WO2016180206A1 - 一种阿魏酸冰片酯注射剂、其制备方法及应用 - Google Patents
一种阿魏酸冰片酯注射剂、其制备方法及应用 Download PDFInfo
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- WO2016180206A1 WO2016180206A1 PCT/CN2016/079896 CN2016079896W WO2016180206A1 WO 2016180206 A1 WO2016180206 A1 WO 2016180206A1 CN 2016079896 W CN2016079896 W CN 2016079896W WO 2016180206 A1 WO2016180206 A1 WO 2016180206A1
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- injection
- borneol
- pharmaceutical composition
- ferulate
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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
- A61K9/08—Solutions
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
Definitions
- the invention belongs to the field of medical chemistry, and particularly relates to a borneol ferulate injection and a preparation method thereof.
- Ferulic acid (4-hydroxy-3-methoxycinnamic acid), originally found in the seeds and leaves of plants, is a phenolic acid extracted from plants such as Angelica, Chuanxiong, and A. It is widely used in health care products, cosmetics, medicines, pesticides and food additives in the fields of anti-oxidation, anti-thrombosis and various physiological activities.
- ferulic acid can inhibit platelet aggregation and release, can significantly inhibit experimental thrombosis, regulate immune, clear and inhibit free radical reactions, ferulic acid molecules can be used in a variety of ways to the structure of biological macromolecules in vivo The function is protective.
- ferulic acid has strong hydrophilicity, poor fat solubility, and its metabolism in the body is fast, the brain is less distributed, and it is difficult to pass through the blood-brain barrier, making it widely restricted in the treatment of cerebrovascular diseases.
- the current clinical application of the drug sodium ferulate injection is mainly focused on the treatment of cardiovascular diseases. Therefore, the modification of ferulic acid molecules to prepare their derivatives to improve the molecular fat solubility is a key to solving the molecular defects of ferulic acid.
- the reaction of ferulic acid with alcohol to ferulate is to improve its fat solubility and use effect. The best way.
- borneol has the effect of refreshing, promoting the drug through the blood-brain barrier, and has two-way regulation and protection of the central nervous system. It also has a good effect on the treatment of stroke diseases; therefore, the researchers reacted with ferulic acid and borneol. , obtained borneol ferric acid ester; it has been confirmed that borneol ferulate has better therapeutic effect than ferulic acid alone.
- the present invention provides an injection of borneol ferulate and a method of preparing the same.
- the borneol ferulate ester injection of the invention has good storage stability and has a good therapeutic effect on cerebrovascular diseases.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising borneol ferulate, the pharmaceutical composition comprising: 0.02 to 2% of borneol ferulate, 0.01 to 60% by mass % solubilizer, 0.01-10% antioxidant, 0.45-5% osmotic pressure regulator, 0.01-1% pH adjuster, the balance is water for injection.
- the solubilizer is selected from one or more of the following: propylene glycol, hydroxypropyl- ⁇ -cyclodextrin, poloxamer, Tween-80, ethanol, polyethylene glycol, povidone Polyoxyethylene (35) castor oil, polyethylene glycol (40) hydrogenated castor oil and polyethylene glycol (15) hydroxystearate.
- the antioxidant is selected from one or more of the group consisting of L-cysteine hydrochloride, disodium ethylenediaminetetraacetate, thiourea, sodium metabisulfite, bamboo leaf flavonoids, sulfurous acid Sodium hydrogenate, vitamin C, sodium succinate, sodium metaphosphate and thioethylene glycol.
- the osmotic pressure adjusting agent is selected from one or more of the group consisting of sodium chloride, potassium chloride and glucose.
- the pH adjusting agent is selected from one or more of the following: hydrochloric acid, acetic acid, phosphoric acid, citric acid, boric acid, sodium hydroxide, and potassium hydroxide.
- the pharmaceutical composition further comprises from 2 to 90% of a lyoprotectant.
- the lyoprotectant is selected from one or more of the group consisting of glucose, mannitol, lactose, dextran, sucrose, dextran, glycine, and povidone.
- the present invention provides a borneol ferulate ester injection which is an aqueous injection or a lyophilized powder injection, comprising or prepared from the pharmaceutical composition according to the first aspect.
- the present invention provides a method for preparing a borneol ferulate ester injection according to the second aspect, which comprises the steps of: weighing each component according to a formula, adding borneol ferulate to a solubilizing agent. After stirring and dissolving, add appropriate amount of water for injection and the rest of the components, adjust the pH to 4-6, dilute the volume of water for injection, decolorize, filter, and sterilize, that is, obtain a water injection;
- the obtained aqueous injection is pre-frozen, sublimed, analyzed, and dried to obtain a lyophilized powder injection.
- the present invention provides the pharmaceutical composition according to the first aspect or the borneol ferulate ester injection according to the second aspect, for use in the preparation of a medicament for treating antithrombotic, hypolipidemic or cerebrovascular diseases;
- the cerebrovascular disease is stroke.
- the ferulic acid borneol ester injection of the present invention and the preparation method thereof have the following beneficial effects:
- the borneol ferulate ester injection of the present invention (including a water injection and a lyophilized powder injection) has excellent storage stability and has a good therapeutic effect on cerebrovascular diseases, particularly stroke.
- the preparation method of the ferulic acid borneol ester injection of the invention is simple, more industrialized, and has good controllability in the preparation process, and the temperature and other preparation conditions can avoid degradation of the main drug and the auxiliary material in the preparation process, and the product is safe. High sex.
- the invention discloses a ferulic acid borneol injection water injection and a lyophilized powder injection.
- the formula of the water injection comprises: 0.02 to 2% borneol ferulate, 0.01 to 60% solubilizer, 0.01 ⁇ 10% antioxidant, 0.45 to 5% osmotic pressure adjusting agent, 0.01 to 1% pH adjusting agent, the balance is water for injection; lyophilized powder injection is prepared by adding 2 to 90% of lyophilized protective agent to the formula of water injection
- the specific preparation method can be further embodied in the following examples.
- This embodiment discloses a preparation method of a ferulic acid borneol ester water injection, which specifically comprises the following steps:
- the first step first weigh each component according to the prescription table of Table 1, and reserve;
- the second step according to the prescribed amount of borneol ferulate, add propylene glycol, heated at 40 ° C to stir to dissolve, add 80% pre-formed volume of sterile water for injection, the water temperature is controlled at 30 ° C, add the remaining auxiliary materials, with hydrochloric acid
- the aqueous solution is adjusted to a pH of 5;
- the third step is to add activated carbon, make up the volume with the remaining 20% of water for injection, stir the decolorization, depyrogen, filter, check the content and dispense.
- Influential factors test Take three parts of the ferulic acid borneol ester water injection prepared according to the above steps, placed at high temperature (60 ° C), high humidity (25 ° C, humidity 92.5%), light (light intensity 4500 ⁇ 500 lx) and other conditions The samples were sampled at 0, 5, and 10 days. The influencing factors test results show that the water injection has good stability. The test results are shown in Table 2 below:
- a method for preparing a ferulic acid borneol aqueous injection which specifically comprises the following steps:
- the first step is to weigh the components according to the prescription table in Table 3 and set aside;
- the second step according to the prescribed amount of borneol ferulate, add polyethylene glycol (15) hydroxystearate, stir at 50 ° C to dissolve, add 80% pre-formed volume of sterile water for injection, control the water temperature At 50 ° C ⁇ 55 ° C, the remaining auxiliary materials, with hydrochloric acid aqueous solution to adjust the pH value of 4.5 ⁇ 5.5;
- the third step is to add activated carbon, make up the volume with the remaining 20% of water for injection, stir the decolorization, depyrogen, filter, check the content and dispense.
- Influential factors test Take three parts of the ferulic acid borneol ester water injection prepared according to the above steps, placed at high temperature (60 ° C), high humidity (25 ° C, humidity 92.5%), light (light intensity 4500 ⁇ 500 lx) and other conditions The samples were sampled at 0, 5, and 10 days. The influencing factors test results show that the water injection has good stability. The test results are shown in Table 4 below:
- a method for preparing a water injection of ferulic acid borneol ester which specifically comprises the following steps:
- the first step first weigh each component according to the prescription table of Table 5, and reserve;
- the second step according to the prescribed amount of borneol ferulate, add polyoxyethylene (35) castor oil, heated at 60 ° C to stir to dissolve, add 80% pre-formed volume of sterile water for injection, the water temperature is controlled at 50 ° C, Add the remaining excipients, use Adding hydrochloric acid aqueous solution to adjust the pH value 6;
- the third step is to add activated carbon, make up the volume with the remaining 20% of water for injection, stir the decolorization, depyrogen, filter, check the content and dispense.
- Influential factors test Take three parts of the ferulic acid borneol ester water injection prepared according to the above steps, placed at high temperature (60 ° C), high humidity (25 ° C, humidity 92.5%), light (light intensity 4500 ⁇ 500 lx) and other conditions The samples were sampled at 0, 5, and 10 days. The influencing factors test results show that the water injection has good stability. The test results are shown in Table 6 below:
- a method for preparing a lyophilized powder of ferulic acid borneol is disclosed, and the specific preparation method is as follows:
- the first step is to weigh the components according to the prescription in Table 7 and set aside;
- the second step according to the prescribed amount of borneol ferulate, add polyethylene glycol (15) hydroxystearate, stir at 50 ° C to dissolve, add 80% pre-formed volume of sterile water for injection, control the water temperature At 15 ° C, the remaining auxiliary materials were added, and the pH value 4 was adjusted with an aqueous solution of hydrochloric acid;
- the third step adding activated carbon, using the remaining 20% of the injected water to make up the volume, stirring decolorization, depyrogenation, filtration, detection of content, packaging;
- the fourth step is to freeze the following steps:
- Influencing factor test Take three parts of ferulic acid borneol ester powder prepared according to the above steps and place it under high temperature (60 ° C), high humidity (25 ° C, humidity 92.5%), light (light intensity 4500 ⁇ 500 lx) and other conditions. The samples were sampled at 0, 5, and 10 days. Influential factors test results show that the powder injection has good stability. The test results are shown in Table 8 below:
- a method for preparing a lyophilized powder of ferulic acid borneol ester is disclosed.
- the lyophilized powder of ferulic acid lyophilized powder is obtained by the lyophilization step of the water injection prepared in Example 2, and lyophilized.
- the lyophilization steps of the powder injection are as follows:
- Analytical drying The temperature is raised by 5 ° C every 1.5 hours until the temperature of the product is about -30 ° C. Thereafter, the temperature is gradually raised to raise the temperature of the product to 20 ° C and kept for 10 hours.
- Influencing factor test Take three parts of ferulic acid borneol ester powder prepared according to the above steps and place it under high temperature (60 ° C), high humidity (25 ° C, humidity 92.5%), light (light intensity 4500 ⁇ 500 lx) and other conditions. The samples were sampled at 0, 5, and 10 days. Influential factors test results show that the powder injection has good stability. The test results are shown in Table 9 below:
- a method for preparing a lyophilized powder of ferulic acid borneol ester is disclosed.
- the lyophilized powder of ferulic acid lyophilized powder is obtained by the lyophilization step of the water injection prepared in Example 3, and lyophilized.
- the lyophilization steps of the powder injection are as follows:
- Influencing factor test Take three parts of ferulic acid borneol ester powder prepared according to the above steps and place it under high temperature (60 ° C), high humidity (25 ° C, humidity 92.5%), light (light intensity 4500 ⁇ 500 lx) and other conditions. The samples were sampled at 0, 5, and 10 days. Influential factors test results show that the powder injection has good stability. The test results are shown in Table 10 below:
- the borneol ferulate ester injection according to the present invention has a water injection and a lyophilized powder injection, and has a good effect on cerebrovascular diseases, and the water injection and the lyophilized powder injection of the present invention have good stability.
- the preparation method of the ferulic acid borneol ester injection of the invention is simple, more industrialized, and has good controllability in the preparation process, and the temperature and other preparation conditions can avoid degradation of the main drug in the preparation process, and the product has high safety.
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Abstract
一种包含阿魏酸冰片酯的药物组合物，包含或者由该药物组合物制成的注射剂，所述注射剂的制备方法及应用。按照质量百分比计，所述药物组合物包括：0.02～2％的阿魏酸冰片酯、0.01～60％的增溶剂、0.01～10％的抗氧剂、0.45～5％的渗透压调节剂、0.01～1％的pH调节剂，余量为注射用水；任选地，还包括2～90％的冻干保护剂。阿魏酸冰片酯注射剂具有很好的储存稳定性，并且对脑血管疾病具有很好的治疗效果，具有很好的临床应用前景。
Description
本发明属于医药化学领域，具体的涉及一种阿魏酸冰片酯注射剂及其制备方法。
阿魏酸(4-羟基-3-甲氧基肉桂酸)，最初在植物的种子和叶子中发现，是一种存在当归、川穹、阿魏等植物中提取的酚酸，其具有抗炎、抗氧化、抗血栓和多种生理活性，广泛应用于保健品、化妆品、医药、农药和食品添加剂等领域。
经过研究发现，阿魏酸能够抑制血小板聚集和释放，能够明显抑制实验性血栓形成，调节机体免疫、清楚和抑制自由基反应，阿魏酸分子可以通过多种途径对体内生物大分子的结构和功能起到保护作用。
但是阿魏酸分子亲水性强，脂溶性差，且其体内代谢速度快，脑分布少，较难透过血脑屏障发挥作用，使其在治疗脑血管疾病领域应用大受限制，已上市药物阿魏酸钠注射液目前在临床上的应用主要偏重于心血管疾病的治疗。因此，对阿魏酸分子进行修饰制备其衍生物以提高分子脂溶性的研究是解决阿魏酸分子缺陷的一个关键，阿魏酸与醇反应成阿魏酸酯是改进其脂溶性和使用效果的最佳方法。
传统中药冰片具有开窍醒神、促进药物透过血脑屏障、对中枢神经系统有双向调节和保护作用等功效，对于脑卒中疾病治疗也有不错的疗效；因此，研究人员用阿魏酸和冰片反应，获得阿魏酸冰片酯；经证实，阿魏酸冰片酯比单纯阿魏酸具有更好的治疗效果。
因此，开发脂溶性好的阿魏酸冰片酯新剂型，使其能够很好地透过血脑屏障来发挥作用，是阿魏酸冰片酯在治疗脑血管疾病特别是脑卒中应用的关键。
发明内容
为弥补现有技术中存在的缺陷，本发明提供了一种阿魏酸冰片酯的注射剂和制备其的方法。本发明的阿魏酸冰片酯注射剂具有很好的储存稳定性，并且对脑血管疾病具有很好的治疗效果。
具体地，第一方面，本发明提供了一种包含阿魏酸冰片酯的药物组合物，按照质量百分比计，所述药物组合物包括：0.02～2％的阿魏酸冰片酯、0.01～60％的增溶剂、0.01～10％的抗氧剂、0.45～5％的渗透压调节剂、0.01～1％的pH调节剂，余量为注射用水。
优选地，所述增溶剂选自以下物质的一种或几种：丙二醇、羟丙基-β-环糊精、泊洛沙姆、吐温-80、乙醇、聚乙二醇、聚维酮、聚氧乙烯(35)蓖麻油、聚乙二醇(40)氢化蓖麻油和聚乙二醇(15)羟硬脂酸酯。
优选地，所述抗氧剂选自以下物质的一种或几种：L-半胱氨酸盐酸盐、乙二胺四乙酸二钠盐、硫脲、焦亚硫酸钠、竹叶黄酮、亚硫酸氢钠、维生素C、琥珀酸钠、偏磷酸钠和硫代乙二醇。
优选地，所述渗透压调节剂选自以下物质的一种或几种：氯化钠、氯化钾和葡萄糖。
优选地，所述pH调节剂选自以下物质的一种或几种：盐酸、醋酸、磷酸、枸橼酸、硼酸、氢氧化钠和氢氧化钾。
在一个具体的实施方案中，所述药物组合物还包括2～90％的冻干保护剂。
优选地，所述冻干保护剂选自以下物质中的一种或几种：葡萄糖、甘露醇、乳糖、葡聚糖、蔗糖、右旋糖酐、甘氨酸和聚维酮。
第二方面，本发明提供了一种阿魏酸冰片酯注射剂，其为水针剂或者冻干粉针剂，包括或者由如第一方面所述的药物组合物制备而成。
第三方面，本发明提供了如第二方面所述的阿魏酸冰片酯注射剂的制备方法，该方法包括如下步骤：按配方称取各组分，将阿魏酸冰片酯加入到增溶剂中，搅拌溶解后，加入适量注射用水和其余组分，调节pH至4～6，注射用水定容，脱色，过滤，灭菌，即得水针剂；
任选地，将所得水针剂进行预冻、升华、解析、干燥，即得冻干粉针剂。
第四方面，本发明提供了如第一方面所述的药物组合物或者如第二方面所述的阿魏酸冰片酯注射剂在制备治疗抗血栓、降血脂或脑血管疾病的药物中的应用；
优选地，所述脑血管疾病为脑卒中。
相比于现有技术，本发明的阿魏酸冰片酯注射剂及其制备方法具有如下有益效果：
(1)本发明的阿魏酸冰片酯注射剂(包括水针剂和冻干粉针剂)具有很好的储存稳定性，并且对脑血管疾病尤其是脑卒中具有良好的治疗效果。
(2)本发明的阿魏酸冰片酯注射剂的制备工艺简单，更易工业化，并且制备过程中条件可控性好，同时温度和其它制备条件可以避免制备过程中主药和辅料降解，产品的安全性高。
为便于理解本发明，以下通过列举具体实施例的方式进一步说明本发明的技术方案。本领域技术人员应该明了，所列举的具体实施例仅仅是帮助理解本发明，不应被视为对本发明的具体限制。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明公开了阿魏酸冰片酯注射剂水针剂和冻干粉针剂，按照质量百分比计，水针剂的配方包括：0.02～2％的阿魏酸冰片酯、0.01～60％的增溶剂、0.01～10％的抗氧剂、
0.45～5％的渗透压调节剂、0.01～1％的pH调节剂、余量为注射用水；冻干粉针剂是在水针剂的配方基础上加入2～90％的冻干保护剂制成的；具体的制备方法可在以下实施例中进一步体现。
实施例1
本实施例公开了一种阿魏酸冰片酯水针剂的制备方法，具体包括以下几个步骤：
第一步、先根据表1的处方表中称取各组分，备用；
第二步、按处方量的阿魏酸冰片酯，加入丙二醇，加热40℃搅拌使溶解，加入80％预配体积的灭菌注射用水，将水温控制在30℃，加入剩余辅料，用加盐酸水溶液调节pH值5；
第三步、加入活性炭，用剩余20％的注射用水补足体积，搅拌脱色、脱热原，过滤，检测含量、分装。
表1
| 组分 | 用量 | 作用 |
| 阿魏酸冰片酯 | 0.2g | 主药 |
| 丙二醇 | 60g | 增溶剂 |
| L-半胱氨酸盐酸 | 1.5g | 抗氧剂 |
| 氯化钾 | 8.5g | 渗透压调节剂 |
| 枸橼酸 | 适量 | pH调节剂 |
| 注射用水加至 | 1000ml |
影响因素试验：分别取三份根据上述步骤制备的阿魏酸冰片酯水针剂放置于高温(60℃)、高湿(25℃、湿度92.5％)、光照(光强4500±500lx)等条件下，于0天、5天、10天取样检测有关物质。影响因素试验结果显示该水针剂具有良好的稳定性。
其检测结果如下表2所示：
表2
实施例2
本实施例中公开了一种阿魏酸冰片酯水针剂的制备方法，具体包括以下几个步骤：
第一步、先根据表3的处方表中称取各组分，备用；
第二步、按处方量的阿魏酸冰片酯，加入聚乙二醇(15)羟硬脂酸酯，加热50℃搅拌使溶解，加入80％预配体积的灭菌注射用水，将水温控制在50℃～55℃，加入剩余辅料，用加盐酸水溶液调节pH值4.5～5.5；
第三步、加入活性炭，用剩余20％的注射用水补足体积，搅拌脱色、脱热原，过滤，检测含量、分装。
表3
| 组分 | 用量 | 作用 |
| 阿魏酸冰片酯 | 1.0g | 主药 |
| 聚乙二醇(15)羟硬脂酸酯 | 10g | 增溶剂 |
| 焦亚硫酸钠 | 1g | 抗氧剂 |
| 葡萄糖 | 35g | 渗透压调节剂 |
| 盐酸 | 适量 | pH调节剂 |
| 注射用水加至 | 1000ml |
影响因素试验：分别取三份根据上述步骤制备的阿魏酸冰片酯水针剂放置于高温(60℃)、高湿(25℃、湿度92.5％)、光照(光强4500±500lx)等条件下，于0天、5天、10天取样检测有关物质。影响因素试验结果显示该水针剂具有良好的稳定性。其检测结果如下表4所示：
表4
实施例3
本实施例中公开了一种制备阿魏酸冰片酯水针剂的方法，具体包括以下几步：
第一步、先根据表5的处方表中称取各组分，备用；
第二步、按处方量的阿魏酸冰片酯，加入聚氧乙烯(35)蓖麻油，加热60℃搅拌使溶解，加入80％预配体积的灭菌注射用水，将水温控制在50℃，加入剩余辅料，用
加盐酸水溶液调节pH值6；
第三步、加入活性炭，用剩余20％的注射用水补足体积，搅拌脱色、脱热原，过滤，检测含量、分装。
表5
| 组分 | 用量 | 作用 |
| 阿魏酸冰片酯 | 10g | 主药 |
| 聚氧乙烯(35)蓖麻油 | 15g | 增溶剂 |
| 乙二胺四乙酸二钠盐 | 1.5g | 抗氧剂 |
| 葡萄糖 | 45g | 渗透压调节剂 |
| 盐酸 | 适量 | pH调节剂 |
| 注射用水加至 | 1000ml |
影响因素试验：分别取三份根据上述步骤制备的阿魏酸冰片酯水针剂放置于高温(60℃)、高湿(25℃、湿度92.5％)、光照(光强4500±500lx)等条件下，于0天、5天、10天取样检测有关物质。影响因素试验结果显示该水针剂具有良好的稳定性。其检测结果如下表6所示：
表6
实施例4
本实施例中公开了一种阿魏酸冰片酯冻干粉针剂的制备方法，其具体制备方法为：
第一步、先根据表7中的处方称取各组分，备用；
第二步、按处方量的阿魏酸冰片酯，加入聚乙二醇(15)羟硬脂酸酯，加热50℃搅拌使溶解，加入80％预配体积的灭菌注射用水，将水温控制在15℃，加入剩余辅料，用加盐酸水溶液调节pH值4；
第三步、加入活性炭，用剩余20％的注射用水补足体积，搅拌脱色、脱热原，过滤，检测含量、分装；
第四步、按照以下步骤冻干：
4.1预冻：将制品置于冻干箱隔板上，使制品冷至-40℃，保温6小时；
4.2升华：将制品升温至-4℃保温1小时，再降至-40℃，保温3小时；并对冷凝器降温至-45℃以下，抽真空，控制真空度在10pa；
4.3解析干燥：以每1.5小时升温5℃，至制品温度约为-30℃，此后缓缓升温将制品温度升至20℃，保温10小时。
表7实施例4的处方表
| 组分 | 用量 | 作用 |
| 阿魏酸冰片酯 | 20g | 主药 |
| 甘露醇 | 200g | 冻干保护剂 |
| 聚乙二醇(15)羟硬脂酸酯 | 25g | 增溶剂 |
| 亚硫酸氢钠 | 2.0g | 抗氧剂 |
| 氯化钠 | 9.0g | 渗透压调节剂 |
| 盐酸 | 适量 | pH调节剂 |
| 注射用水加至 | 1000ml |
影响因素试验：分别取三份根据上述步骤制备的阿魏酸冰片酯粉针剂放置于高温(60℃)、高湿(25℃、湿度92.5％)、光照(光强4500±500lx)等条件下，于0天、5天、10天取样检测有关物质。影响因素试验结果显示该粉针剂具有良好的稳定性。其检测结果如下表8所示：
表8
实施例5
本实施例中公开了一种制备阿魏酸冰片酯冻干粉针剂的方法，所述阿魏酸冰片酯冻干粉针剂是由实施例2制备的水针剂经冻干步骤获得的，冻干粉针剂的冻干步骤如下：
5.1预冻：将制品置于冻干箱隔板上，使制品冷至-45℃，保温4小时；
5.2升华：将制品升温至-6℃保温1小时，再降至-45℃，保温2小时；并对冷凝
器降温至-45℃以下，抽真空，控制真空度在20pa；
5.3解析干燥：以每1.5小时升温5℃，至制品温度约为-30℃，此后缓缓升温将制品温度升至20℃，保温10小时。
影响因素试验：分别取三份根据上述步骤制备的阿魏酸冰片酯粉针剂放置于高温(60℃)、高湿(25℃、湿度92.5％)、光照(光强4500±500lx)等条件下，于0天、5天、10天取样检测有关物质。影响因素试验结果显示该粉针剂具有良好的稳定性。其检测结果如下表9所示：
表9
实施例6
本实施例中公开了一种制备阿魏酸冰片酯冻干粉针剂的方法，所述阿魏酸冰片酯冻干粉针剂是由实施例3制备的水针剂经冻干步骤获得的，冻干粉针剂的冻干步骤如下：
6.1预冻：将制品置于冻干箱隔板上，使制品冷至-43℃，保温5小时；
6.2升华：将制品升温至-5℃保温1小时，再降至-43℃，保温2.5小时；并对冷
凝器降温至-45℃以下，抽真空，控制真空度在15pa；
6.3解析干燥：以每1.5小时升温5℃，至制品温度约为-30℃，此后缓缓升温将制品温度升至20℃，保温10小时。
影响因素试验：分别取三份根据上述步骤制备的阿魏酸冰片酯粉针剂放置于高温(60℃)、高湿(25℃、湿度92.5％)、光照(光强4500±500lx)等条件下，于0天、5天、10天取样检测有关物质。影响因素试验结果显示该粉针剂具有良好的稳定性。其检测结果如下表10所示：
表10
本发明涉及的阿魏酸冰片酯注射剂有水针剂和冻干粉针剂，对脑血管疾病具有良好的作用，并且本发明的水针剂和冻干粉针剂的稳定性好。
本发明涉及的阿魏酸冰片酯注射剂的制备工艺简单、更易工业化，并且制备过程中的条件可控性好，同时温度和其它制备条件可以避免制备过程中主药降解，产品的安全性高。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。
对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (10)
- 一种包含阿魏酸冰片酯的药物组合物，其特征在于，按照质量百分比计，所述药物组合物包括：0.02～2％的阿魏酸冰片酯、0.01～60％的增溶剂、0.01～10％的抗氧剂、0.45～5％的渗透压调节剂、0.01～1％的pH调节剂，余量为注射用水。
- 根据权利要求1所述的药物组合物，其特征在于，所述增溶剂选自以下物质的一种或几种：丙二醇、羟丙基-β-环糊精、泊洛沙姆、吐温-80、乙醇、聚乙二醇、聚维酮、聚氧乙烯(35)蓖麻油、聚乙二醇(40)氢化蓖麻油和聚乙二醇(15)羟硬脂酸酯。
- 根据权利要求1或2所述的药物组合物，其特征在于，所述抗氧剂选自以下物质的一种或几种：L-半胱氨酸盐酸盐、乙二胺四乙酸二钠盐、硫脲、焦亚硫酸钠、竹叶黄酮、亚硫酸氢钠、维生素C、琥珀酸钠、偏磷酸钠和硫代乙二醇。
- 根据权利要求1-3任一项所述的药物组合物，其特征在于，所述渗透压调节剂选自以下物质的一种或几种：氯化钠、氯化钾和葡萄糖。
- 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述pH调节剂选自以下物质的一种或几种：盐酸、醋酸、磷酸、枸橼酸、硼酸、氢氧化钠和氢氧化钾。
- 根据权利要求1-5任一项所述的药物组合物，其特征在于，所述药物组合物还包括2～90％的冻干保护剂。
- 根据权利要求6所述的药物组合物，其特征在于，所述冻干保护剂选自以下物质中的一种或几种：葡萄糖、甘露醇、乳糖、葡聚糖、蔗糖、右旋糖酐、甘氨酸和聚维酮。
- 一种阿魏酸冰片酯注射剂，其为水针剂或者冻干粉针剂，包括或者由如权利要求1-7任一项所述的药物组合物制备而成。
- 如权利要求8所述阿魏酸冰片酯注射剂的制备方法，其特征在于，包括如下步骤：按配方称取各组分，将阿魏酸冰片酯加入到增溶剂中，搅拌溶解后，加入适量注 射用水和其余组分，调节pH至4～6，注射用水定容，脱色，过滤，灭菌，即得水针剂；任选地，将所得水针剂进行预冻、升华、解析、干燥，即得冻干粉针剂。
- 如权利要求1-7任一项所述的药物组合物或者如权利要求8所述的阿魏酸冰片酯注射剂在制备治疗抗血栓、降血脂或脑血管疾病的药物中的应用；优选地，所述脑血管疾病为脑卒中。
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| CN103232347A (zh) * | 2013-04-12 | 2013-08-07 | 合肥工业大学 | 一种cns药物的脑靶向前药及其制备方法以及冰片在cns药物脑靶向前药中的用途 |
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| CN103232347A (zh) * | 2013-04-12 | 2013-08-07 | 合肥工业大学 | 一种cns药物的脑靶向前药及其制备方法以及冰片在cns药物脑靶向前药中的用途 |
| CN104856983A (zh) * | 2015-05-13 | 2015-08-26 | 苏州沪云肿瘤研究中心股份有限公司 | 阿魏酸冰片酯的合成和应用 |
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| CN113456654A (zh) * | 2020-07-20 | 2021-10-01 | 上海和黄药业有限公司 | 一种稳定的药物组合物 |
| CN113456654B (zh) * | 2020-07-20 | 2023-01-10 | 上海和黄药业有限公司 | 一种稳定的药物组合物 |
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