WO2015118546A1 - Compositions mucolytiques et leurs utilisations - Google Patents

Compositions mucolytiques et leurs utilisations Download PDF

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Publication number
WO2015118546A1
WO2015118546A1 PCT/IL2015/050144 IL2015050144W WO2015118546A1 WO 2015118546 A1 WO2015118546 A1 WO 2015118546A1 IL 2015050144 W IL2015050144 W IL 2015050144W WO 2015118546 A1 WO2015118546 A1 WO 2015118546A1
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Prior art keywords
cys
disease
peptide
group
disorder
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PCT/IL2015/050144
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English (en)
Inventor
Josef MOGRABI
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Oneday - Biotech And Pharma Ltd.
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Publication of WO2015118546A1 publication Critical patent/WO2015118546A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser

Definitions

  • the present invention relates to mucolytic compositions comprising short peptides, and uses thereof for promoting clearance of mucus and as mucokinetic agents.
  • Mucus is a viscous secretion produced by, and covering, the epithelial lining of body cavities that communicate with the external environment, including the respiratory, gastrointestinal and urogenital systems in mammals. It is produced by specialized epithelial cells known as goblet cells, and sub-mucosal glands. The main function of mucus is to lubricate and protect these epithelial surfaces against infectious agents such as fungi, bacteria and viruses.
  • mucus aids in the protection of the lungs by trapping inhaled foreign particles.
  • Motile cilia underlying the mucus layer advance the mucus containing the trapped particles towards the oropharynx, where it is either expelled from the body by expectoration (as sputum), or swallowed and destroyed by the digestive system.
  • This mucociliary clearance mechanism serves to keep sterility of the lower respiratory tract and prevent mucus accumulation in the lungs.
  • Mucus is in effect a heterogeneous mixture containing water, salts and various macromolecules.
  • the main polymeric components of mucus are densely glycosylated glycroproteins known as mucins. Mucins are produced and secreted by goblet cells.
  • Mucins are typically secreted as large aggregates in which mucin monomers are linked to one another by covalent and non-covalent interactions.
  • Exemplary interactions include intramolecular disulfide bonds between cystein residues, hydrogen bonds between sugar units, and ionic interactions between positively and negatively charged amino acid residues and sugar units.
  • Mucin hyper-secretion and/or impaired mucus clearance from the lungs and airways are common features of a number of respiratory diseases, including for example, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), sinusitis and pneumonia.
  • Products of inflammation including leukocytes-derived DNA and filamentous actin (F-actin), effete cells, bacteria, and cell debris may alter the physical properties of mucus and contribute to mucus purulence, thickness and viscosity in these conditions. Impaired mucus clearance is also associated with, inter alia, continued exposure to cigarette smoke or atmospheric pollutants.
  • Mucokinetics are a class of drugs that aid in the clearance of respiratory tract secretions, typically administered by inhalation or oral routes.
  • examples include: hypoviscosity agents, such as isotonic or hypotonic saline solutions that decrease mucus viscosity by increasing its water content through osmotic effects; expectorants (bronchomucotropics), such as guaiphenesin that facilitates mucus expectoration by reducing adhesiveness and surface tension of mucus, and increasing bronchial secretion and ciliary action; and mucolytics that decrease mucus viscosity by disrupting cross-links within the mucus gel structure, and by separating between the mucus and the white blood cells that the mucus may contain.
  • hypoviscosity agents such as isotonic or hypotonic saline solutions that decrease mucus viscosity by increasing its water content through osmotic effects
  • expectorants bronchomucotropics
  • mucolytics that
  • the latter includes, for example: N-acetylcysteine (NAC) and carbocisteine, which break disulfide bonds between mucoproteins inclusive of mucin monomers; hypertonic saline, which breaks ionic bonds; and bromhexine, which disrupts the structure of mucopolysaccharides.
  • the group of mucolytics also includes drugs that degrade DNA, fibrin, or F-actin in airway secretions, for example, dornase alpha, which is a solution of recombinant human deoxyribonuclease I (rhDNase).
  • saline solutions may cause bronchospasm and hypernatremia
  • some expectorants are known to cause gastric irritation
  • mucolytic agents such as NAC are characterized by unpalatable taste and smell and associated with adverse effects such as nausea, vomiting, stomatitis and rhinorrhea
  • the dornase alpha DNAse solution has a delayed onset of action of 3-7 days in addition to some undesired side effects.
  • WO 2002/034202 discloses an antioxidant compound characterized by (a) a peptide including at least three amino acid residues of which at least two are cysteine residues, each having a readily oxidizable sulfhydryl group for effecting antioxidation; and at least two peptide bonds, each being cleavable by at least one intracellular peptidase; and (b) a first hydrophobic or non-charged moiety being attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety being attached to a carboxy terminal of the peptide via a second bond, the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to provide the antioxidant compound with membrane miscibility properties for permitting the antioxidant compound to cross cellular membranes; wherein cleavage of the at least two peptide bonds by the at least one intracellular peptidase results in generation of a plurality of antioxidant species, each
  • WO 2012/098546 discloses potent compounds having combined antioxidant, anti-inflammatory, anti-radiation and metal chelating properties.
  • Short peptides having said properties and methods and uses of such short peptides in clinical and cosmetic applications are disclosed.
  • Cys-Lys-Met-Cys SEQ ID NO: 1
  • Cys-Met-Lys-Cys SEQ ID NO: 2
  • WO 2014/016837 discloses compositions and methods utilizing thiol-containing short peptides having the sequence Cys-Lys-Met- Cys (SEQ ID NO: 1) and optionally N- and C- terminal modifications, for increasing carnitine level in muscle tissues, and treating or preventing diseases or disorders affecting muscle tissue.
  • WO 2014/016831 discloses compositions and methods for treating blood disorders associated with glutathione dysregulation, utilizing short thiol-containing peptides selected, inter alia, from Cys-Lys-Met-Cys (SEQ ID NO: 1) and Cys-Met-Lys-Cys (SEQ ID NO: 2), optionally with N- and C- terminal modifications. Further disclosed are compositions and methods for preserving biological samples using the peptides.
  • compositions and methods for reducing viscosity of respiratory secretions to facilitate their clearance are needed. Such compositions and methods may be useful, for example, in the treatment of diseases where excess mucus is present in the respiratory tract.
  • the present invention provides potent mucolytic compositions comprising short peptides.
  • the peptide compounds utilized herein comprise lysine and methionine amino acid residues located between two cysteine residues.
  • the peptides further comprise N- and C- terminal modifications, such as N- and C- terminal blocking groups.
  • the present invention further provides methods for promoting mucus clearance, and methods for treating diseases or disorders where mucus is accumulated in the respiratory tract, utilizing the above compositions.
  • the peptides utilized herein were found to be highly effective in reducing the viscosity of sputum samples collected from patients. Surprisingly, the peptides were able to lower the viscosity and liquefy the sputum samples completely, much more effectively than N-acetylcysteine (NAC) and at significantly lower concentrations. NAC is widely used as a mucolytic drug (through inhalation and oral administration routes).
  • NAC is widely used as a mucolytic drug (through inhalation and oral administration routes).
  • the peptides showed complete liquefaction of the sputum samples within a shorter period of time compared to NAC. Rapid effect of a mucolytic agent may be particularly beneficial, for example, for inhalation administration, in cases where several drugs are administered concurrently. It is contemplated that rapid clearance of mucus from the airways would facilitate better absorption and more effective activity of the coadministered drugs.
  • the present invention provides a method for promoting mucus clearance in a subject in need thereof, the method comprising administering to the subject a mucolytic pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the present invention provides a mucolytic pharmaceutical composition
  • a mucolytic pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the method and composition are used for the treatment of a disease or disorder where airway mucus is accumulated or disturbing breathing.
  • the present invention provides a method for treating a disease or disorder where airway mucus is accumulated or disturbing breathing, the method comprising administering to a subject in need thereof a mucolytic pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the present invention provides a mucolytic pharmaceutical composition
  • a mucolytic pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the disease or disorder is an infectious respiratory disease (including bacterial, fungal or viral).
  • infectious respiratory disease is selected form the group consisting of acute sinusitis, chronic sinusitis, acute bronchitis, bronchiolitis, pneumonia and tuberculosis. Each possibility represents a separate embodiment of the invention.
  • the disease or disorder is a degenerative lung disease.
  • the degenerative lung disease is selected form the group consisting of chronic obstructive pulmonary disease (COPD), emphysema, bronchiectasis and chronic bronchitis. Each possibility represents a separate embodiment of the invention.
  • COPD chronic obstructive pulmonary disease
  • emphysema emphysema
  • bronchiectasis chronic bronchitis
  • the disease or disorder is a genetic disease.
  • the genetic disease is cystic fibrosis (CF).
  • the genetic disease is ciliary dyskinesia (primary or secondary). Each possibility represents a separate embodiment of the invention.
  • the disease or disorder is an interstitial lung disease.
  • the interstitial lung disease is a pulmonary fibrosis, such as idiopathic pulmonary fibrosis.
  • the disease or disorder is lung inflammation.
  • compositions of the present invention are formulated for local administration. In some embodiments, they are formulated for inhalation administration. In additional embodiments, they are formulated for nasal administration.
  • the peptide present in the compositions of the present invention further comprises at least one modification of the peptide's terminus. According to some embodiments, the peptide comprises an amino-terminal modification. According to other embodiments, the peptide comprises a carboxy-terminal modification. According to yet other embodiments, the peptide comprises both amino-terminal and carboxy- terminal modifications. Each possibility represents a separate embodiment of the invention.
  • any group suitable for amino terminus modification, and any group suitable for carboxy terminus modification may be used for the peptide used according to embodiments of the present invention.
  • the amino terminal modification is an amino terminal blocking group.
  • the amino-terminal blocking group is selected from the group consisting of alkyl and acyl. Each possibility represents a separate embodiment of the invention.
  • the amino-terminal blocking group is an acetyl group.
  • the amino terminal modification is a moiety that improves the ability of the peptide to penetrate lipid layers.
  • the moiety that improves that ability of the peptide to penetrate lipid layers is a fatty acid.
  • the fatty acid is selected from the group consisting of palmitic acid, phosphatidic acid, stearic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, and oleic acid. Each possibility represents a separate embodiment of the invention.
  • the amino terminal modification is selected from the group consisting of an amino terminal blocking group and a fatty acid.
  • the amino terminal modification is selected from the group consisting of alkyl, acyl and a fatty acid.
  • the carboxy terminal modification is a carboxy terminal blocking group.
  • the carboxy terminal blocking group is selected from the group consisting of amide, ester and alcohol group. Each possibility represents a separate embodiment of the invention.
  • the carboxy terminal blocking group is an amide group.
  • the compositions comprise the peptide N-acetyl- Cys-Lys-Met-Cys-amide (SEQ ID NO: 3).
  • compositions comprise the peptide N- acetyl-Cys-Met-Lys-Cys-amide (SEQ ID NO: 4).
  • the peptide is in the form of a salt.
  • the salt is selected from the group consisting of trifluoroacetic acid (TFA), acetate and citrate salts. Each possibility represents a separate embodiment of the invention.
  • the present invention provides at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the present invention provides at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the present invention provides the use of at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the present invention is directed to the use of short peptides containing lysine and methionine located between two cysteine residues as mucolytic agents.
  • the peptides are useful for promoting clearance of mucus that is accumulated in the respiratory tract and may interfere with breathing.
  • the peptides are also useful for reducing symptoms of diseases where airway mucus is accumulated, including for example, reducing of coughing.
  • Methods for reducing viscosity of mucus in airways of a subject to facilitate its clearance are provided.
  • methods for treating diseases or disorders with excess mucus present in the respiratory tract are also provided.
  • peptide indicates a sequence of amino acids linked by peptide bonds.
  • a peptide is composed of 10 amino acids or less, 9 amino acids or less, 8 amino acids or less, 7 amino acids or less, 6 amino acids or less, 5 amino acids or less.
  • the peptide is composed of 4-10 amino acids, 4-9 amino acids, 4-8 amino acids, 4-7 amino acids, 4-6 amino acids, 4-5 amino acids, or 4 amino acids.
  • a tetra-peptide is provided.
  • the term "tetra-peptide" indicates a peptide composed of four amino acids.
  • the peptides of the present invention are typically utilized in a linear form, although it will be appreciated that in cases where cyclization does not severely interfere with peptide characteristics, cyclic forms of the peptide can also be utilized.
  • amino acid refers to compounds, which have an amino group and a carboxylic acid group, preferably in a 1,2- 1,3-, or 1,4- substitution pattern on a carbon backbone.
  • the term encompasses natural, non-natural and/or chemically modified amino acid residues.
  • Natural amino acids include those found in proteins, which are L-amino acids.
  • Non-natural and/or chemically modified amino acids include, for example, the corresponding N-methyl amino acids, side chain modified amino acids and the biosynthetically available amino acids which are not found in proteins (e.g., 5-hydroxy- lysine).
  • the amino acid residues are represented throughout the specification and claims by either one or three-letter codes, as is commonly known in the art.
  • the amino acids used in this invention are those which are available commercially or are available by routine synthetic methods. Certain residues may require special methods for incorporation into the peptide, and either sequential, divergent or convergent synthetic approaches to the peptide sequence are useful in this invention.
  • salts of the peptides, and derivatives of the peptides of the invention are also included within the scope of the invention.
  • salts refers to salts of carboxyl groups and to acid addition salts of amino groups of the peptide molecule.
  • Salts of carboxyl groups may be formed by means known in the art and include inorganic salts, for example sodium, calcium, ammonium, ferric or zinc salts, and the like, and salts with organic bases such as salts formed for example with amines such as triethanolamine, piperidine, procaine, and the like.
  • Acid addition salts include, for example, salts with mineral acids such as, acetic acid or oxalic acid. Additional examples of suitable salts include trifluoroacetic acid (TFA), acetate and citrate salts.
  • Esters and amides of carboxy groups and acyl and alkyl derivatives of amino groups may be introduced into the molecule by reacting targeted amino acid residues of the peptide with an organic derivatizing agent that is capable of reacting with terminal residues.
  • Preferred chemical derivatives include peptides that have been C-termini amidated or N-termini acetylated.
  • “Derivatives” of the peptides of the invention as used herein covers derivatives which may be prepared from the functional groups which occur as side chains on the residues or the N- or C-terminal groups, by means known in the art, and are included in the invention as long as they remain pharmaceutically acceptable, i.e., they do not destroy the activity of the peptide, do not confer toxic properties on compositions containing it and do not adversely affect the antigenic properties thereof.
  • These derivatives may, for example, include aliphatic esters of the carboxyl groups, amides of the carboxyl groups produced by reaction with ammonia or with primary or secondary amines, N-acyl derivatives of free amino groups of the amino acid residues formed by reaction with acyl moieties (e.g., alkanoyl or carbocyclic aroyl groups).
  • Permeability refers to the ability of an agent or substance to penetrate, pervade, or diffuse through a barrier, membrane, or a skin layer.
  • a "cell permeability”, “cell- penetration” or “permeability-enhancing” moiety refers to any molecule known in the art which is able to facilitate or enhance penetration of molecules through membranes. Non- limitative examples include: hydrophobic moieties such as lipids, fatty acids, steroids and bulky aromatic or aliphatic compounds.
  • the permeability-enhancing moiety may be connected to any position in the peptide moiety, directly or through a spacer, preferably to the amino or carboxy terminus of the peptide moiety.
  • airway or “airways” and “respiratory tract” refer to any part of the respiratory tract, including the nose, nasal cavity, pharynx, larynx, trachea, bronchi and lungs.
  • disease or disorder where airway mucus is accumulated refers to medical conditions in which mucus accumulation in the respiratory tract is one of the symptoms. In such medical conditions mucus production may be excessive, thick, or otherwise difficult to clear from the respiratory tract.
  • diseases or disorders where airway mucus is disturbing breathing refers to medical conditions in which the presence of mucus in the airways, typically in excessive amounts, interferes with breathing and makes it difficult for the patient to breathe. Occasionally it may also cause coughing.
  • treating refers to reduction, amelioration or even elimination of at least some of the symptoms associated with the relevant disease.
  • the term may include at least one of reducing sputum viscosity, improving cough and airway clearance of mucus, reducing accumulation of airway secretions, enabling better clearance by means of ciliary action, reducing airway obstruction, improving pulmonary function, improving gas exchange, reducing incidence of pulmonary exacerbations, facilitating expectoration, reducing or preventing repeated infection and airway damage.
  • reducing sputum viscosity improving cough and airway clearance of mucus
  • reducing accumulation of airway secretions enabling better clearance by means of ciliary action
  • reducing airway obstruction improving pulmonary function
  • improving gas exchange reducing incidence of pulmonary exacerbations
  • facilitating expectoration reducing or preventing repeated infection and airway damage.
  • the present invention utilizes peptides and/or salts thereof having an amino acid sequence selected from the group consisting of:
  • Cys represents the amino-acid cysteine
  • Lys represents the amino-acid lysine
  • Met represents the amino-acid methionine.
  • the peptides utilized herein were disclosed in WO2012/098546, to the inventor of the present invention and others. Among other properties, their ability to reduce allergic responses in vivo was described. Their use as therapeutic agents for the treatment of allergic diseases, including allergic airways diseases such as asthma, was disclosed. Mucolytic activity of these peptides was not mentioned or suggested in WO2012/098546. It is now disclosed for the first time that these peptides can liquefy sputum samples effectively and rapidly, and can be used as mucolytic agents for promoting clearance of respiratory secretions and reducing symptoms of various diseases where respiratory secretions are difficult to clear.
  • the peptide further comprises at least one modification selected from the group consisting of an amino-terminal modification and a carboxy- terminal modification. According to these embodiments, the peptide is selected from the group consisting of:
  • Z is absent or represents an amino terminal modification and Y is absent or represents a carboxy terminal modification.
  • the N- and C- termini modifications reduce the polarity of the peptides of the present invention, thus facilitating the ability of these peptides to cross cell membranes, enter easily into cells and accumulate within the cells.
  • modifications of the peptide termini may improve bio-stability, for example by blocking the action of peptidases.
  • amino and carboxy termini modifications may be chosen from any amino and carboxy termini modifications conventionally used in the art of peptide chemistry, which will not adversely affect the activities of the peptide.
  • the amino terminal modification comprises addition of an amino terminal blocking group.
  • N-terminus blocking groups include C1-C5 branched or unbranched alkyl groups, acyl groups such as formyl and acetyl groups, and substituted forms thereof, such as the acetamidomethyl (Acm) group.
  • acyl groups such as formyl and acetyl groups
  • substituted forms thereof such as the acetamidomethyl (Acm) group.
  • Acm acetamidomethyl
  • the amino terminal modification comprises covalently linking to the N-terminus of the peptide a permeability-enhancing moiety that improves the ability of the peptide to penetrate lipid layers.
  • the moiety is a fatty acid.
  • the fatty acid may be selected from the group consisting of palmitic acid, phosphatidic acid, stearic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid and oleic acid. Each possibility represents a separate embodiment of the invention.
  • the amino terminal modification is selected from the group consisting of acetyl, alkyl, acyl and a fatty acid.
  • the amino terminal modification is selected from the group consisting of acetyl, alkyl, acyl and a fatty acid.
  • the carboxy terminal modification is a carboxy terminal blocking group.
  • Blocking of the C terminus may be performed, for example, by amidation, reduction or esterification, using methods well known in the art.
  • suitable C-terminal blocking groups include amide, ester, and alcohol groups. Each possibility represents a separate embodiment of the invention.
  • the peptide is a tetra-peptide selected from the group consisting of: Cys-Lys-Met-Cys (SEQ ID NO: 1) and Cys-Met-Lys-Cys (SEQ ID NO: 2).
  • the peptide N-acetyl-Cys-Lys-Met-Cys-amide (SEQ ID NO: 3) is provided.
  • the peptide N-acetyl-Cys-Met-Lys-Cys- amide (SEQ ID NO: 4) is provided.
  • the peptides may be synthesized by any technique known to those skilled in the art of peptide synthesis. These methods include solid phase as well as solution phase synthesis methods.
  • a skilled artesian may synthesize any of the peptides of the present invention by using an automated peptide synthesizer using standard chemistry such as, for example, t- Boc or Fmoc chemistry.
  • the methods include exclusive solid phase synthesis, partial solid phase synthesis methods, fragment condensation, classical solution synthesis.
  • Synthetic peptides can be purified by preparative high performance liquid chromatography (Creighton T. (1983) Proteins, structures and molecular principles. WH Freeman and Co. N.Y.) and the composition of which can be confirmed via amino acid sequencing.
  • Some of the peptides of the invention, which include only natural amino acids, may further be prepared using recombinant DNA techniques known in the art.
  • the conjugation of the peptidic and permeability moieties may be performed using any methods known in the art, either by solid phase or solution phase chemistry.
  • Some of the compounds of the present invention may conveniently be prepared using solution phase synthesis methods. Other methods known in the art to prepare compounds like those of the present invention can be used and are comprised in the scope of the present invention.
  • the permeability-enhancing moiety of the present invention may be connected to any position in the peptide moiety, directly or through a spacer.
  • the cell-permeability moiety is connected to the amino terminus of the peptide moiety.
  • the optional connective spacer may be of varied lengths and conformations comprising any suitable chemistry including but not limited to amine, amide, carbamate, thioether, oxyether, sulfonamide bond and the like.
  • suitable chemistry including but not limited to amine, amide, carbamate, thioether, oxyether, sulfonamide bond and the like.
  • Non-limiting examples for such spacers include amino acids, sulfone amide derivatives, amino thiol derivatives and amino alcohol derivatives.
  • Cyclic versions of the peptides disclosed herein are also within the scope of the present invention. Cyclization of peptides may take place by any means known in the art, for example through free amino and carboxylic groups present in the peptide sequence, or through amino acids or moieties added for cyclization.
  • Non limiting examples of cyclization types are: side chain to side chain cyclization (e.g., through S-S bonds), C-to-N terminal cyclization, side chain to terminal cyclization, and any type of backbone cyclization incorporating at least one N -co- substituted amino acid residue/s as described for example in WO 95/33765.
  • the peptide is in the form of a salt.
  • suitable salts include trifluoroacetic acid (TFA), acetate and citrate salts.
  • compositions comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • compositions of the present invention may be formulated for local administration.
  • the compositions may be formulated for nasal administration e.g. as dropletts.
  • they may formulated for inhalation administration.
  • Formulations for inhalation may be provided, e.g., in the form of an aerosol spray from a pressurized metered dose inhaler with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide, in powder form administered using a dry powder inhaler or in aqueous liquid aerosol form using a nebulizer.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide
  • a pharmacuetical composition suitable for inhalation administration comprising at least one peptide of the present invention or a salt thereof.
  • compositions of the present invention may also be formulated for systemic administration. In some embodiments, they are formulated for oral administration. In other embodiments, they are fomulated for administration by injection.
  • administration routes include oral, rectal, intravenous, intramuscular, transdermal, subcutaneous, intradermal routes. Each possibility represents a separate embodiment of the invention.
  • compositions and methods of the present invention are typically employed for the treatment of a mammal, preferably a human.
  • the composition further comprises a pharmaceutically acceptable diluent, excipient or carrier.
  • the term "pharmaceutically acceptable diluent, excipient, or carrier” refers to a diluent, excipient, or carrier that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered active agent.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA, (Remington: The Science and Practice of Pharmacy, Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, Pa., 20th ed, 2000).
  • the therapeutic composition comprises a pharmaceutically acceptable carrier.
  • a “carrier” refers to any substance suitable as a vehicle for delivering of the agents or molecule of the present invention to a suitable in vivo or in vitro site.
  • carriers can act as a pharmaceutically acceptable excipient of a therapeutic composition of the present invention.
  • Carriers of the present invention include: (1) excipients or formularies that transport, but do not specifically target a molecule to a cell (referred to herein as non-targeting carriers); and (2) excipients or formularies that deliver a molecule to a specific site in a subject or a specific cell (i.e., targeting carriers).
  • non-targeting carriers examples include, but are not limited to water, phosphate buffered saline, Ringer's solution, dextrose solution, serum-containing solutions, Hank's solution, other aqueous physiologically balanced solutions, oils, esters and glycols.
  • Aqueous carriers can contain suitable auxiliary substances required to approximate the physiological conditions of the recipient, for example, by enhancing chemical stability and isotonicity.
  • compositions of the present invention can be sterilized by conventional methods.
  • the composition further comprises at least one more active ingredient.
  • a pharmaceutical composition consisting of the peptide of the present invention or a salt thereof as an active ingredient.
  • compositions of the present invention are present in an amount effective to achieve the intended purpose, for example, in an amount effective to treat a certain disease.
  • compositions of the present invention may be formulated in conventional manners. The proper formulation is dependent upon the route of administration chosen.
  • the compositions of the present invention may be formulated for sustained release of the active ingredient.
  • the active ingredients are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluorome thane, dichloro-tetrafluoroethane, or carbon dioxide.
  • a suitable propellant for example, dichlorodifluoromethane, trichlorofluorome thane, dichloro-tetrafluoroethane, or carbon dioxide.
  • the dosage may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.
  • enteric-coated preparations or dosage forms, microspheres, liposomes and nanoparticles for oral delivery of peptides and proteins may be used.
  • formulations for oral administration include tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Suitable carriers for oral administration are well known in the art.
  • Compositions for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries as desired, to obtain tablets or dragee cores.
  • Non-limiting examples of suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, and sodium carbomethylcellulose, and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added.
  • the active ingredients of the composition may be formulated in aqueous solutions, for example in physiologically compatible buffers including but not limited to Hank's solution, Ringer's solution, or physiological salt buffer.
  • Formulations for injection may be presented in unit dosage forms, for example, in ampoules, or in multi-dose containers with, optionally, an added preservative.
  • the compositions may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • Non-limiting examples of suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents that increase the solubility of the active ingredients, to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, for example, a sterile, pyrogen-free, water-based solution, before use.
  • the exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition.
  • the composition further comprises at least one additive useful in the pharmaceutical fields, including, but not limited to fats, emulsifiers and co- emulsifiers, hydrophilic or lipophilic gelling agents, colorants, fragrances, emollients, humectants, preservatives, vitamins, chelators, solvents, fillers, thickeners, hydrophilic and lipophilic filters, dyestuffs, neutralizers, penetration-enhancing agents and polymers.
  • at least one additive useful in the pharmaceutical fields including, but not limited to fats, emulsifiers and co- emulsifiers, hydrophilic or lipophilic gelling agents, colorants, fragrances, emollients, humectants, preservatives, vitamins, chelators, solvents, fillers, thickeners, hydrophilic and lipophilic filters, dyestuffs, neutralizers, penetration-enhancing agents and polymers.
  • Non-limiting examples of suitable fats include mineral oils, oils of animal origin
  • lanolin lanolin
  • synthetic oils isopropyl myristate, octyldodecyl, isostearyl isostearate, decyl oleate or isopropyl palmitate
  • silicone oils cyclomethicone or dimethicone
  • fluorinated oils Fatty alcohol, fatty acids, waxes and gums, notably silicone gums and elastomers can also be used as fats.
  • Non-limiting examples of suitable emulsifiers and co-emulsifiers include polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitane fatty acid esters, oxyethylene sorbitan fatty acid esters, PEG fatty alcohol ethers, glycerol fatty acid esters, alkyl sulphates, alkyl ether sulphates, alkyl phosphates, alkyl polyglucosides and dimethicone copolyols.
  • Non-limiting examples of suitable hydrophilic gelling include carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers, polyacrylamids, polysaccharides such as xanthan gum, guar gum, natural gums such as cellulose gum and derivatives, clays and 2-acrylamido-2-methylpropane acid copolymers.
  • Non-limiting examples of suitable lipophilic gelling agents include modified clays such as bentones, fatty acid metal salts, hydrophobic silica and ethylcellulose.
  • Non-limiting examples of suitable fillers include talc, kaolin, mica, serecite, magnesium carbonate, aluminum silicate and organic powders such as nylon.
  • suitable dyestuffs include lipophilic dyes, hydrophilic dyes, pigments and mother-of-pearl commonly used in dermatological compositions, and their mixtures.
  • Non-limiting examples of suitable neutralizers include soda, triethanolamine, aminomethyl propanol and potassium hydroxide.
  • Non-limiting examples of suitable penetration enhancing agents include alcohols and glycols (ethanol and propylene glycol), ethoxydiglycol, alcohols and fatty acids (oleic acid), fatty acid esters and dimethyl isosorbide.
  • Non-limiting examples of preservatives compatible with pharmaceutical compositions include benzoic acid, its salts and esters, sorbic acid and its salts, parabens and their salts, triclosan, imidazolidinyl urea, phenoxyethanol, DMDM hydantoin, diazolidinyl urea and chlorphenesin.
  • the filters are UVA and UVB filters.
  • suitable UVA and UVB filters include organic filters such as benzophenone-3, butyl methoxydibenzoyl methane, octocrylene, octyl methoxycinnamate, 4-methylbenzylidene camphor, octyl salicylate, terephthalylidene dicamphor sulfonic acid and drometrizole trisiloxane, and non-organic filters such as titanium oxide and zinc oxide.
  • Non-limiting examples of suitable solvents include water, ethanol, glycerin, propylene glycol, butylene glycol and sorbitol.
  • a method for assisting or improving mucus clearance from the respiratory tract of a subject in need thereof in need thereof.
  • a method for reducing viscosity of airway mucus is provided.
  • the subject is afflicted with a disease or disorder where mucus accumulation is one of the symptoms or complications.
  • a method for treating a subject afflicted with a medical condition where airway mucus is accumulated In some embodiments, a method for treating a subject afflicted with a medical condition characterized by an imbalance between mucus secretion and clearance is provided.
  • the methods of the present invention comprise administering to a subject in need thereof a pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of:
  • the disease or disorder is an infectious respiratory disease (including bacterial, fungal or viral).
  • the disease or disorder is a degenerative lung disease.
  • Degenerative lung diseases are typically characterized by damage to the lungs that progressively worsens over time and interferes with their ability to function.
  • the disease or disorder is a genetic disease.
  • the disease or disorder is an interstitial lung disease.
  • Interstitial lung disease is a group of diseases that mainly affect the tissue and space around the alveoli (air sacs) (inters titium), most of which cause progressive scarring of lung tissue.
  • the disease or disorder is acute sinusitis. In some embodiments, the disease or disorder is acute bronchitis. In some embodiments, the disease or disorder is bronchiolitis. In some embodiments, the disease or disorder is pneumonia. In some embodiments, the disease or disorder is tuberculosis. In some embodiments, the disease or disorder is COPD. In some embodiments, the disease or disorder is emphysema. In some embodiments, the disease or disorder is bronchiectasis. In some embodiments, the disease or disorder is chronic bronchitis. In some embodiments, the disease or disorder is CF. In some embodiments, the disease or disorder is primary ciliary dyskinesia.
  • the disease or disorder is secondary ciliary dyskinesia. In some embodiments, the disease or disorder is pulmonary fibrosis. In some embodiments, the disease or disorder is idiopathic pulmonary fibrosis. In some embodiments, the mucus accumulation is part of the pulmonary manifestations of systemic autoimmune diseases. In some embodiments, the disease or disorder is lung inflammation. In some embodiments, the disease or disorder is hyper-secretion of mucoproteins. In some embodiments, the excessive mucus is produced by the nasal mucosa. In some embodiments, the disease or disorder is post-nasal drip. In some embodiments, the excessive mucus is produced in the lungs. In some embodiments, the mucus accumulation in the lungs is causing coughing. In some embodiments, the disease or disorder is pertussis.
  • the method is used for assisting mucus clearance in a subject afflicted with an autoimmune disease, where the autoimmune disease is associated with airway mucus accumulation.
  • the methods of the present invention may also be utilized for the treatment of pulmonary complications associated with surgery, tracheostomy care, use during anesthesia, post-traumatic chest conditions and atelectasis due to mucous obstruction. Each possibility represents a separate embodiment of the invention.
  • the methods of the present invention are used as an adjuvant therapy in respiratory conditions with excessive and/or thick mucus production.
  • Reduction of mucus viscosity may also be used for diagnostic bronchial studies (bronchograms, bronchospirometry, and bronchial wedge catheterization).
  • the methods of the present invention may be combined with one or more known treatments of the above described disorders/diseases.
  • the methods of the present invention comprise administering a composition comprising at least one tetra-peptide of the present invention or a salt thereof.
  • the methods comprise administering mixtures of peptides of the invention.
  • the present invention provides the use of a peptide of the present invention or a salt thereof for the manufacture of a medicament for the treatment of a medical condition where airway mucus is accumulated.
  • a pharmaceutical composition comprising a peptide of the present invention or a salt thereof as active ingredient, for use in the treatment of a medical condition where airway mucus is accumulated.
  • the present invention provides the use of the peptide Cys-Lys-Met-Cys (SEQ ID NO: 1), in the treatment of a medical condition where airway mucus is accumulated. In additional exemplary embodiments, the present invention provides the use of the peptide Cys-Met-Lys-Cys (SEQ ID NO: 2) in the treatment of a medical condition where airway mucus is accumulated.
  • the amount (dosage) of the pharmaceutical composition of the present invention to be administered for the above indications, the administration regimes as well as their mode of application will depend both on characteristics of the treated individual (age, size, gender, etc.) as well as on parameters associated with the phenomena to be treated.
  • kits for promoting mucus clearance in a subject in need thereof.
  • a kit is provided, for treating a disease or disorder where airway mucus is accumulated.
  • a kit is provided, for reducing viscosity of airway mucus.
  • kits comprise a composition comprising at least one peptide of the present invention or a salt thereof, and may also include instructions for administering said composition to a subject in need thereof.
  • the kit comprises means for administering the composition or compositions.
  • the kit may include a nebulizer, a face mask, an inhaler, a syringe, a dropper, a pipette or a combination thereof.
  • a nebulizer for example, a nebulizer, a face mask, an inhaler, a syringe, a dropper, a pipette or a combination thereof.
  • the kit comprises a composition comprising the at least one peptide or salt thereof (and optionally other active ingredients) dissolved in a suitable solvent.
  • the kit comprises a first composition comprising the peptide (and optionally other active ingredients), e.g. as a dried powder, and a second composition comprising a solvent.
  • a method for promoting mucus clearance in a subject in need thereof comprising administering to the subject a mucolytic pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of: Cys-Lys-Met-Cys (SEQ ID NO: 1); and Cys-Met-Lys-Cys (SEQ ID NO: 2).
  • fatty acid is selected from the group consisting of palmitic acid, phosphatidic acid, stearic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid and oleic acid.
  • a mucolytic pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of: Cys-Lys-Met-Cys (SEQ ID NO: 1); and Cys-Met-Lys-Cys (SEQ ID NO: 2) for use in promoting mucus clearance.
  • a mucolytic pharmaceutical composition comprising as an active ingredient at least one peptide or a salt thereof having an amino acid sequence selected from the group consisting of: Cys-Lys-Met-Cys (SEQ ID NO: 1); and Cys-Met-Lys-Cys (SEQ ID NO: 2) for use in the treatment of a disease or disorder where airway mucus is accumulated or disturbing breathing.
  • N-acetyl-Cys-Lys-Met-Cys-NH 2 designated herein as DY-65 (SEQ ID NO: 3);
  • N-acetyl-Cys-Met-Lys-Cys-NH 2 designated herein as DY-70 (SEQ ID NO: 4).
  • N-acetyl-Cys-pAla-His-Cys-NH 2 designated herein as DY-66 (SEQ ID NO: 7).
  • the peptides were prepared by SPSS in which there are repeated cycles of coupling-deprotection.
  • the first stage of the technique consists of peptide chain assembly with protected amino acid derivatives on a polymeric support.
  • the second stage of the technique is the cleavage of the peptide from the resin support with the concurrent cleavage of all side chain protecting groups to give the crude free peptide.
  • the free N-terminal amine of a solid-phase attached peptide is first coupled to a single N-protected amino acid unit. This unit is then deprotected, revealing a new N- terminal amine to which a further amino acid was attached. After cleavage from the resin, peptides are then purified by reverse phase HPLC using columns.
  • Fmoc deprotection 0.08 mmol of Fmoc-X-Wang resin is loaded into a fritted column equipped with a plastic cap. The resin is washed twice with 3 mL portions of dimethylformamide (DMF) for 1 minute each. Next, 3 ml of 20% piperidine in DMF is added and deprotection allowed to continue for 15 minutes. During this time, the column is gently swirled in order to assure a complete mixing. After the reaction is complete (in about 15 minutes), the reaction column is drained and the resin washed 4 times with 3 mL of DMF.
  • DMF dimethylformamide
  • Amide bond coupling In a small vial, 3 equivalents of the Fmoc amino acid is preactivated by combining it with equal equivalents of O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-uronium-hexafluoro-phosphate (HBTU), 6 equivalents of DIPEA ( ⁇ , ⁇ '- diisopropylethylamine), and 3 mL of DMF. This solution is fully dissolved and then allowed to react for an additional 3-5 minutes. Then this coupling solution is added to the resin. The cap is placed on the reaction column and the resin slurry agitated every 2-3 minutes over a period of 20 minutes.
  • HBTU O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-uronium-hexafluoro-phosphate
  • DIPEA ⁇ , ⁇ '- diisopropylethylamine
  • the ester linkage is cleaved using trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • the resin is treated with 2-3 mL of a solution of TFA and water in a ratio of 95:5.
  • the resin is then agitated over a period of 25 minutes.
  • the column is subsequently drained and the filtrated collected into a glass collection vessel.
  • the material is then dried in diethyl ether and analyzed. Testing mucolytic activity
  • peptides were tested for mucolytic activity on sputum (mucus) samples ex-vivo in comparison to N-acetylcysteine (NAC) and dithiothreitol (DTT).
  • NAC N-acetylcysteine
  • DTT dithiothreitol
  • Induced sputum is a well established non invasive procedure to retrieve inflammatory specimens from the lungs.
  • the specimens contain, inter alia, leukocytes and other cells in an aggregate of mucins, antiseptic enzymes, immunoglobulins, lactoferrin and additional macromolecules. In certain diseases the sputum samples may contain also substantial amount of DNA and/or Bacteria.
  • a mucolytic agent Upon treatment of the specimens with a mucolytic agent, the bonds between the mucu-proteins and also between other different components are disrupted, the cellular material is released (separated from the sputum) and the mucus liquefies.
  • the cellular material can be collected and various types of cells can be counted, to yield a profile of cell distribution in the specimen (i.e., absolute number and percentage of each type of cell within the total cell count).
  • Viscid selected portions of sputum specimens (plugs) that are treated with DTT typically produce final samples that contain well defined cellular material with no contamination of viscous debris.
  • NAC produces a similar mucolytic effect in vitro on sputum samples.
  • Sputolysin® prepared in a dilution of 1 : 10 s with distilled water according to the manufacturer's instructions was added and mixed mechanically with the sputum in a shaking water bath at 37°C for complete homogenization. Following incubation, a double volume of PBS was added to stop the reaction, and the cell suspension containing the phosphate-buffered solution was filtered through a 52 ⁇ nylon gauze (BNSH Thompson, Scarborough, Ontario, Canada) and diluted with RPMI supplemented with fetal calf serum (FCS) to achieve a concentration of 10 3 cells/ ⁇ .
  • FCS fetal calf serum
  • cytospins were prepared at 1000 RPMI supplemented with 10% FCS (Biological Industries, Beit Haemek, Israel) for 5 minutes. Separate cytospin slides were stained by Giemsa. Four hundred (400) nonsquamous cells were counted. The number of neutrophils, eosinophils, mast cells, lymphocytes and macrophages was determined, and the results were expressed as a percentage of the total nonsquamous cell count. Only samples containing ⁇ 20% squamous cells were used.
  • NAC NAC (HSCH 2 CH(NHCOCH 3 )C0 2 H Sigma Grade >99% (TLC) powder Cat No A9165-5G (cell culture tested)) was prepared as follows: 10% NAC were mixed with 1 ml NaOH 0.01M, 1ml 0.025M Tri Sodium Citrate, adjusted to pH ⁇ 7. Sputum and NAC at 1 :1 or 1 :2 volume ratio were mixed mechanically in a shaking water bath at 37°C for the time periods indicated in the tables below, for complete homogenization. Further processing and cell counts were performed as described above for Sputolysin®.
  • Peptides DY-65 and DY-70 were freshly prepared from aliquots of 5mg/ml at a final concentration of 1% or 2%, in water. In some experiments they were prepared in saline or PBS. DY-66 was prepared from aliquots of 5mg/ml in three different concentrations 1%, 5% and 25% in distilled water together with NaOH and Trisodium bicarbonate to arrive to normalization of pH. Sputum and peptide at 1 : 1 or 1 :2 volume ratio were mixed mechanically in a shaking water bath at 37°C for the time periods indicated in the tables below. Further processing and cell counts were performed described above.
  • 1 1 means equal volumes between sputum and compound DY-65 or DY-70.
  • 1 :2 means one volume sputum in two volumes compound DY-65/DY-70 or NAC
  • 1 :2 means one volume sputum in two volumes compound DY-65/DY-70 or NAC
  • 1 1 means equal volumes between sputum and compound DY-65 or NAC Table 6 - DY-70 (1%) in PBS
  • * 1 :2 means one volume sputum in two volumes compound DY-65 or NAC
  • the compounds DY-65 and DY-70 have a good mucolytic effect on sputum specimens and render a similar differential cell distribution as Sputolysin® and NAC preparations.
  • DY-66 prepared as described above in three different concentrations 1%, 5% and 25%, were each added to 0.5 gr sputum and mixed mechanically in a shaking water bath at 37°C for 15 minutes. Sputum was hardly homogenized. The cells were counted but morphology was not optimally preserved. Thus, no mucolytic activity was observed for DY-66 under the examined conditions.
  • Example 2 Mucolytic effect on sputum samples from cystic fibrosis patients
  • Peptides DY-65 and DY-70 are tested in-vitro for mucolytic activity on sputum samples taken from cystic fibrosis (CF) patients.
  • Sputum from CF patients is particularly thick and viscous and contains, inter alia, DNA, F-actin and other products of inflammation.
  • Sputum samples are collected from subjects with CF. Sputum is processed as soon as possible within 2 hours of collection. The samples are split into equal aliquots and treated with DY-65 or DY-70 preparations containing the peptide at a concentration ranging from 1-10% w/v, for example, 1%, 2%, 5% and 10% w/v, in water, saline or PBS.
  • Sputum and peptide at 1 : 1 or 1 :2 volume ratio are mixed mechanically in a shaking water bath at 37°C for time periods ranging from 5-25 minutes, for example 5 minutes, 10 minutes, 15 minutes, 20 minutes and 25 minutes.
  • Example 2 Further processing and cell counts are performed as described above in Example 1. The number of neutrophils, eosinophils, mast cells, lymphocytes and macrophages is determined, and the results are expressed as a percentage of the total nonsquamous cell count. Only samples containing ⁇ 20% squamous cells are used.
  • the activity of the peptides is compared to that of N-acetylcysteine (NAC) and/or dithiothreitol (DTT) prepared as described above.

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Abstract

L'invention concerne des compositions mucolytiques comprenant des peptides courts, et des méthodes d'élimination de sécrétions muqueuses et de traitement de maladies ou de troubles liés à une accumulation de sécrétions muqueuses ou à une perturbation de la respiration.
PCT/IL2015/050144 2014-02-10 2015-02-09 Compositions mucolytiques et leurs utilisations WO2015118546A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024868A2 (fr) * 2002-09-10 2004-03-25 National Jewish Medical And Research Center Produit et procede de fluidification des mucosites ou des expectorations
WO2012098546A2 (fr) * 2011-01-20 2012-07-26 Oneday - Biotech And Pharma Ltd. Composés antioxydants, anti-inflammatoires, antirayons, chélateurs métalliques et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024868A2 (fr) * 2002-09-10 2004-03-25 National Jewish Medical And Research Center Produit et procede de fluidification des mucosites ou des expectorations
WO2012098546A2 (fr) * 2011-01-20 2012-07-26 Oneday - Biotech And Pharma Ltd. Composés antioxydants, anti-inflammatoires, antirayons, chélateurs métalliques et leurs utilisations

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