WO2015039513A1 - 一种替格瑞洛固体分散体及其制备方法 - Google Patents

一种替格瑞洛固体分散体及其制备方法 Download PDF

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WO2015039513A1
WO2015039513A1 PCT/CN2014/084546 CN2014084546W WO2015039513A1 WO 2015039513 A1 WO2015039513 A1 WO 2015039513A1 CN 2014084546 W CN2014084546 W CN 2014084546W WO 2015039513 A1 WO2015039513 A1 WO 2015039513A1
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solid dispersion
ticagrelor
recipe
solvent
copovidone
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PCT/CN2014/084546
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English (en)
French (fr)
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梁力
左佼
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成都盛迪医药有限公司
江苏恒瑞医药股份有限公司
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Publication of WO2015039513A1 publication Critical patent/WO2015039513A1/zh

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    • 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
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to a solid dispersion of ticagrelor and a process for the preparation thereof. Background technique
  • Thromboembolic diseases are common clinical diseases.
  • the formation of blood clots is closely related to blood vessel wall, platelet, blood flow velocity, blood viscosity and clotting activity.
  • High platelet count and increased blood lipids are important factors for thrombosis: Thrombosis increases the chance of platelet adhesion, increased blood lipids will increase blood viscosity, and changes in platelet aggregation and blood flow will promote blood coagulation.
  • Thrombosis is formed, and therefore, anti-thrombotic therapy against platelet aggregation and blood lipid lowering plays an important role.
  • Tigril English name t lcagre i or , is an oral anti-platelet agglutination drug developed by AstraZeneca.
  • Tigrelor is a non-prodrug that can directly work without the activation of liver metabolism. It is a novel and selective anticoagulant drug and the first reversible binding P2Y12 adenosine diphosphate receptor.
  • ADP Antagonist, which can reversibly act on the ⁇ 2 receptor subtype P2Y12 on vascular smooth muscle cells, has a significant inhibitory effect on platelet aggregation induced by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease.
  • Tigrelot was approved by the European Union on December 3, 2010 for the reduction of thrombotic events in patients with acute coronary syndrome (ACS) under the trade name Brilique; FDA approved on July 20, 2011, trade name Brilinta.
  • the early approved anti-platelet agglutination drugs mainly include clopidogrel, but clopidogrel has an irreversible effect on platelets, and after tigrelor stops treatment, the effect can be quickly weakened or reversed, one or two days. Restore the blood coagulation function of platelets.
  • the ticagrelor drug itself and its metabolites are active, so not only can rapidly and potently inhibit ADP-mediated platelet aggregation, but also the effectiveness is not affected by liver CYP 2C19 gene polymorphism, which is clinically Very important.
  • Clopidogrel is a prodrug that must be metabolized into active metabolites by the action of hepatic cytochrome P450 (CYP) in the liver to inhibit platelet effects. Therefore, genetic polymorphism is one of the main causes of variability in clopidogrel reaction, which makes its antiplatelet effect difficult to predict.
  • CYP hepatic cytochrome P450
  • ticagrelor is a good antithrombotic drug, there are still some difficulties. Tigrelor is a poorly soluble drug. Its solubility under physiological conditions is only l ( g / ml). The solubility of this drug in neutral media such as water is extremely low, and water is used to evaluate the dissolution test. The most suitable medium for bioequivalence. Therefore, the development of a prescription preparation with good solubility properties of ticagrelor is currently a problem in the development of oral solid preparations for this medicine.
  • the invention adopts a solid dispersion technique to uniformly disperse ticagrelor in the structure of the drug-loading material by a solvent, thereby solving the problem of poor solubility.
  • the present invention provides a solid dispersion of ticagrelor or a pharmaceutically acceptable salt thereof, wherein the solid dispersion is composed of ticagrelor as an active ingredient or a pharmaceutically acceptable salt thereof and a carrier material
  • the carrier material comprises one or more of polyvinylpyrrolidone, copovidone, and crospovidone.
  • the support material further comprises ethylcellulose.
  • copovidone alone as a carrier solves the problem of poor solubility and allows the drug to dissolve quickly.
  • ticagrelor Occasional adverse reactions to bleeding include intracranial hemorrhage, ocular hemorrhage, hemoptysis, hematemesis, gastrointestinal ulcer bleeding, and oral bleeding. It has been verified that when the composition is dissolved more than 95% at 120 minutes, the adverse reactions of bleeding are greatly increased.
  • the addition of ethyl cellulose can release the drug to some extent. Therefore, the stable dissolution of the drug is ensured, and the sudden collapse of the drug in the body is prevented, causing sudden release of the drug, thereby causing the drug exposure value to be too high, posing a risk to the patient.
  • the carrier material consists of copovidone or polyvinylpyrrolidone and ethylcellulose.
  • copolyvidone may be selected from copolyketone S630
  • povidone may be selected from PVPK30
  • ethyl cellulose may be selected from ethyl cellulose E10, ethyl cellulose E20 or a mixture thereof, preferably ethyl cellulose E20.
  • the weight ratio of the main drug to the carrier can be selected within a wide range, wherein the weight ratio of the drug to the carrier material is preferably 1:0.1-1:1.2, preferably 1:0.3-1:1.0, More preferably 1: 0.5-1: 1.0.
  • the carrier material of the present invention uses ethyl cellulose, copolyvidone or polyvinylpyrrolidone and ethyl cellulose in a weight ratio of 1: 1 to 5: 1 , preferably 1: 1 to 3: 1.
  • the solid dispersion comprises, in percentages, telgrelor or a pharmaceutically acceptable salt thereof, 46% to 85%, polyvinylpyrrolidone or copolyvidone 8%. 49%, ethyl cellulose 5% ⁇ 28%.
  • Another aspect of the present invention provides a process for the preparation of the aforementioned solid dispersion, which is selected from the group consisting of a hot melt extrusion process or a solvent process.
  • the method is a solvent method comprising the steps of: dissolving ticagrelor or a base salt and a carrier in a solvent, stirring uniformly until dissolved, removing the solvent and drying, and obtaining a solid dispersion.
  • the solvent is one or more selected from the group consisting of water, methanol, ethanol, acetone, chloroform, and isopropanol.
  • the solvent is a mixture of ethanol and water, preferably a weight ratio of ethanol to water of from 1.5:1 to 9:1.
  • a pharmaceutical composition comprising ticagrelor or a salt thereof, which comprises the aforementioned solid dispersion, further comprising the following components in an amount by weight:
  • Disintegrant 30% ⁇ 50% Disintegrant
  • Coating material 0.01% ⁇ 3%.
  • the diluent is selected from the group consisting of microcrystalline cellulose, starch, sucrose, preferably microcrystalline cellulose.
  • the disintegrant is selected from the group consisting of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and croscarmellose sodium, preferably crospovidone.
  • the lubricant is selected from the group consisting of magnesium stearate, micronized silica gel, talc, preferably magnesium stearate.
  • the coating material is a common common coating material.
  • the solvent in the solid dispersion may be removed, and the diluent, the disintegrating agent, the binder or the like may be directly added for wet granulation, and then tablets or capsules may be obtained by conventional means.
  • Figure 1 shows the X-ray diffraction pattern of the ticagrelor bulk drug.
  • Figure 2 is an X-ray diffraction pattern of a physical mixture of ticagrelor and copovidone.
  • Figure 3 is an X-ray diffraction pattern of the solid dispersion formulation 45 of Example 8.
  • Figure 4 is an X-ray diffraction pattern of the solid dispersion formulation 50 of Example 9.
  • Figure 5 is an X-ray diffraction pattern of the solid dispersion formulation 65 of Example 11.
  • Figure 6 is a DSC (Differential Thermal Scanning) pattern of ticagrelor bulk drug.
  • Figure 7 is an X-ray diffraction pattern of a ticagrelor tablet prepared in Formulation 85 of Example 15 after one month of investigation at 40 ° C, 75% RH. detailed description
  • Example 2 The raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • Example 2 The raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • Formulation 19 Formulation 20 Formulation 21 Formulation 22 Formulation 23 Formulation 24 Tigrilo 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • the raw materials were weighed according to the formula amount, and completely dissolved in a ten-fold amount of ethanol solution, and the solvent was removed by rotary evaporation, and then dried under reduced pressure in a vacuum drying oven.
  • Formulation 88 Formulation 89 Formulation 90 Formulation 91 ticagrelor 90 90 90 90 Copovidone S630 90 45 67.5 75 Ethylcellulose EC20 0 45 22.5 15 Microcrystalline cellulose 150 150 150 150 150 Cross-linked povidone (within) 210 210 210 210 210
  • ticagrelor and PVP solid dispersion ticagrelor and PVP were dissolved in absolute ethanol to obtain a clear solution, and then the solvent was removed by rotary evaporation and dried in a vacuum oven under reduced pressure.
  • Preparation of ticagrelor and PEG solid dispersion PEG is heated and melted, added to ticagrelor mixture, dissolved to obtain a clear solution, and then rapidly cooled and solidified.
  • the solubility of the ticagrelor bulk drug in 24h was: 16 g / ml, and the solubility of the solid dispersion is shown in Table 1.
  • the solid dispersion prepared by using PVP, copovidone and ticagrelor is significantly more soluble than the solid dispersion prepared by the usual carrier of PEG and hydroxypropyl cellulose and ticagrelor.
  • a solid dispersion prepared by using PVP-K30, copovidone S630 and ticagrelor has a higher solubility.
  • Formulations 85 to 87 of the ticagrelor solid dispersion of Example 15 were compared to Formulations 88 to 90 of Example 16, and Formulation 48 of Example 8 and the marketed product (AstraZeneca-listed Belinda, including Tigri In vitro dissolution test of Relo 90 mg tablets, the specific operation process is as follows:
  • Example 15 120 points of the pharmaceutical composition of Formula 85 to 87 in Example 15 of the present invention can be seen.
  • the cumulative release of the clock is about 90%, which meets the safety requirements, while the composition of Formula 88 reaches 98%, which is very likely to cause bleeding risk.
  • formulas 89 and 48 are too slow to achieve the desired effect.
  • the ticagrelor tablet prepared in Formulation 85 of Example 15 was examined at 40 ° C, 75% RH for one month, and its X-ray diffraction pattern was measured, as shown in Fig. 7, which can be seen from the figure.
  • the ticagrelor solid dispersion prepared by the invention has good stability, and the ticagrelor is still amorphous after one month of investigation under the condition.

Abstract

一种替格瑞洛固体分散体及其制备方法，所述固体分散体是由替格瑞洛分散于载体材料中制成，所述载体材料含有聚乙烯吡咯烷酮、共聚维酮、交联聚维酮中的一种或几种。

Description

一种替格瑞洛固体分散体及其制备方法 技术领域
本发明涉及一种替格瑞洛的固体分散体及其制备方法。 背景技术
血栓栓塞性疾病是临床常见疾病， 血栓的形成与血管壁、 血小板、 血流速度、 血液粘度和凝血活性均有很大关系。 血小板数偏高、 血脂 增高是引起血栓的重要因素： 血小板增多会使血小板粘结的机会增多， 血脂增高会使血液粘度增大， 而血小板粘集和血流状态的改变都会促 进血液发生凝固而形成血栓， 因此， 抗血小板聚集、 降低血脂含量的 药物抗血栓治疗中占有重要地位。
替格瑞洛， 英文名为 tlcagreior， 是由阿斯利康开发的一种口服抗 血小板凝集药物。 替格瑞洛为非前体药， 无须经肝脏代谢激活即可直 接起效， 是一种新型的、 具有选择性的抗凝血药物， 也是首个可逆的 结合型 P2Y12腺苷二磷酸受体 （ADP) 拮抗剂， 能可逆的作用于血管 平滑肌细胞上的嘌呤 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。替格瑞洛于 2010 年 12月 3日获欧盟批准用于减少急性冠状动脉综合征 （ACS) 患者血 栓事件的发生， 商品名为 Brilique; 于 2011年 7月 20日获 FDA批准， 商品名为 Brilinta。
早期批准上市的抗血小板凝集药物主要有氯吡格雷， 但氯吡格雷 会对血小板造成不可逆的影响， 而替格瑞洛停止治疗后， 该作用能很 快被减弱或逆转， 一两天即可恢复血小板的凝血功能。 且替格瑞洛药 物本身及其代谢产物均有活性， 因此不但可快速且强效地抑制 ADP介 导的血小板聚集，且有效性不受肝脏 CYP 2C19基因多态性影响，这一 点在临床上非常重要。 而氯吡格雷是一种前体药物， 须在肝内通过肝 细胞色素 P450酶（CYP) 的作用下经两歩代谢为活性代谢产物方可发 挥抑制血小板效应。 因此， 基因多态性是造成氯吡格雷反应变异性的 主要原因之一， 导致其抗血小板效应难以预测。
虽然替格瑞洛是一种良好的抗血栓药物， 但仍然存在一些难题。 替格瑞洛为一种难溶的药物， 生理条件下其溶解度仅为 l( g/ml， 该药 在水等中性介质中的溶解度极低， 而水恰恰是用于评价溶出试验中非 生物等效性的最为合适的介质。 因此， 开发一种是替格瑞洛具有良好 溶解性质的处方制剂是目前该药口服固体制剂开发的一个难题。 发明内容
由于替格瑞洛为难溶性药物， 且剂量较大， 因此需要解决替格瑞 洛难溶性问题。 本发明采用固体分散技术， 通过溶剂， 将替格瑞洛均 匀分散在载药材料结构中， 从而解决其难溶性问题。
本发明提供了一种替格瑞洛或其药学上可接受的盐的固体分散 体， 其中所述固体分散体由作为活性成分的替格瑞洛或其药学上可接 受的盐和载体材料组成， 所述载体材料含有聚乙烯吡咯垸酮、 共聚维 酮、 交联聚维酮中的一种或几种。
在本发明优选的实施方案中， 所述的载体材料还含有乙基纤维素。 单独使用共聚维酮作为载体， 解决了难溶的问题， 使得药物快速 溶出， 然而作为一种抗凝药物， 如果暴露量过高， 可能造成严重的不 良反应， 例如出血， 研究发现替格瑞洛偶见的出血不良反应包括颅内 出血、 眼出血、 咯血、 呕血、 胃肠道溃疡出血、 口腔出血等。 经验证， 当组合物本外溶出在 120分钟时大于 95%时， 出血不良反应大大增加， 为防止替格瑞洛暴露值过高， 加入了乙基纤维素可使得药物在一定程 度上缓慢释放， 从而保证药物的稳定溶出， 防止了药物在体内溶出时 突然大量崩解， 造成药物突释， 从而导致药物暴露值过高， 给患者造 成风险。
在本发明更为优选的实施方案中， 所述的载体材料由共聚维酮或 聚乙烯吡咯垸酮和乙基纤维素组成。 其中， 共聚维酮可选择共聚维酮 S630, 聚维酮可选择 PVPK30, 乙基纤维素可选择乙基纤维素 E10、 乙 基纤维素 E20或它们的混合物， 优选乙基纤维素 E20。
在固体分散体中， 主药与载体的重量比可以在较宽的范围内选择， 其中药物与载体材料的重量比优选比例为 1 : 0.1-1： 1.2，优选 1 : 0.3-1： 1.0， 更优选 1 : 0.5-1： 1.0。
在本发明中， 载体材料的含量越高， 越容易使替格瑞洛由结晶变 成无定形物， 而载体中乙基纤维素含量越低， 相应的固体分散体的生 物利用度也越高。 考虑到载药量与生物利用度之间的平衡， 本发明中 载体材料用了乙基纤维素， 共聚维酮或聚乙烯吡咯垸酮与乙基纤维素 重量比为 1 : 1〜5： 1， 优选 1 : 1〜3： 1。
在一个最为优选的实施方案中， 以百分比计， 所述的固体分散体 含有替格瑞洛或其药学上可接受的盐 46%~85%， 聚乙烯吡咯垸酮或共 聚维酮 8%~49%， 乙基纤维素 5%~28%。
本发明另一方面提供了前述固体分散体的制备方法， 该方法选自 热熔挤出法或溶剂法。
优选该方法为溶剂法， 该方法包括以下歩骤： 将替格瑞洛或基盐 和载体溶于溶剂中， 搅拌均匀至溶解后除去溶剂并干燥， 整粒即得固 体分散体。 其中所述溶剂选自水、 甲醇、 乙醇、 丙酮、 氯仿、 异丙醇 中的一种或多种。 优选所述溶剂为乙醇与水的混合物， 优选乙醇与水 的重量比为 1.5： 1-9： 1。
本发明再一方面提供了一种含有替格瑞洛或其盐的药物组合物， 其含有前述的固体分散体， 还含有如下重量含量的成分：
稀释剂 15%~45%；
崩解剂 30%~50%;
润滑剂 0.1%~3%;
包衣材料 0.01%~3%。
其中所述稀释剂选自微晶纤维素、 淀粉、 蔗糖， 优选微晶纤维素。 所述崩解剂选自交联聚维酮、 羧甲淀粉钠、 低取代羟丙基纤维素、 交 联羧甲纤维素钠， 优选交联聚维酮。 所述润滑剂选自硬脂酸镁、 微粉 硅胶、 滑石粉， 优选硬脂酸镁。 所述包衣材料为普通的常见包衣材料。
本发明的组合物制备过程中， 也可以不将固体分散体中溶剂去除， 而直接加入稀释剂、 崩解剂、 粘合剂等进行湿法制粒， 然后按常规手 段制得片剂或胶囊等口服形式； 在这一过程中， 加辅料制粒前， 虽未 去除溶剂， 但主药已高度分散于载体中， 呈非晶型状态， 因此未除去 溶剂的混合物也属于本发明所称的固体分散体。 附图说明 结合以下附图， 本发明的以上和其他的目的和特征将会变得显而 易见， 这些附图分别表示：
图 1为替格瑞洛原料药的 X-射线衍射图谱。
图 2为替格瑞洛与共聚维酮的物理混合物的 X-射线衍射图谱。 图 3为实施例 8中固体分散体配方 45的 X-射线衍射图谱。
图 4为实施例 9中固体分散体配方 50的 X-射线衍射图谱。
图 5为实施例 11中固体分散体配方 65的 X-射线衍射图谱。
图 6为替格瑞洛原料药的 DSC (差示热量扫描法） 图谱。
图 7为实施例 15中配方 85所制备的替格瑞洛片剂在 40°C，75%RH 的加速条件下考察一个月后的 X射线衍射图谱。 具体实施方式
通过如下实施例可进一歩解释本发明的内 ， 但它们不限定本发 明的内容。 对于本领域技术人员根据本发明内 所作的类似改进与调 整， 如采用同性质的辅料或者改变包衣外观等 均视为本发明包含的 内容。
1、 替格瑞洛固体分散体的制备
实施例 1
配方：
原辅料用:量 (g)
原 $索料名称
配方 1 配方 2 配方 3 配方 4 配方 5 配方 6 替格瑞洛 90 90 90 90 90 90
PVPP S630 9 27 45 72 90 108 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。 实施例 2
配方：
原辅料用量 （g)
原 $索料名称
配方 7 配方 8 配方 9 配方 10 配方 11 配方 12 替格瑞洛 90 90 90 90 90 90 PVP K15 9.0 13.5 22.73 36 65 108
^制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000006_0001
配方:
原辅料用:量 (g)
原辅料名称 .
配方 13 配方 14 配方 15 配方 16 配方 17 配方 18 替格瑞洛 90 90 90 90 90 90
PVP K30 4.5 13.5 22.73 36 75 105 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000006_0002
原辅料用:量 (g)
原辅料名称 .
配方 19 配方 20 配方 21 配方 22 配方 23 配方 24 替格瑞洛 90 90 90 90 90 90
PVP K60 9.0 13.5 22.73 36 75 100 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000006_0003
原辅料用:量 (g)
原辅料名称 .
配方 25 配方 26 配方 27 配方 28 配方 29 配方 30 替格瑞洛 90 90 90 90 90 90
PVP K90 9.0 13.5 22.73 36 65 90 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。 原辅料用:量 (g)
原辅料名称 .
配方 31 配方 32 配方 33 配方 34 配方 35 配方 36 替格瑞洛 90 90 90 90 90 90
PEG 6000 9.0 13.5 22.73 36 45 80 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000007_0001
原辅料用:量 (g)
原辅料名称 .
配方 37 配方 38 配方 39 配方 40 配方 41 配方 42 替格瑞洛 90 90 90 90 90 90
PEG 4000 4.5 13.5 22.73 36 45 54 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000007_0002
原辅料用:量 (g)
原辅料名称 .
配方 43 配方 44 配方 45 配方 46 配方 47 配方 48 替格瑞洛 90 90 90 90 90 90
PVPP S630 4.5 13.5 22.73 36 45 54
EC20 4.5 13.5 22.28 36 45 54 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000007_0003
原辅料用:量 (g)
原辅料名称 .
配方 49 配方 50 配方 51 配方 52 配方 53 配方 54 替格瑞洛 90 90 90 90 90 90
PVPP S630 6 17.64 30 48 60 72 EC20 3 9.36 15 24 30 36 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000008_0001
原辅料用:量 (g)
原辅料名称 .
配方 55 配方 56 配方 57 配方 58 配方 59 配方 60 替格瑞洛 90 90 90 90 90 90
PVPP S630 6.75 20.25 33.75 54 67.5 81
EC20 2.25 6.75 11.25 18 22.5 27 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000008_0002
原辅料用:量 (g)
原辅料名称 .
配方 61 配方 62 配方 63 配方 64 配方 65 配方 66 替格瑞洛 90 90 90 90 90 90
PVPP S630 7.2 21.6 36 57.6 72 86.4
EC20 1.8 5.4 9 14.4 18 21.6 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000008_0003
原辅料用:量 (g)
原辅料名称 .
配方 67 配方 68 配方 69 配方 70 配方 71 配方 72 替格瑞洛 90 90 90 90 90 90
PVPP S630 7.5 22.5 37.5 60 75 90
EC20 1.5 4.5 7.5 12 15 18 制备方法：
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000009_0001
原辅料用:量 (g)
原辅料名称 .
配方 73 配方 74 配方 75 配方 76 配方 77 配方 78 替格瑞洛 90 90 90 90 90 90
Klucel® EF 4.5 13.5 22.73 36 45 54 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
Figure imgf000009_0002
原辅料用:量 (g)
原辅料名称 .
配方 79 配方 80 配方 81 配方 82 配方 83 配方 84 替格瑞洛 90 90 90 90 90 90
Klucel® LF 4.5 13.5 22.73 36 45 54 制备方法:
按配方量称取原辅料， 并将其完全溶解于十倍量的乙醇溶液中， 旋转蒸发除去溶剂后置真空干燥箱中减压干燥即得。
2、 含替格瑞洛固体分散体的口服制剂的制备
实施例 15
含替格瑞洛 90 mg的片剂配方
每单位剂 J t原辅料用邐 t ( mg)
原 $索料名称
配方 85 配方 86 配方 87 固体分散体配方 45 135
固体分散体配方 50 117
固体分散体配方 65 180
微晶纤维素 124.65 96.33 150 交联聚维酮 (内加） 157.5 148.2 210
硬脂酸镁 1.35 1.17 1.8 交联聚维酮 （外加） 31.5 27.3 58.2 制备方法：
将处方量乙基纤维素 E20用 80%乙醇溶解后， 称取处方量共聚维 酮 S630和替格瑞洛于溶液中， 在 70°C水浴条件下加热搅拌至完全溶 解， 溶液备用， 将处方量的微晶纤维素和交联聚维 （内加） 混合均匀， 用上述溶液作粘合剂湿法制粒， 湿颗粒干燥整粒后与交联聚维酮 （外 加） 混合均匀后， 加硬脂酸镁混合， 压片。
Figure imgf000010_0001
含替格瑞洛 90 mg的片剂配方
每单位剂邐 t原辅料用量 （mg)
原辅料名称
配方 88 配方 89 配方 90 配方 91 替格瑞洛 90 90 90 90 共聚维酮 S630 90 45 67.5 75 乙基纤维素 EC20 0 45 22.5 15 微晶纤维素 150 150 150 150 交联聚维酮 (内加） 210 210 210 210
硬脂酸镁 1.8 1.8 1.8 1.8 交联聚维酮 （外加） 58.2 58.2 58.2 58.2
制备方法:
将处方量乙基纤维素 E20用 80%乙醇溶解后， 称取处方量共聚维 酮 S630和替格瑞洛于溶液中， 在 70°C水浴条件下加热搅拌至完全溶 解， 溶液备用， 将处方量的微晶纤维素和交联聚维酮混合均匀， 用上 述溶液作粘合剂湿法制粒， 湿颗粒干燥整粒后与外加量的交联聚维酮 混合均匀后， 加硬脂酸镁混合， 压成片重为 600mg的素片。 试验例 1 : 不同载体的固体分散体 24h溶解度的测定
称取一定量替格瑞洛原料药及替格瑞洛与各亲水性载体制备的固 体分散体于锥形瓶中， 分别加入 100ml 纯水后置 25±2°C摇床中振摇
24h， 所得溶液离心后取上清液供 HPLC测定其浓度。
替格瑞洛与 PVP固体分散体的制备：将替格瑞洛与 PVP溶解于无 水乙醇中得澄清溶液， 后旋转蒸发除去溶剂并置真空干燥箱中减压干 燥即得。 替格瑞洛与 PEG固体分散体的制备：将 PEG加热熔化后加入替格 瑞洛混合， 溶解得澄清溶液， 后快速冷却固化即得。
其中替格瑞洛原料药 24h溶解度为： 16 g/ml， 固体分散体溶解度 见表 1。
表 1 不同载体固体分散体 24h溶解度结果
Figure imgf000011_0001
由此可以看出， 采用 PVP、 共聚维酮与替格瑞洛制备的固体分散 体其溶解度明显大于采用 PEG与羟丙基纤维素等常用载体和替格瑞洛 制备的固体分散体。 其中， 采用 PVP-K30、 共聚维酮 S630与替格瑞洛 制备的固体分散体， 其溶解度更高。 试验例 2 粉末 X-衍射
仪器： 日本理学 D/max-3B型 X射线衍射仪
测定方法：
分别取固体分散体配方 45 (见图 3 )、 配方 50 (见图 4)、 配方 65 (见图 5 )、 替格瑞洛原料 （见图 1 ) 和替格瑞洛与共聚维酮的物理混 合物适量 （见图 2 )， 在 Cu靶， 电压 45kv， 电流 45mA的条件下记录 粉末 X衍射图谱。 固体分散体图谱未见替格瑞洛吸收峰， 说明所得固 体分散体中没有替格瑞洛晶体， 说明替格瑞洛在固体分散体中是以无 定型状态存在的， 固体分散体成功制备。 由此我们惊喜的发现， 在制 备替格瑞洛固体分散体时， 采用较少量的共聚维酮作载体时， 也能形 成无定形态的固体分散体， 因此共聚维酮等具有较高的载药量。 试验例 3 体外溶出试验
将实施例 15中替格瑞洛固体分散体的配方 85至 87， 对比实施例 16配方 88至 90、 及实施例 8中配方 48以及上市品 （阿斯利康上市的 倍林达， 含替格瑞洛 90 mg的片剂） 进行体外溶出试验， 具体操作过 程如下：
溶出度考察方法： 《中国药典》 2010年版二部附录 XD第二法桨法 溶出介质： 0.2%吐温 80溶液 900ml
转速： 75转 /分
温度： 37 °C
取样时间： 10min、 20min、 30 min、 45min、 60min、 120min 含量测定方法： 紫外分光光度法 （对照品比较法）
测定波长： 300nm
体外溶出实验结果见表 2。
体外溶出对比试验结果
Figure imgf000012_0001
由此可见， 本发明实施例 15中配方 85至 87药物组合物的 120分 钟时累积释放约 90%左右， 符合安全性的要求， 而配方 88的组合物则 达到 98%， 极易产生出血风险； 同时配方 89、 48则释放过慢， 无法达 到应有的疗效。 试验例 4
取实施例 15中配方 85所制备的替格瑞洛片剂在 40°C， 75%RH的 加速条件下考察一个月后， 测试其 X射线衍射图谱， 见图 7， 从图中 可以看出， 本发明制得的替格瑞洛固体分散体具有良好的稳定性， 在 该条件下考察一个月后替格瑞洛仍为非晶型状态。

Claims

权利要求书:
1、 一种替格瑞洛或其药学上可接受的盐的固体分散体， 其中所述 固体分散体由作为活性成分的替格瑞洛或其药学上可接受的盐和载体 材料组成， 所述载体材料含有聚乙烯吡咯垸酮、 共聚维酮、 交联聚维 酮中的一种或几种。
2、 根据权利要求 1所述的固体分散体， 其中所述的载体材料还含 有乙基纤维素。
3、 根据权利要求 2所述的固体分散体， 其中所述的载体材料由聚 乙烯吡咯垸酮和乙基纤维素组成， 或由共聚维酮和乙基纤维素组成。
4、 根据权利要求 1至 3任意一项所述的固体分散体， 其中所述的 聚乙烯吡咯垸酮为 PVPK30, 共聚维酮为共聚维酮 S630。
5、 根据权利要求 2或 3所述的固体分散体， 其中所述的乙基纤维 素选自乙基纤维素 E10、 乙基纤维素 E20或它们的混合物。
6、 根据权利要求 2或 3所述的固体分散体， 其中按重量计， 共聚 维酮或聚乙烯吡咯垸酮用量与乙基纤维素用量比为 1 : 1-5： 1，优选 1 : 1〜3： 1。
7、 根据权利要求 1至 6任意一项所述的固体分散体， 其中所述替 格瑞洛或其药学上可接受的盐与载体材料重量比为 1 : 0.1-1： 1.2， 优 选 1 : 0.3-1： 1.0， 更优选 1 : 0.5-1： 1.0。
8、 根据权利要求 6或 7所述的固体分散体， 以百分比计， 含有替 格瑞洛或其药学上可接受的盐 46%~85%， 共聚维酮或聚乙烯吡咯垸酮 8%~49%, 乙基纤维素 5%~28%。
9、 一种根据权利要求 1至 8任意一项所述的固体分散体的制备方 法， 该方法选自热熔挤出法或溶剂法。
10、 根据权利要求 9所述的制备方法， 该方法为溶剂法， 其包括 将载体材料和替格瑞洛共同溶解于溶剂中， 或将载体材料混悬分散在 替格瑞洛的溶剂中， 采用减压干燥或喷雾干燥的方式除去溶剂得到固 体分散体的歩骤。
11、 根据权利要求 10所述的制备方法， 其中所述溶剂选自水、 甲 醇、 乙醇、 丙酮、 二甲基甲酰胺、 二甲基亚砜、 四氢呋喃中的一种或 多种。
12、 根据权利要求 10所述的制备方法， 其中所述溶剂为无水乙醇 或乙醇与水的混合物， 优选乙醇与水的重量比为 1.5: 1-9： 1。
13、 一种含有替格瑞洛或其盐的药物组合物， 其含有根据权利要 求 1至 8任意一项所述的固体分散体， 还含有如下重量含量的成分： 稀释剂 15%~45%；
崩解剂 30%~50%;
润滑剂 0.1%~3%;
包衣材料 0.01 %~3%。
14、 根据权利要求 13所述的药物组合物， 其中所述稀释剂选自微 晶纤维素、 麦芽糖糊精、 山梨醇、 麦芽糖、 糊精、 部分预胶化淀粉、 甘露醇、 二水合磷酸氢钙、 无水磷酸氢钙等， 优选微晶纤维素。
15、 根据权利要求 13所述的药物组合物， 其中所述崩解剂选自交 联聚维酮、 羧甲淀粉钠、 低取代羟丙基纤维素、 交联羧甲纤维素钠， 优选交联聚维酮。
16、 根据权利要求 13所述的药物组合物， 其中所述润滑剂选自硬 脂酸镁、 微粉硅胶、 滑石粉， 优选硬脂酸镁。
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