CN1165305C - 尼莫地平冻干组合物 - Google Patents
尼莫地平冻干组合物 Download PDFInfo
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- CN1165305C CN1165305C CNB021556458A CN02155645A CN1165305C CN 1165305 C CN1165305 C CN 1165305C CN B021556458 A CNB021556458 A CN B021556458A CN 02155645 A CN02155645 A CN 02155645A CN 1165305 C CN1165305 C CN 1165305C
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Abstract
本发明提供了尼莫地平冻干组合物及其制备方法。本发明组合物中还含有磷脂、环糊精及其衍生物或表面活性剂，该制品具有良好的溶解性和稳定性，适于用作安全、稳定的注射剂型。
Description
技术领域
本发明涉及包含水不溶性尼莫地平的药物组合物，具体地说，是涉及含有尼莫地平的冷冻干燥药物组合物及其制备方法。
背景技术
尼莫地平(分子式为C21H26N2O2，分子量为418.45)是1，4-二氢吡啶类钙通道拮抗剂，能选择性作用于脑血管，具有扩张脑动脉、增加脑部血流量的作用，主要用于治疗缺血型脑血管疾病，预防和治疗蛛网膜下腔出血后脑血管痉挛、突发性耳聋、高血压及偏头痛等。
目前，国内外上市的尼莫地平剂型很多，其中口服剂型包括普通片剂、缓释片剂、胶囊剂、软胶囊；注射剂包括小水针和大输液。由于尼莫地平固体制剂在胃肠液中溶解度很小，肝首过效应明显，一直存在着生物利用度低的缺点。其注射剂型比口服制剂起效更快、效果更好，所以注射剂型在临床上的应用更为广泛。
然而，尼莫地平难溶于水的特性极大地限制了其临床应用。例如，市售的输液中通常需要加入助溶剂(例如聚维酮等)，与尼莫地平形成络合物，来增加尼莫地平的溶解度。但是，这些措施的效力是有限的。通常，输液中含有20％(v/v)以上的乙醇作为溶剂，而小水针中的乙醇量则更大。如此大量的乙醇，在使用中对病人的刺激性和副作用较大(例如，疼痛、脉管炎等)，并且与乙醇不相容的药物不能一并加入到同一个输液瓶中，使用极其不便。
另外，尼莫地平对光非常不稳定(在溶液状态下尤其明显)，市售注射液大多采用避光的包装材料(例如，采用棕色安瓶、瓶子外加套防光照的泡沫层)，这不但增加成本，而且使用也不方便。通常，溶液中需要添加抗氧剂(例如亚硫酸氢钠)以增加溶液的稳定性。有研究表明，含有尼莫地平的常规小水针在自然光照条件下放置约6分钟，其含量即下降约10％，说明小水针对光照极其不稳定。
因此，本领域非常需要将尼莫地平制成具有良好溶解性和稳定性的制剂。
发明内容
我们对制药工艺进行了深入的研究，最终发现采用冷冻干燥工艺可有效地解决上述问题，在此基础上的进一步研究即完成了本发明。
研究发现，常规冻干剂型虽可解决制剂的稳定性问题，但是产品中尼莫地平的溶解性能并未得到明显改善，还需加入其他附加剂，由此产生的不良反应较多。本发明人惊奇地发现，向尼莫地平中加入磷脂、β-环糊精及其衍生物或表面活性剂，经冷冻干燥可制得稳定的冻干制品，在使用时加入药用水性稀释剂，即可迅速重建成胶体分散体或溶液。另外，本发明组合物中不含乙醇等溶剂，因此避免了刺激性反应。
本发明的一个目的是提供含有磷脂的尼莫地平冻干组合物。磷脂具有两亲性，使其特别适于配制本发明水不溶性尼莫地平，这对于改善尼莫地平的溶解性和体内作用时间是非常有益的。采用本领域常规方法，例如薄膜法、反相蒸发法或冷冻干燥法，并对磷脂的用量加以调整，可制得含有尼莫地平的脂质体或脂质复合物，优选为脂质复合物，然后再经冷冻干燥制成稳定的粉末，所得冻干制品经适量药用水性稀释剂后可迅速重建成胶体分散体。本发明所用磷脂并不局限于特定种类的磷脂，所述磷脂应适于冻干处理并且与尼莫地平相容，可以是植物或动物来源的磷脂，包括天然或合成磷脂。示例性磷脂包括但不限于：卵磷脂、大豆磷脂、脑磷脂、磷脂酸、二棕榈酸磷脂酰胆碱、氢磷脂酰乙醇氨、磷脂酰丝氨酸及其混合物。另外，加入固醇对制剂是有利的，所述固醇选自胆固醇、二氨胆固醇、大豆甾酰糖苷、大豆甾醇、麦角固醇及其混合物。有利地，尼莫地平与磷脂的重量比例约1∶1-1∶100，优选为1∶5-1∶80。
本发明的另一个目的是提供含有环糊精的尼莫地平冻干组合物。难溶性药物尼莫地平经环糊精包合物后，可显著改善其物化特性，例如：将药物粉末化后可提高其稳定性，增加其溶解性。优选地，所述环糊精及其衍生物选自β-环糊精、2-羟丙基-β-环糊精、3-羟丙基-β-环糊精、羟乙基-β-环糊精以及它们的混合物，优选为2-羟丙基-β-环糊精。其中尼莫地平与环糊精的摩尔比约1∶1-1∶20，优选为1∶5-1∶10。其中的包合温度、分散力大小和搅拌速度等条件，可采用常规方法来设计选择。
本发明的另一个目的是提供含有表面活性剂的尼莫地平冻干组合物。如上所述，含有尼莫地平的冻干制剂经药用稀释剂稀释后，时常会出现混浊或结晶现象，这给临床应用带来了一定的风险。本发明通过使用表面活性剂(例如吐温)增溶尼莫地平，促进了其快速溶解，同时又避免了的刺激性溶剂使用。研究表明，下列表面活性剂对尼莫地平具有较好的增溶效果：吐温-20、吐温-80、聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚乙烯吡咯烷酮、泊洛沙姆(poloxamer)以及它们组成的混合体系。优选为吐温-80、聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油或它们的混合体系。可通过常规实验确定表面活性剂的用量，以确保重建后得到澄清的溶液。有利地，尼莫地平与表面活性剂的重量比例约1∶30-1∶500，优选为1∶150-1∶300。
任选地，本发明药物组合物中还可加入药用冷冻干燥赋形剂。优选地，所述赋形剂选自甘露醇、山梨醇、氯化钠、葡萄糖、果糖、蔗糖、木糖醇、乳糖以及它们的混合物。优选为：甘露醇。尼莫地平与赋形剂的重量比为1∶100-1∶800，优选为1∶100-1∶300。
以组合物的总重量计，活性物质尼莫地平的用量约为0.5mg-50mg，优选为2mg-10mg。
本领域技术人员可根据临床制剂的需求和具体的生产设备，来调整冻干的周期。通常，可将均匀的制剂置于10至50ml的西林瓶中，预冻温度-20℃至-60℃，优选为-30℃至-40℃，预冻时间1小时至6小时，优选为3-4小时。冻干温度-10℃至-30℃，优选为-20℃至-25℃，冻干时间10小时至40小时，优选为20小时至25小时。冻干组合物的最终水分含量一般低于5％，优选为1％至2％。
本发明尼莫地平冻干组合物适于临床上应用。在使用前，可加入适量无菌药用水性稀释剂(例如，注射用水、生理盐水、葡萄糖水和其他已知的水性载体)，重建成供肌肉注射或静脉滴注(静脉内给药)用的胶体分散体或溶液制剂。
以下实施例旨在进一步说明本发明，并不对本发明的范围加以限制。
实施例1：制备含磷脂的粉针剂
取尼莫地平2mg、磷脂10mg和胆固醇2mg，加入无水乙醇5ml，搅拌至完全溶解，在旋转蒸发仪上进行减压干燥，除去溶剂，加入磷酸盐缓冲液5ml，搅拌至均匀，采用超声振荡，滤过，加入甘露醇100mg，置无菌西林瓶中，置冷冻干燥机内进行冷冻干燥，封口。即得浅黄色-淡黄色的尼莫地平粉针剂。
实施例2：制备含环糊精的粉针剂
取尼莫地平2mg，用2ml无水乙醇，搅拌至完全溶解，另取2-羟丙基-β-环糊精20mg，加7ml水溶解，搅拌下将尼莫地平溶液加入到2-羟丙基-β-环糊精的溶液中，制备成均匀的环糊精包合物。在旋转蒸发仪上进行减压干燥，挥去乙醇。在搅拌条件下，加入甘露醇300mg，溶液用事先经灭菌处理过的垂熔漏斗过滤，滤液置无菌西林瓶中，置冷冻干燥机内进行冷冻干燥，封口。即得浅黄色-淡黄色的尼莫地平粉针剂。
经X-射线衍射法确认，实施例2制得的药物组合物为包合物形式。
实施例3：制备含表面活性剂的粉针剂
取尼莫地平2mg、0.15g吐温-80、0.2g聚乙二醇-400、聚氧乙烯蓖麻油20mg和甘露醇0.3g，加水5ml，搅拌至完全溶解。用0.22μm的微孔滤膜过滤，置无菌西林瓶中，得微黄色澄清溶液，置冷冻干燥机内进行冷冻干燥，封口。即得浅黄色-淡黄色的尼莫地平粉针剂。
实验1：尼莫地平粉针剂的测定
含量的测定：UV-260紫外-可见分光光度计，选择358nm作为检测波长。
降解产物的测定：LC-10A高效液相色谱仪；C18(200×4.6mm，5μm)；乙腈-磷酸盐缓冲液(取磷酸2ml，加水1000ml)＝(70∶30)，流速为1.0ml/min，检测波长为238nm。结果表明，该色谱条件可将主药与各破坏(酸、碱、加热、光照、强氧化)产物分离。尼莫地平的最低检出限为0.5ng。
采用上述方法，对实施例3制得的尼莫地平粉针剂与常规小水针剂的稳定性进行考察，影响因素采用在4500LX照度的光照下放置10天，分别在第五天和第十天取样测定，考察数据如下表1。
表1
| 项目 | 样品 | 0天 | 5天 | 10天 |
| 外观及澄明度 | 粉针剂 | 淡黄色疏松快状，加水溶解后得微黄色澄清液体 | 淡黄色疏松快状，加水溶解后得微黄色澄清液体 | 淡黄色疏松快状，加水溶解后得微黄色澄清液体 |
| 水针剂 | 微黄色透明液体 | 微黄色透明液体 | 微黄色透明液体 | |
| 含量(％) | 粉针剂 | 97.5 | 96.4 | 94.6 |
| 水针剂 | 98.6 | 71.4 | 50.8 | |
| 降解产物(％) | 粉针剂 | 0.641 | 0.967 | 2.163 |
| 水针剂 | 1.030 | - | - |
以上结果表明：本发明粉针剂加水后可迅速重建得到澄清液体；在相同实验条件下，粉针剂的稳定性显著优于小水针剂。这种良好的溶解性和稳定性特性，不但保证了临床用药的安全性，也相应延长了尼莫地平的有效期。
动物试验表明，本发明尼莫地平粉针剂对血管无刺激性、无过敏反应。
尽管通过上述特定实施例对本发明作了描述，但是那些针对本发明所进行并不偏离本发明范畴的变化和改进，对于本领域技术人员是显而易见的。
Claims (8)
1.一种注射用冻干药物组合物，其中包括尼莫地平和选自磷脂、环糊精及其衍生物或表面活性剂的药用辅料，所述表面活性剂选自吐温-20、吐温-80、聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚乙烯吡咯烷酮、泊洛沙姆以及它们组成的混合体系，并且当药用辅料为磷脂时，所述组合物是脂质体或脂质复合物。
2.如权利要求1的组合物，其中磷脂选自：卵磷脂、大豆磷脂、脑磷脂、磷脂酸、二棕榈酸磷脂酰胆碱、氢磷脂酰乙醇氨、磷脂酰丝氨酸以及它们的混合物。
3.如权利要求1或2的组合物，其中尼莫地平与磷脂的重量比例1∶1-1∶100。
4.如权利要求1的组合物，其中环糊精及其衍生物选自β-环糊精、2-羟丙基-β-环糊精、3-羟丙基-β-环糊精、羟乙基-β-环糊精以及它们的混合物。
5.如权利要求1或4的组合物，其中尼莫地平和环糊精及其衍生物的比例1∶1至1∶20。
6.如权利要求1的组合物，其中表面活性剂选自吐温-20、吐温-80、聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、泊洛沙姆以及它们组成的混合体系。
7.如权利要求1或6的组合物，其中尼莫地平与表面活性剂的重量比例为1∶30-1∶500。
8.如权利要求1-7之一的组合物，还包括可药用冷冻干燥赋形剂，所述选自甘露醇、山梨醇、氯化钠、葡萄糖、果糖、蔗糖、木糖醇、乳糖以及它们的混合物。
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| CN102266336A (zh) * | 2010-06-04 | 2011-12-07 | 张兆勇 | 一种盐酸贝尼地平制剂及其制备方法 |
| CN104706597B (zh) * | 2015-04-02 | 2018-04-03 | 天津中医药大学 | 一种用于鼻腔给药的尼莫地平脂质体及其制备方法 |
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