CN1213732C - 用于加压计量吸入器的稳定药用溶液制剂 - Google Patents

用于加压计量吸入器的稳定药用溶液制剂 Download PDF

Info

Publication number
CN1213732C
CN1213732C CNB008195641A CN00819564A CN1213732C CN 1213732 C CN1213732 C CN 1213732C CN B008195641 A CNB008195641 A CN B008195641A CN 00819564 A CN00819564 A CN 00819564A CN 1213732 C CN1213732 C CN 1213732C
Authority
CN
China
Prior art keywords
compositions
solution
hfa
acid
jar
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CNB008195641A
Other languages
English (en)
Other versions
CN1452479A (zh
Inventor
D·李维斯
D·詹德顿
B·麦金
G·布拉姆比拉
A·费拉里斯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chiesi Farmaceutici SpA
Original Assignee
Chiesi Farmaceutici SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=8163952&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1213732(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Chiesi Farmaceutici SpA filed Critical Chiesi Farmaceutici SpA
Publication of CN1452479A publication Critical patent/CN1452479A/zh
Application granted granted Critical
Publication of CN1213732C publication Critical patent/CN1213732C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Otolaryngology (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种用于气溶胶吸入器的气溶胶溶液组合物，它包括一种活性原料、一种含有一种氢氟烷烃的助推剂、一种助溶剂和一种任选的提高吸入器启动时气溶胶颗粒的堆平均空气动力学直径(MMAD)的低挥发性成分。通过应用小量的无机酸和一种适宜的罐稳定此组合物，此罐具有部分或全部金属内表面，其内表面由不锈钢、阳极氧化铝制成或用一种惰性有机涂层衬里。

Description

用于加压计量吸入器的稳定药用溶液制剂
发明领域
本发明涉及与加压计量吸入器(MDIs)一起应用的稳定药用溶液，它适用于气溶胶给药。特别是，本发明涉及与加压计量吸入器(MDIs)一起应用的稳定药用溶液，它适用于含有β2-激动剂的气溶胶给药，并且在室温下在药物可接受的保存期限内是稳定的。
发明背景
已熟知加压计量吸入器是将药用产品通过吸入应用于呼吸道的装置。
通常通过吸入释放的药物包括诸如β2-激动剂和抗胆碱能剂的支气管扩张药、皮质类固醇类、抗-白三烯、抗-变应性药以及其它可通过吸入有效给药而提高治疗指数并减小活性原料副作用的其它原料。
MDI应用一种助推剂，将含有药用产品的小滴喷至呼吸道中，形成一种气溶胶。通过MDI用于气溶胶给药的制剂可以是溶液或悬浮液。溶液的优势在于它是均匀的，其活性成分和赋形剂完全溶解在助推剂载体或者它与诸如乙醇的适宜助溶剂的混合物中。溶液制剂也避免了与悬浮液制剂相关的物理稳定性难题，这样确保一致均匀的定量给药。
多年来在药物应用的气溶胶中应用的优选助推剂是一组含氯氟烃，它们通常称为氟利昂或CFC，诸如CCl3F(氟利昂11或CFC-11)、CCl2F2(氟利昂12或CFC-12)和CClF2-CClF2(氟利昂114或CFC-114)。
近来，推断诸如氟利昂11和氟利昂12等的含氯氟烃(CFC)助推剂对臭氧层造成破坏，它们的产品正在逐步停止使用。
氢氟烷烃[(HFAs)已知也可为氢-氟-碳(HFCs)]不含氯，并且认为它们对臭氧的破坏较小，并且提出这些可替代CFCs。
已经认识到HFAs，特别是1，1，1，2-四氟乙烷(HFA134a)和1，1，1，2，3，3，3-七氟丙烷(HFA227)是非CFC助推剂最佳的候选者，并且已经公开了大量应用这种HFA助推剂***的药用气溶胶制剂。
因为HFA助推剂的极性，特别是HFA134a的极性(介电常数D＞9.5)比CFC载体(D＜2.3)高，HFA溶液制剂与相应的CFC制剂相比可能遇到很多化学稳定性问题。
当涉及属于苯基烷基氨基衍生物的支气管扩张药β2-激动剂时，制备稳定的HFA溶液制剂是更关键的；所说的药物，如福莫特罗和沙丁胺醇(舒喘灵)，由于它们对氧化条件的敏感性，它们将面对固有的化学稳定性难题；而且考虑到某些象甲酰胺的官能基团的存在，此载体较高的极性可加速溶剂分解反应的速率。
就福莫特罗而言，目前市售的CFC溶液制剂(Foradil)的保存期确实有限，即冰箱温度4±2℃下12个月，室温下仅3个月。
对于沙丁胺醇而言，目前市场上尚无任何用于气溶胶给药的HFA溶液的制剂。
考虑到上述这些难题，提供一种通过MDI给药的HFA溶液形式的制剂，目的是提供药用剂量的β2-激动剂，特征是具有足够长的保存期，这样具有明显的优势。
发明内容
本发明的目的是提供一种HFA溶液形式的制剂，它是通过MDI给药、用于将药用剂量的β2-激动剂提供给肺病(诸如哮喘)患者的下呼吸道、特点是保存期足够长。特别是，本发明的目的是提供一种通过MDI给药的HFA溶液形式的制剂，该制剂用于提供药用剂量的福莫特罗，其保存期长于目前市售制剂的保存期。
按照本发明，将提供一种药用组合物，它包括在一种液体HFA助推剂、一种选自药物可接受醇的助溶剂中含有属于苯基烷基氨基衍生物类的一种β2-激动剂，通过加入少量的无机酸已将此溶液表观pH值调节至2.5至5.0之间。将本发明组合物装入一种加压MDI中，此MDI具有部分或全部金属内表面，它由不锈钢、阳极氧化铝制成或用惰性有机涂层衬里。
事实上已经发现，对某些诸如β2-激动剂的活性成分而言，通过一种适宜的、罐的种类和表观pH范围的联合选择，可显著地提高它们在HFA溶液制剂中的化学稳定性。应用属性“表观”是因为pH值确实是水为主要组分(摩尔分数＞0.95)的含水液体的特性。在相对质子惰性溶剂诸如这些研究中所用的HFA-乙醇载体中，质子是非水合的；它们的活性系数明显与含水溶液中的系数不同。尽管采用与EMF相关的Nernst等式，而且按照质子浓度和载体极性，pH计玻璃电极***将产生一个可变的毫伏输出，pH计读数不是一个真实的值。此pH计读数代表一个表观pH或酸度函数(pH’)。
当在一种市售模型载体***中(HFA 43-10MEE，Vertrel XF，Dupont)用一种强酸滴定活性成分时，此pH’曲线表现一个浅负值，至pH’＝5.5；此后酸度函数急剧下降。令人意外的是，相应的HFA制剂在pH’5.5以下更稳定。
另一方面，应用惰性容器可避免由于此制剂中所含的酸作用于容器内壁而发生的金属离子或碱的浸出。分别来源于常规铝或玻璃罐的诸如Al3+的金属离子或碱反过来可催化活性成分的自由基氧化或其它化学反应，这可引起降解产物的形成。
按照本发明的一个特别实施方式，也提供了另外还含有一种低挥发性成分的药用组合物，通过这种方式，除了可在开动吸入器的时候增加此气溶胶颗粒的堆平均空气动力学直径(MMAD)(此在下面进行说明)，而且还可提高此制剂的稳定性。事实上，加入诸如一种酯的其具有比助溶剂的极性低的低挥发性成分，既可减少调节pH的酸的加入量，也可减小介质的极性，这样可限制环境水可能的摄取。对于诸如福莫特罗的活性成分，已熟知后者(例如湿度)可损害贮存期间活性成分的稳定性。因此，还提供了一种用于药用定量给药的加压MDI，它由装有药用组合物的一种阳极氧化铝容器组成，此药用组合物由一种在HFA134a中的福莫特罗延胡索酸酯溶液组成，在此HFA134a充当一种助推剂，它依次含有充当助溶剂的12％w/w乙醇和充当低挥发性成分的1.0％w/w异丙基十四酸酯，加入少量盐酸已将所述溶液的表观pH调节至3.0和3.5之间。％w/w”的表达是指成分与此组合物总重量的重量百分比。
可以预言置于本发明装置中的制剂的保存期在冰箱温度下(4-10℃)大于2年，在室温下大于3个月。
本领域的熟练技术人员可采用本发明的方法容易地制备含有其它活性成分的HFA溶液制剂，这些活性成分具有对水解和/或氧化反应敏感的官能基团，分别例如甲酰胺和cathecol。
WO97/47286、EP513127、EP504112、WO93/11747、WO94/21228、WO94/21229、WO96/18384、WO96/19198、WO96/19968、WO98/05302、WO98/34595和WO00/07567公开了悬浮液形式的HFA制剂，其中的β2-激动剂例如福莫特罗和沙丁胺醇，被列举和/或要求了保护。
WO99/65464提出了含有两个或多个活性成分的HFA制剂，其中至少1个为悬浮液形式。优选的制剂在悬浮液中含有硫酸沙丁胺醇。
在WO98/34596中，申请人描述了在一种气溶胶吸入器中应用的溶液组合物，它包括一种活性原料，一种含有氢氟烷烃(HFA)的助推剂，一种助溶剂，并且还包括一种低挥发性成分，以增加吸入器开动时气溶胶颗粒的堆平均空气动力学直径(MMAD)。所述申请没有处理活性成分化学稳定性的技术难题，相反它只涉及药物至肺的传输。
在99年11月23日提交的国际申请PCT/EP99/09002中，申请人公开了用于一种活性成分的分配溶液的加压MDI，此活性成分在一种氢氟碳助推剂、一种助溶剂和可选的一种低挥发性成分中，其特征是所述吸入器的部分或全部内表面由不锈钢、阳极氧化铝组成，或者用惰性有机涂层衬里。所涉及的实例仅为类固醇和抗胆碱能剂，而没有预见任何酸化溶液。如本申请实施例1中所说明的，应用涂层容器，甚至在一种有机酸存在的情况下，也不足以提供一种诸如沙丁胺醇的苯基烷基氨基衍生物稳定的溶液制剂。
EP673240提出将酸用作稳定剂，以防止含有HFA的气溶胶溶液制剂中活性成分的化学降解。大多数实例涉及异丙托溴铵，它是一种抗胆碱能药物，而仅有一个实例是关于β2-激动剂，即非诺特罗。没有提出任何沙丁胺醇的例证制剂。从此申请的实施例1所报告的数据可清楚的得出加入有机酸并不能使沙丁胺醇稳定，甚至将其贮存在涂层罐中时也如此。而且，除了异丙托溴铵以外，在EP673240中没有对必须加入以稳定药物而不损害罐中整个组合物的稳定性的酸用量进行指导。可在第5页15至16行发现仅有的暗示：加入的无机酸的量应当使pH值为1至7，这是一个非常宽泛和一般性的范围。
WO98/34596涉及含有一种助推剂和一种生理可接受的聚合物的溶液制剂，此聚合物可有助于活性成分的增溶和稳定性。
WO00/06121涉及悬浮液和溶液气溶胶制备中的气溶胶一氧化二氮和一种氢氟烷烃的助推剂混合物。应用一氧化二氮可提高贮存中氧化敏感的活性成分的稳定性。对于β2-激动剂而言，诸如硫酸左旋沙丁胺醇、福莫特罗延胡索酸酯和沙美特罗xinafoate，仅报道了涉及悬浮液的实例。
WO99/65460对含有悬浮液或溶液形式的一种β2-激动剂的稳定制剂的加压MDI要求了保护。实例涉及的福莫特罗延胡索酸酯溶液包括一种HFA助推剂和充当助溶剂的乙醇，它们装在常规铝或塑料涂层玻璃罐中。
在加速条件(40℃，75％相对湿度)下贮存很短时间(1个月)的样品丧失约10％的药物。按照药用稳定性原则，10％活性成分的丧失不符合可接受的标准。而且，从该申请实施例2所报告的数据可明显地的看出，WO99/65460的方法不能提供稳定的福莫特罗溶液制剂。申请人确实已经证明低挥发性成分实质上没有影响此组合物的化学稳定性。在某些情况下，它们甚至可能会促进它。
按照本发明的另一个方面，提供一种将本发明的组合物装入气溶胶吸入器的方法，此方法包括：
(a)制备一种溶于一个或多个助溶剂中的一个或多个活性成分的溶液，可任选含有适宜量的低挥发性成分，
(b)将所述溶液装入此装置，
(c)加入预定量的强无机酸，
(d)加入一种含有氢氟烷烃(HFA)的助推剂，
(e)卷曲阀门，并充气。
可用于本发明气溶胶组合物的活性成分是短效和长效β2-肾上腺素能激动剂，诸如沙丁胺醇、福莫特罗、沙美特罗、TA-2005、它们的盐以及它们与类固醇的组合，类固醇例如为二丙酸倍氯米松、丙酸氟替卡松、布***及其22R-差向立体异构体。具有对氧化和/或水解反应敏感的官能基的其它氨基类型的药物，可以应用。
优选将此组合物装入阳极氧化的铝罐中。也可应用适宜的涂层装置。
可优选应用装配氯丁二烯橡胶制成的垫圈的计量阀，以减少水分的进入，如前所述，这些水分对贮存期间的药物可产生不良影响。可选择地，将此产品包装在一个密封的铝箔袋中可进行进一步保护。
氢氟碳助推剂，优选选自HFA134a、HFA227及其混合物。
助溶剂通常为一种醇，优选乙醇。
当存在低挥发性成分时，其在25℃下的蒸汽压小于0.1kPa，优选小于0.05kPa。低挥发性成分，可选自乙二醇，特别是丙二醇，聚乙二醇和丙三醇，酯例如抗坏血酸棕榈酸酯，十四酸异丙酯和生育酚酯。
本发明组合物中所述低挥发性成分的含量可以为0.2至10％w/w，优选为0.5至2.0％w/w。
丙二醇、聚乙二醇、丙三醇和酯为优选的低挥发性成分。
低挥发性成分的作用是调节气溶胶颗粒的MMAD，并优选进一步提高此制剂的稳定性。对于后一方面，特别优选应用异丙基十四酸酯。
表观pH范围在2.5至5.0之间是有利的，优选在3.0至4.5之间，更优选在3.0至3.5之间。优选应用诸如盐酸、硝酸、磷酸的强无机酸调节表观pH值。
将在前面报告的模型载体中预测达到需要的表观pH所要加入酸的量，该量依赖于活性成分的类型和浓度。在福莫特罗的条件下，优选加入3至3.5μl的1.0M的盐酸。
附图简述
图1显示在含有20％w/w乙醇的Vertrel XF/HFA中盐酸对福莫特罗延胡索酸酯溶液(12μg/100μl)的酸度函数(pH1)的影响。
图2显示在含有12％w/w醇的Vertrel XF/HFA中盐酸对福莫特罗延胡索酸酯溶液(12μg/100μl)的酸度函数的影响。
具体实施方式
下面的实施例将对本发明作进一步的说明。
实施例1
沙丁胺醇(100μg/剂)-HFA134a溶液本身和在不同有机酸存在情况下的稳定性
将在HFA134a中含有24mg沙丁胺醇(100μg/剂)、10-20％(w/w)乙醇的组合物放入12ml涂有环氧酚树脂的罐中，加或不加不同的有机酸，将此组合物在40-50℃下贮存。
稳定性的结果用剩余药物的百分率表示，通过HPLC进行测定，结果显示在表1中。
                            表1
                       ％沙丁胺醇
酸   t＝42天     t＝1.5月，在4℃下
无油酸Xinafoic柠檬酸(0.41w/w)柠檬酸(0.02w/w)30％乙酸(0.4％w/w)30％乙酸(0.14％w/w)   69％69-70％70％----     ---40.055.149.673.8
结果显示即使应用涂层的罐，加入有机酸也没有提高沙丁胺醇的稳定性。
实施例2
环氧酚树脂涂层罐中福莫特罗(12μg/100μl)-HFA134a组合物的稳定性
将1.44mg福莫特罗延胡索酸酯溶解在HFA134a中，其中分别含有15％w/w乙醇和1.3％w/w丙三醇，通过这样制备溶液制剂。将pMDIs在4-50℃下垂直贮存达28天。通过HPLC测定福莫特罗的含量，并与12μg/颗粒标准剂相比计算剩余浓度百分率。剩余福莫特罗浓度百分率显示在表2中。应用导出的Arrhenius参数估计环境温度下(18-25℃)的速率常数，并将溶液贮存在一个家用冰箱中(4-10℃)；这些速率常数用于计算福莫特罗5％降解和10％降解的预测保存期(表3)。
表3中计算的保存期数据提示福莫特罗在这种HFA134a-乙醇-丙三醇载体中是不稳定的。
表2：福莫特罗-HFA134a pMDI溶液(12μg/100μl)的降解速率数据
载体：HFA134a，含有1.3％w/w丙三醇、15.0％w/w乙醇
在环氧酚涂层罐中垂直贮存
    时间(天)                         福莫特罗剩余浓度百分率
    50℃     43℃     40℃     25℃     4℃
    起始24671012141618202428     99.792.587.280.6-74.972.167.064.459.559.554.647.2     99.7-89.4---79.4-75.7-74.568.663.3     99.7---89.0--81.7----71.3     99.7------92.0----86.6     99.7-----------96.7
    r速率常数(天-1×102)     0.9952.53     0.9891.49     0.9931.17     0.9970.51     -0.11
    Arrhenius绘图参数：K＝AeE/RTA＝2.28×106天-1：E＝49.4kJmol-1；r＝0.9985
表3：预测的福莫特罗-HFA134a pMDI溶液(12μg/100μl)的保存期
载体：HFA134a，含有1.3％w/w丙三醇、15％w/w乙醇
在环氧酚涂层罐中垂直贮存
温度4℃10℃20℃25℃     速率常数(天-1×103)1.101.743.514.93     保存期(天)t10％95603021 t5％47291510
实施例3
盐酸对溶液pH’(酸度函数)的影响
(a)将1.0M盐酸增量地加入含有20％w/w乙醇的50ml HFA43-10MEE(Vertrel XF)中，并在每次加入等份酸后测定pH’。附图1显示所得滴定曲线，它是用一个pMDI罐(12ml)常用填充量进行标准化的。pH’曲线显示一种浅的负性斜率，至pH’约为5.5。此后，酸度函数急剧下降。
(b)用含有较低浓度乙醇(12％w/w)的福莫特罗制剂重复试验(a)，并加入1.0％异丙基十四酸酯。所得重现批量溶液的pH曲线显示在附图2中，其形状与每单位增量的酸pH’的急剧下降相似，也是在大约pH’＝5.5时开始。但是，获得相同pH’的下降，仅需要大约一半的酸。这主要是因为乙醇含量的减小；附图2还显示加入异丙基十四酸酯和不加它所获得的曲线是相似的。
实施例4
pH’对含有20％w/w乙醇的在HFA43-10MEE中的福莫特罗溶液的影响
将等份1.0M盐酸加入玻璃管形瓶中的12ml福莫特罗溶液中。测定其pH后，卷曲阀门，在50℃下将管形瓶直立进行贮存。贮存10和20天后，分析含有不同浓度酸的管形瓶样品的剩余福莫特罗。贮存40天后，测定第3个小瓶的pH’。所得结果显示在表4中。表4显示贮存后pH的变化；这可能主要与碱从小瓶的软玻璃中浸出有关。但是，对pH’和福莫特罗含量数据整体考虑提示，加入无机酸将制剂的pH’调整至2.5-5.0之间，通过这样可提高此药物在HFA中的溶液制剂的稳定性。
表4：福莫特罗-Vertrel XF/HFA溶液(12μg/100μl)的pH’和福莫特罗含量
载体：含20％乙醇和盐酸的Vertrel XF/HFA
St Gobain玻璃管形瓶直立贮存
    酸度函数(pH’)     剩余福莫特罗浓度百分率
    起始     40天     起始     10天     20天
    1.8     2.8     100     4.8     无
    2.1     4.4     100     75.1     70.7
    2.6     4.2     100     97.2     86.7
    3.3     4.2     100     97.1     89.9
    5.6     6.6     100     95.8     92.1
    7.4     6.7     100     85.4     67.2
实施例5
阳极化罐中酸化福莫特罗-HFA134a溶液的稳定性
将1.44mg福莫特罗延胡索酸酯溶解在含有12％w/w乙醇的HFA134a中，其中含有或不含1.0％w/w异丙基十四酸酯，通过这样制备福莫特罗制剂(12μg/100μl)。后者可作为一种非挥发性赋形剂，如果需要，它可潜在地提高MMAD。与加入丙三醇相比，它也可提高载体中福莫特罗的溶解度，并降低此载体的极性。
将含3.1-3.4μl 1.0M盐酸的pMDI罐贮存在4℃至50℃下，直立或倒置，并间隔适当的时间抽取样品分析福莫特罗含量。
贮存70天后获得的稳定性数据显示在表5中。
在含有12.0％w/w乙醇的HFA134a中制备一种含有1.44mg(12μg/100μl)福莫特罗延胡索酸酯的制剂基质，其中可含或不含充当非挥发性赋形剂的1.0％w/w异丙基十四酸酯。将等份药物浓缩物转移至阳极化罐中，并在卷曲50μl阀门和充气前加入3.15-3.35μl 1.0M盐酸，制备每个酸强度下的22和28个复制品。
为测定剩余福莫特罗，将30×50μl颗粒排出至DUSA试管中。选择酸的范围，希望将pH’值调整至3.0-3.5，并期望测定此制剂对酸浓度小变化的稳定性。将罐直立和倒置(阀门分别向上和下)放置在25-50℃下贮存。
表5显示贮存11-40天后40和50℃下获得的结果。每个值(表示为标准药物浓度百分率)是从不同的罐中获得的。
起始值是从每种酸强度的2个罐中获得的。数据的检查表明所有分析值符合HPLC的重现性，并且不依赖于酸的强度。贮存时间点的复制品得出相似的结论，即不依赖酸强度(3.2-3.3μl)，或者不论罐直立或倒置。最后，起始(n＝10)和后续时间点(n＝6)的均值用于动力学计算。
在表6中报告了4、10和25℃下的Arrhenius参数以及估计的保存期。预计t5％在环境温度下大于3个月，在4℃下约为2年。
表5：含12.0％乙醇±1.0％异丙基十四酸酯的HFA134a中的福莫特罗延胡索酸酯溶液(12μg/100μl)的稳定性数据(值表达为标准百分率)
装有50μl阀门的阳极化罐/每罐收集30剂
评价每个条件下不同的罐
罐直立贮存(*倒置)
  1.0M盐酸μl/罐                        贮存条件/无异丙基十四酸酯
起始第1罐    第2罐 40℃；40天第1罐    第2罐 50℃；11天第1罐   第2罐 50℃；33天第1罐   第2罐
    3.153.203.253.303.35   99.8     99.6100.8    99.797.9     98.897.3     98.9100.0    98.3   -        -96.0     93.2*93.9     94.3*93.7     93.7*-        -   -       -96.7    96.596.4    96.597.0    89.1-       -   -       -88.5    89.9*92.2    91.590.9    92.8*-       -
    均值C.V.        99.11.1％       94.11.0％        95.43.2％       91.01.8％
  1.0M盐酸μl/罐                            贮存条件/1.0％异丙基十四酸酯
起始第1罐    第2罐 40℃；33天第1罐   第2罐 50℃；11天第1罐   第2罐 50℃；31天第1罐   第2罐
    3.153.203.253.303.35   101.1    99.397.0     100.2101.4    100.299.9     100.899.2     97.2   -       -94.4    93.2*98.6    95.0*92.8    95.3*-       -   -       -93.8    93.696.1    95.995.6    95.7-       -   -       -90.6    92.7*91.6    89.7*90.0    89.6*-       -
    均值C.V.       99.61.5％       94.92.2％       95.11.2％       90.71.4％
表6：含12％w/w乙醇±1.0％w/w异丙基十四酸酯(IPM)的HFA134a中酸化福莫特罗延胡索酸酯溶液(12μg/100μl)的预测保存期阳极氧化铝罐
    时间(天)                  福莫特罗延胡索酸酯(标准百分率)
无IPM                   1％IPM             40℃无IPM                        1％IPM
    011313340     99.195.4-91.0-     99.695.190.7--     99.1---94.1     99.6--94.9-
  速率常数(天-1×103) 2.52 2.94 1.29 1.46
  Arrhenius参数                      频率因子(天-1)                     活化能(KJ mol-1)无IPM                                3.19×106                              56.31％ w/w IPM                          9.63×106                              58.9
    温度4℃10℃25℃               无IPM速度常数      t10％  t5％(天-1)              (天)           1.0％w/w IPM速度常数       t10％  t5％(天-1)              (天)
 7.8×10-5   1344    6571.3×10-4   802     3924.4×10-4   240     117  7.8×10-5    1360    6641.3×10-4    789     3864.4×10-4    225     110

Claims (9)

1、一种气溶胶组合物，它在一种液化HFA助推剂、一种乙醇作为助溶剂的溶液中含有选自福莫特罗或TA-2005及其盐的苯基烷基氨基衍生物的β2激动剂药物，此药物具有对氧化和/或水解反应敏感的官能基，其中通过加入少量选自盐酸，硝酸或磷酸的无机酸将该溶液的表观pH调节为2.5-5.0。
2、权利要求1的组合物，其中此溶液的pH已调节为3.0至3.5。
3、权利要求1或2的组合物，其中此溶液包括一种低挥发性成分，其蒸气压在25℃不大于0.1kPa。
4、权利要求3的组合物，其中所述蒸气压在25℃不大于0.05kPa。
5、权利要求3的组合物，其中低挥发性成分至少为此溶液重量的0.2％，并且不大于10％。
6、权利要求3的组合物，其中低挥发性成分选自乙二醇或一种酯。
7、权利要求3的组合物，其中低挥发性成分为异丙基十四酸酯。
8、权利要求1或2的组合物，其中助推剂包括一个或多个HFA，它选自HFA 134a和HFA 227。
9、一种用于气溶胶给药的加压计量吸入器，它由一种具有部分或全部金属内表面的容器组成，其内表面由不锈钢、阳极氧化铝制成或用一种惰性有机涂层衬里，容纳有权利要求1-8任一项的组合物。
CNB008195641A 2000-05-22 2000-05-22 用于加压计量吸入器的稳定药用溶液制剂 Expired - Lifetime CN1213732C (zh)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2000/004635 WO2001089480A1 (en) 2000-05-22 2000-05-22 Stable pharmaceutical solution formulations for pressurised metered dose inhalers

Publications (2)

Publication Number Publication Date
CN1452479A CN1452479A (zh) 2003-10-29
CN1213732C true CN1213732C (zh) 2005-08-10

Family

ID=8163952

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB008195641A Expired - Lifetime CN1213732C (zh) 2000-05-22 2000-05-22 用于加压计量吸入器的稳定药用溶液制剂

Country Status (41)

Country Link
US (3) US6716414B2 (zh)
EP (4) EP1466594B1 (zh)
JP (1) JP5392880B2 (zh)
CN (1) CN1213732C (zh)
AR (1) AR029523A1 (zh)
AT (4) ATE502624T1 (zh)
AU (2) AU5070100A (zh)
BE (1) BE2011C032I2 (zh)
BG (1) BG65883B1 (zh)
BR (1) BR0015884A (zh)
CA (1) CA2411047C (zh)
CY (6) CY1108833T1 (zh)
CZ (1) CZ303833B6 (zh)
DE (5) DE60144304D1 (zh)
DK (4) DK1466594T3 (zh)
DZ (1) DZ3358A1 (zh)
EA (1) EA005179B1 (zh)
EE (1) EE05167B1 (zh)
ES (4) ES2318217T3 (zh)
FR (1) FR11C0041I2 (zh)
HK (1) HK1058900A1 (zh)
HR (1) HRP20021025B1 (zh)
HU (2) HU230804B1 (zh)
IL (2) IL152955A0 (zh)
JO (1) JO2310B1 (zh)
LT (1) LTC1787639I2 (zh)
LU (1) LU91875I2 (zh)
ME (2) ME00220B (zh)
MX (1) MXPA02011414A (zh)
MY (2) MY127145A (zh)
NL (1) NL300393I2 (zh)
NO (3) NO342935B1 (zh)
PE (1) PE20011323A1 (zh)
PT (4) PT1787639E (zh)
SA (1) SA01220126B1 (zh)
SI (4) SI1157689T1 (zh)
SK (1) SK286694B6 (zh)
TN (1) TNSN01074A1 (zh)
TW (1) TWI284047B (zh)
UA (1) UA73986C2 (zh)
WO (1) WO2001089480A1 (zh)

Families Citing this family (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010031244A1 (en) * 1997-06-13 2001-10-18 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition
DZ2947A1 (fr) * 1998-11-25 2004-03-15 Chiesi Farma Spa Inhalateur à compteur de dose sous pression.
IT1303788B1 (it) * 1998-11-25 2001-02-23 Chiesi Farma Spa Formulazioni di aerosol medicinali.
US6315985B1 (en) * 1999-06-18 2001-11-13 3M Innovative Properties Company C-17/21 OH 20-ketosteroid solution aerosol products with enhanced chemical stability
ES2165768B1 (es) 1999-07-14 2003-04-01 Almirall Prodesfarma Sa Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen.
IT1313553B1 (it) 1999-07-23 2002-09-09 Chiesi Farma Spa Formulazioni ottimizzate costituite da soluzioni di steroidi dasomministrare per inalazione.
ES2234694T3 (es) * 1999-11-23 2005-07-01 Glaxo Group Limited Formulaciones farmaceuticas de salmeterol.
IT1317720B1 (it) * 2000-01-07 2003-07-15 Chiesi Farma Spa Dispositivo per la somministrazione di aerosol dosati pressurizzati inpropellenti idrofluoroalcani.
IT1318514B1 (it) * 2000-05-12 2003-08-27 Chiesi Farma Spa Formulazioni contenenti un farmaco glucocorticosteroide per iltrattamento di patologie broncopolmonari.
US20060257324A1 (en) * 2000-05-22 2006-11-16 Chiesi Farmaceutici S.P.A. Pharmaceutical solution formulations for pressurised metered dose inhalers
SK286694B6 (sk) * 2000-05-22 2009-03-05 Chiesi Farmaceutici S.P.A. Aerosólový farmaceutický prostriedok
AU5858501A (en) * 2000-05-23 2001-12-03 Glaxo Group Ltd Aerosol container for formulations of salmeterol xinafoate
FI20002177A0 (fi) * 2000-10-02 2000-10-02 Orion Yhtymae Oyj Uusi yhdistelmä astman hoitoon
EP1241113A1 (en) 2001-03-12 2002-09-18 CHIESI FARMACEUTICI S.p.A. Inhaler with means for improving chemical stability of medicinal aerosol solution contained therein
ATE375142T1 (de) * 2001-03-30 2007-10-15 Jagotec Ag Medizinische aerosolformulierungen
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
ES2222294T3 (es) 2001-07-02 2005-02-01 Chiesi Farmaceutici S.P.A. Formulacion optimizada de tobramicina para administracion en forma de aerosol.
US7906102B2 (en) 2001-10-03 2011-03-15 Vanderbilt University Ligands to radiation-induced molecules
US7306925B2 (en) 2001-11-09 2007-12-11 Vanderbilt University Phage antibodies to radiation-inducible neoantigens
EP1340492A1 (en) * 2002-03-01 2003-09-03 CHIESI FARMACEUTICI S.p.A. Aerosol formulations for pulmonary administration of medicaments having systemic effects
EP1415647A1 (en) * 2002-10-23 2004-05-06 CHIESI FARMACEUTICI S.p.A. "Long-acting beta-2 agonists ultrafine formulations"
PT3536344T (pt) * 2002-03-01 2020-03-26 Chiesi Farm Spa Formulação superfina de formoterol
CN1674887A (zh) * 2002-08-14 2005-09-28 贝林格尔英格海姆法玛两合公司 含抗胆碱能剂的吸入用的气雾剂制剂
US20040166065A1 (en) 2002-08-14 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aerosol formulation for inhalation comprising an anticholinergic
US7244742B2 (en) * 2002-08-17 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co Kg Pharmaceutical compositions for inhalation containing an anticholinergic, corticosteroid and betamimetic
EP1452179A1 (en) * 2003-02-27 2004-09-01 CHIESI FARMACEUTICI S.p.A. Novel medicament combination of a highly potent long-lasting beta2-agonist and a corticosteroid
US20050003024A1 (en) * 2003-03-04 2005-01-06 The Procter & Gamble Company Regulation of mammalian hair growth
TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
US20050026948A1 (en) * 2003-07-29 2005-02-03 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising an anticholinergic and a betamimetic
EP1651224B1 (en) * 2003-07-31 2011-10-05 Boehringer Ingelheim International GmbH Medicaments for inhalation comprising an anticholinergic and a betamimetic
WO2005013945A2 (en) * 2003-08-05 2005-02-17 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising steroids and a betamimetic
EP1663180A1 (en) * 2003-09-15 2006-06-07 Vectura Limited Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation
GB0323684D0 (en) 2003-10-09 2003-11-12 Jagotec Ag Improvements in or relating to organic compounds
AR041873A1 (es) * 2003-10-30 2005-06-01 Pablo Cassara Srl Lab Una formulacion farmaceutica en aerosol adecuada para la inhalacion oral o nasal que contienen glucocorticoides en solucion estable al almacenamiento; un metodo para estabilzar formulaciones y uso de un agente estabilizante
KR20070000476A (ko) * 2004-02-27 2007-01-02 키에시 파르마슈티시 엣스. 피. 에이. 압축화 계량된 도스흡입용 안정된 약제용액 제제
EP1595531A1 (en) * 2004-05-13 2005-11-16 CHIESI FARMACEUTICI S.p.A. Stable pharmaceutical solution formulations for pressurized metered dose inhalers
CN100457087C (zh) * 2004-02-27 2009-02-04 奇斯药制品公司 用于加压计量吸入器的稳定的药用溶液制剂
JP2007537170A (ja) * 2004-05-13 2007-12-20 チエシイ・ファルマセウテイシイ・エス・ペー・アー 化学的安定性が改良された薬用エーロゾル配合物製品
ES2257152B1 (es) * 2004-05-31 2007-07-01 Laboratorios Almirall S.A. Combinaciones que comprenden agentes antimuscarinicos y agonistas beta-adrenergicos.
GB0501956D0 (en) * 2005-01-31 2005-03-09 Arrow Internat Nebulizer formulation
MX2007010396A (es) * 2005-02-25 2007-10-19 Chiesi Farma Spa Formulaciones farmaceuticas en aerosol para inhaladores presurizados de dosis medida que comprenden un agente secuestrante.
JP2008534611A (ja) * 2005-03-30 2008-08-28 シェーリング コーポレイション 抗コリン作用薬、コルチコステロイドおよび長時間作用性βアゴニストを合わせる薬物および方法
DE102005055960A1 (de) * 2005-11-24 2007-07-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aerosolformulierung für die Inhalation enthaltend ein Anticholinergikum
GB0525680D0 (en) 2005-12-16 2006-01-25 Peplin Ltd Therapeutic compositions
US20070286814A1 (en) * 2006-06-12 2007-12-13 Medispray Laboratories Pvt. Ltd. Stable aerosol pharmaceutical formulations
GB0613761D0 (en) * 2006-07-11 2006-08-23 Norton Healthcare Ltd A pharmaceutical formulation and method for the preparation thereof
EP1982709A1 (en) 2007-04-19 2008-10-22 CHIESI FARMACEUTICI S.p.A. Use of a composition comprising formoterol and beclomethasone dipropionate for the prevention or treatment of an acute condition of asthma
US8227027B2 (en) 2007-12-07 2012-07-24 Presspart Gmbh & Co. Kg Method for applying a polymer coating to an internal surface of a container
EP2077132A1 (en) 2008-01-02 2009-07-08 Boehringer Ingelheim Pharma GmbH & Co. KG Dispensing device, storage device and method for dispensing a formulation
GB0801876D0 (en) * 2008-02-01 2008-03-12 Vectura Group Plc Suspension formulations
US20090208424A1 (en) * 2008-02-19 2009-08-20 Todd Maibach Compositions and methods for delivery of solution to the skin
CA2716936C (en) * 2008-02-26 2018-06-05 Elevation Pharmaceuticals, Inc. Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
US20100055045A1 (en) 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
EP2100598A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease
EP2100599A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease
JP2012506860A (ja) * 2008-10-23 2012-03-22 サノビオン ファーマシューティカルズ インク アルホルモテロール及びチオトロピウムの組成物及びその使用方法
EP2201934A1 (en) * 2008-12-23 2010-06-30 CHIESI FARMACEUTICI S.p.A. Tiotropium aerosol formulation products with improved chemical stability
US10011906B2 (en) 2009-03-31 2018-07-03 Beohringer Ingelheim International Gmbh Method for coating a surface of a component
EP3508239B1 (de) 2009-05-18 2020-12-23 Boehringer Ingelheim International GmbH Adapter, inhalationseinrichtung und zerstäuber
CN103919785B (zh) * 2009-10-02 2016-08-24 奇斯药制品公司 福莫特罗和二丙酸倍氯米松的药用气雾制剂
GB0918150D0 (en) * 2009-10-16 2009-12-02 Jagotec Ag Improved formulations
GB0918149D0 (en) 2009-10-16 2009-12-02 Jagotec Ag Improved medicinal aerosol formulation
WO2011064163A1 (en) 2009-11-25 2011-06-03 Boehringer Ingelheim International Gmbh Nebulizer
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
UA107097C2 (en) 2009-11-25 2014-11-25 Бьорінгер Інгельхайм Інтернаціональ Гмбх Dispenser
EP3020393B1 (en) 2009-12-16 2020-10-07 3M Innovative Properties Company Formulations and methods for controlling mdi particle size delivery
EP2515855B3 (en) * 2009-12-23 2023-05-03 Chiesi Farmaceutici S.p.A. Combination therapy for COPD
WO2011076842A2 (en) 2009-12-23 2011-06-30 Chiesi Farmaceutici S.P.A. Aerosol formulation for copd
ES2468835T3 (es) * 2009-12-23 2014-06-17 Chiesi Farmaceutici S.P.A. Terapia combinada para EPOC
JP5874724B2 (ja) 2010-06-24 2016-03-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ネブライザ
WO2012010854A1 (en) 2010-07-23 2012-01-26 Cipla Limited Inhalation formulations comprising carmoterol in combination with a corticosteroid
EP2694220B1 (de) 2011-04-01 2020-05-06 Boehringer Ingelheim International GmbH Medizinisches gerät mit behälter
EP2510928A1 (en) 2011-04-15 2012-10-17 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
WO2013019730A1 (en) 2011-07-29 2013-02-07 The Washington University Antibodies to tip-1 and grp78
GB201200525D0 (en) 2011-12-19 2012-02-29 Teva Branded Pharmaceutical Prod R & D Inc An inhalable medicament
GB201200504D0 (en) * 2011-12-19 2012-02-22 Teva Branded Pharmaceutical Prod R & D Inc An inhaler
WO2013152894A1 (de) 2012-04-13 2013-10-17 Boehringer Ingelheim International Gmbh Zerstäuber mit kodiermitteln
EP3030298B1 (en) 2013-08-09 2017-10-11 Boehringer Ingelheim International GmbH Nebulizer
ES2836977T3 (es) 2013-08-09 2021-06-28 Boehringer Ingelheim Int Nebulizador
PT3096737T (pt) * 2013-12-30 2018-04-27 Chiesi Farm Spa Composição de solução de aerossol pressurizado estável de brometo de glicopirrónio e formoterol
SG11201605311UA (en) * 2013-12-30 2016-07-28 Chiesi Farma Spa Stable pressurised aerosol solution composition of glycopyrronium bromide and formoterol combination
ES2954961T3 (es) 2014-05-07 2023-11-27 Boehringer Ingelheim Int Unidad, nebulizador y método
ES2874029T3 (es) 2014-05-07 2021-11-04 Boehringer Ingelheim Int Nebulizador
UA121114C2 (uk) 2014-05-07 2020-04-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх Небулайзер, індикаторний пристрій і контейнер
US10034866B2 (en) 2014-06-19 2018-07-31 Teva Branded Pharmaceutical Products R&D, Inc. Inhalable medicament comprising tiotropium
EP3172222A4 (en) 2014-07-24 2018-03-21 Washington University Compositions targeting radiation-induced molecules and methods of use thereof
CN104225739A (zh) * 2014-09-30 2014-12-24 四川普锐特医药科技有限责任公司 一种医用定量吸入气雾剂
WO2017093758A1 (en) 2015-12-04 2017-06-08 Mexichem Fluor S.A. De C.V. Pharmaceutical composition
US10098837B2 (en) 2016-07-28 2018-10-16 Chiesi Farmaceutici S.P.A. Combination therapy for COPD
EP3634459A4 (en) 2017-02-10 2021-01-06 Washington University ANTIBODIES DIRECTED AGAINST TIP1 AND THEIR PROCEDURES FOR USE
MA52756A (fr) 2018-06-04 2021-04-14 Lupin Inc Compositions pharmaceutiques stables pour inhalateurs doseurs sous pression
WO2020152548A1 (en) * 2019-01-24 2020-07-30 Glenmark Pharmaceuticals Limited Stable aerosol inhalation compositions of formoterol
CN112137957B (zh) 2019-06-26 2022-07-29 长风药业股份有限公司 一种药用吸入气雾剂及其制备方法
KR20220108047A (ko) 2019-12-02 2022-08-02 키에시 파르마슈티시 엣스. 피. 에이. 가압 정량 흡입기를 위한 스테인리스 스틸 캔
GB2593283B (en) 2020-01-28 2023-09-13 Chiesi Farm Spa Pressurised metered dose inhalers comprising a buffered pharmaceutical formulation
GB202001537D0 (en) * 2020-02-05 2020-03-18 Consort Medical Plc Pressurised dispensing container
GB2593970A (en) 2020-02-20 2021-10-13 Chiesi Farm Spa Pressurised metered dose inhalers comprising a buffered pharmaceutical formulation
US11826382B2 (en) 2020-05-01 2023-11-28 Tygrus, LLC Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses
US11642372B2 (en) * 2020-05-01 2023-05-09 Tygrus, LLC Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses
AU2021314977A1 (en) 2020-07-31 2023-03-02 Chemo Research, S.L. Combination therapy for inhalation administration
PE20240629A1 (es) * 2020-10-09 2024-03-26 Chiesi Farm Spa Formulacion farmaceutica para inhalador presurizado de dosis medidas
GB2614901A (en) 2022-01-21 2023-07-26 Nanopharm Ltd Inhalable formulations
WO2023196432A1 (en) 2022-04-06 2023-10-12 Rapt Therapeutics, Inc. Chemokine receptor modulators and uses thereof
WO2023227782A1 (en) 2022-05-27 2023-11-30 Chiesi Farmaceutici S.P.A. A pharmaceutical formulation for pressurised metered dose inhaler
WO2023227783A1 (en) 2022-05-27 2023-11-30 Chiesi Farmaceutici S.P.A. A pharmaceutical formulation for pressurised metered dose inhaler

Family Cites Families (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3361306A (en) 1966-03-31 1968-01-02 Merck & Co Inc Aerosol unit dispensing uniform amounts of a medically active ingredient
US3622053A (en) 1969-12-10 1971-11-23 Schering Corp Aerosol inhaler with flip-up nozzle
MX3864E (es) 1975-05-27 1981-08-26 Syntex Corp Un proceso para prepara el compuesto cristalino 6-fluiro-11b 21-dihiroxi-16 17-isopropilidendioxipregna-1 4-dien-3 20-diona
US4185100A (en) 1976-05-13 1980-01-22 Johnson & Johnson Topical anti-inflammatory drug therapy
US4499108A (en) * 1983-06-08 1985-02-12 Schering Corporation Stable pleasant-tasting albuterol sulfate pharmaceutical formulations
GB8334494D0 (en) * 1983-12-24 1984-02-01 Tanabe Seiyaku Co Carbostyril derivatives
IT1196142B (it) 1984-06-11 1988-11-10 Sicor Spa Procedimento per la preparazione di 16,17-acetali di derivati pregnanici e nuovi composti ottenuti
US5192528A (en) 1985-05-22 1993-03-09 Liposome Technology, Inc. Corticosteroid inhalation treatment method
GB8828477D0 (en) * 1988-12-06 1989-01-05 Riker Laboratories Inc Medical aerosol formulations
US5225183A (en) 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
IE67185B1 (en) * 1990-02-02 1996-03-06 Fisons Plc Propellant compositions
WO1992011236A1 (en) 1990-12-19 1992-07-09 Smithkline Beecham Corporation Aerosol formulations
US6006745A (en) 1990-12-21 1999-12-28 Minnesota Mining And Manufacturing Company Device for delivering an aerosol
EP0504112A3 (en) 1991-03-14 1993-04-21 Ciba-Geigy Ag Pharmaceutical aerosol formulations
US5874063A (en) * 1991-04-11 1999-02-23 Astra Aktiebolag Pharmaceutical formulation
KR100229975B1 (ko) 1991-05-21 1999-11-15 스티븐 에프. 웨인스톡 에어로졸 흡입장치
DE59209686D1 (de) 1991-08-29 1999-06-02 Broncho Air Medizintechnik Ag Medizinisches gerät zur inhalation von dosier-aerosolen
IL103238A (en) 1991-09-25 1995-07-31 Fisons Plc Pressed aerosol preparations
IL104068A (en) 1991-12-12 1998-10-30 Glaxo Group Ltd Pharmaceutical preparations in a spray without surfactant containing 1, 1, 1, 2 tetrafluoroethane or 1,1,2,3,3 petafluor N propane as propellant
ES2099415T3 (es) * 1991-12-18 1997-05-16 Minnesota Mining & Mfg Formulaciones de aerosol en suspension.
DE4230876A1 (de) 1992-03-17 1993-09-23 Asta Medica Ag Druckgaspackungen unter verwendung von polyoxyethylen-glyceryl-oleaten
WO1994013262A1 (en) * 1992-12-09 1994-06-23 Boehringer Ingelheim Pharmaceuticals, Inc. Stabilized medicinal aerosol solution formulations
SE9203743D0 (sv) * 1992-12-11 1992-12-11 Astra Ab Efficient use
WO1994014490A1 (de) 1992-12-23 1994-07-07 Bernhard Hugemann Verfestigter arzneistoffvorrat für die mechanische erzeugung inhalierbarer wirkstoffpartikel
EP0689423B1 (en) 1993-03-17 1997-09-17 Minnesota Mining And Manufacturing Company Aerosol formulation containing a diol-diacid derived dispersing aid
US5569450A (en) * 1993-03-17 1996-10-29 Minnesota Mining And Manufacturing Company Aerosol formulation containing an ester-, amide-, or mercaptoester-derived dispersing aid
US6596260B1 (en) 1993-08-27 2003-07-22 Novartis Corporation Aerosol container and a method for storage and administration of a predetermined amount of a pharmaceutically active aerosol
DK0735884T3 (da) 1993-12-20 2000-10-09 Minnesota Mining & Mfg Flunisolid-aerosolformuleringer
GB9425160D0 (en) 1994-12-10 1995-02-08 Glaxo Group Ltd Medicaments
MX9704550A (es) * 1994-12-22 1997-10-31 Astra Ab Formulaciones de medicamentos en aerosol.
GB9426252D0 (en) 1994-12-24 1995-02-22 Glaxo Group Ltd Pharmaceutical composition
DE4446891A1 (de) 1994-12-27 1996-07-04 Falk Pharma Gmbh Stabile wäßrige Budesonid-Lösung
US5653961A (en) 1995-03-31 1997-08-05 Minnesota Mining And Manufacturing Company Butixocort aerosol formulations in hydrofluorocarbon propellant
CA2217954C (en) 1995-04-14 2005-02-15 Glaxo Wellcome Inc. Metered dose inhaler for salmeterol
NZ306281A (en) 1995-04-14 1999-07-29 Glaxo Wellcome Inc Metered dose inhaler with part or all internal surfaces coated with fluorocarbon polymers for dispensing beclomethasone dipropionate
SK284448B6 (sk) 1995-04-14 2005-04-01 Glaxo Wellcome Inc. Merací dávkovací inhalátor
TR199701167T1 (xx) * 1995-04-14 1998-03-21 Glaxo Wellcome Inc. Albuterol i�in �l��lm�� doz inhaleri.
US6135628A (en) * 1995-10-13 2000-10-24 Boehringer Ingelheim Pharmceuticals, Inc. Method and apparatus for homogenizing aerosol formulations
GB9612297D0 (en) * 1996-06-11 1996-08-14 Minnesota Mining & Mfg Medicinal aerosol formulations
JP2000514085A (ja) 1996-07-08 2000-10-24 ローヌ―プーラン・ロウラー・リミテッド 医薬シクロスポリンａエーロゾル溶液処方物
AU3811897A (en) 1996-07-24 1998-02-10 Oglios Therapeutics, Inc. Antisense oligonucleotides as antibacterial agents
GB9616237D0 (en) * 1996-08-01 1996-09-11 Norton Healthcare Ltd Aerosol formulations
GB9620187D0 (en) 1996-09-27 1996-11-13 Minnesota Mining & Mfg Medicinal aerosol formulations
ATE301991T1 (de) * 1996-12-04 2005-09-15 Link Products Ltd Arzneimittel zusammensetzungen und vorrichtungen zu deren verabreichung
US6413496B1 (en) 1996-12-04 2002-07-02 Biogland Ireland (R&D) Limited Pharmaceutical compositions and devices for their administration
DK1014943T3 (da) 1997-02-05 2002-10-14 Jago Res Ag Medicinske aerosolformuleringer
US6126919A (en) 1997-02-07 2000-10-03 3M Innovative Properties Company Biocompatible compounds for pharmaceutical drug delivery systems
US5891419A (en) 1997-04-21 1999-04-06 Aeropharm Technology Limited Environmentally safe flunisolide aerosol formulations for oral inhalation
US6000537A (en) * 1997-06-10 1999-12-14 U.S. Philips Corporation Housing with readable side walls for a disc-shaped information carrier
US20010031244A1 (en) 1997-06-13 2001-10-18 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition
GB2326334A (en) * 1997-06-13 1998-12-23 Chiesi Farma Spa Pharmaceutical aerosol compositions
US6324827B1 (en) * 1997-07-01 2001-12-04 Bp Corporation North America Inc. Method of generating power in a dry low NOx combustion system
BR7702049U (pt) 1997-09-05 1999-09-14 Chiesi Farma Spa Bico pulverizador para utilização em inalador oral para medicamentos aerossóis
NZ504021A (en) 1997-10-17 2003-04-29 Systemic Pulmonary Delivery Lt Method and apparatus for delivering aerosolized medication having air discharged through air tube directly into plume of aerosolized medication
AU2081999A (en) * 1998-01-13 1999-08-02 Astrazeneca Uk Limited Pharmaceutical compostition comprising a compound having dopamine (D2) receptor agonist activity and a compound (B) having Beta2 adrenoreceptor agonist activity
US6045784A (en) 1998-05-07 2000-04-04 The Procter & Gamble Company Aerosol package compositions containing fluorinated hydrocarbon propellants
SE9802073D0 (sv) 1998-06-11 1998-06-11 Astra Ab New use
NZ509418A (en) * 1998-06-18 2003-06-30 Boehringer Ingelheim Pharma Pharmaceutical formulations for aerosols with two or more active substances
US6451285B2 (en) 1998-06-19 2002-09-17 Baker Norton Pharmaceuticals, Inc. Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant
US6241969B1 (en) 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
ATE283033T1 (de) * 1998-07-24 2004-12-15 Jago Res Ag Medizinische aerosolformulierungen
EP1102579B1 (de) * 1998-08-04 2003-03-19 Jago Research Ag Medizinische aerosolformulierungen
US6136294C1 (en) * 1998-09-22 2002-09-24 Aeropharm Technology Inc Amino acid stabilized medical aerosol formulation
DE19847969A1 (de) 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Lagerfähig flüssige Formulierung mit Formoterol
CA2343123C (en) * 1998-10-17 2008-03-25 Boehringer Ingelheim Pharma Kg Active substance concentrate with formoterol, suitable for storage
PT1283036E (pt) 1998-11-13 2008-03-06 Jagotec Ag Inalador de pó seco de dose múltipla com um reservatório de pó
DZ2947A1 (fr) * 1998-11-25 2004-03-15 Chiesi Farma Spa Inhalateur à compteur de dose sous pression.
IT1303788B1 (it) * 1998-11-25 2001-02-23 Chiesi Farma Spa Formulazioni di aerosol medicinali.
US6290930B1 (en) 1998-12-18 2001-09-18 Baker Norton Pharmaceuticals, Inc. Pharmaceutical solution aerosol formulations containing fluoroalkanes and budesonide
US6004537A (en) * 1998-12-18 1999-12-21 Baker Norton Pharmaceuticals, Inc. Pharmaceutical solution aerosol formulations containing fluoroalkanes, budesonide and formoterol
GB9902689D0 (en) * 1999-02-08 1999-03-31 Novartis Ag Organic compounds
TR200102567T2 (tr) 1999-03-05 2002-01-21 Chiesi Farmaceutici S.P.A. İnhalasyon için geliştirilmiş toz halindeki farmasötik bileşimler
US6315985B1 (en) 1999-06-18 2001-11-13 3M Innovative Properties Company C-17/21 OH 20-ketosteroid solution aerosol products with enhanced chemical stability
ES2238334T3 (es) 1999-12-24 2005-09-01 Glaxo Group Limited Formulacion farmaceutica en aerosol de salmeterol y propionato de fluticasona.
IT1317846B1 (it) 2000-02-22 2003-07-15 Chiesi Farma Spa Formulazioni contenenti un farmaco anticolinergico per il trattamentodella broncopneumopatia cronica ostruttiva.
IT1318514B1 (it) 2000-05-12 2003-08-27 Chiesi Farma Spa Formulazioni contenenti un farmaco glucocorticosteroide per iltrattamento di patologie broncopolmonari.
SK286694B6 (sk) 2000-05-22 2009-03-05 Chiesi Farmaceutici S.P.A. Aerosólový farmaceutický prostriedok
PT3536344T (pt) * 2002-03-01 2020-03-26 Chiesi Farm Spa Formulação superfina de formoterol
EP1340492A1 (en) * 2002-03-01 2003-09-03 CHIESI FARMACEUTICI S.p.A. Aerosol formulations for pulmonary administration of medicaments having systemic effects
EP1595531A1 (en) * 2004-05-13 2005-11-16 CHIESI FARMACEUTICI S.p.A. Stable pharmaceutical solution formulations for pressurized metered dose inhalers

Also Published As

Publication number Publication date
SK286694B6 (sk) 2009-03-05
HUS1800032I1 (hu) 2018-08-28
SK16522002A3 (sk) 2003-04-01
EP1466594B1 (en) 2008-12-03
PE20011323A1 (es) 2002-01-22
CY2009009I2 (el) 2014-04-09
EP2223682A1 (en) 2010-09-01
EA005179B1 (ru) 2004-12-30
PL359149A1 (en) 2004-08-23
EP2223682B1 (en) 2012-01-18
HRP20021025A2 (en) 2004-02-29
PT1157689E (pt) 2009-03-23
ES2320194T3 (es) 2009-05-20
AU5070100A (en) 2001-12-03
DE60144304D1 (de) 2011-05-05
HRP20021025B1 (hr) 2013-11-22
TNSN01074A1 (fr) 2005-11-10
JP5392880B2 (ja) 2014-01-22
CZ303833B6 (cs) 2013-05-22
MY127145A (en) 2006-11-30
TWI284047B (en) 2007-07-21
ES2380790T3 (es) 2012-05-18
LTC1787639I2 (lt) 2021-05-25
ES2359991T3 (es) 2011-05-30
US7018618B2 (en) 2006-03-28
MXPA02011414A (es) 2003-06-06
EP1787639A3 (en) 2009-02-25
DK2223682T3 (da) 2012-03-19
DK1787639T3 (da) 2011-05-09
CA2411047A1 (en) 2001-11-29
IL152955A (en) 2010-02-17
FR11C0041I1 (zh) 2011-04-11
US20060083693A1 (en) 2006-04-20
ATE415945T1 (de) 2008-12-15
PT2223682E (pt) 2012-03-22
BG107256A (bg) 2003-06-30
CY2011014I1 (el) 2015-10-07
WO2001089480A1 (en) 2001-11-29
HU230804B1 (hu) 2018-06-28
CN1452479A (zh) 2003-10-29
JP2003534266A (ja) 2003-11-18
DE122009000035I1 (de) 2009-11-05
SA01220126B1 (ar) 2007-04-03
JO2310B1 (en) 2005-09-12
LU91875I2 (fr) 2011-11-21
ME00220B (me) 2010-10-10
EP1466594A2 (en) 2004-10-13
CY1111570T1 (el) 2015-10-07
NL300393I1 (en) 2009-09-01
SI2223682T1 (sl) 2012-04-30
NO342935B1 (no) 2018-09-03
ATE502624T1 (de) 2011-04-15
US20040047809A1 (en) 2004-03-11
DE60137282D1 (de) 2009-02-26
HK1058900A1 (en) 2004-06-11
AR029523A1 (es) 2003-07-02
DZ3358A1 (fr) 2001-11-29
AU2000250701A1 (en) 2002-02-21
IL152955A0 (en) 2003-06-24
CY1108968T1 (el) 2014-04-09
NL300393I2 (en) 2010-02-01
UA73986C2 (uk) 2005-10-17
SI1466594T1 (sl) 2009-06-30
EP1157689A1 (en) 2001-11-28
MEP32108A (en) 2010-10-10
HUP0302007A3 (en) 2006-07-28
CY1108833T1 (el) 2014-07-02
ATE541563T1 (de) 2012-02-15
NO2019030I1 (no) 2019-07-11
EE05167B1 (et) 2009-06-15
ES2318217T3 (es) 2009-05-01
PT1787639E (pt) 2011-06-08
FR11C0041I2 (fr) 2015-09-04
EP1787639A2 (en) 2007-05-23
SI1787639T1 (sl) 2011-07-29
US6716414B2 (en) 2004-04-06
BE2011C032I2 (zh) 2020-08-20
SI1157689T1 (sl) 2009-06-30
CY1113028T1 (el) 2016-04-13
EP1466594A3 (en) 2004-12-01
EE200200649A (et) 2004-06-15
BG65883B1 (bg) 2010-04-30
DK1466594T3 (da) 2009-03-02
MY143733A (en) 2011-07-15
BR0015884A (pt) 2003-07-08
NO20025568L (no) 2002-11-20
AU2000250701B2 (en) 2004-07-01
PT1466594E (pt) 2009-02-13
CY2011014I2 (el) 2015-10-07
NO20025568D0 (no) 2002-11-20
DE60136864D1 (de) 2009-01-15
US20020025299A1 (en) 2002-02-28
CA2411047C (en) 2009-08-04
EP1157689B1 (en) 2009-01-07
NO2019003I1 (no) 2019-01-16
DK1157689T3 (da) 2009-03-16
HUP0302007A2 (hu) 2003-09-29
EP1787639B1 (en) 2011-03-23
DE122011100049I1 (de) 2012-01-19
CZ20023835A3 (cs) 2003-04-16
LTPA2011011I1 (lt) 2019-08-26
CY2009009I1 (el) 2014-04-09
EA200201058A1 (ru) 2003-04-24
ATE419832T1 (de) 2009-01-15

Similar Documents

Publication Publication Date Title
CN1213732C (zh) 用于加压计量吸入器的稳定药用溶液制剂
CN1158996C (zh) 药用气溶胶制剂
US6423298B2 (en) Pharmaceutical formulations for aerosols with two or more active substances
EP1123120B1 (en) Medicinal aerosol formulation
CN1638730A (zh) 福莫特罗超细制剂
CN1085525C (zh) 使用聚氧乙烯丙三基油酸酯类的压气包装
EA004132B1 (ru) Дозирующие ингаляторы вытеснительного типа
CN1310611A (zh) 压力计量剂量吸入器和药物气雾剂
CZ284203B6 (cs) Tekutý aerosolový přípravek obsahující léčivo a způsob stabilisace tohoto prostředku
EA010311B1 (ru) Состав аэрозоля, дозированный ингалятор под давлением и способ его заполнения
CN102665678A (zh) 用于copd的联合治疗
CN1874756A (zh) 药用计量剂量吸入器和其相关方法
IL301617A (en) A pharmaceutical formulation for a pressurized metered dose inhaler
CN108289842A (zh) 药物组合物
CN103520106A (zh) 一种硫酸沙丁胺醇吸入气雾剂及其制备方法
CN1921835A (zh) 用于加压计量吸入器的稳定的药用溶液制剂
CN102362860A (zh) 以氢氟烷烃为抛射剂的布***和福莫特罗气雾剂制剂
CN1048627C (zh) 药用气溶胶制剂
KR20060136446A (ko) 압축화 계량된 도스흡입용 안정된 약제용액 제제
JP7475448B2 (ja) 加圧定量吸入器のためのステンレス鋼缶
JP5409594B2 (ja) 加圧式定量吸入器のための安定な製薬学的溶液製剤
CA3230806A1 (en) Metered dose inhalers and suspension compositions
EA046192B1 (ru) Дозирующие аэрозольные ингаляторы, содержащие забуференный фармацевтический состав

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1058900

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1058900

Country of ref document: HK

CX01 Expiry of patent term
CX01 Expiry of patent term

Granted publication date: 20050810