CN1331081A - Tetraphosphine quatorphosphonium salt, its preparing process, and two-step tetraphosphine medicine kit and its application - Google Patents
Tetraphosphine quatorphosphonium salt, its preparing process, and two-step tetraphosphine medicine kit and its application Download PDFInfo
- Publication number
- CN1331081A CN1331081A CN 00107867 CN00107867A CN1331081A CN 1331081 A CN1331081 A CN 1331081A CN 00107867 CN00107867 CN 00107867 CN 00107867 A CN00107867 A CN 00107867A CN 1331081 A CN1331081 A CN 1331081A
- Authority
- CN
- China
- Prior art keywords
- tetrofosmin
- bottle
- salt
- medicine box
- preparation
- Prior art date
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- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims description 109
- 230000008569 process Effects 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 title abstract 2
- 239000007924 injection Substances 0.000 claims abstract description 56
- 238000002347 injection Methods 0.000 claims abstract description 56
- 230000002285 radioactive effect Effects 0.000 claims abstract description 19
- 210000000056 organ Anatomy 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 5
- 229960004113 tetrofosmin Drugs 0.000 claims description 122
- QCWJONLQSHEGEJ-UHFFFAOYSA-N tetrofosmin Chemical compound CCOCCP(CCOCC)CCP(CCOCC)CCOCC QCWJONLQSHEGEJ-UHFFFAOYSA-N 0.000 claims description 105
- 238000002360 preparation method Methods 0.000 claims description 46
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 150000004714 phosphonium salts Chemical group 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 29
- BVIZIWVHTBDMEX-RCUQKECRSA-R 2-[bis(2-ethoxyethyl)phosphaniumyl]ethyl-bis(2-ethoxyethyl)phosphanium;dioxotechnetium-99 Chemical compound O=[99Tc]=O.CCOCC[PH+](CCOCC)CC[PH+](CCOCC)CCOCC.CCOCC[PH+](CCOCC)CC[PH+](CCOCC)CCOCC BVIZIWVHTBDMEX-RCUQKECRSA-R 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000000463 material Substances 0.000 claims description 21
- -1 halogen salt Chemical class 0.000 claims description 18
- 239000002994 raw material Substances 0.000 claims description 18
- 229920000858 Cyclodextrin Polymers 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000012216 imaging agent Substances 0.000 claims description 14
- 229920000136 polysorbate Polymers 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 10
- 210000004165 myocardium Anatomy 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 229950006191 gluconic acid Drugs 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000003995 emulsifying agent Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 8
- 159000000000 sodium salts Chemical class 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- 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 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 5
- BHDKTFQBRFWJKR-UHFFFAOYSA-N 2-hydroxy-5-sulfobenzoic acid;dihydrate Chemical compound O.O.OC(=O)C1=CC(S(O)(=O)=O)=CC=C1O BHDKTFQBRFWJKR-UHFFFAOYSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 239000001116 FEMA 4028 Substances 0.000 claims description 4
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 4
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 4
- 229960004853 betadex Drugs 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
- 235000012208 gluconic acid Nutrition 0.000 claims description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- OOMQZSZNGQGEEN-UHFFFAOYSA-M sodium 3-carboxy-4-hydroxybenzenesulfonate dihydrate Chemical compound O.O.[Na+].OC(=O)c1cc(ccc1O)S([O-])(=O)=O OOMQZSZNGQGEEN-UHFFFAOYSA-M 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- VPCLRNNXLYIZJF-UHFFFAOYSA-N 2-hydroxy-5-sulfobenzoic acid;sodium Chemical compound [Na].[Na].OC(=O)C1=CC(S(O)(=O)=O)=CC=C1O VPCLRNNXLYIZJF-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 238000011146 sterile filtration Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims 2
- 229940102223 injectable solution Drugs 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- ANOBYBYXJXCGBS-UHFFFAOYSA-L stannous fluoride Chemical compound F[Sn]F ANOBYBYXJXCGBS-UHFFFAOYSA-L 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
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- REJGOFYVRVIODZ-UHFFFAOYSA-N phosphanium;chloride Chemical compound P.Cl REJGOFYVRVIODZ-UHFFFAOYSA-N 0.000 description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
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- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
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- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229910052713 technetium Inorganic materials 0.000 description 3
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 3
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- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- 239000000047 product Substances 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
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- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
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- 208000026310 Breast neoplasm Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
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- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- PCTXBFQNMDKOSP-UHFFFAOYSA-M sodium;(2-carboxyphenyl) sulfate Chemical compound [Na+].OS(=O)(=O)OC1=CC=CC=C1C([O-])=O PCTXBFQNMDKOSP-UHFFFAOYSA-M 0.000 description 1
- SZEQIYURCKBEDK-UHFFFAOYSA-M sodium;2-sulfooxybenzoate;dihydrate Chemical compound O.O.[Na+].OS(=O)(=O)OC1=CC=CC=C1C([O-])=O SZEQIYURCKBEDK-UHFFFAOYSA-M 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a tetraphosphine quaterphosphonium salt with chemical formula: [(C2H5OC2H4)2P(H)C2H4P(H)(C2H4OC2H5)2]2x and its preparing process, the tetraphophine kit prepared from raw tetraphophine and its preparing process including respectively preparing bottles A and B, and the application of the said tetraphosphine kit in preparing the biologically improved radioactive Tc-99m tetraphosphine injection used as the developer of human or animal's organs or tissue are disclosed.
Description
The invention relates to a99mTc-labeled radiopharmaceuticals, in particular bidentate organophosphine compounds, namely tetrofosmin quaternary phosphonium salts and a process for their preparation; the invention also relates to a two-step method tetrofosmin medicine box for preparing tetrofosmin quaternary phosphonium salt from the tetrofosmin bulk drug and a preparation method thereof; in addition, the invention further relates to radioactive technetium prepared by using the two-step tetrofosmin medicine box-99m tetrofosmin injection and a preparation method thereof; meanwhile, the invention also relates to the application of the tetrofosmin medicine box in preparing radioactive technetium-99m tetrofosmin injection as an imaging agent in human or animal organs or tissues, in particular to the application as an imaging agent in cardiac muscle or tumor.
At present, cardiovascular diseases are one of the main diseases seriously harming the life health of the citizens in China. Early diagnosis of cardiovascular diseases is of great significance to the prevention and treatment of diseases. The early diagnosis of cardiovascular diseases can be realized by myocardial perfusion imaging by using radionuclide in the core cardiology, and the diagnosis becomes an important content of the diagnosis and examination of the cardiology at present.
Since the 80 s, the use of Mo-Tc generators and the advent of sterile, pyrogen-free lyophilized kits have led to99mTc-labeled myocardial perfusion imaging agents have rapidly developed. Wherein,99mTc-MIBI, of the structure a (Wackers FJT, Berman DS, Maddahi J et a1. technique-99 mhexakis-2-methoxy-isobutyl-isocyanate: human biodistribution,diversity, safety and precision composition to third-201 for myocardial perfusion imaging. J NucleMed, 1989, 30: 301)99mTc-teboroxime, structure b (Nunn AD et al, J Nucl Med 1986, 27: 893) and99mthe development of three myocardial imaging agents Tc-tetrofosmin (structure see formula c) is mature, and the Tc-tetrofosmin has been approved by the FDA in the United states and is widely applied to clinic.
Several kinds of99mTc-labeled myocardial perfusion imaging agents
In the above three kinds99mIn the Tc-labeled myocardial perfusion imaging agent,99mtc-tetrofosmin (tetrofosmin ═ tetrofosmin) is a latest organophosphine myocardial perfusion imaging agent introduced in the early 90 s by Amersham, UK. The crude drug tetrofosmin (P53) is firstly developed and synthesized by James D.Kelly et al (J Dkelly et al U.S.P.5045302) in 1991 by Amersham company, and the label of the tetrofosmin isNote that compound: [ TcO]2(tetrofosmin)2]+Shows good myocardial uptake rate and blood and liver clearing performance, and is considered to be an ideal myocardial perfusion developer.
Subsequently, the labeled compound was further studied by J.D.Kelly et al, who developed a kit for preparing a sterile lyophilized product of the compound in addition to preparation by a liquid formulation(MyoviewTM) And carrying out further research on the structural determination and the biological performance of the labeled compound. (J.D. Kelly et al, technique-99 m-tetrofosmin as New Radiopharmaceutical for Myocardial Perfusion Imaging J Nucl Med1993, 34: 222) sterile pyrogen-free kit MyoviewTMFDA approval in the United states was obtained at 2 months 1996 and marketed (Myoview)TMkit for the prediction of Tc-99m-tetrofosmin)which can be directly labelled at room temperature to a radiochemical purity of greater than 90%99mTc-tetrofosmin injection is widely and rapidly applied to clinic in foreign countries.
99mBesides being used as a myocardial perfusion imaging agent, a large number of clinical studies show that Tc-tetrofosmin can also be used for diagnosing malignant tumors such as breast cancer, parathyroid cancer and the like and researching tumor multidrug resistance (MDR). ([1]Jain D，et al.，J Nucl Med 1993，34：1354；[2]TarkBasoglu，et al.，Eur J Nucl Med 1995，22：687；[3]Talahashi Norio，Reinhardt，Christopher P，et al.，Circulation 1996，94：2605；[4]Tjeld Jan G，Erichsen Kunt，et al.，J Nucl Med 1997，38：831；[5]Batista J F，Solano M E，et al.，Nucl Med Commun 1997，18：338)
In China, since the literature reports, the synthesis of a tetrofosmin raw material drug (tetrofosmin), the development of a freeze-dried product kit and the labeling of compounds are started in succession from Beijing, Shanghai and the like99mPreparation of Tc-tetrofosmin and study of its biological properties. Such as: beijing Jiang institute of Chinese medicine (Zhangguofeng et al, Tetrofosmin Synthesis and kit development, sixth national academy of academic conference for radiopharmaceuticals and labeling Compounds, P17, 1996), Shanghai university of medical sciencePharmacology institute (e.g. radix Ardisiae Crenatae, a novel imaging agent for myocardial perfusion)99mTc-P53, summary of the sixth national conference of radiopharmaceuticals and labeling compounds, P24, 1996, Beijing collaboration Hospital Nuclear medicine (Chenfang, King Shizhen, myocardial perfusion imaging agent) of the university of Council medicine, China99mTc-tetrofosmin preparation and experimental studies, Chinese Nuclear medicine 17 (1): 13, 1997; myocardial perfusion developer for Chenfang, Weekly, etc99mPreclinical study of Tc-tetrofosmin, Chinese Nuclear medicine 17 (1): 16, 1997), the Beijing Master Macro drug development center, etc., wherein the drug research institute in Beijing river and the Beijing Master1997) And the Beijing Shihong drug development center, wherein the drug research institute in Beijing river and the Beijing Shihong drug development center have carried out the clinical research and declaration of new drugs of the drug.
As the tetrofosmin serving as the raw material medicine is a trivalent organic phosphine compound, the substance is very easy to oxidize in the presence of air, so that the quality problems of the tetrofosmin serving as the raw material medicine and a stannous tetrofosmin medicine box for injection occur in the process of storage and transportation (particularly under the conditions of high temperature and high humidity in summer), and the quality problems of the medicine box can directly influence the preparation of technetium-99m tetrofosmin injection and the image effect of myocardial development. In order to solve the problems, prolong the quality guarantee time of raw material medicines and a medicine box and provide technetium-99m tetrofosmin injection with reliable quality for clinic, tetrofosmin raw material medicines are prepared into phosphonium salt, a two-step tetrofosmin medicine box is further developed, and the technetium-99m tetrofosmin injection with improved biological performance is obtained.
Therefore, the present invention aims to provide a novel tetrofosmin quaternary phosphonium salt and a preparation method thereof;
the invention also aims to provide a tetrofosmin medicine box for preparing tetrofosmin quaternary phosphonium salt from a tetrofosmin raw medicine and a preparation method thereof;
the invention also aims to use the tetrofosmin medicine box for preparing radioactive technetium-99m tetrofosmin injection and a preparation method thereof;
a further object of the invention is the use of said tetrofosmin kit for the preparation of radioactive technetium-99m tetrofosmin injection as an imaging agent in human or animal organs or tissues, in particular in cardiac muscle or tumors.
Tetrofosmin is a known compound having the chemical formula (C)2H5OC2H4)2PC2H4P(C2H4OC2H5)2The tetrofosmin quaternary phosphonium salt is a novel series of compounds, wherein the tetrofosmin quaternary phosphonium salt is a bidentate organic phosphine compound and is prepared by taking the tetrofosmin quaternary phosphonium salt as a raw material and shown in the following formula (I):
[(C2H5OC2H4)2P+(H)C2H4P+(H)(C2H4OC2H5)2]·2X-……(I)
wherein X is a halogen, such as Cl or Br,
or a sulfonate ion of the following formula (II):
R2is-H, -OH or-COOH.
The phosphonium salt reduces the activity of P (III) to react with oxygen, can be stored for a long time, and can be easily converted into the original free tetrofosmin under neutral or alkaline conditions.
The invention relates to a tetrofosmin quaternary phosphonium salt which is characterized by having the following formula (I) [ (C)2H5OC2H4)2P+(H)C2H4P+(H)(C2H4OC2H5)2]·2X-……(I)
In the formula: x can be halogen, such as chlorine or bromine;
or a sulfonate of the formula (II),
in the formula R1is-H or-COOH, preferably-COOH;
R2is-H, -OH or-COOH, preferably-OH.
The invention also relates to a preparation method of the tetrofosmin quaternary phosphonium salt with the following formula (I),
[(C2H5OC2H4)2P+(H)C2H4P+(H)(C2H4OC2H5)2]·2X-……(I)
in the formula: x is a halogen, and X is a halogen,
or a sulfonate of the formula (II),
in the formula: r1is-H or-COOH,
R2is-H, -OH or-COOH,
the method comprises the following steps:
reacting tetrofosmin (C)2H5OC2H4)2PC2H4P(C2H4OC2H5)2With reactants of formula HX
Wherein X is as defined for formula (I),
under the protection of inert gas, the tetrofosmin quaternary phosphonium salt which is easy to dissolve in water and is formed in a nonpolar medium at-10 ℃ to 25 ℃.
In the above preparation method, the inert gas may be nitrogen; the nonpolar medium can be benzene, toluene, diethyl ether or petroleum ether.
The compositions of the two-step tetrofosmin kits A and B prepared from the tetrofosmin quaternary phosphonium salt cannot be accurately expressed at present, so that the compositions can only be characterized by the preparation method.
In addition, the invention relates to a tetrofosmin medicine box for preparing tetrofosmin quaternary phosphonium salt from tetrofosmin bulk drug, which is obtained by respectively preparing a bottle A and a bottle B according to the following two-step method:
preparation of bottle A:
uniformly mixing a reducing agent, an intermediate ligand, an auxiliary material, an excipient and nitrogen-filled secondary water in a weight ratio of (0.01-0.1) to (1-5) to (0.2-2.5) to (1-10) to (0.6-1) so as to fully dissolve the four materials in the nitrogen-filled secondary water, adjusting the pH to 5.0-8.5 by using a pH regulator, performing sterile filtration, subpackaging in containers, performing freeze drying, filling nitrogen and sealing to obtain a freeze-dried medicine box A bottle;
wherein the reducing agent is a Sn (II) halogen salt; the intermediate ligand is D-gluconic acid or alkali metal or alkaline earth metal salt thereof; the auxiliary materials are dihydrate sulfosalicylic acid, dihydrate sodium sulfosalicylate or sodium sulfosalicylate, citric acid or sodium salt thereof, tartaric acid or potassium or sodium salt thereof; the excipient is sodium chloride or mannitol; the pH regulator is sodium hydroxide, sodium bicarbonate or disodium hydrogen phosphate;
preparation of bottle B:
dissolving the tetrofosmin quaternary phosphonium salt serving as the main raw material medicine, auxiliary materials and a solvent in a weight ratio of (1-5) to (1-10) to (0.2-1.0) into the solvent, fully dissolvingthe tetrofosmin quaternary phosphonium salt and the auxiliary materials, and then subpackaging the tetrofosmin quaternary phosphonium salt and the auxiliary materials into containers to prepare medicine box bottles B; wherein the auxiliary material is Tween emulsifier or cyclodextrin; the solvent is water, ethanol water solution or absolute ethanol.
For the tetrofosmin kit, in the preparation of the bottle A, the Sn (II) halogen salt is SnCL2·2H2O or SnF2In the preparation of the bottle B, the tween emulsifier is tween 20, tween 40 or tween 80, and the cyclodextrin is upsilon-cyclodextrin or β -cyclodextrin.
Meanwhile, the invention also relates to a preparation method of the tetrofosmin medicine box, which is prepared by respectively preparing the bottle A and the bottle B according to the two-step method.
In addition, the invention relates to a radioactive technetium-99m tetrofosmin injection prepared by the two-step tetrofosmin medicine box, which is prepared by the following steps:
1) preparation of bottle A:
uniformly mixing a reducing agent, an intermediate ligand, an auxiliary material, an excipient and nitrogen-filled secondary water in a weight ratio of (0.01-0.1) to (1-5) to (0.2-2.5) to (1-10) to (0.6-1) to fully dissolve the four substances in the nitrogen-filled secondary water, adjusting the pH to 5.0-8.5 by using a pH regulator, performing sterile filtration, subpackaging in containers, performing freeze drying, filling nitrogen and sealing to obtain a freeze-dried medicine box A bottle;
wherein the reducing agent is a Sn (II) halogen salt; the intermediate ligand is D-gluconic acid or alkali metal or alkaline earth metal salt thereof; the auxiliary materials are sulfosalicylic acid dihydrate, sodium sulfosalicylate dihydrate or disodium sulfosalicylic acid, citric acid or sodium salt thereof, and tartaric acid or potassium or sodium salt thereof; the excipient is sodium chloride or mannitol; the pH regulator is sodium hydroxide, sodium bicarbonate or disodium hydrogen phosphate;
2) preparation of bottle B:
dissolving the tetrofosmin quaternary phosphonium salt serving as the main raw material medicine, auxiliary materials and a solvent in a weight ratio of (1-5) to (1-10) to (0.2-1.0) into the solvent, fully dissolving the tetrofosmin quaternary phosphonium salt and the auxiliary materials, and then subpackaging the tetrofosmin quaternary phosphonium salt and the auxiliary materials into containers to prepare medicine box bottles B;
wherein the auxiliary material is Tween emulsifier or cyclodextrin; the solvent is water, ethanol water solution or absolute ethanol;
3) under aseptic operation, pertechnetate99mTcO4 -(for medical use)99Mo/99mTc generator), then taking out the solution in the prepared medicine box B bottle, injecting the solution into the bottle A, shaking up, placing the solution at room temperature for 15-20 minutes after shaking up, and obtaining the radioactive technetium-99m tetrofosmin injection.
For the tetrofosmin injection, in the preparation of A bottle, the Sn (II) halogen saltIs Sncl2·2H2O or SnF2In the preparation of bottle B, the Tween emulsifier is Tween 20, Tween 40 or Tween 80, and the cyclodextrin is upsilon-cyclodextrin or β -cyclodextrin.
Meanwhile, the invention also relates to a preparation method of the radioactive technetium-99m tetrofosmin injection, which is prepared according to the steps. The invention further relates to the use of the tetrofosmin kit in the preparation of radioactive technetium-99m tetrofosmin injection as an imaging agent in human or animal organs or tissues, in particular in cardiac muscle or tumors.
The invention is illustrated more clearly by the following preparation examples and examples:
the first preparation example:
synthesis of tetrofosmin:
tetrofosmin [ (C)2H5OC2H4)2PC2H4P(C2H4OC2H5)2]Reference is made to Kelly et al [ Kelly J D, k.w.forster, Ina a. latham. u.s.p.5045302, 1991]. Phosphorus trichloride and absolute ethyl alcohol are taken as raw materials, and the compound is prepared by esterification, halogenation, reduction and free radical addition reaction, and the reaction route is as follows:
the obtained tetrofosmin is colorless or pale yellow viscous liquid and is very easy to oxidize in air. As the tetrofosmin is a trivalent organic phosphine compound, under the protection of inert gases, it can form a phosphonium salt which is easy to dissolve in water with certain organic or inorganic acids (such as sulfosalicylic acid, HCl and the like) in a non-polar medium. The phosphonium salt reduces the activity of P (III) in reaction with oxygen, can be stored for a long time, and can be easily converted into the original free tetrofosmin under neutral or alkaline conditions. Second, embodiment:
example 1: tetrofosmin hydrochloride phosphonium salt
[(C2H5OC2H4)2P+(H)C2H4P+(H)(C2H4OC2H5)2]·2Cl-Preparation of
Adding 3g of tetrofosmin in N2Dissolving in 10ml of anhydrous ether under protection, and cooling in ice bathThe solution was partitioned by passing dry HCl gas through it, and after the massive oil had separated out completely, the oil was separated and dried in vacuo to give about 3.2g of colorless (or pale yellow) viscous liquid in about 90% yield.1H NMR(CDCl3，TMS)：δ1.10-1.17(12H、OCH2CH3)；2.93-2.96(8H、PCH2CH2OEt)；3.12-3.20(4H、PC2H4P)；3.45-3.56(8H、OCH2CH3)；3.79-3.90(8H、PCH2CH2OEt)ppm。31P NMR(CDCl3，H3PO4)：δ14.80ppm。IR：ν(-C-O-C)1157-1017cm-1，ν(P-H)2240cm-1(liquid film) example 2: preparation of tetrofosmin sulfosalicylate
(R1＝COOH，R2＝OH)
10ml of an anhydrous ether solution containing 3g of tetrofosmin is added in N2The guard charge was placed in a 50ml round bottom flask equipped with electromagnetic stirring and an isobaric dropping funnel, then 15ml of a solution of diethyl ether in which 3.4g of salicylic acid sulfonate was dissolved was added dropwise with stirring while cooling in an ice bath, and the precipitate was separated and dried under vacuum to give about 4.7g of a colorless (or pale yellow) solid in about 73% yield.31P NMR(CDCl3，H3PO4)：δ12.75ppm。IR：ν(-C-O-C)1157-1017cm-1，ν(P-H)2310cm-1(liquid film).
Example 3: preparation of a two-step tetrofosmin kit:
the two-step medicine box is divided into two parts, namely a bottle A and a bottle B. Wherein the bottle A is a sterile pyrogen-free freeze-dried medicine box which mainly contains a reducing agent, an intermediate ligand, an excipient and other auxiliary materials for buffering the pH value, and the bottle A has the function of99mTcO4 -The injection is reduced into99mTc (V) valency, so that it forms ligand-exchangeable with tetrofosmin ligands99mTc (V) valent intermediate complexes.
1) And bottle A: preparation of D-sodium gluconate lyophilized medicine box (for example 1000 pieces)
Taking 1000mg of D-sodium gluconate and SnCl.2H2Dissolving O30 mg, sodium sulfosalicylate dihydrate 400mg and mannitol 10000mg in nitrogen-filled secondary water, and mixing with the nitrogen-filled secondary waterThe solution is metered to 1000ml and NaHCO is used3Adjusting the pH value to 7.5-8.5. SterileFiltering the mixed solution, taking 1000 penicillin bottles with each bottle being 10ml, packaging 1.0ml in each bottle, freeze-drying, charging nitrogen, and sealing to obtain bottle A.
2) And bottle B: preparation of tetrofosmin ampoule (1000 pieces for example)
The two-step method medicine box B bottle is colorless sterile pyrogen-free solution filled in an ampoule bottle, and mainly provides the main raw material medicine for preparing the technetium-99m tetrofosmin injection.
1000mg of the tetrofosmin phosphonium hydrochloride prepared in the embodiment 1 and 805000 mg of tween are dissolved in 200ml of absolute ethyl alcohol, 1000 ampoules of 1mg are taken, 0.2ml of the solution is packaged in each ampoule after full dissolution, and a bottle B is obtained after sealing.
Example 4: preparation of radioactive technetium-99m tetrofosmin injection:
under the aseptic condition, 1-6ml of radioactive technetium-99m injection is injected into the two-step medicine box A bottle (a D-sodium gluconate freeze-dried medicine box penicillin bottle) prepared in the embodiment 3 by a syringe, the shaking is carried out, another syringe is taken, the solution in the two-step medicine box B bottle (a tetrofosmin ampoule bottle) prepared in the embodiment 3 is taken out and injected into the bottle A, the solution is fully shaken, and the solution is placed at the room temperature for 15-20 minutes, so that the radioactive technetium-99m tetrofosmin injection is obtained.
The following performance measurements for the two-step tetrofosmin kit are described below:
1. labeling method of kit and determination of radiochemical purity thereof:
1) the marking method comprises the following steps: under the aseptic operation, 1-6 ml of technetium radioactivity of sodium pertechnetium [99m-Tc]acid injection is injected into the bottle A (D-sodium gluconate freeze-dried medicine box) of the two-step medicine box, uniformly shaken, the solution in the bottle B (tetrofosmin ampoule) is taken out by another syringe and injected into the bottle A, and after fully shaking, the solution is placed for 15-20 minutes at room temperature, thus obtaining the technetium-99m-tetrofosmin injection.
2) Intermediates99mDetermination of the radiochemical purity of Tc-gluconic acid (gluconate):
under aseptic operation, technetium-99 m-Tc]And (3) injecting 1-6 ml of the sodium acid injection into a bottle A of the two-step method medicine box, fully shaking up, and standing at room temperature for 5-10 minutes. Using saline/polyamide filmIdentifying by layer chromatography, and observing the chromatography system TcO4 -And TcO2The Rf value of xH2O,judgment of99mTc-gluconic acid was produced and the radiochemical purity of the label was calculated.
3) End product99mDetermination of the radiochemical purity of Tc-tetrofosmin (tetrofosmin):
identifying with acetonitrile/polyamide chromatography system, and observing the chromatography system99mTc-gluconic acid, TcO4 -、TcO2xH2O and99mRF value determination of Tc-tetrofosmin99mTc-tetrofosmin was produced and the radiochemical purity of the label was calculated.
4) Labeling and determination of radiochemical purity of the two-step kit (A, B):
taking 1 each of the D-sodium gluconate lyophilized kit (bottle A) and the tetrofosmin hydrochloride ampoule (bottle B) prepared in example 3, and subjecting technetium-rich [99m-Tc]to aseptic processing]2ml of sodium acid injection (about 555MBq) is injected into a D-sodium gluconate freeze-dried medicine box, shaken evenly and then placed for 5 minutes at room temperature. The intermediate product is obtained by calculation through the identification of physiological saline/polyamide thin layer chromatography (the chromatography result is shown in table 3)99mThe radiochemical purity of Tc-gluconic acid is more than 95 percent.
And taking out the solution in the bottle B (tetrofosmin ampoule) by another syringe, injecting the solution into the marked D-sodium gluconate kit, fully shaking up, and standing at room temperature for 15-20 minutes to obtain the technetium-99m-tetrofosmin injection. Identified by acetonitrile/polyamide chromatography system (the chromatography result is shown in table 3)99mThe radiochemical purity of Tc-tetrofosmin is more than 90 percent.
TABLE 3 chromatographic identification results chromatography system99mTcO4 - 99mTcO2·xH2O9mTc-tetrofosmin99mTc-gluconic acid physiological saline/polyamide 000-0.20.7-1.0 acetonitrile/polyamide 0.3-0.500.8-1.0 0-0.1
2. Study of stability of two-step kit:
1) stability study of A bottle of kit:
and respectively placing the A bottle of medicine box sample in a refrigerator at 0-4 ℃, room temperature and 38-40 ℃ in a sealed water bath for 5 months, 30 days and 10 days, periodically taking out the A bottle of medicine box sample for property observation and labeled radiochemical purity detection, and inspecting the stability of the A bottle of medicine box under the three conditions.
Taking 30D-sodium gluconate lyophilized drug boxes prepared in example 3, storing 10 of the D-sodium gluconate lyophilized drug boxes in three groups in a sealed water bath at 0-4 ℃, room temperature and 38-40 ℃ for 5 months, 30 days and 10 days, periodically taking out the D-sodium gluconate lyophilized drug boxes, performing property observation and labeled radiochemical purity detection, and inspecting the stability of the D-sodium gluconate drug boxes under the three conditions. The stability results are shown in tables 4, 5 and 6 below:
table 4: stability examination of the drug box stored for more than 3 months under refrigerator conditions (0 ℃ -4 ℃)
Standing time (day) radiochemical purity (%) character
199.5 white powder
2098.8 has no obvious change
6097.4 has no obvious change
9096.9 has no obvious change
12096.7 has no obvious change
16096.9 has no obvious change
The data show that the sample is placed for five months, the characters of the sample are not obviously changed, the labeling radiochemical purity is still more than 95 percent, and the requirement is met, which indicates that the two-step tetrofosmin A bottle medicine box is relatively stable under the condition.
Table 5: stability of the kit was examined by leaving it at room temperature (23-25 ℃ C.) for 30 days
Standing time (day) radiochemical purity (%) character
199.5 white powder
798.7 has no obvious change
1598.1 has no obvious change
2897.4 has no obvious change
3597.1 has no obvious change
From the above data, it can be seen that the properties and radiochemical purity of the kit did not change significantly when the kit was left at room temperature for 30 days, indicating that the kit was relatively stable under these conditions.
Table 6: the stability of the medicine box is inspected after the medicine box is placed in a sealed water bath at the temperature of between 38 and 40 ℃ for 10 days
Standing time (day) radiochemical purity (%) character
199.5 white powder
298.7 has no obvious change
398.2 No significant changes
597.4 has no obvious change
797.9 has no obvious change
1097.1 has no obvious change
From the data, the medicine box is placed in a sealed water bath at 38-40 ℃ for 10 days, no obvious change is observed from the character, the radiochemical purity is still more than 95%, and the stability of the medicine box under the condition can meet the requirements of high-heat and humid transportation conditions and time of the medicine box in summer.
2) B, stability test of bottle medicine box:
and respectively placing the B bottle of medicine box samples in a refrigerator at 0-4 ℃, room temperature and 38-40 ℃ in a sealed water bath for 3 months, 15 days and 10 days, periodically taking out the B bottle of medicine box samples for property observation and labeled radiochemical purity detection, and inspecting the stability of the B bottle of medicine box under the three conditions.
Taking 30 tetrofosmin hydrochloride ampoules prepared in example 1, dividing each ampoule into 3 groups, respectively placing 10 ampoules in each group into 3 groups, respectively placing the ampoules in a refrigerator at 0-4 ℃, room temperature and 38-40 ℃ sealed water bath for storing for 3 months, 15 days and 10 days, periodically taking out the ampoules for property observation and detection of labeled radiochemical purity, and inspecting the stability of the tetrofosmin hydrochloride ampoules under the three conditions. The results of the examination are shown in tables 7, 8 and 9 below.
Table 7: storing the tetrofosmin phosphonium hydrochloride ampoule under the refrigerator condition (0-4 ℃) for more than 3 months for stability investigation
Standing time (day) radiochemical purity (%) character
196.5 colorless clear solution
797.0 has no obvious change
1596.0 has no obvious change
3096.5 has no obvious change
6095.8 has no obvious change
9095.4 has no obvious change
The data show that the sample is placed for 3 months, the properties of the sample are not obviously changed, the marking radiochemical purity is still more than 90 percent, and the requirements are met, so that the tetrofosmin phosphonium hydrochloride ampoule is relatively stable under the conditions.
Table 8: the tetrofosmin phosphonium hydrochloride ampoule is placed at room temperature (23 ℃ -25 ℃) for 10 days for stability investigation
Standing time (day) radiochemical purity (%) character
196.5 colorless clear solution
396.9 without significant change
596.5 has no obvious change
795.8 has no obvious change
1096.0 has no obvious change
From the data, the characters and the radiochemical purity of the tetrofosmin phosphonium hydrochloride ampoule are not obviously changed after the tetrofosmin phosphonium hydrochloride ampoule is placed at room temperature for 10 days, which indicates that the medicine box is relatively stable under the condition.
Table 9: the stability of the medicine box of the ampoule bottle of the tetrofosmin hydrochloride phosphonium salt is inspected by placing the medicine box in a sealed water bath at the temperature of between 38 and 40 ℃ for 10 days
Standing time (day) radiochemical purity (%) character
196.0 colorless clear solution
395.8 colorless clear solution
595.4 has no obvious change
795.1 has no obvious change
1095.1 has no obvious change
From the data, the tetrofosmin phosphonium hydrochloride ampoule is placed in a sealed water bath at 38-40 ℃ for 10 days, no obvious change is observed from the character, the radiochemical purity is still more than 90%, and the stability of the medicine box under the condition can meet the requirements of high-heat and humid transportation conditions and time of the medicine box in summer.
3. Acute toxicity test of injection:
referring to the related experimental method of pharmacopoeia, 0.5ml of technetium-99m tetrofosmin injection prepared from a two-step method kit is taken, and the technetium-99m tetrofosmin injection is injected into the tail vein of a mouse with the weight of 18-20g at a constant speed for 4-5 seconds, and 5 mice are observed as required to see whether the mice die abnormally for 48 hours, and after 72 hours, the mice are dissected to see whether the organs such as heart, liver, spleen, lung, kidney and the like are abnormal.
1) Mouse acute toxicity test of injection:
0.5ml of the technetium-99m tetrofosmin injection (370MBq/3ml) prepared in example 4 was injected into the tail vein of a mouse weighing 18-20g at a constant speed for 4-5 seconds, 5 mice were observed to survive for 48 hours as required, and after 72 hours, the heart, liver, spleen, lung, kidney and other organs were anatomically observed to be abnormal.
The experimental result shows that the dosage of Kunming mice in the experiment is converted into 500 times of the dosage of human body according to the dosage per kilogram of body weight, 5 mice survive the experiment completely without any adverse reaction, and the abnormal expression of each organ is not seen in the anatomical examination. The experimental result shows that the injection has lower toxicity, and can be used for clinical trial research after being checked to be qualified by aseptic pyrogen-free.
4. Biological propertiesof the injection:
a Kunming mouse with the weight of 18-20g is taken, tail vein injection is carried out on about 0.74MBq/0.1ml of radioactive technetium-99m-tetrofosmin injection prepared from a two-step method medicine box, the mouse is killed after being broken neck 2-60 minutes after injection, the heart, the liver, the lung, the muscle and the blood are taken out and respectively weighed, the radioactive count is measured in a well type r detector, and the intake dose of tissues per gram is calculated.
1) In vivo distribution experiment of technetium 99m-tetrofosmin injection in mice:
injecting a Kunming mouse with the weight of about 15-17 g into a tail vein, injecting 0.74MBq/0.1mL of radioactive technetium-99m-tetrofosmin injection prepared in example 4, taking the time after injection for 2 min, 15 min, 30 min and 60 min, killing the neck of the mouse, taking out main organs such as heart, liver, lung and kidney, blood and muscle, weighing the organs respectively, measuring the radioactivity count in a well type gamma detector, calculating the absorbed dose per gram of tissue (% ID/g), calculating the percent injected dose (1% ID) by taking 0.1mL (injection amount) of complex solution, diluting the complex solution to 100 times, then taking 0.1mL in three small test tubes respectively, measuring the radioactivity count of the tissue while measuring the radioactivity count, wherein the percent dose is the average value of the radioactivity count in the three small test tubes; and heart was targeted and compared to% ID/g ratio of lung, liver, blood and muscle. The results are shown in Table 10 below.
Table 10: administration time of the labeled compound in vivo in mice after injection (n-3) is 2 min, 5 min, 15 min, 30 min, and 60 min
Mean standard average standard mean standard organization
Value deviation
The dose per gram of tissue taken (% ID/g) was heart 19.21.2518.50.2317.71.0716.00.7613.40.44 liver 9.780.7611.50.429.470.107.670.255.150.41 lung 9.770.788.080.344.590.863.290.111.730.06 kidney 44.03.1732.01.5128.31.3020.64.5212.80.96 muscle 3.460.723.520.723.440.262.560.023.210.17 blood 4.210.472.570.411.380.031.040.220.720.03
Specific ratio of tissue count per gram of myocardium and other organs heart/liver 2.000.171.440.181.960.522.090.342.750.09 heart/lung 1.970.102.540.073.890.114.870.486.930.21 heart/blood 4.621.007.070.5112.61.1917.41.2218.71.01
As can be seen from the in vivo biodistribution data of the mouse, the composition has higher uptake and better retention in the cardiac muscle, has higher heart/blood and heart/lung ratios, and meets the basic requirements of a cardiac muscle developer. The liver takes the image at the bottom initially, and the clearance is fast, the heart/liver ratio is higher, which is beneficial to obtaining clear image.
To further illustrate the stability of the two-step tetrofosmin kit, reference is made to the comparative examples below.
Comparative example 1: the stability of the two-step method medicine box and the original one-step method formula medicine box is compared: table 11 shows the stability of the two-step kit prepared in example 3 (bottles A and B) compared with the one-step kit prepared according to the formulation of Amersham at 38 ℃ to 40 ℃ and the results of stability evaluationAs can be seen by comparison, the two-step medicine box is prepared by mixing the main raw materials which are easy to oxidize: the tetrofosmin is separated from other components in the medicine box, so that the tetrofosmin is kept in a medium environment which is relatively favorable for the stability of the tetrofosmin, thereby improving the stability of the whole medicine box (A, B bottles). The quality stability of the medicine box is improved by the two-step method that the medicine box is superior to the original medicine boxThe components are separated, so that the components are stored in a medium environment which is relatively favorable for the stability of the components, thereby improving the stability of the whole medicine box (A, B bottles). The improvement of the quality stability of the medicine box is an important aspect that the two-step medicine box is superior to the one-step medicine box of the original Amersham company formula. Table 11: comparing the stability of the two-step method medicine box with the stability of the original one-step method formula medicine box under the condition of 38-40 DEG C
| Standing time (sky) | Labeled radiochemical purity (%) |
| Two-step method medicine box and one-step method medicine box | |
| 1 3 5 10 | 96.0 99.0 95.8 96.0 95.4 88.0 95.1 80.0 |
One-step kit data was obtained from rhizopus japonicum, purified Zhu Wei.99mDetermination of Tc-tetrofosmin kit stability, Abstract compilation of the seventh national conference of radiopharmaceuticals and labeling compounds, 1998.173 p.
Due to the effect of the adjuvant added into the two-step method medicine box, the effect of the adjuvant is further improved99mThe biological performance of Tc-tetrofosmin injection. Mainly characterized by the obvious reduction of the initial uptake of the liver and the obvious improvement of the heart/liver ratio in the early stage, thus being more beneficial to obtaining clear and high-quality imaging images clinically and realizing the advanced imaging of cardiac muscle.
Comparative example 2: comparison of in vivo biodistribution of mice prepared with injection prepared from two-step method medicine box and injection prepared from original one-step method medicine box
Table 12 compares the in vivo biological data for the injection prepared in example 4 with the in vivo biological data for mice prepared with reference to the original Amersham kit.
Table 12: biological distribution comparison of two injections in mice (n is 3), administration time is 5 minutes, 30 minutes, 60 minutes injection mean standard deviation
The ratio of the number of per gram of tissue between the injected fluid (11.50.427.670.255.150.41) of the myocardium and other organs is prepared by two-step heart therapy 18.50.2316.00.7613.50.44
Heart/liver 1.440.182.090.342.750.09
One-step heart 15.10.7713.70.3010.90.93 preparation injection for per gram tissue uptake (% ID/g)Liver 15.00.6710.70.667.400.85 injection*Specific tissue count per gram of myocardium to other organs
Heart/liver 1.010.271.280.211.470.08*The biological data of the prior one-step formula injection are obtained from the literature: lu Jie, Wang Xuan bin, Lu Gong Cheng. A new188Preparation of Re-tetrofosmn complex and research on biodistribution thereof. Nuclear technology, 1999, 22: 695
As can be seen from Table 12, prepared with the original one-step kit formulation99mCompared with Tc-tetrofosmin injection, the injection prepared by the two-step method kit has obviously increased myocardial uptake in mice, and obviously reduced initial uptake of liver, thus greatly improving the heart/liver ratio, and being more beneficial to obtaining clear and high-quality imaging images and realizing the advanced imaging of the myocardial.
The invention has the following beneficial effects:
1. the main raw material medicine tetrofosmin is further subjected to phosphonium salinization to obtain tetrofosmin phosphonium salt which is relatively stable in the air, so that the tetrofosmin phosphonium salt can be stored for a long time, thereby not only solving the problem of storage of the raw material medicine, but also ensuring the stability of the quality of the raw material medicine.
2. The two-step method medicine box separates the main raw material medicine which is relatively unstable from other components, so that the main raw material medicine and the other components are stored in a medium environment in which the tetrofosmin is relatively stable, thereby not only preserving the convenience of the one-step method tetrofosmin medicine box in the aspect of preparation of the injection and the quality of the injection, but also prolonging the shelf life of the medicine box, particularly the transportation and the storage under the condition of high temperature in summer.
Claims (10)
1. A tetrofosmin quaternary phosphonium salt is characterized by having the following formula (I) [ (C)2H5OC2H4)2P+(H)C2H4P+(H)(C2H4OC2H5)2]·2X-……(I)
In the formula: x may be a halogen or a halogen,
or a sulfonate of the formula (II),
in the formula: r1: is-H or-COOH,
R2is-H, -OH or-COOH.
2. The tetrofosmin quaternary phosphonium salt according to claim 1, wherein in formula (I), X is chlorine or bromine; r in the formula (II)1is-COOH and R2 is-OH.
3. A process for preparing tetrofosmin quaternary phosphonium salt with the following formula (I),
[(C2H5OC2H4)2P+(H)C2H4P+(H)(C2H4OC2H5)2]·2X-……(I)
in the formula: x is a halogen, and X is a halogen,
or a sulfonate of the formula (II),
in the formula: r1 is-H, -COOH,
R2is-H, -OH or-COOH,
the method comprises the following steps:
reacting tetrofosmin (C)2H5OC2H4)2PC2H4P(C2H4OC2H5)2With reactants of formula HX
Wherein X is as defined for formula (I),
under the protection of inert gas, the tetrofosmin quaternary phosphonium salt which is easy to dissolve in water and is formed in a nonpolar medium at-10 ℃ to 25 ℃.
4. The method for producing a tetrofosmin quaternary phosphonium salt according to claim 3, wherein the inert gas is a nitrogen gas; the nonpolar medium is benzene, toluene, diethyl ether or petroleum ether.
5. A tetrofosmin medicine box for preparing tetrofosmin quaternary phosphonium salt from tetrofosmin raw medicine is characterized in that the tetrofosmin medicine box is obtained by respectively preparing a bottle (A) and a bottle (B) according to the following two-step method:
(A) preparation of the bottle:
uniformly mixing a reducing agent, an intermediate ligand, an auxiliary material, an excipient and nitrogen-filled secondary water in a weight ratio of (0.01-0.1) to (1-5) to (0.2-2.5) to (1-10) to (0.6-1) so as to fully dissolve the four substances in the nitrogen-filled secondary water, adjusting the pH to 5.0-8.5 by using a pH regulator, performing sterile filtration, subpackaging in containers, performing freeze drying, filling nitrogen and sealing to obtain a freeze-dried medicine box (4) bottle;
wherein the reducing agent is a Sn (II) halogen salt; the intermediate ligand is D-gluconic acid or alkali metal or alkaline earth metal salt thereof; the auxiliary materials are sulfosalicylic acid dihydrate, sodium sulfosalicylate dihydrate or disodium sulfosalicylic acid, citric acid or sodium salt thereof, and tartaric acid or potassium or sodium salt thereof; theexcipient is sodium chloride or mannitol; the pH regulator is sodium hydroxide, sodium bicarbonate or disodium hydrogen phosphate;
(B) preparation of the bottle:
dissolving the tetrofosmin phosphonium salt as the main raw material medicine in the weight ratio of (1-5) to (1-10) to (0.2-1.0) to obtain a medicine box bottle (B);
wherein the adjuvants are Tween emulsifier or cyclodextrin; the solvent is water, ethanol water solution or absolute ethanol.
6. A tetrofosmin kit according to claim 5 wherein, in the preparation of vial (A), the Sn (II) halide salt is SnCL2·2H2O or SnF2(ii) a In the preparation of the bottle (B), the Tween emulsifier is Tween 20, Tween 40 or Tween 80The cyclodextrin is gamma-cyclodextrin or β -cyclodextrin.
7. The radioactive technetium-99m tetrofosmin injection is characterized by being prepared by the following steps:
1) preparation of bottle (A):
mixing reducing agent, intermediate ligand, adjuvant, excipient and nitrogen-filled secondary water at weight ratio of 0.01-0.1 to 1-5 to 0.2-2.5 to 1-10 to 0.6-1, dissolving the above four materials in the above nitrogen-filled secondary water, adjusting pH to 5.0-8.5 with pH regulator, sterile filtering, packaging in containers, freeze drying, filling nitrogen gas, and sealing to obtain lyophilized bottle (A);
wherein the reducing agent is a Sn (II) halogen salt; the intermediate ligand is D-gluconic acid or alkali metal or alkaline earth metal salt thereof; the auxiliary materials are sulfosalicylic acid dihydrate, sodium sulfosalicylate dihydrate or disodium sulfosalicylic acid, citric acid or sodium salt thereof, and tartaric acid or potassium or sodium salt thereof; the excipient is sodium chloride or mannitol; the pH regulator is sodium hydroxide, sodium bicarbonate or disodium hydrogen phosphate;
2) and (B) preparation of bottle:
dissolving the tetrofosmin quaternary phosphonium salt serving as the main raw material medicament of claim 1 in an auxiliary material solvent (1-5) to (1-10) to (0.2-1.0) by weight ratio, and filling the tetrofosmin quaternary phosphonium salt and the auxiliary material into containers after full dissolution to prepare medicine box bottles (B);
wherein the auxiliary material is Tween emulsifier or cyclodextrin; the solvent is water, ethanol water solution or absolute ethanol.
3) Under aseptic operation, pertechnetate99mTcO4 -The radioactivity of the product is measured, a proper amount of the product is injected into the prepared medicine box (A), the product is shaken up, the solution in the prepared medicine box (B) is taken out and injected into the medicine box (A), the solution is fully shaken up and placed for 15 to 20 minutes at room temperature, and the radioactive technetium-99m tetrofosmin injection is obtained.
8. The tetrofosmin injection solution as claimed in claim 7, wherein, in the preparation of the (A) bottle, the Sn (II) halogen salt is SnCL2.2H2O or SnF2(ii) a In the preparation of the (B) bottle,the Tween emulsifier is Tween 20, Tween 40 or Tween 80, and the cyclodextrin is upsilon-cyclodextrin or β -cyclodextrin.
9. Use of a tetrofosmin kit according to claim 5 or 6 in the preparation of an injectable solution of radioactive technetium-99m tetrofosmin for use as an imaging agent in human oranimal organs or tissues.
10. The use according to claim 9 of the injectable solution of radioactive technetium-99m tetrofosmin as an imaging agent in the myocardium or in tumours.
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| US20090311178A1 (en) * | 2004-12-15 | 2009-12-17 | Ge Healthcare Limited | Pyrrolinidium derivatives as m3 muscarinic receptors |
| CN104076384A (en) * | 2013-03-28 | 2014-10-01 | 上海原子科兴药业有限公司 | Detection method of 99mTc-MDP brine phase |
| EP2899195A1 (en) | 2014-01-28 | 2015-07-29 | ROTOP Pharmaka AG | Stabilized form of Tetrofosmin and its use |
| US9321095B2 (en) | 2010-06-30 | 2016-04-26 | General Electric Company | Apparatuses and methods for cutting porous substrates |
| CN108884073A (en) * | 2017-03-08 | 2018-11-23 | 朱比兰特通用有限公司（原朱比兰特生命科学有限公司之部门） | A kind of improved method preparing Tetrofosmin or its acid-addition salts |
| CN111050751A (en) * | 2017-11-23 | 2020-04-21 | 朱比兰特通用有限公司(原朱比兰特生命科学有限公司分部) | Pharmaceutical composition comprising tetrofosmin and pharmaceutically acceptable salts thereof |
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| US20090311178A1 (en) * | 2004-12-15 | 2009-12-17 | Ge Healthcare Limited | Pyrrolinidium derivatives as m3 muscarinic receptors |
| US20110008252A9 (en) * | 2004-12-15 | 2011-01-13 | Ge Healthcare Limited | Stabalised 99mtc compositions |
| US9694092B2 (en) * | 2004-12-15 | 2017-07-04 | Ge Healthcare Limited | Stabalised 99mTc compositions |
| US9321095B2 (en) | 2010-06-30 | 2016-04-26 | General Electric Company | Apparatuses and methods for cutting porous substrates |
| CN104076384A (en) * | 2013-03-28 | 2014-10-01 | 上海原子科兴药业有限公司 | Detection method of 99mTc-MDP brine phase |
| EP2899195A1 (en) | 2014-01-28 | 2015-07-29 | ROTOP Pharmaka AG | Stabilized form of Tetrofosmin and its use |
| AU2015212915B2 (en) * | 2014-01-28 | 2016-11-10 | Rotop Pharmaka Gmbh | Stabilized form of Tetrofosmin and its use |
| US9963473B2 (en) | 2014-01-28 | 2018-05-08 | Rotop Pharmaka Gmbh | Stabilized form of tetrofosmin and its use |
| CN108884073A (en) * | 2017-03-08 | 2018-11-23 | 朱比兰特通用有限公司（原朱比兰特生命科学有限公司之部门） | A kind of improved method preparing Tetrofosmin or its acid-addition salts |
| CN111050751A (en) * | 2017-11-23 | 2020-04-21 | 朱比兰特通用有限公司(原朱比兰特生命科学有限公司分部) | Pharmaceutical composition comprising tetrofosmin and pharmaceutically acceptable salts thereof |
| EP3661486A4 (en) * | 2017-11-23 | 2020-12-02 | Jubilant Generics Limited (Formerly a Division of Jubilant Life Sciences Limited) | Pharmaceutical composition comprising tetrofosmin and pharmaceutically acceptable salts thereof |
| WO2021238529A1 (en) * | 2020-05-29 | 2021-12-02 | 成都纽瑞特医疗科技股份有限公司 | Technetium carbon microsphere injection, preparation method therefor and use thereof |
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