CN1251681C - 静脉注射用高浓型水溶性维生素及其制备方法和用途 - Google Patents
静脉注射用高浓型水溶性维生素及其制备方法和用途 Download PDFInfo
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- CN1251681C CN1251681C CN 200410005778 CN200410005778A CN1251681C CN 1251681 C CN1251681 C CN 1251681C CN 200410005778 CN200410005778 CN 200410005778 CN 200410005778 A CN200410005778 A CN 200410005778A CN 1251681 C CN1251681 C CN 1251681C
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- water soluble
- vitamin
- soluble vitamins
- injection
- intravenous injection
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Abstract
本发明涉及一种静脉注射用高浓型水溶性维生素，每瓶含有硝酸硫胺 6.2±1.6mg、核黄素磷酸钠 9.8±2.5mg、烟酰胺 80±20mg、盐酸吡哆辛 9.8±2.5mg、泛酸钠 33.0±8.3mg、维生素C 200±50mg、生物素 120±30ug、叶酸 0.8±0.2mg、维生素B12 10.0±2.5ug。其制法为将上述各组分用注射用水搅拌至完全溶解，于冻干机内冻干，压盖制得静脉注射用水溶性维生素。本发明的静脉注射用水溶性维生素可用于预防和治疗水溶性维生素缺乏引起的营养不良及慢性疾病的辅助治疗，如慢性肝病等；具有补充维生素快速，增强药物疗效，减少副作用等优点，能满足临床因疾病所致的严重水溶性维生素缺乏的补充需要。
Description
技术领域
本发明涉及一种静脉注射用高浓型水溶性维生素及其制备方法和用途。
背景技术
水溶性维生素是维持机体正常功能所必需的，水溶性维生素应每天摄入一定量以供需要。目前临床多采用口服给药、或各种水溶性维生素单独给药、或注射给药补充维生素，因水溶性维生素在体内储留量甚少，一旦超过则被迅速排泄，剂量均依据维生素日需要量稍作提高，没有更高剂量的使用。在特殊病理状态下，如持续高热、烧伤、肝损害、大手术等，对水溶性维生素的需求增加，目前临床给药均无法满足临床严重水溶性维生素缺乏的补充需要。
发明内容
本发明就是针对上述问题提供一种静脉注射用高浓型水溶性维生素及其制备方法和用途，所制得的静脉注射用高浓型水溶性维生素比常规制剂疗效明显提高，尤其适用于临床因疾病所致的严重水溶性维生素缺乏的补充需要。
本发明人通过深入的研究，发现高(剂量)浓型水溶性维生素可比常规制剂明显提高治疗或辅助治疗效果，而且未发现毒副作用的增加，无过敏性、溶血性和血管刺激性，尤其对临床因疾病所致的严重水溶性维生素缺乏的补充更为合理。
本发明提供的技术方案是：静脉注射用高浓型水溶性维生素，每瓶含有硝酸硫胺(VitaminB1)6.2±1.6mg、核黄素磷酸钠(Vitamin B2)9.8±2.5mg、烟酰胺(Nicotinamide)80±20mg、盐酸吡哆辛(Vitamin B6)9.8±2.5mg、泛酸钠(Sodium Pantothenate)33.0±8.3mg、维生素C(Vitamin C)200±50mg、生物素(Biotin)120±30ug、叶酸(Folic Acid)0.8±0.2mg、维生素B12(Vitamin B12)10.0±2.5ug。
上述静脉注射用高浓型水溶性维生素的较佳方案为，每瓶含硝酸硫胺6.2mg、核黄素磷酸钠9.8mg、烟酰胺80mg、盐酸吡哆辛9.8mg、泛酸钠33.0mg、维生素C200mg、生物素120ug、叶酸0.8mg、维生素B1210.0ug。
上述静脉注射用高浓型水溶性维生素还含有0～0.8mg防腐剂、0.3～0.8mg络合剂、0～600mg赋型剂。
上述防腐剂为对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯或山梨醇等；络合剂为乙二胺四醋酸二钠、环己二胺四醋酸钠、N-羟基二乙胺三醋酸或二乙基三胺六醋酸等；赋型剂为甘氨酸、甘露醇、乳糖或水解明胶。
上述水溶性维生素含有0～0.8mg对羟基苯甲酸甲酯(Methylp-hyerosybenzoate)、0.3～0.6mg乙二胺四醋酸二钠(Disodium Ethylenediaminetetraacetate)、0～600mg甘氨酸(Glycine)。
本发明还提供了上述注射用高浓型水溶性维生素的制备方法，将硝酸硫胺、核黄素磷酸钠、烟酰胺、盐酸吡哆辛、泛酸钠、维生素C、生物素、叶酸和维生素上用注射用水溶解配制成水溶液，微孔过滤后装于容器中于冷冻干燥机内冻干，压盖制得静脉注射用水溶性维生素。
在上述配制的水溶液中可加入防腐剂、络合剂和赋型剂，然后微孔过滤后装于容器中于冷冻干燥机内冻干，压盖制得静脉用水溶性维生素。
上述静脉注射用高浓型水溶性维生素在制备因疾病所致的严重水溶性维生素缺乏时补充维生素的药物中的应用，用量为每天静脉滴注1～2次，每次一瓶，使用时加入0.9wt％氯化钠注射液或5wt％或10wt％葡萄糖注射液中静脉滴注。
试验表面，本发明静脉注射用高浓型水溶性维生素可比常规制剂明显提高治疗或辅助治疗效果，而且未发现毒副作用的增加，无过敏性、溶血性和血管刺激性，尤其对临床因疾病所致的严重水溶性维生素缺乏的补充更为合理。本发明的静脉注射用水溶性维生素具有补充维生素快速，增强药物疗效，减少副作用等优点，尤其能满足临床因疾病所致的严重水溶性维生素缺乏的补充需要。实验表明，本发明的静脉注射用高浓型水溶性维生素按剂量使用不仅无毒副作用，而且可迅速补充维生素，提高对疾病的抵抗力和免疫力，具有显著效果。
具体实施方式
本发明通过以下实施例作进一步说明
实施例1：将1.86g硝酸硫胺、2.94g核黄素磷酸钠、24.0g烟酰胺、2.94g盐酸吡哆辛、9.9g泛酸钠、60.0g维生素C、36mg生物素、0.24g叶酸、3.0mg维生素B12、0.15g对羟基苯甲酸甲酯、0.15g乙二胺四醋酸二钠、90g甘氨酸用注射用水溶解，加注射用水调至900ml，0.22μg微孔滤膜过滤，分装成每瓶3ml，于冷冻干燥机内冷冻干燥，压盖即得所需静脉注射用高浓型水溶性维生素冻干粉针剂。
实施例2：将1.86g硝酸硫胺、2.94g核黄素磷酸钠、24.0g烟酰胺、2.94g盐酸吡哆辛、9.9g泛酸钠、60.0g维生素C、36mg生物素、0.24g叶酸、3.0mg维生素B12、90mg乙二胺四醋酸二钠用300ml注射用水溶解，0.22μg微孔滤膜过滤，分装成300瓶，于冻干机内冷冻干燥，压盖即得所需静脉注射用高浓型水溶性维生素冻干粉针剂。
实施例3：将1.42g硝酸硫胺、3.60g核黄素磷酸钠、27.3g烟酰胺、2.28g盐酸吡哆辛、7.63g泛酸钠、53.0g维生素C、42mg生物素、0.20g叶酸、2.4mg维生素B12、90mg乙二胺四醋酸二钠用注射用水300ml溶解，0.22μg微孔滤膜过滤，分装成300瓶，于冻干机内冷冻干燥，压盖即得所需静脉注射用高浓型水溶性维生素冻干粉针剂。
实施例4：将2.30g硝酸硫胺、2.22g核黄素磷酸钠、20.0g烟酰胺、3.03g盐酸吡哆辛、9.9g泛酸钠、70.0g维生素C、30mg生物素、0.27g叶酸、3.6mg维生素B12、甘氨酸180g、山梨醇0.24g、N-羟基二乙胺三醋酸0.18g用注射用水溶解，加注射用水调至1800ml，0.22μg微孔滤膜过滤，分装成每瓶6ml，于冻干机内冷冻干燥，压盖即得所需静脉注射用高浓型水溶性维生素冻干粉针剂。
实施例5：将3.10g硝酸硫胺、4.90g核黄素磷酸钠、40.00g烟酰胺、4.90g盐酸吡哆辛、16.50g泛酸钠、100g维生素C、60mg生物素、0.40g叶酸、5.00mg维生素B12对羟基苯甲酸丙酯0.20g、环己二胺四醋酸钠0.20g、乳糖90g用注射用水溶解，加注射用水调至1000ml，0.22μg微孔滤膜过滤，分装成每瓶2ml，于冷冻干燥机内冷冻干燥，压盖即得所需静脉注射用高浓型水溶性维生素冻干粉针剂。
实施例6：将1.86g硝酸硫胺、2.94g核黄素磷酸钠、24.0g烟酰胺、2.94g盐酸吡哆辛、9.9g泛酸钠、60.0g维生素C、36mg生物素、0.24g叶酸、3.0mg维生素B12、甘氨酸180g、山梨醇0.24g、N-羟基二乙胺三醋酸0.18g用注射用水溶解，加注射用水调至1800ml，0.22μg微孔滤膜过滤，分装成每瓶6ml，于冻干机内冷冻干燥，压盖即得所需静脉注射用高浓型水溶性维生素冻干粉针剂。
实施例7：将3.10g硝酸硫胺、4.90g核黄素磷酸钠、40.00g烟酰胺、4.90g盐酸吡哆辛、16.50g泛酸钠、100g维生素C、60mg生物素、0.40g叶酸、5.00mg维生素B12、对羟基苯甲酸丙酯0.20g、环己二胺四醋酸钠0.20g、乳糖90g用注射用水溶解，加注射用水调至1000ml，0.22μg微孔滤膜过滤，分装成每瓶2ml，于冷冻干燥机内冷冻干燥，压盖即得所需静脉注射用高浓型水溶性维生素冻干粉针剂。
实施例8：将1.86g硝酸硫胺、2.94g核黄素磷酸钠、24.0g烟酰胺、2.94g盐酸吡哆辛、9.9g泛酸钠、60.0g维生素C、36mg生物素、0.24g叶酸、3.0mg维生素B12加入注射用水溶解，加注射用水调至600ml，0.22μg微孔滤膜过滤，分装成每瓶2ml，于冷冻干燥机内冷冻干燥，压盖即得所需注射用高浓型水溶性维生素冻干粉针剂。
注射用高浓型水溶性维生素对四氯化碳肝损伤小鼠作用研究
实验方法：挑选100只昆明小鼠随机分为11组，雌雄各半。除正常组外，其它9组每隔3天sc20％CCL40.02ml/10g植物油液。给药组于第3次造模24小时后开始给药，连续给药15天。(1)正常对照组：ip 10％GS 0.1ml/10g，qd；(2)模型组；(3)模型+低剂量水溶性维生素组：造模小鼠ip水溶性维生素1/6瓶/kg，qd；(4)模型+高剂量水溶性维生素组：造模小鼠ip水溶性维生素(低剂量水溶性维生素组2倍)1/3瓶/kg，qd；(5)模型+基础组：造模小鼠ip甘利欣3mg/kg+肌苷4mg/kg+VitC40mg/kg；(6)模型+低剂量+基础组：造模小鼠ip甘利欣3mg/kg+肌苷4mg/kg+VitC40mg/kg+水溶性维生素1/6瓶/kg，qd；(7)模型+高剂量+基础组：造模小鼠ip甘利欣3mg/kg+肌苷4mg/kg+VitC40mg/kg+水溶性维生素1/3瓶/kg，qd；(8)模型+低剂量水溶性维生素(Bid)组：造模小鼠ip水溶性维生素1/6瓶/kg，Bid；(9)模型+高剂量水溶性维生素(Bid)组：造模小鼠ip水溶性维生素1/3瓶/kg，Bid；(10)模型+低剂量+基础(Bid)组：造模小鼠ip甘利欣3mg/kg+肌苷4mg/kg+VitC40mg/kg+水溶性维生素1/6瓶/kg；(11)模型+高剂量+基础(Bid)组：造模小鼠ip甘利欣3mg/kg+肌苷4mg/kg+VitC40mg/kg+水溶性维生素1/3瓶/kg。
每天称量体重一次，根据体重变化调整给药量实验15天后测定如下指标：
1.体重：观察实验前和实验结束时体重变化。
2.血清谷丙转氨酶(ALT/GPT)：实验结束时，每只小鼠摘眼球取血，用赖氏法测定血清谷丙转氨酶含量，方法见血清谷丙转氨酶试剂盒说明书。
3.血清总胆红素：实验结束时，每只小鼠摘眼球取血，用咖啡因比色法测定血清总胆红素含量，方法见血清总胆红素试剂盒说明书。
4.病理检查：实验结束时，小鼠摘眼球取血后，立即取肝脏，并以4％多聚甲醛固定。HE染色，显微镜下观察，照相。
数据处理
数据以
x±S表示，经方差分析进行统计学处理。
结果
水溶性维生素对CCl4肝损伤小鼠体重的影响
表1结果可见，单独使用水溶性维生素一天一次，对肝损伤小鼠体重下降无明显影响，一天两次给予同等剂量的水溶性维生素，可明显提高损伤小鼠的体重，高剂量作用比低剂量显著提高；与临床常用护肝治疗方案(基础组)联用水溶性维生素，可见水溶性维生素可明显提高小鼠体重增长值。
表1.水溶性维生素对CCl4肝损伤小鼠体重的影响
| 组别 | 样本数 | 实验前体重(g) | 实验结束后体重(g) | 实验前后体重差异(g) |
| 正常对照组模型组模型+低剂量组模型+高剂量组模型+基础组模型+低剂量+基础组模型+高剂量+基础组模型+低剂量组(Bid)模型+高剂量组(Bid)模型+低剂量+基础组(Bid)模型+高剂量+基础组(Bid) | 1077887898109 | 21.1±1.622.7±1.722.3±1.522.4±1.723.4±1.822.8±1.123.8±1.121.6±1.622.1±1.122.6±1.323.6±0.9 | 28.2±1.021.1±2.522.2±1.522.4±1.824.2±0.924.4±1.526.0±1.822.7±1.423.4±1.523.6±2.426.6±1.9 | 7.1±1.6-1.6±1.3**-0.1±0.80±2.40.8±1.3▲▲1.6±0.7▲▲●●2.2±1.8▲▲●●1.1±1.2▲▲1.4±0.7▲▲1.0±1.9▲▲3.0±1.6▲▲●● |
与对照组相比**p＜0.01，与模型组相比▲▲P＜0.01，与基础组相比●●P＜0.01水溶性维生素对CCl4肝损伤小鼠血清谷丙转氨酶、血清总胆红素的影响
单独使用水溶性维生素一天一次，对肝损伤小鼠体重下降无明显影响，低剂量水溶性维生素不降低血清谷丙转氨酶，但能提高血清总胆红素含量，高剂量作用较低剂量显著；一天两次给药可明显降低损伤小鼠血清谷丙转氨酶及总胆红素，高剂量作用优于低剂量；与临床常用护肝治疗方案(基础组)联用水溶性维生素，可见水溶性维生素可明显增强临床常用护肝方案对肝损伤的保护作用，降低血清谷丙转氨酶活性及总胆红素含量，对总胆红素的作用高剂量优于低剂量。结果见表2。
表2.水溶性维生素对CCl4肝损伤小鼠血清谷丙转氨酶、血清总胆红素的影响
| 组别 | 样本数 | 血清谷丙转氨酶(μmol/ml) | 血清总胆红素(μmol/L) |
| 正常对照组模型组模型+低剂量组模型+高剂量组模型+基础组模型+低剂量+基础组模型+高剂量+基础组模型+低剂量组(Bid)模型+高剂量组(Bid)模型+低剂量+基础组(Bid)模型+高剂量+基础组(Bid) | 1077887898109 | 0.401±0.0180.750±0.005**0.721±0.0050.688±0.038▲▲0.689±0.006▲▲0.664±0.021▲▲0.638±0.010▲▲●●0.734±0.0100.672±0.008▲▲0.652±0.010▲▲●●0.650±0.041▲▲●● | 123±40874±149**735±152▲▲570±155▲▲552±132▲▲532±118▲▲371±123▲▲●●622±243516±174▲▲522±143▲▲353±145▲▲●● |
与对照组相比**p＜0.01，与模型组相比▲▲P＜0.01，与基础组相比●●P＜0.01
结论
注射用水溶性维生素对四氯化碳肝损伤有一定的保护作用，并能显著增强临床常用治疗方案的治疗效果，高剂量(本发明建议的临床用量)作用优于低剂量，提示临床可采用注射用高浓型水溶性维生素进行静脉营养，用于多种疾病的辅助治疗时。
注射用高浓型水溶性维生素一般药理学研究
实验方法：应用BL-420生物机能实验系统记录静脉给以10％GS、高、中、低3种不同剂量和正常大鼠的心电、血压、呼吸的变化。给药剂量：10％GS 1ml/200g，低剂量1/6瓶/kg，中、高剂量分别为低剂量的2、4倍。
取大鼠称重，20％乌拉坦5ml/kg ip麻醉，接心电，张力换能器，分离颈总动脉，插管接压力换能器，分别记录心电、呼吸、血压。舌下静脉给药，记录上述指标的变化30分钟。
实验结果
表3注射用高浓型水溶性维生素对心血管系统的影响
1.血压(mmHg)
2.心率(次/分)
3.QRS波(mv)
4.ST波(mv)
5.T波
表4.注射用高浓型水溶性维生素对呼吸系统的影响
1.频率(次/分)
2.深度(g)
结论
高剂量对大鼠对大鼠一般药理无影响，提示注射用本发明的高浓型水溶性维生素应用于临床安全、合理、有效。
注射用高浓型水溶性维生素过敏性、溶血性、血管刺激性试验
按照《药品注册管理办法》(试行)要求，对其进行了全身用药的安全性试验研究，试验结果如下：以10％葡萄糖500ml溶解，以0.5ml/次/只ip致敏三次，1ml/只iv攻击豚鼠来考察其全身过敏反应，结果表明，本发明注射用水溶性维生素不能诱发豚鼠的明显过敏反应。按常规溶血试验方法观察注射用水溶性维生素对红细胞的影响，结果显示注射用水溶性维生素在4小时内无明显溶血作用，也无红细胞凝集现象。水溶性维生素以10ml/kg的剂量给家兔耳缘静脉连续3天静脉注射给药，停药后24小时肉眼观察注射局部情况，并取材进行病理组织学检查。结果显示对照组和给药组自注射点后血管内血栓形成、出血和炎性细胞渗出均无明显差异。镜下见水溶性维生素组与10％葡萄糖注射液组形态相同，兔耳静脉结构完整，无血管内皮细胞肿胀、变性、坏死，静脉壁及其周围组织无炎性细胞浸润，管腔内无血栓形成。
试验结果表明：本发明注射用水溶性维生素不会引起过敏和溶血反应，也没有血管刺激性，临床可用于静脉注射给药。
Claims (8)
1.一种静脉注射用高浓型水溶性维生素，其特征在于：每瓶含有硝酸硫胺6.2±1.6mg、核黄素磷酸钠9.8±2.5mg、烟酰胺80±20mg、盐酸吡哆辛9.8±2.5mg、泛酸钠33.0±8.3mg、维生素C 200±50mg、生物素120±30ug、叶酸0.8±0.2mg、维生素B12 10.0±2.5ug。
2.根据权利要求1所述的维生素，其特征在于：每瓶含有硝酸硫胺6.2mg、核黄素磷酸钠9.8mg、烟酰胺80mg、盐酸吡哆辛9.8mg、泛酸钠33.0mg、维生素C 200mg、生物素120ug、叶酸0.8mg、维生素B12 10.0ug。
3.根据权利要求1或2所述的维生素，其特征在于：含有0～0.8mg防腐剂、0.3～0.8mg络合剂、0～600mg赋型剂。
4.根据权利要求3所述的维生素，其特征在于：防腐剂为对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯或山梨醇；络合剂为乙二胺四醋酸二钠、环己二胺四醋酸钠、N-羟基二乙胺三醋酸或二乙基三胺六醋酸；赋型剂为甘氨酸、甘露醇、乳糖或水解明胶。
5.根据权利要求1或2所述的维生素，其特征在于：含有0～0.8mg对羟基苯甲酸甲酯、0.3～0.6mg乙二胺四醋酸二钠、0～600mg甘氨酸。
6.权利要求1所述的静脉注射用高浓型水溶性维生素的制备方法，其特征在于：将硝酸硫胺、核黄素磷酸钠、烟酰胺、盐酸吡哆辛、泛酸钠、维生素C、生物素、叶酸和维生素用注射用水溶解配制成水溶液，微孔过滤后装于容器中于冷冻干燥机内冻干，压盖制得静脉用水溶性维生素。
7.根据权利要求6所述的制备方法，其特征在于：在配制的水溶液中加入防腐剂、络合剂和赋型剂，然后微孔过滤后装于容器中于冷冻干燥机内冻干，压盖制得静脉用水溶性维生素。
8.如权利要求1所述的静脉用水溶性维生素在制备因疾病所致的严重水溶性维生素缺乏时补充维生素的药物中的应用，用量为每天静脉滴注1～2次，每次一瓶。
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| CN101259278B (zh) * | 2008-04-21 | 2010-06-02 | 黄芝芳 | 一种含抑菌剂的多种水溶性维生素的药物组合物及其制备方法 |
| CN101961342B (zh) * | 2010-08-19 | 2011-12-07 | 海南良方医药有限公司 | 一种注射用水溶性维生素组合物及其制备方法 |
| CN102552294B (zh) * | 2012-01-10 | 2014-03-12 | 辽宁海思科制药有限公司 | 一种注射用复方维生素冻干粉针剂组合物 |
| CN104922142A (zh) * | 2015-05-13 | 2015-09-23 | 邓学峰 | 一种水溶性维生素的药物组合物及其应用 |
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