CN106176676B - 一种脂溶性药物纳米缓释胶囊的制备方法 - Google Patents
一种脂溶性药物纳米缓释胶囊的制备方法 Download PDFInfo
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Abstract
本发明一种脂溶性药物纳米缓释胶囊的制备方法,涉及细乳液聚合和生物高分子等领域。本发明采用改性壳聚糖为基材,脂溶性药物为内容药物,通过细乳液聚合的方法在位形成以改性壳聚糖为壳体脂溶药物为壳体的细乳液乳胶粒子,最后通过喷雾干燥制备了壳聚糖为壳体脂溶性药物缓释胶囊,本发明利用紫外光引发和超声的方法形成稳定剂稳定细乳液预聚体;以改性壳聚糖为纳米胶囊壳体,细乳液粒径一般为200纳米左右,粒径分布均匀;乳胶粒子方法可以形成稳定的脂溶性缓释药物细乳液;通过喷雾干燥方法形成的脂溶性药物的缓释纳米胶囊,缓释性能良好。
Description
技术领域:
本发明涉及以水溶性壳聚糖和油性单体形成胶囊壳体;并用脂溶性药物在位包囊形成核心,制备成纳米缓释胶囊。此方法涉及细乳液聚合和生物高分子等领域。
背景技术:
传统药物释放方式,药物浓度只能在人体内的维持较短的时间,血液或在体内组织中的药物浓度波动较大。因此,制备能够缓慢释放药物成分的缓释性长效。药品在治疗中经常是非常需要的。要制备缓释长效药品,关键是要制备能使被承载的药物缓慢释放的载体材料。现在已发明了多种缓释材料,例如,用聚羟基丁酸酯包裹安定,用壳聚糖作为缓释体等。传统的缓释载体一般尺寸位微米级别,纳米级别的载体由于容易产生团聚,因此一般应用较少。
壳聚糖又称脱乙酰甲壳素,是由自然界广泛存在的几丁质经过脱乙酰作用得到的,化学名称为聚葡萄糖胺(1-4)-2-氨基-B-D葡萄糖。自1859年,法国人Rouget首先得到壳聚糖后,这种天然高分子的生物官能性和相容性、血液相容性、安全性、微生物降解性等优良性能被各行各业广泛关注,在医药、生化和生物医学工程等诸多领域的应用研究取得了重大进展。
细乳液聚合与普通乳液聚合的区别是在体系中引进助乳化剂,并采用了微乳化工艺,这样使原来较大的单体液滴被分散成更小的单体亚微液滴。细乳液聚合在合成上具有一定的优点,比如粒径尺寸为50~500纳米。以胶束形式存在的乳化剂转移到单体亚微液滴表面上,胶束数量减少,因此单体亚微液滴就成为引发成核的主要位置。由于单体液滴成核,单体液滴成为聚合场所,因此一些药物可以溶解在单体或溶剂中,聚合成纳米胶囊。通过研究发现,单体液滴刚成为聚合场所时,一些天然聚合物如壳聚糖等有助于将单体稳定成亚微米单体液滴。因此壳聚糖可以在细乳液聚合中起到稳定单体小液滴的作用。在酸性水溶液中,壳聚糖接枝物的溶解度变大,可以使用一些油溶性单体和壳聚糖在小液滴壳体发生接枝反应,形成纳米胶囊的壳体;同时加入微量的交联剂使脂溶性药物被约束在胶囊内部,在使用中起到缓释作用。
发明内容:
本发明的目的是通过细乳液聚合形成接枝壳聚糖壳体,同时一步法使缓释药物约束在胶囊内部,分离后使药物胶囊可以应用在脂溶性药物缓释方面。
以上聚合物的合成,按照下述步骤进行:
(1)含壳聚糖水相的配制:
室温下,将壳聚糖加入一定酸性的去离子水中,温和搅拌至完全溶解;加入定量丙烯酸钠,搅拌15分钟后形成水相体系;
(2)含药物油相的配制:
在室温下,一定量的药物溶解在油性溶剂中;加入少量的单体和交联剂混合后搅拌15分钟后形成油相体系;
(3)壳聚糖为壳体脂溶性药物缓释胶囊的制备
将步骤(1)形成含壳聚糖水相和步骤(2)含药物油相按照一定的比例混合,混合后用磁力搅拌机搅拌15分钟预乳化,加入少量的光引发剂后,用450W超声细胞粉碎机以90%的输出功率超声5分钟(冰水冷却)。将2000W紫外光源放置在超声波细胞粉碎机内,同时用30%的输出功率超声45分钟,温度维持在60℃,得到稳定的细乳液预聚体;细乳液预聚体转移进入换氮后的反应釜中,加入引发剂升温后引发聚合,反应5小时结束反应。得到的乳液经过喷雾干燥后得到壳聚糖为壳体脂溶性药物缓释胶囊。
其中步骤(1)中壳聚糖用量和去离子水质量用量比为1-4:100,pH值为5;
其中步骤(1)加入的丙烯酸钠用量和去离子水质量用量比为3:100。
其中步骤(2)中脂溶性药物有维生素A、D、E或K等,以及可溶解在油性溶剂中的药物等;油性溶剂可以为植物油,油酸乙酯,苯甲酸苄酯等,脂溶性药物和油性溶剂质量比为5-20:100;单体为甲基丙烯酸甲酯,用量和油性溶剂质量用量比为10-20:100;交联剂为1,3-二甘油醇酸二丙烯酸酯,用量和甲基丙烯酸甲酯单体质量用量比为0.1-1:100。
其中步骤(3)步骤(1)形成含壳聚糖水相和步骤(2)含药物油相混合质量比例比为100:10-30;
其中步骤(3)中光引发剂为2-羟基-2-甲基-1-苯基丙酮、1-羟基环己基苯基甲酮和2-甲基-2-(4-吗啉基)-1-[4-(甲硫基)苯基]-1-丙酮等,用量和含壳聚糖水相质量用量比为2:1000;
其中步骤(3)中引发剂为过硫酸钾,过硫酸钾的用量和含壳聚糖水相质量用量比为5:1000;聚合反应温度为80℃。
本发明的优点在于本发明采用改性壳聚糖为基材,脂溶性药物为内容药物,通过细乳液聚合的方法在位形成以改性壳聚糖为壳体脂溶药物为壳体的细乳液乳胶粒子,最后通过喷雾干燥制备了壳聚糖为壳体脂溶性药物缓释胶囊,具有以下优点:1、利用紫外光引发和超声的方法形成稳定剂稳定细乳液预聚体;2、以改性壳聚糖为纳米胶囊壳体,细乳液粒径一般为200纳米左右,粒径分布均匀;乳胶粒子方法可以形成稳定的脂溶性缓释药物细乳液; 3、通过喷雾干燥方法形成的脂溶性药物的缓释纳米胶囊,缓释性能良好。
具体实施方式
下面结合实例,对本发明作进一步的详细说明。
实施例1
(1)含壳聚糖水相的配制:
室温下,将1克壳聚糖加入pH值为5的100克去离子水中,温和搅拌至完全溶解;加入3克丙烯酸钠,搅拌15分钟后形成水相体系;
(2)含药物油相的配制:
在室温下,5克的维生素A溶解在100克植物油中;加入10克甲基丙烯酸甲酯单体和0.01克1, 3-二甘油醇酸二丙烯酸酯混合后搅拌15分钟后形成油相体系;
(3)壳聚糖为壳体脂溶性药物缓释胶囊的制备
将步骤(1)形成含壳聚糖水相100克和步骤(2)含药物油相10克混合,混合后用磁力搅拌机搅拌15分钟预乳化,加入0.2克2-羟基-2-甲基-1-苯基丙酮光引发剂后,用450W超声细胞粉碎机90%功率超声5分钟(冰水冷却)。将2000W紫外光源放置在超声波细胞粉碎机内,同时用30%功率超声45分钟,得到稳定的细乳液预聚体;细乳液预聚体转移进入换氮后的反应釜中,加入0.5克过硫酸钾引发剂升温至80℃后引发聚合,反应5小时结束反应。得到的乳液经过喷雾干燥后得到壳聚糖为壳体脂溶性药物缓释胶囊。
脂溶性药物缓释胶囊粒径测试为210纳米,分散指数0.06(马尔文激光粒径分析仪数据)。将1克药物放置在流动的70%乙醇溶液中,流动速度为20克/小时,缓释时间为28小时,缓释量平缓,28小时后维生素A在脂溶性药物缓释胶囊残余量为4%(比较初始维生素A在脂溶性药物缓释胶囊的浓度)。
实施例2
(1)含壳聚糖水相的配制:
室温下,将4克壳聚糖加入pH值为5的100克去离子水中,温和搅拌至完全溶解;加入3克丙烯酸钠,搅拌15分钟后形成水相体系;
(2)含药物油相的配制:
在室温下,20克的维生素A溶解在100克植物油中;加入20克甲基丙烯酸甲酯单体和0.2克1, 3-二甘油醇酸二丙烯酸酯混合后搅拌15分钟后形成油相体系;
(3)壳聚糖为壳体脂溶性药物缓释胶囊的制备
将步骤(1)形成含壳聚糖水相100克和步骤(2)含药物油相30克混合,混合后用磁力搅拌机搅拌15分钟预乳化,加入0.2克2-羟基-2-甲基-1-苯基丙酮光引发剂后,用450W超声细胞粉碎机90%功率超声5分钟(冰水冷却)。将2000W紫外光源放置在超声波细胞粉碎机内,同时用30%功率超声45分钟,得到稳定的细乳液预聚体;细乳液预聚体转移进入换氮后的反应釜中,加入0.5克过硫酸钾引发剂升温至80℃后引发聚合,反应5小时结束反应。得到的乳液经过喷雾干燥后得到壳聚糖为壳体脂溶性药物缓释胶囊。
脂溶性药物缓释胶囊粒径测试为160纳米,分散指数0.09(马尔文激光粒径分析仪数据)。将1克药物放置在流动的70%乙醇溶液中,流动速度为20克/小时,缓释时间为72小时,缓释量平缓,72小时后维生素A在脂溶性药物缓释胶囊残余量为3%(比较初始维生素A在脂溶性药物缓释胶囊的浓度)。
上述对实施例的描述是为便于该技术领域的普通技术人员能理解和应用本发明。熟悉本领域的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于这里的实施例,本领域技术人员根据本发明的揭示,对于本发明做出的修改都应该在本发明的保护范围之内。
Claims (1)
1.一种脂溶性药物纳米缓释胶囊的制备方法,其特征在于按照下述步骤进行:
(1)含壳聚糖水相的配制:
室温下,将壳聚糖加入一定酸性的去离子水中,温和搅拌至完全溶解;加入定量丙烯酸钠,搅拌15分钟后形成水相体系;
(2)含药物油相的配制:
在室温下,一定量的药物溶解在油性溶剂中;加入少量的单体和交联剂混合后搅拌15分钟后形成油相体系;
(3)壳聚糖为壳体脂溶性药物缓释胶囊的制备
将步骤(1)形成含壳聚糖水相和步骤(2)含药物油相按照一定的比例混合,混合后用磁力搅拌机搅拌15分钟预乳化,加入少量的光引发剂后,用450W超声细胞粉碎机以90%的输出功率超声5分钟,并保持冰水冷却;
将2000W紫外光源放置在超声波细胞粉碎机内,同时用30%的输出功率超声45分钟,温度维持在60℃,得到稳定的细乳液预聚体;细乳液预聚体转移进入换氮后的反应釜中,加入引发剂升温后引发聚合,反应5小时结束反应;
得到的乳液经过喷雾干燥后得到壳聚糖为壳体脂溶性药物缓释胶囊;
其中步骤(1)中壳聚糖用量和去离子水质量用量比为1-4:100,pH值为5;
其中步骤(1)加入的丙烯酸钠用量和去离子水质量用量比为3:100;
其中步骤(2)中脂溶性药物为维生素A、D、E或K;油性溶剂为植物油,油酸乙酯,苯甲酸苄酯,脂溶性药物和油性溶剂质量比为5-20:100;单体为甲基丙烯酸甲酯,用量和油性溶剂质量用量比为10-20:100;交联剂为1, 3-二甘油醇酸二丙烯酸酯,用量和单体质量用量比为0.1-1:100;
其中步骤(3)中步骤(1)形成的含壳聚糖水相和步骤(2)的含药物油相混合质量比例比为100:10-30;
其中步骤(3)中光引发剂为2-羟基-2-甲基-1-苯基丙酮、1-羟基环己基苯基甲酮或2-甲基-2-(4-吗啉基)-1-[4-(甲硫基)苯基]-1-丙酮,用量和含壳聚糖水相质量用量比为2:1000;
其中步骤(3)中引发剂为过硫酸钾,过硫酸钾的用量和含壳聚糖水相质量用量比为5:1000;聚合反应温度为80℃。
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