CN111603442A - 一种脂肪乳、复方氨基酸和葡萄糖注射液及其制备方法 - Google Patents
一种脂肪乳、复方氨基酸和葡萄糖注射液及其制备方法 Download PDFInfo
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- CN111603442A CN111603442A CN202010497721.3A CN202010497721A CN111603442A CN 111603442 A CN111603442 A CN 111603442A CN 202010497721 A CN202010497721 A CN 202010497721A CN 111603442 A CN111603442 A CN 111603442A
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- injection
- amino acid
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- compound amino
- fat emulsion
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Abstract
本发明属于药物制剂技术领域,具体涉及一种脂肪乳、复方氨基酸和葡萄糖注射液及其制备方法。本发明采用隔膜分开的三个腔室分别盛放脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液,使用时,只需依次用力挤压各腔室,或撕开各腔室间的隔离条,即可将三种注射液混匀,给人体静脉注射,能够在任何环境条件下进行混合操作,极大地降低传统混合操作因微生物污染而导致的输液热源反应、血液感染、败血症等严重不良反应。本发明注射液的总容量较小,适合为极低体重患者提供全肠外营养和一般体重患者提供补充性肠外营养,且对复方氨基酸注射液的配方进行了优化,各种氨基酸的配比更为合理。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种脂肪乳、复方氨基酸和葡萄糖注射液及其制备方法。
背景技术
脂肪、蛋白质和糖是人体需求量最大的三类基本营养物质。在人体胃肠道功能不全或无法吸收足够的上述营养物质时,以脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液进行静脉注射的方式提供,就叫作肠外营养。从营养物质代谢机理上讲,这三种营养素的利用相互依赖,从生理上讲,人体摄入食物时同时摄入了脂肪、蛋白质和糖,因此,理论和实际都证明了同时向人体静脉输入脂肪乳、氨基酸和葡萄糖,最符合人体生理代谢需要,尤其在需要长期使用肠外营养时,对维持人体内各营养素的平衡,维持正常的人体生理机能都有非常重要的意义。在临床实践中,实现脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液同时输入人体的方式为在使用前将这三种产品通过混合管灌入一特别设计的无菌袋中,混合以后通过无菌袋的输液口输入人体。该输液方式最大的缺陷是混合过程为手工操作,即便在无菌条件下操作,也有千分之一以上的概率造成微生物污染。此外,无菌配制室对于中小医院和欠发达地区也是经济上难以承受的。这种混合输液的另一种缺陷在于多次穿刺胶塞,会产生大量的胶塞微粒,引起毛细血管堵塞,造成微循环栓塞。
国内市场上已上市的三腔袋包装的脂肪乳、氨基酸和葡萄糖注射液,大部分规格较大,三腔袋产品规格均在1000mL及以上,这些大规格的三腔袋注射液,对于一般体重需要补充肠外营养的病人或是极低体重需要完全肠内营养的病人来说,都存在能量过剩的问题。一般医院会采取直接倒掉剩余药液的做法,防止过度喂养可能会引起的包括高血糖、肝功能改变、液体和电解质紊乱、免疫功能受损、感染风险增加和不良预后等在内的诸多风险,这不仅造成了大量医疗资源的浪费,而且增加了医疗成本,加重了患者的经济负担。
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以来,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。由于当时人们并不了解这类物质对人体的危害,通常不加限制地大量加入。自1980年以来,越来越多的有关亚硫酸盐的临床副作用的报告引起了人们的普遍重视,促使人们在亚硫酸盐的安全性方面进行了较为深入的研究。临床上最常见的有关副反应是亚硫酸盐过敏,症状是支气管痉挛,喘鸣,呼吸困难,恶心、喉部水肿、低血压、休克、甚至死亡。流行病学的调查发现,哮喘病人对亚硫酸盐最为敏感。
发明内容
本发明所要解决的技术问题在于针对上述现有技术的不足,提供了一种脂肪乳、复方氨基酸和葡萄糖注射液及其制备方法。本发明的注射液采用三腔袋包装,规格较小,适于一般体重需要补充肠外营养或是极低体重需要完全肠内营养的病人。
为解决上述技术问题,本发明采用的技术方案是:一种脂肪乳、复方氨基酸和葡萄糖注射液及其制备方法,具有以下特征:
一种脂肪乳、复方氨基酸和葡萄糖注射液,所述注射液采用三腔袋包装,三腔袋的三个腔室中分别独立地装有脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液,腔室之间利用隔膜或隔离条分开,其中,每159mL脂肪乳注射液中含有23.8-39.8g纯化大豆油、1.75-2.07g精制卵磷脂、3.18-3.82g无水甘油以及能将该注射液pH值调节至7-10的氢氧化钠,每553mL葡萄糖注射液中含有55.3-66.4g葡萄糖,每188mL复方氨基酸注射液中包括下述组分:
余量为注射用水。
所述脂肪乳、复方氨基酸和葡萄糖注射液的制备方法,包括如下步骤:
步骤一、配液
a、脂肪乳注射液配制
(1)将23.8-39.8g大豆油加热至约80℃,强烈搅拌下加入1.75-2.07g精制卵磷脂,继续搅拌至溶解,此为油相;
(2)在注射用水中加入3.18-3.82g无水甘油,搅拌溶解,此为水相;
(3)将油相缓慢加入强烈搅拌的水相中,继续强烈搅拌,得到初乳,利用氢氧化钠溶液调节初乳的pH值至7-10;
(4)将初乳经高压匀化机匀化,匀化压力为400-800kg/cm2,反复数次,得到均匀乳剂;
b、复方氨基酸注射液配制
按照复方氨基酸注射液的成分表称取以下原料:L-丙氨酸2.41-3.61g、L-精氨酸1.70-2.55g、L-天门冬氨酸0.51-0.77g、L-谷氨酸0.84-1.26g、甘氨酸1.19-1.78g、L-组氨酸1.02-1.53g、L-异亮氨酸0.84-1.26g、L-亮氨酸1.19-1.78g、L-盐酸赖氨酸1.70-2.55g、L-甲硫氨酸0.84-1.26g、L-苯丙氨酸1.19-1.78g、L-脯氨酸1.02-1.53g、L-丝氨酸0.68-1.02g、L-苏氨酸0.84-1.26g、L-色氨酸0.29-0.43g、L-酪氨酸0.03-0.05g、L-缬氨酸1.10-1.65g、二水合氯化钙0.15-0.22g、甘油磷酸钠0.76-1.14g、七水合硫酸镁0.49-0.74g、氯化钾0.90-1.35g、三水合醋酸钠1.23-1.84g、冰醋酸0.5-0.8mL,将上述组分逐一加入预先除氧的60-90℃的注射用水中,在惰性气体保护下搅拌至溶解,控制药液中溶解氧浓度不得高于1ppm;
c、葡萄糖注射液配制
取55.3-66.4g葡萄糖溶解于注射用水中,制得葡萄糖注射液;
步骤二、制袋、灌装、密封和装外袋;
步骤三、灭菌。
与现有技术相比,本发明的有益效果是:
1.本发明提供了一种小规格的三腔袋包装的注射液,适于一般体重需要补充肠外营养或是极低体重需要完全肠内营养的病人,能够有效减少临床使用的浪费。本发明产品采用的包装袋分内袋和外袋,分别由两种多层结构的透明塑料膜制成,内袋用于灌装药液,内袋通过热压分隔形成三个腔室,能耐受脂肪、氨基酸和葡萄糖溶液的长期接触而不发生化学反应,也无任何物质溶解于上述三种溶液,脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液分别装入三个腔室中,密封的内袋整体装入外袋中,使用时只需依次用力挤压各腔室,或撕开各腔室间的隔离条,即可将三种注射液混匀,随即给人体静脉输注。外袋对氧气、二氧化碳和其他气体有极佳的物理屏障作用,能阻止这些气体的穿透,保证产品在灭菌和储存期间的稳定性,内袋与外袋都能耐受121℃的高温灭菌。内袋在经受一定大小的与封条垂直的拉力时能打开,使内容物相互混合,混合液能保证污染微生物的概率低于一百万分之一。
2.本发明对复方氨基酸注射液的配方进行了优化:
本发明各种氨基酸的配比更加合理,更适合与脂肪乳和葡萄糖注射液混合后进行静脉输注,且能够工业化生产,在完全封闭的条件下不会破坏产品的密封系统;本发明中复方氨基酸注射液通过制备工艺优化及控制,将药液中的氧含量降低到1ppm以下的水平,从而确保可以将配方中亚硫酸盐类抗氧化剂完全去除,产品质量能保持稳定,从而避免临床副作用的发生。
半胱氨酸在复方氨基酸中易于降解,降解后会产生对人体有害的挥发性杂质,如硫化氢、和乙醛。本发明的配方中去除了原料半胱氨酸,从而有效减少了该原料降解导致的挥发性杂质的产生。
下面通过具体的实施方式对本发明的技术方案作进一步详细说明。
具体实施方式
实施例1
本实施例每袋注射液的总体积为900mL,其中,每袋注射液中脂肪乳注射液为159mL,葡萄糖注射液为553mL,复方氨基酸注射液为188mL,三腔袋包装的脂肪乳、氨基酸和葡萄糖注射液的制备方法,包括如下步骤:
步骤一、制袋
取内袋用塑料膜,在制袋热压机上压制成形并接上灌装口;取外袋用塑料膜,在制袋热压机上压制成形,留出一边敞开。
步骤二、配液
分别在不同的配制设备上配制脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液。
(1)脂肪乳注射液配制
取纯化大豆油31.8克,精制卵磷脂1.91克,无水甘油3.50克,氢氧化钠适量,注射用水119.25克;
将大豆油31.8克加热至约80℃,强烈搅拌下加入精制卵磷脂1.91克,继续搅拌直至溶解,此为油相;
向119.25克注射用水中加入3.50克无水甘油,搅拌溶解,此为水相;
将油相缓慢加入强烈搅拌的水相中,继续强烈搅拌10分钟,得到初乳;
取氢氧化钠溶液,滴入初乳中,调节pH至9;
将初乳经高压匀化机匀化,匀化压力600kg/cm2,反复匀化6次,得到均匀的脂肪乳乳剂。
(2)复方氨基酸注射液配制
取下述各原料,L-丙氨酸3.01g,L-精氨酸2.12g,L-天门冬氨酸0.64g,L-谷氨酸1.05g,甘氨酸1.49g,L-组氨酸1.28g,L-异亮氨酸1.05g,L-亮氨酸1.49g,L-盐酸赖氨酸2.12g,L-甲硫氨酸1.05g,L-苯丙氨酸1.49g,L-脯氨酸1.28g,L-丝氨酸0.85g,L-苏氨酸1.05g,L-色氨酸0.36g,L-酪氨酸0.04g,L-缬氨酸1.37g,二水合氯化钙0.18g,无水甘油磷酸钠0.95g,七水合硫酸镁0.62g,氯化钾1.12g,三水合醋酸钠1.54g,冰醋酸适量,将上述原料加入预先除去氧气的80℃的注射用水中,配成188mL注射液,在氮气保护下搅拌至溶解。药液中溶解氧浓度不得高于1ppm。
(3)葡萄糖注射液
取葡萄糖60.83克,溶解于注射用水中,得到553mL的葡萄糖注射液。
步骤三、灌装、密封和装外袋
将已配制好的脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液分别通过药液过滤器连接在一台有三条管路和灌装单元的灌装机上,该灌装机安装有抽真空-充氮气系统、药液计量系统、密封系统,分别完成对内袋的抽真空-充氮气、药液质量计量与装量控制、内袋密封等功能,根据需要调节好各药液的灌装体积,将预先制好的内袋装上灌装机,灌封并密封,灌装过程在氮气保护下进行;
将灌装好的内袋装入外袋,内、外袋间加入吸氧剂,通过具有给外袋抽真空-充氮气功能的热封机将内、外袋间的氧气除去并热封。
步骤四、灭菌
灭菌设备为过热水循环喷淋式灭菌器,封装好的产品平铺在灭菌器的货架上,将灭菌用循环水加压加热到121℃并喷淋到产品上,最终使产品在121℃下保持15分钟,以彻底杀灭产品中的微生物,达到灭菌的效果。
实施例2
步骤二、配液
(2)复方氨基酸注射液采用如下配方:取下述各原料,L-丙氨酸3.61g,L-精氨酸2.55g,L-天门冬氨酸0.77g,L-谷氨酸1.26g,甘氨酸1.78g,L-组氨酸1.53g,L-异亮氨酸1.26g,L-亮氨酸1.78g,L-盐酸赖氨酸2.55g,L-甲硫氨酸1.26g,L-苯丙氨酸1.78g,L-脯氨酸1.53g,L-丝氨酸1.02g,L-苏氨酸1.26g,L-色氨酸0.43g,L-酪氨酸0.05g,L-缬氨酸1.65g,二水合氯化钙0.22g,无水甘油磷酸钠1.14g,七水合硫酸镁0.74g,氯化钾1.35g,三水合醋酸钠1.84g,冰醋酸适量,将上述原料加入预先除去氧气的80℃的注射用水中,配成188mL注射液,在氮气保护下搅拌至溶解,药液中溶解氧浓度不得高于1ppm。
其余步骤、配方与实施例一相同。
实施例3
步骤二、配液
(2)复方氨基酸注射液采用如下配方:取下述各原料,L-丙氨酸3.01g,L-精氨酸2.12g,L-天门冬氨酸0.64g,L-谷氨酸1.05g,甘氨酸1.49g,L-组氨酸1.28g,L-异亮氨酸1.05g,L-亮氨酸1.49g,L-盐酸赖氨酸2.12g,L-甲硫氨酸1.05g,L-苯丙氨酸1.49g,L-脯氨酸1.28g,L-丝氨酸0.85g,L-苏氨酸1.05g,L-色氨酸0.36g,L-酪氨酸0.04g,L-缬氨酸1.37g,二水合氯化钙0.18g,无水甘油磷酸钠0.95g,七水合硫酸镁0.62g,氯化钾1.12g,三水合醋酸钠1.54g,冰醋酸适量。将上述原料加入预先除去氧气的80℃的注射用水中,配成188mL注射液,在氮气保护下搅拌至溶解,药液中溶解氧浓度不得高于1ppm。
其余步骤、配方与实施例一相同。
实施例4
步骤二、配液
分别在不同的配制设备上配制脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液。
(1)脂肪乳注射液配制
取纯化大豆油23.85克,精制卵磷脂1.75克,无水甘油2.07克,氢氧化钠适量,注射用水127.2克;
将大豆油23.85克加热至80℃,强烈搅拌下加入精制卵磷脂1.75克,继续搅拌直至溶解,此为油相;
在127.2克注射用水中加入2.07克无水甘油,搅拌溶解,此为水相;
将油相缓慢加入强烈搅拌的水相中,继续强烈搅拌10分钟,得到初乳;
取氢氧化钠溶液,滴入初乳中,调节pH至7;
将初乳经高压匀化机匀化,匀化压力400kg/cm2,反复匀化6次,得到均匀的脂肪乳乳剂。
其余步骤、配方与实施例一相同。
实施例5
步骤二、配液
分别在不同的配制设备上配制脂肪乳注射液、复方氨基酸注射液和葡萄糖注射液。
(1)脂肪乳注射液配制
取纯化大豆油39.75克,精制卵磷脂2.07克,无水甘油3.82克,氢氧化钠适量,注射用水111.3克;
将大豆油39.75克加热至约80℃,强烈搅拌下加入精制卵磷脂2.07克,继续搅拌直至溶解,此为油相;
在111.3克注射用水中加入3.82克无水甘油,搅拌溶解,此为水相;
将油相缓慢加入强烈搅拌的水相中,继续强烈搅拌10分钟,得到初乳;
取氢氧化钠溶液,滴入初乳中,调节pH至10;
将初乳经高压匀化机匀化,匀化压力800kg/cm2,反复匀化6次,得到均匀的脂肪乳乳剂。
其余步骤、配方与实施例一相同。
实施例6
(3)葡萄糖注射液
取葡萄糖55.3克,溶解于注射用水中,得到553mL的葡萄糖注射液。
其余步骤、配方与实施例一相同。
实施例7
(3)葡萄糖注射液
取葡萄糖60.36克,溶解于注射用水中,得到553mL的葡萄糖注射液。
其余步骤、配方与实施例一相同。
本发明三腔袋包装的注射液能彻底避免常规混合操作导致的产品易受微生物和微粒污染的风险,并且能在任何环境条件下进行混合操作,使不具备无菌配制条件的中小医院也能方便地使用符合人体营养代谢特点的肠外营养,为患者带来利益,极大地降低传统混合操作因易污染微生物而导致的输液热源反应、血液感染、败血症等严重不良反应。相对于现有注射液1000mL及以上的规格,本发明的规格较小,适于一般体重需要补充肠外营养的病人或是极低体重需要完全肠内营养的病人,能够节约医疗资源,减轻病人的经济负担。
以上所述仅为本发明的优选实施例,并非因此限制本发明的专利范围,凡是在本发明的发明构思下,利用本发明说明书内容所作的等效结构变换,或直接/间接运用在其他相关的技术领域均包括在本发明的专利保护范围内。
Claims (2)
2.权利要求1所述脂肪乳、复方氨基酸和葡萄糖注射液的制备方法,其特征在于,包括如下步骤:
步骤一、配液
a、脂肪乳注射液配制
(1)将23.8-39.8g大豆油加热至约80℃,强烈搅拌下加入1.75-2.07g精制卵磷脂,继续搅拌至溶解,此为油相;
(2)在注射用水中加入3.18-3.82g无水甘油,搅拌溶解,此为水相;
(3)将油相缓慢加入强烈搅拌的水相中,继续强烈搅拌,得到初乳,利用氢氧化钠溶液调节初乳的pH值至7-10;
(4)将初乳经高压匀化机匀化,匀化压力为400-800kg/cm2,反复数次,得到均匀乳剂;
b、复方氨基酸注射液配制
按照复方氨基酸注射液的成分表称取以下原料:L-丙氨酸2.41-3.61g、L-精氨酸1.70-2.55g、L-天门冬氨酸0.51-0.77g、L-谷氨酸0.84-1.26g、甘氨酸1.19-1.78g、L-组氨酸1.02-1.53g、L-异亮氨酸0.84-1.26g、L-亮氨酸1.19-1.78g、L-盐酸赖氨酸1.70-2.55g、L-甲硫氨酸0.84-1.26g、L-苯丙氨酸1.19-1.78g、L-脯氨酸1.02-1.53g、L-丝氨酸0.68-1.02g、L-苏氨酸0.84-1.26g、L-色氨酸0.29-0.43g、L-酪氨酸0.03-0.05g、L-缬氨酸1.10-1.65g、二水合氯化钙0.15-0.22g、甘油磷酸钠0.76-1.14g、七水合硫酸镁0.49-0.74g、氯化钾0.90-1.35g、三水合醋酸钠1.23-1.84g、冰醋酸0.5-0.8mL,将上述组分逐一加入预先除氧的60-90℃的注射用水中,在惰性气体保护下搅拌至溶解,控制药液中溶解氧浓度不得高于1ppm;
c、葡萄糖注射液配制
取55.3-66.4g葡萄糖溶解于注射用水中,制得葡萄糖注射液;
步骤二、制袋、灌装、密封和装外袋;
步骤三、灭菌。
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