Pharmaceutical combination, composition and compound preparation containing glucokinase activator and k-atp channel blocker, preparation method therefor and use thereof

Abstract

The present invention relates to a pharmaceutical combination, the pharmaceutical combination comprising a glucokinase activator or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystal form thereof, a hydrate, a solvate, a diastereomer or enantiomer, and a K-ATP channel blocker. The present invention further relates to a pharmaceutical composition, a fixed dose compound preparation, and a method for preparing the pharmaceutical composition and the fixed dose compound preparation as well as a use thereof.

1 - 13 . (canceled) 
     
     
         14 . A fixed dose combination formulation, comprising:
 (a) a glucokinase activator, which is a compound represented by the following formulae, or a pharmaceutically acceptable salt, an isotope labeled analogue, a crystalline form, a hydrate, a solvate, or a diastereomeric or enantiomeric form thereof,   
       
         
           
           
               
               
           
         
         (b) a K-ATP channel blocker; and 
         (c) one or more excipients. 
       
     
     
         15 . The fixed dose combination formulation of  claim 14 , wherein the weight ratio of the glucokinase activator to the K-ATP channel blocker is about 200:1 to 10:1, about 100:1 to 25:2, about 25:2, about 25:1, about 50:1, about 75:2, about 75:1, or about 100:1. 
     
     
         16 . The fixed dose combination formulation of  claim 14 , wherein the glucokinase activator is about 1-99% by weight; and the K-ATP channel blocker is about 0.1-15% by weight. 
     
     
         17 . The fixed dose combination formulation of  claim 14 , wherein the glucokinase activator is the compound HMS5552 represented by the following formula, or an isotope labeled analogue or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
     
     
         18 . The fixed dose combination formulation of  claim 14 , wherein the glucokinase activator is in the form of a solid dispersion containing a polymer carrier. 
     
     
         19 . The fixed dose combination formulation of  claim 18 , wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4, about 5:6 to 6:5, about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6. 
     
     
         20 . (canceled) 
     
     
         21 . The fixed dose combination formulation of  claim 14 , wherein the glucokinase activator is present in a dose ranging from about 1 mg to about 200 mg, from about 25 mg to about 100 mg, about 25 mg, about 50 mg, about 75 mg or about 100 mg. 
     
     
         22 . The fixed dose combination formulation of  claim 14 , wherein the K-ATP channel blocker is present in a dose ranging from about 0.1 mg to about 10 mg, from about 1 mg to about 5 mg, about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 4 mg or about 5 mg. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The fixed dose combination formulation of  claim 14 , wherein the one or more excipients are selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweetening agents, coloring agents and coating agents. 
     
     
         26 . The fixed dose combination formulation of  claim 25 , wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the filler is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch and pregelatinized starch; the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate; the lubricant is selected from the group consisting of magnesium stearate and sodium stearyl fumarate; and the glidant is selected from the group consisting of colloidal silicon dioxide and talc. 
     
     
         27 . The fixed dose combination formulation of  claim 14 , which is a tablet. 
     
     
         28 . The fixed dose combination formulation of  claim 27 , which is a coated tablet. 
     
     
         29 . The fixed dose combination formulation of  claim 28 , wherein the coated tablet is a film-coated tablet, wherein the film-coating agent comprises:
 film-coating substrate(s), which is hypromellose, hydroxypropyl methyl cellulose, or a mixture thereof;   optional plasticizer(s), such aa which is polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or a mixture thereof;   optional coloring agent(s), which is iron oxide red, iron oxide yellow, or a mixture thereof;   optional opacifier(s), which is titanium dioxide, and   optional glidant(s).   
     
     
         30 . The fixed dose combination formulation of  claim 28 ,
 wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.   
     
     
         31 . The fixed dose combination formulation of  claim 14 , comprising by weight:
 about 1-99% of a solid dispersion containing HMS5552 and a polymer carrier;   about 0.1-15% of the K-ATP channel blocker;   about 0-80% of filler(s);   about 1-25% of binder(s);   about 0-15% of disintegrant(s);   about 0.1-10% of lubricant(s); and   about 0-3% of glidant(s).   
     
     
         32 . (canceled) 
     
     
         33 . The fixed dose combination formulation of  claim 14 , comprising by weight:
 about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;   about 1 mg of glimepiride;   about 0-80% of filler(s);   about 2-8% of binder(s);   about 1-5% of disintegrant(s);   about 0.5-3% of lubricant(s); and   about 0-0.5% of glidant(s).   
     
     
         34 . The fixed dose combination formulation of  claim 14 , comprising by weight:
 about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;   about 1 mg of glimepiride;   about 0-80% of filler(s);   about 2-8% of binder(s);   about 1-5% of disintegrant(s);   about 0.5-3% of lubricant(s); and   about 0-0.5% of glidant(s).   
     
     
         35 . The fixed dose combination formulation of  claim 14 , comprising by weight:
 about 100 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;   about 1 mg of glimepiride;   about 0-80% of filler(s);   about 2-8% of binder(s);   about 1-5% of disintegrant(s);   about 0.5-3% of lubricant(s); and   about 0-0.5% of glidant(s).   
     
     
         36 . The fixed dose combination formulation of  claim 14 , comprising by weight:
 about 25 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;   about 2 mg of glimepiride;   about 0-80% of filler(s);   about 2-8% of binder(s);   about 1-5% of disintegrant(s);   about 0.5-3% of lubricant(s); and   about 0-0.5% of glidant(s).   
     
     
         37 . The fixed dose combination formulation of  claim 14 , comprising by weight:
 about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;   about 2 mg of glimepiride;   about 0-80% of filler(s);   about 2-8% of binder(s);   about 1-5% of disintegrant(s);   about 0.5-3% of lubricant(s); and   about 0-0.5% of glidant(s).   
     
     
         38 . The fixed dose combination formulation of  claim 14 , comprising by weight:
 about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;   about 2 mg of glimepiride;   about 0-80% of filler(s);   about 2-8% of binder(s);   about 1-5% of disintegrant(s);   about 0.5-3% of lubricant(s); and   about 0-0.5% of glidant(s).   
     
     
         39 . The fixed dose combination formulation of  claim 14 , comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and Eudragit L100, about 1.00 mg of glimepiride, about 129.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry. 
     
     
         40 . The fixed dose combination formulation of  claim 14 , comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and Eudragit L100, about 1.00 mg of glimepiride, about 79.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry. 
     
     
         41 . The fixed dose combination formulation of  claim 14 , comprising about 200 mg of a solid dispersion that contains about 1:1 of HMS5552 and Eudragit L100, about 1.00 mg of glimepiride, about 29.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry. 
     
     
         42 . The fixed dose combination formulation of  claim 14 , comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and Eudragit L100, about 2.00 mg of glimepiride, about 128.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry. 
     
     
         43 . The fixed dose combination formulation of  claim 14 , comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and Eudragit L100, about 2.00 mg of glimepiride, about 78.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry. 
     
     
         44 . The fixed dose combination formulation of  claim 14 , comprising about 50 mg of a solid dispersion that contains about 1:1 of HMS5552 and Eudragit L100, about 2.00 mg of glimepiride, about 136.00 microcrystalline cellulose, about 4.00 mg of hydroxypropyl cellulose, about 4.00 mg of croscarmellose sodium, about 2.00 mg of sodium dodecyl sulfate, about 2.00 mg of magnesium stearate, and about 6.00 mg of Opadry. 
     
     
         45 - 51 . (canceled) 
     
     
         52 . A method for preparing the fixed dose combination formulation of  claim 14 , comprising incorporating the active ingredients into one or more excipients for granulation, optionally further filling the obtained granule mixture into a vial, a sachet or a capsule, or compressing it into a tablet with a desired shape; and optionally further coating the obtained tablet. 
     
     
         53 - 56 . (canceled) 
     
     
         57 . A method for preventing, slowing the progression of, delaying, or treating one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, maturity-onset diabetes of the young (MODY), impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diseases associated with islet dysfunction and/or metabolic syndrome; or improving blood glucose control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or reversing complications of diabetes mellitus, comprising administering to a subject a therapeutically effective amount of the fixed dose combination formulation of  claim 14 . 
     
     
         58 . (canceled) 
     
     
         59 . The fixed dose combination formulation of  claim 18 , wherein the polymer carrier is Eudragit. 
     
     
         60 . The fixed dose combination formulation of  claim 59 , wherein the polymer carrier is Eudragit L100. 
     
     
         61 . The fixed dose combination formulation of  claim 14 , wherein the K-ATP channel blocker is glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, or nateglinide, or a pharmaceutically acceptable salt thereof.