CN114246839B - 一种口服纳米乳肠溶胶囊及其制备方法 - Google Patents
一种口服纳米乳肠溶胶囊及其制备方法 Download PDFInfo
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Abstract
本发明属于药物制剂技术领域,具体提供了一种口服纳米乳肠溶胶囊,所述纳米乳肠溶胶囊包含脂溶性活性成分、两亲性聚合物载体、脂肪酸甘油酯和大豆油,通过薄膜水化法制备载药纳米乳溶液后灌装肠溶胶囊即得。本发明制备的口服纳米乳肠溶胶囊,能显著提高紫杉烷类药物的口服生物利用度;不含有易引起人体过敏反应的表面活性剂;能减少药物在胃部的溶出,提高药物在肠道吸收的同时,减少药物对胃部的刺激,减小毒副作用。
Description
技术领域
本发明属于医药制剂技术领域,具体涉及了一种口服纳米乳肠溶胶囊及其制备方法。
背景技术
紫杉烷类抗肿瘤药物从植物中分离得到,作用于微管/微管蛋白系统,通过防止去多聚化过程而使微管稳定,阻滞细胞于G2和M期,从而抑制细胞的有丝分裂和增殖,主要包括紫杉醇、多西他赛、卡巴他赛以及具有紫杉烷骨架结构的衍生物。研究证实,紫杉烷类抗肿瘤药物有广谱抗肿瘤作用,对乳腺癌、卵巢癌、肺癌等均有一定疗效。
由于紫杉烷类药物溶解度均较低且胃肠道渗透性较差,故其口服生物利用度较低。现上市剂型均为静脉注射剂,紫杉烷类药物上市注射液辅料含有聚氧乙烯蓖麻油、吐温-80及乙醇,有严重的过敏反应、神经毒性及肾毒性;如市售制剂泰素(紫杉醇)、多帕菲(多西他赛)、Jevtana(卡巴他赛)。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。其中不含聚氧乙烯蓖麻油的注射紫杉醇白蛋白纳米混悬液已在国内外上市,具有不用抗过敏预处理、疗效较好、毒性较低等特点;我国研发的紫杉醇脂质体也已上市;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。
然而临床上最方便的给药途径被认为是口服途径,但由于紫杉烷类药物的低溶解度及胃肠道中P-糖蛋白的外排以及肠或肝上细胞色素P-4503A4酶的代谢,使得紫杉醇很难跨过胃肠道屏障。研究者们采用了很多策略来提高紫杉醇的生物利用度,但是目前仍没有理想的紫杉烷类口服剂型。
中国专利CN108697683A公开了口服紫杉烷组合物的制备方法,但制备过程使用了易引起人体过敏反应的表面活性剂如聚山梨酯80、聚氧乙烯蓖麻油等。
中国专利CN100544714C公开了增溶紫杉醇的组合物及其制备方法,同样使用了具有一定毒性的乳化剂、表面活性剂等;制备的组合物是颗粒大的粗分散体,在40℃以上组合物才以液体存在,久置易降解,临床上使用不便。
中国专利201911318944.2公开了口服紫杉醇复合胶束的制备方法,但制备过程使用了p-糖蛋白抑制剂如环孢素、他克莫司,产品为口服胶束溶液,紫杉醇的生物利用度仍较低。
发明内容
鉴于现有技术的不足,本发明的目的之一在于提供一种口服纳米乳肠溶胶囊,包含脂溶性活性成分、两亲性聚合物载体、脂肪酸甘油酯和大豆油。本发明制备的纳米乳肠溶胶囊能显著提高脂溶性药物的生物利用度,脂溶性药物可通过与脂质在肠道内形成的乳糜微粒的三酰甘油核结合,选择性进入淋巴循环,从而提高脂溶性药物的淋巴吸收,提高生物利用度;脂肪酸甘油酯可以刺激胆汁囊泡收缩,提高小肠中的胆汁盐、磷脂、胆固醇浓度,刺激淋巴运转,减少代谢影响,提高药物生物利用度;本发明的另一个目的在于提供了一种口服纳米乳肠溶胶囊的制备方法。
具体而言,本发明是通过如下技术实现的:
一种口服纳米乳肠溶胶囊,包含脂溶性活性成分、两亲性聚合物载体、脂肪酸甘油酯和大豆油。
优选的,所述两亲性聚合物载体的亲水端为甲氧基聚乙二醇(mPEG),疏水端为聚丙交酯(PLA),聚乙交酯丙交酯(PLGA),聚己内酯(PCL)或聚原酸酯(POE)。
优选的,所述两亲性聚合物载体的疏水端为聚丙交酯(PLA)、聚己内酯(PCL)。
优选的,所述两亲性聚合物载体的分子量为3,000~12,000道尔顿,优选为5000道尔顿。
优选的,所述亲水端甲氧基聚乙二醇总重量占两亲性聚合物的20%~70%,优选为40%。
优选的,所述脂溶性活性成分为紫杉烷类抗肿瘤药物,为紫杉醇、多西他赛、卡巴他赛中的一种,优选为紫杉醇。
优选的,所述脂肪酸甘油酯选自单亚油酸甘油酯、单油酸甘油酯、油酸聚乙二醇甘油酯、月桂酸聚氧乙烯甘油酯、聚甘油脂肪酸酯、三油酸甘油酯、聚氧乙烯油酸甘油酯中的一种或多种。
优选的,所述脂肪酸甘油酯选自单亚油酸甘油酯、油酸聚乙二醇甘油酯中的一种。
优选的,所述脂溶性活性成分与两亲性聚合物载体的质量比为1:3~6;所述脂溶性活性成分与脂肪酸甘油酯的质量比为1:8~20;所述脂溶性活性成分与大豆油的质量比为1:30~60。
本发明所述的口服纳米乳肠溶胶囊通过薄膜水化法制备,包括如下步骤:
a)称取处方量的脂溶性活性成分和两亲性聚合物,加入有机溶剂超声加热溶解;
b)25~45℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于35~45℃水浴至透明状,加入相同温度预热且溶解处方量的脂肪酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液。
d)将制备得到的纳米乳溶液装于肠溶胶囊。
优选的,所述有机溶剂选自乙腈、甲醇、丙酮、三氯甲烷、乙酸乙酯中的一种;进一步优选的,所述有机溶剂为丙酮或乙酸乙酯。
与现有技术相比,本发明取得的技术效果是:
(1)显著提高脂溶性药物特别是紫杉烷类药物的生物利用度。
(2)粒径分布均匀,PDI<0.5。
(3)口服抗纳米乳肠溶胶囊不含有易引起人体过敏反应的表面活性剂等,生物相容性好。
(4)将制备好的纳米乳装于肠溶胶囊,能减少药物在胃部的溶出,提高药物在肠道吸收的同时,减少药物对胃部的刺激,减小毒副作用。
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。本发明所用的物料,均市售可得。
实施例1
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量丙酮,超声加热溶解;
b)30℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量单亚油酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例2
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量乙酸乙酯,超声加热溶解;
b)40℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量油酸聚乙二醇甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例3
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量乙酸乙酯,超声加热溶解;
b)40℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于40℃水浴至透明状,加入相同温度预热的溶解处方量月桂酸聚氧乙烯甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例4
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量三氯甲烷,超声加热溶解;
b)25℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于35℃水浴至透明状,加入相同温度预热的溶解处方量单油酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例5
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量乙腈,超声加热溶解;
b)45℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量聚氧乙烯油酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例6
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量乙腈,超声加热溶解;
b)45℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量聚甘油脂肪酸酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例7
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量甲醇,超声加热溶解;
b)35℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量三油酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例8
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量乙醇,超声加热溶解;
b)40℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于40℃水浴至透明状,加入相同温度预热的溶解处方量聚甘油脂肪酸酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例9
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量甲醇,超声加热溶解;
b)35℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量三油酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例10
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量乙腈,超声加热溶解;
b)50℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于50℃水浴至透明状,加入40℃预热的溶解处方量油酸聚乙二醇甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例11
1)处方
2)制备步骤:
a)称取处方量的多西他赛和两亲性聚合物于圆底烧瓶,加入处方量乙酸乙酯,超声加热溶解;
b)40℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量油酸聚乙二醇甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
实施例12
1)处方
2)制备步骤:
a)称取处方量的卡巴他赛和两亲性聚合物于圆底烧瓶,加入处方量丙酮,超声加热溶解;
b)35℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于40℃水浴至透明状,加入相同温度预热的溶解处方量单亚油酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
对比实施例1
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量丙酮,超声加热溶解;
b)30℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量单亚油酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装胶囊。
对比实施例2
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量丙酮,超声加热溶解;
b)35℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的处方量单油酸甘油酯和三辛酸甘油酯的混合溶液,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
对比实施例3
1)处方
2)制备步骤:
a)称取处方量的紫杉醇和两亲性聚合物于圆底烧瓶,加入处方量丙酮,超声加热溶解;
b)30℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于45℃水浴至透明状,加入相同温度预热的溶解处方量的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将所述载药纳米乳溶液灌装肠溶胶囊。
对比实施例4
1)处方
紫杉醇 1g
单亚油酸甘油酯 20g
2)制备步骤:
处方量称取紫杉醇和单亚油酸甘油酯,搅拌使溶解成为均一澄清溶液,将该溶液灌装入肠溶胶囊。
验证实施例
1.粒径的测定
取装胶囊前的纳米乳溶液1-1.5mL,采用马尔文动态光散射粒径分析仪测定粒径,测定结果见下表。
表1纳米乳的粒径、均一分散性指数(PDI)测定结果
实施例 | 粒径(nm) | PDI |
实施例1 | 236.4 | 0.206 |
实施例2 | 240.2 | 0.214 |
实施例3 | 239.4 | 0.253 |
实施例4 | 259.2 | 0.346 |
实施例5 | 263.1 | 0.325 |
实施例6 | 269.3 | 0.372 |
实施例7 | 278.5 | 0.385 |
实施例8 | 291.0 | 0.421 |
实施例9 | 296.4 | 0.456 |
实施例10 | 285.6 | 0.487 |
实施例11 | 246.5 | 0.284 |
实施例12 | 264.3 | 0.316 |
对比实施例1 | 236.4 | 0.206 |
对比实施例2 | 853.5 | 0.581 |
对比实施例3 | 256.1 | 0.365 |
2.药代动力学实验
对实施例1~10的口服紫杉醇纳米乳肠溶胶囊和对比实施例1~4的紫杉醇胶囊进行药代动力学实验。以比格犬给药前禁食12小时,静脉注射时,通过前肢静脉缓慢注射,注射速度1mL/min;于给药结束后5min、10min、15min、30min、1h、2h、4h、6h、8h、12h、24h、48h于前肢或后肢静脉采血0.6mL,肝素钠抗凝离心收集血浆,-20℃保存待测。口服给药时,扒开犬嘴,将肠溶胶囊放入咽部送服;于给药结束后10min、30min、45min、1h、1.5h、2h、3h、4h、6h、8h、12h、24h、48h于前肢或后肢静脉采血0.6mL,肝素钠抗凝离心收集血浆,-20℃保存待测。静脉注射制剂为市售紫杉醇注射液(商品名泰素)。
测试结果如表2所示。
表2口服纳米乳肠溶胶囊体内生物利用度测定结果
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Claims (3)
1.一种口服纳米乳肠溶胶囊,其特征在于,包含脂溶性活性成分、两亲性聚合物载体、脂肪酸甘油酯和大豆油;所述脂溶性活性成分为紫杉烷类抗肿瘤药物;所述两亲性聚合物的亲水端甲氧基聚乙二醇总重量占两亲性聚合物的20~70%;所述脂肪酸甘油酯选自单亚油酸甘油酯、单油酸甘油酯、油酸聚乙二醇甘油酯、月桂酸聚氧乙烯甘油酯、聚甘油脂肪酸酯、三油酸甘油酯、聚氧乙烯油酸甘油酯中的一种或多种;所述两亲性聚合物载体的亲水端为甲氧基聚乙二醇,疏水端为聚丙交酯,聚乙交酯丙交酯,聚己内酯或聚原酸酯;所述脂溶性活性成分与两亲性聚合物载体的质量比为1:3~6;所述脂溶性活性成分与脂肪酸甘油酯的质量比为1:8~20;所述脂溶性活性成分与大豆油的质量比为1:30~60;
所述口服纳米乳肠溶胶囊通过薄膜水化法制备,包括如下步骤:
a)称取处方量的脂溶性活性成分和两亲性聚合物载体,加入有机溶剂超声加热溶解;
b)25~45℃旋转蒸发至有机溶剂蒸干,得一混合薄膜;
c)将所制得的混合薄膜于35~45℃水浴至透明状,加入相同温度预热且溶解处方量的脂肪酸甘油酯的大豆油,充分溶解,得透明的载药纳米乳溶液;
d)将制备得到的纳米乳溶液装于肠溶胶囊。
2.如权利要求1所述的口服纳米乳肠溶胶囊,其特征在于,所述两亲性聚合物载体的分子量为3000~12000道尔顿。
3.如权利要求1所述的口服纳米乳肠溶胶囊,其特征在于步骤a)中所述有机溶剂选自乙腈、甲醇、丙酮、三氯甲烷、乙酸乙酯中的一种。
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