CN106361749A - 一种复方氨基酸注射液18aa的制备方法 - Google Patents
一种复方氨基酸注射液18aa的制备方法 Download PDFInfo
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- CN106361749A CN106361749A CN201610936035.5A CN201610936035A CN106361749A CN 106361749 A CN106361749 A CN 106361749A CN 201610936035 A CN201610936035 A CN 201610936035A CN 106361749 A CN106361749 A CN 106361749A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种复方氨基酸注射液18AA的制备方法,它包括以下步骤:(a)对输液瓶进行冲洗,随后运送送至灌装间;(b)精氨酸搅拌溶解,随后按顺序加入缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸和组氨酸搅拌溶解;(c)降温至30~50℃,加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液,搅拌溶解后补注射用水至全量;(d)轧盖封口后灭菌。这样有利于各组分的充分溶解,保证其透光率;而且使得复方氨基酸注射液的性质稳定,有利于延长储存时间,促进吸收。
Description
技术领域
本发明属于注射液领域,涉及一种氨基酸注射液,具体涉及一种复方氨基酸注射液18AA的制备方法。
背景技术
复方氨基酸注射液(18AA)是非常重要的氨基酸补充剂及治疗剂,在临床上起着重要的作用。氨基酸在溶液中很不稳定,极易被氧化而产生一系列复杂的对人体有害的物质。自20世纪60年代,复方氨基酸投入生产使用起,为保证产品的稳定性必须加入具有独特抗氧化性质的亚硫酸盐类化合物,如亚硫酸氢钠、焦亚硫酸钠等。由于人们当时还不了解此类物质对人体有害,因而生产企业为了保证产品的稳定性,通常不加限制地大量加入。然而自20世纪80年代起,随着临床药学、药理学和医学的发展,人们开始认识到亚硫酸盐类物质的副作用并在亚硫酸盐的安全性方面进行了较为深入的研究。同时,西方发达国家的药政当局也加紧收集有关临床不良反应的反告,临床上最常见的有关副反应为亚硫酸盐过敏,症状是支气管痉挛,喘鸣,呼吸困难,恶性、喉部水肿、低血压、休克、甚至死亡。
出现上述症状,主要是因为:(1)胱氨酸几乎不溶于水,生产工艺中的要求较高的配制温度,高温条件下加剧氨基酸降解,影响产品质量;(2)氨基酸易氧化,在高温配制条件下必需采用充氮工艺,同时还需要添加亚硫酸氢钠作为抗氧剂,虽然一定程度上亚硫酸氢钠一定程度上防止了氨基酸降解,可也增加了临床应用的过敏、休克等不良反应;(3)在药物长期贮存过程中,氨基酸受包装容器内已有氧气的影响,继续发生降解,导致产品一般需要阴凉条件放置,且有效期较短。
发明内容
本发明目的是为了克服现有技术的不足而提供一种复方氨基酸注射液18AA的制备方法。
为达到上述目的,本发明所采用的技术方案为:一种复方氨基酸注射液18AA的制备方法,它包括以下步骤:
(a)分别用碱水、饮用水、纯化水和注射用水对输液瓶进行冲洗,随后运送送至灌装间;
(b)取注射用水加热至65~90℃,向其中通入氮气使其含溶解氧不超过0.5ppm,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸和组氨酸搅拌溶解;
(c)降温至30~50℃,加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液,搅拌溶解后补注射用水至全量;
(d)将步骤(c)得到的混合液注入所述输液瓶中,控制其内残氧量控制不超过2.0%,轧盖封口后灭菌。
优化地,步骤(a)中,对所述输液瓶进行开箱检查,确定其规格、批号、合格证和检验单;随后将所述输液瓶运送至操作台上,将凹凸、喇叭口、毛口、裂纹或油污的剔除。
进一步地,步骤(a)中,所述输液瓶内直径≥2mm且<5mm的气泡总数不得超过2个;玻瓶内直径<1mm和<0.5mm的结石总数不得超过3个。
进一步地,步骤(a)中,所述碱水的质量浓度为1~2%、温度为45~55℃。
进一步地,步骤(a)中,用所述碱水、饮用水、纯化水和注射用水对输液瓶进行冲洗时,其压力相互独立地为0.15~0.5MPa。
进一步地,步骤(a)中,所述注射用水温度保持在70℃以上。
进一步地,步骤(c)中,加入所述亚硫酸氢钠溶液和半胱氨酸后向其中加入占其质量分数为0.02~0.1%的针用活性炭,搅拌并控制其pH为6.5~8.0;经熔喷滤芯过滤,再用孔径为0.45μm串联0.22μm的滤膜过滤。
由于上述技术方案运用,本发明与现有技术相比具有下列优点:本发明复方氨基酸注射液18AA的制备方法,一方面通过用不同纯度的水对输液瓶进行冲洗,从而确保输液瓶的洁净;另一方面在不同温度、低溶解氧的条件下以特定顺序加入各种氨基酸形成复方注射液,这样有利于各组分的充分溶解,保证其透光率;而且使得复方氨基酸注射液的性质稳定,有利于延长储存时间,促进吸收。
具体实施方式
下面将对本发明优选实施方案进行详细说明。
实施例1
本实施例提供一种复方氨基酸注射液18AA的制备方法,该复方氨基酸注射液(18AA-Ⅶ)的配方为现有的(下同),如表1所示;它包括以下步骤:
(a)分别用碱水、饮用水、纯化水和注射用水对输液瓶进行冲洗,随后运送送至灌装间;洗瓶具体操作可包括以下步骤:(a1)开箱:检查输液瓶的规格、批号、合格证、检验单;(a2)上瓶:将输液瓶在瓶库去除外包装后,用搬运车送至上瓶操作台边,抬到操作台上;(a3)检瓶:将有明显的凹凸和喇叭口、毛口、有裂纹、油污的瓶子剔除;瓶子底要平,瓶身端正;玻瓶内直径≥2mm且<5mm的气泡总数不得超过2个;玻瓶内直径<1mm和<0.5mm的结石总数不得超过3个;(a4)配水:碱水:调整碱液(NaOH)质量浓度为1~2%、温度45~55℃;生产过程中检测碱液浓度3~6次,并随时观察碱液温度,以便及时调整碱液浓度和温度,贮碱液桶每天洗涮一次;饮用水:饮用水管道每月清理一次;饮用水桶内水温保持适当的温度(也可以是45~55℃,一般可通过蒸汽加热保温),每天清洗一次贮水桶;纯化水:参考饮用水的操作,温度暂无要求,但以加热后(也可以是45~55℃)的纯化水冲洗瓶效果较佳;注射用水:温度保持在70℃以上,每周对注射用水过滤器进行一次完整性试验检查。所有冲水(碱水、饮用水、纯化水、注射用水)压力均应不低于0.15MPa。
(b)取注射用水加热至65℃,向其中通入氮气使其含溶解氧不超过0.5ppm,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸和组氨酸搅拌溶解;
(c)降温至50℃,依次加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液(预先将下述量的亚硫酸氢钠用注射用水溶解),搅拌溶解后补注射用水至全量;
(d)将步骤(d)得到的混合液注入所述输液瓶中,控制其内残氧量控制不超过2.0%,轧盖封口后灭菌。
表1复方氨基酸注射液(18AA-Ⅶ)原辅料清单
实施例2
本实施例提供一种复方氨基酸注射液18AA的制备方法,其配方与实施例1中的基本相同,不同的是:步骤(c)中,补注射用水至全量后加入占其质量分数为0.02%的针用活性炭,搅拌并控制其pH为6.5~8.0;经熔喷滤芯过滤,再用孔径为0.45μm串联0.22μm的滤膜过滤。
实施例3
本实施例提供一种复方氨基酸注射液18AA的制备方法,其配方与实施例2中的基本相同,不同的是配制注射液的温度不同,主要是步骤(b)和步骤(c):
(b)取注射用水加热至90℃,向其中通入氮气使其含溶解氧不超过0.5ppm,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸和组氨酸搅拌溶解;
(c)降温至30℃,加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液,搅拌溶解后补注射用水至全量;加入占其质量分数为0.02%的针用活性炭,搅拌并控制其pH为6.5~8.0;经熔喷滤芯过滤,再用孔径为0.45μm串联0.22μm的滤膜过滤。
实施例4
本实施例提供一种复方氨基酸注射液18AA的制备方法,其配方与实施例2中的基本相同,不同的是配制注射液的温度不同,主要是步骤(b)和步骤(c):
(b)取注射用水加热至80℃,向其中通入氮气使其含溶解氧不超过0.5ppm,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸、缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸和组氨酸搅拌溶解;
(c)降温至45℃,加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液,搅拌溶解后补注射用水至全量,加入占其质量分数为0.02%的针用活性炭,搅拌并控制其pH为6.5~8.0;经熔喷滤芯过滤,再用孔径为0.45μm串联0.22μm的滤膜过滤。
实施例5
本实施例提供一种复方氨基酸注射液18AA的制备方法,其配方与实施例2中的基本相同,不同的是配制注射液的温度不同,主要是步骤(b)和步骤(c):
(b)取注射用水加热至70℃,向其中通入氮气使其含溶解氧不超过0.5ppm,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸、缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸和组氨酸搅拌溶解;
(c)降温至35℃,加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液,搅拌溶解后补注射用水至全量,加入占其质量分数为0.02%的针用活性炭,搅拌并控制其pH为6.5~8.0;经熔喷滤芯过滤,再用孔径为0.45μm串联0.22μm的滤膜过滤。
实施例6
本实施例提供一种复方氨基酸注射液18AA的制备方法,其配方与实施例1中的基本相同,不同的是配制注射液的温度不同,主要是步骤(b)和步骤(c):
(b)取注射用水加热至75℃,向其中通入氮气使其含溶解氧不超过0.5ppm,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸、缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸和组氨酸搅拌溶解;
(c)降温至40℃,加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液,搅拌溶解后补注射用水至全量,加入占其质量分数为0.02%的针用活性炭,搅拌并控制其pH为6.5~8.0;经熔喷滤芯过滤,再用孔径为0.45μm串联0.22μm的滤膜过滤。
对比例1
本实施例提供一种复方氨基酸注射液18AA的制备方法,其配方与实施例2中的基本相同,不同的是配制注射液的加料顺序不一样:步骤(b)中,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入谷氨酸、甘氨酸、酪氨酸、脯氨酸、丝氨酸、谷氨酸、组氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸、缬氨酸、苯丙氨酸、丙氨酸和门冬氨酸搅拌溶解。
表2实施例1至6、对比例1中制得的复方氨基酸注射液的测试数据
取小白鼠100只,分为三组,每组50只;每半个月注射一次,对比观察三个月,区分对比结果:注射实施例6中注射液实验组的小鼠充满活力、肌肉协调能力高,行动非常敏捷,体毛柔软有光泽,体重有很明显增加,总有效率97%;注射实施例4中注射液实验组中小鼠充满活力、肌肉协调能力高,行动非常敏捷,体毛柔软有光泽,体重有很明显增加,总有效率95%;注射实施例5中注射液实验组中小鼠充满活力,行动敏捷,体重很明显增加,总有效率92%;注射对比例1中注射液实验组中小鼠较为活泼,机体健康,体重增加,总有效率80%;同时将实施例4至6、对比例1中制得的复方氨基酸注射液置于10℃下储存,分别能够存放60天、62天、65天、30天。
氮平衡试验:另对20例肝炎后肝硬化病人进行氮平衡试验,其中男10例、女10例,年龄40-65岁,平均50岁,其按标准诊断,Child-Pugh分级均为A级。治疗组的非蛋白热能采用25%葡萄糖和10%脂肪乳剂,脂肪乳剂占非蛋白热能的50%;氮源采用实施例6制备的复方氨基酸注射液,另外补充水溶性维生素、脂溶性维生素、微量元素和电解质;各病例均采用深静脉穿刺置管。对照组的非蛋白热能也采用25%葡萄糖和10%脂肪乳剂,脂肪乳剂占非蛋白热能的50%;氮源采用市售的复方氨基酸注射液(18AA),另外补充水溶性维生素、脂溶性维生素、微量元素和电解质;各病例均采用深静脉穿刺置管。
在整个用药过程中,治疗组和对照组患者的生命体征(体温、心率、呼吸频率、血压)变化都在正常范围内,两组为显著差异。治疗组不良反应发生率少,程度轻,临床应用安全性好。结果显示治疗组的病人迅速获得了正氮平衡,治疗组和对照组6天之间具有显著差异(P<0.05),对比数据如表3所示:
表3氮平衡试验
综上所述,使用本发明复方氨基酸注射液更有利于调节血浆氨基酸谱趋于正常,氨基酸的补充和吸收效果较佳,促使氨基酸的持续补充效果优于现有市售产品,患者机体营养状况和免疫力得到了很好的提升,有利于患者更快的恢复健康,从而提高了疗效。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (7)
1.一种复方氨基酸注射液18AA的制备方法,其特征在于,它包括以下步骤:
(a)分别用碱水、饮用水、纯化水和注射用水对输液瓶进行冲洗,随后运送送至灌装间;
(b)取注射用水加热至65~90℃,向其中通入氮气使其含溶解氧不超过0.5ppm,在不断充氮和搅拌的条件下,加入精氨酸搅拌溶解,随后按顺序加入缬氨酸、苯丙氨酸、丙氨酸、门冬氨酸、脯氨酸、丝氨酸、谷氨酸、甘氨酸、酪氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苏氨酸和组氨酸搅拌溶解;
(c)降温至30~50℃,加入醋酸赖氨酸、色氨酸、半胱氨酸和亚硫酸氢钠溶液,搅拌溶解后补注射用水至全量;
(d)将步骤(c)得到的混合液注入所述输液瓶中,控制其内残氧量控制不超过2.0%,轧盖封口后灭菌。
2.根据权利要求1所述的复方氨基酸注射液18AA的制备方法,其特征在于:步骤(a)中,对所述输液瓶进行开箱检查,确定其规格、批号、合格证和检验单;随后将所述输液瓶运送至操作台上,将凹凸、喇叭口、毛口、裂纹或油污的剔除。
3.根据权利要求2所述复方氨基酸注射液18AA的制备方法,其特征在于:步骤(a)中,所述输液瓶内直径≥2mm且<5mm的气泡总数不得超过2个;玻瓶内直径<1mm和<0.5mm的结石总数不得超过3个。
4.根据权利要求1或2所述的复方氨基酸注射液18AA的制备方法,其特征在于:步骤(a)中,所述碱水的质量浓度为1~2%、温度为45~55℃。
5.根据权利要求1或2所述的复方氨基酸注射液18AA的制备方法,其特征在于:步骤(a)中,用所述碱水、饮用水、纯化水和注射用水对输液瓶进行冲洗时,其压力相互独立地为0.15~0.5 MPa。
6.根据权利要求1或2所述的复方氨基酸注射液18AA的制备方法,其特征在于:步骤(a)中,所述注射用水温度保持在70℃以上。
7.根据权利要求1或2所述的复方氨基酸注射液18AA的制备方法,其特征在于:步骤(c)中,加入所述亚硫酸氢钠溶液和半胱氨酸后向其中加入占其质量分数为0.02~0.1%的针用活性炭,搅拌并控制其pH为6.5~8.0;经熔喷滤芯过滤,再用孔径为0.45µm串联0.22µm的滤膜过滤。
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WO2021203606A1 (zh) * | 2020-04-08 | 2021-10-14 | 河北科星药业有限公司 | 畜用复方氨基酸注射液的制备方法 |
WO2021203605A1 (zh) * | 2020-04-08 | 2021-10-14 | 河北科星药业有限公司 | 畜用复方氨基酸注射液及其制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101933922A (zh) * | 2010-09-08 | 2011-01-05 | 郑飞雄 | 一种含新抗氧化剂的氨基酸组合物 |
-
2016
- 2016-10-24 CN CN201610936035.5A patent/CN106361749A/zh active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101933922A (zh) * | 2010-09-08 | 2011-01-05 | 郑飞雄 | 一种含新抗氧化剂的氨基酸组合物 |
Non-Patent Citations (1)
Title |
---|
张秀清: "影响大输液澄明度因素的研究", 《实用医技杂志》 * |
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WO2021203606A1 (zh) * | 2020-04-08 | 2021-10-14 | 河北科星药业有限公司 | 畜用复方氨基酸注射液的制备方法 |
WO2021203605A1 (zh) * | 2020-04-08 | 2021-10-14 | 河北科星药业有限公司 | 畜用复方氨基酸注射液及其制备方法 |
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