Injectable solution at pH 7 comprising at least one basal insulin wherein the pI is comprised from 5.8 to 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals

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 basal insulin which isoelectric point pI is comprised from 5.8 to 8.5;
• a co-polyamino acid comprising glutamic or aspartic units that is a co-polyamino acid 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,
• Q is Q[*]k, wherein Q[*]k is a divalent linear or branched radical or spacer ([Q′]q)[*]k, where * represents binding sites of the different represented elements, 1≤q≤5 and k=2,
• wherein Q′ is a radical selected from the group consisting of formula III and formula IV and forms ([Q′]q)[*]k:
• wherein:
• 1≤t≤8,
• at least one of u1″ or u2″ is other than 0,
• if u1″≠0 then u1′≠0 and if u2″≠0 then u2″≠0,
• u1′ and u2′ are identical or different,
• 2≤u≤4,
• 0≤u1′≤4,
• 0≤u1″≤4,
• 0≤u2′≤4,
• 0≤u2″≤4, and
• Fa, Fb, Fa′, and Fb′ are identical or different and each represents function —NH— or —CO,
• the co-polyamino acid according to formula I bearing at least one hydrophobic radical -Hy, carboxylate charges and two chains of glutamic or aspartic units PLG bound together by the divalent linear or branched radical or spacer,
• the divalent linear or branched radical or spacer being bound to two glutamic or aspartic unit chains PLG by an amide function and,
• the amide function binding the divalent linear or branched radical or spacer to the two chains of glutamic or aspartic units results from a reaction between an amine function and an acid function respectively borne either by the Q′ that forms the divalent linear or branched radical or spacer or by a glutamic or aspartic unit, and
• the 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,
• wherein the hydrophobic radical -Hy is a radical according to formula X:
• wherein
• GpR is selected from the group consisting of radicals according to formulas VII, VII′ and VII″:
• GpG and GpH are identical or different and selected from the group consisting of radicals according to formulas XI and XI′:
• GpA is a radical according to formula VIII:
• wherein A′ is selected from the group consisting of radicals according to formulas VIII′, VIII″ and VIII′″:
• GpL is a radical according to formula XII:
• GpC is a radical according to formula IX:
• the * indicates the binding sites of the different represented elements 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 1=0 and l′=2 if l=1;
• r is an integer equal to 0, to 1 or to 2, and
• s′ is an integer equal to 0 or 1;
• A, A1, A2 and A3 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 selected from the group consisting of a non-substituted ether comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, non-substituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, a linear alkyl radical comprising from 1 to 9 carbon atoms, a branched alkyl radical comprising from 1 to 9 carbon atoms, a linear alkyl radical comprising an aromatic nucleus and comprising from 1 to 9 carbon atoms, and a branched alkyl radical comprising an aromatic nucleus and comprising from 1 to 9 carbon atoms:
• Cx 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 5 or more -GpC, then 6≤x≤11,
• G is a branched alkyl radical of 1 to 8 carbon atoms, the alkyl radical bearing one or a plurality of free carboxylic acid function(s);
• R is a radical selected 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 —CONH2 and 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, 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 a precursor -Hy′ of the hydrophobic radical -Hy and an acid function borne by a 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;
• and
• free carboxylic acid functions are in a form of alkali cation salt selected from the group consisting of Na+ and K+.