Wet granulation formulation for bisphosphonic acids

Abstract

Pharmaceutical compositions of bisphosphonic acids, and salts thereof, are prepared by wet granulation tablet formulation. These pharmaceutical compositions are useful in the treatment of disturbances involving calcium or phosphate metabolism, in particular, the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metastatic bone disease. These compositions are prepared without the addition of binder; instead, the drug itself acts as a binder.

What is claimed is:  
     
         1 . A process for the preparation of a tablet containing an active ingredient selected from the group consisting of: 
 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;    3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;    3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;    1-hydroxy-3-(N-methyl-N-pentylamino)propyl-idene-1,1-bisphosphonic acid;    1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and    4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine;    or a pharmaceutically acceptable salt thereof;    which process comprises:    (1) forming a powder blend of the active ingredient with diluents,    (2) wet granulating the powder blend with water to form granules,    (3) drying the granules to remove water, and    (4) compressing the dried granules mixture into a desired tablet form.    
     
     
         2 . The process of  claim 1  wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.  
     
     
         3 . The process of  claim 1  wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.  
     
     
         4 . A process for the preparation of a tablet containing an active ingredient selected from the group consisting of: 
 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;    3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;    3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;    1-hydroxy-3-(N-methyl-N-pentylamino)propyl-idene-1,1-bisphosphonic acid;    1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and    4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine;    or a pharmaceutically acceptable salt thereof;    which process comprises:    (1) forming a powder blend of the active ingredient with diluents from 3 to 25 minutes using a mixer such as a planetary or high shear granulator,    (2) wet granulating the powder blend by the addition of water while mixing over a 2 to 30 minute period to form granules,    (3) drying the granules to remove water by the use of heated air for 10 minutes to 24 hours,    (4) milling the dried granules to a uniform size,    (5) adding and blending a disintegrant with the dried milled particles for 2 to 30 minutes,    (6) adding and blending a lubricant to the mixture containing the disintegrant for 30 seconds to 20 minutes, and    (7) compressing the dried granules mixture into a desired tablet form.    
     
     
         5 . The process of  claim 4  wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.  
     
     
         6 . The process of  claim 4  wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.  
     
     
         7 . The process of  claim 4  wherein the diluents are selected from: lactose, microcrystalline cellulose, calcium phosphate, mannitol, powdered cellulose, and pregelatinized starch.  
     
     
         8 . The process of  claim 7  wherein the diluents are lactose and microcrystalline cellulose.  
     
     
         9 . The process of  claim 8  wherein the lactose is lactose NF anhydrous and the microcrystalline cellulose is Avicel PH101.  
     
     
         10 . The process of  claim 4  wherein the disintegrant is selected from the group consisting of modified starch, modified cellulose polymer, and croscarmellose sodium, or a combination thereof.  
     
     
         11 . The process of  claim 10  wherein the disintegrant is croscarmellose sodium.  
     
     
         12 . The process of  claim 11  wherein the disintegrant is croscarmellose sodium NF type A.  
     
     
         13 . The process of  claim 4  wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium lauryl sulfate, propylene glycol, sodium dodecane sulfonate, sodium oleate sulfonate, sodium laurate mixed with stearates and talc, and sodium stearyl fumerate.  
     
     
         14 . The process of  claim 13  wherein the lubricant is magnesium stearate.  
     
     
         15 . The process of  claim 4  which comprises the steps: 
 (1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, and lactose with a high shear granulator for 3 to 5 minutes,  
 (2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with the high shear granulator,  
 (3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a Fluid bed, or 12 to 24 hours in a tray dryer,  
 (4) milling the dried granules to a uniform size using a hammer type mill,  
 (5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,  
 (6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender or a planetary mixer for 3 to 8 minutes,  
 (7) compressing the lubricated granule mixture into a desired tablet form, and  
 (8) dedusting and storing the tablets.  
 
     
     
         16 . The process of  claim 4  which comprises the steps: 
 (1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, and lactose with a planetary granulator for 10 to 25 minutes,  
 (2) wet granulating the powder blend by the addition of water while mixing over a 3 to 10 minute period to form granules with the planetary granulator,  
 (3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in a tray dryer,  
 (4) milling the dried granules to a uniform size using a hammer type mill,  
 (5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,  
 (6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender or a planetary granulator for 3 to 8 minutes, and  
 (7) compressing the lubricated granule mixture into a desired tablet form, and  
 (8) dedusting and storing the tablets.  
 
     
     
         17 . The process of  claim 4  which comprises the steps: 
 (1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, Avicel PH101 microcrystalline cellulose, and lactose with a high shear granulator for 3 to 5 minutes,  
 (2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with a high shear granulator,  
 (3) drying the granules to remove water by the use of heated air for 10 minutes to one hour using a fluid bed dryer,  
 (4) milling the dried granules to a uniform size using a hammer type mill,  
 (5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,  
 (6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender for 3 to 8 minutes,  
 (7) compressing the lubricated granule mixture into a desired tablet form, and  
 (8) dedusting and storing the tablets.  
 
     
     
         18 . A solid dosage form containing an active ingredient selected from the group consisting of: 
 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;    3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;    3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;    1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;    1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and    4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine;    or a pharmaceutically acceptable salt thereof;    wherein the dosage form is prepared by the process of  claim 1 .    
     
     
         19 . A pharmaceutical composition comprising by weight, about 0.5 to 25% by weight of an active ingredient selected from the group consisting of: 
 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;    3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;    3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;    1-hydroxy-3-(N-methyl-N-pentylamino)propyl-idene-1,1-bisphosphonic acid;    1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and    4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine;    or a pharmaceutically acceptable salt thereof;    and from about 30 to 70% by weight of anhydrous lactose or hydrous fast flow lactose; about 30 to 50% by weight of microcrystalline cellulose, and about 0.1 to 2% by weight magnesium stearate.    
     
     
         20 . The pharmaceutical composition of  claim 19  comprising about 1 to 25% by weight of the active ingredient, about 40 to 60% by weight of anhydrous lactose; about 35 to 45% by weight of microcrystalline cellulose; about 0.5 to 2% by weight croscarmellose sodium and about 0.1 to 1% by weight of magnesium stearate.  
     
     
         21 . The pharmaceutical composition of  claim 18  wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.  
     
     
         22 . The pharmaceutical composition of  claim 18  wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.  
     
     
         23 . The pharmaceutical composition of  claim 20  wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.  
     
     
         24  A tablet prepared from the pharmaceutical composition of  claim 23 .  
     
     
         25 . A tablet prepared from the pharmaceutical composition of claim  18 .