CN1223345C - Pharmaceutic composition of anti-platelet aggregation - Google Patents
Pharmaceutic composition of anti-platelet aggregation Download PDFInfo
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Abstract
The present invention relates to platelet aggregation resisting medicinal composition which contains 100 weight portions of ticlopidine hydrochloride and 1.7 to 26 weight portions of nitrendipine, wherein the preferred content of nitrendipine is from 3 to 4 weight portions. The composition prepared according to the weight portions can be made into solid form unit doses. The medicinal composition has a favorable inhibiting effect on platelet aggregation. The medicinal composition is mainly used as an antithrombotic preparation, and is used in a disease occasion in which ticlopidine hydrochloride can be used. The synergistic effect of ticlopidine hydrochloride and nitrendipine can reduce the use doses of ticlopidine hydrochloride on the premise of ensuring or even improving therapeutic effects. The medicinal composition can also reduce the cost, and can lighten the burden of patients. The medicinal composition has favorable economical benefit and social benefit.
Description
Technical field: the present invention relates to a kind of pharmaceutical composition of antiplatelet aggregation, said composition contains ticlopidine hydrochloride (ticlopidine) and nitrendipine.Particularly, pharmaceutical preparation as a kind of antiplatelet aggregation, the ticlopidine hydrochloride and the nitrendipine that contain have synergism, the using dosage of the low hydrochloric acid ticlopidine that can descend in the prerequisite of assurance or even raising curative effect, thus reduction is to the side effect of human body.
Background technology: clinical research shows, diseases such as common clinically cardiovascular and cerebrovascular disease such as hypertension, diabetes, angina pectoris, myocardial infarction, cerebral infarction and cerebral hemorrhage, all change relevant unusually (Tianjin medicine, 1992,20 (11): 684) with hemorheology with platelet function.Therefore, prevent that platelet aggregation is significant.
Ticlopidine hydrochloride is a synthetic wide spectrum medicament for resisting platelet aggregation of new generation seventies, be widely used in treatment cardiovascular and cerebrovascular disease, peripheral vessels and microvascular disease from the eighties, along with the further investigation that platelet is acted in thrombosis, rise day by day in its treatment status in thrombotic disease.Extensive use along with ticlopidine hydrochloride, its side effect displays gradually, that have or even serious adverse, comprise neutrophilic granulocyte deficiency disease, thrombocytopenia, liver toxicity etc. gradually, particularly serious is bone marrow depression to have occurred, mortality rate is 1,000,000/to 2/1000000ths (Chinese Journal of New Drugs, 1995,4 (3): 36).
Domestic relevant side effect report is less, except that use not as external general, domestic using dosage is lower, also be that (external using dosage is 500mg/ days to main cause, domestic is 250mg/ days), can reduce the side effect of ticlopidine hydrochloride so can infer the using dosage that reduces ticlopidine hydrochloride.Therefore, reducing clinical dosage under the prerequisite that guarantees curative effect, is the effective way that reduces rate of side effects.
An important channel that had not only guaranteed curative effect but also reduced side reaction is to make compound preparation.In general, for the mechanism of action difference but the medicine of pharmacological effect unanimity, often produce the drug effect of collaborative or addition after share.At present, the medicine with antiplatelet aggregation of Ying Yonging has aspirin, persantin, natural flavonoid etc. clinically, though ticlopidine hydrochloride is different with above-mentioned several drugs mechanism of action, but experimental results show that ticlopidine hydrochloride and aspirin do not have synergism aspect antiplatelet aggregation, the report of uniting use with other several drugses is rare.
In disclosed Chinese invention patent application (CN1283119), ticlopidine hydrochloride and Semen Ginkgo extrac are made compound preparation, wherein Semen Ginkgo extrac is an antioxidant, has alleviated the side effect of ticlopidine hydrochloride.But this scheme is not optimum, because the preparation more complicated of Semen Ginkgo extrac, difficult quality control, and also limited as the Folium Ginkgo source of raw material.All these have limited the use of ticlopidine hydrochloride Semen Ginkgo extrac compound preparation.
Summary of the invention: the objective of the invention is at above-mentioned the deficiencies in the prior art, and provide a kind of pharmaceutical composition of antiplatelet aggregation to people, mainly be variety of issue in order to solve independent use ticlopidine hydrochloride and to form preparation as antithrombotic, calcium antagonist nitrendipine and ticlopidine hydrochloride that raw material is cheap and easy to get are united use.Because ticlopidine hydrochloride and nitrendipine have synergism, and can reduce the ticlopidine hydrochloride dosage and to the good inhibition effect that has of platelet aggregation.For achieving the above object, the present invention adopts following technical proposals: the pharmaceutical composition of antiplatelet aggregation, contain ticlopidine hydrochloride and nitrendipine.This pharmaceutical composition is mainly as antithrombotic preparation, be used for to use the disease occasion of ticlopidine hydrochloride, by the synergism of ticlopidine hydrochloride and nitrendipine, reduced the ticlopidine hydrochloride dosage and used ticlopidine hydrochloride to cause the purpose of side effect separately and improve inhibition platelet aggregation to reach to improve.
Based on described invention, ticlopidine (5-[(2-chlorphenyl) methyl]-4,5,6, the 7-Tetramethylene sulfide is [3,2-C] pyridine also) and belong to Thienopyridines, because its antithrombotic performance is as the anticoagulant extensive use.Adenosine diphosphate (ADP) (ADP) is the important platelet activating agent that is discharged by erythrocyte activated blood platelet and impaired endotheliocyte, passes through P
2Receptor causes PA and gathering.Ticlopidine hydrochloride is the wide spectrum anti-platelet aggregation agent, by the P of blocking platelet
2ACReceptor and bring into play following effect: 1) prevent the inhibition of the inductive adenyl cyclase of ADP; 2) prevent that the inductive pair cell skeleton associated protein of ADP-vasodilation from stimulating the inhibition of phosphoprotein (VASP) phosphorylation; 3) prevent the combination of G albumen-platelet membrane.But ticlopidine hydrochloride can not suppress the inductive platelet distortion of ADP and calcium ion is striden membrane flow, thereby the leeway of strengthening its antiplatelet aggregation is still arranged.In brief, think that ticlopidine hydrochloride has antithrombotic effect at this.By reducing the Fibrinogen in the blood plasma, ticlopidine hydrochloride has reduced blood viscosity, has the plastic effect of the erythrocyte of raising.Except these advantages, still existence and cytopenia, agranulocytosis, aplastic anemia, problem that the intestinal side reaction is relevant.
Its calcium antagonist can suppress calcium ion and stride stream in the film, and then influences calcium ion and act in cell and whole cell function is changed, comprising anticoagulant, hemorheology when improving hypoxemia, improve erythrocyte deformability, reduce blood viscosity, prevent thrombosis.Other functions of calcium antagonist all help the treatment of diseases relevant with platelet aggregation as reducing myocardium power consumption and oxygen consumption, blood vessel dilating, alleviate oxygen free radical injury, suppress Endothelin secretion etc. in addition.Evidence, calcium antagonists such as nifedipine, nicardipine, ligustrazine, flunarizine all have tangible antiplatelet aggregative activity.Nitrendipine is a chemical synthetic drug, and raw material is cheap and easy to get.Relatively side effect is less for nitrendipine and other calcium antagonist, has gentle persistent hypotensive effect, clinically as antihypertensive.Nitrendipine also has tangible antiplatelet aggregative activity, and simultaneously, its average elimination half-life is 8～12 hours, with 8 hours of ticlopidine hydrochloride quite, can suppose therefore that the two share can produce synergism.
The present invention experimental results show that nitrendipine and ticlopidine hydrochloride have good synergism, greatly reduces the dosage of ticlopidine hydrochloride under the prerequisite that guarantees the ticlopidine hydrochloride curative effect.
Based on described invention, in compositions, contain 100 weight portion ticlopidine hydrochlorides and 1.7～26 weight portion nitrendipines.Preferably contain 3～4 weight portion nitrendipines for 100 weight portion ticlopidine hydrochlorides.
Pharmaceutical composition based on described invention can be through enteral administration, such as oral.Described compositions can be mixed with solid preparations such as tablet, capsule especially.Aspect this, medicament comprises the ticlopidine hydrochloride and the nitrendipine of specified amount, and diluent, carrier and the auxiliary agent used always in medication preparation.For example tablet can comprise activation filler, granule, diluent, bonding agent, resolvent, lubricant, stabilizing agent, color, sweetener or flavouring agent.
The unit dose of the preparation of above-mentioned preparation should contain 25～250mg ticlopidine hydrochloride, or preferred 50～100mg.Correspondingly the unit dose of nitrendipine should be 1～10mg, or preferred 2～4mg.Consumption every day based on the pharmaceutical composition of described invention depends on medication or treatment condition, but under oral situation, adult's preferred administration every day 1-4 time.
Produce the obvious synergistic effect when ticlopidine hydrochloride and nitrendipine share with 29: 1, can make the dosage of ticlopidine hydrochloride reduce half when producing suitable drug effect.With preparation specification (the every hydrochloric ticlopidine 75mg that drafts, nitrendipine 3mg) administration, only need take 150～300mg ticlopidine hydrochloride every day, is lower than list with ticlopidine hydrochloride amount (500mg/ day), correspondingly takes nitrendipine 6～12mg, the lowest dose level of 20mg/ day when also being lower than nitrendipine and being used for resisting hypertension, thereby can not affect greatly patient's blood pressure, side effect such as heart rate that calcium antagonist is common are accelerated flush, headaches etc. also are difficult for producing.Share back mouse tail bleeding time prolongation obviously (compare with ticlopidine, identical tail bleeding time dosage reduces nearly 6 times).
According to the present invention, can draw apparently to use and make the effect that compositions also can reach the pharmaceutical composition of ticlopidine hydrochloride of the present invention and nitrendipine with the ticlopidine of ticlopidine hydrochloride equivalent or other ticlopidine salt and nitrendipine.The salt of described ticlopidine can be organic or inorganic salt.Suitable example has sulphuric acid ticlopidine, hydrobromic acid ticlopidine, methanesulfonic acid ticlopidine, maleic acid ticlopidine, fumaric acid ticlopidine etc.
Characteristics of the present invention are to contain the pharmaceutical composition of described ticlopidine hydrochloride and nitrendipine, have the effect of good restraining platelet aggregation.Ticlopidine hydrochloride is made compound recipe, can reduce dosage, alleviate toxicity, improve curative effect, have certain clinical use value.Can be widely used in diseases such as common clinically cardiovascular and cerebrovascular disease such as hypertension, diabetes, angina pectoris, myocardial infarction, cerebral infarction and cerebral hemorrhage simultaneously, can also reduce cost, relieve patient ' s burden has favorable economic benefit and social benefit.
Embodiment based on following indefiniteness will explain the present invention in more detail.
Preparation embodiment
Embodiment 1: tablet
1) prescription 1
Sheet heart prescription:
Ticlopidine hydrochloride 75g
Nitrendipine 3g
Microcrystalline Cellulose 40g
Carboxymethylstach sodium 12g
15% polyvidone ethanol liquid is an amount of
Pulvis Talci 1g
Magnesium stearate 1g
Poloxamer 3.0g
——————————————————
Make 1000
The film-coat prescription:
Hypromellose 2g
Diethyl phthalate 1g
Titanium dioxide 2g
Pulvis Talci 0.8g
—————————————————————
80% ethanol adds to 100ml
2) technology
Preparation technology: lucifuge operation.Nitrendipine is crossed 100 mesh sieves, ticlopidine hydrochloride was pulverized 100 mesh sieves.Press recipe quantity ticlopidine hydrochloride, nitrendipine, microcrystalline Cellulose, carboxymethylstach sodium poloxamer mixing, cross 60 mesh sieves three times, add an amount of 15% polyvidone ethanol (95%), make soft material, cross 18 mesh sieves and granulate 40 ℃ of dryings, add Pulvis Talci and magnesium stearate, 16 mesh sieve granulate.The shallow circle of 7mm charges and attacks sheet, the heavy 0.135g of sheet.
Qualified label (reject powder, damaged sheet is arranged) is put into coating pan, be blown into hot blast, when treating ℃ left and right sides, label temperature to 40～50, evenly spray into coating solution, the clothing film can not be too thin, to reach shaded effect.The coating gain in weight is controlled at 3～5%, drying, promptly.
Embodiment 2: capsule
1) prescription 2
Ticlopidine hydrochloride 75mg
Nitrendipine 3mg
Pregelatinized Starch 100mg
Poloxamer 4mg
Carboxymethyl starch sodium 10mg
10% polyvidone alcoholic solution is an amount of
2) technology: adopt the composition and the content of the unit dose shown in the prescription 2, the lucifuge operation.Nitrendipine is crossed 100 mesh sieves, and ticlopidine hydrochloride was pulverized 100 mesh sieves.It is standby that other adjuvant is crossed 100 mesh sieves, press recipe quantity with ticlopidine hydrochloride, nitrendipine, pregelatinized Starch, poloxamer, carboxymethyl starch sodium mixing, cross 60 mesh sieves three times, add an amount of 10% polyvidone ethanol (95%) solution system soft material, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed 16 mesh sieve granulate, filling, promptly.
Experimental example
Following experiment condition is adopted in experiment 1～8:
Be subjected to the reagent thing: compound hydrochloric acid ticlopidine (ticlopidine hydrochloride wherein: nitrendipine=29.17: 1.0)
Compound method: be made into the desired concn suspension with 0.5%CMC-Na before the administration.
Administration volume: 20ml/kg.
Animal:
1), rabbit body weight 2.5 ± 0.5kg, male, 5 every group, animal housing of Shenyang Pharmaceutical University provides, white rabbit is planted by New Zealand, the animal one-level is qualified.
2), rat body weight 220 ± 20g, male, 10 every group.
3), mice body weight 20 ± 2g, male, 10 every group, big mice is respectively SD, Kunming kind, the animal quality certification number is provided by animal housing of Shenyang Pharmaceutical University: distant real animal is closed No. 517 experiment 1 of word, ADP is induced the influence of platelet aggregation in the rat body.
Animal subject is divided equally 5 groups, and 10 every group, the dosage that is tried thing is ticlopidine hydrochloride: nitrendipine=140.0mg/kg: 4.8mg/kg, 70.0mg/kg: 2.4mg/kg, 35.0mg/kg: 1.2mg/kg; It is ticlopidine hydrochloride 200mg/kg that the blank group is given suitable volume 0.5%CMCNa positive control drug.Every day 1 time, for three days on end, 1.5h after the last administration, under waking state, get blood from the eyeball rear vein beard, with 3.8% sodium citrate anticoagulant (1: 9), conventional preparation PRP and PPP, aggregating agent prepared therefrom ADP is produced by the biochemical factory in Shanghai, be made into the ADP concentration 0.1mM20ul that makes matched group 50 ± 10% platelet aggregations with 7.4% phosphate buffer, use DAM-3 type dual pathways platelet aggregation instrument mensuration and respectively organize platelet aggregation, by formula:
Assembling inhibition %=(matched group gathering %-administration group gathering %)/matched group gathering % * 100% obtains each and organizes gathering inhibition %.With the aggregation rate is to compare significance test between observation index is organized.
Result of the test is as shown in table 1, and in selected dosage range, each administration group platelet aggregation rate all obviously descends, and with matched group highly significant difference is arranged relatively.It is also in rising trend to increase the gathering suppression ratio with dosage.
Table 1 compound hydrochloric acid ticlopidine is induced the (X ± SD) of platelet aggregation influence in the rat body to ADP
| Group | Dosage mg/kg | Number of animals only | Platelet aggregation % | Suppress % |
| Matched group T+N N | - 140.0+4.8 70.0+2.4 35.0+1.2 200.1 | 10 10 10 10 10 | 51.4±4.8 6.8±2.9 ** 13.8±4.6 ** 22.8±9.5 ** 11.7±4.9 ** | - 88.0±6.4 72.3±9.2 53.9±19.8 77.4±27.5 |
Compare with matched group
*Annotate P＜0.01: T: ticlopidine hydrochloride N: nitrendipine
Experiment 2, to the influence of platelet aggregation in the collagen-induced rat body
Animal subject grouping, administering mode dosage, platelet aggregation assay method are all identical with experiment 1, and aggregating agent prepared therefrom collagen is produced (C-8886, Lot108e 8015) for Sigma company.
Table 2 compound hydrochloric acid ticlopidine is to (the X ± SD) of platelet aggregation influence in the collagen-induced rat body
| Group | Dosage mg/kg | Number of animals only | Platelet aggregation % | Suppress % |
| Matched group T+N N | - 140.0+4.8 70.0+2.4 35.0+1.2 200.0 | 10 10 10 10 10 | 45.7±5.2 15.3±5.0 ** 21.3±7.6 ** 27.9±6.0 ** 21.9±9.9 | - 66.5 53.4 38.9 56.0 |
Compare with matched group
*Annotate P＜0.01: T: ticlopidine hydrochloride N: nitrendipine
Result of the test is as shown in table 2, and in selected dosage range, each administration group platelet aggregation rate obviously descends, and with matched group highly significant difference is arranged relatively, and increases with dosage, and suppression ratio is also in rising trend.
Experiment 3, to the influence of platelet aggregation in the thrombin induction rat body
Animal subject grouping, administering mode, dosage, platelet aggregation assay method are all identical with experiment 1, and the aggregating agent prepared therefrom thrombin is produced (T4265, Lot (5) 36F94781) for Sigma company.
Result of the test is as shown in table 3, and in selected dosage range, each administration group has obvious inhibitory action to platelet aggregation, and its aggregation rate and matched group relatively have highly significant difference.
Table 3 compound hydrochloric acid ticlopidine is to (the X ± SD) of platelet aggregation influence in the thrombin induction rat body
| Group | Dosage mg/kg | Number of animals only | Platelet aggregation % | Suppress % |
| Matched group T+N N | - 140.0+4.8 70.0+2.4 35.0+1.2 200 | 10 10 10 10 10 | 49.3±5.8 10.8±3.2 ** 31.4±7.1 ** 43.2±6.4 ** 23.5±5.6 ** | - 77.3 36.3 19.5 52.3 |
Compare with matched group
*P＜0.01,
*Annotate P＜0.05: T: ticlopidine hydrochloride N: nitrendipine
Experiment 4, to the influence (collagen adhesion method) of platelet adhesion
25 rabbit are divided into 5 groups at random, if blank group, 3 dosage groups of ticlopidine hydrochloride/nitrendipine are respectively 36.4mg/1.25mg/kg, 18.2mg/0.63mg/kg, 9.1mg/0.32mg/kg and ticlopidine hydrochloride 104mg/kg animal subject is by above-mentioned dosage ig administration every day 1 time, for three days on end, 1.5h after the last administration, routine is got blood at auricular vein, preparation PRP, PPP and solubility in acid collagen, (make platelet count with PPP adjusting PRP is 300 to (the collagen final concentration is 0.05mg/ml) back platelet count add collagen in platelet aggregation instrument t measures the silication opacity tube before, 000 ± 20,000/ μ l is by formula:
Wherein A is for adding collagen thromboblast number, and B is a platelet count behind the adding collagen, is observation index with platelet adhesion rate (%), compares the t-check between each administration group and matched group are organized.
Result of the test shows that ig compound hydrochloric acid ticlopidine has obvious inhibitory action to rabbit in vitro method platelet adhesion in selected dosage range.
Table 4 compound hydrochloric acid ticlopidine is to the influence of rabbit platelet adhesion
| Group | Dosage mg/kg | Number of animals only | Platelet count (1 * 10 5/ul) | Platelet adhesion rate % | ||
| Before adding collagen | After adding collagen | Difference | ||||
| Matched group T+N N | - 16.4+1.25 18.2+6.3 9.1+0.32 104.0 | 5 5 5 5 5 | 3.04±0.18 3.00±0.16 2.96±0.18 3.06±0.17 2.94±0.20 | 1.50±0.16 2.26±0.65 1.82±0.34 1.66±0.23 1.94±0.32 | 1.54±0.18 0.74±0.53 ** 0.94±0.29 ** 1.40±0.24 1.00±0.20 ** | 50.7 24.7 38.5 45.8 34.0 |
Compare with matched group
*Annotate P＜0.01: T: ticlopidine hydrochloride N: nitrendipine
Experiment 5, platelet dependency thrombotest: to the thrombotic influence of rabbit common carotid artery
The animal subject grouping, administering mode, dosage are with experiment 4, after the last administration, use pentobarbital sodium with 30mg/kg anesthesia, free common carotid artery, to be about the 3cm silk thread with fine needle penetrates in the total arteries and veins of neck, after intra-arterial is preserved 2 hours, wipe out common carotid artery, remove silk thread, claim wet weight of thrombus, calculate the thrombosis suppression ratio.Thrombosis suppression ratio=[matched group wet weight of thrombus-administration group wet weight of thrombus]/matched group wet weight of thrombus * 100%.
The influence that table 5 compound hydrochloric acid ticlopidine rabbit platelet thrombus forms
| Group | Dosage mg/kg | Number of animals only | Wet weight of thrombus mg | Thrombosis suppression ratio % |
| Matched group T+N N | - 72.8+2.5 36.4+1.25 18.2+0.63 208.0 | 5 5 5 5 5 | 14.1±3.0 5.8±2.6 ** 7.3±2.0 ** 10.0±2.6 * 6.9±1.6 ** | - 58.9 48.2 29.1 51.1 |
Compare with matched group
*P＜0.05,
*Annotate P＜0.01: T: ticlopidine hydrochloride N: nitrendipine
Result of the test is as shown in table 5, and the compound hydrochloric acid ticlopidine forms the rabbit platelet thrombus and is obvious inhibitory action in selected dosage range.
The experiment 6, to platelet dependency thrombosis plasma in rabbit thromboxane B
2With 6-ketone-PGF
1 αThe influence of content
Except that establishing the blank group, all the other respectively organize administering mode, and dosage is all with experiment 5, organize more animal subject all before administration and after making thrombosis 2 hours (before getting thrombosis) take a blood sample respectively, by Chinese People's Liberation Army General Hospital's East Asia immunological technique institute medicine box explanation, with indometacin-EDTA-Na
2Anticoagulant adopts FJ2008 r rabbit epidemic disease enumerator (Xi'an nuclear instruments factory) to measure blood plasma TXB
2, 6Keto-PGF
1 αContent, before above-mentioned two indexes administration, and the difference of content compares significance test between organizing behind the making thrombosis.
Result of the test as shown in table 6 shows that the medication in 3 days in advance of this compound recipe can reduce because the common carotid artery thrombosis is made the TXB that is caused
2Increase.TXB before and after senior middle school's dosage group administration of administration
2TXB before and after content difference and the model control group administration
2Notable difference (P＜0.05) is arranged between difference, but to 6-Keto-PGF
1 αContent does not have obvious influence.Positive control drug ticlopidine folk prescription, though shift to an earlier date administration 3 days, to make the TXB that causes owing to common carotid artery
2Content increases does not have obviously influence, compares no significant difference with model control group.
Blood plasma TXB before and after table 6 compound hydrochloric acid ticlopidine is made rabbit common carotid artery thrombosis
2, 6Keto-PGF
1 αContent influence
| Group | Dosage mg/kg | Number of animals only | Platelet count (1 * 10 5/ul) | 6Keto-PGF 1 | ||
| Before the administration | After the administration (thrombosis system is used) | Difference | TXB 2％ | |||
| Blank control group T+N N | - - 72.8+2.5 36.4+1.25 18.2+0.63 208.0 | 5 5 5 5 5 5 | 324.8±104.7 38.3±16.1 367.2±82.8 38.8±9.1 348.0±91.0 29.5±7.3 378.9±70.0 32.3±9.0 426.4±86.5 32.6±7.7 360.6±78.9 41.7±11.2 | 380.2±91.1 50.2±12.1 1160.4±358.1 110.0±31.9 816.2±133.4 104.7±18.0 819.2±154.2 107.9±24.0 1152.2±155.4 103.4±24.1 1059.8±124.1 104.8±20.5 | 55.4±21.3 9.8±7.2 793.4±298.6 △△ 70.7±24.0 △△ 388.4±71.4 * 75.2±17.9 450.2±138.0 * 75.6±22.5 725.0±150.6 71.0±21.2 699.6±131.2 63.1±9.9 | 17.7 8.9 19.4 16.8 9.8 9.0 |
Compare with matched group
*△ △ P＜0.01 is compared with the blank group in P＜0.05
Annotate: T: ticlopidine hydrochloride N: nitrendipine
Experiment 7, compound hydrochloric acid ticlopidine are to the influence in mouse tail bleeding time
50 male mices are divided equally 5 groups, and being tried the agent amount is that ticlopidine hydrochloride/nitrendipine is respectively 98.0/3.36mg/kg, 49.0/1.68mg/kg, 24.5/0.84mg/kg, and other establishes the positive control drug group: ticlopidine hydrochloride 100mg/kg; The blank group is given quite volumetrical solvent.
Gastric infusion, every day 1 time, for three days on end, after the last administration 1.5 hours, 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 tail 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 7, obviously prolongs the mouse tail bleeding time with blank group comparison compound hydrochloric acid ticlopidine, and highly significant difference is arranged therebetween.
The influence when hemorrhage to mouse tail of table 7 compound hydrochloric acid ticlopidine (X ± SD)
| Group | Dosage mg/kg | Number of animals only | Platelet aggregation % |
| Blank T+N N | - 98.0+3.36 49.0+1.68 24.5+0.84 140.0 | 10 10 10 10 10 | 119.6±23.8 392.9±34.6 ** 284.6±37.0 ** 206.6±33.0 ** 189.0±27.4 ** |
Compare with the blank group
*Annotate P＜0.01: T: ticlopidine hydrochloride N: nitrendipine
Experiment 8, mouse lung thrombotest
100 mices are divided equally 5 groups at random; administering mode dosage is with test 7; 1.5h after the last administration; the strong co-induction agent of mouse tail vein injection collagen and epinephrine 5.0ml/kg (collagen 2.5mg/kg+ epinephrine 2mg/kg); injection speed is 0.1ml/5sec; observing death condition in the mice 3min, is observation index with every group of dead animal number and protective rate.
Result of the test is as shown in table 8, and result of the test is through X
2Check shows in the selective agent weight range that the compound hydrochloric acid ticlopidine causes death to collagen and epinephrine inducing mouse lung thrombosis and is obvious protective effect.
Table 8 compound hydrochloric acid ticlopidine brings out the lethal influence of mouse lung thrombosis to collagen+epinephrine complex
| Group | Dosage mg/kg | Dead animal/animal subject (only) | Protection (%) | ED 50 mg/kg，day | X 2 | P |
| Matched group T+N N | - 98.0+3.36 49.0+1.68 24.5+0.84 100 | 18/20 5/20 9/20 13/20 10/20 | 75.0 55.0 35.0 50.0 | 51.6/1.8 | 14.7315 7.2934 2.2939 5.8333 | ＜0.01 ＜0.01 ＞0.05 ＜0.05 |
Annotate: T: ticlopidine hydrochloride N: nitrendipine
Conclusion (of pressure testing): to sum up result of the test shows; ticlopidine hydrochloride and nitrendipine use by a certain percentage; to adenosine diphosphate (ADP); collagen; platelet such as thrombin induce the inductive animal subject platelet aggregation of aggregating agent prepared therefrom process that obvious inhibitory action is arranged, and collagen one epinephrine complex is brought out mouse lung thrombosis cause death obvious protective effect is also arranged.Obviously prolong the mouse tail bleeding time.Rabbit common carotid artery thrombosis also there is obvious inhibitory action, and obviously reduces because of the blood plasma TXB due to the thrombosis
2Content increases, to blood plasma 6Keto-PGF
1 αContent does not have obvious influence.
Various ingredients is to the test of drug effect or toxic effect in experiment 9, the compound hydrochloric acid ticlopidine
Summary: inducing rat intracorporal method platelet aggregation inhibition rate with ADP is index, with Jin Shi probability additive process research various dose, different proportion ticlopidine hydrochloride and nitrendipine interaction relationship, wherein nitrendipine/ticlopidine hydrochloride=2.4mg/70.0mg/kg organizes q=1.20, and synergism is best.Use orthogonal design method: L9 (3
2) experimentize, the result shows: when nitrendipine/ticlopidine hydrochloride=2.4/70.0mg/kg, to the hematoblastic inhibitory action of the inductive intracorporal method of ADP, based on ticlopidine hydrochloride.Use the direct-vision method deal with data, the extreme difference value of ticlopidine hydrochloride and nitrendipine (R value) is respectively 26.0 and 9.4; The F-assay shows: ticlopidine hydrochloride F value is 36.81 (P＜0.05), and nitrendipine F value is 4.25F (P＞0.05).
Test objective: the inhibitory action to platelet aggregation in the inductive rat body of ADP behind discussion ticlopidine hydrochloride and the nitrendipine compatibility reaches compatibility relationship preferably:
Be subjected to the reagent thing: (ticlopidine, T), lot number: 970302 content: 98.9% is produced in Shenyang Huatai Medicine Inst.'s self-control (existing approved is formally produced) to ticlopidine hydrochloride.
Nitrendipine (nitrendipine) Nanjing Pharmaceutical Plant produces, lot number 960104, content 99.4%.Above-mentioned medicine provides by Shenyang Huatai Medicine Inst..
Nitrendipine faces with preceding and becomes the higher concentration suspension with the 0.5%CMC-Na suspendible: ticlopidine hydrochloride is prepared with 0.9%Na, and each gastric infusion volume is 20.0ml/mg.
Animal housing of animal Shenyang Pharmaceutical University provides Wistar rat, and is male, body weight 250 ± 20g, and 160 of animal sums, 10 every group, the animal quality certification number closes word 517 for distant real kinoplaszm.
Test method:
1, ticlopidine hydrochloride, nitrendipine drug combination Research on effect
(illumination in 12 hours provides the standard bait by animal housing to animal subject for 20 ± 3 ℃ of observation ward's temperature, relative humidity 30～70%, the drink tap water in indoor one week of observation of breeding observing.Animal subject is pressed as the following table random packet.Every day, the ig administration was 1 time, for three days on end, after the last administration 1.0 hours, under waking state, get blood from the optical fundus, with 3.8% sodium citrate anticoagulant, conventional preparation PRP, PPP, selection causes that the ADP final concentration of matched group 50 ± 10% platelet aggregations is 3.0～6.0umol/L, and carry out statistical procedures with the mean and the matched group aggregation rate mean of each administration group platelet aggregation rate of this ADP quantitative determination, significance test, and obtain many administrations group platelet aggregation inhibition rate.% * 100% is assembled in (assemble and suppress %=contrast gathering %-administration gathering %)/contrast).With the suppression ratio is index.By formula
Obtain the group Q-value, nitrendipine/ticlopidine=2.4: 70.0mg/kg wherein, group q value maximum, q=1.2 illustrates that two medicines join value in this ratio and induce the inhibition of intracorporal method platelet aggregation to be synergism (seeing table 10 for details) to ADP.
Table 9 ticlopidine hydrochloride nitrendipine drug combination effect research grouping catalog
| Medicine | Dosage (mg/kg) | ||
| N T N+T | 2.4 35.0 2.4+35.0 4.8+35.0 9.6+35.0 | 4.8 70.0 2.4+70.0 4.8+70.0 9.6+70.0 | 9.6 140.0 2.4+140.0 4.8+140.0 9.6+140.0 |
Annotate: T: ticlopidine hydrochloride N: nitrendipine
2, the optimum organization of ticlopidine hydrochloride-nitrendipine test: test grouping and result of the test are as shown in table 10, press L
9(3
2) the row orthogonal table, be index with the platelet aggregation inhibition rate, by the direct-vision method analysis, the result shows ticlopidine hydrochloride R=22.0, nitrendipine R=9.4; The F-check, the result shows: ticlopidine hydrochloride F=36.810 (P＜0.05), nitrendipine F=4.257 (R＜0.05).
Result of the test: in the compound recipe that ticlopidine hydrochloride, nitrendipine are formed, with ticlopidine hydrochloride 70.0mg/kg, nitrendipine 2.4mg/kg is obvious inhibitory action to the inductive rat intracorporal method of ADP platelet aggregation, prove with the general root rate of Jin Shi additive process, two medicines are in this ratio compatibility, drug effect strengthens, and is synergism, q=1.2.
Table 10 ticlopidine hydrochloride, nitrendipine drug combination effect analysis (ADP being induced the influence of intracorporal method platelet aggregation) n=10
| Group | Dosage mg/kg | Platelet aggregation rate % | Suppression ratio | Q-value |
| Control group nitrendipine group A ticlopidine hydrochloride group B nitrendipine/ticlopidine hydrochloride group | - A 1 9.6 A 2 4.8 A 3 2.4 B 1 140.0 B 2 70.0 B 3 35.0 A 1B 1 A 1B 2 A 1B 3 A 2B 1 A 2B 2 A 2B 3 A 3B 1 A 3B 2 A 3B 3 | 51.4±4.8 13.7±4.8 29.9±13.5 39.2±9.7 11.7±4.9 17.8±7.3 21.4±10.7 10.7±4.5 9.7±5.7 24.1±13.4 8.3±3.4 11.0±2.8 24.1±16.1 8.3±3.1 6.8±2.9 16.9±4.4 | - 73.3±25.1 42.0±23.4 23.6±19.2 77.4±27.5 65.4±10.1 58.4±20.9 79.2±10.2 81.1±9.8 50.2±28.4 83.8±6.6 78.6±5.4 52.6±30.7 83.8±5.9 88.0±6.4 67.0±8.4 | 0.84 0.89 0.56 0.96 0.98 0.70 1.01 1.20 0.96 |
L
9(3
2) table 11 different proportion nitrendipine (A), ticlopidine hydrochloride (B) two recurrence due to taking drug square preparations be right
ADP induces the influence of intracorporal method platelet aggregation
Tested number nitrendipine (A) ticlopidine hydrochloride (B) suppression ratio
(mg/kg) (mg/kg) ％
1 2.4 35.0 67.0±8.4
2 2.4 70.0 88.0±6.4
3 2.4 140.0 83.8±5.9
4 4.8 35.0 52.6±30.7
5 4.8 70.0 78.6±5.4
6 4.8 140.0 83.8±6.6
7 9.6 35.0 50.2±28.4
8 9.6 70.0 81.1±9.8
9 9.6 140.0 79.2±10.2
Factor A, K
1=238.8 factor B K
1=169. ∑ y=664.3
K
2＝215.0 K
2＝247.7 y＝664.3/9＝73.8
K
3＝210.5 K
3＝246.8
K
1＝79.6 K
1＝56.6 ∑y
2＝50592.49
K
2＝71.7 K
2＝82.6
K
3＝70.2 K
3＝82.3
Extreme difference R 9.4 26.0
Table 12 different proportion nitrendipine (A) ticlopidine hydrochloride (B) is assembled inhibitory action analysis of variance table (intracorporal method) F0.05 (2: 2)=19.0 to the ADP induced platelet
| Source of variation (1) | Centrifugal poor quadratic sum (l) (2) | Degree of freedom (n) (3) | Mean square (MS) (4)=(2) ÷ (3) | F 5 | P (6) |
| A factor B factor error amounts to | 154.18 1333.14 72.45 1559.77 | 2 2 4 | 77.09 666.57 18.11 | 4.257 36.81 | ＞0.05 ＜0.05 |
Claims (7)
1. the pharmaceutical composition of an antiplatelet aggregation, it is characterized in that: described compositions is made up of ticlopidine hydrochloride and nitrendipine basically.
2. the pharmaceutical composition of antiplatelet aggregation according to claim 1 is characterized in that containing the ticlopidine hydrochloride of 100 weight portions and the nitrendipine of 1.7-26 weight portion.
3. the pharmaceutical composition of antiplatelet aggregation according to claim 2 is characterized in that containing the ticlopidine hydrochloride of 100 weight portions, and the content of nitrendipine is the 3-4 weight portion.
4. according to the pharmaceutical composition of claim 1,2 or 3 described antiplatelet aggregation, it is characterized in that it is the unit dose of solid form.
5. the pharmaceutical composition of antiplatelet aggregation according to claim 4 is characterized in that it is the unit dose of tablet or Capsule form.
6. the pharmaceutical composition of antiplatelet aggregation according to claim 5 is characterized in that wherein said unit dose contains the ticlopidine hydrochloride of 25-250mg and the nitrendipine of 1-10mg.
7. the pharmaceutical composition of antiplatelet aggregation according to claim 6 is characterized in that wherein said unit dose contains the ticlopidine hydrochloride of 50-100mg and the nitrendipine of 2-4mg.
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