CN101352436B - Novel medicament composition for resisting thrombosis - Google Patents
Novel medicament composition for resisting thrombosis Download PDFInfo
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- CN101352436B CN101352436B CN2008100489296A CN200810048929A CN101352436B CN 101352436 B CN101352436 B CN 101352436B CN 2008100489296 A CN2008100489296 A CN 2008100489296A CN 200810048929 A CN200810048929 A CN 200810048929A CN 101352436 B CN101352436 B CN 101352436B
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Abstract
The invention relates to a medical composition, in particular to a novel antithrombotic medical composition and a preparation method and a purpose thereof. The novel antithrombotic medical composition comprises ADP receptor antagonist with an effective dose of 25-500mg and Indobufen with an effective dose of 50-400mg. The invention reduces the spread effect to gastrointestinal tract and the severe bleeding probability that appears in the application of ticlopidine-aspirin composition and Clopidogrel-aspirin medical composition, more particularly reduces the bleeding incidence rate of the gastrointestinal tract, improves the medication compliance of patients and the clinical medication safety and healing efficiency and has favorable using value.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, specifically a kind of new antithrombotic pharmaceutical composition of forming by adp receptor antagonist, indobufen and one or more an amount of drug excipients and its production and use.
Background technology
The heart, cerebrovascular disease are the serious diseases that threatens human body health in the world today, and its sickness rate surpasses tumor and leaps to the first.Platelet aggregation has crucial effect in hemostasis and thrombosis, multiple material can cause hematoblastic activation and gathering by specific receptor separately, platelet aggregation causes that thrombosis is major reason (the Mills DCD.Thromb Haemost that cardiovascular and cerebrovascular disease takes place, 1996,76:835-856).Antithrombotic reagent commonly used in the market has aspirin, indobufen, ticlopidine, clopidogrel etc.
Take low-dosage aspirin (Aspirin for a long time; ASA; 75-100mg/d); there is the obstructive vascular events to comprise acute myocardial infarction (AMI) or Ischemic Stroke to those; stablize or unstable angina pectoris, old heart infarction or cerebral ischemia, the patient of peripheral arterial disease or atrial fibrillation has protective effect; can lower the generation again of cardiovascular event, reduce case fatality rate.But it is in fact, known to from arachidonic acid to prostaglandin with the plain A of the accumulative thromboxane of induced platelet
2(TXA
2) in the approach, the cox-2 inhibitors aspirin has played the effect of irreversible " suicide " inhibitor of the required Cycloxygenase of this approach.In addition, the life-time service aspirin produces the gastric mucosa infringement, significantly increased the risk of gastrointestinal hemorrhage, the danger of aspirin upper gastrointestinal hemorrhage in the antithrombotic agents weight range of 75-100mg/d increases twice, takes all indeterminable when this is any other means of employing such as enteric and feed.
Adenosine diphosphate (ADP) (ADP) be it is found that the earliest, also be the accumulative material of most important induced platelet in the body.Ticlopidine (Ticlopidine) and clopidogrel (Clopidogrel) belong to thienopyridine derivative together, be the platelet ADP receptor antagonist of French SANOFI company exploitation, it is by changing the interaction of platelet membrane and interference membrane fiber proteinogen, glycoprotein iib/iiia receptor on the blocking platelet film, inhibition reaches antiplatelet aggregative activity by ADP and the inductive platelet aggregation reaction of other platelet activating agents.
Ticlopidine the prevention cerebral infarction, treat angina pectoris, prevent and treat myocardial infarction and change aspect such as peripheral vascular occlusive disease evident in efficacy.But ticlopidine can cause neutrophilic granulocyte minimizing, thrombocytopenia, thrombotic thrombocytopenic purpura serious adverse such as (TTP), and has plenty of fatefulue.U.S. FDA is only ratified ticlopidine and is used for the invalid patient that maybe can not tolerate of aspirin, and the ticlopidine onset is slow in addition, is not suitable for the early treatment of ACS.Clopidogrel is higher 6 times than the anti-platelet activity of ticlopidine, and action intensity and toleration all are higher than ticlopidine, and its ADR is then little than ticlopidine.Clopidogrel is applied to treat restenosis and thrombotic complications etc. in arteriosclerosis disease, acute coronary syndrome, the prevention intracoronary stent implantation after-poppet clinically.
In order to be combined in the advantage that platelet aggregation inhibitor is imitated, report aspect aspirin associating ticlopidine, the treatments such as thrombosis of aspirin associating clopidogrel medication after prevention in-stent restenosis and thrombotic complications, percutaneous transluminal coronary angioplasty (PTCA) after the intracoronary stent implantation has abroad been arranged and obtained curative effect preferably, clopidogrel share aspirin and share aspirin surely with respect to thiophene chlorine pyrrole significant superiority is being arranged aspect safety and the toleration.
The combination of claimed ticlopidine of patent FR19750012084 (1978-12-17) and aspirin is as the application of platelet aggregation resistance of giving the blood dynamic effect; all much superior than independent ticlopidine on it is qualitative and quantitative, these results are proved to be by means of the study of pharmacy of being undertaken by mensuration ADP or collagen-induced platelet aggregation with the rejection capability of platelet aggregation qualitative correlation.Clinically, aspirin associating ticlopidine is used hematoblastic inhibitory action is strengthened, effect is fine in the thrombosis after percutaneous transluminal coronary angioplasty (PTCA), make the danger of formation, reconstructive vascular operation of patient's death, myocardial infarction, thrombosis all lower, compare with the aspirin group and descend 75%.
In patent WO9729753 (1997-8-21), a kind of pharmaceutical preparations composition that contains clopidogrel and aspirin is disclosed, for collagen-induced platelet aggregation, said composition has produced remarkable role in synergy, and the mechanism of the two synergistic function that underdrawed.Although but the compositions of clopidogrel and aspirin has the synergistic function of significant antiplatelet aggregation, but said composition does not still solve the TTP of clopidogrel merging than the risk of the easier recurrence of TTP of ticlopidine merging and the problem that the two is relevant to the gastrointestinal side reaction, therefore this method is not optimum, can not be as basic solution.And discovery such as McQuaid, the probability of aspirin (75mg) and clopidogrel (75mg) therapeutic alliance further having increased severe haemorrhage.Severe haemorrhage danger is significantly higher than arbitrary medicine list usefulness due to the two medicine couplings, and the advantages outweigh the disadvantages with the patient who inserts coronary artery bracket (especially bracket for eluting medicament) to acute coronary syndrome, then more harm than good in cardiovascular diseases's primary prevention.More than all these have all limited the application of the compositions compound preparation of clopidogrel and aspirin.
Summary of the invention
The objective of the invention is at above-mentioned the deficiencies in the prior art, and provide a kind of new antithrombotic pharmaceutical composition to people, it is to take GI irritation, the gastric mucosa infringement that produces in the process for a long time in order to solve aspirin, reduce the compositions of ticlopidine and aspirin and reduce the severe haemorrhage probability that pharmaceutical composition that chlorine adjoins Gray and aspirin occurs in application, particularly reduce the gastrointestinal hemorrhage incidence rate, improve the compliance of patient's medication, improve clinical drug safety.
Another object of the present invention provides this preparation of drug combination method and purposes.
Mention based on of the present invention being reported in the above-mentioned literary composition about the side effect in aspirin, ticlopidine, clopidogrel and the use in conjunction process thereof.In addition, using dosage also is the reason (aspirin 160 ~ 325mg/ day that causes that side effect increases; Ticlopidine is 500mg/ day; Clopidogrel is 75mg/ day).Can reduce its side effect separately so can infer the using dosage that reduces ticlopidine or clopidogrel.Therefore, guaranteeing to reduce clinical using dosage under the prerequisite of curative effect, be the effective way that reduces rate of side effects, and both guaranteed that the important channel that clinical efficacy reduces side effect made compound preparation exactly.In addition, in general roughly the same for mechanism of action but the also consistent medicine of clinical effectiveness that produces is used the relatively little medicine of one of them side effect instead with behind another drug combination, tend to produce the potentiation of collaborative or addition.
Indobufen (Indobufen) is the same with aspirin, be all antiplatelet drug, it can selectively act on the circulation platelet, blocking-up thrombosis, by influencing arachidonic acid metabolic, suppress platelet factor (as adenosine diphosphate (ADP), 5-hydroxy tryptamine, platelet factor 3,4 and β-thromoboglobulin etc.) release reaction that causes and bring into play antiplatelet aggregative activity, this inhibition is reversible, do not change plasma parameters, do not change the prostacyclin blood concentration, harmless platelet function, and make the normal platelet function of variation recover normal, also make endotheliocyte produce the blood vessel dilating effect simultaneously.The clinical using dosage of indobufen is 200-400mg/ day, be used to prevent thrombosis, be applicable to ischemic cerebrovascular, heart disease, peripheral blood vessel, phlebothrombosis, disorders of lipid metabolism, diabetes and the extracorporeal circulation patients such as (hemodialysis) that atherosclerosis causes.Indobufen can be brought into play than the more strong antiplatelet effects of aspirin, on auxiliary thromboembolism treatment, also more have superiority than aspirin, evidence, case fatality rate is more effective than aspirin in hospital improving urokinase fibrinolytic effect, the emerging ischemic event of prevention and minimizing for indobufen, and indobufen is with respect to aspirin, more can alleviating pain, the gastrointestinal stimulation is also reduced greatly.
Clinically, ticlopidine and clopidogrel are all used as the platelet ADP receptor antagonist.Elimination half-life (the t of ticlopidine
1/2 β) be 6 hours, the t of clopidogrel
1/2 βBe 7～8 hours, and the t of indobufen
1/2 βBe 6～7h.Can think that the half-life of ticlopidine and indobufen, clopidogrel and indobufen is suitable.Therefore confirming that the two share can produce synergism.
Consider that from the science and the reasonability of pharmaceutical compositions preparation we test by drug compatibility, proved these two groups of medicines of ticlopidine and indobufen, clopidogrel and indobufen this has the good compatibility on physical property and chemical.Therefore we will become pharmaceutical composition to the little indobufen of GI irritation, clopidogrel and an amount of drug excipient combined preparation, experimental results show that effect is fine.
In order to realize purpose of the present invention, the present invention by the following technical solutions: it comprises adp receptor antagonist and the effective dose that effective dose is 25-500mg is the indobufen of 50-400mg.
Wherein said adp receptor antagonist is ticlopidine, clopidogrel or they are at pharmaceutically acceptable salt.Ticlopidine chemistry 5-(2-chlorphenyl) methyl-4,5,6 by name, the 7-Tetramethylene sulfide is [3,2-c] pyridine also.Clopidogrel chemistry (S)-α by name-(2-chlorphenyl)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H) methyl acetate also.
The present invention's technical scheme preferably is: it comprises ticlopidine and the effective dose that effective dose is 50-200mg is the indobufen of 100-300mg.Optimized technical scheme is that to comprise clopidogrel and the effective dose that effective dose is 25-75mg be the indobufen of 100-300mg.
Wherein said pharmaceutically acceptable salt is: hydrochlorate, sulfate, tartrate, acetate, benzoate, fumarate, maleate, citrate, 2,5-resorcylic acid salt, mesylate, esilate, benzene sulfonate, tosilate, camsilate, lauryl sulfonate, Dobesilate or hydrobromate.
The present invention also comprises one or more in amylum pregelatinisatum, β-Lactis Anhydrous, silica sol, microcrystalline Cellulose, castor oil hydrogenated, mannitol, polyethylene glycol 6000, hydroxypropyl cellulose, sodium carboxymethyl cellulose, Pulvis Talci, magnesium stearate or the gelatin.
We are surprised to find in pharmacological evaluation, with indobufen and clopidogrel combination, have obtained the beneficial effect that we want.The compositions of indobufen and clopidogrel has good platelet aggregation inhibitory action and thrombosis inhibitory action, the summation of the effect when the anticoagulant effect when particularly finding indobufen and clopidogrel combined administration is used respectively than these two kinds of components is good, promptly between this two component synergistic function is arranged.Zoopery shows that the compositions of indobufen and clopidogrel prolongs obviously (compare with clopidogrel, the identical tail bleeding time, used drug dose reduced) to the mouse tail bleeding time.
But we are by further pharmacological evaluation, indobufen of the present invention and clopidogrel pharmaceutical composition are to antiplatelet aggregation and thrombotic inhibitory action, suitable with the pharmaceutical composition of aspirin and clopidogrel to the inhibitory action of platelet aggregation, and there was no significant difference.
In addition, we also find, pharmaceutical composition of the present invention, under the prerequisite that guarantees curative effect, reduce the dosage of indobufen and these two kinds of active component of clopidogrel, platelet aggregation and thrombosis are had good inhibition effect with sample, and the result also can reduce the side effect relevant with these active substances.
Animal acute toxicity experiment proves, the safety range of the pharmaceutical composition of indobufen and clopidogrel also is the pharmaceutical composition greater than aspirin and clopidogrel, and pharmaceutical composition of the present invention, the gastrointestinal zest is obviously reduced, the gastrointestinal hemorrhage incidence rate is also significantly reduced, the long-term prescription that this also will be very beneficial for the patient improves the compliance of patient's medication, improves patient's drug safety.
Because this pharmaceutical composition has good platelet aggregation inhibitory action and thrombosis inhibitory action, can be used as the preventive drug or the curative of the disease that is caused by thrombosis or thromboembolism, is used for preventing and treating the generation of cardiovascular and cerebrovascular vessel thrombotic disease and incident.This pharmaceutical composition can be prepared into the antithrombotic drug combination preparation of solid form unit dose, be used for to use the disease occasion of adp receptor antagonist, synergism by adp receptor antagonist and indobufen, can under the prerequisite of assurance or even raising curative effect, reduce the using dosage of adp receptor antagonist, reduce medicine to the gastrointestinal zest, reduce serious adverse such as the thrombotic thrombocytopenic purpura that untoward reaction caused (TTP) that produces owing to independent prolonged and repeated use adp receptor antagonist and gastrointestinal hemorrhage incidence rate.Simultaneously, can also reduce cost, relieve patient ' s burden has favorable economic benefit and social benefit.
Equally, we become drug combination preparation with indobufen with the ticlopidine combined preparation, have also obtained above-mentioned identical conclusion.
Be specially: pass through pharmacological evaluation, we find that the compositions of indobufen and ticlopidine has good platelet aggregation inhibitory action and thrombosis inhibitory action equally, the summation of the effect when the anticoagulant effect when particularly finding indobufen and ticlopidine combined administration is used respectively than these two kinds of components is good, promptly between this two component synergistic function is arranged.The pharmaceutical composition of indobufen and ticlopidine is also higher than the platelet aggregation inhibition rate of the pharmaceutical preparations composition of aspirin and ticlopidine.
By further pharmacological evaluation, we find that the compositions of indobufen and ticlopidine is to antiplatelet aggregation and thrombotic inhibitory action, suitable with the pharmaceutical composition of aspirin and ticlopidine to the inhibitory action of platelet aggregation, there was no significant difference.
In addition, under the prerequisite that guarantees curative effect, reduce the dosage of indobufen and these two kinds of active component of ticlopidine, platelet aggregation and thrombosis are had good inhibition effect with sample, the result also can reduce the side effect relevant with these active substances.
Animal acute toxicity experiment proves, the safety range of the pharmaceutical composition of indobufen and ticlopidine also is the pharmaceutical composition greater than aspirin and ticlopidine, and pharmaceutical composition of the present invention, the gastrointestinal zest is obviously reduced, the gastrointestinal hemorrhage incidence rate is also significantly reduced, the long-term prescription that this also will be very beneficial for the patient improves the compliance of patient's medication, improves patient's drug safety.
This pharmaceutical composition of the present invention, be the unit dose combination that contains two kinds of active substances (a kind of adp receptor antagonist and indobufen) for the treatment of effective dose, wherein the active matter quality of Cun Zaiing makes the amount of application of every day that suitable therapeutic effect can be provided.Also other diseases that can treat or prevent comprise the patient that need do intracoronary stent implantation, percutaneous tranluminal coronary angioplasty, angioplasty or atherosclerotic blood vessel excision.
About ticlopidine, the effective daily dose that is used to prevent or treat cardiovascular disease and incident in framework of the present invention is about 25mg/ days-500mg/ days, be preferably about 50-200mg/ days.
About clopidogrel, the effective daily dose that is used to prevent or treat cardiovascular disease and incident in framework of the present invention is about 25mg/ days-250mg/ days, be preferably about 25-75mg/ days.
About indobufen, the effective daily dose that is used to prevent or treat cardiovascular disease and incident in framework of the present invention is about 50mg/ days-400mg/ days, be preferably about 100-300mg/ days.
The pharmaceutical preparation of this compositions of the present invention is the solid preparation of suitable for oral administration, can be prepared into solid forms such as tablet, capsule, granule or powder agent.Be preferably tablet and capsule.Medicament comprises indobufen and a kind of adp receptor antagonist of specified amount, and uses diluent, carrier and the auxiliary agent that arrives always in medication preparation.For example tablet can comprise activation filler, granule, diluent, lubricant, fluidizer, color, sweetener or flavouring agent etc.
When being prepared into the solid composition preparation of gelatine capsule agent form, main active and one or more mixing diluents and by the mixture that obtains is poured into soft or hard gelatin capsule in obtain.
The pharmaceutical preparation manufacture method of this compositions of the present invention uses preparation methoies such as simple mixing method or direct powder compression to prepare pharmaceutical composition of the present invention for containing adp receptor antagonist, indobufen and one or more pharmaceutically acceptable mixed with excipients subsequently.
The above-mentioned pharmaceutical composition for preparing can be divided into according to the treatment effective dose:
When under the situation of ticlopidine-indobufen pharmaceutical composition, use that to contain ticlopidine unit's daily dose for the treatment of effective dose be 25mg-500mg, preferred 50-200mg; Use that to contain indobufen unit's daily dose for the treatment of effective dose be 50mg-400mg, preferred 100-300mg.
When under the situation of clopidogrel-indobufen pharmaceutical composition, use that to contain clopidogrel unit's daily dose for the treatment of effective dose be 25mg-250mg, preferred 25-75mg; Use that to contain indobufen unit's daily dose for the treatment of effective dose be 50mg-400mg, preferred 100-300mg.
Based on the pharmaceutical composition of described invention every day consumption medication and treatment condition, under oral situation, adult's oral administration every day 1-3 time, preferably administration is 1-2 time.
When containing ticlopidine 50-200mg and share, can produce the obvious synergistic effect with the pharmaceutical composition that contains indobufen 100-300mg.(contain ticlopidine 100mg with the preparation specification of working out as per unit dosage, indobufen 150mg) administration, only need take the ticlopidine that 100-200mg contains effective therapeutic dose every day, correspondingly take the indobufen that 150-300mg contains effective therapeutic dose, two kinds of medicine effective doses of said composition all are lower than single with ticlopidine (500mg/ day) and single dosage with indobufen (400mg/ day), so severely adverse event occurs after can reducing patient's medication greatly.
When chloride pyrrole Gray 25-75mg share with the pharmaceutical composition that contains indobufen 100-300mg, can produce the obvious synergistic effect.(contain ticlopidine 25mg with the preparation specification of working out as per unit dosage, indobufen 150mg) administration, only need take the clopidogrel that 25-50mg contains effective therapeutic dose every day, correspondingly take the indobufen that 150-300mg contains effective therapeutic dose, two kinds of medicine effective doses of said composition all are lower than single with clopidogrel (75mg/ day) and single dosage with indobufen (400mg/ day), so severely adverse event occurs after can reducing patient's medication greatly.
Contain the pharmaceutical composition that active component is clopidogrel and indobufen in the most preferred pharmaceutical composition of the present invention, use that to contain clopidogrel unit's daily dose for the treatment of effective dose be 25-50mg; Use that to contain indobufen unit's daily dose for the treatment of effective dose be 100-300mg.The pharmaceutical preparation that is prepared into, preferred administration every day 1-2 time.
Characteristics of the present invention have been to provide a kind of new antithrombotic pharmaceutical composition that contains adp receptor antagonist, indobufen and one or more pharmaceutically acceptable excipient, this pharmaceutical composition has good platelet aggregation inhibitory action and thrombosis inhibitory action, the preventive drug or the curative that can be used as the disease that is caused by thrombosis or thromboembolism are used for preventing and treating the generation of cardiovascular and cerebrovascular vessel thrombotic disease and incident.The preparation of compositions of indobufen and adp receptor antagonist is become the antithrombotic drug combination preparation of solid form unit dose, be used for to use the disease occasion of adp receptor antagonist, synergism by adp receptor antagonist and indobufen, prevention and treatment cardiovascular and cerebrovascular vessel thrombotic disease, can under the prerequisite of assurance or even raising curative effect, reduce adp receptor antagonist and indobufen using dosage separately, reduce medicine to the gastrointestinal zest, reduce serious adverse such as the thrombotic thrombocytopenic purpura that untoward reaction caused (TTP) that produces owing to independent prolonged and repeated use adp receptor antagonist and gastrointestinal hemorrhage incidence rate.
Therefore, the present invention has reduced the gastrointestinal stimulation, and the severe haemorrhage probability that in application, occurs of the pharmaceutical composition that has reduced the compositions of ticlopidine-aspirin and clopidogrel-aspirin, particularly reduce the gastrointestinal hemorrhage incidence rate, improve the compliance of patient's medication, improve clinical drug safety and curative effect, had good clinical use value.Simultaneously, can also reduce cost, relieve patient ' s burden has favorable economic benefit and social benefit.
The specific embodiment
Below we embodiment by indefiniteness further explain technical scheme of the present invention.Any equivalent transformation according to technical solution of the present invention is done all should belong to protection scope of the present invention.
The drug compatibility experiment of embodiment 1 clopidogrel and indobufen
The purpose of this experiment is exactly whether checking clopidogrel and these two kinds of medicines of indobufen have the good compatibility on physical property and chemical.With these two kinds of medicines of clopidogrel and indobufen prepare be stored in 3 kinds of different temperature humidity environment under, i.e. 25 ℃/10%RH; 30 ℃/60%RH; 40 ℃/75%RH.Medicine is divided into combined group and unmixed group compares, place respectively under these three kinds of temperature.Sample carried out the evaluation of color, physical behavior, chemical stability (passing through chromatographer) at the 1st day, the 2nd day, the 7th day, the 14th day, the 30th day, the degree of each active component activation recovering under all storage requirements (% combined group/% matched group), clopidogrel is 94.3%-103.7%, and indobufen is 96.2%-104.4%.Combined group and matched group analytically do not have significant difference at physical form and chemical colour system method in the observation, and after the compositions that these two kinds of medicines are described was mixed, physical property of the two and chemical still had the good compatibility.
We with identical method validation indobufen and these two kinds of medicines of ticlopidine have good physics and chemical compatibility equally.
Embodiment 2 contains the compound tablet of clopidogrel 25mg and indobufen 100mg
1) prescription:
2) preparation method: direct powder compression
With 25g clopidogrel, 40g amylum pregelatinisatum, 40g β-Lactis Anhydrous and 0.7g colloidal silica anhydrous mix homogeneously; With 100g indobufen, 40g β-Lactis Anhydrous, 40g microcrystalline Cellulose mix homogeneously.Add castor oil hydrogenated and Pulvis Talci, behind the common fully mixing, after 12 order nylon mesh granulate, granule is through after the assay was approved, with particle powder with 12mm towards direct compression, promptly.
Embodiment 3 contains the compound tablet of clopidogrel 50mg and indobufen 150mg
1) prescription:
2) preparation method: direct powder compression
Clopidogrel, indobufen and macrogol6000 are stirred the 15min mix homogeneously in Fastmixinggranulator; Add castor oil hydrogenated, continue to stir the 5min mix homogeneously, cross 12 order nylon mesh granulate.Granule directly carries out tabletting with final mix powder by the unit dose quality through after the assay was approved, makes about 1000.
Embodiment 4 contains the compound tablet of ticlopidine 50mg and indobufen 100mg
1) prescription:
2) preparation method: with embodiment 3
Embodiment 5 contains the compound tablet of ticlopidine 75mg and indobufen 100mg
1) prescription:
2) preparation method: with embodiment 3
Embodiment 6 contains the compound tablet of clopidogrel 25mg and indobufen 100mg
1) prescription:
2) preparation method: with embodiment 3
Embodiment 7 contains the compound capsules agent of clopidogrel 50mg and indobufen 200mg
1) prescription:
2) preparation method:
Clopidogrel, indobufen are stirred the 15min mix homogeneously in Fastmixinggranulator; Add soybean oil and Cera Flava, continue to stir the 5min mix homogeneously, make about 1000 of soft capsule, promptly.
Embodiment 8 contains the compound capsules agent of ticlopidine 100mg and indobufen 200mg
1) prescription:
2) preparation method: with embodiment 7.
Embodiment 9 pharmaceutical compositions of the present invention are to the experiment of the right neck artery-vein of rat bypass thrombosis
Experimental drug:
Normal saline
Indobufen
Clopidogrel
The pharmaceutical composition of clopidogrel-indobufen (dividing large, medium and small dosage group)
The pharmaceutical composition of clopidogrel-aspirin
Laboratory animal: 70 of Wistar rats, male and female half and half, body weight 250 ± 10g.
Rat is divided into 7 groups at random, 10 every group.Drug dose is (A) blank (0.9% sodium chloride solution), (B) indobufen group (240.0mgkg
-1), (C) clopidogrel group (120.0mgkg
-1), (D) pharmaceutical composition group (120.0/320.0mgkg of clopidogrel-indobufen
-1), (E) pharmaceutical composition group (80.0/240.0mgkg of clopidogrel-indobufen
-1), (F) pharmaceutical composition group (40.0/160.0mgkg of clopidogrel-indobufen
-1).(G) the pharmaceutical composition group (120.0/240.0mgkg of clopidogrel-aspirin
-1)
Experimental technique:
Each treated animal is by above-mentioned dosage intraperitoneal administration, and blank group is given the equivalent normal saline, every day 1 time, and continuous 5d, 30min is with chloral hydrate (350mgkg after the last administration
-1) anesthesia, dorsal position is fixed, and separates trachea, inserts a plastic bushing, and isolates right carotid and left external jugular vein.Put long 6cm of people silk thread of having weighed in the polyethylene tube stage casing.With heparin (50Uml
-1) be full of polyethylene tube.One end of pipe inserts left jugular vein, and the other end injects heparin (50U/kg) anticoagulant, inserts right carotid.Open bulldog clamp, blood returns left jugular vein by the right carotid polyethylene tube of flowing through.Open blood flow 15min, middle Herba Clinopodii takes out silk thread rapidly and weighs, and gross weight subtracts line and heavily promptly gets wet weight of thrombus.Measurement result sees Table 1:
The table 1 pair thrombotic influence of rat artery-vein bypass (X ± S, n=10)
Compare with the normal saline group, * P＜0.05,
Compare * with the pharmaceutical composition group of clopidogrel-aspirin
△P＜0.01
The result shows: clopidogrel-indobufen group 120.0/320.0mgkg
-1, 80.0/240.0mgkg
-1And 40.0/160.0mgkg
-1All can significantly reduce wet weight of thrombus, present certain dose-effect relationship, with normal saline matched group comparing difference significance (P＜0.05, P＜0.01) is arranged, illustrate that pharmaceutical composition of the present invention is having synergistic function aspect the antithrombotic formation, as medicament for resisting platelet aggregation the thrombotic effect of obvious inhibition is arranged, with chloride pyrrole Gray-indobufen 120.0/320.0mgkg
-1The group activity is more excellent.But the research experiment to rat also shows: the pharmaceutical composition of clopidogrel-indobufen is with respect to the pharmaceutical composition of clopidogrel-aspirin, and is suitable to antiplatelet aggregation and thrombotic inhibitory action, and there was no significant difference.
Embodiment 10 pharmaceutical compositions of the present invention are to the influence in mouse tail bleeding time
60 male mices are divided into 6 groups, are tried the agent amount and be: blank A group, give quite volumetrical solvent; Positive control drug B group: clopidogrel 80.0mgkg
-1Clopidogrel/indobufen is respectively C group: 40.0/160.0mgkg
-1, D group: 80.0/240.0mgkg
-1, E group: 120.0/320.0mgkg
-1
Gastric infusion, every day 1 time, for three days on end, 1.5h after the last administration, mice is fixed, tail is vertical, cut off afterbody apart from tail point 1.5mm place after, afterbody is inserted in 37 ℃ of normal saline, write down every group every Mus bleeding time: till promptly cutting off the tail point and beginning to stop outflow to blood.Bleeding time surpasses 10 minutes persons and calculates with 600s (10min).
Result of the test is as shown in table 2, compares with the blank group, and the pharmaceutical composition of clopidogrel-indobufen obviously prolongs the mouse tail bleeding time, and the difference of highly significant is arranged therebetween.
Table 2 clopidogrel-indobufen compositions to the influence in mouse tail bleeding time (X ± S, n=10)
Compare * * P＜0.01 with the blank group
The result shows: clopidogrel-indobufen compositions prolonged obviously the mouse tail bleeding time.Compare with clopidogrel, the identical tail bleeding time, used drug dose reduced.
Embodiment 11 pharmaceutical compositions of the present invention are exempted from the gastric stimulation test to family
Test method:
For understanding the safety of pharmaceutical composition provided by the invention, carry out house by the requirement of new drug approval and method and exempt from the gastric stimulation test.
Material and reagent:
16 of large ear rabbits, regular grade.Be divided into 4 groups at random: A group (pharmaceutical composition of indobufen and clopidogrel), B group (pharmaceutical composition of aspirin and clopidogrel), C group (aspirin tablet) and D group (contrast).
Each organizes the dosage design:
Every treated animal quantity is 4, male and female half and half.A, B, three groups of dosages of C only are 0.32g/.The D group: negative control group does not give any medicine.Per os gives medicine, notes preventing that rabbit from chewing medicine, frequency: 1 time/d, and continuous 7d (fasting before each administration).
Observation index: 1. ordinary circumstance is observed: 30min observation rabbit has or not phenomenons such as abnormal response, diarrhoea or vomiting after each administration.Finish back weighing the weight of animals with experiment before the experiment.2. histopathologic examination: each test group rabbit is 48h carotid artery sacrificed by exsanguination behind the oral administration the last time.Take off whole stomach, cut off, clean, and observe the gastric mucosal damage degree with normal saline along greater gastric curvature.Degree of injury grading standard: 0 grade: normal (not damaged, hyperemia and latent lesion); 0.5 level: extensively congested; 1.0 level: minor injury's (2 ~ 3 point-like damages); 2.0 level: major injury (successive wire damage or 5 ~ 6 point-like damages); 3.0 level: utmost point major injury (several successive wire damages); 4.0 level: wire damage widely or fill the air damage.
Observation finishes serosal surface is affixed on and puts 10% formalin solution on the hardboard and fix specimens paraffin embedding slices.H.E. dyeing.Tissues observed changes under the light microscopic.Whether decision retains the part animal and does convalescent period histopathologic examination according to the perusal situation.If there is damage in perusal, retains and do histopathologic examination after half animal is observed 7d.
The result:
(1) each treated animal body weight change Non Apparent Abnormality after test.
(2) observe and cut open inspection and change
Observe and cut open the inspection result and show: two groups of administration phase A, D test rabbit gastric tissue shows no obvious abnormalities, and B, C organize visible gastric mucosa surface and be dispersed in the faint yellow pseudomembrane of button size, the visible mucous hyperemia in subregion.Convalescent period is cutd open inspection A, B, C, D4 treated animal gastric tissue shows no obvious abnormalities.Cut open the inspection standards of grading according to histopathologic examination and mark to cuing open extremely the rabbit gastric tissue, appraisal result sees Table 3.
Each group test lagophthalmos of table 3 is seen scoring
(3) result of histopathologic examination
The administration phase is respectively organized gastric tissue histopathology result of variations:
The A group: gastric tissue mucomembranous epithelial cell structure is clear substantially, complete, does not see tangible hyperemia, edema or inflammatory cell infiltration.B group: the gastric epithelial cell structural deterioration, the visible epithelial cell shedding in top, and combine with the mucomembranous epithelial cell top layer and to form homogenizing shape thing; The visible tela submucosa congestion of blood vessel of part.C group: the gastric epithelial cell structural deterioration, the visible epithelial cell shedding in top, and combine with the mucomembranous epithelial cell top layer and to form homogenizing shape thing; The subregion is dispersed in inflammatory cell infiltration.The D group: gastric tissue mucomembranous epithelial cell clear in structure, complete, do not see hyperemia, edema or inflammatory cell infiltration.
Convalescent period is respectively organized the gastric tissue histopathology and changes no bright difference, and each is organized gastric tissue and has all recovered normal.
This result of the test shows that there is stronger stimulation in aspirin and aspirin-clopidogrel pharmaceutical composition to tame rabbit gastric mucosa, mainly shows the destruction gastric epithelial cell.And cause gastric mucosa hyperemia.Pharmaceutical composition energy better protect gastric mucosa provided by the invention, the pharmaceutical composition that continuous 7d per os gives indobufen and clopidogrel is lower than the pharmaceutical composition of aspirin and aspirin-clopidogrel to rabbit gastric stimulation significant reaction.
Claims (5)
1. antithrombotic pharmaceutical composition, it comprises adp receptor antagonist and the effective dose that effective dose is 25-500mg is the indobufen of 50-400mg, and wherein said adp receptor antagonist is ticlopidine, clopidogrel or they are at pharmaceutically acceptable salt.
2. a kind of antithrombotic pharmaceutical composition according to claim 1, wherein it to comprise ticlopidine and the effective dose that effective dose is 50-200mg be the indobufen of 100-300mg.
3. a kind of antithrombotic pharmaceutical composition according to claim 1, wherein it to comprise clopidogrel and the effective dose that effective dose is 25-75mg be the indobufen of 100-300mg.
4. a kind of antithrombotic pharmaceutical composition according to claim 1, wherein said pharmaceutically acceptable salt is: hydrochlorate, sulfate, tartrate, acetate, benzoate, fumarate, maleate, citrate, 2,5-resorcylic acid salt, mesylate, esilate, benzene sulfonate, tosilate, camsilate, lauryl sulfonate, Dobesilate or hydrobromate.
5. a kind of antithrombotic pharmaceutical composition according to claim 2, it comprises in amylum pregelatinisatum, β-Lactis Anhydrous, silica sol, microcrystalline Cellulose, castor oil hydrogenated, mannitol, polyethylene glycol 6000, hydroxypropyl cellulose, sodium carboxymethyl cellulose, Pulvis Talci, magnesium stearate or the gelatin one or more.
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| CN2008100489296A CN101352436B (en) | 2008-08-21 | 2008-08-21 | Novel medicament composition for resisting thrombosis |
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| CN103040846A (en) * | 2011-11-30 | 2013-04-17 | 成都盛尔嘉科技有限公司 | Medicament for resisting platelet aggregation |
| CN103239444A (en) * | 2012-12-26 | 2013-08-14 | 辽宁亿灵科创生物医药科技有限公司 | Dextroindobufen and clopidogrel compound drug composition |
| CN103800336A (en) * | 2014-03-06 | 2014-05-21 | 北京恩成康泰生物科技有限公司 | Composition with anti-thrombus active medicine |
| CN112336720B (en) * | 2020-11-20 | 2021-12-28 | 北京诺康达医药科技股份有限公司 | Aspirin and ticlopidine compound preparation and preparation method thereof |
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