CN100438855C - 重酒石酸长春瑞滨脂质体及其冻干粉针与制备方法 - Google Patents
重酒石酸长春瑞滨脂质体及其冻干粉针与制备方法 Download PDFInfo
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- CN100438855C CN100438855C CNB2006100013187A CN200610001318A CN100438855C CN 100438855 C CN100438855 C CN 100438855C CN B2006100013187 A CNB2006100013187 A CN B2006100013187A CN 200610001318 A CN200610001318 A CN 200610001318A CN 100438855 C CN100438855 C CN 100438855C
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- vinorelbine
- phospholipid
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Abstract
本发明涉及一种抗肿瘤药物重酒石酸长春瑞滨脂质体及其冻干粉针与制备方法,本发明的重酒石酸长春瑞滨脂质体制剂,由抗癌药物重酒石酸长春瑞滨的脂质体和药物可接受的载体组成,其中所述抗癌药物重酒石酸长春瑞滨的脂质体含有以下成分:重酒石酸长春瑞滨、磷脂、胆固醇、维生素E,它们之间的重量比为1份∶5-100份∶1-15份∶0.01-0.05份。
Description
技术领域:
本发明涉及一种抗肿瘤药物重酒石酸长春瑞滨的脂质体制剂。
背景技术:
重酒石酸长春瑞滨(Vinorelbine Bitartrate通用名长春瑞宾),是一种半合成的长春花生物碱,其作用机理与长春花碱(VLB)和长春新碱(VCR)基本相同,主要通过阻滞细胞有丝分裂过程中的微管形成,使细胞分裂停止于有丝分裂中期,为细胞周期特异性药物。和其它长春碱一样,长春瑞滨也可以抑制氨基酸前后的循环和谷胱甘肽的代谢;依赖钙调素的Ca甘-ATP酶的活性;细胞的生物氧化作用及核酸与油脂的生物合成。临床主要用于非小细胞肺癌、转移性乳腺癌、晚期卵巢癌、恶性淋巴瘤等。但是该药物静脉注射后,毒副作用比较的大,常见的为骨髓抑制、胃肠道毒性及脱发等,除此之外,长期用药会出现下肢无力。这些毒副作用使长春瑞宾的临床应用受到了很大的限制。急需寻求一种有效的方法,可以在不增加药物剂量的情况下,延长药物的半衰期,提高药物的抗肿瘤效果,减少药物的毒副作用,增强药物的临床应用性。
脂质体是一种定向药物载体,属于靶向给药系统的一种新剂型。它可以将药物由巨噬系统吞噬而激活机体的自身免疫功能,并改变被包封药物的体内分布,使药物主要在肝、脾、肺和骨髓等组织器官中积蓄,从而提高药物的治疗指数,减少药物的治疗剂量和降低药物的毒性。
80年代中期,一些专门从事脂质体开发的公司相继成立,开展了用脂质体包封抗癌药的研究,近年有许多抗癌药物的脂质体剂型相继上市。脂质体作为抗肿瘤药物的载体将会得到越来越普遍的应用。
发明内容:
本发明根据脂质体载体材料的特性及重酒石酸长春瑞滨产品本身的特性,发明了一种新的重酒石酸长春瑞滨脂质体药物制剂。
本发明的重酒石酸长春瑞滨脂质体制剂是一种注射用冻干粉针剂,本发明经过筛选找到了既能使脂质体中药物持续释放,提高血药浓度、延长药物在血液中循环时间,提高药物的生物利用度,同时又可以降低药物的毒副作用,增强病人的顺应性的有效的药物配方。
本发明的重酒石酸长春瑞滨脂质体制剂,由抗癌药物重酒石酸长春瑞滨的脂质体和药物可接受的载体组成。其中所述抗癌药物重酒石酸长春瑞滨的脂质体含有以下成分:重酒石酸长春瑞滨、磷脂、胆固醇、维生素E,它们之间的重量比为1份∶5-100份∶1-15份∶0.01-0.05份。
其较好的比例为:长春瑞宾1份,磷脂30-70份,胆固醇5-15份,维生素E0.02-0.04份。
最优选的是重酒石酸长春瑞滨1份,磷脂60份,胆固醇10份,维生素E0.03份。
其中所述磷脂为大豆磷脂、卵磷脂或和合成磷脂。
以上药物原料均可以从市场上买到。
以上脂质体配方制成的脂质体和制成本发明制剂所必须的药物可接受的载体结合,制成本发明的重酒石酸长春瑞滨脂质体制剂,所述药物可接受的载体是制备药物制剂,特别是注射用冻干粉针剂所需要的常规载体,如PH值调节剂,缓冲系统,冻干支持剂,抗氧化剂,防腐剂,注射用溶剂等,这些载体的加入量也是常规的。
本发明还提供本发明的重酒石酸长春瑞滨脂质体制剂的可工业化生产的方法。
本发明的重酒石酸长春瑞滨脂质体制剂可以采用以下方法制备:
方法一:
1)按重量比取重酒石酸长春瑞滨1份、磷脂5-100份,维生素E0.01-0.05份,与胆固醇1-15份,溶于有机溶剂中,混合均匀;
2)将脂质溶液于薄膜蒸发器上,减压除去有机溶剂;
3)按处方配置PH6-8的磷酸盐缓冲液;
4)将形成的脂膜中加入有机溶剂溶解,再加入磷酸盐缓冲液,混匀,乳化,继续在薄膜蒸发器上,减压除去有机溶剂;得脂质体混悬液;
将所得脂质体混悬液进行高压乳匀,减小粒径即得,将适量的冻干支持物溶解在脂质体中,无菌过滤;
5)检验合格,装瓶,封盖,冻干,即得成品。
方法二:
1)按重量比取重酒石酸长春瑞滨1份、磷脂5-100份,维生素E0.01-0.05份,与胆固醇1-15份,溶于有机溶剂中,混合均匀;
2)按处方配置PH6-8的磷酸盐缓冲液;
3)将步骤1)溶液与步骤2)溶液混和,乳化,在薄膜蒸发器上减压除去有机溶剂;得脂质体混悬液;
4)将所得脂质体混悬液进行高压乳匀,减小粒径。将适量处方量的冻干支持物溶解在脂质体中,无菌过滤。
5)检验合格,装瓶,封盖,冻干,即得成品。
优选的制备方法如下:
方法一:
1)按重量比取重酒石酸长春瑞滨1份、磷脂30-70份,维生素E0.02-0.04份与胆固醇5-15份,溶于有机溶剂中,混合均匀;
2)将上述脂质溶液于薄膜蒸发器上,减压除去有机溶剂;
3)按处方配置PH6-8的磷酸盐缓冲液;
4)将形成的脂膜中加入有机溶剂溶解,再加入磷酸盐缓冲液,混匀,乳化,继续在薄膜蒸发器上,减压除去有机溶剂;得脂质体混悬液;
5)将所得脂质体混悬液进行高压乳匀,减小粒径即得。将适量处方量的冻干支持物溶解在脂质体中,无菌过滤;
6)检验合格,装瓶,封盖,冻干,即得成品。
方法二:
1)按重量比取重酒石酸长春瑞滨1份、磷脂30-70份,维生素E0.02-0.04份与胆固醇5-15份,溶于有机溶剂中,混合均匀;
2)按处方配置PH6-8的磷酸盐缓冲液;
3)将溶液1与溶液2混和,乳化,在薄膜蒸发器上减压除去有机溶剂;得脂质体混悬液;
4)将所得脂质体混悬液进行高压乳匀,减小粒径,将适量处方量的冻干支持物溶解在脂质体中,无菌过滤。
5)检验合格,装瓶,封盖,冻干,即得成品。
所述制备方法中,配置PH6-8的磷酸盐缓冲液时,可以加入PH值调节剂调节PH值,所述PH值调节剂选自氢氧化钠、氯化钾、氯化钠、磷酸盐、碳酸盐、柠檬酸盐、烟酰胺、苯甲酰胺、脲、硫脲、乙二胺、二乙胺、乙醇胺、二乙醇胺、三乙醇胺和三乙胺等。
所述制备方法中,步骤1)的有机溶剂选自乙醚和氯仿。
所述制备方法中,所述冻干支持剂选自右旋糖酐、单糖、双糖和多糖;其中单糖为甘露醇、葡萄糖,双糖为乳糖、蔗糖,多糖为海藻糖。
本发明的重酒石酸长春瑞滨脂质体的冻干粉针剂,在以适当比例与注射用大输液混合使用时,其包封率为60~90%,粒径为40nm~1μm。所述适当比例指以药学上适用比例用注射用大输液稀释。所述注射用大输液选自:葡萄糖注射液,氯化钠注射液,右旋糖酐注射液,多种氨基酸和维生素混合注射液等。
本发明所述脂质体中,每ml脂质体混悬液中含有1-10mg重酒石酸长春瑞滨。
本发明的脂质体可用旋转蒸发法、逆相蒸发法、复乳法及PH梯度法等现有技术制备。
对本发明重酒石酸长春瑞滨脂质体进行急性毒性试验,大鼠静脉注射普通长春瑞宾制剂LD50为11.2mg/kg,95%置信限10.32-12.24mg/kg;注射长春瑞宾脂质体LD50为21.38mg/kg,95%置信限20.25-22.41mg/kg。与普通长春瑞宾比较LD50提高了0.91倍。对胃肠道及神经的毒性明显减轻。
本发明重酒石酸长春瑞滨脂质体制剂,特别是本发明优选的配方,其单位体积中的重酒石酸长春瑞滨含量高,包封率高,稳定性好,又有稳定的载药量。脂质体中药物持续释放,显著提高了血药浓度,延长药物在血液中的循环时间。本发明重酒石酸长春瑞滨脂质体注射用冻干粉针剂的明显降低了药物的毒副作用,提高了药物的疗效,增强了药物的临床使用性。
具体实施方式:
以下通过实施例进一步说明本发明,但不作为对本发明的限制。
实施例1
称取600mg大豆磷脂(纯度>76%磷脂酰胆碱)和100mg胆固醇溶解于乙醚中,混合均匀,将该溶液置于磨口圆底烧瓶中,于30-32℃恒温水浴上用旋转蒸发仪在100rpm并减压的条件下蒸去有机溶剂,使磷脂等成膜材料在烧瓶底部形成一均匀类脂膜;在上述脂膜中加入30ml乙醚溶解,另将10mg长春瑞宾加入5ml(2-10ml)PH7.4磷酸盐缓冲液中,再将其加入到上述脂膜溶液中中,在32℃用旋转蒸发仪转动去除有机溶剂,直至类脂薄膜水合变成乳白色脂质体混悬液,冰浴点阵式超声(超声波细胞粉碎机)减小粒径即得。将维生素E0.3mg,300mg甘露醇溶解在脂质体中,无菌过滤后(膜滤器孔径0.2μm),将最终分散物分装在西林瓶中,然后冷冻干燥。
本发明的长春瑞宾脂质体制剂为注射用冻干品,产品质量稳定,稳定性实验在25±2℃下进行,结果表明,本品25±2℃时稳定,各项指标均在质量标准规定的范围内;低温留样考察1年,各项指标均稳定,稳定性实验研究提示本品在低温条件下贮存为好。
实施例2
称取600mg卵磷脂(纯度>93%磷脂酰胆碱)和100mg胆固醇溶于30ml乙醚中;再将长春瑞宾溶于10mlPH7.4的缓冲液中,将上述两液混合进行乳化,然后在32℃用旋转蒸发仪转动去除有机溶剂,直至混合液变成乳白色脂质体混悬液。冰浴点阵式超声(超声波细胞粉碎仪)减小粒径即得。将维生素E0.3mg,300mg甘露醇溶解在脂质体中,无菌过滤后(膜滤器孔径0.2μm),将最终分散物分装在西林瓶中,然后冷冻干燥。
本发明的长春瑞宾脂质体制剂为注射用冻干品,产品质量稳定,稳定性实验在25±2℃下进行,结果表明,本品25±2℃时稳定,各项指标均在质量标准规定的范围内;低温留样考察1年,各项指标均稳定,稳定性实验研究提示本品在低温条件下贮存为好。
实施例3
称取5mg重酒石酸长春瑞滨、300mg大豆磷脂(纯度>76%磷脂酰胆碱)和30mg胆固醇溶解于乙醚中,混合均匀,将该溶液置于磨口圆底烧瓶中,于30-32℃恒温水浴上用旋转蒸发仪在100rpm并减压的条件下蒸去有机溶剂,使磷脂等成膜材料在烧瓶底部形成一均匀类脂膜;在上述脂膜中加入30ml乙醚溶解,另加入5ml(2-10ml)PH7.4磷酸盐缓冲液,水浴超声成乳,在30℃用旋转蒸发仪去除有机溶剂,直至变成乳白色脂质体混悬液,高压乳匀减小粒径即得。将维生素E0.3mg,500mg甘露醇溶解在脂质体中,无菌过滤后(膜滤器孔径0.2μm),将最终分散物分装在西林瓶中,然后冷冻干燥。
实施例4
称取1mg重酒石酸长春瑞滨、100mg大豆磷脂(纯度>76%磷脂酰胆碱)和15mg胆固醇溶解于乙醚中,混合均匀,将该溶液置于磨口圆底烧瓶中,于30-32℃恒温水浴上用旋转蒸发仪在100rpm并减压的条件下蒸去有机溶剂,使磷脂等成膜材料在烧瓶底部形成一均匀类脂膜;在上述脂膜中加入30ml乙醚溶解,另加入5ml(2-10ml)PH7.4磷酸盐缓冲液,水浴超声成乳,在30℃用旋转蒸发仪去除有机溶剂,直至变成乳白色脂质体混悬液,高压乳匀减小粒径即得。将维生素E0.3mg,500mg甘露醇溶解在脂质体中,无菌过滤后(膜滤器孔径0.2μm),将最终分散物分装在西林瓶中,然后冷冻干燥。
实施例5
称取1mg重酒石酸长春瑞滨、5mg大豆磷脂(纯度>76%磷脂酰胆碱)和1mg胆固醇溶解于乙醚中,混合均匀,将该溶液置于磨口圆底烧瓶中,于30-32℃恒温水浴上用旋转蒸发仪在100rpm并减压的条件下蒸去有机溶剂,使磷脂等成膜材料在烧瓶底部形成一均匀类脂膜;在上述脂膜中加入30ml乙醚溶解,另加入5ml(2-10ml)PH7.4磷酸盐缓冲液,水浴超声成乳,在30℃用旋转蒸发仪去除有机溶剂,直至变成乳白色脂质体混悬液,高压乳匀减小粒径即得。将维生素E0.01mg,500mg甘露醇溶解在脂质体中,无菌过滤后(膜滤器孔径0.2μm),将最终分散物分装在西林瓶中,然后冷冻干燥。
实施例6
称取1mg重酒石酸长春瑞滨、100mg大豆磷脂(纯度>76%磷脂酰胆碱)和15mg胆固醇溶解于乙醚中,混合均匀,将该溶液置于磨口圆底烧瓶中,于30-32℃恒温水浴上用旋转蒸发仪在100rpm并减压的条件下蒸去有机溶剂,使磷脂等成膜材料在烧瓶底部形成一均匀类脂膜;在上述脂膜中加入30ml乙醚溶解,另加入5ml(2-10ml)PH7.4磷酸盐缓冲液,水浴超声成乳,在30℃用旋转蒸发仪去除有机溶剂,直至变成乳白色脂质体混悬液,高压乳匀减小粒径即得。将维生素E0.05mg,500mg甘露醇溶解在脂质体中,无菌过滤后(膜滤器孔径0.2μm),将最终分散物分装在西林瓶中,然后冷冻干燥。
Claims (7)
1.一种脂质体冻干粉针制剂,其特征在于:由抗癌药物重酒石酸长春瑞滨的脂质体和药物可接受的载体组成,所述抗癌药物重酒石酸长春瑞滨的脂质体含有重酒石酸长春瑞滨、磷脂、胆固醇、维生素E,它们的重量比为1∶5-100∶1-15∶0.01-0.05。
2.权利要求2的制剂,其特征在于:所述脂质体含有重酒石酸长春瑞滨1份,磷脂30-70份,胆固醇5-15份,维生素E0.02-0.04份。
3.权利要求3的制剂,其特征在于:所述脂质体含有重酒石酸长春瑞滨1份,磷脂60份,胆固醇10份,维生素E0.03份。
4.权利要求4的制剂,其特征在于:所述磷脂选自大豆磷脂、卵磷脂和合成磷脂。
5.权利要求1的制剂,其特征在于:所述药物可接受的载体选自PH值调节剂,缓冲系统,冻干支持剂,抗氧化剂,防腐剂。
6.权利要求6的制剂,其特征在于:所述PH值调节剂选自:氢氧化钠、氯化钾、氯化钠、磷酸盐、碳酸盐、柠檬酸盐、烟酰胺、苯甲酰胺、脲、硫脲、乙二胺、二乙胺、乙醇胺、二乙醇胺、三乙醇胺和三乙胺;缓冲系统选自:磷酸盐缓冲系统、柠檬酸盐缓冲系统、碳酸盐缓冲系统;冻干支持剂选自:右旋酐糖、单糖、双糖和多糖,其中单糖为甘露醇、葡萄糖,双糖为乳糖、蔗糖,多糖为海藻糖;抗氧化剂选自:维生素E、维生素E酯、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠;防腐剂选自:对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、苯甲酸、苯甲酸钠、山梨酸。
7.权利要求1的制剂,其特征在于:冻干支持剂的加入量,按磷脂重量比计算,1份磷脂加入0.2-4份冻干支持剂,所述制剂在以适当比例与注射用大输液混合使用时,其包封率为60~90%,粒径为40nm-1μm。
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