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WO2011142677A1 - Méthodes et compositions pour le traitement de troubles pulmonaires - Google Patents

Méthodes et compositions pour le traitement de troubles pulmonaires Download PDF

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Publication number
WO2011142677A1
WO2011142677A1 PCT/NZ2011/000070 NZ2011000070W WO2011142677A1 WO 2011142677 A1 WO2011142677 A1 WO 2011142677A1 NZ 2011000070 W NZ2011000070 W NZ 2011000070W WO 2011142677 A1 WO2011142677 A1 WO 2011142677A1
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WO
WIPO (PCT)
Prior art keywords
composition
sodium citrate
sputum
viscosity
mucus
Prior art date
Application number
PCT/NZ2011/000070
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English (en)
Inventor
Robert B. Elliot
Original Assignee
Breathe Easy Ltd
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 Breathe Easy Ltd filed Critical Breathe Easy Ltd
Publication of WO2011142677A1 publication Critical patent/WO2011142677A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61P11/12—Mucolytics

Definitions

  • the present invention relates to methods and compositions for the treatment of lung disorders, such as cystic fibrosis, by reducing the viscosity and/or the cohesiveness of bodily secretions, such sputum, mucus and other secretions.
  • Cystic fibrosis is an inherited chronic life-threatening disorder that affects the lungs and digestive system of about 70,000 children and adults worldwide. CF causes serious lung damage due to a persistent cycle of bacterial infection and inflammatory response, and may also induce gastrointestinal dysfunction, with resulting nutritional deficiencies.
  • the underlying cause of CF is one of a number of inherited mutations in the gene encoding a chloride channel protein (the CF transmembrane conductance regulator) which regulates the normal movement of chloride ions across- cell membranes and affects cells that produce mucus, sputum, sweat, saliva and digestive liquids. These secretions are normally thin and watery, and act as lubricants. In patients suffering from CF, lung function is severely comprised by the presence of thick, sticky, highly viscous tracheo-bronchial secretions, which clog the lungs and lead to recurrent infections.
  • Pseudomonas aeruginosa is an infectious pathogen that is found in the secretions of CF patients as well as immuno-compromised host and burn patients.
  • P. aeruginosa strains isolated from CF patients are typically mucoid.
  • Non-mucoid strains of P. aeruginosa are generally treatable with antimicrobials.
  • aeruginosa are much more difficult to treat and produce large quantities of the mucoid exopolysaccharide alginic acid (alginate), which appears to have several effects including interference with complement-mediated polymorphonuclear leukocyte (PMN) chemotaxis, reduction in nonopsonic phagocytosis by PMNs, resistance to bacterial killing and interference with effective antimicrobial penetration of bacterial cells.
  • Biofilms composed of mucoid alginate and acellular debris, including extracellular host and bacterial DNA, are formed and become virtually impenetrable.
  • Alginate from P. aeruginosa can also form insoluble calcium salts, which contributes to the impermeability of the hydrogel.
  • aeruginosa strains in CF patients has been elusive, at least in part because the thick secretions produced by the mucoid strains and the chronic bacterial infections associated with alginate biofilms block entry of both antimicrobials and elements of the patient's immune system.
  • the difficulty of treatment has been exacerbated by the emergence of strains of Pseudomonas and species of Bordetella that are resistant to available antimicrobials.
  • Pulmozyme ® (dornase alfa or rhDNase), which was approved for treatment of CF in
  • Pulmozyme ® acts by reducing the presence of excess extracellular DNA arising from cellular death and subsequent gelling of the DNA, thereby reducing the viscosity of the sputum.
  • Treatment with Pulmozyme ® generally results in a reduction in the number and severity of pulmonary infections and improved lung function. It is a standard of treatment for CF patients with intractable infective exacerbations, and is generally taken by aerosol inhalation by mouth once or twice daily.
  • Alginate can be depolymerized to oligosaccharides by the enzyme alginate lyase (also referred to as "alginase").
  • alginate lyase has been studied as an agent for modifying the course of pseudomonal infection caused by mucoid strains of P. aeruginosa.
  • the coadministration of alginate lyase with an amikacin regimen appeared to be effective in removing the exopolysaccharide from the surface of mucoid pseudomonal cells and enhancing the clearance of mucoid pseudomonal strains from the infection foci (Bayer, A.S.
  • Alginase has also been shown to reduce CF sputum viscosity and enhance macrophage or antimicrobial killing of the organism in vitro (Eftekhar, F. and Speer, D., Alginase Treatment of Mucoid Pseudomonas aeruginosa Enhances Phagocytosis by Human Monocyte-Derived Macrophages, Infection and Immunity, 56:2788-2793 (1998)).
  • alginase has also been shown to reduce CF sputum viscosity and enhance macrophage or antimicrobial killing of the organism in vitro (Eftekhar, F. and Speer, D., Alginase Treatment of Mucoid Pseudomonas aeruginosa Enhances Phagocytosis by Human Monocyte-Derived Macrophages, Infection and Immunity, 56:2788-2793 (1998)).
  • the use of alginase in humans causes a severe allergic reaction.
  • glycosaminoglycan degrading enzymes such as heparanase
  • heparanase could be used to reduce the amount of mucopolysaccharide and thereby reduce sputum viscosity (see, for example, US Patents 6,153,187 and 6,423,312).
  • No clinical data is available on the use of heparanase to treat CF.
  • EDTA edetate sodium
  • the level of calcium salts has been shown to be elevated in cells of tracheal mucosa and, to a lesser extent, mucus glands of CF patients. These calcium salts tend to appear as apatite-like crystals (Cantet et al., Virchows Arch. 439:683-90 (2001)). The presence of calcium in mucosa has been shown to increase inflammatory reactions (Ribeiro et al., J. Biol. Chem. 208: 17798-806 (2005)). In addition, it is believed that lowering calcium levels in mucosa has beneficial effects on the chloride pump defect that is the hallmark of CF (Middleton et al., Am. J. Respir. Crit.
  • the present invention provides methods and compositions for reducing the viscosity and/or cohesiveness of mucus and/or sputum in a patient in need thereof.
  • the disclosed methods and compositions can be effectively employed in the treatment of disorders characterized by the presence of bodily secretions, such as sputum or mucus, having an abnormal or excessive viscosity, and/or characterized by the presence of excess amounts of mucus and/or sputum.
  • CF cystic fibrosis
  • COPD chronic obstructive pulmonary disease
  • methods comprise administering to a patient a composition comprising sodium citrate in an amount effective to decrease the viscosity and/or cohesiveness of the mucus or sputum compared to prior administration.
  • the composition is administered in an amount effective to decrease the viscosity and/or cohesiveness of the mucus or sputum by at least 25-50%.
  • the compositions may be administered with one or more known therapeutic agents, such as DNase, alginase, heparanase and antimicrobial agents.
  • the disclosed compositions maybe administered prior, to administration of the known therapeutic, for example at least four hours prior to administration of the known therapeutic.
  • the disclosed compositions may be administered concurrently with the known therapeutic provided there is no adverse interaction with the known therapeutic agent.
  • compositions are administered in either an aerosol form or in a dry powder form, and are delivered to a target site selected from the group consisting of: the respiratory tract, gastrointestinal tract and reproductive tract.
  • compositions for use in the disclosed methods comprising, or consisting essentially of, sodium citrate in an amount effective to decrease the viscosity and/or cohesiveness of the mucus and/or sputum of a patient when administered to a patient in need thereof compared to prior administration.
  • the sodium citrate is present in an amount effective to decrease the viscosity and/or cohesiveness of the mucus and/or sputum by at least 25-50%.
  • the disclosed compositions are preferably formulated for delivery to the respiratory tract, the gastrointestinal tract or to the reproductive tract.
  • Fig. 1 shows the viscosity of a sputum sample at 0 sec, 30 sec, 90 sec and 150 sec after addition of different volumes of 50mM sodium citrate.
  • the present invention provides methods for the treatment of a disorder in which abnormal or excessive viscosity and/or cohesiveness of one or more bodily secretions, such as mucus or sputum, is a symptom or cause of the disorder, by administering to a patient in need thereof a composition comprising sodium citrate.
  • Mucus or sputum that is abnormally or excessively viscous and/or cohesive has a viscosity or cohesiveness that is measurably more viscous or cohesive than mucus or sputum from a normal, healthy patient.
  • Such mucus or sputum may cause discomfort in a patient and/or cause or exacerbate a disease in the patient.
  • the disclosed methods and compositions are effectively employed in the treatment of lung disorders including, but not limited to, cystic fibrosis (CF), bronchiectasis, (in particular bronchiectasis patients who are colonized with mucoid Pseudomonas species), asthma, bronchitis, sinusitis, chronic obstructive pulmonary disease (COPD), asthma, neonatal meconium aspiration syndrome and smokers' cough.
  • CF cystic fibrosis
  • COPD chronic obstructive pulmonary disease
  • the methods and compositions can also be used to treat bacterial, fungal and/or viral infections of the lungs and respiratory tract, such as bacterial pneumonia (for example caused by Streptococcus pneumonia), influenza (for example, H1N1), the common cold and other disorders characterized by the presence of increased sputum production.
  • bacterial pneumonia for example caused by Streptococcus pneumonia
  • influenza for example, H1N1
  • H1N1 the common cold and other disorders characterized by the presence of increased sputum production.
  • Sodium citrate is non-toxic and is a normal body metabolite that is removed from the body in the citric acid cycle. As detailed below, the inventor has determined that sodium citrate is effective in reducing sputum viscosity, at least in vitro, is well tolerated when administered via nebulization, and is effective in the treatment of cystic fibrosis.
  • sodium citrate decreases the viscosity and/or cohesiveness of sputum and/or mucus by (a) converting insoluble calcium salts of alginate, extracellular DNA and mucopolysaccharides to soluble salts; (b) reducing the calcium content of tracheal secretions and thereby enhancing the defective chloride pump; and/or (c) reducing intracellular calcium.
  • intracellular calcium crystals causes inflammation of the lung in patients with CF.
  • compositions that comprise sodium citrate in an amount effective to reduce the viscosity and/or cohesiveness of sputum or mucus as compared to the viscosity prior to contact with the composition.
  • the disclosed compositions comprise sodium citrate in an amount effective to reduce the viscosity of sputum or mucus by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, a.t least 45%, at least 50%, or at least 55%, compared to the viscosity prior to contact with the composition.
  • Techniques for measuring the viscosity of sputum are well known in the art and include, for example, a pourability test, as described below and the use of a viscometer, such as those available from proRheo GmbH (Germany).
  • the disclosed compositions comprise sodium citrate at a concentration of about 10 mM to about 60 raM, such as 10 mM, 15 mM, 20 raM. 25 mM, 30 raM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM or 60 mM.
  • the compositions may also comprise one or more components selected from the group consisting of: pharmaceutically acceptable carriers, such as water, phosphate buffered saline, Ringer's solution, dextrose solution; preservatives; and the like.
  • the sodium citrate is diluted in 1 ml to about 5 ml water, such as 1 ml, 1.5 ml, 2 ml, 2.5 ml, 3 ml, 3.5 ml, 4 ml, 4.5 ml or 5 ml.
  • the compositions are adniinistered one to two times a day.
  • 20 mM - 60 mM, for example, 25 mM or 55 mM sodium citrate diluted in 3 ml water is administered to a patient in need thereof, one or two times a day.
  • the sodium citrate composition is administered to a patient in an amount effective to provide a statistically significant increase in the liquefaction of the mucus and/or sputum.
  • the amount of sodium citrate administered to the patient is sufficient to result in a change in the liquefaction of the mucus or sputum such by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 55%.
  • the sodium citrate composition is administered in an amount sufficient to clear a blockage or inhibition-of function caused by the mucus or sputum as indicated by an improvement in the forced expiratory volume in one second (FEV1) of at least 5%, at least 9% or at least 12% after prolonged administration compared with the pre- administration value.
  • FEV1 forced expiratory volume in one second
  • compositions consist essentially of sodium citrate.
  • compositions consisting of sodium citrate is used to indicate compositions in which sodium citrate is the only component that is effective in reducing the viscosity of sputum by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 55%.
  • the preferred dosing regimen can be varied depending on the route of administration, symptoms, body weight, health and condition of the patient, and the like, and that the preferred dosing regimen can be readily determined using known techniques.
  • the disclosed compositions are delivered to one or more target site(s) characterized by (i) an accumulation of bodily secretions having an undesirably high viscosity and/or cohesiveness; and/or (ii) an undesirably high accumulation of secretions.
  • Target sites may include passageways in the lungs, airways within and leading to the lungs, nasal passageways, gastro-intestinal lumens, and lumens and cavities in the pancreas, digestive organs or reproductive organs.
  • the disclosed compositions are contacted with a bodily secretion, such as mucus or sputum, located in the respiratory tract, the gastrointestinal tract and/or the reproductive tract of a patient, preferably a mammal, such as a human.
  • compositions are delivered by inhalation or nasally, for example using a nebulizer or an aerosol, mist or vapor delivery system.
  • the sodium citrate compositions are formulated for delivery to the airways as mist or particles entrained in gaseous or liquid carriers using a nebulizer such as an ultrasonic nebulizer, electronic micropump, liquid projection apparatus or mist/vapor generating apparatus, which are well known in the art.
  • the compositions are delivered preferably at zero or low velocity to the mouth or nose, preferably during the inspiratory cycle only.
  • the disclosed compositions may be formulated for delivery to the airways using dry particle delivery devices.
  • sodium citrate can be administered to the respiratory tract in the form of a dry powder by means of inhalation. Powdered sodium citrate is administered at a concentration, and at a dosing frequency, similar to those enjoyed with sodium citrate solutions. In certain embodiments, powdered sodium citrate is administered in an amount of about 5 mg to about 50 mg, about 10 mg to about 20 mg, or about 15 mg of dry sodium citrate one or two times per day. Dry sodium citrate may be administered either with or without an excipient, such as lactose.
  • dry sodium citrate may be administered using a dry powder inhaler, such as those described in US Patents 6,209,538, 6,889,690, 7,617,822, 7,694,676 and 7,708,01 1.
  • the sodium citrate compositions disclosed herein are administered to a patient in combination with one or more known therapies currently employed in the treatment of CF.
  • the sodium citrate compositions can be used in combination with at least one of DNase (e.g., Pulmozyme®), heparanase and alginase.
  • DNase e.g., Pulmozyme®
  • the sodium citrate- containing composition and the DNase, heparanase and/or alginase may be provided in a common formulation or in separate formulations, and may be administered at the same time or at different times.
  • DNase is typically formulated in a calcium-containing buffer, it is advantageous to separate the administration of DNase and a sodium citrate composition by between 4-12 hours, such as 8 hours.
  • a sodium citrate composition when employed in combination with heparanse and/or alginase, the treatments can be separated by between 4-12 hours, such as 8 hours.
  • a sodium citrate composition disclosed herein is administered to a patient in need thereof approximately 8 hours prior to the administration of DNase.
  • the DNase, heparanase and/or alginase are administered using standard dosage regimes known to those of skill in the art.
  • Administration of the disclosed sodium citrate compositions may be accompanied by co-administration with an antimicrobial agent effective in reducing P. aeruginosa and/or other complex bacterial populations such as ZithromaxTM, Tobramycin, and the like.
  • Co- administration of an antimicrobial agent may be at the same time or at a different time from administration of the sodium citrate composition, and the antimicrobial agent may be provided in the same formulation or in a different formulation.
  • sample 1 was of a runny consistency
  • sample 2 was of an intermediate consistency
  • sample 3 was of a heavy consistency.
  • lOOul samples were measured and transferred to assay tubes in duplicate (except for sample 1 which was in short supply) and placed in a 37°C preheated Thermomixer.
  • lOul of saline (0.9% NaCl) was used as a negative control.
  • 5ul, lOul, 50ul or lOOul of 55mM aqueous sodium citrate solution was added per tube and mixed (400 rpm).
  • Each tube was checked for pourability, or viscosity, at 30 sec, 90 sec and 150 sec by observing the movement of the sputum sample along the wall of the tube.
  • the results of the study are shown below in Table 1 for samples 1-3, and in Fig. 1.
  • sample 1 no change in its watery nature was seen at any addition of either saline or citrate at any time after incubation.
  • sample 2 intermediate sputum viscosity
  • sample 3 which contained the most viscous sputum, was more resistant to the effects of citrate and took five minutes before the full effects were seen.
  • aqueous sodium citrate solution was examined as follows. Treatment solutions were prepared by diluting 0 mM, 11 mM and 22 mM sodium citrate in 2 ml of water. The solutions were nebulized and administered to three healthy volunteers in successive treatments, with ascending sodium citrate dosage volumes and a 5 min break between each treatment. The forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) were recorded 5 minutes after each treatment. The volunteer profiles are shown in Table 2. Table 2
  • Treatment solutions were 0.55mM sodium citrate dissolved in water. For each treatment, 3 ml was administered. The solutions were nebulized and administered to a 17 year old male with cystic fibrosis once per day for ten days. At the time of the trial, the patient was taking tobramycin, erythromycin and Pulmozyme 1M , all of which were continued throughout the trail period. Sodium citrate was administered in the morning and Pulmozyme 1 M at night, with there being at least six hours between the two administrations. The forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) were measured daily between 5 and 10 minutes after administration of nebulized sodium citrate. As shown in Table 4, below, both FEV1 and FVC were found to increase during the trial period.
  • FEV1 and FVC forced vital capacity

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Abstract

La présente invention a pour objet des méthodes et des compositions pour le traitement de troubles caractérisés par la présence d'une sécrétion corporelle anormalement visqueuse et/ou cohésive, telle que le mucus et le crachat. Les troubles qui peuvent être efficacement traités à l'aide des compositions et des méthodes selon la présente invention comprennent la fibrose kystique, la bronchiectasie, la maladie pulmonaire obstructive chronique, l'asthme, la bronchite, et les infections virales, fongiques et bactériennes qui affectent les poumons (telles que la grippe). Les compositions, qui contiennent une quantité efficace de citrate de sodium, peuvent être administrées seules ou en combinaison avec un ou plusieurs agents thérapeutiques connus.
PCT/NZ2011/000070 2010-05-11 2011-05-09 Méthodes et compositions pour le traitement de troubles pulmonaires WO2011142677A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2014189392A1 (fr) * 2013-05-23 2014-11-27 Breathe Easy Limited Méthodes et compositions destinées à la rupture des biofilms et au traitement des troubles caractérisés par la présence de biofilms
JP2020524172A (ja) * 2017-06-20 2020-08-13 レスピリオン・ファーマシューティカルズ・プロプライエタリー・リミテッド 肺感染症を低減させる方法

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WO1996035452A1 (fr) * 1995-05-10 1996-11-14 Adcock Ingram Limited Composition pharmaceutique contenant de l'acetylcysteine, de la carbocysteine ou de l'erdosteine en association avec un beta 2 agoniste et un expectorant pour le traitement des affections des voies respiratoires
US20080108592A1 (en) * 1997-12-31 2008-05-08 Astrazeneca Ab New method
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US20080008772A1 (en) * 2006-07-05 2008-01-10 Everett Laboratories, Inc. Narcotic biphasic release compositions and methods for treatment of coughing, sneezing, rhinorrhea, and/or nasal obstruction

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014189392A1 (fr) * 2013-05-23 2014-11-27 Breathe Easy Limited Méthodes et compositions destinées à la rupture des biofilms et au traitement des troubles caractérisés par la présence de biofilms
US20160120898A1 (en) * 2013-05-23 2016-05-05 Breathe Easy Limited Methods and compositions for the disruption of biofilms and treatment of disorders characterized by the presence of biofilms
EP2999464A4 (fr) * 2013-05-23 2017-01-11 Breathe Easy Ltd Méthodes et compositions destinées à la rupture des biofilms et au traitement des troubles caractérisés par la présence de biofilms
JP2020524172A (ja) * 2017-06-20 2020-08-13 レスピリオン・ファーマシューティカルズ・プロプライエタリー・リミテッド 肺感染症を低減させる方法
EP3641750A4 (fr) * 2017-06-20 2021-03-24 Respirion Pharmaceuticals Pty Ltd Procédé destiné à réduire les infections pulmonaires
US11382884B2 (en) 2017-06-20 2022-07-12 Respirion Pharmaceuticals Pty Ltd Method for reducing lung infection
JP7389653B2 (ja) 2017-06-20 2023-11-30 レスピリオン・ファーマシューティカルズ・プロプライエタリー・リミテッド 肺感染症を低減させる方法

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