Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog and a co-polyamino acid

Abstract

The invention relates to a composition in the form of an injectable aqueous solution, wherein the pH is comprised from 6.0 to 8.0, comprising at least:a) amylin, an amylin receptor agonist or an amylin analog;b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy,characterized in that the composition does not comprise a basal insulin wherein the isoelectric point pI is comprised from 5.8 to 8.5.It also relates to a composition characterized in that it further comprises a prandial insulin.

1 . A composition in the form of an injectable aqueous solution, wherein the pH is comprised from 6.0 to 8.0, comprising at least:
 amylin, an amylin receptor agonist or an amylin analog;   a co-polyamino acid bearing carboxylate charges carboxylates and at least one hydrophobic radical -Hy according to formula X, said co-polyamino acid being chosen among the co-polyamino acids according to formula I:
   [Q(PLG) k ][Hy] j [Hy] j′   Formula I
 
   
       wherein:
 j≥1; 0≤j′≤n′1 and j+j′≥1 and k≥2 
 said co-polyamino acid according to formula I bearing at least one hydrophobic radical -Hy, carboxylate charges and consisting of at least two chains of glutamic or aspartic units PLG bound together by an at least divalent linear or branched radical or spacer Q[-*] k  consisting of an alkyl chain comprising one or a plurality of heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and/or bearing one or a plurality of heteroatoms consisting of nitrogen and oxygen radicals and/or radicals bearing one or a plurality of heteroatoms consisting of nitrogen and oxygen atoms and/or carboxyl functions. 
 said radical or spacer Q[-*]k being bound to at least two glutamic or aspartic unit chains PLG by an amide function and, 
 said amide bonds binding said radical or spacer Q[-*]k bound to said at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively borne either by the precursor Q′ of the radical or spacer Q[-*]k or by a glutamic or aspartic unit, 
 said hydrophobic radical -Hy being bound either to a terminal “amino acid” unit and then j≥1, or to a carboxyl function borne by one of the chains of the glutamic or aspartic units PLG and then j′=n′ 1 and n′ 1 is the mean number of monomeric units bearing a hydrophobic radical -Hy. 
 
     
     
         2 . The composition according to  claim 1 , wherein said radical or spacer Q[-*] k  is chosen among the radicals according to formula II:
   Q[-*] k =([Q′] q )[-*] k   Formula II
   
       wherein 1≤q≤5. 
     
     
         3 . The composition according to  claim 2 , wherein said radicals Q′, identical or different, are chosen from the group consisting of the radicals according to formulas III to VII hereinafter, to form Q[-*] k :
 by a radical according to Formula III: 
 
       
         
           
           
               
               
           
         
         
           wherein 1≤t≤8,
 by a radical according to formula IV: 
 
         
       
       
         
           
           
               
               
           
         
         wherein:
 at least one of u″ 1  or u″ 2  is different to 0, 
 if u″ 1 ≠0 then u′ 1 ≠0 and if u″ 2 ≠0 then u′ 2 ≠0, 
 u′ 1  and u′ 2  are identical and different, 
 2≤u≤4, 
 0≤u′ 1 ≤4, 
 0≤u″ 1 ≤4, 
 0≤u′ 2 ≤4, 
 0≤u″ 2 ≤4; 
 
         by a radical according to formula V: 
       
       
         
           
           
               
               
           
         
         wherein: 
         v, v′ and v″ identical or different, are integers ≥0, 
         v+v′+v″≤15, 
         by a radical according to formula VI: 
       
       
         
           
           
               
               
           
         
         wherein: 
         w′ 1  is different to 0, 
         0≤w″ 2 ≤1, 
         w 1 ≤6 and w′ 1 ≤6 and/or w 2 ≤6 and w′ 2 ≤6,
 where F x =F a , F b , F c , F d , F a′ , F b′ , F e′ , F c″  et F d′  are identical or different representing functions —NH— or —CO— and F y  representing a trivalent nitrogen atom —N═, and 
 two radicals Q′ being bound together by a covalent bond between a carbonyl function, F x =—CO—, and an amine function F x =—NH— or F y =—N═, thus forming an amide function. 
 
       
     
     
         4 . The composition according to  claim 1 , wherein the hydrophobic radical -Hy is chosen among the radicals according to formula X as defined hereinafter: 
       
         
           
           
               
               
           
         
       
       wherein
 GpR is chosen among the radicals according to formulas VII, VII′ or VII″: 
 
       
         
           
           
               
               
           
         
         GpG and GpH identical or different are chosen among the radicals according to formulas XI or XI′: 
       
       
         
           
           
               
               
           
         
         GpA is chosen among the radicals according to formula VIII: 
       
       
         
           
           
               
               
           
         
         
           wherein A′ is chosen among the radicals according to VIII′, VIII″ or VIII′″: 
         
       
       
         
           
           
               
               
           
         
         GpL is chosen among the radicals according to formula XII: 
       
       
         
           
           
               
               
           
         
         GpC is a radical according to formula IX: 
       
       
         
           
           
               
               
           
         
         the * indicates the binding sites of the different groups bound by amide functions; 
         a is an integer equal to 0 or to 1 and a′=1 if a=0 and a′=1, 2 or 3 if a=1; 
         a′ is an integer equal to 1, to 2 or to 3; 
         b is an integer equal to 0 or to 1; 
         c is an integer equal to 0 or to 1, and if c is equal to 0 then d is equal to 1 or to 2; 
         d is an integer equal to 0, to 1 or to 2; 
         e is an integer equal to 0 or to 1; 
         g is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6; 
         h is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6; 
         l is an integer equal to 0 or 1 and l′=1 if l=0 and l′=2 if l=1; 
         l′ is an integer equal to 1 or to 2; 
         r is an integer equal to 0, to 1 or to 2, and 
         s′ is an integer equal to 0 or 1; 
         A, A 1 , A 2  and A 3  identical or different are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and/or substituted by a radical from a saturated, unsaturated or aromatic ring; 
         B is a radical chosen from the group consisting of a non-substituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, and/or comprising an aromatic nucleus, comprising from 1 to 9 carbon atoms; 
         C x  is a linear or branched monovalent alkyl radical, and/or comprising a cyclic part, wherein x indicates the number of carbon atoms and:
 when the hydrophobic radical -Hy bears 1 -GpC, then 9≤x≤25, 
 when the hydrophobic radical -Hy bears 2 -GpC, then 9≤x≤15, 
 when the hydrophobic radical -Hy bears 3 -GpC, then 7≤x≤13, 
 when the hydrophobic radical -Hy bears 4 -GpC, then 7≤x≤11, 
 when the hydrophobic radical -Hy bears at least 5 -GpC, then 6≤x≤11, 
 
         G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical bearing one or a plurality of free carboxylic acid function(s); 
         R is a radical chosen from the group consisting of a linear or branched, divalent alkyl radical comprising from 1 to 12 carbon atoms, a linear or branched, divalent alkyl radical comprising from 1 to 12 carbon atoms bearing one or a plurality of functions —CONH 2  or a non-substituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms; 
         the hydrophobic radical(s) -Hy according to formula X being bound to the PLG:
 via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom borne by the PLG thus forming an amide function obtained from the reaction of an amine function borne by the PLG and an acid function borne by the precursor Hy′ of the hydrophobic radical -Hy, and 
 via a covalent bond between a nitrogen atom of the hydrophobic radical -Hy and a carbonyl borne by the PLG thus forming an amide function obtained from the reaction of an amine function of the precursor Hy′ of the hydrophobic radical -Hy and an acid function borne by the PLG, 
 
         a ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0<M≤0.5; 
         when a plurality of hydrophobic radicals are borne by a co-polyamino acid then they are identical or different, 
         a degree of polymerization DP in glutamic or aspartic units for the PLG chains is comprised from 5 to 250; 
         the free carboxylic acid functions being in the form of alkali cation salt chosen from the group consisting of Na +  and K + . 
       
     
     
         5 . The composition according to  claim 1 , wherein the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen among the co-polyamino acids according to formula XXXa hereinafter: 
       
         
           
           
               
               
           
         
       
       wherein,
 D represents, independently, either a group —CH 2 — (aspartic acid) or a group —CH 2 —CH 2 — (glutamic acid), 
 X represents a cationic entity chosen from the group comprising alkali cations, 
 Ra and R′a, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of a H, a C 2  to C 10  linear acyl group, a C 3  to C 10  branched acyl group, a benzyl, a terminal “amino acid” unit and a pyroglutamate,
 at least one of Ra and R′a being a hydrophobic radical -Hy, 
 
 Q and -Hy are as defined above, 
 n+m represents the degree of polymerization DP of the co-polyamino acid, namely the mean number of monomeric units per co-polyamino acid chain and 5≤n+m≤250. 
 
     
     
         6 . The composition according to  claim 1 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen among the co-polyamino acids according to formula XXXa′ 
       
         
           
           
               
               
           
         
       
       wherein:
 D represents, independently, either a group —CH 2 — (aspartic acid) or a group —CH 2 —CH 2 — (glutamic acid), 
 X represents a cationic entity chosen from the group comprising alkali cations, 
 Ra and R′a, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of an H, a C 2  to C 10  linear acyl group, a C3 to C 10  branched acyl group, a benzyl, a terminal “amino acid” unit and a pyroglutamate,
 at least one of Ra and R′a being a hydrophobic radical -Hy, 
 
 Q and Hy are as defined above, 
 n 1 +m 1  represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid bearing a radical -Hy, 
 n 2 +m 2  represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid not bearing a radical -Hy, 
 n 1 +n 2 =n′ and m 1 +m 2 =m′, 
 n′+m′ represents the degree of polymerization DP of the co-polyamino acid, namely the mean number of monomeric units per co-polyamino acid chain and 5≤n′+m′≤250. 
 
     
     
         7 . The composition according to  claim 1 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen among the co-polyamino acids according to formula XXXb hereinafter: 
       
         
           
           
               
               
           
         
       
       wherein,
 D represents, independently, either a group —CH 2 — (aspartic acid) or a group —CH 2 —CH 2 — (glutamic acid), 
 X represents a cationic entity chosen from the group comprising alkali cations, 
 Rb and R′b, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of an H, a C 2  to C 10  linear acyl group, a C 3  to C 10  branched acyl group, a benzyl, a terminal “amino acid” unit and a pyroglutamate,
 at least one of Rb and R′b is a hydrophobic radical -Hy, 
 
 Q and Hy are as defined above, 
 n+m represents the degree of polymerization DP of the co-polyamino acid, namely the mean number of monomeric units per co-polyamino acid chain and 5≤n+m≤250. 
 
     
     
         8 . The composition according to  claim 1 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen among the co-polyamino acids according to formula XXXb′ hereinafter: 
       
         
           
           
               
               
           
         
       
       wherein:
 D represents, independently, either a group —CH 2 — (aspartic acid) or a group —CH 2 —CH 2 — (glutamic acid), 
 X represents a cationic entity chosen from the group comprising alkali cations, 
 Q and Hy are as defined above, 
 Rb and R′b, identical or different, are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of an —OH, an amine group, a terminal “amino acid” unit and a pyroglutamate,
 at least one of Rb and R′b is a hydrophobic radical -Hy, 
 
 n1+m1 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid bearing a radical -Hy, 
 n2+m2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid not bearing a radical -Hy, 
 n1+n2=n′ and m1+m2=m′, 
 n′+m′ represents the degree of polymerization DP of the co-polyamino acid, namely the mean number of monomeric units per co-polyamino acid chain and 5≤n′+m′≤250. 
 
     
     
         9 . The composition according to  claim 1 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radical is chosen from among the co-polyamino acids according to formulas XXXa, XXXa′, XXXb or XXXb′: 
       
         
           
           
               
               
           
         
       
       wherein the group D is a group —CH 2 — (aspartic unit). 
     
     
         10 . The composition according to  claim 1 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from among the co-polyamino acids according to formulas XXXa, XXXa′, XXXb or XXXb′: 
       
         
           
           
               
               
           
         
       
       wherein the group D is a group —CH 2 —CH 2 — (glutamic unit). 
     
     
         11 . The composition according to  claim 1 , wherein the molar ratio of co-polyamino acid/amylin, amylin receptor agonist or amylin analog is greater than or equal to 1. 
     
     
         12 . The composition according to  claim 1 , wherein the amylin, amylin receptor agonist or amylin analog is amylin. 
     
     
         13 . The composition according to  claim 1 , wherein the amylin, amylin receptor agonist or amylin analog is pramlintide. 
     
     
         14 . The composition according to  claim 1 , wherein it further comprises a prandial insulin. 
     
     
         15 . The composition according to  claim 1 , wherein the molar ratio of co-polyamino acid/insulin is greater than or equal to 1. 
     
     
         16 . The composition according to  claim 1 , wherein said composition has a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or an amylin agonist but not comprising co-polyamino acid bearing carboxylate charges and hydrophobic radicals -Hy, said ThT monitoring being carried out under accelerated stability conditions: under stirring and at 37° C. 
     
     
         17 . A co-polyamino acid bearing carboxylate charges carboxylates and at least one hydrophobic radical according to formula X, said co-polyamino acid being chosen among the co-polyamino acids according to formula I:
   [Q(PLG) k ][H y ] j [H y ] j′   Formula I
   
       wherein:
 j≥1; 0≤j′≤n′1 and j+j′≥1 and k≥2 
 said co-polyamino acid according to formula I bearing at least one hydrophobic radical -Hy, carboxylate charges and consisting of at least two chains of glutamic or aspartic units PLG bound together by an at least divalent linear or branched radical or spacer Q[-*] k  consisting of an alkyl chain comprising one or a plurality of heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and/or bearing one or a plurality of heteroatoms consisting of nitrogen and oxygen radicals and/or radicals bearing one or a plurality of heteroatoms consisting of nitrogen and oxygen atoms and/or carboxyl functions, 
 said radical or spacer Q[-*]k being bound to at least two glutamic or aspartic unit chains PLG by an amide function and, 
 said amide bonds binding said radical or spacer Q[-*]k bound to said at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively borne either by the precursor Q′ of the radical or spacer Q[-*]k or by a glutamic or aspartic unit, 
 said hydrophobic radical -Hy being bound either to a terminal “amino acid” unit and then j≥1, or to a carboxyl function borne by one of the chains of the glutamic or aspartic units PLG and then j′=n′1 and n′1 is the mean number of monomeric units bearing a hydrophobic radical -Hy, 
 and wherein the at least one hydrophobic radical -Hy according to formula X is as defined hereinafter: 
 
       
         
           
           
               
               
           
         
       
       wherein
 GpR is chosen among the radicals according to formulas VII, VII′ or VII″: 
 
       
         
           
           
               
               
           
         
         GpG and GpH identical or different are chosen among the radicals according to formulas XI or XI′: 
       
       
         
           
           
               
               
           
         
         GpA is chosen among the radicals according to formula VIII: 
       
       
         
           
           
               
               
           
         
         
           wherein A′ is chosen among the radicals according to VIII′, VIII″ or VIII′″: 
         
       
       
         
           
           
               
               
           
         
         GpL is chosen among the radicals according to formula XII: 
       
       
         
           
           
               
               
           
         
         GpC is a radical according to formula IX: 
       
       
         
           
           
               
               
           
         
         the * indicates the binding sites of the different groups bound by amide functions; 
         a is an integer equal to 0 or to 1 and a′=1 if a=0 and a′=1, 2 or 3 if a=1; 
         a′ is an integer equal to 1, to 2 or to 3; 
         b is an integer equal to 0 or to 1; 
         c is an integer equal to 0 or to 1, and if c is equal to 0 then d is equal to 1 or to 2; 
         d is an integer equal to 0, to 1 or to 2; 
         e is an integer equal to 0 or to 1; 
         g is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6; 
         h is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6; 
         l is an integer equal to 0 or 1 and l′=1 if l=0 and l′=2 if l=1; 
         l′ is an integer equal to 1 or to 2; 
         r is an integer equal to 0, to 1 or to 2, and 
         s′ is an integer equal to 0 or 1; 
         A, A 1 , A 2  and A 3  identical or different are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and/or substituted by a radical from a saturated, unsaturated or aromatic ring; 
         B is a radical chosen from the group consisting of a non-substituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, and/or comprising an aromatic nucleus, comprising from 1 to 9 carbon atoms; 
         C x  is a linear or branched monovalent alkyl radical, and/or comprising a cyclic part, wherein x indicates the number of carbon atoms and:
 when the hydrophobic radical -Hy bears 1 -GpC, then 9≤x≤25, 
 when the hydrophobic radical -Hy bears 2 -GpC, then 9≤x≤15, 
 when the hydrophobic radical -Hy bears 3 -GpC, then 7≤x≤13, 
 when the hydrophobic radical -Hy bears 4 -GpC, then 7≤x≤11, 
 when the hydrophobic radical -Hy bears at least 5 -GpC, then 6≤x≤11, 
 
         G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical bearing one or a plurality of free carboxylic acid function(s); 
         R is a radical chosen from the group consisting of a linear or branched, divalent alkyl radical comprising from 1 to 12 carbon atoms, a linear or branched, divalent alkyl radical comprising from 1 to 12 carbon atoms bearing one or a plurality of functions —CONH 2  or a non-substituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms; 
         the hydrophobic radical(s) -Hy according to formula X being bound to the PLG:
 via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom borne by the PLG thus forming an amide function obtained from the reaction of an amine function borne by the PLG and an acid function borne by the precursor Hy′ of the hydrophobic radical -Hy, and 
 via a covalent bond between a nitrogen atom of the hydrophobic radical -Hy and a carbonyl borne by the PLG thus forming an amide function obtained from the reaction of an amine function of the precursor Hy′ of the hydrophobic radical -Hy and an acid function borne by the PLG, 
 
         a ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0<M≤0.5; 
         when a plurality of hydrophobic radicals are borne by a co-polyamino acid then they are identical or different; 
         a degree of polymerization DP in glutamic or aspartic units for the PLG chains is comprised from 5 to 250; 
         the free carboxylic acid functions being in the form of alkali cation salt chosen from the group consisting of Na +  and K + . 
       
     
     
         18 . A hydrophobic radical precursor Hy′ chosen among the compounds according to formula X′ as defined hereinafter: 
       
         
           
           
               
               
           
         
       
       wherein
 GpR is chosen among the radicals according to formulas VII, VII′ or VII″: 
 
       
         
           
           
               
               
           
         
         GpG and GpH identical or different are chosen among the radicals according to formulas XI or XI′: 
       
       
         
           
           
               
               
           
         
         GpA is chosen among the radicals according to formula VIII: 
       
       
         
           
           
               
               
           
         
         
           wherein A′ is chosen among the radicals according to VIII′, VIII″ or VIII′″: 
         
       
       
         
           
           
               
               
           
         
         GpL is chosen among the radicals according to formula XII: 
       
       
         
           
           
               
               
           
         
         GpC is a radical according to formula IX: 
       
       
         
           
           
               
               
           
         
         the * indicates the binding sites of the different groups bound by amide functions; 
         a is an integer equal to 0 or to 1 and a′=1 if a=0 and a′=1, 2 or 3 if a=1; 
         a′ is an integer equal to 1, to 2 or to 3; 
         b is an integer equal to 0 or to 1; 
         c is an integer equal to 0 or to 1, and if c is equal to 0 then d is equal to 1 or to 2; 
         d is an integer equal to 0, to 1 or to 2; 
         e is an integer equal to 0 or to 1; 
         g is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6; 
         h is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6; 
         l is an integer equal to 0 or 1 and l′=1 if l=0 and l′=2 if l=1; 
         l′ is an integer equal to 1 or to 2; 
         r is an integer equal to 0, 1 or to 2, and 
         s′ is an integer equal to 0 or 1; 
         A, A 1 , A 2  and A 3  identical or different are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and/or substituted by a radical from a saturated, unsaturated or aromatic ring; 
         B is a radical chosen from the group consisting of a non-substituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, and/or comprising an aromatic nucleus, comprising from 1 to 9 carbon atoms; 
         C x  is a radical chosen from the group consisting of a linear or branched monovalent alkyl radical, and/or comprising a cyclic part, wherein x indicates the number of carbon atoms and 6≤x≤25:
 when the hydrophobic radical -Hy bears 1 -GpC, then 9≤x≤25, 
 when the hydrophobic radical -Hy bears 2 -GpC, then 9≤x≤15, 
 when the hydrophobic radical -Hy bears 3 -GpC, then 7≤x≤13, 
 when the hydrophobic radical -Hy bears 4 -GpC, then 7≤x≤11, 
 when the hydrophobic radical -Hy bears at least 5 -GpC, then 6≤x≤11; 
 
         G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical bearing one or a plurality of free carboxylic acid function(s); 
         R is a radical chosen from the group consisting of a linear or branched, divalent alkyl radical comprising from 1 to 12 carbon atoms, a linear or branched, divalent alkyl radical comprising from 1 to 12 carbon atoms bearing one or a plurality of functions —CONH 2  or a non-substituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms; 
         the hydrophobic radical(s) -Hy according to formula X being bound to the PLG:
 via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom borne by the PLG thus forming an amide function obtained from the reaction of an amine function borne by the PLG and an acid function borne by the precursor Hy′ of the hydrophobic radical -Hy and/or 
 via a covalent bond between a nitrogen atom of the hydrophobic radical -Hy and a carbonyl borne by the PLG thus forming an amide function obtained from the reaction of an amine function of the precursor Hy′ of the hydrophobic radical -Hy and an acid function borne by the PLG; 
 
         a ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0<M≤0.5; 
         when a plurality of hydrophobic radicals are borne by a co-polyamino acid then they are identical or different; 
         a degree of polymerization DP in glutamic or aspartic units for the PLG chains is comprised from 5 to 250; 
         the free acid functions being in the form of alkali cation salt chosen from the group consisting of Na +  and K + . 
       
     
     
         19 . A method for improving the physicochemical stability of the composition according to  claim 1 , by adding one or more ionic species chosen from the group of anions, cations and zwitterions.