CN1493283A - Edalavon powder for ampoul injection having good stability and its preparation method - Google Patents
Edalavon powder for ampoul injection having good stability and its preparation method Download PDFInfo
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- CN1493283A CN1493283A CNA031567797A CN03156779A CN1493283A CN 1493283 A CN1493283 A CN 1493283A CN A031567797 A CNA031567797 A CN A031567797A CN 03156779 A CN03156779 A CN 03156779A CN 1493283 A CN1493283 A CN 1493283A
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- CN
- China
- Prior art keywords
- edaravone
- water
- injection
- injectable powder
- soluble filler
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000007924 injection Substances 0.000 title claims abstract description 42
- 238000002347 injection Methods 0.000 title claims abstract description 42
- 239000000843 powder Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims description 22
- 239000000945 filler Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 16
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 claims description 68
- 229950009041 edaravone Drugs 0.000 claims description 67
- 239000003963 antioxidant agent Substances 0.000 claims description 17
- 230000003078 antioxidant effect Effects 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- 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
- 235000002639 sodium chloride Nutrition 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000001694 spray drying Methods 0.000 claims description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 235000010265 sodium sulphite Nutrition 0.000 claims description 8
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Natural products SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 5
- 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
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 239000004201 L-cysteine Substances 0.000 claims description 4
- 235000013878 L-cysteine Nutrition 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 239000003708 ampul Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 230000003064 anti-oxidating effect Effects 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 28
- 235000006708 antioxidants Nutrition 0.000 description 11
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000003863 ammonium salts Chemical class 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QIJRTFXNRTXDIP-JIZZDEOASA-N L-cysteine hydrochloride hydrate Chemical compound O.Cl.SC[C@H](N)C(O)=O QIJRTFXNRTXDIP-JIZZDEOASA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 229960002433 cysteine Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- FXXMNCZOYVUJEE-UHFFFAOYSA-N C1(=CC=CC=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O Chemical compound C1(=CC=CC=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O FXXMNCZOYVUJEE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 238000009924 canning Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 238000005262 decarbonization Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 235000012459 muffins Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- PBDAWQLIMPWEEF-JEDNCBNOSA-M sodium;(2s)-2,6-diaminohexanoate Chemical compound [Na+].NCCCC[C@H](N)C([O-])=O PBDAWQLIMPWEEF-JEDNCBNOSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Abstract
A powder injection of Yidalafeng with high stability and its preparing process are disclosed. Said powder injection contains Yidalafeng 1-10%, water-soluble filler 90-99%, antioxidizing agent and pH regulator.
Description
Technical field
The present invention relates to injection Edaravone injectable powder that has good stability and preparation method thereof.
Background technology
Edaravone is central nervous system's medication of new generation, is used for nervous symptoms, activities of daily life obstacle and the dysfunction of cerebral infarction acute stage generation, also is used for the subarachnoid hemorrhage acute stages treated.English name: Edaravone; Chemical name: 3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one, English chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one.Structural formula is:
The preparation of listing is an aqueous injection at present, and specification is 20ml: 30mg, with normal saline dilution posterior vein instillation medication.Because Edaravone is insoluble in water, rare aqueous solution instability.Present injection need add more L-cysteine and sodium sulfite as stabilizing agent and cosolvent.Because the poor stability of aqueous solution in the heating for dissolving and the difficult control of high temperature sterilize of preparation process, decomposes easily, the stability of manufactured goods is relatively more responsive to condition of storage, and effect duration is shorter.
Summary of the invention
The purpose of this invention is to provide a kind of injection Edaravone injectable powder and preparation method thereof with better storage stability.
The Edaravone of so-called injection is according to " the definition among two appendix IB of Chinese pharmacopoeia version in 2000, refer to be sealed in the sterile solid in the container, this container can be a glass ampule, more suitably be that vial adds plug and adds aluminium lid sealing again, add suitable solvent for injection dissolving back during use for parenterai administration, i.e. the preparation of muscle, subcutaneous, vein or intra-arterial injection.
Test finds that Edaravone is highly stable under solid state, and room temperature was placed 2 years, places half a year for 37 ℃, places 10 days, and does not all observe decomposition for 60 ℃.In above-mentioned powder ampoule agent for injection, Edaravone exists with solid state.But the dissolution velocity of the Edaravone of solid crystal state in water is slower, for make injectable powder face with before can form the acceptable solution of physiology in rapid dissolving, need to solve from two approach.
The one, in the injectable powder of preparation, the solid particle size of Edaravone must be enough tiny.Can be by under the aseptic condition, micronization processing makes the pressed powder particle diameter less than 10 microns, and the powder direct packaging makes then; Also can adopt solvent crystallization, the preparation crystallite; Can also use the powder of the trickle particle diameter of spray drying method for preparation; Better method is to adopt freeze-drying, adds suitable water-soluble filler, makes loose muffin, and Edaravone therebetween is very thin crystallization.
The 2nd, the solvent when selecting suitable redissolution.This solvent must satisfy the requirements such as aseptic no thermal source of injection.Utilize Edaravone to be soluble in the aqueous solution of meta-alkalescence and the physicochemical property of rare alcohol, select the above-mentioned solution of injection specification for use, earlier the powder body in the Edaravone powder pin is dissolved into concentrated solution, is diluted to then in the sodium chloride injection or glucose injection of larger volume, for intravenous drip.
The present invention has prepared the injection Edaravone injectable powder with better storage stability by introduce water-soluble filler in prescription, and it is made by following component:
(A) 0.1%-50%, preferred 1%-30%, the more preferably Edaravone of 1%-10% is based on the two total amount of Edaravone and water-soluble filler;
(B) 50%-99.9%, preferred 70%-99%, the more preferably water-soluble filler of 90%-99% is based on the two total amount of Edaravone and water-soluble filler;
(C) an amount of antioxidant; With
(D) Ren Xuan an amount of pH regulator agent.
Wherein water-soluble filler is selected from following one or more: sugar alcohol, monosaccharide, disaccharide, oligosaccharide, polysaccharide, water-soluble amino acid and salt or derivatives thereof thereof, taurine and salt thereof, inorganic salts, polyvinyl pyrrolidone, gelatin, organic acid.Concrete example is mannitol, sorbitol, lactose, maltose, gelatin, polyvidone, dextran, glucose, citric acid, potassium chloride, sodium chloride, sodium hydrogen phosphate, sodium carbonate, glycine, lysine etc.
Antioxidant is antioxidant commonly used in the medicine, for example L-cysteine or its salt, sodium sulfite, ascorbic acid or its salt etc., or their mixture.
Second purpose of the present invention provides the method for the Edaravone preparation used of preparation injection for intravenous.In a preferred embodiment, this method may further comprise the steps: in being the alcoholic solution of 1-50vol%, water for injection or concentration adds Edaravone, and water-soluble filler, antioxidant and optional pH regulator agent, freeze drying process carries out lyophilizing routinely.
In another embodiment, this method may further comprise the steps: with Edaravone, and water-soluble filler, antioxidant and optional pH regulator agent are mixed together, micronization (for example adopting the supersonic airstream comminuting method) under aseptic condition perhaps together dissolves with water or rare alcohol, spray drying again then.
In another embodiment, this method may further comprise the steps: with Edaravone, and water-soluble filler, antioxidant and optional pH regulator agent pulverize separately mix then.
In a further embodiment, this method may further comprise the steps: the employing solvent crystallization prepares the crystallite of Edaravone, with water-soluble filler, antioxidant and optional pH regulator agent are pulverized and (are for example adopted spray drying method, the supersonic airstream comminuting method grinds etc.), remix.
Under above-mentioned all situations, pulverizing should reach below the 10 μ m, and 1nm is to the granularity of 1 μ m usually.The consumption of antioxidant generally is the 10%-800% of Edaravone consumption, is preferably 10-30%.
When freeze-drying prepares the sterile injection powder of Edaravone, must add water miscible filler.When freeze-drying prepares the sterile injection powder of Edaravone, can also add the pH regulator agent.
Water-soluble filler can be one or more of following compositions: mannitol, sorbitol, lactose, maltose, gelatin, polyvidone, dextran, glucose, citric acid, potassium chloride, sodium chloride, sodium hydrogen phosphate, sodium carbonate etc.The water-soluble filler consumption is that every bottle of 5mg is to 500mg.Comparatively suitable consumption is that 50mg is to 200mg.Only consumption is about 100mg.By weight percentage, above-mentioned water-soluble filler accounts for the 50%-99.9% of water-soluble filler and Edaravone total amount, comparatively suitable ratio 70%-99%, and the best is 90%-99%.
Here the pharmaceutic adjuvant that is suitable for regulator solution pH can be nonvolatile acid such as citric acid, malic acid, phosphoric acid, sulphuric acid, sulfurous acid, and sodium hydroxide or potassium or ammonium, sodium carbonate or potassium or ammonium salt, sodium bicarbonate or potassium or ammonium salt, sodium phosphate or potassium or ammonium salt, disodium-hydrogen or potassium or ammonium salt, sodium dihydrogen phosphate or potassium or acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of physiology and salt such as ammonium salt, citric acid trisodium salt, sodium acetate or ammonium salt.The consumption of pH regulator agent requires required amount with the pH that regulates solution before the lyophilizing to regulation.
Through the sterilized powder of air-flow micronization or solvent crystallization or spray drying method for preparation, sterilized powder packing again makes in the technology of injection Edaravone, also needs above-mentioned water-soluble filler and pH regulator agent, and consumption is identical.Can be mixed together before processing, and then supersonic airstream pulverizing or water and rare alcohol together dissolves, spray drying also can be mixed behind the pulverize separately again, or directly and the crystallite mix homogeneously.
Specification at freeze-drying preparation injection Edaravone is every unit preparation, i.e. every bottle of 30mg.By weight percentage, Edaravone accounts for the 0.1%-50% of water-soluble filler and Edaravone total amount (disregarding solvent), comparatively suitable ratio 1%-30%, and the best is 1%-10%.
In the technology of freeze-drying preparation injection Edaravone, need be prepared into stock solution with appropriate solvent.Solvent for meet " water for injection of two regulations of Chinese pharmacopoeia version in 2000, or concentration at 1%v/v to the alcoholic solution between the 50%v/v.Edaravone concentration therein at 30mg/2ml between the 30mg/20ml.Add above-mentioned water-soluble filler wiring solution-forming, the water-soluble filler consumption calculates according to solid weight in the prescription, illustrates in preamble.Be guaranteed quality, also need add in the stock solution concentration preferably 0.1% to the antioxidant of 5%w/v, these antioxidant can be a kind of of L-cysteine or its salt, sodium sulfite, ascorbic acid or its salt or use simultaneously that general only the need uses its minimal effective concentration just enough.The pH value of solution is between 3 to 9, and more suitably pH value is between 3.5 to 8, and only pH scope is the arbitrary value between 3.5 to 7.5.Being used to regulate pH value reagent is pH regulator agent and the phase application quantity that preamble has been mentioned.In fact, generally do not need to regulate pH value, electrolytical existence may be unfavorable to stability.After being mixed with stock solution as stated above, freeze drying process carries out lyophilizing routinely, makes injectable powder.The moisture of control injectable powder is preferably in below the 3%w/w below 5%w/w.
The redissolution solvent of lyophilized injectable powder is necessary for and meets injection and require solvent, can be water for injection, the 0.9%w/v sodium chloride injection, the 5%w/v% glucose injection, the ethanol injection liquid of 20%v/v, sodium bicarbonate injection (" two sodium bicarbonate injections that record of Chinese pharmacopoeia version in 2000).
Zhi Bei Edaravone freeze-dried powder as stated above is with reference to " two appendix of Chinese pharmacopoeia version in 2000 carry out stable accelerated test about the guideline of stability test.
Test method: get three batches of this product,, put into climatic chamber, be controlled under the condition of 40 ℃ and relative humidity 75%,, observe by the investigation project and to measure respectively at 0,1,2,3 and 6 months several point in time sampling by listing packing.
Result of the test: six months accelerated test result shows that outward appearance, color and luster, pH value etc. are not seen obvious change with 0 month result, the minor variations irregularities of its content, and also nonsignificance, HPLC measures and does not detect other catabolites (seeing the following form).The result shows to have excellent storage stability, can infer that stability can reach 3 years.
Injection Edaravone accelerated stability test result
(experimental enviroment: 40 ℃ of humidity 75% temperature)
Time clarity of solution related substance
Appearance luster pH value content (%)
(moon) and color (%)
Lot number
0 white lyophilizing block clarifies colourless 8.61 0.01 101.0
1 white lyophilizing block clarifies colourless 8.59 0.02 98.9
020,601 2 white lyophilizing blocks clarify colourless 8.62 0.04 100.7
3 white lyophilizing blocks clarify colourless 8.61 0.03 101.9
6 white lyophilizing blocks clarify colourless 8.60 0.03 97.3
0 white lyophilizing block clarifies colourless 8.58 0.02 100.5
1 white lyophilizing block clarifies colourless 8.60 0.03 99.8
020,602 2 white lyophilizing blocks clarify colourless 8.57 0.02 98.4
3 white lyophilizing blocks clarify colourless 8.61 0.02 101.1
6 white lyophilizing blocks clarify colourless 8.60 0.03 100.6
0 white lyophilizing block clarifies colourless 8.60 0.03 99.4
1 white lyophilizing block clarifies colourless 8.57 0.02 98.0
020,603 2 white lyophilizing blocks clarify colourless 8.61 0.03 101.6
3 white lyophilizing blocks clarify colourless 8.60 0.03 99.8
6 white lyophilizing blocks clarify colourless 8.61 0.03 99.3
The effect that the present invention is useful:
1. has excellent storage stability.
2. only need add less antioxidant.
3. enrich clinical dosage form.
The specific embodiment
Following examples are to further annotation of the present invention, but not limitation of the present invention.
Embodiment 1 freeze-drying prepares the injection Edaravone
Prescription:
Edaravone 30g
L-cysteine hydrochloride (water) 5g
Mannitol 265g
Water for injection adds to 7000ml
Make 1000 bottles
Preparation technology:
Get the mannitol and the cysteine hydrochloride of recipe quantity, add injection water 5000ml stirring and make dissolving, be warming up to 60 ℃, the Edaravone that adds recipe quantity stirs and makes dissolving, adds to the full amount of water for injection, be cooled to room temperature, add 0.01% active carbon and stirred 15 minutes, filtering decarbonization is again through 0.22 μ m microporous filter membrane malleation aseptic filtration; After the inspection of semifinished product was qualified, aseptic canning was in the 20ml vial, every bottled amount 7ml; Through frozen drying about 24 hours, seal promptly.The qualified back of product inspection packing.
Embodiment 2 freeze-dryings prepare the injection Edaravone
Prescription:
Edaravone 30g
L-cysteine hydrochloride (water) 5g
Glucose 600g
Ethanol 500ml
Water for injection adds to 5000ml
Make 1000 bottles
Preparation method is with embodiment 1.
Embodiment 3 spray drying method for preparation injection Edaravones
Prescription:
Edaravone 30g
Sodium sulfite 5g
Lactose 750g
Water adds to 5000ml
Make 1000 bottles
Add in the entry Edaravone, sodium sulfite and lactose and dissolving, use the spray dryer spray drying then, be sub-packed in 1000 vials.
Embodiment 4 spray drying method for preparation injection Edaravones
Prescription:
Edaravone 30g
Sodium sulfite 5g
L-Lysine sodium salt 750g
Water adds to 5000ml
Make 1000 bottles
Edaravone, sodium sulfite and lactose are mixed, pulverize with the supersonic airstream comminuting method then, be sub-packed in 1000 vials.
Embodiment 5 solvent crystallization legal systems are equipped with the injection Edaravone
Prescription:
Edaravone 60g
L-cysteine hydrochloride (water) 10g
Glucose 1000g
Ethanol 500ml
Make 1000 bottles
With the crystallization in 500ml ethanol of 30g Edaravone, make the crystallite Edaravone, mix with L-cysteine hydrochloride and glucose then, be packed as 1000 bottles.
Claims (10)
1, the injection Edaravone injectable powder of high stability, it is made by following component:
(A) 0.1%-50%, preferred 1%-30%, the more preferably Edaravone of 1%-10% is based on the two total amount of Edaravone and water-soluble filler;
(B) 50%-99.9%, preferred 70%-99%, the more preferably water-soluble filler of 90%-99% is based on the two total amount of Edaravone and water-soluble filler;
(C) an amount of antioxidant; With
(D) Ren Xuan an amount of pH regulator agent.
2, according to the described injection Edaravone of claim 1 injectable powder, it is characterized in that the Edaravone in the preparation exists with solid state.
3, injection Edaravone injectable powder according to claim 1 is characterized in that the amount that each unit preparation (per ampoule or every bottle) contains Edaravone is 30 milligrams or 60 milligrams or 90 milligrams.
4, injection Edaravone injectable powder according to claim 1 is characterized in that the method for preparing is a freeze-drying, and the moisture of lyophilizing finished product is measured with Ka Feixiushi method or boulton process, contains moisture and is not higher than 5%, and is best for not being higher than 3%.
5, injection Edaravone injectable powder according to claim 1 is characterized in that described water-soluble filler is one or more of following ingredients: mannitol, sorbitol, lactose, maltose, gelatin, polyvidone, dextran, glucose, citric acid, potassium chloride, sodium chloride, sodium hydrogen phosphate, sodium carbonate.
6, injection Edaravone injectable powder according to claim 1 is characterized in that antioxidant is L-cysteine or its salt or sodium sulfite.
7, the method for preparing the described injection Edaravone of claim 1 injectable powder, be included in the alcoholic solution that water for injection or concentration are 1-50vol% and add Edaravone, water-soluble filler, antioxidant and optional pH regulator agent, freeze drying process carries out lyophilizing routinely.
8, prepare the method for the described injection Edaravone of claim 1 injectable powder, comprise with Edaravone water-soluble filler, antioxidant and optional pH regulator agent are mixed together, micronization under aseptic condition perhaps together dissolves with water or rare alcohol, spray drying again then.
9, prepare the method for the described injection Edaravone of claim 1 injectable powder, comprise Edaravone, water-soluble filler, antioxidant and optional pH regulator agent pulverize separately mix then.
10, the method for preparing the described injection Edaravone of claim 1 injectable powder comprises the crystallite that adopts solvent crystallization to prepare Edaravone, and with water-soluble filler, remix is pulverized in antioxidant and optional pH regulator agent.
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| JP2020525458A (en) * | 2017-07-06 | 2020-08-27 | ツリーウェイ ティーダブリュー００１ ビー．ブイ．Ｔｒｅｅｗａｙ ＴＷ００１ Ｂ．Ｖ． | Use of edaravone in the oral treatment of oxidative stress-mediated neurodegenerative disorders |
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