Pharmaceutical composition

Abstract

Oral pharmaceutical formulations containing ditosylate salts of 4-quinazolineamines are described as well as methods of using the same in the treatment of disorders characterized by aberrant erbB family PTK activity.

1 . An oral pharmaceutical composition, comprising
 (i) an active ingredient selected from a compound of formula (II),   
       
         
           
           
               
               
           
         
       
       or salts or solvates thereof, wherein said active ingredient is present at a concentration of 30-60 percent by weight;
 (ii) at least one binder wherein said binder is present at a concentration of 4 to 9 percent by weight; 
 (iii) at least one disintegrant wherein the disintegrant is present in a range of 2 to 8 percent by weight; 
 (iv) at least one lubricant wherein the at least one lubricant, is present in a range of 0.6 to 1.3 percent by weight; and 
 (v) at least one diluent wherein the at least one diluent, is present in a range of 35 to 50 percent by weight. 
 
     
     
         2 . The oral pharmaceutical composition of  claim 1  wherein at least one diluent is microcrystalline cellulose. 
     
     
         3 . The oral pharmaceutical composition of  claim 1  wherein the at least one diluent, is present in a range of 40 to 46 percent by weight. 
     
     
         4 . The oral pharmaceutical composition of  claim 1  wherein at least one lubricant is magnesium stearate. 
     
     
         5 . The oral pharmaceutical composition of  claim 1  wherein the at least one lubricant, is present in a range of 0.8 to 1 percent by weight. 
     
     
         6 . The oral pharmaceutical composition of  claim 1  wherein at least one disintegrant is sodium starch glycolate. 
     
     
         7 . The oral pharmaceutical composition of  claim 1  wherein the disintegrant is present in a range of 3.5 to 5 percent by weight. 
     
     
         8 . The oral pharmaceutical composition of  claim 1  wherein said active ingredient is the ditosylate salt of the compound of formula (II). 
     
     
         9 . The oral pharmaceutical composition of  claim 8  wherein said active ingredient is N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate. 
     
     
         10 . The oral pharmaceutical composition of  claim 1  wherein said active ingredient is present in a range of 45-51 percent by weight. 
     
     
         11 . The oral pharmaceutical composition of  claim 1  wherein said active ingredient, binder, disintegrant, lubricant, and diluent are comprised within a core tablet composition. 
     
     
         12 . The oral pharmaceutical composition of  claim 11  wherein said oral composition additionally comprises a film coat. 
     
     
         13 . The oral pharmaceutical composition of  claim 12  wherein said film coat is present in the range of 2.5 to 3.5 percent by weight of the core tablet composition. 
     
     
         14 . The oral pharmaceutical composition of  claim 13  wherein said film coat is present in the range of 2.8 to 3.2 percent by weight of the core tablet composition. 
     
     
         15 . The oral pharmaceutical composition of  claim 9 , wherein the at least one binder is povidone. 
     
     
         16 . The oral pharmaceutical composition of  claim 1  wherein said binder is present at a concentration of 5.5 to 7.5 percent by weight. 
     
     
         17 . An oral pharmaceutical composition comprising:
 (i) N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate;   (ii) povidone;   (iii) sodium starch glycolate;   (iv) microcrystalline cellulose; and   (v) magnesium stearate.   
     
     
         18 . The oral pharmaceutical composition of  claim 17  wherein:
 (i) said N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate is present in a range of 30 to 47 percent by weight; 
 (ii) said povidone is present in a range of 4 to 9 percent by weight; 
 (iii) said sodium starch glycolate is present in a range of 2 to 8 percent by weight; 
 (iv) said microcrystalline cellulose is present in a range of 35 to 50 percent by weight; and 
 (v) said magnesium stearate is present in a range of 0.6 to 1.3 percent by weight. 
 
     
     
         19 . The oral pharmaceutical composition of  claim 18  herein:
 (i) said N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate is present in a range of 30 to 60 percent by weight; 
 (ii) said povidone is present in a range of 4 to 9 percent by weight; 
 (iii) said sodium starch glycolate is present in a range of 2 to 8 percent by weight; 
 (iv) said microcrystalline cellulose is present in a range of 35 to 50 percent by weight; and 
 (v) said magnesium stearate is present in a range of 0.6 to 1.3 percent by weight. 
 
     
     
         20 . The oral pharmaceutical composition of  claim 19  wherein:
 (i) said N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate is present in a range of 42 to 48 percent by weight; 
 (ii) said povidone is present in a range of 5.5 to 7.5 percent by weight; 
 (iii) said sodium starch glycolate is present in a range of 3.5 to 5.5 percent by weight; 
 (iv) said microcrystalline cellulose is present in a range of 40 to 46 percent by weight; and 
 (v) said magnesium stearate, is present in a range of 0.8 to 1.2 percent by weight. 
 
     
     
         21 . The oral pharmaceutical composition of  claim 20  wherein:
 (i) said N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate is present in a range of 45 to 51 percent by weight; 
 (ii) said povidone is present in a range of 5.5 to 7.5 percent by weight; 
 (iii) said sodium starch glycolate is present in a range of 3.5 to 5.5 percent by weight; 
 (iv) said microcrystalline cellulose is present in a range of 40 to 46 percent by weight; and 
 (v) said magnesium stearate is present in a range of 0.8 to 1.2 percent by weight.