Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate

Abstract

Solid pharmaceutical dosage forms comprising (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate (telotristat) are disclosed, as well as methods of making them and compositions useful in their manufacture.

What is claimed is: 
     
         1 . A tablet comprising telotristat or a pharmaceutically acceptable salt thereof, which forms less than 1.0, 0.8 or 0.5 percent (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid when stored at about 40° C. and about 75% relative humidity for six months. 
     
     
         2 . The tablet of  claim 1 , which forms less than 0.5 or 0.4 percent (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid when stored at about 40° C. and about 75% relative humidity for three months. 
     
     
         3 . A tablet having a core consisting essentially of telotristat etiprate, lactose, hyrdroxy propyl cellulose, croscarmellose sodium, magnesium stearate, and silicon dioxide. 
     
     
         4 . A bottle comprising a tablet of any of  claims 1 - 3  and a desiccant. 
     
     
         5 . A granule comprising telotristat etiprate, lactose, hydroxyl propyl cellulose, croscarmellose sodium, magnesium stearate, and silicon dioxide. 
     
     
         6 . The granule of  claim 5 , wherein magnesium stearate is present in an amount greater than about 3, 4 or 5 weight percent. 
     
     
         7 . The granule of  claim 5 , wherein the cellulose is hydroxyl propyl cellulose and/or microcrystalline cellulose. 
     
     
         8 . A granulate comprising granules of  claim 5 , which has an average flow rate index of greater than about 0.3, 0.35, or 0.4 kg/sec. 
     
     
         9 . A method of making a tablet, which comprises:
 combining granules comprising intragranular ingredients with at least one extragranular ingredient, and   compressing the granules to provide a tablet;   wherein the intragranular ingredients comprise telotristat or a pharmaceutically acceptable salt thereof, magnesium stearate, and lactose; and   the at least one extragranular ingredient is lactose.   
     
     
         10 . The method of  claim 9 , wherein the cellulose is hydroxyl propyl cellulose or microcrystalline cellulose. 
     
     
         11 . The method of  claim 9 , wherein the intragranular ingredients further comprise croscarmellose sodium. 
     
     
         12 . The method of  claim 9 , wherein the at least one extragranular ingredient further comprises one or more of croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. 
     
     
         13 . The method of  claim 9 , wherein the granules are prepared by milling a ribbon made by roller compaction of the intragranular ingredients. 
     
     
         14 . The method of  claim 9 , which further comprises coating the tablet with an enteric coating.