WO2016169296A1 - 一种含有替格瑞洛的药物组合物 - Google Patents

一种含有替格瑞洛的药物组合物 Download PDF

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WO2016169296A1
WO2016169296A1 PCT/CN2016/000141 CN2016000141W WO2016169296A1 WO 2016169296 A1 WO2016169296 A1 WO 2016169296A1 CN 2016000141 W CN2016000141 W CN 2016000141W WO 2016169296 A1 WO2016169296 A1 WO 2016169296A1
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ticagrelor
group
drug
triflumuron
triflusal
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PCT/CN2016/000141
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English (en)
French (fr)
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陈秀兰
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广州诺威生物技术有限公司
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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a medicament for inhibiting thrombus formation.
  • thrombotic diseases such as myocardial infarction and cerebral thrombosis are among the highest in various diseases.
  • Coronary artery or cerebrovascular artery stenosis and thrombosis are caused by repeated damage to blood vessels based on atherosclerosis.
  • platelets adhere to the exposed subendothelial tissue, and the adhered platelets release the contents of the granules, adenosine diphosphate (ADP) and thromboxane A 2 (TXA 2 ) formed by metabolism of membrane phospholipids.
  • ADP adenosine diphosphate
  • TXA 2 thromboxane A 2
  • Vascular injury also activates the coagulation system, and the resulting thrombin promotes further aggregation of platelets, which also leads to the formation of fibrin, which is stabilized by cross-linking.
  • Antiplatelet drugs can inhibit the adhesion, aggregation and release of platelets, inhibit thrombosis, and therefore play an important role in the prevention and treatment of thrombotic diseases.
  • Triflumuride anti-platelet coagulant has more specific effects than acetylsalicylic acid (aspirin) in the prevention and treatment of thromboembolic diseases and complications. Compared with aspirin, it can simultaneously antagonize the activities of cyclooxygenase and c-AMP phosphodiesterase, and has strong anti-platelet aggregation ability, but has little effect on prostacyclin biosynthesis at therapeutic dose, and the bleeding risk is also very high. small. Studies have shown that trifluralin and aspirin do not differ in the prevention of severe cardiovascular events in patients with peripheral arteriosclerotic occlusive disease (PAOD), but the incidence of severe bleeding complications is significantly lower than aspirin.
  • PAOD peripheral arteriosclerotic occlusive disease
  • Tigrelor is a novel, selective small molecule anticoagulant and the first reversible combined oral P2Y12 adenosine diphosphate receptor antagonist, reversible
  • the ⁇ 2 receptor subtype P2Y12 which acts on vascular smooth muscle cells (VSMC), has a significant inhibitory effect on platelet aggregation induced by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. Because of the reversible antiplatelet effect of ticagrelor, it is especially suitable for patients who need to undergo surgery before anticoagulation.
  • the invention provides a drug for inhibiting thrombus formation with good efficacy and safety.
  • the medicament for inhibiting thrombus formation provided by the invention is characterized in that the active ingredient thereof is trifluoro-recipe and ticagrelor; the mass ratio of triflumuron to ticagrelor is (50-350): 30-150).
  • the mass ratio of the trifluorolius and ticagrelor in the active ingredient of the drug may be (50-600): (30-350, preferably (50-300): (50-100).
  • the unit dose of the drug may contain 130-800 mg of the active ingredient, preferably 130-700 mg of the active ingredient.
  • the unit dose of the drug may contain 30-300 mg of triflumur and 30-100 mg of ticagrelor.
  • the unit dose of the drug preferably contains 100-300 mg of triflumur and 50-100 mg of ticagrelor.
  • the drug can be in the form of an oral formulation.
  • the drug may be in the form of a tablet, capsule, granule or dry suspension.
  • the medicament may further comprise an adjuvant; the adjuvant being at least one of the following components: microcrystalline cellulose, sodium carboxymethyl starch, dextrin, lactose, magnesium stearate.
  • the medicament can be applied to the treatment of cardiovascular and cerebrovascular diseases.
  • cardiovascular and cerebrovascular diseases may specifically be cardiovascular and cerebrovascular diseases caused by platelet aggregation.
  • the cardio-cerebral vascular disease may specifically be at least one of angina pectoris, coronary embolism, and cerebrovascular embolization.
  • the medicament can be applied to inhibit platelet aggregation and/or inhibit thrombus formation.
  • ticagrelor can be used in the form of preparation of ticagrelor drug cocrystal according to the disclosed invention CN201310637333.0.
  • Example 1 Inhibition of thrombosis and platelet aggregation by the drug of the present invention
  • the polyethylene tube was accurately injected with heparin anticoagulation, and then the other end of the polyethylene tube was inserted into the right carotid artery, the artery clamp was opened, the AV was bypassed, the blood flow was opened for 15 min, the polyethylene tube was taken out, and the silk thread was taken out ( Containing thrombus), placed in a small weighing dish that has been weighed, the balance of the thrombus is weighed by the analytical balance, and the weight of the wire is subtracted from the weight of the wire to obtain the weight of the thrombus.
  • Thrombosis inhibition rate (%) (normal saline control group - weight of the administration group) / physiological saline control group weight ⁇ 100%. The results are shown in Table 1.
  • Triflumuron combined with clopidogrel and ticagrelor in combination with anti-thrombotic effects anti-thrombotic effect in 1:1 ratio of triflural willow and ticagrelor group (group G) It is superior to triflumuron group (group B), ticagrelor group (group H), group J (weight ratio of aspirin and clopidogrel is 1:1); at other mass ratios, trifluoro-willow and tigri
  • the pharmaceutical composition of rulo is preferably in a mass ratio of 6:1 and 3:1; the combination of triflumur and tigrelor is superior to the trifluoro-salt and tigrelor unilateral as well as aspirin and chlorine.
  • a composition of pirogram A composition of pirogram.
  • the supernatant plasma PRP
  • the remaining plasma was centrifuged at 3000 r/min for 20 minutes, and the lower transparent liquid was PPP.
  • the number of platelets in the PRP was counted, and the platelets in the PRP were adjusted to 200 ⁇ 10 9 /L with PPP.
  • the siliconized pipette takes 450 ul of PPP and PRP into the turbidity tube respectively.
  • the PPP specimen is used to adjust the transmittance of the recorder to 100, and then the PRP specimen is placed in the measuring hole to adjust the transmittance.
  • Example 2 Determination of rat ulcer inhibition rate
  • Group A the composition of the drug aspirin and clopidogrel (weight ratio of aspirin and clopidogrel was 1:1);
  • Group B administration of the drug aspirin Composition with clopidogrel and omeprazole (weight ratio of aspirin and clopidogrel and omeprazole is 2:2:1);
  • group C administration of drugs (three The weight ratio of fluocinol to ticagrelor is 20:1);
  • D the drug is administered: the weight ratio of triflumuron to ticagrelor is 12:1;
  • group E administration of drugs (trifluoro-willa and ticagrelor) The weight ratio was 6:1);
  • Group F administration of the drug (weight ratio of triflumuron to ticagrelor was 3:1);
  • Group G administration of the drug (the weight ratio of triflumuron to ticagrelor was 1:1);
  • Group H administration of the drug (the weight ratio of triflumuron to ticagrelor was 1:1);
  • Group H administration of the drug (the weight
  • mice Each group was intragastrically administered, and 2 ml of physiological saline was administered to each group in the blank control. The other groups were added to 2 ml of physiological saline, stirred, and administered once a day, each dose of 10 mg of drug/kg body weight ( To the composition drug, 10 mg is the total mass of the components added for a total of 14 days. After 2 hours of the last administration, the rats were weighed and the neck was sacrificed. The stomach of the rats was cut along the stomach curvature, and the stomach wall was cut. After being turned over, it was rinsed with water, soaked in physiological saline for 10 minutes, and then spread on a glass plate to observe gastric mucosal damage.
  • the ulcer index and the ulcer inhibition rate were calculated. Ulcer degree evaluation: Guth standard score - point bleeding 1 point; linear bleeding, if the width ⁇ 1mm, erosion length ⁇ 1mm, 2 points, 1 ⁇ 2mm 3 points, 2 ⁇ 4mm 4 points, > 4mm 5 points; if the width is >1mm, the above score is ⁇ 2.
  • the ulcer index of each group was calculated. The results are shown in Table 3:
  • test group of ticagrelor and triflumuron composition was less likely to develop gastric ulcer, and the incidence of ulcer was slightly lower than that of group B (aspirin and clopidogrel and omeprazole group), while group J (aspirin and chloropyridin) Gray group) has a higher incidence of ulcers, suggesting that the combination of ticagrelor and triflumuron has better safety.
  • Example 3 Stability of the drug of the present invention
  • Drug I the mass ratio of triflumuron and ticagrelor is 1:1;
  • Drug II the mass ratio of triflumuron and ticagrelor is 3:1;
  • Drug III the mass ratio of triflumuron and ticagrelor is 6:1;
  • Drug IV the mass ratio of triflumuron and ticagrelor is 12:1;
  • Drug V trifluoro-willow and ticagrelor mass ratio of 20:1;
  • the active ingredient was determined by high performance liquid chromatography.
  • the column was a cyano column
  • the mobile phase was methanol-water-triethylamine (500:500:2 by volume
  • the pH was adjusted to 3.8 by phosphoric acid)
  • the flow rate was 1 mL.
  • ⁇ min -1 the detection wavelength is 235 nm
  • the column temperature is 35 ° C
  • the injection volume is 20 ⁇ L.
  • Example 3 Preparation of a medicament (capsule) for treating cardiovascular and cerebrovascular diseases
  • Example 4 Preparation of a drug (tablet) for treating cardiovascular and cerebrovascular diseases
  • the above ticagrelor was mixed with silica, then pregelatinized corn starch and lactose were added, and trifluoro-salt and microcrystalline cellulose were added and compressed.
  • the invention provides a medicament for treating cardiovascular and cerebrovascular diseases.
  • the active ingredients of the medicament provided by the present invention are triflumur and ticagrelor, and the two have a synergistic effect.
  • the results of the experiment showed that the trifluoro-Terinomycin composition inhibited thrombosis and anti-platelet aggregation better than the combination of triflumur and ticagrelor alone and aspirin and clopidogrel, and the incidence of gastric ulcer.
  • a composition lower than aspirin and clopidogrel.

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Abstract

一种抑制血栓形成的药物，它的活性成分由一定比例的三氟柳和替格瑞洛组成；三氟柳和替格瑞洛的质量比为(20∶1-1∶6)。实验结果表明：三氟柳-替格瑞洛组合物与阿司匹林氯吡格雷组合物(对照)相比，抑制血栓形成和抗血小板聚集的效果要好的多，更优于单独三氟柳和单独替格瑞洛，且溃疡发生率低于对照组；经过6个月的稳定性试验观察，表明三氟柳-替格瑞洛组合物稳定性较好，适于做成口服制剂。

Description

一种含有替格瑞洛的药物组合物 技术领域
本发明涉及一种抑制血栓形成的药物。
背景技术
心肌梗塞和脑血栓等血栓性疾病的发病率、致残率和死亡率在各种疾病中居前列。冠状动脉或脑血管动脉狭窄及血栓形成，是在动脉粥样硬化的基础上，血管反复损伤所致。血管损伤时，血小板粘附于暴露的内皮下组织，粘附的血小板释放其颗粒中的内容物，二磷酸腺苷(ADP)及经膜磷脂代谢形成的血栓素A2(TXA2)，二者激活循环中的血小板，在纤维蛋白原的参与下，血小板聚集成团，形成血小板血栓。血管损伤亦激活凝血系统，生成的凝血酶促使血小板进一步聚集，亦导致纤维蛋白的形成，经交联使动脉血栓稳固。抗血小板药可抑制血小板的粘附、聚集和释放功能，阻抑血栓形成，因此在血栓性疾病的防治中具有重要地位。
三氟柳属抗血小板凝聚剂，在预防和治疗血栓栓塞性疾病及并发症上比乙酰水杨酸(阿司匹林)具有更特殊的效果。与阿司匹林相比，可同时拮抗环氧合酶和c-AMP磷酸二酯酶的活性，抗血小板聚集能力强，但在治疗剂量时对前列环素生物合成的影响很小，出血危险性也很小。研究表明，三氟柳与阿司匹林在预防周围动脉硬化闭塞性疾病(PAOD)患者严重心血管事件方面无差别，但其严重出血并发症的发生率显著低于阿司匹林。
替格瑞洛(ticagrelor，替卡格雷)是一种新型的、具有选择性的小分子抗凝血药，也是第一个可逆的结合型口服P2Y12腺苷二磷酸受体拮抗剂，能可逆性地作用于血管平滑肌细胞(VSMC)上的嘌呤2受体亚型P2Y12，对ADP引起的血小板聚集有明显的抑制作用，能有效改善急性冠心病患者的症状。因为替格瑞洛的可逆性抗血小板作用，尤为适用于那些需在先期进行抗凝治疗后再行手术的病人。
发明公开
本发明提供了一种抑制血栓形成的药物具有较好的药效和安全性。
我们发现替格瑞洛和三氟柳的组合物具有较好的协同作用，动物实验表明抑制血栓凝集的作用大于单方组以及阿司匹林和氯吡格雷组，这是由于不同的 作用机制的活性成分形成的互补作用，能够达到单一药物所不能达到的效果。为了进一步观察替格瑞洛和三氟柳的组合物的安全性，我们同时设计试验进行胃溃疡反应发生率的比较，设定阿司匹林氯吡格雷对照组以及阿司匹林和氯吡格雷和奥美拉唑对照组，结果显示一定比例的三氟柳和替格瑞洛组的胃溃疡发生率比阿司匹林和氯吡格雷和奥美拉唑组合物稍低，且小于阿司匹林和氯吡格雷组，由此说明一定比例下的替格瑞洛和三氟柳的组合物药效及安全性均优于对照组，是一个优选的组合物。同时由于稳定性是决定复方制剂是否能够成药的重要因素，我们通过6个月的稳定性试验发现替格瑞洛和三氟柳可以制备成复方口服制剂在临床使用中用于抑制血栓的形成。
本发明提供的抑制血栓形成的药物，其特征在于：它的活性成分为三氟柳和替格瑞洛(ticagrelor)；三氟柳和替格瑞洛的质量比为(50-350)∶(30-150)。
所述药物的活性成分中，三氟柳和替格瑞洛的质量比可为(50-600)∶(30-350，优选为(50-300)∶(50-100)。
以上任一所述药物中，单位剂量的所述药物可含有130-800mg所述活性成分，优选含有130-700mg所述活性成分。
单位剂量的所述药物中，可含有30-300mg三氟柳和30-100mg替格瑞洛。单位剂量的所述药物中，优选含有100-300mg三氟柳和50-100mg替格瑞洛。
所述药物可为口服制剂的剂型。
所述药物可为片剂、胶囊剂、颗粒剂或干混悬剂。
所述药物还可包括辅料；所述辅料为如下成分中的至少一种：微晶纤维素、羧甲基淀粉钠、糊精、乳糖、硬脂酸镁。
所述药物可应用于治疗心脑血管疾病。所述心脑血管疾病具体可为因血小板凝集而引起的心脑血管疾病。所述心脑血管疾病具体可为心绞痛、冠状动脉栓塞、脑血管栓塞中的至少一种。
所述药物可应用于抑制血小板凝集和/或抑制血栓形成。
其中替格瑞洛可以依据已公开发明CN201310637333.0制备成替格瑞洛药物共晶的形式使用。
实施发明的最佳方式
以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料， 如无特殊说明，均为自常规生化试剂商店购买得到的。下述实施例中的％，如无特殊说明，均为质量百分含量。三氟柳、替格瑞洛、阿司匹林、氯吡格雷、奥美拉唑等均为市场购买。
实施例1：本发明药物对血栓形成的和血小板凝集的抑制作用
一、药物对大白鼠血栓形成的抑制作用
体重300-400克的SD大白鼠100只，雌雄各半。随机分为10组，每组10只，给药情况如下：A组：空白对照：给予生理盐水；B组：三氟柳对照组：给予药物三氟柳；C组：给予药物(三氟柳和替格瑞洛重量比为20∶1)；D：给予药物：三氟柳和替格瑞洛的重量比为12∶1；E组：给予药物(三氟柳和替格瑞洛的重量比为6∶1)；F组：给予药物(三氟柳和替格瑞洛的重量比为3∶1)；G组：给予药物(三氟柳和替格瑞洛的重量比为1∶1)；H组：替格瑞洛组：给予替格瑞洛；I组：给予药物(三氟柳和替格瑞洛的重量比为1∶6)；J组：给予药物(阿司匹林和氯吡格雷的重量比为1∶1)
实验方法：各组灌胃给药，空白对照给予每次2ml生理盐水，其它各组将药物加入到2ml生理盐水中，搅拌，每天给药1次，每次按10mg药物/kg体重给药(给予组合物药物的，10mg为各组分相加的总质量)，共5天。
大鼠给药第5天，末次给药1小时后，动物称重，注射3％戊巴比妥纳麻醉(1ml/kg体重)。仰卧位固定，取颈正中切口，分离气管，分离双侧颈总动、静脉，在聚乙烯管中穿6cm丝线，以肝素生理盐水溶液充满聚乙烯管，当聚乙烯管的一端插入左侧颈外静脉后，由聚乙烯管准确的注入肝素抗凝，再将聚乙烯管另一端插入右侧颈动脉，打开动脉夹，造成A-V旁路，开放血流15min，取出聚乙烯管，抽出丝线(含血栓)，按号置于已称重的小培养皿中，分析天平称取血栓湿重，总重量减去丝线重量即得血栓重量。血栓形成抑制率(％)＝(生理盐水对照组栓重-给药组栓重)/生理盐水对照组栓重×100％。结果见表1。
表1 各给药组的血栓重量比较
Figure PCTCN2016000141-appb-000001
Figure PCTCN2016000141-appb-000002
三氟柳和氯吡格雷及替格瑞洛复方配伍使用后在抗血栓形成方面有协同作用；质量比为1∶1的三氟柳和替格瑞洛组(G组)抑制血栓形成的效果优于三氟柳组(B组)、替格瑞洛组(H组)、J组(阿司匹林和氯吡格雷的重量比为1∶1)；其它各个质量比下，三氟柳和替格瑞洛的药物组合物中以6∶1和3∶1的质量比比较好；三氟柳和替格瑞洛的组合物优于三氟柳单方组和替格瑞洛单方组以及阿司匹林和氯吡格雷的组合物。
二、药物对大白鼠血小板聚集性的影响(比浊法)
体重300-400克的SD大白鼠100只，雌雄各半。随机分为10组，每组10只，给药情况如下：A组：空白对照：给予生理盐水；B组：三氟柳对照组：给予药物三氟柳；C组：给予药物(三氟柳和替格瑞洛重量比为20∶1)；D：给予药物：三氟柳和替格瑞洛的重量比为12∶1；E组：给予药物(三氟柳和替格瑞洛的重量比为6∶1)；F组：给予药物(三氟柳和替格瑞洛的重量比为3∶1)；G组：给予药物(三氟柳和替格瑞洛的重量比为1∶1)；H组：替格瑞洛组：给予替格瑞洛；I组：给予药物(三氟柳和替格瑞洛的重量比为1∶6)；J组：给予药物(阿司匹林和氯吡格雷的重量比为1∶1)
实验方法：各组灌胃给药，空白对照给予每次2ml生理盐水，其它各组将药物加入到2ml生理盐水中，搅拌，每天给药1次，每次按10mg药物/kg体重给药(给予组合物药物的，10mg为各组分相加的总质量)，共7天。
大鼠给药第7天，末次给药半小时后，从大鼠眼后动脉取血，0.13％构缘酸 钠抗凝(血液与抗凝剂容积比为9∶1)，将血液注入硅化试管内，用塑料薄膜覆盖离心管口，将离心管倒转3-4次使血液与抗凝剂充分混匀，用清洁的滤纸吸去附着在管壁残留的血液，并加紧盖盖紧离心管。以1000r/min离心10分钟，小心取出上层血浆(PRP)，将剩余血浆以3000r/min离心20分钟，下层透明液体为PPP。计数PRP中的血小板数，用PPP将PRP中的血小板调至200×109/L。硅化处理的移液管取PPP和PRP各450ul分别置入比浊管内，测定时先以PPP标本将记录仪的透光度调节到100，然后将PRP标本放入测定孔，调节透光度为10，并加搅拌磁棒，在37℃预热3分钟，打开记录仪，在PRP中加入ADP(二磷酸腺苷)诱导血小板聚集剂，用CHROND-Log血小板聚集仪(美国)，通过聚集曲线算出血小板最大聚集率(％)，Amax＝h1/h0×100％；血小板聚集抑制率，抑制率＝[(生理盐水Amax-用药Amax)/生理盐水Amax]×100％。
结果见表2。
表2 各给药组的对大鼠血小板聚集性影响
Figure PCTCN2016000141-appb-000003
Figure PCTCN2016000141-appb-000004
结果与药物对大白鼠血栓形成的抑制作用试验结果基本相符。
实施例2：大鼠溃疡抑制率的测定
体重300-400克的SD大白鼠90只，雌雄各半。随机分为9组，每组10只，给药情况如下：A组：给予药物阿司匹林和氯吡格雷的组合物(阿司匹林和氯吡格雷的重量比为1∶1)；B组：给予药物阿司匹林和氯吡格雷和奥美拉唑的组合物(阿司匹林和氯吡格雷和奥美拉唑的重量比为2∶2∶1)；C组：给予药物(三 氟柳和替格瑞洛重量比为20∶1)；D：给予药物：三氟柳和替格瑞洛的重量比为12∶1；E组：给予药物(三氟柳和替格瑞洛的重量比为6∶1)；F组：给予药物(三氟柳和替格瑞洛的重量比为3∶1)；G组：给予药物(三氟柳和替格瑞洛的重量比为1∶1)；H组：替格瑞洛组：给予替格瑞洛；I组：给予药物(三氟柳和替格瑞洛的重量比为1∶6)；
实验方法：各组灌胃给药，空白对照给予每次2ml生理盐水，其它各组将药物加入到2ml生理盐水中，搅拌，每天给药1次，每次按10mg药物/kg体重给药(给予组合物药物的，10mg为各组分相加的总质量)，共14天。于末次给药2小时后称重，拉颈处死，将大鼠的胃沿胃大弯处剪开胃壁，翻转后用清水冲洗，生理盐水浸泡10分钟后在玻璃板上展开，观察胃粘膜损伤情况，计算溃疡指数及溃疡抑制率。溃疡程度评定：Guth标准记分-点状出血记1分；线状出血，若宽度＜1mm，糜烂长度＜1mm，记2分，1～2mm记3分，2～4mm记4分，＞4mm记5分；若宽度＞1mm，以上分值×2。计算各组溃疡指数，结果见表3：
表3 组合物各组溃疡指数比较(平均值±标准差)
组别 溃疡指数
A 4.80±1.10
B 2.45±1.10
C 1.89±1.10
D 2.01±1.10
E 2.14±1.10
F 2.22±1.10
G 1.99±1.10
H 1.78±1.10
I 2.16±1.10
替格瑞洛和三氟柳组合物的试验组较少发生胃溃疡，且溃疡发生率稍低于B组(阿司匹林和氯吡格雷和奥美拉唑组)，而J组(阿司匹林和氯吡格雷组)则具有较高的溃疡发生率，提示替格瑞洛和三氟柳的组合物具有较好的安全性。
实施例3：本发明药物的稳定性
分别将采用如下配比制备各种药物：
药物I：三氟柳和替格瑞洛的质量比为1∶1；
药物II：三氟柳和替格瑞洛的质量比为3∶1；
药物III：三氟柳和替格瑞洛的质量比为6∶1；
药物IV：三氟柳和替格瑞洛的质量比为12∶1；
药物V：三氟柳和替格瑞洛的质量比为20∶1；
称取10g各种药物，分别装入药用塑料瓶中，置温度40℃±2℃、相对湿度75％±5％条件下放置6个月，于0、1、3、6月考察外观性状、有效成分质量。有效成分的测定使用高效液相色谱法测定，色谱柱为氰基柱，流动相为甲醇-水-三乙胺(体积比为500∶500∶2，磷酸调节pH值至3.8)，流速为1mL·min-1，检测波长为235nm，柱温为35℃，进样量为20μL。结果在该色谱条件下，替格瑞洛与三氟柳均能够完全分离，具有良好的分离度，替格瑞洛在12.0～100.0mg·L-1内质量浓度与峰面积呈良好的线性关系，回归方程A＝0.176C+0.0474r＝0.9995；三氟柳在38.4～320.0mg·L-1内质量浓度与峰面积呈良好的线性关系，回归方程A＝0.2991C+0.9882r＝0.9997；替格瑞洛三氟柳的平均回收率分别为99.7±1.80％、99.2±1.01％；HPLC法适用于替格瑞洛、三氟柳的测定。三氟柳的保留时间约为7.682分钟，替格瑞洛的保留时间约为35.298分钟。药物稳定性研究的结果见表3。
表3 不同存放期药物中替格瑞洛和三氟柳的残余质量
Figure PCTCN2016000141-appb-000005
以上结果说明在各个质量比下，三氟柳与替格瑞洛的药物组合物室温下的稳定性适于制备口服固体制剂。
实施例3：治疗心脑血管疾病的药物(胶囊剂)的制备
1、三氟柳和替格瑞洛胶囊的制备
三氟柳600g、替格瑞洛100g混匀加入适量糊精，制粒，填充胶囊，制成1000粒。
2、复方三氟柳和替格瑞洛胶囊的制备
三氟柳300g、替格瑞洛90g，羧甲基淀粉100g，硬脂酸镁2.1g，填充1000粒胶囊。
实施例4：治疗心脑血管疾病的药物(片剂)的制备
含有三氟柳600mg和替格瑞洛90mg片剂的制备：
三氟柳600mg
替格瑞洛90mg
预胶化玉米淀粉30mg
无水胶体二氧化硅2mg
无水乳糖20mg
微晶纤维素30mg
将上述替格瑞洛与二氧化硅混合，然后加入预胶化玉米淀粉和乳糖混合，加入三氟柳和微晶纤维素，压片。
复方三氟柳(300mg)和替格瑞洛片(90mg)的制备：
取三氟柳300g，替格瑞洛90g，均匀混合后加入150g微晶纤维素，10g交联聚乙烯吡咯烷酮，粉碎，乙醇软化，过60目筛后制粒，50℃干燥，过60目筛整粒，加入10g羧甲基淀粉钠，2g阿斯帕坦，30g硬脂酸镁均匀混合，压制成1000片，即得。
复方三氟柳(600mg)和替格瑞洛(90mg)片的制备：
三氟柳600g、替格瑞洛90g，加入淀粉适量，硬脂酸镁少许，直接压片，制成1000片。
工业应用
本发明提供了一种治疗心脑血管疾病的药物。本发明提供的药物的活性成分为三氟柳和替格瑞洛，两者具有协同作用。实验结果表明：三氟柳-替格瑞洛组合物抑制血栓形成和抗血小板聚集的效果优于单独三氟柳和单独替格瑞洛以及阿司匹林和氯吡格雷的组合物，并且胃溃疡发生率低于阿司匹林和氯吡格雷的组合物。

Claims (6)

  1. 一种抑制血栓形成的药物，其特征在于：它的活性成分为三氟柳和替格瑞洛；三氟柳和替格瑞洛的质量比为20∶1-1∶6。
  2. 如权利要求1所述的药物，其特征在于：所述药物的活性成分中，三氟柳和替格瑞洛的质量比为6∶1-1∶1。
  3. 如权利要求1至2中任一所述的药物，其特征在为片剂、胶囊剂、颗粒剂或干混悬剂。
  4. 如权利要求1至3中任一所述的药物，其特征在于：所述药物还包括辅料；所述辅料为如下成分中的至少一种：微晶纤维素、羧甲基淀粉钠、糊精、乳糖、硬脂酸镁。
  5. 权利要求1至12中任一所述药物在治疗心脑血管疾病中的应用。
  6. 如权力要求1至5所述的药物，其中替格瑞洛为包含替格瑞洛的共晶。
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CN102406938A (zh) * 2011-11-29 2012-04-11 北京阜康仁生物制药科技有限公司 一种抗血栓的药物组合物
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