CN105561309B - A kind of pharmaceutical composition and its preparation method and application containing ginkolide B and thrombin inhibitor - Google Patents
A kind of pharmaceutical composition and its preparation method and application containing ginkolide B and thrombin inhibitor Download PDFInfo
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Abstract
The present invention provides the pharmaceutical compositions of bilobalide-containing B a kind of, it contains ginkolide B and thrombin inhibitor.The present invention also provides the preparation method of the pharmaceutical composition and purposes.In the present composition, ginkolide B and thrombin inhibitor can play synergistic function, anticoagulant excellent effect, Small side effects, and potential applicability in clinical practice is excellent.Pharmaceutical composition novel formula of the present invention, component is simple, mechanism of action is clear and it is significant in efficacy, be not likely to produce tolerance, it can be achieved that industrialized production.
Description
Technical field
The present invention relates to the pharmaceutical compositions of bilobalide-containing B a kind of.
Background technique
Heparin is a kind of anti-coagulants, is the polymer being alternately formed by connecting by two kinds of polysaccharide, there is anticoagulation in vivo and in vitro
Effect.Clinically be mainly used for thrombotic disease, myocardial infarction, cardiovascular surgery, cardia catheterization, extracorporal circulatory system,
Haemodialysis etc..With pharmacology and clinical medical progress, the application of heparin constantly expands.
Heparin is the choice drug for needing to be rapidly reached anticoagulation, can be used for surgery antithrombotic and gestation person
Anticoagulant therapy can use heparin prevention patient that venous embolism disease occurs, and bulk can be prevented patients of acute myocardial infarction
Arterial embolism etc. occurs for antetheca transmural myocardial infarction patient.Another important clinical application of heparin is in heart, operation and kidney
Maintain blood extracorporeal circulation unimpeded when dirty dialysis.Heparin can be used for disseminated intravascular coagulation caused by treating a variety of causes
(DIC), treatment glomerulonephritis, nephrotic syndrome, rheumatoid arthritis etc. are also used for.
The main adverse reaction of heparin is easily to cause hematostaxis, show as various mucosa hemorrhages, articular cavity hematocele and
Wound bleeding etc., and heparin-induced thrombocytopenia is a kind of drug-induced thrombopenia, is in heparin therapy
A kind of severe complication.The thrombopenia of drug-induced is broadly divided into amphitypy: (1) marrow is inhibited by dealed with medicine went
It is caused；(2) drug is destroyed caused by blood platelet by immunologic mechanism.With heparin, quinine, quinindium, gold salt and sulfamido in the latter
Drug morbidity is higher.Clinical symptoms are extremely inconsistent, decrease of platelet to (1.0~80) × 109/ L, less serious case is asymptomatic, and severe one can
Because intracranialing hemorrhage or because heparin leads to the immune impairment of endothelial cell, the pulmonary embolism and Arterial thrombosis for merging threat to life are caused
Extremely.
Low molecular weight heparin is the general name for the lower heparin of molecule amount being prepared by unfractionated heparin depolymerization.It is main to make
It is clinically used for anticoagulant and antithrombotic, is clinically used for thromboembolism, prevention of deep vein thrombosis shape after prevention operation
At, pulmonary embolism, haemodialysis when the anti-coagulants of extracorporal circulatory system, peripheral vessel lesion and the established venae profunda conducted for the treatment of
Deng.The replacement therapy of allergy or thrombopenia caused by a small number of document announcements are still used for because of heparin.It still has been reported that and is used for
The special treatment of some embolism class diseases.Its adverse reaction is similar to heparin.
Hirudin (Hirudin) is that activity has been extracted in a variety of active ingredients in leech (Leech) and its salivary gland most
A kind of significant and most studied ingredient, the small protein (polypeptide) that it is made of 65-66 amino acid.Water
Leech element has extremely strong inhibiting effect to fibrin ferment, is the natural specific inhibitor of strongest fibrin ferment found so far.Animal
Test shows that hirudin can efficiently anticoagulation, antithrombus formation, and the coagulation factor of prevention catalyzed by thrombin with clinical research
The further blood stasis phenomenon such as activation and platelet response.In addition, it can also inhibit fibroblastic proliferation of thrombin induction
With the stimulation of fibrin ferment Human Umbilical Vein Endothelial Cells.It is a kind of up-and-coming anticoagulant stagnation resolvation drug, it can be used for treating various thrombus diseases
Disease, still it is the treatment of phlebothrombosis and diffusivity blood vessel blood coagulation；It can also be used for the formation of surgical site infections prevention of arterial thrombus,
Prevent after thrombus or after revascularization thrombus formation；Improve extracorporeal circulation of blood and blood dialysis.Micro- outer
Section operation in the anastomosis Chang Yinwei blood vessel embolism and lead to the failure, wound healing can promote using hirudin.Research is it is also shown that water
Leech element can also play a role in oncotherapy.It can prevent the transfer of tumour cell, it has therefore proved that medicable tumour such as fiber
Sarcoma, osteosarcoma, angiosarcoma, melanoma and leukaemia etc..Hirudin can also fiting chemical treatment and radiotherapy, due to promote
It heightens the effect of a treatment into the blood flow in tumour.But its dosage may excessively cause bleeding.
Argatroban is a kind of thrombin inhibitor, reversibly in conjunction with thrombin activity site.It is mainly used for morbidity 48
(walking is stood up, seat guarantor for the nervous symptoms (motor paralysis) of Ischemic Cerebral Infarction Patients with Acute in hour, daily routines
Hold, diet) improvement etc., main adverse reaction has hemorrhagic Cerebral Infarction, and cerebral hemorrhage, hemorrhage of digestive tract, shock, anaphylaxis are stopped
Gram (nettle rash, blood pressure reduce, expiratory dyspnea etc.) occur.
Therefore, how in the case where guaranteeing therapeutic effect, the use of the drugs such as heparin is reduced to reduce side effect urgently
It solves.
Ginkolide B is the active constituent extracted from natural drug ginkgo leaf, and Small side effects, it is so far that activity is strong
It was found that strongest platelet-activating factor antagonist, can be used for anticoagulation, but price is high, the cost of clinical use is too
It is high.
Summary of the invention
It is an object of the invention to overcome said medicine that the one kind developed in the side effect that anticoagulation generates is being applied alone
New pharmaceutical composition with synergy.
The present invention provides the pharmaceutical compositions of bilobalide-containing B a kind of, it contains ginkolide B and anti-coagulants.
Wherein, the anti-coagulants is thrombin inhibitor.The thrombin inhibitor be heparin, low molecular weight heparin,
Hirudin, argatroban.
Wherein, the weight proportion of the raw material are as follows: 1-20 parts and heparin 10-500 parts of ginkolide B.
Preferably, the weight proportion of the raw material are as follows: 5-15 parts and heparin 20-400 parts of ginkolide B.Further preferably
Ground, the weight proportion of the raw material are as follows: 8-12 parts and heparin 10-200 parts of ginkolide B.Still further preferably, the raw material
Weight proportion are as follows: 10 parts of ginkolide B and 100 parts of heparin.
Alternatively, the weight proportion of the raw material are as follows: 1-20 parts and low molecular weight heparin 20-100 parts of ginkolide B.
Preferably, the weight proportion of the raw material are as follows: 5-15 parts and low molecular weight heparin 30-80 parts of ginkolide B.Into one
It walks preferably, the weight proportion of the raw material are as follows: 10 parts and 50 parts of low molecular weight heparin of ginkolide B.
Alternatively, the weight proportion of the raw material are as follows: 1-20 parts and hirudin 4-40 parts of ginkolide B.
Preferably, the weight proportion of the raw material are as follows: 5-15 parts and hirudin 8-20 parts of ginkolide B.Further preferably
Ground, the weight proportion of the raw material are as follows: 10 parts and 5 parts of hirudin 1 of ginkolide B.
Alternatively, the weight proportion of the raw material are as follows: 1-20 parts and argatroban 10-100 parts of ginkolide B.
Preferably, the weight proportion of the raw material are as follows: 5-15 parts and argatroban 20-80 parts of ginkolide B.Further
Preferably, the weight proportion of the raw material are as follows: 10 parts and 50 parts of argatroban of ginkolide B.
Preferably, the weight proportion of the ginkolide B and heparin is 1:10~20:10；
The ginkolide B and the weight proportion of low molecular weight heparin are 10:50~20:20；
The weight proportion of the ginkolide B and hirudin is 10:15~20:4；
The weight proportion of the ginkolide B and argatroban is 10:50~20:10.
1-20 parts and hirudin 4-40 parts of ginkolide B.
The present invention also provides a kind of method for preparing pharmaceutical composition above-mentioned, it the following steps are included:
S1: raw material ginkolide B and anti-coagulants are weighed by component and weight ratio；
S2: after raw material is mixed, pharmaceutically acceptable auxiliary material is added and is prepared into pharmaceutically common pharmaceutical preparation.
Wherein, the pharmaceutically acceptable auxiliary material includes: starch, pregelatinized starch, lactose, sucrose, talcum powder, paste
Essence, cyclodextrin, microcrystalline cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinking
Povidone, glucose, meglumine, magnesium stearate, dextran, glycerol, ethyl alcohol, propylene glycol, polyethylene glycol, mannitol, sorb
Alcohol, xylitol, fibre plant oil, sodium benzoate, sodium salicylate, hydrochloric acid, citric acid, citric acid receive, sodium dihydrogen phosphate, phosphoric acid hydrogen
One of disodium, gelatin, lecithin, vitamin C or several.
Wherein, the pharmaceutical preparation include: tablet, capsule, soft capsule, oral solution, granule, pill, pill,
Powder, paste, sublimed preparation, injection, suppository, patch, drops, spray, creme, suspension, tincture, emulsion, liquid drugs injection, powder needle
Agent, targeting preparation, sustained release preparation, controlled release preparation.
The present invention also provides the preceding pharmaceutical compositions to prepare the purposes in anticoagulation medicine.
The present invention also provides ginkolide Bs and anti-coagulants drug combination to prepare the application in anticoagulation medicine.
Wherein, the anti-coagulants is thrombin inhibitor.The thrombin inhibitor is heparin, low molecular weight heparin.
Wherein, the weight proportion of the raw material are as follows: 1-20 parts and heparin 10-500 parts of ginkolide B.Preferably, in ginkgo
B5-15 parts and heparin 20-400 parts of ester.It is further preferred that the weight proportion of each raw material are as follows: 8-12 parts of ginkolide B and
40-200 parts of heparin.Still further preferably, the weight proportion of each raw material are as follows: 10 parts and 100 parts of heparin of ginkolide B.
Alternatively, the weight proportion of the raw material are as follows: 1-20 parts and low molecular weight heparin 20-100 parts of ginkolide B.
Preferably, the weight proportion of the raw material are as follows: 5-15 parts and low molecular weight heparin 30-80 parts of ginkolide B.Into one
It walks preferably, the weight proportion of the raw material are as follows: 10 parts and 50 parts of low molecular weight heparin of ginkolide B.
Alternatively, the weight proportion of the raw material are as follows: 1-20 parts and hirudin 4-40 parts of ginkolide B.
Preferably, the weight proportion of the raw material are as follows: 5-15 parts and hirudin 8-20 parts of ginkolide B.Further preferably
Ground, the weight proportion of the raw material are as follows: 10 parts and 5 parts of hirudin 1 of ginkolide B.
Alternatively, the weight proportion of the raw material are as follows: 1-20 parts and argatroban 10-100 parts of ginkolide B.
Preferably, the weight proportion of the raw material are as follows: 5-15 parts and argatroban 20-80 parts of ginkolide B.Further
Preferably, the weight proportion of the raw material are as follows: 10 parts and 50 parts of argatroban of ginkolide B.
Preferably, the weight proportion of the ginkolide B and heparin is 1:10~20:10；
The ginkolide B and the weight proportion of low molecular weight heparin are 10:50~20:20；
The weight proportion of the ginkolide B and hirudin is 10:15~20:4；
The weight proportion of the ginkolide B and argatroban is 10:50~20:10.
1-20 parts and hirudin 4-40 parts of ginkolide B.
Pharmaceutical composition provided by the invention can be with because wherein containing ginkolide B and thrombin inhibitor activity ingredient
By different mechanism of action anticoagulations, ginkolide B can remarkably promote the anticoagulant functions of said medicine, can also eliminate/drop
The low side effect because generation is applied alone, the two have the function of synergy, clinical use can reduce thrombin inhibitor dose,
Increase drug effect, reduce cost, reduces side effect, provide better choice for clinical research.
Pharmaceutical composition novel formula of the present invention, component is simple, mechanism of action is clear and it is significant in efficacy, be not likely to produce it is resistance to
By property, it can be achieved that industrialized production.
Ginkolide B and thrombin inhibitor are used in combination the present invention, and the two can play synergistic function, inhibit
Platelet aggregation, anticoagulant excellent effect, when clinical application, can reduce the dosage of thrombin inhibitor, and then it is big to reduce it
Amount uses bring side effect, can also reduce the usage amount of ginkolide B, reduce cost, potential applicability in clinical practice is excellent.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Specific embodiment
Ginkolide B monomeric compound of the present invention can be obtained by buying commercial product, or by by ginkgo
Lactone carries out isolating and purifying in existing method obtained；Thrombin inhibitor can also be obtained by buying commercial product, Yi Huotong
Existing method is crossed to be synthesized into.Through examining, all monomeric compounds are consistent with corresponding reference substance structure, and detect it through HPLC
Purity is 95% or more.
Embodiment 1
10 parts of ginkolide B
100 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Embodiment 2
8 parts of ginkolide B
40 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, be added pharmaceutically acceptable customary adjuvant according to common process be prepared into capsule or
Soft capsule.
Embodiment 3
12 parts of ginkolide B
200 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into tablet.
Embodiment 4
15 parts of ginkolide B
400 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into oral solution.
Embodiment 5
10 parts of ginkolide B
200 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Embodiment 6
5 parts of ginkolide B
20 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into spray.
Embodiment 7
1 part of ginkolide B
500 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, be added pharmaceutically acceptable customary adjuvant according to common process be prepared into liquid drugs injection or
Powder-injection.
Embodiment 8
20 parts of ginkolide B
200 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into sustained release preparation
Or controlled release preparation.
Embodiment 9
10 parts of ginkolide B
40 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into targeting system
Agent.
Embodiment 10
10 parts of ginkolide B
200 parts of heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, be added pharmaceutically acceptable customary adjuvant according to common process be prepared into granule or
Suspension.
Embodiment 11
10 parts of ginkolide B
50 parts of low molecular weight heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Embodiment 12
1 part of ginkolide B
20 parts of low molecular weight heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, be added pharmaceutically acceptable customary adjuvant according to common process be prepared into capsule or
Soft capsule.
Embodiment 13
20 parts of ginkolide B
100 parts of low molecular weight heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into tablet.
Embodiment 14
15 parts of ginkolide B
80 parts of low molecular weight heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into oral solution.
Embodiment 15
5 parts of ginkolide B
30 parts of low molecular weight heparin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Embodiment 16
10 parts of ginkolide B
5 parts of hirudin 1
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Embodiment 17
5 parts of ginkolide B
8 parts of hirudin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, be added pharmaceutically acceptable customary adjuvant according to common process be prepared into capsule or
Soft capsule.
Embodiment 18
20 parts of ginkolide B
40 parts of hirudin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into tablet.
Embodiment 19
15 parts of ginkolide B
20 parts of hirudin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into oral solution.
Embodiment 20
1 part of ginkolide B
4 parts of hirudin
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Embodiment 21
10 parts of ginkolide B
50 parts of argatroban
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Embodiment 22
5 parts of ginkolide B
20 parts of argatroban
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, be added pharmaceutically acceptable customary adjuvant according to common process be prepared into capsule or
Soft capsule.
Embodiment 23
15 parts of ginkolide B
80 parts of argatroban
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into tablet.
Embodiment 24
1 part of ginkolide B
10 parts of argatroban
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into oral solution.
Embodiment 25
20 parts of ginkolide B
100 parts of argatroban
Pharmaceutically acceptable customary adjuvant
After above-mentioned raw materials are mixed, pharmaceutically acceptable customary adjuvant is added according to common process and is prepared into pill.
Illustrate beneficial effects of the present invention with the mode of test example below:
1 ginkolide B of test example and thrombin inhibitor composition inhibit Platelet Aggregation in Rabbits to act on experimental study
1 materials and methods
1.1 experimental animal
Japan large ear rabbit 312, weight (2.0 ± 0.2) kg, half male and half female, by Medical University Of Chongqing experimental animal
The heart provides [animal certificate number: XCXK (Chongqing) 20020001].
1.2 experimental drug
Ginkolide B (self-control), heparin (self-control), low molecular weight heparin (self-control), leech (self-control), argatroban are (certainly
System), composition 1 (ginkolide B: heparin=1:10), composition 2 (ginkolide B: heparin=1:500), composition 3 (silver
Apricot lactone B: heparin=20:10), composition 4 (ginkolide B: heparin=20:500), (ginkolide B: heparin of composition 5
=5:20), composition 6 (ginkolide B: heparin=5:400), composition 7 (ginkolide B: heparin=15:20), composition 8
(ginkolide B: heparin=15:400), composition 9 (ginkolide B: low molecular weight heparin=10:50), composition 10 are (in ginkgo
Ester B: low molecular weight heparin=1:20), composition 11 (ginkolide B: low molecular weight heparin=1:100), composition 12 is (in ginkgo
Ester B: low molecular weight heparin=20:20), composition 13 (ginkolide B: low molecular weight heparin=5:30), 14 (ginkgolides of composition
B: low molecular weight heparin=5:80), composition 15 (ginkolide B: low molecular weight heparin=15:30), 16 (ginkgolides of composition
B: low molecular weight heparin=15:80), composition 17 (ginkolide B: leech=10:15), (ginkolide B: leech of composition 18
=1:4), composition 19 (ginkolide B: leech=1:40), composition 20 (ginkolide B: leech=20:4), composition
21 (ginkolide Bs: leech=20:40), composition 22 (ginkolide B: leech=5:8), composition 23 (ginkolide B:
Leech=5:20), composition 24 (ginkolide B: leech=15:8), composition 25 (ginkolide B: leech=15:20),
Composition 26 (ginkolide B: argatroban=10:50), composition 27 (ginkolide B: argatroban=1:10), composition
28 (ginkolide Bs: argatroban=1:100), composition 29 (ginkolide B: argatroban=20:10), (silver of composition 30
Apricot lactone B: argatroban=5:20), composition 31 (ginkolide B: argatroban=5:80), 32 (ginkgolides of composition
B: argatroban=15:20), composition 33 (ginkolide B: argatroban=15:80).
1.3 reagents and instrument
(cayman, lot number: 011219) be dissolved in PH is 7.6 containing 0.25% small ox blood to platelet activating factor (PAF)
In albuminised Tris-NaCl solution, final concentration of 3.6nmoL/L；Sodium citrate (Beijing biotech company, Zhong Shan Golden Bridge,
Lot number: 20130117) distilled water is made into 3.8% concentration；Rabbit β-thromboglobulin (β-TG) ELISA kit (FOCUS,
Lot number: 20130224), and the rabbit platelet factor 4 (PF-4) ELISA kit (FOCUS, lot number: 20130301).TYXN-96 is more
Function Intelligent blood agglomerates instrument (development of Shanghai GM technical research institute)；(Hitachi, Japan is public by scanning electron microscope S-3000 N
Department)；ELX-800 microplate reader (Bao Te company, the U.S.).
1.4 groupings and medication
Japan large ear rabbit 312, it is randomly divided into 39 groups, every group 8: (1) physiological saline group, (2) ginkolide B group,
(3) heparin group, (4) low molecular weight heparin group, (5) leech group, (6) argatroban group, 1 group of (7) composition, 2 groups of (8) composition,
(9) 3 groups of composition, 4 groups of (10) composition, 5 groups of (11) composition, 6 groups of (12) composition, 7 groups of (13) composition, (14) group
8 groups of object are closed, 9 groups of (15) composition, 10 groups of (16) composition, 11 groups of (17) composition, 12 groups of (18) composition, (19) are combined
13 groups of object, 14 groups of (20) composition, 15 groups of (21) composition, 16 groups of (22) composition, 17 groups of (23) composition, (24) combination
18 groups of object, 19 groups of (25) composition, 20 groups of (26) composition, 21 groups of (27) composition, 22 groups of (28) composition, (29) combination
23 groups of object, 24 groups of (30) composition, 25 groups of (31) composition, 26 groups of (32) composition, 27 groups of (33) composition, (34) combination
28 groups of object.(35) 29 groups of composition, 30 groups of (36) composition, 31 groups of (37) composition, 32 groups of (38) composition, (39) combination
33 groups of object.Each group presses clinical use approach, administration number of times administration, is used in conjunction 7 days.Each group dosage is as follows:
| Group | Dosage | It is administered daily number |
| Physiological saline | 2ml | 1 |
| Ginkolide B | 5.0mg/kg | 1 |
| Heparin | 5.0mg/kg | 1 |
| Low molecular weight heparin | 5.0mg/kg | 1 |
| Leech | 5.0mg/kg | 1 |
| Argatroban | 5.0mg/kg | 1 |
| 1 group of composition | 5.0mg/kg | 1 |
| 2 groups of composition | 5.0mg/kg | 1 |
| 3 groups of composition | 5.0mg/kg | 1 |
| 4 groups of composition | 5.0mg/kg | 1 |
| 5 groups of composition | 5.0mg/kg | 1 |
| 6 groups of composition | 5.0mg/kg | 1 |
| 7 groups of composition | 5.0mg/kg | 1 |
| 8 groups of composition | 5.0mg/kg | 1 |
| 9 groups of composition | 5.0mg/kg | 1 |
| 10 groups of composition | 5.0mg/kg | 1 |
| 11 groups of composition | 5.0mg/kg | 1 |
| 12 groups of composition | 5.0mg/kg | 1 |
| 13 groups of composition | 5.0mg/kg | 1 |
| 14 groups of composition | 5.0mg/kg | 1 |
| 15 groups of composition | 5.0mg/kg | 1 |
| 16 groups of composition | 5.0mg/kg | 1 |
| 17 groups of composition | 5.0mg/kg | 1 |
| 18 groups of composition | 5.0mg/kg | 1 |
| 19 groups of composition | 5.0mg/kg | 1 |
| 20 groups of composition | 5.0mg/kg | 1 |
| 21 groups of composition | 5.0mg/kg | 1 |
| 22 groups of composition | 5.0mg/kg | 1 |
| 23 groups of composition | 5.0mg/kg | 1 |
| 24 groups of composition | 5.0mg/kg | 1 |
| 25 groups of composition | 5.0mg/kg | 1 |
| 26 groups of composition | 5.0mg/kg | 1 |
| 27 groups of composition | 5.0mg/kg | 1 |
| 28 groups of composition | 5.0mg/kg | 1 |
| 29 groups of composition | 5.0mg/kg | 1 |
| 30 groups of composition | 5.0mg/kg | 1 |
| 31 groups of composition | 5.0mg/kg | 1 |
| 32 groups of composition | 5.0mg/kg | 1 |
| 33 groups of composition | 5.0mg/kg | 1 |
1.5 detection platelet aggregation rates
After 7d is administered, every animal hearts take blood 10.5mL, separate 1.5mL blood plasma and take serum, remaining 9mL blood plasma is used
3.8% sodium citrate 1:9 is anticoagulant, and 800r/min is centrifuged 10min, takes supernatant to obtain platelet rich plasma (PRP), separates 100 μ
LPRP is used for Electronic Speculum inspection, remaining PRP is used for the detection of platelet aggregation rate；The centrifugation of remainder 3000r/min speed
15min takes platelet poor plasma (PPP).PRP is adjusted with PPP, makes PRP number of platelets 360 × 109/L.It measures and records
1min, 5min and max platelet rate under the induction of 10 μ L PAF inducers.
The observation of 1.6 platelets
The 100 μ LPRP isolated are placed in silication EP pipe, the aggregation of the PAF induced platelet of 1 μ L, effect is added
After 15min, PRP is placed in the copper mesh specimen support for being covered with Formar film, 37 DEG C of incubation 10min, ultrapure water, 3% penta 2
Aldehyde fixes 5min, then clean with ultrapure water, after the sample on copper mesh spontaneously dries, plates the gold of one layer of 20nm on its surface
Film, electron microscope S-3000N scanning cellular morphology, observes 100 blood platelets, calculates various blood platelet proportion.
Blood platelet parting includes: (1) circle under Electronic Speculum: rounded or oval.Small in size, center is fine and close, and core is big, periphery oolemma
It is low narrow.(2) tree-like: to issue single or multiple podocytic processes from central dense area, elongated or sheet has branch sometimes.(3) shape is flattened:
There is dense-core in center, and peripheral oolemma is wider, and periphery is smooth or has small protrusion.(4) assemble shape: often by several to tens
A blood platelet composition, aggregation differ in size, wherein visible blood platelet is connected with each other, some complete fusions are integral, peripheral part
Blood platelet podocytic process is obvious.
The measurement of PF-4 and β-TG contents level in 1.7 serum
The PAF of 1 μ L is added into 1.5mL blood plasma, induces the release of PF-4 and β-TG, blood plasma takes 200 μ in 4 DEG C of standing 4h
L serum, is detected.Concrete operations are carried out according to kit specification, and microplate reader reads result data.
1.8 statistical procedures
Experimental result with mean ± standard deviation () indicate, it is for statistical analysis with SPSS18.0 software, using difference
The t inspection that this mean compares counts each group platelet aggregation rate, platelet PLA2 percentage and PF-4 and β-TG content
Credit analysis.P < 0.05 is that difference is statistically significant.
2 results
2.1 platelet aggregation test results
The results are shown in Table 1:
1 PAF of table induction platelet aggregation (, n=8)
Compared with physiological saline group, p < 0.05 * * p < 0.01, *
Under PAF induction, ginkolide B group, ginkolide B+heparin, ginkolide B+low molecular weight heparin, ginkolide B
Compared with physiological saline group conspicuousness occurs for the max platelet rate of each groups such as+leech, ginkolide B+argatroban
Sex differernce (p < 0.01, p < 0.05), each group L-Arginine is significantly increased, and illustrates each composition of the present invention
With effective anticoagulation；And significant changes do not occur for each monomer group of heparin, low molecular weight heparin, leech, argatroban, illustrate ginkgo
Lactone B and heparin, low molecular weight heparin, leech, argatroban produce synergistic effect；
In each group of ginkolide B+heparin compostions, the effect of composition 1,3,5,7 is preferable, composition 1, composition
The effect of 3 better effect, composition 1 is best, and therefore, the proportion of ginkolide B and silaenafil of the present invention is preferably 1:10
~20:10 is more preferably 1:10 in conjunction with cost；When the proportion of ginkolide B and heparin is 1:10~20:10 in the composition,
Ginkolide B dosage is few, and the dosage of heparin is more, aggregation inhibiting rate but be significantly larger than the same dose of heparin of composition, and with
The aggregation inhibiting rate of the same dose of ginkolide Bs of composition is quite or slightly lower, illustrates in this ratio range, ginkgolides
The synergistic function highly significant of B and heparin；
In each group of ginkolide B+low molecular weight heparin composition, the effect of composition 9,12,15 is preferable, therefore, this
The proportion of invention ginkolide B and low molecular weight heparin is preferably 10:50~20:20, is more preferably 10:50 in conjunction with cost；In group
When the proportion of ginkolide B and low molecular weight heparin is 10:50 in conjunction object, ginkolide B dosage is few, the dosage of low molecular weight heparin
It is more, aggregation inhibiting rate but be significantly larger than the same dose of heparin of composition, and with the same dose of ginkolide Bs of composition
It is suitable to assemble inhibiting rate, illustrates in this ratio range, the synergistic function of ginkolide B and low molecular weight heparin is very aobvious
It writes；
In each group of ginkolide B+leech composition, the effect of composition 17,20,24 is preferable, therefore, present invention silver
The proportion of apricot lactone B and leech is preferably 10:15~20:4, is more preferably 10:15 in conjunction with cost；Ginkgolides in the composition
When the proportion of B and leech is 10:15, ginkolide B dosage is few, and the dosage of leech is more, and aggregation inhibiting rate is but significantly larger than group
The same dose of leech of object are closed, and suitable with the aggregation inhibiting rate of the same dose of ginkolide Bs of composition, illustrates to match herein
When range, the synergistic function highly significant of ginkolide B and leech；
In each group of ginkolide B+argatroban composition, the effect of composition 26,29,32 is preferable, therefore, this hair
The proportion of bright ginkolide B and argatroban is preferably 10:50~20:10, is more preferably 10:50 in conjunction with cost；In composition
When the proportion of middle ginkolide B and argatroban is 10:50, ginkolide B dosage is few, and the dosage of argatroban is more, aggregation
Inhibiting rate is but significantly larger than the same dose of argatrobans of composition, and the aggregation with the same dose of ginkolide Bs of composition
Inhibiting rate is suitable, illustrates in this ratio range, the synergistic function highly significant of ginkolide B and argatroban.
2.2 platelets testing results
Experimental result is as shown in table 2:
Table 2 be added PAF after each group platelet PLA2 compare (, n=8)
Compared with physiological saline group, p < 0.05 * * p < 0.01, *
Four kinds of platelet PLA2s are mainly observed under 2000 times of scanning electron microscope: round, tree-like, flattening shape and aggregation
Shape.PAF induction under, ginkolide B, ginkolide B+heparin, ginkolide B+low molecular weight heparin, ginkolide B+leech,
Ginkolide B+argatroban each group Platelet Size is more consistent, and surface is smooth, and accumulation type blood platelet is more rare.Physiological saline group
Strong activation, platelet adhesion reaction power enhancing, it is seen that red blood cell adhesion is on blood platelet occur for blood platelet；Platelet PLA2 is not advised
Rule, volume increase, stretch out and increase in gemma shape pseudopodium outstanding, aggregation shape platelet counts, illustrate that each composition of the present invention is equal
It can effective anticoagulation.And heparin, low molecular weight heparin, leech, argatroban each group Platelet Size are different, there is pseudopodium on surface,
It is more to assemble shape blood platelet.Illustrate that ginkolide B produces synergistic effect to heparin, low molecular weight heparin, leech, argatroban；
In each group of ginkolide B+heparin compostions, the effect of composition 1,3,5,7 is preferable, composition 1, composition
The effect of 3 better effect, composition 1 is best, and therefore, the proportion of ginkolide B and silaenafil of the present invention is preferably 1:10
~20:10 is more preferably 1:10 in conjunction with cost；When the proportion of ginkolide B and heparin is 1:10~20:10 in the composition,
Ginkolide B dosage is few, and the dosage of heparin is more, and accumulation type blood platelet is but far less than the same dose of heparin of composition, and
It is suitable with the quantity of accumulation type blood platelet of the same dose of ginkolide Bs of composition, when the proportion of ginkolide B and heparin is
The accumulation type platelet counts of 1:10~20:10, ginkolide Bs more the same dose of than composition are less, illustrate to match model herein
In enclosing, the synergistic function highly significant of ginkolide B and heparin；
In each group of ginkolide B+low molecular weight heparin composition, the effect of composition 9,12,15 is preferable, therefore, this
The proportion of invention ginkolide B and low molecular weight heparin is preferably 10:50~20:20, is more preferably 10:50 in conjunction with cost；In group
When the proportion of ginkolide B and low molecular weight heparin is 10:50 in conjunction object, ginkolide B dosage is few, the dosage of low molecular weight heparin
More, the quantity of accumulation type blood platelet is but far less than the same dose of heparin of composition, and with the same dose of silver of composition
The quantity of the accumulation type blood platelet of apricot lactone B is suitable, illustrates in this ratio range, the association of ginkolide B and low molecular weight heparin
With synergistic effect is highly significant；
In each group of ginkolide B+leech composition, the effect of composition 17,20,24 is preferable, therefore, present invention silver
The proportion of apricot lactone B and leech is preferably 10:15~20:4, is more preferably 10:15 in conjunction with cost；Ginkgolides in the composition
When the proportion of B and leech is 10:15, ginkolide B dosage is few, and the dosage of leech is more, and the quantity of accumulation type blood platelet is remote
Far fewer than the same dose of leech of composition, and the quantity with the accumulation type blood platelet of the same dose of ginkolide Bs of composition
Quite, illustrate in this ratio range, the synergistic function highly significant of ginkolide B and leech；
In each group of ginkolide B+argatroban composition, the effect of composition 26,29,32 is preferable, therefore, this hair
The proportion of bright ginkolide B and argatroban is preferably 10:50~20:10, is more preferably 10:50 in conjunction with cost；In composition
When the proportion of middle ginkolide B and argatroban is 10:50~20:10, ginkolide B dosage is few, and the dosage of argatroban is more,
Its accumulation type blood platelet is but far less than the same dose of argatrobans of composition, and with the same dose of ginkgolides of composition
The quantity of the accumulation type blood platelet of B is suitable, illustrates in this ratio range, the synergy of ginkolide B and low molecular weight heparin
Act on highly significant.
2.3 blood platelet PF-4 and β-TG testing results
The results are shown in Table 3: 3 blood platelet PF-4 and β-TG testing result of table (, n=8)
Compared with physiological saline group, p < 0.05 * * p < 0.01, *
PF-4 and β-TG level reduces, and illustrates that platelet release function is suppressed.
Compared with physiological saline group, ginkolide B, ginkolide B+heparin, ginkolide B+low molecular weight heparin, in ginkgo
Each groups PF-4 and β-the TG level such as ester B+ leech, ginkolide B+argatroban significantly reduces (p < 0.01, p < 0.05), explanation
Each composition of the present invention can effective anticoagulation, and each monomer group of heparin, low molecular weight heparin, leech, argatroban is not
It significantly reduces, illustrates that ginkolide B produces synergistic effect to heparin, low molecular weight heparin, leech, argatroban.PF-4 and β-
TG level reduces, and illustrates that platelet release function is suppressed；
In each group of ginkolide B+heparin compostions, the effect of composition 1,3,5,7 is preferable, composition 1, composition
The effect of 3 better effect, composition 1 is best, and therefore, the proportion of ginkolide B and silaenafil of the present invention is preferably 1:10
~20:10 is more preferably 1:10 in conjunction with cost；When the proportion of ginkolide B and heparin is 1:10~20:10 in the composition,
Ginkolide B dosage is few, and the dosage of heparin is more, PF-4 and β-TG level but well below the same dose of heparin of composition,
And be on close level with PF-4 the and β-TG of the same dose of ginkolide Bs of composition, illustrate in this ratio range, ginkgolides
The synergistic function highly significant of B and heparin；
In each group of ginkolide B+low molecular weight heparin composition, the effect of composition 9,12,15 is preferable, therefore, this
The proportion of invention ginkolide B and low molecular weight heparin is preferably 10:50~20:20, is more preferably 10:50 in conjunction with cost；In group
When the proportion of ginkolide B and low molecular weight heparin is 10:50 in conjunction object, ginkolide B dosage is few, the dosage of low molecular weight heparin
It is more, PF-4 and β-TG level but well below the same dose of heparin of composition, and in the same dose of ginkgoes of composition
PF-4 the and β-TG of ester B is on close level, and illustrates in this ratio range, and ginkolide B and the synergistic of low molecular weight heparin are made
Use highly significant；
In each group of ginkolide B+leech composition, the effect of composition 17,20,24 is preferable, therefore, present invention silver
The proportion of apricot lactone B and leech is preferably 10:15~20:4, is more preferably 10:15 in conjunction with cost；Ginkgolides in the composition
When the proportion of B and leech is 10:15, ginkolide B dosage is few, and the dosage of leech is more, PF-4 and β-TG level is but much low
It is on close level in the same dose of leech of composition, and with PF-4 the and β-TG of the same dose of ginkolide Bs of composition, explanation
In this ratio range, the synergistic function highly significant of ginkolide B and leech；
In each group of ginkolide B+argatroban composition, the effect of composition 26,29,32 is preferable, therefore, this hair
The proportion of bright ginkolide B and argatroban is preferably 10:50~20:10, is more preferably 10:50 in conjunction with cost；In composition
When the proportion of middle ginkolide B and argatroban is 10:50~20:10, ginkolide B dosage is few, and the dosage of argatroban is more,
Itself PF-4 and β-TG level but well below the same dose of argatrobans of composition, and in the same dose of ginkgoes of composition
PF-4 the and β-TG of ester B is on close level, and illustrates in this ratio range, and ginkolide B and the synergistic of low molecular weight heparin are made
Use highly significant.
To sum up, ginkolide B and heparin, low molecular weight heparin, hirudin or argatroban are used in combination the present invention, can be with
Play synergistic function, the drug that ginkolide B of the present invention and heparin, low molecular weight heparin, hirudin or argatroban form
Composition, can effectively inhibit platelet aggregation, anticoagulation, excellent effect, and potential applicability in clinical practice is excellent.
Claims (10)
1. a kind of pharmaceutical composition of anticoagulant bilobalide-containing B, it is characterised in that: it contains ginkolide B and fibrin ferment
Inhibitor；
The thrombin inhibitor is heparin, low molecular weight heparin, hirudin, argatroban；
The weight proportion of the ginkolide B and thrombin inhibitor are as follows: 1-15 parts and heparin 10-400 parts of ginkolide B；Silver
B1-20 parts and low molecular weight heparin 20-100 parts of apricot lactone；10-20 parts and hirudin 4-15 parts of ginkolide B；Ginkolide B 1-
20 parts and argatroban 10-100 parts.
2. pharmaceutical composition according to claim 1, it is characterised in that:
The weight proportion of the ginkolide B and thrombin inhibitor are as follows: 5-15 parts and heparin 20-400 parts of ginkolide B, silver
B5-15 parts and low molecular weight heparin 30-80 parts of apricot lactone, 10 parts and 5 parts of hirudin 1 of ginkolide B；5-15 parts of ginkolide B and
20-80 parts of argatroban.
3. pharmaceutical composition according to claim 1, it is characterised in that:
The weight proportion of the ginkolide B and thrombin inhibitor are as follows: 10 parts and 100 parts of heparin of ginkolide B；Ginkgolides
B10 parts and 50 parts of low molecular weight heparin；10 parts and 5 parts of hirudin 1 of ginkolide B；10 parts and 50 parts of argatroban of ginkolide B.
4. pharmaceutical composition according to claim 1, it is characterised in that:
The weight proportion of the ginkolide B and heparin is 1:10 ~ 15:10；
The ginkolide B and the weight proportion of low molecular weight heparin are 10:50 ~ 20:20；
The weight proportion of the ginkolide B and hirudin is 10:15 ~ 20:4；
The weight proportion of the ginkolide B and argatroban is 10:50 ~ 20:10.
5. a kind of method for preparing pharmaceutical composition described in claim 1,2 or 3, it is characterised in that: it the following steps are included:
S1: raw material ginkolide B and thrombin inhibitor are weighed by component and weight ratio；
S2: after raw material is mixed, pharmaceutically acceptable auxiliary material is added and is prepared into pharmaceutical preparation.
6. pharmaceutical composition described in claim 1,2 or 3 is preparing the purposes in anticoagulation medicine.
7. ginkolide B and thrombin inhibitor are preparing the purposes in anticoagulant combination medicine；
The thrombin inhibitor is heparin, low molecular weight heparin, hirudin, argatroban；
The weight proportion of the ginkolide B and thrombin inhibitor are as follows: 1-15 parts and heparin 10-400 parts of ginkolide B；Silver
B1-20 parts and low molecular weight heparin 20-100 parts of apricot lactone；10-20 parts and hirudin 4-15 parts of ginkolide B；Ginkolide B 1-
20 parts and argatroban 10-100 parts.
8. purposes according to claim 7, it is characterised in that: the weight of the ginkolide B and thrombin inhibitor is matched
Than are as follows: 5-15 parts and heparin 20-400 parts of ginkolide B；5-15 parts and low molecular weight heparin 30-80 parts of ginkolide B；In ginkgo
B10 parts and 5 parts of hirudin 1 of ester；5-15 parts and argatroban 20-80 parts of ginkolide B.
9. purposes according to claim 7, it is characterised in that: the weight of the ginkolide B and thrombin inhibitor is matched
Than are as follows: 10 parts and 100 parts of heparin of ginkolide B；10 parts and 50 parts of low molecular weight heparin of ginkolide B；10 parts of ginkolide B and water
15 parts of leech element；10 parts and 50 parts of argatroban of ginkolide B.
10. purposes according to claim 7, it is characterised in that:
The weight proportion of the ginkolide B and heparin is 1:10 ~ 15:10；
The ginkolide B and the weight proportion of low molecular weight heparin are 10:50 ~ 20:20；
The weight proportion of the ginkolide B and hirudin is 10:15 ~ 20:4；
The weight proportion of the ginkolide B and argatroban is 10:50 ~ 20:10.
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Citations (2)
| 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 |
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| US7078434B1 (en) * | 1999-08-12 | 2006-07-18 | Societe De Conseils De Recherches Et D'applications Scientifiques Sas | Use of Ginkgo extract |
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| 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 |
Non-Patent Citations (2)
| Title |
|---|
| 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;刘国庆;《河北医学》;20101031;第16卷(第10期);摘要部分 |
| 阿加曲班联合舒血宁治疗急性脑梗死的有效性和安全性研究;孟丽莉，等;《牡丹江医学院学报》;20101231;第31卷(第4期);第35页左栏第1段；第35-36页讨论部分 |
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