CN100355426C - 注射用三磷酸腺苷二钠固体组合物及其制备方法 - Google Patents
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Abstract
一种注射用三磷酸腺苷二钠固体组合物，由三磷酸腺苷二钠、氯化镁、稳定剂糖醇和缓冲剂氨基酸组成，其组成含量为25.0-50.0ωt%三磷酸腺苷二钠，8.0-16.0ωt%氯化镁，0.5-50.0ωt%稳定剂糖醇，0.5-50ωt%缓冲剂氨基酸。其中三磷酸腺苷二钠与氯化镁的重量比为100∶32。该固体组合物稳定性好、溶解度好，临床应用方便，避免了将三磷酸腺苷二钠的注射液与氯化镁注射液直接混合配制容易发生沉淀等不稳定因素，提高了三磷酸腺苷二钠—氯化镁注射液的临床应用水平及安全性。该固体组合物制备工艺简单，适于工业化生产。
Description
技术领域
本发明涉及一种含有三磷酸腺苷二钠的药物组合物，是关于一种三磷酸腺苷二钠注射用制剂的改进技术。
背景技术
三磷酸腺苷二钠氯化镁为高能复合物，可透过各重要脏器的细胞膜，增加组织和细胞内三磷酸腺苷(又称三磷酸腺苷二钠，简称ATP)水平。在缺血缺氧状态下给细胞直接供能，从而改善细胞能量代谢及细胞膜钠泵机制，减轻细胞肿胀，改善微循环障碍，恢复脏器功能。能改善休克所致的大鼠肝细胞膜通透性，有效恢复缺血性肝细胞功能，能改善细胞能量代谢、改善微循环障碍、改善巨噬细胞系统功能。本品能够进入缺血缺氧的心肌细胞线粒体，支持细胞供能，改善细胞内外的钠、钾、镁平衡失调，抑制细胞内Ca2+聚集。本品有一定清除氧自由基的作用，保护细胞，促进功能恢复。主要用于急性黄疸型肝炎、慢性活动型肝炎、缺血性脑血管病后遗症、脑损伤、脑性小儿麻痹、心肌炎等病症的辅助治疗。
目前，三磷酸腺苷二钠和氯化镁它们的原料和注射液已作为中华人民共和国国家的基本药物。市场上供应的三磷酸腺苷二钠氯化镁注射液为三磷酸腺苷二钠(ATP)的注射液(简称A液)与氯化镁的注射液(简称M液)等比例组合包装，肌肉或静脉注射。由于临床上应用三磷酸腺苷二钠和氯化镁注射前需要取三磷酸腺苷二钠的注射液(简称A液)与氯化镁的注射液(简称M液)混合配制，不仅手续繁琐，而且配制应用时不够稳定，容易发生沉淀，存在着严重的隐患，给临床应用带来很大的麻烦和不稳定因素。
发明内容
本发明目的之一是研制一种稳定性好、方便临床使用的三磷酸腺苷二钠注射用制剂。本发明的另一个目的是研制这种注射制剂的制备方法。
本发明的解决方案是：把注射用三磷酸腺苷二钠制备成一种固体组合物。在所说的固体组合物中包含有三磷酸腺苷二钠、氯化镁与稳定剂、缓冲剂等组分，其组分含量以重量百分数计为：25.0-50.0wt％的三磷酸腺苷二钠，8.0-16.0wt％的氯化镁，0.5-50.0wt％稳定剂，0.5-50.0wt％的缓冲剂及4.0wt％以下的水。
在本发明的三磷酸腺苷二钠固体组合物中三磷酸腺苷二钠和氯化镁的优选重量比为100∶32。
本发明中所用的稳定剂为糖醇，它选自甘露醇、山梨醇、葡萄糖、甘露糖、乳糖中的一种或两种以上的混合物均可。优选的为甘露醇，其优选的组分含量为15.0-45.0wt％。
选用的缓冲剂为氨基酸，它选自L-精氨酸、L-半胱氨酸、L-赖氨酸中的一种或两种以上的混合物。其中优选的为L-精氨酸，其优选的组分含量为5.0-35.0wt％。
本发明注射用三磷酸腺苷二钠固体组合物的制备方法是：首先把定量的三磷酸腺苷二钠、氯化镁、稳定剂、缓冲剂等组分，分别用一定体积的注射用水溶解；先将三磷酸腺苷二钠溶液和氯化镁溶液混匀，加入稳定剂，再用氨基酸水溶液的调节pH值为4.5-6.5；加入溶液量0.05％的活性炭吸附，过滤除炭后，再经0.22μm微孔滤膜过滤除菌，分装，冷冻干燥至水分少于4％之后，密封包装，即得本产品。
为表明本发明的进步性，我们对本发明三磷酸腺苷二钠固体组合物进行了稳定性试验，结果见表1、表2和表3。
表1三磷酸腺苷二钠氯化镁稳定性试验结果
| 试验条件 | 时间(天) | 性状 | 酸度 | 溶液澄清度与颜色 | 标示含量％ | |
| ATP | 氯化镁 | |||||
| 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.4 | 99.9 | |
| 光照4500±500Lx | 5 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.8 |
| 10 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.5 | 99.8 | |
| 高温60℃ | 5 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.4 | 99.7 |
| 10 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.0 | 99.7 | |
| 低温4℃ | 5 | 白色冻干块状物 | 5.4 | 澄清无色 | 100.6 | 99.5 |
| 10 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.1 | 99.6 | |
表2三磷酸腺苷二钠氯化镁40℃加速试验结果
| 批号 | 时间(月) | 性状 | 酸度 | 溶液的澄清度与颜色 | 标示含量(％) | |
| ATP | 氯化镁 | |||||
| 1 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.4 | 99.9 |
| 3 | 白色冻干块状物 | 5.8 | 澄清无色 | 100.1 | 99.8 | |
| 6 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.6 | |
| 2 | 0 | 白色冻干块状物 | 5.4 | 澄清无色 | 100.0 | 99.4 |
| 3 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.0 | 99.6 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 99.7 | 99.7 | |
| 3 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.2 | 100.0 |
| 3 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.1 | 99.9 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.3 | 99.9 | |
表3三磷酸腺苷二钠氯化镁室温25℃长期留样试验结果
| 批号 | 时间(月) | 性状 | 酸度 | 溶液的澄清度与颜色 | 标示含量(％) | |
| ATP | 氯化镁 | |||||
| 1 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.4 | 99.9 |
| 3 | 白色冻干块状物 | 5.8 | 澄清无色 | 100.0 | 99.9 | |
| 6 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.7 | |
| 9 | 白色冻干块状物 | 5.8 | 澄清无色 | 100.0 | 99.8 | |
| 12 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.6 | |
| 2 | 0 | 白色冻干块状物 | 5.4 | 澄清无色 | 100.0 | 99.4 |
| 3 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.1 | 99.7 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 99.8 | 99.8 | |
| 9 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.0 | 99.5 | |
| 12 | 白色冻干块状物 | 5.6 | 澄清无色 | 99.8 | 99.7 | |
| 3 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.2 | 100.0 |
| 3 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.0 | 99.9 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.3 | 99.8 | |
| 9 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.0 | 99.8 | |
| 12 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.1 | 99.9 | |
试验结果表明，本品在光照、高温、低温、加速试验、长期放置等条件下表现出很好的稳定性。
对本品进行了安全性试验，包括溶血性、过敏反应及血管刺激性试验。本品供试液对豚鼠的过敏试验表明，本品无过敏反应；溶血性试验结果表明，本品供试液对红细胞不产生溶血和凝集作用；对家兔的刺激试验结果表明，本品供试液几乎无刺激性。
本发明的优点是很明显的：本发明的注射用三磷酸腺苷二钠固体组合物稳定性好、溶解度好，临床应用方便，避免了将三磷酸腺苷二钠的注射液与氯化镁的注射液直接混合配制容易发生沉淀的等不稳定因素带来的严重隐患，提高了三磷酸腺苷二钠-氯化镁注射液的临床应用水平及安全性；本发明的注射用三磷酸腺苷二钠固体组合物制备方法简单，适用于工业化生产。
具体实施方式：
下面再用实施例方式对本发明作进一步说明，给出本发明的实施细节，但并不旨在限定本发明的保护范围。
制备注射用三磷酸腺苷二钠100mg-氯化镁32mg固体组合物
三磷酸腺苷二钠 100g
氯化镁 32g
L-精氨酸 50g
甘露醇 150g
注射用水 2000ml
1000瓶
操作步骤：(1)按处方量称取三磷酸腺苷二钠，加入注射用水60％溶解后，加L-精氨酸80％，搅拌使溶解；(2)称取处方量氯化镁，加入注射用水25％，搅拌使溶解；(3)将两溶液混合均匀。加入甘露醇搅拌至溶解，加剩余L-精氨酸控制pH为4.5~6.5；(4)补加注射用水至处方量；加入溶液量0.05％(g/ml)的药用活性炭，搅拌30分钟，粗滤除炭；(5)用0.22μm微孔滤膜过滤；(6)灌装于西林瓶中；(7)冷冻干燥至水分小于4％；(8)压塞、轧铝盖；(9)全检，包装。
如此制成的注射用三磷酸腺二钠固体组合物，每瓶中含三磷酸腺苷二钠100mg，氯化镁32mg。使用时，用5％葡萄糖注射液稀释至10-50ml，肌肉或静脉注射。
下面再用几个实例进一步说明本发明，见表4
| 实施例组分％ | 1 | 2 | 3 | 4 | 5 | 6 |
| 三磷酸腺苷二钠 | 28.92 | 43.24 | 30.24 | 34.25 | 35.20 | 44.6 |
| 氯化镁 | 9.25 | 13.84 | 9.68 | 10.96 | 11.26 | 14.27 |
| L-精氨酸 | 15.66 | 21.62 | 16.52 | 19.37 | ||
| L-半胱氨酸 | 14.32 | |||||
| L-赖氨酸 | 17.84 | |||||
| 甘露醇 | 43.37 | 18.80 | ||||
| 山梨醇 | 43.76 | |||||
| 葡萄糖 | 33.45 | |||||
| 甘露糖 | 59.56 | |||||
| 乳糖 | 33.92 | |||||
| 水 | 2.8 | 2.5 | 2.0 | 3.5 | 3.1 | 2.2 |
| 性能 三磷酸腺二钠标示含量％ | ||||||
| 高温60℃10天 | 100.1 | 99.9 | 99.7 | 100.1 | 99.7 | 99.6 |
| 40℃ 6个月 | 99.9 | 99.8 | 99.8 | 99.8 | 99.7 | 99.7 |
| 25℃ 12个月 | 99.9 | 100.0 | 99.8 | 99.7 | 99.8 | 99.6 |
(续)
| 实施例 | 7 | 8 | 9 | 10 | ||
| 组分 ％ | ||||||
| 三磷酸腺苷二钠 | 36.54 | 28.89 | 40.25 | 53.22 | ||
| 氯化镁 | 11.69 | 9.24 | 12.88 | 17.03 | ||
| L-精氨酸 | 11.23 | 15.23 | ||||
| L-半胱氨酸 | 7.56 | 7.25 | ||||
| L-赖氨酸 | 5.63 | |||||
| 甘露醇 | 21.73 | 31.58 | ||||
| 山梨醇 | 18.98 | 9.46 | ||||
| 葡萄糖 | 21.71 | |||||
| 甘露糖 | 9.44 | |||||
| 乳糖 | 18.96 | |||||
| 水 | 2.6 | 3.2 | 2.1 | 3.6 | ||
| 性能 三磷酸腺二钠标示含量 ％ | ||||||
| 高温60℃ 10天 | 99.8 | 99.7 | 99.6 | 99.7 | ||
| 40℃ 6个月 | 99.6 | 99.6 | 99.6 | 99.8 | ||
| 25℃ 12个月 | 99.7 | 99.8 | 99.7 | 99.7 | ||
本配方制备的注射用三磷酸腺苷二钠100mg-氯化镁32mg固体组合物用5％配成的注射液与市售的三磷酸腺苷二钠(ATP)的注射液(A液)与氯化镁的注射液(M液)配制的注射液稳定性比较。结果表明市售的三磷酸腺苷二钠(ATP)的注射液(A液)与氯化镁的注射液(M液)配制的注射液在室温放置6-12小时后往往会发生沉淀等变质现象，而本品在光照、高温、低温、长期放置等条件下表现出很好的稳定性。结果见表5
表5：实施例1得到的本品用5％葡萄糖配制注射液和市售A-M配制注射液光照、高温、低温、长期放置等条件下，观察注射液澄清度试验结果。
样品1：实施例1得到的本品用5％葡萄糖配制的注射液
样品2：市售A-M配制的注射液
| 放置条件 | 1注射液澄清度 | 2注射液澄清度 |
| 40℃ 6小时 | 澄清 | 浑浊 |
| 25℃ 24小时 | 澄清 | 浑浊 |
| 光照12小时 | 澄清 | 浑浊 |
| 0℃ 24小时 | 澄清 | 稍浊 |
Claims (2)
1、一种注射用三磷酸腺苷二钠固体组合物，由三磷酸腺苷二钠及药用载体组成，其特征在于所说的固体组合物由以下组分组成，以重量百分数计为：25.0-50.0ωt％的三磷酸腺苷二纳；8.0-16.0ωt％氯化镁，0.5-50.0ωt％稳定剂，它选自甘露醇、山梨醇、葡萄糖、甘露糖、乳糖中的一种或几种的混合物；0.5-50ωt％缓冲剂，它选自L-精氨酸、L半胱氨酸、L赖氨酸中的一种或几种的混合物；及4％以下的水，其中三磷酸腺苷二钠与氯化镁的重量比为100∶32。
2、权利要求1所述的固体组合物的制备方法，其特征在于包括以下主要步骤：
(1)把定量的三磷酸腺苷二钠、氯化镁、稳定剂、缓冲剂分别用适量注射用水溶解；
(2)先将三磷酸腺苷溶液与氯化镁溶液混匀；
(3)加入稳定剂混匀后，用氨基酸溶液调节PH值4.5-6.5；
(4)加入药用活性炭吸附后，过滤除炭；
(5)用0.22μm微孔滤膜过滤除菌；
(6)分装，冷冻干燥至水分小于4％后，密封包装，制造本产品。
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