CN114246831A - 一种注射用紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂 - Google Patents
一种注射用紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂 Download PDFInfo
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- CN114246831A CN114246831A CN202010999347.7A CN202010999347A CN114246831A CN 114246831 A CN114246831 A CN 114246831A CN 202010999347 A CN202010999347 A CN 202010999347A CN 114246831 A CN114246831 A CN 114246831A
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- taxane
- micelle
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- organic solvent
- povidone
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Classifications
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
本发明提供了一种紫衫烷聚合物胶束冻干制剂,包含紫衫烷类药物、聚维酮、聚醚/聚酯嵌段共聚物;并提供了相关制备方法。本发明的紫衫烷聚合物胶束冻干制剂,提高用药安全性的同时,大大改善了药液稳定性。
Description
技术领域
本发明属于医药制剂技术领域,具体涉及了一种注射用的紫杉烷类聚合物胶束冻干制剂。
背景技术
在临床肿瘤学中,化学疗法是主要的治疗途径。然而,传统的化疗制剂,如小分子抗肿瘤药物,由于溶解度低、稳定性差、降解率快和非靶向性的组织分布,并未取得良好的疗效,同时还具有严重不良反应。目前,临床应用的大多数抗肿瘤药物是疏水性药物,如紫杉烷类的紫杉醇、多西紫杉醇,以及羟基喜树碱等;上述药物虽然已经在临床上广泛使用,但市售制剂仍然存在如下诸多问题,如市售制剂泰素(Taxol)是由聚氧乙烯蓖麻油/无水乙醇(50/50)制成的无色黏稠状溶液。但制剂中的聚氧乙烯蓖麻油引起病人严重的副反应,例如过敏反应、神经毒性和肾毒性。所述的多西紫杉醇的市售制剂中也加入高浓度的吐温-80作为增溶剂,大量的吐温容易引起溶血及过敏等不良反应,为了防止上述过敏反应的发生,患者在用药前需用地塞米松等抗过敏药进行预处理等等,这些问题都给临床用药带来诸多不便,同时也严重影响药物疗效和安全性。
为降低紫杉醇制剂的毒性提高其疗效,近年来临床上陆续开发了紫杉醇的新剂型。聚合物胶束给药系统可以有效改善难溶性药物的溶解性,生物相容性好以及增溶能力强,并对其包载的药物具有保护作用等优点,提高难溶药物水溶性同时,有效减少药物对人体的毒副作用。近年来,紫杉醇聚合物胶束的研究受到广泛关注。韩国上市的紫杉醇聚合物胶束剂型Genexol-PM在美国临床前和临床Ⅰ-Ⅲ期研究中,显示了良好的前景。
但是,聚合物胶束制备成胶束溶液后,存在药液稳定性差问题,常温放置一段时间后,药物即析出,造成药液变混浊。为了改善载药聚合物胶束的载药量和稳定性不高等技术问题,现有技术一方面试图通过选择不同聚合物提高载体聚合物稳定性,另一方面尝试添加不同添加剂提高胶束稳定性。
中国专利CN201110105540.2,公开了一种紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂及其制备方法和应用,选择聚醚/聚酯嵌段共聚物为胶束载体材料。中国专利CN201610802372.5对CN201110105540.2的进一步优化,使用经超滤、冷冻干燥处理后的聚醚/聚酯嵌段共聚物制备的紫杉烷类抗肿瘤药物聚合物胶束,意在降低过敏反应发生率,提高紫杉烷类抗肿瘤药物聚合物胶束的安全性。两篇专利均采用聚醚/聚酯嵌段共聚物通过分子自组装形成胶束,其中难溶性肿瘤药物包载于聚酯形成的疏水性内核中而制得。专利CN200610145383.7公开了一种以两亲性前段共聚物mPEG-PDLLA与磷脂作为载体的紫杉醇混合聚合物胶束;其在混合聚合物胶束稳定性相较于聚合物胶束取得提高;但当相同技术方案制备的紫衫烷类多西他赛胶束制剂,其稳定性无改观。专利CN201010001047.1公开了一种两亲性前段共聚物mPEG-PDLLA为载体,添加氨基酸优选精氨酸制备的紫杉醇聚合物胶束、多西他赛聚合物胶束,其胶束溶液25℃静置维持24小时,目测澄清透明,无沉淀。专利CN201410196183.9公开了一种采用mPEG-PLA-谷氨酸三嵌段共聚物为胶束载体的紫杉醇胶束,其体外稳定性测试显示,在室温下(25℃)保持稳定的时间最高仅达到24小时。专利CN201510250848.4公开了聚维酮-聚乳酸嵌段共聚物为载体的紫杉醇及多西他赛胶束冻干制剂,其载药能力有所改善,但胶束稳定性较差。由此,现有技术试图改变紫衫烷类胶束稳定性的方案,一方面保持稳定时间仍不理想;另一方面,适用普遍性不理想,特别是针对紫衫烷类药物,增加其胶束稳定性的技术方案可以改善紫杉醇胶束稳定性,但对其紫衫烷类其他药物胶束稳定性改善不明显。
综上,现有制备的紫杉烷类胶束,稳定性等方面仍不能满足要求,研究并提供一种聚合物胶束组合物技术方案,进一步改善稳定性并适用于同类难溶药物,仍是亟待解决的问题。
发明内容
本发明的目的在于克服上述现有技术的不足,提供一种包载紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂。本发明制备的紫杉烷类胶束冻干制剂进一步提高载药胶束的稳定性、安全性问题。
发明人首先制备胶束溶液,然后尝试提高该溶液的稳定性,意外的发现,加入聚维酮后,溶液稳定性大大提高,即使在室温条件下,静置180小时,仍然保持良好的稳定性。在此实验的基础上,发明人创造性的制备出一种稳定的胶束制剂。
具体而言,本发明是通过如下技术实现的:
本发明的所述的一种紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂,该制剂含有紫杉烷类药物、聚维酮、聚醚/聚酯嵌段共聚物。
优选地,所述聚维酮为聚维酮K-12、K-17、K-25、K-30、K-90中的一种或其组合;进一步优选为聚维酮K-12、K-17、K-25。
优选地,所述聚醚嵌段为聚乙二醇(PEG),聚乙二醇单甲醚、聚丙二醇或聚丁二醇中的一种。数均分子量为1000-5000,优选分子量为2000的聚乙二醇单甲醚。
优选地,所述聚酯嵌段为聚丙交酯(PDLLA),聚乙交酯丙交酯(PLGA),聚己内酯(PCL),聚原酸酯(POE)中的一种。数均分子量为1000-5000,优选分子量为2000的聚丙交酯。
在本发明的聚醚/聚酯嵌段共聚物中,所述的聚醚/聚酯嵌段共聚物优选为聚乙二醇单甲醚2000-聚丙交酯。
优选地,所述聚醚嵌段总重量占两亲性聚合物的30%~70%,更进一步优选为50%。
优选地,所述紫杉烷类药物为紫杉醇、多西他赛、卡巴他赛或其混合物。
优选地,所述的紫杉烷类药物与聚醚/聚酯嵌段共聚物的重量比为1:1~99;进一步,所述的紫杉烷类药物与聚醚/聚酯嵌段共聚物的重量比优选为1:4~50。
优选地,所述紫杉烷类药物与聚维酮的重量比为1:1~3。
本发明进一步目的是提供一种紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂的制备方法。
本发明的紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂的制备方法,为薄膜水化法,具体包括如下步骤:
a)称取处方量的紫杉烷类、聚醚/聚酯嵌段共聚物,加入有机溶剂超声加热溶解;
b)将有机溶剂在室温至有机溶剂沸点间常压或减压浓缩至干,得一混合薄膜;
c)加入溶有聚维酮的水溶液,充分水化薄膜,得透明的载药胶束溶液。
d)载药胶束溶液经除菌过滤、冷冻干燥,得载有紫杉烷类药物的聚合物胶束冻干粉针剂。
优选地,所述有机溶剂选自乙醇、甲醇、乙腈、丙酮、三氯甲烷、乙酸乙酯中的一种或两种,进一步优选乙醇、甲醇。乙腈中的一种或两种;所述有机溶剂用量为紫杉烷类与聚醚/聚酯嵌段共聚物总重量的2~10倍。
本发明中,所述的胶束溶液可直接冻干,也可加入冻干保护剂后冻干,所用的冻干保护剂可选自甘露醇、葡萄糖、无水乳糖、乳糖、海藻糖、右旋糖酐、甘氨酸、聚乙二醇中的任意一种或混合物;优选地,冻干保护剂的用量为处方总量的0.5%-15%。
在一优选实施方案中,上述聚醚/聚酯嵌段共聚物可以通过如下方法制备:
在氮气保护下,向玻璃聚合瓶中加入聚醚,125~130℃保温搅拌抽真空除水。加入金属催化剂/甲苯溶液,搅拌分散,125~130℃保温搅拌抽真空除甲苯。加入聚酯,125~130℃保温搅拌反应。反应结束后降温,加入二氯甲烷搅拌溶解,加入金属清除剂处理。抽滤,滤除金属清除剂,滤液加入到无水乙醚中,溶解析晶。滤饼用二氯甲烷溶解后,经PTFE膜过滤,滤液加入到无水乙醚中析晶,过滤,滤饼干燥,得聚醚-聚酯两嵌段共聚物。
优选地,所述的催化剂选自辛酸亚锡、氯化亚锡、二乙基锡、氯化锌或三乙基铝中的一种或两种;优选地,催化剂的用量为反应物总重量的0.05%-0.5%。
在一实施方案中,上述所得滤饼的干燥方法为真空干燥,详细干燥过程可为:将滤饼先在20℃以下,-0.08~-0.1MPa真空干燥6~10h,翻料,再控温20~30℃、-0.08~-0.1MPa真空干燥10~24h,得聚醚-聚酯两嵌段共聚物。
本发明的有益效果:
本发明在胶束制剂中添加聚维酮的技术方案,普遍适用于紫衫烷类药物,改善了紫衫烷类药物胶束稳定性。制备的紫杉醇胶束制剂复溶后,在室温下保持稳定的时间可达8天;其他紫衫烷类难溶药物胶束制剂稳定性较现有技术均取得了较大提高。
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给出,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。本发明实施例所有产品、试剂可参照现有技术制备,也可购买得到。
实施例1聚乙二醇-聚原酸酯嵌段共聚物的制备
在氮气保护下,向玻璃聚合瓶中加入聚乙二醇200070g,125~130℃保温搅拌抽真空除水4h;加入异辛酸亚锡(0.5g)/甲苯溶液,搅拌分散30min,125~130℃保温搅拌抽真空除甲苯1.5h;加入聚原酸酯30g,125~130℃保温搅拌反应3~4h;反应结束后降温,加入二氯甲烷搅拌溶解,加入金属清除剂处理三次。抽滤,滤除金属清除剂,滤液加入到无水乙醚中,溶解析晶两次;用二氯甲烷溶解后,经PTFE膜(3μm)过滤,滤液加入到无水乙醚中析晶;所得产物先在20℃以下,-0.08~-0.1MPa真空干燥6h,翻料,再控温20~30℃、-0.08~-0.1MPa真空干燥24h,即得聚乙二醇2000-聚原酸酯两嵌段共聚物。
实施例2聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物的制备
在氮气保护下,向玻璃聚合瓶中加入聚乙二醇单甲醚2000 50g,125~130℃保温搅拌抽真空除水4h;加入异辛酸亚锡(0.128g)/甲苯溶液,搅拌分散30min,125~130℃保温搅拌抽真空除甲苯1.5h;加入DL-丙交酯50g,125~130℃保温搅拌反应3~4h;反应结束后降温,加入二氯甲烷搅拌溶解,加入金属清除剂处理三次。抽滤,滤除金属清除剂,滤液加入到无水乙醚中,溶解析晶两次;用二氯甲烷溶解后,经PTFE膜(3μm)过滤,滤液加入到无水乙醚中析晶;所得产物先在20℃以下,-0.08~-0.1MPa真空干燥6h,翻料,再控温20~30℃、-0.08~-0.1MPa真空干燥24h,即得甲氧基聚乙二醇2000-聚丙交酯两嵌段共聚物。
实施例3聚丙二醇-聚乙交酯丙交酯嵌段共聚物的制备
在氮气保护下,向玻璃聚合瓶中加入聚丙二醇1000 30g,125~130℃保温搅拌抽真空除水4h;加入异辛酸亚锡(0.05g)/甲苯溶液,搅拌分散30min,125~130℃保温搅拌抽真空除甲苯1.5h;加入聚乙交酯丙交酯70g,125~130℃保温搅拌反应3~4h;反应结束后降温,加入二氯甲烷搅拌溶解,加入金属清除剂处理三次。抽滤,滤除金属清除剂,滤液加入到无水乙醚中,溶解析晶两次;用二氯甲烷溶解后,经PTFE膜(3μm)过滤,滤液加入到无水乙醚中析晶;所得产物先在20℃以下,-0.08~-0.1MPa真空干燥6h,翻料,再控温20~30℃、-0.08~-0.1MPa真空干燥24h,即得聚丙二醇-聚乙交酯丙交酯两嵌段共聚物。
实施例4紫杉醇聚乙二醇-聚原酸酯嵌段共聚物胶束的制备
称取紫杉醇0.6g、聚乙二醇-聚原酸酯嵌段共聚物(实施例1制备)2.4g,加入有机溶剂乙腈(约15g),50℃加热超声溶解;将上述有机溶剂50℃减压旋蒸至干,得一混合薄膜;加入6mg/ml的聚维酮K-25水溶液(100ml),充分水化薄膜,得透明的载药胶束溶液;将上述载有紫杉醇药物的聚合物胶束溶液除菌过滤、冷冻干燥,得紫杉醇聚合物胶束冻干制剂。
实施例5紫杉醇聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物胶束的制备
称取紫杉醇0.6g、聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物(实施例2制备)6g,加入有机溶剂乙醇(约30g),50℃加热超声溶解;将上述有机溶剂45℃减压旋蒸至干,得一混合薄膜;加入12mg/ml的聚维酮K-12水溶液(100ml),充分水化薄膜,得透明的载药胶束溶液;将上述载有紫杉醇药物的聚合物胶束溶液中加入冻干保护剂乳糖(1.5g),除菌过滤、冷冻干燥,得紫杉醇聚合物胶束冻干制剂。
实施例6紫杉醇聚丙二醇-聚乙交酯丙交酯嵌段共聚物胶束的制备
称取紫杉醇0.6g、聚丙二醇-聚乙交酯丙交酯嵌段共聚物(实施例3制备)3g,加入有机溶剂甲醇(约35ml),50℃超声加热溶解;将上述有机溶剂40℃减压旋蒸至干,得一混合薄膜;加入18mg/ml的聚维酮K-17水溶液(100ml),充分水化薄膜,得透明的载药胶束溶液;将上述载有紫杉醇药物的聚合物胶束溶液加入冻干保护剂甘露醇(2g),除菌过滤、冷冻干燥,得紫杉醇聚合物胶束冻干制剂。
实施例7多西他赛聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物胶束的制备
称取多西他赛0.6g、聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物(实施例2制备)12g,加入有机溶剂乙腈(约60g),50℃加热超声溶解;将上述有机溶剂50℃减压旋蒸至干,得一混合薄膜;加入12mg/ml的聚维酮K-12水溶液(100ml),充分水化薄膜,得透明的载药胶束溶液;将上述载有多西他赛药物的聚合物胶束溶液中加入冻干保护剂乳糖(1.5g),除菌过滤、冷冻干燥,得多西他赛聚合物胶束冻干制剂。
实施例8卡巴他赛聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物胶束的制备
称取卡巴他赛0.6g、聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物(实施例2制备)24g,加入有机溶剂乙醇(约70g),50℃加热超声溶解;将上述有机溶剂45℃减压旋蒸至干,得一混合薄膜;加入12mg/ml的聚维酮K-12水溶液(100ml),充分水化薄膜,得透明的载药胶束溶液;将上述载有卡巴他赛药物的聚合物胶束溶液中加入冻干保护剂乳糖(1.5g),除菌过滤、冷冻干燥,得卡巴他赛聚合物胶束冻干制剂。
对比实施例1
称取紫杉醇0.6g、聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物(实施例2制备)6g,加入有机溶剂乙醇(约30g),50℃加热超声溶解;将上述有机溶剂45℃减压旋蒸至干,得一混合薄膜;加入注射用水约100ml,充分水化薄膜,得透明的载药胶束溶液;将上述载有紫杉醇药物的聚合物胶束溶液中加入冻干保护剂乳糖(1.5g),除菌过滤、冷冻干燥,得紫杉醇聚合物胶束冻干制剂。
对比实施例2
取约26.5g聚乙二醇单甲醚(分子量2000)、25.8g D,L-丙交酯加入到充分干燥的聚合瓶中,加入浓度为0.1g/ml的辛酸亚锡/二氯甲烷溶液1ml;加热至80℃溶解聚乙二醇单甲醚,开启搅拌并抽真空去除体系中残存的水分和二氯甲烷;抽真空6h后,在真空下熔封聚合瓶,加热180℃的聚合反应1h;取产物溶解于去离子水,室温搅拌24h后升温至70℃析出聚合物,将沉淀物真空干燥后溶解于二氯甲烷,以10000转/分钟的速度离心10min,上层清液用大量无水乙醚沉淀后,真空干燥得共聚物mPEG2000-PLA;
取约0.3g紫杉醇、2.5g mPEG2000-PLA置500ml圆底烧瓶中,加入乙腈100ml,搅拌至溶解,加热50℃旋蒸除去乙腈,得到透明的凝胶状药膜;室温下,置真空干燥箱中,干燥过夜;加入50℃的pH=7.0的磷酸缓冲液(20mM、50ml),溶解分散药膜,得到带有淡蓝色乳光的聚合物胶束溶液;用0.22um的无菌滤膜过滤除菌后,分装冷冻干燥,制得紫杉醇聚合物冻干胶束制剂。
对比实施例3
称取甲基聚乙二醇16g、丙交酯24g,加入密闭的反应器中,加入辛酸亚锡50mg,在氮气气流下升温至130℃使固体熔化后,继续升高温度至160℃反应6小时。冷却,得白色固体粗品。粗品以二氯甲烷1ml溶解后,在搅拌下加入100ml乙醚中,滤过,乙醚洗涤三次,产品真空干燥24小时后,得聚合物;
取50mg/ml聚合物乙腈溶液6ml、10mg/ml紫杉醇乙腈溶液6ml,加入茄型瓶中,置于旋转蒸发仪上,水浴温度50℃、减压(-0.1MPa),以20转/分转速,旋转蒸发30分钟,加入0.2mg/ml天冬氨酸水溶液25ml,旋转水化1分钟,取下茄型瓶,至涡旋仪涡旋1分钟,所得溶液经0.22μm滤膜过滤,冻干得白色固体。
对比实施例4
称取甲基聚乙二醇16g、丙交酯24g,加入密闭的反应器中,加入辛酸亚锡50mg,在氮气气流下升温至130℃使固体熔化后,继续升高温度至160℃反应6小时。冷却,得白色固体粗品。粗品以二氯甲烷1ml溶解后,在搅拌下加入100ml乙醚中,滤过,乙醚洗涤三次,产品真空干燥24小时后,得聚合物;
取50mg/ml聚合物乙腈溶液10ml、5mg/ml多西他赛乙腈溶液10ml,加入茄型瓶中,置于旋转蒸发仪上,水浴温度50℃、减压(-0.1MPa),以20转/分转速,旋转蒸发30分钟,加入0.2mg/ml精氨酸水溶液50ml,旋转水化1分钟,取下茄型瓶,至涡旋仪涡旋1分钟,所得溶液经0.22μm滤膜过滤,冻干得白色固体。
对比实施例5
称取甲基聚乙二醇16g、丙交酯24g,加入密闭的反应器中,加入辛酸亚锡50mg,、甲苯溶液2ml,在氮气气流下升温至130℃使固体熔化后蒸除甲苯;继续升高温度至160℃反应6小时。冷却,得白色固体粗品。粗品以二氯甲烷1ml溶解后,在搅拌下加入100ml乙醚中,滤过,乙醚洗涤三次,产品真空干燥24小时后,得PEG-PDLLA聚合物;
取紫杉醇300mg、PEG-PDLLA聚合物1mg、卵磷脂100mg置于烧瓶中,加入150ml乙腈,搅拌溶解;加热60℃减压蒸除乙腈;加入60℃注射用水150ml,水化得浅蓝色乳光混合物,高速匀质机匀化30秒后,经0.22μm滤膜过滤除菌后冷冻干燥,得紫杉醇聚合物胶束。
对比实施例6
称取多西他赛0.6g、聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物(实施例2制备)12g、0.2g卵磷脂加入有机溶剂乙腈(约60g),50℃加热超声溶解;将上述有机溶剂50℃减压旋蒸至干,得一混合薄膜;加入注射用水约100ml,充分水化薄膜,得透明的载药胶束溶液;将上述载有多西他赛药物的聚合物胶束溶液中加入冻干保护剂乳糖(1.5g),除菌过滤、冷冻干燥,得多西他赛聚合物胶束冻干制剂。
对比实施例7
称取卡巴他赛0.6g、聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物(实施例2制备)24g、0.2g卵磷脂加入有机溶剂乙腈(约70g),50℃加热超声溶解;将上述有机溶剂50℃减压旋蒸至干,得一混合薄膜;加入注射用水约100ml,充分水化薄膜,得透明的载药胶束溶液;将上述载有卡巴他赛药物的聚合物胶束溶液中加入冻干保护剂乳糖(1.5g),除菌过滤、冷冻干燥,得卡巴他赛聚合物胶束冻干制剂。
对比实施例8
称取卡巴他赛0.6g、聚乙二醇单甲醚-聚(D,L)丙交酯嵌段共聚物(实施例2制备)24g,加入有机溶剂乙醇(约70g),50℃加热超声溶解;将上述有机溶剂45℃减压旋蒸至干,得一混合薄膜;加入6mg/ml的精氨酸水溶液(100ml),充分水化薄膜,得透明的载药胶束溶液;将上述载有卡巴他赛药物的聚合物胶束溶液中加入冻干保护剂乳糖(1.5g),除菌过滤、冷冻干燥,得卡巴他赛聚合物胶束冻干制剂。
对比实施例9
在干燥高纯氮气保护下,称取聚维酮20g,聚乳酸20g于充分干燥的聚合反应器中,加入辛酸亚锡0.08g,加热溶解聚维酮,在真空条件下,150℃油浴中进行聚合反应约10h;聚合反应结束后,向反应器得到的固体物中加入二氯甲烷18g溶解;将上述溶液加入到盛有180g异丙醚(-20℃预冷)的容器中,沉淀目标产物,过滤收集沉淀;将收集的沉淀再重复上述操作1次,得到白色固体,室温真空干燥48小时,得聚维酮-聚乳酸嵌段共聚物。
称取紫杉醇0.3g、聚维酮-聚乳酸嵌段共聚物1.5g加入配液罐,加入15g乙醇,控温70℃搅拌溶解,得澄清液后,加热蒸除乙醇得混合药膜;加入注射用水配制的5mM的磷酸盐缓冲液30L至配液罐中,充分溶解凝胶状药膜,得到紫杉醇胶束溶液;活性炭吸附,碳棒过滤器滤除活性碳后,经0.22μm的过滤除菌后,冷冻干燥,得紫杉醇胶束冻干制剂。
稳定性测定试验
分别取上述实施例4~8及对比实施例1~9制备的冻干粉针加0.9%的氯化钠注射液复溶,于4℃、25℃,正常室内光照条件下,约每2小时在澄明度检测仪下用肉眼观察溶液是否有沉淀或者浑浊产生。如果有沉淀或者浑浊产生,说明胶束溶液结束了稳定状态,检测结果见表1。
表1不同实施例载药胶束稳定性对比
Claims (10)
1.一种紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂,其特征在于,该制剂含有紫杉烷类药物、聚维酮、聚醚/聚酯嵌段共聚物。
2.如权利要求1所述的聚合物胶束冻干制剂,其特征在于,所述紫杉烷类药物与聚维酮的重量比为1:1~3。
3.如权利要求1所述的聚合物胶束冻干制剂,其特征在于,所述的紫杉烷类药物与聚醚/聚酯嵌段共聚物的重量比为1:1~99;优选为1:4~50。
4.如权利要求1所述的聚合物胶束冻干制剂,其特征在于,所述的紫杉烷类药物为紫杉醇、多西他赛、卡巴他赛或其混合物。
5.如权利要求1所述的聚合物胶束冻干制剂,其特征在于,所述聚维酮为聚维酮K-12、K-17、K-25、K-30、K-90中的一种或其组合,优选为聚维酮K-12、K-17、K-25中的一种或其组合。
6.如权利要求1所述的聚合物胶束冻干制剂,其特征在于,所述聚醚嵌段为聚乙二醇、聚乙二醇单甲醚、聚丙二醇或聚丁二醇中的一种或其组合。
7.如权利要求1所述的聚合物胶束冻干制剂,其特征在于,所述聚酯嵌段为聚丙交酯、聚乙交酯丙交酯、聚己内酯、聚原酸酯中的一种或其组合。
8.如权利要求1所述的聚合物胶束冻干制剂,其特征在于,所述的聚醚/聚酯嵌段共聚物为聚乙二醇单甲醚2000-聚丙交酯。
9.一种权利要求1-8任一一项所述的聚合物胶束冻干制剂的制备方法,其特征在于,所述制备方法包括以下步骤:
a)称取处方量的紫杉烷类、聚醚/聚酯嵌段共聚物,加入有机溶剂超声加热溶解;
b)将有机溶剂在室温至有机溶剂沸点间常压或减压浓缩至干,得一混合薄膜;
c)加入溶有聚维酮的水溶液,充分水化薄膜,得透明的载药胶束溶液;
d)载药胶束溶液经除菌过滤、冷冻干燥,得载有紫杉烷类药物的聚合物胶束冻干粉针剂。
10.如权利要求9所述的制备方法,其特征在于,所述有机溶剂选自乙醇、甲醇、乙腈、丙酮、三氯甲烷、乙酸乙酯中的一种或两种,进一步优选为乙醇、甲醇、乙腈中的一种或两种。
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