CN1197578C - 含有尼维瑞平半水合物的药物悬浮液 - Google Patents

含有尼维瑞平半水合物的药物悬浮液 Download PDF

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CN1197578C
CN1197578C CNB988084899A CN98808489A CN1197578C CN 1197578 C CN1197578 C CN 1197578C CN B988084899 A CNB988084899 A CN B988084899A CN 98808489 A CN98808489 A CN 98808489A CN 1197578 C CN1197578 C CN 1197578C
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nevirapine
hemihydrate
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nevirapine hemihydrate
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卡尔·G·格罗齐格
阿马尔·A·哈维
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Abstract

本发明是关于一种水性药物悬浮液，其中主要包含粒径介于约1至150微米的尼维瑞平(nevirapine)半水合物。

Description

含有尼维瑞平半水合物 的药物悬浮液
本发明是关于一种新颖组合物，它是包含尼维瑞平(nevirapine)半水合物的一种药物悬浮液。
尼维瑞平，或是11-环丙基-5，11-二氢-4-甲基-6H-二吡啶并[3，2-b：2′，3’-e][1，4]二氮杂_-6-酮是一种用于治疗由HIV-1(I型人类免疫缺陷)感染的已知制剂，其作用是通过特异性的抑制HIV-1(I型人类免疫缺陷病毒)的逆转录酶。其合成和用途已描述于不同的专利，包括，特别是，美国专利No.5,366,972；欧洲专利申请No.0 429 987，美国专利申请系列No08/515093(代理案号No 09/051-3-C3，已付出版费)和美国专利申请系列号No 08/371622(代理案号No 1/981，已付出版费)。维若敏(Viramune_)片剂，是一种包含尼维瑞平的药物片剂，最近刚被美国食品药物检验局准许用于治疗HIV-1(I型人类免疫缺陷病毒)感染。
安琪等人(Angel et al.)[美国电子显微镜协会第50届年会手册，1326-1327页(1992)]曾发表尼维瑞平是以半水合物的稳定态存在及以无水的亚稳态存在。同一篇文献中曾提到企图由该化合物的无水态制成适于儿科使用的尼维瑞平水性悬浮液。该尝试并未成功，因为一旦被制成水性悬浮液后，无水的尼维瑞平会缓慢的转换成半水合物态，产生半水合物结晶，随着时间的过程，结晶变大而对药物的溶解和药物的效用产生负影响。
本发明是尼维瑞平半水合物的水性悬浮液。意外地发现，在水性悬浮液中，半水合物的结晶在时间过程是稳定的。因此，尼维瑞平半水合物的水性悬浮液是药物上可接受的。
可利用包括上述提及的文献中的已知的多种方法中的任一种制备无水尼维瑞平。
该半水合物可简便地由水性液中将无水物料经再结晶而制成。它可通过将自由碱的无水物料的水性悬浮液与强酸反应，如盐酸，则产生酸加成盐。再将该盐与强碱反应，如氢氧化钠，以产生半水合物态的自由碱沉淀。将沉淀以过滤方式由水性液中取出，以水洗后，使之干燥至水含量为约3.1至3.9重量％。过度干燥将使半水合物转换为无水态，所以应避免。术语半水合物是指含有约0.5mole水的尼维瑞平。
为用于药物上可接受的水性悬浮液，半水合物的粒径应在约1至150微米。根据上述所产生的半水合物，若有需要，可经研磨以使颗粒大小落入该范围内。
一种药物上可接受的尼维瑞平半水合物水性悬浮液的制备，是将半水合物以1至50毫克尼维瑞平半水合物对1毫升水的比率加入纯水中，接着搅拌混合。该制剂中可另外含有传统的药物添加剂，如下述，但不仅限于这些，悬浮制剂和/或粘度增稠剂，如，纤维素基的聚合物或合成的聚合物，优选为交联的聚合物，如卡勃姆(carbomers)；湿润剂如，聚环氧乙烷或聚氧乙烯脱水山梨醇脂肪酸酯(多乙氧基醚)；甜味剂或调味剂，如蔗糖；和防腐剂，如对氧苯甲酸酯。
通过非限制性的描述，根据本发明的典型制剂将示于下表。
    组成     用量(克/100毫升)
尼维瑞平半水合物     0.1-5.0
卡勃姆(Carbomer)934P，NF     0.17-0.22
多乙氧基醚80，NF     0.01-0.2
山梨糖醇溶液，USP     5-30
蔗糖，NF     5-30
对氧苯甲酸甲酯，NF     0.15-0.2
对氧苯甲酸丙酯，NF     0.02-0.24
氢氧化钠，N.F.*     适量以调整至pH5.5-6.0
纯水，USP     适量以调整至100.0毫升
*制成20％溶液
更具体地，本发明的典型制剂包含下述指定相对量范围内的组成：
    组成     用量范围(克/100毫升)
尼维瑞平半水合物     1.035
卡勃姆(Carbomer)934P，NF     0.1900
多乙氧基醚80，NF     0.05000
山梨糖醇溶液，USP     23.13
蔗糖，NF     15.00
对氧苯甲酸甲酯，NF     0.1800
对氧苯甲酸丙酯，NF     0.02400
氢氧化钠，N.F.*   适量以调整至pH5.5-6.0
纯水，USP   适量以调整至100.0毫升
*制成20％溶液
本发明更以下述非限制性实例以进一步说明。
实施例1
尼维瑞平半水合物的制备
对含有318公斤的尼维瑞平(无水)的玻璃衬反应器中以低流速加入319公斤的37％盐酸，以维持内部的温度低于35℃。将该混合物在25-35℃下搅拌至所有的物料都溶解。将溶液过滤后，并以160升的纯水稀释。以25％氢氧化钠溶液中和，但需维持其温度低于40℃。使所得的结晶悬浮液冷却至15-20℃达30分钟。将该结晶离心后，以纯水洗，并使其于30-40℃下干燥。利用通常的真空转筒干燥器在真空下干燥该结晶8-24小时，再以空气循环槽式干燥器进行24-72小时，或是在Titus_离心干燥器(TZD)中进行1-8小时。使所得的半水合物药品持续干燥至利用湿度计于100℃下测量30分钟，其水含量为介于3.1-3.9％。
实施例2
尼维瑞平半水合物的制备
将26克尼维瑞平(无水)悬浮于100毫升水中。在冷却下将30毫升浓盐酸加入搅拌中的混合物，以保持温度低于30℃。10-20分钟后，将有色的溶液过滤，并添加溶于50毫升水中的14.4克氢氧化钠以进行中和。将所得的沉淀过滤后并以水洗。将湿的结晶物移入槽内，并于35-45℃中干燥至水含量为介于3.1-3.9％为止。所得的半水合物的熔点是242-245℃，且经分析含有3.1-3.6％的水，或是约0.5mole的水。
实施例3
制备水性50毫克/毫升的尼维瑞平半水合物的药物悬浮液
    组成     用量(克/100毫升)
尼维瑞平半水合物     1.035
卡勃姆(Carbomer)934P，NF     0.2100
多乙氧基醚80，NF     0.05000
山梨糖醇溶液，USP     23.13
蔗糖，NF     15.0
对氧苯甲酸甲酯，NF     0.1800
对氧苯甲酸丙酯，NF     0.02400
氢氧化钠，N.F.*     适量以调整至pH5.5-6.0
纯水，USP     适量以调整至100.0毫升
*制成20％溶液
制备方法
将部分纯水加热至约70℃，在连续搅拌混合下加入对氧苯甲酸甲酯和对氧苯甲酸丙酯。当对氧苯甲酸酯完全溶解后，使溶液冷却至35℃以下，再在搅拌下分散加入卡勃姆934P於该经防腐的溶液中。以20％氢氧化纳溶液调节pH值至5.5-5.8。将该胶状物持续搅拌约20分钟，再重测pH值。在搅拌下添加山梨糖醇溶液。再加入蔗糖且继续搅拌30分钟。将多乙氧基醚80溶于一部分纯水中，再将尼维瑞平加入多氧乙基醚80溶液中，并将该混合物均质搅拌至少40分钟。将尼维瑞平/多氧乙基醚80药物浓缩物完全混入卡勃姆胶中。以纯水调节该悬浮液的体积或重量，且搅拌30分钟。

Claims (7)

1.一种制备尼维瑞平半水合物的方法，该方法包括：
a)用强酸处理无水尼维瑞平的水悬浮液以制得酸加成盐的溶液；
b)将上一步骤中所得的酸加成盐的溶液用强碱处理，以制得尼维瑞平游离碱的沉淀，呈半水合物形式；
c)通过过滤由水介质中分离沉淀出的尼维瑞平半水合物；
d)用水洗涤在上一步骤得到的尼维瑞平半水合物沉淀。
2.按权利要求1的制备尼维瑞平半水合物的方法，进一步包括分离及干燥步骤(d)中得到的尼维瑞平半水合物，在得到的尼维瑞平半水合物中的水含量在3.1～3.9％重量之间。
3.一种制备尼维瑞平水性悬浮液的方法，其中，尼维瑞平半水合物的晶粒大小是药物可接受的，并随时间保持稳定，该方法包括：
a)用强酸处理无水尼维瑞平的水悬浮液，以制得酸加成盐；
b)将上一步骤所得的酸加成盐用强碱处理，以制得尼维瑞平游离碱的沉淀，呈半水合物形式；
c)通过过滤，由水介质中分离沉淀的尼维瑞平半水合物；
d)用水洗涤分离的尼维瑞平半水合物；
如果颗粒不符合要求，则研磨干燥的尼维瑞平半水合物以制得适于生产药物可接受的悬浮液的颗粒大小；并且
e)用水混合干燥的和研磨过的或未研磨过的尼维瑞平半水合物以制得水悬浮液。
4.一种由权利要求3方法制备的呈悬浮液形式的药物组合物，它包括具有粒径为1～150微米的尼维瑞平半水合物和水。
5.根据权利要求4的药物组合物，其中主要含有下述指定相对量范围内的组成：
组成     用量范围(克/100毫升) 尼维瑞平半水合物     0.1-5.0 卡勃姆(Carbomer)934P，NF     0.17-0.22 多乙氧基醚80，NF     0.01-0.2 山梨糖醇溶液，USP     5-30 蔗糖，NF     5-30 对氧苯甲酸甲酯，NF     0.15-0.2 对氧苯甲酸丙酯，NF     0.02-0.24 氢氧化钠，N.F.*     适量以调整至pH5.5-6.0 纯水，USP     适量以调整至100.0毫升
*制成20％溶液。
6.根据权利要求5的药物组合物，其中主要包含下述指定相对量范围内的组成： 组成     用量范围(克/100毫升) 尼维瑞平半水合物     1.035 卡勃姆(Carbomer)934P，NF     0.1900 多乙氧基醚80，NF     0.05000 山梨糖醇溶液，USP     23.13 蔗糖，NF     15.00 对氧苯甲酸甲酯，NF     0.1800 对氧苯甲酸丙酯，NF     0.02400 氢氧化钠，N.F.*     适量以调整至pH5.5-6.0 纯水，USP     适量以调整至100.0毫升
*制成20％溶液。
7.尼维瑞平半水合物水性悬浮液在用于制备治疗HIV-1感染的药物组合物中的用途。
CNB988084899A 1997-08-25 1998-08-11 含有尼维瑞平半水合物的药物悬浮液 Expired - Fee Related CN1197578C (zh)

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