CN106063779A - 一种维生素k1药物的新剂型及制备方法 - Google Patents

一种维生素k1药物的新剂型及制备方法 Download PDF

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CN106063779A
CN106063779A CN201610406120.0A CN201610406120A CN106063779A CN 106063779 A CN106063779 A CN 106063779A CN 201610406120 A CN201610406120 A CN 201610406120A CN 106063779 A CN106063779 A CN 106063779A
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顾春燕
刘蓓
黄臻辉
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Add Medicine To First Biochemical Pharmaceutcal Corp Ltd In Shanghai
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Abstract

本发明公开了一种维生素K1 的新剂型，形成胶束载药系统及其制备方法，所述维生素K1 胶束载药系统是维生素K1 与聚乙二醇化磷脂的共聚物，其能在水中形成自组装纳米粒。本发明创新的将维生素K1 包载于mPEG‑PE聚合物胶束之中，提高了其在水中的溶解度，避免了聚山梨酯80 具有导致过敏毒性的辅料，可以减少或避免维生素K1 注射液的不良反应，增加了药物的安全性。

Description

一种维生素K1药物的新剂型及制备方法
技术领域
本发明属于药物制剂领域，具体涉及一种安全的，稳定的维生素K1胶束载药系统及其制备方法。
背景技术
维生素K1是2-甲基-3-(3,7,11,15-四甲基-2-十六碳烯基)-1,4-萘二酮的反式和顺式异构体的混合物，同时也是植物中维生素K的主要形式，其结构式如图1所示。
维生素K1属于脂溶性维生素类药物，是肝脏合成因子所必须的物质 补充适量的维生素K1可促使肝脏合成凝血酶原，起到止血的作用。目前维生素K1主要制备成注射液，在临床上应用于凝血酶原过低维生素K1缺乏症新生儿自然出血症等疾病的治疗。然而，目前临床上使用的维生素K1注射液存在严重的不良反应，有研究者认为其不良反应可能与注射剂中含有助溶剂聚山梨酯80和丙二醇等有关。2011年12月国家食品药品监督管理局和国家药品不良反应监测中心同时公布，警惕维生素K1注射液的严重过敏反应。因此，有必要开发一种新剂型使得维生素K1溶解度增加的同时减少或避免其不良反应的发生。
胶束载体是一种由疏水嵌段和亲水嵌段的双亲性聚合物分子自组装成的纳米颗粒，与低分子量表面活性剂相比，双亲性聚合物的临界胶团浓度(CMC)更低，这使得聚合物胶束更能对抗溶液的稀释，同时疏水嵌段组成的胶束核结构紧密，在生理环境中被大量体液稀释后，不容易解离，稳定性更好。聚乙二醇(PEG)是一种中性、无毒、具有生物相容性的亲水性聚合物，在药物制剂方面有着广泛的应用。磷脂是生物膜的组成成分，具有良好的生物降解性和生物兼容性。PEG衍生化磷脂作为药用辅料具有较好的应用价值。目前国外主要是聚乙二醇磷脂酰乙醇胺(PEG-PE)应用较多，但价格昂贵，在一定程度上制约了其广泛的应用。
发明内容
本发明提供了一种维生素K1胶束载药系统及制备方法，胶束聚合物如图2所示。
与现有技术相比，本发明具有以下优点：
(1).本发明创新的将维生素K1包载于mPEG-PE聚合物胶束之中，提高了其在水中的溶解度，避免了聚山梨酯80具有导致过敏毒性的辅料，可以减少或避免维生素K1注射液的不良反应，增加了药物的安全性。
(2).本发明的mPEG-PE是一种新型的两亲性聚合物胶束载体材料，具有较好的生物相容性和生物可降解性，毒副作用较小。该发明的聚合物胶束是一种由两亲性聚合物自发形成的热力学稳定体系，其稳定性好，载药量高。同时由于其较小的粒径，可避免内皮网状系统的吞噬，增加药物在体内的循环时间，延长药效。
(3). 本发明制剂的制备工艺简单，重现性良好，可以实现工业化生产。该制剂的包封率可达85%以上，制备工艺过程中药物的损耗较少。
附图说明
图1为本发明中维生素K1的结构式；
图2为本发明中胶束聚合物的结构式；
图3为本发明中实施例1中维生素K1磷脂酰聚乙二醇单甲醚胶束聚合物的流体力学粒径分布图；
图4为本发明中实施例1中维生素K1磷脂酰聚乙二醇单甲醚胶束聚合物的透射电子显微镜照片。
具体实施方式
通过以下具体实施例对本发明进行说明，但本发明不受这些具体实施例限定。
实验所用的聚乙二醇单甲醚，甘油二酯均购自西格玛奥德里奇（中国）公司，二异丙基乙胺和吡啶均购自梯希爱（上海）化成工业发展有限公司，维生素K1购自山东广通宝医药有限公司。
在本申请中，如无特殊说明，其余所用试剂和溶剂均购自国药集团（上海）化学试剂有限公司。
本发明提供维生素K1-mPEG-PE的制备方法，步骤如下：
(a).通过化学反应制备mPEG-PE：在氮气保护下，将甘油二酯的四氢呋喃溶液于0℃滴加到二异丙基乙胺和三氯氧磷的四氢呋喃溶液中，滴加完毕后继续搅拌2h，在0℃下，继续滴加聚乙二醇单甲醚和吡啶溶的四氢呋喃溶液，滴加完毕后于室温反应6h。过滤，向滤液中加入与三氯氧磷等摩尔量的水，搅拌1~2h，蒸掉溶剂，得固体，乙醚沉降透析后得mPEG-PE。
(b).将mPEG-PE与维生素K1以一定比例混合后，加入适量的三氯甲烷溶解，旋转蒸发除去三氯甲烷，形成聚合物药物混合膜，真空干燥过夜，除去残留的有机溶剂，加入适量注射用水，水浴超声，过滤，冻干即得维生素K1-mPEG-PE胶束。
上述mPEG-PE与维生素K1混合比例为6~20:1，优选10:1。
上述水浴超声温度为25~60℃，优选37℃；超声时间为40min；滤膜选用0.22μm。
实施例1.薄膜水化法制备维生素K1-mPEG-PE胶束
精密称取1g维生素K1与6g mPEG-PE（通过上述化学反应制得）溶解在300mL三氯甲烷中，旋转蒸发除去三氯甲烷，形成聚合物药物混合膜，真空干燥过夜，除去残留的有机溶剂。加入100mL注射用水，25℃水浴超声40min后，经0.22µm无菌微孔滤膜过滤，冻干即得。
实施例2.薄膜水化法制备维生素K1-mPEG-PE胶束
精密称取1g维生素K1与6g mPEG-PE（通过上述化学反应制得）溶解在300mL三氯甲烷中，旋转蒸发除去三氯甲烷，形成聚合物药物混合膜，真空干燥过夜，除去残留的有机溶剂。加入100mL注射用水，37℃水浴超声40min后，经0.22µm无菌微孔滤膜过滤，冻干即得。
实施例3.薄膜水化法制备维生素K1-mPEG-PE胶束
精密称取1g维生素K1与6g mPEG-PE（通过上述化学反应制得）溶解在300mL三氯甲烷中，旋转蒸发除去三氯甲烷，形成聚合物药物混合膜，真空干燥过夜，除去残留的有机溶剂。加入100mL注射用水，60℃水浴超声40min后，经0.22µm无菌微孔滤膜过滤，冻干即得。
实施例4.薄膜水化法制备维生素K1-mPEG-PE胶束
精密称取1g维生素K1与10g mPEG-PE（通过上述化学反应制得）溶解在400mL三氯甲烷中，旋转蒸发除去三氯甲烷，形成聚合物药物混合膜，真空干燥过夜，除去残留的有机溶剂。加入100mL注射用水，37℃水浴超声40min后，经0.22µm无菌微孔滤膜过滤，冻干即得。
实施例5.薄膜水化法制备维生素K1-mPEG-PE胶束
精密称取1g维生素K1与20g mPEG-PE（通过上述化学反应制得）溶解在400mL三氯甲烷中，旋转蒸发除去三氯甲烷，形成聚合物药物混合膜，真空干燥过夜，除去残留的有机溶剂。加入100mL注射用水，37℃水浴超声40min后，经0.22µm无菌微孔滤膜过滤，冻干即得。
实施例6.透析法制备维生素K1-mPEG-PE胶束
精密称取1g维生素K1与10g mPEG-PE（通过上述化学反应制得）溶解在400mL丙酮中，溶解完全后，将其装入透析袋中用水透析至丙酮除干净，经0.22µm无菌微孔滤膜过滤，冻干即得。
为了考察本制剂的一些基本的理化性质，本发明进行了如下实验：
(1).胶束粒径测定
将实施例1所得的胶束冻干制剂，加入一定的生理盐水，10秒内复溶，稀释至适当的倍数后于粒度仪下检测粒度，并通过透射电镜观察样品的形貌和大小，如图3和4所示，维生素K1-mPEG-PE胶束微观形态为分布均匀的类似球形实体，粒径约为50nm，与粒径测定结果很好的契合：
(2).包封率与载药量测定
将实施例1~6所得的胶束冻干制剂，加入一定量的生理盐水，10秒内复溶，以高效液相色谱法测得维生素K1的含量，计算包封率(EE)与载药量(DL)，具体计算公式如下，实验结果见下表1：
表1 实施例1~6所得胶束制剂包封率与载药量
序号 包封率（%） 载药量（%）
1 87.32 0.92
2 88.12 0.97
3 87.33 1.02
4 88.54 0.98
5 86.32 1.04
6 87.86 0.98
由表中结果可以看出，药物的包封率都在85%以上，制剂制备过程中药物的损耗较少。
(3). 测定本发明实施例1~6、与市售维生素K1注射液按照《中国药典》2015年版四部通则原料药与药物制剂稳定性试验指导原则进行，加速试验条件为40℃±2℃，相对湿度为75%±5%，测定样品的含量及有关物质，结果如下表2所示：
表2 实施例1~6与市售制剂加速实验结果
试验结果表明：本发明所制的样品加速6个月各项质量指标均符合质量标准要求，说明本发明制备的样品具有良好的质量稳定性。

Claims (8)

1.一种维生素K1药物新剂型，其特征在于通过磷脂酰聚乙二醇单甲醚(mPEG-PE)和维生素K1自组装，通过化学反应制备磷脂酰聚乙二醇单甲醚（mPEG-PE）后与维生素K1混合，通过水浴超声、过滤、冻干得到一种维生素K1胶束载药系统。
2.如权利要求1所述的维生素K1药物新剂型，其特征在于聚乙二醇单甲醚(mPEG)分子量为500~5000，优选mPEG1000~3000，最优选mPEG为2000。
3.如权利要求1所述的维生素K1药物新剂型，其特征在于述的磷脂酰聚乙二醇单甲醚（mPEG-PE）亲水嵌段为聚乙二醇单甲醚和疏水嵌段甘油二酯通过三氯氧磷作为过渡枢纽将两部分连接起来。
4.如权利要求1所述的维生素K1药物新剂型，其特征在于mPEG-PE与维生素K1混合比例为6~20:1，优选10:1。
5.如权利要求1所述的维生素K1药物新剂型，其特征在于上述水浴超声温度为25~60℃，优选37℃。
6.如权利要求1所述的维生素K1药物新剂型，其特征在于超声时间为40min。
7.如权利要求1所述的维生素K1药物新剂型，其特征在于滤膜选用0.22μm。
8.如权利要求1所述的维生素K1药物新剂型，其特征在于胶束粒径为20~200nm。
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