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CN1067809A - 对酸不稳定的活性化合物的口服剂型 - Google Patents

对酸不稳定的活性化合物的口服剂型 Download PDF

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CN1067809A
CN1067809A CN92104690A CN92104690A CN1067809A CN 1067809 A CN1067809 A CN 1067809A CN 92104690 A CN92104690 A CN 92104690A CN 92104690 A CN92104690 A CN 92104690A CN 1067809 A CN1067809 A CN 1067809A
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R·迪特里希
H·柰伊
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Abstract

本发明有关于口服剂型的pantoprazole，它包括 芯体，中间层和能耐受胃液的外层。

Description

欧洲专利申请EP-A-244，380描述了具有吡啶基甲基亚磺酰基-1H-苯并咪唑结构的H+/K+腺苷三磷酸酶抑制剂一类对酸不稳定的活性化合物的口服剂型。它具有一个芯体，一层中间层和一层能耐受胃液的外层。欧洲专利申请EP-A-247，983对EP-A-244，380中与H+/K+腺苷三磷酸酶抑制剂Omeprazole（即，5-甲氧基-2[[（4-甲氧基-3，5-二甲基-2-吡啶基）甲基]亚硫酰基]-1H-苯并咪唑的简称）有关的公开的配方进行了描述，并提出了权利要求。
在欧洲专利申请EP-A-244，380和EP-A-247，983中申请专利的剂型的情况中，对酸不稳定的活性化合物的稳定化作用，具体是通过往芯体中加入碱类物质从而增加pH值来达到的。但是为达到适当的储存稳定性，在制备期间和在储存期间都必须满足一些条件，这些可以用最佳的药物配方来满足，不过很难做到没有问题的长期库存。为此EP-A-247，983适当地提到：“为达到储存过程中长期的稳定性，最重要的是包含活性化合物Omeprazole的剂型（带有能耐受胃液的涂层的片剂，胶囊和丸剂）中的含水量应保持很低，最好不超过1.5%重量百分数。因此，用带有能耐受胃液的涂层并包含在硬明胶胶囊中的丸剂形成的最后包装中最好是提供有干燥剂，以降低明胶壳层的含水量到这种程度，使得丸剂中的含水量不超过1.5%重量百分数。
为了稳定的理由，在丸剂芯体的制备过程中要保持很低的含水量，这意味着在制备丸剂芯体时被挤压的物质不再具有为以后挤压而加工成球形颗粒所需要的充分的可塑性，结果是形成园柱体，它在以后的涂布步骤中，端部只形成很薄的漆料涂层，因而这些部位不能对胃液具有所需的耐受性，进而不能通过再次涂布使能耐受胃液的涂层可靠地保护芯体，而这对于稳定性是很重要的。
如果想把欧洲专利申请EP-A-244，380和EP-A-247，983中描述的H+/K+腺苷三磷酸酶抑制剂pantoprazole（5-（二氟甲氧基）-2-[（3，4-二甲氧基-2-吡啶基）甲基亚磺酰基]-1H-苯并咪唑这化合物的简称）进行配方，也会引起上述稳定性问题。
现已令人惊奇地发现，如果不用某些通常用作片剂辅助剂的填充剂和粘合剂，诸如在欧洲专利申请EP-A-244，380和EP-A-247，983中叙述的为制备丸剂和片剂芯体时使用的那些，则上述稳定性的问题不复存在。这些填充剂和粘合剂具体地说是乳糖，微晶纤维素和羟丙基纤维素。
这样，本发明有关于一种丸剂或片剂型的药物，它含有活性化合物pantoprazole，是供口服的，是能耐受胃液的，它包括一个碱性的丸芯或片芯，一层或多层惰性的，水溶性的中间层，和一层能耐受胃液的外层，其特征为芯体除pantoprazole或除pantoprazole盐以外，还包含聚乙烯基吡咯烷酮和/或羟丙基甲基纤维素作为粘合剂，以及如果需要，另外还有甘露糖醇作为惰性填充剂。
为使丸芯或片芯呈碱性反应-如果所希望的pH值的增加通过使用活性化合物的盐还是不能达到的话-可往其中混入无机碱。可以提到的实例有药物上可接受的弱酸的碱金属盐，碱土金属盐或土金属盐，以及药物上可接受的碱土金属或土金属的氢氧化物和氧化物。碳酸钠可被叙述为选拔出来的碱的实例。
除填充剂和粘合剂以外，在制备片芯时也可使用别的辅助剂，特别是润滑剂和解脱剂，以及片剂崩解剂。
可以提到的润滑剂和解脱剂的实例有高级脂肪酸的钙盐，诸如硬脂酸钙。
可能的片剂崩解剂具体地有化学上惰性的试剂。（横向）交联的聚乙烯基吡咯烷酮（例如Crospovidone）可被叙述为一种经优选的片剂崩解剂。
关于用作丸芯或片芯的水溶性的中间层，可参考那些诸如通常在使用能耐受胃液的涂层以前所用的水溶性涂层，或诸如在例如DE-OS3901151中所描述的那些。可被提及的能用作中间层的膜状高聚物的实例有羟丙基甲基纤维素和/或聚乙烯基吡咯烷酮，如果需要，还可往其中加入增塑剂（诸如，例如，丙二醇）和/或其它的添加剂和辅助剂（例如缓冲剂，赋形剂或颜料）。
基于他的技术知识，专家们知道能使用什么耐受胃液的外层。最好是使用合适的能耐受胃液的高聚物的水分散液，诸如，例如甲基丙烯酸/甲基丙烯酸甲酯共聚物，如果需要还可加入增塑剂（例如柠檬酸三乙酯）。（以避免使用有机溶剂并且因为按本发明制出的芯体不像先有技术中知道的那样对水有敏感性）。
由于欧洲专利166，287活性化合物pantoprazole是已知的。可以提到的pantoprazole盐的实例有欧洲专利166，287中叙述的那些盐。钠盐是经优选的盐。
用甘露糖醇作为片剂单一的填充剂的需要适合的粘合剂，它必须赋予芯体以适当的硬度。用于芯体制备中作粘合剂的聚乙烯基吡咯烷酮具体地说是一种高分子量（大约300，000至400，000）的产物。PVP90（分子量约为360，000）可被叙述为一种经优选的聚乙烯基吡咯烷酮。
与先有技术中已知的具有吡啶基甲基亚磺酰基-1H-苯并咪唑结构的其它H+/K+腺苷三磷酸酶抑制剂的剂型相比，本发明的口服剂型具体的特点是片芯中的含水量超过1.5%重量百分数时不会导致活性化合物的变色（分解）。即使在颗粒中有比较高的残留湿气含量（例如5%至8%重量百分数）时仍能获得稳定的片剂。
为制得丸剂，可往蔗糖起始丸粒上涂布预隔离层，然后再涂布活性化合物在异丙醇中的30%的溶液，用羟甲基丙基纤维素作为粘合剂。
也可以像片剂那样，用相应的预先制成的分散液（例如Opadry）来涂布隔离层，涂布能耐受胃液的涂层可按照类似于片剂的程序来进行。
下面的配方实例更详尽地解释了本发明，但不是对本发明的限制。
实例
1.片剂
Ⅰ.片剂芯体
a）pantoprazole钠盐倍半水合物  45.1毫克
b）碳酸钠  10.0毫克
c）甘露糖醇  42.7毫克
d）交联聚乙烯基吡咯烷酮  50.0毫克
e）PVP90（聚乙烯基吡咯烷酮）  4.0毫克
f）硬脂酸钙  3.2毫克
155.0毫克
a）与一些b），c）和d）混合，其余的b）和c）被加到e）的清亮的水溶液中，并用b）把pH值调节到>10。在流化床中用这溶液可得到粒状物。其余的d）和f）被加到干燥的颗粒上，然后在适当的压片机上压片。
Ⅱ.预隔离层（中间层）
g）HPMC  2910，3CPS  15.83毫克
（羟丙基甲基纤维素）
h）PVP25  0.32毫克
（聚乙烯基吡咯烷酮）
i）二氧化钛  0.28毫克
j）LB氧化铁黄  100E  172  0.025毫克
k）丙二醇  3.54毫克
20.00毫克
每片经预隔离的芯体的总重量  175.00毫克
g）被溶于水，加入h）并使之也溶解，得溶液（A）。用适当的搅拌器使i）和j）悬浮于水中，得（B）。把（A）和（B）汇合。加入k）以后，在进一步加工之前立即把悬浮液筛分，然后把Ⅰ中获得的片剂芯体在适当的装置中涂布适当厚度的一层悬浮液。
Ⅲ.涂布能耐受胃液的涂层。
l）Eudragit
Figure 921046901_IMG1
L30D 13.64毫克
m）柠檬酸三乙酯  1.36毫克
15.00毫克
每片经涂布一层耐受胃液的膜以后的片剂总重量  190.00毫克
1）用水稀释，并加入m），悬浮液在加工前被筛分。
Ⅲ.是在适当装置中把上述悬浮液喷雾到按Ⅱ.获得的经预隔离的芯体上而形成的。
2.丸剂
Ⅰ.起始丸粒
a）蔗糖丸粒（0.7-0.85毫米）  950.0克
b）羟丙基甲基纤维素  50.0克
在流化床中用b）的水溶液对a）喷雾（Wurster方法）。
Ⅱ.活性丸粒
c）pantoprazole钠盐倍半水合物  403.0克
d）羟丙基甲基纤维素  40.3克
c）和d）被依次溶于30%的异丙醇中，然后在流化床中把这溶液喷雾到900克按Ⅰ制得的起始丸粒上。
Ⅲ.预隔离层（中间层）
涂布操作是按类似于片剂中所叙述的程序，在涂布锅或在流化床中进行的。
Ⅳ.涂布能耐受胃液的涂层
涂布操作是按类似于片剂中所叙述的程序，在涂布锅或在流化床中进行的。
然后用上述丸粒填充在适当大小（例如1）的胶囊中。

Claims (6)

1、一种丸剂或片剂形式的药剂，它是供口服的并能耐受胃液，所说的丸剂或片剂包括：
-芯体，其中活性化合物或它的生理上可接受的盐以与一种或多种粘合剂，填充剂，如果需要还可有其它的片剂辅助剂和一种或多种碱性的生理上可接受的无机化合物形成的混合物的形式存在，
-围绕芯体的一层或多层惰性的，水溶性的中间层，
-能耐受胃液的外层。
其特征为，在芯体中，pantoprazole被用作活性化合物，聚乙烯基吡咯烷酮和/或羟丙基甲基纤维素被用作粘合剂，并且如果需要，甘露糖醇被用作填充剂。
2、根据权利要求1所说的片剂剂型的药剂，其特征为聚乙烯基吡咯烷酮和/或羟丙基甲基纤维素被用作粘合剂，甘露糖醇被用作填充剂。
3、根据权利要求1所说的丸剂剂型的药剂，其特征为聚乙烯基吡咯烷酮和/或羟丙基甲基纤维素被用作粘合剂。
4、根据权利要求1，2或3所说的药剂，其特征为panatoprazole钠盐被用作生理上可接受的活性化合物盐。
5、根据权利要求1，2或3所说的药剂，其特征为药物上可接受的弱酸的碱金属盐，碱土金属盐或土金属盐，或药物上可接受的碱土金属或土金属的氢氧化物或氧化物被用作碱性的，生理上可接受的无机化合物。
6、根据权利要求1，2或3所说的药剂，其特征为碳酸钠被用作碱性的，生理上可接受的无机化合物。
CN92104690A 1991-06-17 1992-06-17 能耐受胃液的口服片剂和丸剂剂型药剂的制备方法 Expired - Lifetime CN1037932C (zh)

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CN103260607A (zh) * 2010-11-29 2013-08-21 泰姆勒集团股份有限责任公司 含ppi药物产品的制备方法
CN103260607B (zh) * 2010-11-29 2016-05-04 泰姆勒集团股份有限责任公司 含ppi药物产品的制备方法
CN108065443A (zh) * 2017-12-30 2018-05-25 厦门金达威维生素有限公司 斥水型双包被微胶囊及其制备方法
CN108065443B (zh) * 2017-12-30 2020-02-28 厦门金达威维生素有限公司 斥水型双包被微胶囊及其制备方法

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