CN1377689A - 一种治疗心脑血管和眼底病的中药针剂及其制备方法 - Google Patents

一种治疗心脑血管和眼底病的中药针剂及其制备方法 Download PDF

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CN1377689A
CN1377689A CN02109532A CN02109532A CN1377689A CN 1377689 A CN1377689 A CN 1377689A CN 02109532 A CN02109532 A CN 02109532A CN 02109532 A CN02109532 A CN 02109532A CN 1377689 A CN1377689 A CN 1377689A
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瓮林祥
刘丹
孙红卫
张瑞香
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Wang Maoxiang
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Abstract

本发明公开了一种治疗心脑血管病和眼底病的中药针剂及其制备方法,针剂为碟脉灵冻干粉针剂,冻干粉针剂中黄酮与腺苷的含量比为5mg:15ug或5mg:30ug;取洁净的苦碟子加水煎煮经粗滤,微滤,浓缩至每1ml相当于原生药0.5g;加入氧化钙乳、过滤、将沉淀物悬浮于乙醇中,加入硫酸溶液过滤;将滤液中加入氢氧化钠溶液过滤,加注射用水制成每1ml相当原生药4g;置于－8℃以下冷藏过滤;加活性炭煮沸,再于－5℃下放置过滤,灌封,灭菌,再加入稳定剂、或再加入支持剂,得无热源澄明溶液,干燥制成冻干粉针剂;克服了碟脉灵注射液水针剂存在的质量不稳定腺苷及黄酮易损失的缺点,实现了产品质量稳定易于控制,保证了用药的安全有效、利于产品储存。

Description

一种治疗心脑血管和眼底病的中药针剂及其制备方法
技术领域：
本发明涉及一种中药针剂及其制备方法，更具体地说是涉及一种碟脉灵冻干粉针剂及其制备方法，适合于治疗心脑血管病和眼底病。
背景技术：
目前，治疗心脑血管病和眼底病的中药针剂有碟脉灵注射剂，临床所用碟脉灵注射剂为棕黄色澄明液体，来源于菊科植物苦碟子(抱茎苦荬菜Ixeris Sonchifolia Hance)，以全草为原料提取制成静脉注射液，其主要的药用成分为黄酮和腺苷。由于苦碟子中所含的植物腺苷与黄酮共存，所以对于心脑血管疾病的治疗具有非常显著的互补性，并通过药效学和临床得到证实。碟脉灵注射剂的药理作用是：1.增加冠脉流量、降低心脏血管阻力、抗心肌梗塞、增加侧枝循环、降低心肌耗氧、改善心脏微循环，应用于冠心病、心绞痛、胸闷气短、心肌梗塞治疗。2.降低血小板聚集功能、增加纤维蛋白溶解酶活性、抑制血栓形成、降低血浆血清粘度、增加红细胞电泳速度、降低脑血管阻力、增加脑血容量、促进神经功能恢复，应用于脑梗塞(脑血栓形成)治疗。3.改善细菌所致微循环障碍、改善高分子右旋糖酐所致全身微循环障碍、改善眼底微循环、扩张眼底动脉血管，应用于治疗眼底病，如中心视网膜炎、视神经萎缩、视网膜色素变性等病的治疗。但是，碟脉灵注射剂稳定性能差、储存时间短，用高效液相色谱法和衍生化法测定腺苷和黄酮的含量，在水针剂完成前和完成后腺苷由15.0ug/ml降为6.7ug/ml，黄酮由0.25mg/ml降为0.169mg/ml，分别损失投药量的55.3％和32.4％，6个月后腺苷为6.5ug/ml，黄酮0.133mg/ml；还可以通过取黄酮和腺苷含量分别为5.07mg/ml、24.37ug/ml的碟脉灵注射液置于80℃烘箱中进行加速破坏10天检验，然后再测定黄酮和腺苷含量，这时，则黄酮和腺苷含量只剩下3.16mg/ml、12.18ug/ml(表1)，由于黄酮与腺苷两种有效成份在生产和存储中的大量损失，严重影响了药品的治疗效果。同时，碟脉灵注射液溶液的色泽变化明显，由原料提取物配制成水针剂的过程中用紫外分光光度计在400nm处测试吸收度，其值由灭菌前的0.338变为灭菌后的0.423，放置6个月变为0.443，色泽加深；还有制剂的高效液相图谱相似度差，相同原料所制的提取物配制的不同批号的水针剂，其高效液相图谱存在较大差异。随机抽样市售同类水针剂的稳定性情况(批号20000303，20000503，20010120)黄酮含量分别为0.27mg/ml、0.51mg/ml、0.30mg/ml，腺苷含量1.11ug/ml、0.147ug/ml、0.00ug/ml；综上所述，碟脉灵水针剂易受制作、储存等诸多因素的影响，很难控制水针剂的产品质量，大大影响了碟脉灵注射剂的治疗效果。
发明内容：
本发明的目的是提供一种治疗心脑血管和眼底病的中药针剂及其制备方法，它不仅能克服碟脉灵注射液水针剂存在的不足，而且产品质量稳定易于控制、腺苷及黄酮的成份不易损失、保证了临床用药的安全、有效，有利于产品储存。
本发明的目的是这样实现的，一种治疗心脑血管病和眼底病的中药针剂，其特征在于针剂为碟脉灵冻干粉针剂，冻干粉针剂中黄酮与腺苷的含量比为5mg∶15ug或5mg∶30ug。
本发明中药针剂的制备方法是：取洁净的苦碟子加25～30倍量水煎煮3小时，粗滤，微滤，浓缩至每1ml相当于原生药0.5g；将浓缩的煎煮液冷却至40℃以下，在搅拌下加入10％的氧化钙乳调pH10～11，过滤，沉淀物称重；将上述沉淀物悬浮于5.3倍乙醇中，加入浓度为25％的硫酸溶液调pH3～4，再充分搅拌过滤；将滤液中加入40％氢氧化钠溶液，调pH至7～7.5，过滤，从滤液中回收乙醇并挥尽乙醇，加注射用水制成每1ml相当原生药4g；置于-8℃以下冷藏12小时，过滤；加0.1～0.2％活性炭煮沸15分钟，再于-5℃下放置24小时以上，过滤，调pH7.0～7.5，再用纸板、垂熔漏斗、微孔滤膜(孔径0.45um)过滤，灌封，灭菌(115℃30分钟)，制成提取物；取上述提取物加入稳定剂、或再加入支持剂，搅拌使之完全溶解，再加入针用活性炭处理，过滤，得无热源澄明溶液，分装于西林瓶或安瓿中，于-40～-60℃预冻1~3小时，随后抽真空(真空度为1~20pa)，升温干燥，最终温度为25~40℃、干燥20~40小时，即可制成碟脉灵冻干粉针剂制品。
本发明的优点是，由于将含有黄酮和腺苷的苦碟子中草药制成了碟脉灵冻干粉针剂，不仅克服了上述碟脉灵注射液水针剂存在的产品质量不稳定、腺苷及黄酮易损失的缺点，而且实现了产品质量易于控制，腺苷及黄酮成份不易损失，保证了临床用药的安全、有效，有利于产品储存。
具体实施方式：
实施例一：
取洁净的苦碟子(抱茎苦荬菜)1kg置入煎煮锅内，加25～30倍量水煎煮3小时，粗滤，微滤，置于浓缩罐中进行浓缩处理至每1ml相当于原生药0.5g；将浓缩液放冷至39℃，搅拌、加含量为10％的氧化钙乳调pH至10，过滤，取沉淀物称重，再放入沉淀物重量的5.3倍的乙醇中悬浮，再加入浓度为25％硫酸溶液调节pH至3；充分搅拌过滤，再向滤液中加入含量为40％氢氧化钠溶液，调pH至7，过滤，滤液回收乙醇并挥尽乙醇，加注射用水使每1ml相当原生药4g，置-9℃冷藏12小时，过滤，加0.1％活性炭煮沸15分钟，再于-5℃下放置24小时，过滤，调pH至7，再用纸板、垂熔漏斗、微孔滤膜(孔径0.45um)过滤，灌封，灭菌(115℃30分钟)，制成提取物；取上述提取物加入0.05％的乙二胺四乙酸二钠或柠檬酸钠稳定剂，搅拌使之完全溶解，再加入0.1％针用活性炭处理，过滤，得无热源澄明溶液，分装于西林瓶或安瓿中，每支2ml，于-40℃预冻3小时，随后抽真空(真空度为15pa)，升温干燥，最终温度为25℃、干燥20小时，即可制成碟脉灵冻干粉针剂制品。
实施例二：
取洁净的苦碟子(抱茎苦荬菜)1kg置入煎煮锅内，加25～30倍量水煎煮3小时，粗滤，微滤，置于浓缩罐中进行浓缩处理至每1ml相当于原生药0.5g；将浓缩液放冷至35℃，搅拌、加含量为10％的氧化钙乳调至pH10，过滤，将沉淀物称重，再放入沉淀物重量的5.3倍的乙醇中悬浮，再加入浓度为25％硫酸溶液调节至pH3.5；充分搅拌过滤，再向滤液中加入含量为40％氢氧化钠溶液，调pH至7.3，过滤，滤液回收乙醇并挥尽乙醇，加注射用水使成每1ml相当原生药4g，置-10℃冷藏12小时，过滤，加0.12％活性炭煮沸15分钟，再于-5℃下放置25小时，过滤，调pH至7.2，再用纸板、垂熔漏斗、微孔滤膜(孔径0.45um)过滤，灌封，灭菌(115℃30分钟)，制成提取物；取上述提取物加入0.1％的亚硫酸氢钠或焦亚硫酸钠稳定剂或其混合物、3％的甘露醇支持剂，搅拌使之完全溶解，再加入0.05％针用活性炭处理，过滤，得无热源澄明溶液，分装于西林瓶或安瓿中，每支3ml，于-45℃预冻2.5小时，随后抽真空(真空度为18pa)，升温干燥，最终温度为30℃、干燥30小时，即可制成碟脉灵冻干粉针剂制品。
实施例三：
取洁净的苦碟子(抱茎苦荬菜)1kg置入煎煮锅内，加25～30倍量水煎煮3小时，粗滤，微滤，置于浓缩罐中进行浓缩处理至每1ml相当于原生药0.5g；将浓缩液放冷至20℃，搅拌、加含量为10％的氧化钙乳调pH至10.5，放置12小时，滤出沉淀物，将沉淀物称重，再放入沉淀物重量的5.3倍的乙醇中悬浮，再加入浓度为25％硫酸溶液调节pH至4；充分搅拌过滤，再向滤液中加入含量为40％氢氧化钠溶液，调pH至7，过滤，滤液回收乙醇并挥尽乙醇，加注射用水使成每1ml相当原生药4g，置-11℃冷藏12小时，过滤，加0.15％活性炭煮沸15分钟，再于-5℃下放置24小时，过滤，调pH至7.4，再用纸板、垂熔漏斗、微孔滤膜(孔径0.45um)过滤，灌封，灭菌(115℃30分钟)，制成提取物；取上述提取物加入0.05％的稳定剂亚硫酸钠或维生素C或其混合物、或充氮气，再加入3％的右旋糖苷支持剂，搅拌使之完全溶解，加0.05％针用活性炭处理，过滤，得无热源澄明溶液，分装于西林瓶或安瓿中，每支1ml，于-50℃预冻2小时，随后抽真空(真空度为10pa)，升温干燥，最终温度为35℃干燥25小时，即可制成碟脉灵冻干粉针剂制品。
实施例四：
取洁净的苦碟子(抱茎苦荬菜)1kg置入煎煮锅内，加25～30倍量水煎煮3小时，粗滤，微滤，置于浓缩罐中进行浓缩处理至每1ml相当于原生药0.5g；将浓缩液放冷至10℃，搅拌、加含量为10％的氧化钙乳调pH至11，过滤，将沉淀物称重，放入沉淀物重量的5.3倍的乙醇中悬浮，加入浓度为25％硫酸溶液调节pH至3；充分搅拌过滤，再向滤液中加入含量为40％氢氧化钠溶液，调pH至7，过滤，滤液回收乙醇并挥尽乙醇，加注射用水使成每1ml相当原生药4g，置-12℃冷藏12小时，过滤，加0.2％活性炭煮沸15分钟，再于-5℃下放置24小时，过滤，调pH7.5，再用纸板，垂熔漏斗，微孔滤膜(孔径0.45um)过滤，灌封，灭菌(115℃30分钟)，制成提取物；取上述提取物加入0.02％硫代硫酸钠稳定剂和加入支持剂5％的乳糖或葡萄糖或其混合物，搅拌使之完全溶解，加0.01％针用活性炭处理，过滤，得无热源澄明溶液，分装于西林瓶或安瓿中，每支4ml或5ml，于-60℃预冻1小时，随后抽真空(真空度为20pa)，升温干燥，最终温度为40℃干燥40小时，即可制成碟脉灵冻干粉针剂制品。
表1是冻干粉针剂与注射液内的黄酮和腺苷含量对高热的稳定性试验对照表：
 序号     剂型  黄酮(试验前)(mg/ml)  黄酮(试验后)(mg/ml)  腺苷(试验前)(ug/ml)  腺苷(试验后)(ug/ml)     外观
  1 冻干粉针      5.07      5.03      24.37      23.88 加水溶解后呈黄棕色
  2   注射液      5.07      3.16      24.37      12.18 呈深棕黄色
取碟脉灵冻干粉针剂配制成黄酮和腺苷含量分别为5.07mg/ml、24.37ug/ml的碟脉灵冻干粉针剂注射液，置于80℃烘箱中进行加速破坏10天试验，然后再测定黄酮和腺苷含量，这时，则黄酮和腺苷含量分别为5.03mg/ml、23.88ug/ml，黄酮与腺苷的含量几乎未发生改变。而注射液却降至原含量的62.33％和49.99％。
临床使用时，根据患者病情的要求，可取不同规格的碟脉灵冻干粉针剂加入注射用水溶解，然后加入250ml氯化钠注射液或葡萄糖注射液中，进行静脉点滴。

Claims (6)

1、一种治疗心脑血管病和眼底病的中药针剂，其特征在于针剂为碟脉灵冻干粉针剂，冻干粉针剂中黄酮与腺苷的含量比为5mg∶15ug或5mg∶30ug。
2、一种权利要求1中药针剂的制备方法，其特征是：取洁净的苦碟子加25～30倍量水煎煮3小时，粗滤，微滤，滤液浓缩至每1ml相当于原生药0.5g；将浓缩的煎煮液冷却至40℃以下，在搅拌下加入10％的氧化钙乳调pH10～11，过滤，沉淀物称重；将沉淀物悬浮于5.3倍乙醇中，加入浓度为25％的硫酸溶液调pH3～4，再充分搅拌过滤；将滤液中加入40％氢氧化钠溶液，调pH至7～7.5，过滤，从滤液中回收乙醇并挥尽乙醇，加注射用水制成每1ml相当原生药4g；置于-8℃以下冷藏12小时，过滤；加0.1～0.2％活性炭煮沸15分钟，再于-5℃下放置24小时以上，过滤，调pH7.0～7.5再用纸板、垂熔漏斗、微孔滤膜(孔径0.45um)过滤，灌封，灭菌(115℃30分钟)，制成提取物；取上述提取物加入稳定剂、或再加入支持剂，搅拌使之完全溶解，再加入针用活性炭处理，过滤，得无热源澄明溶液，分装于西林瓶或安瓿中，于-40～-60℃预冻1~3小时，随后抽真空(真空度为1~20pa)，升温干燥，最终温度为25~40℃、干燥20~40小时，即可制成碟脉灵冻干粉针剂制品。
3、根据权利要求2所述的制备方法，其特征在于所说的稳定剂是乙二胺四乙酸二钠、柠檬酸(钠)、亚硫酸氢钠、亚硫酸钠、焦亚硫酸钠、硫代硫酸钠、维生素C或氮气。
4、根据权力要求2所述的制备工艺，其特征在于所说的支持剂是甘露醇、右旋糖苷、乳糖或葡萄糖。
5、根据权利要求2或3所述的制备方法，其特征在于加入的稳定剂为一种或两种以上的混合物。
6、根据权利要求2或4所述的制备方法，其特征在于加入的支持剂为一种、或两种以上的混合物。
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US10/511,902 US7163704B2 (en) 2002-04-23 2003-04-21 Injection made from Ixeris Sonchifolia Hance for treatment of cardio-cerebral vascular diseases and fundus diseases and method of producing thereof
JP2003587400A JP4521192B2 (ja) 2002-04-23 2003-04-21 心・脳血管病および眼底病の治療のための漢方薬注射剤ならびにその製造方法
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