Novel dosage formulation

Abstract

The invention relates to a process for preparing a pharmaceutical tablet composition which comprises an active pharmaceutical ingredient of formula I wherein the definitions are described in claim 1 , or pharmaceutically acceptable acid addition salts thereof and a water soluble poloxamer in which the compound of formula I and the water soluble poloxamer are processed by hot melt extrusion, and then the hot melt extrudate is mixed with other ingredients to form a tablet, that is optionally coated with a composition comprising an immediate release film coating system and purified water. The invention also relates to such pharmaceutical compositions and hot melt extrudates.

1 . A process for preparing a pharmaceutical composition comprising
 1) blending an active pharmaceutical ingredient and a water soluble poloxamer to form a powder blend;   2) extruding the powder blend form step 1) to form a hot melt extrudate;   3) passing the hot melt extrudate through a sieving machine to obtain milled material, whereby more than one sieving step may be necessary to obtain material in the desired particle size range;   4) blending the milled extrudate from step 3) with a filler(s) and a disintegrant;   5) blending the mixture from step 4) with a processing aid and a glidant; and   6) compressing the final blend prepared in step 5) into tablets.   
     
     
         2 . The process of  claim 1 , wherein the active pharmaceutical ingredient is a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R is lower alkyl, lower alkoxy, halogen or trifluoromethyl 
 R 1  is halogen or hydrogen; and when p is 1, R 1  may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—; 
 R 2  and R 2′  are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; 
 
       and when n is 1, R 2  and R 2′  may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
 R 3  and R 3′  are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group; 
 R 4  is hydrogen, —N(R 5 )(CH 2 ) n OH, —N(R 5 )S(O) 2 -lower alkyl, —N(R 5 )S(O) 2 -phenyl, —N═CH—N(R 5 ) 2 , —N(R 5 )C(O)R 5 , 
 
       
         
           
           
               
               
           
         
         R 5  is hydrogen, C 3-6 -cycloalkyl, benzyl, or lower alkyl; 
         R 6  is hydrogen, hydroxy, lower alkyl, —(CH 2 ) n COO—(R 5 ), —N(R 5 )CO-lower alkyl, hydroxy-lower alkyl, —(CH 2 ) n CN, —(CH 2 ) n O(CH 2 ) n OH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule; 
       
       
         
           
           
               
               
           
         
         is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH 2 )—N(R 5 )—; 
         X is —C(O)N(R 5 )—, —(CH 2 ) m O—, —(CH 2 ) m , —N(R 5 )C(O)—, or —N(R 5 )(CH 2 ) m —; 
         n, p, and q are each independently 1 to 4; and 
         m is 1 or 2; 
       
       or pharmaceutically acceptable acid addition salts thereof. 
     
     
         3 . The process of  claim 2 , wherein the water soluble poloxamer is poloxamer  188 . 
     
     
         4 . The process of  claim 2 , wherein the compound of formula I is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride. 
     
     
         5 . The process of  claim 4 , wherein the water soluble poloxamer is poloxamer  188 . 
     
     
         6 . The process of  claim 1 , which comprises
 1) placing about 50% of the active pharmaceutical ingredient/drug substance is placed in a blender, e.g. PK, Bin or Bohle mixer,   2) adding the water soluble poloxamer, followed by the remainder of the drug substance,   3) mixing the material from step 2) for about 30 minutes to form a powder blend,   4) transferring the powder blend from step 3) into a hot melt extruder (e.g. Leistritz) using a hopper-feeder (e.g. K-Tron Soder)   5) extruding the powder blend through the hot melt extruder,   6) collecting the hot melt extrudate at room temperature,   7) passing the hot melt extrudate through a sieving machine, e.g. FitzMill, on a first pass set using slow speed knives forward through a #3 screen and then a second pass at medium speed knives forward through a #2 screen,   8) placing about 50% of the milled material in a PK blender or equivalent along with a filler (e.g. Avicel PH 102 or Parteck M 200, after passing through a #40 mesh screen), Corn Starch, a disintegrant (e.g. POLYPLASDONE® XL; crosprovidone), and other excipients (e.g. Aerosil, 380 after passing through a # 12 mesh screen),   9) adding the remaining milled material and mixing for about 30 minutes,   10) removing about 50% of the powder mixture,   11) adding a glidant (e.g. Magnesiun Stereate, after passing through a #40 mesh screen) to the remaining material in the blender, followed by readding the balance of the powder mixture and mixing for about 5 minutes, and   12) compressing the final blend into to tablets using, for instance, a 0.738″×0.344″ oval shaped punches.   
     
     
         7 . A process for preparing a pharmaceutical tablet composition comprising an active pharmaceutical ingredient of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R is lower alkyl, lower alkoxy, halogen or trifluoromethyl 
 R 1  is halogen or hydrogen; and when p is 1, R 1  may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—; 
 R 2  and R 2′  are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; 
 
       and when n is 1, R 2  and R 2′  may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
 R 3  and R 3′  are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group; 
 R 4  is hydrogen, —N(R 5 )(CH 2 ) n OH, —N(R 5 )S(O) 2 -lower alkyl, —N(R 5 )S(O) 2 -phenyl, —N═CH—N(R 5 ) 2 , —N(R 5 )C(O)R 5 , 
 
       
         
           
           
               
               
           
         
         R 5  is hydrogen, C 3-6 -cycloalkyl, benzyl, or lower alkyl; 
         R 6  is hydrogen, hydroxy, lower alkyl, —(CH 2 ) n COO—(R 5 ), —N(R 5 )CO-lower alkyl, hydroxy-lower alkyl, —(CH 2 ) n CN, —(CH 2 ) n O(CH 2 ) n OH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule; 
       
       
         
           
           
               
               
           
         
         is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH 2 )—N(R 5 )—; 
         X is —C(O)N(R 5 )—, —(CH 2 ) m O—, —(CH 2 ) m N(R 5 )—, —N(R 5 )C(O)—, or —N(R 5 )(CF 2 ) m —; 
         n, p, and q are each independently 1 to 4; and 
         m is 1 or 2; 
       
       or pharmaceutically acceptable acid addition salts thereof 
       and a water soluble poloxamer which comprises processing the compound of formula I and the water soluble poloxamer by hot melt extrusion and then mixing the hot melt extrudate with other ingredients to form a tablet, that is optionally coated with a composition comprising an immediate release film coating system and purified water. 
     
     
         8 . A pharmaceutical composition in the form of a tablet comprising the following components
 a) an extrudate of 30-60% of a compound of formula I   
       
         
           
           
               
               
           
         
       
       wherein
 R is lower alkyl, lower alkoxy, halogen or trifluoromethyl 
 R 1  is halogen or hydrogen; and when p is 1, R 1  may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—; 
 R 2  and R 2′  are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; 
 
       and when n is 1, R 2  and R 2′  may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
 R 3  and R 3′  are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group; 
 R 4  is hydrogen, —N(R 5 )(CH 2 ) n OH, —N(R 5 )S(O) 2 -lower alkyl, —N(R 5 )S(O) 2 -phenyl, —N═CH—N(R 5 ) 2 , —N(R 5 )C(O)R 5 , 
 
       
         
           
           
               
               
           
         
         R 5  is hydrogen, C 3-6 -cycloalkyl, benzyl, or lower alkyl; 
         R 6  is hydrogen, hydroxy, lower alkyl, —(CH 2 ) n COO—(R 5 ), —N(R 5 )CO-lower alkyl, hydroxy-lower alkyl, —(CH 2 ) n CN, —(CH 2 ) n O(CH 2 ) n OH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule; 
       
       
         
           
           
               
               
           
         
         is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH 2 )—N(R 5 )—; 
         X is —C(O)N(R 5 )—, —(CH 2 ) m O—, —(CH 2 ) m N(R 5 )—, —N(R 5 )C(O)—, or —N(R 5 )(CH 2 ) m —; 
         n, p, and q are each independently 1 to 4; and 
         m is 1 or 2; 
       
       or pharmaceutically acceptable acid addition salts thereof and 10-20% of a water soluble poloxamer 
       
         
           
                 
                 
               
                     
                 
                   b) a filler 
                   20-30% 
                 
                   c) a disintegrant 
                    1-10% 
                 
                   d) processing aid 
                   0-5% and 
                 
                   e) glidant 
                   0-5%, and if desired 
                 
                   f) immediate release film coating system 
                   2-5% of the tablet weight 
                 
                   and 
                 
                   g) purified water. 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         9 . A pharmaceutical composition of  claim 8 , wherein the compound of formula I is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide. 
     
     
         10 . A pharmaceutical composition of  claim 8 , in the form of a tablet. 
     
     
         11 . A pharmaceutical composition of  claim 10 , wherein the tablet contains 400 mg of an active pharmaceutical ingredient. 
     
     
         12 . A pharmaceutical composition of  claim 8 , wherein the water soluble poloxamer is poloxamer  188 . 
     
     
         13 . A pharmaceutical composition of  claim 8 , wherein the filler is a mixture of starch, microcrystalline cellulose and sugar alcohol. 
     
     
         14 . A pharmaceutical composition of  claim 13 , wherein the filler is selected from the group consisting of corn starch, wheat starch, microcrystalline cellulose having a bulk density of 0.2-0.4 g/cc, microcrystalline cellulose having a bulk density of 0.4-0.6 g/cc, mannitol, and tablet white. 
     
     
         15 . A pharmaceutical composition of  claim 8 , wherein the processing aid is colloidal silicon dioxide. 
     
     
         16 . A pharmaceutical composition of  claim 15 , wherein the processing aid is a colloidal silicon dioxide having a surface area of 380 m 2 /g. 
     
     
         17 . A pharmaceutical composition of  claim 8 , wherein the disintegrant is crosprovidone. 
     
     
         18 . A pharmaceutical composition of  claim 8 , wherein the glidant is magnesium stearate. 
     
     
         19 . A pharmaceutical tablet composition according to  claim 10 , comprising 
       
         
           
                 
                 
               
                     
                 
                   2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin- 
                   400.00 mg 
                 
                   4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide hydrochloride 
                 
                   poloxomer 188 
                   133.35 mg 
                 
                   Microcrystalline Cellulose 
                   162.65 mg 
                 
                   Mannitol 
                    30.00 mg 
                 
                   crosprovidone 
                    16.00 mg 
                 
                   Colloidal Silicon Dioxide 
                    16.00 mg 
                 
                   Corn Starch 
                    30.00 mg 
                 
                   Magnesium Stearate 
                    12.00 mg 
                 
                   Opadry ® Yellow 03K 12429 (film coating) 
                    25.00 mg 
                 
                     
                   and 
                 
                   Purified Water 
                   131.25 ml. 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         20 . A hot melt extrudate comprising an active pharmaceutical ingredient and a water-soluble poloxamer. 
     
     
         21 . The hot melt extrudate of  claim 20 , wherein the active pharmaceutical ingredient is a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R is lower alkyl, lower alkoxy, halogen or trifluoromethyl 
 R 1  is halogen or hydrogen; and when p is 1, R 1  may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—; 
 R 2  and R 2′  are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; 
 
       and when n is 1, R 2  and R 2′  may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
 R 3  and R 3′  are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group; 
 R 4  is hydrogen, —N(R 5 )(CH 2 ) n OH, —N(R 5 )S(O) 2 -lower alkyl, —N(R 5 )S(O) 2 -phenyl, —N═CH—N(R 5 ) 2 , —N(R 5 )C(O)R 5 , 
 
       
         
           
           
               
               
           
         
         R 5  is hydrogen, C 3-6 -cycloalkyl, benzyl, or lower alkyl; 
         R 6  is hydrogen, hydroxy, lower alkyl, —(CH 2 ) n COO—(R 5 ), —N(R 5 )CO-lower alkyl, hydroxy-lower alkyl, —(CH 2 ) n CN, —(CH 2 ) n O(CH 2 ) n OH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule; 
       
       
         
           
           
               
               
           
         
         is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH 2 )—N(R 5 )—; 
         X is —C(O)N(R 5 )—, —(CH 2 ) m O—, —(CH 2 ) m N(R 5 )—, —N(R 5 )C(O)—, or —N(R 5 )(CH 2 ) m —; 
         n, p, and q are each independently 1 to 4; and 
         m is 1 or 2; 
       
       or pharmaceutically acceptable acid addition salts thereof. 
     
     
         22 . The hot melt extrudate of  claim 21 , wherein the compound of formula I is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide. 
     
     
         23 . The hot melt extrudate of  claim 22 , wherein the water soluble poloxamer is poloxamer  188 .