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CN101961311B - 一种5α-雄甾(烷)-3β,5,6β-三醇注射剂及其制备方法 - Google Patents

一种5α-雄甾(烷)-3β,5,6β-三醇注射剂及其制备方法 Download PDF

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CN101961311B
CN101961311B CN201010292234XA CN201010292234A CN101961311B CN 101961311 B CN101961311 B CN 101961311B CN 201010292234X A CN201010292234X A CN 201010292234XA CN 201010292234 A CN201010292234 A CN 201010292234A CN 101961311 B CN101961311 B CN 101961311B
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CN101961311A (zh
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颜光美
胡海燕
张静夏
邱鹏新
李玲
田宁
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Guangzhou Cellprotek Pharmaceutical Co Ltd
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Sun Yat Sen University
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Abstract

本发明公开了一种5α-雄甾(烷)-3β，5，6β-三醇注射剂(简称YC-6)及其制备方法。方案为：使用羟丙基-β-环糊精作为增溶剂，优选比例为：YC-6占1-20份，羟丙基-β-环糊精占40-500份。其他组份的比例可以优选：等渗调节剂1-100份，冻干填充剂0-200份，溶剂0-2000份。制备方法是，将羟丙基-β-环糊精溶液、YC-6和其他可溶性辅料按顺序分别溶于注射用水中，经脱色去热原、过滤；滤液灭菌后制得液态注射剂；滤液干燥后制得固态注射剂。本发明的优点在于：使YC-6作为急救用药，注射给药成为可能。并具有溶解度稳定，无刺激性、疗效稳定和制备工艺简单易得等优点。

Description

一种5α-雄甾(烷)-3β,5,6β-三醇注射剂及其制备方法
技术领域
本发明涉及制药领域，具体涉及一种5α-雄甾(烷)-3β，5，6β-三醇注射剂及其制备方法。
背景技术
5α-雄甾(烷)-3β，5，6β-三醇(下面简称为YC-6)是我们新发现的神经保护剂。目前，急性缺血性脑卒中的治疗主要通过两个途径：一为溶解血栓，二为神经保护。由于神经保护剂可减少脑梗死面积，不引发出血，无溶栓、抗凝治疗出血的并发症，用前无需进行详细的病因鉴别诊断，使得早期治疗成为可能，已成为脑卒中治疗的研究热点。
然而，迄今为止还没有发现已证明为安全有效的神经保护剂，目前正在进行临床试验的、具有潜在临床应用前景的药物有钙通道阻滞剂(CCB)、钙通道调节剂、谷氨酸释放抑制剂、GABA受体激动剂、自由基清除剂、抗细胞间黏附分子抗体等。在众多化合物中，神经活性甾体对神经保护具有广泛效应而日益受到关注。特别是YC-6，作为新发现的神经保护剂，其作用不限于神经保护。在体内外对脑缺血及脊髓缺血均有效，日剂量为50-100mg。但由于YC-6在水中溶解度小，常用的非水溶剂及其混合溶剂虽然可提高其溶解度，但均存在较大的刺激性，并且有经水稀释后析出的现象，从而影响了该制剂的疗效和安全性，限制了注射剂的YC-6的广泛应用。
发明内容
为了克服以上缺陷，本发明提供了一种YC-6注射剂及其制备方法。该发明使用羟丙基-β-环糊精作为增溶剂，成功地解决了目前YC-6注射剂使用过程中澄明度不稳定和刺激性的问题。
为实现上述目的，本发明的YC-6注射剂，包括液态注射液或固态注射液。注射液配方的可溶性辅料中含有羟丙基-β-环糊精。当然，该注射液的可溶性辅料还可以包括等渗调节剂或冻干填充剂。
YC-6与羟丙基-β-环糊精重量的优选重量份数比为：1-20∶40-500。
注射剂中各组分占的重量百分比也可按：YC-61-20份，羟丙基-β-环糊精40-500份，等渗调节剂1-100份，冻干填充剂0-200份，溶剂0-2000份，进行配制。
所述的等渗调节剂可以包括氯化钠、葡萄糖、甘露醇、乳糖、木糖醇、山梨醇或麦芽糖醇中的一种或几种。
所述的冻干填充剂包括氯化钠、葡萄糖、甘露醇、乳糖、木糖醇、山梨醇或麦芽糖醇中的一种或几种。
如果配制液态注射剂，溶剂可以选用丙二醇、乙醇、聚乙二醇400、聚乙二醇200、甘油或水中的一种或几种。
本发明的注射液可以通过以下制备方法得到：首先，将羟丙基-β-环糊精溶液、YC-6和其他可溶性辅料按顺序分别溶于注射用水中，经脱色、过滤、灭菌得“注射液”。
制备“冻干粉针”的方法是：将上述过滤后的滤液灌装于安瓿中，冷冻干燥，得“冻干粉针”。
制备“无菌粉针”的方法是：将上述滤液喷雾干燥，分装得到“无菌粉针”。
上述方法中，可以使用0.1-0.3％的活性炭进行脱色，灭菌的温度和时间为115℃灭菌30分钟或121℃灭菌15分钟。
当然，也可以利用同原理将YC-6制成葡萄糖注射液、氯化钠注射液或葡萄糖氯化钠注射液。
本发明与现有技术相比具有以下优越的技术效果：
本发明通过采用了羟丙基-β-环糊精或非水溶剂/混合溶剂，提高了YC-6的溶解度，使YC-6可以制成以水、非水溶剂或混合溶剂为溶剂的注射液、注射用无菌粉末、冻干粉针、葡萄糖注射液、氯化钠注射液或葡萄糖氯化钠注射液。使YC-6作为急救用药，注射给药成为可能。并具有溶解度稳定，无刺激性、疗效稳定和制备工艺简单易得等优点。
具体实施方式
实施例1：本实施例制备200支YC-6注射液(规格5ml:50mg)。
配方为：
YC-6                      10g
2-羟丙基-β-环糊精        200g
氯化钠                    1.25g
注射用水加至              1000ml
制备工艺：取羟丙基-β-环糊精，溶于处方量80％的新鲜注射用水中，加入YC-6室温搅拌10-20分钟，使全溶。加入氯化钠，搅拌使溶解，添加注射用水至足量，遂加入0.1％的活性碳60℃保温15分钟，放冷，经0.22μm微孔滤膜过滤。滤液灌封为5ml注射液，121℃灭菌15分钟，即得。
实施例2：本实施例制备200支YC-6注射剂(规格10ml:80mg)
YC-6                 16g
3-羟丙基-β-环糊精   400g
葡萄糖               13.9g
注射用水加至         2000ml
制备工艺：取羟丙基-β-环糊精，溶于处方量80％的新鲜注射用水中，加入YC-6室温搅拌10-20分钟，使全溶。加入葡萄糖，搅拌使溶解，添加注射用水至足量，遂加入0.1％的活性碳60℃保温15分钟，放冷，经0.22μm微孔滤膜过滤。滤液灌封得10ml注射液。121℃灭菌15分钟，即得。
实施例3：本实施例制备200支YC-6注射剂(规格5ml:100mg)
YC-6                 20g
2-羟丙基-β-环糊精   400g
注射用水加至         1000ml
制备工艺：取羟丙基-β-环糊精，溶于处方量80％的新鲜注射用水中，加入YC-6，室温搅拌10-20分钟使全溶，添加注射用水至足量，遂加入0.1％的活性碳60℃保温15分钟，放冷，经0.22μm微孔滤膜过滤。滤液灌封得5ml注射液。115℃灭菌30分钟，即得。
实施例4：本实施例制备200支YC-6无菌粉末(规格80mg/支)
YC-6                   16g
2-羟丙基-β-环糊精     400g
氯化钠                 2.5g
分装成                 200支
制备工艺：取羟丙基-β-环糊精溶于处方量80％的新鲜注射用水中，溶解后，加入YC-6，室温搅拌10-20分钟，使全溶。加入氯化钠，搅拌使溶解，添加注射用水至2000ml。遂加入0.1％的活性碳60℃保温15分钟，放冷，经0.22μm微孔滤膜过滤。滤液喷雾干燥，分装成200支，即得。
实施例5：本实施例制备200支YC-6冻干粉针(规格5ml:60mg)
YC-6                   12g
3-羟丙基-β-环糊精     200g
葡萄糖                 7g
注射用水加至           1000ml
制备工艺：取羟丙基-β-环糊精溶于处方量80％的新鲜注射用水中，溶解后，加入YC-6，室温搅拌10-20分钟，使全溶。加入氯化钠，搅拌使溶解，添加注射用水至2000ml。遂加入0.1％的活性碳60℃保温15分钟，放冷，经0.22μm微孔滤膜过滤，滤液分装为5ml/西林瓶，冷冻干燥，即得。
实施例6 YC-6注射剂与常用输液配伍的稳定性研究取实施例1中所述的YC-6注射液2支(5ml×2)加入常用输液中，考察YC-6注射剂与常用输液8h内的配伍稳定性。考察项目包括色泽、澄明度、pH及YC-6含量，结果如下表所示。
表1YC-6注射剂与常用输液配伍方案
  样品号   配伍(25-30℃)
  A   YC-6注射液5ml*2支+5％葡萄糖注射液250ml
  B   YC-6注射液5ml*2支+0.9％氯化钠注射液250ml
  C   YC-6注射液5ml*2支+葡萄糖氯化钠注射液250ml
  D   YC-6注射液5ml*2支+复方氯化钠注射液500ml
  E   YC-6注射液5ml*2支+5％碳酸氢钠注射液250ml
表2常用输液与YC-6注射液配伍后色泽与澄明度的变化
表3常用输液与YC-6注射液配伍后pH的变化
Figure BSA00000283721600062
Figure BSA00000283721600071
表4常用输液与YC-6注射液配伍后输液中YC-6的含量变化(μg/ml)
  样品号   0h   2h   8h   24h
  A   375.4   364.7   367.7   363.4
  B   379.2   373.5   380.4   386.1
  C   385.6   387.6   383.4   384.5
  D   382.0   383.7   387.2   380.8
  E   386.7   375.1   381.3   376.5
实施例7 YC-6的初步安全性评价
将昆明小鼠按体重分笼后，随机分为五组，每组10只，雌雄各半。尾静脉注射不同剂量的实施例3项下的YC-6注射液(20mg/ml)，并立即记录现象，存活小鼠观察一周后处死，逐天记录动物毒性反应情况及死亡数，计算LD50及95％可信限。YC-6的LD50＞400±121mg/kg。
取新鲜新西兰兔血，按常规方法制备血球，并用生理盐水稀释成2％的混悬液，加入注射剂，37℃温孵3小时，比色法测定溶血率。结果表明，注射剂溶血率小于1％。
取白色豚鼠，按常规方法进行过敏试验，结果表明YC-6注射液不引起豚鼠过敏反应。
用新西兰兔进行静脉注射血管刺激性试验。结果表明用药组耳缘静脉的组织变化与对照组相似，各兔耳缘静脉血管壁完整，未见内皮损伤、周围组织水肿等病理变化，静脉血管结构正常。

Claims (9)

1.5α-雄甾(烷)-3β，5，6β-三醇注射剂，包括液态注射剂或固态注射剂，所述注射剂的配方由5α-雄甾(烷)-3β，5，6β-三醇、注射用溶剂及可溶性辅料组成，其特征在于：所述的可溶性辅料包括增溶剂，所述的增溶剂为羟丙基-β-环糊精；其中5α-雄甾(烷)-3β，5，6β-三醇与羟丙基-β-环糊精的重量份数比为：1-20∶40-500。
2.如权利要求1所述的注射剂，其特征在于：所述的可溶性辅料还包括等渗调节剂或冻干填充剂中的一种或两种。
3.如权利要求2所述的注射剂，其特征在于，该注射剂中各组分占的重量份数比是：5α-雄甾(烷)-3β，5，6β-三醇1-20份，羟丙基-β-环糊精40-500份，等渗调节剂1-100份，冻干填充剂0-200份，注射用溶剂0-2000份。
4.如权利要求2所述的注射剂，其特征在于，所述的等渗调节剂选自氯化钠、葡萄糖、甘露醇、乳糖、木糖醇、山梨醇或麦芽糖醇中的一种或几种。
5.如权利要求2所述的注射剂，其特征在于，所述的冻干填充剂选自氯化钠、葡萄糖、甘露醇、乳糖、木糖醇、山梨醇或麦芽糖醇中的一种或几种。
6.如权利要求2所述的注射剂，其特征在于，所述的注射用溶剂选自丙二醇、乙醇、聚乙二醇400、聚乙二醇200、甘油或水中的一种或几种。
7.如权利要求1所述的注射剂的制备方法，其特征在于，将羟丙基-β-环糊精、5α-雄甾(烷)-3β，5，6β-三醇和其他可溶性辅料按顺序分别溶于注射用溶剂中，经脱色去热原、过滤得滤液，上述滤液灭菌得“注射液”；或将上述滤液灌装于安瓿中，冷冻干燥，得“冻干粉针”；或将上述滤液喷雾干燥，分装得“无菌粉针”。
8.如权利要求7所述的注射剂的制备方法，其特征在于，所述的脱色步骤中所用的吸附剂是活性炭，用量为注射剂的质量百分比的0.05-0.3％。
9.如权利要求8所述的注射剂的制备方法，其特征在于，所述的灭菌步骤的温度和时间分别是：115℃灭菌30分钟或121℃灭菌15分钟。
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PCT/CN2011/076968 WO2012037834A1 (zh) 2010-09-21 2011-07-08 一种5α-雄甾（烷）-3β，5，6β-三醇注射剂及其制备方法
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JP2013527453A JP5750680B2 (ja) 2010-09-21 2011-07-08 ５α−アンドロスタン−３β，５，６β−トリオール注射剤及びその調製方法
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