CN112274533B - 一种甘油果糖氯化钠注射液及其制备方法 - Google Patents
一种甘油果糖氯化钠注射液及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种甘油果糖氯化钠注射液及其制备方法,其处方组成按重量/体积百分比为:甘油10%,果糖5%,氯化钠0.9%,聚乙二醇‑二硬脂酰磷脂酰乙醇胺0.1‑0.5%。本发明解决了甘油果糖氯化钠注射液无法耐受过度灭菌法(F0≥12)的灭菌问题。通过仅添加聚乙二醇‑二硬脂酰磷脂酰乙醇胺作为辅料,不仅在高温蒸汽灭菌的过程中稳定了果糖和pH值,更解决了甘油果糖氯化钠注射液在长期贮存放置时,有关物质5‑HMF会超标的问题,极大地提高了甘油果糖氯化钠注射液作为临床用药的安全性。
Description
技术领域
本发明涉及一种注射液及其制备方法,具体涉及甘油果糖氯化钠注射液及其制备方法。
背景技术
基于甘油的高渗性脱水作用,甘油果糖氯化钠注射液主要用于降低颅内压、眼内压,治疗脑水肿、青光眼、白内障等。在其注射液生产过程中,特别是高温灭菌过程中,很容易产生其果糖成分的降解产物5-羟甲基糠醛(5-Hydroxymethylfurfural, 5-HMF)。
5-HMF是葡萄糖、果糖等单糖在高温或酸性条件的作用下脱水生成的一种醛类化合物。迄今为止已发表的许多研究表明,5-HMF对人体健康具有多种危害,其可能对眼睛,上呼吸道和皮肤有刺激性,并且可能具有致癌性,肝毒性,肾毒性或导致肿瘤转化。另外,5-HMF在体内大部分转化为5-磺氧甲基糠醛(5-SMF),其具有诱变性和遗传毒性。根据现有证据, 5-HMF对健康的影响与剂量密切相关(Lee C H, Chen K T, Lin J A, et al. Recentadvances in processing technology to reduce 5-hydroxymethylfurfural in foods[J]. Trends in Food Science & Technology, 2019, 93: 271-280.),故减少其在甘油果糖氯化钠注射液中的含量至关重要。
在《中国药典》2020年版二部中,甘油果糖氯化钠注射液检查项下中用UV法来控制该杂质,要求其在284nm波长处的吸光度不得超过0.80。发明人按照现有文献所公开的处方和制备工艺进行试验发现,现有处方及工艺可保证5-HMF的量在安全限度以内,但为减少杂质5-HMF的产生量,采用的灭菌工艺普遍为灭菌温度115℃,灭菌时间30min;灭菌温度121℃,灭菌时间8min,其F0远小于12;CN201410317630.1公开制备甘油果糖氯化钠注射液的方法中未采用终端灭菌,无法达到《化学药品注射剂基本技术要求(试行)》中终端灭菌工艺首选过度灭菌法(F0≥12)的要求,有产品残留微生物的风险。
为解决果糖在高温灭菌以及放置过程中因不稳定而降解成5-HMF的问题,多采用添加缓冲剂和抗氧剂的方法。CN201010121919.8公开的一种中添加了抗氧剂、金属络合剂、pH调节剂及缓冲剂等作为辅料、活性炭作为吸附剂的甘油果糖氯化钠注射液,然而,大量种类的辅料的添加无法确保其注射剂的安全性,可能会对机体造成伤害。
目前公开的制备工艺大部分在实际生产过程中对设备的要求高,不易实现。CN201110220697.X和CN201510053310.4公开的甘油果糖氯化钠注射液制备方法,虽然未加任何辅料及活性炭,但其采用的低温配制成本较高。CN201611225834.8 和CN201811609945.8公开的甘油果糖氯化钠注射液制备方法,分别在在制备的过程中需要充氮气和抽真空。CN201310344690.8公开了一种甘油果糖氯化钠注射液,通过低温配液及复杂的灭菌后降温程序,制备出的样品5-HMF吸光度值大于0.45,长期试验末期的其5-HMF吸光度值接近0.6,不仅工序复杂也显示出其稳定性差,缺乏用药的安全性。
CN201510515596.3中提出聚乙二醇-12-羟基硬脂酸酯可以通过抑制果糖脱水产生5-HMF,并在枸橼酸作为pH调节剂时,可以使果糖在长期贮存中保持稳定。但发明人查阅相关文献发现聚乙二醇- 12-羟基硬脂酸酯有相当明显的致溶血或致肌肉损伤,相较于其他辅料,安全性较低(张海燕, 齐云, 廖永红, 等. 注射剂常用增溶性药用辅料的安全与增溶研究[J]. 中国实验方剂学杂志, 2011, 17(11): 1-4.),因此应慎重用于注射剂。
发明内容
本发明的目的在于提供一种的甘油果糖氯化钠注射液及其制备制备方法,以克服以上技术的众多缺陷。
果糖含有酮羰基,属于多羟基酮类。而聚乙二醇-二硬脂酰磷脂酰乙醇胺磷原子上羟基中的氧原子有较强的的电子倾向,氮原子有较强的失电子倾向。发明人再多次试验中发现,在调节到一定的pH值后,其可以明显抑制高温灭菌及长期贮存时果糖的脱水反应,并且维持pH值的稳定,因此可以耐受121℃蒸汽灭菌15分钟。且为聚乙二醇-二硬脂酰磷脂酰乙醇胺为磷脂衍生物,其与细胞有较强的亲和性,毒副作用低、安全性好。
本发明目的是通过如下的技术方案实现的:
本发明甘油果糖氯化钠注射液处方组成按重量/体积百分比为:
甘油 | 10% |
果糖 | 5% |
氯化钠 | 0.9% |
聚乙二醇-二硬脂酰磷脂酰乙醇胺 | 0.1-0.5% |
pH调节剂 | 适量 |
余量为注射用水。 |
其中所述的pH调节剂为L-苹果酸、马来酸、琥铂酸、枸橼酸、盐酸的一种,优选枸橼酸。
pH值调节范围为4.0-4.4。
本发明甘油果糖氯化钠注射液能够耐受F0≥12的过度灭菌法,这样就解决了产品残留微生物的风险,确保了临床用药的安全性。
本发明甘油果糖氯化钠注射液的制备方法如下:
(1)按处方称取原料和辅料,备用。
(2)取总体积60-80%的注射用水,加入甘油搅拌混合均匀后加入氯化钠。
(3)待氯化钠完全溶解后,加入pH调节剂调节pH值为4.0-4.5。
(4)调节完成后,加入聚乙二醇-二硬脂酰磷脂酰乙醇胺,搅拌溶解后,再加入果糖,搅拌使其完全溶解,加入注射用水至全量。
(5)搅拌均匀,用0.22μm微孔滤膜过滤,超滤膜过滤。
(6)灌装至非PVC软袋,终端灭菌F0≥12,灯检合格后,贴标签,包装。
本发明甘油果糖氯化钠注射液其优点在于:解决了甘油果糖氯化钠注射液无法耐受过度灭菌法(F0≥12)的灭菌问题。通过仅添加聚乙二醇-二硬脂酰磷脂酰乙醇胺作为辅料,不仅在高温蒸汽灭菌的过程中稳定了果糖和pH值,更解决了甘油果糖氯化钠注射液在长期贮存放置时,有关物质5-HMF会超标的问题。其稳定性明显优于现有的市售处方工艺,极大地提高了甘油果糖氯化钠注射液作为临床用药的安全性。
下面就本发明中聚乙二醇-二硬脂酰磷脂酰乙醇胺用量、pH范围选择和pH调节剂等的摸索过程,简要进行描述。本发明中pH值和5-HMF检测方法均按照《中国药典》2020年版二部“甘油果糖氯化钠注射液”检查项下规定。
一、最佳聚乙二醇-二硬脂酰磷脂酰乙醇胺用量
甘油果糖氯化钠注射液面临的最大问题是,在高温蒸汽灭菌和长期放置贮存过程中,产生的5-HMF超标。故先针对果糖稳定性不佳这一问题,选用聚乙二醇-二硬脂酰磷脂酰乙醇胺,对其用量进行筛选试验。分别考察了聚乙二醇-二硬脂酰磷脂酰乙醇胺用量为0、0.05%、0.1%、0.2%、0.5%、0.8%时,甘油果糖氯化钠注射液的稳定性。实验结果简述见表1。
表1最佳聚乙二醇-二硬脂酰磷脂酰乙醇胺用量的筛选
试验结果表明,加入聚乙二醇-二硬脂酰磷脂酰乙醇胺后,在高温蒸汽灭菌和长期放置贮存过程中,其均能显著的稳定甘油果糖氯化钠注射液的果糖和pH值。当加入的聚乙二醇-二硬脂酰磷脂酰乙醇胺重量/体积百分比在0.1-0.5%之内时,可获得甘油果糖氯化钠注射液的最佳稳定效果。
二、最佳pH范围选择
通过对加入的聚乙二醇-二硬脂酰磷脂酰乙醇胺用量的筛选,优选出重量/体积百分比在0.1-0.5%为其最佳用量。为了得到本发明最佳的pH范围,进一步试制多个方案进行筛选,部分试验结果简述见表2。
表2最佳pH范围的筛选
以上试验结果表明,5-HMF的生成受到pH的影响较大。pH值调节至4.5以上时,5-HMF检测结果较大,增长较快;pH值调节至4.0以下时,不仅有关物质5-HMF的量产生和增长的较多,且其在40℃放置1个月后,pH值低于《中国药典》规定的最低要求。因此,选择的最佳pH值范围为4.0-5.0。
三、pH调节剂的选择
本发明选用了L-苹果酸、马来酸、琥铂酸、枸橼酸、盐酸其中的一种作为pH调节剂,通过试验表明,L-苹果酸、马来酸、琥铂酸、枸橼酸、盐酸均可作为甘油果糖氯化钠注射液的调节剂,优选枸橼酸。
表3不同pH调节剂对稳定性的影响
具体实施方式
本发明中pH值和5-HMF检测方法均按照《中国药典》2020年版二部“甘油果糖氯化钠注射液”检查项下规定。
实施例1
甘油 | 25g |
果糖 | 12.5g |
氯化钠 | 2.25g |
聚乙二醇-二硬脂酰磷脂酰乙醇胺 | 0.25g |
0.25%枸橼酸水溶液 | 适量 |
注射用水 | 加至250ml |
制备方法:
按处方称取原料和辅料,备用。取总体积200ml的注射用水,加入甘油搅拌混合均匀后加入氯化钠。待氯化钠完全溶解后,加入0.25%枸橼酸水溶液调节pH值为4.2。调节完成后,加入聚乙二醇-二硬脂酰磷脂酰乙醇胺,搅拌溶解后,再加入果糖,搅拌使其完全溶解,加入注射用水至250ml。搅拌均匀,用0.22μm微孔滤膜过滤,超滤膜过滤。检测含量符合规定后,灌装至非PVC软袋,于121℃蒸汽灭菌15分钟,灯检合格后,贴标签,包装。
实施例2
甘油 | 25g |
果糖 | 12.5g |
氯化钠 | 2.25g |
聚乙二醇-二硬脂酰磷脂酰乙醇胺 | 0.5g |
0.25%枸橼酸水溶液 | 适量 |
注射用水 | 加至250ml |
制备方法:
按处方称取原料和辅料,备用。取总体积200ml的注射用水,加入甘油搅拌混合均匀后加入氯化钠。待氯化钠完全溶解后,加入0.25%枸橼酸水溶液调节pH值为4.2。调节完成后,加入聚乙二醇-二硬脂酰磷脂酰乙醇胺,搅拌溶解后,再加入果糖,搅拌使其完全溶解,加入注射用水至250ml。搅拌均匀,用0.22μm微孔滤膜过滤,超滤膜过滤。检测含量符合规定后,灌装至非PVC软袋,于121℃蒸汽灭菌15分钟,灯检合格后,贴标签,包装。
实施例3
甘油 | 25g |
果糖 | 12.5g |
氯化钠 | 2.25g |
聚乙二醇-二硬脂酰磷脂酰乙醇胺 | 1.25g |
0.25%枸橼酸水溶液 | 适量 |
注射用水 | 加至250ml |
制备方法:
按处方称取原料和辅料,备用。取总体积200ml的注射用水,加入甘油搅拌混合均匀后加入氯化钠。待氯化钠完全溶解后,加入0.25%枸橼酸水溶液调节pH值为4.2。调节完成后,加入聚乙二醇-二硬脂酰磷脂酰乙醇胺,搅拌溶解后,再加入果糖,搅拌使其完全溶解,加入注射用水至250ml。搅拌均匀,用0.22μm微孔滤膜过滤,超滤膜过滤。检测含量符合规定后,灌装至非PVC软袋,于121℃蒸汽灭菌15分钟,灯检合格后,贴标签,包装。
实施例1、2、3的稳定性试验数据如下表所示:
表4甘油果糖氯化钠注射液稳定性实验结果
Claims (5)
1.一种甘油果糖氯化钠注射液,其特征在于:该注射液处方组成按重量/体积百分比为:甘油10%、果糖5%、氯化钠0.9%、聚乙二醇-二硬脂酰磷脂酰乙醇胺0.1-0.5%、pH调节剂适量以及余量的注射用水,其中制备过程中加入pH调节剂,调节pH值为4.0-4.5。
2.根据权利要求1所述的甘油果糖氯化钠注射液,其特征在于:每250ml注射液由以下组分构成:甘油25g,果糖12.5g,氯化钠2.25g,聚乙二醇-二硬脂酰磷脂酰乙醇胺0.25-1.25g,pH调节剂适量,注射用水加至250ml。
3.根据权利要求1所述的甘油果糖氯化钠注射液,其特征在于,所述pH调节剂为L-苹果酸、马来酸、琥珀酸、枸橼酸、盐酸的一种。
4.根据权利要求3所述的甘油果糖氯化钠注射液,其特征在于,pH调节剂为枸橼酸。
5.制备权利要求1所述的甘油果糖氯化钠注射液的方法,其特征在于,其具体步骤为:按处方称取原料和辅料,备用;取总体积60-80%的注射用水,加入甘油搅拌混合均匀后加入氯化钠;待氯化钠完全溶解后,加入pH调节剂调节pH值为4.0-4.5;调节完成后,加入聚乙二醇-二硬脂酰磷脂酰乙醇胺,搅拌溶解后,再加入果糖,搅拌使其完全溶解,加入注射用水至全量;搅拌均匀,用0.22μm微孔滤膜过滤,超滤膜过滤;灌装至非PVC软袋,终端灭菌F0≥12,灯检合格后,贴标签,包装。
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