CN110404048A - 一种复方氨基酸双肽注射液及其制备方法和应用 - Google Patents
一种复方氨基酸双肽注射液及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物领域,提供了一种复方氨基酸双肽注射液及其制备方法和用途,所述注射液包括三个腔袋,其三腔袋采用间隔分开的三个腔室分别装入支链氨基酸溶液、L‑丙氨酰‑L‑谷氨酰胺溶液以及含盐酸精氨酸和维生素B6的混合溶液;其中,每1000mL注射液中,含所述氨基酸总质量为50g~130g;且所述支链氨基酸质量占所述氨基酸总质量的10‑80%;所述L‑丙氨酰‑L‑谷氨酰胺质量占所述氨基酸总质量的5~70%;所述盐酸精氨酸质量占所述氨基酸总质量的0~50%;所述维生素B6质量为0~1g。本发明注射液在提供产品安全性的同时,还提高了产品稳定性和有效性,技术方案简便,利于产业化生产。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种复方氨基酸双肽注射液及其制备方法和应用。
背景技术
氨基酸是生物体内构成蛋白质分子的基本单位,与生物的生命活动有着密切的关系,是生物体内必不可少的营养成分之一,蛋白质在机体内的消化和吸收是通过氨基酸来完成,人体对蛋白质的需要实际上是对氨基酸的需要。低蛋白血症是各种原因所致负氮平衡的结果,其主要病因有:蛋白摄入不足或吸收不良,各种原因引起的食欲不振及厌食;蛋白质合成障碍,各种原因的肝损害使肝脏蛋白合成能力减低,血浆蛋白质合成减少,长期大量蛋白质丢失;蛋白质分解加速等。多种氨基酸(包括双肽等)适当配比组成复方氨基酸制剂,可以改善体内蛋白质代谢,纠止负氮平衡。
围术期会引起机体的应激反应,进而导致神经—内分泌系统和代谢的一系列改变,其中变化明显的是:蛋白质分解和合成均增加,脂肪动员,糖异生加强和糖利用能力下降引起血糖升高;并且,此时机体不能有效利用三大营养物质,特别是脂肪供能常不完全,可产生大量酮体堆积于体内,引起酮血、酮尿;在通常的物质能量代谢底物产生和利用发生障碍时,就需要调整和补充合适的营养物质。但目前市售氨基酸注射液并不针对此类围手术麻醉期(术前、术中、术后早期)病人,不能适应此类病人物质能量代谢的需求。现有技术中缺少开展围手术麻醉期间输注复方氨基酸注射液的技术方案,多在术后7-10天病人仍无法有效进食才考虑给予病人输注葡萄糖之外的能量物质(氨基酸、脂肪),这样可能错过了最佳改善机体物质能量代谢、提升机体免疫力以及促进机体伤口愈合的时机。
另外,临床使用时将多个组分混合在一起制备成注射液往往需要加入大量的附加剂以维持注射液的稳定,但是附加剂的加入有可能造成不良反应问题。目前已上市的氨基酸注射液多均含有抗氧剂如亚硫酸氢钠、焦亚硫酸钠等,由于亚硫酸盐的存在虽然解决了氨基酸容易被氧化的问题,其也可以引起常见的副反应,如支气管痉挛、呼吸困难、恶性喉部水肿、低血压、休克等。各国药典对注射剂中附加量虽有差异,但从安全性考虑用量越少越好,《中国药典》收载的复方氨基酸产品含有的抗氧剂亚硫酸氢钠或焦亚硫酸钠用量一般为0.04%~0.08%,从相关注射液使用的安全角度出发,制备出不含抗氧剂的复方氨基酸注射液是亟待解决的问题。
发明内容
针对现有技术中的缺陷,本发明提供一种复方氨基酸双肽注射液及其制备方法和应用,为实现上述发明目的,本发明采用了以下技术方案:
本发明的第一方面,提供了一种复方氨基酸双肽注射液,包括三个腔袋,其三腔袋采用间隔分开的三个腔室分别装入支链氨基酸溶液、L-丙氨酰-L-谷氨酰胺溶液以及含盐酸精氨酸、维生素B6的混合溶液;
其中,每1000mL注射液中,
含所述氨基酸总质量为50g~130g,且所述支链氨基酸质量占所述氨基酸总质量的10-80%;
所述L-丙氨酰-L-谷氨酰胺质量占所述氨基酸总质量的5~70%;
所述盐酸精氨酸质量占所述氨基酸总质量的0~50%;
所述维生素B6质量为0~1g。
进一步的,所述支链氨基酸溶液由L-亮氨酸、L-异亮氨酸、L-缬氨酸和注射用水组成;
更进一步的,所述L-亮氨酸、L-异亮氨酸和L-缬氨酸的质量之比为1:(0.5~0.9):(0.5~0.8);
更进一步的,所述L-亮氨酸、L-异亮氨酸和L-缬氨酸的物质的量之比为1:0.8:0.6;
进一步的,所述L-丙氨酰-L-谷氨酰胺溶液由L-丙氨酰-L-谷氨酰胺和注射用水组成,且所述L-丙氨酰-L-谷氨酰胺质量为3~80g;
进一步的,所述含精氨酸、维生素B6的混合溶液由L-盐酸精氨酸、维生素B6、甘油、木糖醇、L-苹果酸和注射用水组成,其中,L-盐酸精氨酸、维生素B6、甘油、木糖醇、L-苹果酸的质量分别是0~40g、0~1g、0~50g、0~80g、0~8g;
进一步可选的,所述L-盐酸精氨酸、维生素B6、甘油、木糖醇、L-苹果酸的质量均为0g;
进一步可选的,所述L-盐酸精氨酸的质量为10~30g,其余组分的质量均为0g;优选的,所述L-盐酸精氨酸的质量为25g;
进一步可选的,所述维生素B6的质量为10~100mg,其余组分的质量均为0g;优选的,所述维生素B6的质量为100mg;
进一步可选的,所述L-盐酸精氨酸、维生素B6质量分别为10~30g、10~100mg,其余组分的质量均为0g;
进一步可选的,所述L-盐酸精氨酸、维生素B6、L-苹果酸质量分别为10~30g、10~100mg、2~6g,其余组分的质量均为0g;
进一步可选的,所述L-盐酸精氨酸、维生素B6、甘油、木糖醇分别为10~30g、10~100mg、10~40g、10~80g,其余组分的质量均为0g;
进一步的,所述复方氨基酸双肽注射液的pH为5.5~6.5。
本发明的第二方面,还提供了一种上述任一种复方氨基酸双肽注射液的制备方法,包括以下步骤:
按处方量将上述各组分逐一加入预先除氧气的40~95℃的注射用水中,然后在N2保护下搅拌至各组分药物溶解完全,控制药液中溶解O2浓度不得高于1ppm,然后将上述药液分别加入到预先抽真空且充满N2的三腔室包装袋中,加水定容后密封,其中,以总量1000mL计算,三个腔室分别装入支链氨基酸溶液100~925mL、L-丙氨酰-L-谷氨酰胺溶液25~400mL以及含盐酸精氨酸和维生素B6混合溶液0~500mL;且三个腔室pH值分别为5.5~7.0、5.0~6.5以及3.0~5.5;然后再将密封后的三腔室包装袋置于灭菌设备中于115℃~125℃中灭菌10~30min,即得。
本发明的第三方面,还提供了上述任一种复方氨基酸双肽注射液在制备围手术麻醉期药物中的用途;
进一步的,所述的围手术麻醉期指手术前、手术中或手术后早期;
进一步的,所述药物具有改善机体物质能量代谢的作用;优选的,所述的改善机体物质能量代谢为抑制机体分解代谢或促进机体合成代谢;
进一步的,所述药物具有保护肠道细胞、提高机体免疫功能、调节机体氮平衡和/或促进康复的作用。
有益效果
1.高剂量使用支链氨基酸、丙氨酰谷氨酰胺双肽、精氨酸以及维生素B6配制本发明复方氨基酸注射液,提供围手术麻醉期特异蛋白,并给予甘油木糖醇提供能量,这样不仅具有保护肠道的作用,还能显著抑制骨骼肌蛋白分解,减少脂肪动员、改善机体物质能量代谢;改善围手术期,特别是术前、术中或术后早期的低温;纠正负氮平衡,并且无明显副作用,不损害肝肾功能,升高血糖,但在安全范围内,能安全用于糖尿病病人。
2.本发明复方氨基酸注射液在配方中减少了氨基酸种类,减少了药物相互作用产生的风险和发生过敏反应的几率,增加了药物的稳定性。
3.本发明复方氨基酸注射液在配方中不含亚硫酸氢钠等抗氧剂,降低了此类物质摄入人体而产生的不良反应,同时,药物的稳定性仍然能达到预期,从而提高了药物的安全性。
具体实施方式
下面将对本发明技术方案的实施例进行详细的描述。以下实施例仅用于更加清楚地说明本发明的技术方案,因此只是作为示例,而不能以此来限制本发明的保护范围。
需要注意的是,除非另有说明,本申请使用的技术术语或者科学术语应当为本发明所属领域技术人员所理解的通常意义。
(一)实施例1~6
1.处方:实施例1~6的处方如下表1所示:
表1
2.制备方法
按照实施例1~6的处方配比将上述各组分逐一加入预先除氧气的40~95℃的注射用水中,然后在N2保护下搅拌至各组分药物溶解完全,控制药液中溶解O2浓度不得高于1ppm,然后将上述药液分别加入到预先抽真空且充满N2的三腔室包装袋中,加水定容后密封,其中,以总量1000mL计算,三个腔室分别装入支链氨基酸溶液100~925mL、L-丙氨酰-L-谷氨酰胺溶液25~400mL以及含盐酸精氨酸和维生素B6混合溶液0~500mL;且三个腔室pH值分别为5.5~7.0、5.0~6.5以及3.0~5.5;然后再将密封后的三腔室包装袋置于灭菌设备中于115℃~125℃中灭菌10~30min,即得。
3.使用方法
按照氨基酸及L-丙氨酰-L-谷氨酰胺的剂量为每天0.5-2.0g/kg进行给药,经静脉输注或作为口服/肠内营养的补充。
(二)对比例1~6
1.处方
表2
2.制备方法
按照对比例1~6的处方配比将上述各组分逐一加入预先除氧气的40~95℃的注射用水中,然后在N2保护下搅拌至各组分药物溶解完全,控制药液中溶解O2浓度不得高于1ppm,然后将上述药液分别加入到预先抽真空且充满N2的单室包装袋中,加水定容后,采用冰醋酸调节pH值至5.5~6.5后密封,再将密封后的包装袋置于灭菌设备中于115℃~125℃中灭菌10~30min,即得。
(三)实验例
1.稳定性实验
分别以实施例1和对比例1、实施例6和对比例6为例进行实验,将制备好的注射液置于凉暗处保存0~6个月,实验结果如下表3、4所示:
表3实施例1和对比例1注射液稳定性实验
由此可见,实施例1和对比例1的稳定性均符合规定,且实施例1的稳定性更好。
表4实施例6和对比例6注射液稳定性实验
由此可见,实施例6和对比例6的稳定性均符合规定,且实施例6的稳定性更好。
2.血管刺激性试验
血管刺激性试验结果显示,实施例1、6、对比例1家兔耳缘静脉受试实验显示家兔耳缘静脉无充血、出血和变性坏死现象出现,亦无病理性损害,表明本发明的复方氨基酸注射液静脉滴注对家兔耳血管未产生刺激反应,检查符合规定;而对比例6显示家兔耳缘静脉具有轻微充血显现。
3.肌肉刺激性试验
肌肉刺激性试验结果显示,实施例1、6以及对比例1、6的家兔腿股四头肌受试一侧均无红肿、充血和变性坏死现象出现,亦无病理性损害,表明本发明的复方氨基酸注射液肌内注射对家兔股四头肌未产生刺激反应,检查符合规定。
4.溶血试验
溶血试验结果显示,实施例1、6以及对比例1、6均无溶血现象发生,振摇后红细胞可分散,表明无凝聚现象,表明本发明的复方氨基酸注射液溶血性试验检查符合规定。
5.过敏性试验
过敏性试验结果显示,实施例1、6、对比例6受试组豚鼠激发时(脚背静脉注射)均未出现竖毛、搔鼻、喷嚏、咳嗽、呼吸困难、痉挛等全身过敏反应,表明本发明的复方注射液豚鼠全身过敏试验检查符合规定;而对比例1受试组豚鼠激发时(脚背静脉注射)有1例出现竖毛、搔鼻现象。
由于本发明所述的复方氨基酸注射液不含亚硫酸氢钠,并且减少了氨基酸种类,因此在增加安全性的同时也提高了产品的稳定性,减少了杂质的生成。与现有技术中的复方氨基酸注射液相比,临床使用副作用更少。
6.药效实验
6.1研究动物
研究对象为12~16kg健康成年杂种犬30只,随机分为3组。研究方案获得复旦大学附属中山医院动物实验伦理委员会通过。实验用犬饲养于复旦大学附属中山医院动物实验中心。
6.2麻醉、手术及围术期处理
术前7天,肌注氯胺酮与安定基础麻醉下行右颈外静脉切开置管术,经皮下隧道固定于颈后,肝素封管。之后饲养于犬代谢笼内7天,定量喂养素食。术前禁食12小时,不禁水。
手术日晨8:00由右颈外静脉注射丙泊酚(5~10mg·kg-1)实施麻醉,之后将其四肢朝天绑在狗板上,颈外静脉连接三通,输注乳酸钠林格注射液。静脉注射罗库溴铵、芬太尼,气管插管,麻醉机控制呼吸。吸入氧浓度(FiO2)100%,根据情况调整分钟通气量,使呼气末二氧化碳分压维持在30~40mmHg。持续吸入七氟醚(2%~3%),间断静注罗库溴铵、芬太尼维持麻醉。监测心电图、脉搏血氧饱和度、呼气末二氧化碳分压,左股动脉穿刺置管监测动脉压,置食管探头监测食管温度。右股静脉穿刺置管用于抽血化验。
8:45由同一小组普外科医师行小肠部分切除术(切除小肠长度约20cm)。进腹后立即行膀胱造瘘,保留导尿。切皮即刻记为手术开始时间,完全缝合手术切口时间记为手术结束时间。术后停用七氟醚,持续使用罗库溴铵维持肌松、咪达唑仑镇静、吗啡镇痛,根据心率、血压调整用药量,持续机械通气支持。按外科常规输入生理盐水,不使用葡萄糖。术后静脉滴注庆大霉素8万u。术后24h为实验终点。整个实验过程中维持心率为80~120bpm,平均动脉压为80~120mmHg。
6.3实验分组及方法
将30只杂种犬随机分为3组:乳酸钠林格注射液(对照组)、复方氨基酸双肽亚硫注射液(对照例6记为对6组)和复方氨基酸双肽注射液(实施例6记为实6组)。自切皮即刻至完全缝合手术切口期间在持续静脉输注乳酸钠林格注射液5mL·kg-1·h-1基础上,再分别输注乳酸钠林格注射液(对照组)、复方氨基酸双肽注射液(实6组)8mL·kg-1·h-1。因为复方氨基酸双肽亚硫注射液含有其他氨基酸成分,浓度为10.14%,而复方氨基酸双肽注射液浓度为9%,为保证输入氨基酸/双肽总量一致,自切皮即刻至完全缝合手术切口期间在持续静脉输注乳酸钠林格注射液5.9mL·kg-1·h-1基础上,再输注复方氨基酸双肽亚硫注射液(对6组)7.1mL·kg-1·h-1。手术结束12h后三组再分别输注乳酸钠林格注射液(对照组)8mL·kg-1·h-1、复方氨基酸双肽亚硫注射液(对6组)7.1mL·kg-1·h-1(为维持总补液量一致,本组生理盐水输入量增加0.9mL·kg-1·h-1)、复方氨基酸双肽注射液(实6组)8mL·kg-1·h-1,共2h。
6.4监测指标
手术当日于诱导气管插管后手术前(插管后15min)、手术开始后30min、60min、手术结束即刻、手术后2h、4h、8h、24h,抽静脉血测血糖(便携式血糖监测仪,拜安捷,BayerHealthCare)。
手术当日诱导气管插管前及手术后24h,抽取静脉血,使用流式细胞仪检测淋巴细胞CD4+/CD8+比值。
于手术前7天试验犬第一次排尿之后至术前,收集犬所有尿液,计算24h尿量,留尿样-80℃冰箱保存,备成批测量。手术日收集手术开始即刻至手术开始后24h尿液,记录手术日24h尿量,留尿样-80℃冰箱保存,备成批测量。
采用谷氨酸脱氢酶法测量尿尿素水平,采用高效液相色谱仪测量尿三甲基组氨酸(3-MH)水平。根据出入氮量计算术前与手术日氮平衡:氮平衡(g)=摄入氮量(g/d)-(24h尿素氮+4g)
6.5统计分析
采用SPSS统计软件包进行数据分析。计数资料采用卡方检验和Fisher’s确切检验。计量资料用均数±标准差表示,组间比较采用单因素方差分析,组内比较采用重复测量的单因素方差分析(with post hoc:方差齐时用LSD法,如方差不齐时用Games-Howell法)。取双侧检验,P<0.05时认为差异有统计学意义。
6.6实验结果
三组杂种犬性别、体重、手术时间、术中出血量、术中补液量、术后补液量、术中尿量均无显著差异(P>0.05)(见表5)。
表5三组一般情况及手术相关情况比较(n=10,mean±SD)
三组手术过程中至术后4h血糖较术前显著升高(P<0.05);两个实验组在切皮后60min至手术结束血糖较对照组显著升高(P<0.05),但均在10mmol/L以内;两个实验组间比较无显著差异(P>0.05)(见表6)。
表6三组围手术期血糖情况比较(单位:mmol/L,n=10,mean±SD)
*:与对照组相比,P<0.05;#:与术前相比,P<0.05
术前三组24h摄入氮量均记为0g,24h排氮量与氮平衡情况无显著差异;手术日对照组24h摄入氮量仍为0g,对6组为6.97±2.21g,实6组为7.01±2.47g;三组手术日24h排出氮量均较术前显著升高(P<0.05),且对6组排出氮量显著高于对照组和实6组(P<0.05);手术日对照组负氮平衡较术前显著加剧(P<0.05),而两个实验组则显著改善(P<0.05),且实6组的改善更为明显(P<0.05)(见表7)。
表7三组氮平衡情况比较(单位:g/d,n=10,mean±SD)
*:与对照组相比,P<0.05;#:与术前相比,P<0.05,Δ:实6组与对6组相比,P<0.05
术前三组24h 3-MH排出量无显著差异;手术日对照组24h 3-MH排出量较术前显著增加(P<0.05),两个实验组与术前相比也有所增加,但无统计学差异(P>0.05);组间比较两个实验组手术日24h 3-MH排出量均较对照组显著减少(P<0.05),实6组较对6组排出量有所减少,但无统计学差异(P>0.05)(见表8)。
表8三组尿3-MH排出情况比较(单位:μg/d,n=10,mean±SD)
*:与对照组相比,P<0.05;#:与术前相比,P<0.05
手术前三组淋巴细胞CD4+/CD8+比值无显著差异(P>0.05);手术后24h三组均显著下降(P<0.05)。手术后24h三组CD4+/CD8+比值相比,对照组显著低于对6组和实6组(P<0.05),对6组显著低于实6组(P<0.05)(见表9)。
表9三组淋巴细胞CD4+/CD8+比值(n=10,mean±SD)
*:与对照组相比,P<0.05;#:术前相比,P<0.05;Δ:实6组与对6组相比,P<0.05
由此可见,围手术麻醉期间输注本发明复方氨基酸注射液可改善手术日负氮平衡,减少尿3-MH排出量,减少骨骼肌蛋白分解,且不额外增加手术日排氮量;改善术后免疫状况;升高血糖,但在允许范围内。另外,本发明所述复方氨基酸注射液与现有技术中的复方氨基酸双肽亚硫注射液相比,在改善负氮平衡和术后免疫状况方面效果更优。
以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围,其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (10)
1.一种复方氨基酸双肽注射液,其特征在于,包括三个腔袋,其三腔袋采用间隔分开的三个腔室分别装入支链氨基酸溶液、L-丙氨酰-L-谷氨酰胺溶液以及含盐酸精氨酸和维生素B6的混合溶液;其中,每1000mL注射液中,
含所述氨基酸总质量为50g~130g;
且所述支链氨基酸质量占所述氨基酸总质量的10-80%;
所述L-丙氨酰-L-谷氨酰胺质量占所述氨基酸总质量的5~70%;
所述盐酸精氨酸质量占所述氨基酸总质量的0~50%;所述维生素B6质量为0~1g。
2.根据权利要求1所述的复方氨基酸双肽注射液,其特征在于,所述支链氨基酸溶液由L-亮氨酸、L-异亮氨酸、L-缬氨酸和注射用水组成;更进一步的,所述L-亮氨酸、L-异亮氨酸和L-缬氨酸的质量之比为1:(0.5~0.9):(0.5~0.8)。
3.根据权利要求1所述的复方氨基酸双肽注射液,其特征在于,所述L-丙氨酰-L-谷氨酰胺溶液由L-丙氨酰-L-谷氨酰胺和注射用水组成,且所述L-丙氨酰-L-谷氨酰胺质量为3~80g。
4.根据权利要求1所述的复方氨基酸双肽注射液,其特征在于,所述含精氨酸和维生素B6的混合溶液由L-盐酸精氨酸、维生素B6、甘油、木糖醇、L-苹果酸和注射用水组成,其中,L-盐酸精氨酸、维生素B6、甘油、木糖醇、L-苹果酸的质量分别是0~40g、0~1g、0~50g、0~80g、0~8g。
5.根据权利要求1~4任一项所述的复方氨基酸双肽注射液,其特征在于,所述复方氨基酸双肽注射液的pH为5.5~6.5。
6.根据权利要求1~4任一项所述的复方氨基酸双肽注射液的制备方法,其特征在于,包括以下步骤:
按处方量将上述各组分逐一加入预先除氧气的40~95℃的注射用水中,然后在N2保护下搅拌至各组分药物溶解完全,控制药液中溶解O2浓度不得高于1ppm,然后将上述药液分别加入到预先抽真空且充满N2的三腔室包装袋中,加水定容后密封,其中,以总量1000mL计算,三个腔室分别装入支链氨基酸溶液100~925mL、L-丙氨酰-L-谷氨酰胺溶液25~400mL以及含盐酸精氨酸和维生素B6混合溶液0~500mL;且三个腔室pH值分别为5.5~7.0、5.0~6.5以及3.0~5.5;然后再将密封后的三腔室包装袋置于灭菌设备中于115℃~125℃中灭菌10~30min,即得。
7.权利要求1~4任一项所述的复方氨基酸双肽注射液在制备围手术麻醉期药物中的用途。
8.根据权利要求7所述的用途,其特征在于,所述的围手术麻醉期指手术前、手术中或手术后早期。
9.根据权利要求7或8所述的用途,其特征在于,所述药物具有改善机体物质能量代谢的作用;优选的,所述的改善机体物质能量代谢为抑制机体分解代谢或促进机体合成代谢。
10.据权利要求7或8所述的用途,其特征在于,所述药物具有保护肠道细胞、提高机体免疫功能、调节机体氮平衡和/或促进康复的作用。
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