CN101632681A - 甘油果糖脂质体药物组合物注射剂及制备方法 - Google Patents
甘油果糖脂质体药物组合物注射剂及制备方法 Download PDFInfo
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- CN101632681A CN101632681A CN200910141964A CN200910141964A CN101632681A CN 101632681 A CN101632681 A CN 101632681A CN 200910141964 A CN200910141964 A CN 200910141964A CN 200910141964 A CN200910141964 A CN 200910141964A CN 101632681 A CN101632681 A CN 101632681A
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Abstract
本发明提供一种甘油果糖脂质体药物组合物注射剂及制备方法。所述的甘油果糖脂质体药物组合物，其特征在于由如下重量份组分制成：甘油2份，果糖1份，磷脂5～20份，胆固醇1.5～2份，脱氧胆酸钠1～1.5份，氯化钠0.1～0.5份。本发明通过特定辅料和原辅料配比，采用逆相蒸发法制成本发明的甘油果糖脂质体注射剂，制剂稳定，解决了现有技术中甘油果糖注射剂稳定性不好、pH值变化大的问题，更适于临床应用。
Description
技术领域
本发明涉及一种脂质体制剂，具体涉及甘油果糖脂质体药物组合物注射剂及制备方法，属于医药技术领域。
背景技术
甘油果糖注射液是高渗制剂，通过高渗透性脱水，能使脑水分含量减少，消除脑水肿，降低颅内压，使病人昏迷状态早日清醒，减轻致残，它能透过血脑屏障进入脑组织，氧化成磷酸化基质，是脑组织中唯一热量来源，可以改善脑循环，增加脑血流量，增加脑氧消耗量，用于头部外伤、脑血栓、颅内出血等疾患。
颅高压是神经外科最常见的疾病，长期以来临床上一直是使用甘露醇进行治疗，效果良好，但其有反跳现象、电解质紊乱、肾功能损害等许多副作用，自1961年美国Virno使用甘油降压，因其有溶血副作用而未能广泛推广。80年代以来对甘油的配伍制剂研究取得了重大的成功，在甘油中加入果糖可减少其溶血副作用，因此广泛应用于临床。
甘油果糖注射液具有对肾功能损害少和对电解质平衡干扰少的特点，使其更适于用在慢性高颅压、肾功能不全或需要较长时间脱水的病人。
现有的甘油果糖注射液，其生产工艺不合理，稳定性不好，pH值变化大，影响制剂的临床应用。中国专利CN1864693A中介绍了一种甘油果糖注射液的制备方法，同样采用普通的配方和生产工艺，并没有解决其稳定性问题。本发明将靶向给药系统的一种新剂型脂质体应用于甘油果糖注射制剂中，解决了甘油果糖稳定性不好的问题，取得意想不到的发明效果，从而完成了本发明。
脂质体(liposomes)最初是由英国学者Bangham和Standish将磷脂分散在水中进行电镜观察时发现的。磷脂分散在水中自然形成多层泡囊，每层均为脂质的双分子层；囊泡中央和各层之间被水相隔开，双分子层厚度约4nm，后来将这种类似生物膜结构的双分子小囊成为脂质体。
脂质体研究是当前一个十分活跃的领域，脂质体最早是指天然脂类化合物悬浮在水中形成的具有双层封闭结构的泡囊，现在也可以由人工合成的磷脂化合物来制备。20世纪60年代末Rahman等人首先将脂质体作为药物载体应用。脂质体适合体内降解、无毒性和无免疫原性，特别是大量试验数据证明脂质体作为药物载体可以提高药物治疗指数、降低药物毒性和减少药物副作用，并减少药物剂量等优点。
发明内容
针对目前的甘油果糖注射剂稳定性不好的问题，本发明的目的在于提供一种稳定的甘油果糖注射剂，具体地说，本发明涉及一种甘油果糖脂质体注射剂，通过特定辅料和原辅料配比，采用逆相蒸发法用脂质体进行包裹，制成甘油果糖脂质体注射剂，解决了上述存在的问题。
本发明解决的技术方案如下：
本发明提供一种甘油果糖脂质体注射剂，其特征在于由如下重量份组分制成：甘油2份，果糖1份，磷脂5～20份，胆固醇1.5～2份，脱氧胆酸钠1～1.5份，氯化钠0.1～0.5份。
作为本发明优选实施方案，上述所述的甘油果糖脂质体注射剂，其特征在于由如下重量份组分制成：甘油2份，果糖1份，磷脂8～20份，胆固醇1.5～2份，脱氧胆酸钠1～1.2份，氯化钠0.15～0.2份。
进一步地，作为优选，上述所述的甘油果糖脂质体注射剂，其特征在于组分还包括1～3份、优选1.5～2.5份的抗氧剂。所述抗氧剂没有特别限制，可以为药学上常规的抗氧化剂，例如抗氧剂选自亚硫酸氢钠、焦亚硫酸钠、L-半胱氨酸、硫脲、甲醛合亚硫酸氢钠、维生素E、抗坏血酸棕榈酸酯、叔丁基对羟基茴香醚中的一种或几种。
如果需要，本发明上述所述的甘油果糖脂质体注射剂，其特征在于组分还可以包括使pH值调节至4.5～5.5的药学上可接受的缓冲盐溶液，例如缓冲盐溶液选自磷酸盐缓冲液、枸橼酸盐缓冲液、碳酸盐缓冲液、硼酸盐缓冲液、醋酸盐缓冲液中的一种或几种。
其中，上述所述的甘油果糖脂质体注射剂，其中所述的磷脂可以选自天然磷脂或者合成磷脂，天然磷脂例如为蛋黄卵磷脂、氢化蛋黄磷脂、蛋黄磷脂酰甘油、蛋黄磷脂酰丝氨酸、蛋黄磷脂酰肌醇、大豆磷脂、氢化大豆磷脂、大豆磷脂酰甘油、大豆磷脂酰丝氨酸或大豆磷脂酰肌醇中的一种或几种；合成磷脂例如为二油酰磷脂酰胆碱、二硬脂酸磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二油酰磷脂酰甘油、二硬脂酸磷脂酰甘油、二棕榈酰磷脂酰甘油、二肉豆蔻酰磷脂酰甘油或二月桂酰磷脂酰甘油中的一种或几种。
作为本发明最优选实施方式之一，所述的甘油果糖脂质体注射剂，其特征在于由如下组分制成1瓶甘油果糖脂质体注射剂：甘油25g，果糖12.5g，蛋黄卵磷脂250g，胆固醇20g，脱氧胆酸钠15g，维生素E 30g，氯化钠2.25g，pH值4.5的醋酸-醋酸钠缓冲液50mL。
作为本发明另一最优选实施方式，所述的甘油果糖脂质体注射剂，其特征在于由如下组分制成1瓶甘油果糖脂质体注射剂：甘油50g，果糖25g，大豆磷脂酰肌醇200g，胆固醇50g，脱氧胆酸钠25g，叔丁基对羟基茴香醚40g，氯化钠4.5g，pH值5.0的磷酸二氢钠-磷酸氢二钠缓冲液50mL。
本发明上述所述的甘油果糖脂质体注射剂，其特征在于是通过包括如下步骤制成的：(1)将磷脂、胆固醇、脱氧胆酸钠和抗氧剂溶于有机溶剂中成油相；(2)将甘油、果糖和氯化钠溶于水或缓冲盐溶液中成水相；(3)将上述油相和水相混合，搅拌形成水/油型(W/O型)乳剂，加热搅拌蒸发，当达到粘稠状态时，再加入水或缓冲盐溶液，继续加热搅拌蒸发除去残留有机溶剂，超声，转移至高速匀质搅拌机中，搅拌匀质，即得甘油果糖脂质体注射剂。
上述所述的甘油果糖脂质体注射剂，其中所述有机溶剂，可以选自氯仿、乙醇、甲醇、叔丁醇、正丁醇、异丙醇、丙酮、乙醚、苯甲醇、正己烷中的一种或几种。
作为本发明另一个发明目的，提供一种制备上述所述的甘油果糖脂质体注射剂的方法，制备步骤为：(1)将磷脂、胆固醇、脱氧胆酸钠和抗氧剂溶于有机溶剂中成油相；(2)将甘油、果糖和氯化钠溶于水或缓冲盐溶液中成水相；(3)将上述油相和水相混合，搅拌形成水/油型(W/O型)乳剂，加热搅拌蒸发，当达到粘稠状态时，再加入水或缓冲盐溶液，继续加热搅拌蒸发除去残留有机溶剂，超声，转移至高速匀质搅拌机中，搅拌匀质，即得甘油果糖脂质体注射剂。
上述所述的制备方法，其中的有机溶剂，例如可以选自氯仿、乙醇、甲醇、叔丁醇、正丁醇、异丙醇、丙酮、乙醚、苯甲醇、正己烷中的一种或几种。
本发明提供的甘油果糖脂质体注射剂，进行稳定性试验考察，在高温60℃、光照4500Lx条件下放置10天，各项检测指标均无明显变化；在高温40℃、相对湿度75％±5％条件下加速试验6个月，各项检测指标没有明显变化；在高温25℃、相对湿度60％±10％条件下长期试验18个月，各项检测指标没有明显变化。
本发明提供的甘油果糖脂质体制剂，进行急性毒性试验、异常毒性试验和热源检查，均符合规定，安全性得到证明。
本发明提供的甘油果糖脂质体注射剂，与现有技术相比，具有意想不到的效果，主要优点如下：
(1)甘油和果糖被包裹于脂质体内，解决了稳定性不好的问题，保证了产品质量；
(2)药物载体脂质体体内降解、无毒性和无免疫原性，而且可以提高药物治疗指数、降低药物毒性和减少药物副作用；
(3)采用常规的工艺设备，可工业规模、高效率生产，产品质量稳定，是一种独特和普遍适用的，低成本的工业化制备方法。
具体实施方式
以下通过实施例进一步说明本发明，但不应理解为对本发明的限制。
实施例1 甘油果糖脂质体的制备
处方：甘油 25g
果糖 12.5g
蛋黄卵磷脂 250g
胆固醇 20g
脱氧胆酸钠 15g
维生素E 30g
氯化钠 2.25g
制备工艺
(1)将250g蛋黄卵磷脂、20g胆固醇、15g脱氧胆酸钠和30g维生素E溶于500ml的正己烷中；
(2)将甘油25g、果糖12.5g和氯化钠2.25g溶于200ml水中；
(3)将二者混合，搅拌，形成W/O型乳剂，加热搅拌蒸发，当混合物达到粘稠状态时，再加入50mlpH值4.5醋酸-醋酸钠缓冲液，继续加热搅拌蒸发除去残留正己烷，超声30min，转移至高速匀质搅拌机中，搅拌匀质30min，得甘油果糖脂质体注射液。
对比例1 甘油果糖脂质体的制备
处方： 甘油 25g
果糖 12.5g
蛋黄卵磷脂 260g
胆固醇 18g
脱氧胆酸钠 10g
维生素E 10g
氯化钠 2.25g
制备工艺
(1)将260g蛋黄卵磷脂、18g胆固醇、10g脱氧胆酸钠和10g维生素E溶于500ml的正己烷中；
(2)将甘油25g、果糖12.5g和氯化钠2.25g溶于200ml水中；
(3)将二者混合，搅拌，形成W/O型乳剂，加热搅拌蒸发，当混合物达到粘稠状态时，再加入50mlpH值4.5醋酸-醋酸钠缓冲液，继续加热搅拌蒸发除去残留正己烷，超声30min，转移至高速匀质搅拌机中，搅拌匀质30min，得甘油果糖脂质体注射液。
实施例2 甘油果糖脂质体的制备
处方： 甘油 50g
果糖 25g
大豆磷脂酰肌醇 200g
胆固醇 50g
脱氧胆酸钠 25g
叔丁基对羟基茴香醚 40g
氯化钠 4.5g
制备工艺
(1)将200g大豆磷脂酰肌醇、50g胆固醇、25g脱氧胆酸钠和40g叔丁基对羟基茴香醚溶于500ml的正丁醇中；
(2)将甘油50g、果糖25g和氯化钠4.5g溶于200ml水中；
(3)将二者混合，搅拌，形成W/O型乳剂，加热搅拌蒸发，当混合物达到粘稠状态时，再加入50mlpH值5.0磷酸二氢钠-磷酸氢二钠缓冲液，继续加热搅拌蒸发除去残留正己烷，超声30min，转移至高速匀质搅拌机中，搅拌匀质30min，得甘油果糖脂质体注射液。
对比例2 甘油果糖脂质体的制备
处方： 甘油 50g
果糖 25g
大豆磷脂酰肌醇 120g
胆固醇 55g
脱氧胆酸钠 20g
叔丁基对羟基茴香醚 80g
氯化钠 4.5g
制备工艺
(1)将120g大豆磷脂酰肌醇、55g胆固醇、20g脱氧胆酸钠和80g叔丁基对羟基茴香醚溶于800ml的正丁醇中；
(2)将甘油50g、果糖25g和氯化钠4.5g溶于200ml水中；
(3)将二者混合，搅拌，形成W/O型乳剂，加热搅拌蒸发，当混合物达到粘稠状态时，再加入50mlpH值5.0磷酸二氢钠-磷酸氢二钠缓冲液，继续加热搅拌蒸发除去残留正己烷，超声30min，转移至高速匀质搅拌机中，搅拌匀质30min，得甘油果糖脂质体注射液。
试验例1 包封率的测定
取实施例制备的脂质体制剂，高效液相色谱法检测甘油和果糖的总含量为M，选用柱色谱法分离脂质体。
取1.5g葡聚糖凝胶G-50，用pH6.8磷酸盐缓冲液浸泡溶胀12h以上，装入层析柱内(200×10mm)，用上述磷酸盐缓冲液冲洗平衡，分别取实施例1-2和对比例1-2得到的甘油果糖脂质体制剂1.5ml，加入层析住顶部，用磷酸盐缓冲液50ml洗脱，流速1.0ml/min，收集的洗脱液加入破膜剂(乙醇∶苯甲醇＝6∶1)50ml，混匀，高效液相色谱法检测甘油和果糖的含量M1。
包封率％＝M1/M×100％.
表1包封率测定结果
由以上结果可知，本发明范围内的实施例处方配比制得的脂质体包封率很高，基本符合实际生产要求；而本发明范围外的对比例处方配比制得的脂质体包封率很低，和实施例相比有明显的差距，不适合生产要求。
试验例2 粒径的检测
取实施例1-2和对比例1-2制备的脂质体制剂，采用显微图像分析仪测定脂质体的粒径分布，结果如表2：
表2粒径检测结果
由以上结果可知，实施例1-2制得的脂质体显球状、椭圆状，粒径均匀，范围为80-200nm；对比例1-2制得的脂质体形状不定，大小不一，粒径不均匀，范围为200-800nm。
稳定性考察
将以上各实施例制备的样品与上市的甘油果糖注射液(山东华鲁制药有限公司生产，批号20081024)在高温60℃、光照4500Lx条件下放置10天进行影响因素试验考察，结果见表1；在高温40℃、相对湿度75％±5％条件下6个月，进行加速试验考察，结果见表2；在高温25℃、相对湿度60％±10％条件下18个月，进行长期试验考察，检测各项质量指标的变化，结果见表3。
表1影响因素结果
表2 加速试验结果
表3 长期试验结果
由以上结果发现加速3月、6月，长期12月、18月时上市的甘油果糖注射液澄明度不符合规定，pH值下降较大，含量降低明显，有关物质升高；而本发明制备的样品外观性状没有明显变化，为无色澄明液体，澄明度、pH值、含量和有关物质也没有明显的变化。说明本发明制备的样品长期贮存质量稳定性更好。
已经根据优选实施例对本发明作了描述。应当理解的是前面的描述和实施例仅仅为了举例说明本发明而已。在不偏离本发明的精神和范围的前提下，本领域技术人员可以设计出本发明的多种替换方案和改进方案，其均应被理解为在本发明的保护范围之内。
Claims (9)
1、一种甘油果糖脂质体注射剂，其特征在于由如下重量份组分制成：甘油2份，果糖1份，磷脂5～20份，胆固醇1.5～2份，脱氧胆酸钠1～1.5份，氯化钠0.1～0.5份。
2、一种甘油果糖脂质体注射剂，其特征在于由如下重量份组分制成：甘油2份，果糖1份，磷脂8～20份，胆固醇1.5～2份，脱氧胆酸钠1～1.2份，氯化钠0.15～0.2份。
3、根据权利要求1-2所述的甘油果糖脂质体注射剂药物组合物，其特征在于组分还可包括1～3份、优选1.5～2.5份的抗氧剂，例如抗氧剂选自亚硫酸氢钠、焦亚硫酸钠、L-半胱氨酸、硫脲、甲醛合亚硫酸氢钠、维生素E、抗坏血酸棕榈酸酯、叔丁基对羟基茴香醚中的一种或几种。
4、根据权利要求1-3所述的甘油果糖脂质体注射剂，其特征在于组分还可以包括使pH值调节至4.5～5.5的药学上可接受的缓冲盐溶液，例如缓冲盐溶液选自磷酸盐缓冲液、枸橼酸盐缓冲液、碳酸盐缓冲液、硼酸盐缓冲液、醋酸盐缓冲液中的一种或几种。
5、根据权利要求1-4所述的甘油果糖脂质体注射剂，其特征在于磷脂选自天然磷脂或者合成磷脂，天然磷脂例如为蛋黄卵磷脂、氢化蛋黄磷脂、蛋黄磷脂酰甘油、蛋黄磷脂酰丝氨酸、蛋黄磷脂酰肌醇、大豆磷脂、氢化大豆磷脂、大豆磷脂酰甘油、大豆磷脂酰丝氨酸或大豆磷脂酰肌醇中的一种或几种；合成磷脂例如为二油酰磷脂酰胆碱、二硬脂酸磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二油酰磷脂酰甘油、二硬脂酸磷脂酰甘油、二棕榈酰磷脂酰甘油、二肉豆蔻酰磷脂酰甘油或二月桂酰磷脂酰甘油中的一种或几种。
6、根据权利要求1-5所述的甘油果糖脂质体注射剂，其特征在于由如下组分制成1瓶甘油果糖脂质体注射剂：甘油25g，果糖12.5g，蛋黄卵磷脂250g，胆固醇20g，脱氧胆酸钠15g，维生素E 30g，氯化钠2.25g，pH值4.5的醋酸-醋酸钠缓冲液50mL。
7、根据权利要求1-5所述的甘油果糖脂质体注射剂，其特征在于由如下组分制成1瓶甘油果糖脂质体注射剂：甘油50g，果糖25g，大豆磷脂酰肌醇200g，胆固醇50g，脱氧胆酸钠25g，叔丁基对羟基茴香醚40g，氯化钠4.5g，pH值5.0的磷酸二氢钠-磷酸氢二钠缓冲液50mL。
8、根据权利要求1-7所述的甘油果糖脂质体注射剂，其特征在于是通过包括如下步骤制成的：(1)将磷脂、胆固醇、脱氧胆酸钠和抗氧剂溶于有机溶剂中成油相；(2)将甘油、果糖和氯化钠溶于水或缓冲盐溶液中成水相；(3)将上述油相和水相混合，搅拌形成水/油型(W/O型)乳剂，加热搅拌蒸发，当达到粘稠状态时，再加入水或缓冲盐溶液，继续加热搅拌蒸发除去残留有机溶剂，超声，转移至高速匀质搅拌机中，搅拌匀质，即得甘油果糖脂质体注射剂。
9、根据权利要求6所述的甘油果糖脂质体注射剂，其中所述有机溶剂选自氯仿、乙醇、甲醇、叔丁醇、正丁醇、异丙醇、丙酮、乙醚、苯甲醇、正己烷中的一种或几种。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102526099A (zh) * | 2011-12-23 | 2012-07-04 | 蚌埠丰原涂山制药有限公司 | 一种甘油果糖氯化钠注射液及其制备方法 |
| CN102657677A (zh) * | 2012-04-28 | 2012-09-12 | 天津金耀集团有限公司 | 一种甘油果糖氯化钠注射液 |
| CN103083230A (zh) * | 2013-01-18 | 2013-05-08 | 蚌埠丰原涂山制药有限公司 | 一种含果糖的注射液及其制备方法 |
| CN112624018A (zh) * | 2021-01-27 | 2021-04-09 | 罗祥富 | 一种神经外科用甘油果糖装罐机器 |
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| CN1864693A (zh) * | 2005-05-18 | 2006-11-22 | 曾列丹 | 一种甘油果糖注射液及其制备方法 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526099A (zh) * | 2011-12-23 | 2012-07-04 | 蚌埠丰原涂山制药有限公司 | 一种甘油果糖氯化钠注射液及其制备方法 |
| CN102657677A (zh) * | 2012-04-28 | 2012-09-12 | 天津金耀集团有限公司 | 一种甘油果糖氯化钠注射液 |
| CN102657677B (zh) * | 2012-04-28 | 2013-03-06 | 天津金耀集团有限公司 | 一种甘油果糖氯化钠注射液 |
| CN103083230A (zh) * | 2013-01-18 | 2013-05-08 | 蚌埠丰原涂山制药有限公司 | 一种含果糖的注射液及其制备方法 |
| CN103083230B (zh) * | 2013-01-18 | 2014-07-30 | 安徽丰原药业股份有限公司 | 一种含果糖的注射液及其制备方法 |
| CN112624018A (zh) * | 2021-01-27 | 2021-04-09 | 罗祥富 | 一种神经外科用甘油果糖装罐机器 |
| CN112624018B (zh) * | 2021-01-27 | 2022-06-28 | 青岛大学附属医院 | 一种神经外科用甘油果糖装罐机器 |
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