CN112043674A - 一种注射用七叶皂苷钠冻干制剂及其制备方法 - Google Patents
一种注射用七叶皂苷钠冻干制剂及其制备方法 Download PDFInfo
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- CN112043674A CN112043674A CN202011020669.9A CN202011020669A CN112043674A CN 112043674 A CN112043674 A CN 112043674A CN 202011020669 A CN202011020669 A CN 202011020669A CN 112043674 A CN112043674 A CN 112043674A
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Abstract
本发明公开了一种注射用七叶皂苷钠冻干制剂及其制备方法，属于医药领域，所述叶皂苷钠冻干制剂的组分有且仅有七叶皂苷钠，所述制备方法是将七叶皂苷钠溶液调节pH值后用微孔滤膜过滤，灌装后经三个阶段的冷冻干燥即得。本发明方法所得七叶皂苷钠冻干制剂外形良好，复溶效果良好，主药纯度高，不易吸潮，质量稳定，提升了药物纯度和用药安全性。
Description
技术领域
本发明属于医药领域，具体涉及一种注射用七叶皂苷钠冻干制剂及其制备方法。
背景技术
七叶皂苷钠为七叶树科或天师栗的干燥成熟种子中提取得到的总皂苷。多方面的药理研究表明，七叶皂苷钠具有抗渗出及增加静脉张力、消肿、抗炎、抗氧自由基、促进胃肠蠕动和改善血液循环的作用。临床上广泛用于治疗脑水肿、创伤或手术后引起的肿胀，也用于治疗静脉回流障碍性等疾病，并具有良好的治疗效果。
七叶皂苷为七叶树种子中30多种皂苷的总称，其化学成分的研究始于19世纪从欧洲七叶树的种子中分离皂苷混合物，迄今为止，从该属植物中发现了皂苷类、黄酮类、香豆素类等多种成分，因其结构复杂，极性相似，给早期的研究工作者带来了很大的麻烦。
目前七叶皂苷钠的剂型主要有注射制剂、口服制剂和外用制剂。由于七叶皂苷钠分子结构中含有酚羟基和内酯结构，遇到光、空气中的氧和湿气极易氧化和水解，进而影响口服片剂和外用制剂的质量和疗效。目前已上市的注射制剂虽然克服了易氧化和水解的弊端，但肌肉注射疼痛难忍，静脉给药对血管刺激强。据对现有七叶皂苷钠使用情况的统计，其不良反应主要有过敏反应、过敏性休克，致肝损害、血尿和急性肾功能衰竭、心动过缓、静脉疼痛和静脉炎等。
为了减少七叶皂苷钠的不良反应，降低七叶皂苷钠注射制剂对血管的刺激性，中国专利CN101084911B提供的“七叶皂苷钠冻干乳剂及其制备方法”中，通过加入磷脂、乳化剂、水溶性辅料和冻干稳定剂，以形成乳剂，避免晶态固化，达到降低对血管刺激性的目的。但该冻干乳剂在制备过程中添加了过多的辅料，导致制品的化学性质不单一，易产生其他不良性反应。此外，该专利通过冻干乳剂来保证制品在贮藏及运输过程中的稳定，延长有效期，提高药品质量，但是由于过程中一直属于乳液状态，在使用过程中会由于复溶性不好导致澄清度不过关。中国专利CN 102836133 B提供的“一种七叶皂苷钠冻干粉针及其制备方法”中加入叔丁醇保护剂，但是叔丁醇吸入或口服对身体有害，对眼睛、皮肤、粘膜和呼吸道有刺激作用。中毒表现可有头痛、恶心、眩晕。且本品易燃，具刺激性，而且大鼠(经口)LD50为3500mg/kg。采用此方式引入风险物质，不利于商业化生产。中国专利CN106511282A中提供的“一种七叶皂苷A注射剂及其制备方法”加入氨基酸、甘露醇辅料，导致制品的化学性质不单一，易产生其他不良性反应。
发明内容
本发明的目的是克服现有技术不足，提供一种成分简单、质量稳定、无刺激性、有效期长，且复溶性好的七叶皂苷钠冻干制剂及其制备方法。
本发明的目的是通过如下技术方案实现的：
一种注射用七叶皂苷钠冻干制剂的制备方法：将七叶皂苷钠用注射用水配成浓度为3mg/mL～15mg/mL的七叶皂苷钠溶液，调节pH值后用微孔滤膜过滤，然后灌装于西林瓶中，经冷冻干燥后关闭真空系统，充入无菌空气至1个大气压，压胶塞即得，所述冷冻干燥按照以下三个阶段进行：
1)预冻阶段：将灌装七叶皂苷钠溶液后的西林瓶半压塞，置于冻干机箱内预冻，用时1-2小时降温至-30℃～-45℃，保温1-2小时，进入升华阶段；
2)升华阶段：将温度升至5℃～10℃，真空度保持10pa～30pa，保温7～12小时后进入再干燥阶段；
3)干燥阶段：将温度升至25℃～30℃，真空控制0-10pa，干燥时间为3-4小时。
进一步的，所述调节pH值是指将pH值调至5.3-6.7。
所述过滤是依次经0.45μm、0.22μm微孔滤膜过滤。
与现有技术相比，本发明的有益效果体现在：
1)七叶皂苷钠作为唯一成分做成冻干制剂，减少了辅料的加入，使制品的化学性质单一，防止了各种由于辅料添加引起的不良反应，同时辅料的减少为生产的操作提供了方便，提升了药物纯度和用药安全性，为临床安全性提供了更加可靠的保障。
2)本发明所得七叶皂苷钠冻干制剂剂，外观良好，复溶效果良好，符合我国药典规定标准。
3)加速试验表明本发明所得七叶皂苷钠冻干制剂主药纯度高，不易吸潮，质量稳定。
4)本发明所得七叶皂苷钠冻干制剂的制备中常温溶解，克服了现有技术中的高温溶解所带来的产品的有关物质增加，不溶性微粒增加，从而增加七叶皂苷钠注射液的不良反应。
5)本发明所得七叶皂苷钠冻干制剂的制备工艺缩短了生产工艺步骤，操作简单易控，降低了生产过程中风险的引入。
附图说明
图1为注射用七叶皂苷钠冻干曲线图。
具体实施方式
下面结合具体实施例对本发明作进一步说明，以助于理解本发明的内容。
实施例1
一、工艺处方：(以千瓶计)
七叶皂苷钠10g
注射用水加至1000ml
共制成1000支
包材：
管制瓶：5ml，1000个
丁基胶塞：13-D1，1000个
铝塑组合盖：13mm，1000个
制成：1000支
二、工艺制备过程：
1.玻璃管制注射剂瓶等的洗涤与灭菌
玻璃管制注射剂瓶、丁基橡胶塞按无菌注射剂的常规要求洗涤、灭菌后备用，铝塑组合盖经灭菌后备用。
2.配料过程：
(1)溶解：按生产指令称取总量70％的注射用水于配液罐中，控制水温在40℃以下，加入指令量七叶皂苷钠，室温搅拌使溶解，补加注射用水至全量，搅匀后，测定pH值应为5.3～6.7；
(2)除菌过滤：将完整性试验检查合格的0.45μm和0.22μm微孔滤膜串联，进行精滤。精滤后取样检测，合格后灌装；
(3)分别按标示量(10mg/瓶)分装至5ml玻璃管制注射剂瓶中，半加塞后进箱。
3.冻干：
(1)预冻温度：-35℃；预冻总时间：4小时。
(2)升华温度：9℃(搁板温度)；升华时间：约10.5h。
(3)再干燥温度：28℃(搁板温度)；再干燥时间：约4h，放气压塞。
(4)冻干周期：约18h。冻干曲线如图1所示。
4.抽检符合规定后压塞、出箱、轧盖、灯检。
5.包装、全检、入库。
对照例1
对照例处方同实施例1，加入3000g叔丁醇，搅拌使其溶解，加入注射用水1000g混合搅拌得澄明溶液，用氢氧化钠调节pH值为5.7。冻干工艺同实例1。
对照例2
对照例处方同实施例1，加入6000g甘露醇，搅拌使其溶解，加入注射用水1000g混合搅拌得澄明溶液，用乳酸调节调节pH值为5.5。冻干工艺同实例1。
表1注射用七叶皂苷钠辅料筛选
由以上实验可见，冻干后三者的外观都显白色疏松块状，溶解性方面，实施例1优于对照例1和2。
对照例3
在实施例1的处方中加入活性炭，其中，活性炭的加入量为：0.2％的药用活性炭(w/v)，检测细菌内毒、溶液澄清度与颜色、以及含量。结果见表2。
表2药用活性炭对主药的吸附情况
| 样品 | 外观性状 | 含量(％) | 热源 |
| 未用活性炭(实施例1) | 无色澄明液体 | 99.51 | 无 |
| 0.2％(对照例3) | 无色澄明液体 | 56.4 | 无 |
试验结果表明，活性炭对主药有明显的吸附作用，通过对原料药以及生产工具、包材以及注射用用水进行严格热源的控制，不加活性炭也可以使溶液澄明无热源，因此选择不加活性炭，直接用0.22um微孔滤膜精滤除菌的方式配制。
试验例1
对本发明实施例1四个批次(010604、010901、010902、010903)的产品进行质量稳定性研究，其结果如下：
(1)影响因素试验
A.强光试验
将注射用七叶皂苷钠样品(010604)放置于装有日光灯的光照箱中，于照度为4500lx的强光条件下放置10天，分别于第5、10天取样检查，并与0天结果比较，结果见表3。
表3注射用七叶皂苷钠强光照试验结果
表3结果表明：本品在强光4500lx光照条件下放置10天后，取样检查，有关物质略有所增加，变化不明显，其他各项检测指标均无明显变化，说明本品无须刻意遮光保存。
B.高温试验
取注射用七叶皂苷钠样品(010604)，打开外包装，置于60℃恒温箱中放置10天，分别于第5、10天取样检查，并与0天结果比较，结果见表4。
表4注射用七叶皂苷钠60℃高温试验结果
表4结果表明：本品在60℃条件下放置10天后，取样检查，有关物质增加，其他各项检测指标均无明显变化，故本品在阴凉条件下保存。
C.高湿试验
取注射用七叶皂苷钠样品(010604)，打开外包装，置于25℃相对湿度90％±5％条件下放置10天，分别于第5、10天取样检查，并与0天结果比较，结果见表5。
表5注射用七叶皂苷钠高湿试验结果
表5结果表明：本品在高湿条件下放置10天后，取样检查，各项检测指标均无明显变化，故本品在高湿条件下稳定。
(2)加速试验
取本品质量研究的样品(批号：010901、010902、010903)三批，置温度40℃±2℃，RH75％调温调湿箱中，分别于0、1、2、3、6月取样，测定各项指标，结果见表6。
(3)室温长期留样考察试验
取质量研究的三批样品，放置在25℃±2℃，RH60％±10％条件下，分别于0、3、6、9、12个月取样，测定相关各项指标，结果见表6。
表6注射用七叶皂苷钠加速试验结果
结论：通过对三批样品的加速试验表明，本发明注射用七叶皂苷钠各项指标均无明显变化，质量稳定。
试验例2
检查及含量测定方法
1、检查
酸碱度：取本品适量，加水制成每1ml中含1mg溶液，依法测定，pH值应为5.0～7.0。
吸收度：取本品，加水制成每1ml中含5mg的溶液，照紫外-可见分光光度法测定，在300nm的波长处测定吸光度不得大于0.10。
热原：取本品，加灭菌氯化钠溶液制成每1ml中含0.4mg的溶液，按热原检查法检查，剂量按家兔体重每1Kg注射5ml。应符合规定。
有关物质：色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂；以乙腈-磷酸溶液(取85％磷酸5.5ml，用水稀释至1000ml)(33：67)为流动相；调节pH值为2.1，检测波长为220nm；流速为2ml/min。理论板数按七叶皂苷A峰计应不低于5000。七叶皂苷A和七叶皂苷B的分离度应符合规定。测定法取本品内容物适量(约相当于七叶皂苷钠25mg)，置10ml量瓶中，加甲醇溶解并稀释至刻度，摇匀，作为供试品溶液；取供试品溶液20ul注入液相色谱仪，调节检测灵敏度，使D主成分的峰高约为记录仪满量程的10％；再取供试品溶液20ul，注入液相色谱仪，记录色谱图至D主成分色谱峰保留时间的2倍，供试品溶液的色谱图中出4个主成分峰，以出峰前后分别为七叶皂苷钠A、B、C、D。如显杂质峰，以面积归一化法计算。除七叶皂苷A、B、C、D峰和溶液峰面积，其他杂质峰面积总和不得大于10.0％。
无菌：取本品60瓶使用DGB330一次性全封闭集菌培养器(三联)一套将每瓶均匀泵入滤桶内(泵入之前应用少量0.1％蛋白胨水溶液润湿滤膜)，每瓶用3-4ml0.1％蛋白胨水溶液(约300ml)溶解完全，蠕动泵的转速为100R。将剩余的0.1％蛋白胨水溶液泵入滤桶内，过滤，待药液滤尽后，蠕动泵的转速调为160R，向其中两桶分别泵入硫乙醇酸盐流体培养基100ml，一桶作为供试品阳性对照管，一桶作为供试品厌氧菌培养管；另一桶泵入胰酪大豆胨液体培养基100ml，作为供试品需氧菌、真菌培养管。另取DGB220一次性全封闭集菌培养器(二联)一套依法分别泵入硫乙醇酸盐流体培养基、胰酪大豆胨液体培养基各100ml作为阴性对照管。
阳性对照的接种：将供试品阳性对照管移入阳性对照(接种)室，用无菌注射器注入金黄色葡萄球菌菌悬液(小于100cfu/ml)1ml，使菌液与培养基充分混匀。
培养：将供试品厌氧菌培养管，供试品需氧菌、真菌培养管，供试品阳性对照管置规定的培养条件下培养，逐日观察培养结果并记录。
热源：取本品，加灭菌氯化钠溶液制成每1ml中含0.4mg的溶液，按《热原检查法》检查，剂量按家兔体重每1Kg注射5ml。
2.结果判定
2.1判定合格
初试3只家兔中，体温升高均在0.6℃以下，并且3只家兔体温升高总和低于1.3℃以下可判断为符合规定。复试5只家兔中，体温升高0.6℃或0.6℃以上的家兔数不超过1只，并且初复试合并,8只家兔的升温总和为3.5℃或3.5℃以下，可判断为符合规定。
2.2判定不合格
初试3只家兔中，体温升高0.6℃或0.6℃以上的家兔有2只或3只，可判断为不符合规定。复试的5只家兔中，体温升高0.6℃或0.6℃以上的家有2只或多于2只，可判断为不符合规定。初试复试合并8只家兔的体温升高总和超过3.5℃，可判断为不符合规定。
2.3判定复试
(1)初试3只家兔中仅有1只体温升高0.6℃或0.6℃以上，或3只家兔升温均低于0.6℃，但升温的总数达1.3℃或1.3℃(生物制品规定1.4℃或1.4℃以上)，应另取5只家兔复试。
(2)3只家兔升温均为0，其中有1只降温值≥0.6℃，或3只家兔中有2只降温值在0.5℃，为防止降温影响热原检查，可考虑在消除降温的影响因素后，应另取3只家兔复试。
3.含量测定
取本品30支(10mg取15支)，加乙醇-水(10:1)溶解，定量转移至25ml量瓶中，并稀释至刻度，摇匀，精密量取10ml至100ml三角瓶中，加酚酞指示液2滴，用氢氧化钠溶液(0.01mol/L)滴定至溶液显微红色后，再精密加氢氧化钠滴定液(0.05mol/L)5ml，加热回流4小时，用乙醇-水(10:1)2ml洗净冷凝管及瓶口，取出，放冷至室温，用盐酸滴定液(0.01mol/L)滴定。并将滴定的结果用空白实验校正。每1ml的氢氧化钠滴定液(0.05mol/L)相当于28.80mg的七叶皂苷钠。
Claims (8)
1.一种注射用七叶皂苷钠冻干制剂的制备方法，其特征在于，将七叶皂苷钠用注射用水配成浓度为3mg/mL～15mg/mL的七叶皂苷钠溶液，调节pH值后用微孔滤膜过滤，然后灌装于西林瓶中，经冷冻干燥即得，所述冷冻干燥按照以下三个阶段进行：
1)预冻阶段：将灌装七叶皂苷钠溶液后的西林瓶半压塞，置于冻干机箱内预冻，预冻温度不高于-35℃，保温1-2小时，进入升华阶段；
2)升华阶段：将温度升至5℃～10℃，真空度保持10pa～30pa，保温7～12小时后进入再干燥阶段；
3)干燥阶段：将温度升至25℃～30℃，真空控制0-10pa，再干燥时间为3-4小时。
2.根据权利要求1所述的一种注射用七叶皂苷钠冻干制剂的制备方法，其特征在于，所述调节pH值是指将pH值调至5.3-6.7。
3.根据权利要求1所述的一种注射用七叶皂苷钠冻干制剂的制备方法，其特征在于，所述过滤是依次经0.45μm、0.22μm微孔滤膜过滤。
4.根据权利要求1所述的一种注射用七叶皂苷钠冻干制剂的制备方法，其特征在于，所述预冻温度为-30℃～-45℃。
5.根据权利要求1所述的一种注射用七叶皂苷钠冻干制剂的制备方法，其-2特征在于，冻干机箱内预冻降至不高于-35℃所用时间为1-2小时。
6.根据权利要求1所述的一种注射用七叶皂苷钠冻干制剂的制备方法，其特征在于，冷冻干燥后关闭真空系统，充入无菌空气至1个大气压，压胶塞即得七叶皂苷钠冻干制剂。
7.根据权利要求6所述的一种注射用七叶皂苷钠冻干制剂的制备方法，其特征在于，灌装量为每瓶1mL～2mL/。
8.根据权利要求1-7任一项所述的制备方法得到的七叶皂苷钠冻干制剂。
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