Oral preparation of glucokinase activator and preparation method therefor

Abstract

Disclosed is a solid dispersion and a preparation method therefor. The solid dispersion contains a glucokinase activator, an isotopic label thereof, or a medicinal salt thereof and a polymer support. Further disclosed is a solid dispersion composition containing the solid dispersion and an excipient. Also disclosed is an oral preparation of the glucokinase activator, containing the solid dispersion or the solid dispersion composition. Also disclosed is a tablet and a capsule of the glucokinase activator and a preparation method therefor. In addition, also disclosed is the uses of the solid dispersion, the solid dispersion composition and the oral preparations comprising the tablet and the capsule, which can be used for treating and/or preventing selected diseases or medical conditions and especially one or more diseases selected from type I diabetes mellitus, type II diabetes mellitus, impaired glucose tolerance, impaired fasting glucose and hyperglycemia.

1 . A solid dispersion, which comprises a glucokinase activator, or isotope-labeled analogs thereof or pharmaceutically acceptable salts thereof, and a polymer carrier,
 wherein the glucokinase activator is selected from the following compounds, or isotope-labeled analogs or pharmaceutically acceptable salts thereof,   
       
         
           
           
               
               
           
         
         wherein the polymer carrier is selected from the group consisting of a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1), a copolymer of methacrylic acid and ethyl acrylate (1:1), a copolymer of methacrylic acid and methyl methacrylate (1:2), a copolymer of ethyl acrylate, methyl methacrylate and chlorotrimethylamino ethyl methacrylate (1:2:0.2), a copolymer of ethyl acrylate, methyl methacrylate and chlorotrimethylamino ethyl methacrylate (1:2:0.1), a copolymer of ethyl acrylate and methyl methacrylate (2:1), a copolymer of methacrylic acid and butyl acrylate (35:65), a copolymer of methacrylic acid and methyl methacrylate (1:1), and a copolymer of methacrylic acid and methyl methacrylate (35:65). 
       
     
     
         2 . The solid dispersion according to  claim 1 , wherein the polymer carrier is a copolymer of methacrylic acid and methyl methacrylate (1:1). 
     
     
         3 . The solid dispersion according to  claim 1 , wherein the polymer carrier is Eudragit L100. 
     
     
         4 . The solid dispersion according to  claim 1 , wherein the glucokinase activator is HMS5552, or isotope-labeled analogs or pharmaceutically acceptable salts thereof. 
     
     
         5 . The solid dispersion according to  claim 1 , wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:10 to 10:1, 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, or 4:5 to 5:4. 
     
     
         6 . The solid dispersion according to  claim 1 , wherein the weight ratio of the glucokinase activator to the polymer carrier is 5:6 to 6:5, or 1:1. 
     
     
         7 . A solid dispersion composition, which comprises the solid dispersion according to  claim 1  and excipients. 
     
     
         8 . A tablet of the glucokinase activator, wherein the tablet comprises the solid dispersion according to  claim 1  and one or more selected from the group consisting of filler, binder, disintegrant, and lubricant, wherein the content of the solid dispersion in the tablet is 1 weight % to 90 weight %, the content of filler is 1 weight % to 95 weight %, the content of the binder is 0.5 weight % to 10 weight %, the content of the disintegrant is 0.5 weight % to 7.5 weight %, and the content of the lubricant is 0.25 weight % to 5 weight %, and
 wherein the amount of the glucokinase activator in the unit tablet is about 5 mg to about 200 mg. 
 
     
     
         9 . The tablet according to  claim 8 , wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:10 to 10:1, 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, or 4:5 to 5:4, or 5:6 to 6:5, or 1:1. 
     
     
         10 . The tablet according to  claim 9 , which has a dissolution of <45% at pH1.2˜4.5 at 30 min, and a dissolution of >85% at pH6.0˜7.0 at 30 min. 
     
     
         11 . The tablet of the glucokinase activator according to  claim 8 , wherein the tablet comprises 10 mg of the solid dispersion of the compound HMS5552, 297.5 mg silicified microcrystalline cellulose, 7.5 mg hydroxypropyl cellulose, 2.5 mg croscarmellose sodium, and 2.5 mg magnesium stearate, and wherein the solid dispersion of the compound HMS5552 comprises 5 mg of the compound HMS5552. 
     
     
         12 . The tablet according to  claim 8 , which is coated tablet. 
     
     
         13 . The tablet according to  claim 12 , wherein the coating agent in the coated tablet is Opadry. 
     
     
         14 . The tablet according to  claim 12 , wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:10 to 10:1, 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, or 4:5 to 5:4, or 5:6 to 6:5, or 1:1. 
     
     
         15 . The tablet according to  claim 14 , which has a dissolution of <45% at pH1.2˜4.5 at 30 min, and a dissolution of >85% at pH6.0˜7.0 at 30 min. 
     
     
         16 . A capsule of the glucokinase activator, wherein the capsule comprises the solid dispersion of  claim 1  and one or more materials selected from the group consisting of filler, binder, disintegrant, and lubricant,
 wherein the content of the solid dispersion is 1 weight % to 90 weight %, the content of filler is 5 weight % to 95 weight %, the content of the binder is 0 weight % to 10 weight %, the content of the disintegrant is 0.5 weight % to 7.5 weight %, and the content of the lubricant is 0 weight % to 5 weight %, and 
 wherein in the unit formulation, the content of the glucokinase activator is about 5 mg to about 200 mg. 
 
     
     
         17 . The capsule according to  claim 16 , wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:10 to 10:1, 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, or 4:5 to 5:4, or 5:6 to 6:5, or 1:1. 
     
     
         18 . The capsule according to  claim 17 , which has a dissolution of <45% at pH1.2-4.5 at 30 min, and a dissolution of >85% at pH6.0-7.0 at 30 min. 
     
     
         19 . A method for treating or preventing one or more diseases selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, and hyperglycemia, comprising administering to a patient a therapeutically effective amount of the tablet of  claim 8 . 
     
     
         20 . A method for treating or preventing one or more diseases selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, and hyperglycemia, comprising administering to a patient a therapeutically effective amount of the capsule of  claim 16 .