CN105561309A - Pharmaceutical composition containing ginkgolide B and thrombin inhibitor and preparation method and application of pharmaceutical composition - Google Patents
Pharmaceutical composition containing ginkgolide B and thrombin inhibitor and preparation method and application of pharmaceutical composition Download PDFInfo
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Abstract
The invention provides a pharmaceutical composition containing ginkgolide B. The pharmaceutical composition comprises the ginkgolide B and thrombin inhibitor. The invention further provides a preparation method and application of the pharmaceutical composition. The pharmaceutical composition has the advantages that the ginkgolide B and the thrombin inhibitor are combined to achieve a synergic effect, and the pharmaceutical composition is excellent in anticoagulation effect, low in side effect and promising in clinical application prospect; the pharmaceutical composition is novel in prescription, simple in component, clear in action mechanism, evident in curative effect, less prone to tolerance generating and capable of achieving large-scale industrial production.
Description
Technical field
The present invention relates to the pharmaceutical composition of a kind of bilobalide-containing B.
Background technology
Heparin is a kind of anticoagulant, is the polymer be alternately formed by connecting by two kinds of polysaccharide, has blood coagulation resisting function in vivo and in vitro.Be mainly used in thrombotic disease, myocardial infarction, operation on vessels of heart, cardia catheterization, extracorporeal circulation, hemodialysis etc. clinically.Along with pharmacology and clinical medical progress, the application of heparin constantly expands.
Heparin is the choice drug needing to reach rapidly anticoagulation, can be used for the anticoagulant therapy of surgery antithrombotic and pregnant person, for patients of acute myocardial infarction, there is venous thrombosis disease in available heparin prevention patient, and can prevent the antetheca transmural myocardial infarction patient of bulk that arterial thrombosis etc. occurs.Heparin another important clinical application be heart, operation and Kidney Dialysis time maintain blood extracorporeal circulation unimpeded.Heparin can be used for the disseminated inravascular coagulation (DIC) that treatment a variety of causes causes, and is also used for the treatment of glomerulonephritis, nephrotic syndrome, rheumatoid arthritis etc.
The main adverse reaction of heparin easily causes hematostaxis, show as various mucosa hemorrhage, articular cavity hematocele and wound bleeding etc., and heparin-induced thrombocytopenia is a kind of drug-induced thrombocytopenia, it is a kind of severe complication in heparin therapy.The thrombocytopenia of drug-induced is mainly divided into amphitypy: caused by (1) bone marrow is suppressed by dealed with medicine went; (2) medicine is destroyed caused by platelet by immunologic mechanism.Fall ill higher with heparin, quinine, quinidine, golden salt and sulfa drugs in the latter.Clinical symptoms is extremely inconsistent, and thrombocytopenia is to (1.0 ~ 80) × 10
9/ L, the lighter is asymptomatic, and severe one can cause the immune impairment of endotheliocyte because of intracranial hemorrhage or because of heparin, merge life-threatening pulmonary infarction and artery thrombosis lethal.
Low molecular heparin is the general name of the heparin that the molecule amount that is prepared from by unfractionated heparin depolymerization is lower.Use clinically mainly as anticoagulant and antithrombotic, clinical for preventing the formation of Post operation thromboembolism, prevention of deep vein thrombosis, pulmonary infarction, hemodialysis time extracorporeal circulation anticoagulant, peripheral vessel pathological changes and treat established venae profunda conducted etc.Minority document announcement still can be used for the replacement therapy of allergy because heparin causes or thrombocytopenia.Still there is report for the special treatment of some embolism class diseases.Its untoward reaction is similar to heparin.
Hirudin (Hirudin) be extracted in Hirudo (Leech) and salivary gland thereof in various active composition active significantly and a kind of composition studying at most, the small protein (polypeptide) that it is made up of 65-66 aminoacid.Hirudin has extremely strong inhibitory action to thrombin, be up to now find the natural specific inhibitor of the strongest thrombin.Animal experiment and clinical research show, the blood coagulation of hirudin energy Effective Anti, antithrombus formation, and the blood stasis phenomenon further such as the thrombin activation of prevention catalyzed by thrombin and platelet response.In addition, it can also fibroblastic propagation of enzyme induction anticoagulant and the stimulation of thrombin Human Umbilical Vein Endothelial Cells.Be a class up-and-coming anticoagulant blood stasis dispelling medicine, it can be used for treating various thrombus disease, and still it is the treatment of phlebothrombosis and the blood coagulation of diffusivity blood vessel; Also can be used for the formation of surgical site infections prevention of arterial thrombosis, after prevention thrombus or the formation of thrombosis after revascularization; Improve extracorporeal circulation of blood and blood dialysis.Chang Yinwei anastomosis blood vessel embolism in microsurgery and leading to the failure, adopts hirudin to promote wound healing.Research also shows, hirudin also can play a role in oncotherapy.It can stop the transfer of tumor cell, has proved that medicable tumor is as fibrosarcoma, osteosarcoma, angiosarcoma, melanoma and leukemia etc.Hirudin also can be treated and radiotherapy by fiting chemical, heightens the effect of a treatment owing to promoting the blood flow in tumor.But its consumption is excessive may cause bleeding.
Argatroban is a kind of thrombin inhibitor, is reversibly combined with thrombin activity site.Be mainly used in the nervous symptoms (paralysis motorica) of the Ischemic Cerebral Infarction Patients with Acute in morbidity 48 hours, daily routines (walking, stand up, seat keeps, diet) improvement etc.; its main adverse reaction has hemorrhagic Cerebral Infarction, and cerebral hemorrhage, digestive tract hemorrhage, shock, anaphylactic shock (reduction of urticaria, blood pressure, dyspnea etc.) occur.
Therefore, how when ensureing therapeutic effect, the use reducing the medicines such as heparin is urgently to be resolved hurrily to reduce side effect.
Ginkalide B is the active component extracted from natural drug Folium Ginkgo, and its side effect is little, and active strong, be the strongest platelet activating factor antagonist found so far, may be used for anticoagulation, but price be high, the cost of Clinical practice is too high.
Summary of the invention
The object of the invention is to overcome a kind of that said medicine develops in the alone side effect that produces in anticoagulation and there is synergistic new pharmaceutical composition.
The invention provides the pharmaceutical composition of a kind of bilobalide-containing B, it contains ginkalide B and anticoagulant.
Wherein, described anticoagulant is thrombin inhibitor.Described thrombin inhibitor is heparin, Low molecular heparin, hirudin, argatroban.
Wherein, the weight proportion of described raw material is: ginkalide B 1-20 part and heparin 10-500 part.
Preferably, the weight proportion of described raw material is: ginkalide B 5-15 part and heparin 20-400 part.Further preferably, the weight proportion of described raw material is: ginkalide B 8-12 part and heparin 10-200 part.Again further preferably, the weight proportion of described raw material is: ginkalide B 10 parts and heparin 100 parts.
Or the weight proportion of described raw material is: ginkalide B 1-20 part and Low molecular heparin 20-100 part.
Preferably, the weight proportion of described raw material is: ginkalide B 5-15 part and Low molecular heparin 30-80 part.Further preferably, the weight proportion of described raw material is: ginkalide B 10 parts and Low molecular heparin 50 parts.
Or the weight proportion of described raw material is: ginkalide B 1-20 part and hirudin 4-40 part.
Preferably, the weight proportion of described raw material is: ginkalide B 5-15 part and hirudin 8-20 part.Further preferably, the weight proportion of described raw material is: ginkalide B 10 parts and HV1 5 parts.
Or the weight proportion of described raw material is: ginkalide B 1-20 part and argatroban 10-100 part.
Preferably, the weight proportion of described raw material is: ginkalide B 5-15 part and argatroban 20-80 part.Further preferably, the weight proportion of described raw material is: ginkalide B 10 parts and argatroban 50 parts.
Preferably, the weight proportion of described ginkalide B and heparin is 1:10 ~ 20:10;
The weight proportion of described ginkalide B and Low molecular heparin is 10:50 ~ 20:20;
The weight proportion of described ginkalide B and hirudin is 10:15 ~ 20:4;
The weight proportion of described ginkalide B and argatroban is 10:50 ~ 20:10.
Ginkalide B 1-20 part and hirudin 4-40 part.
Present invention also offers a kind of method preparing aforesaid pharmaceutical composition, it comprises the following steps:
S1: take raw material ginkalide B and anticoagulant by component and weight ratio;
S2: after being mixed by raw material, adds pharmaceutically acceptable adjuvant and is prepared into pharmaceutically conventional pharmaceutical preparation.
Wherein, described pharmaceutically acceptable adjuvant comprises: starch, pregelatinized Starch, lactose, sucrose, Pulvis Talci, dextrin, cyclodextrin, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, glucose, meglumine, magnesium stearate, dextran, glycerol, ethanol, propylene glycol, Polyethylene Glycol, mannitol, sorbitol, xylitol, fibre plant oil, sodium benzoate, sodium salicylate, hydrochloric acid, citric acid, citric acid is received, sodium dihydrogen phosphate, sodium hydrogen phosphate, gelatin, lecithin, one in vitamin C or several.
Wherein, described pharmaceutical preparation comprises: tablet, capsule, soft capsule, oral liquid, granule, pill, drop pill, powder, unguentum, sublimed preparation, injection, suppository, patch, drop, spray, cream, suspensoid, tincture, Emulsion, aqueous injection, injectable powder, targeting preparation, slow releasing preparation, controlled release preparation.
Pharmaceutical composition described before present invention also offers is preparing the purposes in anticoagulation medicine.
Present invention also offers ginkalide B and anticoagulant drug combination is preparing the application in anticoagulation medicine.
Wherein, described anticoagulant is thrombin inhibitor.Described thrombin inhibitor is heparin, Low molecular heparin.
Wherein, the weight proportion of described raw material is: ginkalide B 1-20 part and heparin 10-500 part.Preferably, ginkalide B 5-15 part and heparin 20-400 part.Further preferably, the weight proportion of described each raw material is: ginkalide B 8-12 part and heparin 40-200 part.Again further preferably, the weight proportion of described each raw material is: ginkalide B 10 parts and heparin 100 parts.
Or the weight proportion of described raw material is: ginkalide B 1-20 part and Low molecular heparin 20-100 part.
Preferably, the weight proportion of described raw material is: ginkalide B 5-15 part and Low molecular heparin 30-80 part.Further preferably, the weight proportion of described raw material is: ginkalide B 10 parts and Low molecular heparin 50 parts.
Or the weight proportion of described raw material is: ginkalide B 1-20 part and hirudin 4-40 part.
Preferably, the weight proportion of described raw material is: ginkalide B 5-15 part and hirudin 8-20 part.Further preferably, the weight proportion of described raw material is: ginkalide B 10 parts and HV1 5 parts.
Or the weight proportion of described raw material is: ginkalide B 1-20 part and argatroban 10-100 part.
Preferably, the weight proportion of described raw material is: ginkalide B 5-15 part and argatroban 20-80 part.Further preferably, the weight proportion of described raw material is: ginkalide B 10 parts and argatroban 50 parts.
Preferably, the weight proportion of described ginkalide B and heparin is 1:10 ~ 20:10;
The weight proportion of described ginkalide B and Low molecular heparin is 10:50 ~ 20:20;
The weight proportion of described ginkalide B and hirudin is 10:15 ~ 20:4;
The weight proportion of described ginkalide B and argatroban is 10:50 ~ 20:10.
Ginkalide B 1-20 part and hirudin 4-40 part.
Pharmaceutical composition provided by the invention, because wherein containing ginkalide B and thrombin inhibitor activity composition, can by different mechanism of action anticoagulations, ginkalide B significantly can promote the anticoagulant functions of said medicine, and also can eliminate/reduce the side effect because of alone generation, both have the effect of Synergistic, Clinical practice can reduce thrombin inhibitor dose, increase drug effect, reduce costs, reduce side effect, for clinical research provides better selection.
Pharmaceutical composition novel formula of the present invention, component is simple, mechanism of action is clear and definite and evident in efficacy, not easily produce toleration, can industrialized great production be realized.
The present invention is by ginkalide B and thrombin inhibitor conbined usage, the two can play synergistic function, anticoagulant, anticoagulant excellent effect, the consumption of thrombin inhibitor can be reduced during clinical practice, and then reduce it and use the side effect brought in a large number, can also reduce the use amount of ginkalide B, reduce costs, potential applicability in clinical practice is excellent.
Obviously, according to foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, not departing under the present invention's above-mentioned basic fundamental thought prerequisite, the amendment of other various ways, replacement or change can also be made.
The detailed description of the invention of form by the following examples, is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Detailed description of the invention
Ginkalide B monomeric compound of the present invention, can obtain by buying commercially available prod, or obtain by bilobalide is carried out separation and purification in existing method; Thrombin inhibitor also obtains by buying commercially available prod, also or by existing method is synthesized into.Through inspection, all monomeric compounds all conform to corresponding reference substance structure, and detect its purity all more than 95% through HPLC.
Embodiment 1
Ginkalide B 10 parts
Heparin 100 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into pill.
Embodiment 2
Ginkalide B 8 parts
Heparin 40 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into capsule or soft capsule.
Embodiment 3
Ginkalide B 12 parts
Heparin 200 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into tablet.
Embodiment 4
Ginkalide B 15 parts
Heparin 400 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into oral liquid.
Embodiment 5
Ginkalide B 10 parts
Heparin 200 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into drop pill.
Embodiment 6
Ginkalide B 5 parts
Heparin 20 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into spray.
Embodiment 7
Ginkalide B 1 part
Heparin 500 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into aqueous injection or injectable powder.
Embodiment 8
Ginkalide B 20 parts
Heparin 200 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into slow releasing preparation or controlled release preparation.
Embodiment 9
Ginkalide B 10 parts
Heparin 40 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into targeting preparation.
Embodiment 10
Ginkalide B 10 parts
Heparin 200 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into granule or suspensoid.
Embodiment 11
Ginkalide B 10 parts
Low molecular heparin 50 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into pill.
Embodiment 12
Ginkalide B 1 part
Low molecular heparin 20 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into capsule or soft capsule.
Embodiment 13
Ginkalide B 20 parts
Low molecular heparin 100 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into tablet.
Embodiment 14
Ginkalide B 15 parts
Low molecular heparin 80 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into oral liquid.
Embodiment 15
Ginkalide B 5 parts
Low molecular heparin 30 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into drop pill.
Embodiment 16
Ginkalide B 10 parts
HV1 5 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into pill.
Embodiment 17
Ginkalide B 5 parts
Hirudin 8 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into capsule or soft capsule.
Embodiment 18
Ginkalide B 20 parts
Hirudin 40 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into tablet.
Embodiment 19
Ginkalide B 15 parts
Hirudin 20 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into oral liquid.
Embodiment 20
Ginkalide B 1 part
Hirudin 4 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into drop pill.
Embodiment 21
Ginkalide B 10 parts
Argatroban 50 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into pill.
Embodiment 22
Ginkalide B 5 parts
Argatroban 20 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into capsule or soft capsule.
Embodiment 23
Ginkalide B 15 parts
Argatroban 80 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into tablet.
Embodiment 24
Ginkalide B 1 part
Argatroban 10 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into oral liquid.
Embodiment 25
Ginkalide B 20 parts
Argatroban 100 parts
Pharmaceutically acceptable customary adjuvant
By above-mentioned raw materials mix after, add pharmaceutically acceptable customary adjuvant conveniently technique be prepared into drop pill.
Below by the mode of test example, beneficial effect of the present invention is described:
Test example 1 ginkalide B and thrombin inhibitor compositions suppress Platelet Aggregation in Rabbits effect experimentation
1 materials and methods
1.1 laboratory animal
Japan large ear rabbit 312, body weight (2.0 ± 0.2) kg, male and female half and half, are provided [the animal quality certification number: XCXK (Chongqing) 20020001] by Medical University Of Chongqing's Experimental Animal Center.
1.2 Experimental agents
Ginkalide B (self-control), heparin (self-control), Low molecular heparin (self-control), Hirudo (self-control), argatroban (self-control), compositions 1 (ginkalide B: heparin=1:10), compositions 2 (ginkalide B: heparin=1:500), compositions 3 (ginkalide B: heparin=20:10), compositions 4 (ginkalide B: heparin=20:500), compositions 5 (ginkalide B: heparin=5:20), compositions 6 (ginkalide B: heparin=5:400), compositions 7 (ginkalide B: heparin=15:20), compositions 8 (ginkalide B: heparin=15:400), compositions 9 (ginkalide B: Low molecular heparin=10:50), compositions 10 (ginkalide B: Low molecular heparin=1:20), compositions 11 (ginkalide B: Low molecular heparin=1:100), compositions 12 (ginkalide B: Low molecular heparin=20:20), compositions 13 (ginkalide B: Low molecular heparin=5:30), compositions 14 (ginkalide B: Low molecular heparin=5:80), compositions 15 (ginkalide B: Low molecular heparin=15:30), compositions 16 (ginkalide B: Low molecular heparin=15:80), compositions 17 (ginkalide B: Hirudo=10:15), compositions 18 (ginkalide B: Hirudo=1:4), compositions 19 (ginkalide B: Hirudo=1:40), compositions 20 (ginkalide B: Hirudo=20:4), compositions 21 (ginkalide B: Hirudo=20:40), compositions 22 (ginkalide B: Hirudo=5:8), compositions 23 (ginkalide B: Hirudo=5:20), compositions 24 (ginkalide B: Hirudo=15:8), compositions 25 (ginkalide B: Hirudo=15:20), compositions 26 (ginkalide B: argatroban=10:50), compositions 27 (ginkalide B: argatroban=1:10), compositions 28 (ginkalide B: argatroban=1:100), compositions 29 (ginkalide B: argatroban=20:10), compositions 30 (ginkalide B: argatroban=5:20), compositions 31 (ginkalide B: argatroban=5:80), compositions 32 (ginkalide B: argatroban=15:20), compositions 33 (ginkalide B: argatroban=15:80).
1.3 reagent and instrument
Platelet activating factor (PAF) (cayman, lot number: 011219) be dissolved in PH be 7.6 containing 0.25% bovin serum albumin Tris-NaCl solution in, final concentration is 3.6nmoL/L; Sodium citrate (Beijing biotech company of Zhong Shan Golden Bridge, lot number: 20130117) distilled water is made into the concentration of 3.8%; Rabbit β-thromboglobulin (β-TG) ELISA kit (FOCUS, lot number: 20130224), the rabbit platelet factor 4 (PF-4) ELISA kit (FOCUS, lot number: 20130301).TYXN-96 multifunctional intellectual blood pool instrument (development of Shanghai GM technical research institute); Scanning electron microscope S-3000N (HIT); ELX-800 microplate reader (Bao Te company of the U.S.).
1.4 grouping and medication
Japan large ear rabbit 312, be divided into 39 groups at random, often organize 8: (1) normal saline group, (2) ginkalide B group, (3) heparin group, (4) Low molecular heparin group, (5) Hirudo group, (6) argatroban group, (7) compositions 1 group, (8) compositions 2 groups, (9) compositions 3 groups, (10) compositions 4 groups, (11) compositions 5 groups, (12) compositions 6 groups, (13) compositions 7 groups, (14) compositions 8 groups, (15) compositions 9 groups, (16) compositions 10 groups, (17) compositions 11 groups, (18) compositions 12 groups, (19) compositions 13 groups, (20) compositions 14 groups, (21) compositions 15 groups, (22) compositions 16 groups, (23) compositions 17 groups, (24) compositions 18 groups, (25) compositions 19 groups, (26) compositions 20 groups, (27) compositions 21 groups, (28) compositions 22 groups, (29) compositions 23 groups, (30) compositions 24 groups, (31) compositions 25 groups, (32) compositions 26 groups, (33) compositions 27 groups, (34) compositions 28 groups.(35) compositions 29 groups, (36) compositions 30 groups, (37) compositions 31 groups, (38) compositions 32 groups, (39) compositions 33 groups.Each group, all by Clinical practice approach, administration number of times administration, is used in conjunction 7 days.Each group of dosage is as following table:
| Group | Dosage | Daily number of times |
| Normal saline | 2ml | 1 |
| Ginkalide B | 5.0mg/kg | 1 |
| Heparin | 5.0mg/kg | 1 |
| Low molecular heparin | 5.0mg/kg | 1 |
| Hirudo | 5.0mg/kg | 1 |
| Argatroban | 5.0mg/kg | 1 |
| Compositions 1 group | 5.0mg/kg | 1 |
| Compositions 2 groups | 5.0mg/kg | 1 |
| Compositions 3 groups | 5.0mg/kg | 1 |
| Compositions 4 groups | 5.0mg/kg | 1 |
| Compositions 5 groups | 5.0mg/kg | 1 |
| Compositions 6 groups | 5.0mg/kg | 1 |
| Compositions 7 groups | 5.0mg/kg | 1 |
| Compositions 8 groups | 5.0mg/kg | 1 |
| Compositions 9 groups | 5.0mg/kg | 1 |
| Compositions 10 groups | 5.0mg/kg | 1 |
| Compositions 11 groups | 5.0mg/kg | 1 |
| Compositions 12 groups | 5.0mg/kg | 1 |
| Compositions 13 groups | 5.0mg/kg | 1 |
| Compositions 14 groups | 5.0mg/kg | 1 |
| Compositions 15 groups | 5.0mg/kg | 1 |
| Compositions 16 groups | 5.0mg/kg | 1 |
| Compositions 17 groups | 5.0mg/kg | 1 |
| Compositions 18 groups | 5.0mg/kg | 1 |
| Compositions 19 groups | 5.0mg/kg | 1 |
| Compositions 20 groups | 5.0mg/kg | 1 |
| Compositions 21 groups | 5.0mg/kg | 1 |
| Compositions 22 groups | 5.0mg/kg | 1 |
| Compositions 23 groups | 5.0mg/kg | 1 |
| Compositions 24 groups | 5.0mg/kg | 1 |
| Compositions 25 groups | 5.0mg/kg | 1 |
| Compositions 26 groups | 5.0mg/kg | 1 |
| Compositions 27 groups | 5.0mg/kg | 1 |
| Compositions 28 groups | 5.0mg/kg | 1 |
| Compositions 29 groups | 5.0mg/kg | 1 |
| Compositions 30 groups | 5.0mg/kg | 1 |
| Compositions 31 groups | 5.0mg/kg | 1 |
| Compositions 32 groups | 5.0mg/kg | 1 |
| Compositions 33 groups | 5.0mg/kg | 1 |
1.5 detect platelet aggregation rate
After administration 7d, every animal hearts gets blood 10.5mL, separate 1.5mL blood plasma and get serum, the 3.8% sodium citrate 1:9 anticoagulant of all the other 9mL blood plasma, the centrifugal 10min of 800r/min, get supernatant and obtain platelet rich plasma (PRP), separate 100 μ LPRP for electron microscopic examination, all the other PRP are used for the detection of platelet aggregation rate; Remainder 3000r/min centrifugation 15min, gets platelet poor plasma (PPP).Regulate PRP with PPP, make PRP number of platelets 360 × 10
9/ L.Measure and be recorded in 10 μ LPAF derivant inductions lower 1min, 5min and max platelet rate.
1.6 platelets are observed
Isolated 100 μ LPRP are placed in silication EP pipe, add the gathering of the PAF induced platelet of 1 μ L, after effect 15min, PRP is placed in and is covered with in the copper mesh specimen holder of Formar film, hatch 10min, ultrapure water for 37 DEG C, 3% glutaraldehyde fixes 5min, clean with ultrapure water again, after the specimen natural drying on copper mesh, at the golden film of its plated surface one deck 20nm, ultramicroscope S-3000N scanning cellular morphology, observe 100 platelet, calculate various platelet proportion.Under Electronic Speculum, platelet typing comprises: (1) is circular: rounded or oval.Volume is little, and central authorities are fine and close, and core is large, and periphery zona pellucida is low narrow.(2) tree-like: to send single or multiple podocytic process from central dense area, elongated or lamellar, has branch sometimes.(3) shape is flattened: there are dense-core in central authorities, and peripheral zona pellucida is wider, and periphery is smooth or have little projection.(4) assemble shape: be often made up of to tens platelet several, aggregation differs in size, wherein visible platelet is interconnected, and some complete fusion are integral, and peripheral part platelet podocytic process is obvious.
The mensuration of PF-4 and β-TG contents level in 1.7 serum
In 1.5mL blood plasma, add the PAF of 1 μ L, the release of induction PF-4 and β-TG, blood plasma, in 4 DEG C of standing 4h, is got 200 μ L serum, is detected.Concrete operations are carried out according to test kit description, and microplate reader reads result data.
1.8 statistical procedures
Experimental result mean ± standard deviation (
) represent, carry out statistical analysis with SPSS18.0 software, the t inspection adopting two sample averages to compare carries out statistical analysis to each group of platelet aggregation rate, platelet PLA2 percent and PF-4 and β-TG content.P<0.05 is that difference has statistical significance.
2 results
2.1 platelet aggregation test results
Result is as shown in table 1:
Table 1PAF induction platelet aggregation (
, n=8)
Compare with normal saline group, * * p<0.01, * p<0.05
Under PAF induction, the max platelet rate that ginkalide B group, ginkalide B+heparin, ginkalide B+Low molecular heparin, ginkalide B+Hirudo, ginkalide B+argatroban etc. are respectively organized is compared with normal saline group, all there is significance sex differernce (p<0.01, p < 0.05), each group of platelet aggregation inhibition rate is significantly increased, and illustrates that each compositions of the present invention all can effective anticoagulation; And significant change does not occur for heparin, Low molecular heparin, Hirudo, argatroban each set of monomers, illustrate that ginkalide B and heparin, Low molecular heparin, Hirudo, argatroban create synergism;
In each group of ginkalide B+heparin compostions, the effect of compositions 1,3,5,7 is better, and the effect of compositions 1, compositions 3 is better, the best results of compositions 1, therefore, the proportioning of ginkalide B of the present invention and sldenafil is preferably 1:10 ~ 20:10, is more preferably 1:10 in conjunction with cost; When the proportioning of ginkalide B and heparin is 1:10 ~ 20:10 in the composition, ginkalide B consumption is few, the consumption of heparin is many, it assembles suppression ratio but far away higher than the heparin of compositions Isodose, and with the gathering suppression ratio of the ginkalide B of compositions Isodose quite or lower slightly, illustrate in this ratio range, the synergistic function highly significant of ginkalide B and heparin;
In each group of ginkalide B+Low molecular heparin compositions, the effect of compositions 9,12,15 is better, and therefore, the proportioning of ginkalide B of the present invention and Low molecular heparin is preferably 10:50 ~ 20:20, is more preferably 10:50 in conjunction with cost; When the proportioning of ginkalide B and Low molecular heparin is 10:50 in the composition, ginkalide B consumption is few, the consumption of Low molecular heparin is many, it assembles suppression ratio but far away higher than the heparin of compositions Isodose, and it is suitable with the gathering suppression ratio of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Low molecular heparin;
In each group of ginkalide B+Hirudo compositions, the effect of compositions 17,20,24 is better, and therefore, the proportioning of ginkalide B of the present invention and Hirudo is preferably 10:15 ~ 20:4, is more preferably 10:15 in conjunction with cost; When the proportioning of ginkalide B and Hirudo is 10:15 in the composition, ginkalide B consumption is few, the consumption of Hirudo is many, it assembles suppression ratio but far away higher than the Hirudo of compositions Isodose, and it is suitable with the gathering suppression ratio of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Hirudo;
In each group of ginkalide B+argatroban compositions, the effect of compositions 26,29,32 is better, and therefore, the proportioning of ginkalide B of the present invention and argatroban is preferably 10:50 ~ 20:10, is more preferably 10:50 in conjunction with cost; When the proportioning of ginkalide B and argatroban is 10:50 in the composition, ginkalide B consumption is few, the consumption of argatroban is many, it assembles suppression ratio but far away higher than the argatroban of compositions Isodose, and it is suitable with the gathering suppression ratio of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Low molecular heparin.
2.2 platelets testing results
Experimental result is as shown in table 2:
After table 2 adds PAF each group platelet PLA2 compare (
, n=8)
Compare with normal saline group, * * p<0.01, * p<0.05
Under the scanning electron microscope of 2000 times, be mainly observed four kinds of platelet PLA2: circular, tree-like, flatten shape and assemble shape.Under PAF induction, ginkalide B, ginkalide B+heparin, ginkalide B+Low molecular heparin, ginkalide B+Hirudo, ginkalide B+argatroban respectively organize Platelet Size comparatively unanimously, and smooth surface, accumulation type platelet is more rare.Normal saline group platelet generation strong activation, platelet adhesion power strengthens, and can see red blood cell adhesion in platelet; Platelet PLA2 is irregular, volume increases, to stretch out in spore shape outstanding pseudopodium, assemble shape platelet counts increases, and illustrates that each compositions of the present invention all can effective anticoagulation.And heparin, Low molecular heparin, Hirudo, argatroban are respectively organized Platelet Size and differed, there is pseudopodium on surface, and it is more to assemble shape platelet.Illustrate that ginkalide B creates synergism to heparin, Low molecular heparin, Hirudo, argatroban;
In each group of ginkalide B+heparin compostions, the effect of compositions 1,3,5,7 is better, and the effect of compositions 1, compositions 3 is better, the best results of compositions 1, therefore, the proportioning of ginkalide B of the present invention and sldenafil is preferably 1:10 ~ 20:10, is more preferably 1:10 in conjunction with cost; When the proportioning of ginkalide B and heparin is 1:10 ~ 20:10 in the composition, ginkalide B consumption is few, the consumption of heparin is many, its accumulation type platelet is but far less than the heparin of compositions Isodose, and it is suitable with the hematoblastic quantity of the accumulation type of the ginkalide B of compositions Isodose, when the proportioning of ginkalide B and heparin is 1:10 ~ 20:10, more less than the accumulation type platelet counts of the ginkalide B of compositions Isodose, illustrate in this ratio range, the synergistic function highly significant of ginkalide B and heparin;
In each group of ginkalide B+Low molecular heparin compositions, the effect of compositions 9,12,15 is better, and therefore, the proportioning of ginkalide B of the present invention and Low molecular heparin is preferably 10:50 ~ 20:20, is more preferably 10:50 in conjunction with cost; When the proportioning of ginkalide B and Low molecular heparin is 10:50 in the composition, ginkalide B consumption is few, the consumption of Low molecular heparin is many, the hematoblastic quantity of its accumulation type is but far less than the heparin of compositions Isodose, and it is suitable with the hematoblastic quantity of the accumulation type of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Low molecular heparin;
In each group of ginkalide B+Hirudo compositions, the effect of compositions 17,20,24 is better, and therefore, the proportioning of ginkalide B of the present invention and Hirudo is preferably 10:15 ~ 20:4, is more preferably 10:15 in conjunction with cost; When the proportioning of ginkalide B and Hirudo is 10:15 in the composition, ginkalide B consumption is few, the consumption of Hirudo is many, the hematoblastic quantity of its accumulation type is but far less than the Hirudo of compositions Isodose, and it is suitable with the hematoblastic quantity of the accumulation type of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Hirudo;
In each group of ginkalide B+argatroban compositions, the effect of compositions 26,29,32 is better, and therefore, the proportioning of ginkalide B of the present invention and argatroban is preferably 10:50 ~ 20:10, is more preferably 10:50 in conjunction with cost; When the proportioning of ginkalide B and argatroban is 10:50 ~ 20:10 in the composition, ginkalide B consumption is few, the consumption of argatroban is many, its accumulation type platelet is but far less than the argatroban of compositions Isodose, and it is suitable with the hematoblastic quantity of the accumulation type of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Low molecular heparin.
2.3 platelet PF-4 and β-TG testing result
Result is as shown in table 3: table 3 platelet PF-4 and β-TG testing result (
, n=8)
Compare with normal saline group, * * p<0.01, * p<0.05
PF-4 and β-TG level reduces, and illustrates that platelet release function is suppressed.
Compared with normal saline group, ginkalide B, ginkalide B+heparin, ginkalide B+Low molecular heparin, ginkalide B+Hirudo, ginkalide B+argatroban etc. respectively group PF-4 and β-TG level all significantly reduce (p<0.01, p<0.05), illustrate that each compositions of the present invention all can effective anticoagulation, and heparin, Low molecular heparin, Hirudo, each set of monomers of argatroban not significantly do not reduce, illustrate that ginkalide B creates synergism to heparin, Low molecular heparin, Hirudo, argatroban.PF-4 and β-TG level reduces, and illustrates that platelet release function is suppressed;
In each group of ginkalide B+heparin compostions, the effect of compositions 1,3,5,7 is better, and the effect of compositions 1, compositions 3 is better, the best results of compositions 1, therefore, the proportioning of ginkalide B of the present invention and sldenafil is preferably 1:10 ~ 20:10, is more preferably 1:10 in conjunction with cost; When the proportioning of ginkalide B and heparin is 1:10 ~ 20:10 in the composition, ginkalide B consumption is few, the consumption of heparin is many, itself PF-4 and β-TG level is but well below the heparin of compositions Isodose, and be on close level with PF-4 and the β-TG of the ginkalide B of compositions Isodose, illustrate in this ratio range, the synergistic function highly significant of ginkalide B and heparin;
In each group of ginkalide B+Low molecular heparin compositions, the effect of compositions 9,12,15 is better, and therefore, the proportioning of ginkalide B of the present invention and Low molecular heparin is preferably 10:50 ~ 20:20, is more preferably 10:50 in conjunction with cost; When the proportioning of ginkalide B and Low molecular heparin is 10:50 in the composition, ginkalide B consumption is few, the consumption of Low molecular heparin is many, itself PF-4 and β-TG level is but well below the heparin of compositions Isodose, and be on close level with PF-4 and the β-TG of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Low molecular heparin;
In each group of ginkalide B+Hirudo compositions, the effect of compositions 17,20,24 is better, and therefore, the proportioning of ginkalide B of the present invention and Hirudo is preferably 10:15 ~ 20:4, is more preferably 10:15 in conjunction with cost; When the proportioning of ginkalide B and Hirudo is 10:15 in the composition, ginkalide B consumption is few, the consumption of Hirudo is many, itself PF-4 and β-TG level is but well below the Hirudo of compositions Isodose, and be on close level with PF-4 and the β-TG of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Hirudo;
In each group of ginkalide B+argatroban compositions, the effect of compositions 26,29,32 is better, and therefore, the proportioning of ginkalide B of the present invention and argatroban is preferably 10:50 ~ 20:10, is more preferably 10:50 in conjunction with cost; When the proportioning of ginkalide B and argatroban is 10:50 ~ 20:10 in the composition, ginkalide B consumption is few, the consumption of argatroban is many, itself PF-4 and β-TG level is but well below the argatroban of compositions Isodose, and be on close level with PF-4 and the β-TG of the ginkalide B of compositions Isodose, illustrate when this ratio range, the synergistic function highly significant of ginkalide B and Low molecular heparin.
To sum up, the present invention is by ginkalide B and heparin, Low molecular heparin, hirudin or argatroban conbined usage, synergistic function can be played, the pharmaceutical composition that ginkalide B of the present invention and heparin, Low molecular heparin, hirudin or argatroban form, can effectively anticoagulant, anticoagulation, excellent effect, potential applicability in clinical practice is excellent.
Claims (10)
1. a pharmaceutical composition of bilobalide-containing B, is characterized in that: it contains ginkalide B and thrombin inhibitor.
2. pharmaceutical composition according to claim 1, is characterized in that: described thrombin inhibitor is heparin, Low molecular heparin, hirudin, argatroban.
3. pharmaceutical composition according to claim 2, is characterized in that:
The weight proportion of described ginkalide B and heparin is: ginkalide B 1-20 part and heparin 10-500 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and heparin 20-400 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and heparin 100 parts;
The weight proportion of described ginkalide B and Low molecular heparin is: ginkalide B 1-20 part and Low molecular heparin 20-100 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and Low molecular heparin 30-80 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and Low molecular heparin 50 parts;
The weight proportion of described ginkalide B and hirudin is: ginkalide B 1-20 part and hirudin 4-40 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and hirudin 8-20 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and HV1 5 parts;
The weight proportion of described ginkalide B and argatroban is: ginkalide B 1-20 part and argatroban 10-100 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and argatroban 20-80 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and argatroban 50 parts.
4. pharmaceutical composition according to claim 3, is characterized in that:
The weight proportion of described ginkalide B and heparin is 1:10 ~ 20:10;
The weight proportion of described ginkalide B and Low molecular heparin is 10:50 ~ 20:20;
The weight proportion of described ginkalide B and hirudin is 10:15 ~ 20:4;
The weight proportion of described ginkalide B and argatroban is 10:50 ~ 20:10.
5. prepare a method for the pharmaceutical composition in Claims 1 to 4 described in any one, it comprises the following steps:
S1: take raw material ginkalide B and thrombin inhibitor by component and weight ratio;
S2: after being mixed by raw material, adds pharmaceutically acceptable adjuvant and is prepared into pharmaceutically conventional pharmaceutical preparation.
6. the pharmaceutical composition described in Claims 1 to 4 any one is preparing the purposes in anticoagulation medicine.
7. ginkalide B and thrombin inhibitor are preparing the application in anticoagulant combination medicine.
8. purposes according to claim 7, is characterized in that: described thrombin inhibitor is heparin, Low molecular heparin, hirudin, argatroban.
9. pharmaceutical composition according to claim 8, is characterized in that:
The weight proportion of described ginkalide B and heparin is: ginkalide B 1-20 part and heparin 10-500 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and heparin 20-400 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and heparin 100 parts;
The weight proportion of described ginkalide B and Low molecular heparin is: ginkalide B 1-20 part and Low molecular heparin 20-100 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and Low molecular heparin 30-80 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and Low molecular heparin 50 parts;
The weight proportion of described ginkalide B and hirudin is: ginkalide B 1-20 part and hirudin 4-40 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and hirudin 8-20 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and HV1 5 parts;
The weight proportion of described ginkalide B and argatroban is: ginkalide B 1-20 part and argatroban 10-100 part; Preferably, the weight proportion of the two is: ginkalide B 5-15 part and argatroban 20-80 part; Further preferably, the weight proportion of the two is: ginkalide B 10 parts and argatroban 50 parts.
10. pharmaceutical composition according to claim 9, is characterized in that:
The weight proportion of described ginkalide B and heparin is 1:10 ~ 20:10;
The weight proportion of described ginkalide B and Low molecular heparin is 10:50 ~ 20:20;
The weight proportion of described ginkalide B and hirudin is 10:15 ~ 20:4;
The weight proportion of described ginkalide B and argatroban is 10:50 ~ 20:10.
Ginkalide B 1-20 part and hirudin 4-40 part.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679942A (en) * | 2005-02-04 | 2005-10-12 | 北京阜康仁生物制药科技有限公司 | Compound preparation of aspirin and ginkgo biloba extract and use thereof |
| CN1768753A (en) * | 2005-10-28 | 2006-05-10 | 阿尔贝拉医药控股(通化)有限公司 | Medicinal composition containing bilobalide B and its preparation process and usage |
| US20060182821A1 (en) * | 1999-08-12 | 2006-08-17 | Katy Drieu | Use of a plant extract |
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2015
- 2015-10-28 CN CN201510716804.6A patent/CN105561309B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060182821A1 (en) * | 1999-08-12 | 2006-08-17 | Katy Drieu | Use of a plant extract |
| CN1679942A (en) * | 2005-02-04 | 2005-10-12 | 北京阜康仁生物制药科技有限公司 | Compound preparation of aspirin and ginkgo biloba extract and use thereof |
| CN1768753A (en) * | 2005-10-28 | 2006-05-10 | 阿尔贝拉医药控股(通化)有限公司 | Medicinal composition containing bilobalide B and its preparation process and usage |
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| 刘国庆: "低分子肝素联合舒血宁治疗伴颈动脉斑块的脑梗死临床研究", 《河北医学》 * |
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