Organic Compounds

Abstract

A solid pharmaceutical composition suitable for oral administration, comprising: (a) S 1 P receptor agonist; and (b) a sugar alcohol.

1 . A process for producing a pharmaceutical composition in form of a solid formulation suitable for oral administration, comprising:
 (a) mixing an S1P receptor agonist with a sugar alcohol which is selected from the group consisting of mannitol, maltitol, inositol, xylitol, or lactitol;   (b) milling and/or granulating the mixture obtained in (a); and   (c) mixing the milled and/or granulated mixture obtained in (b) with a lubricant, wherein the S1P receptor agonist is selected from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a pharmaceutically acceptable salt thereof, and the phosphate of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol which has the formula   
       
         
           
           
               
               
           
         
       
       in which R 2a  is H, R 3a  is OH, X a  is O, and R 1a  and R 1b  are OH. 
     
     
         2 . Process according to  claim 1  wherein step (a) comprise the step of forming a pre-mix by mixing the total amount of S1P receptor agonist with part of the sugar alcohol. 
     
     
         3 . Process according to  claim 2  wherein the pre-mix formed in step (a) comprises from 5 to 25% by weight of the total weight of the sugar alcohol. 
     
     
         4 . Process according to  claim 1 , wherein the S1P receptor agonist is micronized and/or pre-screened before step (a). 
     
     
         5 . Process according to  claim 1 , wherein the mixing step (a) comprises blending the S1P receptor agonist and the sugar alcohol in a suitable blender or mixer. 
     
     
         6 . Process according to  claim 5  wherein the blending of the S1P receptor agonist and the sugar alcohol is performed for a total of 100 to 400 revolutions. 
     
     
         7 . Process according to  claim 1 , wherein the components are dry mixed. 
     
     
         8 . Process according to  claim 7 , wherein the milling step (b) comprises passing the mixture obtained in (a) through a screen. 
     
     
         9 . Process according to  claim 1 , wherein step (a) further comprises the step of adding a binder solution to the mixture. 
     
     
         10 . Process according to  claim 1 , wherein step (a) further comprises the step of adding a binder to the mix dry and water is added in the granulation step. 
     
     
         11 . Process according to  claim 1 , wherein the milled mixture obtained in (b) is blended before mixing with the lubricant. 
     
     
         12 . Process according to  claim 1 , wherein the lubricant is pre-screened before mixing. 
     
     
         13 . Process according to  claim 1 , wherein an additional amount of binder is added in step (c) to the mixture obtained in (b). 
     
     
         14 . Process according to  claim 1 , wherein steps (a) and (b) comprise the following steps:
 within step (a)
 i) the S1P receptor agonist is dry-mixed with the sugar alcohol, 
 ii) the obtained sugar alcohol/S1P receptor agonist mixture is dry-mixed with a binder, 
 iii) water is added, and, 
   within step (b),
 iv) the mixture is granulated, and 
 v) the granulation is dried and milled. 
   
     
     
         15 . Process according to  claim 1 , wherein the composition contains 0.01 to 20% by weight of S1P receptor agonist, based on the total weight of the composition. 
     
     
         16 . Process according to  claim 1 , wherein the composition contains 75 to 99.99% by weight of the sugar alcohol, based on the total weight of the composition. 
     
     
         17 . Process according to  claim 1 , wherein the S1P receptor agonist is selected from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and a pharmaceutically acceptable salt thereof. 
     
     
         18 . Process according to  claim 1 , wherein the S1P receptor agonist is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, or the hydrochloride salt thereof. 
     
     
         19 . Process according to  claim 1 , wherein the sugar alcohol is mannitol. 
     
     
         20 . Process according to  claim 1 , wherein the sugar alcohol is D-mannitol. 
     
     
         21 . Process according to  claim 18  wherein the sugar alcohol is D-mannitol 
     
     
         22 . Process according to  claim 1 , wherein the sugar alcohol is a mixture of mannitol and xylitol.