WO2021008084A1 - 一种肾上腺素注射液及其制备方法 - Google Patents
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- 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
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- the invention relates to the technical field of pharmaceutical preparations, in particular to an epinephrine injection and a preparation method thereof.
- Adrenaline directly excites adrenaline ⁇ and ⁇ receptors, and through the activation of bronchial smooth muscle ⁇ 2 receptors, it can relieve bronchospasm, relax the bronchus, improve ventilation, and inhibit the release of allergic mediators, resulting in an anti-asthmatic effect and inhibiting vascular endothelial permeability Sex increase, promote mucus secretion and cilia movement, promote the synthesis and secretion of surface active substances in alveolar type II cells.
- Cardiovascular ⁇ 1 receptor excitement can strengthen myocardial contractility, increase heart rate, and increase cardiac output. Because of its many adverse reactions, it is rarely used as an anti-asthmatic treatment in clinical practice, and it is only used in severe bronchial asthma, especially in acute attacks of allergic asthma.
- Allergic reactions may occur within minutes of exposure and include flushing, fear, fainting, tachycardia, chest pain or unavailable pulse, and drop in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary urination, wheezing, breathing Difficulties, related to laryngospasm, itching, rash, urticaria or angioedema.
- Adrenaline is a substance naturally produced in the human body. In the emergency treatment of allergies, the first choice for injection is outside the thigh, because the medicine can take effect as soon as possible and allergic symptoms will soon disappear. Adrenaline can increase blood pressure, improve dizziness, fainting or loss of consciousness due to anaphylactic shock, relax the tracheal muscles, reduce throat swelling, and improve the patient's breathing.
- the epinephrine injection pen EPIPEN produced by the original research manufacturer Mylan Specialty.
- the raw materials include 0.3mg epinephrine, 1.8mg sodium chloride, 0.5mg sodium metabisulfite, and hydrochloric acid to adjust the pH to 2.2-5.0 per 0.3mL in the auto-injector.
- the composition of the entire process formulation is simple, in actual operation the formulation system has no stable buffer system for pH, and there will be a sudden change in pH adjustment. This change will cause local over acid or over alkali in the solution, which will seriously affect
- the stability of the main component leads to a decrease in the stability of the product, and the adrenaline is insoluble in water, and the original research formula did not explain the solution. Therefore, it is necessary to develop an epinephrine injection with good stability and simple preparation process.
- the purpose of the present invention is to provide an epinephrine injection and a preparation method thereof.
- the stability test results show that the adrenaline injection provided by the present invention has good stability, which is manifested in the increase and change of total impurities, pH and content.
- the preparation method of the present invention not only has simple operation steps, but also solves the problems of epinephrine solubility and instability when adjusting pH in the prior art.
- the present invention provides an epinephrine injection, which is composed of the following components by weight percentage:
- the buffer is selected from one or two of sodium dihydrogen phosphate and disodium hydrogen phosphate;
- the pH adjusting agent includes an acidic pH adjusting agent and an alkaline pH adjusting agent.
- the adrenaline injection is composed of the following components in weight percentage:
- every 1000 g adrenaline injection consists of the following components:
- the salt of epinephrine is the hydrochloride salt of epinephrine, that is, epinephrine hydrochloride.
- the osmotic pressure regulator is selected from one or two of sodium chloride and glucose;
- the antioxidant is selected from one or more of sodium bisulfite, sodium metabisulfite and sodium thiosulfate;
- the acidic pH adjuster is hydrochloric acid with a mass percentage concentration of 0.2-0.8%; the alkaline pH adjuster is selected from sodium hydroxide, and the concentration of the alkaline pH adjuster is 0.5M.
- every 1000 g adrenaline injection consists of the following components:
- the present invention also provides a preparation method of the adrenaline injection, including:
- Step 1 Dissolve epinephrine in an acidic pH regulator to make a first solution
- Step 2 Take the osmotic pressure regulator, antioxidant, and buffer plus the first water for injection and mix them evenly to obtain a second solution;
- Step 3 After mixing the first solution and the second solution, add the second water for injection, then adjust the pH to 2.5-4.5 with an alkaline pH regulator, constant volume, filter with membrane to obtain epinephrine injection.
- the epinephrine injection consists of the following components in weight percentage:
- every 1000 g adrenaline injection consists of the following components:
- the acidic pH adjuster in step 1 is hydrochloric acid with a concentration of 0.2 to 0.8% by mass;
- the osmotic pressure adjuster in step 2 is selected from one or two of sodium chloride and glucose
- the antioxidant is selected from one or more of sodium bisulfite, sodium metabisulfite and sodium thiosulfate;
- the alkaline pH regulator in step 3 is selected from sodium hydroxide, the alkaline pH is adjusted
- the concentration of the agent is 0.5M.
- the amount of the first water for injection is 600-700 g, and the second water for injection is added to 900-950 g.
- the pore size of the filter membrane in step 3 is 0.22 ⁇ m.
- step 3 the alkaline pH adjuster is used to adjust the pH to 2.6-4.2.
- the invention also provides the adrenaline injection prepared by the above preparation method.
- the present invention also provides an epinephrine injection pen.
- the epinephrine injection of the present invention is filled with nitrogen and then filled into a cassette bottle, and then filled into the pen.
- Adrenaline injection is composed of the following components in weight percentage: epinephrine 0.03 ⁇ 0.15%, osmotic pressure regulator 0.03 ⁇ 0.08%, antioxidant 0.008 ⁇ 0.025%, buffering agent 0.05 ⁇ 0.2%, pH regulator 8 ⁇ 15% And the remainder of the water for injection; the buffer is selected from one or two of sodium dihydrogen phosphate and disodium hydrogen phosphate; the pH regulator includes an acidic pH regulator and an alkaline pH regulator.
- the adrenaline injection provided by the present invention optimizes and adjusts the dosage of each component, and adds a specific buffer, and each component has a synergistic effect and has better stability than existing products.
- the preparation method of the present invention not only has simple operation steps, but also solves the problems of epinephrine solubility and instability when adjusting pH in the prior art.
- the invention discloses an epinephrine injection and a preparation method thereof. Those skilled in the art can learn from the content of this article and appropriately improve the process parameters. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
- the method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant personnel can modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
- test materials used in the present invention are all common commercially available products, which are all available in the market.
- EPIPEN was purchased from Mylan Specialty
- adrenaline was purchased from Shenzhen Voland Pharmaceutical Co., Ltd.
- hydrochloric acid was purchased from Merck
- sodium metabisulfite was purchased from Merck
- sodium chloride was purchased from Hunan Erkang
- disodium hydrogen phosphate was purchased from Roquette Freres.
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Abstract
一种肾上腺素注射液及其制备方法。该肾上腺素注射液由如下重量百分比的组分组成:肾上腺素或其盐0.03~0.15%、渗透压调节剂0.03~0.08%、抗氧化剂0.08~0.25%、缓冲剂0.05~0.2%、pH调节剂8~15%和余量的注射用水;所述缓冲剂选自磷酸二氢钠和磷酸氢二钠中的一种或两种;所述pH调节剂包括酸性pH调节剂和碱性pH调节剂。
Description
本申请要求于2019年7月15日提交中国专利局、申请号为201910636140.0、发明名称为“一种肾上腺素注射液及其制备方法”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本发明涉及药物制剂技术领域,尤其涉及一种肾上腺素注射液及其制备方法。
肾上腺素直接兴奋肾上腺素α和β受体,通过兴奋支气管平滑肌β2受体能缓解支气管痉挛,舒张支气管,改善通气功能,并抑制过敏介质的释放,产生平喘效应,还能抑制血管内皮通透性增高,促进黏液分泌和纤毛运动,促进肺泡Ⅱ型细胞合成和分泌表面活性物质。同时兴奋支气管黏膜血管α受体,引起黏膜血管过度收缩,毛细血管压增加,这可能导致黏膜水肿和充血加重,减弱平喘效应。心脏血管β1受体兴奋,可使心肌收缩力加强,心率加快,心排血量增加。因其不良反应较多,目前临床上已很少用作平喘治疗,仅在严重支气管哮喘,尤其是过敏性哮喘急性发作时应用。过敏反应可能在暴露后几分钟内发生,包括潮红、恐惧、晕厥、心动过速、胸痛或无法获得的脉搏,与血压下降、抽搐、呕吐、腹泻和腹部绞痛、非自主排尿、喘息、呼吸困难、因喉痉挛、瘙痒、皮疹、荨麻疹或血管性水肿有关。
肾上腺素是人体内自然产生的物质。过敏紧急治疗中的紧急情况下注射位置的首选是大腿外则,因为能令药物尽快见效,过敏症状很快会减退。肾上腺素会提高血压,改善因过敏性休克而头晕、晕倒或失去知觉的情况,同时放松气管肌肉,减少喉咙肿胀,改善患者呼吸。
目前,肾上腺素注射笔市场主要品种为EPIPEN和仿制品Symjepi,目的是作为紧急支持治疗的直接管理,并不能代替立即的医疗护理。国内市场现今还未有急救注射笔的剂型出现,也无应急性的治疗方式。
原研厂家Mylan Specialty生产的肾上腺素注射笔EPIPEN,原辅料包括自动注射器中每0.3mL含有0.3mg肾上腺素,1.8mg氯化钠,0.5mg焦亚硫酸钠,盐酸调节pH 2.2-5.0。虽然整个工艺处方组成简单,但在实际操作中处方体系中由于对pH无稳定的缓冲体系,pH调节时会有突跃性变化,这种变化会导致溶液中局部过酸或者过碱,严重影响主成分的稳定性,从而导致产品的稳定性下降,而且肾上腺素不溶于水,而原研处方工艺中并未说明解决方法。因此,需要开发一种稳定性良好、制备工艺简单的肾上腺素注射液。
发明内容
有鉴于此,本发明的目的在于提供一种肾上腺素注射液及其制备方法。稳定性测试结果表明,本发明提供的肾上腺素注射液具有良好的稳定性,表现在总杂质、pH和含量的增长变化方面。同时,本发明制备方法不仅操作步骤简单,而且解决了现有工艺存在的肾上腺素溶解性与调节pH时不稳定的问题。
为了实现本发明的目的,本发明采用如下技术方案:
本发明提供了一种肾上腺素注射液,由如下重量百分比的组分组成:
所述缓冲剂选自磷酸二氢钠、磷酸氢二钠中的一种或两种;
所述pH调节剂包括酸性pH调节剂和碱性pH调节剂。
一些实施方案中,所述肾上腺素注射液由如下重量百分比的组分组成:
一些实施方案中,每1000g肾上腺素注射液中,由以下组分组成:
本发明中,所述肾上腺素的盐为肾上腺素的盐酸盐,即盐酸肾上腺素。
本发明提供的肾上腺素注射液中,所述渗透压调节剂选自氯化钠、葡萄糖中的一种或两种;
所述抗氧剂选自亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠中的一种或多种;
所述酸性pH调节剂为质量百分浓度为0.2~0.8%的盐酸;所述碱性pH调节剂选自氢氧化钠,所述碱性pH调节剂的浓度为0.5M。
在一些具体实施例中,每1000g肾上腺素注射液由以下组分组成:
本发明还提供了所述肾上腺素注射液的制备方法,包括:
步骤1:将肾上腺素溶于酸性pH调节剂中制成第一溶液;
步骤2:取渗透压调节剂、抗氧剂和缓冲剂加第一注射用水,混合均匀,得第二溶液;
步骤3:将第一溶液和第二溶液混匀后加第二注射用水,然后用碱性pH调节剂调节pH至2.5~4.5,定容、滤膜过滤,获得肾上腺素注射液。
本发明提供的肾上腺素注射液制备方法中,所述肾上腺素注射液由如下重量百分比的组分组成:
一些实施方案中,每1000g肾上腺素注射液由以下组分组成:
一些实施方案中,步骤1中所述酸性pH调节剂为质量百分浓度为0.2~0.8%的盐酸;步骤2中所述渗透压调节剂选自氯化钠、葡萄糖中的一种或两种;所述抗氧剂选自亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠中的一种或多种;步骤3中所述碱性pH调节剂选自氢氧化钠,所述碱性pH调节剂的浓度为0.5M。
一些实施方案中,制备每1000g肾上腺素注射液,所述第一注射用水的用量为600~700g,加入所述第二注射用水至900~950g。
一些实施方案中,步骤3中所述滤膜的孔径为0.22μm。
一些实施方案中,步骤3中,所述用碱性pH调节剂调节pH至2.6~4.2。
本发明还提供了由以上制备方法制得的肾上腺素注射液。
本发明还提供了一种肾上腺素注射笔,将本发明肾上腺素注射液充氮后灌装于卡式瓶中,再装入笔中。
肾上腺素注射液由如下重量百分比的组分组成:肾上腺素0.03~0.15%、渗透压调节剂0.03~0.08%、抗氧化剂0.008~0.025%、缓冲 剂0.05~0.2%、pH调节剂8~15%和余量的注射用水;所述缓冲剂选自磷酸二氢钠、磷酸氢二钠中的一种或两种;所述pH调节剂包括酸性pH调节剂和碱性pH调节剂。本发明提供的肾上腺素注射液对各组分的用量进行了优化调整,并加入特定的缓冲剂,各组分协同作用,相比现有产品具有更好的稳定性。同时,本发明制备方法不仅操作步骤简单,而且解决了现有技术存在的肾上腺素溶解性与调节pH时不稳定的问题。
本发明公开了一种肾上腺素注射液及其制备方法,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
对所公开的实施例的说明,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。
本发明采用的试材皆为普通市售品,皆可于市场购得。
其中,EPIPEN购自Mylan Specialty,肾上腺素购自深圳沃兰德药业有限公司;盐酸购自Merck;焦亚硫酸钠购自Merck;氯化钠购自湖南尔康;磷酸氢二钠购自Roquette Freres。
下面结合实施例,进一步阐述本发明:
实施例1:肾上腺素注射笔的制备
(1)将1.5g的肾上腺素溶解于150g 0.8%的盐酸中,搅拌均匀制成溶液;
(2)将0.8g的氯化钠、2.5g的焦亚硫酸钠和2g磷酸氢二钠用注射用水600~700g溶解;
(3)将上述的两种溶液混合均匀,加注射用水至900~950g;
(4)用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
(5)用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例2:肾上腺素注射笔的制备
1:将1.0g的肾上腺素溶解于120g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.5g的氯化钠、1.5g的焦亚硫酸钠和1g磷酸氢二钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用2.60g 0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例3:肾上腺素注射笔的制备
1:将1.0g的肾上腺素溶解于120g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.5g的氯化钠、1.5g的焦亚硫酸钠和0.6g磷酸氢二钠和0.4g磷酸二氢钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例4:肾上腺素注射笔的制备
1:将0.8g的肾上腺素溶解于115g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.6g的葡萄糖、1.6g的焦亚硫酸钠和1g磷酸氢二钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M碳酸氢钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例5:肾上腺素注射笔的制备
1:将0.8g的肾上腺素溶解于110g 0.3%的盐酸中,搅拌均匀制成溶 液;
2:将0.7g的氯化钠、1.4g的亚硫酸氢钠和0.9g磷酸氢二钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例6:肾上腺素注射笔的制备
1:将0.8g的肾上腺素溶解于110g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.7g的氯化钠、1.4g的硫代硫酸钠和0.9g磷酸氢二钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例7:肾上腺素注射笔的制备
1:将0.8g的肾上腺素溶解于110g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.7g的氯化钠、1.4g的焦亚硫酸钠和0.9g磷酸二氢钠用注射 用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例8:肾上腺素注射笔的制备
1:将0.9g的肾上腺素溶解于110g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.6g的氯化钠、1.4g的硫代硫酸钠和1.1g磷酸二氢钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例9:肾上腺素注射笔的制备
1:将1.0g的肾上腺素溶解于110g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.7g的氯化钠、1.5g的亚硫酸氢钠和1.1g磷酸二氢钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
对比例1 肾上腺素注射笔的制备
1:将0.9g的肾上腺素溶解于120g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将0.5g的氯化钠、1.5g的焦亚硫酸钠和1.1g碳酸氢钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M碳酸氢钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
对比例2 肾上腺素注射笔的制备
1:将1.0g的肾上腺素溶解于120g 0.3%的盐酸中,搅拌均匀制成溶液;
2:将1.0g的氯化钠、3.0g的焦亚硫酸钠和3.0g磷酸氢二钠用注射用水600~700g溶解;
3:将上述的两种溶液混合均匀,加注射用水至900~950g;
4:用0.5M氢氧化钠调节pH至2.5~4.5后定容至1000g;
5:用0.22μm滤膜过滤后充氮灌装于卡式瓶中,装入笔中。
实施例10
取实施例1~9制备的产品与市售品(EPIPEN),将几种样品在高温40℃条件下分别存放10、30天,考察制剂中的有关物质、pH、含量和外观变化,来对比几种制剂的稳定性。
表1制剂稳定性试验结果
表2制剂稳定性试验变化率
从上述结果可以看出,实施例2~9的产品在加速40℃条件下总杂质、pH和含量的增长变化,均比原研产品和对比例1~2要低,证明本发明产品具有更优异的稳定性。
以上仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
- 根据权利要求1~3任一项所述的肾上腺素注射液,其特征在于,所述肾上腺素的盐为盐酸肾上腺素。
- 根据权利要求1~3任一项所述的肾上腺素注射液,其特征在于,所述渗透压调节剂选自氯化钠、葡萄糖中的一种或两种;所述抗氧剂选自 亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠中的一种或多种;所述酸性pH调节剂为质量百分浓度为0.2~0.8%的盐酸;所述碱性pH调节为氢氧化钠,所述碱性pH调节剂的浓度为0.5M。
- 权利要求1~5任一项所述的肾上腺素注射液的制备方法,其特征在于,包括:步骤1:将肾上腺素溶于酸性pH调节剂中制成第一溶液;步骤2:取渗透压调节剂、抗氧剂和缓冲剂加第一注射用水,混合均匀,得第二溶液;步骤3:将第一溶液和第二溶液混匀后加第二注射用水,然后用碱性pH调节剂调节pH至2.5~4.5,定容、滤膜过滤,获得肾上腺素注射液。
- 根据权利要求6所述的制备方法,其特征在于,制备每1000g肾上腺素注射液,所述第一注射用水的用量为600~700g,加入所述第二注射用水至900~950g。
- 根据权利要求6所述的制备方法,其特征在于,步骤3中所述滤膜的孔径为0.22μm。
- 权利要求6~8任一项所述的制备方法制得的肾上腺素注射液。
- 一种肾上腺素注射笔,其特征在于,由以下方法制得:将权利要求1~5、9任一项所述的肾上腺素注射液或权利要求6~8任一项所述的制备方法制得的肾上腺素注射液充氮后灌装于卡式瓶中,再装入笔中。
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