CN1270516A - 含氯甲双磷酸盐活性成分和硅化微晶纤维素赋形剂的药物制剂 - Google Patents
含氯甲双磷酸盐活性成分和硅化微晶纤维素赋形剂的药物制剂 Download PDFInfo
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Abstract
本发明的目的在于口服用的药物制剂,尤其是片剂,它含有药理可接受的二氯亚甲基二膦酸盐,即氯甲双磷酸盐,特别是氯甲双磷酸二钠作为活性成分,所述制剂还含有硅化微晶纤维素作为赋形剂。本发明另一目的在于生产所述药物制剂的方法及硅化微晶纤维素在生产所述药物制剂中的用途。
Description
本发明的目的在于口服用的药物制剂，尤其是片剂，它含有药理上可接受的二氯亚甲基二膦酸盐，即氯甲双磷酸盐，特别是氯甲双磷酸二钠盐作为其活性成分，并且含有硅化微晶纤维素作为赋形剂。本发明又一目的在于生产所述药物制剂的方法，以及硅化微晶纤维素在生产所述药物制剂中的用途。
四水合氯甲双磷酸盐或二氯亚甲基二膦酸二钠盐，在例如治疗和预防钙代谢障碍，如骨吸收、高钙血和骨质疏松中是有效的。基于其与Ca2+-离子形成强配位物的能力，氯甲双磷酸盐可去除循环系统中的过量钙，阻止骨中磷酸钙溶解和/或经细胞传递机理而起作用。
氯甲双磷酸盐以前就曾以常规压片或胶囊的剂型经口服给药。这种片剂或胶囊在病人的胃里分解而释放出活性物质，活性物质在胃的酸性环境下转化成游离酸的形式。因为氯甲双磷酸不易被吸收，所以活性物质的生物可用性低，从而使氯甲双磷酸盐不得不在较长的时间内使用大剂量。因此，氯甲双磷酸盐制剂所存在的问题在于如何使活性物质在胶囊或片剂中达到足够高的含量和浓度，而使所使用的胶囊或片剂的尺寸不会大到令病人不愉快。
氯甲双磷酸盐制剂的另一问题是未处理的氯甲双磷酸盐原料与制剂中所存在的其他赋形剂和活性物质难以混合成为均匀的混合物。例如EP275468公开了一种方法，其中氯甲双磷酸盐原料与赋形剂干式混合，然后添加成粒液体，将混合物用湿法进行造粒，然后干燥所得的颗粒。然而，由于氯甲双磷酸盐的性质，这样获得的氯甲双磷酸盐粉末，其组成是不准确的，而且很明显难于操作(粘稠，流动性非常差)。因此，实际上很难使之与制剂中所用的其他物质混合，而且进一步加工也非常困难，例如，需要相当大量的滑移剂。从均匀的原料粉末获得的是不均匀、而且流动性差的块状产物，它影响最终药物制剂的剂量准确性。
上述有关氯甲双磷酸盐原料的问题已部分为WO95/13054描述的方法所解决，其中氯甲双磷酸盐是晶体状的，尤其是以四水合氯甲双磷酸二钠盐的形式存在，通过以能保存四水合氯甲双磷酸二钠盐晶体结构的方式进行压制接着进行干法造粒。该方法被认为能产生具有均匀质量和易于加工特性的备用颗粒，由此，所需赋形剂的用量较以前的方法明显减少。然而，这种方法并没有解决用湿法造粒时氯甲双磷酸盐剂型制备时所产生的问题。
在制备固体剂型的药物工业中广泛使用的湿法造粒，由于其优点，使其能与干法造粒和直接压片法相比。通常，湿法造粒时所需赋形剂的量较直接压片法所需的为少，因此，可以获得可接受尺寸的片剂，湿法造粒还可提供具有更润湿性的待压片物质并且使所得造粒的颗粒具有优化的粒径和形状。另外，颗粒中的药物量大致相同，因而最终制剂的内含物的均匀性一般能得到改进。
微晶纤维素是压片前用湿性造粒配方中所用的一般赋形剂。它不仅适合增加最终产物的体积，而且还能产生有助于丸片成形的另外特性。不幸的是，微晶纤维素一旦遇到湿法造粒工艺过程中的水份时，会严重降低这种赋形剂的压缩性。在具有高含量活性物质的药物制剂的情况，如氯甲双磷酸盐的情况下，则尤其严重，因为微晶纤维素的压缩性丧失意味着需要大量的赋形剂才能获得可接受的压片最终产物。这样，就会增加体积，使最终产物难以吞咽，从而降低了病人的顺应性。
根据本发明，现已发现有可能获得可接受尺寸和均匀质量的氯甲双磷酸盐的口服剂型，而且，制剂中的活性物质的量和浓度都足够高。在氯甲双磷酸盐新型口服剂型的制备工艺过程中，不仅有可能使用干法造粒，而且还有可能使用湿法造粒和直接压片技术。当药物制剂是含有易于密实的硅化微晶纤维素作为赋形剂的口服剂型时，这一点是能实现的。
用于本发明制剂中所用的硅化微晶纤维素是和基于微晶纤维素用量约0.1～约20％的二氧化硅，SiO2，进行共处理的微晶纤维素。它是微晶纤维素和二氧化硅的附聚物，其中微晶纤维素和二氧化硅彼此紧密结合。这意味着二氧化硅与微晶纤维素颗粒已成为整体，但在两种物质之间没有化学反应。实际上，可通过例如喷雾干燥微晶纤维素和二氧化硅的悬浮液而得以实现。
氯甲双磷酸盐制剂中使用硅化微晶纤维素的优点在于就粉末的流动性、密实性、片剂强度，尤其是降低易碎性来说，具有综合改进的功能性。含有高负载量的氯甲双磷酸盐的固体剂型，现在可通过直接压片、干法造粒或湿法造粒技术而获得。在获得可接受的固体剂型制备工艺过程中，所必须使用的硅化微晶纤维素的用量，与同一目的所必须使用的微晶纤维素用量，明显减少。这会导致片剂尺寸的明显减小。另外，本发明固体氯甲双磷酸盐制剂的质量均匀，且具有优良的崩解性能和溶解性能。
尤其是在含氯甲双磷酸盐片剂中大量易碎性，一直是存在的问题。大量易碎性意味着片剂易于破碎或分裂成小片。出人意料的是，通过使用硅化微晶纤维素这个问题也得到了解决。所属领域的一般技术人员会料想当用于氯甲双磷酸盐制剂中时，二氧化硅在硅化微晶纤维素中起相反的作用，也就是，像通常使用滑移剂那样降低抗碎强度和提高易碎性。
然而，在生产氯甲双磷酸盐制剂中，使用硅化微晶纤维素的优点之一是硅化微晶纤维素的二氧化硅也起到滑移剂的作用同时它也改进了微晶纤维素性能。
在制备含硅化微晶纤维素的氯甲双磷酸盐片剂的工艺过程中，有可能先使氯甲双磷酸盐造粒(既可通过湿法造粒也可通过干法造粒技术)，然后再使干燥的颗粒与硅化微晶纤维素混合，如有必要，在混合物直接压片之前，还可与其他赋形剂混合。这种工艺在技术上是很方便的，而且提供具有上述全部优点的氯甲双磷酸盐的片剂。
在生产氯甲双磷酸盐制剂，尤其是氯甲双磷酸盐片剂中使用硅化微晶纤维素，的另一些优点是提高生产率，因此，该方法无论在技术上还是经济上都是可行的。含氯甲双磷酸盐和一般微晶纤维素的片剂，与含氯甲双磷酸盐和硅化微晶纤维素的片剂相比，仅能以非常低的速度制成片剂。使用硅化微晶纤维素能使生产率大大提高，而对片剂的质量没有有害的作用，正如实施例8所示。
如有必要，在本发明的固体剂型中，除了硅化微晶纤维素外，还可使用其它赋形剂。这些赋形剂为所属领域的一般技术人员所熟知，且其在氯甲双磷酸盐制剂的生产中的应用已公开于例如EP336851、US3683080和US4234645中。
本发明的制剂，还可另外含有常规的滑移剂和润滑剂，如硬脂酸或其盐(Mg-，Ca-)、滑石、淀粉或两种或多种滑移剂的混合物。如有必要，除了硅化微晶纤维素中所包含的外，还可添加另外的胶体二氧化硅。
可使用的填充剂(重量平衡剂)是例如乳糖、淀粉或其衍生物、甘露糖醇、葡萄糖、蔗糖、微晶纤维素或者两种或多种填充剂的混合物。另外也可使用天然的或人造的食用香料和甜味剂。
如有必要，还可在制剂中添加崩解剂。这些崩解剂通常在现有技术中是已知的，例如交联羧甲基纤维素钠，淀粉或其衍生物、交联羧甲醚纤维素(croscarmellos)、交联的聚烯吡酮(crospovidone)或者两种或多种崩解剂的混合物。
如有必要，通过使用某些赋形剂，人们还可调节制剂是否在胃里分解，还是在后面的胃肠道里才分解，并且还可调节其溶解速度。制剂可包上一层已知的成膜剂，它在预定的pH下溶解，例如紫胶片、乙酸邻苯二甲酸纤维素、邻苯二甲酸羟丙基甲基纤维素、聚乙酸邻苯二甲酸乙烯酯、乙酸苯三酸纤维素或各种丙烯酸和甲基丙烯酸的衍生物。成膜剂为所属领域的一般技术人员所知晓并且可以商购。
含氯甲双磷酸盐和硅化微晶纤维素的组合物，不仅适于以片剂，而且还适于以不同的制剂形式给药。例如充填入胶囊，或者按照一般现有技术已知的方法制成颗粒或粉末，如有必要，还可进行包衣。最好的是片剂和胶囊。
在按本发明的药物分送剂型中，氯甲双磷酸盐的用量可在很宽的范围内变化，例如10～95％(重量)，通常为50～90％(重量)。硅化微晶纤维素的用量例如可从约1％到约50％(重量)变化，通常是约5-约25％(重量)。优选的本发明的制剂含有60～80％(重量)的无水氯甲双磷酸二钠，约8～20％(重量)的硅化微晶纤维素和0.5～10％的其他赋形剂如润滑剂和崩解剂。
下列实施例用以说明本发明而不对其进行限制。实施例1
制备每片具有下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg硅化微晶纤维素 205mg羧甲醚纤维素钠 22mg硬脂酸 15mg硬脂酸镁 8mg
所用硅化微晶纤维素(Prosolv 90，Mendell，USA)中的二氧化硅浓度为2％w/w。
在片剂制备的第一步骤中，用硬脂酸在乙醇中的溶液润湿干燥成粒的氯甲双磷酸盐，然后在约30℃下干燥至水含量约18.5～20％。干燥过的颗粒经1.5mm筛子过筛。之后，将氯甲双磷酸盐-硬脂酸颗粒与羧甲醚纤维素钠、硅化微晶纤维素和硬脂酸镁混合。在压片装置内使用9×20mm冲压机，把混合物制成片剂以制成平均重量为1177mg(±2.5％)和例如有4-10kg适当强度的片剂。
如有必要，把制得的片剂用涂料溶液包衣，每片涂料溶液的组成如下所示：邻苯二甲酸甲基羟丙基纤维素 42.8mg邻苯二甲酸二乙酯 6.4mg乙醇 适量净化水 适量实施例2
制备每片具有下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg硅化微晶纤维素 155mg羧甲醚纤维素钠 22mg硬脂酸 15mg硬脂酸镁 8mg
采用与实施例1同类的硅化微晶纤维素，基本上按实施例1所述制备片剂。实施例3
制备每片含下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg硅化微晶纤维素 155mg羧甲醚纤维素钠 22mg硬脂酸 15mg硬脂酸镁 8mg
所用硅化微晶纤维素(Prosolv 50，Mendell，USA)中的二氧化硅浓度为2％w/w。基本上按实施例1所述制备片剂。实施例4
制备每片具有下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg硅化微晶纤维素 140mg羧甲醚纤维素钠 22mg硬脂酸 15mg聚乙烯吡咯烷酮 15mg硬脂酸镁 8mg
所用硅化微晶纤维素(Prosolv 90，Mendell，USA)中的二氧化硅浓度为2％w/w。除了将硬脂酸溶于聚乙烯吡咯烷酮以代替乙醇外，基本上按实施例1所述制备片剂。实施例5
制备每片含下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg硅化微晶纤维素 125mg羧甲醚纤维素钠 22mg硬脂酸 15mg硬脂酸镁 8mg
使用与实施例1同类的硅化微晶纤维素，基本上按实施例1所述制备片剂。实施例6
制备每片含下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg硅化微晶纤维素 132mg羧甲醚纤维素钠 22mg硬脂酸 15mg硬脂酸镁 8mg
使用与实施例1同类的硅化微晶纤维素，基本上按实施例1所述制备片剂。实施例7
制备每片含下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg硅化微晶纤维素 165mg羧甲醚纤维素钠 22mg硬脂酸 15mg硬脂酸镁 8mg
所用硅化微晶纤维素(Prosolv 90，Mendell，USA)中的二氧化硅浓度为2％w/w。采用如表1所示的压片速度，基本上按实施例1所述制备片剂。由抗碎强度和易碎性测量的结果也示于表1中。表1 在不同的压片速度下制备的实施例7的片剂的抗碎强度和易碎性
实施例8
| 压片速度 | 抗碎强度 | 易碎性 |
| 30000片/小时 | 16kp | 0.11％ |
| 40000片/小时 | 18kp | 0.20％ |
在不同的压片速度下制备具有与实施例6制得的片剂相同组成的片剂。为了比较，还在不同的压片速度下制备每片具有下列组成的片剂：四水合氯甲双磷酸二钠1000mg相当于无水氯甲双磷酸二钠 800mg微晶纤维素(Emcocel 50M) 132mg羧甲醚纤维素钠 22mg硬脂酸 15mg硬脂酸镁 8mg
测量所得片剂的抗碎强度和易碎性。结果列于表2中。表2含硅化微晶纤维素(A)片剂和含普通微晶纤维素(B)片剂的抗碎强度和易碎性。片剂是在如表2所示的不同压片速度下制备的。
np未实施*不能压成片
| 压片速度 | 片A的强度 | 片B的强度 | 片A的易碎性 | 片B的易碎性 |
| 15000片/小时 | np | 13kp | np | 3.0％ |
| 30000片/小时 | 18kp | 11kp | 0.39％ | 38.0％ |
| 50000片/小时 | 18kp | * | 2.50％ | * |
采用高于30000片/小时的压片速度下含普通微晶纤维素的片剂不能成片，因为片剂已破裂。
Claims (10)
1.含药理可接受的二氯亚甲基二膦酸盐作活性物质的药物制剂，其特征在于，它是含硅化微晶纤维素的口服固体剂型。
2.按权利要求1所述的制剂，其特征在于，它含有5～25％(重量)的硅化微晶纤维素。
3.按权利要求1所述的制剂，其特征在于，它含有：
(a)约60-80％(重量)的无水氯甲双磷酸二钠盐；
(b)约8～20％(重量)的硅化微晶纤维素；和
(c)约0.5～10％(重量)的润滑剂和/或崩解剂。
4.按前述权利要求中任一项所述制剂，其特征在于，基于微晶纤维素的重量，二氧化硅在硅化微晶纤维素中所存在的量，为约0.1～20％(重量)。
5.按前述权利要求中任一项所述制剂，其特征在于，该制剂是片剂或胶囊。
6.按前述权利要求中任一项所述制剂，其特征在于，二氯亚甲基二膦酸盐是二钠盐。
7.生产权利要求1的药物制剂的方法，其特征在于，使用湿法造粒技术。
8.生产权利要求1的药物制剂的方法，其特征在于，使用干法造粒技术。
9.生产权利要求1的药物制剂的方法，其特征在于，使用直接压片技术。
10.硅化微晶纤维素的用途，它用于生产含药理可接受的二氯亚甲基二膦酸盐作活性物质的药物制剂中。
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| CN102698281A (zh) * | 2012-05-29 | 2012-10-03 | 安吉东来药用辅料有限责任公司 | 海带多糖片剂赋形剂、药物片剂及药物片剂的制备方法 |
| CN104771761A (zh) * | 2015-03-19 | 2015-07-15 | 深圳国源国药有限公司 | 一种创新药用辅料硅化微晶纤维素及其制备方法 |
| CN110787140A (zh) * | 2018-08-01 | 2020-02-14 | 北京万全德众医药生物技术有限公司 | 比拉斯汀片剂及其制备方法 |
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| DE3767998D1 (de) * | 1986-12-20 | 1991-03-14 | Boehringer Mannheim Gmbh | Clodronat-haltige arzneimittel und verfahren zur herstellung derselben. |
| NZ254765A (en) * | 1993-05-15 | 1997-02-24 | Boehringer Mannheim Gmbh | Tablet medicament; comprises dichloromethylene diphosphonic acid (clodronic acid) or a pharmaceutically acceptable salt thereof as active ingredient and microcrystalline cellulose as auxiliary |
| FI94926C (fi) * | 1993-11-12 | 1995-11-27 | Leiras Oy | Menetelmä klodronaattivalmisteen valmistamiseksi |
| US5585115A (en) * | 1995-01-09 | 1996-12-17 | Edward H. Mendell Co., Inc. | Pharmaceutical excipient having improved compressability |
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