Mucoactive agents for treating a pulmonary disease

Abstract

The present invention relates to pharmaceutical compositions which are useful in the treatment of diseases where excess mucus is present in the respiratory tract, such as cystic fibrosis and chronic obstructive pulmonary disease. In particular, the invention relates to pharmaceutical compositions for administration by pulmonary inhalation.

1 . A composition for assisting mucus clearance, the composition comprising one or more mucoactive agents which assist mucous clearance through one or more of the following mechanisms: reducing cross-linking within the mucus, diluting the mucus, and digesting naked DNA and cell debris within the mucus. 
     
     
         2 . A composition as claimed in  claim 1 , wherein one or more of the mucoactive agents are able to reduce inflammation. 
     
     
         3 . A composition as claimed in  claim 1 , comprising two or more mucoactive agents. 
     
     
         4 . (canceled) 
     
     
         5 . A composition as claimed in  claim 1 , comprising one or more glycosaminoglycans. 
     
     
         6 . A composition as claimed in  claim 5 , wherein the glycosaminoglycan is one or more of the following: heparin and a heparinoid. 
     
     
         7 . A composition as claimed in  claim 6 , wherein the heparinoid is one or more of the following: danaparoid sodium and dermatan sulphate. 
     
     
         8 . A composition as claimed in  claim 6 , wherein the heparinoid contains heparin, dermatan sulphate and chondroitin sulphate. 
     
     
         9 . A composition as claimed in  claim 1 , comprising a compound selected from the group consisting of: sulfated glucosaminoglycans, glycosaminoglycan polysulphate compounds, and sulfated mucopolysaccharides. 
     
     
         10 . A composition as claimed in  claim 1 , further comprising one or more of: a monosaccharide, a disaccharide, and an oligosaccharide. 
     
     
         11 . A composition as claimed in  claim 1 , further comprising one or more of: dextran, dextrin, glucose and mannitol. 
     
     
         12 . A composition as claimed in  claim 1 , further comprising an amino acid. 
     
     
         13 . A composition as claimed in  claim 1 , further comprising one or more of: rhDNase, gelsolin and thymosin β4. 
     
     
         14 . A composition as claimed in  claim 1 , further comprising one or more of: acetylcysteine and Nacystelyn. 
     
     
         15 . A composition as claimed in  claim 1 , wherein the composition is a dry powder for pulmonary inhalation. 
     
     
         16 . A composition as claimed in  claim 15 , wherein the composition has a less than 5 μm fine particle fraction of at least 50%. 
     
     
         17 . A composition as claimed in  claim 15 , wherein the composition has a fine particle dose of between 50 and 90%. 
     
     
         18 . A composition as claimed in  claim 15 , comprising particles of at least one mucoactive agent and a force control agent. 
     
     
         19 . A composition as claimed in  claim 18 , wherein the force control agent is selected from the group consisting of: an amino acid peptide or derivatives thereof, a phospholipid and a metal stearate. 
     
     
         20 . A composition as claimed in  claim 19 , wherein the force control agent is selected from the group consisting of: leucine, lysine, cysteine, and mixtures thereof. 
     
     
         21 . A composition as claimed in  claim 18 , wherein the force control agent is included in an amount of up to 50% w/w. 
     
     
         22 . A composition as claimed in  claim 15 , wherein the composition comprises particles of mucoactive agent having a MMAD of less than 10 μm. 
     
     
         23 . A composition as claimed in  claim 22 , wherein the particles of mucoactive agent have a MMAD of from about 2 to about 5 μm. 
     
     
         24 . A composition as claimed in  claim 15 , wherein the composition further comprises carrier particles. 
     
     
         25 . A pharmaceutical composition as claimed in  claim 1 , for the treatment of a human patient in need of such therapy. 
     
     
         26 . A pharmaceutical composition as claimed in  claim 25 , for treating a pulmonary disease. 
     
     
         27 . A pharmaceutical composition as claimed in  claim 26 , wherein the pulmonary disease is selected from the group consisting of: hypersecretion of mucus and abnormal viscoelasticity of mucus. 
     
     
         28 . A pharmaceutical composition as claimed in  claim 26 , wherein the pulmonary disease is selected from the group consisting of: chronic bronchitis, acute asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and bronchiectasis. 
     
     
         29 . A method of treating a pulmonary disease comprising the administration of a therapeutically effective amount of a pharmaceutical composition as claimed in  claim 1  to a subject in need of such treatment. 
     
     
         30 . A method of producing particles for use in a composition as claimed in  claim 1 , the method comprising spray drying the one or more mucoactive agents in a spray drier. 
     
     
         31 . A method as claimed in  claim 30 , wherein the step of spray drying further includes producing droplets moving at a controlled velocity. 
     
     
         32 . A method as claimed in  claim 31 , wherein the velocity of droplets at 5 mm from their point of generation is less than 20 m/s. 
     
     
         33 . A method as claimed in  claim 31 , wherein the spray drier comprises an ultrasonic nebuliser. 
     
     
         34 . A method as claimed in  claim 31 , wherein the one or more mucoactive agents are co-spray dried with a force control agent. 
     
     
         35 . A method of producing particles for use in a composition as claimed in  claim 1 , the method comprising the step of jet milling particles of the one or more mucoactive agents in the presence of an element selected from the group consisting of: air, a compressible gas, and a fluid. 
     
     
         36 . A method as claimed in  claim 35 , wherein the particles are jet milled in the presence of a force control agent. 
     
     
         37 . A method as claimed in  claim 35 , wherein the step of jet milling is carried out at an inlet pressure of between 0.1 and 3 bar. 
     
     
         38 . A method as claimed in  claim 35 , wherein the step of jet milling is carried out at an inlet pressure of between 3 and 12 bar. 
     
     
         39 . A method as claimed in  claim 35 , wherein at least 90% by volume of the active particles are less than 20 μm in diameter prior to jet milling. 
     
     
         40 . A method as claimed in  claim 30 , wherein 90% of the resulting dried particles have a size of less than 10 μm, as measured by laser diffraction. 
     
     
         41 . The composition as claimed in  claim 15 , wherein said composition has a fine particle fraction of between 70 and 99%. 
     
     
         42 . The composition as claimed in  claim 15 , wherein said composition has a fine particle fraction of between 80 and 99%. 
     
     
         43 . The composition as claimed in  claim 15 , herein said composition has a fine particle dose of between 60 and 70%. 
     
     
         44 . The composition as claimed in  claim 18 , wherein the force control agent is included in an amount of less than 10% w/w. 
     
     
         45 . The composition as claimed in  claim 18 , wherein the force control agent is included in an amount of less than 5% w/w. 
     
     
         46 . The composition as claimed in  claim 15 , wherein the carrier particles have a particle size of at least 20 μm.