WO2002009689A1 - Procede pour reduire les exacerbations associees a la bpco - Google Patents

Procede pour reduire les exacerbations associees a la bpco Download PDF

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Publication number
WO2002009689A1
WO2002009689A1 PCT/US2001/023542 US0123542W WO0209689A1 WO 2002009689 A1 WO2002009689 A1 WO 2002009689A1 US 0123542 W US0123542 W US 0123542W WO 0209689 A1 WO0209689 A1 WO 0209689A1
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WO
WIPO (PCT)
Prior art keywords
copd
exacerbations
patients
pde
inhibitors
Prior art date
Application number
PCT/US2001/023542
Other languages
English (en)
Inventor
Jeffrey D. Edelson
Original Assignee
Smithkline Beecham Corporation
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
Priority to CA002417336A priority Critical patent/CA2417336A1/fr
Priority to BR0112682-2A priority patent/BR0112682A/pt
Priority to MXPA03000714A priority patent/MXPA03000714A/es
Priority to JP2002515242A priority patent/JP2004505039A/ja
Priority to AU7902301A priority patent/AU7902301A/xx
Priority to IL15391901A priority patent/IL153919A0/xx
Priority to US10/343,078 priority patent/US20040005995A1/en
Priority to KR10-2003-7001144A priority patent/KR20030019620A/ko
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU2001279023A priority patent/AU2001279023B2/en
Priority to EP01957262A priority patent/EP1320361A4/fr
Priority to HU0300685A priority patent/HUP0300685A3/hu
Publication of WO2002009689A1 publication Critical patent/WO2002009689A1/fr
Priority to NO20030332A priority patent/NO20030332D0/no
Priority to US11/280,089 priority patent/US20060069155A1/en

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a method for reducing the incidences and/or the severity of exacerbations of COPD by administering a phosphodiesterase 4 (PDE4) inhibitor.
  • PDE4 phosphodiesterase 4
  • COPD Chronic obstructive pulmonary disease
  • the disease is primarily caused by smoking, has a high incidence of mortality and morbidity and is poorly served by existing therapies.
  • COPD accounts for approximately 6% of deaths in men and 4% of deaths in women and is the third most common cause of death (2).
  • the World Health Organization Global Burden of Disease study showed COPD to be the sixth leading cause of death worldwide in 1990 and is predicted to rise to third position by 2020.
  • COPD is associated with major healthcare costs, largely due to expensive treatments such as long-term oxygen therapy and hospital admissions, as well as indirect costs including loss of working capacity.
  • Cyclic nucleotide phosphodiesterases represent a family of enzymes that hydrolyze the ubiquitous intracellular second messengers, adenosine 3',5'-monophosphate (cAMP) and guanosine 3',5 -monophosphate (cGMP) to their corresponding inactive 5 - monophosphate metabolites.
  • PDEs Cyclic nucleotide phosphodiesterases
  • cAMP adenosine 3',5'-monophosphate
  • cGMP guanosine 3',5 -monophosphate
  • the target enzyme for use of the formulations of this invention is the PDE 4 isozyme in all its various forms and in the full domain of its distributions in all cells.
  • inflammatory cells may contain a relatively high proportion of the form that binds rolipram with a low affinity while brain and parietal cells may contain a relatively high proportion of the form that binds rolipram with a high affinity.
  • the targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states.
  • isozyme-selective PDE inhibitors should represent an improvement over non-selective inhibitors
  • the selective inhibitors tested to date are not devoid of side effects produced as an extension of inhibiting the isozyme of interest in an inappropriate or untargeted tissue.
  • clinical studies with the selective PDE 4 inhibitor rolipram which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis.
  • side effects of denbufylline, another PDE 4 inhibitor targeted for the treatment of multi-inf arct dementia may include pyrosis, nausea and emesis as well.
  • this invention relates to a method for reducing the incidences and/or severity of exacerbations of COPD in a mammal suffering from COPD, the method comprising administering an effective amount of a PDE4 inhibitor to a patient whom is suffering from COPD.
  • this invention relates to the use of a PDE4 inhibitor in the manufacture of a medicament for reducing the incidences and or severity of exacerbations of COPD.
  • Fig 2 Kaplan-Meier Estimates of Percentage of Patients Exacerbation-free - ITT in Clinical Study B
  • Fig 4 Relative Risk (95% Cl) of a COPD Exacerbation in Principal Studies.
  • Acute COPD exacerbations defined as worsening of COPD symptoms that required changes in treatment including antimicrobial therapy, a short course of oral corticosteroids or other bronchodilator therapy. Exacerbations were categorized to three levels:
  • Level 1 self-managed by the patient at home by increasing usual medication for COPD.
  • Level 2 requiring additional treatment prescribed by a family or primary care physician or as a result of a hospital outpatient visit including a visit to the Emergency Room.
  • Level 3 requiring the patient to be admitted to the hospital for treatment.
  • Ariflo® cis-4- cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l-carboxylic acid
  • 15mg immediate release tablet, BID had a lower incidence of all categories of exacerbations as well as the more severe exacerbations (Levels 2 and 3) requiring treatment by a physician or hospitalization than patients who received placebo.
  • Exacerbation-free survival rate is estimated using Kaplan-Meier estimates of time-to-first exacerbation. P-values based on log-rank test.
  • a preferred group of inhibitors are those that have an IC50 ratio (high/low binding) of about 0J or greater, as that IC50 ratio determination is described in U.S. patent 5,998,428. It is incorporated herein in full by reference as if fully set forth herein.
  • a preferred standard for PDE 4-s ⁇ ecific inhibitors which can be used in this invention is one where the compound has an IC50 ratio of about 0.1 or greater; said ratio being the ratio of the IC50 value for competing with the binding of InM of pH]R-rolipram to a form of PDE 4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE 4 catalytic activity of a form which binds rolipram with a low affinity using 1 uM[ ⁇ H]-cAMP as the substrate.
  • PDE 4 inhibitors that may be included in these formulations include those set out in U.S. patent 5,552,438 issued 03 September 1996. This patent and the compounds it discloses are incorporated herein in full by reference.
  • the compound of particular interest which is disclosed in U.S. patent 5,552,438, is c ⁇ -4-cyano-4-[3- (cyclopentyloxy)- 4-methoxyphenyl]cyclohexane-l-carboxylic acid and its salts, esters, pro-drugs or physical forms.
  • This compound is identified here by its IUPAC name, by its registered trademark Ariflo, by its generic name cilomilast, and by an alphanumeric SB207499.
  • PDE 4 inhibitors which may be of interest include: AWD-12-281 from Astra (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98); a 9- benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Warner-Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V- 11294A from Napp (Landells, LJ. et al.
  • Preferred compounds of this invention are those which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
  • the most preferred compounds are roflumilast and cw-4-cyano-4-[3- (cyclopentyloxy)-4- methoxyphenyl]cyclohexane- 1-carboxylic acid.
  • drugs useful in treating PDE4-related diseases can be incorporated into this therapy as well.
  • examples of other therapeutics by category are drugs which treat: inflammatory respiratory diseases such as bronchodilators, leukotriene receptor antagonists and leukotriene biosynthesis inhibitors; non-respiratory inflammatory diseases such as irritable bowel disease (IBD); immunomodulating drugs, cognition enhancers; drugs for treating rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; adult respiratory distress syndrome; cerebral malaria; silicosis; pulmonary sarcoidosis; drugs for treating bone resorption diseases; reperfusion injury; graft vs.
  • AIDS cachexia secondary to infection or malignancy
  • cachexia secondary to human acquired immune deficiency syndrome AIDS
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation; Crohn's disease; ulcerative colitis; pyresis; autoimmune diseases such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis
  • drugs for treating viral infections such as cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus, and drugs for treating yeast and fungal infections.
  • CMV cytomegalovirus
  • Exemplary types of compounds for treating respiratory diseases are leukotriene antagonists; mucolytics; antitussives and expectorants; antibiotics; oral or inhaled beta- agonists; phosphodiesterase inhibitors other that PDE4-specific inhibitors; nasal decongestants; elastase inhibitors; protein therapeutics such as IL4, IL5, IL8, and IL13 monoclonal antibodies, anti-IgE; or oral or inhaled corticosteriods.
  • Particularly preferred combination therapies are the use of a therapeutic amount of a corticosteriod, a beta agonist, an anticholinergic, an inhaled cromone, a leukotriene antagonist, or an antibiotic to treat secondary infections.
  • the amount of inhibitor that is effective in this treatment method falls between 100 micrograms and 100 mg per dose, administered as needed from one to four times per day.
  • a preferred range is 1-60 mg per dose administered once or twice a day. More preferred is a 5-30 mg dose administered one or twice a day. Most preferred is a 10-20, or 10-15mg dose administered once or twice per day, e.g. a twice-a-day 15 mg dose, or once-a-day 30 or 60 mg dose.
  • the dose for reducing exacerbations and/or the severity of them can be smaller than that which is used to treat COPD per se.
  • the inhibitor will be administered by conventional means. For example, it will be administered orally or as an inhaled powder or aerosol. It may be possible to formulate some of these inhibitors in the form of a topical patch, a sustained release injectable or a suppository, it is believed that an oral preparation or one administered as an inhalant will be the superior route of delivery.
  • the preferred formulation will be an immediate release or controlled release oral tablet containing between about lmg to 200 mg of Ariflo, more preferably 5 to lOOmg, and most preferably between 5, or 10 to 60mg of the active ingredient. Additional preferred dosage amounts within these ranges are 10, 15, 20, 30, 40, 50, 60, 70, 80 or 90mg per preparation. Specific Examples
  • the clinical studies protocol were carried out generally as follows: Eligible patients had a clinical diagnosis of COPD (according to international treatment guidelines), a % predicted FEV j > 30% and ⁇ 70% post-bronchodilator, a FEVi/FNC of ⁇ 0.7, and fixed airway obstruction defined by ⁇ 15% reversibility following administration of a beta2-agonist.
  • patients with COPD entered a 4-week placebo run-in period and were then randomized to receive Ariflo 15 mg twice daily or placebo in a ratio of 2 to 1. Patients were monitored following 1, 2 and 4 weeks of treatment and subsequently at 4- week intervals. Patients were permitted to receive concomitant salbutamol (prn) and/or short acting anticholinergic therapy at a stable dose during these studies.
  • Study B included a 2-week, randomised, double-blind, run-out phase to examine the effects of discontinuation of treatment. Patients who received Ariflo during the initial 24 week period, were randomized (1:1 ratio) to Ariflo 15mg BID or placebo for the run-out phase; patients who received placebo during the initial 24 weeks, continued on placebo during the run-out phase.
  • Pulmonary function measurements were performed at each visit (with the exception of Week 1).
  • the St. George's Respiratory Questionnaire (SGRQ) was administered at Baseline, and Weeks 12 and 24 (or at the time of withdrawal).
  • efficacy measures were analyzed for the intent-to-treat population (ITT), defined as all patients who received randomized study medication and had a baseline evaluation and at least one on-therapy efficacy evaluation during the double-blind period.
  • Efficacy analyses for the per protocol population (PP) were limited to trough FEVp and the total score of the SGRQ, the co-primary measures of efficacy, and the secondary parameters, exercise tolerance test, post-exercise breathlessness, summary symptom score, and trough FNC.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention se rapporte à un procédé servant à réduire les incidences et/ou la gravité des exacerbations de la broncho-pneumopathie chronique obstructive (BPCO), en administrant un inhibiteur de phosphodiestérase 4 (PDE4).
PCT/US2001/023542 2000-07-27 2001-07-26 Procede pour reduire les exacerbations associees a la bpco WO2002009689A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US10/343,078 US20040005995A1 (en) 2001-07-26 2001-07-26 Method for reducing exacerbations associated with copd
MXPA03000714A MXPA03000714A (es) 2000-07-27 2001-07-26 Metodo para reducir exacerbaciones relacionadas con enfermedad de obstruccion pulmonar cronica.
JP2002515242A JP2004505039A (ja) 2000-07-27 2001-07-26 Ｃｏｐｄに付随する増悪の減少方法
AU7902301A AU7902301A (en) 2000-07-27 2001-07-26 Method for reducing exacerbations associated with copd
IL15391901A IL153919A0 (en) 2000-07-27 2001-07-26 Method for reducing exacerbations associated with copd
CA002417336A CA2417336A1 (fr) 2000-07-27 2001-07-26 Procede pour reduire les exacerbations associees a la bpco
KR10-2003-7001144A KR20030019620A (ko) 2000-07-27 2001-07-26 Ｃｏｐｄ와 관련된 증상 악화의 감소 방법
BR0112682-2A BR0112682A (pt) 2000-07-27 2001-07-26 Método para reduzir exacerbações associadas com copd
AU2001279023A AU2001279023B2 (en) 2000-07-27 2001-07-26 Method for reducing exacerbations associated with COPD
EP01957262A EP1320361A4 (fr) 2000-07-27 2001-07-26 Procede pour reduire les exacerbations associees a la bpco
HU0300685A HUP0300685A3 (en) 2000-07-27 2001-07-26 Method for reducing exacerbations associated with copd
NO20030332A NO20030332D0 (no) 2000-07-27 2003-01-22 Fremgangsmåte for å redusere eksaserbasjon assosiert med COPD
US11/280,089 US20060069155A1 (en) 2000-07-27 2005-11-16 Method for reducing exacerbations associated with COPD

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22127500P 2000-07-27 2000-07-27
US60/221,275 2000-07-27

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/343,078 A-371-Of-International US20040005995A1 (en) 2000-07-27 2001-07-26 Method for reducing exacerbations associated with copd
US10/856,460 Continuation US20040219137A1 (en) 2000-07-27 2004-05-28 Method for reducing exacerbations associated with COPD

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WO2002009689A1 true WO2002009689A1 (fr) 2002-02-07

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PCT/US2001/023542 WO2002009689A1 (fr) 2000-07-27 2001-07-26 Procede pour reduire les exacerbations associees a la bpco

Country Status (16)

Country Link
EP (1) EP1320361A4 (fr)
JP (1) JP2004505039A (fr)
KR (1) KR20030019620A (fr)
CN (1) CN1444476A (fr)
AR (1) AR029984A1 (fr)
AU (2) AU7902301A (fr)
BR (1) BR0112682A (fr)
CA (1) CA2417336A1 (fr)
CZ (1) CZ2003141A3 (fr)
HU (1) HUP0300685A3 (fr)
IL (1) IL153919A0 (fr)
MX (1) MXPA03000714A (fr)
NO (1) NO20030332D0 (fr)
PL (1) PL365612A1 (fr)
WO (1) WO2002009689A1 (fr)
ZA (1) ZA200300476B (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002069945A3 (fr) * 2001-03-07 2003-01-30 Boehringer Ingelheim Pharma Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv
WO2003011274A2 (fr) * 2001-07-27 2003-02-13 Glaxo Group Limited Methode therapeutique
WO2004004704A1 (fr) * 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et inhibiteurs de pde-iv
US7776315B2 (en) 2000-10-31 2010-08-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and additional active ingredients
US8536206B2 (en) 2003-03-08 2013-09-17 Takeda Gmbh Process for the preparation of roflumilast
US9056100B2 (en) 1999-07-14 2015-06-16 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102087661B1 (ko) * 2018-07-27 2020-03-11 강원대학교산학협력단 Ｇｅｂｒ―７ｂ 화합물을 유효성분으로 포함하는 만성폐쇄성 폐질환의 예방 또는 치료용 조성물

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DZ3019A1 (fr) * 1999-03-01 2005-05-20 Smithkline Beecham Corp Utilisation d'un inhibiteur de pde4 dans la préparation d'un médicament contre la copd.
SE9902937D0 (sv) * 1999-08-18 1999-08-18 Astra Pharma Prod Pharmaceutical compositions
AU772909B2 (en) * 1999-10-29 2004-05-13 Smithkline Beecham Corporation Method for administering a phosphodiesterase 4 inhibitor

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] SILVESTRE J. ET AL.: "SB-207499. Antiasthmatic/antiinflammatory, phosphodiesterase IV inhibitor", XP002905178, accession no. STN Database accession no. 130:79 *
DRUGS FUTURE, vol. 23, no. 6, 1998, pages 607 - 615 *
See also references of EP1320361A4 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10588895B2 (en) 1999-07-14 2020-03-17 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US10034867B2 (en) 1999-07-14 2018-07-31 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9056100B2 (en) 1999-07-14 2015-06-16 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9687478B2 (en) 1999-07-14 2017-06-27 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9333195B2 (en) 1999-07-14 2016-05-10 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US7776315B2 (en) 2000-10-31 2010-08-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and additional active ingredients
WO2002069945A3 (fr) * 2001-03-07 2003-01-30 Boehringer Ingelheim Pharma Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv
AU2002257587B2 (en) * 2001-03-07 2007-05-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel medicament compositions on the basis of anticholinergics and PDE IV inhibitors
EA009989B1 (ru) * 2001-03-07 2008-04-28 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Лекарственное средство и его применение для лечения воспалительных и/или обструктивных заболеваний дыхательных путей
WO2003011274A2 (fr) * 2001-07-27 2003-02-13 Glaxo Group Limited Methode therapeutique
WO2003011274A3 (fr) * 2001-07-27 2003-09-18 Glaxo Group Ltd Methode therapeutique
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
JP2005532379A (ja) * 2002-07-09 2005-10-27 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 新規な抗コリン作動薬およびｐｄｅ−ｉｖ阻害剤を基本とする新規な医薬組成物
WO2004004704A1 (fr) * 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions medicamenteuses a base de nouveaux anticholinergiques et inhibiteurs de pde-iv
US8536206B2 (en) 2003-03-08 2013-09-17 Takeda Gmbh Process for the preparation of roflumilast
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US11000517B2 (en) 2008-03-13 2021-05-11 Almirall, S.A. Dosage and formulation
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients

Also Published As

Publication number Publication date
AU7902301A (en) 2002-02-13
BR0112682A (pt) 2003-06-24
AR029984A1 (es) 2003-07-23
AU2001279023B2 (en) 2005-11-10
ZA200300476B (en) 2004-04-23
CN1444476A (zh) 2003-09-24
NO20030332L (no) 2003-01-22
EP1320361A1 (fr) 2003-06-25
MXPA03000714A (es) 2003-06-04
EP1320361A4 (fr) 2006-04-05
IL153919A0 (en) 2003-07-31
JP2004505039A (ja) 2004-02-19
PL365612A1 (en) 2005-01-10
CA2417336A1 (fr) 2002-02-07
CZ2003141A3 (cs) 2004-07-14
HUP0300685A3 (en) 2004-10-28
KR20030019620A (ko) 2003-03-06
NO20030332D0 (no) 2003-01-22
HUP0300685A2 (hu) 2003-12-29

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