Injectable solution at ph 7 comprising at least one basal insulin whose pi is between 5.8 and 8.5

Abstract

A composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, includes at least a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5; and a dextran substituted by radicals carrying carboxylate charges and hydrophobic radicals. Single-dose formulations at a pH of between 7 and 7.8 includes a basal insulin whose isoelectric point is between 5.8 and 8.5 and a prandial insulin.

1 . A composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
 a) a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5; and   b) dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals of formula I or of formula II:   
       
         
           
           
               
               
           
         
         in which:
 R is —OH or chosen from the group consisting of the radicals:
 -(f-[A]-COOH) n ; and 
 -(g-[B]-k-[D]) m , D comprising at least one alkyl chain comprising at least 8 carbon atoms; wherein: 
 
 n represents the degree of substitution of the glucoside units by -f-[A]-COOH and 0.3≤n≤2; 
 m represents the degree of substitution of the glucoside units by -g-[B]-k-[D] and 0.02<m≤0.2; 
 q represents the degree of polymerization as glucoside units, that is to say the mean number of glucoside units per polysaccharide chain, and 3≤q≤40;
 -A- is a linear or branched radical comprising from 1 to 4 carbon atoms; the said -A- radical: 
 being bonded to a glucoside unit via a functional group f chosen from the group consisting of ether, ester and carbamate functional groups; 
 -B- is a linear or branched, at least divalent, radical comprising from 1 to 4 carbon atoms; the said -B- radical: 
 being bonded to a glucoside unit via a functional group g chosen from the group consisting of ether, ester and carbamate functional groups; 
 being bonded to a -D radical via a functional group k; k chosen from the group consisting of ester, amide and carbamate functional groups; the said -D radical:
 being an -X(-l-Y) p  radical, X being an at least divalent radical comprising from 1 to 12 atoms chosen from the group consisting of C, N and O atoms, optionally carrying carboxyl or amine functional groups; Y being a linear or cyclic alkyl group, an alkylaryl or an arylalkyl, of 8 to 30 carbon atoms, optionally substituted by one or several C1 to C3 alkyl groups; p≥1 and 1 a functional group chosen from the group consisting of ester, amide and carbamate functional groups; 
 
 
 f, g and k being identical or different; 
 the free acid functional groups being in the form of salts of alkali metal cations chosen from the group consisting of Na +  and K + ; 
 and, when p=1, if Y is a C 8  to C 14  alkyl, then q*m≥2, if Y is a C 15  alkyl, then q*m≥2; if Y is a C 16  to C 20  alkyl, then q*m≥1; and if Y is a C 21  to C 30  group, then q*m≥1; 
 and, when p≥2, if Y is a C 8  to C 9  alkyl, then q*m≥2 and, if Y is a C 10  to C 16  alkyl, then q*m≥0.2; 
 
       
       
         
           
           
               
               
           
         
         in which:
 R is —OH or a -(f-[A]-COOH) n  radical:
 -A- is a linear or branched radical comprising from 1 to 4 carbon atoms; the said radical -A-: 
 being bonded to a glucoside unit via a functional group f chosen from the group consisting of ether, ester or carbamate functional groups; 
 n represents the degree of substitution of the glucoside units by -f-[A]-COOH and 0.3≤n≤2; 
 
 R′ is chosen from the group consisting of the radicals:
 —C(O)NH-[E]-(o-[F]) t ; and 
 —CH 2 N(L) z -[E]-(o-[F]) t ; 
 
 
         in which:
 z is a positive integer equal to 1 or 2, 
 L is chosen from the group consisting of:
 —H and z is equal to 1, and/or 
 -[A]-COOH and z is equal to 1 or 2, if f is an ether functional group, 
 —CO-[A]-COOH and z is equal to 1 if f is an ester functional group, and 
 —CO—NH-[A]-COOH and z is equal to 1 if f is a carbamate functional group; 
 
 -[E]-(o-[F]) t :
 -E- is a linear or branched, at least divalent, radical comprising from 1 to 8 carbon atoms and optionally comprising heteroatoms, such as O, N or S; 
 -F- is a linear or cyclic alkyl group, an alkylaryl or an arylalkyl, of 12 to 30 carbon atoms, optionally substituted by one or several C1 to C3 alkyl groups; 
 o is a functional group chosen from the group consisting of ether, ester, amide or carbamate functional groups; 
 t is a positive integer equal to 1 or 2; 
 
 q represents the degree of polymerization as glucoside units, that is to say the mean number of glucoside units per polysaccharide chain, and 3≤q≤40; 
 the free acid functional groups being in the form of salts of alkali metal cations chosen from the group consisting of Na +  and K + ; and 
 when z=2, the nitrogen atom is in the form of a quaternary ammonium. 
 
       
     
     
         2 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula I. 
     
     
         3 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula II. 
     
     
         4 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula I in which the -(f-[A]-COOH) n  radical is chosen from the group consisting of the following sequences, f having the meaning given above: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula I in which the -(g-[B]-k-[D]) m  radical is chosen from the group consisting of the following sequences, g, k and D having the meanings given above: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula I in which the -(g-[B]-k-[D]) m  radical is such that:
 -B- is a radical comprising one carbon atom; the said -B- radical being bonded to a glucoside unit via an ether functional group g, and X is a radical resulting from an amino acid.   
     
     
         7 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula I in which the X radical is an at least divalent radical resulting from an amino acid chosen from the group consisting of glycine, leucine, phenylalanine, lysine, isoleucine, alanine, valine, aspartic acid and glutamic acid. 
     
     
         8 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula I in which the Y group is chosen from the group consisting of a hydrophobic alcohol, a hydrophobic acid, a sterol or a tocopherol. 
     
     
         9 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula I in which the Y group is a sterol chosen from cholesterol derivatives. 
     
     
         10 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula II in which the R′ group is such that the -E- radical results from a diamine. 
     
     
         11 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the dextran polymers of formula II in which the R′ group is such that the -F- group results from a cholesterol derivative. 
     
     
         12 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the group consisting of the following dextran polymers of formula I:
 Sodium dextranmethylcarboxylate modified by octyl glycinate,   Sodium dextranmethylcarboxylate modified by cetyl glycinate,   Sodium dextranmethylcarboxylate modified by octyl phenylalaninate,   Sodium dextranmethylcarboxylate modified by 3,7-dimethyl-1-octyl phenylalaninate,   Sodium dextranmethylcarboxylate modified by dioctyl aspartate,   Sodium dextranmethylcarboxylate modified by didecyl aspartate,   Sodium dextranmethylcarboxylate modified by dilauryl aspartate,   Sodium dextranmethylcarboxylate modified by N-(2-aminoethyl)dodecanamide,   Sodium dextransuccinate modified by lauryl glycinate,   N-(sodium methylcarboxylate) dextran carbamate modified by dioctyl aspartate,   Sodium dextranmethylcarboxylate modified by 2-(2-aminoethoxy)ethyl dodecanoate,   Sodium dextranmethylcarboxylate modified by 2-(2-{2-[dodecanoylamino]ethoxy}ethoxy)ethylamine,   Sodium dextranmethylcarboxylate modified by 2-(2-{2-[hexadecanoylamino]ethoxy}ethoxy)ethylamine,   Sodium dextranmethylcarboxylate modified by cholesteryl leucinate,   Sodium dextranmethylcarboxylate modified by cholesteryl 1-ethylenediaminecarboxylate, and   N-(sodium methylcarboxylate) dextran carbamate modified by cholesteryl leucinate.   
     
     
         13 . The composition according to  claim 1 , wherein the dextran polymers substituted by radicals carrying carboxylate charges and hydrophobic radicals is chosen from the group consisting of the dextran polymers of formula II and is:
 Sodium dextranmethylcarboxylate modified by cholesteryl 1-ethylenediaminecarboxylate grafted by reductive amination to the reducing chain end.   
     
     
         14 . The composition according to  claim 1 , wherein the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine. 
     
     
         15 . The composition according to  claim 1 , wherein the composition comprises between 40 IU/ml and 500 IU/ml of the basal insulin whose isoelectric point is between 5.8 and 8.5. 
     
     
         16 . The composition according to  claim 1 , wherein the composition additionally comprises a prandial insulin. 
     
     
         17 . The composition according to  claim 1 , wherein the composition comprises between 40 and 800 IU/ml of total insulin. 
     
     
         18 . The composition according to  claim 16 , wherein the composition comprises proportions, expressed as percentage, between the basal insulin whose isoelectric point is between 5.8 and 8.5 and a prandial insulin of 25/75, 30/70, 40/60, 50/50, 60/40, 70/30, 80/20 and 90/10. 
     
     
         19 . The composition according to  claim 1 , wherein the composition additionally comprises a GLP-1, a GLP-1 analogue or a GLP-1 derivative. 
     
     
         20 . The composition according to  claim 1 , wherein the composition additionally comprises zinc salts at a concentration of between 0 and 5000 μM. 
     
     
         21 . The composition according to  claim 1 , wherein the composition comprises buffers chosen from the group consisting of Tris, citrates and phosphates at concentrations of between 0 and 100 mM, preferably between 0 and 50 mM. 
     
     
         22 . The composition according to  claim 16 , wherein the prandial insulin is chosen from the group formed by human insulin, insulin glulisine, insulin lispro and insulin aspart. 
     
     
         23 . A single-dose formulation comprising a composition according to  claim 1 , at a pH of between 6.6 and 7.8, and a prandial insulin. 
     
     
         24 . A single-dose formulation comprising a composition according to  claim 1 , at a pH of between 6.6 and 7.8, and a GLP-1, a GLP-1 derivative or a GLP-1 analogue. 
     
     
         25 . A single-dose formulation according to  claim 23 , wherein the prandial insulin is chosen from the group comprising of human insulin. 
     
     
         26 . A single-dose formulation according to  claim 23 , wherein the prandial insulin is chosen from the group consisting of insulin lispro, insulin glulisine and insulin aspart.