CN108926556A - Composition and its medical usage containing ginkgoterpene lactone - Google Patents
Composition and its medical usage containing ginkgoterpene lactone Download PDFInfo
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- CN108926556A CN108926556A CN201710370698.XA CN201710370698A CN108926556A CN 108926556 A CN108926556 A CN 108926556A CN 201710370698 A CN201710370698 A CN 201710370698A CN 108926556 A CN108926556 A CN 108926556A
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- lactone
- composition
- bilobalide
- ginkalide
- ginkgoterpene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Abstract
The present invention relates to a kind of ginkgoterpene lactone compositions to prepare the purposes in the drug for preventing and/or treating venous thromboembolic disease.The invention further relates to a kind of composition containing ginkgoterpene lactone and Sha Ban class drug, and its preparing the purposes in the drug for preventing and/or treating venous thromboembolic disease.Ginkgoterpene lactone composition provided by the invention and composition containing ginkgoterpene lactone and Sha Ban class drug effectively anti-venous thronbosis (anticoagulant, improve blood constituent) and can treat and are related to the related disease of venous thromboembolism, its application range for extending ginkgoterpene lactone class compound, and provide for the treatment of phlebothrombosis with lower bleeding risk, affordable and new selection curative for effect, safe and reliable, easy to use.
Description
Technical field
The present invention relates to pharmaceutical fields, and in particular to a kind of ginkgoterpene lactone composition is in preparation for preventing and/or controlling
Treat the purposes in the drug of venous thromboembolic disease；The invention further relates to one kind to contain ginkgoterpene lactone and Sha Ban class drug
Composition, and its preparing the purposes in drug for preventing and/or treating venous thromboembolic disease.
Background technique
As China gradually steps into aging society, the diseases such as cardiovascular and cerebrovascular relevant to thrombosis, deep vein embolism
The disease incidence of disease rises year by year, and becomes the principal element for threatening China middle-aged and the old health.
Thrombosis is the blood clot for refering in particular to be formed in vascular system lumen.The mechanism of thrombosis is sufficiently complex, mesh
It is preceding still to there are problems to need to be illustrated.The three elements hypothesis that 18th century mid-term Virchow propose concisely summarises thrombus
The pathogenesis of formation does not lose its realistic meaning still after assigning modern science intension so far.The theory thinks that vascular wall is (interior
Skin) damage, blood flow form (haemodynamics) variation and blood constituent change (blood platelet, coagulation factor, it is anticoagulant because
Son, fibrinolytic and anti-fibrinolytic factor) be thrombosis Fundamentals.The work that three elements play in vein and Arterial thrombosis
With different with the status that occupies, the relationship of blood vessel endothelium injury and platelet activation and Arterial thrombosis is more close,
And meaning of the variation of stasis of blood stream and blood plasma blood coagulation correlation factor in venous thronbosis is more prominent.Blood platelet is in artery
The primary hemostatic stage and the thrombosis initial stage all play a significant role.Therefore, (i.e. antiplatelet is living for platelet suppressant drug
Change the factor (PAF) reagent) it is mainly used for the prevention and treatment of Arterial thrombosis disease.And the treatment master of venous thronbosis disease
To pass through anticoagulant realization.In venous thrombosis cascade system, a kind of entitled Xa factor (the also referred to as Stuart-Prower factor)
Serine endopeptidase plays the role of very important in multiple stages.Clinical practice shows that a variety of drugs can be multiple
Inhibit the activity of Xa factor in degree.
Drug currently used for treating arterial thromboembolism disease mainly has：Thrombolytic Drugs (rt-PA), protection blood vessel endothelium medicine
(such as statins), platelet aggregation inhibitor (such as aspirin, clopidogrel), fibrin solution synandrium (such as tirofiban)
With the fine medicine (such as urokinase) of drop.And the drug for treating venous thromboembolism disease is mainly anticoagulation, such as conventional medicament is low
Molecular heparin, Enoxaparin, neodicoumarin etc., and a new generation inhibit husky class's class drug of approach only for Xa factor：Razaxaban,
Ah's paisa class and Yi Dushaban etc..Although husky class's class drug clinically embodies preferable anticoagulant effect, its still face
Face the problems such as bleeding risk is high, liver renal toxicity is big and cost of use is expensive.
Summary of the invention
The present invention provides following technical scheme for solving the above problems：
A kind of use of ginkgoterpene lactone composition in the drug of preparation prevention and/or treatment venous thromboembolic disease
On the way.
Preferably, the ginkgoterpene lactone composition includes Bilobalide and ginkgo diterpenoid-lactone.
Preferably, the ginkgo diterpenoid-lactone includes ginkalide A, ginkolide B, ginkalide C, bilobalide J, silver
One or more of apricot lactone K, ginkgolides L, ginkgolides M, ginkgolides N, ginkgolides Q.
It is highly preferred that the ginkgo diterpenoid-lactone is selected from as composed by ginkalide A, ginkolide B and ginkalide C
Group.
It is highly preferred that the ginkgo diterpenoid-lactone is ginkolide B or the ginkgo diterpenoid-lactone is ginkolide B
And ginkalide C or the ginkgo diterpenoid-lactone are ginkalide A, ginkolide B and ginkalide C.
Preferably, the mass ratio in the ginkgoterpene lactone composition between Bilobalide and ginkgo diterpenoid-lactone each component is
(1:8)~(8:1).
Preferably, it is (1~4) that the ginkgoterpene lactone composition, which is mass ratio,:(1~4):The Bilobalide of (4~1),
Ginkolide B and ginkalide C；Or it is (1~8) that the composition, which is mass ratio,:(1~8):(1~4):(1~8) it is white
Fruit lactone, ginkalide A, ginkolide B and ginkalide C.
It preferably, is (1~2) comprising mass ratio in the ginkgoterpene lactone composition:1 Bilobalide and ginkgolides
B。
The present invention also provides a kind of composition containing ginkgoterpene lactone and Sha Ban class drug, wherein in the Ginkgo biloba terpenes
Ester includes ginkgo diterpenoid-lactone and Bilobalide.
Preferably, the ginkgo diterpenoid-lactone includes ginkalide A, ginkolide B, ginkalide C, bilobalide J, silver
One or more of apricot lactone K, ginkgolides L, ginkgolides M, ginkgolides N, ginkgolides Q.
It is highly preferred that the ginkgo diterpenoid-lactone is selected from as composed by ginkalide A, ginkolide B and ginkalide C
Group.
It is highly preferred that the ginkgo diterpenoid-lactone is ginkolide B or the ginkgo diterpenoid-lactone is ginkolide B
And ginkalide C or the diterpene ginkgolides are ginkalide A, ginkolide B and ginkalide C.
Preferably, the mass ratio in the ginkgoterpene lactone composition between Bilobalide and ginkgo diterpenoid-lactone each component is
(1:8)~(8:1).
Preferably, it is (1~4) that the ginkgoterpene lactone composition, which is mass ratio,:(1~4):The Bilobalide of (4~1),
Ginkolide B and ginkalide C；Or it is (1~8) that the composition, which is mass ratio,:(1~8):(1~4):(1~8) it is white
Fruit lactone, ginkalide A, ginkolide B and ginkalide C.
It preferably, is (1~2) comprising mass ratio in the ginkgoterpene lactone composition:1 Bilobalide and ginkgolides
B。
Preferably, the husky class class drug includes razaxaban, Eliquis, Yi Dushaban, otamixaban, razaxaban
And one of their pharmaceutically acceptable salt, hydrate and solvates or a variety of.
Preferably, husky class's class drug is selected from one or more of razaxaban, Eliquis, Yi Dushaban,
More preferably described husky class's class drug is razaxaban or Yi Dushaban.
Preferably, the mass ratio of the ginkgoterpene lactone and husky class class drug is (5:6)~(20:1).
The present invention also provides the above-mentioned compositions containing ginkgoterpene lactone and Sha Ban class drug in preparation prevention and/or treatment
Purposes in the drug of venous thromboembolic disease.
Preferably, venous thromboembolic disease of the present invention include deep-vein thrombosis embolism, it is pulmonary embolism, congested
Venous thromboembolism caused by heart failure, fracture and major surgery, the major surgery include joint replacement
Art.
The present invention so-called ginkgo diterpenoid-lactone contains 6 oxygen-enriched five-membered rings (including spiral shell [4.4]-nonyl in structure
Alkane, a tetrahydrofuran ring and three lactonic rings), 10-12 Stereocenter and distinctive tert-butyl.Separated ginkgo out
Difference of the diterpenoid-lactone in structure is only that the number and location of hydroxyl.The so-called Bilobalide of the present invention is containing there are three lactones
Ring, a tert-butyl and a full carbocyclic ring, belong to sesquiterpene lactone.
The so-called husky class class drug of the present invention is a kind of blood coagulation Xa factor inhibitor, wherein the Xa factor is coagulation cascade
Key regulator in reaction can promote the formation of phlebothrombosis.
Ginkgoterpene lactone composition provided by the invention and composition containing ginkgoterpene lactone and Sha Ban class drug can
It effectively anti-venous thronbosis (anticoagulant, improve blood constituent) and treats and is related to the related disease of venous thromboembolism, extend
The application range of ginkgoterpene lactone class compound, and provide for the treatment of phlebothrombosis with lower bleeding risk, valence
Lattice are suitable and new selection curative for effect, safe and reliable, easy to use.
Specific embodiment
1 ginkgoterpene lactone composition of embodiment forms the anticoagulation of model to rabbit thrombus of deep vein in traumatic limbs and trunk
Materials and methods
1.1 experimental animal
I grades of Japanese white big ear rabbits 500 (4 spare), 2.0~3.0kg of weight when test, all-male.
1.2 experimental drug
Bilobalide, ginkalide A, ginkolide B, ginkalide C and ginkgoterpene lactone composition 1-24, detailed prescription
It is as follows：
1. ginkgoterpene lactone prescription of table matches table in detail
1.3 reagents and instrument
Instrument：
(1) rabbit weighing inspection apparatus
ACS-15LED electronic platform scale, resolution value 1g, maximum capacity 6kg, instrument number BKY-YB-002, Shanghai hawk board weighing apparatus
Device Co., Ltd produces, for claiming rabbit weight.
(2) pathologic finding instrument
German Sartorius BS124S type electronic balance (scale division value：0.0001g), instrument is numbered：BKY-TJ-002, moral
The production of Sartorius limited liability company of state.
ZT-14V2 automatic water extracter for biological tissue, instrument number：BKY-BL-016, Xiaogan City matt medical electronic technology
Co., Ltd produces.
III type embedding machine of prestige BMJ- in Changzhou, instrument number：BKY-BL-002, Jiangsu Province Zhongwei Electronic Instrument Factory, Zhangzhou City
It produces.
Instrument, instrument number are dried in the drift of III pathological tissue of prestige PHY- in Changzhou：BKY-BL-003, prestige electronics in Jiangsu Province's Changzhou
Instrument plant produces.
Come card RM2126 cycle type slicer, instrument number：BKY-BL-004, Shanghai Lai Ka Instrument Ltd. produce.
Japanese Olympus BX41-32P01 microscope, instrument number：BKY-BL-013, Japanese Olympus Co., Ltd.
It produces.
YR-21 biological tissue automatic staining machine, instrument number：BKY-BL-015, Xiaogan City matt medical electronic technology have
Limit company produces.
The desk-top drying box of light 202-0 type, instrument are numbered forever in Beijing：BKY-BL-005, Beijing's bright Medical Instruments forever
Factory produces.
Reagent：
(1) test sample is with reagent needed for liquid
The third methylcellulose of carboxylic, lactose, mannitol.
(3) anesthetic
Yellow Jackets are used for family's rabbit anesthesia.Yellow Jackets are configured to 3% concentration with purified water when use.It prepares
At 3% Nembutal sodium solution (g/v).Family's rabbit anesthesia when for modeling.
1.4 modeling
Take quarantine and 496 progress modelings of Japanese white big ear rabbit of adaptability observation qualification, 2.0~3.0kg of weight, entirely
Male first takes 8 to be only used as normal group, remaining is all made of beating unit, and impact contact disc diameter is 1.5cm, and traumatic energy is pressed
Ep=mgh is calculated, and the every strike primary energy of iron staff is 7.5J.Specific method：Rabbit auricular vein injects 3% yellow Jackets 1ml/
Kg anesthesia, right side prone position, left thigh root are set on strike platform, and clear rabbit left femur greater trochanter is touched, and impact head plane is close to
Under greater trochanter of femur to greater trochanter within the scope of 1.5cm, using self-control beating unit, rabbit thigh proximal lateral is struck, gypsum is fixed
After left lower extremity checks right hip activity freely when hip enuflex position in the wrong, upper plaster bandage, prone position waits for that gypsum is formed, animal after modeling
Free water, pellet raising, does not have to anti-coagulants and antibiotic.
1.5 groupings and administration mode
1.5.1 method for preparation of drug
Drug (mg)：The third methylcellulose of carboxylic (mg)：Lactose (mg)：Mannitol (mg)=1:2:10:After 20 grindings uniformly, then
Add water to enter purified water 1ml, stir evenly to get.Citing：50mg drug+100mg carboxylic the third methylcellulose+500mg lactose+
1000mg mannitol, grinding uniformly, add water 50ml, stir evenly the medical fluid to get 1mg/ml.
1.5.2 dosage regimen
The successful animal of modeling is taken to be grouped, every group 8, according to the form below dosage regimen gastric infusion, successive administration 14 days,
Daily administration 2 times.
2 animal deep-vein thrombosis of table forms model dosage regimen
The measurement of 1.6 Deep vain thrombosis
Sacrificed by exsanguination animal after last dose 30min, cuts femoral vein, HE dyeing, and light microscopic microscopy checks intravascular skin lesion
Situations such as wound, thrombosis and angiorrhoxis, and rank scores are carried out to the above lesion degree, specific standards of grading are detailed in down
Table.
3 Deep vain thrombosis histopathologic examination lesion degree standards of grading of table
1.7 statistical procedures
Deep vain thrombosis determination data is ranked data data, using software SPSS13.0's " non-parametric test "
" multiple independent samples " is for statistical analysis.
Result of study and Analysis of conclusion
4 test sample gastric infusion of table forms model femoral vein Histopathology to rabbit thrombus of deep vein in traumatic limbs and trunk and becomes
The influence of change
Note：Compared with model group, #P<0.05,##P<0.01,###P<0.001.
Result of study is shown：
1) composition 24 (8:8:4:8, i.e., 2:2:1:2) anticoagulation is most strong, and the protections of Human Umbilical Vein Endothelial Cells, blood vessel
The effect of integrality and thrombosis is most balanced, is prescription best in this test each group, is secondly composition 15 (4:0:4:
1), composition 10 (2:0:2:And composition 19 (4 2):8:2:8, i.e., 2:4:1:4).
2) it is found by carrying out analysis to data and prescription：The ratio of Bilobalide and ginkgo diterpenoid-lactone is 2:1 and 1:1
When, the anticoagulation of composition is preferable.
3) therefore subsequent experiment is with Bilobalide：Ginkolide B=2:1,1:1 carries out for representative and husky class's class pharmaceutical representative
Experimental study.
2 ginkgoterpene lactone of embodiment and husky class's class pharmaceutical composition form model to rabbit thrombus of deep vein in traumatic limbs and trunk
Anticoagulation
Materials and methods
2.1 experimental animals and modeling method
With embodiment 1
2.2 experimental drugs and dosage regimen
1:1 Bilobalide and ginkgolides, 2:1 Bilobalide：Ginkolide B, razaxaban, Eliquis, according to
Du Shaban and combinations thereof.
Because razaxaban, Eliquis, Yi Dushaban human clinical recommended dose are different, with reference to its specification：Benefit cuts down sand
The daily clinical recommended dose of class：10mg；Eliquis clinical recommended dose daily：2.5mg and Yi Dushaban maximum clinical are recommended
Dosage：It 60mg/ days, is converted in conjunction with the clinical recommended dose of drug by equivalent dose.
Dosage is as shown in table 5 below
2.3 reagents and instrument
With embodiment 1
2.4 modeling
With embodiment 1
2.5 groupings and administration mode
2.5.1 method for preparation of drug
With embodiment 1
2.5.2 dosage regimen
See the above table table 5
The measurement of 2.6 Deep vain thrombosis
With embodiment 1
2.7 statistical procedures
With embodiment 1.
Result of study and Analysis of conclusion
6 test sample gastric infusion of table forms model femoral artery, femoral vein pathology to rabbit thrombus of deep vein in traumatic limbs and trunk
The influence of histological change
Note：Compared with model group, #P<0.05,##P<0.01,###P<0.001.
Result of study is shown：Using razaxaban, Eliquis, Yi Dushaban as the Xa factor inhibitor sand class class medicine of representative
Object has very strong anticoagulation, and forming model to rabbit Traumatic Deep Vein Thrombosis has significant therapeutic effect, can not obtain
Obtain the clinical efficacy of ginkgoterpene lactone composition and husky class use in conjunction.
Therefore direct each dosage, which halves, is tested, and is formed with exploring each prescription to rabbit thrombus of deep vein in traumatic limbs and trunk
Influence, it is other same.
Table 7
Result of study is as shown in table 8 below:
Result of study is shown:
1) ginkgoterpene lactone composition and razaxaban, Eliquis, Yi Dusha well matched 5, it is anticoagulant to vein to play association
Same synergistic effect.
2) ginkgoterpene lactone composition and the compatibility vein anticoagulation of razaxaban, Yi Dushaban become apparent from.This may
Smaller with the clinical daily dose of Eliquis, drug mixing is uneven related.
3) the vein anticoagulation of ginkgoterpene lactone composition and husky class class compatibility of drugs is better than ginkolide B and husky class class
The vein anticoagulation of compatibility of drugs.
Claims (12)
1. a kind of use of ginkgoterpene lactone composition in the drug of preparation prevention and/or treatment venous thromboembolic disease
On the way.
2. purposes according to claim 1, wherein the ginkgoterpene lactone composition includes Bilobalide and ginkgo diterpene
Lactone；The ginkgo diterpenoid-lactone includes ginkalide A, ginkolide B, ginkalide C, bilobalide J, bilobalide K, silver
One of apricot lactone L, ginkgolides M, ginkgolides N, ginkgolides Q are two or more.
3. purposes according to claim 2, wherein in the ginkgoterpene lactone composition in Bilobalide and ginkgo diterpene
Mass ratio between ester each component is (1:8)~(8:1).
4. described in any item purposes according to claim 1~3, wherein the ginkgoterpene lactone composition be mass ratio be (1~
4):(1~4):Bilobalide, ginkolide B and the ginkalide C of (4~1)；Or the composition be mass ratio be (1~
8):(1~8):(1~4):Bilobalide, ginkalide A, ginkolide B and the ginkalide C of (1~8).
5. described in any item purposes according to claim 1~3, wherein being comprising mass ratio in the ginkgoterpene lactone composition
(1~2):1 Bilobalide and ginkolide B.
6. a kind of composition containing ginkgoterpene lactone and Sha Ban class drug, wherein the ginkgoterpene lactone include Bilobalide and
Ginkgo diterpenoid-lactone；The ginkgo diterpenoid-lactone includes ginkalide A, ginkolide B, ginkalide C, bilobalide J, ginkgo
One of lactone K, ginkgolides L, ginkgolides M, ginkgolides N, ginkgolides Q are two or more.
7. composition according to claim 6, wherein Bilobalide and ginkgo diterpene in the ginkgoterpene lactone composition
Mass ratio between lactone each component is (1:8)~(8:1).
8. composition according to claim 6 or 7, wherein it is (1~4) that the ginkgoterpene lactone composition, which is mass ratio,:
(1~4):Bilobalide, ginkolide B and the ginkalide C of (4~1)；Or it is (1~8) that the composition, which is mass ratio,:
(1~8):(1~4):Bilobalide, ginkalide A, ginkolide B and the ginkalide C of (1~8).
9. composition according to claim 6 or 7, wherein be comprising mass ratio in the ginkgoterpene lactone composition (1~
2):1 Bilobalide and ginkolide B.
10. according to the described in any item compositions of claim 6-9, wherein the quality of the ginkgoterpene lactone and husky class class drug
Than being (5:6)~(20:1).
11. the described in any item compositions of claim 6-10 are in preparation prevention and/or treat venous thromboembolic disease
Purposes in drug.
12. purposes described according to claim 1~any one of 5 and claim 11, wherein the venous thrombo-embolic
Disease includes vein caused by deep-vein thrombosis embolism, pulmonary embolism, congestive heart failure, fracture and major surgery
Thromboembolism, the major surgery include joint replacement.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020207398A1 (en) * | 2019-04-10 | 2020-10-15 | 成都百裕制药股份有限公司 | Use of ginkgo terpene lactone in preparing drug for preventing and/or treating guillain-barré-strohl syndrome |
| CN111803487A (en) * | 2019-04-10 | 2020-10-23 | 成都百裕制药股份有限公司 | Application of ginkgolide in preparation of medicine for preventing and/or treating Guillain-Barre syndrome |
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| CN1887283A (en) * | 2006-07-26 | 2007-01-03 | 孙毅 | Medicine composition containing bailobalide |
| CN101011405A (en) * | 2007-01-09 | 2007-08-08 | 贵州信邦远东药业有限公司 | Pharmaceutical composition for treating ischemic cerebral vascular disease |
| EP2494979A1 (en) * | 2011-03-04 | 2012-09-05 | Dr. Willmar Schwabe GmbH & Co. KG | Use of ginkgo biloba leaf extract to prevent and treat complications following arteriosclerosis surgery and reappearance of arteriosclerosis |
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| WO2020207398A1 (en) * | 2019-04-10 | 2020-10-15 | 成都百裕制药股份有限公司 | Use of ginkgo terpene lactone in preparing drug for preventing and/or treating guillain-barré-strohl syndrome |
| CN111803487A (en) * | 2019-04-10 | 2020-10-23 | 成都百裕制药股份有限公司 | Application of ginkgolide in preparation of medicine for preventing and/or treating Guillain-Barre syndrome |
| CN111803487B (en) * | 2019-04-10 | 2022-12-02 | 成都百裕制药股份有限公司 | Application of ginkgolide in preparation of medicine for preventing and/or treating Guillain-Barre syndrome |
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| CN108926556B (en) | 2022-07-05 |
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