sodium hydroxide to obtain a solution C, and stopping nitrogen aeration; and (3) passing the solution C through a polyvinylidene fluoride membrane with the diameter of 0.2 mu m, and filling 5 ml.
Comparative example 5
1) Prescription
2) Preparation process
(a) Preparing a lysine-hydrochloric acid buffer solution with the pH value of 3.0, and measuring the buffer solution with the amount according to the prescription for standby;
(b) adding polyethylene glycol 1000 into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of phosphate buffer solution into the solution obtained in the step (c), and adjusting the pH value to 4.5;
(e) adding sodium chloride into the solution obtained in the step (d) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
Comparative example 6
1) Prescription
2) Preparation process
(a) Preparing a glycine-hydrochloric acid buffer solution with the pH value of 3.5, measuring the buffer solution with the prescription amount, and uniformly mixing for later use;
(b) adding rocuronium bromide into the buffer solution obtained in the step (a), and stirring for dissolving;
(c) adding a proper amount of succinate buffer solution into the solution obtained in the step (b), and adjusting the pH value to 4.0;
(d) adding sodium chloride into the solution obtained in the step (c) to adjust the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(e) quantifying, sterilizing, filtering, filling, pressing, and capping.
Verification examples
1. Long term stability test
To further prove the superiority of the present invention, the inventors conducted long-term stability experiments on the products obtained in the examples of the present invention and comparative examples.
The rocuronium bromide injection solutions prepared in examples 1-10 of the present invention and comparative examples 1-6 were stored at 25 ℃ ± 2 ℃ and 60% RH ± 5% RH for one year, and the related substances of the examined samples were measured at 0 month, 3 months, 6 months, 9 months, and 12 months, respectively, and the specific data are shown in the following table:
TABLE 1 Long-term stability test results
2. Accelerated test
The rocuronium bromide injection prepared in the examples 1-10 of the present invention and the comparative examples 1-6 was placed in a constant temperature and humidity chamber with 40 ℃. + -. 2 ℃ and 75%. + -. 5% relative humidity for 6 months, and samples were periodically taken at 0, 1, 2, 3, and 6 months to measure the contents of the related substances, and the results of the measurements are shown in the following table.
TABLE 2 stability results of accelerated testing
In the examples 1 to 10 of the invention, the content of the impurity C is only 2.36% at most in the accelerated test of 6 months, the polyethylene glycol 1000 vitamin E succinate is not added in the comparative example 6, and the content of the impurity C reaches 3.68% in the accelerated test of 6 months, which shows that the stability of the rocuronium bromide injection can be remarkably improved by selecting the polyethylene glycol 1000 vitamin E succinate as the stabilizer. Example 7 is a buffer system, and after the formula of example 10 is changed, the prepared injection solutions have poor stability compared with examples 1-6, which shows that the double buffer system of buffer solution and pH regulator can improve the stability of rocuronium bromide to a certain extent.
Claims (7)
1. The steroid muscle relaxant injection is characterized by comprising rocuronium bromide, a buffer solution, a pH regulator, an osmotic pressure regulator and polyethylene glycol 1000 vitamin E succinate, wherein the buffer solution is an amino acid-hydrochloric acid buffer solution; the pH regulator is one of acetate buffer solution, citrate buffer solution, mesylate buffer solution, tartrate buffer solution and succinate buffer solution; the pH value of the steroid muscle relaxant injection is 3.5-5.0.
2. The steroid muscle relaxant injection according to claim 1, wherein the buffer is one of glycine-hydrochloric acid and alanine-hydrochloric acid.
3. The steroid muscle relaxant injection according to claim 1, wherein the pH adjuster is one of a tartrate buffer and a succinate buffer.
4. The steroid muscle relaxant injection according to claim 1, wherein the osmolality adjusting agent is sodium chloride.
6. a method for preparing the steroid muscle relaxant injection according to any one of claims 1 to 5, comprising the steps of:
(a) preparing a buffer solution with a certain pH value, and measuring the buffer solution with a prescribed amount for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of pH regulator into the solution obtained in the step (c) to regulate the pH value;
(e) adding an osmotic pressure regulator into the solution obtained in the step (d) to regulate the osmotic pressure, and stirring for dissolving;
(f) quantifying, sterilizing, filtering and filling.
7. The method of claim 6, further comprising the steps of:
(a) preparing a buffer solution with the pH value of 3.0-4.0, and measuring the buffer solution with the amount according to the prescription for later use;
(b) adding polyethylene glycol 1000 vitamin E succinate into the buffer solution in the step (a), and stirring until the solution is clear;
(c) adding rocuronium bromide into the solution obtained in the step (b), and stirring for dissolving;
(d) adding a proper amount of pH regulator into the solution obtained in the step (c), and regulating the pH value to 3.5-5.0;
(e) adding an osmotic pressure regulator into the solution obtained in the step (d) to regulate the osmotic pressure to be 285-320 mOsmol/kg, and stirring for dissolving;
(f) quantifying, sterilizing, filtering, filling, pressing and capping.
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