CN111840231B - 一种吡罗昔康纳米晶的制备方法 - Google Patents
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Abstract
一种吡罗昔康纳米晶的制备方法:称取吡罗昔康和聚丙烯酸树脂IV混合均匀后,加入到双螺杆热熔挤出机中,在95~160℃下以10~100转/分钟的转速挤出,所得挤出物冷却后粉碎,过60~120目筛,即得所述吡罗昔康纳米晶;本发明所制备的吡罗昔康纳米晶固体粉末,具有较快的溶出速率和良好的稳定性,可用于制备各种吡罗昔康制剂。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种吡罗昔康纳米晶的制备方法。
背景技术
吡罗昔康是一种常见的非甾体抗炎药,主要用于骨关节炎、类风湿关节炎和强直性脊柱炎的症状缓解。吡罗昔康最早于1972年由Lombardino等人合成,1985年3月在英国上市,现已有片剂、胶囊剂、注射剂、搽剂和凝胶等多种剂型上市。
吡罗昔康在水中几乎不溶,但黏膜渗透性好,属于典型的生物药剂学分类中的II类药物。因此,提高吡罗昔康的溶解度和溶出速度具有重要的意义。目前,提高难溶性药物溶解度和溶出度的方法主要有微粉化、成盐、制成包合物、共晶和固体分散体等。其中将药物粒径减少到纳米大小而制得纳米晶,是一种近年来迅速发展起来的新型制剂技术。迄今为止,已有近二十个药物纳米结晶制剂产品推向市场。将药物制成纳米晶不仅可显著提高药物和胃肠液的接触面积,还可提高药物的饱和溶解度,故能大大提高药物的溶出度,并且对药物的黏膜滞留性也有很大的改善,故能显著地提高难溶性药物的生物利用度,减少吸收导致的个体差异,在口服给药中有重要的应用。此外,在注射给药、眼部给药、肺部给药、经皮给药中也有广阔的应用前景。
目前报道的药物纳米晶制备方法很多,就其本质上来讲无非是“自小而大(bottomup)”的凝聚法和“自大而小(top down)”的分散法。Bottom up技术是用溶剂将药物溶解,然后通过各种方法使药物以纳米大小的微粒析出。这种技术需要选择合适的溶剂和控制药物的析晶尺寸,控制过程复杂、重复性差,至今未有产品上市。Top down技术主要利用机械能将药物颗粒分散成纳米级别的药物粒子,包括介质研磨法和高压均质法等,虽然这种方法已有产品上市,但存在能耗大、生产效率低、易磨损和介质脱落等问题。近年来,有很多学者采用两种技术的联合应用来优化产品性能,但仍具有控制过程复杂、设备要求高、生产效率低等问题。
发明内容
本发明目的是提供一种经济高效、绿色环保的吡罗昔康纳米晶的制备方法,利用该法制得的吡罗昔康纳米晶有极高的溶出速度,且具有较好的稳定性,能在5min内释放80%以上的药物,从而提高用该产品所制制剂的生物利用度。
本发明的技术方案如下:
一种吡罗昔康纳米晶的制备方法,所述制备方法为:
称取吡罗昔康和聚丙烯酸树脂IV混合均匀后,加入到双螺杆热熔挤出机中,在95~160℃(优选130℃)下以10~100转/分钟的转速挤出,所得挤出物冷却后粉碎,过60~120目筛,即得所述吡罗昔康纳米晶(固体粉末状);
所述吡罗昔康和聚丙烯酸树脂IV的质量比为4~1:1,优选4:1。
本发明所制备的吡罗昔康纳米晶固体粉末,具有较快的溶出速率和良好的稳定性,可用于制备各种吡罗昔康制剂。
附图说明
图1实施例一在盐酸中的固有溶出速率。
图2实施例二粉末在盐酸中的溶出曲线。
图3实施例三和实施例四在盐酸中的固有溶出速率。
图4实施例五、原料药及原料药与载体混合物在盐酸中的固有溶出速率(PRX:吡罗昔康原料药;1:1PM:物理混合物;4:1PRX-EPO:纳米晶体)。
图5实施例六在盐酸中的固有溶出速率。
图6实施例七粉末在盐酸中的溶出曲线。
图8实施例九各稳定性样品体外溶出曲线(A)及X-射线衍射图谱(B)。
图9实施例十测得各样品的可压性(PRX:吡罗昔康原料药;PRX-EPO 4:1PM:物理混合物;PRX-EPO 4:1NCs:纳米晶体)。
具体实施方式
下面通过具体实施例对本发明作进一步说明,但本发明的保护范围并不仅限于此。
实施例一:
称取吡罗昔康(上海毕得医药科技有限公司)5g,聚丙烯酸树脂EPO(赢创工业集团)5g,混合均匀后加于双螺杆热熔挤出机(赛默飞世尔科技有限公司)中,于95℃下以25转/分钟的速度挤出,冷却后粉碎,过120目筛,即得。
取该挤出物粉末300mg填充于固有溶出测定装置的模具中,用225MPa的压力压成片剂,将压好的片剂连同模具通过冲杆固定在快速搅拌器中,测定其在pH为1.0的盐酸溶液中的固有溶出速率。结果发现挤出物具有很高的溶解速度,固有溶出速率为4.91mg/min/cm2(见图1)。
实施例二:
取所得挤出物粉末30mg,按《中国药典》溶出度第二法测定药物的溶出度,溶出介质为900mL pH为1.0的盐酸溶液,转速为75r·min-1,取样时间分别为5,10,15,20,30,45,60min。结果测得挤出物粉末具有很快的溶解速度,在5min内的溶出量超过80%(见图2)。
实施例三:
取该挤出物粉末200mg与EPO 120mg均匀混合后,填充于固有溶出测定装置的模具中,用225MPa的压力压成片剂,将压好的片剂连同模具通过冲杆固定在快速搅拌器中,测定其在pH为1.0的盐酸溶液中的固有溶出速率。结果发现挤出物的溶出很快,固有溶出速率为5.59mg/min/cm2(见图3)。
实施例四:
取该挤出物粉末200mg与EPO 120mg均匀混合后,填充于固有溶出测定装置的模具中,用225MPa的压力压成片剂,将压好的片剂连同模具通过冲杆固定在快速搅拌器中,测定其在pH为1.0的盐酸溶液中的固有溶出速率,结果发现挤出物的固有溶出速率为6.16mg/min/cm2。(见图3)。
实施例五:
取该纳米晶体粉末200mg与EPO 120mg均匀混合后,填充于固有溶出测定装置的模具中,用225MPa的压力压成片剂,将压好的片剂连同模具通过冲杆固定在快速搅拌器中,测定其在pH为1.0的盐酸溶液中的固有溶出速率。同法测定吡罗昔康与丙烯酸树脂物理混合物以及吡罗昔康原料药固有溶出速率。结果发现挤出物的固有溶出速率为5.75mg/min/cm2,远高于吡罗昔康原料药的0.07mg/min/cm2和物理混合物的0.12mg/min/cm2。相对于吡罗昔康原料药其溶出速率提高了82倍(见图4)。
实施例六:
取该挤出物粉末200mg与EPO 120mg均匀混合后,填充于固有溶出测定装置的模具中,用225MPa的压力压成片剂,将压好的片剂连同模具通过冲杆固定在快速搅拌器中,测定其在pH为1.0的盐酸溶液中的固有溶出速率,结果发现吡罗昔康原料药的固有溶出速率为5.31mg/min/cm2。(见图5)。
实施例七:
取产物25mg,按《中国药典》溶出度第二法测定药物的溶出度,溶出介质为900mLpH为1.0的盐酸溶液,转速为75r·min-1,取样时间分别为5,10,15,20,30,45,60min。结果在5min内的溶出超过80%(见图6)。
实施例八:
取实施例五制得粉末产品用X射线粉末衍射仪测定其衍射图谱,并与吡罗昔康原料、聚丙烯酸树脂EPO及它们的物理混合物比较。结果发现吡罗昔康原料药和物理混合物在2θ为8.66°,11.68°,12.52°,14.54°,17.74°,27.44°处显示出晶型I的特征衍射峰,在9.02°,10.18°,15.6°,19.68°处显示出晶型II的特征衍射峰,挤出物的衍射峰与原料药相比并无明显差异,但强度略有降低,这说明挤出物中吡罗昔康主要仍是晶体状态(见图7)。
实施例九:
取实施例五制得粉末产品装于密封铝箔袋中,置于装有饱和氯化钠溶液(75%RH)的干燥器中,放入40℃的烘箱中,进行稳定性考察。结果发现6月内的样品未见粉末团聚,药物含量无明显改变。与0月相比,1、2、6月的样品粉末在5min时的溶出超过80%,且吡罗昔康的晶型未发生改变(见图8)。
实施例十:
将实施例五制得的粉末产品分别在28MPa~338MPa下压成片剂,测定其抗张强度,并与吡罗昔康原料药、吡罗昔康和丙烯酸树脂物理混合物(质量比为4:1)比较其可压性。结果发现,单独吡罗昔康原料药的可压性很差,在28MPa压力下压成的片剂抗张强度仅为0.5MPa,随着压片压力的增加,所得片剂的抗张强度略有增加,但都不超过2MPa,当压力超过225MPa时,将会发生明显的裂片。与丙烯酸树脂EPO混合后,吡罗昔康的可压性显著提高,在28MPa压力下压成的片剂抗张强度可达1.4MPa左右,随着压片压力的增加,所制的片剂的抗张强度明显增加,当压力达到338MPa时,片剂的抗张强度可达3.8MPa左右。采用热熔挤出法制成纳米晶体后,所得产品的可压性与物理混合物相似,225Mpa内的抗张强度为吡罗昔康的2倍(图9)。
对比例
文献【Lai F,Pini E,Angioni G,et al.Nanocrystals as tool to improvepiroxicam dissolution rate in novel orally disintegrating tablets[J].Europeanjournal of pharmaceutics&biopharmaceutics,2011,79(3):552-558.】报告了一种吡罗昔康纳米晶的制备方法。他们将吡罗昔康分散在含0.5%、1%和1.5%的普洛沙姆188水溶液中,用Ultra Turrax T25高速分散机在8000转的速度下处理1分钟,然后超声1h,最后用高压均质机先在50MPa循环3次,再在150MPa下循环30次,从而制得Z均粒径分别为432.3nm、553.1nm和414.3nm的吡罗昔康纳米晶。
这种采用高压均质法制备吡罗昔康纳米晶,不仅有介质脱落、生产效率差等缺点,而且制备的产品粒径较大。而采用实施例五制备吡罗昔康纳米晶,具有快速高效,可连续生产,且可直接获得固体成品,将其分散在盐酸中测得了Z均粒径为213.6nm。
Claims (2)
1.一种吡罗昔康纳米晶的制备方法,其特征在于,所述制备方法为:
称取吡罗昔康和聚丙烯酸树脂IV混合均匀后,加入到双螺杆热熔挤出机中,在130~160℃下以10~100转/分钟的转速挤出,所得挤出物冷却后粉碎,过60~120目筛,即得所述吡罗昔康纳米晶;
所述吡罗昔康和聚丙烯酸树脂IV的质量比为4:1。
2.如权利要求1所述吡罗昔康纳米晶的制备方法,其特征在于,挤出温度为130℃。
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固体分散体在提高难溶性药物口服生物利用度中的应用;董雅芬等;《药学与临床研究》;20151231;第51-54页 * |
固体分散技术与包合技术对吡罗昔康溶出度的影响;胡鹏翼等;《药物制剂》;20070531;第26卷(第5期);第530-532页 * |
微粉化和固体分散体技术对吡罗昔康在Beagle犬体内口服生物利用度的影响;李模勇等;《中国医药工业杂志》;20151231;第46卷(第1期);第32-35页 * |
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