CN1160066C - Freeze-dried ginkgolide powder injection and its preparing process - Google Patents
Freeze-dried ginkgolide powder injection and its preparing process Download PDFInfo
- Publication number
- CN1160066C CN1160066C CNB021342237A CN02134223A CN1160066C CN 1160066 C CN1160066 C CN 1160066C CN B021342237 A CNB021342237 A CN B021342237A CN 02134223 A CN02134223 A CN 02134223A CN 1160066 C CN1160066 C CN 1160066C
- Authority
- CN
- China
- Prior art keywords
- injection
- freeze
- ginkalide
- ginkgolide
- bilobalide
- 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
- 238000002347 injection Methods 0.000 title claims abstract description 42
- 239000007924 injection Substances 0.000 title claims abstract description 42
- 229930184727 ginkgolide Natural products 0.000 title claims abstract description 13
- 239000000843 powder Substances 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title abstract description 9
- 239000000243 solution Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 5
- 229930195725 Mannitol Natural products 0.000 claims abstract description 5
- 238000004108 freeze drying Methods 0.000 claims abstract description 5
- 239000000594 mannitol Substances 0.000 claims abstract description 5
- 235000010355 mannitol Nutrition 0.000 claims abstract description 5
- 238000004090 dissolution Methods 0.000 claims abstract description 3
- 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 claims description 69
- 241000218628 Ginkgo Species 0.000 claims description 10
- 235000011201 Ginkgo Nutrition 0.000 claims description 10
- 235000008100 Ginkgo biloba Nutrition 0.000 claims description 10
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 8
- 229960003194 meglumine Drugs 0.000 claims description 8
- 150000002596 lactones Chemical class 0.000 claims description 7
- 210000000582 semen Anatomy 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 19
- 239000006184 cosolvent Substances 0.000 abstract description 2
- 239000008215 water for injection Substances 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 3
- 125000000686 lactone group Chemical group 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 150000003839 salts Chemical group 0.000 abstract 1
- 239000008176 lyophilized powder Substances 0.000 description 23
- 241000700159 Rattus Species 0.000 description 18
- 210000004556 brain Anatomy 0.000 description 15
- UIAGMCDKSXEBJQ-UHFFFAOYSA-N nimodipine Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-UHFFFAOYSA-N 0.000 description 12
- 230000002490 cerebral effect Effects 0.000 description 9
- 239000013642 negative control Substances 0.000 description 9
- 229940072101 nimotop Drugs 0.000 description 9
- 210000001168 carotid artery common Anatomy 0.000 description 7
- 206010008118 cerebral infarction Diseases 0.000 description 7
- 239000010212 ginaton Substances 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 210000000269 carotid artery external Anatomy 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 201000006474 Brain Ischemia Diseases 0.000 description 5
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 229960003699 evans blue Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 230000003727 cerebral blood flow Effects 0.000 description 4
- 230000035487 diastolic blood pressure Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 210000004004 carotid artery internal Anatomy 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000028527 righting reflex Effects 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-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 compound 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
- 239000004677 Nylon Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000003925 brain function Effects 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
- 230000004087 circulation Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 229960000715 nimodipine Drugs 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000003848 thrombocyte activating factor antagonist Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 210000002385 vertebral artery Anatomy 0.000 description 2
- 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 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003084 Areflexia Diseases 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000009429 Ginkgo biloba extract Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101100293261 Mus musculus Naa15 gene Proteins 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 229940123251 Platelet activating factor antagonist Drugs 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 240000005578 Rivina humilis Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 210000002551 anterior cerebral artery Anatomy 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000003188 neurobehavioral effect Effects 0.000 description 1
- 210000003977 optic chiasm Anatomy 0.000 description 1
- 230000004413 optic chiasma Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940011964 pentobarbital sodium 30 mg Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 210000000779 thoracic wall Anatomy 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses a preparation method of a ginkgolide freeze-dried powder injection, which comprises the following procedures: (1) raw materials of mixed ginkgolide are dissolved in alkali solutions and prepared into alkali solutions containing the ginkalide; (2) the alkali solutions are sufficiently stirred for causing the ginkalide to be totally dissolved; (3) mannitol is added into the solutions, dissolved and filtered; (4) the ginkgolide freeze-dried powder injection can be obtained by sterile subpackage and freeze drying of filter liquid. Because the ginkalide is difficultly dissolved in water, a certain difficulty is brought to the preparation of a water injection, and the ginkalide is unstable in the water. The ginkalide is dissolved in the water by a salt form formed by a utilizable lactone part in the structure of the ginkalide, then, prepared into freeze-dried powders, thereby being stably stored. The method of the present invention has the advantages of simple process and good water solubility of the product which can be used by dissolution by water for injection without any other cosolvent addition.
Description
Affiliated technical field
The present invention relates to a kind of preparation method of ginkgolide medicinal preparation, more particularly, relate to a kind of preparation method of freeze-dried ginkgolide powder injection.
Background technology
Folium Ginkgo extract is more to its research both at home and abroad, its production technology, the equal comparative maturity of pharmacological research and clinical practice, market product is also more, the ginkgo leaf extract capsule that for example domestic Chinese Academy of Sciences Shanghai medicine is succeeded in developing, tablet in clinical practice in diseases of cardiovascular and cerebrovascular systems such as coronary heart disease, the dizziness that angina pectoris and cerebral arteriosclerosis and cerebral blood supply insufficiency cause, headache, dizzy, anxiety, tinnitus, symptoms such as hypomnesis, clinical effectiveness is comparatively satisfied, Germany Schwabe company and French EPSEN company are used to prevent and treat senile dementia to Folium Ginkgo extract and also succeed in U.S.'s clinical trial, this medicine side effect is minimum, so good market prospect.
Mainly contain bioactive substance ginkalide A and B in the Folium Ginkgo extract, it is the strong platelet plate of a class activation factor PAF antagonist, and these compositions only find to be present in Semen Ginkgo one kind of plant at present, because this constituent structure complexity also cannot be produced with methodology of organic synthesis at present.Platelet activating factor is the biological active substances of a kind of mammal endogenous, main morbidity with the allosome repulsion of allergy, ulcer, asthma, thrombosis, some inflammation, organ transplantation, the myocardial damage that the coronary disease patient causes owing to anoxia etc. is closely related, so platelet activating factor antagonist might be used for the control of above-mentioned disease.
Because bilobalide has unique pharmacological action, native land Medicine and Surgery scholar has carried out many researchs to it, but does not still have formal product at present abroad, and the dosage form that clinical trial was once used mainly is a tablet, the employing inhalant dosage form is also arranged, and ginkalide B also has the injection of employing to carry out clinical trial.But the dosage form to bilobalide is reported seldom at present, because bilobalide itself is very difficult water-soluble, therefore the employing lyophilized injectable powder still is not reported as form of medication at present.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of freeze-dried ginkgolide powder injection, bilobalide is directly entered blood to improve bioavailability with the form of injection, and overcome because of bilobalide and be insoluble in the difficulty that water brings injection preparation, thereby bilobalide is made freeze-dried ginkgolide powder injection soluble in water, make it more stable, onset is faster.
The method for preparing freeze-dried ginkgolide powder injection provided by the invention may further comprise the steps:
(1) Semen Ginkgo is mixed the lactone material dissolution in meglumine solution, be mixed with the meglumine solution of bilobalide-containing;
(2) the meglumine solution with above-mentioned bilobalide-containing fully stirs, and bilobalide is all dissolved;
(3) in above-mentioned solution, add mannitol and make dissolving, filter;
(4) filtrate is aseptic subpackaged, lyophilization, promptly.
Semen Ginkgo of the present invention mixes lactone A, the B structural formula is as follows:
Wherein:
| R 1 | R 2 | R 3 | |
| Ginkalide A | OH | H | H |
| Ginkalide B | OH | OH | H |
Because bilobalide is insoluble in water, bring certain difficulty to being prepared into aqueous injection, bilobalide is unstable in water again, and the present invention adopts that available lactone part makes its salifiable form and bilobalide is dissolved in the water in the bilobalide structure, and then make lyophilized powder, make its stable preservation.The inventive method technology is simple, and the product good water solubility can not add any other cosolvent, can use with the water for injection dissolving.
The present invention is further illustrated below in conjunction with embodiment and Pharmacodynamic test of active extract.
Embodiment 1
Get Semen Ginkgo and mix lactone crude drug 55g, the solution 5000ml that places the 52g meglumine to be made into adds 60g mannitol again, fully stirs and makes its dissolving, be chilled to room temperature, filter, aseptic subpackaged in cillin bottle, after the lyophilization, tamponade, gland promptly gets freeze-dried ginkgolide powder injection of the present invention.
Embodiment 2
Get Semen Ginkgo and mix lactone crude drug 45g, the solution 5000ml that places the 50g meglumine to be made into adds 50g mannitol again, fully stirs and makes its dissolving, be chilled to room temperature, filter, aseptic subpackaged in cillin bottle, after the lyophilization, tamponade, gland promptly gets freeze-dried ginkgolide powder injection of the present invention.
Pharmacodynamics test
One, injection bilobalide lyophilized powder iv is to the influence of focal rats with cerebral ischemia brain function, infraction rate and brain water content
Get 70 of male SD rats, body weight 300-400g, be divided into 7 groups at random by body weight, be respectively bilobalide lyophilized powder high dose group 30.0mg/kg, middle dosage group 15.0mg/kg, low dose group 7.5mg/kg, positive control nimotop injection group 0.2mg/kg, positive control Ginaton injection group 1.0ml/kg, sham operated rats and ischemia model matched group (all giving equivalent normal saline 0.6ml/100g).In preceding four days of experiment, every day, tail vein injection was administered once, and the 4th day for the last time in ischemia administration in preceding 30 minutes.With reference to people's such as Longa method, adopt internal jugular vein line bolt legal system to be equipped with intraluminal middle cerebral artery occlusion in rats obturation (MCAO) model.Rat is anaesthetized with 10% chloral hydrate (300mg/kg) ip, the cervical region median incision on the constant temperature operating-table of lying on the back, expose right carotid, outwards draw digastric and sternocleidomastoid, free successively by common carotid artery crotch head-end, ligation is also cut off external carotid artery and is made its trunk free standby, separates internal carotid artery then, make a call to one with silk thread at the external carotid artery root and release, folder closes common carotid artery and internal carotid artery.With nylon wire (long 4cm, diameter 0.26mm) through external carotid artery trunk otch, slowly going into the cranium direction to internal carotid artery advances, with the common carotid artery crotch is labelling, feel resistance when advancing the 20mm left and right sides, promptly reached blocked MCA in the thinner anterior cerebral artery all blood for the source, tighten the external carotid artery root and release.After one hour, extract nylon wire, tighten the tremulous pulse stump.Skin suture is finished MCAO and is caused focal cerebral ischemia-irritate again model.Behind the sham operated rats rat anesthesia, only expose the inside and outside aortic bifurcation of neck, not inaccessible MCA.
Postoperative 24h carries out rank scores by the method for Bederson to the behavioral deficiency of animal, and standard is as follows:
0 grade: do not observe nervous symptoms;
1 grade: carry tail when unsettled, the operation offside forelimb of animal shows as wrist elbow flexing, the shoulder inward turning, and the elbow abduction is close to thoracic wall;
2 grades: animal is placed on the smooth flat, and pushing hands art side is takeed on to side shifting the time, and resistance reduces;
3 grades: side ring is changeed or turn-take to operation during the animal walking freely;
4 grades: collapse from physical exhaustion, limbs do not have spontaneous activity.
Behind the MCAO 24h, the sacrificed by decapitation rat is taken out full brain, and left and right sides brain cuts respectively, weighs.At right brain optic chiasma and each 2mm place, front and back thereof, do crown cutting, brain section lucifuge in 1%TTC solution was hatched 25 minutes for 37 ℃, separated pale district (stalk playing area) and white area, non-storehouse (normal district) with the ophthalmology tweezer, calculated infraction percentage ratio..
Infraction percentage ratio (%)=pale district weight/(pale district weight+non-pale district weight) * 100%
Cerebral tissue after the dyeing is placed 110 ℃ of oven for drying, and it is as follows that contrast brain weight in wet base is obtained brain water content:
Brain water content (%)=(1-cerebral tissue dry weight/cerebral tissue weight in wet base) * 100%
Table 1 injection bilobalide lyophilized powder iv to the influence of focal rats with cerebral ischemia neurobehavioral, cerebral infarction rate, brain water content (x ± s, n=10)
Group dosage (mg/kg) neural behavior scoring cerebral infarction rate (%) brain water content (%)
Sham operated rats-0.3 ± 0.5 0 77.0 ± 0.9
Model contrast-3.3 ± 1.1 21.0 ± 2.3 80.9 ± 1.0
30.0 1.4±1.0
** 13.8±2.0
** 78.1±0.9
**
Lyophilized powder 15.0 1.8 ± 1.0
*16.4 ± 2.4
*78.9 ± 0.7
*
7.5 2.4±0.8
* 18.4±2.0
* 79.3±0.8
*
Ginaton group 1ml/kg 1.8 ± 1.1
*15.6 ± 3.0
*78.7 ± 1.0
*
Nimotop group 0.2 1.9 ± 0.7
*16.9 ± 1.9
* *78.3 ± 1.3
*
*P＜0.05
*P＜0.01 υ s model contrast
Conclusion: injection bilobalide lyophilized powder intravenously administrable 7.5,15.0,30.0mg/kg iv can make the apoplexy scoring of MCAO rat reduce, the MCAO infarction size dwindles, and brain water content reduces (P＜0.01) its action intensity and the Ginaton injection compares no significant difference.
Two, injection bilobalide lyophilized powder iv is to the protective effect of rat experiment dispersivity completeness cerebral ischemia
Get 70 of male SD rats, body weight 300-400g is divided into 7 groups at random, 10 every group.Be divided into injection bilobalide lyophilized powder high dose group 30.0mg/kg, middle dosage group 15.0mg/kg, low dose group 7.5mg/kg, nimotop injection group 0.2mg/kg, Ginaton group 1.0ml/kg, model control group and sham operated rats (all giving equivalent normal saline 0.6ml/100g).In the experiment first three day, every day tail vein injection once.30min after the administration in the 3rd day, with 10% chloral hydrate anesthesia (30.0mg/kg, ip).Rat back of the body position is fixing, separate bilateral common carotid arteries.30min rat waking state closes bilateral common carotid arteries with the small artery folder folder of silica gel tube down after administration, visible rat consciousness and righting reflex loss, and eye bleaches, perpendicular hair, accelerated breathing.Remove bulldog clamp behind the 30min, cause re-perfusion model, irritate vena femoralis injection 60mg/kg azovan blue simultaneously again.The rat broken end is got brain behind the 60min, use normal saline and acetone mixed liquor (3: 7v/v) make 10% homogenate (W/V) then, after sealing is placed and is spent the night, the centrifugal 15min of 2500rpm, get supernatant, with normal saline-acetone mixed liquor zeroing, survey absorbance at the 620nm place and represent azovan blue content in the cerebral tissue [is the standard curve that solvent is set up azovan blue light absorption value and concentration with normal saline-acetone mixed liquor], reflect the influence of administration with this to cerebrovascular permeability.The result is by shown in the table 2, injection bilobalide lyophilized powder 7.5,15.0, but 30.0mg/kg 4 days dosage correlation ground of continuous intravenous injection shorten four artery ligations irritate again and again due to righting reflex recovery time of full brain dispersivity ischemia rat, reduce brain homogenate azovan blue content (high dose group p＜0.001).Brain function after injection bilobalide lyophilized powder can be protected ischemia is described, reduces capillary permeability.
Table 2 bilobalide lyophilized powder iv is to the protective effect of rat experiment dispersivity completeness cerebral ischemia (n=10, x ± s)
Group dosage righting reflex azovan blue recovery time content
(mg/kg) (min) (μ g/g brain is heavy)
Sham operated rats-7.51 ± 1.0
Model contrast-30.1 ± 4.3 17.5 ± 1.6
Nimotop group 0.2 24.7 ± 4.8
*15.5 ± 2.2
*
Ginaton group 1.0ml/kg 24.1 ± 5.5
*15.2 ± 1.9
*
30.0 23.9±5.1
*** 15.0±1.5
***
Lyophilized powder 15.0 26.4 ± 3.3
*15.3 ± 2.0
*
7.5 26.5±3.2
** 15.9±1.6
**
*P＞0.05,
*P＜0.05
* *P＜0.01 υ s model control group
Three, injection bilobalide lyophilized powder iv is to the influence of mice hypoxia-bearing capability
Get 50 of mices, body weight is 18-22g, is divided into 5 groups at random, 10 every group, and male and female half and half.Be respectively injection bilobalide lyophilized powder 48.0,24.0,12.0mg/kg; Ginaton injection group (2.0ml/kg); Nimotop injection group (0.4mg/kg); Ischemic control group (giving the normal saline of equivalent).In the experiment first three day, every day the tail intravenously administrable once, with variable concentrations isometric(al) administration 0.1ml/10g body weight.After the last administration in the 4th day 10 minutes, mice is placed the airtight wide mouthed bottle of the 60ml that the 25g sodica calx is housed, the death time of record mice.But table 3 result shows the time-to-live (P＜0.01) of bilobalide lyophilized powder intravenous fluid significant prolongation mice under anaerobic condition.
Table 3 injection bilobalide lyophilized powder is to the influence of mice hypoxia-bearing capability (n=10, x ± s)
Group dosage (mg/kg) time-to-live (min)
Negative control 14.4 ± 1.7
Nimotop group 0.4 17.0 ± 1.5
* *
Ginaton group 2.0ml/kg 18.41.6
* *
48.0 19.61.6
***
Lactone lyophilized powder 24.0 16.3 ± 1.6
*
12.0 14.6±1.9
*
*P＞0.05,
*P＜0.05
* *P＜0.01 υ s model control group
Four, injection bilobalide lyophilized powder iv is to the influence of anesthetized dog cerebral circulation
25 of hybrid dogs, the male and female dual-purpose is divided into 5 groups at random, 5 every group.Be the basic, normal, high dosage group of injection bilobalide lyophilized powder (2.5,5.0,10.0mg/kg), positive control nimotop injection group (0.1mg/kg), normal saline matched group.Animal is fixed with pentobarbital sodium 30mg/kg iv. anesthesia back position, the polyethylene tube that will be full of 0.1% heparin-saline inserts ventral aorta through anesthetized dog one side femoral artery, link to each other with RM6000 type polygraph by TP-200T type pressure transducer, directly read femoral artery systolic pressure (SAP), diastolic pressure (DAP), mean arterial pressure (MAP) and heart rate (HR).Separate common carotid artery and external carotid artery, and the ligation external carotid artery, with electromagnetic flowmeter (MFV-1200) probe placement of diameter 3mm on common carotid artery, to measure ICAF amount (JCBF).Go out vertebral artery in the C7 horizontal separation, put electromagnetic flowmeter (MFV-3100) probe of internal diameter 2mm, to measure vertebral artery blood flow (VCBF).Observe by ECG6511 type electrocardiograph and record II lead electrocardiogram with pin type electrode simultaneously.Cerebral blood flow (CBF) and cerebral vascular resistance (CVR) are pressed document [5] formula and are calculated.Femoral venous catheter is to append anesthesia maintenance dose and administration.Treat the stable back of every index record normal parameter value, and administration.Every dog is administered once, administration volume 4ml/kg.The variation of every index in the 120min after observation and the record administration.
By the visible injection bilobalide lyophilized powder intravenously administrable 2.5 of table 4,5.0,10.0mg/kg to CBF and CVR, HR does not have obvious influence, with before the administration and matched group comparison P＞0.05, and nimodipine can make cerebral blood flow increase, and cerebral vascular resistance reduces, and shows that the Folium Ginkgo intravenously administrable does not influence the cerebral blood flow and the cerebral vascular resistance of anesthetized dog.
By the visible injection bilobalide lyophilized powder intravenously administrable 2.5 of table 5,5.0,10.0mg/kg to SPA, DAP, MAP does not have obvious influence, with before the administration and matched group than P＞0.05, and blood pressure begins to descend immediately after the Nimodipine venous administration, with before the administration and matched group comparison P＜0.05, more than the lasting 2h of blood pressure drops.
Table 4 injection bilobalide lyophilized powder (GBI) iv to the influence of anesthetized dog cerebral circulation (x ± s, n=5)
Behind the index group dosed administration (min)
(mg/kg) administration preceding 135 10 20 30 45 60 90 120
Negative control 146.0 ± 8.8 148.9 ± 9.9 147.4 ± 8.3 14.6.2 ± 10.0 148.8 ± 9.7 14.8.8 ± 10.5 149.9 ± 6.4 146.7 ± 8.6 143.9 ± 10.4 148.0 ± 10.4 148.2 ± 14.1
Cerebral blood flow 10.0 155.3 ± 41.9 155.3 ± 40.5 163.7 ± 41.5 162.3 ± 42.1 164.6 ± 42.5 167.3 ± 4 1.4165.7 ± 4 1.6158.0 ± 4 1.9157.8 ± 39.6 156.6 ± 42.2 156.6 ± 41.2
(ml/100g. GBI 5.0 141.1±33.4 141.1±30.1 139.7±30.2 139.1±30.5 141.7±29.8 138.3±28.6 141.1±28.5 142.3±31.4 139.7±35.9 141.1±37.2 141.7±34.9
min) 2.5 128.4±16.9 127.5±18.5 129.7±16.3 132.4±15.4 131.1±18.9 128.9±19.4 133.6±20.2 132.6±18.3 137.2±18.6 133.1±13.9 132.4±16.2
Nimotop 0.1 140.9 ± 16.9 121.8 ± 21.5
*134.6 ± 20.3 159.5 ± 36.4 189.1 ± 37.2#, 201.1 ± 51.9## 180.1 ± 34.6# 160.3 ± 28.1 153.3 ± 28.1 148.2 ± 27.1 144.5 ± 26.6
Negative control 0.11 ± 0.01 0.11 ± 0.01 0.11 ± 0.01 0.11 ± 0.01 0.11 ± 0.01 0.12 ± 0.02 0.11 ± 0.01 0.12 ± 0.01 0.12 ± 0.01 0.11 ± 0.01 0.11 ± 0.01
Vascular resistance 10.0 0.10 ± 0.02 0.10 ± 0.02 0.10 ± 0.02 0.10 ± 0.01 0.10 ± 0.02 0.10 ± 0 02 0.10 ± 0.01 0.10 ± 0.02 0.10 ± 0.02 0.10 ± 0.02 0.10 ± 0.01
(Kpa/mL GB1 5.0 0.11±0.01 0.11±0.03 0.11±0.03 0.11±0.03 0.11±0.03 0.11±0.03 0.11±0.03 0.11±0.03 0.11±0.03 0.12±0.03 0.11±0.03
100g.mm) 2.5 0.13±0.02 0.13±0.02 0.13±0.02 0.13±0.02 0.13±0.02 0.14±0.03 0.13±0.03 0.13±0.02 0.13±0.02 0.13±0.02 0.13±0.03
Nimotop 0.1 0.11 ± 0.03 0.04 ± 0.01##
*0.04 ± 0.02##
*0.05 ± 0.0###
*0.04 ± 0.01##
*0.05 ± 0.02##
*0.05 ± 0.02##
*0.07 ± 0.02## 0.08 ± 0.02##
*0.08 ± 0.02#
*0.10 ± 0.02
Negative control 186.0 ± 34.5 185.2 ± 33.1 185.4 ± 33.0 184.8 ± 33.1 184.8 ± 33.1 186.2 ± 38.8 187.6 ± 40.4 184.6 ± 33.6 185.2 ± 38.9 181.4 ± 35.1 184.6 ± 36.5
Heart rate 10.0 176.0 ± 52.1 170.4 ± 52.5 167.2 ± 56.7 165.4 ± 58.2 165.0 ± 59.5 165.8 ± 64.0 164.4 ± 62.2 160.8 ± 59.2 165.4 ± 62.8 162.6 ± 59.7 164.8 ± 57.4
(inferior/minute) GBI 5.0 176.0 ± 46.4 175.0 ± 46.5 172.0 ± 46.2 172.0 ± 46.5 171.2 ± 47.9 171.2 ± 48.9 170.8 ± 47.4 172.4 ± 49.4 175.0 ± 52.9 173.0 ± 47.4 170.4 ± 49.7
2.5 187.4±35.4 187.0±38.2 186.4±38.8 186.4±37.8 186.4±37.7 187.4±38.0 186.2±38.0 188.2±39.5 190.8±41.2 180.4±34.2 187.4±39.8
Nimotop 0.1 161.0 ± 51.2 85.6 ± 18.2#
*79.0 ± 24.1#
*80.6 ± 24.8#
*86.0 ± 31.0#
*99.4 ± 20.9
*121.6 ± 32.6#
*132.2 ± 40.3# 136.2 ± 42.6 140.2 ± 46.8 143.4 ± 47.9
Before #P＜0.05##P＜0.01 υ s administration
*P＜0.05
*P＜0.01 υ s negative control
Table 5 injection bilobalide lyophilized powder (GBO) iv to the influence of anaesthetized dog blood pressure (x ± s, n=5)
Behind the index group dosed administration (min)
(mg/kg) administration preceding 135 10 20 30 45 60 90 120
Negative control 21.7 ± 2.9 21.4 ± 2.2 21.7 ± 2.5 21.7 ± 2.5 21.6 ± 2.2 22.8 ± 3.1 22.7 ± 3.1 22.8 ± 3.6 22.7 ± 3.0 21.8 ± 3.12 2.0 ± 2.6
SPA 10.0 22.2±4.8 21.8±5.2 21.4±5.6 21.0±5.5 21.3±5.7 21.7±7.1 21.0±5.8 20.0±5.1 19.6±4. 220.8±5.0 20.6±4.3
(Kpa) GBI 5.0 21.0±5.0 20.9±4.8 20.5±4.7 21.1±5.7 20.7±5.5 20.5±4.7 20.6±5.0 21.1±5.1 20.8±4 21.1±5.0 20.9±5.2
2.5 21.7±3.9 21.9±4.1 22.2±3.8 21.6±2.7 22.1±3.6 23.5±4.3 22.3±3.0 23.0±3.4 23.4±3.3 22.8±4.6 23.3±4.7
Nimotop 0.1 21.4 ± 3.8 11.8 ± 3.4##
*12.1 ± 2.1 14.6 ± 1.7##
*15.5 ± 2.5##
*17.7 ± 5.5#
*17.8 ± 4.7#
*18.9 ± 3.0#
*19.6 ± 3.2#
*19.7 ± 3.3 21.2 ± 3.4
Negative control 14.2 ± 0.8 14.2 ± 1.1 14.3 ± 0.8 14.2 ± 1.1 14.2 ± 1.0 14.1 ± 1.0 14.3 ± 1.3 14.1 ± 1.4 14.2 ± 1.2 14.0 ± 1.5 14.3 ± 1.0
DAP 10.0 13.0±1.6 12.8±1.8 12.7±1.9 12.3±2.3 12.6±2.4 12.7±3.0 12.4±2.6 12.3±2.1 12.2±1.7 12.3±2.2 12.2±1.6
(Kpa) GBI 5.0 12.7±0.3 12.9±1.8 12.7±3.0 12.6±3.0 12.7±2.9 12.5±3.0 12.9±3.2 12.6±2.7 12.5±1.8 12.8±2.5 12.7±2.3
2.5 13.8±1.0 13.9±1.3 13.8±1.4 13.8±1.4 13.7±1.4 14.2±1.2 14.3±2.0 14.2±1.5 14.5±1.6 14.2±0.6 13.9±1.0
Nimotop 0.1 11.7 ± 2.4 1.7 ± 0.9##
*1.9 ± 1.5##
*3.2 ± 1.5##
*3.4 ± 1.3##
*4.0 ± 1.3##
*4.9 ± 1.6##
*6.2 ± 1.6##
*6.8 ± 1.6##
*8.2 ± 1.##
*10.3 ± 1.4##
*
Negative control 16.7 ± 0.9 16.6 ± 0.7 16.8 ± 0.7 16.7 ± 0.6 16.7 ± 0.7 17.0 ± 1.2 17.1 ± 1.2 17.0 ± 1.2 17.1 ± 1.2 16.6 ± 0.6 16.9 ± 1.1
MAP 10.0 160±2.6 15.8±2.8 15.6±3.0 15.2±3.2 15.5±3.4 15.7±4.3 15.3±3.6 14.9±2.9 14.7±2.4 15.1±3.0 15.0±2.0
(Kpa) GBI 5.0 15.5±3.5 15.6±3.3 15.3±3.5 15.4±3.8 15.4±3.6 15.2±3.4 15.5±3.6 15.4±3.4 15.3±3.2 15.6±3.2 15.4±3.2
2.5 16.5±1.4 16.6±1.6 16.7±1.7 16.5±1.3 16.5±1.7 17.3±1.7 16.9±1.8 17.1±1.7 17.5±1.9 17.1±1.9 17.1±2.0
0.1 14.9±2.7 5.0±1.6##
** 5.3±1.6##
** 7.0±1.4##
** 7.5±1.5##
** 8.6±2.2##
** 9.2±2.5##
** 10.5±2.0##
** 11.1±2.1##
** 12.0±1.8#
** 13.9±2.0#
**
Before #P＜0.5 ##P＜0.01 υ s administration
*P＜0.05
*P＜0.01 υ s negative control
Claims (1)
1, a kind of preparation method of freeze-dried ginkgolide powder injection may further comprise the steps:
(1) Semen Ginkgo is mixed the lactone material dissolution in meglumine solution, be mixed with the meglumine solution of bilobalide-containing;
(2) the meglumine solution with above-mentioned bilobalide-containing fully stirs, and bilobalide is all dissolved;
(3) in above-mentioned solution, add mannitol and make dissolving, filter;
(4) filtrate is aseptic subpackaged, lyophilization, promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021342237A CN1160066C (en) | 2002-06-21 | 2002-06-21 | Freeze-dried ginkgolide powder injection and its preparing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021342237A CN1160066C (en) | 2002-06-21 | 2002-06-21 | Freeze-dried ginkgolide powder injection and its preparing process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1390542A CN1390542A (en) | 2003-01-15 |
| CN1160066C true CN1160066C (en) | 2004-08-04 |
Family
ID=4747638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021342237A Expired - Fee Related CN1160066C (en) | 2002-06-21 | 2002-06-21 | Freeze-dried ginkgolide powder injection and its preparing process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1160066C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100525759C (en) * | 2003-08-06 | 2009-08-12 | 吴梅春 | Ready-made medicine of traditional chinese medicine for treating ischemic cranial vascular disease |
| CN100402024C (en) * | 2004-01-14 | 2008-07-16 | 海口龙南医药科技开发有限公司 | Gingko lactone freeze dried powder injection and its preparation method |
| CN100341502C (en) * | 2006-04-18 | 2007-10-10 | 张国清 | Vein administration ginkgolactone B powder injection and its preparation method |
| CN101249085B (en) * | 2008-03-31 | 2010-04-21 | 广州艾格生物科技有限公司 | Bilobalide A, B compound injection and preparation method and application thereof |
| CN110433157B (en) * | 2018-05-02 | 2022-10-18 | 成都百裕制药股份有限公司 | Application of ginkgolide in preparation of medicine for preventing and/or treating vertigo |
-
2002
- 2002-06-21 CN CNB021342237A patent/CN1160066C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1390542A (en) | 2003-01-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2414472T3 (en) | Pharmaceutical composition of sustained release of octreotide acetate | |
| CN1160066C (en) | Freeze-dried ginkgolide powder injection and its preparing process | |
| CN1846734A (en) | Prince's-feather prepn and its prepn process and application | |
| CN1403088A (en) | Medicine composition containing polydatin or its salt and its use in preparing medicine | |
| CN1772020A (en) | Freeze dried pubescent holly powder for injection and its prepn | |
| CN1160067C (en) | Soft bilobalide capsule and its prepn. | |
| CN108929372B (en) | 1R-methyl-beta-tetrahydrocarboline acyl-K (GRPAK) -RGDV, and synthesis, activity and application thereof | |
| CN108853043B (en) | Medicine for treating central diabetes insipidus and application thereof | |
| CN101190937B (en) | Compound with liver-protecting activity | |
| CN1192784C (en) | Medicine prepared from extract of pubescent holly root for treating erection disfunction and preparing process thereof | |
| CN101190935B (en) | Compound used for viral infect | |
| CN1424315A (en) | Ginkgo lactone compound and its preparation and medicinal composition containing it | |
| CN1163104A (en) | Medicinal preparation containing shikimic acid and its derivatives, and its use in preparing anti-thrombosis and analgesic medicine | |
| CN1939328A (en) | Puerarin injection | |
| CN1092661A (en) | A kind of medicine for the treatment of acquired immune deficiency syndrome (AIDS) | |
| CN110693882A (en) | Sublingual pharmaceutical composition | |
| CN1286458C (en) | Application of cnidium fruit element in the preparing process of medicine for preventing and treating Sexual dysfunction | |
| CN1482124A (en) | Preparation process for dragon's blood total flavonoids | |
| CN101190936A (en) | Compound with antiviral activity | |
| TWI262081B (en) | Immunopotentiator and method for preparing the same | |
| CN1857293A (en) | Medicine composition containing wild astragaloside and paeoniforin | |
| CN1557402A (en) | Chinese herbal medicine preparation and its preparing process and application | |
| CN1308008C (en) | Pharmaceutical composition for treaitng coronary heart disease | |
| CN1596954A (en) | Red ginseng and ophiopogon root preparation and its making method | |
| CN111529560A (en) | Pharmaceutical composition containing dihydroartemisinin and herba Polygoni orientalis, preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: TIANJIN TASLY PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: ZHANG PING Effective date: 20051230 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20051230 Address after: 300402 Beichen science and Technology Park, Tianjin Patentee after: Tianjin Tianshili Pharmaceutical Co., Ltd. Address before: 510610 Guangdong city of Guangzhou province forest and Road No. 150, Room 802 on the eighth floor of Tianyu Garden Plaza Accord Patentee before: Zhang Ping |
|
| ASS | Succession or assignment of patent right |
Owner name: OUHUA MEDICINE BIOTECHNOLOGY CO., LTD., GUANGZHOU Free format text: FORMER OWNER: TIANJIN TIANSHILI PHARMACEUTICAL CO., LTD. Effective date: 20100719 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 300402 BEICHEN SCI-TECH PARK, TIANJIN CITY TO: 100036 ROOM 201, UNIT 1, BUILDING 11, NO.17, ZIJINCHANGAN RESIDENTIAL QUARTER, XICUI ROAD, HAIDIAN DISTRICT, BEIJING CITY |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20100719 Address after: 100036 Beijing City, Haidian District Zijin Xicui road Changan District No. 17 Hospital No. 11 Building 1 unit 201 room Patentee after: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Address before: 300402 Beichen science and Technology Park, Tianjin Patentee before: Tianjin Tianshili Pharmaceutical Co., Ltd. |
|
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: 100052, Beijing, Xicheng District East River along Hutong No. 73, Xuanwumen building, 11 floor Patentee after: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Address before: 100036 Beijing City, Haidian District Zijin Xicui road Changan District No. 17 Hospital No. 11 Building 1 unit 201 room Patentee before: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou |
|
| DD01 | Delivery of document by public notice |
Addressee: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Document name: Notification to Pay the Fees |
|
| DD01 | Delivery of document by public notice |
Addressee: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Document name: Notification of Termination of Patent Right |
|
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: 100052, Beijing, Xicheng District, 28 West woolen Hutong No. 1202 Tian An sinks room Patentee after: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Address before: 100052, Beijing, Xicheng District East River along Hutong No. 73, Xuanwumen building, 11 floor Patentee before: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou |
|
| DD01 | Delivery of document by public notice |
Addressee: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Document name: Notification of Passing Examination on Formalities |
|
| DD01 | Delivery of document by public notice |
Addressee: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Document name: Notification to Go Through Formalities Rectification of Restoration of Right |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040804 Termination date: 20140621 |
|
| EXPY | Termination of patent right or utility model | ||
| DD01 | Delivery of document by public notice |
Addressee: Ouhua Medicine Biotechnology Co., Ltd., Guangzhou Document name: Notification of Decision on Request for Restoration of Right |