CN109925310B - Hypotensive agent containing therapeutically effective amount of ginkgolides - Google Patents
Hypotensive agent containing therapeutically effective amount of ginkgolides Download PDFInfo
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Abstract
The invention provides a blood pressure lowering medicine containing effective amount of ginkgolide, which is one or more of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M and bilobalide. The study of the invention shows that the bilobalide monomer compound and the composition thereof have good blood pressure reducing effect, particularly under the limited proportion of the invention, the blood pressure reducing effect is remarkably improved, and a new choice is provided for clinical medication.
Description
The invention is as follows: 2014/12/10, respectively; the application numbers are: 201410756745.0, respectively; the invention creates a divisional application named as the application of the ginkgolide in preparing the medicine for reducing the blood pressure.
Technical Field
The present invention relates to a hypotensive agent containing a therapeutically effective amount of ginkgolides.
Background
Hypertension is the most common chronic disease and the most main risk factor of cardiovascular and cerebrovascular diseases, and stroke, myocardial infarction, heart failure and chronic kidney disease are main complications of the hypertension. The practice at home and abroad proves that the hypertension is a disease which can be prevented and controlled, the blood pressure level of a hypertension patient is reduced, the stroke and the heart disease events can be obviously reduced, the life quality of the patient is obviously improved, and the disease burden is effectively reduced. The risk of hypertension is related to the blood pressure level of the patient and depends on the risk factors of other cardiovascular diseases, target organ damage and other diseases combined. Therefore, in the definition and classification of hypertension, the diagnostic criteria of hypertension are defined as systolic pressure ≥ 140mmHg and/or diastolic pressure ≥ 90mmHg, and are classified according to blood pressure level into normal, normal high-value blood pressure and 1, 2, 3-stage blood pressure, and at the same time, risk stratification is performed according to risk factors, target organ damage and other diseases which are simultaneously complicated. The prevalence of hypertension increases with age; the prevalence rate of women is slightly lower than that of men before menopause, but rises rapidly after menopause, even higher than that of men; the prevalence rate of the high-latitude cold area is higher than that of the low-latitude warm area, and the prevalence rate of the high-altitude area is higher than that of the low-altitude area; in connection with dietary habits, the higher the intake of salt and saturated fat, the higher the average blood pressure level and the prevalence. The hypertension prevalence of the population in China has two remarkable characteristics: from south to north, hypertension prevalence presents an increasing trend; the prevalence rate of hypertension is different among different nationalities, the prevalence rate of the nationalities living in northern areas or plateau areas is high, the prevalence rate of the nationalities living in southern areas or non-plateau areas is low, the difference can be related to geographical environments, life styles and the like, and obvious genetic background difference among the nationalities is not found. The main goal of treating hypertension is to minimize the overall risk of cardiovascular morbidity and mortality, thus requiring physicians to intervene in all reversible cardiovascular risk factors, target organ damage and the clinical complications present in patients while treating hypertension. The blood pressure reduction target is below 140/90mmHg for general hypertensive patients, and the blood pressure is reduced to a lower level as appropriate under the condition that the patients can tolerate the high-risk patients with combined diabetes or nephropathy.
A ginkgolide (English name: ginkggolide) compound belongs to a terpenoid, consists of sesquiterpene lactone and diterpene lactone, and is an important active ingredient in ginkgo leaves. At present, the reported ginkgolides have the effects of resisting allergy, inflammation and shock, protecting ischemic injury and protecting organ transplant rejection (pipexiaozhu, the research on pharmacological action of ginkgolides progresses, No. 3 of No. 22 in 1995), Xujiang Ping, and the like, the influence of the ginkgolides on the blood flow of dogs and dogs is reported in the Chinese and Western medicine combined science report, 2005-01-15, and the report that the ginkgolides can reduce the cerebral vascular resistance of dogs under anesthesia, increase the cerebral blood flow and do not influence the heart rate and the blood pressure is reported.
Disclosure of Invention
One of the objects of the present invention is to provide a blood pressure lowering drug containing a therapeutically effective amount of ginkgolides; the invention also aims to provide a blood pressure reducing pharmaceutical preparation containing effective amount of ginkgolide.
A hypotensive agent contains a therapeutically effective amount of a ginkgolide selected from the group consisting of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M, and bilobalide.
Preferably, the bilobalide is bilobalide and diterpenoid lactone.
Preferably, the ginkgoditerpenoid lactone is one or two or more selected from ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and ginkgolide M.
Preferably, the weight ratio of the ginkgoditerpenoid lactone to the bilobalide is (5-60) to (5-65).
Preferably, the ginkgolide: bilobalide is (5: 5) w/w or (5: 65) w/w or (60: 5) w/w or (5: 10) w/w or (15: 5) w/w.
Preferably, the ginkgolide is selected from one of the following combinations:
(1) the ginkgolide A and the ginkgolide B are (10-45) to (5-40) w/w;
(2) ginkgolide A and ginkgolide C are (10-45) to (3-35) w/w;
(3) ginkgolide B and ginkgolide C are (5-40) to (3-35) w/w;
(4) ginkgolide A, ginkgolide B and ginkgolide C are (10-45) to (5-40) to (3-35) w/w/w.
Wherein the dosage and the mass ratio of the three combinations of the ginkgolide A, B, C are as follows: bilobalide A, bilobalide B and bilobalide C in the ratio of 20 to 30 to 10, 10 to 5 to 3, 45 to 5 to 35, 10 to 40 to 35 or 30 to 10.
The invention also provides a preparation of the blood pressure lowering medicine containing effective dose of ginkgolide, and the preparation is an oral preparation, an injection preparation or a transdermal absorption preparation.
The invention provides an application of a composition containing the following components in parts by weight in preparing a blood pressure lowering medicine: ginkgo diterpene lactone: bilobalide (5-60) w/w (5-65).
Further preferably, the weight ratio of the ginkgoditerpenoid lactone to the bilobalide is as follows: ginkgo diterpene lactone: bilobalide is 5:5W/W or 5:65W/W or 60:5W/W or 5:10W/W or 15: 5W/W.
Wherein the ginkgoditerpenoid lactone is one or the combination of more than two of ginkgolide A, B, C, J, M.
Further preferably, the ginkgo diterpenoid lactone is selected from one or a combination of more than two of the ginkgo lactones A, B, C.
Wherein the combination of more than two ginkgolides A, B, C is selected from one of the following components:
(1) ginkgolide a: and (5) bilobalide B is (10-45): (5-40);
(2) ginkgolide a: and ginkgolide C (10-45): (3-35);
(3) ginkgolide B: and ginkgolide C (5-40): (3-35);
(4) ginkgolide a: ginkgolide B: and ginkgolide C (10-45): (5-40): (3-35).
Further preferably, the dosage ratio of the three combinations of the ginkgolide A, B, C is as follows: ginkgolide a: ginkgolide B: ginkgolide C ═ 20: 30:10 or 10:5:3 or 45:5:35 or 10:40:35 or 30:10: 10.
Wherein the medicament is a medicament for treating hypertension.
Wherein, the medicine preparation is an oral preparation, an injection preparation or a transdermal absorption preparation.
The invention also provides the application of the ginkgolide in preparing the antihypertensive drug.
The study of the invention shows that the ginkgolide composition has good blood pressure lowering effect by controlling the weight ratio of the ginkgolide to the bilobalide, particularly, the blood pressure lowering effect is remarkably improved under the limited ratio of the ginkgolide composition, and a new choice is provided for clinical medication.
Detailed Description
The ginkgolide monomer compound can be obtained by purchasing products sold in the market or prepared by separating and purifying by the existing method. Through inspection, all the monomer compounds are consistent with the structures of corresponding reference substances, and the purity of the monomer compounds is over 98 percent through HPLC detection.
The composition of more than two ginkgo diterpenoid lactones can be prepared by combining corresponding monomer compounds.
The composition containing ginkgolide ABC and bilobalide can be prepared by directly purchasing a commercially available ginkgolide injection, or a method of ZL200610103626.0 or ZL200610103625.6, or can be prepared by combining monomer compounds.
The advantageous effects of the present invention are specifically described below by way of test examples.
Test example 1 Effect of ginkgolide injection on blood pressure of renal hypertension model rabbits
1. Experimental equipment
1.1 reagents and drugs: sodium pentobarbital 1% (Shanghai national drug group chemical agents Co., Ltd.), epinephrine injection, and ginkgolide injection (manufactured by Chengdou Baiyu science and technology pharmaceutical Co., Ltd., prepared by the method of example II in granted patent ZL200610103625.6, wherein ginkgolide A: ginkgolide B: ginkgolide C ═ 20: 30:10, the weight ratio of the total amount of ginkgolide A, B, C to bilobalide is 1:1, and the ginkgolide content: 4.91mg/ml), ginkgolide A (provided by Chengdou science and technology pharmaceutical Co., Ltd., content: 5.0mg/ml), ginkgolide B (provided in Chengdou Baiyu, content: 5.0mg/ml), ginkgolide C (provided in Chengdou Baiyu, content: 5.0mg/ml), bilobalide composition 1 (provided in Chengdou Baiyu, ginkgolide a: ginkgolide B: ginkgolide C ═ 10:5:3, the weight ratio of the total amount of the ginkgolide A, B, C to the bilobalide is 60:5, and the content of the ginkgolide: 5.0mg/ml), bilobalide composition 2 (provided in abundance by capitals, bilobalide a: ginkgolide B: ginkgolide C ═ 45:5:35, the weight ratio of the total amount of the ginkgolide A, B, C to the bilobalide is 5:65, bilobalide content: 5.0mg/ml), bilobalide composition 3 (provided in abundance by capitals, bilobalide a: ginkgolide B: ginkgolide C ═ 10:40:35, the weight ratio of the total amount of the ginkgolide A, B, C to the bilobalide is 5:10, and the content of the ginkgolide: 5.0mg/ml), ginkgolide composition 4 (provided in abundance by capitals, ginkgolide a: ginkgolide B: ginkgolide C ═ 30:10:10, the weight ratio of the total amount of the ginkgolide A, B, C to the bilobalide is 15:5, and the content of the ginkgolide: 5.0mg/ml), physiological saline, heparin physiological saline solution, enalaprilat injection (Changzhou pharmaceutical).
1.2 Experimental instruments: BL-420E biosignal acquisition processing system (Gentle science Inc.), pressure transducer.
1.3 Experimental animals: 84 healthy adult rabbits (provided by Experimental animals center in Sichuan province) with weight of 2-2.5 kg and unlimited male and female.
2. Experimental methods
2.1 animal grouping and modeling: 84 rabbits are randomly divided into 14 groups, namely, 14 groups of high, medium and low dosages of ginkgolide injection, model control, positive control, normal control, ginkgolide A, ginkgolide B, ginkgolide C, bilobalide, composition 1, composition 2, composition 3 and composition 4, and 6 rabbits are selected in each group. Except for the normal control group, the rabbits were subjected to a double renal artery stenosis improvement, and the left and right renal artery trunks were ligated together with silver clips, resulting in renal artery insufficiency and renal hypertension model. After feeding for 4 weeks, experiments were performed.
2.2, anesthesia: rabbits were weighed and anesthetized by periaural intravenous injection of 1% sodium pentobarbital (30 mg/kg).
2.3, operation: fixing the anesthetized rabbit on a rabbit dissecting table, cutting a 5-7 cm skin incision in the center of the neck, separating a section of common carotid artery, tying the distal end with a line, tying a virtual knot at the proximal end with a line for standby, clamping the proximal end with an artery clamp, cutting a small opening close to the common carotid artery, inserting an arterial tube filled with heparin normal saline into the common carotid artery, immediately tying and fixing, inputting the blood pressure change into a biological signal acquisition and processing system through a pressure transducer for recording and processing, and applying a preload of about 160 mmHg.
2.4 administration: and (5) releasing the artery clamp, measuring the blood pressure, and recording the blood pressure before administration after the blood pressure of the rabbits is stable. Then injecting 2.5mg/kg, 1.25mg/kg and 0.625mg/kg of ginkgolide injection into the ear vein of the high, medium and low dose groups respectively (the clinical application dose of the ginkgolide injection is converted into the equivalent dose of the rabbit), injecting 1.25mg/kg of ginkgolide group A, ginkgolide group B, ginkgolide group C, bilobalide group, ginkgolide composition group 1, ginkgolide composition group 2, ginkgolide composition group 3 and ginkgolide composition group 4, injecting 0.125mg/kg of enalaprilat injection into the positive control group (the clinical common dose of the enalaprilat injection is converted into the equivalent dose of the rabbit), injecting physiological saline into the model control group and the normal control group, and observing the change and recovery time of blood pressure.
2.5 observation indexes: mean arterial pressure (diastolic +1/3 pulse differential pressure), percent blood pressure drop.
2.6 statistical treatment
SPSS15.0 statistical software is adopted for analysis, and the data are all subjected to average number plus standardTolerance of the laser
And (4) showing. Statistical analysis and processing were performed using the t-test with P < 0.05 as the criterion for significance of differences.
3. Results of the experiment
TABLE 1 antihypertensive test results for renal hypertension rabbits
The blood pressure comparison between the model control group and the normal control group is less than 0.05, and the comparison between the positive control group, the ginkgolide injection high, medium and low dose groups, the ginkgolide B group, the bilobalide group, the composition 1 group, the composition 2 group, the composition 3 group, the composition 4 group and the model group is less than 0.05.
According to the results, after the injection of the ginkgolide injection into the hypertension model rabbits, the blood pressure is immediately and remarkably reduced, the action intensity is dose-dependent, the blood pressure of the individual rabbits in a high-dose group is reduced by 75%, the blood pressure reduction effect of the ginkgolide injection in a medium-dose group is equivalent to that of the enalaprilat injection serving as a positive control, the effect of the high-dose group is better, the blood pressure of the high-dose group does not rise after 2 hours after the administration, the blood pressure of the medium-and-low-dose groups starts to rise after 50 minutes after the administration, and the blood pressure does not recover to the level before the administration after 2 hours; the blood pressure of the ginkgolide B group, the bilobalide group, the composition 1 group, the composition 2 group, the composition 3 group and the composition 4 group is also obviously reduced, but the blood pressure reducing effect of the ginkgolide injection and the ginkgolide composition group is better than that of the ginkgolide B and the bilobalide which are singly used. The results of this experiment were further validated in spontaneously hypertensive rats.
Experimental example 2 Effect of ginkgolide injection on blood pressure of spontaneously hypertensive rat
1. Experimental equipment
1.1 reagents and drugs: bilobalide injection (manufactured by Chengdu Baiyu science and technology pharmaceutical Co., Ltd., prepared by the method of example II in patent ZL200610103625.6, wherein bilobalide A: bilobalide B: bilobalide C: 20: 30:10, the weight ratio of the total amount of bilobalide A, B, C to bilobalide is 1:1, the bilobalide content is 4.91mg/ml), bilobalide A (provided by Chengdu Baiyu science and technology pharmaceutical Co., Ltd., content: 5.0mg/ml), bilobalide B (provided by Chengdu Baiyu science and technology pharmaceutical Co., Ltd., content: 5.0mg/ml), bilobalide C (provided by Chengdu Baiyu science and technology pharmaceutical Co., Ltd., content: 5.0mg/ml), bilobalide composition 1 (provided by Chengdu Baiyu, bilobalide A: bilobalide B: bilobalide C: 10:5:3, bilobalide A, bilobalide B, bilobalide A, B. The weight ratio of the total amount of C to bilobalide is 60:5, and the content of bilobalide is as follows: 5.0mg/ml), bilobalide composition 2 (provided in abundance by capitals, bilobalide a: ginkgolide B: ginkgolide C ═ 45:5:35, the weight ratio of the total amount of the ginkgolide A, B, C to the bilobalide is 5:65, bilobalide content: 5.0mg/ml), bilobalide composition 3 (provided in abundance by capitals, bilobalide a: ginkgolide B: ginkgolide C ═ 10:40:35, the weight ratio of the total amount of the ginkgolide A, B, C to the bilobalide is 5:10, and the content of the ginkgolide: 5.0mg/ml), ginkgolide composition 4 (provided in abundance by capitals, ginkgolide a: ginkgolide B: ginkgolide C ═ 30:10:10, the weight ratio of the total amount of the ginkgolide A, B, C to the bilobalide is 15:5, and the content of the ginkgolide: 5.0mg/ml), physiological saline and enalaprilat injection (Changzhou pharmacy).
1.2 Experimental instruments: BP-100A full-automatic rat and rat noninvasive blood pressure measuring system (Chengdutai allied science and technology Co., Ltd.)
1.3 Experimental animals: 130 spontaneous hypertensive rats (provided by the experimental animal center of Sichuan province) with the age of 16 weeks are 200-250 g in body weight and are not limited to males and females.
2. Experimental methods
2.1 grouping: 130 spontaneous hypertensive rats were randomly divided into 10 per group of high, medium and low dose bilobalide injection, bilobalide a, bilobalide B, bilobalide C, bilobalide, composition 1, composition 2, composition 3, composition 4, model control group and positive control group. The clinical application dose of the ginkgolide injection is converted to 5mg/kg of equivalent dose of rats, the dose of each group is set, wherein 10mg/kg of high dose group, 5mg/kg of medium dose group and 2.5mg/kg of low dose group, 5mg/kg of ginkgolide A group, 5mg/kg of ginkgolide B group, 5mg/kg of ginkgolide C group, 3 groups of ginkgolide composition, 1 group of ginkgolide composition, 2 groups of ginkgolide composition, 3 groups of ginkgolide composition and 4 groups of ginkgolide composition are injected into the abdominal cavity, 0.25mg/kg of enalaprilat injection is injected into the abdominal cavity of a positive control group (converted according to the surface area between animals and the like), and the normal saline is injected into a model control group.
2.2, anesthesia: rats were weighed and anesthetized with 1% sodium pentobarbital (30mg/kg) i.p..
2.3 blood pressure determination and administration: the tail arterial systolic pressure of the rat is measured by a full-automatic rat noninvasive blood pressure measuring system. Recording the blood pressure before administration, then respectively administering to high, medium and low dose SHR rats with intraperitoneal injection of ginkgolide injection with different concentrations, and groups of intraperitoneal injection of ginkgolide B, ginkgolide, composition 1, composition 2, composition 3 and composition 4, injecting enalaprilat injection into a positive control group, injecting physiological saline into the abdominal cavity of a model control group, and observing the change of the blood pressure and the recovery time.
2.5 observation indexes: systolic blood pressure, percent blood pressure decrease.
2.6 statistical treatment
SPSS15.0 statistical software is adopted for analysis, and the data are average and standard deviation
And (4) showing. Statistical analysis and processing were performed using the t-test with P < 0.05 as the criterion for significance of differences.
3. Results of the experiment
TABLE 2 spontaneous hypertensive rat antihypertensive experimental results
The positive control group, the ginkgolide B group, the bilobalide group, the composition 1 group, the composition 2 group, the composition 3 group, the composition 4 group and the ginkgolide injection high, medium and low dose groups are all less than 0.05 compared with the model group.
The experiment further verifies the blood pressure reducing effect of the ginkgolide injection, after the rat injects the ginkgolide injection, the blood pressure is rapidly reduced, wherein the reduction degree of a high-dose group is higher than that of a positive control group, a medium-low dose group is slightly lower than that of the positive control group, the blood pressure of the high-dose group does not rise after 2 hours, the blood pressure begins to rise after 50 minutes of a medium-low dose group, and the blood pressure does not recover to the level before administration after 2 hours, so that the intensity and the duration of the effect of the ginkgolide injection on reducing the blood pressure are obviously related to the administration dose; the blood pressure of the ginkgolide B group, the bilobalide group, the composition 1 group, the composition 2 group, the composition 3 group and the composition 4 group is also obviously reduced, but the blood pressure reducing effect of the ginkgolide injection and the ginkgolide composition group is better than that of the ginkgolide B and the bilobalide which are singly used.
The two experiments show that the ginkgolide B, the bilobalide, the ginkgolide composition and the ginkgolide injection have the function of reducing blood pressure, and the blood pressure reducing function of the ginkgolide composition and the ginkgolide injection is obviously better than that of the ginkgolide B and the bilobalide which are single components, so that the ginkgolide B and the bilobalide injection can be used for treating hypertension.
Claims (2)
1. The antihypertensive drug containing a therapeutically effective amount of ginkgolide is characterized in that the ginkgolide is ginkgolide and bilobalide, the ginkgolide is ginkgolide A, ginkgolide B and ginkgolide C, wherein the ginkgolide: bilobalide is (5: 10) w/w, and the dosage and mass ratio of the three combinations of ginkgolide A, B, C are as follows: ginkgolide A, ginkgolide B and ginkgolide C are 10:40: 35; or the mass ratio of the ginkgolide to the bilobalide is (15: 5) w/w, and the three combinations of the ginkgolide A, B, C are as follows: ginkgolide A, ginkgolide B and ginkgolide C are respectively 30: 10.
2. A formulation comprising the agent of claim 1, wherein said formulation is an oral formulation, an injectable formulation or a transdermal formulation.
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| CN201910318522.9A CN109925310B (en) | 2013-12-10 | 2014-12-10 | Hypotensive agent containing therapeutically effective amount of ginkgolides |
| CN201410756745.0A CN104688784B (en) | 2013-12-10 | 2014-12-10 | Purposes of the ginkgolides in the drug for preparing blood pressure lowering |
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| CN108096241B (en) * | 2017-11-24 | 2020-06-16 | 江苏康缘药业股份有限公司 | Medical application of ginkgolide composition |
| CN110292637B (en) * | 2018-03-21 | 2022-04-08 | 成都百裕制药股份有限公司 | A pharmaceutical composition for preventing and treating hypertension |
| CN110638902A (en) * | 2019-09-30 | 2020-01-03 | 白冬平 | Application of tomato extract in preparation of antihypertensive drug and antihypertensive composition thereof |
| CN116437911A (en) * | 2021-03-05 | 2023-07-14 | 成都百裕制药股份有限公司 | Pharmaceutical composition containing bilobalide compound and cannabidiol and application thereof in medicine |
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| US6030621A (en) * | 1998-03-19 | 2000-02-29 | De Long; Xie | Ginkgo biloba composition, method to prepare the same and uses thereof |
| EP1314433A1 (en) * | 2001-11-23 | 2003-05-28 | Cognis Iberia, S.L. | Process of preparation of extracts from Ginkgo biloba |
| CN1965870A (en) * | 2005-11-18 | 2007-05-23 | 北京天新园医药科技开发有限公司 | Pharmaceutical composition containing ligustrazine and effective component of ginkgo leaf and formulation thereof |
| CN1977868B (en) * | 2005-12-05 | 2010-12-29 | 浙江海正药业股份有限公司 | Ginkgo biloba leaf total terpene lactone extract, and its preparing method, medicinal composition and use |
| CN1804614A (en) * | 2005-12-30 | 2006-07-19 | 孙毅 | Method for determining gingko lactone content in gingko extraction and medical preparation |
| CN101049324A (en) * | 2006-04-07 | 2007-10-10 | 黄振华 | Composition of medication prepared from ginkgo leaves and puerarin |
| CN100518734C (en) * | 2006-07-26 | 2009-07-29 | 孙毅 | Medicine composition containing bailobalide |
| CN100464747C (en) * | 2006-07-26 | 2009-03-04 | 孙毅 | Medicine composition containing bailobalide |
| CN101011405A (en) * | 2007-01-09 | 2007-08-08 | 贵州信邦远东药业有限公司 | Pharmaceutical composition for treating ischemic cerebral vascular disease |
| CN101411728A (en) * | 2007-10-18 | 2009-04-22 | 郭鸿旭 | Shuxuening injection formulation and preparation method thereof |
| CN102416027B (en) * | 2011-12-01 | 2015-11-25 | 徐州医学院 | The application of active substance in treatment cardiovascular and cerebrovascular diseases medicament of Semen Ginkgo active component extraction separating method and extraction |
| CN103091412B (en) * | 2012-04-23 | 2015-02-25 | 成都百裕科技制药有限公司 | Method for detecting ginkgolide effective parts |
| CN103202839B (en) * | 2012-04-23 | 2014-09-10 | 成都百裕科技制药有限公司 | Ginkgolide composition for treating cardiovascular and cerebrovascular diseases |
| CN102659808B (en) * | 2012-04-23 | 2014-10-29 | 成都百裕科技制药有限公司 | Extraction separation method of ginkgolides |
| CN102626383A (en) * | 2012-04-23 | 2012-08-08 | 成都百裕科技制药有限公司 | Bilobalide injection and preparation method thereof |
| CN103494802B (en) * | 2013-10-12 | 2015-07-15 | 成都百裕科技制药有限公司 | Uses of bilobalide |
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| CN104688784A (en) | 2015-06-10 |
| CN104688784B (en) | 2019-05-28 |
| CN109925310A (en) | 2019-06-25 |
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Denomination of invention: Antihypertensive drugs containing therapeutic effective amount of Ginkgolide Effective date of registration: 20230721 Granted publication date: 20220408 Pledgee: Bank of Shanghai Limited by Share Ltd. Chengdu branch Pledgor: CHENGDU BAIYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980049267 |
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