CN1271993C - 注入堆积密度为0.28～0.38g/ml的吸入用新配方、该配方的制备方法及其用途 - Google Patents

注入堆积密度为0.28～0.38g/ml的吸入用新配方、该配方的制备方法及其用途 Download PDF

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CN1271993C
CN1271993C CNB988019000A CN98801900A CN1271993C CN 1271993 C CN1271993 C CN 1271993C CN B988019000 A CNB988019000 A CN B988019000A CN 98801900 A CN98801900 A CN 98801900A CN 1271993 C CN1271993 C CN 1271993C
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Abstract

一种干粉剂组合物，其中包含一种或多种强效药物活性物质和载体物质，这些物质全部都呈微细形式，其中该配方的注入堆积密度为0.28～0.38g/ml。这种干粉剂组合物在治疗呼吸系统疾病方面是有用的。

Description

注入堆积密度为0.28～0.38g/mL的 吸入用新配方、该配方的制备方法及其用途
发明领域
本发明提供一种新药物配方、其制备及其用途。
发明背景
吸入法给药用的强效药因其制备精确剂量的问题，一般是与乳糖等载体相缔合来配制的。当这样的药物稀释时，配方重量的差异导致与它们未被稀释时比较更小的药物剂量差异。这些配方一般由载体的粗大颗粒和药物的微细颗粒组成，这种组合一般称为订做的混合物。
本发明提供一种改进的配方，在为模仿吸入而设计的系统中，已发现该配方能改善药物的分散。
本发明说明
按照本发明，提供的是一种干粉剂组合物，其中包含一种或多种强效药物活性物质和一种载体物质，这些物质全部都呈微细形式，其中该配方的注入堆积密度为0.28～0.38g/mL，较好为0.30～0.36g/mL。
按照本发明的注入堆积密度是用已知技术测定的，例如“粉末测试指南：散装粉末物理性能测定方法”L.Svarovsky，ElsevierApplied Science 1987，pP 84-86中描述的那些。
适用于本发明的一种强效药物活性物质是诸如一种抗心律失常药、安定药、强心甙、激素、高血压药、抗糖尿病或抗癌药、镇静或止痛药、抗生素、抗风湿药、免疫治疗、抗真菌或抗低血压药、菌苗、抗病毒药、蛋白质(例如胰岛素)、肽、维生素、或一种细胞表面受体阻滞剂。较好的是一种糖皮质类甾醇、尤其一种能迅速代谢者，例如双丙酸倍氯美松(BDP)、单丙酸倍氯美松(BMP)、氟尼缩松、丙酮缩去炎舒松、氟替卡松丙酸盐、ciclesonide、布地奈德、rofleponide或其衍生物、momethasone、替泼尼旦、RPR106541和/或一种β2-兴奋剂，例如特布他林、舒喘灵、福莫特罗(formoterol)、沙美特罗、TA2005、pircumarol或其药物上可接受的盐；和/或一种预防性药剂，例如sodium chromoglycate或奈多罗米钠盐。
适用的生理上可接受的盐包括从无机酸和有机酸衍生的酸加成盐，例如氯化物、溴化物、硫酸盐、磷酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、4-甲氧基苯甲酸盐、2-或4-羟基苯甲酸盐、4-氯苯甲酸盐、对甲苯磺酸盐、甲磺酸盐、抗坏血酸盐、乙酸盐、琥珀酸盐、乳酸盐、戊二酸盐、葡糖酸盐、丙三羧酸盐、羟基萘羧酸盐或油酸盐或其溶剂化物。
载体物质较好的是一种单糖、二糖或多糖，一种糖醇或一种多醇。适用的载体是诸如乳糖、葡萄糖、棉子糖、松三糖、乳糖醇、麦牙糖醇、茧蜜糖、蔗糖、甘露糖；和淀粉。乳糖是特别好，特别是其一水合物形式。
按照本发明的配方的各组分必须均呈微细形式，即它们的质量中值直径一般应当小于10μm，较好的是1～7μm，是用激光衍射仪或coulter计数器测定的。这些组分可以用有本门技术技能的人员已知的方法例如研磨、微粉化或直接沉淀，以所希望的粒度产生。
布地奈德和福莫特罗的组合是特别好的。福莫特罗较好以其富马酸盐、特别是二水合物的形式使用。
当本发明中使用的一种或多种强效药物活性物质是福莫特罗和布地奈德时，本发明组合物中福莫特罗与布地奈德的摩尔比较好的是1∶2500～12∶1，更好的是1∶555～2∶1，最好的是1∶133～1∶6。按照本发明的组合物，较好的是配制得能提供2～120nmol(更好的是7～70nmol)福莫特罗的日剂量。当福莫特罗是以福莫特罗富马酸盐二水合物的形式使用时，该组合物较好配制得能提供1～50μg，更好的是3～30μg福莫特罗富马酸盐二水合物的日剂量。按照本发明的组合物较好配制得能提供45～2200μg、更好的是65～1700μg布地奈德的日剂量。
更好的是，本发明的组合物以单元剂量形式含有6μg福莫特罗富马酸盐二水合物和100μg布地奈德，或4.5μg福莫特罗富马酸盐二水合物和80μg布地奈德，其中任意一种均可一天给药多达4次。此外，本发明组合物也可以单元剂量形式含有12μg福莫特罗富马酸盐二水合物和200μg布地奈德，或9μg福莫特罗富马酸盐二水合物和160μg布地奈德，其中任意一种均可一天给药一次或两次。
最好的是，本发明中使用的组合物，作为单元剂量，含有6μg福莫特罗富马酸盐二水合物和200μg布地奈德，或4.5μg福莫特罗富马酸盐二水合物和160μg布地奈德，其中任意一种均可一天给药多达4次。此外，本发明组合物，作为单元剂量，含有12μg福莫特罗富马酸盐二水合物和400μg布地奈德，或9μg福莫特罗富马酸盐二水合物和320μg布地奈德，其中任意一种均可一天给药一次或两次。
按照本发明，进一步提供的是按照本发明的一种组合物的制备方法，包括
(a)使一种或多种强效药物活性物质和载体物质微粉化；
(b)任选地调理该产品；和
(c)球形化直至得到所希望的堆积密度。
本工艺在步骤(b)之后较好进一步包含一个低能量再微粉化步骤。
按照本发明的配方可以用本身已知的常用技术制作。这样的生产工艺一般包括使这些组分微粉化成所需要的粒度，用诸如WO92/18110或WO 95/05805中所述的方法除去所得到颗粒上的任何无定形区域，然后将所得到的粉末造粒、球形化和过筛。所得到团粒的粒度较好在100～2000μm的范围内，更好的是在100～800μm。所生产配方的堆积密度可以根据经验通过改变成分和工艺来调节，例如，可以通过延长颗粒在球形化装置中翻滚的时间来提高堆积密度。
在固-固混合中，最重要的特色之一是确保含量均匀。微细粉末的粉末混合中遇到的主要问题是混合机不能使粉末团粒破碎。已经发现，微细粉末调理步骤之后用低能量输入的再微粉化步骤是有利的。它一般应当用足以使粉末团粒破碎的能量进行，但不要用如此多的能量，以致影响颗粒本身的粒度。这样一个步骤给出一种组合物，其中，活性物质和载体物质大体上均匀分布，例如相对标准偏差小于3％(较好小于1％)，且不影响微细颗粒的结晶性。
按照本发明的配方可用任何已知干粉吸入器给药，例如该吸入器可以是单剂量或多剂量吸入器，还可以是一种呼吸驱动干粉吸入器，例如Turbuhaler(商品名)。本发明进一步提供按照本发明的组合物在制造用于治疗的药物方面的用途。按照本发明的组合物在治疗呼吸系统疾病，特别是气喘病方面是有用的。本发明也提供治疗受呼吸系统疾病困扰的病人的方法，该方法包括对患者施用治疗有效量的按照本发明的组合物。
下列实例说明，但不限制本发明。
实例1
0.0315份福莫特罗富马酸盐二水合物和2.969份乳糖一水合物在转鼓混合机(Turbula)中混合成均匀分布的混合物，然后以某一压力和适合于获得小于3μm粒度(用coulter计数计测得的质量平均直径)的进料速率将混合物送入螺旋喷射磨中进行微粉化。然后用WO95/05805中所公开的方法对微粉化后的颗粒进行处理，以除去其晶体结构中的非晶区域。然后将该粉末喂入双螺杆进料机(K-Tron)中使粉末聚集，在振动筛(0.5mm目径)中过筛，在圆周速度0.5m/s的旋转盘中进行球形化4分钟，然后再用同样的筛子过筛，随后再球形化6分钟，最后再过筛(目径1.0mm)，得到堆积密度为0.32g/ml的粉末。
实例2
重复实例1，但粉末在微粉化之后在螺旋喷射磨中在低压(约1巴)下再次进行微粉化，并作如下调整，即无需按WO 95/05805中所述方法处理颗粒这一步骤，得到堆积密度为0.32g/ml的粉末。
实例3
9份布地奈德和91份乳糖一水合物在约6～7巴压力下分别在螺旋喷射磨中单独进行微粉化，得到小于3μm的颗粒尺寸，然后在Turbula混炼机中充分混合。混合之前，乳糖一水合物粉末按WO 95/05805所述方法进行处理。混合物在仅约1巴的压力下在螺旋喷射磨中再次进行微粉化，以便得到均匀的混合物。然后按实例1所述方法使粉末聚集和球形化，得到0.35g/ml的堆积密度。
实例4
60份特布他林硫酸盐在Alpin磨100AFG中进行微粉化直至质量平均直径小于2μm，然后按US 5562923所述方法处理。40份乳糖一水合物微粉化至质量平均直径小于3μm，然后按WO 95/05805所述方法进行处理。经微粉化和处理后的特布他林硫酸盐和乳糖一水合物在Turbula混炼机中充分混合。混合物在螺旋喷射磨中在仅约1巴的压力下再次微粉化，得到均匀分布的混合物。然后按实例1所述方法使粉末聚集和球形化，得到0.28g/ml的堆积密度。
实例5
用30份特布他林硫酸盐和70份乳糖一水合物重复实例4，得到堆积密度为0.31g/ml的粉末。
实例6
5.2份福莫特罗富马酸盐二水合物和896.8份乳糖一水合物在转鼓混合机(Trubula)中混合成均匀分布的混合物，然后以某一压力和适合于获得小于3μm粒度(用coulter计数计测得的质量平均直径)的进料速率将混合物送入螺旋喷射磨中进行微粉化。然后用WO 95/05805中所述方法对微粉化后的颗粒进行处理，以除去其晶体结构中的非晶区域。加入98份微粉化布地奈德，混合物在低压下在螺旋喷射磨中再次微粉化，成为均匀混合物。然后将该粉末喂入螺杆进料机(K-Tron)中使粉末聚集，在振动筛(0.5mm目径)中过筛，在转速为23rpm的旋转盘中进行球形化10分钟，然后再过筛(0.5m目径)，再球形一次，最后再过筛(目径0.8mm)，得到堆积密度为0.34g/ml的粉末。
实例7
以同样的条件，但用5.2份微粉化的福莫特罗富马酸盐二水合物、798.8份微粉化的乳糖一水合物和196份微粉化的布地奈德重复实例6。所得到的堆积密度为0.34g/ml。

Claims (8)

1.一种干粉剂组合物，它包含
a)布地奈德，
b)福莫特罗和
c)一种选自单糖、二糖、多糖和糖醇的载体物质，
所有这些物质的质量中值直径均小于10μm，其中该组合物的注入堆积密度为0.28～0.38g/ml。
2.按照权利要求1的组合物，其中所述堆积密度是0.30～0.36g/ml。
3.按照权利要求1或2的组合物，其中所述布地奈德、福莫特罗和载体物质基本上是均匀分布的。
4.按照权利要求1或2的组合物，其中福莫特罗是福莫特罗富马酸盐二水合物。
5.按照权利要求1或2的组合物，其中所述载体物质是乳糖一水合物。
6.制备按照权利要求1的组合物的方法，该方法包括：
(a)使布地奈德、福莫特罗和载体物质微粉化；
(b)任选地调理该产品；和
(c)球形化直至得到所希望的堆积密度。
7.按照权利要求6的方法，该方法还包括在步骤(b)之后的低能量再微粉化步骤。
8.按照权利要求1～5中任何一项的组合物在制造用于治疗呼吸系统疾病的药物方面的用途。
CNB988019000A 1997-01-20 1998-01-13 注入堆积密度为0.28～0.38g/ml的吸入用新配方、该配方的制备方法及其用途 Expired - Lifetime CN1271993C (zh)

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CA2277913A1 (en) 1998-07-23
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EP1007017A1 (en) 2000-06-14
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EE9900295A (et) 2000-02-15
EP1007017B1 (en) 2005-02-02
PL334527A1 (en) 2000-02-28
US6287540B1 (en) 2001-09-11
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US6030604A (en) 2000-02-29
UA57764C2 (uk) 2003-07-15
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DE69828886D1 (de) 2005-03-10
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WO1998031352A1 (en) 1998-07-23
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IL130838A0 (en) 2001-01-28
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ES2235311T5 (es) 2011-03-31
IS5108A (is) 1999-07-06
AU5785998A (en) 1998-08-07
JP2001508793A (ja) 2001-07-03
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DE69828886T3 (de) 2011-06-01
AR011080A1 (es) 2000-08-02
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SK283950B6 (sk) 2004-05-04
HU228622B1 (en) 2013-04-29
DK1007017T3 (da) 2005-05-02
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JP4512204B2 (ja) 2010-07-28
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CN1243436A (zh) 2000-02-02
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