CN111116392B - 一种盐酸赖氨酸化合物及其药物组合物 - Google Patents
一种盐酸赖氨酸化合物及其药物组合物 Download PDFInfo
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Abstract
本发明提供一种盐酸赖氨酸化合物及其药物组合物，其先通过3‑氨基甲基叔丁酯基己内酰胺和氯化氢乙酸乙酯反应制得盐酸赖氨酸粗品，然后再溶解析晶，制得盐酸赖氨酸精制品。该化合物用粉末X射线衍射测定法测定，以2θ±0.2°衍射角表示在4.3°，8.8°，13.3°，16.9°，17.8°，20.0°，23.2°，25.5°处显示出特征衍射峰。本发明制备的盐酸赖氨酸化合物具纯度高、工艺稳定，重复性强，适合于工业化生产。
Description
技术领域
本发明涉及医药技术领域，特别涉及一种盐酸赖氨酸化合物及其药物组合物。
背景技术
盐酸赖氨酸(Lysine Hydrochloride)，化学名：L-2，6二氨基己酸盐酸盐，分子式：C6H14N2O2·HCl，分子量为182.65，白色结晶或结晶性粉末，在水中易溶，在乙醇中极微溶解，在乙醛中几乎不溶，结构式如下所示，
赖氨酸是人体必需氨基酸之一，由于谷物食品中的赖氨酸含量甚低，且在加工过程中易被破坏而缺乏，故称为第一限制性氨基酸。赖氨酸每日的建议摄入量是儿童每磅体重10mg，成年人每天在3000-9000mg之间。赖氨酸是控制人体生长的重要物质抑长素中最重要的也是最必需的成份，对人的中枢神经和周围神经系统都起着重要作用；现研究同时表明赖氨酸在治疗颅脑外伤、慢性脑组织缺血、缺氧性疾病也发挥着疗效，同时还具有治疗单纯疱疹病毒和带状疱疹引起的唇疱疹，摄入赖氨酸可以大大缩短治愈的时间；改善免疫系统，抵制单纯疱疹和带状疱疹病毒的功效；防止骨质流失，因为它能够帮助身体组织吸收钙，结合其他氨基酸可以促进骨骼活力，并通过增加女性胶原蛋白预防骨质疏松症，增加胶原蛋白可以促进骨骼和结缔组织更强大和更柔韧；与某些非甾体抗炎药结合，能够成功的治疗与经前综合症和月经初潮相关的偏头痛和腹部绞痛。
赖氨酸主要用于食品、医药、饲料中，市场上出售的赖氨酸盐产品主要为盐酸赖氨酸晶体和纯度为65％左右的赖氨酸硫酸盐，由于赖氨酸属碱性氨基酸，现在使用的赖氨酸，主要是用发酵法生产的盐酸赖氨酸，提取法和发酵法得到的都是L-赖氨酸。在发酵法中，有经由二氨基庚二酸的二步法和以糖为原料的一步法，糖类发酵采用得较多。有关L-赖氨酸的结晶提取方法研究较少，而且其提取工艺主要集中在发酵后使用大孔吸附树脂进行提取，然后使用活性炭脱色后直接进行结晶得到L-赖氨酸产品。但是这种提取结晶工艺在提纯过程中存在一些缺陷：如盐酸赖氨酸结晶的介稳区较窄；在水溶液中盐酸赖氨酸因溶解性大不易结晶，而在高温环境下又易结块；收率较低；提纯过程能耗高；母液直接排放环境污染大等。
目前的盐酸赖氨酸的生产工艺以及结晶方法的收率均较低，如何开发一种高收率、高纯度、工艺稳定的方法对于降低盐酸赖氨酸的生产成本以及大规模应用具有重要的意义和价值，而且利用高纯度原料制备的盐酸赖氨酸药物组合物制剂更是成为市场需要的产品。
发明内容
鉴于此，本发明提出一种生产工艺稳定、纯度高的盐酸赖氨酸化合物，克服目前市场上盐酸赖氨酸原料药的杂质多、纯度低，不良反应高等问题。
本发明的技术方案是这样实现的：
一种盐酸赖氨酸化合物，其特征在于，先通过3-氨基甲基叔丁酯基己内酰胺和氯化氢乙酸乙酯反应制得盐酸赖氨酸粗品，然后再溶解析晶，制得盐酸赖氨酸精制品；其用粉末X射线衍射测定法测定，以2θ±0.2°衍射角表示的X射线粉末衍射图谱如图1所示，在4.3°，8.8°，13.3°，16.9°，17.8°，20.0°，23.2°，25.5°处显示出特征衍射峰。
进一步的，其制备方法包括以下步骤：
(1)先后加入3-氨基甲基叔丁酯基己内酰胺和氯化氢乙酸乙酯溶液，室温下反应，有大量固体析出，过滤，得到盐酸赖氨酸粗品；
(2)加入80-90v/v％乙醇溶液、盐酸赖氨酸粗品及活性炭，升温，回流脱色，趁热过滤；
(3)滤液降温析晶，过滤；
(4)将过滤得到的晶体减压干燥，得盐酸赖氨酸。
进一步的，步骤(1)中，3-氨基甲基叔丁酯基己内酰胺和氯化氢乙酸乙酯溶液的质量体积比Kg/L为1:4-6；步骤(2)中，所述盐酸赖氨酸粗品和乙醇溶液的质量体积比Kg/L为1:9-11。
进一步的，步骤(1)中，所述氯化氢乙酸乙酯溶液中氯化氢的体积百分比为8-12％。
进一步的，步骤(1)中，反应时间为10～14h。
进一步的，所述活性炭的加入量为盐酸赖氨酸粗品质量的0.8％～1％。
进一步的，步骤(2)中，升温至65～80℃，回流脱色25～45min。
进一步的，步骤(3)中，滤液降温至室温，析晶4～6h。
进一步的，步骤(4)中，所述减压干燥条件：35～50℃减压干燥30～50min。
一种药物组合物，包含本发明任一项所述的盐酸赖氨酸化合物。
与现有技术相比，本发明的有益效果是：
(1)本发明的盐酸赖氨酸化合物，纯度高，在合成步骤带入的工艺杂质含量少。
(2)本发明的盐酸赖氨酸化合物，其制备方法工艺简单，收率高，重复性强，适合于工业化生产。
(3)采用本发明盐酸赖氨酸化合物制备的药物组合物，稳定性很好，从而提高了用药安全性和有效性，降低了不良反应的发生率。
附图说明
图1为本发明的盐酸赖氨酸化合物的X射线粉末衍射图。
具体实施方式
为了更好理解本发明技术内容，下面提供具体实施例，对本发明做进一步的说明。
本发明实施例所用的实验方法如无特殊说明，均为常规方法。
本发明实施例所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1-盐酸赖氨酸化合物的制备
(1)向反应器中先后加入3-氨基甲基叔丁酯基己内酰胺5.321Kg和10v/v％氯化氢乙酸乙酯溶液25L，搅拌，室温下反应10h，有大量固体析出，过滤，得到类白色盐酸赖氨酸3.547Kg，收率83.32％。
(2)取盐酸赖氨酸粗品3.478Kg，加入85v/v％乙醇溶液35L及活性炭20.87g，活性炭吸附脱色，升温至80℃，回流脱色25min，趁热过滤。
(3)滤液降至室温析晶6小时，过滤。
(4)固体35℃减压干燥50min，得到纯盐酸赖氨酸3.286Kg，收率94.48％。
实施例2-盐酸赖氨酸化合物的制备
(1)向反应器中先后加入3-氨基甲基叔丁酯基己内酰胺5.453Kg和10v/v％氯化氢乙酸乙酯溶液27L，搅拌，室温下反应12h，有大量固体析出，过滤，得到类白色盐酸赖氨酸3.712Kg，收率85.09％。
(2)取盐酸赖氨酸粗品3.605Kg，加入85v/v％乙醇溶液36L及活性炭28.84g，活性炭吸附脱色，升温至70℃，回流脱色30min，趁热过滤。
(3)滤液降温析晶5小时，过滤。
(4)固体45℃减压干燥40min，得到纯盐酸赖氨酸3.426Kg，收率95.03％。
实施例3-盐酸赖氨酸化合物的制备
(1)向反应器中先后加入3-氨基甲基叔丁酯基己内酰胺5.639Kg和10v/v％氯化氢乙酸乙酯溶液28L，搅拌，室温下反应14h，有大量固体析出，过滤，得到类白色盐酸赖氨酸3.814Kg，收率84.54％。
(2)取盐酸赖氨酸粗品3.700Kg，加入85v/v％乙醇溶液37L及活性炭37g，活性炭吸附脱色，升温至65℃，回流脱色45min，趁热过滤。
(3)滤液降温析晶4小时，过滤。
(4)固体50℃减压干燥30min，得到纯盐酸赖氨酸3.454Kg，收率93.35％。
实施例4-盐酸赖氨酸药物组合物的制备
处方：盐酸赖氨酸3Kg，注射用水加至10L。制备过程：
(1)安瓿瓶处理：安瓿瓶经超声波清洗，注射用水精洗，高温干燥后使用。
(2)在配料罐中加入90％总配量的注射用水，保持水温60～80℃，加入处方量的盐酸赖氨酸，搅拌溶解，得盐酸赖氨酸溶液。加入10g活性炭，搅拌均匀，煮沸20min。补加注射用水至全量，充分搅拌至药液均匀，药液通过钛棒过滤器过滤脱炭，再经过0.45μm和0.22μm过滤器过滤至储液罐中，搅拌均匀；
(3)灌装、封口并按要求检查装量。
(4)流通蒸汽115℃灭菌30min，检漏。
(5)灯检、包装、检验、入库。
对比例1-盐酸赖氨酸化合物的制备
根据专利CN201910470388.4公开的一种L-赖氨酸盐酸盐的结晶方法制备，具体如下：
将浓度为65％的L-赖氨酸盐酸盐的水溶液在80℃下进行初次浓缩，将浓度浓缩至80％，然后加入温度为73℃的正丁醇，正丁醇与L-赖氨酸盐酸盐的水溶液的体积比为1:7，同时在饱和蒸汽的鼓入25min下降温至15℃，过滤后使用温度为70℃的空气进行风干得到L-赖氨酸盐酸盐。
对比例2-盐酸赖氨酸药物组合物的制备
采用购买于广西南宁邕江药业有限公司的批准文号为国药准字H20000554的盐酸赖氨酸注射液，商品名：镇通。
试验例1含量比较
对本发明实施例1～3和对比例1制备的盐酸赖氨酸进行了含量测定，结果如下：
| 实施例 | 实施例1 | 实施例2 | 实施例3 | 对比例1 |
| 含量(％) | 99.24 | 99.37 | 99.25 | 99.09 |
结论：由上表数据可明显看出，本发明实施例1～3制备的盐酸赖氨酸含量明显高于对比例1制备的样品，说明了本发明技术方案对提高盐酸赖氨酸含量具有显著效果。
试验例2热稳定性试验
将本发明实施例1～3和对比例1制备的盐酸赖氨酸置于温度60℃，相对湿度75％条件下30天，分别于0、10、20、30天进行检测，考察指标为性状、溶液的透光率、含量。结果如下：
结论：由上表数据可明显看出，本发明实施例1～3制备的盐酸赖氨酸热稳定性明显好于对比例1制备的样品，说明了本发明技术方案对提高盐酸赖氨酸热稳定性具有显著效果。
试验例3稳定性考察
将本发明实施例4和对比例2的盐酸赖氨酸药物组合物进行加速和长期稳定性考察试验。加速试验考察条件为温度40±2℃，相对湿度75％±5％，放置6个月，分别于0、1、2、3、6月取样；长期试验考察条件为温度25±2℃，相对湿度60％±5％，放置24个月，分别于0、3、6、9、12月取样。考察指标为性状、pH、颜色和含量。结果如下：
加速试验结果：
长期试验结果：
结论：由上表数据可明显看出，本发明实施例4制备的盐酸赖氨酸药物组合物稳定性优于对比例2的样品，说明了本发明技术方案对提高盐酸赖氨酸药物组合物稳定性具有显著效果。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种盐酸赖氨酸晶体的制备方法，其特征在于，先通过3-氨基甲基叔丁酯基己内酰胺和氯化氢乙酸乙酯反应制得盐酸赖氨酸粗品，然后再溶解析晶，制得盐酸赖氨酸精制品；其用粉末X射线衍射测定法测定，以2θ±0.2°衍射角表示的X射线粉末衍射图谱，在4.3°，8.8°，13.3°，16.9°，17.8°，20.0°，23.2°，25.5°处显示出特征衍射峰；其制备方法具体包括以下步骤：
（1）先后加入3-氨基甲基叔丁酯基己内酰胺和氯化氢乙酸乙酯溶液，室温下反应10~14h，有大量固体析出，过滤，得到盐酸赖氨酸粗品；3-氨基甲基叔丁酯基己内酰胺和氯化氢乙酸乙酯溶液的质量体积比kg/L为1:4-6；
（2）加入80-90v/v%乙醇溶液、盐酸赖氨酸粗品及活性炭，升温至65~80℃，回流脱色25~45min，趁热过滤；所述盐酸赖氨酸粗品和乙醇溶液的质量体积比kg/L为1:9-11；所述活性炭的加入量为盐酸赖氨酸粗品质量的0.6%~1%；
（3）滤液降温至室温析晶4~6h，过滤；
（4）将过滤得到的晶体35~50℃减压干燥30~50min，得盐酸赖氨酸晶体。
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