Compositions Comprising Sphingosine 1 Phosphate (S1P) Receptor Modulators

Abstract

The present invention relates to stable compositions comprising a sphingosine 1 phosphate (S1P) receptor modulator, suitable for use as a dosage form. The S1P receptor modulators are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives, e. g. a compound comprising a group of formula Y.

1 . A stable composition comprising:
 (i) a compound comprising a group of formula Y   
       
         
           
           
               
               
           
         
         wherein Z is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, phenyl substituted by OH, C 1-6 alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C 3-8 cycloalkyl, phenyl and phenyl substituted by OH, or CH 2 —R 4z  wherein R 4z  is OH, acyloxy or a residue of formula (a) 
       
       
         
           
           
               
               
           
         
         wherein Z 1  is a direct bond or O; 
         each of R 5z  and R 6z , independently, is H, or C 1-4 alkyl optionally substituted by 1, 2 or 3 halogen atoms; 
         R 1z  is OH, acyloxy or a residue of formula (a); and each of R 2z  and R 3z  independently, is H, C 1-4 alkyl or acyl; and 
         (ii) one or more of the following excipients: 
         (a) one or more Fillers selected from the group consisting of Lactose monohydrate, Lactose anhydrous, Maize starch, Mannitol, Xylitol, sorbitol, sucrose, and Microcrystalline cellulose; 
         (b) one or more Binders selected from the group consisting of HPMC, L-HPC, Povidone, and HPC; 
         (c) one or more Disintegrants selected from the group consisting of Maize starch, Crospovidone, Croscarmellose sodium, Sodium carboxymethylstarch, pregelatinized starch, and calcium silicate; 
         (d) one or more Lubricants selected from the group consisting of Hydrogenated castor oil, Glycerol behenate, magnesium stearate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine, and sodium stearyl fumarate; 
         (e) one or more Flow regulators selected from the group consisting of Colloidal silicone dioxide, and Talc; 
         (f) one or more Matrix formers selected from the group consisting of Hydroxypropyl methyl cellulose, Hydroxypropyl cellulose, Methyl cellulose, Ethyl cellulose, Pullulan, Starch, e.g. Pure Cote, and Povidone; 
         (g) one or more Plastisizers selected from the group consisting of PEG 400, Dibutyl sebacate, and Sorbitol; 
         (h) one or more Flavoring agents selected from the group consisting of Menthol, and tutti fruit; and 
         (i) one or more Sweeteners selected from the group consisting of Sucralose, and Sodium saccharine. 
       
     
     
         2 . The composition of  claim 1 , wherein the excipients are selected from the group consisting of Sorbitol, Xylitol, dicalcium phosphate, Lactose, microcrystalline cellulose, HPMC, HPC, Crospovidone, croscarmellose sodium, starch, calcium silicate, colloidal silicone dioxide, talc, magnesium stearate and calcium stearate. 
     
     
         3 . The composition of  claim 1 , wherein the composition comprises a binary blend consisting of a compound comprising a group of formula Y and one excipient. 
     
     
         4 . The composition of  claim 1 , wherein the compound containing a group of formula Y is selected from the group consisting of 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol (FTY720) in free form, a pharmaceutically acceptable salt thereof, FTY720-phosphate, 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid, and a prodrug thereof. 
     
     
         5 . The composition of  claim 1 , wherein the level of impurities is not more than 4.5 wt % and/or no more than 2 wt % for an individual impurity. 
     
     
         6 . The composition of  claim 1  for use as a pharmaceutical. 
     
     
         7 . The composition of  claim 1  in the form of a tablet or capsule. 
     
     
         8 . A method for the treatment of organ or tissue transplant rejection, graft versus host disease, autoimmune diseases, inflammatory conditions, viral myocarditis, viral diseases caused by viral myocarditis or cancers comprising administration of the composition of  claim 1 . 
     
     
         9 . The method of  claim 8  for the treatment of an autoimmune disease. 
     
     
         10 . The method of  claim 8  for the treatment of multiple sclerosis. 
     
     
         11 . The method of  claim 8  wherein the compound of formula Y is selected from the group consisting of 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol (FTY720) in free form, a pharmaceutically acceptable salt thereof, FTY720-phosphate, 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid, and a prodrug thereof. 
     
     
         12 . The composition of  claim 4  wherein the compound containing a group of formula Y is FTY720 in free form or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 11  wherein the compound containing a group of formula Y is FTY720 in free form or a pharmaceutically acceptable salt thereof.