CN113786393A - 一种利伐沙班微球及其制备方法与应用 - Google Patents
一种利伐沙班微球及其制备方法与应用 Download PDFInfo
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- CN113786393A CN113786393A CN202111042718.3A CN202111042718A CN113786393A CN 113786393 A CN113786393 A CN 113786393A CN 202111042718 A CN202111042718 A CN 202111042718A CN 113786393 A CN113786393 A CN 113786393A
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- rivaroxaban
- microspheres
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- molecular polymer
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Abstract
本发明公开了一种利伐沙班微球及其制备方法与应用,所述利伐沙班微球包含利伐沙班和生物可降解高分子聚合物载体;所述生物可降解高分子聚合物载体为丙交酯‑乙交酯共聚物、聚丙交酯、聚乙交酯或聚己内酯。本发明利伐沙班微球,呈白色或类白色粉末状细粒,圆整度较好,粒径均一,D50在50‑100μm,体外缓慢释放时间长达45天以上,将微球粉末混悬于分散溶媒中经SD大鼠后腿肌内注射,动物体内释药长达6周,42天仍维持在有效血药浓度范围内。因此本发明的利伐沙班微球有望开发一种利伐沙班长效缓释新剂型,经胃肠道外一次给药,药效持续数周,提高患者用药依从性,具有明显的临床优势。
Description
(一)技术领域
本发明涉及一种利伐沙班的长效注射微球,以实现药物在较长周期内持续缓慢释放,提高患者用药依从性。
(二)背景技术
利伐沙班是凝血因子Xa抑制剂,可剂量依赖性地抑制血浆游离因子Xa和凝血酶原复合物中的因子Xa,以阻止凝血活化过程,实现对血栓的预防和治疗[门剑龙,翟建国等,利伐沙班治疗监测新进展,中华检验医学杂志,2019,42(8):710-714]。
利伐沙班药代动力学稳定,治疗窗宽,不需常规监测,可满足预防性治疗长期给药需求等优势,使利伐沙班在临床应用的日益广泛,成为抗凝血药物及预防血栓药物市场的主流品种。目前利伐沙班上市的剂型只有片剂且需每日服药,一日一次或两次,片剂剂量有2.5mg,10mg,15mg和20mg,临床上主要适用于预防在进行膝关节或髋关节置换手术的患者中可能导致肺栓塞(PE)及深静脉血栓形成(DVT)形成,也可治疗深静脉血栓和肺栓塞及预防其复发,并减少非瓣膜性心房颤动脑卒中和全身栓塞的风险。根据临床上治疗目的,可选择相应的剂量及给药方案,治疗周期长达12天至6个月不等。
在服用利伐沙班片时存在以下问题:1、长期每日给药,导致患者服药困难,顺应性差,增加了每天因漏服或错服导致治疗效果达不到或出血风险;2、食物对不同剂量利伐沙班口服片的生物利用度影响不同,低剂量2.5mg、10mg利伐沙班片口服吸收不受食物的限制,而高剂量利伐沙班口服片(20mg剂量)的生物利用度为66%,与食物合用可使20mg剂量的生物利用度增加,故利伐沙班的15mg和20mg剂量建议与晚餐共服用。因此开发利伐沙班长效、胃肠道外给药剂型可以改善患者顺应性、规避食物对药物口服生物利用度的影响,具有明显的临床优势。
(三)发明内容
本发明目的是为了改善只以长期口服的形式进行给药的利伐沙班的用药依从性和规避食物对药物口服生物利用度的影响,提供一种利伐沙班微球及其制备方法与应用,开发一种可延长药物释药周期的利伐沙班微球及其制备方法与在制备长效注射液中的应用。
本发明采用的技术方案:
本发明提供一种利伐沙班微球,所述利伐沙班微球包含利伐沙班和生物可降解高分子聚合物载体;所述生物可降解高分子聚合物载体为丙交酯-乙交酯共聚物(PLGA)、聚丙交酯(PLA)、聚乙交酯(PGA)或聚己内酯(PCLs),优选为PLGA,PLGA中丙交酯和乙交酯的摩尔比为25:75~90:10,特性粘度为0.15-0.8dl/g;更优选的PLGA是端基为羧基,丙交酯和乙交酯摩尔比50:50~75:25,粘度0.25-0.5dl/g。
进一步,优选所述丙交酯-乙交酯共聚物中丙交酯和乙交酯的摩尔比为50:50,特性粘度为0.25~0.50dl/g,端基为羧基。
所述利伐沙班微球中利伐沙班的质量含量为5~35%,优选为10~30%。所述利伐沙班微球的粒径大小为10~200μm,优选为10~180μm,D50在50-100μm。
另外,因利伐沙班几乎不溶于水,以固体形式分散在PLGA溶液中,为调节释药速率,可在处方中加入一些水溶性较好的小分子附加剂如糖、盐等作为增孔剂,在乳液形成过程中,水溶性小分子易吸收水分进入乳滴,在PLGA固化成膜过程中,小分子附加剂溶于水后扩散至水相中,微球孔隙率增加。以上所述小分子附加剂可为蔗糖、甘露醇、氯化钠、甘氨酸、丙氨酸等,添加量在处方中质量含量为0-5%,质量百分数为0%表示处方中不加小分子附加剂,优选0~3%。
本发明所述利伐沙班微球由利伐沙班、生物可降解高分子聚合物载体和/或小分子附加剂组成,所述利伐沙班质量含量为5~35%,小分子附加剂质量含量为0-5%,余量为载体,总量100%。
进一步,优选所述利伐沙班微球由利伐沙班和生物可降解高分子聚合物载体组成,所述利伐沙班质量含量为5~35%,余量为载体;或者所述利伐沙班微球由利伐沙班、生物可降解高分子聚合物载体和小分子附加剂组成,所述利伐沙班质量含量为5~35%,小分子附加剂质量含量为1-3%,余量为载体。
本发明所述利伐沙班微球可采用凝聚法、乳化-溶剂挥发法(液中干燥法)或喷雾干燥等方法制得,优选S/O/W乳化-溶剂挥发法,制备步骤如下:将生物可降解高分子聚合物载体溶解在有机溶剂中,得到载体溶液,作为O相;将利伐沙班粉末和/或小分子附加剂加入到载体溶液中,高速剪切或探头超声分散均匀,得到利伐沙班-高分子聚合物混悬液,作为S/O相;将利伐沙班-高分子聚合物混悬液迅速滴入亲水性高分子聚合物水溶液中,乳化,挥干有机溶剂,过滤或过筛,收集微球,用水洗去微球表面残留的亲水性高分子,干燥,既得利伐沙班微球。
所述利伐沙班与生物可降解高分子聚合物载体质量比为1:10~1:2(优选1:5~1:3);载体溶液的质量浓度为100~150mg/ml;所述亲水性高分水溶液质量浓度1~3%(优选2~3%),亲水性高分子水溶液与载体溶液的体积比为5:1~20:1(优选10:1);所述小分子附加剂与利伐沙班质量比为(0~1):3(优选0.13:1)。
本发明所述利伐沙班的粒径<20μm,优选D90<10μm,更优选D90<5μm。
所述有机溶剂是指不与水混溶且室温下易挥发,可为二氯甲烷、三氯甲烷及乙酸乙酯的一种或其中两种的混合溶剂,优选为二氯甲烷或二氯甲烷与乙酸乙酯体积比7:3(v/v)的混合溶剂。
所述亲水性高分子聚合物可用聚乙烯醇、泊洛沙姆188、羟丙基纤维素或聚氧乙烯40脂肪酸酯,优选为聚乙烯醇,分子量Mn=3~7万。
所述乳化方式可采用静态混合、挤压过膜、微通道、磁力搅拌、机械搅拌或刮壁搅拌的方式,优选1200-1500r/min搅拌乳化10min。所述干燥是指冷冻干燥。
本发明还提供一种所述利伐沙班微球在制备长效缓释注射剂中的应用,将利伐沙班微球混悬于药学可接受的分散溶媒中,经胃肠外一次给药,例如皮下注射或肌肉注射后,利伐沙班在体内缓慢释放,数周后药物浓度仍维持在有效血药浓度范围内,具有提高患者用药依从性的临床优势。
分散溶媒可由助悬剂、等渗调节剂、润湿剂、水或生理盐水组成;所述助悬剂可选羧甲基纤维素钠、海藻酸钠或聚乙烯醇;所述等渗调节剂可选氯化钠、甘露醇或葡萄糖;所述润湿剂为非离子表面活性剂,如聚山梨酯系列和泊洛沙姆系列。更优选所述分散溶媒组成:质量浓度0.8~1.0%羧甲基纤维素钠(型号:300~800mPa.s)、质量浓度0.1%吐温20,溶剂为生理盐水,分散溶媒25℃粘度为35~65mPa.s。
与现有技术相比,本发明有益效果主要体现在:
本发明采用S/O/W(油包水包固)乳化-溶剂挥发法制备的利伐沙班-PLGA微球,呈白色或类白色粉末状细粒,圆整度较好,粒径均一,D50在50-100μm,体外缓慢释放时间长达45天以上,将微球粉末混悬于分散溶媒中经SD大鼠后腿肌内注射,动物体内释药长达6周,42天仍维持在有效血药浓度范围内。因此本发明的利伐沙班微球有望开发一种利伐沙班长效缓释新剂型,经胃肠道外一次给药,药效持续数周,提高患者用药依从性,具有明显的临床优势。
(四)附图说明
图1是实施例1、实施例4和实施例5制备微球的扫描电镜图。
图2是实施例1微球的粒度分布图。
图3是利伐沙班原料药、实施例1~6微球体外释药曲线(n=3)。
图4是利伐沙班原料药、实施例1和实施例4微球体内药时曲线(c-t)(n=3)。
图5是图4体内药时曲线(c-t)0~24h的局部放大图。
(五)具体实施方式
下面以具体实施例对本发明的技术方案做进一步说明,但本发明的保护范围不限于此。
本发明实施例所用利伐沙班原料药(Alembic Pharmaceuticals Limited)粒径为:d(0.1)=1.974μm,d(0.5)=4.165μm,d(0.9)=8.037μm,d(1.00)=13.49μm。所述实验用水为哇哈哈纯净水。
实施例1、利伐沙班-PLGA微球的制备
按照表1处方,将240mg的PLGA(PLGA 50DLG 3A,购自Lakeshore Biomaterials)溶于2ml二氯甲烷中,制得PLGA溶液,向其中加入处方量(48mg)的利伐沙班,得到利伐沙班-PLGA混悬液,将该混悬液通过均质机(10000-15000r/min)分散均匀;在500r/min搅拌转速下将利伐沙班-PLGA混悬液迅速注入20ml质量浓度2%聚乙烯醇(Sigma,分子量Mn=3~7万)水溶液中,注入后迅速将转速升至1200r/min搅拌乳化10min;将乳化液迅速转入200ml水中,低速搅拌4-6h使有机溶剂挥发,微球固化,10μm微孔滤膜过滤,收集滤饼,纯水洗涤3次除去微球表面残留PVA,冷冻干燥24h,即得利伐沙班-PLGA微球,收率见表2。
实施例2-3、利伐沙班-PLGA微球的制备
按表1处方制备不同的利伐沙班-PLGA微球,其中实施例2乳化时搅拌转速为1500r/min,其他均同实施例1方法,
表1实施例1~3制备处方表
备注:PLGA型号中50DLG表示丙交酯和乙交酯的摩尔比为50:50,3和4.5分别表示特性粘度为0.25~0.40dl/g和0.40~0.50dl/g,A表示端基为羧基。
实施例4、利伐沙班-PLGA微球的制备
称取300mg的PLGA50DLG 3A溶于2ml二氯甲烷中,制得PLGA溶液,分别称取8mg甘露醇和60mg利伐沙班原料先后加入PLGA溶液中,将混悬液通过均质机(10000-15000r/min)分散均匀;在500r/min转速下将利伐沙班-PLGA混悬液迅速注入20ml质量浓度2%聚乙烯醇(Sigma,分子量Mn=3~7万)水溶液中,注入后迅速将转速升至1500r/min搅拌乳化10min;将乳化液迅速转入200ml水中,低速搅拌4-6h使有机溶剂挥发,微球固化,10μm微孔滤膜过滤,收集滤饼,水洗涤3次除去微球表面残留PVA,冷冻干燥24h,即得利伐沙班-PLGA微球,收率见表2。
实施例5、利伐沙班-PLGA微球的制备
称取240mg的PLGA50DLG 3A溶于2ml混合溶剂(二氯甲烷-乙酸乙酯7:3(v/v))中,制得PLGA溶液,称取48mg利伐沙班加入PLGA溶液中,得利伐沙班-PLGA混悬液,将该混悬液通过均质机(10000-15000r/min)分散均匀;在500r/min转速下将利伐沙班-PLGA混悬液迅速注入20ml质量浓度2%聚乙烯醇(Sigma,分子量Mn=3~7万)水溶液中,注入后迅速将转速升至1200r/min搅拌乳化10min;将乳化液迅速转入200ml水中,低速搅拌4-6h使有机溶剂挥发,微球固化,10μm微孔滤膜过滤,收集滤饼,水洗涤3次除去微球表面残留PVA,冷冻干燥24h,即得利伐沙班-PLGA微球,收率见表2。
实施例6、利伐沙班-PLGA微球的制备
称取300mg的PLGA50DLG 3A溶于2ml二氯甲烷中,制得PLGA溶液,称取100mg利伐沙班加入PLGA溶液中,得利伐沙班-PLGA混悬液,将该混悬液通过均质机(10000-15000r/min)分散均匀;在500r/min转速下将利伐沙班-PLGA混悬液迅速注入20ml质量浓度3%聚乙烯醇(Sigma,分子量Mn=3~7万)水溶液中,注入后迅速将转速升至1500r/min搅拌乳化10min;将乳化液迅速转入200ml水中,低速搅拌4-6h使有机溶剂挥发,微球固化,10μm微孔滤膜过滤,收集滤饼,水洗涤3次除去微球表面残留PVA,冷冻干燥24h,即得利伐沙班-PLGA微球,收率见表2。
实施例7、体外表征
1、微球形态观察:
取实施例1、4和5方法制备的利伐沙班-PLGA微球少量(约2mg)均匀分散于导电胶上,15mA电流下喷金50s后,采用扫描电子显微镜(日立SU8010)观察微球形态,结果见图1所示。各实施例制备的微球形态均较圆整,实施例1微球表面较光滑,有少许孔隙;相比于实施例1,实施例4微球表面的孔隙明显增多。实施例5微球形态圆整,粒径均一,相比于实施例1,微球表面呈明显褶皱状。
2、粒径分布测定:
粒径及粒径分布采用马尔文激光粒度仪(Malvern,Mastersizer3000)测定:取实施例1-实施例6制备的利伐沙班-PLGA微球样品粉末20mg均匀分散在1ml质量浓度0.2%吐温20水溶液中,再将微球混悬液加入至样品池进行测定,所得粒径测定结果:
实施例1:d(10)=50.6μm,d(50)=89.3μm,d(90)=152μm,Span=1.14;
实施例2:d(10)=51.7μm,d(50)=92.8μm,d(90)=164μm,Span=1.21;
实施例3:d(10)=43.5μm,d(50)=89.6μm,d(90)=158μm,Span=1.28;
实施例4:d(10)=49.4μm,d(50)=95.2μm,d(90)=159μm,Span=1.15;
实施例5:d(10)=59.1μm,d(50)=83.8μm,d(90)=117μm,Span=0.69;
实施例6:d(10)=44.3μm,d(50)=78.2μm,d(90)=125μm,Span=1.03。
其中实施例1微球典型粒径分布图见图2。
3、载药量、包封率和收率测定:
高效液相色谱条件:色谱柱:C18(150mm×4.6mm,5μm),流动相A相为水,B相为乙腈,检测波长:250nm,流速1.0ml/min,柱温:40℃,进样量:10μl,梯度洗脱:0~10.0min流动相B13%→65%,10.0~10.1min流动相B 65%→13%,10.1min~15.0min流动相B持续13%。
分别精密称取实施例1~实施例6方法制备的利伐沙班-PLGA微球5mg,加入溶剂(乙腈:水=9:1(v/v))在室温下水浴超声10min溶解,加溶剂稀释至10ml,摇匀,0.22μm微孔滤膜过滤后,取滤液采用HPLC测定峰面积,外标一点法,按下式计算载药量和包封率:
载药量DL%=(微球中药物含量/微球总重量)×100%
包封率EE%=(实际载药量/理论载药量)×100%
各实施例制备的微球样品的收率按下式计算:
收率%=(所得微球样品量mg/总投料量mg)×100%
表2各实施例所得微球载药量、包封率和收率结果(n=3)
实施例 | 载药量(%) | 包封率(%) | 收率(%) |
实施例1 | 16.5 | 99.2 | 81.7 |
实施例2 | 16.8 | 98.9 | 86.3 |
实施例3 | 16.7 | 99.3 | 87.7 |
实施例4 | 15.6 | 92.9 | 79.4 |
实施例5 | 16.4 | 99.2 | 78.3 |
实施例6 | 23.4 | 97.1 | 82.5 |
各实施例制备的微球样品,包封率均在90%以上,收率在78%以上。
4、体外药物释放实验:
取样分离法测定药物释放,精密称取2mg利伐沙班原料药或5mg实施例1-实施例6方法制备的利伐沙班-PLGA微球,置于40ml pH7.4磷酸盐缓冲液中(20mM、0.5%SDS、0.02%NaN3),100r/min,37℃恒温水浴振荡器中振摇,定时取样,每次取出4.0ml,并补充等量新鲜磷酸盐缓冲液介质,高效液相色谱法(进样量:20μl,其他色谱条件同载药量测定方法)测定药物释放曲线,见图3。
体外释放结果表明:相同体外释放条件下,利伐沙班原料药24h基本释放完全(24h释放量达98%以上);相比利伐沙班原料药,各实施例制备的利伐沙班-PLGA微球均具有明显的缓释效果;微球中药物释放呈现典型的“三相”释放剖面:初始“突释”后(所有实施例微球24h的药物突释量均<20%),经一定时间的“释药平台期”后,随后二次释放至药物释放完全,体外释药周期长达45天以上。
实施例8、利伐沙班-PLGA微球和利伐沙班原料药大鼠体内释放动力学实验
1、试验材料
试验药物:利伐沙班原料药、实施例1和实施例4方法制备的微球样品。
试验动物:健康雄性Sprague-Dawley大鼠,体重200±20g,共9只,随机分为3组,每组3只。
试验仪器:LC-30AD(日本Shimadzu公司),Triple Quad 5500液质联用仪,Analyst1.6.3数据处理软件(美国Sciex公司)。
2、方法与结果
微球样品组给药剂量:参照上市利伐沙班片临床用药剂量,利伐沙班用于静脉血栓预防时,常规剂量成人口服利伐沙班10mg,每天一次,假设连续6周给药,总剂量为420mg,按体重比表面积(kg/m2)计大鼠给药剂量约为人的6.17倍(人重60kg,大鼠200g),则微球样品大鼠给药剂量约为6.17*420/60mg/kg=43.19mg/kg。
利伐沙班原料药组给药剂量:为评估单独利伐沙班原料药在肌肉生理环境下的吸收及代谢行为,本实验设计原料药对比给药组。利伐沙班片人体每日剂量5-40mg是有效且安全的,按人日剂量40mg进行换算原料药大鼠日给药剂量:40/60*6.17=4.11mg/Kg。
按给药剂量称取所需利伐沙班原料药、实施例1和实施例4方法制备的利伐沙班-PLGA微球,分别加至0.8ml用生理盐水配制的含质量浓度为0.8%CMC-Na和质量浓度0.1%吐温20的分散溶媒中(25℃粘度:40mPa.s),振摇,分散均匀成混悬液,经SD大鼠后腿肌肉一次注射给药,给药后1h、2h、4h、6h、12h、24h、2d、4d、6d、8d、10d、12d、14d、16d、18d、20d、22d、24d、26d、28d、30d、33d、36d、38d、40d和42d分别从各大鼠眼眶静脉丛取血1ml,立即放入经肝素钠处理的离心管中,相对离心力3250rcf,离心10min分离出血浆,于-20℃冰箱中保存待测。
取大鼠血浆样品50μL,加入300μL的乙腈(含内标阿哌沙班1ng/mL),涡旋振荡3min后,20000rcf,4℃离心10min,取上清液进行LC-MS/MS测定药物浓度。色谱条件如下:色谱柱为ACQUITYBEH C18 2.1x50mm 1.7μm;流动相A相为0.1%甲酸水溶液,B相为乙腈;流速为0.35ml/min;柱温40℃;进样量1μl;梯度洗脱:0.00~0.50min流动相B持续10%,0.50~1.50min流动相B 10%→90%,1.50min~2.50min流动相B持续90%,2.50~2.51min流动相B90%→10%,2.51min~3.50min流动相B持续10%。
测得血药浓度曲线见图4~5,结果表明:利伐沙班原料药肌内注射后,体内释放及吸收较快,约2h达到最高血药浓度(约315ng/ml),随后浓度不断下降至血药浓度<LLOQ(1ng/ml),无缓释作用;制备的微球肌内注射后,经一定量的初始突释后,药物可缓慢释放,两实施例微球样品42d天大鼠体内药物浓度仍维持在15ng/ml以上,实施例1血药浓度波动范围为15~175ng/ml,实施例4血药浓度波动范围为22~210ng/ml,均在利伐沙班有效且安全血药浓度范围内,有较好的缓释效果。
本发明所述的实施例都只能认为是对本发明的说明而不能限制本发明,权利要求书指出了本发明的范围,因此,在与本发明的权利要求书相当的含义和范围内的任何改变,都应认为是包括在本发明的权利要求书的范围内。
Claims (10)
1.一种利伐沙班微球,其特征在于所述利伐沙班微球包含利伐沙班和生物可降解高分子聚合物载体;所述生物可降解高分子聚合物载体为丙交酯-乙交酯共聚物、聚丙交酯、聚乙交酯或聚己内酯。
2.如权利要求1利伐沙班微球,其特征在于所述利伐沙班微球中利伐沙班的质量含量为5~35%,所述利伐沙班微球的粒径大小为10~200μm。
3.如权利要求1利伐沙班微球,其特征在于所述生物可降解高分子聚合物载体为丙交酯-乙交酯共聚物,丙交酯和乙交酯的摩尔比为25:75~90:10,特性粘度为0.15-0.8dl/g。
4.如权利要求1利伐沙班微球,其特征在于所述利伐沙班微球由利伐沙班、生物可降解高分子聚合物载体和/或小分子附加剂组成,所述利伐沙班质量含量为5~35%,小分子附加剂质量含量为0~5%,余量为载体;所述小分子附加剂为蔗糖、甘露醇、氯化钠、甘氨酸或丙氨酸。
5.一种权利要求1所述利伐沙班微球的制备方法,其特征在于所述方法按如下步骤制备:将生物可降解高分子聚合物载体溶于有机溶剂中,制得载体溶液;将利伐沙班和/或小分子附加剂加入载体溶液中,分散均匀成混悬液;将混悬液迅速注入亲水性高分子水溶液中,乳化,挥干有机溶剂;过滤或过筛,收集微球,水洗,冷冻干燥,既得利伐沙班微球。
6.如权利要求5所述的制备方法,其特征在于所述利伐沙班粒径<20μm。
7.如权利要求5所述的制备方法,其特征在于所述有机溶剂为二氯甲烷、三氯甲烷及乙酸乙酯的一种或其中两种的混合溶剂。
8.如权利要求5所述的制备方法,其特征在于所述亲水性高分子为聚乙烯醇、泊洛沙姆188、羟丙基纤维素或聚氧乙烯40脂肪酸酯。
9.如权利要求5所述的制备方法,其特征在于所述利伐沙班与生物可降解高分子聚合物载体质量比为1:10~1:2;载体溶液的质量浓度为100~150mg/ml;所述亲水性高分水溶液质量浓度1~3%,亲水性高分子水溶液与载体溶液的体积比为5:1~20:1;所述小分子附加剂与利伐沙班质量比为(0~1):3。
10.一种权利要求1所述利伐沙班微球在制备长效缓释注射剂中的应用。
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