Oleyl phosphocholine containing granulates

Abstract

The present invention relates to tablet dosage formulations of oleyl phosphocholine for oral administration and the processes for their preparation. Specifically, the present invention provides a process for preparing an oleyl phosphocholine containing granulate. The present invention further provides a process for preparing a pharmaceutical dosage formulation, such as a tablet or a capsule, comprising the oleyl phosphocholine containing granulate. The invention further provides any intermediate and/or en product resulting from these steps and processes.

1 . A process for making an olelyl phosphocholine (OlPC) containing granulate, said process comprises the consecutive steps of:
 a) preparing a mixture of olelyl phosphocholine, an anti-oxidant, a filler and, optionally, a granulation liquid and/or one or more further granulation excipients;   b) processing the mixture prepared in step a) into a dry granulate; and   c) milling the granulate produced in step b);   
       characterized in that the antioxidant is vitamin E, vitamin E TPGS, apha-tocopherol acetate and/or alpha-tocopherol. 
     
     
         2 . A process according to  claim 1 , wherein the filler is selected from the group consisting of calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol, silicon dioxide, and mixtures thereof. 
     
     
         3 . A process according to  claim 1 , wherein step b) comprises a melt-agglomeration process, preferably a hot-melt extrusion process. 
     
     
         4 . A process according to  claim 4 , wherein no solvent is added during any one of steps a), b) and c). 
     
     
         5 . A process according to  claim 1 , wherein step b) comprises a wet granulation process, preferably a high-shear wet granulation process. 
     
     
         6 . A process according to  claim 5 , wherein step a) comprises: a1) providing a dry powder (blend) of the filler and optional further granulation excipients; a2) preparing a solution of the OLPC and anti-oxidant in the granulation liquid; and adding to the dry powder (blend) of step a1), the solution prepared in step a2). 
     
     
         7 . A process according to  claim 1 , wherein step b) does not comprise a hot-melt extrusion process wherein no solvent is added during the process. 
     
     
         8 . An olelyl phosphocholine (OlPC) containing granulate obtainable by a process as defined in  claim 1 . 
     
     
         9 . A pharmaceutical formulation comprising the OLPC containing granulate of  claim 8 . 
     
     
         10 . A pharmaceutical formulation according to  claim 9 , wherein the formulation is selected from the group consisting a tablet, a filled capsule, a powder, 
     
     
         11 . A process for preparing an OLPC containing capsule dosage formulation comprising:
 I. a process for making an OlPC containing granulate according to  claim 1 ;   II. optionally mixing the OlPC containing granulate with one or more excipients;   III. filling of the mixture produced in step II) into hollow capsules.   
     
     
         12 . A capsule dosage formulation obtainable by the process according to  claim 11 . 
     
     
         13 . A process for preparing a tablet dosage formulation comprising:
 i. a process for making an OlPC containing granulate according to  claim 1 ;   ii. preparing a compression mixture by mixing the OlPC containing granulate with compression excipients,   iii. wherein said compression excipients comprise at least a filler and a lubricant, and optionally a binder and/or a disintegrant;   iv. compressing the mixture produced in step ii) into a tablet; and, optionally   v. coating the compressed tablet obtained in step iii).   
     
     
         14 . A tablet dosage formulation obtainable by the process according to  claim 13 . 
     
     
         15 . A dosage formulation according to  claims 12 , wherein, if said dosage formulation is stored for at least 24 months at a temperature of 30° C. and at a relative humidity of 75%,
 the concentration of each active pharmaceutical ingredient in said dosage formulation does not change by more than 2.5 weight percent, preferably by no more than 1 weight percent; and 
 each active pharmaceutical ingredient in said dosage formulation has a stable dissolution release profile. 
 
     
     
         16 .- 17 . (canceled) 
     
     
         18 . A method for the treatment of a parasitic diseases, preferably a parasitic disease selected from the group consisting of leishmaniasis, chagas, malaria and cancer, the method comprising administering the dosage formulation according to  claim 12  to a subject in need thereof.