CN101874817A - 鸦胆子油肠溶微囊及其制备方法和应用 - Google Patents
鸦胆子油肠溶微囊及其制备方法和应用 Download PDFInfo
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- CN101874817A CN101874817A CN201010186774XA CN201010186774A CN101874817A CN 101874817 A CN101874817 A CN 101874817A CN 201010186774X A CN201010186774X A CN 201010186774XA CN 201010186774 A CN201010186774 A CN 201010186774A CN 101874817 A CN101874817 A CN 101874817A
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- China
- Prior art keywords
- enteric
- oil
- brucea javanica
- coated microcapsule
- oleum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及医药和食品技术领域,是一种油性药物或食物的肠溶微囊及其制备方法和应用,尤其涉及一种鸦胆子油肠溶微囊及其制备方法和应用。本发明主要通过两个步骤实现的:首先,向鸦胆子油中加入卵磷脂和抗氧剂后将油吸附到多孔淀粉中,制备成含油软材,并向其中加入粘合剂,高速搅拌造粒、过筛得到囊心物。其次,将囊心物置于底喷式流化床中,喷肠溶包衣液制备成肠溶微囊。鸦胆子油肠溶微囊可以掩盖鸦胆子油的腥臭味、避免恶心及胃刺激性,更易被患者接受,其稳定性也比口服乳液好,释药比单粒胶囊更稳定、更规律。鸦胆子油肠溶微囊及其进一步的制剂适用于肺癌、肺癌脑转移、及肝癌等各种癌症的治疗和放化疗后的辅助治疗。
Description
技术领域
本发明涉及医药和食品技术领域,是一种油性药物或食物的肠溶微囊及其制备方法和应用,尤其涉及一种鸦胆子油肠溶微囊及其制备方法和应用。
背景技术
鸦胆子油是从鸦胆子果实所提取的油性成份,油中主要成分油酸是抗肿瘤的活性成分之一。临床用于治疗肺癌,肺癌脑转移,消化道肿瘤及肝癌的辅助治疗剂,疗效好。目前临床应用的鸦胆子油制剂主要以液体形式提供,如以鸦胆子石油醚提取物为原料,采用精制大豆磷脂为乳化剂制成的水包油型鸦胆子油乳剂。但鸦胆子油的静脉乳注射液和口服乳液均存在诸多缺陷。例如工艺不稳定,温度、乳化时间和生产设备都对产品质量产生影响,而造成乳粒不均匀:产品贮存中易出现油、水分层、破裂、转相、絮凝和败坏等现象而无法使用;贮存条件需要避光、控制温度在6±2℃范围内保存;使用期限仅为1年,且在实际使用中受环境影响大,产品常在有效期内即失效或性状不合格;鸦胆子油的静脉乳注射液在临床使用中,出现静脉炎、血管硬化、血管瘤、肌肉和血管刺激性、过敏反应等副作用,病人耐受性差。鸦胆子油口服乳剂有腥臭味口味差,多数患者服用鸦胆子油口服乳剂后还存在胃部灼热不适,油腻、恶心、厌食、呕吐等消化道不适反应,患者的服用依从性显著降低(鸦胆子油的研究进展,林宏英等,中国实验方剂学杂志,2006,12(04):64-69)。为了解决乳剂贮存不稳定的问题,干燥乳剂和颗粒剂虽然被开发出来,但是研究发现颗粒剂和干燥乳剂在光照、高温、高湿条件下发生变色及有效成份油酸含量降低的现象(武凤兰等.鸦胆子油喷雾干燥乳剂的制备与药效学的研究,中国药学杂志,1999,34(2):101-104),而且也没能有效改善鸦胆子油口服制剂的腥臭味和油腻感。鸦胆子油乳软胶囊、滴丸虽然一定程度上解决了口感差的问题,但是因为囊材使用明胶而发现这两种剂型贮藏期间容易发生烂丸、崩解超时限的问题,而且对胃刺激性,油腻感的副作用无实质性改善。将鸦胆子油乳制备成肠溶制剂可以根本改善上述问题。微囊剂属于多元给药系统,药物的整体释放效果不会因为个别释药单元的释药不规律而导致整体释药规律的改变。肠溶微囊剂可以使药物隔绝空气及湿气能够有效避免油酸的氧化降解可以提高药物的稳定性。
发明内容
本发明的主要目的是制备一种鸦胆子油的肠溶微囊,以消除鸦胆子油乳口服液的油腻感,胃刺激性,掩盖腥臭的不良口味,提高药物的适口性和稳定性。本发明涉及的微囊化技术同样可以用于制备不挥发油性药物或油性食物的肠溶微囊。
本发明是通过以下技术方案及操作步骤实现的:
(1)、微囊由囊心物和肠溶衣两部分组成:
A.囊心物:鸦胆子油100份,磷脂10-20份,抗氧剂0-0.1份,多孔淀粉100-300份,粘合剂0-10份。
B.肠溶衣:肠溶性聚合物为囊心物质量的5-200%,增塑剂为肠溶性聚合物质量的0-30%,钛白粉或色淀为肠溶衣膜材料质量的0-50%。
(2)、鸦胆子油和多孔淀粉质量比为1∶0.1-100。最优为1∶1-10。
(3)、所用的磷脂包括但不限于天然大豆磷脂、天然卵磷脂、或者它们的衍生化物,磷脂用量与鸦胆子油的质量比为1∶1-100,最优为1∶5-10。
(4)、微囊的囊心物成分中所述的抗氧剂为天然或合成的药用或食用的抗氧剂或者它们的混合物,包括但不局限于天然维生素E、生育酚醋酸酯、迷迭香油、叔丁基对羟基茴香醚、2,6-二叔丁基对甲酚,特丁基对苯二酚,2,5-二特丁基对苯二酚、叔丁基对苯二酚、没食子酸丙脂,抗氧剂的用量为0-0.1%,优选抗氧剂为特丁基对苯二酚,其用量为0-0.06%,最优为0.01-0.03%。
(5)、所述的粘合剂包括但不局限于羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、聚乙烯吡咯烷酮(PVP)、羧甲基纤维素钠(CMC-Na)的水溶液或乙醇溶液或者乙醇水混合溶液。其优选粘合剂为PVP-K90,用量为多孔淀粉用量的0.1-10%,较优为1-5%,更优为2-3%。
(6)、所用的肠溶衣中肠溶性聚合物为本领域常用的肠用衣料,包括但不仅限于甲醛明胶、虫胶(Shellac)、苯二甲酸醋酸纤维素(CAP),丙烯酸和甲基丙烯酸的共聚物、甲基丙烯酸-甲基丙烯酸甲酯共聚物、甲基丙烯酸-丙烯酸甲酯(或乙酯、丁酯)共聚物、丙烯酸乙酯-甲基丙烯酸酯共聚物、醋酸纤维素、乙基纤维素、聚丙烯酸树脂、丙烯酸乙酯-甲基丙烯酸甲酯(2∶1)共聚物、硅酮弹性体(硅橡胶)、聚醋酸乙烯苯二甲酸酯(PVAP)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)、羟丙基甲基纤维素肽酸酯、琥珀酸醋酸羟丙甲基纤维素(HPMCAS)或交联海藻酸盐等,囊心物与肠溶衣膜的质量比为1∶0.05-2,较优为1∶0.1-0.5,最优为1∶0.2-0.4。
(7)、在肠溶包衣液中可以加入增塑剂,用量为肠溶聚合物的0-35%,优选10-30%,增塑剂包括但不仅限于柠檬酸三乙酯、醋酸甘油酯、甘油、PEG6000、PEG4000、吐温80、1,2-丙二醇、单硬酯酸甘油酯,优选为柠檬酸三乙酯。
(8)、在肠溶包衣液中加入肠溶聚合物质量2-40%的钛白粉或者其它色淀,较优为10-30%,最优为15-20%。
本发明的具体操作步骤如下:
第一步,制备含油的囊心物颗粒。将处方量的磷脂和抗氧剂加入鸦胆子油中,搅拌至溶解,静止,过滤。将过滤后的鸦胆子油,加入处方量的多孔淀粉中,不断搅拌使多孔淀粉吸附鸦胆子油充分均匀,并喷入处方量的粘合剂溶液制得软材后,在高速搅拌剪切造粒机上制得颗粒,过筛最终形成鸦胆子油囊心物。
第二步,将制得的囊心物置入流化床包衣机中,采用空气悬浮发包肠溶膜制备肠溶性微囊。
本发明中,鸦胆子油可以被鱼油鱼油、海狗油、海豹油、蛇油、月见草油、白平子油、红花油、大豆油、芝麻油、花生油、玉米油、小麦胚芽油、葵花籽油、沙棘油、蓖麻油、罂粟籽油、维生素A、鱼肝油、维生素D、维生素E或它们的组合物代替。
本发明的优点是:
1.鸦胆子油肠溶微囊及实施例制剂将液态油性药物固体化,携带贮藏方便,克服了鸦胆子油口服乳液易分层、破乳的不稳定问题,也解决鸦胆子油口服乳液的胃刺激性及口感差的问题,易于被患者接受,从而提高疗效降低了临床副反应。
2.鸦胆子油肠溶胶囊、肠溶软胶囊或者肠溶片剂可以将鸦胆子油固体化也能解决胃刺激性问题,但是对于吞咽困难的癌症患者,特别是对于吞咽功能衰退的老年患者而言,胶囊或片剂的显然不合适;而鸦胆子油口服乳因其不良气味和口感,食欲较差的肿瘤患常常拒绝服用,即使勉强服用也通常发生呕吐现象。而鸦胆子油肠溶微囊可以在服用时混悬在果汁中,或者进一步制备成口感好的吞咽型颗粒剂使患者易于服用。
3.此发明的鸦胆子油肠溶微囊或以此微囊为基础制备的药剂属于多元释药系统,由本领域公知的理论和实际经验可知多元释药系统比单元释药系统(如胶囊、片剂)的药物释放更加规律,受饮食影响较小,吸收也更稳定。
附图说明
图1为本发明鸦胆子油未包膜囊心物。
图2为本发明鸦胆子油肠溶微囊。
图3为本发明鸦胆子油肠溶微囊置37℃的pH1.2盐酸溶液2h后状态图。
图4为本发明鸦胆子油肠溶微囊置37℃的pH1.2盐酸溶液2h后,再置于37℃的pH6.8磷酸缓冲液15min后状态图。
具体实施方式
以下将结合实施例1-4具体说明本发明,本发明的实施例仅用于说明本发明的技术方案,并非限定本发明的实质。
实施例1
处方1
囊心物处方
鸦胆子油 30g
大豆磷脂 5g
特丁基对苯二酚(TBHQ) 0.006g
多孔淀粉 60g
PVP-K90 2g
95%乙醇 20ml
肠溶包衣液处方
Eudragit L 30D-55 30g(按聚合物干重计算)
柠檬酸三乙酯 4.5g
钛白粉 4.5g
去离子水 20g
第一步,囊心物的制备。将处方量的大豆磷脂和抗氧剂TBHQ加入鸦胆子油中,搅拌至溶解,静止,过滤。将过滤后的鸦胆子油,加入处方量的多孔淀粉中,不断搅拌使多孔淀粉吸附鸦胆子油充分均匀,并喷入处方量的粘合剂溶液制得软材后,在高速搅拌剪切造粒机上制得颗粒,过筛,收集50目-20目之间的颗粒,粒径不合格颗粒收集后再次高速搅拌剪切造粒,并过筛,收集粒径符合要求颗粒,如此反复直至软材全部被制成粒径符合要求的囊心物颗粒(参见附图1)。
第二步,包肠溶囊膜。将制得的囊心物置入流化床包衣机中,以底喷方式采用空气悬浮法包肠溶衣膜制备肠溶性微囊,喷气压力0.1-0.12Mpa,包衣液输送速率1-10ml/min,包衣液在包衣操作时需不断搅拌,进风口温度55-70℃,出风口温度35℃,包衣完成后继续在流化床内干燥5min,再置40℃烘箱内干燥2h,得到肠溶微囊(参见附图2),称重,计算包衣效率为97.8。
计算公式如下:
其中,未包衣微囊质量为50目筛下颗粒质量。
实施例2
处方2
囊心物处方
鸦胆子油 30g
卵磷脂 4g
特丁基对苯二酚(TBHQ) 0.003g
维生素E 0.005
多孔淀粉 40g
85%乙醇 8ml
肠溶包衣液处方
Eudragit L 30D-55 60g(按聚合物干重计算)
柠檬酸三乙酯 15g
具体操作步骤及计算同实施例1,包衣效率为98.1%。
实施例3
处方3
囊心物处方
鸦胆子油 30g
大豆磷脂 0.3g
维生素E 0.005
多孔淀粉 30g
PVP-K90 0.3g
95%乙醇 5ml
肠溶包衣液处方
邻苯二甲酸二丁酯 30g(按聚合物干重计算)
滑石粉 10g
85%乙醇 500
具体操作步骤及计算同实施例1,包衣效率91.3%。
实施例4
将实施例1中制备的鸦胆子油肠溶微囊,与2%的微粉硅胶混匀后,按本领域内公知的方法灌装硬胶囊,制得含有鸦胆子油肠溶微囊的胶囊制剂。
实施例5
将实施例1中制备的鸦胆子油肠溶微囊50g,与40g甘露醇,8g糊精混匀后,置于流化床造粒机中流化,喷以3%PVP-K90水溶液为粘合剂,按本领域内公知的方法造粒,制得鸦胆子油的吞服型肠溶干混悬剂。
实施例6
鸦胆子油肠溶微囊的耐酸实验。将鸦胆子油肠溶微囊置于37℃pH1.2盐酸溶液2h后,发现微囊完整未破裂(参见附图3)。
实施例7
鸦胆子油肠溶微囊的崩解实验。将鸦胆子油肠溶微囊置于37℃pH1.2盐酸溶液2h后,加入磷酸缓冲盐,调整pH值至6.8,15min后观察,发现微囊全部崩解(参见附图4)。
实施例8鸦胆子油肠溶微囊的加速稳定性考察
取实施利1-3所得的鸦胆子油肠溶微囊,在温度为40±2℃,相对湿度75±5%的实验条件下,放置0、1、2、3个月,逐月考察外观,模拟胃液pH1.2盐酸溶液耐酸崩解实验,模拟肠液pH6.8磷酸盐溶液中崩解实验,结果见表1。
表1鸦胆子油肠溶微囊的加速稳定性考察
Claims (12)
1.一种鸦胆子油肠溶微囊,包括囊心物和肠溶衣,其特征在于,各成分质量组成如下:
囊心物:鸦胆子油100份,磷脂10-20份,抗氧剂0-0.1份,多孔淀粉100-300份,粘合剂0-10份;
肠溶衣:肠溶性聚合物为囊心物质量的5-200%,增塑剂为肠溶性聚合物质量的0-30%,钛白粉或色淀为肠溶衣膜材料质量的0-50%。
2.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:所述的鸦胆子油和多孔淀粉质量比为1∶0.1-100。
3.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:所述的鸦胆子油和多孔淀粉质量比最优为1∶1-10。
4.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:所述的磷脂包括但不限于天然大豆磷脂、天然卵磷脂、或它们的衍生化产品,磷脂用量与鸦胆子油的质量比为1∶1-100。
5.根据权利要求4所述的鸦胆子油肠溶微囊,其特征在于:磷脂用量与鸦胆子油的质量比最优为1∶5-10。
6.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:所述的抗氧剂为天然或合成的药用或食用的抗氧剂或者它们的混合物,包括但不局限于天然维生素E、生育酚醋酸酯、迷迭香油、叔丁基对羟基茴香醚、2,6-二叔丁基对甲酚,特丁基对苯二酚,2,5-二特丁基对苯二酚、叔丁基对苯二酚、没食子酸丙脂,优选抗氧剂为特丁基对苯二酚,其用量为0-0.06%。
7.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:所述的粘合剂包括但不局限于羟丙基甲基纤维素、羟丙基纤维素、聚乙烯吡咯烷酮、羧甲基纤维素钠,聚乙二醇的水溶液或乙醇溶液或者乙醇水混合溶液,粘合剂的用量为多孔淀粉用量的0-10%。
8.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:所用的肠溶衣膜材料包括但不限于甲醛明胶、虫胶、苯二甲酸醋酸纤维素,丙烯酸和甲基丙烯酸的共聚物、甲基丙烯酸-甲基丙烯酸甲酯共聚物、甲基丙烯酸-丙烯酸甲酯共聚物、甲基丙烯酸-丙烯酸乙酯共聚物、甲基丙烯酸-丙烯酸丁酯共聚物、丙烯酸乙酯-甲基丙烯酸酯共聚物、醋酸纤维素、乙基纤维素、聚丙烯酸树脂、丙烯酸乙酯-甲基丙烯酸甲酯(2∶1)共聚物、硅酮弹性体(硅橡胶)、聚醋酸乙烯苯二甲酸酯、邻苯二甲酸羟丙甲纤维素酯、羟丙基甲基纤维素肽酸酯、琥珀酸醋酸羟丙甲基纤维素或交联海藻酸盐。
9.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:囊心物与肠溶衣膜的质量比为1∶0.05-2。
10.根据权利要求1所述的鸦胆子油肠溶微囊,其特征在于:所述的增塑剂包括但不限于柠檬酸三乙酯、醋酸甘油酯、甘油、PEG6000、PEG4000、吐温80、1,2-丙二醇、单硬酯酸甘油酯,优选为柠檬酸三乙酯。
11.一种如权利要求1所述的鸦胆子油肠溶微囊的制备方法,其特征在于:其步骤如下:
1)制备含油的囊心物颗粒:将处方量的磷脂和抗氧剂加入鸦胆子油中,搅拌至溶解,静止,过滤,将过滤后的鸦胆子油,加入处方量的多孔淀粉中,不断搅拌使多孔淀粉吸附鸦胆子油充分均匀,并喷入处方量的粘合剂溶液制得软材后,在高速搅拌剪切造粒机上制得颗粒,过筛最终形成鸦胆子油囊心物;
2)配制肠溶包衣液,将制得的囊心物置入流化床包衣机中,采用空气悬浮发包肠溶衣膜制备肠溶性微囊。
12.根据权利要求1所述的一种鸦胆子油肠溶微囊,其特征在于:鸦胆子油可以被鱼油、海狗油、海豹油、蛇油、月见草油、白平子油、红花油、大豆油、芝麻油、花生油、玉米油、小麦胚芽油、葵花籽油、沙棘油、蓖麻油、罂粟籽油、维生素A、鱼肝油、维生素D、维生素E或它们的组合物代替。
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CN102513045A (zh) * | 2011-12-20 | 2012-06-27 | 山东昊月树脂有限公司 | 具有缓释特性的水溶性芳香微胶囊及其制备方法 |
CN102579398A (zh) * | 2011-12-31 | 2012-07-18 | 沈阳药科大学 | 一种具有掩盖药物不良口味作用的肠溶微囊及制备方法 |
CN104585761A (zh) * | 2015-01-16 | 2015-05-06 | 福建农林大学 | 一种海洋动物磷脂微胶囊及其制备方法 |
CN104622773A (zh) * | 2015-02-06 | 2015-05-20 | 深圳唯美度生物科技有限公司 | 一种高稳定性的蛇油制剂及其制备方法 |
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Cited By (4)
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CN102513045A (zh) * | 2011-12-20 | 2012-06-27 | 山东昊月树脂有限公司 | 具有缓释特性的水溶性芳香微胶囊及其制备方法 |
CN102579398A (zh) * | 2011-12-31 | 2012-07-18 | 沈阳药科大学 | 一种具有掩盖药物不良口味作用的肠溶微囊及制备方法 |
CN104585761A (zh) * | 2015-01-16 | 2015-05-06 | 福建农林大学 | 一种海洋动物磷脂微胶囊及其制备方法 |
CN104622773A (zh) * | 2015-02-06 | 2015-05-20 | 深圳唯美度生物科技有限公司 | 一种高稳定性的蛇油制剂及其制备方法 |
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