CN112386571A - 一种稳定的丁苯酞氯化钠注射液、其制备方法及用途 - Google Patents
一种稳定的丁苯酞氯化钠注射液、其制备方法及用途 Download PDFInfo
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- CN112386571A CN112386571A CN202011398099.7A CN202011398099A CN112386571A CN 112386571 A CN112386571 A CN 112386571A CN 202011398099 A CN202011398099 A CN 202011398099A CN 112386571 A CN112386571 A CN 112386571A
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- Prior art keywords
- butylphthalide
- sodium chloride
- sodium
- chloride injection
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- IJWOSBPNNYDGPE-UHFFFAOYSA-M sodium 3-butyl-3H-2-benzofuran-1-one chloride Chemical compound [Na+].[Cl-].C1=CC=C2C(CCCC)OC(=O)C2=C1 IJWOSBPNNYDGPE-UHFFFAOYSA-M 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 claims abstract description 177
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Abstract
本发明公开了一种稳定的丁苯酞氯化钠注射液、其制备方法及用途,属于药物制剂技术领域,解决了现有技术中丁苯酞氯化钠注射液安全性和稳定性不好的问题。本发明的一种稳定的丁苯酞氯化钠注射液,包括丁苯酞‑磺丁基倍他环糊精钠包合物、氯化钠和水,所述丁苯酞氯化钠注射液的pH值为4.0~5.0。本发明的制备方法包括:称取处方量的磺丁基倍他环糊精钠、氯化钠,加水溶解,制得辅料溶液;称取处方量的丁苯酞加入辅料溶液中,搅拌,使磺丁基倍他环糊精钠包合丁苯酞,丁苯酞包合完毕后,调节溶液pH值至4.0~5.0;过滤、灌装、灭菌,即得。本发明设计科学,思路巧妙,本发明的丁苯酞氯化钠注射液具有良好的稳定性和安全性。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种治疗脑卒中的药物制剂,更具体涉及一种稳定的丁苯酞氯化钠注射液、其制备方法及用途。
背景技术
丁苯酞:(3-n-butylphthalide,简称NBP),全名3-丁基-1(H)-异苯并呋喃酮,又名芹菜甲素,是从芹菜籽中提取出而得,也可人工合成。丁苯酞是一种油状液体,不溶于水,具有浓烈的芹菜味,分子中含有一个手性碳原子,因此它存在两种光学异构体,即左旋丁苯酞和右旋丁苯酞。丁苯酞可缩小局灶性脑缺血后的梗死灶,增加缺血区脑血流量和改善脑缺血区微循环,保护线粒体功能,减轻神经功能损伤的程度,改善全脑缺血后脑的能量代谢等,作用于脑缺血病理的多个环节。
化学结构式:
中国专利200410012533.8公开了一种丁苯酞冻干粉针剂,由丁苯酞、乳化剂和助乳化剂、赋形剂和注射用水组成。中国专利200510102355.2公开了一种丁苯酞静脉乳剂,由丁苯酞、油、乳化剂、等渗剂、注射用水组成,用二步乳化分散法进行乳化制得。该两种剂型增加了丁苯酞的溶解度,同时增加了丁苯酞脑组织的靶向性,降低了其毒副作用。但其制备工艺较为复杂,并且属于非热稳定体系,可能会发生破乳现象,影响产品质量。
中国专利201210214131.0公开了一种丁苯酞注射液及其制备方法,由丁苯酞或其衍生物、表面活性剂及注射用水组成。可分装成小体积的制剂,该制剂为小容量注射液,既可用于静脉注射又可用于肌肉注射。该剂型用于静脉注射时,需与葡萄糖注射液或氯化钠注射液进行配伍,临床应用稀释时较难操作,临床应用困难且制备过程中使用活性炭,对产品质量有一定影响。
目前,丁苯酞已上市产品有胶囊剂和注射剂。注射剂采用羟丙基环倍他糊精包合技术。羟丙基环倍他糊精用量极大,注射液中有超过原料将近30倍左右的羟丙基-β-环糊精;并且由于羟丙基环倍他环糊精通过肾小球滤过清除,对患者的肌酐清除率有一定的限制(肌酐清除率<30ml/min的患者慎用)。因此,上市产品丁苯酞注射剂仍不能很好的满足临床用药的需求。
磺丁基倍他环糊精钠具有羟丙倍他环糊精无可比拟的优点:良好的水溶性,血浆蛋白结合率低,体内无缔合,可快速以原型清除;溶血作用减小,肾毒性很低,对粘膜的刺激性也小。磺丁基倍他环糊精钠应用于注射给药,主要是能够提高药物溶解度,使药物在注射时快速达到所需药量,降低注射对给药部位的刺激性,提高溶液状态下药物的稳定性,缓和溶血作用,提高用药安全性。磺丁基倍他环糊精钠水溶性比羟丙基-β-环糊精更强、肾脏毒性更小、注射用更安全的药用辅料。将丁苯酞包裹于磺丁基倍他环糊精钠中,可有效提高丁苯酞溶解度,更好改善注射剂的安全性。
修宪等人于医药导报2018年6月第37卷第6期中报道了一种丁苯酞—磺丁基醚-β-环糊精包合物的制备工艺:包合温度67℃、时间2.09h、磺丁基醚-β-环糊精与丁苯酞投料比2.6:1,丁苯酞的包合率预测值与实际值的偏差为2.4%。但未对氯化钠注射液的pH、有关物质、磺丁基醚-β-环糊精钠的取代度等进行系统的研究,不能满足临床用药的安全性要求。
综上所述,现有技术公开的丁苯酞制剂工艺较为复杂,或者临床应用不方便,且注射剂制剂过程使用活性炭,不能完全减少了患者对活性炭的不适应性,质量不完全稳定,或采用羟丙基-β-环糊精增加了肾毒性风险,或注射液制备过程中pH值也未进行很好的控制,也未对pH、有关物质、磺丁基醚-β-环糊精钠的取代度等进行系统的研究,不能很好的满足临床应用本品的需求。
发明内容
本发明的目的之一在于,提供一种稳定的丁苯酞氯化钠注射液,其稳定性好,安全性高。
本发明的目的之二在于,提供该稳定的丁苯酞氯化钠注射液的制备方法。
本发明的目的之三在于,提供该稳定的丁苯酞氯化钠注射液的用途。
为实现上述目的,本发明采用的技术方案如下:
本发明所述的一种稳定的丁苯酞氯化钠注射液,包括丁苯酞-磺丁基倍他环糊精钠包合物、氯化钠和水,所述丁苯酞氯化钠注射液的pH值为4.0~5.0。
本发明创造性地在丁苯酞氯化钠注射液中采用磺丁基倍他环糊精钠包合丁苯酞。磺丁基倍他环糊精钠具有羟丙倍他环糊精无可比拟的优点:良好的水溶性,血浆蛋白结合率低,体内无缔合,可快速以原型清除;溶血作用减小,肾毒性很低,对粘膜的刺激性也小。将丁苯酞包裹于磺丁基倍他环糊精钠中,可有效提高丁苯酞溶解度,更好改善注射剂的安全性。
作为本发明的部分实施方案,所述丁苯酞-磺丁基倍他环糊精钠包合物由磺丁基倍他环糊精钠对丁苯酞包合形成;
优选地,丁苯酞与磺丁基倍他环糊精钠的摩尔比为1:1.60~2.20,更优选为1:1.77;
优选地,所述磺丁基倍他环糊精钠的取代度为6.2~6.9。
磺丁基倍他环糊精钠的溶血作用明显依赖取代度,随取代度增加,溶血作用减少。本发明创造性地在注射液制剂处方中限定了磺丁基倍他环糊精钠的取代度,有效地保证药品安全性。本发明另外通过创造性的劳动发现,磺丁基醚-β-环糊精钠的用量与丁苯酞氯化钠注射液的稳定性密切相关,当丁苯酞与磺丁基倍他环糊精钠的摩尔比为1:1.60~2.20时,制备所得丁苯酞氯化钠注射液具有良好的稳定性。
作为本发明的部分实施方案,每100mL所述丁苯酞氯化钠注射液中,丁苯酞的含量为25mg;
作为本发明的部分实施方案,每100mL所述丁苯酞氯化钠注射液中,氯化钠的含量为0.9g。
作为本发明的部分实施方案,所述丁苯酞氯化钠注射液的pH值为4.5。
本发明意外地发现,丁苯酞氯化钠注射液的pH值与丁苯酞的稳定性有很大关系,丁苯酞氯化钠注射液的pH值为4.0~5.0时,优选为4.5时,丁苯酞氯化钠注射液具有良好的稳定性。
本发明所述的一种稳定的丁苯酞氯化钠注射液的制备方法,包括以下步骤:
步骤1.制备辅料溶液:称取处方量的磺丁基倍他环糊精钠、氯化钠,加水溶解,制得辅料溶液;
步骤2.配液包合:称取处方量的丁苯酞加入步骤1制得的辅料溶液中,搅拌,使磺丁基倍他环糊精钠包合丁苯酞,丁苯酞包合完毕后,调节溶液pH值至4.0~5.0;
步骤3.将步骤2中调节pH值后的溶液过滤、灌装、灭菌,即得。
作为本发明的部分实施方案,所述步骤2中,磺丁基倍他环糊精钠包合丁苯酞时溶液的温度保持为60~80℃,优选为80℃。
作为本发明的部分实施方案,所述步骤2中,磺丁基倍他环糊精钠包合丁苯酞的时间为60~90min,优选90min。
本发明意外地发现,步骤2中,磺丁基倍他环糊精钠包合丁苯酞时的温度及时间与丁苯酞氯化钠注射液的稳定性直接相关。本发明付出了创造性的劳动后发现,包合温度为60~80℃,包合时间为60~90min,制备所得丁苯酞氯化钠注射液具有良好的稳定性。
作为本发明的部分实施方案,所述步骤2中,丁苯酞加入步骤1制得的辅料溶液中,搅拌至完全溶解后,放冷至室温,补充水至规定量,调节pH值。
优选地,加药学上可接受的酸溶液调节pH值。所述药学上可接受的酸为无机酸或有机酸,其中所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸、硼酸、磷酸及其任意组合;所述有机酸选自甲酸、醋酸、乙酸酐、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、苹果酸、枸橼酸、酒石酸、偏酒石酸、抗坏血酸、没食子酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、植酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、1,5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸及其任意组合;优选地,所述药学上可接受的酸为盐酸、硫酸、磷酸、醋酸、乳酸、苹果酸、酒石酸、富马酸。
本发明所述的丁苯酞氯化钠注射液在制备用作预防和治疗脑卒中的药物中的用途。
与现有技术相比,本发明具有以下有益效果:
本发明设计科学,思路巧妙,本发明的丁苯酞氯化钠注射液具有良好的稳定性和安全性。
本发明将羟丙基环倍他环糊精替换为磺丁基醚倍他环糊精钠,在增加丁苯酞溶解度的同时,还降低了辅料用量、以及辅料引起的肾毒性潜力。
本发明意外地发现,注射液pH值与其稳定性密切相关。pH值为4.0~5.0的注射液其在高温灭菌前后有关物质的含量无显著性变化,稳定性良好;而pH值为5.5~7.5的注射液在高温灭菌后有关物质显著增加。
此外,本发明的注射液辅料用量少,包合率高,包合时间短,为80-90min(文献报道为2.09h)。本发明所制备的丁苯酞氯化钠注射液在储存后性状不发生改变,无油滴析出。
附图说明
图1为pH4.0丁苯酞氯化钠注射液在121℃,15min灭菌前、后的杂质检测色谱图;其中A图为灭菌前杂质检测色谱图,B图为灭菌后杂质检测色谱图;
图2为pH4.5丁苯酞氯化钠注射液在121℃,15min灭菌前、后的杂质检测色谱图;其中A图为灭菌前杂质检测色谱图,B图为灭菌后杂质检测色谱图;
图3为pH5.0丁苯酞氯化钠注射液在121℃,15min灭菌前、后的杂质检测色谱图;其中A图为灭菌前杂质检测色谱图,B图为灭菌后杂质检测色谱图;
图4为pH5.5丁苯酞氯化钠注射液在121℃,15min灭菌前、后的杂质检测色谱图;其中A图为灭菌前杂质检测色谱图,B图为灭菌后杂质检测色谱图;
图5为pH6.5丁苯酞氯化钠注射液在121℃,15min灭菌前、后的杂质检测色谱图;其中A图为灭菌前杂质检测色谱图,B图为灭菌后杂质检测色谱图;
图6为pH7.5丁苯酞氯化钠注射液在121℃,15min灭菌前、后的杂质检测色谱图;其中A图为灭菌前杂质检测色谱图,B图为灭菌后杂质检测色谱图。
具体实施方式
下面结合具体实施例对本发明的具体实施方案做进一步说明,但不应理解为本发明的范围仅限于以下的实例,根据本发明的发明思路和全文内容,可以将以下实例中的各个技术特征做适当的组合/替换/调整/修改等,这对于本领域技术人员而言是显而易见的,仍属于本发明保护的范畴。若无特别说明,本发明中所采用的各组分均可通过市场购买得到。
实施例1
本实施例公开了本发明的丁苯酞氯化钠注射液的制备方法。其制剂处方(处方量100支)为:
制备方法:取处方量纯化水,煮沸后冷却至80℃。称取磺丁基倍他环糊精钠(取代度6.2~6.9,平均取代度6.4,分子量2145.2g/mol)80g,氯化钠90g,加入8L 80℃纯化水中,搅拌使完全溶解。称取丁苯酞2.5g,加入磺丁基倍他环糊精钠溶液中,油浴80℃搅拌90min使完全溶解。放冷至室温,加0.2M盐酸溶液调pH值至4.5,补充纯化水至10L。用循环水式多用真空泵经0.45μm滤膜滤过。将配好的溶液按100ml/支灌装。灌装后于121℃下,高温灭菌15分钟,得到实施例样品。
实施例2
本实施例公开了磺丁基倍他环糊精钠用量对丁苯酞的增溶能力考察,具体为:
按照实施例1的方法制备丁苯酞氯化钠注射液,区别仅在于磺丁基倍他环糊精钠的用量不同。然后考察制得的各丁苯酞氯化钠注射液的性状及注射液中丁苯酞含量。结果如表1所示:
表1,不同用量的磺丁基倍他环糊精钠的增溶能力比较结果表
由上表可知:磺丁基倍他环糊精钠:丁苯酞摩尔比大于2.8(编号1和4)时,充分搅拌后,丁苯酞可以完全溶解;当摩尔比降低到1.5时,剩余少量丁苯酞油状液滴;当摩尔比降低到0.44时,剩余大量丁苯酞油状液滴,说明编号3中磺丁基倍他环糊精钠用量为0.44摩尔的丁苯酞用量时,其增溶能力严重不足。取编号1、2、4样品检测丁苯酞含量,分别为101.3%、94.8%、104.4%,也进一步印证了前面的结果。
磺丁基倍他环糊精钠:丁苯酞摩尔≤1.51未能完全溶解,有少量液滴,含量为94.8%,可见磺丁基倍他环糊精钠:丁苯酞摩尔为1.51为临界值。
进一步地,对磺丁基倍他环糊精钠的用量进行考察,具体用量及结果如表2所示。
表2,进一步不同比例的磺丁基倍他环糊精钠的增溶能力比较
由表2可知,编号5-8中,经充分搅拌后丁苯酞均能完全溶解。说明当磺丁基倍他环糊精钠:丁苯酞摩尔比达到1.60,丁苯酞能完全溶解,考虑到药用的要求,特殊增溶性辅料越少越好,磺丁基倍他环糊精钠:丁苯酞摩尔比为1.60~2.22之间为最佳比例,考虑到大生产要求,优选1.77。
实施例3
本实施例考察了pH值对丁苯酞氯化钠注射液稳定性影响。
按照实施例1的方法制备丁苯酞氯化钠注射液,区别仅在于调节的丁苯酞氯化钠注射液的pH值不同,制备的各丁苯酞氯化钠注射液具体的pH值如表3所示。并对灌装灭菌前后的注射液中的杂质含量进行了考察,考察结果如表3所示。
表3,不同pH对实施例处方稳定性影响
由表3可知,pH值为4.0~5.0的丁苯酞氯化钠注射液在121℃,15min条件灭菌后,杂质含量无显著变化,最大未知单杂来源于原料药,说明丁苯酞氯化钠注射液在pH值4.0~5.0范围内稳定性良好,如附图1-3所示。。
如附图4-6所示,pH值大于5.0的丁苯酞氯化钠注射液在灭菌前后的最大单杂含量变化较大。灭菌前,pH值5.0~7.5的丁苯酞氯化钠注射液中最大单杂的相对保留时间为0.262,相对保留时间0.325(出峰时间5.878左右)处并没有检测到有关物质。灭菌后,pH值5.0~7.5的丁苯酞氯化钠注射液中最大单杂的相对保留时间相对保留时间0.325(出峰时间5.878左右),说明灭菌后在相对保留时间0.325(出峰时间5.878左右)处出现了新的单杂。经结构分析为,pH值5.0~7.5的丁苯酞氯化钠注射液中丁苯酞会开环,从而引入新的杂质。
上述结果说明,pH值为4.0~5.0的丁苯酞氯化钠注射液灭菌后稳定性好,考虑到注射液的酸性,优选PH值为4.5。
实施例4
本实施例考察了不同包合温度及时间对丁苯酞溶解情况的影响。
按照实施例1的方法制备丁苯酞氯化钠注射液,区别仅在于包合温度及时间(即实施例1所述的油浴温度和搅拌时间)不同。具体的如表4所示。然后考察制得的各丁苯酞氯化钠注射液的性状及注射液中丁苯酞含量。结果如表4所示:
表4,包合温度及时间考察结果表
由上表可知,包合条件为60℃搅拌90min时,丁苯酞未完全溶解;60℃搅拌120min丁苯酞才能完全溶解。包合条件为80℃搅拌90min,丁苯酞完全溶解。考虑到大生产和药用要求,优选80℃搅拌90min。
对比例1
本对比例公开了采用羟丙基倍他环糊精包合丁苯酞,制备丁苯酞氯化钠注射液。其制剂处方(处方量100支)为:
制备方法:取处方量纯化水,煮沸后冷却至80℃。称取羟丙基倍他环糊精50g,氯化钠90g,加入8L 80℃纯化水中,搅拌使完全溶解。称取丁苯酞2.5g,加入羟丙基倍他环糊精溶液中,搅拌时间达120min未溶解。放冷至室温,加0.2M盐酸溶液调pH值至4.5,补充纯化水至10L。油浴80℃搅拌120min,未完全溶解。
对比例2
本对比例公开了采用羟丙基倍他环糊精包合丁苯酞,制备丁苯酞氯化钠注射液。其制剂处方(处方量100支)为:
制备方法:取处方量纯化水,煮沸后冷却至80℃。称取羟丙基倍他环糊精62.5g,氯化钠90g,加入8L 80℃纯化水中,搅拌使完全溶解。称取丁苯酞2.5g,加入羟丙基倍他环糊精溶液中,油浴80℃搅拌90min使完全溶解。放冷至室温,加0.2M盐酸溶液调pH值至4.5,补充纯化水至10L。用循环水式多用真空泵经0.45μm滤膜滤过。将配好的溶液按100ml/支灌装。灌装后于121℃下,高温灭菌15分钟,得到对比例2的样品。
对比例3
本对比例公开了采用羟丙基倍他环糊精包合丁苯酞,制备丁苯酞氯化钠注射液。其制剂处方(处方量100支)为:
制备方法:取处方量纯化水,煮沸后冷却至80℃。称取羟丙基倍他环糊精75g,氯化钠90g,加入8L 80℃纯化水中,搅拌使完全溶解。称取丁苯酞2.5g,加入羟丙基倍他环糊精溶液中,油浴80℃搅拌90min使完全溶解。放冷至室温,加0.2M盐酸溶液调pH值至4.5,补充纯化水至10L。用循环水式多用真空泵经0.45μm滤膜滤过。将配好的溶液按100ml/支灌装。灌装后于121℃下,高温灭菌15分钟,得到对比例3的样品。
对比例1-3采用了与实施例1相同的浓配体积、相同的pH值考察了羟丙基倍他环糊精包合丁苯酞的能力。由于相同摩尔数的羟丙基倍他环糊精和磺丁基倍他环糊精钠产生相同摩尔数的倍他环糊精,肾毒性由倍他环糊精产生,因此减少羟丙基倍他环糊精或磺丁基倍他环糊精摩尔数,就减少了肾毒性。
考察对比例1-3制得的各丁苯酞氯化钠注射液的性状及注射液中丁苯酞含量。结果如下表所示,
表5,羟丙基倍他环糊精对丁苯酞的增溶能力考察比较
由上表可知,当羟丙基倍他环糊精:丁苯酞摩尔比为2.60时,即使搅拌时间达120min,也有丁苯酞未被羟丙基倍他环糊精包合(呈现油滴状)。当羟丙基倍他环糊精:丁苯酞摩尔比大于3.24时,丁苯酞才能被羟丙基倍他环糊精很好的包合。为了达到较好的包合能力,羟丙基倍他环糊精:丁苯酞摩尔比(3.24)远大于磺丁基倍他环糊精钠:丁苯酞摩尔比(1.60)。因此,磺丁基倍他环糊精钠的用量小于羟丙基倍他环糊精的用量,磺丁基倍他环糊精钠有更好包合能力,也减少了丁苯酞氯化钠注射液的肾毒性。
最后应说明的是:以上各实施例仅仅为本发明的较优实施例用以说明本发明的技术方案,而非对其限制,当然更不是限制本发明的专利范围;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围;也就是说,但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色,其所解决的技术问题仍然与本发明一致的,均应当包含在本发明的保护范围之内;另外,将本发明的技术方案直接或间接的运用在其他相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (10)
1.一种稳定的丁苯酞氯化钠注射液,其特征在于,包括丁苯酞-磺丁基倍他环糊精钠包合物、氯化钠和水,所述丁苯酞氯化钠注射液的pH值为4.0~5.0。
2.根据权利要求1所述的一种稳定的丁苯酞氯化钠注射液,其特征在于,所述丁苯酞-磺丁基倍他环糊精钠包合物由磺丁基倍他环糊精钠对丁苯酞包合形成;
优选地,丁苯酞与磺丁基倍他环糊精钠的摩尔比为1:1.60~2.20,更优选为1:1.77;
优选地,所述磺丁基倍他环糊精钠的取代度为6.2~6.9。
3.根据权利要求1或2所述的一种稳定的丁苯酞氯化钠注射液,其特征在于,每100mL所述丁苯酞氯化钠注射液中,丁苯酞的含量为25mg。
4.根据权利要求1或2所述的一种稳定的丁苯酞氯化钠注射液,其特征在于,每100mL所述丁苯酞氯化钠注射液中,氯化钠的含量为0.9g。
5.根据权利要求1或2所述的一种稳定的丁苯酞氯化钠注射液,其特征在于,所述丁苯酞氯化钠注射液的pH值为4.5。
6.根据权利要求1-5任意一项所述的一种稳定的丁苯酞氯化钠注射液的制备方法,其特征在于,包括以下步骤:
步骤1.制备辅料溶液:称取处方量的磺丁基倍他环糊精钠、氯化钠,加水溶解,制得辅料溶液;
步骤2.配液包合:称取处方量的丁苯酞加入步骤1制得的辅料溶液中,搅拌,使磺丁基倍他环糊精钠包合丁苯酞,丁苯酞包合完毕后,调节溶液pH值至4.0~5.0;
步骤3.将步骤2中调节pH值后的溶液过滤、灌装、灭菌,即得。
7.根据权利要求6所述的制备方法,其特征在于,所述步骤2中,磺丁基倍他环糊精钠包合丁苯酞时溶液的温度保持为60~80℃,优选为80℃。
8.根据权利要求6或7所述的制备方法,其特征在于,所述步骤2中,磺丁基倍他环糊精钠包合丁苯酞的时间为60~90min,优选90min。
9.根据权利要求6或7所述的制备方法,其特征在于,所述步骤2中,丁苯酞加入步骤1制得的辅料溶液中,搅拌至完全溶解后,放冷至室温,调节溶液PH值。
10.权利要求1-5任意一项所述的丁苯酞氯化钠注射液在制备用作预防和治疗脑卒中的药物中的用途。
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