CN110974794B - Apixaban and clopidogrel pharmaceutical composition and preparation method thereof - Google Patents

Apixaban and clopidogrel pharmaceutical composition and preparation method thereof Download PDF

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CN110974794B
CN110974794B CN201911372191.3A CN201911372191A CN110974794B CN 110974794 B CN110974794 B CN 110974794B CN 201911372191 A CN201911372191 A CN 201911372191A CN 110974794 B CN110974794 B CN 110974794B
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apixaban
clopidogrel
pharmaceutical composition
prescription
platelet aggregation
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CN110974794A (en
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赵军军
孙长安
钟春华
李孝壁
宗书敏
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Changzhou Hengbang Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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Abstract

The invention provides an apixaban and clopidogrel pharmaceutical composition and a preparation method thereof. In particular to a drug combination containing apixaban, which contains apixaban and clopidogrel as an anti-platelet aggregation drug. The invention also provides a preparation method and application of the pharmaceutical composition. In the composition, clopidogrel and apixaban can play a role in synergy, and compared with the sole use of apixaban or clopidogrel drugs, the clopidogrel-containing composition has the advantages of increased platelet aggregation inhibition capability, enhanced activity of resisting Xa factors, greatly improved antithrombotic capability, small side effect and clinical application prospect.

Description

Apixaban and clopidogrel pharmaceutical composition and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of apixaban and clopidogrel and a preparation method thereof.
Background
Apixaban, as an oral selective activated factor Xa inhibitor, is a variant of Lei Zasha class, developed by feverfew in combination with beverfew, is approved by the european union in 3 months 2011 and approved by the FDA in 12 months 2012 to be marketed in the united states, and obtains imported drug licenses issued by the national food and drug administration in 2013 and marketed in china. Apixaban is useful for the prevention of thrombosis in patients who have undergone hip or knee replacement surgery. However, in clinical trial studies it was found that in patients with acute coronary syndrome, investigators observed a trend towards increased dose-dependent bleeding events and decreased ischemic events with apixaban in addition to antiplatelet therapy. The safety and efficacy of apixaban may depend on the underlying antiplatelet therapy.
Platelet aggregation is a key link in the normal blood coagulation mechanism, and the adhesion, aggregation and release reactions of platelets often cause thrombosis. Therefore, drugs that inhibit platelet aggregation play an important role in the treatment of thrombotic diseases. Clopidogrel bisulfate (trade name: bolivix, plavix) is an anti-platelet aggregation drug developed by Sanofi-Aventis, france in 1986, which inhibits platelet aggregation by selectively and irreversibly inhibiting the binding of Adenosine Diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the gpiib/iiia complex. In addition, clopidogrel can also block platelet activation and amplification caused by ADP release, thereby inhibiting platelet aggregation induced by other agonists. The composition is clinically suitable for treating atherosclerosis and acute coronary syndrome, and preventing restenosis and thrombotic complications after coronary stent implantation.
Apixaban is a factor Xa inhibitor, clopidogrel is an anti-platelet aggregation drug, and the two drugs act on different stages of thrombosis respectively. Therefore, the two medicines can play a certain synergistic effect when being simultaneously administered, and become a safer and more effective antithrombotic medicine.
Disclosure of Invention
The invention aims to prepare the medicinal composition of apixaban and clopidogrel, so that the medicinal composition has more remarkable anti-platelet aggregation activity, anti-Xa factor activity and higher antithrombotic capacity, and a patient can select a safer and more effective medicament.
The antithrombotic activity of the apixaban and clopidogrel medicinal composition prepared by the invention is obviously higher than that of the apixaban or clopidogrel which is singly used, and the dosage of the apixaban can be obviously reduced, and the bleeding side effect caused by the apixaban can be reduced.
In one aspect, the present invention is directed to a pharmaceutical composition comprising apixaban and clopidogrel.
Preferably, the weight ratio of apixaban to clopidogrel is 1:2-1:7, preferably 1:2-1:5, more preferably 1:3.
More preferably, the medicinal composition of apixaban and clopidogrel further comprises one or two of mannitol or lactose, preferably further comprises mannitol and lactose;
wherein the weight ratio of mannose to lactose is 1:3-3:1, preferably 1:2-2:1, more preferably 1:1.
Further preferred is that the apixaban and clopidogrel pharmaceutical composition further comprises one or more of a diluent, a disintegrant, a binder, a lubricant or a surface ion active agent.
Wherein,
the diluent is selected from one or more of anhydrous lactose, microcrystalline cellulose, mannitol, pregelatinized starch, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, sorbitol or corn starch; preferably one or more of anhydrous lactose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate, sorbitol, or corn starch; more preferably one or more of anhydrous lactose, microcrystalline cellulose or mannitol; further preferred is a mixture of microcrystalline cellulose and mannitol.
The disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl cellulose, crospovidone or dry starch; preferably one or more of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl cellulose or crospovidone; further preferred is one or more of croscarmellose sodium, sodium carboxymethyl starch, or crospovidone.
The adhesive is selected from one or more of hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol or hydroxypropyl methylcellulose; preferably one or more of hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose or polyvinylpyrrolidone; further preferably one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyvinylpyrrolidone.
The lubricant is selected from one or more of stearic acid, magnesium stearate, talcum powder, superfine silica gel powder, glyceryl stearate or glyceryl behenate; preferably one or more of magnesium stearate, glyceryl stearate or glyceryl behenate; further preferred are one or both of magnesium stearate and glyceryl behenate.
The surfactant is selected from one or more of sodium dodecyl sulfate, tween 80 or poloxamer; preferably tween 80.
In a further preferable scheme, in the apixaban and clopidogrel pharmaceutical composition, the content of the apixaban and the clopidogrel in the pharmaceutical composition is 15-30% by weight, preferably 20-30% by weight, and more preferably 24% by weight.
The diluent is present in the pharmaceutical composition in an amount of 30-70% by weight, preferably 40-60% by weight, more preferably 50% by weight.
The content of disintegrant is 5-15%, preferably 8-15%, more preferably 12% by weight of the pharmaceutical composition.
The binder is present in the pharmaceutical composition in an amount of 5-15%, preferably 5-10%, more preferably 8% by weight.
The lubricant is present in an amount of 2-10%, preferably 2-6%, more preferably 4% by weight of the pharmaceutical composition.
The surfactant is 1-3 wt%, preferably 1-2 wt%, and more preferably 2 wt% of the pharmaceutical composition.
On the other hand, the invention aims to provide a preparation method of the apixaban and clopidogrel pharmaceutical composition, which comprises the following specific steps:
(1) Adding the adhesive into water, and stirring to dissolve;
(2) Stirring and mixing apixaban, clopidogrel, diluent, disintegrant and surface ionic active agent;
(3) Adding a binding agent into the step (2), granulating, finishing granules, adding a lubricating agent, mixing and tabletting;
(4) Optionally, a coating step is also included.
The preferable scheme is that the preparation method of the apixaban and clopidogrel pharmaceutical composition comprises the following specific steps:
(1) Sieving the adhesive with a 60-mesh sieve for later use;
(2) Adding the adhesive into water, stirring and dissolving until the mixture is clear and transparent;
(3) Adding the formula amount of apixaban, clopidogrel, diluent, disintegrant and surface ion active agent into a mixing granulator, and mixing at the rotating speed of a stirring paddle of 120rpm for 900s;
(4) Adding the adhesive into the granulator in the step (3), wherein the rotating speed of a stirring paddle is 10rpm, and the rotating speed of a peristaltic pump is 500rpm;
(5) Carrying out dry granulation or wet granulation on the granules in the step (4);
(6) Granulating the granules obtained in the step (5), and then adding the granules into a boiling granulator for drying;
(7) Adding the intermediate obtained in the step (6) into a granulating machine for granulating;
(8) Adding the intermediate obtained in the step (7) into a hopper mixer, and adding a lubricant for mixing;
(9) Tabletting the intermediate obtained in the step (8) by using a conventional method;
(10) Optionally, a coating step is also included.
The pharmaceutical composition of the present invention is used for the treatment of thrombosis.
Detailed Description
1. Preparation of apixaban and clopidogrel pharmaceutical composition prescription
Prescription 1
Figure BDA0002339977130000041
Prescription 2
Figure BDA0002339977130000042
Prescription 3
Figure BDA0002339977130000043
Figure BDA0002339977130000051
Prescription 4
Figure BDA0002339977130000052
Prescription 5
Figure BDA0002339977130000053
Prescription 6
Figure BDA0002339977130000054
Figure BDA0002339977130000061
Prescription 7
Figure BDA0002339977130000062
Prescription 8
Figure BDA0002339977130000063
Prescription 9
Figure BDA0002339977130000064
Prescription 10
Figure BDA0002339977130000071
Prescription 11
Figure BDA0002339977130000072
Prescription 12
Figure BDA0002339977130000073
Prescription 13
Figure BDA0002339977130000074
Figure BDA0002339977130000081
Wherein, the preparation method of the composition with the prescription 1-13 is as follows:
(1) Sieving the adhesive with a 60-mesh sieve for later use;
(2) Adding the adhesive into water, stirring and dissolving until the mixture is clear and transparent;
(3) Adding the formula amount of apixaban, clopidogrel, diluent, disintegrant and surface ion active agent into a mixing granulator, and mixing at the rotating speed of a stirring paddle of 120rpm for 900s;
(4) Adding the adhesive into the wet granulator in the step (3), wherein the rotating speed of a stirring paddle is 10rpm, and the rotating speed of a peristaltic pump is 500rpm;
(5) Carrying out wet granulation on the granules in the step (4);
(6) Granulating the granules obtained in the step (5), and then adding the granules into a boiling granulator for drying;
(7) Adding the intermediate obtained in the step (6) into a granulating machine for granulating;
(8) Adding the intermediate obtained in the step (7) into a hopper mixer, and adding a lubricant for mixing;
(9) And (5) tabletting the intermediate obtained in the step (8) by using a conventional method.
2. Apixaban and clopidogrel in vitro anti-PAF induced platelet aggregation and influence on Xa activity
2.1 Experimental purposes:
and evaluating the PAF-induced platelet aggregation resistance and the influence on the Xa activity of the apixaban and clopidogrel medicinal composition in vitro by adopting a microplate enzyme-labeling instrument turbidimetry method.
2.2 materials and methods
2.2.1 Experimental animals
Japanese white rabbit, SPF grade, half male and female, body weight 2.2-2.5kg.
2.2.2 Experimental drugs
Pharmaceutical compositions prepared according to formulas 1-13.
2.3 reagents and instruments
2.3.1 Instrument:
electronic balance model BS124S in Sartorius germany (division value: 0.0001 g), instrument number: BKY-YB-001; ACS-15LED electronic platform scale, manufactured by Shanghai eagle brand weighing apparatus Limited, and numbered BKY-YB-002; the Changshan Xiangzhi DL-5M small vertical low-speed large-capacity refrigerated centrifuge has the following instrument numbers: BKY-ZX-040, changshan Intelligent centrifuge instruments ltd; haier DW-40L188 low-temperature storage box, instrument number: BKY-ZX-012, for preserving plasma, etc.; LSC-316C type star vertical showcase, instrument number: BKY-ZX-041, preservation reagent; multiskan MK3 model enzyme calibrator, instrument No.: BKY-ZX-014; wellwash 4MK2 plate washer, instrument No.: BKY-ZX-022; german Brand S, D-1000 micropipette, instrument number: BKY-ZX-036; german Brand S, D-100 micropipette, instrument number: BKY-ZX-038; MB-1830 model full-automatic blood analyzer, sichuan Meisheng science and technology Co., ltd, instrument number: BKY-ZX-023.
2.3.2 reagents:
3.8% sodium citrate (500 g/bottle, duyu Kelong chemical reagent factory, lot number: 20130601); platelet Activating Factor (PAF) (1 mg/count, sigma, lot number: P7568); hemagglutinating factor (Xa) assay reagent (chromogenic substrate method) (10X 71nkat, italy Chromogenix, lot No. N1243555); polyethylene glycol (PEG) 6000 (50 g, batch number: LB50P76, beijing Bailingwei science and technology Co., ltd.); heparin sodium (1 g/vial, bomei, lot number: 9041-08-1).
2.4 dose design and drug formulation methods
The dose and frequency of administration and method for each group are shown in table 1:
TABLE 1
Figure BDA0002339977130000091
Figure BDA0002339977130000101
2.5 measurement of platelet aggregation Rate
Collecting blood from animal heart puncture, anticoagulating with sodium citrate (3.8%) 1:9, centrifuging at 4 deg.C x 1000r/min for 10min, collecting Platelet Rich Plasma (PRP), centrifuging the rest at 3000r/min for 15min, collecting Platelet Poor Plasma (PPP), adjusting PRP to 200 + -50 x 10 using PPP 9 /L。
Adding 250 μ l of PRP into the small holes of the microplate, adding 10 μ l of the corresponding concentration drug, making two holes in parallel for each concentration, and finally adding 10 μ l of PAF polymerization agent (concentration is 0.38 μ g/ml); adding 250 μ l of PPP and 10 μ l of physiological saline into the blank control hole for zero adjustment; the vehicle control wells were zeroed by adding 250. Mu.l of PPP and 10. Mu.l of dimethyl sulfoxide. The absorbance was recorded at different times until the absorbance did not decrease any more. The time at this time is the time required for maximum aggregation of platelets, and the inhibition rate of platelets is calculated by the following formula:
aggregation inhibition = (time required for maximum aggregation in administration group-time required for maximum aggregation in blank control group)/time required for maximum aggregation in blank control group × 100%
2.6 testing the Activity of anti-coagulation factor Xa
Plasma anti-Xa activity was measured on a microplate reader using chromogenic substrate method according to the kit instructions and references.
2.7 statistical treatment
The test data are measured data, the aggregation inhibition rate and the anti-Xa activity are calculated according to corresponding calculation formulas, and the average is calculated by using Excel software.
2.8 results of the experiment
2.8.1 platelet aggregation test results
The experimental results of the in vitro PAF-induced platelet aggregation resistant effect of the apixaban and clopidogrel pharmaceutical composition are shown in Table 2:
TABLE 2
Figure BDA0002339977130000102
Figure BDA0002339977130000111
As can be seen from table 2, under the induction of PAF, the platelet aggregation rates of the pharmaceutical compositions of the respective prescriptions are greatly different from those of physiological saline, which indicates that the pharmaceutical compositions of the present invention can effectively inhibit platelet aggregation; however, compared with the apixaban or clopidogrel single medicinal composition, the medicinal composition of the apixaban and the clopidogrel has the advantage that the platelet aggregation resisting function is obviously improved, so that the synergistic effect of the joint use of the apixaban and the clopidogrel on the platelet aggregation resisting is realized.
2.8.2 results of the anti-blood coagulation factor Xa Activity test
The in vitro anti-blood coagulation factor Xa activity of the apixaban and clopidogrel pharmaceutical composition is shown in the table 3:
TABLE 3
Figure BDA0002339977130000112
Figure BDA0002339977130000121
The results in table 3 show that the anti-blood coagulation factor Xa activities of the combination formulas 1 to 13 are different from those of the normal saline group, which indicates that each pharmaceutical composition of the present invention can effectively inhibit the Xa activity and inhibit platelet aggregation; compared with the sole use of the apixaban or the clopidogrel drug, the invention obviously improves the activity of the in vitro anti-blood coagulation factor Xa when the apixaban and the clopidogrel drug are used together, which shows that the apixaban and the clopidogrel drug have synergistic effect when used together.
3. Determination of antithrombotic effect of apixaban-clopidogrel composition on rat inferior vena cava
3.1 drugs and reagents:
suspending the composition of formulas 1-13 with 1% of CMC-Na;
total protein assay kit, ningbo Kangmei Biotech Co., ltd product, batch number: 110991. the operation was performed as per the instructions.
3.2 animals
SD rats, supplied by Experimental animals technology, inc. of Weitonglihua, beijing.
3.3 instruments
VITALAB Selectra 2 model full-automatic biochemical analyzer, dutch Wildiagram science and technology company.
LD5-2A centrifuge, manufactured by Beijing medical centrifuge factory.
Sartorius electronic analytical balance, beijing sidoris balance ltd.
3.4 methods
Half of the male and female SD rats were randomly divided into 14 groups of 10 animals for each group as a control group and 1-13 groups for the prescription. Orally administering 5mg/kg for 7 days continuously, after 1 hour of the last administration, injecting 12% chloral hydrate (0.36 g/kg) into abdominal cavity of rat for anesthesia, fixing supine position, opening abdominal cavity along abdominal midline, exposing inferior vena cava, threading on main trunk part below renal vein branch of inferior vena cava, and sequentially ligating posterior vena cava such as third lumbar vein, left iliac lumbar vein, fourth lumbar vein, right spermatic cord internal vein (male) or right uterine vein (female), right iliac lumbar vein, etc. The main trunk of the inferior vena cava of the rat was ligated 1 hour after the administration to form a state of venous blood vessel stagnation. After the vein of the rat is ligated for 1.5h, the blood vessel is clamped at a position 2cm below the ligation position of the main trunk of the inferior vena cava, and the blood vessel is dissected to take out the thrombus. The thrombus surface blood was aspirated by a filter paper, weighed by an electronic balance, digested with 0.5N NaOH, and the thrombus base mass was measured, and the results are shown in Table 4.
TABLE 4
Group of Wet weight of thrombus (mg) Thrombus matrix weight (mg)
Physiological saline 47.81 5.31
Prescription 1 23.83 2.53
Prescription 2 29.35 3.16
Prescription 3 9.82 1.02
Prescription 4 10.53 1.23
Prescription 5 11.24 1.26
Prescription 6 10.90 1.17
Prescription 7 13.61 1.41
Prescription 8 14.87 1.62
Prescription 9 13.72 1.50
Prescription 10 15.02 1.62
Prescription 11 22.51 2.41
Prescription 12 20.94 2.23
Prescription 13 19.73 2.15
The results in table 4 show that the composition of the present invention has significant differences in antithrombotic effect relative to physiological saline, which indicates that the formulation of the present invention can inhibit the formation of thrombus to some extent, but compared with apixaban or a clopidogrel single pharmaceutical composition, the pharmaceutical composition of apixaban and clopidogrel has significantly improved antithrombotic effect, which indicates that the concomitant use of apixaban and clopidogrel has synergistic effect on antithrombotic effect.
From the experimental results, compared with the apixaban or the clopidogrel single pharmaceutical composition, the apixaban and clopidogrel pharmaceutical composition prepared by the invention has the advantages that the in-vitro anti-platelet aggregation effect is obviously enhanced, the activity of resisting Xa factors is obviously improved, the effect of resisting thrombosis is obviously improved, and the synergistic effect of the apixaban and the clopidogrel on resisting thrombosis is realized.

Claims (2)

1. A pharmaceutical composition comprising:
Figure FDF0000020350340000011
wherein the composition is for use in the treatment of thrombosis.
2. A method for preparing the pharmaceutical composition of claim 1, comprising the steps of:
(1) Adding polyvinylpyrrolidone into water, stirring and dissolving;
(2) Stirring and mixing apixaban, clopidogrel, mannitol, microcrystalline cellulose, sodium carboxymethyl starch and tween 80;
(3) Adding polyvinylpyrrolidone into the step (2), granulating, grading, adding magnesium stearate, mixing, and tabletting;
(4) Optionally, a coating step is also included.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107400131A (en) * 2017-08-24 2017-11-28 沈阳药科大学 Eliquis derivative and its production and use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107400131A (en) * 2017-08-24 2017-11-28 沈阳药科大学 Eliquis derivative and its production and use

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation;Renato D. Lopes等;《N Engl J Med》;20190317;第380卷;第1509-1524页 *
Apixaban+DAPT in Lowering Platelet Reactivity and Thrombin Generation (SEARCH);CirQuest Labs;《https://clinicaltrials.gov/ct2/history/NCT03746782?V_1=View#StudyPageTop》;20181120;第1-5页 *
Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits;P.C.WONG等;《Journal of Thrombosis and Haemostasis》;20081231;第6卷;第1736-1741页 *

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