CN106074386A - 一种依维莫司自微乳制剂及其制备方法 - Google Patents

一种依维莫司自微乳制剂及其制备方法 Download PDF

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CN106074386A
CN106074386A CN201610761979.3A CN201610761979A CN106074386A CN 106074386 A CN106074386 A CN 106074386A CN 201610761979 A CN201610761979 A CN 201610761979A CN 106074386 A CN106074386 A CN 106074386A
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everolimus
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micro emulsion
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雷林芳
王亚囡
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Foshan Hongtai Pharmaceutical Development Co Ltd
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Abstract

本发明公开了一种依维莫司自微乳制剂及其制备方法，其是将依维莫司、油相、乳化剂、助乳化剂组成液体自微乳制剂，或将所得液体自微乳制剂进一步与赋形剂制成固体自微乳制剂。本发明的治疗肿瘤、免疫抑制剂的药物组合，配比合理，可以快速释放药物，对所述病症能产生很好的疗效。

Description

一种依维莫司自微乳制剂及其制备方法
技术领域
本发明属于医药技术领域，具体涉及一种依维莫司自微乳制剂及其制备方法。
依维莫司(Everolimus)，化学名：40-O-(2-羟乙基)-雷帕霉素，分子式:C53H83NO14，分子量：958.2244。是用于治疗肿瘤、免疫抑制剂的三类新药，目前正在进行临床前研究。
背景技术
依维莫司临床上主要用来预防肾移植和心脏移植手术后的排斥反应。其作用机制主要包括免疫抑制作用、抗肿瘤作用、抗病毒作用、血管保护作用。常与环孢素等其他免疫抑制剂联合使用以降低毒性。
与西罗莫司相比，依维莫司的药物代谢动力学更加优越。
依维莫司由瑞士诺华公司（Novartis）最先研制开发，有片剂和分散片等剂型。商品名Certican。2003年首次在瑞典上市，在2006年已全面占领欧洲市场。
依维莫司(Everolimus)是一种大环内酯类药物，结构上属于雷帕霉素(rapamycin)的衍生物，故又称为40-O-(2-羟乙基)-雷帕霉素，功能上其属于mTOR激酶抑制剂，作用机制主要是与细胞内蛋白FKBP-12结合形成抑制复合物，从而抑制mTOR激酶的活性，降低mTOR的下游效应物S6核糖体蛋白激酶(S6K1)和真核延伸因子4E结合蛋白(4E-BP)的活性，干扰癌细胞的生长、分化和代谢，发挥抗肿瘤效应。研究显示，依维莫司具有免疫抑制作用、抗肿瘤作用、抗病毒作用、血管保护作用等。目前，临床上依维莫司主要用来预防有轻中度免疫排斥风险的肾脏移植患者出现的肾脏移植的排异反应，以及用于舒尼替尼或索拉非尼治疗无效的晚期肾癌患者。此外，依维莫司在美国也获批共计6个适应症（晚期乳腺癌、内分泌肿瘤、肾细胞癌、肾血管肌脂肪瘤和结节性硬化症）。
此外，除了肾细胞癌，依维莫司也正在进行对神经内分泌肿瘤、淋巴瘤、其他癌症以及结节性硬化症的研究，可作为单一制剂或者与现有的癌症治疗方法合用。 作为研究药物，依维莫司的安全性和有效性还没有在肿瘤领域完全建立起来，现在正处于严格控制和监测进行的临床试验阶段。这些试验的设计是为了更好地理解该化合物的潜在效益以及相应的风险。由于临床试验的不确定性，现在还不能确保依维莫司可以作为肿瘤适应症的药品在全球范围商业出售。
【专利及市场分析】依维莫司化合物及其制剂专利于2016年过期，国内申报家数较少，原料药存在合成技术壁垒。依维莫司已批准用于晚期乳腺癌、内分泌肿瘤、肾细胞癌、肾血管肌脂肪瘤和结节性硬化症等。后续还在继续开发其他适应症，应用前景非常广泛。2010年该药的销售额为297.1百万美元，2011年销售额为492.4百万美元。销售额增长较快，预测前景较好。
发明内容
本发明的目的在于提供一种依维莫司自微乳制剂及其制备方法，其可显著提高依维莫司体外溶出度及体内生物利用率，且原料易得，制备工艺简单可行，产率高、成本低，可以实现工业化大规模生产，具有显著的经济效益。
为实现上述目的，本发明采用如下技术方案：
一种依维莫司自微乳制剂，其具体为一种液体自微乳制剂或一种固体自微乳制剂。
所述液体自微乳制剂由依维莫司、油相、乳化剂、助乳化剂组成；其所用各原料按重量百分数计为：依维莫司0.1%~10%、油相5%~80%、乳化剂5%~60%、助乳化剂5%~60%，各原料重量百分数之和为100%；
其中，所述油相为亚油酸单甘油酯、油酸聚乙二醇甘油酯、油酸乙酯、辛酸癸酸三甘油酯、油酸中的一种或几种；
所述乳化剂为辛酸癸酸聚乙二醇甘油酯、吐温-80、聚乙二醇15-羟基硬脂酸酯、聚氧乙烯35蓖麻油、聚乙二醇-40氢化蓖麻油中的一种或几种；
所述助乳化剂为二乙二醇单乙基醚、丙二醇、聚乙二醇400、甘油中的一种或几种。
所述液体自微乳制剂的制备方法是将依维莫司加入到油相、乳化剂或助乳化剂中溶解后，再加入其他原料混合均匀，采用常规方法灌装于软胶囊中即得。
所述固体自微乳制剂是将由依维莫司、油相、乳化剂、助乳化剂组成的液体自微乳制剂进一步与赋形剂制成；所用液体自微乳制剂与赋形剂的重量比为1:1~1:60；
其中，所述赋形剂为微晶纤维素、乳糖、聚乙烯吡咯烷酮K30、二氧化硅中的一种或几种。
所述固体自微乳制剂的制备方法是将依维莫司加入到油相、乳化剂或助乳化剂中溶解后，加入制备液体自微乳制剂所需的其他原料混合均匀，再将制得的液体自微乳制剂与赋形剂混合均匀，采用粉末直接压片法制备成片剂；或采用干法制粒或湿法制粒工艺，将其与其他辅料混合、压片制备成片剂；或通过挤出滚圆法、离心造粒法制备成微丸，装入硬胶囊中；
所述其他辅料包括崩解剂、粘合剂、润滑剂。
本发明的显著优点在于：自微乳化给药系统可使依维莫司在制剂和小肠液中保持溶解状态，且自乳化后所形成的微乳滴具有极小的粒径，保证了较大的分散度，可显著提高依维莫司在胃肠液中的溶解度和溶出速率；处方中的脂质辅料可促进乳糜微粒分泌，进而促进依维莫司经淋巴转运。
本发明将依维莫司制备成自微乳制剂可达到提高体外溶出度及体内生物利用率的效果，且制剂所需原料易得，制备工艺简单可行，产率高、成本低，可以实现工业化大规模生产，具有显著的经济效益。
具体实施方式
为了使本发明所述的内容更加便于理解，下面结合具体实施方式对本发明所述的技术方案做进一步的说明，但是本发明不仅限于此。
实施例1：依维莫司自微乳软胶囊的制备
依维莫司 1g
亚油酸单甘油酯 100g
辛酸癸酸聚乙二醇甘油酯 50g
二乙二醇单乙基醚 50g
制备工艺：
将依维莫司加入亚油酸单甘油酯中搅拌使其溶解，再依次加入辛酸癸酸聚乙二醇甘油酯、二乙二醇单乙基醚，搅拌使其混合均匀后，灌装于软胶囊中即得。
实施例2：依维莫司自微乳软胶囊的制备
依维莫司 1g
油酸聚乙二醇甘油酯 100g
油酸乙酯 50g
吐温-80 25g
丙二醇 25g
制备工艺：
将依维莫司加入油酸聚乙二醇甘油酯中搅拌使其溶解，再依次加入油酸乙酯、吐温-80、丙二醇，搅拌使其混合均匀后，灌装于软胶囊中即得。
实施例3：依维莫司自微乳软胶囊的制备
依维莫司 1g
聚乙二醇15-羟基硬脂酸酯 75g
辛酸葵酸三甘油酯 50g
油酸 25g
聚氧乙烯35蓖麻油 25g
聚乙二醇400 25g
制备工艺：
将依维莫司加入聚乙二醇15-羟基硬脂酸酯中搅拌使其溶解，再依次加入辛酸葵酸三甘油酯、油酸、聚氧乙烯35蓖麻油、聚乙二醇400，搅拌使其混合均匀后，灌装于软胶囊中即得。
实施例4：依维莫司固体自微乳片的制备
依维莫司 1g
二乙二醇单乙基醚 75g
亚油酸单甘油酯 10g
辛酸葵酸聚乙二醇甘油酯 15g
微晶纤维素 85g
羧甲基淀粉钠 15g
制备工艺：
将依维莫司加入二乙二醇单乙基醚中搅拌使其溶解，再依次加入亚油酸单甘油酯、辛酸葵酸聚乙二醇甘油酯，搅拌使其混合均匀后，加入微晶纤维素、羧甲基淀粉钠，湿法制粒压片，即得。
实施例5：依维莫司固体自微乳片的制备
依维莫司 1g
油酸聚乙二醇甘油酯 35g
油酸乙酯 10g
吐温-80 15g
丙二醇 15g
乳糖 95g
交联聚乙烯吡咯烷酮 15g
硬脂酸镁 5g
制备工艺：
油酸聚乙二醇甘油酯、油酸乙酯混匀后，将依维莫司加入其中搅拌使其溶解，再依次加入吐温-80、丙二醇，搅拌使其混合均匀后，加入乳糖、交联聚乙烯吡咯烷酮，干法制粒后，加入硬脂酸镁压片，即得。
实施例6：依维莫司固体自微乳片的制备
依维莫司 1g
辛酸癸酸三甘油酯 35g
油酸 10g
聚乙二醇15-羟基硬脂酸酯 15g
聚乙二醇-40氢化蓖麻油 15g
乳糖 95g
交联聚乙烯吡咯烷酮 15g
二氧化硅 5g
制备工艺：
辛酸癸酸三甘油酯、油酸混匀后，将依维莫司加入其中搅拌使其溶解，再依次加入聚乙二醇15-羟基硬脂酸酯、聚乙二醇-40氢化蓖麻油，搅拌使其混合均匀后，加入乳糖、交联聚乙烯吡咯烷酮、二氧化硅，粉末直接压片，即得。
实施例7：依维莫司固体自微乳微丸胶囊的制备
依维莫司 1g
二乙二醇单乙基醚 70g
亚油酸单甘油酯 5g
辛酸癸酸聚乙二醇甘油酯 5g
微晶纤维素 75g
乳糖 25g
羧甲基淀粉钠 10g
制备工艺：
将依维莫司加入二乙二醇单乙基醚中搅拌使其溶解，再依次加入亚油酸单甘油酯、辛酸癸酸聚乙二醇甘油酯，搅拌使其混合均匀后，加入微晶纤维素、乳糖、羧甲基淀粉钠，混匀，挤出滚圆法制备成微丸，装胶囊即得。
实施例8：依维莫司固体自微乳微丸胶囊的制备
依维莫司 1g
油酸聚乙二醇甘油酯 50g
油酸乙酯 25g
吐温-80 5g
丙二醇 5g
微晶纤维素 95g
羧甲基淀粉钠 10g
制备工艺：
油酸聚乙二醇甘油酯、油酸乙酯混匀后，将依维莫司加入其中搅拌使其溶解，再依次加入吐温-80、丙二醇，搅拌使其混合均匀后，加入微晶纤维素、羧甲基淀粉钠，混匀，以水为粘合剂采用离心造粒法制备微丸，装胶囊即得。
实施例9：依维莫司固体自微乳微丸胶囊的制备
依维莫司 1g
二乙二醇单乙基醚 70g
辛酸癸酸三甘油酯 5g
聚乙二醇15-羟基硬脂酸酯 5g
聚氧乙烯35蓖麻油 5g
微晶纤维素 95g
羧甲基淀粉钠 10g
制备工艺：
将依维莫司加入二乙二醇单乙基醚中搅拌使其溶解，再依次加入辛酸癸酸三甘油酯、聚乙二醇15-羟基硬脂酸酯、聚氧乙烯35蓖麻油，搅拌使其混合均匀后，加入微晶纤维素、羧甲基淀粉钠，混匀，挤出滚圆法制备微丸，装胶囊即得。
依维莫司固体自微乳制剂溶出度测定方法:
采用中国药典（2015版）中溶出度与释放度测定法第三法（小杯法）测定实施例4、5、7、9 所得依维莫司固体自微乳制剂的溶出度：取片剂或胶囊，将其分别装入沉降篮中，以0.4% SDS溶液（或其他缓冲液）250mL为溶出介质，转速为每分钟100转进行试验，在5，10，30，45， 60min分别取溶液5mL，同时补加相同温度、相同体积的蒸馏水，所取样品立即滤过，取续滤 液采用高效液相色谱法进行测定，取对照品适量，按外标法计算溶出度，其结果如下：
处方 5分钟 10分钟 30分钟 45分钟 60分钟
4 83% 99.3% 100.2% 100.4% 99.9%
5 85% 99.6% 100.1% 100.2% 100.1%
6 87% 99.4% 100.4% 100.3% 99.8%
7 81% 100.3% 100.2% 100.4% 99.7%
8 88% 99.8% 100.1% 100.1% 100.4%
9 82% 100.1% 100.4% 100.1% 100.2%
由上表可以看出，10min后所得依维莫司固体自微乳制剂基本完全释放。
以上所述仅为本发明的较好实施例，凡依本发明申请专利范围所做的变化与修改，皆应属本发明的涵盖范围。

Claims (6)

1.一种依维莫司自微乳制剂，其特征在于：所述依维莫司自微乳制剂为液体自微乳制剂，其由依维莫司、油相、乳化剂、助乳化剂组成。
2.一种依维莫司自微乳制剂，其特征在于：所述依维莫司自微乳制剂为固体自微乳制剂，其是由依维莫司、油相、乳化剂、助乳化剂组成液体自微乳制剂后，再进一步与赋形剂制成。
3.根据权利要求1或2所述依维莫司自微乳制剂，其特征在于：液体自微乳制剂所用各原料按重量百分数计为：依维莫司0.1%~10%、油相5%~80%、乳化剂5%~60%、助乳化剂5%~60%，各原料重量百分数之和为100%；
其中，所述油相为亚油酸单甘油酯、油酸聚乙二醇甘油酯、油酸乙酯、辛酸癸酸三甘油酯、油酸中的一种或几种；
所述乳化剂为辛酸癸酸聚乙二醇甘油酯、吐温-80、聚乙二醇15-羟基硬脂酸酯、聚氧乙烯35蓖麻油、聚乙二醇-40氢化蓖麻油中的一种或几种；
所述助乳化剂为二乙二醇单乙基醚、丙二醇、聚乙二醇400、甘油中的一种或几种。
4.根据权利要求2所述依维莫司自微乳制剂，其特征在于：液体自微乳制剂与赋形剂的重量比为1:1~1:60；
所述赋形剂为微晶纤维素、乳糖、聚乙烯吡咯烷酮K30、二氧化硅中的一种或几种。
5.一种如权利要求1所述依维莫司自微乳制剂的制备方法，其特征在于：将依维莫司加入到油相、乳化剂或助乳化剂中溶解后，再加入其他原料混合均匀，灌装于软胶囊中即得。
6.一种如权利要求2所述依维莫司自微乳制剂的制备方法，其特征在于：将依维莫司加入到油相、乳化剂或助乳化剂中溶解后，加入制备液体自微乳制剂所需的其他原料混合均匀，再将制得的液体自微乳制剂与赋形剂混合均匀，采用粉末直接压片法制备成片剂；或采用干法制粒或湿法制粒工艺，将其与其他辅料混合、压片制备成片剂；或通过挤出滚圆法、离心造粒法制备成微丸，装入硬胶囊中；
所述其他辅料包括崩解剂、粘合剂、润滑剂。
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