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WO2004098596A1 - Composition comprenant roflumilast et il-1 trap - Google Patents

Composition comprenant roflumilast et il-1 trap Download PDF

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Publication number
WO2004098596A1
WO2004098596A1 PCT/EP2004/050743 EP2004050743W WO2004098596A1 WO 2004098596 A1 WO2004098596 A1 WO 2004098596A1 EP 2004050743 W EP2004050743 W EP 2004050743W WO 2004098596 A1 WO2004098596 A1 WO 2004098596A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
roflumilast
pde4
interleukin
phosphodiesterase
Prior art date
Application number
PCT/EP2004/050743
Other languages
English (en)
Inventor
Johannes Barsig
Original Assignee
Altana Pharma Ag
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
Application filed by Altana Pharma Ag filed Critical Altana Pharma Ag
Publication of WO2004098596A1 publication Critical patent/WO2004098596A1/fr

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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
    • A61K31/33—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the combination of certain known active compounds for therapeutic purposes.
  • the substances used in the combination according to the invention are known active compounds from the PDE4 inhibitor class and known active compounds from the interleukin-1 (IL-1) antagonist class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.
  • the invention relates to pharmaceutical compositions and methods for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention relates in a first aspect to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental by administering to a patient in need thereof simultaneously an effective amount of (1) roflumilast and (2) IL-1 Trap.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention in a second aspect relates to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin- 1 (IL-1) activity is detrimental by administering to a patient in need thereof in succession, close in time or remote in time, in any order whatever an effective amount of (1) roflumilast and (2) IL-1 Trap.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention also relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, comprising as a fixed combination an effective amount of
  • the invention further relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, comprising as a free combination an effective amount of
  • the invention additionally relates to a method for preparing a pharmaceutical composition which is effective for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, which method comprises mixing an effective amount of roflumilast and IL-1 Trap with a pharmaceutically acceptable carrier.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention furthermore relates to the use of a combination of roflumilast and IL-1 Trap for the preparation of a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin- 1 (IL-1) activity is detrimental.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the combination therapy which is the subject matter of this invention comprises administering roflumilast with IL-1 Trap to prevent onset of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental or to treat such an existing condition.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • the invention thus relates to the combined use of roflumilast and IL-1 Trap in preventing the symptoms of, or treating a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental.
  • PDE4 phosphodiesterase 4
  • IL-1 interleukin-1
  • roflumilast is understood to include the pharmaceutically acceptable salts and the N-oxide of ROFLUMILAST, which can likewise be used according to the invention.
  • ROFLUMILAST is the international non proprietary name (INN) for 3-cyclopropylmethoxy-4-difluoro- methoxy-N-(3,5-dichloropyrid-4-yl)benzamide [structure of formula (1.1)].
  • Suitable pharmaceutically acceptable salts of ROFLUMILAST are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, metha ⁇ esulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.
  • acids such as, for example, hydroch
  • active compounds and their pharmaceutically acceptable salts mentioned can also be present, for example, in the form of their pharmaceutically acceptable solvates, in particular in the form of their hydrates.
  • IL-1 Trap is understood to represent the IL-1 Trap of Regen- eron Pharmaceuticals Inc.
  • the IL-1 Trap is an Fc fusion protein consisting of both the IL-1 Type I Receptor and the IL-1 Receptor Accessory Protein.
  • U.S. Patents Nos. 5,844,099 and 6,472,179 methods of making and using the Interleukin-1 (IL-1) Trap of Regeneron Pharmaceuticals Inc are disclosed.
  • the pharmaceutical compositions according to the invention can furthermore be used in the treatment of conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia; in the treatment of malignancies to inhibit tumor growth, or metastasis, and/or to alleviate cachexia secondary to malignancy; in the treatment of infectious diseases like bacterial meningitis, cachexia or cerebral malaria; and in the treatment of diseases like inflammatory bone disease, bone resorption disease, hepatitis, viral hepatitis, reperfusion injury, scar tissue formation, pyrexia, periodontal disease and radiation toxicity.
  • the pharmaceutical compositions according to the invention can as well be used in the treatment of chronic fever syndromes, metabolic syndrome and sequalae, e.g. type 2 diabetes.
  • combined use (or “combination”) embraces the administration of roflumilast and IL-1 Trap as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually, minutes, hours, days or weeks depending upon the combination selected).
  • Combined use generally is not intended to encompass the administration of two of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • Combined use or “combination” within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament - fixed combination) or more or less simultaneously, respectively in succession (from separate pack units -free combination; directly in succession or else alternatively at a relatively large time interval).
  • one therapeutic agent could be taken in the morning and one later in the day.
  • one therapeutic agent could be taken once daily and the other once weekly or only once in a 2 weeks time interval.
  • Simultaneous administration preferably is accomplished by administering to the subject in need thereof, for example, a single intravenous injection having a fixed ratio of each therapeutic agent.
  • More or less simultaneous administration or administration in succession of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and by infusion techniques.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous or subcutaneous injection while the other therapeutic agent of the combination may be administered orally.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • the therapeutic agent(s) according to the invention may be administered in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., inject- able and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes or suppositories.
  • liquid solutions e.g., inject- able and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes or suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application.
  • roflumilast is oral.
  • roflumilast is administered by intravenous infusion or injection.
  • roflumilast is administered by intramuscular or subcutaneous injection.
  • Other routes of administration are also contemplated, including intranasal and transdermal routes, and by inhalation.
  • compositions for use according to the invention include the IL-1 Trap in a pharmacologically acceptable liquid, solid or semi-solid carrier, linked to a carrier or targeting molecule (e.g., antibody, hormone, growth factor, etc.) and/or incorporated into liposomes, microcapsules, and controlled release preparation (including antagonist expressing cells) prior to administration in vivo.
  • a carrier or targeting molecule e.g., antibody, hormone, growth factor, etc.
  • controlled release preparation including antagonist expressing cells
  • the pharmaceutical composition comprise the IL-1 Trap in an aqueous solution, such as sterile water, saline, phosphate buffer or dextrose solution.
  • IL-1 Trap may be comprised in a solid (e.g. wax) or semi-solid (e.g.
  • the administration route may be any mode of administration known in the art, including but not limited to intravenously, intrathecally, subcutaneously, by injection into involved tissue, intraarterially, intranasally, orally, or via an implanted device.
  • the therapeutic agent(s) according to the invention will be administered in the form of a composition comprising the therapeutic agent in conjunction with pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial, and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, giycerol, ethanol and the like, as well as combinations thereof.
  • isotonic agents for example sug- ars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life and the effectiveness of the therapeutic agent(s).
  • compositions typically must be sterile and stable under the condition of manufacture and storage.
  • the composition can be formulated, for example, as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating the therapeutic agent(s) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the therapeutic agent(s) into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the therapeutic agent(s) plus any additional desired ingredient from the previously sterile filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, mono- stearate salts and gelatin.
  • the therapeutic agent(s) of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route of administration for a fixed combination of roflumilast and the IL-1 Trap according to the invention is intravenous injection or infusion.
  • the therapeutic agent(s) may be prepared with a carrier that will protect the agent against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhyd rides, polyglycolic acid, collagen, polyorthoesters, and poylactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art.
  • the therapeutic agent(s) of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic agent(s) may also be enclosed in a hard or soft shell gelatine capsule or compressed into tablets.
  • the therapeutic agent(s) may be incorporated with excipients and used in the form of ingesta- ble tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • To administer the therapeutic agent(s) according to the invention it may be necessary to coat the therapeutic agent(s) with, or co-administer with the therapeutic agent(s) with, a material to prevent its inac- tivation.
  • the therapeutic agent(s) are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the therapeutic agent(s) with the norm.
  • the adult daily dose is in the range from 50 - 1000 ⁇ g, preferably in the range from 250 - 500 ⁇ g, preferably by once daily administration.
  • the adult daily dose is in the range from 50 - 1000 ⁇ g, preferably in the range from 250 - 500 ⁇ g.
  • the adult daily dose is in the range from 50 - 600 ⁇ g, preferably in the range from 150 - 300 ⁇ g.
  • An exemplary, non-limiting range for the IL-1 Trap is 50-800 ⁇ g/kg body weight of the subject to be treated by a once weekly administration.
  • the adult dose of the IL-1 Trap is 25-100 mg administered by a once weekly subcutaneous injection.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cell Biology (AREA)
  • Rheumatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'administration combinée de roflumilast et IL-1 Trap afin de traiter une maladie dans laquelle l'activité de la phosphodiestérase 4 (PDE4) et/ou de l'interleukine 1 (IL-1) est nocive.
PCT/EP2004/050743 2003-05-12 2004-05-10 Composition comprenant roflumilast et il-1 trap WO2004098596A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03010590 2003-05-12
EP03010590.2 2003-05-12

Publications (1)

Publication Number Publication Date
WO2004098596A1 true WO2004098596A1 (fr) 2004-11-18

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PCT/EP2004/050743 WO2004098596A1 (fr) 2003-05-12 2004-05-10 Composition comprenant roflumilast et il-1 trap

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Country Link
WO (1) WO2004098596A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7776893B2 (en) 2003-09-05 2010-08-17 Nycomed Gmbh Use of PDE4 inhibitors for the treatment of diabetes mellitus
US8017633B2 (en) 2005-03-08 2011-09-13 Nycomed Gmbh Roflumilast for the treatment of diabetes mellitus
EP2068889B1 (fr) * 2006-08-10 2019-10-23 Roy C. Levitt Anakinra pour l'utilisation dans le traitement du syndrome de bronchiolite oblitérante

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001338A1 (fr) * 1993-07-02 1995-01-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux benzamides a substituants fluoroalcoxy et leur utilisation comme inhibiteurs de la phosphodiesterase nucleotidique cyclique
US6472179B2 (en) * 1998-09-25 2002-10-29 Regeneron Pharmaceuticals, Inc. Receptor based antagonists and methods of making and using

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001338A1 (fr) * 1993-07-02 1995-01-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux benzamides a substituants fluoroalcoxy et leur utilisation comme inhibiteurs de la phosphodiesterase nucleotidique cyclique
US6472179B2 (en) * 1998-09-25 2002-10-29 Regeneron Pharmaceuticals, Inc. Receptor based antagonists and methods of making and using

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BARSIG J ET AL: "THE NOVEL PHOSPHODIESTERASE-4 INHIBITOR ROFLUMILAST SUPPRESSES TNF-ALPHA PRODUCTION AND EFFICIENTLY PROTECTS MICE AGAINST COLLAGEN-INDUCED ARTHRITIS ALONE AND IN COMBINATION WITH METHOTREXATE", ARTHRITIS AND RHEUMATISM, LIPPINCOTT, PHILADELPHIA, US, vol. 9, SUPPL, no. 44, September 2001 (2001-09-01), pages ABSTRACT1885, XP001062875, ISSN: 0004-3591 *
ECONOMIDES ARIS N ET AL: "Cytokine traps: Multi-component, high-affinity blockers of cytokine action.", NATURE MEDICINE, vol. 9, no. 1, 20 January 2003 (2003-01-20), pages 47 - 52, XP002255761, ISSN: 1078-8956 *
GABAY CEM: "IL-1 trap. Regeneron/Novartis.", CURRENT OPINION IN INVESTIGATIONAL DRUGS (LONDON, ENGLAND: 2000) ENGLAND MAY 2003, vol. 4, no. 5, 1 May 2003 (2003-05-01), pages 593 - 597, XP009017868, ISSN: 1472-4472 *
HATZELMANN A ET AL: "ANTI-INFLAMMATORY AND IMMUNOMODULATORY POTENTIAL OF THE NOVEL PDE4 INHIBITOR ROFLUMILAST IN VITRO", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND, US, vol. 297, no. 1, 2001, pages 267 - 279, XP001024814, ISSN: 0022-3565 *
REID P: "ROFLUMILAST", CURRENT OPINION IN INVESTIGATIONAL DRUGS, CURRENT DRUGS, LONDON, GB, vol. 3, no. 8, August 2002 (2002-08-01), pages 1165 - 1170, XP001119630, ISSN: 0967-8298 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7776893B2 (en) 2003-09-05 2010-08-17 Nycomed Gmbh Use of PDE4 inhibitors for the treatment of diabetes mellitus
US8017633B2 (en) 2005-03-08 2011-09-13 Nycomed Gmbh Roflumilast for the treatment of diabetes mellitus
US8541456B2 (en) 2005-03-08 2013-09-24 Takeda Gmbh Roflumilast for the treatment of diabetes mellitus type 2
EP2068889B1 (fr) * 2006-08-10 2019-10-23 Roy C. Levitt Anakinra pour l'utilisation dans le traitement du syndrome de bronchiolite oblitérante
US10550389B2 (en) 2006-08-10 2020-02-04 Roy C. Levitt Localized therapy of lower airways inflammatory disorders with proinflammatory cytokine inhibitors
EP3669878A1 (fr) * 2006-08-10 2020-06-24 Roy C. Levitt Thérapie localisée des troubles inflammatoires des voies respiratoires inférieures avec des inhibiteurs de cytokines inflammatoires
US11091763B2 (en) 2006-08-10 2021-08-17 Altavant Sciences Gmbh Localized therapy of lower airways inflammatory disorders with proinflammatory cytokine inhibitors
US11718853B2 (en) 2006-08-10 2023-08-08 Onspira Therapeutics, Inc. Localized therapy of lower airways inflammatory disorders with proinflammatory cytokine inhibitors

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