CN1195507C - 注入堆积密度为0.28～0.38g/ml的含有特布他林硫酸盐的吸入用新配方法、该配方的制备及其用途 - Google Patents
注入堆积密度为0.28～0.38g/ml的含有特布他林硫酸盐的吸入用新配方法、该配方的制备及其用途 Download PDFInfo
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- A61K9/0012—Galenical forms characterised by the site of application
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Abstract
一种干粉剂组合物，其中包含特布他林硫酸盐和一种载体物质，这两种物质都呈微细形式，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
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，其中包含特布他林硫酸盐和一种载体物质，这两种物质都呈微细形式，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。
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。
按照本发明的组合物配制成含有优选50μg～8mg，更优选100μg～4mg，最优选125μg～2mg特布他林硫酸盐的日剂量。更好是将该组合物配制成能提供125、250或500μg特布他林硫酸盐的单元剂量。该组合物配制成每单元剂量含有优选50μg～25mg，更优选50μg～10mg，最优选100～4000μg的载体物质。
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)将特布他林硫酸盐和载体物质进行微粉化；
(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
60份特布他林硫酸盐在Alpin磨100 AFG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0.28g/ml的粉末。
实例2
用30份特布他林硫酸盐和70份乳糖一水合物重复实例1，得到堆积密度为0.31g/ml的粉末。
Claims (6)
1.一种干粉剂组合物，其中包含
a)特布他林硫酸盐和
b)一种选自单糖、二糖、多糖和糖醇的载体物质，
其中活性物质和载体物质的质量中值直径小于10μm，且其中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，其中所述载体物质是乳糖一水合物。
4.制备按照权利要求1的组合物的方法，该方法包括：
(a)将特布他林硫酸盐和载体物质进行微粉化；
(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。
5.按照权利要求4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。
6.按照权利要求1～3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。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE97001366 | 1997-01-20 | ||
| SE9700136A SE9700136D0 (sv) | 1997-01-20 | 1997-01-20 | New formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1244120A CN1244120A (zh) | 2000-02-09 |
| CN1195507C true CN1195507C (zh) | 2005-04-06 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988019019A Expired - Fee Related CN1195507C (zh) | 1997-01-20 | 1998-01-13 | 注入堆积密度为0.28～0.38g/ml的含有特布他林硫酸盐的吸入用新配方法、该配方的制备及其用途 |
Country Status (30)
| Country | Link |
|---|---|
| EP (1) | EP1014955B1 (zh) |
| JP (1) | JP2001509812A (zh) |
| KR (1) | KR100528415B1 (zh) |
| CN (1) | CN1195507C (zh) |
| AT (1) | ATE263552T1 (zh) |
| AU (1) | AU728768B2 (zh) |
| BE (1) | BE1012009A5 (zh) |
| BR (1) | BR9806893A (zh) |
| CA (1) | CA2277891C (zh) |
| CZ (1) | CZ295665B6 (zh) |
| DE (1) | DE69823045T2 (zh) |
| EE (1) | EE03950B1 (zh) |
| ES (2) | ES2217535T3 (zh) |
| FR (1) | FR2759905B1 (zh) |
| GR (1) | GR980100023A (zh) |
| HU (1) | HUP0000755A3 (zh) |
| ID (1) | ID21929A (zh) |
| IE (1) | IE980026A1 (zh) |
| IL (1) | IL130839A (zh) |
| IS (1) | IS2072B (zh) |
| NL (1) | NL1008020C2 (zh) |
| NO (1) | NO993540L (zh) |
| NZ (1) | NZ336595A (zh) |
| PL (1) | PL189551B1 (zh) |
| RU (1) | RU2180562C2 (zh) |
| SE (1) | SE9700136D0 (zh) |
| SK (1) | SK283943B6 (zh) |
| TR (1) | TR199901689T2 (zh) |
| UA (1) | UA57765C2 (zh) |
| WO (1) | WO1998031353A1 (zh) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI991582A1 (it) | 1999-07-16 | 2001-01-16 | Chiesi Farma Spa | Polveri costituite da particelle aventi la superficie perfettamente levigata da utilizzare come veicoli per la preparazione di miscele inala |
| JP2001151673A (ja) * | 1999-09-06 | 2001-06-05 | Nikken Chem Co Ltd | 吸入用粉末製剤の製造方法 |
| GB0009469D0 (en) | 2000-04-17 | 2000-06-07 | Vectura Ltd | Improvements in or relating to formalities for use in inhaler devices |
| PE20011227A1 (es) | 2000-04-17 | 2002-01-07 | Chiesi Farma Spa | Formulaciones farmaceuticas para inhaladores de polvo seco en la forma de aglomerados duros |
| GB0012261D0 (en) * | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel process |
| SE0200657D0 (sv) * | 2002-03-04 | 2002-03-04 | Astrazeneca Ab | Novel Formulation |
| GB0219511D0 (en) | 2002-08-21 | 2002-10-02 | Norton Healthcare Ltd | Method of preparing dry powder inhalation compositions |
| EP1599209B1 (en) | 2002-08-21 | 2011-08-17 | Norton Healthcare Limited | Inhalation composition |
| DE102007049931A1 (de) | 2007-10-18 | 2009-04-23 | Pharmatech Gmbh | Vorrichtung und Verfahren zur kontinuierlichen Herstellung von sphärischen Pulveragglomeraten |
| EP2255807A1 (en) | 2009-05-26 | 2010-12-01 | Sanofi-Aventis | Method of treating sleep disorders using the combination of eplivanserin and zolpidem |
| US20110262502A1 (en) * | 2010-02-08 | 2011-10-27 | Prairie Pharmaceuticals LLC | Pulmonary delivery of 17-hydroxyprogesterone caproate (17-hpc) |
| GB201305825D0 (en) | 2013-03-28 | 2013-05-15 | Vectura Ltd | New use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0072046B1 (en) * | 1981-07-24 | 1986-01-15 | FISONS plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
| ATE17441T1 (de) * | 1981-07-24 | 1986-02-15 | Fisons Plc | Inhalierbare arzneimittel, verfahren zu deren herstellung und pharmazeutische formulierungen diese enthaltend. |
| IL111080A (en) * | 1993-10-01 | 1999-08-17 | Astra Ab | Method for treating a finely divided powder medicament |
| SE9603669D0 (sv) * | 1996-10-08 | 1996-10-08 | Astra Ab | New combination |
-
1997
- 1997-01-20 SE SE9700136A patent/SE9700136D0/xx unknown
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1998
- 1998-01-13 CZ CZ19992558A patent/CZ295665B6/cs not_active IP Right Cessation
- 1998-01-13 CA CA002277891A patent/CA2277891C/en not_active Expired - Fee Related
- 1998-01-13 ES ES98901619T patent/ES2217535T3/es not_active Expired - Lifetime
- 1998-01-13 RU RU99118586/14A patent/RU2180562C2/ru not_active IP Right Cessation
- 1998-01-13 AT AT98901619T patent/ATE263552T1/de not_active IP Right Cessation
- 1998-01-13 AU AU57860/98A patent/AU728768B2/en not_active Ceased
- 1998-01-13 HU HU0000755A patent/HUP0000755A3/hu unknown
- 1998-01-13 CN CNB988019019A patent/CN1195507C/zh not_active Expired - Fee Related
- 1998-01-13 UA UA99074045A patent/UA57765C2/uk unknown
- 1998-01-13 JP JP53421998A patent/JP2001509812A/ja not_active Ceased
- 1998-01-13 IL IL13083998A patent/IL130839A/en not_active IP Right Cessation
- 1998-01-13 WO PCT/SE1998/000041 patent/WO1998031353A1/en active IP Right Grant
- 1998-01-13 DE DE69823045T patent/DE69823045T2/de not_active Expired - Fee Related
- 1998-01-13 TR TR1999/01689T patent/TR199901689T2/xx unknown
- 1998-01-13 NL NL1008020A patent/NL1008020C2/nl not_active IP Right Cessation
- 1998-01-13 SK SK960-99A patent/SK283943B6/sk unknown
- 1998-01-13 EP EP98901619A patent/EP1014955B1/en not_active Expired - Lifetime
- 1998-01-13 EE EEP199900293A patent/EE03950B1/xx not_active IP Right Cessation
- 1998-01-13 KR KR10-1999-7006415A patent/KR100528415B1/ko not_active IP Right Cessation
- 1998-01-13 PL PL98334526A patent/PL189551B1/pl not_active IP Right Cessation
- 1998-01-13 BR BR9806893-8A patent/BR9806893A/pt not_active Application Discontinuation
- 1998-01-13 NZ NZ336595A patent/NZ336595A/xx unknown
- 1998-01-14 GR GR980100023A patent/GR980100023A/el not_active IP Right Cessation
- 1998-01-15 BE BE9800030A patent/BE1012009A5/fr active
- 1998-01-16 FR FR9800460A patent/FR2759905B1/fr not_active Expired - Fee Related
- 1998-01-16 IE IE980026A patent/IE980026A1/en not_active Application Discontinuation
- 1998-01-16 ES ES009800080A patent/ES2149083B1/es not_active Expired - Fee Related
- 1998-01-30 ID IDW990662A patent/ID21929A/id unknown
-
1999
- 1999-07-06 IS IS5107A patent/IS2072B/is unknown
- 1999-07-19 NO NO993540A patent/NO993540L/no not_active Application Discontinuation
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