Tablet formulations containing 8-[-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one salts and tablets made therefrom

Abstract

Pharmaceutical formulations containing a salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I, which are suitable for forming into a tablet dosage form, as well as tablet dosage forms are disclosed. Disclosed also are methods of treatment utilizing such dosage forms.

What is claimed is 
     
         1 ) a powdered pharmaceutical formulation comprising: (a) a granulate comprising at least one crystalline salt of formula I, intragranular microcrystalline cellulose, lactose monohydrate, a first disintegrant, and a binder; and dry-blended therewith (b) extragranular microcrystalline cellulose, a second disintegrant, and magnesium stearate, wherein the formulation provides, upon compression in a tablet press, a pressed tablet having a hardness of at least 10kp. 
     
     
         2 ) the formulation of  claim 1  wherein said first and said second disintegrant are croscarmellose sodium. 
     
     
         3 ) the formulation of  claim 1  wherein said binder is selected from providone k30, pregelatinized starch and hypromellose 2910, 6cps. 
     
     
         4 ) the formulation of  claim 3  wherein: (a) when the binder used to form the granulate is starch it is used in an amount the provides the product formulation with from about 10 wt. % to about 20 wt. % starch; (b) when the binder used to form the granulate is providone k30 it is used in an amount that provides the product formulation with from about 3 wt. % to about 10 wt. % of providone k30; and (c) when the binder used to form the granulate is hypromellose 2910, 6cps, it is used in an amount that provides the product formulation with from about 3 wt. % to about 6 wt. % of hypromellose 2910, 6 cps. 
     
     
         5 ) a granulate comprising a crystalline hydrochloride salt of (5s,8s)-8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, intragranular microcrystalline cellulose, lactose monohydrate, intragranular croscarmellose sodium and providone k30 as a binder, wherein the granulate has a bulk density of from about 0.54 g/ml to about 0.57 g/ml and a tapped density of from about 0.67 g/ml to about 0.7 g/ml. 
     
     
         6 ) The granulate of  claim 5  wherein the hydrochloride salt comprises the monohydrate hydrochloride salt form I of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one. 
     
     
         7 ) A compressible powder formulation comprising the granulate of either  claim 5  or  claim 6 , dry blended with extragranular microcrystalline cellulose, extragranular croscarmellose sodium, and magnesium stearate, wherein the formulation provides, upon compression in a tablet press, a pressed tablet having a hardness of at least 10 kp. 
     
     
         8 ) The formulation of  claim 7  wherein the total amount of croscarmellose sodium used in the formulation is from about 2 wt. % to about 8 wt. % and the wt. ratio of intragranular to extragranular croscarmellose sodium is from about 1:1 to about 1:1.5. 
     
     
         9 ) The formulation of  claim 1  wherein the wt. ratio of first disintegrant to second disintegrant is about 1:1.5. 
     
     
         10 ) The formulation of any of  claims 1  to  6  and  9  wherein the granulate is prepared using an intragranular microcrystalline cellulose having a mean average particle diameter of less than about 70 microns. 
     
     
         11 ) The formulation of any of  claims 1  to  4  wherein the extragranular microcrystalline cellulose has a mean average particle diameter of greater than about 70 microns. 
     
     
         12 ) The formulation of any of  claims 1  to  6  and  9 , wherein the intragranular microcrystalline cellulose is used in an amount comprising from about 8 wt. % to about 20 wt. % of the product formulation. 
     
     
         13 ) The formulation of  claim 12  wherein the extragranular microcrystalline cellulose is used in an amount comprising from about 19 wt. % to about 40 wt. % 
     
     
         14 ) The formulation of any of  claims 1  to  4  wherein the lactose monohydrate in the granulate is impalpable grade lactose monohydrate. 
     
     
         15 ) The formulation of any of  claims 1  to  6  and  9  wherein said granulate is prepared by a process comprising:
 (a) dry blending:
 (i) a crystalline form 1 hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (API); 
 (ii) intragranular microcrystalline cellulose having a mean particle size of less than about 70 microns; 
 (iii) lactose monohydrate (impalpable grade); and 
 (iv) intragranular croscarmellose sodium, to provide a first dry-blended powder; 
 
 (f) agglomerating the first dry-blended powder prepared in Step “a” in a high shear granulator using a granulating fluid comprising water and providone K-30; 
 (g) forming a granulate by wet milling the agglomerate prepared in Step “b”; 
 (h) drying the wet milled granulate from step “c”; and 
 (i) dry-milling the dried granulate from Step “d” to provide a granulate having an average particle size of 250 microns. 
 
     
     
         16 ) The formulation of  claim 15 , wherein the first dry-blended powder contains intragranular croscarmellose sodium in an amount that is about 5.0 wt. % of the amount of API contained in the first dry-blended powder. 
     
     
         17 ) The formulation of  claim 15  wherein the intragranular microcrystalline cellulose is present in said first dry-blended powder in an amount that is about 25 wt. % of the amount of API present in the first dry-blended powder. 
     
     
         18 ) The formulation of any of  claims 15  to  17 , wherein the amount of lactose monohydrate present in said first dry-blended powder is from about 51 wt. % to about 52 wt. % of the amount of API present in said first dry-blended powder. 
     
     
         19 ) The formulation of any of  claims 15  to  18 , wherein said agglomerated first dry-blended powder prepared in Step “b” contains an amount of providone K30 that is about 12.5 wt. % of the amount of API. 
     
     
         20 ) The formulation of any of  claims 15  to  19  wherein the agglomeration end point of Step “b” comprises the appearance of small granules without powder loss from the granulator. 
     
     
         21 ) The formulation of any of  claims 15  to  20  wherein the wet milling process in Step “c” is carried out to produce a granulate having an average particle size of 2mm. 
     
     
         22 ) The formulation of any of  claims 15  to  21  wherein the dried granulate in Step “d” has a moisture content of less than about 3.0 wt. %. 
     
     
         23 ) The formulation of any of  claims 15  to  22  wherein the dried granulate in Step “d” has a bulk density of from about 0.54 g/ml to about 0.57 g/ml and a tapped density of from about 0.67 g/ml to about 0.7 g/ml. 
     
     
         24 ) The formulation of any of  claims 15  to  23  wherein said crystalline form 1 hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one used in Step “a(i)” provides an X-ray Powder Diffraction Pattern containing the following characteristic peaks expressed in terms of diffraction angle (in 2 0, all values reflect an accuracy of ±0.2): 16.1; 18.4; 21.6; 23.5. 
     
     
         25 ) A tablet made by direct compression of the formulation of any of  claims 1  to  24 . 
     
     
         26 ) The tablet of  claim 25  having a hardness of from about 10 kp to about 16 kp and a friability of less than 0.8%. 
     
     
         27 ) The tablet of  claim 26  comprising a configuration which includes tabular projections. 
     
     
         28 ) The tablet any of  claims 25  to  27  comprising an amount of crystalline form 1 hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one providing a 100 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium dodecyl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle Stirrer, without sinkers, operated at 75 RPM. 
       
         
           
                 
                 
                 
               
                     
                 
                   Time 
                   Average % of active 
                   Range of % active 
                 
                   (min.) 
                   initially present released 
                   released 
                 
                     
                 
                     
                 
                 
                 
                 
               
                   10 
                   92% 
                   89%-95%  
                 
                   20 
                   97% 
                   95%-101% 
                 
                   30 
                   97% 
                   96%-101% 
                 
                   45 
                   98% 
                   96%-102% 
                 
                   60 
                   100% 
                   97%-103% 
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         29 ) The tablet of any of  claims 25  to  28  further comprising a film coating. 
     
     
         30 ) The tablet of  claim 29  comprising an amount of crystalline form 1 hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one providing a 100 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium dodecyl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle Stirrer, without sinkers, operated at 75 RPM. 
       
         
           
                 
                 
                 
               
                     
                 
                   Time 
                   Average % of the active 
                   Range of % active 
                 
                   (min.) 
                   initially present released 
                   released 
                 
                     
                 
                     
                 
                 
                 
                 
               
                   10 
                   93% 
                   92%-94%  
                 
                   20 
                   98% 
                   95%-100% 
                 
                   30 
                   98% 
                   95%-100% 
                 
                   45 
                   99% 
                   96%-101% 
                 
                   60 
                   100% 
                   97%-102% 
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         31 ) A method of treating and/or preventing emesis and/or nausea in a mammal comprising administering to the mammal a therapeutically effective amount of the formulation of any of  claims 1  to  24 . 
     
     
         32 ) A method of treating and/or preventing emesis and/or nausea in a mammal comprising administering to the mammal a therapeutically effective amount of the formulation of any of  claims 25  to  30 . 
     
     
         33 ) The formulation of any of  claims 1  to  4  wherein the type and amount of binder employed, and the amount of residual moisture in the granulate made therefrom is selected to provide a granulate having a bulk density of from about 0.54 g/ml to about 0.57 g/ml. 
     
     
         34 ) The formulation of  claim 1  wherein the first disintegrant and the second disintegrant comprise croscarmellose sodium, and the total amount of croscarmellose sodium used in the formulation is from about 2 wt. % to about 8 wt. %, and the wt. ratio of the amount of first disintegrant to second disintegrant used is from about 1:1 to about 1:1.5. 
     
     
         35 ) The formulation of  claim 8  wherein the granulate is prepared using an intragranular microcrystalline cellulose having a mean average particle diameter of less than about 70 microns. 
     
     
         36 ) The formulation of  claim 9  wherein the granulate is prepared using an intragranular microcrystalline cellulose having a mean average particle diameter of less than about 70 microns. 
     
     
         37 ) The formulation of  claim 7  wherein the extragranular microcrystalline to cellulose blended with the granulate has a mean average particle diameter of greater than about 70 microns. 
     
     
         38 ) The formulation of  claim 8  wherein the extragranular microcrystalline cellulose blended with the granulate has a mean average particle diameter of greater than about 70 microns. 
     
     
         39 ) The formulation of  claim 10 , wherein the intragranular microcrystalline cellulose is used in an amount comprising from about 8 wt. % to about 20 wt. % of the product formulation. 
     
     
         40 ) The formulation of  claim 11 , wherein the intragranular microcrystalline cellulose is used in an amount comprising from about 8 wt. % to about 20 wt. % of the product formulation. 
     
     
         41 ) The formulation of  claim 16  wherein the intragranular microcrystalline cellulose is present in said first dry-blended powder in an amount that is about 25 wt. % of the amount of API present in the first dry-blended powder. 
     
     
         42 ) The formulation of  claim 10  wherein the extragranular microcrystalline cellulose blended with the granulate has a mean average particle diameter of greater than about 70 microns. 
     
     
         43 ) The formulation of  claim 15  wherein in step “d”, the drying step, of the process for preparing the granulate, drying is carried out in a fluid bed dryer. 
     
     
         44 ) A tablet comprising: (a) a granulate comprising: at least one crystalline salt of Formula I; intragranular microcrystalline cellulose; lactose monohydrate; intragranular disintegrant; and a binder; and (b) extragranular microcrystalline cellulose; extragranular disintegrant; and magnesium stearate, wherein said tablet has a hardness of at least 10 kp and a friability of less than 0.8%. 
     
     
         45 ) The tablet of  claim 44  wherein the crystalline salt of Formula I comprises a monohydrate hydrochloride salt. 
     
     
         46 ) The tablet of  claim 45  wherein the intragranular disintegrant and extragranular disintegrant comprise croscarmellose sodium. 
     
     
         47 ) The table of  claim 46  wherein the intragranular microcrystalline cellulose derives from a powder having a mean average particle diameter of less than about 70 microns. 
     
     
         48 ) The tablet of  claim 47  wherein the extragranular microcrystalline cellulose derives from a powder having a mean average particle diameter of greater that about 70 microns.