WO1997029738A1 - Procedes et compositions de traitement par inhalation du dysfonctionnement de la trompe d'eustache - Google Patents

Procedes et compositions de traitement par inhalation du dysfonctionnement de la trompe d'eustache Download PDF

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Publication number
WO1997029738A1
WO1997029738A1 PCT/US1996/002294 US9602294W WO9729738A1 WO 1997029738 A1 WO1997029738 A1 WO 1997029738A1 US 9602294 W US9602294 W US 9602294W WO 9729738 A1 WO9729738 A1 WO 9729738A1
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Prior art keywords
surfactant
eustachian tube
dysfunction
content
acute
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PCT/US1996/002294
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English (en)
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Andrew J. Nemechek
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The Administrators Of The Tulane Educational Fund
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Publication of WO1997029738A1 publication Critical patent/WO1997029738A1/fr

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    • 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
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • the present invention relates to the use of surfactant in the treatment of eustachian tube dysfunction.
  • the eustachian tube for the treatment of disorders associated with eustachian tube dysfunction such as otitis media with effusion.
  • Otitis media inflammation of the middle ear, is a common disorder in children with 84% having one or more episodes by age three (Teele et al., 1989, J . Infect . Dis .
  • OME otitis media with effusion
  • Eustachian tube dysfunction is associated with OM and/or OME.
  • Structural factors affecting eustachian tube function in pediatric patients include short tube length, proximity of chronically infected adenoidal tissue and inefficient active tube opening by palatal musculature. While these are contributing factors in many pediatric patients, other factors that affect the population at large include mass lesions in the nasopharynx, iatrogenic injury to the eustachian tube orifice (Fornadley and Burns, 1994, Otolaryngol .
  • Efforts to improve eustachian tube function or bypass a poorly functioning eustachian tube include antimicrobial therapy, ventilation tube placement and adenoidectomy. These approaches focus on both the microbiologic and structural etiologies of poor eustachian tube function, especially in the pediatric patient. Failure to correct eustachian tube function and persistent OME result in hearing loss, delays in speech development and complications of chronic OM.
  • F opening force (transluminal pressure)
  • F T/R T - surface tension (force per unit length)
  • R radius (tube or sphere)
  • the present invention relates to methods of treating eustachian tube dysfunction using a surfactant, and pharmaceutical compositions in which surfactant is the active therapeutic agent.
  • it relates to the delivery of a surfactant by inhalation to the eustachian tube for the treatment of otologic disorders, and pharmaceutical compositions of surfactant in a formulation that facilitates entry into the eustachian tube following inhalation via the nasal cavity or via a combination of the oral and nasal cavities.
  • the present invention is based, in part, on Applicant's discovery of a clinically practical, non-invasive and efficacious method of delivering a surfactant to the eustachian tube.
  • inhaled nebulized surfactant is an efficacious therapeutic agent in reestablishing normal eustachian tube function by reducing its opening pressure.
  • eustachian tube dysfunction encompasses any clinical condition resulting from structural and/or physiological abnormalities of the eustachian tube, in which the common endpoint is reduced ventilation of the middle ear. 4 .
  • Figure 2 Apparatus used to deliver nebulized surfactant to affected subjects .
  • Figure 4 Mean values of eustachian tube opening pressure for non-affected healthy ears and affected, surfactant-treated ears.
  • the present invention provides a clinically novel and practical method of delivering a surfactant to the eustachian tube of an individual.
  • the invention further provides novel surfactant compositions suited for delivery to the eustachian tube via the nasal route by inhalation.
  • OME was induced in gerbils by transtympanic inoculation of heat-killed Streptococcus pneumoniae .
  • a surfactant composition can be effectively delivered through inhalation to the eustachian tube to reduce its opening pressure for the treatment of eustachian tube dysfunction and its associated disorders.
  • the present invention relates to a non-invasive method for delivering any surfactant composition to the eustachian tube.
  • surfactant refers to any pharmaceutically acceptable surface active substance that reduces surface tension.
  • Surfactant is generally composed of lipids and certain associated proteins.
  • a well known example of such a substance is pulmonary surfactant produced by cells lining the pulmonary alveoli, preventing collapse during the respiratory cycle by reducing surface tension.
  • Pulmonary surfactants have been produced artificially (United States Patent 4,312,860) and extracted from human or animal lung (EP 119056) .
  • One pharmaceutically acceptable natural animal pulmonary surfactant that has been used successfully to treat human respiratory disorders contains a high concentration of phospholipids (99%), a protein content of less than 1-1.5% and is devoid of free carbohydrates, cholesterol, triglycerides and cholesterol esters (United States Patent 5,024,995). This preparation was used therapeutically at about 200 mg of phospholipids/kg of body weight.
  • SURVANTA is a surfactant comprising a natural bovine lung extract that contains phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins to which colfosceril palmitate (dipalmitoylphosphatidylcholine) , palmitic acid, and tripalmitin are added to standardize the composition and to mimic surface-tension lowering properties of natural lung surfactant (United States Patent 5,013,720).
  • the resulting composition provides 25 mg/ml phospholipids (including 11.0-15.5 mg/ml disaturated phosphatidylcholine), 0.5-1.75 mg/ml triglycerides, 1.4-3.5 mg/ml free fatty acids, and less than 1.0 mg/ml protein. It is suspended in 0.9% sodium chloride solution, heat-sterilized and it contains no preservatives. Its protein content consists of two hydrophobic, low molecular weight, surfactant-associated proteins commonly known as SP-B and SP-C (United States Patent 5,302,581). It does not contain the hydrophilic, large molecular weight surfactant-associated protein known as SP-A.
  • Each ml of "SURVANTA” contains 25 mg of phospholipids.
  • Mammalian pulmonary surfactants suitable for use in the present invention include, but are not limited to, porcine, bovine, canine and human surfactants.
  • surfactant compositions contain dipalmitoyl- phosphatidylcholine (DPPC) as their phospholipid in an aqueous carrier, either alone or in combination with other phospholipids (United States Patent 5,299,566) .
  • DPPC dipalmitoyl- phosphatidylcholine
  • Such surfactant compositions may be obtained from natural sources such as the lung or chemically synthesized (United States Patents 4,861,756; 4,826,821 and 4,312,860) .
  • surfactant-associated proteins may be produced by recombinant DNA technologies (United States Patent 4,912,038; 5,169,761; 4,933,280).
  • SURFACTANT TA is a surfactant comprising a mammalian lung extract that contains a phospholipid content of 75-95.5%, a neutral lipid content of 1.8-14%, total cholesterol content of 0-3%, carbohydrate content of 0.1-1.5% and protein content of 0.5-5% (United States Patent 4,338,301).
  • EXOSURF NEONATAL is a protein- free synthetic lung surfactant stored under vacuum as a sterile lyophilized powder.
  • Each 10 ml vial contains 108 mg dipal itoylphosphatidylcholine, 12 mg cetyl alcohol such as hexadecanol, 8 mg of a non-toxic nonionic surface active agent such as tyloxapol and 47 mg sodium chloride (United States Patent 4,826,821).
  • Additional suitable compositions include biosynthetic mammalian lung surfactant described in United States Patent 5,387,746, "CUROSURF" described in United States Patent 5,024,995 and "LIQUIVENT".
  • CUROSURF is a porcine pulmonary surfactant that contains a polar lipid content of 98.5-99% and a protein content of less than 1.5% (United States Patent 5,024,995).
  • LIQUIVENT is an unemulsified neat perfluorooctylbromide-based oxygen carrier/surfactant (United States Patents 5,437,272; 4,987,154) . Furthermore, since the phospholipid content of surfactant in the middle ear system differs from pulmonary surfactant (Coticchia et al., 1991, Acta Otolaryngol .
  • surfactant extracted from the middle ear or synthetically produced that mimics its natural composition may also be used for the practice of the present invention.
  • 5.2. ADMINISTRATION OF SURFACTANT The preferred route of administering surfactant compositions for the practice of the present invention is by inhalation. The treatment continues until an improvement of the eustachian tube dysfunction is observed, e.g., a reduction in opening pressure. Generally, the treated patient is evaluated 10 to 14 days after treatment. While inhalation via the nasal cavity is the preferred method of delivery, surfactants may also be delivered via both nasal and oral cavities. In this connection, surfactant is delivered by a mask which is placed over both the nose and mouth of the individual in need of treatment.
  • the surfactant composition can be administered in an aerosol formulation as a dry powder or in a solution or suspension with a diluent.
  • a dispersing agent or dispersant can be administered in an aerosol formulation as a dry powder or in a solution or suspension with a diluent.
  • the term "dispersant” refers to an agent that assists aerosolization of the surfactant.
  • surfactant is itself often used in the art as a dispersant to reduce surface tension caused by atomization of the solution forming a liquid aerosol, an additional dispersant may not be necessary. Amounts of surfactant used vary, being generally within the range of 0.001 and 4% by weight of the formulation.
  • SURVANTA may be prepared in the range of 0.001-25 mg/ml, and an optimal dose for administering any surfactant in accordance with the present invention can be readily determined by titration experiments that are well known in the art. Suitable surfactant can be selected on the basis of desired properties, depending on the specific formulation, diluent (in a liquid formulation) or form of powder (in a dry powder formulation) , etc.
  • the formulation must be aerosolized, i.e., it must be broken down into liquid or solid particles in order to ensure that the aerosolized dose reaches the eustachian tube.
  • the mass median dynamic diameter is 1-10 micrometers in order to ensure that the particles reach the eustachian tube. It is preferred that the particles be in the range of 3-9 micrometers to facilitate entry into the nasopharynx, and minimize entry into the lung (See Damms et al., 1995, Biotechol . 13:1438-1440).
  • aerosol particle is used herein to describe the liquid or solid particle suitable for nasal administration, i.e., that will reach the eustachian tube.
  • any form of aerosolization known in the art including but not limited to nebulization, atomization or pump aerosolization of a liquid formulation, and aerosolization of a dry powder formulation, can be used in the practice of the invention. Often, the aerosolization of a liquid or a dry powder formulation requires a propellent.
  • the propellent includes, but is not limited to, halogenated hydrocarbon such as chlorofluorocarbon, a hydrofluorocarbon, a hydrochlorofluorocarbon, or a hydrocarbon such as triflouromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof.
  • halogenated hydrocarbon such as chlorofluorocarbon, a hydrofluorocarbon, a hydrochlorofluorocarbon, or a hydrocarbon such as triflouromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof.
  • the device for aerosolization is a metered dose inhaler.
  • a metered dose inhaler provides a specific dosage when administered, rather than a variable dose depending on administration.
  • Such a metered dose inhaler can be used with either a liquid or a dry powder aerosol formulation.
  • Metered dose inhalers are well known in the art. Systems of aerosol delivery, such as the pressurized metered dose inhaler and the dry powder inhaler are disclosed in Newman, S.P., Aerosol and the Lung, Clarke, S.W. and Davia, D. editors, pp. 197-22. Alternatively, a jet nebulizer (United States Patent 4,832,012) or an ultrasonic nebulizer (The DeVilbiss Co., Somerset, PA) may be used.
  • the present invention provides liquid aerosol formulations and dosage forms of surfactant for use in treating subjects suffering from eustachian tube dysfunction.
  • dosage forms contain surfactant composition in a pharmaceutically acceptable diluent.
  • Pharmaceutically acceptable diluents include, but are not limited to, sterile water, saline, buffered saline, dextrose solution, and the like.
  • a diluent that may be used in the present invention or the pharmaceutical formulation of the present invention is phosphate buffered saline, or a buffered saline solution generally between the pH 7.0-8.0 range, or sterile water.
  • the liquid aerosol formulation of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and excipients.
  • the liquid aerosol formulations of the present invention will typically be used with a nebulizer.
  • the nebulizer can be either air driven via a compressor or ultrasonically. Any nebulizer known in the art can be used in conjunction with the present invention including, but not limited to, Ultravent, Mallinckrodt, Inc. (St. Louis, MO) and the Acorn II nebulizer (Marquest Medical Products, Englewood, CO) . Other nebulizers useful in conjunction with the present invention are described in United States Patents 4,624,251; 3,703,173; 3,561,444; and 4,635,627.
  • the formulations of the present embodiment may also include other agents useful for stabilization or for the regulation of osmotic pressure.
  • agents include, but are not limited to, salts, such as sodium chloride, or potassium chloride, and carbohydrates, such as glucose, galactose or mannose, and the like.
  • a surfactant composition is used as a dry powder inhaler formulation comprising a finely divided powder form of the surfactant and a dispersant.
  • the form of the surfactant is generally a lyophilized powder. Lyophilized forms of surfactant can be obtained through standard techniques well known in the art.
  • the dry powder formulation is composed of a finely divided dry powder containing a surfactant, a dispersing agent and also a bulking agent. Bulking agents useful in conjunction with the present formulation include such agents as lactose, sorbitol, sucrose or mannitol, in amounts that facilitate the dispersal of the powder from the device.
  • the delivery of surfactants by inhalation according to the present invention is used to treat any disorders that are associated with and known to cause eustachian tube dysfunction. These include, but are not limited to, trauma,
  • disorders that benefit from the present invention include, but are not limited to, otologic disorders such as acute OM,
  • the present invention is used in situations of eustachian tube dysfunction secondary to acute changes in altitude, e.g., ascent and descent during air flight.
  • Streptococcus pneumoniae (ATCC 6305) was 0 subcultured for each experiment in beef heart infusion broth. Stationary phase bacteria were washed and suspended in phosphate-buffered saline to a concentration of 108 colony forming units per milliliter. Aliquots of heat-killed pneumococci were obtained by placing the bacterial suspension 5 in a water bath at 200°C for 45 minutes. Sterility of these aliquots was confirmed with subsequent replating on nutrient agar. Because of their relatively large tympanic bullae and lack of native middle ear disease, gerbils inoculated with nonviable bacteria have been the established animal model for OME.
  • the experimental protocol was approved in advance by the Tulane University School of Medicine Advisory Committee for Animal Resources. All experiments were conducted in compliance with the Committee's applicable regulations. Twenty gerbils were anesthetized with ketamine and xylazine via intramuscular injection. Each external auditory canal was cleaned with alcohol. Examination of the canal, the tympanic membrane and the middle ear was accomplished with an operating microscope. 0.1 ml of heat- killed bacterial suspension was introduced into the middle ear space through the tympanic membrane using a 27 gauge spinal needle. After 5 days, the animals were reanesthetized using the same intramuscular injection of ketamine and xylazine. Microscopic evaluation revealed either the presence or absence of effusion. The animals without an effusion in either ear were considered healthy, non-affected subjects, whereas the animals with an effusion in at least one ear were considered affected subjects.
  • Eustachian tube opening pressure was measured as follows. Immediately following sacrifice of each animal, their tympanic bulla were surgically exposed and cannulated with a 21 gauge butterfly needle. This needle was fixed in place with Krazy Glue (Borden, Inc., Columbus, OH). The external ear canals were filled with epoxy glue (Loctite
  • Epoxy was also placed over the cannulation site at the tympanic bullae to ensure an airtight system for pressure measurement.
  • the butterfly needle was connected to a closed circuit consisting of a pressure transducer, a stopcock and a syringe attached to a infusion pump and a monitor. Air was slowly introduced into the tympanic bullae at a rate of 5 ml/minute providing steady pressurization of the system. This pressurization was monitored until an abrupt loss of pressure in the system was noted indicative of eustachian tube opening and release of pressure into the nasopharynx. The pressure at which this occurred was defined as the eustachian tube opening pressure. With each measurement, the system was opened to atmospheric pressure allowing the eustachian tube to close. This procedure was repeated for a total of five cycles and the mean value for the set was calculated and recorded. 6.2. RESULTS

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Abstract

La présente invention concerne des procédés de traitement du dysfonctionnement de la trompe d'Eustache par utilisation d'agents tensio-actifs. L'invention consiste en l'administration dans la trompe d'Eustache, par inhalation, d'agents tensio-actifs destinés à réduire sa pression d'ouverture. Les compositions d'agents tensio-actifs convenant à l'utilisation dans le cadre de l'invention s'obtiennent à partir de sources naturelles ou sont produites par synthèse. On dispose actuellement à cet effet dans le commerce de l'agent tensio-actif pulmonaire bovin. Les compositions d'agents tensio-actifs sont administrées par inhalation via les cavités nasales et/ou orales sous forme d'aérosols liquides ou de poudres sèches. La présente invention permet de concevoir une grande variété d'utilisations concernant, de façon non exhaustive, le traitement des troubles otologiques associés au dysfonctionnement de la trompe d'Eustache tels que l'otite moyenne et le dysfonctionnement imputable aux brusques changements d'altitude.
PCT/US1996/002294 1996-02-16 1996-02-20 Procedes et compositions de traitement par inhalation du dysfonctionnement de la trompe d'eustache WO1997029738A1 (fr)

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Cited By (15)

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Publication number Priority date Publication date Assignee Title
GB2331925A (en) * 1997-12-03 1999-06-09 Britannia Pharmaceuticals Ltd Phospholipids for the Treatment of Asthma
WO1999027920A2 (fr) * 1997-12-03 1999-06-10 Britannia Pharmaceuticals Limited Ameliorations apportees a des medicaments pour traiter l'asthme
GB2332626A (en) * 1997-12-24 1999-06-30 Britannia Pharmaceuticals Ltd Phospholipids in the Treatment of Disorders of the Middle Ear
WO1999033472A1 (fr) * 1997-12-24 1999-07-08 Britannia Pharmaceuticals Limited Utilisation d'un tensioactif pour la preparation d'un medicament conçu pour le traitement de troubles de l'oreilles moyenne
US6156294A (en) * 1999-11-28 2000-12-05 Scientific Development And Research, Inc. Composition and method for treatment of otitis media
WO2003047521A2 (fr) * 2001-12-04 2003-06-12 Scientific Development And Research, Inc. Composition et methode de traitement de l'otite moyenne
US6599883B1 (en) * 1998-10-30 2003-07-29 Nastech Pharmaceutical Company, Inc. Nasal delivery of xylitol
WO2003055410A3 (fr) * 2001-12-11 2003-10-16 Scient Dev And Res Inc Composition et methode de traitement d'une otite externe
US6824761B1 (en) 1999-05-28 2004-11-30 Britannia Pharmaceuticals Limited Anti-asthmatic combinations comprising surface active phospholipids
WO2005037246A2 (fr) * 2003-10-15 2005-04-28 Pari Gmbh Preparation aqueuse sous forme d'aerosol
EP1531795A1 (fr) * 2002-05-02 2005-05-25 The President And Fellows Of Harvard College Formulations limitant l'extension d'infections pulmonaires
US7833282B2 (en) 2006-02-27 2010-11-16 Mandpe Aditi H Eustachian tube device and method
WO2017095905A1 (fr) * 2015-11-30 2017-06-08 Flesher Gregory J Compositions et procédés de traitement et de prophylaxie otologique
US20220040203A1 (en) * 2014-08-08 2022-02-10 Shenzhen Hightide Biopharmaceutical, Ltd. Liquid formulation compositions, medicament delivery devices, and methods of preparation and use thereof
EP3914323A4 (fr) * 2019-01-23 2022-10-05 Alrich Partners, Inc. Procédé pour améliorer la perméabilité d'une trompe d'eustache et le traitement de l'otite moyenne

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999027920A2 (fr) * 1997-12-03 1999-06-10 Britannia Pharmaceuticals Limited Ameliorations apportees a des medicaments pour traiter l'asthme
WO1999027920A3 (fr) * 1997-12-03 1999-09-10 Britannia Pharmaceuticals Ltd Ameliorations apportees a des medicaments pour traiter l'asthme
US7473416B2 (en) 1997-12-03 2009-01-06 Britannia Pharmaceuticals, Ltd. Medicaments for asthma treatment
US6482391B1 (en) 1997-12-03 2002-11-19 Britannia Pharmaceuticals Limited Medicaments for asthma treatment
GB2331925A (en) * 1997-12-03 1999-06-09 Britannia Pharmaceuticals Ltd Phospholipids for the Treatment of Asthma
GB2332626A (en) * 1997-12-24 1999-06-30 Britannia Pharmaceuticals Ltd Phospholipids in the Treatment of Disorders of the Middle Ear
WO1999033472A1 (fr) * 1997-12-24 1999-07-08 Britannia Pharmaceuticals Limited Utilisation d'un tensioactif pour la preparation d'un medicament conçu pour le traitement de troubles de l'oreilles moyenne
US6395295B1 (en) 1997-12-24 2002-05-28 Britannia Pharmaceuticals Limited Use of surface active agent for the manufacture of a medicament for treatment of disorders of the middle ear
GB2332626B (en) * 1997-12-24 2002-07-03 Britannia Pharmaceuticals Ltd Medicaments for treatment of disorders of the middle ear
US6599883B1 (en) * 1998-10-30 2003-07-29 Nastech Pharmaceutical Company, Inc. Nasal delivery of xylitol
US7273604B2 (en) 1998-11-26 2007-09-25 Britannia Pharmaceuticals Limited Anti-asthmatic combinations comprising surface active phospholipids
US6824761B1 (en) 1999-05-28 2004-11-30 Britannia Pharmaceuticals Limited Anti-asthmatic combinations comprising surface active phospholipids
US6676930B2 (en) 1999-11-28 2004-01-13 Scientific Development And Research, Inc. Composition and method for treatment of otitis media
EP1233753A1 (fr) * 1999-11-28 2002-08-28 Scientific Development & Research, Inc. Composition et methode de traitement de l'otite moyenne
US6521213B1 (en) * 1999-11-28 2003-02-18 Scientific Development And Research, Inc. Composition and method for treatment of otitis externa
US6616913B1 (en) * 1999-11-28 2003-09-09 Scientific Development And Research, Inc. Composition and method for treatment of otitis media
EP1233753A4 (fr) * 1999-11-28 2009-09-23 Scient Dev & Res Inc Composition et methode de traitement de l'otite moyenne
US6156294A (en) * 1999-11-28 2000-12-05 Scientific Development And Research, Inc. Composition and method for treatment of otitis media
US7064132B2 (en) 1999-11-28 2006-06-20 Scientific Development And Research, Inc. Composition and method for treatment of otitis external
WO2003047521A3 (fr) * 2001-12-04 2003-09-18 Scient Dev And Res Inc Composition et methode de traitement de l'otite moyenne
WO2003047521A2 (fr) * 2001-12-04 2003-06-12 Scientific Development And Research, Inc. Composition et methode de traitement de l'otite moyenne
WO2003055410A3 (fr) * 2001-12-11 2003-10-16 Scient Dev And Res Inc Composition et methode de traitement d'une otite externe
US8858917B2 (en) 2002-05-02 2014-10-14 President And Fellows Of Harvard College Methods for limiting spread of pulmonary infections
EP1531795A1 (fr) * 2002-05-02 2005-05-25 The President And Fellows Of Harvard College Formulations limitant l'extension d'infections pulmonaires
EP1531795A4 (fr) * 2002-05-02 2011-02-23 Harvard College Formulations limitant l'extension d'infections pulmonaires
WO2005037246A3 (fr) * 2003-10-15 2005-12-08 Pari Gmbh Preparation aqueuse sous forme d'aerosol
US7758886B2 (en) 2003-10-15 2010-07-20 Pari Gmbh Pharmaceutical aerosol composition
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