Insulin containing pharmaceutical compositions

Abstract

The present invention is in the field of pharmaceutical compositions for the treatment of medical conditions relating to diabetes. More specifically the invention provides pharmaceutical compositions comprising a long-acting acylated derivative of a human insulin analogue, and to the medical use of such compositions for basal insulin administration therapy.

1 . A pharmaceutical composition comprising an insulin derivative selected from the group consisting of
 A14E, B16H, B25H, B29K((N ε -Eicosanedioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]-acetylamino}ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1);   A14E, B16H, B25H, B29K(Nε-Hexadecandioyl-γGlu), desB30 human insulin (Compound 2);   A14E, B16H, B25H, B29K(N ε -Eicosanedioyl-γGlu), desB30 human insulin (Compound 3); and   A14E, B25H, desB27, B29K(N ε -Octadecandioyl-γGlu), desB30 human insulin (Compound 4); and further comprising   of from about 1 to about 2% (weight/weight) of glycerol; of from about 45 to about 75 mM of phenol; of from about 0 to about 19 mM of m-cresol; of from about 1.5 to about 2.5 moles of zinc ions per six moles of said insulin derivative; not more than about 75 mM of sodium chloride; and having a pH value in the range of from 7.2 to 8.0.   
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the insulin derivative is A14E, B16H, B25H, B29K((N ε -Eicosanedioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]-acetylamino}ethoxy)ethoxy]acetyl)), desB30 human insulin (Compound 1). 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the amount of insulin derivative is in the range of from about 3.5 to about 5.0 mM. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , comprising of from about 1 to about 2% (weight/weight) of glycerol. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , comprising of from about 45 to about 75 mM of phenol, such as from about 55 mM to about 65 mM of phenol; or comprising of 50 mM, 51 mM, 52 mM, 53 mM, 54 mM, 55 mM, 56 mM, 57 mM, 58 mM, 59 mM, 60 mM, 61 mM, 62 mM, 63 mM, 64 mM, 65 mM, 66 mM, 67 mM, 68 mM, 69 mM, or 70 mM of phenol. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , comprising of from about 0 to about 19 mM of m-cresol, such as from about 0 mM to about 15 mM of m-cresol; or comprising of 0 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, or 15 mM of m-cresol. 
     
     
         7 . The pharmaceutical formulation according to  claim 1 , comprising of from about 1.5 to about 2.5 moles of zinc ions per six moles of insulin derivative. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , comprising less than about 25 mM of sodium chloride. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , having a pH value in the range of from 7.2 to 8.0. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , comprising
 of from about 4.0 to about 4.5 mM of insulin derivative;   of from about 1 to about 2% (weight/weight) of glycerol;   of from about 50 to about 70 mM of phenol;   of from about 0 to about 15 mM of m-cresol; of from about 2.0 to about 2.5 moles of zinc ions per six moles of insulin derivative;   no more than about 25 mM of sodium chloride; and   having a pH value in the range of from 7.2 to 7.6.   
     
     
         11 . The pharmaceutical composition according to  claim 1 , comprising
 of about 4.2 mM of insulin derivative;   of about 1.5% (weight/weight) of glycerol;   of about 60 mM of phenol;   of about 0 mM of m-cresol;   of about 2.2 moles of zinc ions per six moles of insulin derivative;   of about 20 mM of sodium chloride; and   having a pH value of about 7.4.   
     
     
         12 . The pharmaceutical composition according to  claim 1 , comprising
 of about 4.2 mM of insulin derivative;   of about 1.5% (weight/weight) of glycerol;   of about 60 mM of phenol;   of about 10 mM of m-cresol;   of about 2.2 moles of zinc ions per six moles of insulin derivative;   of about 20 mM of sodium chloride; and   having a pH value of about 7.4.   
     
     
         13 . The pharmaceutical composition according to  claim 1 , further comprising semaglutide. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein the amount of semaglutide is in the range of from about 0.30 to about 0.70 mM. 
     
     
         15 . The pharmaceutical composition according to  claim 2 , wherein the amount of insulin derivative is in the range of from about 3.5 to about 5.0 mM. 
     
     
         16 . The pharmaceutical composition according to  claim 2 , comprising of from about 1 to about 2% (weight/weight) of glycerol. 
     
     
         17 . The pharmaceutical composition according to  claim 2 , comprising of from about 45 to about 75 mM of phenol, such as from about 55 mM to about 65 mM of phenol; or comprising of 50 mM, 51 mM, 52 mM, 53 mM, 54 mM, 55 mM, 56 mM, 57 mM, 58 mM, 59 mM, 60 mM, 61 mM, 62 mM, 63 mM, 64 mM, 65 mM, 66 mM, 67 mM, 68 mM, 69 mM, or 70 mM of phenol. 
     
     
         18 . The pharmaceutical composition according to  claim 2 , comprising of from about 0 to about 19 mM of m-cresol, such as from about 0 mM to about 15 mM of m-cresol; or comprising of 0 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, or 15 mM of m-cresol. 
     
     
         19 . The pharmaceutical formulation according to  claim 2 , comprising of from about 1.5 to about 2.5 moles of zinc ions per six moles of insulin derivative. 
     
     
         20 . The pharmaceutical composition according to  claim 2 , comprising less than about 25 mM of sodium chloride. 
     
     
         21 . The pharmaceutical composition according to  claim 2 , having a pH value in the range of from 7.2 to 8.0. 
     
     
         22 . The pharmaceutical composition according to  claim 2 , comprising of from about 4.0 to about 4.5 mM of insulin derivative;
 of from about 1 to about 2% (weight/weight) of glycerol;   of from about 50 to about 70 mM of phenol;   of from about 0 to about 15 mM of m-cresol; of from about 2.0 to about 2.5 moles of zinc ions per six moles of insulin derivative;   no more than about 25 mM of sodium chloride; and   having a pH value in the range of from 7.2 to 7.6.   
     
     
         23 . The pharmaceutical composition according to  claim 2 , comprising
 of about 4.2 mM of insulin derivative;   of about 1.5% (weight/weight) of glycerol;   of about 60 mM of phenol;   of about 0 mM of m-cresol;   of about 2.2 moles of zinc ions per six moles of insulin derivative;   of about 20 mM of sodium chloride; and   having a pH value of about 7.4.   
     
     
         24 . The pharmaceutical composition according to  claim 2 , comprising
 of about 4.2 mM of insulin derivative;   of about 1.5% (weight/weight) of glycerol;   of about 60 mM of phenol;   of about 10 mM of m-cresol;   of about 2.2 moles of zinc ions per six moles of insulin derivative;   of about 20 mM of sodium chloride; and   having a pH value of about 7.4.   
     
     
         25 . The pharmaceutical composition according to  claim 2 , further comprising semaglutide. 
     
     
         26 . The pharmaceutical composition according to  claim 25 , wherein the amount of semaglutide is in the range of from about 0.30 to about 0.70 mM. 
     
     
         27 . A method of treating a metabolic disorder, comprising administering the pharmaceutical composition according to  claim 1  to a subject in need thereof.