WO2020029443A1 - 一种盐酸替罗非班注射液及其制备方法 - Google Patents

一种盐酸替罗非班注射液及其制备方法 Download PDF

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WO2020029443A1
WO2020029443A1 PCT/CN2018/113330 CN2018113330W WO2020029443A1 WO 2020029443 A1 WO2020029443 A1 WO 2020029443A1 CN 2018113330 W CN2018113330 W CN 2018113330W WO 2020029443 A1 WO2020029443 A1 WO 2020029443A1
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tirofiban hydrochloride
water
sodium
preparation
injection
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张贵民
王昭钦
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山东新时代药业有限公司
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • 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
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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  • the invention relates to tirofiban hydrochloride injection and a preparation method thereof, and belongs to the field of medical preparations.
  • Tirofiban is a non-peptide platelet membrane glycoprotein IIb / IIIa (GPIIb / IIIa) receptor antagonist, which can block platelet cross-linking and platelet aggregation.
  • Its chemical name is (S) -N- (n-butylsulfonyl-O- [4- (4-piperidinyl) butane] -L-tyrosine), and its hydrochloride monohydrate is generally used in medicine. .
  • Tirofiban hydrochloride inhibits the binding of fibrinogen to platelet membrane GPIIb / IIIa receptors, thereby blocking platelet cross-linking and platelet aggregation. It is clinically used to treat patients with acute coronary syndrome (ACS), and is also suitable for patients with acute coronary syndrome for coronary angioplasty or intracoronary plaque resection, which can reduce death, myocardial infarction and refractory Incidence of a composite endpoint of myocardial ischemia / revascularization.
  • ACS acute coronary syndrome
  • intracoronary plaque resection which can reduce death, myocardial infarction and refractory Incidence of a composite endpoint of myocardial ischemia / revascularization.
  • ACS is a series of disease spectrum caused by acute severe ischemia and even necrosis of the myocardium, including unstable angina pectoris (UA), non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STE- MI) and sudden cardiac death.
  • the main mechanism of this is the triggering of platelet activation, aggregation and thrombosis after atherosclerotic plaque rupture in the coronary arteries. Therefore, antithrombotic drugs play a pivotal role in the treatment of ACS.
  • Unlike classic antiplatelet drugs such aspirin and clopidogrel, tirofiban hydrochloride does not inhibit platelet activation, but inhibits platelets by binding to GPIIb / IIIa receptors on platelet membranes. Gather.
  • the world invention patent application WO1997 / 015328 discloses a pharmaceutical composition containing tirofiban, wherein the amount of tirofiban is 0.05-0.25 mg / ml, and it is prepared into a 200 ml large infusion solution.
  • Chinese patent application 200410061014.0 discloses a tirofiban hydrochloride infusion solution containing sodium chloride and a preparation method thereof. Each unit of infusion contains 0.056 g / L of tirofiban hydrochloride.
  • Chinese patent application 200510018284.8, Chinese patent application 200510015295.0, and Chinese patent application 200510018440.0 each disclose a respective tirofiban hydrochloride powder injection and a preparation method thereof.
  • Tirofiban was first developed by Merk Corporation in the United States. It is a highly selective GPIIb / IIIa receptor antagonist. It is mainly used in the treatment of thrombotic diseases in clinical practice. Compared with similar drugs, tirofiban has the advantages of novel mechanism of action, precise clinical efficacy, and low side effects.
  • the tirofiban hydrochloride injection in the international market mainly has three specifications: 50ml: 12.5mg, 100ml: 5mg and 250ml: 12.5mg.
  • the clinical dosage requires that tirofiban hydrochloride is dissolved in 0.9% sodium chloride injection or 5% glucose injection, the final concentration is 50 ⁇ g / ml, and intravenous infusion.
  • tirofiban hydrochloride injection can be easily decomposed during storage, and its properties are unstable, and the content of related substances has risen, which brings certain safety risks to clinical use.
  • the object of the present invention is to provide a high-quality, intravenous infusion of tirofiban hydrochloride injection.
  • the inventor has obtained a technical solution to solve the technical problem of the present invention through a large number of experiments, screening prescription composition and dosage, and optimizing process operation and process parameters, as follows:
  • the injection containing tirofiban hydrochloride of the present invention is composed of an effective amount of tirofiban hydrochloride, an osmotic pressure regulator, a pH regulator and water.
  • the percentage of each component in the total volume of the injection is: calculated in g / L, and the content formula is as follows:
  • the percentage of each component of the tirofiban hydrochloride injection of the present invention to the total volume of the injection is: calculated in g / L, and the content formulation is as follows:
  • the invention provides a method for preparing tirofiban hydrochloride injection, including the following steps:
  • the pH adjusting agent is selected from the group consisting of hydrochloric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate, or Many kinds are preferred, and potassium dihydrogen phosphate or dipotassium hydrogen phosphate is preferred.
  • the pH of the mixed solution is adjusted to 6.0 using a pH adjuster.
  • Adjust step 2) The pH value of the obtained mixed solution is 6.0. After filtering through a 0.22 ⁇ m microporous filter membrane, aliquot it into a glass infusion bottle, stoppering, capping, sterilizing, light inspection, and packaging.
  • the present invention has the following improvements:
  • the invention optimizes the osmotic pressure regulator, especially after using sodium alginate, the active substance content is high, the stability of the main medicine can be maintained under conditions such as high temperature, light, etc., the preparation process is simple, and after accelerated testing and long-term stability The tests have confirmed that the embodiments of the present invention have better stability effects, and the solution with a better appearance is a colorless transparent liquid with the content of related substances below 0.12%, which is suitable for industrial production and convenient for market promotion.
  • the prescribed amounts of tirofiban hydrochloride and sodium alginate were stirred and dissolved with an appropriate amount of water. After mixing, the solution was colorless and clear, and no turbidity occurred. Add water to the full amount and mix. Uniform, no significant difference in measured content, related substances, and pH value, so the prescription composition of the present invention will not have a negative impact on product quality.
  • the injection solution obtained by using mannitol and lactose as osmotic pressure regulators has a cloudy color. Related substances The higher content of H2O has potential safety hazards for future clinical applications.
  • the test results show that the quality of tirofiban hydrochloride injection is stable in the range of pH 5.0-7.0, and the test results of the samples stored at 60 ° C for 10 days have no significant difference compared with the test results of 0 days. Therefore, in the present invention, the pH range of tirofiban hydrochloride injection is preferably 6.0.
  • step 2) Use dipotassium hydrogen phosphate to adjust the pH value of step 2) to 6.0, filter it through a 0.22 ⁇ m microporous filter, and dispense it into a glass infusion bottle, stopper, cap, sterilize, inspect and package .
  • step 2) Use dipotassium hydrogen phosphate to adjust the pH value of step 2) to 6.0, filter it through a 0.22 ⁇ m microporous filter, and dispense it into a glass infusion bottle. .
  • step 2) Use dipotassium hydrogen phosphate to adjust the pH value of step 2) to 6.0, filter it through a 0.22 ⁇ m microporous filter, and dispense it into a glass infusion bottle, stopper, cap, sterilize, inspect and package .
  • step 2) Use dipotassium hydrogen phosphate to adjust the pH value of step 2) to 6.0, filter it through a 0.22 ⁇ m microporous filter, and dispense it into a glass infusion bottle, stopper, cap, sterilize, inspect and package .
  • step 2) Use sodium hydroxide to adjust the pH value of the mixed solution obtained in step 2) to 7.0, filter it through a 0.22 ⁇ m microporous filter, and dispense it into a glass infusion bottle, stopper, cap, sterilize, inspect the light, and package.
  • step 3) Use hydrochloric acid in step 2).
  • the pH value of the obtained mixed solution is 5.0, filtered through a 0.22 ⁇ m microporous filter, and then packed in glass infusion bottles, stoppered, capped, sterilized, inspected by light, and packed.
  • step 2) Use dipotassium hydrogen phosphate to adjust the pH value of step 2) to 6.0, filter it through a 0.22 ⁇ m microporous filter, and dispense it into a glass infusion bottle, stopper, cap, sterilize, inspect and package .
  • step 3 The sulfuric acid is used to adjust the pH value of the mixed solution obtained in step 2) to 5.0. After filtering through a 0.22 ⁇ m microporous filter membrane, it is divided into glass infusion bottles, stoppered, capped, sterilized, inspected by light, and packed.
  • step 2) Use dipotassium hydrogen phosphate to adjust the pH value of step 2) to 5.0, filter it through a 0.22 ⁇ m microporous filter and dispense it into a glass infusion bottle, stopper, cap, sterilize, inspect and package. .
  • Tirofiban hydrochloride 1.405g 1,2-propanediol 100ml Ethanol 50ml Water for injection 1000ml Use hydrochloric acid to adjust the pH to 4.5
  • the liquid is light yellow, which may be caused by the sulfate ion which accelerates the decomposition of tirofiban hydrochloride; Comparative Example 3 uses different preparation methods to increase the content of related substances; the preparation method of Comparative Example 4 and The components are different, and the technical effects of the present invention cannot be achieved.

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Abstract

一种盐酸替罗非班注射液及其制备方法，所述注射液含有盐酸替罗非班、海藻酸钠、pH调节剂和水；制备方法为先将枸橼酸、枸橼酸钠溶于10~50%的水中制备成枸橼酸-枸橼酸钠缓冲液，然后将盐酸替罗非班、海藻酸钠溶于水中，将两种溶液混合，调节pH，过滤，分装，灭菌，灯检，包装即得。

Description

一种盐酸替罗非班注射液及其制备方法 技术领域
本发明涉及一种盐酸替罗非班注射液及其制备方法，属于医药制剂领域。
 背景技术
替罗非班(Tirofiban)是一种非肽类的血小板膜糖蛋白Ⅱb/Ⅲa (GPⅡb/Ⅲa)受体拮抗剂，具有阻断血小板交联和血小板聚集的作用。其化学名为(S)-N-(正丁基磺酰基-O-[4-(4-哌啶基)丁烷]-L-酪氨酸，药学上一般使用其盐酸盐一水合物。
盐酸替罗非班抑制血纤维蛋白原与血小板膜GPⅡb/Ⅲa受体结合，从而阻断血小板的交联和血小板的聚集。在临床上用于治疗急性冠脉综合征(ACS)病人，同时也适用于急性冠脉综合征病人进行冠脉血管成形或冠脉内斑块切除术，可减少死亡、心肌梗死、难治性心肌缺血/血运重建的复合终点的发生率。ACS是由心肌的急性严重缺血甚至坏死导致的一系列疾病谱组成，包括不稳定性心绞痛(UA)，非ST段抬高型心肌梗死(NSTEMI)，ST段抬高型心肌梗死(STE—MI)以及心源性猝死等。其发生的主要机制是冠状动脉内粥样硬化斑块破裂后触发血小板激活、聚集和血栓形成，因此抗血栓药物在ACS的治疗中起着举足轻重的作用。盐酸替罗非班与经典的抗血小板药物如阿司匹林和氯吡格雷不同，GPⅡb/Ⅲa受体阻断剂并不抑制血小板激活，而是通过与血小板膜上GPⅡb/Ⅲa受体结合，从而抑制血小板聚集。
世界发明专利申请WO1997/015328公开了一种含有替罗非班的药物组合物，其中替罗非班的量为0.05～0.25mg/ml，且将其制备成了200ml的大输液。
中国专利申请200410061014.0公开了一种含有氯化钠的盐酸替罗非班输液及其制备方法，每单位的输液中含有盐酸替罗非班0.056g/L。
中国专利申请200510018284.8、中国专利申请200510015295.0和中国专利申请200510018440.0分别公开了各自的一种盐酸替罗非班粉针及其制备方法。
替罗非班最早由美国Merk公司研制开发，是一种高选择性的GPⅡb/Ⅲa受体拮抗剂，临床主要用于血栓类疾病的治疗。与同类药物相比，替罗非班具有作用机制新颖、临床疗效确切、副作用低等优点。
目前国际市场上的盐酸替罗非班注射液主要有50ml∶12.5mg、100ml∶5mg和250ml∶12.5mg三种规格。
临床用法用量要求将盐酸替罗非班溶于0.9%氯化钠注射液或5%葡萄糖注射液中，终浓度为50μg/ml，静脉输注。
目前，盐酸替罗非班注射液在储存过程中见光易分解，并且性质不稳定，有关物质的含量上升，这给临床用药带来一定的安全隐患。
 技术问题
本发明的目的在于提供一种优质、静脉输注的的盐酸替罗非班注射液。
 技术解决方案
为了达到本发明的目的，发明人通过大量试验，筛选处方组成及用量，优化工艺操作和工艺参数，最终得到了解决本发明技术问题的技术方案，如下：
本发明的含有盐酸替罗非班的注射液，由有效量的盐酸替罗非班、渗透压调节剂、pH调节剂和水组成。各组分占注射液总体积的百分比为：以g/L计算，含量配比如下：
 
盐酸替罗非班 0.01～0.50（w/v）
海藻酸钠 0.05～2.5（w/v）
pH调节剂 适量
加水至 100ml
优选地，本发明的盐酸替罗非班注射液的各组分占注射液总体积的百分比为：以g/L计算，含量配比如下：
 
盐酸替罗非班 0.05～0.25（w/v）
海藻酸钠 0.5～1.5（w/v）
pH调节剂 适量
加水至 100ml
本发明提供了一种制备盐酸替罗非班注射液的方法，包括如下步骤：
将枸橼酸、枸橼酸钠溶于10～50%的水中制备成枸橼酸-枸橼酸钠缓冲液，再将盐酸替罗非班、海藻酸钠溶于50～80%的水中，两液混合，定容；使用pH值调节剂对混合液调节pH值至5.0-7.0，然后过滤、分装、灭菌、灯检、包装即得。
调节pH值的调节剂选自盐酸、枸橼酸、氢氧化钠、氢氧化钾、碳酸氢钠、磷酸氢二钠、磷酸二氢钠、磷酸氢二钾、磷酸二氢钾中的一种或多种，优选为磷酸二氢钾或磷酸氢二钾。
进一步地，使用pH值调节剂对混合液调节pH值至6.0。
进一步地，盐酸替罗非班注射液的制备方法为：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量，备用；
3）调节步骤2）所得混合液 pH值至6.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
与现有技术相比，本发明具有如下进步性：
本发明优选了渗透压调节剂，尤其是使用了海藻酸钠之后，活性物质含量高，在高温、光照等条件下能保持主药的稳定性，制备工艺简单，经过加速试验和长期稳定性的试验，均证实本发明实施例稳定性效果较好，外观较好溶液呈现无色透明液体，有关物质的含量在0.12%以下，适于工业化生产，便于市场推广。
 有益效果
下面通过盐酸替罗非班注射液的处方和研究试验来对本发明的技术方案进一步描述：
（ 1 ）不同处方组成及用量对产品质量的影响
结合原辅料性质、剂型特点及工业化生产要求，发明人通过一系列的试验摸索处方组成及其用量。具体地，按表1的处方组成，将盐酸替罗非班、海藻酸钠、枸橼酸、枸橼酸钠分别用适量水搅拌全溶，混合，加水至全量后混匀，取样检测。试验内容和结果见表1。
表1  不同处方组成以及用量对产品质量的影响试验
 
Figure 709805dest_path_image001
由试验结果可知，按表1的处方组成，处方量的盐酸替罗非班、海藻酸钠分别用适量水搅拌全溶，混合后药液无色澄明，无浑浊现象发生，加水至全量，混合均匀，测得含量、有关物质、pH值均无显著性差异，因此本发明的处方组成不会对产品质量造成负面影响，采用甘露醇和乳糖作为渗透压调节剂得到的注射液颜色浑浊，有关物质的含量较高，对以后的临床应用产生安全隐患。
不同 pH 值对产品质量的影响
按照表3的处方和pH值，将制备的样品置于60℃条件下10天后，考察产品pH值、含量和有关物质的变化，结果见表2。
 
Figure 626945dest_path_image002
表3  60℃条件下20天后，各处方的pH值、含量和有关物质的变化情况
 
Figure 593633dest_path_image003
试验结果表明，盐酸替罗非班注射液在pH值为5.0～7.0的范围之内质量稳定，60℃条件下放置10天的样品检测结果与0天检测结果相比无显著性差异。因此在本发明中，盐酸替罗非班注射液的pH值范围优选为6.0。
 
 本发明的实施方式
以下通过实施例进一步说明本发明，但这些实施例不以任何方式限制本发明。
实施例 1 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 50mg
海藻酸钠 500mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用磷酸氢二钾调节步骤2）所得混合液 pH值至6.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
实施例 2 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 10mg
海藻酸钠 50mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用磷酸氢二钾调节步骤2）所得混合液 pH值至6.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
实施例 3 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 10mg
海藻酸钠 50mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用磷酸氢二钾调节步骤2）所得混合液 pH值至6.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
实施例 4 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 500mg
海藻酸钠 2500mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用磷酸氢二钾调节步骤2）所得混合液 pH值至6.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
实施例 5 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 50mg
海藻酸钠 500mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用氢氧化钠调节步骤2）所得混合液 pH值至7.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
实施例 6 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 50mg
海藻酸钠 500mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用盐酸步骤2）所得混合液 pH值至5.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
对比实施例 1 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 50mg
海藻酸钠 40mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用磷酸氢二钾调节步骤2）所得混合液 pH值至6.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
对比实施例 2 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 50mg
海藻酸钠 500mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用硫酸调节步骤2）所得混合液 pH值至5.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
对比实施例 3 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 20mg
海藻酸钠 100mg
PH调节剂 适量
制备工艺：
1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，再将海藻酸钠溶于缓冲液中，备用；
2）将盐酸替罗非班溶解于50%水中，与步骤1）的缓冲液混合，定容至全量1000ml，备用；
3）使用磷酸氢二钾调节步骤2）所得混合液 pH值至5.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
对比实施例 4 ： 10 瓶盐酸替罗非班处方及其制备方法如下：
处方：
盐酸替罗非班 1.405g
1,2-丙二醇 100ml
乙醇 50ml
注射用水加至 1000ml
用盐酸调pH值至 4.5
制备工艺：
(1)分别将处方量的1,2-丙二醇和乙醇加入到50～60℃的全量30%注射用水，搅拌混匀；
(2)加入0.1~0.3%(w/v)活性炭，保温搅拌20分钟，过滤除炭；
(3)将处方量的盐酸替罗非班加入至上述的溶液中，搅拌均匀后，用注射用水定量至全量，用盐酸调pH值至4.5，然后用0.22μm的微孔滤膜过滤；
(4) 分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
结合具体实施方案，进一步考察处方的稳定性，如下：
、影响因素试验
高温试验
对具体实施例1- 6和对比实施例1-4中，盐酸替罗非班注射液样品进行60℃±2℃高温试验。分别于第5天、10天取样检测，试验的结果见表4。
表4盐酸替罗非班注射液高温试验结果
 
Figure 926525dest_path_image004
结果表明，在高温条件下放置，第5、10天样品的检测结果与0天样品的检测结果相比均无显著性差异，重现性良好，因此高温试验条件下产品质量稳定。
光照试验
对具体实施例1- 6和对比实施例1-4中，取盐酸替罗非班注射液样品进行4500lx±500lx光照试验。分别于第5天、10天取样检测，试验的结果见表5。
表5盐酸替罗非班注射液光照试验结果
 
Figure 740898dest_path_image005
结果表明，在光照条件下放置，第5、10天样品的性状、含量、pH值等检测结果与0天样品的检测结果相比均无显著性差异，重现性良好，有关物质则有较显著增加。
从表4、5可以看出：本发明实施例1-6的有关物质的含量在0.10以下，经过高温和光照仍能够保持稳定，优势实施例1和实施例2的有关物质为0.09%。看以看出，本发明的输液可以长时间储存不发生变化；对比文件1采用不用本发明的处方，制备完之后发现析晶现象；对比文件2采用硫酸作为pH值调节剂制备出的输液瓶液体为浅黄色，有可能是其中的硫酸根离子加速了盐酸替罗非班的分解导致的；对比实施例3采用不同的制备方法有关物质的含量有所提升；对比实施例4的制备方法和组分各不相同，也达不到本发明的技术效果。

Claims (9)

  1. 一种含有盐酸替罗非班的注射液，其特征在于，所述的注射液含有以下成分，以g/L计算，
    盐酸替罗非班 0.01～0.50（w/v） 海藻酸钠 0.05～2.5（w/v） pH调节剂 适量 加水至 100ml
    。
  2. 如权利要求1所述的注射液，其特征在于，所述的注射液含有以下成分：
    盐酸替罗非班 0.05～0.25（w/v） 海藻酸钠 0.5～1.5（w/v） pH调节剂 适量 加水至 100ml
    。
  3. 一种制备权利要求1所述注射液的方法，其特征在于，制备方法如下：
    将枸橼酸、枸橼酸钠溶于10～50%的水中制备成枸橼酸-枸橼酸钠缓冲液，然后将盐酸替罗非班、海藻酸钠溶于水中，两液混合，定容；调节pH值，然后过滤、分装、灭菌、灯检、包装即得。
  4. 如权利要求3所述的方法，其特征在于，所述的橼酸-枸橼酸钠缓冲液制备方法为：将枸橼酸、枸橼酸钠溶于全量水的10～50%的水中制备成枸橼酸-枸橼酸钠缓冲液。
  5. 如权利要求3所述的方法，其特征在于，所述的pH值为5.0-7.0。
  6. 如权利要求3所述的方法，其特征在于，所述的pH值为6.0。
  7. 如权利要求3所述的方法液，其特征在于，所述的pH值的调节剂为盐酸、枸橼酸、氢氧化钠、氢氧化钾、碳酸氢钠、磷酸氢二钠、磷酸二氢钠、磷酸氢二钾、磷酸二氢钾中的一种或多种。
  8. 如权利要求7所述的方法，其特征在于，所述的pH值的调节剂为磷酸二氢钾或磷酸氢二钾。
  9. 如权利要求3所述的方法，其特征在于，所述的制备方法如下：
    1）将枸橼酸、枸橼酸溶解于30%水中，制备成枸橼酸-枸橼酸钠缓冲液，备用；
    2）将盐酸替罗非班、海藻酸钠溶解于50%水中，与步骤1）的缓冲液混合，定容至全量，备用；
    3）调节步骤2）所得混合液 pH值至6.0，经0.22μm微孔滤膜过滤后分装于玻璃输液瓶中，加塞，轧盖，灭菌，灯检，包装即得。
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