CN100384408C - 新的组合物 - Google Patents
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Abstract
本发明涉及新的药物组合物,它可用于治疗呼吸道疾病如哮喘、鼻炎或慢性阻塞性肺病(COPD)。
Description
发明领域
本发明涉及一种含有福莫特罗或其对映体,糖皮质类固醇和载体或稀释剂,用于治疗发炎症/病症,尤其是呼吸系统疾病,例如哮喘、慢性阻塞性肺病和鼻炎的稳定粉末制剂。
发明背景
对于一种化合物或者化合物的混合物来说,能否将其开发成可用于治疗疾病的药物,其中最重要的因素之一就是它的稳定性。当将各种不同的成分混合成药物制剂时,存在有各成分之间相互作用的可能性。另外,每一种成分可能有不同的降解特性。
福莫特罗是一种高效的选择性β2-激动剂,吸入后的持续作用时间长。同其他的β-肾上腺素化合物相比,它有独特的化学结构,即在苯环上有甲酰氨基基团。由于在其分子中有两个不对称的碳原子,因此使得它可以构成四种不同的立体异构体。大多数的科学研究,不管是临床的还是临床前的,基本都是由R;R+S;S型的对映体混合物的延胡索酸盐(如二水化合物)来实现的。而R;R型的对映体是四种对映体中最有效的一种。
药物福莫特罗(如延胡索酸盐二水合物)的稳定性的可以通过研究像储存时间、温度、相对湿度、光线和pH值这些变量对福莫特罗的影响和确定色谱杂质的数量来进行评价。福莫特罗(延胡索酸盐二水合物)已经被证实即使在高温和高的相对湿度条件下长时间存储,仍然具有很好的稳定性。
可是,福莫特罗的化学结构使得当接触到比如反应物像醛或者是在压力条件下比如碾磨过程中时,分子容易发生化学降解。
通过吸入方式给药的强效药物一般都与诸如乳糖之类的载体/稀释液相结合,以便更容易地精确控制吸入计量。这些制剂一般由粗载体颗粒与细药物颗粒,也可以有用载体/稀释剂的细微颗粒一起构成,而这种组合方式一般称作有序混合。另一种制剂是将细小的药物和载体/稀释剂颗粒掺和附聚物。
福莫特罗(如延胡索酸盐二水合物)和碳水化合物例如乳糖(优选的是一水合物)各自都是很稳定的化合物,但是当两种混合物混合时会形成降解产物。福莫特罗延胡索酸盐二水合物和乳糖一水合物的混合物可以被认作是一种由福莫特罗延胡索酸盐二水合物、乳糖和水组成的三成分体系。通过水的吸附作用,饱和的水性乳糖溶液会在粉状混合物表面形成。一定量的福莫特罗延胡索酸盐溶解在这个水性溶液中并且因此容易降解。所以,相对湿度和存储温度将会影响到粉末混合物的稳定性。
当向混合物中加入第三种组分时,由于许多降解过程的复杂性和可能性,所以更有可能生成降解产物。所以需要开发一种,即使是具有化学反应功能的化合物,例如胺(福莫特罗),甲酰胺(福莫特罗),碳水化合物(例如乳糖等)和酮类功能(糖皮类固醇)复杂混合物也仍然具有很好稳定性的制剂。水合物的存在(福莫特罗延胡索酸盐二水化合物,乳糖一水合物)会使混合物更加复杂。
发明的描述
依照本发明,它提供了固体形式的药物组合物,它包含混合形式的第一种活性组分,它是被微粉化的福莫特罗或者是它的一种对映体;第一种活性组分,它是一种微粉化的糖皮质类固醇;和载体或稀释剂。该组合物具有很高的存储稳定性。
术语“高存储稳定性”意指当福莫特罗的含量低于约1.0%(w/w),优选低于0.8%(w/w),最好是0.6%(w/w)时,存储在40℃和相对湿度75%的开放器皿中六个月时,制剂中福莫特罗的分解应低于10%,或者福莫特罗在同样的条件下存储在干粉装置中时,它的分解低于约2.5%。
通过运用以下新的方法,可以得到具有理想稳定性的制剂:
1、制备微粉化的第一种活性组分和微粉化的载体/稀释剂的混合物;
2、任选地向混合物中加入更多的微粉化的载体/稀释剂;
3、加入并混合预微粉化疏水的第二种活性组分,该第二种活性组分任选地与微粉化的载体/稀释剂预先混合;和
4、要么将该混合物团聚并球状化,要么加入粗粒的载体/稀释剂。
依照步骤1,既可以通过将第一活性组分与载体/稀释剂混合后再微粉化,也可以通过将其各自先微粉化,再将其混合来制备第一种活性组合和载体/稀释剂。优选将两种成分一起混合再微粉化。
在步骤3中优选在进一步微粉化载体/稀释剂前,单独加入预微粉化的疏水的第二种活性组分。
步骤四优选使混合物团聚并球状化。
“微粉化”意指通过研磨形成预期的颗粒大小或者通过任何产生小颗粒的其它方式得到所需的颗粒大小例如直接沉淀。
混合物/组分可以任选地在该方法的任意适当的阶段进行调节,例如步骤1和2之间,及(或)在第2步加入前可以调节进一步预微粉化的载体/稀释剂,及(或)在第3步加入前可以调节进一步预微粉化的载体/稀释剂,及(或)可在步骤4的团聚和球状化之间调节混合物。
我们可以参照WO 95/05805中描述的方法来调节,也可以通过选样诸如相对湿度等的方法参数的方式来调节,这样如US 5,874,063所描述和测定的,只要物质平均颗粒小于10μm,最终的产品结合于水蒸气的时候,每克物质释放的热量小于1.2焦耳。
这项发明因此提供了一种固体形式的并且有高的贮存稳定性的药物制剂,它包含:混合形式的第一种活性组分,它是被微粉化的福莫特罗或者是它的一种对映体;第二种活性成分,它是微粉化的糖皮质类固醇;和载体或稀释剂。其特征在于该制剂是通过第一种活性成分和载体/稀释剂微粉化,进而任选地混入粗糙的预微粉化载体/稀释剂,混入微粉化疏水的第二种活性组分,并且最终要么使混合物团聚并球状化,要么加入粗粒载体/稀释剂来制备。
福莫特罗可以是对映体混合物的形式。优选是单一的对映体形式,优选是R,R的对映优选体。福莫特罗可以是游离碱基、盐或溶剂化物、或者是盐的溶剂化物的形式,福莫特罗优选是其延胡索酸盐二水化合物的形式。其它适宜的生理盐包括盐酸盐、溴氢酸盐、硫酸盐、磷酸盐、顺丁烯二酸盐、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、苯磺酸盐、抗坏血酸盐、醋酸盐、琥珀酸盐、乳酸盐、戊二酸盐、葡(萄)糖酸盐、tricaballate、hydroxynapaphthalenecarboxylate、或油酸盐。
第二种活性组分优选是微粉化糖皮质类固醇,例如省地奈德、氟替卡松丙酸盐、莫米松糠酸盐、ciclesonide和这些化合物的差向异构体、酯这些化合物的、盐和溶剂化物。第二种活性成分更优选布地奈德或它的差向异构体,最好是布地奈德的22R-差向异构体。
载体优选是有高度存储稳定性的碳水化合物,优选还原剂碳水化物,例如乳糖、葡萄糖、半乳糖、甘露糖、木糖、麦芽糖、纤维二糖、蜜二糖、麦芽三糖(例如一水合物)。载体更优选乳糖。
本文所用的术语微粉化载体/稀释剂是指平均颗粒大小小于25μm的载体/稀释剂,优选小于10μm,最好能小于5μm。微粉化载体能通过本领域已知的技术方法获得,例如微粉化或直接沉淀。术语粗质载体/稀释剂是指平均颗粒大小大于25μm的载体/稀释剂。
本文所用的术语微粉化的第一种活性组分或微粉化第二种活性组分是指活性组分平均颗粒大小小于10μm,优选小于5μm。
本发明药物组合物可以用于治疗或预防呼吸疾病,特别是治疗和预防哮喘,鼻炎或慢性阻塞性肺病。
更进一步地说,本发明提供了一种治疗呼吸性疾病的方法,特别是治疗和预防哺乳动物哮喘,鼻炎或慢性阻塞行肺病,此方法包括给予患者本文定义的药物组合物。
本发明的药品组合物可以通过喷雾器或压力流量计量吸入器吸入,或者以干粉的形式通过干粉吸入器(干粉末吸入器既可以是AstraZeneca或Schering-Plough的多计量储存系统,也可以是使用胶质、塑料或其它其它胶囊)、药筒或水泡包吸入。剂量取决于病症的严重程度和患者的类型。
本发明的方法显示在附图3中。
试验部分
以下的实施例将举例说明本发明,但并不是限制本申请的范围。在这些例子中,对每一种活性成分都进行了微粉化,以使微粒尺寸适于吸入给药。测定福莫特罗的降解产物是通过反相液体光谱法来实现的,选用了LiChrospher 60RP-select B的双柱系统,以5μm的正辛基硅烷颗粒为静态相位。UV探测器设在214nm。由于对降解产物不完全了解,因此以峰面积%来进行评估。
实施例1
下面的例子是一个以传统方式进行配制的参照实施例。
福莫特罗延胡索酸盐二水合物(26g)和乳糖一水合物(4.974kg)在翻滚混合器里混合1或2小时。将这个混合物在螺旋喷射研磨机机中微粉化以获得适合吸入的颗粒大小。将物质微粉化到低微米范围(1-5um)可能会对物质的结晶度产生干扰。无定型区域会因此产生,尤其是在微粉化物质的表面。这个物质形态学上的变化会增加其对湿度的敏感性,并且成为对稳定性问题产生影响的一种潜在的因素。物质混合的结晶结构按照一定的控制方式(参照US 5.874.063或者US 5.709.884)进行恢复。
为了改善粘着粉末的流动性,在室温、相对湿度控制在50%以下的条件下将其球化成团。
图1(A)是福莫特罗延胡索酸盐二水合物(5mg/g)/乳糖一水合物(995mg/g)微粉化的混合物存储在40℃、相对湿度75%的敞开器皿6个月的稳定性数据结果。
实施例2
下面的例子是一个对照例子,采用的传统方式来制备制剂形式。
实施例3
福莫特罗延胡索酸盐二水合物(0.2kg)和乳糖一水合物(34kg)在翻滚混合器中混合1或2小时。这个混合物在螺旋喷射器研磨机中微粉化以获得适合吸入的粒子尺寸。物质的结晶结构按照一定的约束控制(参照US 5.874.063或者US 5.709.884)进行恢复。再把所得产物同微粉化的布地奈德(3kg)一起在翻转搅拌器中混合30-60分钟。在第二步混合中,粉末被加入一个改进的螺旋喷射器研磨机,在高流动氮和很低的研磨压力的条件下运转。这样能在不导致粒子尺寸的进一步缩减(从而形成无定型区域结果使得稳定性降低)的情况下打碎大块,并且提高了布地奈德球化粉末分布的均一性。
为了改善粘着粉末的流动性,将其在室温、相对湿度控制在50%以下的条件下球化成团。
图1(B)是福莫特罗延胡索酸盐二水化合物(5mg/g)/布地奈备90mg/g)/乳糖一水化合物(905mg/g)微粉化的混合物储藏在40℃、相对湿度75%的敞开器皿6个月的稳定性数据结果。
实施例4
按照例3的方法,将微粉化和球化的福莫特罗延胡索酸盐二水化合物(5mg/g)/布地奈备(90mg/g)/乳糖一水化合物(905mg/g)填充到干粉装置Turbuhaler(AstraZeneca)中,储藏条件为40℃、相对湿度75%、6个月,测量结果见图2(B)。
Claims (7)
1.一种制备药物组合物的方法,其中所述组合物包含下述组分的混合物:第一种活性组分,它是被微粉化的福莫特罗或其盐、溶剂化物或其盐的溶剂化物;第二种活性组分,它是微粉化的糖皮质类固醇;和可药用载体/稀释剂;所述方法包括:
(a):制备微粉化形式的第一种活性组分与微粉化形式的第一部分载体/稀释剂的混合物;
(b):在步骤(a)的混合物中加入并混合预微粉化的第二种活性组分;和
(c):在步骤(b)之后加入第二部分粗质形式的载体/稀释剂以形成为有序混合物的组合物。
2.权利要求1的方法,还包括:
(d):在室温以上的温度储藏至少部分组合物至少一个月;和
(e):在步骤(d)后测试该组合物以测定该组合物中福莫特罗的分解程度。
3.权利要求2的方法,其中步骤(d)包含在至少40℃的温度下储藏所述组合物。
4.权利要求2的方法,其中步骤(d)还包含在至少75%的相对湿度储藏所述组合物。
5.权利要求2的方法,其中步骤(d)包含储藏所述组合物至少6个月。
6.权利要求2的方法,其中在步骤(c)后不进行微粉化步骤。
7.权利要求2的方法,其中所述福莫特罗在步骤(c)的组合物中的含量低于1.0%w/w。
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CNB018097863A Expired - Lifetime CN100384408C (zh) | 2000-05-19 | 2001-05-17 | 新的组合物 |
Country Status (22)
Country | Link |
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US (2) | US6869942B2 (zh) |
EP (3) | EP1289506B1 (zh) |
JP (3) | JP5663125B2 (zh) |
KR (1) | KR100799432B1 (zh) |
CN (1) | CN100384408C (zh) |
AT (2) | ATE274345T1 (zh) |
AU (2) | AU5900701A (zh) |
BR (1) | BR0110946A (zh) |
CA (1) | CA2409665C (zh) |
CY (1) | CY1110379T1 (zh) |
DE (2) | DE60105147T2 (zh) |
DK (2) | DK1289506T3 (zh) |
ES (2) | ES2223844T3 (zh) |
GB (1) | GB0012260D0 (zh) |
IL (1) | IL152470A0 (zh) |
MX (1) | MXPA02011311A (zh) |
NO (1) | NO333899B1 (zh) |
NZ (1) | NZ522420A (zh) |
PT (2) | PT1289506E (zh) |
SI (1) | SI1289506T1 (zh) |
WO (1) | WO2001089492A1 (zh) |
ZA (1) | ZA200208709B (zh) |
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AR028948A1 (es) | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | Compuestos novedosos |
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US20030055026A1 (en) | 2001-04-17 | 2003-03-20 | Dey L.P. | Formoterol/steroid bronchodilating compositions and methods of use thereof |
SE0200312D0 (sv) | 2002-02-01 | 2002-02-01 | Astrazeneca Ab | Novel composition |
GB0219511D0 (en) | 2002-08-21 | 2002-10-02 | Norton Healthcare Ltd | Method of preparing dry powder inhalation compositions |
GB0219512D0 (en) * | 2002-08-21 | 2002-10-02 | Norton Healthcare Ltd | Inhalation compositions with high drug ratios |
JP4744876B2 (ja) * | 2002-08-21 | 2011-08-10 | ノートン・ヘルスケアー リミテッド | 乾燥粉末吸入組成物の製造方法 |
EP1556018A1 (en) * | 2002-09-30 | 2005-07-27 | Acusphere, Inc. | Sustained release porous microparticles for inhalation |
US6962006B2 (en) * | 2002-12-19 | 2005-11-08 | Acusphere, Inc. | Methods and apparatus for making particles using spray dryer and in-line jet mill |
US20040121003A1 (en) * | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
GB0312148D0 (en) * | 2003-05-28 | 2003-07-02 | Aventis Pharma Ltd | Stabilized pharmaceutical products |
SE526509C2 (sv) * | 2003-06-19 | 2005-09-27 | Microdrug Ag | Kombinerade doser av formoterol och budesonid separerade på en gemensam dosbädd |
GB0315889D0 (en) | 2003-07-08 | 2003-08-13 | Aventis Pharma Ltd | Stable pharmaceutical products |
TWI359675B (en) | 2003-07-10 | 2012-03-11 | Dey L P | Bronchodilating β-agonist compositions |
GB0321607D0 (en) * | 2003-09-15 | 2003-10-15 | Vectura Ltd | Manufacture of pharmaceutical compositions |
CN1856296A (zh) * | 2003-09-30 | 2006-11-01 | 阿库斯菲尔公司 | 可注射的、口服、或局部用缓释药物制剂 |
GB0323684D0 (en) | 2003-10-09 | 2003-11-12 | Jagotec Ag | Improvements in or relating to organic compounds |
BRPI0416534A (pt) * | 2003-12-04 | 2007-01-09 | Pfizer Prod Inc | composições multiparticuladas com estabilidade melhorada |
US20050277602A1 (en) * | 2004-05-21 | 2005-12-15 | Grunstein Michael M | Methods employing agonists of P38 map kinase for the treatment of asthma |
GB0501956D0 (en) * | 2005-01-31 | 2005-03-09 | Arrow Internat | Nebulizer formulation |
RU2007133547A (ru) | 2005-02-10 | 2009-03-20 | Глаксо Груп Лимитед (GB) | Способы получения лактозы с использованием методов предварительной сортировки и приготовляемые из нее фармацевтические композиции |
EP1896002A4 (en) * | 2005-06-27 | 2009-11-25 | Biovail Lab Int Srl | BUPROPIONAL SALT FORMULATIONS WITH MODIFIED RELEASE |
JP4778053B2 (ja) | 2005-07-14 | 2011-09-21 | リセラ,インコーポレイテッド | 局所的脂肪組織処置のための徐放性増強脂肪分解処方物 |
TW200738634A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
TW200734305A (en) * | 2005-08-02 | 2007-09-16 | Astrazeneca Ab | New salt III |
TW200738635A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
MX2009004198A (es) * | 2006-10-17 | 2009-10-19 | Lithera Inc | Metodos, composiciones y formulaciones para el tratamiento de enfermedad ocular tiroidea. |
EP2022796A1 (en) * | 2007-08-07 | 2009-02-11 | Nycomed GmbH | Amorphous ciclesonide |
CN101474191B (zh) * | 2009-01-21 | 2011-03-23 | 李虎山 | 一种治疗哮喘和慢性阻塞性肺病的药物组合物 |
EP2221048A1 (en) * | 2009-02-18 | 2010-08-25 | Siegfried Generics International AG | Pharmaceutical composition for inhalation |
US9132084B2 (en) | 2009-05-27 | 2015-09-15 | Neothetics, Inc. | Methods for administration and formulations for the treatment of regional adipose tissue |
GB0918149D0 (en) | 2009-10-16 | 2009-12-02 | Jagotec Ag | Improved medicinal aerosol formulation |
GB2487868B (en) * | 2010-01-15 | 2014-12-10 | Neothetics Inc | Lyophilized cake formulations |
PT2538922T (pt) | 2010-02-25 | 2016-07-11 | Andi-Ventis Ltd | Formulação de composições para o tratamento de doenças inflamatórias |
EP2646012A4 (en) | 2010-11-24 | 2014-12-10 | Neothetics Inc | MONOTHERAPEUTIC FORMULATIONS OF SELECTIVE, LIPOPHILIC AND PROLONGED BETA AGONISTS AND METHODS OF COSMETIC TREATMENT OF SILHOUETTE ADPOSITY AND REINFORCEMENT |
WO2013091006A1 (en) * | 2011-12-23 | 2013-06-27 | Monash University | Process for dry powder blending |
UA118861C2 (uk) * | 2013-12-06 | 2019-03-25 | Оріон Корпорейшн | Спосіб отримання сухих порошкових композицій для інгаляцій |
WO2016052897A1 (en) * | 2014-09-30 | 2016-04-07 | Hanmi Pharm. Co., Ltd. | Dry powder for inhalation formulation having improved stability of combined active ingredients |
AU2020356243A1 (en) | 2019-09-24 | 2022-03-24 | Chiesi Farmaceutici S.P.A. | Novel carrier particles for dry powder formulations for inhalation |
WO2023128918A1 (en) * | 2021-12-31 | 2023-07-06 | Arven Ilac Sanayi Ve Ticaret Anonim Sirketi | A process including a feeding gas system for preparing dry powder inhalation compositions |
CN115364075B (zh) * | 2022-09-16 | 2023-11-10 | 苏州易合医药有限公司 | 一种吸入颗粒组合物及其制备方法 |
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US5874063A (en) * | 1991-04-11 | 1999-02-23 | Astra Aktiebolag | Pharmaceutical formulation |
DE69232462T2 (de) * | 1991-12-18 | 2002-10-10 | Astrazeneca Ab, Soedertaelje | Formoterol und budesonide enthaltende zusammensetzung |
SE9700134D0 (sv) | 1997-01-20 | 1997-01-20 | Astra Ab | New formulation |
SE9603669D0 (sv) * | 1996-10-08 | 1996-10-08 | Astra Ab | New combination |
AU722859B2 (en) * | 1996-11-11 | 2000-08-10 | Sepracor, Inc. | Process for the preparation of optically pure isomers of formoterol |
SE9703407D0 (sv) * | 1997-09-19 | 1997-09-19 | Astra Ab | New use |
SE9802073D0 (sv) | 1998-06-11 | 1998-06-11 | Astra Ab | New use |
IT1302657B1 (it) * | 1998-10-13 | 2000-09-29 | Farmabios Srl | Processo stereoselettivo per la preparazione di budesonide nella formadi epimero 22-r. |
NZ511527A (en) | 1998-11-13 | 2002-10-25 | Jago Res A | Dry powder for inhalation |
GB9903759D0 (en) | 1999-02-18 | 1999-04-14 | Novartis Ag | Organic compounds |
GB9904919D0 (en) | 1999-03-03 | 1999-04-28 | Novartis Ag | Organic compounds |
SE9900834D0 (sv) * | 1999-03-09 | 1999-03-09 | Astra Ab | Novel combination |
DE19947235A1 (de) * | 1999-09-30 | 2001-04-05 | Asta Medica Ag | Neue Kombination von Loteprednol und beta¶2¶-Adrenorezeptor-Agonisten |
PE20011227A1 (es) | 2000-04-17 | 2002-01-07 | Chiesi Farma Spa | Formulaciones farmaceuticas para inhaladores de polvo seco en la forma de aglomerados duros |
GB0009607D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medical compositions |
GB0009584D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Pharmaceutical compositions |
GB0009591D0 (en) | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medical combinations |
GB0012260D0 (en) * | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel composition |
-
2000
- 2000-05-19 GB GBGB0012260.6A patent/GB0012260D0/en not_active Ceased
-
2001
- 2001-05-17 EP EP01932485A patent/EP1289506B1/en not_active Expired - Lifetime
- 2001-05-17 PT PT01932485T patent/PT1289506E/pt unknown
- 2001-05-17 ES ES01932485T patent/ES2223844T3/es not_active Expired - Lifetime
- 2001-05-17 CN CNB018097863A patent/CN100384408C/zh not_active Expired - Lifetime
- 2001-05-17 KR KR1020027015535A patent/KR100799432B1/ko active IP Right Grant
- 2001-05-17 EP EP08150239A patent/EP1977740A1/en not_active Withdrawn
- 2001-05-17 CA CA2409665A patent/CA2409665C/en not_active Expired - Lifetime
- 2001-05-17 SI SI200130218T patent/SI1289506T1/xx unknown
- 2001-05-17 EP EP04007922A patent/EP1462100B1/en not_active Revoked
- 2001-05-17 AU AU5900701A patent/AU5900701A/xx active Pending
- 2001-05-17 DE DE60105147T patent/DE60105147T2/de not_active Expired - Lifetime
- 2001-05-17 MX MXPA02011311A patent/MXPA02011311A/es active IP Right Grant
- 2001-05-17 AT AT01932485T patent/ATE274345T1/de active
- 2001-05-17 ES ES04007922T patent/ES2298643T3/es not_active Expired - Lifetime
- 2001-05-17 IL IL15247001A patent/IL152470A0/xx active IP Right Grant
- 2001-05-17 WO PCT/SE2001/001118 patent/WO2001089492A1/en active IP Right Grant
- 2001-05-17 PT PT04007922T patent/PT1462100E/pt unknown
- 2001-05-17 AT AT04007922T patent/ATE385788T1/de not_active IP Right Cessation
- 2001-05-17 BR BR0110946-4A patent/BR0110946A/pt not_active Application Discontinuation
- 2001-05-17 DK DK01932485T patent/DK1289506T3/da active
- 2001-05-17 US US10/276,497 patent/US6869942B2/en not_active Expired - Lifetime
- 2001-05-17 DE DE60132828T patent/DE60132828T2/de not_active Revoked
- 2001-05-17 DK DK04007922T patent/DK1462100T3/da active
- 2001-05-17 JP JP2001585737A patent/JP5663125B2/ja not_active Expired - Lifetime
- 2001-05-17 AU AU2001259007A patent/AU2001259007B2/en not_active Expired
- 2001-05-17 NZ NZ522420A patent/NZ522420A/en not_active IP Right Cessation
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2002
- 2002-10-28 ZA ZA200208709A patent/ZA200208709B/en unknown
- 2002-10-31 NO NO20025221A patent/NO333899B1/no not_active IP Right Cessation
-
2005
- 2005-02-08 US US11/054,707 patent/US7354913B2/en not_active Expired - Lifetime
-
2008
- 2008-04-09 CY CY20081100387T patent/CY1110379T1/el unknown
-
2012
- 2012-07-06 JP JP2012152721A patent/JP2012184271A/ja active Pending
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2014
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Patent Citations (1)
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US6030604A (en) * | 1997-01-20 | 2000-02-29 | Astra Aktiebolag | Formulation for inhalation |
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