CN1125396A - 阿司咪唑和假麻黄碱的缓释薄膜包衣片 - Google Patents

阿司咪唑和假麻黄碱的缓释薄膜包衣片 Download PDF

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CN1125396A
CN1125396A CN94192441A CN94192441A CN1125396A CN 1125396 A CN1125396 A CN 1125396A CN 94192441 A CN94192441 A CN 94192441A CN 94192441 A CN94192441 A CN 94192441A CN 1125396 A CN1125396 A CN 1125396A
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P·M·V·吉里斯
E·M·J·简斯
G·J·M·吉斯
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Abstract

本发明涉及缓释薄膜包衣片以及制备该片剂的方法，本发明的片剂含有作为有效成分的抗组织胺剂、抗过敏剂阿司咪唑和肾上腺素能药、减充血药盐酸假麻黄碱。

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阿司咪唑和假麻黄碱的缓释薄膜包衣片
本发明涉及含有作为抗组织胺剂、抗过敏剂的有效成分阿司咪唑(astemizole)和含有作为肾上腺素能剂、减充血剂的有效成分盐酸假麻黄碱的缓释薄膜包衣片，还涉及制备该片剂的方法。
抗组织胺剂、抗过敏剂阿司咪唑，其制备方法和作用可从US-4,219,559中了解。从Drug Dev.Res.，8(1-4)，71-78，1986中可知道阿司咪唑在人体内的药代动力学，尤其是它可迅速分布到组织中并且其极限半衰期约为1天。假麻黄碱，尤其是其盐酸盐，已知是半衰期为数小时(通常为约6-8小时)的减充血剂。因此通常以分次剂量60mg应用，每天3或4次，或者以缓释制剂给药，剂量通常为每12小时约120mg。
有效的治疗患有过敏性疾病(如过敏性鼻炎、全年性鼻炎等)的患者需要服用组合物，该组合物释放抗组织胺剂和减充血剂，结果该两种有效成分有效的血浆浓度一直保持到第二天，即直至下一次服药时。
本发明涉及一组合物，该组合物包括(ⅰ)极限半衰期为约24小时并迅速分布的阿司咪唑，因此它不需要特别的保护措施，以及(ⅱ)盐酸假麻黄碱，它具有太短的半衰期，以至于不能达到所希望的24小时有效血浆浓度，因此需要特别的技术措施进行处理。
尤其是本发明涉及含有下述成分的片剂
(a)缓释骨架片芯，它包括作为有效成分的盐酸假麻黄碱、作为骨架基质的高粘滞的亲水聚合物、固体稀释剂以及先有技术中已知的其他任选制剂附加剂如制粒剂、助流剂、片剂粘合剂、溶剂、抗结块剂、防腐剂或润滑剂；
(b)缓释包衣
(c)含有作为有效成分的阿司咪唑和盐酸假麻黄碱、亲水聚合物以及在先有技术中已知的其他任选制剂附加剂(如表面活性剂、增塑剂和润滑剂的药物包衣)；以及
(d)封闭包衣。
所述片剂在片芯中最好含有约75％现有的盐酸假麻黄碱，从片芯中盐酸假麻黄碱在延长的时间内释放，剩余的25％加在药物包衣中，它与抗组织胺药阿司咪唑一起在消化后立即释放和吸收。
所述片剂在片芯中含有60mg-240mg盐酸假麻黄碱，在药物包衣中含有20mg-80mg盐酸假麻黄碱以及5mg-20mg阿司咪唑。成年人服用的片剂在片芯中最好含有约180mg，在药物包衣中含有约60mg盐酸假麻黄碱以及约10mg阿司咪唑。具有较低体重的人应用的片剂，例如儿童用片剂最好仅为成年人片重的一半，因此在片芯中含有约90mg盐酸假麻黄碱，在药物包衣中含有约30mg盐酸假麻黄碱和约5mg阿司咪唑。
片芯中高粘滞的亲水聚合物应该从其中逐渐地释放有效成分，最好为零级释放动力学。合适的高粘滞的亲水聚合物具有粘滞度范围为约3.500mPa.s-约100.000mPa.s，尤其合适的范围为约4.000mPa.s-约20.000用Pa.s。所述聚合物的实例有羟丙基甲基纤维素、羟丙基纤维素和羟乙基纤维素。对于有效成分盐酸假麻黄碱，上述要求可以应用粘滞度约为15厘司(15.000mPa.s)的羟丙基甲基纤维素(例如羟丙基甲基纤维素2208)，或应用有粘滞度约为4.000-6.000mPa.s的羟丙基纤维素聚合物达到。在片芯中需应用的亲水聚合物的数量依据其中盐酸假麻黄碱的数量和聚合物的粘滞度而定。在盐酸假麻黄碱的数量增加和/或粘滞度减小时，需要更多的聚合物。按盐酸假麻黄碱的重量，应用的羟丙基甲基纤维素(15.000mPa.s)的数量可以在约50％-约90％，优选约80％-约75％范围。
片芯中固体稀释剂可以选自可溶性稀释剂例如蔗糖、乳糖、海藻糖、麦芽糖、甘露糖醇、山梨糖醇、淀粉(谷物淀粉、小麦淀粉、玉米淀粉、大米淀粉、马铃薯淀粉)、淀粉水解产物、微晶淀粉、预明胶化的淀粉，以及选自不可溶性稀释剂例如磷酸氢二钙或磷酸三钙。最好的是乳糖，并且按应用的盐酸假麻黄碱的重量，它的用量在约75％-约85％范围。
在所述片芯中可以进一步包括的任选制剂附加剂，可以提到的有例如具有混悬和分散特点的并且在本申请组合物中还有常用的片剂粘合和制粒作用的聚乙烯吡咯烷酮：溶剂，尤其在制备中应用的溶剂，例如水和低级醇例如乙醇和异丙醇；助流剂如胶态二氧化硅；润滑剂如硬脂酸镁和/或棕榈酸镁、硬脂酸；抗粘附剂如滑石和谷物淀粉。
在本发明的片剂中，聚乙烯吡咯烷酮的用量可以为2％-6％，尤其是约5％；助流剂的用量可以为0.5％-1％，润滑剂的用量可以为1.5％-4％(所有的百分比均是按片芯中所用的盐酸假麻黄碱的重量进行计算的)。
包裹片芯的缓释包衣应设计为这样的：它缓慢地进行释放内容物，尤其是在药物包衣中起始剂量的盐酸假麻黄碱被释放之前它不释放片芯内容物。通过从包衣中起始的、快速的释放盐酸假麻黄碱，接着从片芯释放延缓的假麻黄碱，结果在1小时之内达到有效的假麻黄碱血浆浓度，并且保持约24小时。缓释的包衣含有乙基纤维素和低粘滞度的羟丙基纤维素或羟丙基甲基纤维素，例如羟丙基甲基纤维素2910(粘滞度为5mPa.s)，以及任选的增塑料如聚乙二醇(例如PEG-400)。乙基纤维素∶羟丙基甲基纤维素∶增塑剂的比例可以为约7∶3∶2-约9∶1∶2，优选为约4∶1∶1。按片芯总重量计算，缓释包衣的用量通常为约2％-约3％，优选为约2.5％-约2.75％。
药物包衣含有有效成分阿司咪唑(最好为微粉化的小粒子)以及盐酸假麻黄碱，其用量为以上所述的，将其混悬于低粘滞度的亲水聚合物如羟丙基甲基纤维素(例如粘滞度为5mPa.s的羟丙基甲基纤维素2910)和表面活性剂如脱水山梨糖醇酯的聚氧乙烯衍生物(例如吐温20、吐温40、吐温60或吐温80)中。在药物包衣中还可以应用的任选制剂附加剂有增塑剂如聚乙二醇(例如PEG-400)以及先有技术中已知的其他制剂附加剂
在药物包衣中应用的亲水聚合物的用量应该保持最小，以便限制片子的大小和制备成功。另一方面，它应该充分有效地包裹有效成分阿司咪唑和盐酸假麻黄碱，以便在缓释片芯上紧接释放。所述用量范围为每mg阿司咪唑约6-约10mg，最好为每mg阿司咪唑约7mg(或总的药物量∶聚合物的用量令人满意地为约1∶1)。每mg阿司咪唑，增塑剂和表面活性剂的用量分别约为1mg-2mg和0.025-0.035mg。
封闭包衣包括亲水聚合物羟丙基甲基纤维素如羟丙基甲基纤维素2910(粘滞度为5mPa.s)、增塑剂如聚乙二醇，其比例为4∶1。封闭包衣可以任选不透明的，例如与色料如二氧化钛一起应用。封闭包衣不仅防止经磨损使药物直接释放而损失，而且还改进了贮藏期(稳定性)，尤其改进了片子的器官感觉的特点。
优选的片子约包括
(a)在片芯中：
-180mg盐酸假麻黄碱
-142.65mg乳糖
-9mg聚乙烯吡咯烷酮
-1.35mg胶态二氧化硅
-117mg羟丙基甲基纤维素2208，15000mPa.s
-4.5mg硬脂酸镁
(6)在缓释包衣中：
-8mg乙基纤维素，20mPa.s
-2mg羟丙基甲基纤维素2910，5mPa.s
-2mg PEG-400
(c)在药物包衣中：
-60mg盐酸假麻黄碱
-10mg阿司咪唑，微细小粒
-70mg羟丙基甲基纤维素2910，5mPa.s
-16.8mg PEG400
-0.3mg吐温80：
(d)在封闭包衣材料中：
-8mg羟丙基甲基纤维素2910，5mPa.s
-2mg聚乙二醇
本发明的片子可以方便地按下述方法制备。
充分地混合盐酸假麻黄碱和固体稀释剂(最好是乳糖)，制得片芯。将混合物加到流动床制粒机(例如Glatt WSG-30型)中，并进一步地混合直至均匀。应用喷雾空气压缩机组开到接近最大强度，将水、醇(如异丙醇)和制粒剂(如聚乙烯吡咯烷酮K90)组成的制粒液体喷到上述混合物上。干燥颗粒经合适的筛网进行过筛。亲水聚合物(最好为羟丙基甲基纤维素2208，15000mPa.s)和助流剂(胶态二氧化硅)也过筛，并与颗粒充分地混合。然后加入润滑剂，再使混合物充分地混合直至均匀。混合物压制成白色的片子。
缓释包衣按下法制备：将乙基纤维素(20mPa.s)和羟丙基甲基纤维素2910(5mPa.s)慢慢地加到乙醇、二氯甲烷和增塑剂的溶液中，并搅拌直至溶解。片芯装入包衣锅(例如Glatt GC-750型)中，并用空气温热直到出口空气温度为约35℃-40℃。用空气压缩进行喷雾，将缓释包衣溶液施于片芯上。完成之后使包衣的片芯经干燥空气干燥。
通过慢慢地将亲水聚合物、增塑剂和表面活性剂加到搅拌的和温热的定量水中制得药物包衣。连续地加水和二种有效成分，并使该混悬液剂均匀。边搅拌边使该混合物冷至环境温度。将已包衣的片芯装入包衣锅内并用空气温热直到出口空气温度为约45℃-50℃。将药物包衣混悬液喷雾到已包衣的片芯上，完成之后将包裹药物的片剂经干燥空气干燥。
将亲水聚合物和增塑剂加到搅拌的和加热的定量水中制得封闭包衣。再加入水，并使该溶液冷却至环境温度。将药物包衣的片子装入包衣锅中并用空气温热直至出口空气温度为约45℃-50℃。将封闭包衣溶液喷雾到药物包衣的片子上，完成之后，将制成的片子经干燥空气干燥。包衣片应装入不可渗透水蒸汽的容器如硬质泡沫塑料垫包装(alu-alu；PVDC，PE，PVC-alu)中。
应用上述的工艺特点，可以得到制备阿司咪唑和盐酸假麻黄碱缓释的、薄膜包衣片剂的方便的、具有重现性的方法。药代动力学研究表明，按上述方法制得的片剂在消化中可产生即刻释放阿司咪唑和药物包衣中25％盐酸假麻黄碱，接着从缓释骨架片中盐酸假麻黄碱为零级释放。所述二种有效成分的有效血浆浓度可保持至少24小时。实施例a.制得片芯
12.6Kg盐酸假麻黄碱和9.986Kg乳糖在行星式混合器中混合。将混合物加到流动床式制粒机中，再次混合，并在约0.35Mpa喷雾空气压力下喷雾315g聚乙烯吡咯烷酮K90的2.03l水和4.76l异丙醇的溶液。颗粒经干燥空气进一步干燥。干燥的颗粒经振荡筛过筛(筛网孔1mm)。在同样条件下使8.19kg羟丙基甲基纤维素2208(15000mPa.s)和94.5kg胶态二氧化硅(Aerosil)过筛，并于行星式混合器与颗粒一起混合直至均匀。加入315g硬脂酸镁，并且充分地混合。然后将颗粒于旋转式压片机(Kersch PH106)中压成70,000片白色片剂，每片450mg。b.制备缓释包衣溶液
将11.01kg乙醇、7.315kg二氯甲烷和154g PEG400装在不锈钢容器中。边搅拌边慢慢地加入616g乙基纤维素(20mPa.s)和154g羟丙基甲基纤维素2910(5mPa.s)。c.制备药物包衣混悬液
将35.007kg水加热至约70℃，边搅拌边慢慢地加入5.39kg羟丙基甲基纤维素2910(5mPa.s)、1.294kg PEG400和23.1g吐温80。加入17.503kg水，接着慢慢地加入4.62kg盐酸假麻黄碱和770g阿司咪唑微粒。连续地搅拌使混悬液均匀并使其冷至室温。d.制备封闭包衣溶液
将3.593kg水加热至约70℃，加入616g羟丙基甲基纤维素2910(5mPa.s)和154g聚乙二醇。加入1.797kg水，搅拌混合物直至完全溶解。e.片芯包衣
将片芯置于包衣锅(Glatt GC-750)中并用温热的空气加热至出口空气温度为约35℃-40℃。在片芯上喷雾缓释包衣溶液。喷完之后停止加热，但空气供应维持约10分钟，以便干燥片子。从设备中取出包衣的片芯并储存备用。
再将包衣的片芯置于包衣锅(Glatt GC-750)中并用温热空气加热至出口空气温度为约45℃-50℃。在包衣的片芯上喷雾药物包衣溶液。喷雾完成之后，停止加热，但空气供应维持约10分钟，以便干燥片子。从设备中取出药物包衣的片芯并储存备用。
再将药物包衣的片芯置于包衣锅(Glatt GC-750)中并用温热空气加热至出口空气温度为约45℃-50℃。在药物包衣的片芯上喷雾封闭包衣溶液。喷雾完成之后，停止加热，但空气供应维持约10分钟，以便干燥片子。从设备中取出片子并储存。

Claims (10)

1.合有下述成分的片剂：
(a)缓释骨架片芯，它包括作为有效成分的盐酸假麻黄碱、作为基质的高粘滞的亲水聚合物和固体稀释剂；
(b)缓释包衣
(c)药物包衣，它包括作为有效成分的阿司咪唑和盐酸假麻黄碱、以及亲水聚合物；以及
(d)封闭包衣。
2.权利要求1所述的片剂，其中75％现有的盐酸假麻黄碱是在片芯中，其余25％是在药物包衣中。
3.权利要求2所述的片剂，其中该片芯含有约60mg-240mg盐酸假麻黄碱，药物包衣含有约20mg-80mg盐酸假麻黄碱和约5-20mg阿司咪唑。
4.权利要求1所述的片剂，其中高粘滞的亲水聚合物是粘滞度为约15000mPa.s的羟丙基甲基纤维素，而固体稀释剂是乳糖。
5.权利要求1所述的片剂，其中缓释包衣含有乙基纤维素以及低粘滞度羟丙基甲基纤维素。
6.权利要求1所述的片剂，其中药物包衣含有混悬在亲水聚合物中的有效成分阿司咪唑和盐酸假麻黄碱。
7.权利要求6所述的片剂，其中药物包衣还含有增塑剂和表面活性剂。
8.权利要求1所述的片剂，其中封闭包衣含有亲水聚合物和增塑剂。
9.权利要求1所述的片剂，它约含有
(a)在片芯中：
-180mg盐酸假麻黄碱
-142.65mg乳糖
-9mg聚乙烯吡咯烷酮
-1.35mg胶态二氧化硅
-117mg羟丙基甲基纤维素2208，15000mPa.s
-4.5mg硬脂酸镁
(b)在缓释包衣中：
-8mg乙基纤维素，20mPa.s
-2mg羟丙基甲基纤维素2910，5mPa.s
-2mg PEG-400
(c)在药物包衣中：
-60mg盐酸假麻黄碱
-10mg阿司咪唑微粒
-70mg羟丙基甲基纤维素2910，5mPa.s
-16.8mg PEG400
-0.3mg吐温80；以及
(d)在封闭包衣中：
-8mg羟丙基甲基纤维素2910，5mPa.s
-2mg聚乙二醇
10.制备权利要求1-9中任何一项所述片剂的方法，其特征在于
通过充分地混合盐酸假麻黄碱和固体稀释剂以及亲水聚合物，同时混合该混合物直至均匀，制备片芯；
压制该混合物成片芯
在片芯上喷雾缓释包衣；
在包衣片芯上喷雾药物包衣混悬液，该混悬液含有阿司咪唑、盐酸假麻黄碱和亲水聚合物：
在药物包衣片上喷雾封闭包衣溶液。
CN94192441A 1993-06-14 1994-06-07 阿司咪唑和假麻黄碱的缓释薄膜包衣片 Expired - Fee Related CN1071570C (zh)

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