CN108096187B - Propofol injection and preparation method thereof - Google Patents
Propofol injection and preparation method thereof Download PDFInfo
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- CN108096187B CN108096187B CN201810031544.2A CN201810031544A CN108096187B CN 108096187 B CN108096187 B CN 108096187B CN 201810031544 A CN201810031544 A CN 201810031544A CN 108096187 B CN108096187 B CN 108096187B
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- injection
- propofol
- triglyceride
- water
- propofol injection
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- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title claims abstract description 116
- 229960004134 propofol Drugs 0.000 title claims abstract description 116
- 238000002347 injection Methods 0.000 title claims abstract description 100
- 239000007924 injection Substances 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 24
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000008215 water for injection Substances 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000000839 emulsion Substances 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000010008 shearing Methods 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 claims description 4
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 claims description 4
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical group CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 4
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 230000002572 peristaltic effect Effects 0.000 claims description 3
- 150000003904 phospholipids Chemical class 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- 230000001502 supplementing effect Effects 0.000 claims description 3
- 238000005809 transesterification reaction Methods 0.000 claims description 3
- 229940117972 triolein Drugs 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 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 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims 7
- 239000008346 aqueous phase Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 15
- 229940079593 drug Drugs 0.000 abstract description 10
- 206010002091 Anaesthesia Diseases 0.000 abstract description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 9
- 230000037005 anaesthesia Effects 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 6
- 230000036407 pain Effects 0.000 abstract description 6
- 235000012424 soybean oil Nutrition 0.000 abstract description 5
- 239000003549 soybean oil Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 239000008139 complexing agent Substances 0.000 abstract description 4
- 238000005538 encapsulation Methods 0.000 abstract description 4
- 229910021645 metal ion Inorganic materials 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000007794 irritation Effects 0.000 abstract description 2
- 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 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 77
- 239000002245 particle Substances 0.000 description 23
- 238000012360 testing method Methods 0.000 description 17
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 229940057917 medium chain triglycerides Drugs 0.000 description 7
- 239000008156 Ringer's lactate solution Substances 0.000 description 6
- 229940025300 lidocaine injection Drugs 0.000 description 6
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 5
- 230000003444 anaesthetic effect Effects 0.000 description 5
- 229960004203 carnitine Drugs 0.000 description 5
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 229940009662 edetate Drugs 0.000 description 4
- 235000004626 essential fatty acids Nutrition 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 150000004667 medium chain fatty acids Chemical class 0.000 description 4
- 230000028527 righting reflex Effects 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000002960 lipid emulsion Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 150000004668 long chain fatty acids Chemical class 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 210000003470 mitochondria Anatomy 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000006677 mitochondrial metabolism Effects 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000003918 potentiometric titration Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003626 triacylglycerols Chemical class 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a propofol injection and a preparation method thereof. The propofol injection provided by the invention is prepared from propofol serving as an active ingredient, and triglyceride serving as an auxiliary material structure, egg yolk lecithin, an isotonic regulator, water for injection and disodium hydrogen phosphate. The propofol injection provided by the invention is characterized by not containing disodium edetate serving as a metal ion complexing agent, replacing soybean oil with structural triglyceride as an auxiliary material, and replacing sodium hydroxide with disodium hydrogen phosphate to adjust the pH value. The propofol injection provided by the invention has the advantages of reasonable compatibility, small irritation and good stability, and also has the effects of relieving injection pain of the traditional propofol injection in clinical use and enhancing the anesthesia effect of the traditional propofol injection. And the propofol injection has good encapsulation efficiency after long-time storage, and the content, related substances and other quality parameters of the propofol injection also meet the quality standard.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a propofol injection and a preparation method thereof.
Background
Propofol is a short-acting non-barbiturate intravenous whole anesthetic used for induction and maintenance of anesthesia and sedation. Has the characteristics of quick response, no accumulation, definite effect, convenient adjustment of the depth of general anesthesia, quick revival, no drunkenness after awakening and the like. Hypnotic effect is usually produced 40 seconds after intravenous injection of therapeutic dose, and the excitatory effect is very small. Has been widely used in clinic since the first time of market in 1986. Anesthesia has been approved for children in europe and the united states, and is also approved for neurosurgery in the united states.
Propofol injection has been marketed by Astrazeneca, UK in the United states, Germany, and the like. The annual sale amount reaches 5.6 hundred million dollars. Enters the domestic market of China for 94 years for sale and is popularized and applied clinically. The trade name is diprenia, and the import registration numbers are X930362 and X930363. The concentration is 1%, and the specification is 20ml and 50 ml. The former is mainly used for induction anesthesia and short surgical anesthesia, and the latter is used for maintenance anesthesia. Propofol can also be used in combination with local anesthetic drugs, such as lidocaine, to block nerve conduction and relieve or eliminate pain at the injection site.
The following injection patents exist in China, such as propofol-containing fat emulsion disclosed in Chinese patent application No. CN200610025320.8, and propofol injection (trade name of Deplypland) produced by overseas US 005731355 and Astrazeneca corporation. In the formula of the medicine injection, a metal ion complexing agent disodium Edetate (EDTA) is adopted to improve the stability of propofol, and a sodium hydroxide solution is used for adjusting the pH value. However, the national food and drug administration (SFDA) searches many documents at home and abroad, and it is considered that disodium edetate can be combined with calcium ions in blood to form a soluble complex, which causes reduction of calcium, and that the use of disodium edetate in intravenous preparations causes reduction of blood calcium. Therefore, close attention and strict control of the amount of EDTA in the formulation for intravenous administration are required.
Some propofol injection of various manufacturers clinically used in China are added with EDTA. Some manufacturers do not add EDTA into propofol injection, but have more problems in physicochemical properties. For example, the compatibility with lidocaine injection and lactated ringer's injection is unstable, the span value (polydispersity coefficient derived from cumulative analysis of light intensity weighted particle size distribution) in emulsion particle distribution, the Zeta potential, the emulsion particle size larger than 5 μm in propofol injection distributed by oil and water phases are not good enough, and the clinical medication risk is increased.
Furthermore, soybean oil is commonly used as a commercially available adjuvant for propofol injection. The soybean oil contains long-chain triglyceride (LCT) as main component, and can provide essential fatty acid and energy, but LCT is dependent on carnitine transport when entering mitochondria for metabolism, and has slow oxidative metabolism speed and easy accumulation in liver. Medium Chain Triglycerides (MCT) have the advantages of direct entry into mitochondria independent of carnitine transport, hydrolysis and oxidation in vivo, rapid clearance, and difficulty in infiltration in the liver and peripheral tissues, but MCT does not contain essential fatty acids.
In contrast, the physically mixed MCT/LCT, which contains two different lipids, can compensate for the deficiency of the single form of fat emulsion to some extent, but interfere with each other's metabolism when used in combination. Injection pain of propofol injection is a common side effect in clinical use, and the injection pain is probably caused by free drug in emulsion. Therefore, there is still a need to develop a propofol injection with reasonable compatibility, less irritation, good stability, and quality parameters such as content and related substances meeting quality standards.
Disclosure of Invention
The invention aims to provide a propofol injection which does not contain disodium edetate serving as a metal ion complexing agent, adopts structural triglyceride as an auxiliary material to replace soybean oil, medium-chain fatty acid triglyceride or a composition of soybean oil and medium-chain fatty acid triglyceride, and uses disodium hydrogen phosphate to adjust the pH value of the injection. The propofol injection has good stability, and the quality parameters of the content, related substances and the like all accord with the quality standard. The medicine liquid has good stability within 24h by using the medicine compatibility research at the end of the effective period. The propofol, the structural triglyceride and the egg yolk lecithin are reasonably proportioned to act synergistically, so that injection pain in clinical use can be relieved, and the anesthetic effect of the injection can be enhanced.
The invention also aims to provide a preparation method of the propofol injection. The propofol injection prepared by the method has better parameters such as particle size, distribution, Zeta potential and particles larger than 0.5 mu.
The invention provides a propofol injection, which comprises the following components by weight:
5-15g of propofol, 50-150g of structural triglyceride, 8-15g of egg yolk lecithin, 18-25g of isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0.
Preferably, the propofol injection consists of the following components in parts by weight:
7-13g of propofol, 70-130g of structural triglyceride, 10-13g of egg yolk lecithin, 20-24g of isotonic regulator and water for injection, wherein the water for injection is added to 1000ml, and disodium hydrogen phosphate is added to regulate the pH value to 7.0-9.0.
Preferably, the propofol injection consists of the following components in parts by weight:
10g of propofol, 100g of structural triglyceride, 12g of egg yolk lecithin, 22.5g of isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0.
Preferably, the propofol injection consists of the following components in parts by weight:
10g of propofol, 130g of structural triglyceride, 13g of egg yolk lecithin, 22.5g of isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0.
Preferably, the propofol injection consists of the following components in parts by weight:
10g of propofol, 70g of structural triglyceride, 10g of egg yolk lecithin, 22.5g of isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0.
Further, the isotonic regulator is one or a mixture of glycerol, xylitol and mannitol.
Further, the preparation method of the structural triglyceride comprises the following steps:
uniformly mixing long-chain triglyceride and medium-chain triglyceride with equal molar number, adding the mixture into a sealed vacuum reaction container, heating the obtained mixture of the long-chain triglyceride and the medium-chain triglyceride to 70-90 ℃, then adding sodium methoxide with the total weight of the medium-chain triglyceride and the long-chain triglyceride being 0.2-0.6% to perform transesterification reaction, stopping heating after 30-80min, finally adding citric acid aqueous solution with the concentration of 1mol/L and the total weight of the medium-chain triglyceride and the long-chain triglyceride to stop the reaction to obtain triglyceride with a coarse structure, and sequentially washing, centrifuging and vacuum drying the triglyceride with the coarse structure to obtain the triglyceride.
Further, the medium chain triglyceride is one of capric triglyceride, undecanoic triglyceride and dodecanoic triglyceride or a combination thereof.
Further, the long-chain triglyceride is one of glycerol trioleate, glycerol tristearate and glycerol tripalmitate or a combination thereof.
In addition, the invention also provides a preparation method of the propofol injection, which comprises the following steps:
s1, weighing structural triglyceride, egg yolk lecithin and propofol, placing the materials in a container in a nitrogen environment, heating to 30-70 ℃, and shearing at a high speed of 1500-10000 rpm/min until the phospholipids are dissolved to serve as an oil phase;
s2, adding the isoosmotic adjusting agent into injection water which is not less than 80% of the prescription amount in a nitrogen environment, uniformly mixing, and filtering to obtain a water phase;
s3, under the nitrogen environment, regulating the oil phase and the water phase by a peristaltic pump to enable the volume ratio of the oil phase to the water phase to be 1:5-1:1, regulating the rotating speed of an online shearing machine to be 5000-15000 rpm/min, and mixing the oil phase and the water phase to prepare primary emulsion;
s4, homogenizing the primary emulsion by a high-pressure homogenizer, supplementing water for injection to the amount of the prescription, continuing homogenizing until the average particle size is qualified, adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0, filtering, filling, introducing nitrogen, sealing by melting, sterilizing in a rotary steam sterilizer, and cooling to obtain the product.
The propofol injection prepared by the invention does not contain disodium edetate which is a metal ion complexing agent, solves the problem of blood calcium reduction caused by the combination of disodium edetate and calcium ions into soluble complex compounds in the existing propofol injection, and improves the safety of clinical medication. In addition, the invention adopts the buffer salt disodium hydrogen phosphate as a pH value regulator to prepare the medicament, and the medicament is respectively compatible with lidocaine injection, lactic acid ringer injection and glucose injection in clinical application, and after 24 hours, the quality parameters of emulsion particles larger than 5 mu m, Zeta potential, particle size, distribution and the like are stable, thereby effectively improving the clinical medication safety.
Furthermore, the invention also adopts structural triglyceride as an auxiliary material, which has both long-chain fatty acid (LCFA) and medium-chain fatty acid (MCFA), and the LCFA and the MCFL are randomly distributed. LCT can provide essential fatty acid and energy, but LCT enters mitochondria metabolism depending on carnitine transport, the oxidation metabolism speed is slow, MCT has better water solubility than LCT, can enter mitochondria for rapid oxidation without depending on carnitine, has faster clearance speed in blood circulation than LCT and is not easy to accumulate in liver, which is undoubtedly beneficial to carnitine-deficient critical patients and newborns. MCT, however, do not provide essential fatty acids and the use of pure MCT can cause metabolic acidosis and neurological side effects. Therefore, the fat emulsion prepared by the structured triglyceride can achieve the effects of promoting the growth and avoiding the weakness.
In the process of preparing the propofol injection, the oil phase and the water phase are uniformly mixed by using an online shearing method to obtain the primary emulsion, wherein the proportion of the oil phase and the water phase and the online shearing speed are controlled within a certain range, so that the prepared emulsion particles are more stable and the parameters of span, Zeta potential, large particles, D10, D50 and D90 are better than those of the method in the prior art.
Furthermore, experiments show that the combined use of the structural triglyceride and the egg yolk lecithin can effectively enhance the anesthetic effect of propofol under the condition that disodium hydrogen phosphate is used as a pH value regulator, and the beneficial effects are achieved.
Compared with the prior art, the invention has the following beneficial effects:
1. the propofol, the structural triglyceride and the egg yolk lecithin are reasonably proportioned, and the disodium hydrogen phosphate is used as the pH regulator, so that the encapsulation rate of the propofol injection provided by the invention can be improved, the injection pain of the traditional propofol injection in clinical use can be relieved, and the anesthetic effect of the traditional propofol injection can be enhanced.
2. The propofol injection prepared by the invention has good compatibility stability with lactic acid ringer injection and lidocaine injection in clinical use, the particle size and the particle size distribution of 24 hours of compatibility are qualified, and the clinical medication safety is improved, wherein the particle size distribution is larger than 0.5 mu m.
3. The propofol injection prepared by the invention has the advantage of good stability, and when the propofol injection is stored at normal temperature for 2 years, the propofol injection has stable quality attributes such as content, related substances, anisidine value, emulsion particles and the like, and can greatly improve the clinical medication safety.
Detailed Description
The present invention is further described in the following description of the specific embodiments, which is not intended to limit the invention, but various modifications and improvements can be made by those skilled in the art according to the basic idea of the invention, within the scope of the invention, as long as they do not depart from the basic idea of the invention.
Example 1, preparation of structural triglycerides:
uniformly mixing 879.4g of triolein and 554.9g of capric triglyceride, adding the mixture into a sealed vacuum reaction container, heating the obtained mixture of triolein and capric triglyceride to 80 ℃ in the vacuum reaction container, adding 6.0g of sodium methoxide to perform transesterification reaction, stopping heating after 50min, adding 140mL of 1mol/L citric acid aqueous solution to terminate the reaction to obtain coarse-structure triglyceride, and washing, centrifuging and vacuum-drying the coarse-structure triglyceride to obtain the finished product.
Example 2 Propofol injection
The propofol injection consists of the following components:
7g of propofol, 70g of structural triglyceride, 10g of egg yolk lecithin, 20g of an isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.9;
the preparation method comprises the following steps:
s1, weighing structural triglyceride, egg yolk lecithin and propofol, placing in a container, heating to 50 ℃, and shearing at a high speed of 8000rpm/min until phospholipid is dissolved to serve as an oil phase;
s2, adding the isoosmotic adjusting agent into injection water which is not less than 80% of the prescription amount in a nitrogen environment, uniformly mixing, and filtering to obtain a water phase;
s3, under the nitrogen environment, regulating the oil phase and the water phase by a peristaltic pump to ensure that the volume ratio of the oil phase to the water phase is 1:3, regulating the rotating speed of an online shearing machine to 5000rpm/min, and mixing the oil phase and the water phase to prepare primary emulsion;
s4, homogenizing the primary emulsion by a high-pressure homogenizer, supplementing water for injection to the amount of the prescription, continuing homogenizing until the average particle size is qualified, adding disodium hydrogen phosphate to adjust the pH value to 7.9, filtering, filling, introducing nitrogen, sealing by melting, sterilizing in a rotary steam sterilizer, and cooling to obtain the product.
Example 3 Propofol injection
The propofol injection consists of the following components:
10g of propofol, 100g of structural triglyceride, 12g of egg yolk lecithin, 22.5g of an isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0;
the preparation method is similar to example 2.
Example 4 Propofol injection
The propofol injection consists of the following components:
13g of propofol, 130g of structural triglyceride, 13g of egg yolk lecithin, 24g of isotonic regulator and 1000ml of water for injection, and adding disodium hydrogen phosphate to regulate the pH value to 9.0;
the preparation method is similar to example 2.
Comparative example 1 Propofol injection
The propofol injection comprises the following components in parts by weight:
10g of propofol, 100g of structural triglyceride, 12g of soybean phospholipid, 22.5g of isotonic regulator and 1000ml of water for injection, and adding disodium hydrogen phosphate to regulate the pH value to 7.9;
the preparation method is similar to example 2.
Comparative example 2 Propofol injection
The propofol injection comprises the following components in parts by weight:
10g of propofol, 100g of structural triglyceride, 12g of egg yolk lecithin, 22.5g of glycerol and 1000ml of water for injection, and adding sodium hydroxide to adjust the pH value to 7.9;
the preparation method is similar to example 2.
Test example one, particle detection test of propofol injection
1. Test materials: propofol injection prepared in example 2, example 3 and example 4.
2. The test method comprises the following steps: the propofol injections prepared in examples 2, 3 and 4 were tested by marvens MS2000, nicontinao Z, shimadzu 1280, and the like.
3. The results are shown in table 1:
TABLE 1 particle detection results for propofol injection
| Sample (I) | Zeta potential | Average particle diameter | span | Encapsulation efficiency | Particles > 5 μm |
| Example 2 | -40 | 151nm | 1.06 | 99.8％ | 0.0081％ |
| Example 3 | -39 | 153nm | 1.02 | 99.7％ | 0.0079％ |
| Example 4 | -39 | 157nm | 1.03 | 99.7％ | 0.0075％ |
As can be seen from Table 1, the propofol injection solutions prepared in example 2, example 3 and example 4 of the present invention all meet the quality standards in terms of Zeta potential, mean particle size, span, encapsulation efficiency and test results for particles > 5 μm. Test example II test of stability at room temperature of Propofol injection
1. Test materials: propofol injection prepared in example 2, example 3 and example 4.
2. The test method comprises the following steps: the prepared examples 2, 3 and 4 were filled into brown glass bottles, and each sample was 30. Each example sample was divided into 3 groups. The first group was the original sample of the propofol injection just prepared, the second group was the 1 year sample of the propofol injection left for one year, and the third group was the 2 year sample of the propofol injection left for 2 years. When the specified time is reached, the detection is carried out by using a Malvern MS2000, a SevenExcellence pH meter, a potentiometric titration method and the like, and the detection result is the average value of each group.
3. The results are shown in table 2:
TABLE 2 results of the room temperature stability test of propofol injection
The propofol injection prepared in example 2, example 3 and example 4 was incubated for 2 years and visually observed to have no delamination and no discoloration. As can be seen from Table 2, the propofol injection prepared by the invention has good stability, and the quality parameters of the content, related substances and the like all accord with the quality standard.
Test example III end-of-term sample compatibility test for Propofol injection
1. Test materials: propofol injection, lidocaine injection, and lactated ringer's injection prepared in example 3.
2. The test method comprises the following steps: the propofol injection prepared in example 3 is mixed with lidocaine injection in a ratio of 1:40, and mixed with lactated ringer's injection in a ratio of 1:4, and the pH value, the particle size (Malvern MS2000) and the particle size larger than 5 μm are respectively tested for 0h, 6h and 24 h.
3. The test results are shown in table 3:
TABLE 3 end-of-term sample compatibility test results for propofol injection
As can be seen from Table 3, the propofol injection prepared by the invention is compatible with lidocaine injection and lactated ringer's injection, and has stable physical properties within 24 h.
Test example four, Propofol injection anesthesia test
1. Test materials: propofol injection solutions prepared in example 2, example 3, example 4, comparative example 1 and comparative example 2.
2. The experimental method comprises the following steps: 20 Guangzhou white mice (weight 18-22g) were randomly divided into 2 groups of 10 mice each, and propofol injections of 20mg/kg propofol were injected into the tail vein of the propofol injection solutions prepared in example 2, example 3, example 4, comparative example 1 and comparative example 2. Behavioral changes of mice after administration were observed, and the duration of disappearance of righting reflex was recorded with disappearance of righting reflex as a sign of anesthesia (refer to 2 nd edition of pharmacological test method, edited by Xushuyun et al, 1994: 968-969). The duration of disappearance of righting reflex was expressed as mean ± standard deviation (x ± s) and analyzed using SPSS10.0 statistical software using paired t-test.
3. The test results are shown in table 4:
TABLE 4 anesthesia test results for Propofol injection
As can be seen from table 4, after the propofol injection solutions prepared in examples 2, 3 and 4 are injected into the tail vein of a mouse, the duration of disappearance of the average righting reflex is prolonged by 42.9% compared with the propofol injection solution prepared in comparative example 1 with the same dose, and is prolonged by 11.1% compared with the propofol injection solution prepared in comparative example 2, which indicates that the anesthetic effect of the propofol injection solution can be enhanced by reasonably proportioning propofol, structural triglyceride and egg yolk lecithin, and by synergistic action of the propofol injection solution, the structural triglyceride and the egg yolk lecithin under the action of disodium hydrogen phosphate.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (7)
1. The propofol injection is characterized by comprising the following components in parts by weight:
5-15g of propofol, 50-150g of structural triglyceride, 8-15g of egg yolk lecithin, 18-25g of isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0;
the preparation method of the structural triglyceride comprises the following steps:
uniformly mixing long-chain triglyceride and medium-chain triglyceride with equal molar number, adding the mixture into a sealed vacuum reaction container, heating the obtained mixture of the long-chain triglyceride and the medium-chain triglyceride to 70-90 ℃, then adding sodium methoxide with the total weight of the medium-chain triglyceride and the long-chain triglyceride being 0.2-0.6% to perform transesterification reaction, stopping heating after 30-80min, finally adding citric acid aqueous solution with the concentration of 1mol/L and the total weight of the medium-chain triglyceride and the long-chain triglyceride to stop the reaction to obtain coarse-structure triglyceride, and sequentially washing, centrifuging and vacuum drying the coarse-structure triglyceride to obtain the product;
the medium chain triglyceride is capric triglyceride;
the long-chain triglyceride is triolein.
2. The propofol injection of claim 1, wherein the propofol injection comprises the following components by weight:
7-13g of propofol, 70-130g of structural triglyceride, 10-13g of egg yolk lecithin, 20-24g of isotonic regulator and water for injection, wherein the water for injection is added to 1000ml, and disodium hydrogen phosphate is added to regulate the pH value to 7.0-9.0.
3. The propofol injection of claim 1, wherein the propofol injection comprises the following components by weight:
10g of propofol, 100g of structural triglyceride, 12g of egg yolk lecithin, 22.5g of isoosmotic adjusting agent and water for injection
Adding disodium hydrogen phosphate to adjust pH to 7.0-9.0 to 1000 ml.
4. The propofol injection of claim 1, wherein the propofol injection comprises the following components by weight:
10g of propofol, 130g of structural triglyceride, 13g of egg yolk lecithin, 22.5g of isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0.
5. The propofol injection of claim 1, wherein the propofol injection comprises the following components by weight:
10g of propofol, 70g of structural triglyceride, 10g of egg yolk lecithin, 22.5g of isoosmotic adjusting agent and 1000ml of water for injection, and adding disodium hydrogen phosphate to adjust the pH value to 7.0-9.0.
6. The propofol injection according to any one of claims 1 to 5, wherein the isotonicity modifying agent is glycerol, or mixtures thereof,
One or a combination of xylitol and mannitol.
7. The method of preparing a propofol injection as claimed in any of claims 1-6, comprising the steps of:
s1, weighing the structural triglyceride, the egg yolk lecithin and the propofol into a container in a nitrogen environment, and heating to the temperature
Shearing at 30-70 deg.C under high speed shearing at 1500-10000 rpm/min until phospholipid is dissolved to obtain oil phase;
s2, adding the isoosmotic adjusting agent into water for injection with the amount not less than 80% of the prescription amount under the nitrogen environment, mixing uniformly, and filtering to obtain the product
An aqueous phase;
s3, under the nitrogen environment, regulating the oil phase and the water phase by a peristaltic pump to ensure that the volume ratio of the oil phase to the water phase is 1:5-1:1,
adjusting the rotation speed of the on-line shearing machine to 5000-15000 rpm/min to mix the oil phase and the water phase to prepare primary emulsion;
s4, homogenizing the primary emulsion by a high-pressure homogenizer, supplementing water for injection to the prescription amount, continuously homogenizing until the average grain diameter is qualified,
adding disodium hydrogen phosphate to adjust pH to 7.0-9.0, filtering, bottling, introducing nitrogen, sealing, and placing in rotary steam sterilizer
Sterilizing and cooling to obtain the product.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319212A (en) * | 2011-09-01 | 2012-01-18 | 辽宁中海康生物药业有限公司 | Clevidipine butyrate structured lipid emulsion and preparation method thereof |
| CN104434783A (en) * | 2014-11-13 | 2015-03-25 | 广东嘉博制药有限公司 | Diazepam medium/long-chain fat emulsion preparation and preparation method thereof |
| CN104490778A (en) * | 2014-12-26 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Propofol fat emulsion injection |
| JP5801586B2 (en) * | 2011-03-31 | 2015-10-28 | テルモ株式会社 | Fat emulsion prefilled syringe formulation |
| CN105395482A (en) * | 2015-11-24 | 2016-03-16 | 四川百利药业有限责任公司 | Propofol composition for injection and preparation method thereof |
| EP3156045A1 (en) * | 2014-06-16 | 2017-04-19 | Shenyang Pharmaceutical University | Application of large-dose glycerinum in freeze-thawing tolerable lipid emulsion |
-
2018
- 2018-01-12 CN CN201810031544.2A patent/CN108096187B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5801586B2 (en) * | 2011-03-31 | 2015-10-28 | テルモ株式会社 | Fat emulsion prefilled syringe formulation |
| CN102319212A (en) * | 2011-09-01 | 2012-01-18 | 辽宁中海康生物药业有限公司 | Clevidipine butyrate structured lipid emulsion and preparation method thereof |
| EP3156045A1 (en) * | 2014-06-16 | 2017-04-19 | Shenyang Pharmaceutical University | Application of large-dose glycerinum in freeze-thawing tolerable lipid emulsion |
| CN104434783A (en) * | 2014-11-13 | 2015-03-25 | 广东嘉博制药有限公司 | Diazepam medium/long-chain fat emulsion preparation and preparation method thereof |
| CN104490778A (en) * | 2014-12-26 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Propofol fat emulsion injection |
| CN105395482A (en) * | 2015-11-24 | 2016-03-16 | 四川百利药业有限责任公司 | Propofol composition for injection and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| 影响静脉注射用脂肪乳剂稳定性的因素;杨梅;《临床药物治疗杂志》;20100930;第17-20页 * |
| 新型丙泊酚制剂和传统丙泊酚制剂临床药理学特性的比较;徐进;《中国优秀硕士学位论文全文数据库（电子期刊）》;20110315;第13-14页 * |
| 脂肪乳注射液不良反应临床分析;刘丁;《北京医学》;20101231;第467-468页 * |
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