CN1726013A - 具有改善的屏障性能的非凝胶薄膜 - Google Patents
具有改善的屏障性能的非凝胶薄膜 Download PDFInfo
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Abstract
非凝胶薄膜材料,例如羟丙基甲基纤维素,其包括一种或多种添加剂,例如有机酸,所述有机酸例如羟基羧酸,其形成屏障组合物。人类使用该薄膜是安全的,并且发现该薄膜作为可摄入递送胶囊的壁材料的用途,例如,包含一定剂量的药物制剂的递送胶囊。
Description
发明领域
本发明涉及改性的聚合材料,更具体而言,本发明涉及改性纤维素材料羟丙基甲基纤维素(HPMC)的薄膜,以及这种薄膜的用途。
发明背景
HPMC是一种合成的塑料材料,是天然存在的聚合物、纤维素的化学修饰形式。HPMC的薄膜(或者片或者膜)是市售的,并且具有多种用途,所述用途包括建议作为递送胶囊的壁材料的用途,即设计用来保留和保护它们的内容物直至遇到预定递送位点或者递送条件时释放胶囊内容物的胶囊。HPMC适于人类摄入,因此发现有HPMC壁的递送胶囊作为可摄入胶囊的潜在应用,例如,作为以明胶为基质胶囊的可能替代品,用于递送精确计量剂量的药物制剂和膳食的补助剂,参见例如WO 97/35537、WO00/27367和WO01/03676。HPMC可以被用于包裹物质,例如药品或者食品补助剂如鱼油。众所周知,某些药品和食品补助剂长期暴露易于被侵蚀,例如暴露于空气中,优选将大量未精制的植物油和鱼油装入胶囊来防止它们酸败。然而,即使当这些物质被装入胶囊,例如包裹在HPMC薄膜中,它们仍然易于氧化,例如胶囊的薄膜壁允许胶囊外存在于空气的氧气通过胶囊的薄膜壁穿入到胶囊的内部,并且接触到胶囊的内容物,并以某些方式反应而破坏内容物。
HPMC与其它的水解胶体成膜材料相比,具有低抗氧气传输力,所述水解胶体成膜材料例如明胶、藻酸盐、果胶和一些其它的天然聚合物。为了改善HPMC薄膜的氧气屏障性能,该薄膜可以用水解胶体包覆,所述水解胶体例如藻酸盐。然而,这些薄膜的包覆会导致某些缺点,例如造成多层材料的薄膜每层可能具有不同的物理/化学性质,因此造成增加的处理复杂性,并且由此出现问题,导致薄膜生产时间和成本的增加。
乙二醇和乙酸甘油酯是已知的某些薄膜材料的薄膜添加剂,但是未处理的薄膜和乙酸甘油酯和/或其它添加剂处理的薄膜表现出非常低的抗氧气渗透性。然而,现在令人惊讶的发现,通过加入各种羧酸至HPMC薄膜里面,特别是α羟基酸和β羟基酸,可以减少包裹于由这种薄膜制成的胶囊中的植物油和鱼油以及其它可氧化填充物质的氧化。
应该注意,本发明不仅仅局限于HPMC薄膜材料。HPC(羟丙基纤维素)、MHFC(甲基羟乙基纤维素)、HEC(羟乙基纤维素)、EHEC(乙基羟乙基纤维素)、EC(乙基纤维素)和MC(甲基纤维素)也都包括在内。
发明概述
在本发明最广的范围内,可预期更多的聚合材料包括在被定义为非凝胶聚合物薄膜的组之内。
在本发明的一个方面,提供羟丙基甲基纤维素薄膜,其包括羟丙基甲基纤维素和添加剂,所述添加剂包含有机酸或这些酸的衍生物或其盐。
适宜的有机酸是羧酸类,例如一、二、三或者四或者其它多价羧酸。
根据本发明的羧酸包括下述羧酸:
具有1、2、3或4个羧基的C1-C6饱和的或者不饱和的、直链或者支链的羧酸,
由1、2、3、4羟基/羧基任意组合的C1-C6羟基酸,包括α羟基酸(AHA′s)和β羟基酸(BHA′s)
环酸和环羟基酸
根据本发明的酸的具体实例包括下述的酸:
羧酸
己二酸
富马酸
马来酸
丙酸(Proprionic acid)
水杨酸
乙酸
丙酸
丁酸
戊酸
己酸
羟基酸
α羟基丁酸
扁桃酸
酒石酸
乳酸
柠檬酸
苹果酸
羟基乙酸
羟基柠檬酸
环酸和环羟基酸
γ丁内酯
γ戊内酯
β丙内酯(propriolactone)
HPMC薄膜可以用α和β羟基酸以及衍生自水果酸的其它的羧酸处理来制备透明的薄膜,然后将该薄膜用于生产胶囊,该胶囊同由例如丙三醇、丙二醇、聚乙二醇和乙酸甘油酯的化合物处理的HPMC薄膜制备的类似的胶囊相比,显著地降低了其中包裹的某些物质的氧化作用。这些在减少氧化方面显著的改善被认为是归因于掺入薄膜内的酸添加剂可能阻碍了氧传递通过薄膜。
这些薄膜通过用包含根据本发明的酸的水溶液包覆,可以进一步得到改善或者改进以适于应用。
因此,在本发明的第一方面,通过混合酸与成膜树脂将一种或者多种酸加入到薄膜内,然后形成薄膜。
在本发明的第二方面,酸的水溶液被施用于预成型薄膜的表面。
在本发明的第三方面,将一种或者多种酸的水溶液施用于薄膜的表面,然后将薄膜粘合在一起。
在本发明的第四方面,将一种或者多种酸的水溶液施用于根据本发明的薄膜制备的一个或多个胶囊的表面。
薄膜的制备
将HPMC与本发明的一种或多种酸溶解在水中,所述酸例如柠檬酸,以制备总固体在10-20%w/w之间的溶液。(在该生产过程中,可以加入任选的成分例如染料、甜味剂和制备助剂。)然后,将产生的粘性的溶液脱气,并且以固定的厚度挤出到移动(环形的)钢带上,在它的移动期间,将该溶液加热到80-100摄氏度。在该加热过程中,水从薄膜中蒸发,剩下厚度在20-150微米的干燥薄膜。然后,将该薄膜从带子上移开,并且进一步加工用于使用,所述加工例如切开至最终轮宽度、层压单层薄膜形成双层薄膜,或者用外涂层来包覆以获得特殊期望的特性。或者,为了制备更少量的薄膜,可以将粘性溶液倾倒在玻璃平片上,并且使其静止以在玻璃顶部形成粘性溶液的平板。然后在期望的温度将该玻璃放入烤箱,在其中将其干燥形成期望的薄膜片层。
对上述而言,可以选择的是,可以制备与上述相同的薄膜,但是在薄膜形成的时候在薄膜中不包含上述的一种或者多种酸。一旦薄膜已经形成,将该一种或者多种酸的水溶液施用于薄膜表面。
胶囊的制备
将包含HPMC和根据本发明的酸的薄膜溶液(总固体10%)浇铸到玻璃平板上至固定的厚度。然后,将浇铸成型的薄膜放置在热烘箱(50-80摄氏度)中,形成坚硬的薄膜,接着将该薄膜从玻璃平板上移开,并且在室温下放置至平衡。然后将所制备的薄膜放置在真空成型床上,并且热成型为腔或者半胶囊。用鱼油或者植物油填满(过满)每个腔,并且用同样的HPMC薄膜片覆盖上。之后,用加热的工具密封整个薄膜,并切割制成的胶囊,使之不含有腔体周围多余不用的薄膜。将该制成的胶囊从成型床移开并包装,放置储存。
稳定性试验
评价按照本发明制备的胶囊中鱼油和植物油的稳定性。通过分析过氧化值(P.V.)随时间的变化来评价胶囊中油的稳定性。
使用标准的药学实验,制备样品并在30摄氏度、60%相对湿度下储存于HDPE瓶中。定期地,取样并且依据欧洲药典中描述的方法进行分析:过氧化值,欧洲药典方法2.5.5。
将结果绘图以表示随时间推移的P.V.相对变化。
对照胶囊是由掺入乙酸甘油酯的HPMC薄膜(甘油单和二乙酸酯)制成的。
可以这样解释结果:油中产生的过氧化物比例越高,成品越不稳定。因此,性能最好的薄膜显示较低的过氧化值。
制剂:
图表/图1、2和4 %w/w
HPMC(Methocel E50ex Dow) 77
甘油二乙酸酯 23
HPMC 77
乳酸 23
HPMC 77
乳酸 11
柠檬酸 12
HPMC 77
柠檬酸(无水的) 20
丙三醇 3
HPMC 77
柠檬酸(无水的) 23
图表/图3
HPMC 77
甘油单乙酸酯 23
HPMC 77
乳酸 23
HPMC 77
马来酸 23
HPMC 77
柠檬酸 23
解释
图1-图表1包含月见草油(EPO)的胶囊
在5个月的时期内,显示出的通常较低的和缓慢增加的过氧化值,证实了在胶囊薄膜内掺入柠檬酸或者柠檬酸/丙三醇组合物的HPMC的优良的性能。在薄膜中,1∶1的乳酸/柠檬酸组合物仍然证实了非常好的性能,并且用乳酸单独处理的薄膜的性能与用已知的薄膜添加剂甘油二乙酸酯(对照)处理的薄膜的性能相比,仍然显示出显著的改善。
图2-图表2包含鱼油(Lipromega TG60)的胶囊
此处也证实了图表1显示的一般倾向。在保持低P.V.方面显示了很大的改善。其是通过柠檬酸的完全稳定效应(stark stablizing effect)证实的。
图3-图表3包括鱼油(LipromegaTG60)的胶囊
在该测试中,将胶囊直接暴露于大气中(胶囊周围没有任何包装)。包括柠檬酸、马来酸和乳酸(特别是柠檬酸和马来酸)的HPMC薄膜被证实在过氧化值方面比包括甘油单乙酸酯的HPMC薄膜具有更优良的性能。
图4-图表4包裹EPO的含有多种增塑剂藻酸钠包覆的HPMC薄膜。
与图表1相比,本图显示出额外的过氧化值稳定性,由于在HPMC薄膜上包覆了藻酸钠,其可以保持更长的时间。
Claims (26)
1.非凝胶聚合薄膜,其包括非凝胶聚合物和屏障组合物,所述屏障组合物包括有机酸或者有机酸盐。
2.根据权利要求1的非凝胶薄膜,其中薄膜包括HPMC、MHEC、HEC、EHEC、EC和/或MC中的一种或者多种。
3.非凝胶聚合薄膜,其包括羟丙基甲基纤维素和屏障组合物,所述屏障组合物包括有机酸或者有机酸盐。
4.羟丙基甲基纤维素薄膜,其包括羟丙基甲基纤维素和屏障组合物,所述屏障组合物包括有机酸或者有机酸盐。
5.根据权利要求1的薄膜,其中有机酸是羧酸。
6.根据权利要求1的薄膜,其中有机酸包括马来酸、富马酸、己二酸、柠檬酸、乳酸中的一种或者多种。
7.根据权利要求1的薄膜,其中有机酸包括柠檬酸。
8.根据权利要求1的薄膜,其中有机酸包括马来酸。
9.根据权利要求1-5的薄膜,其中有机酸的量以重量计占薄膜总重量的5到40%。
10.根据权利要求1-6的薄膜,其包括以重量计大约23%的有机酸和77%的HPMC。
11.根据前述任一项权利要求的薄膜,其中薄膜是起泡的、膨胀的或者气化的。
12.根据前述任一项权利要求的薄膜,其中薄膜具有20到250微米的厚度。
13.根据前述任一项权利要求的薄膜,其中薄膜是另外用包括前述任一项权利要求定义的一种或者多种酸的溶液处理的。
14.根据前述任一项权利要求的薄膜制备的2-层薄膜,其中所述的2层薄膜由包括前述任一权利要求定义的一种或者多种酸的溶液彼此粘合和/或用所述酸进一步处理。
15.递送胶囊,其具有包括根据前述任一项权利要求的组合物的薄膜的包裹壁。
16.制备适于形成胶囊的HPMC薄膜的方法,其包括在薄膜形成胶囊之前和/或形成过程中,用前述任一项权利要求的酸处理HPMC薄膜。
17.递送胶囊,它的壁提供连续的屏障来保护和包含胶囊的内容物,所述的屏障包括:
a)非凝胶聚合薄膜
b)有机酸。
18.如权利要求16定义的递送胶囊,其中非凝胶薄膜包括HPMC。
19.如权利要求16定义的递送胶囊,其中有机酸是羧酸。
20.处理非凝胶聚合薄膜的方法,包括:
a)制备一种或者多种有机酸的溶液,
b)将所述的溶液施用于所述薄膜的一个或多个表面。
21.处理HPMC薄膜的方法,包括:
a)制备一种或者多种有机酸的溶液,
b)将所述的溶液施用于所述薄膜的一个或多个表面。
22.处理HPMC薄膜的方法,包括:
a)制备一种或者多种羧酸的溶液,
b)将所述的溶液施用于所述薄膜的一个或多个表面。
23.递送胶囊,其壁从壁的外面已经吸附或者吸收包括一种或者多种羧酸的屏障溶液。
24.递送胶囊,其壁在壁的厚度内具有一种或者多种羧酸的浓度梯度。
25.递送胶囊,其壁在壁的厚度内具有一种或者多种羧酸的浓度梯度,其中壁的外部具有最高的浓度并且壁的内部具有最高的浓度。
26.递送胶囊,其壁在壁的厚度内具有一种或者多种羧酸的浓度梯度,其中壁的内部具有最高的浓度并且壁的外部具有有最低的浓度。
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GBGB0221986.3A GB0221986D0 (en) | 2002-09-21 | 2002-09-21 | Films with improved barrier properties |
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AU2010299527A1 (en) | 2009-09-24 | 2012-04-19 | Capsugel Belgium Nv | Acid resistant capsules |
CN108997598B (zh) * | 2018-08-09 | 2020-08-04 | 厦门大学 | 具有近紫外激发功能高光透过性复合乙基纤维素膜的制备 |
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US5026559A (en) * | 1989-04-03 | 1991-06-25 | Kinaform Technology, Inc. | Sustained-release pharmaceutical preparation |
EP0569408B1 (en) * | 1990-12-20 | 2000-05-03 | Warner-Jenkinson Company, Inc. | Wet powder film-forming compositions |
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GB2408231A (en) | 2005-05-25 |
AU2003269169B2 (en) | 2007-12-20 |
TR200501021T1 (tr) | 2005-09-21 |
US20060165774A1 (en) | 2006-07-27 |
WO2004026284A1 (en) | 2004-04-01 |
GB0506072D0 (en) | 2005-05-04 |
LU91148B1 (fr) | 2005-03-22 |
FI20050297A (fi) | 2005-03-21 |
DE10393319T5 (de) | 2005-09-01 |
DK200500407A (da) | 2005-05-30 |
ZA200502621B (en) | 2009-02-25 |
CA2499472A1 (en) | 2004-04-01 |
GB2408231B (en) | 2006-06-14 |
SE0500631L (sv) | 2005-05-10 |
GB0221986D0 (en) | 2002-10-30 |
AU2003269169A1 (en) | 2004-04-08 |
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