CN1161112C - 含氯雷他定和伪麻黄碱的药物胶囊组合物 - Google Patents
含氯雷他定和伪麻黄碱的药物胶囊组合物 Download PDFInfo
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Abstract
本发明涉及口服药物胶囊组合物,它包含:含氯雷他定和伪麻黄碱或其药物上可接受的盐的快速释放丸(丸A)与含伪麻黄碱或其药物上可接受的盐的缓释丸(丸B),其中,丸B被涂布了水不溶性聚合物和阻湿剂。
Description
技术领域
本发明涉及含氯雷他定和伪麻黄碱的药物胶囊组合物,更具体地说,涉及口服药物胶囊组合物,它包括:含氯雷他定和伪麻黄碱或其药物上可接受的盐的快速释放丸(丸A)与含伪麻黄碱或其药物上可接受的盐的缓释丸(丸B),其中,丸B被涂布了水不溶性聚合物和阻湿剂。
背景技术
伪麻黄碱或其药物上可接受的盐(例如硫酸伪麻黄碱)被本领域技术人员认作有效地治疗鼻充血的拟交感神经药物。还已知氯雷他定(一种无镇静作用的抗组胺剂)适用作治疗季节性过敏性鼻炎症状(例如打喷嚏和发痒)的抗过敏剂。所以,既含氯雷他定又含伪麻黄碱或其药物上可接受的盐的口服剂量组合物适用于治疗表现与上呼吸道疾病和过敏性鼻炎相关的迹象和症状的患者(
参见美国专利No.5,314,697)。
但是,硫酸伪麻黄碱的生物半衰期只有约6.3小时,而氯雷他定(它在通过胃肠道吸收后与血浆蛋白质结合)具有长得多的生物半衰期(12~15小时)。此外,氯雷他定的水溶性差,而且表现很低的溶出度。所以,通过仅仅将氯雷他定和伪麻黄碱或其盐混合而制备的常规制剂不能同时保持两种组分的治疗有效血液浓度达规定的时期。
为了解决上述问题,美国专利No.5,314,697启示了一种薄膜包衣片,它包含:含硫酸伪麻黄碱和亲水性凝胶的缓释基质芯,含在所述芯上形成的氯雷他定的包衣层。当摄食这种制剂时,在具有更短生物半衰期的硫酸伪麻黄碱从缓释基质芯被释放之前,具有更长生物半衰期的氯雷他定就从包衣层被释放。
然而,在高pH环境中,外层的氯雷他定的溶解度和溶出度都显著降低了,由于这个原因,硫酸伪麻黄碱从缓释基质芯的溶出可能过度地延迟。也就是说,硫酸伪麻黄碱的溶出大大受润湿程度和外层中氯雷他定的溶出的影响,因此,硫酸伪麻黄碱的释放分布以不能预料的方式随着胃肠液的pH而波动,胃肠液的pH取决于各种因素(例如摄食的食物量和类别)而变化很大。
另外,美国专利No.5,807,579公开了一种片剂组合物,它包含:含伪麻黄碱或其盐的缓释丸,它们被分散于含抗组胺剂和任选的伪麻黄碱或其盐的基质中。然而,这种组合物也遭受氯雷他定在高pH条件下的差润湿性问题,它可能导致不令人满意的伪麻黄碱送递方式。
本发明人进行了广泛研究以解决上述问题;于是发现了一种药物胶囊组合物,它包含:含氯雷他定和伪麻黄碱或其盐的快速释放丸,以及含伪麻黄碱或其盐的缓释丸,它们被涂布了水不溶性聚合物和阻湿剂,不存在上述问题并且表现出两种组分可控的、令人满意的释放分布。
发明内容
因此,本发明的一个目的是提供一种改良的口服药物胶囊组合物,它包含氯雷他定和伪麻黄碱或其药物上可接受的盐。
按本发明,提供了一种口服药物胶囊组合物,它包含:
(a)很多快速释放丸(丸A),每颗丸包含(i)治疗有效量的氯雷他定,(ii)伪麻黄碱或其药物上可接受的盐,与(iii)一种或多种药物上可接受的赋形剂;以及
(b)很多缓释丸(丸B),每颗丸包含(i)伪麻黄碱或其药物上可接受的盐和(ii)一种或多种药物上可接受的赋形剂,缓释丸被涂布了水不溶性聚合物(涂布量在2~30重量%范围内)与选自下组物质的阻湿剂:硬脂酸镁、滑石粉、脂肪酸酯及其混合物(涂布量基于丸B的总重量在2~30重量%范围内)。
本文应用的术语“丸”表示直径在约300~1500微米范围内的含药物的颗粒。术语“快速释放”表示药物成分的特性,其中,活性药物的全部剂量可被生物利用而基本上没有延迟。术语“缓释”如美国药典(USPXXIV,1999)所表达的那样,它表示药物成分的特性,其中,包含的活性药物在被摄食后长时间内被生物利用。
本文应用的术语氯雷他定和伪麻黄碱的“治疗有效量”表示口服后产生期望的治疗响应所需的量,它容易由本领域技术人员来确定。在确定治疗有效量时,应考虑一些因素,但不限于:被施用的药物组合物的生物利用率特性、选定的剂量方案和其它相关情况。例如,氯雷他定和硫酸伪麻黄碱的有效剂量分别是每天10mg和240mg。此外,就一天两次的单元剂型来说,氯雷他定和硫酸伪麻黄碱的有效剂量分别可以是5mg和120mg。
本发明的药物胶囊组合物的快速释放丸(丸A)包含治疗有效量的氯雷他定、硫酸伪麻黄碱或其药物上可接受的盐,以及一种或多种药物上可接受的赋形剂。当施用本发明的组合物时,高度水溶性的伪麻黄碱或其盐容易从快速释放丸渗出,此时丸崩解而释放氯雷他定到水性胃环境中,于是增强氯雷他定的溶出度,同时从一开始就迅速达到伪麻黄碱或其盐的治疗有效血液水平。
丸A包含伪麻黄碱或其盐,含量足以产生治疗有效的伪麻黄碱初始浓度,所述含量基于丸A和丸B中的伪麻黄碱或其盐的总量可在5~50重量%的范围内。
本发明的药物组合物的快速释放丸可包含一种或多种药物上可接受的赋形剂,包括崩解剂、粘合剂或润滑剂。
合适的崩解剂(它可被用来改善氯雷他定的溶出度)包括:微晶纤维素、低取代度的羟丙基纤维素(USPXXIV,1999)、蔗糖、聚乙烯聚吡咯烷酮、羟基乙酸淀粉钠及其混合物。在所述崩解剂中,优选的是聚乙烯聚吡咯烷酮。可应用的崩解剂的量基于快速释放丸的重量在约5~约50重量%、优选10~约30重量%的范围内,从而产生令人满意的氯雷他定溶出分布。
所述快速释放丸还可包含一种或多种常规赋形剂,例如粘合剂(例如聚乙烯吡咯烷酮、羟丙基纤维素、明胶等);以及润滑剂(例如胶态二氧化硅、二氧化硅、滑石粉等)。
快速释放丸可按本领域熟知的方法制备,即挤出&团粒法[参见药物制粒技术(Pharmaceutical PelletizationTechnology),1989,p187~216],溶液&悬浮液层叠法[
参见药物开发与工业制药(Drug Dev.Ind.Pharm.),1989,15(8),p1137~1159]以及干粉层叠法[
参见药物制粒技术,1989,p187~216]。
例如,如果快速释放丸是通过干粉层叠法制备的,当在离心制粒机中将粘合剂溶液喷到惰性载体[例如蔗糖晶种和微晶纤维素晶种(例如Celphere,Asahi Chemical Co.)]上时,将氯雷他定、伪麻黄碱或其盐和药物赋形剂的混合物涂粉于惰性载体上而给出本发明的快速释放丸。
本发明的药物胶囊组合物的缓释丸(丸B)包含伪麻黄碱或其药物上可接受的盐与一种或多种药物上可接受的赋形剂,被涂布了水不溶性聚合物(涂布量基于丸B的总重量在2~30重量%范围内)和选自硬脂酸镁、滑石粉、脂肪酸酯及其混合物的阻湿剂(涂布量基于丸B的总重量在2~30重量%范围内)。
伪麻黄碱从缓释丸中的溶出不受氯雷他定的溶出的影响,所以,可获得所需的该活性组分释放分布。
缓释丸(即丸B)可通过这样制备:用水不溶性聚合物和阻湿剂涂布含伪麻黄碱或其盐的芯丸,或者将伪麻黄碱或其盐分散入含阻湿剂的水不溶性聚合物基质中。
如果用水不溶性聚合物和阻湿剂涂布含伪麻黄碱或其盐的芯丸而在芯丸上形成包被层,丸B的包被层的构造和/或厚度容易控制,于是所需的伪麻黄碱的溶出分布(S形溶出曲线),它不依赖于胃肠液的pH。所以,涂布型丸剂优选被用作本发明组合物的缓释丸。
可用于本发明的合适的水不溶性聚合物可选自下组物质:乙基纤维素、甲基丙烯酸共聚物(例如Eudragit L、Eudragit RS、EudragitRL和Eudragit S)、氢化蓖麻油、紫胶及其混合物。
所述缓释丸的芯丸可按本领域熟知的方法制备,即挤出&团粒法[
参见药物制粒技术,1989,p187~216],溶液&悬浮液层叠法[
参 见药物开发与工业制药,1989,15(8),p1137~1159]以及干粉层叠法[
参见药物制粒技术,1989,p187~216]。
例如,按照千粉层叠法,当在离心制粒机中将粘合剂溶液喷到惰性载体[例如蔗糖晶种和微晶纤维素晶种(例如Celphere,AsahiChemical Co.)]上时,将伪麻黄碱或其盐的粉末和药物赋形剂的混合物涂粉于惰性载体上而给出本发明的缓释丸的芯丸。然后,用包含水不溶性聚合物和阻湿剂于适当溶剂中的溶液涂布所述芯丸而提供本发明的缓释丸。可应用于本发明的适当溶剂包括丙酮、乙醇、异丙醇、二氯甲烷及其混合物。
可用来制备本发明的缓释丸的药物赋形剂包括一种或多种本领域已知的常规赋形剂,例如:增塑剂,例如聚乙二醇6000、邻苯二甲酸二乙酯和癸二酸二丁酯;稀释剂,例如微晶纤维素和蔗糖;崩解剂,例如低取代度的羟丙基纤维素、聚乙烯聚吡咯烷酮、羟基乙酸淀粉钠及其混合物;粘合剂,例如聚乙烯吡咯烷酮、羟丙基纤维素和明胶;以及润滑剂,例如胶态二氧化硅、二氧化硅、硬脂酸镁和滑石粉。
本发明的药物胶囊组合物可容易地通过将上述快速释放丸和缓释丸填充入合适的胶囊而配制成胶囊形式。
当口服本发明的胶囊组合物时,与从常规片剂组合物释放相比,氯雷他定容易以更高的速度从胶囊组合物释放。
此外,比氯雷他定具有更短的生物半衰期的伪麻黄碱或其盐首先从快速释放丸、然后从缓释丸溶出,从而即刻和缓慢溶解送递伪麻黄碱。缓释丸被涂布了水不溶性聚合物而给出有效的缓释活性。特别是,缓释丸的涂层具有阻湿剂,于是提供假-多重溶出分布。
所以,当施药时,不受与胃肠环境相关的各种因素的限制,本发明的药物胶囊组合物表现出迅速的和长期作用的效果。
给出如下实施例和测试实施例只是为了阐述而不想限制本发明的范围。
实施例1:含氯雷他定和硫酸伪麻黄碱的快速释放丸的制备
通过将5.0g聚乙烯吡咯烷酮溶于120g水而制备了粘合剂溶液。将25g氯雷他定、180g硫酸伪麻黄碱、25g微晶纤维素、75g低取代度的羟丙基纤维素、75g聚乙烯聚吡咯烷酮和1.5g胶态二氧化硅混合并通过20目筛筛分而给出混合粉末。在将上文制备的粘合剂溶液喷到离心制粒机中的250g糖晶种上时,将所述混合粉末撒粉于离心制粒机中的糖晶种上而提供丸。(转盘速度:140~200rpm,粘合剂溶液喷洒速度:2~20ml/min,空气喷射压力:1~2kg/cm2,空气喷射量:5~300L/min,粉末喷撒速度:5~30g/min)
实施例2和3:含氯雷他定和硫酸伪麻黄碱的快速释放丸的制备
重复了实施例1的操作,不同的是如表1中所示那样改变组分的量而获得含硫酸伪麻黄碱和氯雷他定的快速释放丸的另外样品。
表1
实施例2 | 实施例3 | ||
活性组分 | 氯雷他定 | 25g | 25g |
硫酸伪麻黄碱 | 240g | 270g | |
稀释剂 | 微晶纤维素 | 25g | 25g |
崩解剂 | 低取代度羟丙基纤维素 | 75g | 50g |
聚乙烯聚吡咯烷酮 | 75g | 50g | |
润滑剂 | 胶态二氧化硅 | 1.5g | 1.5g |
粘合剂 | 聚乙烯吡咯烷酮 | 5.0g | 5.0g |
惰性载体 | 糖晶种 | 250g | 250g |
实施例4:含硫酸伪麻黄碱的芯丸的制备
通过将20g羟丙基纤维素溶于480g水而制备了粘合剂溶液。将1200g硫酸伪麻黄碱和3g胶态二氧化硅混合并通过20目筛筛分而给出混合粉末。在将上文制备的粘合剂溶液喷到离心制粒机中的600g糖晶种上时,将所述混合粉末撒粉于离心制粒机中的糖晶种上而提供丸。在50℃下干燥获得的丸直至用Kett-水分分析仪测定它的水含量少于2%而给出含硫酸伪麻黄碱的芯丸。
实施例5和6:含硫酸伪麻黄碱的芯丸的制备
重复了实施例4的操作,不同的是如表2中所示那样改变组分的量而获得含硫酸伪麻黄碱和氯雷他定的芯丸的另外样品。
表2
实施例5 | 实施例6 | ||
活性组分 | 硫酸伪麻黄碱 | 1200g | 1200g |
粘合剂 | 羟丙基纤维素 | - | 20g |
聚乙烯吡咯烷酮 | 20g | - | |
润滑剂 | 胶态二氧化硅 | 3g | 3g |
硬脂酸镁 | - | 240g | |
惰性载体 | 糖晶种 | 600g | 600g |
实施例7~10:含硫酸伪麻黄碱的缓释丸的制备
应用实施例4中制备的芯丸和表3中所示的原料,通过下述方法制备了含硫酸伪麻黄碱的缓释丸。
在离-360制粒机中将水不溶性聚合物、硬脂酸镁和其它组分于丙酮和异丙醇中的悬浮液喷到含硫酸伪麻黄碱的芯丸上,然后在50℃下干燥直至水含量降到低于2%而给出含硫酸伪麻黄碱的缓释丸。
实施例11:含硫酸伪麻黄碱的缓释丸的制备
重复了实施例7~10的操作,通过应用实施例6中获得的芯丸和表3中所示的原料而获得含硫酸伪麻黄碱的缓释丸。
表3
Ex.7 | Ex.8 | Ex.9 | Ex.10 | Ex.11 | |
硫酸伪麻黄碱芯丸 | 280 | 280 | 280 | 280 | 280 |
乙基纤维素 | 15 | 30 | - | 26 | 15 |
Eudragit RS | - | - | 40 | 13 | - |
邻苯二甲酸二乙酯 | 1.5 | 3.0 | 4.0 | 3.9 | 1.5 |
硬脂酸镁 | 18 | - | - | 13 | - |
滑石粉 | - | 10 | 10 | - | - |
丙酮 | 150 | 300 | 400 | 390 | 150 |
异丙醇 | 150 | 300 | 400 | 390 | 150 |
实施例12~15:胶囊的制备
将127.3g、139.3g和135.3g实施例1、2和3中制备的快速释放丸分别与143.3g、122.9g和112.6g实施例7中制备的缓释丸混合而提供三批混合丸,将它们填充入No.1胶囊而分别给出实施例12、13和14的胶囊。另外,将127.3g实施例1中制备的快速释放丸与153.1g实施例10中制备的缓释丸混合而获得丸混合物,将它填充入No.1胶囊而给出实施例15的胶囊。每颗胶囊中组分的量与表4中的相同。
表4
Ex.12(Ex.1+7) | Ex.13(Ex.2+7) | Ex.14(Ex.3+7) | Ex.15(Ex.1+10) | ||
氯雷他定 | 5 | 5 | 5 | 5 | |
硫酸伪麻黄碱 | 快速释放丸 | 36 | 48 | 54 | 36 |
缓释丸 | 84 | 72 | 66 | 84 | |
微晶纤维素 | 5 | 8.6 | 8.6 | 8.6 | |
低取代度羟丙基纤维素 | 15 | 15 | 15 | 15 | |
聚乙烯聚吡咯烷酮 | 15 | 15 | 15 | 15 | |
胶态二氧化硅 | 0.5 | 0.48 | 0.47 | 0.5 | |
羟丙基纤维素 | 1.4 | 1.2 | 1.1 | 1.4 | |
聚乙烯吡咯烷酮 | 1 | 1 | 1 | 1 | |
乙基纤维素 | 7.5 | 15 | - | 13 | |
Eudragit RS | - | - | 20 | 6.5 | |
邻苯二甲酸二乙酯 | 0.75 | 1.5 | 2.0 | 3.9 | |
硬脂酸镁 | 9 | - | - | 6.5 | |
滑石粉 | - | 5 | 5 | - |
测试实施例1:溶出试验(1)
将测定量的实施例7~11中制备的缓释丸的每一种填入篮中,经历下列条件下的溶出试验。结果示于表5中。
溶出试验条件:
测试溶液:0.1N盐酸900ml
温度:37±0.5℃
方法:篮式法(美国药典)
表5.硫酸伪麻黄碱的溶出率(%)
1小时 | 2小时 | 4小时 | 6小时 | |
Ex.7 | 15.5 | 25.5 | 64.1 | 82.6 |
Ex.8 | 21.5 | 41.9 | 63.3 | 84.6 |
Ex.9 | 15.5 | 37.8 | 58.2 | 78.6 |
Ex.10 | 19.7 | 45.4 | 66.9 | 88.4 |
Ex.11 | 15.5 | 52.1 | 65.6 | 79.0 |
如表5所示,本发明的缓释丸在各情况下都表现为:硫酸伪麻黄碱在6小时以上的时段令人满意的溶出分布。
测试实施例2:溶出试验(2)
将测定量的实施例12~15中制备的胶囊的每一种填入篮中,然后经历下列条件下的溶出试验。还将相同量的Clarinase(Sheringplough,USA)填充入篮中进行测试。结果示于表6和7中。
溶出试验条件:
测试溶液:0.1N盐酸900ml
pH4.0乙酸盐缓冲液900ml
pH6.8磷酸盐缓冲液900ml
温度:37±0.5℃
方法:篮式法(美国药典)
表6.氯雷他定1小时的溶出率(%)
pH | Clarinase | Ex.12 | Ex.13 | Ex.14 | Ex.15 |
1.0 | 88.5 | 91.7 | 94.5 | 97.2 | 95.3 |
4.0 | 53.4 | 51.5 | 52.9 | 55.1 | 54.1 |
6.8 | 0 | 10.2 | 10.9 | 12.1 | 9.7 |
表7.硫酸伪麻黄碱的溶出率(%)
pH | 1小时 | 2小时 | 4小时 | 6小时 | |
1.0 | Clarinase | 48.8 | 49.0 | n.m. | 82.6 |
Ex.12 | 40.9 | 47.9 | 74.8 | 87.8 | |
Ex.13 | 49.3 | 55.3 | 78.4 | 89.6 | |
Ex.14 | 53.5 | 59.0 | 80.2 | 90.4 | |
Ex.15 | 43.8 | 61.8 | 76.8 | 91.9 | |
4.0 | C1arinase | 47.4 | 47.8 | n.m. | 50.1 |
Ex.12 | 39.1 | 49.1 | n.m. | 84.9 | |
Ex.13 | 48.4 | 55.1 | n.m. | 87.9 | |
Ex.14 | 51.3 | 57.9 | n.m. | 88.5 | |
Ex.15 | 44.3 | 60.9 | n.m. | 92.7 | |
6.8 | Clarinase | 44.1 | 48.1 | n.m. | 49.7 |
Ex.12 | 40.8 | 52.3 | n.m. | 85.1 | |
Ex.13 | 50.1 | 57.1 | n.m. | 89.9 | |
Ex.14 | 52.7 | 59.1 | n.m. | 87.9 | |
Ex.15 | 46.2 | 63.7 | n.m. | 93.1 |
*n.m.:未测定
如表6所示,在pH1.0时,氯雷他定从各种测试的组合物被快速释放。但是,在pH4.0和pH6.8时,氯雷他定从Clarinase的溶出完全受抑制了。
如表7所示,在pH1.0时,在测试的组合物中,硫酸伪麻黄碱的溶出度没有显著不同。
然而,在pH4.0或pH6.8时,硫酸伪麻黄碱从Clarinase的释放量在6小时的测试期间保持低到约50%。这说明了,在高pH条件下保持不溶解的氯雷他定阻滞了伪麻黄碱的溶出。明显不同的是,硫酸伪麻黄碱从本发明组合物中的溶出不受pH的影响,在1.0~6.8的pH范围内释放分布相同。
另外,其实,硫酸伪麻黄碱从本发明组合物中的溶出表现的S形曲线特别有利于提供硫酸伪麻黄碱的假-多次施药。
虽然描述和阐释了本发明的实施方案,但显然可在其中作各种变化和修饰而不偏离本发明的精神(它只应受附后权利要求的限制)。
Claims (3)
1.一种口服药物胶囊组合物,它包含:
(a)快速释放丸—丸A,每颗丸包含(i)治疗有效量的氯雷他定,(ii)伪麻黄碱或其药物上可接受的盐,与(iii)一种或多种药物上可接受的赋形剂;以及
(b)缓释丸—丸B,每颗丸包含(i)伪麻黄碱或其药物上可接受的盐和(ii)一种或多种药物上可接受的赋形剂,缓释丸被涂布了涂布量在2~30重量%范围内的水不溶性聚合物与选自下组物质的阻湿剂:硬脂酸镁、滑石粉、脂肪酸酯及其混合物,涂布量基于丸B的总重量在2~30重量%范围内。
2.权利要求1的胶囊组合物,其中,含于丸A中的伪麻黄碱或其药物上可接受的盐的量基于胶囊中存在的伪麻黄碱或其盐的总量在5~50重量%范围内。
3.权利要求1或2的胶囊组合物,其中,所述水不溶性聚合物选自下组物质:乙基纤维素、甲基丙烯酸共聚物、氢化蓖麻油、紫胶及其混合物。
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US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
WO2001021161A2 (en) * | 1999-09-21 | 2001-03-29 | Schering Corporation | Use of desloratadine for treating allergic and inflammatory conditions |
JP2004534820A (ja) * | 2001-06-20 | 2004-11-18 | シェーリング コーポレイション | 鼻うっ血および鼻閉塞の処置のための抗ヒスタミン薬 |
FR2830447B1 (fr) * | 2001-10-09 | 2004-04-16 | Flamel Tech Sa | Forme galenique orale microparticulaire pour la liberation retardee et controlee de principes actifs pharmaceutiques |
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US20040033257A1 (en) * | 2002-05-30 | 2004-02-19 | Strides Inc. | Pharmaceutical formulation in a drug delivery system and process for preparing the same |
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US20070190125A1 (en) | 2004-03-03 | 2007-08-16 | Constantine Georgiades | Positioning feature for aiding use of film or strip product |
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US5314697A (en) * | 1992-10-23 | 1994-05-24 | Schering Corporation | Stable extended release oral dosage composition comprising loratadine and pseudoephedrine |
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