CN112791066A - 一种注射用西罗莫司缓释微球及其制备方法 - Google Patents
一种注射用西罗莫司缓释微球及其制备方法 Download PDFInfo
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Abstract
本发明属于药物缓释制剂的技术领域,具体公开了一种注射用西罗莫司缓释微球及其制备方法。其中,注射用西罗莫司缓释微球包括以下重量百分比的组分:西罗莫司5%~50%、丙交酯乙交酯共聚物50%~95%。在本发明中,采用了混合溶剂体系介入的O/W单乳化‑溶剂挥发法来制备所述微球。与现有技术相比,本发明具有以下优点:(1)延长了药物的释药周期,显著地降低了药物的给药频率;(2)有效地促进了药物的释放,累积释放量高达95%,药物生物利用度得到大幅度地提高,同时降低了药物的给药剂量;(3)具有工艺放大优势,产业化生产工艺参数无明显变化,易实现产业化的可重现性。
Description
技术领域
本发明属于药物缓释制剂的技术领域,具体涉及一种注射用西罗莫司缓释微球及其制备方法。
背景技术
西罗莫司作为一种强效免疫抑制剂,临床上用于预防器官移植后的排斥反应及自身免疫性疾病的治疗。在细胞内部,西罗莫司结合免疫嗜素(FK结合蛋白-12,FKBP-12),生成一个免疫抑制复合物。该复合物对钙调磷酸酶的活性无影响,但可以与哺乳动物的西罗莫司靶分子(mTOR,一种关键的调节激酶)结合,并抑制其活性;此种抑制阻遏了细胞周期中G1期向S期的发展,进而抑制了由抗原和细胞因子(白介素[IL]-2、IL-4和IL-15)激发的T淋巴细胞的活化和增殖T细胞的增殖。
西罗莫司是一类大环内酯类抗生素,分子式:C51H79NO13,相对分子质量:914.2。目前市场上仅有西罗莫司的口服制剂,但是由于其较高的相对分子量和较低的水溶性,口服制剂的生物利用度均较低(口服溶液约为14%;片剂约为41%)。同时有报道指出西罗莫司具有与浓度相关不良反应,高剂量时,伴有贫血、高胆固醇血症、血小板减少症、高三酯血症等。基于器官移植患者终身服药的临床需求及西罗莫司片的用药现状,迫切需要对现有剂型进行改进,提高药物生物利用度,降低药物的不良反应。
长效缓释制剂是一种高端创新剂型,药物分子随着载体材料在给药部位的降解,缓慢地释放出来,经吸收进入血液循环,并且可根据材料的分子量、聚合度、单体比例等因素来控制药物释放速度,达到长效、控释的给药目的,显著降低了给药频率,提高了患者的治疗顺应性。文献报道采用聚羟基丁酸戊酯(PHBV)作为载体,制备的西罗莫司-PHBV微球,粒径186.73(±12.62)nm,体外释药周期为7day,对淋巴细胞增殖的具有一定的抑制作用,但是包封率仅为73%,未达到药典要求(刘炜等,西罗莫司缓释微球的制备及其对淋巴细胞增殖的抑制作用研究,中国临床药理学杂志,2017年,第10期,933-935页)。
发明内容
鉴于器官移植患者终身服药的临床需求及西罗莫司片的用药现状,本发明第一个目的在于在于提供一种注射用西罗莫司缓释微球。该微球形态良好、粒径适宜、载药量与包封率良好、释放周期长且稳定。
本发明的第二个目的在于提供一种注射用西罗莫司缓释微球的制备方法,所述制备方法简单、可行,满足现代工业规模化生产的需求。
本发明具体技术方案如下:
一种注射用西罗莫司缓释微球,所述注射用西罗莫司缓释微球包括以下重量百分比的组分:西罗莫司5%~50%、丙交酯乙交酯共聚物(PLGA)50%~95%。其中,所述PLGA可以为羧基封端、酯封端、羟基封端,优选为羧基封端。
优选地,PLGA中丙交酯单元和乙交酯单元的摩尔比为(40~80):(20~60),重均分子量(Mw)为10000~50000道尔顿;更为优选的,PLGA中丙交酯单元和乙交酯单元的摩尔比为(50~75):(25~50),重均分子量(Mw)为15000~35000道尔顿。
优选地,所述西罗莫司缓释微球的粒径范围为10μm~200μm。
优选地,所述西罗莫司缓释微球的粒径范围为28μm~150μm。
本发明提供了一种注射用西罗莫司缓释微球的制备方法,采用混合溶剂体系介入的O/W单乳化-溶剂挥发法,制备所述微球。
优选地,所述制备方法具体包括如下步骤:
(1)连续相的制备
a.选用混合溶剂作为连续相的溶剂体系;
b.将西罗莫司和PLGA溶于所述溶剂体系,形成无色澄明溶液;
(2)将聚乙烯醇(PVA)溶于注射用水中,制得分散相;
(3)将连续相缓慢加入至分散相中,在线剪切乳化,乳液收集至溶剂挥发罐,继续低速搅拌,挥干溶剂;
(4)将步骤(3)所得微球离心,采用注射用水洗涤,过筛,收集微球;
(5)将步骤(4)所得微球进行冷冻干燥处理;
(6)分装:将步骤(5)所得微球分装于西林瓶中,压塞,轧盖,辐照灭菌,包装即得。
进一步优选地,所述制备方法具体包括如下步骤:
(1)连续相的制备
a.选用混合溶剂作为连续相的溶剂体系;
b.将西罗莫司和PLGA溶于所述溶剂体系,形成无色澄明溶液;
(2)将聚乙烯醇(PVA)溶于注射用水中,制得分散相;
(3)将连续相缓慢加入至分散相中,在线剪切乳化,乳液收集至溶剂挥发罐,继续低速搅拌,挥干溶剂;
(4)将步骤(3)所得微球离心,采用注射用水洗涤,过筛,收集微球;
(5)将步骤(4)所得微球进行冷冻干燥处理;
a.预冻阶段:将微球产品分装至冻干盘中,放入冷冻干燥机,板层温度降至-40℃~-50℃,保温2h~4h,真空度0.50~0.40mbar;
b.升华干燥:预冻阶段结束后,板层在2~5h内逐渐升温至-10℃~-5℃,保温5~10h,真空度0.40~0.15mbar;
c.解析干燥:升华干燥结束后,板层在2~10h内逐渐升温至15℃~28℃,保温5~16h,真空度0.00mbar;
(6)分装:将步骤(5)所得微球分装于西林瓶中,压塞,轧盖,辐照灭菌,包装即得。
优选地,所述的混合溶剂体系为溶剂A/溶剂B,其中溶剂A选自二氯甲烷或乙酸乙酯,溶剂B选自苯甲醇、碳酸丙烯酯或异丙醇,溶剂A/溶剂B的体积为1:1~5。
优选地,步骤(2)中所述分散相的浓度为3~30mg/mL。
与现有技术相比,本发明取得有益的技术效果如下:
a.本发明首次以生物降解材料PLGA为载体,制备了西罗莫司的注射用缓释微球,延长了药物的释药周期,显著地降低了药物的给药频率(由1日/次降至1月/次),避免了口服给药引起血药浓度“峰谷”现象及药物不良反应。
b.本发明采用混合溶剂体系为溶剂A/溶剂B,其中溶剂A选自二氯甲烷或乙酸乙酯,溶剂B选自苯甲醇、碳酸丙烯酯或异丙醇制备了西罗莫司的缓释微球,由于亲水性有机溶剂在微球制备过程中发挥了致孔剂的作用,使微球内部结构相对疏松,有效地促进了药物的释放,累积释放量高达95%,药物生物利用度得到大幅度地提高,同时降低了药物的给药剂量。
c.本发明采用O/W在线剪切乳化-溶剂挥发法制备了西罗莫司的缓释微球,球体形态圆整,粒径适宜,载药量可达50%,包封率可达95%以上;该制备工艺具有放大优势,产业化生产工艺参数无明显变化,易实现产业化的可重现性。
附图说明
图1.实施例1-6微球的扫描电镜照片。
图2.实施例7-12微球的扫描电镜照片。
图3.对比例1-5微球的扫描电镜照片。
图4.实施例1-6微球剖面的扫描电镜照片。
图5.实施例7-12微球剖面的扫描电镜照片。
图6.对比例1-5微球剖面的扫描电镜照片。
图7.实施例1-8与对比例1微球产品的体外释放曲线。
图8.实施例9-12与对比例1-5微球产品的体外释放曲线。
具体实施方式
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
实施例1
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至碳酸丙烯酯和乙酸乙酯的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成3mg/mL的PVA溶液;
3)将溶液1缓慢加入至3mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例2
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至异丙醇和二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成30mg/mL的PVA溶液;
3)将溶液1缓慢加入至30mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-4℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例3
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至苯甲醇和二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成8mg/mL的PVA溶液;
3)将溶液1缓慢加入至8mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例4
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至异丙醇和二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成5mg/mL的PVA溶液;
3)将溶液1缓慢加入至5mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例5
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至苯甲醇和二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成10mg/mL的PVA溶液;
3)将溶液1缓慢加入至10mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例6
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至异丙醇和乙酸乙酯的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成15mg/mL的PVA溶液;
3)将溶液1缓慢加入至15mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例7
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至碳酸丙烯酯和乙酸乙酯的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成20mg/mL的PVA溶液;
3)将溶液1缓慢加入至20mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.4 0mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例8
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至碳酸丙烯酯和二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成25mg/mL的PVA溶液;
3)将溶液1缓慢加入至25mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例9
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成8mg/mL的PVA溶液;
3)将溶液1缓慢加入至8mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h真空度0.00mbar。
实施例10
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至苯甲醇与二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成2mg/mL的PVA溶液;
3)将溶液1缓慢加入至2mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例11
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至异丙醇和二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成40mg/mL的PVA溶液;
3)将溶液1缓慢加入至40mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
实施例12
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至苯甲醇和二氯甲烷的混合溶剂体系(8ml)搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成8mg/mL的PVA溶液;
3)将溶液1缓慢加入至8mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)过滤收集微球于800ml的25mg/mL泊洛沙姆乙醇水溶液(15/85,v/v),继续搅拌1h,将所得微球混悬液经120目过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
对比例1
处方:
制备步骤:
1)称取处方量的西罗莫司和PLGA,加至8ml的二氯甲烷中搅拌溶解,配制成溶液1;
2)称取处方量的PVA加入至500ml注射用水中(100℃),搅拌至溶解,将PVA溶液冷却至25℃,补加注射用水至800ml,配成8mg/mL的PVA溶液;
3)将溶液1缓慢加入至8mg/mL PVA溶液,1500rpm均质乳化1min;
4)乳化结束后,开启机械搅拌挥发溶剂,3h后停止搅拌;
5)过滤收集微球于800ml的2.5mg/mL泊洛沙姆乙醇水溶液(15/85,v/v),继续搅拌1h,将所得微球混悬液经120目筛网过滤收集微球,并以注射用水冲洗微球3遍后,转移至培养皿中,于冷冻干燥机中冻干;
6)冻干产品经120目筛网过筛,分装于西林瓶中,压塞,轧盖,辐照灭菌,即得。
冷冻干燥曲线:
a.预冻阶段:将微球产品放入冷冻干燥机,板层温度降至-40℃,保温3h,真空度0.40mbar;
b.升华干燥:预冻阶段结束后,板层在3h内逐渐升温至-15℃,保温6h,真空度0.35mbar;
c.解析干燥:升华干燥结束后,板层在5h内逐渐升温至25℃,保温10h,真空度0.00mbar。
对比例2
处方:
西罗莫司 0.875g
PLGA(A/B=50:50,90000道尔顿) 1.625g
二氧六环:二氯甲烷(v/v) 25:75
制备步骤:
1)称取处方量的西罗莫司和PLGA,加入至二氧六环和二氯甲烷的混合溶剂中(8ml),涡旋溶解;
2)将1)中所制备的溶液加到PVA(20mg/mL,160ml)(8000r/min)0.5min制备O/W初乳;
3)将2)中所制备的初乳转入PVA(10mg/mL,800ml)溶液中,40℃下磁力搅拌3h,离心(3000r/min)2min后收集微球,冷冻干燥,即得。
对比例3
处方:
西罗莫司 0.875g
PLGA(A/B=50:50,90000道尔顿) 1.625g
乙酸乙酯:二氯甲烷(v/v) 25:75
制备步骤:
1)称取处方量的西罗莫司和PLGA,加入至乙酸乙酯和二氯甲烷的混合溶剂中(8ml),涡旋溶解;
2)将1)中所制备的溶液加到PVA(20mg/mL,160ml)(8000r/min)0.5min制备O/W初乳;
3)将2)中所制备的初乳转入PVA(10mg/mL,800ml)溶液中,40℃下磁力搅拌3h,离心(3000r/min)2min后收集微球,冷冻干燥,即得。
对比例4
处方:
西罗莫司 0.875g
PLGA(A/B=50:50,90000道尔顿) 1.625g
丙酮:二氯甲烷(v/v) 25:75
制备步骤:
1)称取处方量的西罗莫司和PLGA,加入至丙酮和二氯甲烷的混合溶剂中(8ml),涡旋溶解;
2)将1)中所制备的溶液加到PVA(20mg/mL,160ml)(8000r/min)0.5min制备O/W初乳;
3)将2)中所制备的初乳转入PVA(10mg/mL,800ml)溶液中,40℃下磁力搅拌3h,离心(3000r/min)2min后收集微球,冷冻干燥,即得。
对比例5
处方:
西罗莫司 0.875g
PLGA(A/B=50:50,90000道尔顿) 1.625g
乙腈:二氯甲烷(v/v) 25:75
制备步骤:
1)称取处方量的西罗莫司和PLGA,加入至乙腈和二氯甲烷的混合溶剂体中(8ml),涡旋溶解;
2)将1)中所制备的溶液加到PVA(20mg/mL,160ml)(8000r/min)0.5min制备O/W初乳;
3)将2)中所制备的初乳转入PVA(10mg/mL,800ml)溶液中,40℃下磁力搅拌3h,离心(3000r/min)2min后收集微球,冷冻干燥,即得。
验证实施例
(1)载药量与包封率测定
含量测定:精密称取注射用西罗莫司缓释微球适量置于50ml容量瓶中,加入1mlDMSO,超声至溶解,甲醇定容至刻度线,摇匀。采用0.22μm聚四氟乙烯滤膜过滤,滤液稀释10倍后,HPLC法测定药物含量。
HPLC检测方法:Diamonsil C18柱(200mm×4.6mm,5μm);流动相为甲醇-水(85:15);UV检测波长278nm;流速:1.0ml/min;柱温:50℃;进样量:20μL。在此色谱条件下,西罗莫司保留时间为7.4min。
表1实施例及对比例测定结果
通过表1的实验数据可以看出采用本发明技术制备的西罗莫司微球粒径分布范围窄,具有较高的载药量与包封率。
(2)微球外观及形态
本发明制备微球及其剖面的扫描电镜照片见图1-6,由微球的电镜照片可见(图1-3):当连续相的混合溶剂中不含乙酸乙酯,制备所得微球产品表面光滑,球体形态圆整,粒径分布较均一,分散性较好,无聚集粘连的现象;当连续相的混合溶剂中含有乙酸乙酯,制备所得微球产品面有皱缩现象且存在少量孔洞,如实施例1、6、7及对比例3。对比例1-5制备微球产品相对于实施例形态较差,粒径分布较不均匀,微球之间存在粘连现象。由微球剖面的电镜照片可见(4-6):当连续相的溶剂体系为单一溶剂,微球剖面较为光滑,紧密,如对比例1;当连续相的溶剂体系为混合溶剂,微球剖面中有少量孔洞存在;对比例2-5微球产品相比实施例3,微球剖面较为粗糙。
(3)体外溶出曲线测定
本试验对实施例与对比例制备的西罗莫司缓释微球进行体外释放行为的研究。采用USP4自动溶出仪(Sotax CE7-smart)闭环模式测定。取微球样品约25.0mg,精确称量,置于锥形部装满1mm玻璃珠的流通池内,保证溶出介质在流通池内以层流方式流动,释放介质为脱气处理的pH 7.4的磷酸盐缓冲液(0.05mol/L,0.1%NaN3,50mL),活塞泵流速为8mL/min,温度37℃,启动活塞泵,自溶出介质浸过样品时开始计时,于设定时间点(第4h、8h、2天、5天、8天、11天、14天、17天、20天、23天、26天、29天、32天、35天、38天、41天、44天、47天)取样1mL,同时补充等温等体积的释放介质;采用HPLC法测定并计算微球累积释放量,体外药物累积释放曲线见图7和图8。
由图7和图8可知采用本制备工艺制备的微球产品,无明显突释,释放恒定,具有较好的缓释效果。释放速率:实施例>相应的对比例。当采用的PLGA的丙交酯单元和乙交酯单元摩尔比相同时,药物的载药量越高,PLGA的分子量越小,微球产品的释放速率越快;实施例1的载药量仅为5%,但是其释放速率仍高于载药量为20%的对比实施例1。当采用的PLGA的丙交酯单元和乙交酯单元摩尔比不同时,其摩尔比越大,微球产品的释放速率越慢;释放速率:50/50>60/40>75/25>90/10(所用载体PLGA中丙交酯单元和乙交酯单元的摩尔比);实施例4、9采用90/10的PLGA为载体,微球产品的释放速率相对较慢,而实施例2、6、7、10采用50/50的PLGA为载体,微球产品的释放速率相对较快。对比例2、3、4、5微球产品相对于实施例3,微球释放速率较慢,释放周期略长。本实施例制备的微球释放速率快且稳定,可以较快地达到药物的有效治疗浓度,临床上所需给药剂量低,患者的顺应性好;另一方面实施例的药物累积释放量均高于相应的对比实施例,即药物的利用率高,大大地提高了药物的生物利用度。
Claims (10)
1.一种注射用西罗莫司缓释微球,其特征在于,包括以下重量百分比的组分:西罗莫司5%~50%、丙交酯乙交酯共聚物PLGA 50%~95%。
2.根据权利要求1所述的缓释微球,其特征在于,所述的PLGA中丙交酯单元和乙交酯单元的摩尔比为40~80:20~60,重均分子量为10000~50000道尔顿。
3.根据权利要求2所述的缓释微球,其特征在于,所述的PLGA中丙交酯单元和乙交酯单元的摩尔比为50~75:25~50,重均分子量为15000~35000道尔顿。
4.根据权利要求2所述的缓释微球,其特征在于,所述的西罗莫司缓释微球的粒径范围为10μm~200μm。
5.根据权利要求2所述的缓释微球,其特征在于,所述的西罗莫司缓释微球的粒径范围为28μm~150μm。
6.一种权利要求1~5中任一项所述缓释微球的制备方法,其特征在于,包括如下步骤:
1)连续相的制备
a.选用混合溶剂作为连续相的溶剂体系;
b.将西罗莫司和PLGA溶于所述溶剂体系,形成无色澄明溶液;
2)将PVA溶于注射用水中,制得分散相;
3)将连续相缓慢加入至分散相中,在线剪切乳化,乳液收集至溶剂挥发罐,继续低速搅拌,挥干溶剂;
4)将步骤3)所得微球离心,采用注射用水洗涤,过筛,收集微球;
5)将步骤4)所得微球进行冷冻干燥处理;
6)分装:将步骤5)所得微球分装于西林瓶中,压塞,轧盖,辐照灭菌,包装即得。
7.一种注射用西罗莫司缓释微球的制备方法,其特征在于,采用混合溶剂体系介入的O/W单乳化-溶剂挥发法制备所述微球。
8.一种注射用西罗莫司缓释微球的制备方法,其特征在于,包括如下步骤:
1)连续相的制备
a.选用混合溶剂作为连续相的溶剂体系;
b.将西罗莫司和PLGA溶于所述溶剂体系,形成无色澄明溶液;
2)将PVA溶于注射用水中,制得分散相;
3)将连续相缓慢加入至分散相中,在线剪切乳化,乳液收集至溶剂挥发罐,继续低速搅拌,挥干溶剂;
4)将步骤3)所得微球离心,采用注射用水洗涤,过筛,收集微球;
5)将步骤4)所得微球进行冷冻干燥处理;
6)分装:将步骤5)所得微球分装于西林瓶中,压塞,轧盖,辐照灭菌,包装即得。
9.根据权利要求6或8所述的制备方法,其特征在于,步骤1)所述的混合溶剂体系为溶剂A/溶剂B,其中溶剂A选自二氯甲烷或乙酸乙酯,溶剂B选自苯甲醇、碳酸丙烯酯或异丙醇。
10.根据权利要求9所述的制备方法,其特征在于,所述溶剂A/溶剂B体积为1:1~5。
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060210638A1 (en) * | 2005-03-17 | 2006-09-21 | Elan Pharma International Limited | Injectable compositions of nanoparticulate immunosuppressive compounds |
CN100998868A (zh) * | 2007-01-16 | 2007-07-18 | 济南帅华医药科技有限公司 | 一种抗实体肿瘤组合物 |
CN101023919A (zh) * | 2006-12-26 | 2007-08-29 | 济南康泉医药科技有限公司 | 一种抗实体肿瘤缓释剂 |
CN101094650A (zh) * | 2003-05-07 | 2007-12-26 | Af药物公司 | 减少瘢痕组织形成的组合物和方法 |
CN101336890A (zh) * | 2008-05-30 | 2009-01-07 | 济南基福医药科技有限公司 | 一种抗癌缓释凝胶注射剂 |
CN101708164A (zh) * | 2009-12-18 | 2010-05-19 | 苏州大学 | 一种卡巴拉汀缓释微球及其制备方法 |
CN101708163A (zh) * | 2009-12-18 | 2010-05-19 | 苏州大学 | 一种司来吉兰缓释微球及其制备方法 |
US20130273167A1 (en) * | 2010-12-24 | 2013-10-17 | Samyang Biopharmaceuticals Corporation | Sustained-release polymeric microparticles containing poorly water-soluble drug and method for preparing the same |
CN106474070A (zh) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | 一种克服停滞期、恒速释放疏水性药物的微球及制备方法 |
WO2017107906A1 (zh) * | 2015-12-22 | 2017-06-29 | 四川科伦药物研究院有限公司 | 一种艾塞那肽微球制剂及其制备方法 |
-
2019
- 2019-11-13 CN CN201911103280.8A patent/CN112791066B/zh active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101094650A (zh) * | 2003-05-07 | 2007-12-26 | Af药物公司 | 减少瘢痕组织形成的组合物和方法 |
US20060210638A1 (en) * | 2005-03-17 | 2006-09-21 | Elan Pharma International Limited | Injectable compositions of nanoparticulate immunosuppressive compounds |
CN101023919A (zh) * | 2006-12-26 | 2007-08-29 | 济南康泉医药科技有限公司 | 一种抗实体肿瘤缓释剂 |
CN100998868A (zh) * | 2007-01-16 | 2007-07-18 | 济南帅华医药科技有限公司 | 一种抗实体肿瘤组合物 |
CN101336890A (zh) * | 2008-05-30 | 2009-01-07 | 济南基福医药科技有限公司 | 一种抗癌缓释凝胶注射剂 |
CN101708164A (zh) * | 2009-12-18 | 2010-05-19 | 苏州大学 | 一种卡巴拉汀缓释微球及其制备方法 |
CN101708163A (zh) * | 2009-12-18 | 2010-05-19 | 苏州大学 | 一种司来吉兰缓释微球及其制备方法 |
US20130273167A1 (en) * | 2010-12-24 | 2013-10-17 | Samyang Biopharmaceuticals Corporation | Sustained-release polymeric microparticles containing poorly water-soluble drug and method for preparing the same |
CN106474070A (zh) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | 一种克服停滞期、恒速释放疏水性药物的微球及制备方法 |
WO2017107906A1 (zh) * | 2015-12-22 | 2017-06-29 | 四川科伦药物研究院有限公司 | 一种艾塞那肽微球制剂及其制备方法 |
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