CN116712468B - Extraction method of ginkgo leaf extract and preparation method of Shuxuening injection - Google Patents
Extraction method of ginkgo leaf extract and preparation method of Shuxuening injection Download PDFInfo
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- CN116712468B CN116712468B CN202310633718.3A CN202310633718A CN116712468B CN 116712468 B CN116712468 B CN 116712468B CN 202310633718 A CN202310633718 A CN 202310633718A CN 116712468 B CN116712468 B CN 116712468B
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- ginkgo leaf
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- 239000009429 Ginkgo biloba extract Substances 0.000 title claims abstract description 68
- 238000002347 injection Methods 0.000 title claims abstract description 66
- 239000007924 injection Substances 0.000 title claims abstract description 66
- 239000010068 shuxuening Substances 0.000 title claims abstract description 66
- 238000000605 extraction Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000004090 dissolution Methods 0.000 claims abstract description 8
- 239000000284 extract Substances 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 34
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 235000011201 Ginkgo Nutrition 0.000 claims description 10
- 241000218628 Ginkgo Species 0.000 claims description 10
- 235000008100 Ginkgo biloba Nutrition 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 8
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 8
- 239000000920 calcium hydroxide Substances 0.000 claims description 8
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000002244 precipitate Substances 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 5
- 229960004063 propylene glycol Drugs 0.000 claims description 5
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical group O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- 230000001502 supplementing effect Effects 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 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 238000000108 ultra-filtration Methods 0.000 claims 1
- YXHVCZZLWZYHSA-UHFFFAOYSA-N (Z)-6-[8-pentadecenyl]salicylic acid Natural products CCCCCCC=CCCCCCCCC1=CC=CC(O)=C1C(O)=O YXHVCZZLWZYHSA-UHFFFAOYSA-N 0.000 abstract description 43
- YXHVCZZLWZYHSA-FPLPWBNLSA-N Ginkgoic acid Chemical compound CCCCCC\C=C/CCCCCCCC1=CC=CC(O)=C1C(O)=O YXHVCZZLWZYHSA-FPLPWBNLSA-N 0.000 abstract description 43
- 239000001648 tannin Substances 0.000 abstract description 41
- 235000018553 tannin Nutrition 0.000 abstract description 41
- 229920001864 tannin Polymers 0.000 abstract description 41
- 239000003814 drug Substances 0.000 abstract description 7
- 206010070834 Sensitisation Diseases 0.000 abstract description 6
- 230000008313 sensitization Effects 0.000 abstract description 6
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- 102000004169 proteins and genes Human genes 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 10
- XUDNWQSXPROHLK-OACYRQNASA-N 2-phenyl-3-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=CC=CC=2)OC2=CC=CC=C2C1=O XUDNWQSXPROHLK-OACYRQNASA-N 0.000 description 8
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 8
- 229930003944 flavone Natural products 0.000 description 8
- 150000002212 flavone derivatives Chemical class 0.000 description 8
- 235000011949 flavones Nutrition 0.000 description 8
- 229930184727 ginkgolide Natural products 0.000 description 8
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 8
- -1 flavonoid compounds Chemical class 0.000 description 7
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 5
- 229910001424 calcium ion Inorganic materials 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
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- 238000001514 detection method Methods 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000014103 egg white Nutrition 0.000 description 2
- 210000000969 egg white Anatomy 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 229940068052 ginkgo biloba extract Drugs 0.000 description 2
- 235000020686 ginkgo biloba extract Nutrition 0.000 description 2
- SQOJOAFXDQDRGF-WJHVHIKBSA-N ginkgolide B Natural products O=C1[C@@H](C)[C@@]2(O)[C@@H]([C@H](O)[C@]34[C@@H]5OC(=O)[C@]23O[C@H]2OC(=O)[C@H](O)[C@@]42[C@H](C(C)(C)C)C5)O1 SQOJOAFXDQDRGF-WJHVHIKBSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- 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
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- AMOGMTLMADGEOQ-FNZROXQESA-N Ginkgolide C Chemical compound O([C@H]1O2)C(=O)[C@H](O)C31[C@]14[C@@H](O)[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@@H](O)[C@H]3C(C)(C)C AMOGMTLMADGEOQ-FNZROXQESA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Natural products O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 description 1
- 235000011957 flavonols Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- FPUXKXIZEIDQKW-MFJLLLFKSA-N ginkgolide A Natural products O=C1[C@H](C)[C@@]2(O)[C@@H](O1)C[C@]13[C@@H]4OC(=O)[C@]21O[C@@H]1OC(=O)[C@H](O)[C@]31[C@@H](C(C)(C)C)C4 FPUXKXIZEIDQKW-MFJLLLFKSA-N 0.000 description 1
- AMOGMTLMADGEOQ-DPFZUGDXSA-N ginkgolide C Natural products O=C1[C@@H](C)[C@]2(O)[C@H]([C@H](O)[C@@]34[C@H]5[C@H](O)[C@@H](C(C)(C)C)[C@]63[C@H](O)C(=O)O[C@H]6O[C@@]24C(=O)O5)O1 AMOGMTLMADGEOQ-DPFZUGDXSA-N 0.000 description 1
- FPUXKXIZEIDQKW-VKMVSBOZSA-N ginkgolide-a Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13C[C@@H]1OC(=O)[C@@H](C)[C@]21O FPUXKXIZEIDQKW-VKMVSBOZSA-N 0.000 description 1
- SQOJOAFXDQDRGF-MMQTXUMRSA-N ginkgolide-b Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13[C@@H](O)[C@@H]1OC(=O)[C@@H](C)[C@]21O SQOJOAFXDQDRGF-MMQTXUMRSA-N 0.000 description 1
- 229930182470 glycoside Natural products 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
- 238000009776 industrial production Methods 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000005493 rutin Nutrition 0.000 description 1
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 1
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 1
- 229960004555 rutoside Drugs 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
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Abstract
The invention provides an extraction method of ginkgo leaf extract and a preparation method of Shuxuening injection, belonging to the technical field of traditional Chinese medicine extraction. The Shuxuening injection is prepared by utilizing the ginkgo leaf extract. The invention effectively extracts the effective components by selecting a specific extractant system, inhibits the dissolution of the sensitization components, can effectively remove the sensitization components such as tannins, ginkgolic acid and the like without column chromatography in the whole process, has simple and convenient operation in the whole extraction process, reduces the solvent consumption and reduces the production cost.
Description
Technical Field
The invention relates to extraction of traditional Chinese medicines, in particular to an extraction method of ginkgo leaf extract and a preparation method of Shuxuening injection.
Background
The Shuxuening injection has the functions of dilating blood vessel and improving microcirculation, and is mainly used for ischemic cardiovascular and cerebrovascular diseases, coronary heart disease, angina, cerebral embolism, cerebral vasospasm and the like. Shuxuening injection is a sterilized water solution prepared by extracting ginkgo leaf. The ginkgo leaf extract prepared by direct extraction still contains a large amount of ginkgolic acid, tannins and the like, and can not be directly used for producing the Shuxuening injection, and the ginkgo leaf extract can be used for producing the Shuxuening injection after the ginkgolic acid, the tannins and the like are removed. And when substances such as ginkgolic acid, tannins and the like in the ginkgo leaf extract are not removed cleanly, sensitization reaction can be initiated, so that the application risk of the prepared Shuxuening injection is increased.
In order to ensure the medication safety of the Shuxuening injection, the existing method adopts a column chromatography mode to remove easily sensitized substances such as ginkgolic acid, tannins and the like aiming at the ginkgo leaf extract; meanwhile, in order to retain the effective components such as flavonoid compounds, lactone compounds and the like, filling materials in the adsorption column are limited. However, in the actual production process, substances such as ginkgolic acid, tannins and the like in the ginkgo leaf extract are treated by adopting a column chromatography mode, and the method has the defects of large solvent consumption, long time consumption, complex process and the like.
Disclosure of Invention
The invention provides an extraction method of ginkgo leaf extract and a preparation method of Shuxuening injection.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
An extraction method of ginkgo leaf extract includes such steps as adding the aqueous solution of 45-50 wt% alcohol and proper amount of calcium carbonate to ginkgo leaf, heating, extracting, filtering, extracting for 3 times, mixing the filtrates, concentrating, adding alcohol to 85-90 wt% alcohol, cold storage, depositing in alcohol, filtering, adding aqueous solution of calcium hydroxide while stirring, coarse filtering, ultrafiltering, concentrating and drying.
Further, in each extraction process, the weight ratio of the ginkgo leaf to the calcium carbonate in the extractant is 1:0.15-0.2.
Further, in each extraction process, the weight-to-volume ratio of the ginkgo leaf to the ethanol aqueous solution in the extractant is 1g: 8-9 mL.
Further, the temperature of each extraction is 65-70 ℃ and the time is 3-4 hours.
Further, after concentration, the relative density (70 ℃) of the fluid extract is 1.15 to 1.20.
Further, the time of refrigerated alcohol precipitation is more than or equal to 24 hours.
A preparation method of Shuxuening injection comprises the step of preparing the Shuxuening injection by utilizing ginkgo leaf extract extracted by the extraction method.
Further, the preparation method comprises the steps of preparing a buffer solution from disodium hydrogen phosphate and sodium dihydrogen phosphate, adding an antioxidant and 1, 2-propylene glycol for dissolution, adding the ginkgo leaf extract for dissolution, supplementing water to a full amount, filtering, and ultrafiltering to obtain the Shuxuening injection.
Further, the pH of the buffer is 7.5 to 8.0.
Further, the weight-to-volume ratio of the ginkgo leaf extract to the buffer solution to the antioxidant to the 1, 2-propanediol is 14g:200mL:1.8 to 2.2g: 400-450 mL;
The make-up water to full is make-up water to 4000mL.
The extraction method of the ginkgo leaf extract and the preparation method of the Shuxuening injection have the beneficial effects that:
According to the invention, the concentration of the ethanol water solution with specific concentration is selected, and calcium carbonate is added in the extraction process, so that the system is alkalescent, and the dissolution of flavonoid compounds and lactone compounds such as rutin, flavonol glycoside and terpene lactone into the ethanol water solution is promoted; in the extraction process, calcium ions in the system react to form a precipitate after contacting with dissolved tannins, so that the tannins are restrained from being dissolved in the system, and meanwhile, the calcium ions are increased due to the fact that carbonate ions and hydrogen ions are unstable under heating conditions after being combined and converted into carbon dioxide gas to overflow from the system, so that the reaction of the tannins and the calcium ions for forming the precipitate is promoted to be carried out positively;
In addition, in the extraction process, calcium carbonate can be complexed with ginkgolic acid to form insoluble matters, so that dissolution of ginkgolic acid in a system is inhibited;
Because the insoluble matters formed by the tannins and the calcium ions and the precipitate formed by complexing the ginkgolic acid and the calcium carbonate cannot be dissolved in the extractant system of the invention, the insoluble matters can be removed together with the residues through filtration, thereby effectively reducing the content of the tannins and the ginkgolic acid in the filtrate and ensuring the medication safety of the subsequently prepared ginkgo leaf extract;
Furthermore, the invention removes macromolecular proteins through further alcohol precipitation, and removes residual tannins through further adding calcium hydroxide, thereby effectively removing sensitization components in the prepared ginkgo leaf extract;
The invention effectively extracts the effective components by selecting a specific extractant system, inhibits the dissolution of the sensitization components, can effectively remove the sensitization components such as tannins, ginkgolic acid and the like without column chromatography in the whole process, has simple and convenient operation in the whole extraction process, reduces the solvent consumption and reduces the production cost;
the invention has simple process route and convenient operation, and is suitable for industrial production.
Detailed Description
The following description of the technical solution in the embodiments of the present invention is clear and complete. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Example 1A method for extracting Ginkgo biloba extract and method for preparing Shuxuening injection
The embodiment is an extraction method of ginkgo leaf extract and a preparation method of Shuxuening injection, and specifically comprises the following steps:
1. extraction method of ginkgo leaf extract
Adding 8L of 45wt% ethanol aqueous solution and 0.15kg of calcium carbonate into 1kg of ginkgo leaf, stirring and heating to 65 ℃ for 3h, filtering to obtain filtrate and filter residue, adding 8L of 45wt% ethanol aqueous solution and 0.15kg of calcium carbonate into the filter residue again, stirring and heating to 65 ℃ for 3h, filtering to obtain filtrate and filter residue, adding 8L of 45wt% ethanol aqueous solution and 0.15kg of calcium carbonate into the filter residue for the last time, stirring and heating to 65 ℃ for 3h, filtering to obtain filtrate, merging the filtrate, concentrating to obtain fluid extract with relative density of 1.15 at 70 ℃, adding ethanol to 90wt% and precipitating with ethanol at 4+/-2 ℃, filtering, adding 10wt% calcium hydroxide aqueous solution into the obtained filtrate dropwise until no precipitate is generated while stirring, stopping dropwise adding, removing insoluble substances by rough filtration, concentrating to dryness, and crushing to obtain ginkgo leaf extract marked as Y1, wherein the content of acid in ginkgo leaf extract Y1 is 0.122 mu g/g and the protein is detected.
Wherein, the content of ginkgolic acid in the ginkgo leaf extract Y1 is detected according to the method recorded in Shuxuening injection quality control research (Lin Shan, 6 months in 2014, university of Fujian traditional Chinese medicine and university of Chinese medical science articles).
Detection of tannins: taking 20mg of a sample (three groups are parallel), precisely weighing, adding 5mL of water for injection to dissolve the sample, taking 1mL of the solution, adding 5mL of a freshly prepared physiological sodium chloride solution containing 1% egg white, standing for 10min, and observing the occurrence phenomenon. As a result of tannin detection, turbidity or precipitation does not appear in all three groups of samples.
Protein detection: taking 20mg of a sample (three groups are parallel), precisely weighing, adding 5mL of water for injection to dissolve the sample, taking 1mL of the sample, adding 1 to 3 drops of newly prepared 30% sulfosalicylic acid solution 1mL of the solution, uniformly mixing the solution, standing the solution for 5min, and observing the occurrence of a phenomenon (whether turbidity or precipitation occurs or not is observed). As a result of protein examination, none of the three groups of samples showed turbidity or precipitation.
Therefore, the ginkgolic acid extract Y1 has extremely low ginkgolic acid content, does not contain tannins and proteins, and the subsequent Shuxuening injection prepared by using the ginkgolic acid extract Y1 does not further examine ginkgolic acid, tannins and proteins.
2. Preparation method of Shuxuening injection
Taking 12.47g of disodium hydrogen phosphate dodecahydrate and 0.81g of sodium dihydrogen phosphate dihydrate to prepare 200mL of buffer solution with pH value of 7.6, adding 2g of sodium sulfite and 400mL of 1, 2-propanediol, stirring and dissolving, adding 14g of ginkgo leaf extract Y1, stirring until the ginkgo leaf extract Y1 is completely dissolved, supplementing water to 4000mL of the whole, filtering, and ultrafiltering the obtained filtrate to obtain the Shuxuening injection marked as N1. Wherein, the total ginkgolide contained in the Shuxuening injection N1 is 467.37 mug/mL, the total flavone is 1467.32 mug/mL, and the total flavonol glycoside is 921.57 mug/mL.
Wherein the ginkgolide sum is the sum of ginkgolide A, ginkgolide B and ginkgolide C.
The total content of ginkgolide and total flavone in the Shuxuening injection N1 are detected according to the method described in Shuxuening injection quality control research (Lin Shan, 6 months of 2014, university of Fujian Chinese medicine and university of Chinese medical treatises).
The content of total flavonol glycosides in Shuxuening injection N1 is determined according to high performance liquid chromatography (Tian Ji, et al, tianjin traditional Chinese medicine. 2017,34 (06)).
EXAMPLES 2-5 extraction method of Ginkgo biloba extract and preparation method of Shuxuening injection
Examples 2 to 5 are a method for extracting ginkgo leaf extract and a method for preparing Shuxuening injection, respectively, which are basically the same as example 1, except that the process parameters are different, and the details are shown in table 1:
table 1 list of process parameters in examples 2 to 5
The process steps and parameters of the other parts of examples 2 to 5 are the same as those of example 1.
Experimental example 1 comparative test
Comparative examples 1 to 7 are comparative experiments of the extraction method of ginkgo leaf extract and the preparation method of Shuxuening injection in example 1, and the ginkgo leaves used are the same batch of ginkgo leaf medicinal materials as in example 1, and the process and the raw material consumption are basically the same, except that:
The extraction agent used in each extraction in comparative example 1 was 8L of 20wt% ethanol aqueous solution and 0.15kg calcium carbonate, the obtained ginkgo leaf extract was labeled DY1, and Shuxuening injection was prepared using the ginkgo leaf extract DY1 and labeled DN1. Wherein, the content of ginkgolic acid in the ginkgo leaf extract DY1 is 0.127 mug/g, and tannins and proteins are not detected; the Shuxuening injection DN1 contains ginkgolide of 216.54 mu g/mL, total flavone of 705.91 mu g/mL and total flavonol glycoside of 432.76 mu g/mL. It can be seen that, although the reduction of the ethanol concentration in the extractant does not affect the removal of ginkgolic acid, tannins and proteins, the reduction of the content of the active ingredients in the Shuxuening injection DN1 can be caused, thereby affecting the curative effect of the Shuxuening injection DN1.
The extraction agent used in each extraction in comparative example 2 was 8L of 80wt% ethanol aqueous solution and 0.15kg calcium carbonate, the obtained ginkgo leaf extract was labeled DY2, and Shuxuening injection was prepared using the ginkgo leaf extract DY2 and labeled DN2. Wherein the ginkgolic acid content in the ginkgo leaf extract DY2 is 12.246 mug/g (the ginkgolic acid content in the ginkgo leaf extract DY2 exceeds the standard), and no tannins and proteins are detected; the Shuxuening injection DN2 contains total ginkgolide compound 465.93 mug/mL, total flavone 1468.36 mug/mL, total flavonol glycoside 920.76 mug/mL and ginkgolic acid 0.043 mug/mL. Therefore, the ethanol concentration in the extractant is increased to influence the removal of ginkgolic acid, but not the removal of tannins and proteins, and the content of active ingredients in the Shuxuening injection DN2. The increase of the content of ginkgolic acid in the ginkgo leaf extract DY2 can lead to the increase of the content of ginkgolic acid in the Shuxuening injection DN2 prepared by using the ginkgo leaf extract DY2, thereby leading to the increase of the application risk of the Shuxuening injection DN2.
The content of ginkgolic acid in the Shuxuening injection DN2 is detected according to the method recorded in the Shuxuening injection quality control research (Lin Shan, 6 months in 2014, university of Fujian traditional Chinese medicine and university of Chinese medical science articles).
In comparative example 3, the extractant used for each extraction was 8L of 45wt% ethanol aqueous solution and 0.05kg calcium carbonate, the calcium hydroxide usage was significantly increased (about 2 times) during the preparation process, the obtained ginkgo leaf extract was labeled DY3, and the ginkgo leaf extract DY3 was used to prepare Shuxuening injection, labeled DN3. Wherein the ginkgolic acid content in the ginkgo leaf extract DY3 is 25.581 mug/g (the ginkgolic acid content in the ginkgo leaf extract DY3 exceeds the standard), tannins (trace precipitates) are detected, and no protein is detected; ginkgolide contained in the Shuxuening injection DN3 is 464.62 mug/mL, total flavone is 1465.94 mug/mL, total flavonol glycoside is 922.05 mug/mL, ginkgolic acid is 0.090 mug/mL, and tannins (slight turbidity) are detected. Therefore, the dosage of calcium hydroxide is obviously increased in the subsequent process of removing tannins by using the calcium hydroxide, and the tannins in a system containing more tannins can not be well removed by directly using the calcium hydroxide, so that the dosage of calcium carbonate in the extractant is reduced, the removal of ginkgolic acid and the tannins can be obviously influenced, the content of ginkgolic acid in the Shuxuening injection DN3 prepared by using the ginkgo leaf extract DY3 exceeds the standard, the tannins are detected, and the application risk of the Shuxuening injection DN3 is greatly improved.
The detection method of tannin in the Shuxuening injection DN3 comprises the following steps: 1mL of a sample (three groups are parallel), precisely weighing, adding 5mL of a freshly prepared physiological sodium chloride solution containing 1% egg white, standing for 10min, observing the occurrence of a phenomenon, and observing that turbidity appears.
The extraction agent used in each extraction in comparative example 4 was 6L of 45wt% ethanol aqueous solution and 0.15kg calcium carbonate, the obtained ginkgo leaf extract was labeled DY4, and Shuxuening injection was prepared using the ginkgo leaf extract DY4 and labeled DN4. Wherein the content of ginkgolic acid in the ginkgo leaf extract DY4 is 0.119 mug/g, and tannins and proteins are not detected; the bilobalide contained in the Shuxuening injection DN4 is 316.82 mug/mL, the total flavone is 313.97 mug/mL, and the total flavonol glycoside is 574.35 mug/mL. Therefore, although the reduction of the dosage of the ethanol aqueous solution in the extractant does not affect the removal of ginkgolic acid, tannins and proteins, the reduction of the content of the active ingredients in the Shuxuening injection DN4 can be caused, thereby affecting the curative effect of the Shuxuening injection DN4.
The extraction agent used in each extraction in comparative example 5 was 15L of 45wt% ethanol aqueous solution and 0.15kg calcium carbonate, the obtained ginkgo leaf extract was labeled DY5, and Shuxuening injection was prepared using the ginkgo leaf extract DY5 and labeled DN5. Wherein the ginkgolic acid content in the ginkgo leaf extract DY5 is 16.732 mug/g (the ginkgolic acid content in the ginkgo leaf extract DY5 exceeds the standard), tannins are detected (turbidity appears), and proteins are not detected; ginkgolide contained in the Shuxuening injection DN5 is 465.92 mug/mL, total flavone is 1466.89 mug/mL, total flavonol glycoside is 920.45 mug/mL, ginkgolic acid is 0.059 mug/mL, and tannins (turbidity) are detected. Therefore, increasing the dosage of the ethanol aqueous solution in the extractant can reduce the concentration of calcium carbonate in the extractant, thereby affecting the removal of ginkgolic acid and tannins, simultaneously, the content of ginkgolic acid in the Shuxuening injection DN5 prepared by using the ginkgo leaf extract DY5 is correspondingly improved, and the tannins can be detected, so that the application risk of the Shuxuening injection DN5 is greatly improved.
The temperature of each extraction in comparative example 6 was 50 ℃, the obtained ginkgo leaf extract was labeled DY6, and Shuxuening injection, labeled DN6, was prepared using the ginkgo leaf extract DY 6. Wherein, the content of ginkgolic acid in the ginkgo leaf extract DY6 is 1.192 mug/g, tannins are detected, and proteins are not detected; ginkgolides contained in the Shuxuening injection DN6 are 315.47 mug/mL, 1464.98 mug/mL and 920.93 mug/mL, and tannins (turbidity) are detected. It can be seen that although lowering the extraction temperature affects the removal of tannins, in particular tannins, it is possible that the lowering of the temperature is detrimental to the carbon dioxide dissipation in the system and to the forward progress of the reaction of tannins with calcium ions to form precipitates. The content of ginkgolic acid in the Shuxuening injection DN6 prepared by the ginkgo leaf extract DY6 is correspondingly improved, and the application risk of the Shuxuening injection DN6 is greatly improved.
The temperature of each extraction in comparative example 7 was 80 ℃, the obtained ginkgo leaf extract was labeled DY7, and the ginkgo leaf extract DY7 was used to prepare a Shuxuening injection, labeled DN7. Wherein, the content of ginkgolic acid in the ginkgo leaf extract DY7 is 8.942 mug/g, and tannins and proteins are not detected; the bilobalide contained in the Shuxuening injection DN7 is 466.63 mug/mL, the total flavone is 1462.40 mug/mL, the total flavonol glycoside is 919.68 mug/mL, and the ginkgolic acid is 0.031 mug/mL. Therefore, increasing the extraction temperature can affect the removal of ginkgolic acid, and simultaneously the content of ginkgolic acid in the Shuxuening injection DN7 prepared by utilizing the ginkgo leaf extract DY7 is correspondingly increased, so that the application risk of the Shuxuening injection DN7 is increased.
It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Claims (4)
1. The extraction method of the ginkgo leaf extract is characterized by comprising the steps of adding an extractant into ginkgo leaves, heating for extraction, filtering, extracting for 3 times, wherein each extractant is ethanol water solution with the concentration of 45-50wt% and calcium carbonate, mixing filtrates, concentrating, adding ethanol into the obtained fluid extract until the concentration of the ethanol is 85-90wt%, refrigerating for alcohol precipitation, filtering, dropwise adding calcium hydroxide water solution into the filtrate while stirring until no precipitate is generated, carrying out rough filtration, ultrafiltration, concentrating to dryness, and obtaining the ginkgo leaf extract;
In each extraction process, the weight ratio of the ginkgo leaf to the calcium carbonate in the extractant is 1:0.15-0.2, and the weight volume ratio of the ginkgo leaf to the ethanol water solution in the extractant is 1g: 8-9 mL;
The temperature of each extraction is 65-70 ℃ and the time is 3-4 hours.
2. The method according to claim 1, wherein the relative density of the extract after concentration is 1.15-1.20.
3. The method for extracting ginkgo leaf extract according to claim 1, wherein the time of refrigerated alcohol precipitation is not less than 24 hours.
4. A preparation method of Shuxuening injection is characterized in that the preparation method of Shuxuening injection comprises the steps of firstly extracting ginkgo leaf extract and then preparing the Shuxuening injection by utilizing the extracted ginkgo leaf extract;
wherein the extraction process of the ginkgo leaf extract is prepared by extracting the ginkgo leaf extract according to any one of claims 1 to 3;
The specific process for preparing the Shuxuening injection comprises the steps of preparing buffer solution with pH value of 7.5-8.0 from disodium hydrogen phosphate and sodium dihydrogen phosphate, adding sodium sulfite and 1, 2-propylene glycol for dissolution, adding the ginkgo leaf extract for dissolution, supplementing water to full quantity, filtering, and ultrafiltering to obtain the Shuxuening injection; wherein, the weight volume ratio of the ginkgo leaf extract to the buffer solution to the sodium sulfite to the 1, 2-propylene glycol is 14g:200mL: 1.8-2.2 g: 400-450 mL; make-up water to full is make-up water to 4000mL.
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