CN112137961A - 一种雷帕霉素组合物及其制备方法 - Google Patents
一种雷帕霉素组合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种雷帕霉素组合物及其制备方法,雷帕霉素组合物包括按重量份计的有效成分:雷帕霉素1‑10份;高分子聚合物载体0.5‑20份;淋巴靶向物0.1‑1份;淋巴靶向物为透明质酸钠、适配体和抗体中的至少一种;制备方法包括:有机相溶液制备步骤:将雷帕霉素加入有机相溶剂中,得到有机相溶液;乳液制备步骤:将高分子聚合物载体加入水相溶剂,然后将有机相溶液滴加至水相溶剂,得到乳液;均质步骤:在乳液中加入淋巴靶向物,混合后均质,得到雷帕霉素组合物;该雷帕霉素组合物能够靶向淋巴系统,通过淋巴系统治疗动脉粥样硬化疾病及相关的心脑血管疾病等。
Description
技术领域
本发明涉及一种雷帕霉素组合物及其制备方法,属于医药技术领域。
背景技术
动脉粥样硬化是一种慢性炎症性疾病,是血管壁对各种损伤的异常反应,但是其作用机制一直存在疑问。在早期的研究中发现,动脉粥样硬化血管周围存在大量淋巴管,但两者之间的关系一直不清楚。近期研究发现淋巴管不仅参与动脉炎症的起始和消退,在胆固醇逆转运中也发挥着积极作用。淋巴管伴随着组织中的血管,具有回流组织液、免疫细胞和脂蛋白等功能,此外,斑块胆固醇的排出也需要依赖淋巴管运输。研究已证实随着淋巴引流的减速,在血管壁将发生一个血浆物质的局部蓄积。大动脉外膜中的淋巴管在中膜和外膜的边缘地带组成了一个网状组织,淋巴管的引流对于从动脉壁排出浸润的胶质和大分子方面起重要作用,而这些胶质和大分子的蓄积被认为是动脉粥样硬化病变发生的关键要素。
雷帕霉素(Rapamycin,RAPA)是一种大环内酯类抗生素,主要用于移植中免疫排斥的治疗。近几年越来越多的研究和临床用药发现,雷帕霉素在治疗罕见的淋巴异常疾病中有很好的效果。在临床治疗用药中发现,雷帕霉素在治疗卡波西样淋巴管瘤(kaposiformlymphangiomatosis,KLA),淋巴管肌瘤病(lymphangioleiomyomatosis,LAM),大面积毛细血管-淋巴管-静脉畸形,淋巴错构瘤病等均有成功的临床案例。但对于雷帕霉素在动脉粥样硬化方面的研究,还未有报道。
发明内容
为了克服现有技术的不足,本发明的第一个目的在于提供一种雷帕霉素组合物,该雷帕霉素组合物能够靶向淋巴系统,通过淋巴系统治疗动脉粥样硬化疾病及相关的心脑血管疾病等。
本发明的第二个目的在于提供上述雷帕霉素组合物的制备方法。
实现本发明的第一个目的可以通过采取如下技术方案达到:一种雷帕霉素组合物,包括按重量份计的以下有效成分:
雷帕霉素 1-10份;
高分子聚合物载体 0.5-20份;
淋巴靶向物 0.1-1份;
淋巴靶向物为透明质酸钠、适配体和抗体中的至少一种;
适配体对于特异性结合淋巴内皮细胞的能力≥50%;
抗体为淋巴管内皮透明质酸受体抗体和人源重组prox蛋白抗体中的至少一种。
进一步地,高分子聚合物载体为聚乙二醇、PLGA、PEO、PVP、聚丙烯、聚氨基酸、聚山梨酯,聚氧乙烯酯脂肪酸,甲氧基聚乙二醇嵌段共聚物和mPEG-PLA中至少一种。
进一步地,透明质酸钠的分子量为5000-20000。
进一步地,适配体的碱基数为20-120bp。
进一步地,适配体的核苷酸序列与SEQ ID NO.1-10中的一种序列的重叠率≥50%。
进一步地,雷帕霉素组合物还包括磷脂;磷脂为卵磷脂、脑磷脂、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、鞘磷脂、二磷脂酰甘油、二棕榈酰磷脂酰胆碱、二油酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺中的至少一种。
进一步地,磷脂的重量份为1-20份。
进一步地,雷帕霉素组合物还包括胆固醇。
进一步地,胆固醇的重量份为0.1-1份。
实现本发明的第二个目的可以通过采取如下技术方案达到:一种雷帕霉素组合物的制备方法,包括:
有机相溶液制备步骤:将雷帕霉素加入有机相溶剂中,得到有机相溶液;
乳液制备步骤:将高分子聚合物载体加入水相溶剂中,然后将有机相溶液滴加至水相溶剂中并混合,得到乳液;
均质步骤:在乳液中加入淋巴靶向物,混合后均质,得到雷帕霉素组合物。
进一步地,有机相溶液制备步骤中,有机溶剂为无水乙醇、二氯甲烷、叔丁醇,丙酮和甲醇中的至少一种。
进一步地,乳液制备步骤中,混合方式为:室温搅拌30min-3h,搅拌速度为300-1200rpm。
进一步地,还包括冻干步骤:在雷帕霉素组合物中加入冻干保护剂,然后微孔滤膜过滤除菌,冷冻干燥。
进一步地,冻干步骤中,冻干保护剂的加入量为5-20g/100mL雷帕霉素组合物。
相比现有技术,本发明的有益效果在于:
1、本发明雷帕霉素组合物能够靶向淋巴系统,提高了雷帕霉素在淋巴系统中的药物累积,在血液内的半衰期可高达50个小时以上,能直达淋巴系统处,持续用药,能治疗淋巴相关疾病如动脉粥样硬化,使动脉粥样硬化斑块减少,通过淋巴系统治疗动脉粥样硬化疾病及相关的心脑血管疾病等;
2、本发明雷帕霉素组合物的制备方法,以淋巴靶向物进行亲水表面修饰,平均粒径控制在50-200nm之间,载药量为0.1-20%,包封率可达70%以上,其具有均一且稳定的粒径分布;
3、本发明雷帕霉素组合物的制备方法通过高分子聚合物载体对雷帕霉素形成包覆作用,同时在其表面嵌入淋巴靶向物,同时通过有机相溶剂与水相溶剂的分散性,将包覆结构分散成纳米级的包覆粒子。
附图说明
图1为实施例1-5的外观视图;
图2为实施例4的雷帕霉素组合物的脂质体模拟图;
图3为雷帕霉素组合物的粒径分布图;
图4为雷帕霉素组合物的TEM图;
图5为细胞存活率曲线图;
图6雷帕霉素富集量柱形图;
图7空白组的动脉粥样硬化效果图;
图8对照组的动脉粥样硬化效果图;
图9药物组的动脉粥样硬化效果图;
图10斑块面积柱形图。
具体实施方式
下面,结合附图以及具体实施方式,对本发明做进一步描述:
一种雷帕霉素组合物,包括按重量份计的以下有效成分:
其中,淋巴靶向物为透明质酸钠、适配体和抗体中的至少一种。
其中,透明质酸钠的分子量为5000-20000。
其中,所述适配体的核苷酸序列与SEQ ID NO.1-10中的一种序列的重叠率≥50%,重叠率≥50%可以是至少50%、至少60%、至少70%、至少80%或至少90%,对于特异性结合淋巴内皮细胞的能力≥50%,能力≥50%即至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或至少100%。
其中,抗体为淋巴管内皮透明质酸受体抗体(LYVE-1)和人源重组prox蛋白抗体中的至少一种。
淋巴靶向物对淋巴内皮细胞进行特异性识别,使雷帕霉素组合物实现靶向淋巴的效果。
其中,高分子聚合物载体为聚乙二醇(包括聚乙二醇-2000、聚乙二醇-4000、聚乙二醇-10000、聚乙二醇-15000等)、PLGA(聚乳酸-羟基乙酸共聚物)、PEO(聚氧化乙烯)、PVP(聚乙烯吡咯烷酮)、聚丙烯、聚氨基酸、聚山梨酯,聚氧乙烯酯脂肪酸,甲氧基聚乙二醇嵌段共聚物和mPEG-PLA中至少一种;相对于小分子量的载体,以上高分子聚合物载体形成的缓释剂的亲水时间相对较长,可以提高雷帕霉素形成的注射液在体内的缓释时间,延长半衰期;载体可在自然生理条件下降解,从而被通过代谢排出体外,不会对机体产生刺激或异物反应。
其中,磷脂为卵磷脂、脑磷脂、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、鞘磷脂、二磷脂酰甘油、二棕榈酰磷脂酰胆碱、二油酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺中的至少一种。
对淋巴靶向物上修饰高分子聚合物和磷脂、胆固醇等物质,使其能更好地形成雷帕霉素组合物。
雷帕霉素组合物的制备方法,包括:
有机相溶液制备步骤:将雷帕霉素、磷脂和胆固醇加入40-200份有机相溶剂中,得到有机相溶液;
乳液制备步骤:将高分子聚合物载体加入水相溶剂中,然后将有机相溶液按1-10滴/min滴加至300-20000份水相溶剂中并室温(25℃)搅拌30min-3h,搅拌速度为300-1200rpm混合,得到乳液;室温条件下,原料比较稳定,且有机相溶剂易于挥发;
均质步骤:在乳液中加入淋巴靶向物搅拌30min-3h,混合后均质5-20次,均质压力为300-1000bar,得到雷帕霉素组合物;
冻干步骤:在雷帕霉素组合物中加入冻干保护剂,冻干保护剂的加入量为5-20g/100mL雷帕霉素组合物,然后0.22-0.45μm孔径的微孔滤膜过滤除菌,冷冻干燥。
其中,有机溶剂为无水乙醇、二氯甲烷、叔丁醇,丙酮和甲醇中的至少一种,有机溶剂需满足对雷帕霉素及磷脂,胆固醇,高分子聚合物载体具有较佳的溶解性,先制备有机相溶液,再通过将有机相溶液缓慢地释放至水相溶剂中,溶解速率的差异且随着水相溶剂的搅拌,以物理作用力使雷帕霉素、磷脂、胆固醇和高分子聚合物载体形成纳米级的溶液,并通过过滤的方式,去除游离雷帕霉素,从而得到对血液健康风险低的雷帕霉素组合物。
其中,水相溶剂为蒸馏水、生理冲液、细胞培养液、体液、缓冲液和葡萄糖注射液中的至少一种;水相溶剂为有机相溶剂提供较佳的分散介质,通过亲水性的高分子聚合物载体以及有机相溶剂的分散作用,可以有效地提高雷帕霉素在水相溶剂中的分散性,从而形成纳米级别的粒子。
其中,冻干保护剂为乳糖、葡萄糖、甘露醇和蔗糖中的至少一种。
本发明雷帕霉素组合物能够靶向淋巴系统,提高了雷帕霉素在淋巴系统中的药物累积,在淋巴系统中的停留时间为24-48h,具有缓释效果,在血液内的半衰期可高达50个小时以上,能直达淋巴系统处,持续用药,该雷帕霉素组合物以有效成分计雷帕霉素的注射量为10μg/mL以上,持续用药后动脉粥样硬化斑块减少。
实施例1:
实施例1的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL无水乙醇;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法,包括:
有机相溶液制备步骤:将雷帕霉素、卵磷脂和胆固醇加入有机相溶剂中,得到有机相溶液;
乳液制备步骤:将PEG2000-DSPE加入水相溶剂中,然后将有机相溶液按5滴/min滴加至水相溶剂中,搅拌速度为500rpm混合,600rpm室温搅拌1h,得到乳液;
均质步骤:在乳液中加入透明质酸钠搅拌1h,混合后均质6次,均质压力为600bar,得到雷帕霉素组合物;
冻干步骤:在雷帕霉素组合物中加入乳糖(冻干保护剂),冻干保护剂的加入量为10g/100mL雷帕霉素组合物,然后0.22μm孔径的微孔滤膜过滤除菌,冷冻干燥。
实施例2:
实施例2的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL无水乙醇;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法同实施例1。
实施例3:
实施例3的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL二氯甲烷;水相溶剂:15mL PBS缓冲液+150mL纯水。雷帕霉素组合物的制备方法同实施例1。
实施例4:
实施例4的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL无水乙醇;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法同实施例1。
实施例5:
实施例5的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL二氯甲烷;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法同实施例1。
实施例6:
实施例6的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL无水乙醇;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法,包括:
有机相溶液制备步骤:将雷帕霉素、卵磷脂和胆固醇加入有机相溶剂中,得到有机相溶液;
乳液制备步骤:将PEG2000-DSPE加入水相溶剂中,然后将有机相溶液按5滴/min滴加至水相溶剂中,搅拌速度为450rpm混合,600rpm室温搅拌1h,得到乳液;
均质步骤:在乳液中加入透明质酸钠搅拌1h,混合后均质10次,均质压力为500bar,得到雷帕霉素组合物;
冻干步骤:在雷帕霉素组合物中加入乳糖(冻干保护剂),冻干保护剂的加入量为10g/100mL雷帕霉素组合物,然后0.22μm孔径的微孔滤膜过滤除菌,冷冻干燥。
实施例7:
实施例7的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL无水乙醇;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法同实施例6。
实施例8:
实施例8的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL无水乙醇;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法,包括:
有机相溶液制备步骤:将雷帕霉素、卵磷脂和胆固醇加入有机相溶剂中,得到有机相溶液;
乳液制备步骤:将PEG2000-DSPE加入水相溶剂中,然后将有机相溶液按5滴/min滴加至水相溶剂中,搅拌速度为500rpm混合,500rpm室温搅拌1h,得到乳液;
均质步骤:在乳液中加入淋巴管内皮透明质酸受体抗体(LYVE-1)搅拌1h,混合后均质10次,均质压力为400bar,得到雷帕霉素组合物;
冻干步骤:在雷帕霉素组合物中加入乳糖(冻干保护剂),冻干保护剂的加入量为10g/100mL雷帕霉素组合物,然后0.45μm孔径的微孔滤膜过滤除菌,冷冻干燥。
实施例9:
实施例9的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL无水乙醇;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法,包括:
有机相溶液制备步骤:将雷帕霉素、卵磷脂和胆固醇加入有机相溶剂中,得到有机相溶液;
乳液制备步骤:将PEG2000-DSPE加入水相溶剂中,然后将有机相溶液按5滴/min滴加至水相溶剂中,搅拌速度为500rpm混合,500rpm室温搅拌1h,得到乳液;
均质步骤:在乳液中加入适配体SEQ ID NO.1搅拌1h,混合后均质10次,均质压力为400bar,得到雷帕霉素组合物;
冻干步骤:在雷帕霉素组合物中加入乳糖(冻干保护剂),冻干保护剂的加入量为10g/100mL雷帕霉素组合物,然后0.22μm孔径的微孔滤膜过滤除菌,冷冻干燥。
实施例10:
实施例10的雷帕霉素组合物,包括以下有效成分:
有机相溶剂:10mL二氯甲烷;水相溶剂:15mL PBS缓冲液+150mL纯水。
雷帕霉素组合物的制备方法,包括:
有机相溶液制备步骤:将雷帕霉素、卵磷脂和胆固醇加入有机相溶剂中,得到有机相溶液;
乳液制备步骤:将PEG2000-DSPE加入水相溶剂中,然后将有机相溶液按5滴/min滴加至水相溶剂中,搅拌速度为500rpm混合,600rpm室温搅拌1h,得到乳液;
均质步骤:在乳液中加入适配体SEQ ID NO.3搅拌1h,混合后均质6次,均质压力为600bar,得到雷帕霉素组合物;
冻干步骤:在雷帕霉素组合物中加入乳糖(冻干保护剂),冻干保护剂的加入量为10g/100mL雷帕霉素组合物,然后0.22μm孔径的微孔滤膜过滤除菌,冷冻干燥。
性能检测:
1)对实施例1-10得到的雷帕霉素组合物进行外观评价、平均粒径、电位和包封率的测定;
其中,外观评价标准:以维持原体积,不坍陷,不皱缩,色泽均匀,无花斑,质地细腻为佳;外观如图1所示,自左至右依次为实施例1-5的组合物。
平均粒径:采用马尔文激光粒度仪测定纳米粒的粒径及粒径分布,其原理为利用粒子被光照射时发生光散射以及光发生衍射的特征,并光的散射强度和衍射强度与粒子大小以及光学特征有关的原理来测定粒子大小。
如图2所示为实施例4的雷帕霉素组合物的脂质体模拟图,其中球状物为有效成分雷帕霉素,线状部分为高分子聚合物载体和淋巴靶向物;图3为雷帕霉素组合物的粒径分布图;图4为雷帕霉素组合物的TEM图。
包封率:包封率在70%以上较佳。
参照含量测定项方法,测定药物总含量。
药物含量采用高效液相色谱法测定,以甲醇-乙腈-水(体积比为43:40:17)为流动相,流速为1mL/min,柱温为40℃,检测波长为278nm。
包封率计算公式为:包封率=包封的药量/主药总含量×100%
表格1雷帕霉素组合物的外观、再分散性、包封率和平均粒径的变化
本发明得到的雷帕霉素组合物的包封率在70%以上。
2)使用MTT试剂盒法以及HCT116细胞,人血管平滑肌细胞(VSMC),人脐静脉内皮细胞(HUVEC)进行细胞毒性实验,HCT116细胞以1×104个/孔的接种量,VSMC细胞以7×103个/孔的接种量,HUVEC细胞以1×104个/孔的接种量接种于96孔板中/5%CO2/37℃培养箱中培养24小时,分别给予浓度(以雷帕霉素纳有效成分计)为80μg/mL、40.00μg/mL、30.00μg/mL、20.00μg/mL、10.00μg/mL、5.00μg/mL、2.50μg/mL、1.25μg/mL、0.65μg/mL、0.3125μg/mL和0μg/mL的实施例4的雷帕霉素组合物分别处理48h后,结果见图5,该组合物显著抑制上述细胞的增殖,给药48h后,HCT116的IC50为5ug/mL,VSMC的IC50为13ug/mL,HUVEC细胞17ug/mL。
3)雷帕霉素靶向纳米制剂的淋巴靶向作用
动物:新西兰大白兔,4-6kg,购自广东省实验动物中心。
组别及实验方案:空白组:生理盐水,耳缘静脉注射体积为1mL,对照组(R):使用雷帕霉素原料药,用生理盐水稀释到所需浓度(给药量0.5mg/kg),耳缘静脉注射,药物组(Target-RL):耳缘静脉注射1.5mg/mL实施例4,在注射完后1h,2h,4h,8h,24h取兔子淋巴液,提取淋巴液中的雷帕霉素,测量淋巴液中的雷帕霉素含量。以其药物含量确定雷帕霉素组合物是否靶向至淋巴系统。结果见图6,可以看到,与原料药相比,雷帕霉素组合物在不同时间点在淋巴液中富集更多,差异具有显著性,证明该雷帕霉素组合物具有淋巴靶向作用。
4)雷帕霉素组合物对动脉粥样硬化的治疗作用
动物:载脂蛋白基因敲除小鼠(ApoE-/-小鼠),18-25g,购自北京大学实验动物部。
动脉粥样硬化模型小鼠的制备:在SPF级环境(室温:23℃,相对湿度:65%,12h明暗交替)饲养至8周龄后,开始喂养高脂饲料,喂食高脂饲料12周后,建模成功,开始给药。给药方案见组别和给药方案,取血管染色,计算斑块面积所占分数,斑块面积分数计算公式为:AA∶AA=P/P0。数据用均值土标准差表示,统计学分析采用t检验,P<0.05有显著性差异,所有数据均通过软件进行分析。
组别及给药方案:空白组:生理盐水,腹腔注射,每两天注射一次,体积为0.2mL;对照组:雷帕霉素原溶液,用生理盐水稀释到所需浓度(给药量1.5mg/kg),腹腔注射,每两天注射一次;药物组:给药量:1.5mg/kg实施例4,腹腔注射,每两天注射一次,连续3个月。期间,观察小鼠状态变化。给药结束后,小鼠麻醉,取血检测血脂及一些炎症因子,取血管观察斑块情况,如图7-9所示为空白组、对照组和药物组的动脉粥样硬化效果图,给药后,血管斑块明显减少,如图10所示,各组斑块面积/总血管面积分别是:空白组:52.18%±3.497%,对照组:48.33%±2.851%,药物组:28.32%±5.461%,(p<0.05)。
对于本领域的技术人员来说,可根据以上描述的技术方案以及构思,做出其它各种相应的改变以及变形,而所有的这些改变以及变形都应该属于本发明权利要求的保护范围之内。
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Claims (10)
1.一种雷帕霉素组合物,其特征在于包括按重量份计的以下有效成分:
雷帕霉素 1-10份;
高分子聚合物载体 0.5-20份;
淋巴靶向物 0.1-1份;
所述淋巴靶向物为透明质酸钠、适配体和抗体中的至少一种;
所述适配体对于特异性结合淋巴内皮细胞的能力≥50%;
所述抗体为淋巴管内皮透明质酸受体抗体和人源重组prox蛋白抗体中的至少一种。
2.如权利要求1所述的雷帕霉素组合物,其特征在于,所述高分子聚合物载体为聚乙二醇、PLGA、PEO、PVP、聚丙烯、聚氨基酸、聚山梨酯,聚氧乙烯酯脂肪酸,甲氧基聚乙二醇嵌段共聚物和mPEG-PLA中至少一种。
3.如权利要求1所述的雷帕霉素组合物,其特征在于,所述适配体的核苷酸序列与SEQID NO.1-10中的一种序列的重叠率≥50%。
4.如权利要求1所述的雷帕霉素组合物,其特征在于,所述雷帕霉素组合物还包括磷脂;所述磷脂为卵磷脂、脑磷脂、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、鞘磷脂、二磷脂酰甘油、二棕榈酰磷脂酰胆碱、二油酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺中的至少一种。
5.如权利要求1所述的雷帕霉素组合物,其特征在于,所述雷帕霉素组合物还包括胆固醇。
6.一种雷帕霉素组合物的制备方法,其特征在于包括:
有机相溶液制备步骤:将雷帕霉素加入有机相溶剂中,得到有机相溶液;
乳液制备步骤:将高分子聚合物载体加入水相溶剂,然后将有机相溶液滴加至水相溶剂,得到乳液;
均质步骤:在乳液中加入淋巴靶向物,混合后均质,得到雷帕霉素组合物。
7.如权利要求6所述的雷帕霉素组合物的制备方法,其特征在于,有机相溶液制备步骤中,所述有机溶剂为无水乙醇、二氯甲烷、叔丁醇,丙酮和甲醇中的至少一种。
8.如权利要求6所述的雷帕霉素组合物的制备方法,其特征在于,乳液制备步骤中,混合方式为:室温搅拌30min-3h,搅拌速度为300-1200rpm。
9.如权利要求6所述的雷帕霉素组合物的制备方法,其特征在于还包括冻干步骤:在雷帕霉素组合物中加入冻干保护剂,然后微孔滤膜过滤除菌,冷冻干燥。
10.如权利要求9所述的雷帕霉素组合物的制备方法,其特征在于,冻干步骤中,冻干保护剂的加入量为5-20g/100mL雷帕霉素组合物。
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CN115337468B (zh) * | 2022-08-23 | 2024-01-30 | 苏州中天医疗器械科技有限公司 | 一种细胞靶向性雷帕霉素药物球囊及其制备方法和应用 |
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