CN100418522C - High-dose hydroxy safflower yellow A or its medically-acceptable salt application for preparing medicine for cerebral apoplexy induced from being ischemic - Google Patents
High-dose hydroxy safflower yellow A or its medically-acceptable salt application for preparing medicine for cerebral apoplexy induced from being ischemic Download PDFInfo
- Publication number
- CN100418522C CN100418522C CNB200410023508XA CN200410023508A CN100418522C CN 100418522 C CN100418522 C CN 100418522C CN B200410023508X A CNB200410023508X A CN B200410023508XA CN 200410023508 A CN200410023508 A CN 200410023508A CN 100418522 C CN100418522 C CN 100418522C
- Authority
- CN
- China
- Prior art keywords
- administration
- dosage
- dose
- hydroxysafflor yellow
- ischemic
- 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.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 title claims abstract description 11
- 208000006011 Stroke Diseases 0.000 title claims abstract description 10
- 206010008190 Cerebrovascular accident Diseases 0.000 title claims abstract description 7
- 230000000302 ischemic effect Effects 0.000 title abstract description 12
- 230000002490 cerebral effect Effects 0.000 title abstract description 5
- KINGXFAMZNIVNL-SXQDSXCISA-N safflor yellow A Natural products OC[C@@H]1O[C@H]2[C@H](OC3=C2C(=O)C(=C(O)C=Cc4ccc(O)cc4)C(=O)[C@]3(O)[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[C@@H](O)[C@H]1O KINGXFAMZNIVNL-SXQDSXCISA-N 0.000 title abstract 3
- 238000001990 intravenous administration Methods 0.000 claims abstract description 10
- 230000003203 everyday effect Effects 0.000 claims abstract description 5
- IAVUBSCVWHLRGE-UXEKTNMQSA-N (6e)-2,5-dihydroxy-6-[(e)-1-hydroxy-3-(4-hydroxyphenyl)prop-2-enylidene]-2,4-bis[(2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]cyclohex-4-ene-1,3-dione Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C(C(C(O)([C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)C1=O)=O)=C(O)\C1=C(/O)\C=C\C1=CC=C(O)C=C1 IAVUBSCVWHLRGE-UXEKTNMQSA-N 0.000 claims description 57
- ZZMASNSDVDSYKO-UHFFFAOYSA-N hydroxysafflor yellow A Natural products OCC1OC(C(O)C(O)C1O)C2=C(O)C(O)(C3OC(CO)C(O)C(O)C3O)C(=O)C(=C2O)C(=O)C=Cc4ccc(O)cc4 ZZMASNSDVDSYKO-UHFFFAOYSA-N 0.000 claims description 56
- 208000028867 ischemia Diseases 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 9
- 230000001154 acute effect Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 24
- 206010053567 Coagulopathies Diseases 0.000 description 15
- 230000035602 clotting Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 241000282472 Canis lupus familiaris Species 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 206010028851 Necrosis Diseases 0.000 description 10
- 210000000269 carotid artery external Anatomy 0.000 description 10
- 230000017074 necrotic cell death Effects 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 206010008120 Cerebral ischaemia Diseases 0.000 description 8
- 206010008118 cerebral infarction Diseases 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- 238000010253 intravenous injection Methods 0.000 description 6
- 208000005189 Embolism Diseases 0.000 description 5
- 241000628997 Flos Species 0.000 description 5
- 208000001435 Thromboembolism Diseases 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000001168 carotid artery common Anatomy 0.000 description 4
- 210000004004 carotid artery internal Anatomy 0.000 description 4
- 238000004043 dyeing Methods 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012982 microporous membrane Substances 0.000 description 4
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 206010000117 Abnormal behaviour Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000003194 forelimb Anatomy 0.000 description 3
- 210000003657 middle cerebral artery Anatomy 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- HUGRHFXHKFEGEY-UHFFFAOYSA-K trisodium 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid trichloride Chemical compound [Na+].[Na+].[Na+].[Cl-].[Cl-].[Cl-].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O HUGRHFXHKFEGEY-UHFFFAOYSA-K 0.000 description 3
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 2
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical group COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 244000020518 Carthamus tinctorius Species 0.000 description 2
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 2
- 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 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 108010003541 Platelet Activating Factor Proteins 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000000133 brain stem Anatomy 0.000 description 2
- 210000001638 cerebellum Anatomy 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 210000003739 neck Anatomy 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 210000000956 olfactory bulb Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000012109 statistical procedure Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 206010042772 syncope Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001364 upper extremity Anatomy 0.000 description 2
- 210000000707 wrist Anatomy 0.000 description 2
- 241000195622 Astasia Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- DYQVDISPPLTLLR-HJQYTNQXSA-N Carthamin Natural products CC[C@H]1O[C@H]([C@H](O)[C@@H](O)[C@@H]1O)[C@]2(O)C(=C(C=C/3C(=O)C(=C(O)[C@](O)([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C3=O)C(=O)C=Cc5ccc(O)cc5)C(=O)C(=C2O)C(=O)C=Cc6ccc(O)cc6)O DYQVDISPPLTLLR-HJQYTNQXSA-N 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 244000192528 Chrysanthemum parthenium Species 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- 206010010947 Coordination abnormal Diseases 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 241000053227 Themus Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 208000024756 faint Diseases 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical group [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- -1 hydroxyl carthamin Chemical compound 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- SBNFWQZLDJGRLK-UHFFFAOYSA-N phenothrin Chemical compound CC1(C)C(C=C(C)C)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 SBNFWQZLDJGRLK-UHFFFAOYSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003405 preventing effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides high-dose hydroxy safflower yellow A or the application of the medical salt thereof in medicines for curing brain ischemic diseases, particularly hydroxy safflower yellow A or the application of the medical salt thereof in preparing medicines for acute cerebral apoplexy induced from being ischemic. The dosage of the present invention is 80 to 1600 mg every day, and the path of administration is intravenous drip administration.
Description
Technical field
The present invention relates to a kind of S-A Hydroxysafflor yellow A or the application of its officinal salt in the medicine of treatment cerebral ischemia diseases of heavy dose, specially refer to S-A Hydroxysafflor yellow A or the application of its officinal salt in the medicine of the acute cerebral stroke that ischemia causes, its dosage is 80-1600mg/ day, and the approach of administration is the intravenous drip administration.
Background technology
Along with the acceleration of aged tendency of population process and the change of life style, cerebrovascular, particularly ischemia apoplexy have become one of principal disease of harm humans health.The exploitation of medicine that prevents and treats cerebrovascular disease more safely and effectively is very urgent.
Flos Carthami Carthamus tinctorius L. records in " 2 years versions of Pharmacopoeia of People's Republic of China " (one one), is traditional blood-activating and stasis-removing.The single preparation of Flos Carthami now has " Flos Carthami injection " (national drug standards WS clinically
3-B-3825-98), be used for the treatment of obliterated cerebral vascular disease, coronary heart disease, vasculitis etc.Clinical practice for many years proves that its curative effect certainly.But this kind is traditional Chinese medicine, and material base is indeterminate, and mechanism of action is unclear, and complicated component, less than the method that its quality is control effectively, thereby causes the clinical effectiveness instability, the rate of side effects height.
S-A Hydroxysafflor yellow A is the effective ingredient that extracts from the dried floral of feverfew Flos Carthami Carthamus tinctorius L..
The S-A Hydroxysafflor yellow A structure
Document [Zang Baoxia, gold ring, compass in ancient China etc., S-A Hydroxysafflor yellow A is to the antagonism [J] of platelet activating factor. Acta Pharmaceutica Sinica, 2002,37 (9): 696] show that S-A Hydroxysafflor yellow A suppresses hematoblastic gathering by the effect of antagonism platelet activating factor.Chinese patent [the open CN1422616 of application, denomination of invention: the medicinal usage of S-A Hydroxysafflor yellow A aspect preparation treatment, prevention cardiovascular and cerebrovascular disease] in describe in detail at rat dosage be 6,3, under the 1.5mg/kg situation, the S-A Hydroxysafflor yellow A dose dependent improves the behavior disorder of rats with cerebral ischemia due to the middle cerebral artery thromboembolism, reduce cerebral ischemia district area, the formation and the inductive rats with cerebral ischemia platelet aggregation of ADP that suppress the rat thrombus in vivo reduce whole blood viscosity, plasma viscosity and the packed cell volume of rat; Be 12,6 at dosage, during 3mg/kg, it has prolonged clotting time of mice.Above-mentioned open source literature is clear and definite, and S-A Hydroxysafflor yellow A has prevention and therapeutical effect to ischemia apoplexy.Make a general survey of the experimental technique in the document, can determine that early stage (in the 30 minutes) administration of S-A Hydroxysafflor yellow A prevention administration or morbidity (modeling) back has reliable effect.The chance that obtains medical treatment in back 30 minutes is seldom but clinical practice midbrain stroke patient is fallen ill, and most patient is to be found behind 3-6 hour of morbidity and to obtain medical treatment.The inventor is by a large amount of discovering, S-A Hydroxysafflor yellow A is in the dosage range described in the open CN1422616 of Chinese patent application, to downright bad the no therapeutical effect of morbidity (modeling) cerebral ischemia after 3 hours, and proof only under more heavy dose of could morbidity after 3 hours during administration performance treat effect.
Technology contents
The invention provides the application in the medicine of the acute cerebral stroke that preparation treatment ischemia causes of a kind of heavy dose of S-A Hydroxysafflor yellow A or its officinal salt, its using dosage is 80-1600mg/ day, and the preferred dose scope is preferably 80-500mg/ day.
The route of administration of S-A Hydroxysafflor yellow A provided by the invention or its officinal salt is an intravenously administrable, is preferably intravenous drip.
The invention provides the S-A Hydroxysafflor yellow A of a kind of 80mg-1600mg of containing or the pharmaceutical composition of its officinal salt.
Pharmaceutical composition provided by the invention exists with injection, transfusion or freeze-dried powder form, is preferably freeze-dried powder, and it all can be prepared from conventional method pharmaceutically.
S-A Hydroxysafflor yellow A salt provided by the invention is pharmaceutically acceptable salt.
Below by preparation embodiment and test example this is illustrated, but be not limited only to this.
The specific embodiment
Embodiment 1: the preparation of S-A Hydroxysafflor yellow A
Get dry Flos Carthami, 80 ℃ of following water extraction 3 times, each 1 hour, add 20 times of water for the first time, add 15 times of water for the second time, add 15 times of water for the third time, merge extractive liquid; Filter, it is 1.05 (80 ℃) that filtrate decompression is concentrated into density, and adding ethanol to determining alcohol is 80%, precipitates 24 hours down in 4 ℃, filters; Filtrate is not distinguished the flavor of to there being alcohol in 60 ℃ of decompression recycling ethanols, add to the DM-130 macroporous adsorbent resin of handling well on 10 times of water dilution backs, applied sample amount (being equivalent to the crude drug amount) is 1: 1 (w/v) with the ratio of resin demand, with 4 column volumes of 5% ethanol elution, collects eluent.Eluent is splined on the polyamide column of handling well, and the ratio that applied sample amount is equivalent to crude drug amount and resin demand is 3: 1 (w/v), earlier with 3 column volumes of 5% ethanol elution, discards; Continue with 8 column volumes of 95% alcoholic solution eluting, the collection eluent is in 60 ℃ of decompression recycling ethanols and be concentrated into debita spissitudo; Lyophilization obtains S-A Hydroxysafflor yellow A.
Embodiment 2: the preparation of S-A Hydroxysafflor yellow A lyophilized injectable powder
Take by weighing 40g mannitol, place in the appropriate containers, add 200ml water for injection, add pin, be heated to 80 ℃, stir 30min, 0.22 μ m filtering with microporous membrane, filtrate for later use with charcoal 0.2g (0.1%w/v).
Take by weighing the 80g S-A Hydroxysafflor yellow A, add the injection water to 1000ml, stirring is dissolved S-A Hydroxysafflor yellow A fully.Mix S-A Hydroxysafflor yellow A solution and mannitol solution, add water for injection to 2000ml, with 0.22 μ m filtering with microporous membrane, packing, loading amount is every hydroxyl carthamin yellow A-containing 80mg, lyophilization.Lid is rolled in the vacuum tamponade, labeling, and packing is promptly.
Embodiment 3: the preparation of S-A Hydroxysafflor yellow A sodium chloride injection
The preparation of sodium chloride-disodium ethylene diamine tetra-acetic acid aqueous solution: in 1000ml water for injection, add the 30mg disodiumedetate, stir and make it dissolving, add 9g sodium chloride again, stirring makes it to dissolve fully, gets sodium chloride-disodium ethylene diamine tetra-acetic acid aqueous solution; Take by weighing the 800mg S-A Hydroxysafflor yellow A, join in above-mentioned sodium chloride-disodium ethylene diamine tetra-acetic acid aqueous solution, stirring makes it to dissolve fully, gets pale yellow solution; Regulate pH value to 5.0～6.0 of above-mentioned solution with dilute NaOH solution and rare HCl solution; Adding activated carbon 0.5g in the solution of above-mentioned modulated good pH value (0.05%, w/v),, get coarse filtration liquid in 20 minutes after-filtration of 80 ℃ of stirrings; Check intermediate content, determine that S-A Hydroxysafflor yellow A content is 80mg/100ml in the filtrate; With 0.22 μ m filtering with microporous membrane, get fine straining liquid.Embedding, gland; In 105 ℃ of heating sterilization in 30 minutes; Labeling detects qualified back packing, gets finished product.
Embodiment 4: the preparation of S-A Hydroxysafflor yellow A injection
Take by weighing the 0.5g disodiumedetate, join in the 1000ml water for injection, stirring makes it to dissolve fully, gets solution 1; Take by weighing the 20.0g S-A Hydroxysafflor yellow A, join in the solution 1, stirring makes it to dissolve fully, gets solution 2; The pH value to 5.0 of regulator solution 2～6.0; Add 1g activated carbon (0.1%) in the above-mentioned solution that regulates pH, in 80 ℃ of heating 15 minutes, filter to get filtrate 1: intermediate content is surveyed in sampling, determines that the every ml of filtrate contains the 20mg S-A Hydroxysafflor yellow A; With 0.22 μ m filtering with microporous membrane, get filtrate 2; Embedding, every ampoule embedding 1.0ml medicinal liquid, sealing by fusing; 100 ℃ of flowing steam sterilizations 20 minutes; Get finished product through after the assay was approved.
Experimental example 1
S-A Hydroxysafflor yellow A administration time and dosage are to the influence of ischemic necrosis due to the intraluminal middle cerebral artery occlusion in rats thromboembolism
Animal is divided into sham operated rats (i.v excipient) at random, model control group (i.v excipient), the nimodipine group (i.v Nim, 1mg/kg), each dosage of S-A Hydroxysafflor yellow A (HSYA) and time point group (table 1), 10 every group.After the fasting 12 hours, and chloral hydrate (350mg/kg, i.p.) anesthesia separates right carotid, and folder closes in the neck, common carotid artery, external carotid artery proximal part and distal end ligation, cut off the centre.The external carotid artery free-end is pulled to internal carotid artery in alignment, bolt line (selecting diameter 0.24mm nylon wire for use, length 5.0cm) is inserted into intracranial by external carotid artery, stop when meeting slight resistance, insertion depth is about 2cm.Ligation external carotid artery opening, and open the common carotid artery bulldog clamp, the disinfection and stitching wound causes right side middle cerebral artery ischemia model; Sham operated rats is only carried out the separation (above experiment is all carried out at 23 ℃～25 ℃) of right carotid, internal carotid artery, external carotid artery.Each treated animal postoperative different time points tail vein injection relative medicine.Modeling is pressed the described method of document and is put to death rat after 24 hours, get brain, remove olfactory bulb, cerebellum and low brain stem, crownly be cut into 5, the brain sheet takes on a red color after normal structure is dyed with red tetrazolium (TTC) dyeing, and blocking tissue is white in color, taking a picture in dyeing back, asks the infarct size ratio with Chinese Aero-Space university pathological image analysis software.Data are represented with X ± s, carry out statistical procedures with t check between group.
The result shows (table 2), and ischemia is after 24 hours, and tangible kitchen range shape ischemic necrosis district appears in rat cerebral tissue, reaches about 25% of full brain; Give the HSYA of various dose, except that the 1mg/kg administration, modeling 0.5h administration all can make rat cerebral ischemia district necrosis area obviously dwindle.3h administration after the modeling has only dosage to reach that 8mg/kg is above could to reduce the ischemic necrosis area.When dosage reached 32mg/kg, variant time administration group (comprise 0.5,1,3,6,10h) all can make the ischemic necrosis area reduce.Show administration behind the rat cerebral ischemia 3h, the dosage of S-A Hydroxysafflor yellow A must reach more than the 8mg/kg just can have more definite curative effect, be (the many clinical treatments that more than 3-6h after the morbidity, just enter of patient) ischemia apoplexy morbidity acute stage patient in the clinical practice, with the S-A Hydroxysafflor yellow A treatment, effective dosage can not be less than 80mg/ day.
Table 1 S-A Hydroxysafflor yellow A administration time and dosage are to the influence of ischemic necrosis due to the intraluminal middle cerebral artery occlusion in rats thromboembolism
Ischemic areas: sham operated rats 0; Model control group 24.0 ± 4.1; Nim group 18.6 ± 3.0.Compare with model control group.Compare with model control group,
*, P＜0.05;
*, P＜0.01.
Test example 2
The S-A Hydroxysafflor yellow A route of administration is to the influence of ischemic necrosis due to the intraluminal middle cerebral artery occlusion in rats thromboembolism
Animal is divided into sham operated rats (i.v excipient) at random, model control group (i.v excipient), the nimodipine group (i.v Nim, 1mg/kg), HSYA different way of administration and time point group (table 2), 10 every group.After the fasting 12 hours, and chloral hydrate (350mg/kg, i.p.) anesthesia separates right carotid, and folder closes in the neck, common carotid artery, external carotid artery proximal part and distal end ligation, cut off the centre.The external carotid artery free-end is pulled to internal carotid artery in alignment, bolt line (selecting diameter 0.24mm nylon wire for use, length 5.0cm) is inserted into intracranial by external carotid artery, stop when meeting slight resistance, insertion depth is about 2cm.Ligation external carotid artery opening, and open the common carotid artery bulldog clamp, the disinfection and stitching wound causes right side middle cerebral artery ischemia model; Sham operated rats is only carried out the separation (above experiment is all carried out at 23 ℃～25 ℃) of right carotid, internal carotid artery, external carotid artery.Each treated animal postoperative different time points tail vein injection or gavage relative medicine.The behavior disorder of rat is observed and write down in modeling by literature method after 24 hours: (1) is carried the Mus tail and is observed forelimb flexing situation, stretch to ground as two forelimb symmetries, count 0 fen, as the offside forelimb of performing the operation the wrist flexing occurs and counts 1 fen, the elbow flexing is counted 2 fens, and the shoulder inward turning is counted 3 fens, existing wrist flexing and/or elbow flexing, shoulder inward turning person is arranged again, count 4 fens.(2) animal is placed on the plane earth, push away both shoulders respectively, check resistance to side shifting.As bilateral resistance equity and strong, count 0 fen, as resistance descender when the operation offside promotes, according to decline degree difference be divided into gently, in, weigh three degree, count 1,2 and 3 fen respectively.(3) the two forelimbs of animal are put on the wire netting, observed the muscular tension of two forelimbs.Two muscle of anterior limb tension force equities and strong person count 0 fen.Count 1,2 and 3 fen according to operation offside muscular tension decline degree difference equally.(4) animal has ceaselessly to a side person of turn-taking, and counts 1 fen.According to the standard scoring, full marks are 11 minutes, and mark is high more, and expression animal behavior obstacle is serious more.Put to death rat behind the behavior scoring, get brain, remove olfactory bulb, cerebellum and low brain stem, crownly be cut into 5, the brain sheet takes on a red color after normal structure is dyed with red tetrazolium (TTC) dyeing, and blocking tissue is white in color, taking a picture in dyeing back, asks the infarct size ratio with Chinese Aero-Space university pathological image analysis software.Data are represented with X ± s, carry out statistical procedures with t check between group.
The result shows (table 2), and ischemia is after 24 hours, and tangible kitchen range shape ischemic necrosis district appears in model group rat cerebral tissue, reaches nearly 25% of full brain; The tail vein gives the HSYA of various dose, and the necrosis of rat cerebral ischemia district has obviously to be dwindled; And it is not obvious to gavage the administration effect.Show that intravenously administrable is effective route of administration of HSYA treatment acute period of disease ischemia apoplexy.
Table 2 S-A Hydroxysafflor yellow A route of administration is to the influence of ischemic necrosis due to the intraluminal middle cerebral artery occlusion in rats thromboembolism
| Behavior disorder | Ischemic areas (%) | |
| Sham operated rats | 0 | 0 |
| Model control group | 9.2±1.1 | 24.4±4.5 |
| The Nim group | 5.4±2.5 ** | 18.8±3.4 ** |
| HSYA 8mg/kg 3h tail intravenously administrable | 6.7±1.3 ** | 18.1±3.8 ** |
| HSYA 8mg/kg 3h gavages administration | 8.7±1.4 * | 22.8±3.7 * |
| HSYA 32mg/kg 10h tail intravenously administrable | 6.0±1.2 ** | 17.6±3.5 ** |
| HSYA 32mg/kg 10h gavages administration | 8.6±1.7 * | 23.4±3.0 * |
Compare with model control group.Compare with model control group,
*, P＞0.05;
*, P＜0.05.
Test example 3
Dog untoward reaction due to the intravenous injection S-A Hydroxysafflor yellow A
With the beagle dog is experimental animal.The heavy dose of group of design HSYA medicine is 45mg/kg, middle dosage group 15mg/kg, small dose group 5mg/kg.Other establishes the solvent matched group.The administration volume is 2ml/kg, slow intravenous injection, and about per minute is injected 3ml.Per two weeks of experimental session claim a body weight, adjust dosage according to body weight.Observation index comprises ordinary circumstance and coagulation indexes.Clotting time is 24h after administration, measures before the administration on the same day.
The result shows the continuous intravenous injection administration of (table 3): injection HSYA 42 days, and its main toxicity performance is: (1) big or middle dosage group dog clotting time and the apparent in view prolongation of solvent matched group.Drug withdrawal after 15 days clotting time recover normal.(2) dog astasia occurs and falls down after (45mg/kg) administration of heavy dose of group, crosses property like patient's and faints, may to expand the effect of peripheral vessels relevant with HSYA, and the lethargy that the back of fainting occurs is depressed.Clotting time (test tube method): administration 21 days and 42 days big or middle dosage group dog clotting times and the apparent in view prolongation of solvent matched group (P＜0.01), small dose group and solvent matched group be the clotting time no significant difference relatively.Drug withdrawal after 15 days clotting time recover normal, with solvent matched group Non Apparent Abnormality (P＞0.05) relatively.
Above result shows, can keep 24h to the influence of clotting time after dosage in the S-A Hydroxysafflor yellow A (15mg/kg) administration, and intravenous injection administration meeting causes tangible untoward reaction (falling in a swoon) when its dosage reaches 45mg/kg.The dosage of calculating the people in view of the above acts on for having preferably " blood circulation promoting and blood stasis dispelling " 558mg/ day, and reaches 1674mg/ can cause untoward reaction during day generation (in view of the above, the dosage of S-A Hydroxysafflor yellow A must not reach 1674mg/ day).
Table 3. S-A Hydroxysafflor yellow A various dose (is divided X ± SD) to the influence of dog clotting time
* compares P＜0.01 with matched group.
Test example 4
Intravenous drip is to the influence of general situation of dog and coagulation indexes
Animal grouping and administration: dog is divided into 4 groups at random, is respectively normal saline matched group, S-A Hydroxysafflor yellow A high dose group (180mg/kg), middle dosage group (60mg/kg) and low dose group (20mg/kg).The administration volume is 250ml/.The dosage of every dog is added to 250ml normal saline iv drip with medicine by every day, and drip velocity is about 250ml/1h.Be administered once every day, and successive administration 45 days is adjusted dosage according to body weight weekly.Observation index comprises ordinary circumstance and coagulation indexes.Clotting time about 24h after the administration day before yesterday measures.
The result shows (table 4), in the administration process, general situation such as each administration group dog feed, activity can, the phenomenon of falling in a swoon when intravenous injection not occurring.Clotting time (test tube method): administration 21 days and 42 days each dosage group dog clotting times and the apparent in view prolongation of solvent matched group (P＜0.01).Drug withdrawal after 15 days clotting time recover normal, relatively do not have obviously different (P＞0.05) with the solvent matched group.
Above result shows, more heavy dose of (reckoning by rat dosage 180mg/kg, people's dosage is 6696mg/ day) S-A Hydroxysafflor yellow A intravenous drip administration can not cause bad generations such as " falling in a swoon ", i.e. intravenous drip administration has better safety than intravenous injection (injecting).Because of clinical application (intravenous drip) because of the people because of the time cause the injection speed difference and (calculate by the amount that gives S-A Hydroxysafflor yellow A, might reach the injection speed that test example 3 medium-sized veins are injected during high concentration intravenous drip administration), for guaranteeing medication patient's safety, dosage must be controlled at the test example 3 in the proof 558mg/ day with interior (serve as the manufacturing and the clinical application convenience of calculation, with every day dosage control be advisable at 500mg).
Table 4. various dose S-A Hydroxysafflor yellow A (divides X ± SD) to the influence of dog clotting time
* compares P＜0.01 with matched group.
The result of compbined test example 1-4, S-A Hydroxysafflor yellow A is clinical when being used for brain during acute ischemia patient's treatment, must adopt intravenously administrable, and the dosage of administration must reach 80mg/ more than day.For guaranteeing safety of clinical administration, should take the mode of intravenous drip administration.The dosage of administration should be controlled at 500mg/ in day.
Claims (5)
1. Da Jiliang S-A Hydroxysafflor yellow A or its officinal salt application in the disease medicine after preparation treatment ischemia apoplexy morbidity 3 hours, its, application dose was 80-1600mg every day.
2. application according to claim 1, its dosage are 80-500mg/ day.
3. application according to claim 2, its dosage are 80-160mg/ day.
4. according to the described application of the arbitrary claim of claim 1-3, it is characterized in that medicine is the intravenously administrable medicine.
5. application according to claim 4 is characterized in that medicine is the intravenous drip medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410023508XA CN100418522C (en) | 2004-01-08 | 2004-01-08 | High-dose hydroxy safflower yellow A or its medically-acceptable salt application for preparing medicine for cerebral apoplexy induced from being ischemic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410023508XA CN100418522C (en) | 2004-01-08 | 2004-01-08 | High-dose hydroxy safflower yellow A or its medically-acceptable salt application for preparing medicine for cerebral apoplexy induced from being ischemic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1640392A CN1640392A (en) | 2005-07-20 |
| CN100418522C true CN100418522C (en) | 2008-09-17 |
Family
ID=34868430
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200410023508XA Expired - Fee Related CN100418522C (en) | 2004-01-08 | 2004-01-08 | High-dose hydroxy safflower yellow A or its medically-acceptable salt application for preparing medicine for cerebral apoplexy induced from being ischemic |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100418522C (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195647B (en) * | 2006-12-06 | 2010-08-18 | 山西华辉凯德制药有限公司 | Hydroxyl carthamus tinctorius yellow colour A, preparation method and application thereof |
| CN102614166B (en) * | 2011-12-07 | 2014-04-09 | 中国人民解放军第四军医大学 | Injection solution prepared from Safflomin A and Sodium danshensu and preparation method thereof |
| CN103980239B (en) * | 2013-02-07 | 2016-04-13 | 浙江永宁药业股份有限公司 | Hydroxyl radical carthamin yellow carthamus A sodium and production method thereof and purposes |
| CN104230864A (en) * | 2013-06-08 | 2014-12-24 | 浙江永宁药业股份有限公司 | Novel hydroxysafflor yellow A divalent medicinal salts, and preparing method and uses thereof |
| CN103127197B (en) * | 2013-03-21 | 2015-02-18 | 悦康药业集团有限公司 | Preparation method of freeze-drying preparation for safflower yellow injection |
| CN113350357B (en) * | 2020-03-05 | 2022-11-01 | 上海市普陀区中心医院 | Application of composition of hydroxysafflor yellow A and polygala tenuifolia sapogenin in preparation of medicine for treating ischemic stroke |
| CN112142806B (en) * | 2020-09-22 | 2023-03-03 | 山西德元堂药业有限公司 | Compound and salt, pharmaceutical composition and application thereof |
| CN113350358B (en) * | 2021-07-08 | 2022-11-04 | 上海市普陀区中心医院 | Application of tenuigenin single or combined with hydroxysafflor yellow A in preparation of medicine for improving cognitive impairment after ischemic stroke |
| CN114848626A (en) * | 2022-05-09 | 2022-08-05 | 山西中医药大学 | Application of hydroxysafflor yellow A in regulating and controlling cerebral arterial thrombosis |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264708A (en) * | 1998-11-24 | 2000-08-30 | 北京市心肺血管疾病研究所 | Total safflower yellow and its preparing process and application |
| CN1272500A (en) * | 1998-11-24 | 2000-11-08 | 北京市心肺血管疾病研究所 | Safflower total uranidin, its preparation and application |
| CN1422616A (en) * | 2001-12-06 | 2003-06-11 | 长春三真实业有限公司 | Use of hydroxy saflor yellow pigment A in preparing medicine for treating and preventing cardiovascular and cerebrovascular disease |
| CN1429830A (en) * | 2001-12-29 | 2003-07-16 | 山东绿叶制药股份有限公司 | Water-soluble safflower extract and its oral preparation for treating and preventing angiocardiopathy andcerebrova scular disease |
-
2004
- 2004-01-08 CN CNB200410023508XA patent/CN100418522C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264708A (en) * | 1998-11-24 | 2000-08-30 | 北京市心肺血管疾病研究所 | Total safflower yellow and its preparing process and application |
| CN1272500A (en) * | 1998-11-24 | 2000-11-08 | 北京市心肺血管疾病研究所 | Safflower total uranidin, its preparation and application |
| CN1422616A (en) * | 2001-12-06 | 2003-06-11 | 长春三真实业有限公司 | Use of hydroxy saflor yellow pigment A in preparing medicine for treating and preventing cardiovascular and cerebrovascular disease |
| CN1429830A (en) * | 2001-12-29 | 2003-07-16 | 山东绿叶制药股份有限公司 | Water-soluble safflower extract and its oral preparation for treating and preventing angiocardiopathy andcerebrova scular disease |
Non-Patent Citations (2)
| Title |
|---|
| 红花提取物抗血小板聚集己抗血栓作用的观察. 刘志峰，李萍，李桂生，傅风华，刘珂.中药药理与临床，第16卷第6期. 2000 |
| 红花提取物抗血小板聚集己抗血栓作用的观察. 刘志峰，李萍，李桂生，傅风华，刘珂.中药药理与临床，第16卷第6期. 2000 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1640392A (en) | 2005-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4708949A (en) | Therapeutic composition from plant extracts | |
| US4795742A (en) | Therapeutic composition from plant extracts | |
| CN109906077B (en) | Sublingual pharmaceutical composition of edaravone and (+) -2-borneol | |
| CN104587087A (en) | Pharmaceutical composition for treating cardiovascular and cerebrovascular diseases | |
| CN100418522C (en) | High-dose hydroxy safflower yellow A or its medically-acceptable salt application for preparing medicine for cerebral apoplexy induced from being ischemic | |
| CN101342274B (en) | Curculigo orchioides extract, preparation method and uses thereof | |
| CN102274260A (en) | Medicinal composition of notoginseng root extract and preparation method thereof | |
| CN1067577C (en) | Preparation of isotomic Shengmei injecta | |
| JPS626687B2 (en) | ||
| CN103638096A (en) | Gentianella acuta extract for treating arrhythmia and preparation method and application thereof | |
| JP4718443B2 (en) | Radixnotoginshen saponin family intravenous injection and method for its preparation | |
| CN100540017C (en) | A kind of Chinese medicine preparation for the treatment of angina pectoris and preparation method thereof | |
| CN1686111A (en) | Ginkgo lactone injection agent and its preparation method | |
| CN1977838A (en) | Pharmaceutical use of senkyunolide A, and medicinal composition containing it and its prepairng method | |
| CN104473989A (en) | Traditional Chinese medicine tablet for preventing and treating cardiovascular and cerebrovascular diseases and preparation method thereof | |
| CN101176750A (en) | Chaihuang freeze dried injection and preparation method thereof | |
| CN101176772B (en) | Pharmaceutical composition made of cattail pollen and safflower | |
| CN1053817C (en) | Acanthopanax root injection freeze-dried powder injection and producing technology for acanthopanax root extract | |
| CN100431532C (en) | Breviscapine and borneol constituted composite injection formulation and preparation method thereof | |
| CN102716231A (en) | Traditional Chinese medicinal composition for treating brain damage and brain edema and application thereof | |
| CN1303976C (en) | Maple knotweed mixture for intestine and stomach hualth and its manufacturing method | |
| CN101152246A (en) | Pharmaceutical composition for cardiovascular and cerebrovascular diseases and method for preparing the same | |
| CN101485671B (en) | Novel medicinal use of 8-O-acetyl shanzhiside methylester | |
| CN1785988A (en) | Saflor yellow pigment rich in saflor yellow pigment B, its preparation method and use | |
| CN107569475A (en) | A kind of injection that there is the pharmaceutical composition for improving blood circulation effect and its application and formed by its preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20051014 Address after: No. 6 Erlang Road, Yiyuan County, Shandong, Zibo Applicant after: Shandong Ruiyang Pharmaceutical Co., Ltd. Address before: No. 9, Po Yuen Road, Laishan District, Yantai, Shandong Applicant before: Luye Natural Medicinal Research Developing Co., Ltd., Shandong Prov. |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: RUIYANG PHARMACY CO., LTD. Free format text: FORMER NAME OR ADDRESS: SHANGDONG RUIYANG PHARMACEUTICAL CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: No. 6 Erlang Road, Yiyuan County, Shandong, Zibo Patentee after: Reyoung Pharmaceutical Co., Ltd. Address before: No. 6 Erlang Road, Yiyuan County, Shandong, Zibo Patentee before: Shandong Ruiyang Pharmaceutical Co., Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: High-dose hydroxy safflower yellow A or its medically-acceptable salt application for preparing medicine for cerebral apoplexy induced from being ischemic Effective date of registration: 20161027 Granted publication date: 20080917 Pledgee: Agricultural Bank of China, Limited by Share Ltd, Yiyuan county subbranch Pledgor: Reyoung Pharmaceutical Co., Ltd. Registration number: 2016990000912 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080917 Termination date: 20200108 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20201228 Granted publication date: 20080917 Pledgee: Agricultural Bank of China Limited by Share Ltd. Yiyuan county subbranch Pledgor: REYOUNG PHARMACEUTICAL Co.,Ltd. Registration number: 2016990000912 |