CN108926556B - Composition containing ginkgolide and medical application thereof - Google Patents
Composition containing ginkgolide and medical application thereof Download PDFInfo
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Abstract
The invention relates to application of a ginkgolide composition in preparation of a medicament for preventing and/or treating venous thromboembolic diseases. The invention also relates to a composition containing the ginkgolide and the sapanban medicaments, and application of the composition in preparing medicaments for preventing and/or treating venous thromboembolic diseases. The ginkgolide composition and the composition containing ginkgolide and sapanban medicaments provided by the invention can effectively resist venous thrombosis (anticoagulation and improve blood components) and treat related diseases related to venous thromboembolism, expand the application range of ginkgolide compounds, and provide a new choice with lower bleeding risk, proper price, exact curative effect, safety, reliability and convenience in use for the treatment of venous thrombosis.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to application of a ginkgolide composition in preparing a medicament for preventing and/or treating venous thromboembolic diseases; the invention also relates to a composition containing the ginkgolide and the sapanban medicaments, and application of the composition in preparing medicaments for preventing and/or treating venous thromboembolic diseases.
Background
With the gradual introduction of China into the aging society, the incidence of diseases such as cardiovascular and cerebrovascular diseases, deep venous embolism and the like related to thrombosis is gradually increased year by year, and the disease becomes a main factor threatening the health of middle-aged and old people in China.
Thrombosis is in particular a blood clot formed in the lumen of the vascular system. The mechanism of thrombosis is very complex, and many problems still need to be elucidated at present. The three-element hypothesis proposed by Virchow in the middle of the 18 th century briefly summarizes the pathogenesis of thrombosis, and the practical significance of the hypothesis is not lost until now after the modern scientific connotation is given. The theory holds that vascular wall (endothelium) damage, changes in the blood flow pattern (hemodynamics) and changes in blood composition (platelets, coagulation factors, anticoagulation factors, fibrinolysis and antifibrinolysis factors) are essential factors for thrombus formation. The roles and the occupation positions of three factors in the venous thrombosis and the arterial thrombosis are different, the relationship between vascular endothelial injury and platelet activation and the arterial thrombosis is closer, and the significance of blood flow stasis and the change of plasma coagulation related factors in the venous thrombosis is more prominent. Platelets play an important role in both the primary hemostasis stage and the initial stage of thrombosis in an artery. Therefore, platelet inhibitors (i.e., antiplatelet activating factor (PAF) agents) are mainly used for the prevention and treatment of arterial thrombotic diseases. Whereas treatment of venous thrombotic disease is achieved primarily by anticoagulation. In the venous coagulation cascade, a serine endopeptidase known as factor Xa (also known as Stuart-pro factor) plays a very important role in several stages. Clinical practice has shown that various drugs can inhibit factor Xa activity to various degrees.
The main drugs currently used for treating arterial thromboembolic diseases are: thrombolytic drugs (rt-PA), vascular endothelial protective drugs (e.g., statins), anti-platelet aggregation drugs (e.g., aspirin, clopidogrel), fibrinolytic drugs (e.g., tirofiban), and fiber-degrading drugs (e.g., urokinase). The drugs for treating venous thromboembolic diseases are mainly anticoagulant drugs, such as traditional drugs of low molecular weight heparin, enoxaparin, warfarin and the like, and new generation of sapanban drugs only aiming at the Xa factor inhibition pathway: rivaroxaban, apixaban, edoxaban, and the like. Although the saproban medicines have a better anticoagulation effect clinically, the saproban medicines still face the problems of high bleeding risk, high liver and kidney toxicity, high use cost and the like.
Disclosure of Invention
The invention provides the following technical scheme for solving the problems:
use of ginkgolide composition in preparing medicine for preventing and/or treating venous thromboembolic disease is provided.
Preferably, the ginkgolide composition comprises bilobalide and ginkgolide.
Preferably, the ginkgolide comprises one or more of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide K, ginkgolide L, ginkgolide M, ginkgolide N and ginkgolide Q.
More preferably, the ginkgo diterpene lactone is selected from the group consisting of ginkgolide a, ginkgolide B and ginkgolide C.
More preferably, the ginkgolide is ginkgolide B, or the ginkgolide is ginkgolide B and ginkgolide C, or the ginkgolide is ginkgolide A, ginkgolide B and ginkgolide C.
Preferably, the mass ratio of the bilobalide to the ginkgolide in the ginkgolide composition is (1:8) - (8: 1).
Preferably, the ginkgolide composition is bilobalide, ginkgolide B and ginkgolide C in a mass ratio of (1-4): 4-1; or the composition comprises bilobalide, ginkgolide A, ginkgolide B and ginkgolide C in a mass ratio of (1-8) to (1-4) to (1-8).
Preferably, the ginkgolide composition comprises bilobalide and ginkgolide B in a mass ratio of (1-2): 1.
The invention also provides a composition containing ginkgo terpene lactones and sapanban drugs, wherein the ginkgo terpene lactones comprise ginkgo diterpene lactones and bilobalide.
Preferably, the ginkgolide comprises one or more of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide K, ginkgolide L, ginkgolide M, ginkgolide N and ginkgolide Q.
More preferably, the ginkgolide is selected from the group consisting of ginkgolide a, ginkgolide B and ginkgolide C.
More preferably, the ginkgolide is ginkgolide B, or the ginkgolide is ginkgolide B and ginkgolide C, or the diterpene ginkgolide is ginkgolide A, ginkgolide B and ginkgolide C.
Preferably, the mass ratio of the bilobalide to the ginkgolide in the ginkgolide composition is (1:8) - (8: 1).
Preferably, the ginkgolide composition is bilobalide, ginkgolide B and ginkgolide C in a mass ratio of (1-4): 4-1; or the composition comprises bilobalide, bilobalide A, bilobalide B and bilobalide C in a mass ratio of (1-8) to (1-4) to (1-8).
Preferably, the ginkgolide composition comprises bilobalide and ginkgolide B in a mass ratio of (1-2): 1.
Preferably, the saproban-like drug comprises one or more of rivaroxaban, apixaban, edoxaban, otamixaban, rasxaban and pharmaceutically acceptable salts, hydrates and solvates thereof.
Preferably, the saproban medicine is selected from one or more of rivaroxaban, apixaban and edoxaban, and more preferably, the saproban medicine is rivaroxaban or edoxaban. .
Preferably, the mass ratio of the ginkgolide to the saban medicines is (5:6) - (20: 1).
The invention also provides application of the composition containing the ginkgolide and the sapanban medicaments in preparing medicaments for preventing and/or treating venous thromboembolic diseases.
Preferably, the venous thromboembolic disorders of the present invention include deep vein thromboembolism, pulmonary embolism, congestive heart failure, bone fractures, and venous thromboembolism as a result of major surgical procedures, including joint replacement procedures.
The structure of the ginkgolide is composed of 6 oxygen-rich five-membered rings (including a spiro [4.4] -nonane ring, a tetrahydrofuran ring and three lactone rings), 10-12 stereocenters and a special tert-butyl group. The isolated ginkgolides differ only in the number and position of hydroxyl groups in structure. The bilobalide comprises three lactone rings, a tertiary butyl ring and an all-carbon ring, and belongs to sesquiterpene lactone.
The Saxaban drugs are blood coagulation factor Xa inhibitors, wherein the factor Xa is a key regulatory factor in blood coagulation cascade reaction and can promote the formation of venous thrombosis.
The ginkgolide composition and the composition containing ginkgolide and sapanban medicaments provided by the invention can effectively resist venous thrombosis (anticoagulation and improve blood components) and treat related diseases related to venous thromboembolism, expand the application range of ginkgolide compounds, and provide a new choice with lower bleeding risk, proper price, exact curative effect, safety, reliability and convenience in use for the treatment of venous thrombosis.
Detailed Description
Example 1 anticoagulant effect of ginkgolide composition on rabbit traumatic limb deep vein thrombosis model
Materials and methods
1.1 Experimental animals
The I-grade Japanese big ear white rabbit is 500 rabbits (4 rabbits for standby), the weight is 2.0-3.0 kg during the test, and the rabbit is all male.
1.2 Experimental drugs
Bilobalide, bilobalide A, bilobalide B, bilobalide C and bilobalide composition 1-24, and the detailed formula is as follows:
TABLE 1 detailed composition table of ginkgolide formulation
1.3 reagents and instruments
The instrument comprises the following steps:
(1) rabbit weighing and checking instrument
The ACS-15LED electronic platform scale has a resolution value of 1g, a maximum weight of 6kg, an instrument number of BKY-YB-002, is produced by Shanghai eagle brand weighing apparatus Limited company and is used for weighing the weight of the rabbit.
(2) Pathological examination instrument
Electronic balance model BS124S, Sartorius germany (index: 0.0001g), instrument number: BKY-TJ-002, manufactured by Sartorius, Inc., Germany.
ZT-14V2 biological tissue automatic dehydrator, instrument number: BKY-BL-016, produced by Sudoku medical electronics Limited in Xiaogan City.
Wuzhongwei BMJ-iii embedding machine, instrument number: BKY-BL-002, available from Wei electronics factories in Changzhou city, Jiangsu province.
The PHY-III pathological tissue bleaching and drying instrument in Changzhou is numbered as follows: BKY-BL-003, available from Wei electronics industries, Changzhou, Jiangsu province.
Laika RM2126 rotary slicer, instrument number: BKY-BL-004, available from Shanghai come instruments Co., Ltd.
Olympus BX41-32P01 microscope, Japan, Instrument No.: BKY-BL-013, available from Olympus corporation, Japan.
YR-21 biological tissue automatic dyeing machine, instrument number: BKY-BL-015, produced by Xiangan medical electronic technology Limited in Mingxian City.
Beijing Yongguanming 202-0 type desk type drying box, the instrument number: BKY-BL-005, available from Yongguang medical instruments and instruments, Beijing.
Reagent:
(1) reagent for preparing test solution
Carboxymethyl cellulose, lactose and mannitol.
(3) Anesthetic agent
Pentobarbital sodium for rabbit anesthesia. The application method comprises preparing 3% sodium pentobarbital with purified water. A3% sodium pentobarbital solution (g/v) was prepared. Is used for anaesthetizing rabbits during molding.
1.4 Molding
496 numbers of Japanese big-ear white rabbits qualified in quarantine and adaptability observation are selected for molding, the weight of the rabbits is 2.0-3.0 kg, the rabbits are all male, firstly 8 numbers of the rabbits are selected as normal groups, the rest of the rabbits are all beating devices, the diameter of a beating contact circular surface is 1.5cm, the wound energy is calculated according to Ep-mgh, and the energy of an iron rod per beating is 7.5J. The specific method comprises the following steps: injecting 3% sodium pentobarbital 1ml/kg intravenously to rabbit ear margin for anesthesia, placing the root of left thigh on a striking platform at right prone position, touching and cleaning left femur greater trochanter of rabbit, tightly attaching the striking head plane to the femur greater trochanter within 1.5cm below the greater trochanter, striking the outer side of the near end of rabbit thigh by using a self-made striking device, fixing left lower limb by plaster at hip bending and knee bending position, checking that right hip moves freely when applying plaster bandage, treating prone position for shaping plaster, making animal drinking water freely after molding, feeding pellet feed, and not using anticoagulant and antibiotic.
1.5 grouping and administration
1.5.1 Process for preparing medicine
Drug (mg): carboxypropyl methylcellulose (mg): lactose (mg): grinding mannitol (mg) to be 1:2:10:20 uniformly, adding 1ml of purified water, and stirring uniformly to obtain the finished product. Examples are: 50mg of the medicine, 100mg of the carboxymethyl cellulose, 500mg of the lactose and 1000mg of the mannitol are uniformly ground, 50ml of water is added, and the mixture is uniformly stirred to obtain 1mg/ml liquid medicine.
1.5.2 dosing regimens
Animals successfully molded were divided into groups of 8 animals each, and the administration was gavaged according to the administration schedule shown below for 14 days with 2 administrations per day.
TABLE 2 animal model of deep vein thrombosis dosing regimen
1.6 deep vein thrombosis assay
The animals are killed by bleeding 30min after the last administration, femoral veins are cut, HE staining is carried out, the conditions of vascular endothelial injury, thrombosis, vascular rupture and the like are examined by optical microscopy, the lesion degrees are graded and scored, and the detailed scoring standard is shown in the table below.
TABLE 3 Scoring standard for pathological degree of deep venous thrombosis histopathological examination
1.7 statistical treatment
The deep vein thrombosis measurement data is grade data, and statistical analysis is carried out by adopting software SPSS13.0 'nonparametric test' of 'a plurality of independent samples'.
Study results and conclusions analysis
TABLE 4 influence of intragastric administration of test substances on pathological histological changes of femoral vein of rabbit traumatic limb deep vein thrombosis model
Note: compared to the model group, # P <0.05, # P <0.01, # P < 0.001.
The research result shows that:
1) composition 24(8:8:4:8, i.e. 2:2:1:2) was the most anticoagulant and had the most balanced protective effects on endothelial cells, vascular integrity and thrombosis, the best formulation in each group of this experiment, followed by composition 15(4:0:4:1), composition 10(2:0:2:2) and composition 19(4:8:2:8, i.e. 2:4:1: 4).
2) The data and the formula are analyzed to find that: the anticoagulant effect of the composition is better when the ratio of the bilobalide to the ginkgolide is 2:1 and 1: 1.
3) The subsequent experiments were therefore carried out with bilobalide: the ginkgolide B is represented by 2:1 and 1:1, and is subjected to experimental study with a sandban medicament.
Example 2 anticoagulant Effect of Ginkgo terpene lactones and Salban pharmaceutical composition on rabbit traumatic limb deep vein thrombosis model
Materials and methods
2.1 Experimental animals and modeling method
Same as example 1
2.2 Experimental drugs and dosing regimens
1:1 bilobalide and ginkgolide, 2:1 bilobalide: bilobalide B, rivaroxaban, apixaban, edoxaban and combinations thereof.
Because the rivaroxaban, apixaban and edoxaban are different in human body clinical recommended dose, refer to the description: rivaroxaban daily clinical recommended dose: 10 mg; the daily clinical recommended dose of apixaban: 2.5mg and edoxaban maximum clinically recommended dose: 60 mg/day, the clinically recommended dose of the combination drug is converted to the equivalent dose.
The administered doses are shown in Table 5 below
2.3 reagents and instruments
Same as example 1
2.4 Molding
Same as example 1
2.5 grouping and administration
2.5.1 Process for preparing medicine
Same as example 1
2.5.2 dosing regimens
See Table 5 above
2.6 deep vein thrombosis assay
Same as example 1
2.7 statistical treatment
The same as in example 1.
Study results and conclusions analysis
TABLE 6 influence of gastric lavage of test samples on pathological histological changes of femoral artery and femoral vein of rabbit traumatic limb deep vein thrombosis model
Note: compared to the model group, # P <0.05, # P <0.01, # P < 0.001.
The research result shows that: the Xa factor inhibitor sapanban drugs represented by rivaroxaban, apixaban and edoxaban have strong anticoagulation effect, have obvious treatment effect on rabbit traumatic deep vein thrombosis model, and cannot obtain clinical treatment effect of combined application of the ginkgolide composition and sapanban.
Therefore, experiments are directly carried out by halving each dosage to explore the influence of each formula on the formation of the rabbit traumatic limb deep vein thrombosis, and the rest are the same.
TABLE 7
The results of the study are shown in table 8 below:
the research result shows that:
1) the ginkgolide composition is compatible with rivaroxaban, apixaban and edoxaban, and has a synergistic effect on intravenous anticoagulation.
2) The ginkgo terpene lactone composition has more obvious vein anticoagulation effect with rivaroxaban and edoxaban. This may be associated with a smaller clinical daily dose of apixaban and uneven drug mixing.
3) The intravenous anticoagulation effect of the ginkgolide composition and the sapanban medicaments is superior to that of the ginkgolide B and the sapanban medicaments.
Claims (13)
1. Use of a ginkgolide composition in the preparation of a medicament for the prevention and/or treatment of venous thromboembolic diseases, wherein the ginkgolide composition comprises bilobalide and ginkgolide B in a mass ratio of 2: 1.
2. The use of claim 1, wherein the ginkgo terpene lactone composition comprises bilobalide and ginkgo diterpene lactone; the bilobalide comprises one or more of bilobalide A, bilobalide B, bilobalide C, bilobalide J, bilobalide K, bilobalide L, bilobalide M, bilobalide N and bilobalide Q.
3. The use according to claim 2, wherein the mass ratio between the components of bilobalide and ginkgolide in the ginkgolide composition is (1:8) - (8: 1).
4. Use according to any one of claims 1 to 3, wherein the ginkgolide composition is bilobalide, ginkgolide B and ginkgolide C in a mass ratio of (1-4): (4-1); or the composition comprises bilobalide, bilobalide A, bilobalide B and bilobalide C in a mass ratio of (1-8) to (1-4) to (1-8).
5. Use of a composition comprising ginkgo terpene lactones and ginkgo diterpene lactones for the manufacture of a medicament for the prevention and/or treatment of venous thromboembolic disorders, wherein said ginkgo terpene lactones comprise bilobalide and ginkgo diterpene lactones; the ginkgolide comprises one or more of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide K, ginkgolide L, ginkgolide M, ginkgolide N and ginkgolide Q, wherein the ginkgolide composition comprises bilobalide and ginkgolide B in a mass ratio of 2: 1.
6. The use according to claim 5, wherein the mass ratio between the components of bilobalide and ginkgolide in the ginkgolide composition is (1:8) - (8: 1).
7. The use of claim 5 or 6, wherein the ginkgolide composition is bilobalide, ginkgolide B and ginkgolide C in a mass ratio of (1-4): (4-1); or the composition comprises bilobalide, bilobalide A, bilobalide B and bilobalide C in a mass ratio of (1-8) to (1-4) to (1-8).
8. The use according to claim 5, wherein the mass ratio of the ginkgolides to the sapanban drug is (5:6) - (20: 1).
9. The use of any one of claims 1-3, wherein the venous thromboembolic disorder comprises deep vein thromboembolism, pulmonary embolism, congestive heart failure, bone fractures, and venous thromboembolism as a result of major surgical procedures, including joint replacement procedures.
10. The use of claim 4, wherein the venous thromboembolic disorder comprises deep vein thromboembolism, pulmonary embolism, congestive heart failure, bone fractures, and venous thromboembolism from major surgical procedures, including joint replacement procedures.
11. The use of claim 5 or 6, wherein the venous thromboembolic disorder comprises deep vein thromboembolism, pulmonary embolism, congestive heart failure, bone fractures, and venous thromboembolism as a result of major surgical procedures, including joint replacement procedures.
12. The use of claim 7, wherein the venous thromboembolic disorder comprises deep vein thromboembolism, pulmonary embolism, congestive heart failure, bone fracture, and venous thromboembolism as a result of large surgical procedures including joint replacement procedures.
13. The use of claim 8, wherein the venous thromboembolic disorder comprises deep vein thromboembolism, pulmonary embolism, congestive heart failure, bone fractures, and venous thromboembolism from major surgical procedures, including joint replacement procedures.
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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 |
| 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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| 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 |
| CN102302525A (en) * | 2011-09-02 | 2012-01-04 | 黑龙江珍宝岛药业股份有限公司 | Gingko leaf composition and preparation method thereof |
| 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 |
| CN105561310A (en) * | 2014-10-30 | 2016-05-11 | 成都百裕科技制药有限公司 | Pharmaceutical composition containing ginkgolide B and factor Xa inhibitor and preparation method and application of pharmaceutical composition |
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- 2017-05-23 CN CN201710370698.XA patent/CN108926556B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN102302525A (en) * | 2011-09-02 | 2012-01-04 | 黑龙江珍宝岛药业股份有限公司 | Gingko leaf composition and preparation method thereof |
| CN105561310A (en) * | 2014-10-30 | 2016-05-11 | 成都百裕科技制药有限公司 | Pharmaceutical composition containing ginkgolide B and factor Xa inhibitor and preparation method and application of pharmaceutical composition |
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