Novel anti-inflammatory androstane derivative compositions

Abstract

There is provided a crystalline chemical composition comprising a compound of formula (I) in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P 2 1 2 1 2 1 having unit cell dimensions of about 7.6±0.6 Å, 12.7±0.7 Å, and 33±3 Å when determined at 120K, wherein at about 295K said composition exhibits one or more of the following XRPD profiles: (i) a peak in the range of around 4.3-5.0; (ii) a peak in the range of around 6.6-6.9; or (iii) a peak in the range of around 11.5-11.8.

What is claimed is:  
     
         1 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7+0.7 Å, and 37±3 Å when determined at 120K, 
 wherein at about 295K said composition exhibits one or more of the following XRPD profiles:  
 (i) a peak in the range of around 4.3-5.0;  
 (ii) a peak in the range of around 6.6-6.9; or  
 (iii) a peak in the range of around 11.5-11.8.  
 
     
     
         2 . The composition of  claim 1 , which exhibits XRPD profiles (i)-(iii).  
     
     
         3 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K,  
         wherein at about 295K said composition exhibits one or more of the following XRPD profiles:  
         (a) absence of a peak at around 7.3;  
         (b) absence of a peak at around 7.5;  
         (c) absence of a peak at around 12.5;  
         (d) absence of a peak at around 8.8-9.6;  
         (e) absence of a peak at around 10.5-11.1; or  
         (f) absence of a peak at around 12.2-12.6.  
       
     
     
         4 . The composition of  claim 3 , which exhibits 3 or more of XRPD profiles (a)-(f).  
     
     
         5 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K,  
         wherein the compound of formula (I) is a nonsolvated Form 1 polymorph.  
       
     
     
         6 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K,  
         which is non-pressurised and adapted to be administered as a dry powder topically to the lung via the buccal cavity.  
       
     
     
         7 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7+0.6 Å, 13.7±0.7 Å, and 37+3 Å when determined at 120K,  
         which is non-pressurised and adapted to be administered topically to the nasal cavity.  
       
     
     
         8 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7+0.7 Å, and 37+3 Å when determined at 120K,  
         which further comprises a PDE4 inhibitor.  
       
     
     
         9 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7+0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K,  
         wherein the composition is selected from the group consisting of an ointment, lotion, cream, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation and microencapsulation preparation.  
       
     
     
         10 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37+3 Å when determined at 120K,  
         wherein the composition is a dry powder or spray.  
       
     
     
         11 . The composition according to  claim 10 , wherein the composition is a dry powder.  
     
     
         12 . The composition according to  claim 10 , wherein the composition is a spray.  
     
     
         13 . A pharmaceutical composition comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K in combination with another therapeutically active agent, wherein the other therapeutically active ingredient is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol and terbutaline and salts thereof.  
       
     
     
         14 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K, wherein said compound of formula (I) is present in the amount of 0.001 to 10% by weight of said composition.  
       
     
     
         15 . A pharmaceutical composition comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K, 
 in combination with another therapeutically active agent, wherein said another therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent.  
 
     
     
         16 . The composition according to  claim 15 , wherein said anti-histamine is methapyrilene or loratadine, said anti-inflammatory agent is an NSAID and said antiinfective agent is an antibiotic or antiviral.  
     
     
         17 . A method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition comprising administering to said human or animal subject an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K, 
 wherein said effective amount of the composition is administered topically to said human or animal subject.  
 
     
     
         18 . The method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition according to  claim 17 , wherein said effective amount of the composition is administered topically as a dry powder to the lung via the buccal cavity.  
     
     
         19 . The method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition comprising administering to said human or animal subject an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1   2   1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K, 
 wherein said effective amount of the composition is administered once per day.  
 
     
     
         20 . A method for the treatment of at least one condition selected from the group consisting of skin disease, inflammatory condition of the nose, throat or lungs, inflammatory bowel condition, auto-immune disease, conjunctiva and conjunctivitis in a human or animal subject, which comprises administering an effective amount of a pharmaceutical composition comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2±212, having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K, 
 and delivering said pharmaceutical composition to said human or animal subject in need thereof for the treatment of said at least one condition.  
 
     
     
         21 . The method of treatment as recited in  claim 20 , wherein the skin disease is at least one selected from the group consisting of eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions.  
     
     
         22 . The method of treatment as recited in  claim 20 , wherein the inflammatory condition of the nose, throat or lungs is at least one selected from the group consisting of asthma, rhinitis, nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease and fibrosis.  
     
     
         23 . The method of treatment as recited in  claim 22 , wherein the inflammatory condition of the nose, throat or lungs is asthma.  
     
     
         24 . The method of treatment as recited in  claim 22 , wherein the inflammatory condition of the nose, throat or lungs is rhinitis.  
     
     
         25 . The method of treatment as recited in  claim 22 , wherein the inflammatory condition of the nose, throat or lungs is chronic obstructive pulmonary disease.  
     
     
         26 . The method of treatment as recited in  claim 22 , wherein the inflammatory bowel condition is at least one selected from the group consisting of ulcerative colitis and Crohn's disease.  
     
     
         27 . The method of treatment as recited in  claim 20 , wherein said composition is administered by inhalation or by nebulisation.  
     
     
         28 . The method of treatment as recited in  claim 20 , wherein said composition is administered orally, buccally, sublingually, parenterally, locally or rectally.  
     
     
         29 . The method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition according to  claim 20 , wherein said effective amount of the composition is administered topically to said human or animal subject.  
     
     
         30 . An inhaler comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K.  
     
     
         31 . The inhaler of  claim 30 , further comprising propellant.  
     
     
         32 . The inhaler of  claim 30 , further comprising at least one excipient selected from the group consisting of surfactant and cosolvent.  
     
     
         33 . The inhaler of  claim 30 , wherein the composition is free of excipient.  
     
     
         34 . The inhaler of  claim 30 , wherein the composition is retained in a pressurized canister closed with a valve.  
     
     
         35 . The inhaler of  claim 30 , wherein said composition has a particle size in the range of 1-10 μm.  
     
     
         36 . A process for preparing a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K,  
       which process comprises 
 (a) crystallising the composition from a solution containing a compound of formula (I) and the guest molecule; or  
 (b) contacting the compound of formula (I) or another composition according  claim 1  in solid form with a liquid containing the guest molecule and obtaining the composition therefrom; or  
 contacting a compound of formula (I) or another composition according to  claim 1  in solid form with a vapour containing the guest molecule,  
 wherein the compound of formula (I), which is crystallized in (a), or contacted with a liquid containing the guest molecule in (b), or contacted with a vapor containing the guest molecule in (c), is in the form of a substantially amorphous solid.  
 
     
     
         37 . The process of  claim 36 , wherein the compound of formula (I) is in the form of substantially amorphous paticles.  
     
     
         38 . The process of  claim 36 , wherein the compound of formula (I) as crystalline unsolvated Form 1 polymorph is prepared by dissolving the compound of formula (I) in methylisobutylketone or ethyl acetate and producing the compound of formula (I) as unsolvated Form 1 by addition of an anti-solvent.  
     
     
         39 . The process of  claim 36 , wherein the compound of formula (I) as crystalline unsolvated Form 1 polymorph is prepared by dissolving the compound of formula (I) in ethyl acetate and producing the compound of formula (I) as unsolvated Form 1 by addition of toluene as the anti-solvent.  
     
     
         40 . The process of  claim 36 , wherein the compound of formula (I) as crystalline unsolvated Form 1 polymorph is prepared by dissolving the compound of formula (I) in methylisobutylketone and producing the compound of formula (I) as unsolvated Form 1 by addition of isooctane as the anti-solvent.