Pharmaceutical composition comprising small molecule egfr inhibitor and preparation method therefor

Abstract

A pharmaceutical composition comprising a small molecule EGFR inhibitor and a preparation method therefor, the composition comprising N-(5-((4-(1-cyclopropyl-TH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, an isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, or a combination thereof that acts as an active ingredient, and at least one pharmaceutically acceptable excipient.

1 . A pharmaceutical composition, comprising N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, an isomer, solvate, hydrate, pharmaceutically acceptable salt thereof or a combination thereof as the active ingredient, and at least one pharmaceutically acceptable excipient. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the active ingredient is a mesylate salt of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the active ingredient is present in an amount of 1 to 60%. 
     
     
         4 . The pharmaceutical composition according to  claim 3 , wherein the unit dose of the active ingredient is 10 to 200 mg. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the excipient comprises one or more filler(s), comprising at least one disaccharide or polysaccharide, such as glucan, starch, cellulose, lactose, maltose or sucrose. 
     
     
         6 . The pharmaceutical composition according to  claim 5 , wherein the disaccharide or polysaccharide is present in an amount of 1 to 60%; and wherein the filler is a disaccharide. 
     
     
         7 . The pharmaceutical composition according to  claim 5 , wherein the filler also comprises one or more of microcrystalline cellulose, mannitol, sorbitol, calcium hydrophosphate and calcium sulfate. 
     
     
         8 . The pharmaceutical composition according to  claim 5 , wherein the filler is selected from the group consisting of microcrystalline cellulose and lactose. 
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein the microcrystalline cellulose is present in an amount of 1 to 60%; and the lactose is present in an amount of 1 to 60%. 
     
     
         10 . The pharmaceutical composition according to  claim 8 , wherein the weight ratio of microcrystalline cellulose to lactose is 1:3 to 3:1. 
     
     
         11 . The pharmaceutical composition according to  claim 5 , wherein the filler is selected from the group consisting of microcrystalline cellulose and anhydrous lactose. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the microcrystalline cellulose is present in an amount of 1 to 60%; and the anhydrous lactose is present in an amount of 1 to 60%. 
     
     
         13 . The pharmaceutical composition according to  claim 11 , wherein the weight ratio of microcrystalline cellulose to anhydrous lactose is 1:3 to 3:1. 
     
     
         14 . The pharmaceutical composition according to  claim 5 , wherein the filler is present in an amount of 20 to 80%. 
     
     
         15 . The pharmaceutical composition according to  claim 1 , wherein the excipient comprises one or more disintegrant(s). 
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium and crospovidone. 
     
     
         17 . The pharmaceutical composition according to  claim 15 , wherein the disintegrant is present in an amount of 1 to 30%. 
     
     
         18 . The pharmaceutical composition according to  claim 15 , wherein the disintegrant is added intragranularly. 
     
     
         19 . The pharmaceutical composition according to  claim 1 , wherein the excipient comprises one or more lubricant(s). 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the lubricant is one or more selected from the group consisting of talc, stearic acid, sodium stearyl fumarate, glyceryl behenate, magnesium stearate and micronized silica gel. 
     
     
         21 . The pharmaceutical composition according to  claim 19 , wherein the lubricant is present in an amount of 0.1 to 10%. 
     
     
         22 . The pharmaceutical composition according to  claim 19 , wherein the lubricant is selected from the group consisting of sodium stearyl fumarate and magnesium stearate, the sodium stearyl fumarate is present in an amount of 0.1 to 5%. 
     
     
         23 . The pharmaceutical composition according to  claim 1 , characterized by comprising the following components: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   active ingredient 
                   35 to 50% 
                 
                     
                   lactose 
                    5 to 15% 
                 
                     
                   microcrystalline cellulose 
                   30 to 50% 
                 
                     
                   carboxymethyl starch sodium 
                   10 to 20% 
                 
                     
                   lubricant 
                    0.5 to 5%. 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         24 . The pharmaceutical composition according to  claim 23 , characterized by comprising the following components: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   active ingredient 
                   43.3% 
                 
                     
                   lactose 
                   10.2% 
                 
                     
                   microcrystalline cellulose 
                   30.0% 
                 
                     
                   carboxymethyl starch sodium 
                       14% 
                 
                     
                   lubricant 
                   0.5 to 5%.  
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         25 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is an oral formulation. 
     
     
         26 . (canceled) 
     
     
         27 . A method for preparing the pharmaceutical composition according to  claim 1 , the method comprising:
 1) pre-treatment of raw materials: sieving the filler, disintegrant and intragranular lubricant for later use;   2) mixing: weighing the intragranular raw materials according to specified amounts and mixing them;   3) dry granulation: granulating the above mixed powder by dry granulation;   4) total mixing: mixing the resulting granules and extragranular lubricant;   5) optionally, tableting; and   6) optionally, coating.   
     
     
         28 . The method according to  claim 27 , comprising:
 1) pre-treatment of raw materials: sieving microcrystalline cellulose, lactose, sodium stearyl fumarate and carboxymethyl starch sodium for later use;   2) mixing: weighing the intragranular raw materials according to prescription amounts, and mixing microcrystalline cellulose, lactose, carboxymethyl starch sodium, sodium stearyl fumarate, the active ingredient and magnesium stearate with a hopper mixer;   3) dry granulation: granulating the above mixed powder with a dry granulator;   4) total mixing: mixing the resulting fine granules and prescription amount of extragranular sodium stearyl fumarate with a hopper mixer;   5) optionally, tableting; and   6) optionally, coating: i) formulation of a coating liquid, adding a prescription amount of Opadry to purified water under stirring to formulate a coating liquid with a solid content of 10%, stirring the coating liquid evenly, and sieving the coating liquid for later use; and ii) finishing the coating until the coating weight gain reaches about 2.0% to 4.0%.   
     
     
         29 . The pharmaceutical composition according to  claim 6 , wherein the disaccharide or polysaccharide is present in an amount of 5 to 15%. 
     
     
         30 . The pharmaceutical composition according to  claim 6 , wherein the filler is lactose. 
     
     
         31 . The pharmaceutical composition according to  claim 11 , wherein the microcrystalline cellulose is present in an amount of 20 to 40%, and the lactose is present in an amount of 5 to 15%. 
     
     
         32 . The pharmaceutical composition according to  claim 20 , wherein the disintegrant is present in an amount of 10 to 20%.