CN1257424A - 包含布地缩松细碎结晶颗粒的组合物 - Google Patents

包含布地缩松细碎结晶颗粒的组合物 Download PDF

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CN1257424A
CN1257424A CN98805338A CN98805338A CN1257424A CN 1257424 A CN1257424 A CN 1257424A CN 98805338 A CN98805338 A CN 98805338A CN 98805338 A CN98805338 A CN 98805338A CN 1257424 A CN1257424 A CN 1257424A
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M·比斯拉特
S·莫沙沙伊
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Abstract

本发明提供细碎的,实际上是结晶的布地缩松颗粒,其特征在于,它们实质上是匀滑的,BET值在1—4.5m2/g之间;本发明还提供了它们的制备方法,含有上述颗粒的药物组合物,上述颗粒在治疗呼吸疾病中的应用,以及在制造治疗呼吸疾病药物方面的应用;此外,本发明还包括供药给患者治疗呼吸疾病的方法。

Description

包含布地缩松细碎结晶颗粒的组合物
本发明提供布地缩松的细碎结晶颗粒及其制备方法。本发明也涉及含有上述颗粒的药物组合物，涉及上述颗粒在制备治疗呼吸疾病药剂方面的应用及其治疗作用，以及给需要治疗的患者供药以治疗呼吸疾病的方法。
布地缩松细碎颗粒在治疗中，是采用吸入法供药的，因此，希望药物颗粒能深透入肺内。这种细碎的药物颗粒，通常是采用微粉化或研磨技术来制备的。其它的一些制备技术也可能采用。那样一些技术，具体在微粉化中，产生的颗粒，具有无定形结构部分，不规则的形状，但一般地对于制备药物方面的应用都足够稳定。然而，这些颗粒在不利的环境下，倾向于改变它们的结构，如在贮存中(例如，高温度条件能引起它结块)或/和在病人服用时，通常发生这种情况。过去，无定形区域的问题，通过调节制备条件已得到克服，如WO 95/05805公开的那样，但是颗粒的不规则形状问题，仍然存在。颗粒形状很重要，因为不规则性的存在会增加颗粒结块的倾向，结果，它们在肺中就难以分散。对这些问题，现在找到了解决的办法。
按照本发明，此问题已经解块，其方法是通过提供细碎的实质上是结晶的布地缩松颗粒来解决的。这种颗粒的特征在于，它们是均匀流畅的，其表面积BET气体吸附值自1，优选自2到4.5m2/g，优选至3.6m2/g。
本发明严格限定的细小颗粒是有效吸入制剂的先决条件，可以这样来考察，例如，增加了到肺里的剂量份额。具有较低表面积的晶体比具有较高表面积的晶体，例如不规则晶体，的结块倾向低。
表面积的测量是采用BET气体吸附法，例如用美国Micromeritics公司的Flowsorb II 2300或者Gemini 2370，在ISO/TC24SC4N55(第7稿)，和其中参考文献中有介绍。
本发明的颗粒的匀滑程度，请见图1所示的本发明颗粒的电子扫描图(SEM)，该图是用JEOL扫描电镜JSM-5200观察到的。
本发明的细碎颗粒的平均直径(MMD)小于10μm为宜，优选的是小于5μm，更优选的是小于3μm。
本发明的颗粒，基本上都是结晶形式，优选的，其结晶形式占95％(重量百分)，实际上没有无定形区域。本发明晶体颗粒的结晶度示于X-光衍射图，见图2。本发明颗粒的重结晶能量以小于1.0J/g为宜，更优选的是小于0.5J/g，重结晶能量是采用ThermoMetric 227热活性监测器测量的。测量方法是将样品在25℃温度，94％相对湿度环境中，放置24小时，记录样品释放的热量。
本发明的细碎颗粒的制备，是将布地缩松在溶剂中的溶液和超临界流体同时导入一个装置中，控制其中的温度和压力，使得超临界流体作用下的分散和溶剂萃取作用，实际上同时发生。这样，活性物质布地缩松直接沉淀到具有所需要的物理化学性质的细小的，可吸入的颗粒上。一般说来，超临界流体是处于或高于它的临界压力和临界温度两者的流体，优选的是二氧化碳。
用以溶解布地缩松的溶剂，以有机溶剂为宜，例如丙酮或甲醇。方法优选采用公开于WO 95/01221的装置。
本发明的细碎颗粒，优选地用于治疗呼吸失调，例如哮喘病。本发明进一步提供了包含所发明的细碎颗粒的药物组合物，以及药用载体及稀释剂，例如乳糖。本发明还涉及所发明的细碎颗粒在制备用于治疗呼吸疾病医药方面的应用。
本发明的细碎颗粒，可能用于制备各种药物剂型，例如，制备口服的片剂，或装胶囊。然而优选把该细分颗粒用于吸入制剂。本发明的细碎颗粒。可能单独使用，也可与赋形剂混合使用，例如乳糖，这些赋形剂的颗粒比药物颗粒大些或相同。这样制备出来的粉末形式，可能用来装胶囊，例如Spinhaler，或者装入其它的吸入装置中，例如Turbuhaler，Rotahaler、Diskhaler或Diskus。本发明的细碎粉末、也能用已知的技术，作进一步的处理，例如，使之球形化，制成软的药丸，或者软颗粒，其强度足以填入容器内，而不致于离散开。但也不能太结实、当通过吸入法供药时，它又可以离散成细碎的颗粒。
下面例子用来阐明本发明，但不作为对本发明的限制。
                           例1
制备含有1.0％(W/V)布地缩松的丙酮溶液，通过0.15μm的喷咀，以0.3ml/min速度装入在WO 95/01221中描述的装置内。超临界二氧化碳的流速是10.0mL/min。工作条件是100巴和60℃。结果获得布地缩松的细的，匀滑的白色结晶粉末，产率88％，BET值3.6m2/g(用Germini 2375 V1.01测量)，颗粒度2.25μm(MMD)。粉末的电镜扫描图见图1。
                          例2
制备含有2.5％(W/V)布地缩松的丙酮溶液，以0.2mL/min速率，装入与例1相同的装置中。超临界二氧化碳的流速是9.0mL/min。工作条件是100巴和80℃。结果得到布地缩松的细的、匀滑的、白色结晶粉末，其X射线粉末衍射图见图2。
                          例3
制备含有1.0％布地缩松的丙酮溶液，通过0.35μm的喷咀，以1.5mL/min的流速装进在WO95/01221描述的装置中。超临界二氧化碳的流速是45mL/min。工作条件为100巴，60℃。结果得到布地缩松细的、匀滑的、白色结晶粉末，BET值2.0m2/g(用Gumini 2375 V1.01测量)，颗粒度4.62μm(MMD)，产率82％。
例4
制备含有2.5％布地缩松的丙酮溶液，通过0.35μm的喷咀，以1.5mL/min的流速装进WO 95/01221描述的装置中。超临界二氧化碳的流速是45mL/min。工作条件是100巴，80℃。结果获得布地缩松细的、匀滑的、白色结晶粉末，BET值为2.5m2/g(采用Gemini 2375 V1.01测量的)，颗粒度3.33μm(MMD)，产率83％。

Claims (10)

1.细碎的、实质上是结晶的布地缩松颗粒，其特征在于实际上是匀滑的，BET值在1-4.5m2/g之间。
2.按照权利要求1的细碎的颗粒，其特征在于BET值为2.0-3.6m2/g。
3.按照权利要求1或2的细碎颗粒，其特征在于其重结晶能量少于1J/g。
4.按照权利要求1，2或3的细碎颗粒，其特征在于颗粒的中值直径小于10μm。
5.按照上述各项权利要求的任一项的细碎的颗粒，是用于治疗呼吸疾病。
6.含有按照上述权利要求任一项的细碎颗粒与药用载体或稀释剂结合的药物组合物。
7.按照权利要求1-5中任一项的细碎颗粒，用于制备治疗呼吸疾病的药物。
8.治疗呼吸疾病的方法，包括给需要治疗的患者使用有效剂量的按照权利要求1-4任一项的细颗粒。
9.按照权利要求1-5任一项的细碎颗粒的制备方法，其特征在于，将布地缩松溶液与超临界流体，同时引入一个装置中，控制其温度和压力，以便在超临界流体作用下的分散作用和溶剂萃取过程实际上同时发生。
10.按照权利要求9的方法，其中超临界流体是二氧化碳。
CNB988053381A 1997-05-23 1998-05-15 包含布地缩松细碎结晶颗粒的组合物 Expired - Fee Related CN1146406C (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102975731A (zh) * 2012-04-24 2013-03-20 南车南京浦镇车辆有限公司 轨道车辆司机室骨架与车体的安装结构
CN102975731B (zh) * 2012-04-24 2015-08-12 南车南京浦镇车辆有限公司 轨道车辆司机室骨架与车体的安装结构

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PT1005328E (pt) 2003-11-28
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HUP0002212A3 (en) 2001-04-28
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NO995540L (no) 1999-11-12
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EP1005328A1 (en) 2000-06-07
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US6346523B1 (en) 2002-02-12
ES2205496T3 (es) 2004-05-01
CN1146406C (zh) 2004-04-21
TW518236B (en) 2003-01-21
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ATE246492T1 (de) 2003-08-15
US20020037257A1 (en) 2002-03-28
SE9701956D0 (sv) 1997-05-23
AU7680098A (en) 1998-12-11
KR20010012821A (ko) 2001-02-26
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IS5254A (is) 1999-11-18
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