CN87102493A - 对药物上可接受的盐的改进 - Google Patents

对药物上可接受的盐的改进 Download PDF

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CN87102493A
CN87102493A CN87102493.4A CN87102493A CN87102493A CN 87102493 A CN87102493 A CN 87102493A CN 87102493 A CN87102493 A CN 87102493A CN 87102493 A CN87102493 A CN 87102493A
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amlodipine
benzene sulfonate
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mixture
tablet
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爱德华·戴维森
詹姆斯·英格拉姆·韦尔斯
坎特伯雷·温厄姆
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Abstract

本发明有关amlodipine药用盐，尤其是苯磺酸盐的改进，和它们的药物组合物。这些盐可用作抗局部缺血和抗高血压剂。

Description

本发明涉及amlodipine的药用盐及它们的药物组合物的改进。
化合物amlodipine（3-乙基5-甲基2-（2-氨基乙氧基甲基）-4-（2-氯代苯基）-1，4-二氢-6-甲基吡啶-3，5-二羧酸盐）是一个有效并长效的钙通道阻滞剂，可用作抗局部缺血及抗高血压剂。
在欧洲专利申请公报第89167号中，揭示了amlodipine的几种不同形式的药物上可接受的盐。尤其那些被认为是从酸形成的在药物上可接受的酸加成盐，这些酸形成了含有药物上可接受的阴离子的无毒性酸加成盐如：盐酸盐、氢溴酸盐、硫酸盐、磷酸盐或酸式磷酸盐、醋酸盐、马来酸盐、富马酸盐、乳酸盐、酒石酸盐、柠檬酸盐和葡糖酸盐。在这些盐中，马来酸盐显示为特别好。
现在，人们意外地发现苯磺酸盐（下文称为besylate盐）比已知的amlodipine的盐具有许多优点，另外，已意外地发现苯磺酸盐具有多种良好配方性质的一种独特的结合，因此使它特别适合于制备amlodipine的药物配方。
因而，根据本发明，本文提供了amlodipine的苯磺酸盐。
另一方面，本发明提供了amlodipine苯磺酸盐与药物上可接受的稀释剂或载体一起，形成的药物组合物。
本发明进一步提供了包括amlodipine苯磺酸盐与赋形剂的混合物的片剂配方，最好的配方包括苯磺酸盐，压缩辅助剂如微晶纤维素，提供片剂表面光泽的添加剂如无水的磷酸二钙，崩解剂如淀粉乙醇酸钠及润滑剂如硬脂酸镁。
此外，本发明提供了一个包括amlodipine苯磺酸盐与赋形剂的混合物的胶囊配方，最好的配方包括苯磺酸盐，惰性稀释剂，干燥崩解剂及上述的润滑剂。
本发明进一步提供了用于肠胃外施药的amlodipine苯磺酸盐的无菌水溶液。这个溶液以含有10-40%体积的丙二醇较好并最好还有足够的氯化钠如：约1%重量/体积，以避免溶血作用。
本发明还提供了amlodipine苯磺酸盐用于治疗人体局部缺血的心脏疾病，尤其是心绞痛或高血压。
本发明亦提供了制备amlodipine苯磺酸盐的方法，即通过amlodipine碱与苯磺酸或它的铵盐溶液在惰性溶剂中反应，并分离amlodipine苯磺酸盐。
最好的惰性溶剂是工业用的甲基化醇。
虽然amlodipine的游离碱是有效的，但在实施中，它最好以药物上可接受的酸的盐的形式施药。为了达到这个目的，药物上可接受的盐必须符合下列四个生物化学标准：（1）良好的溶解度;（2）良好的稳定性;（3）非一吸湿性;（4）片剂配方的加工性能等。
我们发现虽然上文略提到的许多盐能符合这些标准中的某些标准，但是它们中没有一个，甚至于最好的马来酸盐也不能全部符合标准，虽然马来酸盐显示卓越的溶解度，但在溶液中于数周后易于分解。因而，已经制定出amlodipine的药物上可接受的盐的范围，并可用下列这些标准评价：
1.通常，本技术领域的人习知，药物的良好的水溶度对于有良好的生物利用度是必须的。一般，所寻求的溶解度为在PH1-7.5时＞1毫克/毫升，然而对配制注射液则需要有较高的溶解度。在加入的盐中较好的盐是使溶液具有的PH值接近于血液PH（7.4）的盐，因为它们易于生物相容，并可容易地被缓冲至所需的PH范围，而不改变它的溶解度。
从下列比较数据可以看出，amlodipine的苯磺酸盐与其它盐相比，显示出良好的溶解度特性。
表1
盐    溶解度    毫克/毫升    在饱和状态PH
苯磺酸盐    4.6    6.6
对甲苯磺酸盐    0.9    5.9
甲基磺酸盐    25    3.1
琥珀酸盐    4.4    4.9
水杨酸盐    1.0    7.0
马来酸盐    4.5    4.8
醋酸盐    50    6.6
盐酸盐    50    3.5
2.在固态时有良好的稳定性对于片剂和胶囊是非常重要的，而对于水性的注射液剂需要具有在溶液中的良好稳定性。
为了筛选化学稳定性，将每种盐与粉末赋形剂混合，形成片剂或装入胶囊。至于片剂的赋形剂，包括微晶纤维素与无水的磷酸二钙以50∶50结合。至于胶囊的赋形剂，包括甘露糖醇与干燥玉米淀粉以4∶1结合。然后将它们封入小药瓶，在50-75℃贮藏3周。药物和任何被破坏的产物用甲醇∶氯仿（50∶50）萃取，经硅胶薄层层析板，用不同的溶剂***分离。
比较其结果，并将盐按照其所生成的分解物的数目及数量来排列。
通过比较结果，下列排列程序显示了苯磺酸盐是最稳定的盐，盐酸盐最不稳定。
盐                                                                    稳定性
苯磺酸盐                                                        最稳定
甲基磺酸盐                                                        ↓
对甲苯磺酸盐
琥珀酸盐
水杨酸盐
马来酸盐
醋酸盐
盐酸盐                                                            不稳定
3.为了提供稳定的配方，我们希望有非吸湿性的盐。在固态时药物的含量是高的，当表层吸潮后，可以起水解和化学分解的媒介物的作用。药物或它的盐的吸湿性促使游离水份，这通常产生不稳定的后果。
当把它们置于37℃及相对湿度为75%的环境中暴露24小时，只有马来酸盐、对甲苯磺酸盐和苯磺酸盐没有任何吸潮现象。甚至于当在30℃，相对湿度为95%的环境中暴露3天时，苯磺酸盐和马来酸盐均继续保持干燥，对甲苯磺酸盐形成二水合盐。因而可以认为苯磺酸盐是非吸湿性的，并可提供稳定的配方，减少内部化学分解的危险。
4.药物上可接受的盐需要考虑的最后一个特点是加工性能，即压制的特性及不滞留或粘附于制片机上的性能。
对于高剂量的配方，良好的压缩性能对于制造精致的片剂是非常重要的。对于低剂量片剂来说，由于应用被称作压缩辅料的适当稀释赋形剂，对于良好压缩性能的要求，可被减少到某种程度。微晶纤微素通常用作压缩辅料。然而，无论什么剂量都必须避免药物对于片剂冲压机的粘附。当药物累积在冲床表面时，片剂表面就会变成凹坑，因而也就不合格了。当药片从机器上移开时，以这种方式粘附的药物也会导致高的排出力。实际上，应用湿一聚团、仔细地选择赋形剂，并用高级的抗胶粘体，如硬脂酸镁，有可能减少粘附。然而，选择具有良好的抗粘附特性的盐，可以减少这些问题。
为了比较amlodipine的不同盐的粘附性，可以通过下列操作，用常规制片机进行：将含有硫酸钙二水合物，微晶纤维素和amlodipine苯磺酸盐（47.5∶47.5∶5）制成50片药片，将粘附于药片冲压机的物料用甲醇萃取，经光谱仪测定含量。然后同样操作重复制备100，150，200，250和300片药片。在每次压片运转之后，将粘附于制片冲压机上的物料量，用甲醇萃取后测定。将测得的数值作图表示，从得出的线的斜度计算平均值。
然后将amlodipine的每种盐重复上述相同的操作。在表2中显示了测得每种amlodipine盐粘附于制片冲压机上的量，及相对于马来酸盐的量。
表2
盐    粘附性
每平方厘米amlodipine    相对于马来酸盐
的量微克/每片
甲基磺酸盐    1.16    58%
苯磺酸盐    1.17    59
对甲苯磺酸盐    1.95    98
马来酸盐    1.98    100
游离碱    2.02    102
琥珀酸盐    2.39    121
盐酸盐    2.51    127
水杨酸盐    2.85    144
很清楚，苯磺酸盐的抗粘附特性优于马来酸盐，而甲基磺酸盐也表明良好的加工性能，其酸酐易于分离，但是它相称的单水合物在制造后引起组成变化，使它不适宜在片剂中使用。
因而，amlodipine的苯磺酸盐，表现出良好的溶解度、稳定性，非吸湿性，良好的加工性能等性能的一种独特的结合，这种结合使它特别适合于配制amlodipine的药物配方。
为了更易理解本发明，下列实例可作为参考。
实例1
制备Amlodipine苯磺酸盐
取Amlodipine碱（65.6克，0.161摩尔），悬浮于工业的甲基化醇中（326.4毫升），冷却至5℃，在5℃时向此碱的悬浮液中，加入溶于工业甲基化醇中的苯磺酸（26.2克，0.168摩尔）。然后得到的悬浮液形成颗粒，过滤，并用2倍体积工业甲基化醇（65.6毫升）洗涤。使该湿固体在5℃于工业甲基化醇（327.6毫升）中悬浮1小时，过滤，用2倍体积的工业甲基化醇（65.6毫升）洗涤，在真空下于55℃干燥24小时，得76.5克（吸率83.8%）。分析如下：
熔点：201.0℃
元素分析%    C    H    N
计算值    55.07    5.51    4.94
实测值    54.91    5.46    4.93
实例2
含有Amlodipine苯磺酸盐的片剂
将Amlodipine苯磺酸盐与乙醇酸钠淀粉和无水磷酸二钙拌合5分钟。然后将混合物过筛，再拌合及再过筛，接着与微晶纤维素混合，得到的混合物过筛，并再进一步拌合10分钟，最后加入硬脂酸镁，并将整个混合物搅拌5分钟，用常规制片机将混合物压成片剂。
这个方法用于制备含有不同浓度的amlodipine苯磺酸盐的片剂，列于表3。
表3    片剂组成
苯磺酸盐    微晶纤维素    无水磷酸二钙    乙醇酸钠淀粉    硬脂酸镁
（毫克）    （毫克）    （毫克）    （毫克）    （毫克）
1.736    63.514    31.750    2.00    1.00
3.472    62.028    31.500    2.00    1.00
6.944    124.056    63.000    4.00    2.00
13.889    248.111    126.000    8.00    4.00
实例3
含Amlodipine苯磺酸盐的胶囊配方：
将微晶纤维素和干燥的玉米淀粉预先混合。取amlodipine苯磺酸盐与一些上述混合物一起混合，然后过筛，继续加入剩余的预先混合的淀粉等再混合10分钟，然后再次过筛，进一步混合5分钟。
这个方法用于制备含有不同浓度的列于表4的amlodipine苯磺酸盐混合物，然后将这些混合物装入适当大小的胶囊中。
表4    胶囊组成
苯磺酸盐    微晶纤维素    干燥玉米淀粉    硬脂酸镁    胶囊总重量
（毫克）    （毫克）    （毫克）    （毫克）    （毫克）
1.736    38.014    10.00    0.250    50
3.472    76.028    20.00    0.500    100
6.944    72.556    20.00    0.500    100
13.889    145.111    40.00    1.00    200
实例4
Amlodipine苯磺酸盐无菌水溶液配方：
氯化钠溶于注射用水中，与丙二醇混合，加入amlodipine苯磺酸盐，当其溶解后，进一步加入注射用水，调节体积达到所需的amlodipine浓度（1毫克/毫升）。然后将溶液通过无菌滤器过滤，装入适当的无菌容器如安瓿中，用于肠胃外投药如静脉给药。
该方法用于配制列于表5的配方
表5    无菌水溶液
（1）    （2）
amlodipine苯磺酸盐    1.389克    1.389克
氯化钠    9.000克    9.000克
丙二醇    200.000克    400.00克
注射用水    至1升    至1升
实例5
另一个制备Amlodipine苯磺酸盐的方法
取苯磺酸铵（0.943克）加至amlodipine碱（2克）的工业用甲基化醇淤浆中，得到的溶液加热回流10分钟。反应混合物冷却，在5℃制颗粒1小时，过滤amlodipine苯磺酸盐，以工业用甲基化醇（2×2毫升）洗涤，于真空干燥，得1.9克（理论量的70%）。熔点201.0℃
分析%：
实测值：C，54.98;H，5.46;N，4.90;
计算值：C，55.07;H，5.51;N，4.95。

Claims (10)

1、一种制备amlodipine苯磺酸盐的方法，其特征在于amlodipine碱与苯磺酸或它的铵盐溶液在惰性溶剂中反应，并分离amlodipine苯磺酸盐。
2、按权利要求1所述之方法，其中惰性溶剂是工业的甲基化醇。
3、一种制备药物组合物的方法，其特征在于将amlodipine苯磺酸盐与药物上可接受的稀释剂或载体相混合。
4、一种如权利要求3所述的制备片剂配方的方法，其特征在于amlodipine苯磺酸盐与赋形剂混合，并压成片剂。
5、一种如权利要求4所述之方法，其特征在于应用下列步骤：
（a）amlodipine苯磺酸盐与淀粉乙醇酸钠和无水磷酸二钙混合;
（b）过筛，再混合及过筛;
（c）与微晶纤维素混合;
（d）过筛及再混合;
（e）与硬脂酸镁混合;和
（f）压缩成片剂。
6、一种如权利要求3所述之制备胶囊配方的方法，其特征在于amlodipine与赋形剂混合后，填入胶囊。
7、一种如权利要求6所述之方法，其特征在于应用下列步骤：
（a）预先将微晶纤维素和干燥玉米淀粉混合;
（b）amlodipine苯磺酸盐与一些（a）的混合物混合并过筛;
（c）将剩余的（a）的混合物加入并混合，过筛和再混合;和
（d）将混合物填入胶囊。
8、一种如权利要求3制备不经胃肠道施用的amlodipine苯磺酸盐无菌水溶液的方法，其特征在于在无菌水载体中形成amlodipine的苯磺酸盐溶液的步骤。
9、一种如权利要求8中所述的方法，其特征在于应用下列步骤：
（a）将amlodipine苯磺酸盐的氯化钠无菌溶液溶于注射用水及丙二醇的混合物中;
（b）用注射用水进一步调节溶液的体积;
（c）通过无菌滤器过滤溶液;和
（d）将滤液注入无菌容器内。
10、一种如权利要求8或权利要求9所述之方法，其中溶液含有20-40%（重量/体积）丙二醇和约1%（重量/体积）氯化钠。
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