Injectable solution at ph 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer

Abstract

The invention relates to a composition in the form of an injectable aqueous solution, the pH of which is between 6.6 and 7.8, including at least: a) a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5; and b) a hydrophobized anionic polymer. In one embodiment, the compositions according to the invention also include a prandial insulin.

1 .- 17 . (canceled) 
     
     
         18 . A composition in the form of an injectable aqueous solution, the pH of which is between 6.6 and 7.8, comprising at least:
 a) a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5;   b) a hydrophobized anionic polymer of formula II-XII:   
       
         
           
           
               
               
           
         
       
       in which,
 l=0 or 1, 
 m=0, 1 or 2, 
 a=0 or 1, 
 n being the degree of polymerization, of between 3 and 1000, and 
 R 1  is a hydrogen —H, 
 R 3  is a radical —CH 2 R′, 
 R 5  is either a —COOH group, or a radical —CH 2 R′, or a radical -k-[D], 
 in which:
 -[D] is a radical -[Hy] or -[E]-(o-[Hy]) t ; 
 -[E]- is an at least divalent radical comprising from 1 to 15 carbon atoms comprising at least one heteroatom chosen from O, N and S, optionally bearing carboxyl or amine functions and/or -k-[E]-(o) t , comprising from 2 to 16 carbon atoms, is derived from an amino acid, from a dialcohol, from a diamine or from an amine alcohol; 
 -[Hy] is a C 8  to C 30  linear or cyclic alkyl group or a C 8  to C 30  alkylaryl or arylalkyl, optionally substituted with one or more C 1  to C 3  alkyl groups, which is derived from a hydrophobic compound; 
 k resulting from the reaction between a carboxyl, amine or alcohol function of the precursor of -k-[E]-(o) t  and an alcohol, carboxyl or amine function of the polymer and is a function chosen from the group consisting of ester, amide, carbonate and carbamate functions; 
 o resulting from the reaction between a carboxyl, amine or alcohol function of the precursor of -k-[E]-(o) t  and an alcohol or acid function of the precursor of -[Hy] is a function chosen from the group consisting of ester, amide, urea (carbamide), carbonate and carbamate functions; 
 t is a positive integer equal to 1 or 2; 
 
 
       or
 -R 1  and -R 3  form a six-membered ring -R 1 -R 3 -=—CH(NHCOCH 3 )—, and 
 -R′ is chosen from the group consisting of the radicals:
 —OH 
 —O-Alk, Alk being a C 1  to C 3  alkyl chain, 
 -(f-[A]-COOH), in which:
 -[A]- is an at least divalent radical comprising from 1 to 15 carbon atoms comprising at least one heteroatom chosen from O, N and S, optionally bearing carboxyl or amine functions and/or -f-[A]-COOH is derived from an amino acid, from a diacid or from an alcohol acid and is bonded to the backbone of the molecule via a function f; 
 f resulting from the reaction between a carboxyl or alcohol or amine function of the precursor of -f-[A]-COOH and a hydroxyl function of the backbone is chosen from the group consisting of ether, ester, carbamate or carbonate functions; 
 
 -g-[B]-(k-[D]) p , in which:
 -[B]- is an at least divalent radical comprising from 1 to 15 carbon atoms comprising at least one heteroatom chosen from O, N and S, optionally bearing carboxyl or amine functions and/or -g-[B]-(k-) p  is derived from an amino acid, from a diacid, from a dialcohol, from an alcohol acid, from a diamine or from an amine alcohol and is bonded to the backbone of the molecule via a function g and is bonded to at least one radical -[D] via a function k, 
 g resulting from the reaction between a carboxyl or alcohol or amine function of the precursor of -g-[B]-(k-) p  and a function of the backbone is chosen from the group consisting of ether, amine, ester, carbamate or carbonate functions, 
 k resulting from the reaction between a carboxyl or alcohol or amine function of the precursor of -g-[B]-(k-) p  and an alcohol or acid function of the precursor of -[D] is chosen from the group consisting of ester, amide or carbamate functions;
 p is a positive integer equal to 1 or 2; 
 
 
 
 and -[A]-, -[B]- and -[E]- are identical or different, 
 and k and o are identical or different; 
 and, if -[B]- is a trivalent radical, then -[D] is a radical -[Hy], and the degree of substitution with carboxylate charges is the average number of carboxylate charges per monomer divided by (l+m) and is greater than or equal to 0.4, 
 
       and the degree of substitution with hydrophobic radicals is the average number of hydrophobic radicals per monomer divided by (l+m) and is less than or equal to 0.5, and, if the hydrophobized anionic polymer is a polysaccharide, then the identical or different glycosidic linkages may be of a type and/or of β type. 
     
     
         19 . The composition according to  claim 18 , wherein in the hydrophobized anionic polymer of formula II-XII, l=0 and m=1, such that the hydrophobized anionic polymer is chosen from hydrophobized anionic polymers of formula II-IV: 
       
         
           
           
               
               
           
         
         in which -R 5  is either a —COOH group, or a radical —CH 2 R′, or a radical -k-[D]. 
       
     
     
         20 . The composition according to  claim 19 , wherein in the hydrophobized anionic polymer of formula II-IV, -R 5  is the radical —CH 2 R′. 
     
     
         21 . The composition according to  claim 18 , wherein in the hydrophobized anionic polymer of formula II-XII, m=0, l=1 and a=0, such that the hydrophobized anionic polymer is chosen from hydrophobized anionic polymers of formula II-V: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The composition according to  claim 18 , wherein in the hydrophobized anionic polymer of formula II-XII, l=1, m=2 and a=0, such that the hydrophobized anionic polymer is chosen from hydrophobized anionic polymers of formula II-VI: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The composition according to  claim 18 , wherein in the hydrophobized anionic polymer of formula II-XII, m=1, l=1, a=1, -R 1 -R 3 -=—CH(NHCOCH 3 )—, -R 2 =—CH 2 R′, -R 4 =—CH 2 R′, -R 5  is either a —COOH group, or a radical -k-[D], and -R 6 =-CH 2 R′, such that the hydrophobized anionic polymer is chosen from hydrophobized anionic polymers of formula II-VII: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The composition according to  claim 18 , wherein the radical -f-[A]-COOH is chosen from the radicals of formula II-II below: 
       
         
           
           
               
               
           
         
         in which:
 i is greater than or equal to 1 and less than or equal to 12, and 
 —R 7  and -R 8 , which may be identical or different, are chosen from the group consisting of a hydrogen atom, a saturated or unsaturated, linear, branched or cyclic C 1  to C 6  alkyl, a benzyl, an alkylaryl, optionally comprising heteroatoms chosen from the group consisting of O, N and/or S, or functions chosen from the group consisting of carboxylic acid, amine, alcohol and thiol functions. 
 
       
     
     
         25 . The composition according to  claim 18 , wherein the radical -f-[A]-COOH, comprising from 2 to 8 carbon atoms, is derived from an amino acid, from a dialcohol, from a diamine, from a diacid or from an amine alcohol. 
     
     
         26 . The composition according to  claim 18 , wherein the radical -f-[A]-COOH, comprising from 2 to 6 carbon atoms, is derived from an amino acid, from a dialcohol, from a diamine, from a diacid or from an amine alcohol. 
     
     
         27 . The composition according to  claim 18 , wherein:
 when -g-[B]-(k-[D]) p  comprises one Hy chain and Hy is a C 8  to C 15  alkyl, then the product of the degree of substitution with hydrophobic radicals and the average degree of polymerization (n) is greater than or equal to 2,   when -g-[B]-(k-[D]) p  comprises one Hy chain and Hy is a C 16  to C 20  alkyl, then the product of the degree of substitution with hydrophobic radicals and the average degree of polymerization (n) is greater than or equal to 1,   when -g-[B]-(k-[D]) p  comprises two Hy chains and Hy is a C 8  to C 9  alkyl, then the product of the degree of substitution with hydrophobic radicals and the average degree of polymerization (n) is greater than or equal to 2,   when -g-[B]-(k-[D]) p  comprises two Hy chains and Hy is a C 10  to C 16  alkyl, then the product of the degree of substitution with hydrophobic radicals and the average degree of polymerization (n) is greater than or equal to 0.2.   
     
     
         28 . The composition according to  claim 18 , wherein the radical -f-[A]-COOH is chosen from the group consisting of the following radicals: 
       
         
           
           
               
               
           
         
         or the salts thereof with alkali metal cations chosen from the group consisting of Na +  and K + . 
       
     
     
         29 . The composition according to  claim 18 , wherein the basal insulin, the isoelectric point of which is between 5.8 and 8.5, is insulin glargine. 
     
     
         30 . The composition according to  claim 18 , which comprises between 40 and 500 IU/ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5. 
     
     
         31 . The composition according to  claim 18 , wherein the concentration of hydrophobized anionic polymer is at most 100 mg/ml. 
     
     
         32 . The composition according to  claim 18 , which also comprises a prandial insulin. 
     
     
         33 . The composition according to  claim 18 , which comprises in total between 40 and 800 IU/ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8.5. 
     
     
         34 . The composition according to  claim 33 , wherein the proportions between the basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the prandial insulin are, as a percentage, 25/75, 30/70, 40/60, 50/50, 60/40, 70/30, 75/25, 80/20, or 90/10 for formulations comprising from 40 to 800 IU/ml. 
     
     
         35 . A single-dose formulation at a pH of between 6.6 and 7.8, which comprises a basal insulin, the isoelectric point of which is between 5.8 and 8.5, and a prandial insulin.