CN116098872A - 一种注射用阿哌沙班长效微球及其制备方法 - Google Patents
一种注射用阿哌沙班长效微球及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种注射用阿哌沙班长效微球及其制备方法,先将可降解聚合物溶解于有机溶剂中,得到聚合物溶液;再将阿哌沙班微粉均匀分散在聚合物溶液中,形成油包固(S/O)混悬液;在搅拌条件下,将S/O混悬液滴加到水相中,去除混悬液中的有机溶剂并固化,洗涤并收集微球,冷冻干燥,即得微球成品。其中所述有机溶剂选自乙酸乙酯、二氯甲烷、甲醇和二甲基亚砜等;所述水相中含有添加剂,所述添加剂的浓度为0.001~0.05 g/mL。本发明的阿哌沙班微球制备工艺简单,粒径适宜,载药量高,突释小,具有明显的缓释作用,可用于血栓的预防,并降低出血风险。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种注射用阿哌沙班长效微球的制备方法。
背景技术
阿哌沙班是新一代Xa强效、可逆、直接且高度选择性的活性部位抑制剂,其结构如下图所示。用于治疗骨关节炎相关的疾病,包括预防髋关节或膝关节置换术后患者发生的静脉血栓栓塞症;心房颤动患者的卒中预防;用于急性冠脉综合征。它主要作用于Xa 因子,与Xa 因子活性位点之间以高度互补的方式结合,可以抑制游离以及与血凝块结合的 FXa,并由此抑制凝血酶活性。通过抑制 FXa,可以抑制凝血酶的产生、预防血栓形成。
目前国内外上市的主要是阿哌沙班的口服制剂,针对髋关节置换建议给药35天,针对心房颤动患者建议连续给药36个月,针对急性冠脉综合征建议连续给药3个月,然而阿哌沙班口服制剂必须每天按时服药,患者依从性差;其片剂中也含有较多的辅料成份,一些对辅料成份过敏的患者是禁用的。同时阿哌沙班主要的不良反应是出血现象,普通的口服速释制剂容易达到较高需要浓度,且血药浓度波动较大,导致严重的不良反应。因此,为了提高患者的顺应性,降低出血风险,扩大患者应用范围,研制阿哌沙班长效微球具有重要意义。现有技术关于阿哌沙班长效微球的报道很少,仅见的一种技术方案以卤素有机溶剂为溶剂,将脂肪酸或甘油三酯加入分散相,使用乳化溶剂挥发法和微流控法制备微球,其处方中使用了辅料脂肪酸(C12-C18)或甘油三酯抑制药物结晶和形成聚合物-阿哌沙班沉淀物,其中长链脂肪酸进入线粒体氧化供能时需要肉毒碱作为载体,而肉毒碱在人体的肝脏和肾中产生,所以副作用偏大,尤其对于肝肾功能不良的患者存在使用限制。另外,采用传统的O/W乳化法很难保证微球的高包封率和载药量,且具有较大的突释现象,引起不良反应和出血现象。
发明内容
为解决上述技术问题,本发明中未使用非常规脂肪酸或脂类材料,采用水包油包固(S/O/W)技术,制备得到一种注射用的阿哌沙班微球,制备方法简单,显著提高了包封率和载药量,且能降低突释,进一步降低不良反应和出血现象。
本发明是通过以下技术方案实现的:
一种注射用阿哌沙班长效微球的制备方法,包括以下步骤:将阿哌沙班微粉分散在聚合物溶液中,形成混悬液;然后将混悬液滴加到水相溶液中,再去除有机溶剂,然后洗涤,得到注射用阿哌沙班长效微球。优选的,将混悬液滴加到水相溶液中,再挥发去除有机溶剂,并在水中固化,然后洗涤,最后冷冻干燥,得到注射用阿哌沙班长效微球。
具体的,上述注射用阿哌沙班长效微球的制备方法包括以下步骤:
(1)先将聚合物溶解于有机溶剂中,得到聚合物溶液;
(2)将阿哌沙班微粉均匀分散在聚合物溶液中,形成S/O混悬液;
(3)将添加剂溶于水中,得到水相溶液;
(4)在搅拌条件下,将步骤(2)的混悬液滴加到步骤(3) 的水相溶液中,然后去除有机溶剂,再洗涤并收集微球,冷冻干燥,即得注射用阿哌沙班长效微球。
本发明中,所述聚合物选自聚乳酸-羟基乙酸共聚物、聚乳酸、聚乳酸-聚乙二醇和聚己内酯中的一种或几种,优选聚乳酸-羟基乙酸共聚物。优选的,聚乳酸-羟基乙酸共聚物的数均分子量为5 kDa~150 kDa;丙交脂与乙交酯的摩尔比为85∶15~50∶50;优选聚乳酸-羟基乙酸共聚物分子量为12 kDa~150 kDa;优选丙交脂与乙交酯的摩尔比为50∶50。
本发明中,所述阿哌沙班微粉与聚合物的重量比为1∶2~50,优选1∶3~10。
本发明中,所述添加剂选自聚乙烯醇、聚山梨酯20、聚山梨酯80、聚乙二醇和十二烷基硫酸钠的一种或几种;优选聚乙烯醇;添加剂的浓度为0.001 g/mL~0.05 g/mL;优选0.01 g/mL~0.02 g/mL。
本发明中,所述混悬液与水相溶液的体积比为1∶5~50,优选1∶10~20,比如1∶15。
本发明中,阿哌沙班原料药制备为阿哌沙班微粉;阿哌沙班微粉的D50粒径为1~10 μm;优选的,将阿哌沙班原料药研磨,制备为阿哌沙班微粉;或者将阿哌沙班原料药经过溶剂析出,制备为阿哌沙班微粉。
本发明公开了上述注射用阿哌沙班长效微球的制备方法制备的注射用阿哌沙班长效微球以及所述注射用阿哌沙班长效微球在制备缓释药物中的应用;进一步的,上述注射用阿哌沙班长效微球在制备治疗骨关节炎术后血栓预防相关疾病的药物、心房颤动患者的卒中预防药物、急性冠脉综合征等抗血栓相关药物中的应用。
本发明的有益效果是:本发明采用了新S/O/W制备法,显著提高了包封率和载药量,且能降低突释,进一步降低不良反应和出血现象;尤其是,本发明以聚合物、有机溶剂、添加剂、水与阿哌沙班微粉为原料,无需其他物质比如无需小分子试剂、无需脂肪酸、甘油酯等,得到的阿哌沙班长效微球包封率和载药量高,且释放性能优异。
上述说明仅是本发明技术方案的的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1为发明实施例2制备的阿哌沙班微球扫描电镜图;
图2为发明实施例6制备的阿哌沙班微球扫描电镜图;
图3为发明实施例7制备的阿哌沙班微球扫描电镜图;
图4为实施例1和实施例2制备的阿哌沙班微球的37℃体外释放度曲线;
图5为实施例6和实施例7制备的阿哌沙班微球的37℃体外释放度曲线。
具体实施方式
以下结合实施例及附图对本发明进一步说明。本发明采用的原料为现有产品,具体制备操作以及性能测试为常规技术。将阿哌沙班原料药在研钵内研磨,得到D50为5 μm的阿哌沙班微粉,用于除了对比例1、对比例2之外的其他例子。实施例中,S/O混悬液的滴加为液面以下连续滴加;在通风橱内,采用常规搅拌挥发法去除有机溶剂;利用不锈钢筛(孔径分别为38.5 μm和150 μm,取两者之间)收集微球;冷冻干燥机型号:FDU-2110。
实施例1
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL的聚乙烯醇水溶液中,继续搅拌17 min(挥发乙酸乙酯),然后加入225 mL水中,固化10 min,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
实施例2
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=60kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL的聚乙烯醇水溶液中,继续搅拌17 min(挥发乙酸乙酯),然后加入225 mL水中固化10 min,收集微球并用水洗涤3次,混悬放入-80℃冰箱预冻10 h后,冷冻干燥48h,得到微球粉末阿哌沙班微球。
实施例3
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=12kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01g/mL聚乙烯醇水溶液中,继续搅拌17 min(挥发乙酸乙酯),然后加入225 mL水中,固化10 min,收集微球并用水洗涤3次,混悬放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
实施例4
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于5 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL的聚乙烯醇水溶液中,继续搅拌17 min(挥发乙酸乙酯),然后加入225 mL水中,固化10 min,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
实施例5
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL的聚乙烯醇水溶液中,继续搅拌17 min(挥发乙酸乙酯),然后加入225 mL水中,固化2 h,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
实施例6
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL聚乙烯醇水溶液中,继续搅拌17 min,挥发乙酸乙酯,收集微球并用水洗涤3次,混悬放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
实施例7
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=75∶25,Mw=90kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL聚乙烯醇水溶液中,继续搅拌17 min,挥发乙酸乙酯,收集微球并用水洗涤3次,混悬放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
实施例8
先将200 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3.5 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;500 rpm磁力搅拌下,将此S/O混悬液滴加到50mL浓度为0.01 g/mL的聚乙烯醇水溶液中,继续搅拌20 min(挥发乙酸乙酯),然后加入200mL水中,固化10 min,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
实施例9
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于2.5 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到40mL浓度为0.01 g/mL的聚乙烯醇水溶液中,继续搅拌15 min(挥发乙酸乙酯),然后加入250mL水中,固化10 min,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48h,得到微球粉末阿哌沙班微球。
实施例10
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;700 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.02 g/mL的聚乙烯醇水溶液中,继续搅拌15 min(挥发乙酸乙酯),然后加入200 mL水中,固化15 min,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
对比例1
将阿哌沙班原料药溶解在二氯甲烷中,形成油相,将油相滴加到浓度为0.01g/mL吐温80溶液中,先在5000 rpm条件下,均质8 min,然后在磁力搅拌(800 rpm)条件下挥干有机溶剂至药物析出,离心,弃上清;用水洗涤,收集沉淀于-80℃冰箱预冻10 h,再冷冻干燥48 h,得到D50为5 μm的阿哌沙班微粉。
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3 mL乙酸乙酯中,再将上述溶剂析出法得到的50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL聚乙烯醇水溶液中,继续搅拌17 min(挥发乙酸乙酯),然后加入225 mL水中,固化10 min,收集微球并用水洗涤3次,混悬放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
对比例2
将阿哌沙班原料药在研钵内研磨,得到D50为30 μm的阿哌沙班微粉。
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉(D50:30 μm)均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液滴加到45 mL浓度为0.01 g/mL的聚乙烯醇水溶液中,继续搅拌17 min(挥发乙酸乙酯),然后加入225 mL水中,固化10 min,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
对比例3
先将150 mg的聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50∶50,Mw=88kDa)溶解于3 mL乙酸乙酯中,再将50 mg阿哌沙班微粉均匀分散在含有聚乳酸-羟基乙酸共聚物的乙酸乙酯溶液中,形成S/O混悬液;600 rpm磁力搅拌下,将此S/O混悬液3 s内迅速加入到45 mL浓度为0.01g/mL聚乙烯醇水溶液中,1500 rpm磁力搅拌10分钟,然后将形成的乳液10 s内迅速加入到225 mL水中,500 rpm磁力搅拌5小时,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
对比例4
称取50 mg 阿哌沙班微粉、150 mg 聚乳酸-羟基乙酸共聚物(丙交脂与乙交酯的摩尔比=50:50,Mw=88 kDa)一起溶于3 mL二氯甲烷中,形成油相,在350 rpm条件下,将此油相连续滴加到45 mL质量浓度为0.01g/mL聚乙烯醇水溶液中乳化,继续搅拌10分钟,挥发二氯甲烷;将初步形成的微球,加入到225 mL水中,固化10 min,收集微球并用水洗涤3次,放入-80℃冰箱预冻10 h后,冷冻干燥48 h,得到微球粉末阿哌沙班微球。
测试例1 微球粒径
取实施例1~10,对比例1~4制备的微球分别分散在水中,采用BT-2001激光粒度分布仪进行微球粒径测定。结果见表1,实施例微球的粒径(特指中位径)范围在90 mm以下,适合注射使用。
由表1可以看出,与实施例1相比,对比例1微球粒径较大,与采用溶剂析出法减小的原料药相比,研磨法减小的原料药其分散性好,制备的微球粒径较适宜。与实施例相比,对比例4制备的微球粒径较大,主要微球成形性和分散性较差有关。
测试例2 微球形态
取实施例2、6、7制备的微球,用扫描电镜观察微球形态,结果分别见图1、图2以及图3,可以看出,阿哌沙班微球呈球形或类球形,表面光滑。
测试例3微球载药量与包封率
用十八烷基硅烷键合硅胶为填充剂;以10 mmol/L乙酸铵∶乙腈(65∶35)为流动相,调节流速使主峰出峰时间为约9分钟,检测波长为280 nm;称取阿哌沙班对照品10 mg,置50mL容量瓶中,加流动相溶解并稀释至刻度,摇匀;量取1 mL,置10 mL容量瓶中,用流动相稀释至刻度,摇匀,即为对照溶液;分别取实施例1-10制备的微球10 mg,精密称定,置10 mL离心管中,加入1mL乙腈完全溶解后,加入7 mL甲醇沉淀聚乳酸-羟基乙酸共聚物,然后离心(10000 r/min,10 min),取上清于50 mL容量瓶中,加甲醇定容至刻度。精密量取20 mL,注入液相色谱仪,记录色谱图;另取阿哌沙班对照品,同法测定,按外标法以峰面积计算,即得总药物量。进一步换算为微球的载药量与包封率。结果见表2。载药量与包封率的计算公式如下:
实施例制备的微球包封率均比对比例制备的高。可以看到改变PLGA50/50分子量及浓度对微球包封率与载药量影响不大。PLGA类型虽对微球包封率没有明显影响,但对微球后期的释放有较大影响,PLGA50/50较PLGA75/25释放度好。工艺中增加固化,可在一定程度上改善微球包封率,但固化时间由10 min提高至120 min后,导致微球包封率有下降。阿哌沙班原料药D50小对包封率有较大程度提高,采用溶剂析出法虽然也能将阿哌沙班原料药D50降至5 μm,但相比研磨法,其减小粒径后的原料药形成的微球粒径较大且药物包载效果较差,包封率在84%左右。
对比例3的结果显示,利用现有载药微球的制备方法制备的阿哌沙班微球,其包封率结果相对较差,达不到预期理想的效果,表明现有载药微球的制备方法不适用阿哌沙班微球的制备。对比例4的结果显示,采用O/W法制备阿哌沙班微球,制备过程中出现“流沙”现象(药物析出),导致微球较难包封,微球包封率较低,只有37%左右。本发明采用S/O/W法制备阿哌沙班微球,可避免药物出现“流沙”现象,包封率均在85%以上,尤其是本发明没有使用脂肪酸等辅料,成分相对更简单,载药量更高,更安全。
测试例4微球的体外释放度
称取2 g氢氧化钠溶于500 mL水中,弃去105 mL,加入6.8 g磷酸二氢钾和605 mL水一起溶解,加入0.02% (w/v)吐温20,得到释放介质为pH7.4的含0.02%吐温20的PBS溶液。
别称取20 mg实施例1~2、实施例6~7制备的阿哌沙班微球于50 mL具塞锥形瓶中,加入50 mL含0.02%吐温20的PBS溶液,放入37℃的水浴恒温振荡锅内,于4 h、1 d、2 d、3d、7 d……不同时间点取1 mL,离心(10000 rpm,10 min),取上清0.7 mL,并补上0.7 mL含0.02%吐温20的PBS溶液,隔天换液,然后进行HPLC分析,计算累积释放百分率,绘制累积释放百分率-时间的释放度曲线图。结果见图4~5。从图4的释放度曲线来看,实施例1微球突释较小,4 h内的突释仅为2.26%,24 h内累积释放度为8.27%,整体释放缓慢,可持续释放至84天,累积释放度达90%,具有明显的缓释作用。从图5的释放度曲线来看,实施例6的体外释放度要慢于实施例7的体外释放度,说明采用聚乳酸-羟基乙酸共聚物的比例为50/50时,具有较优的体外释放度,其释放可持续至42天或更久。这对于骨关节炎术后血栓预防、心房颤动患者的卒中预防、急性冠脉综合征等抗血栓性相关疾病的治疗具有适用性。
综上所述,本发明采用S/W/O法,结合研磨法控制原料药粒径,可获得较好的包封率与载药量,尤其是阿哌沙班微球的释放性能非常好。
Claims (10)
1.一种注射用阿哌沙班长效微球的制备方法,其特征在于,包括以下步骤:将阿哌沙班微粉分散在聚合物溶液中,形成混悬液;然后在搅拌条件下,将混悬液加到水相溶液中,挥发有机溶剂并固化,然后洗涤收集,冷冻干燥,得到注射用阿哌沙班长效微球。
2.根据权利要求1所述注射用阿哌沙班长效微球的制备方法,其特征在于,所述聚合物溶液中,聚合物选自聚乳酸-羟基乙酸共聚物、聚乳酸、聚乳酸-聚乙二醇和聚己内酯中的一种或几种,溶剂包括乙酸乙酯。
3.根据权利要求1所述注射用阿哌沙班长效微球的制备方法,其特征在于,将阿哌沙班原料药制备为阿哌沙班微粉;阿哌沙班微粉的D50粒径为1~10 μm;混悬液中,所述阿哌沙班微粉与可降解聚合物的重量比为1:2~50。
4.根据权利要求3所述注射用阿哌沙班长效微球的制备方法,其特征在于,将阿哌沙班原料药研磨,制备为阿哌沙班微粉。
5.根据权利要求1所述注射用阿哌沙班长效微球的制备方法,其特征在于,混悬液、水相溶液的体积比为1∶5~50。
6.根据权利要求1所述注射用阿哌沙班长效微球的制备方法,其特征在于,将混悬液滴加到水相溶液中。
7.根据权利要求1所述注射用阿哌沙班长效微球的制备方法,其特征在于,水相溶液包括添加剂与水,添加剂选自聚乙烯醇、聚山梨酯、聚乙二醇和十二烷基硫酸钠的一种或几种;添加剂的浓度为0.001~0.05 g/mL。
8.根据权利要求1所述注射用阿哌沙班长效微球的制备方法制备的注射用阿哌沙班长效微球。
9.权利要求1所述注射用阿哌沙班长效微球在制备缓释药物中的应用。
10.权利要求1所述注射用阿哌沙班长效微球在制备治疗骨关节炎术后血栓预防相关疾病的药物、心房颤动患者的卒中预防药物、急性冠脉综合征等抗血栓性相关药物中的应用。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109010273A (zh) * | 2018-10-08 | 2018-12-18 | 中国药科大学 | 一种阿哌沙班纳米混悬剂及其制备方法 |
KR102045721B1 (ko) * | 2019-03-27 | 2019-11-18 | 주식회사 씨트리 | 아픽사반 함유 미립구 제조용 분산상의 조성물 및 이로부터 제조되는 생체적합성 고분자 기반 아픽사반 함유 미립구 |
WO2020165379A1 (en) * | 2019-02-15 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Plga-based microspheres, preparation methods and uses thereof |
CN113786393A (zh) * | 2021-09-07 | 2021-12-14 | 浙江工业大学 | 一种利伐沙班微球及其制备方法与应用 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109010273A (zh) * | 2018-10-08 | 2018-12-18 | 中国药科大学 | 一种阿哌沙班纳米混悬剂及其制备方法 |
WO2020165379A1 (en) * | 2019-02-15 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Plga-based microspheres, preparation methods and uses thereof |
KR102045721B1 (ko) * | 2019-03-27 | 2019-11-18 | 주식회사 씨트리 | 아픽사반 함유 미립구 제조용 분산상의 조성물 및 이로부터 제조되는 생체적합성 고분자 기반 아픽사반 함유 미립구 |
CN113786393A (zh) * | 2021-09-07 | 2021-12-14 | 浙江工业大学 | 一种利伐沙班微球及其制备方法与应用 |
Non-Patent Citations (1)
Title |
---|
韦超等: "《药剂学 第2版》", 河南科学技术出版社, pages: 63 - 65 * |
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