CN105456228B - 一种包载阿瑞吡坦纳米晶体脂质微囊及其制备方法 - Google Patents
一种包载阿瑞吡坦纳米晶体脂质微囊及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种包载阿瑞吡坦纳米晶体脂质微囊及其制备方法，属于医药技术领域。通过如下方法制备：采用研磨法、高速气流粉碎或高压均质将阿瑞吡坦制备成阿瑞吡坦纳米晶体，再将磷脂与阿瑞吡坦纳米晶体混合乳化，除去液相干燥即可得到阿瑞吡坦纳米晶体脂质微囊。制得的包载阿瑞吡坦纳米晶体脂质微囊提高了阿瑞吡坦纳米晶体的稳定性，且脂质包载的纳米晶体增加其被机体胃肠粘膜吸收的速度和吸收量，从而达到较高的生物利用度和快速发挥药效的作用；包载阿瑞吡坦纳米晶体脂质微囊制备方法条件温和，简单可控，制备成本低，适宜于规模化生产。
Description
技术领域
本发明属于医药技术领域，具体涉及包载阿瑞吡坦纳米晶体的脂质微囊，还涉及该脂质微囊的制备方法。
背景技术
阿瑞吡坦(aprepitant)临床用于化疗后的急性和延迟性恶心或呕吐发作，是美国FDA批准上市的第一个神经激肽-l(neurokinin-l，NK-1)受体拮抗剂，可通过与NK-1受体结合来阻滞P物质，从而治疗由P物质介导的呕吐、抑郁等相关疾病。但阿瑞吡坦在水中的溶解度仅为0.55μg/m1，胃肠道吸收少，口服生物利用度低，限制了阿瑞吡坦药效的发挥。因此，研究一种有效的剂型和技术提高阿瑞吡坦的口服吸收非常必要。
纳米晶体技术即将药物晶体减小到纳米尺度的技术，是一种新颖的增加难溶性药物溶解度的药剂学技术。纳米晶体技术通过降低药物粒径至纳米级，可显著增加药物饱和溶解度和溶出速率。药物纳米结晶又称药物纳米混悬剂，即由药物纳米晶体和表面活性剂或聚合物等产生稳定空间结构的稳定剂组成的多相分散体系，其载药量可达到100％，有利于药物临床应用。
专利(申请号200310208880.7)公开了一种阿瑞吡坦混悬剂及其制备方法，该专利以共聚维酮和聚维酮作为稳定剂，采用了溶剂沉淀法制备了粒子平均粒径为100nm～500nm、药物浓度为0.1～0.5mg/ml的阿瑞吡坦纳米混悬剂。陆小洁等(中国医药工业杂志,2013,44(12):1236-1239)也报道了一种阿瑞吡坦纳米混悬剂的制备工艺。其采用高压均质法制备了平均粒径为352.4nm、45分钟溶出率为93.5％的阿瑞吡坦纳米混悬剂。但是，他们制备的阿瑞吡坦纳米混悬剂为液体制剂，稳定性差，纳米晶体颗粒容易凝聚为大颗粒，从而降低其吸收和生物利用度。再者，其制备的纳米混悬液不宜进一步开发其他制剂，限制了其应用。
发明内容
本发明的目的在于解决阿瑞吡坦溶解度低，吸收差，生物利用度低，以及其他方法制备的阿瑞吡坦混悬液的缺点，提供一种包载阿瑞吡坦纳米晶体脂质微囊新剂型；另一目的在于提供其制备方法。
本发明的目的是通过以下技术方案实现的：
首先采用研磨法、高速气流粉碎或高压均质将阿瑞吡坦制备成阿瑞吡坦纳米晶体，再将磷脂与阿瑞吡坦纳米晶体混合乳化，除去液相干燥即可得到阿瑞吡坦纳米晶体脂质微囊。
具体包括下列步骤：
将阿瑞吡坦和稳定剂通过研磨、高速气流粉碎或高压均质制备成阿瑞吡坦平均粒径范围为50nm～400nm纳米晶体，分散在水中形成混悬液；之后，将磷脂溶于有机溶剂后与阿瑞吡坦纳米晶体混悬液混合乳化，随即除去液相干燥即可制成阿瑞吡坦纳米晶体脂质微囊。阿瑞吡坦纳米晶体脂质微囊的粒径范围为10μm～500μm。
所述稳定剂为聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、聚乙烯吡咯烷酮、羟丙甲基纤维素和泊洛沙姆等中的一种或两种及以上的混合物。
本发明所述的阿瑞吡坦与稳定剂的质量比为1:0.5～1:5。
本发明所述的磷脂为大豆磷脂、卵磷脂和氢化磷脂中的一种或两种及以上的混合物。
本发明所述的除去液相干燥的方法为冷冻干燥或喷雾干燥。
本发明所述的阿瑞吡坦纳米晶体脂质微囊可以直接与药学上可接受的辅料结合制成片剂、胶囊或颗粒等剂型。
本发明的优点是：阿瑞吡坦纳米晶体脂质微囊提高了阿瑞吡坦纳米晶体的稳定性，且脂质包载的纳米晶体增加其被机体胃肠粘膜吸收的速度和吸收量，体内吸收好，从而达到较高的生物利用度和快速发挥药效的作用；包载阿瑞吡坦纳米晶体脂质微囊制备条件温和，简单可控，适宜于规模化生产，制备成本低。
附图说明
图1为阿瑞吡坦纳米晶体粒径分布图；
图2为本发明制得的包载阿瑞吡坦纳米晶体脂质微囊的投射电子显微镜图。
具体实施方式
下面实施例仅对本发明作进一步的详细说明，但应注意本发明的保护范围不应受这些实例的任何限制。
实施例1
将阿瑞吡坦20mg和聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物10mg混合后，加入适量去离子水于P7微型行星式高能球磨机中研磨60分钟(研磨15分钟，间歇10分钟，循环4次)，即得阿瑞吡坦纳米晶体混悬剂，阿瑞吡坦的浓度为0.5mg/ml。测定阿瑞吡坦纳米晶体的平均粒径为280nm。将200mg大豆磷脂溶于适量无水乙醇中，再加入上述阿瑞吡坦纳米晶体混悬液乳化，冷冻干燥即可制成阿瑞吡坦纳米晶体脂质微囊，测定其平均粒径为130μm。
实施例2
将阿瑞吡坦50mg和泊洛沙姆18850mg分散于适量去离子水中，用M-110L高压微射流纳米均质机在9000PSI压力条件下均质10个循环，即得阿瑞吡坦纳米晶体混悬剂，阿瑞吡坦的浓度为0.5mg/ml。测定阿瑞吡坦纳米晶体的平均粒径为380nm。将300mg大豆磷脂和200mg卵磷脂溶于适量无水乙醇中，再加入上述阿瑞吡坦纳米晶体混悬液乳化，冷冻干燥即可制成阿瑞吡坦纳米晶体脂质微囊，测定其平均粒径为150μm。
实施例3
将阿瑞吡坦20mg和聚乙烯吡咯烷酮K2515mg混合均匀采用高速气流粉碎机粉碎，之后分散于适量去离子水中，即得阿瑞吡坦纳米晶体混悬剂，阿瑞吡坦的浓度为1.0mg/ml。测定阿瑞吡坦纳米晶体的平均粒径为475nm。将100mg大豆磷脂和50mg氢化磷脂溶于适量无水乙醇中，再加入上述阿瑞吡坦纳米晶体混悬液乳化，喷雾干燥即可制成阿瑞吡坦纳米晶体脂质微囊，测定其平均粒径为420μm。
实施例4
将阿瑞吡坦20mg和羟丙甲基纤维素10mg混合后，加入适量去离子水于P7微型行星式高能球磨机中研磨60分钟(研磨15分钟，间歇10分钟，循环4次)，即得阿瑞吡坦纳米晶体混悬剂，阿瑞吡坦的浓度为0.5mg/ml。测定阿瑞吡坦纳米晶体的平均粒径为150nm。将200mg大豆磷脂溶于适量无水乙醇中，再加入上述阿瑞吡坦纳米晶体混悬液乳化，喷雾干燥即可制成阿瑞吡坦纳米晶体脂质微囊，测定其平均粒径为380μm。
实施例5
将阿瑞吡坦50mg、聚乙烯吡咯烷酮K2520mg和泊洛沙姆18830mg分散于适量去离子水中，用M-110L高压微射流纳米均质机在9000PSI压力条件下均质10个循环，即得阿瑞吡坦纳米晶体混悬剂，阿瑞吡坦的浓度为0.5mg/ml。测定阿瑞吡坦纳米晶体的平均粒径为340nm。将300mg卵磷脂和200mg氢化磷脂溶于适量无水乙醇中，再加入上述阿瑞吡坦纳米晶体混悬液乳化，冷冻干燥即可制成阿瑞吡坦纳米晶体脂质微囊，测定其平均粒径为150μm。
实施例6
将阿瑞吡坦20mg和聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物10mg混合均匀采用高速气流粉碎机粉碎，之后分散于适量去离子水中，即得阿瑞吡坦纳米晶体混悬剂，阿瑞吡坦的浓度为0.5mg/ml。测定阿瑞吡坦纳米晶体的平均粒径为425nm。将150mg卵磷脂溶于适量无水乙醇中，再加入上述阿瑞吡坦纳米晶体混悬液乳化，喷雾干燥即可制成阿瑞吡坦纳米晶体脂质微囊，测定其平均粒径为350μm。
应用例1
本发明制得的阿瑞吡坦纳米晶体脂质微囊的体内吸收
以大鼠在体肠循环的方法测定阿瑞吡坦纳米晶体脂质微囊的体内吸收率，与阿瑞吡坦原料粉末作对比，表示其生物利用度。方法为：取禁食12h(自由饮水)的200g左右雄性大鼠，腹腔注射戊巴比妥钠溶液(40mg/kg)，麻醉固定在手术台板上，红外灯照射保持37℃体温。沿腹中线剪开腹部约4cm,采用全肠段回流，对十二指肠上部至回肠下部剪切后分别插入直径约0.4cm的玻璃管并结扎；用37℃生理盐水冲洗肠道内容物，再换成37℃K氏营养液循环10分钟，将插管与恒流泵连接，形成回路，再换成37℃K氏营养液循环10分钟。接着将60ml供试样液(阿瑞吡坦纳米晶体脂质微囊液为复水后的分散液，浓度0.5mg/ml；阿瑞吡坦原料粉末的样液为其水分散液，浓度0.5mg/ml)以5ml/min的流速循环10min，记为0时。后将流速调至2.5ml/min，分别作为阿瑞吡坦各时间点上的样品，同时向烧杯中补加1.5ml的37℃K氏营养液，共取样7次，停止循环。采用HPLC法测定肠循环液所取样品中阿瑞吡坦的浓度。吸收半衰期计算：T1/2＝0.693/Ka(Ka为吸收速率常数)
结果显示，在2小时内，脂质微囊的吸收率为56.7％，粉末吸收率为7.6％，说明阿瑞吡坦纳米晶体脂质微囊在动物体内的生物利用度明显优于阿瑞吡坦原料粉末，2小时中生物利用度提高7.46倍。
应用例2
本发明制得的阿瑞吡坦纳米晶体脂质微囊的稳定性
将阿瑞吡坦纳米晶体脂质微囊粉末在25℃的干燥环境中放置6个月，阿瑞吡坦纳米晶体作为对照品。于第0、3和6月末取适量阿瑞吡坦纳米晶体粉末和阿瑞吡坦纳米晶体脂质微囊粉末分别分散到水中，用投射电子显微镜观察拍照，之后用imageJ软件测定统计其粒径，结果见表1。
表1纳米晶体和脂质微囊的粒径(μm)变化
由表中数据可知，随着储存时间的延长，阿瑞吡坦纳米晶体粒径显著增大，阿瑞吡坦纳米晶体脂质微囊和脂质微囊包裹的纳米晶体的粒径均无显著增大。结果表明，在25℃干燥的环境中脂质微囊包裹的纳米晶体的稳定性显著高于纳米晶体。
Claims (4)
1.包载阿瑞吡坦纳米晶体脂质微囊，其特征在于，通过如下步骤制备而成：
将阿瑞吡坦和稳定剂通过研磨、高速气流粉碎或高压均质制备成阿瑞吡坦平均粒径范围为50nm~400nm纳米晶体，分散在水中形成混悬液；之后，将磷脂溶于有机溶剂后与阿瑞吡坦纳米晶体混悬液混合乳化，随即除去液相干燥即可制成阿瑞吡坦纳米晶体脂质微囊；阿瑞吡坦纳米晶体脂质微囊的粒径范围为10μm~500μm；
所述稳定剂为聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、聚乙烯吡咯烷酮、羟丙甲基纤维素和泊洛沙姆中的一种或两种及以上的混合物；
所述磷脂为大豆磷脂、卵磷脂和氢化磷脂中的一种或两种及以上的混合物。
2.制备如权利要求1所述的包载阿瑞吡坦纳米晶体脂质微囊的方法，其特征在于：通过如下步骤实现：
将阿瑞吡坦和稳定剂通过研磨、高速气流粉碎或高压均质制备成阿瑞吡坦平均粒径范围为50nm~400nm纳米晶体，分散在水中形成混悬液；之后，将磷脂溶于有机溶剂后与阿瑞吡坦纳米晶体混悬液混合乳化，随即除去液相干燥即可制成阿瑞吡坦纳米晶体脂质微囊；阿瑞吡坦纳米晶体脂质微囊的粒径范围为10μm~500μm；
所述稳定剂为聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、聚乙烯吡咯烷酮、羟丙甲基纤维素和泊洛沙姆中的一种或两种及以上的混合物；
所述磷脂为大豆磷脂、卵磷脂和氢化磷脂中的一种或两种及以上的混合物。
3.如权利要求2所述的制备包载阿瑞吡坦纳米晶体脂质微囊的方法，其特征在于：所述阿瑞吡坦与稳定剂的质量比为1:0.5~1:5。
4.如权利要求2所述的制备包载阿瑞吡坦纳米晶体脂质微囊的方法，其特征在于：所述除去液相干燥的方法为冷冻干燥或喷雾干燥。
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