WO2020245470A1 - Injectable solution at ph 7 containing at least one basal insulin, the pi of which is between 5.8 and 8.5, liraglutide, and a copolyamino acid carrying carboxylate charges and hydrophobic radicals - Google Patents

Injectable solution at ph 7 containing at least one basal insulin, the pi of which is between 5.8 and 8.5, liraglutide, and a copolyamino acid carrying carboxylate charges and hydrophobic radicals Download PDF

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Publication number
WO2020245470A1
WO2020245470A1 PCT/EP2020/065884 EP2020065884W WO2020245470A1 WO 2020245470 A1 WO2020245470 A1 WO 2020245470A1 EP 2020065884 W EP2020065884 W EP 2020065884W WO 2020245470 A1 WO2020245470 A1 WO 2020245470A1
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formula
radical
hydrophobic
polyamino acid
chosen
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PCT/EP2020/065884
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French (fr)
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Alexandre Geissler
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Adocia
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the invention relates to insulin injection therapy (s) for treating diabetes.
  • the invention relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least one basal insulin whose isoelectric point (pi) is between 5.8 and 8.5, liraglutide and a co-polyamino acid carrying carboxylate charges and hydrophobic radicals.
  • Insulin glargine is considered today to be the most widely used basal insulin.
  • the necessarily acidic pH of the basal insulin formulations, the isoelectric point of which is between 5.8 and 8.5, of the insulin glargine type, can be a real drawback, because this acidic pH of the formulation of insulin glargine sometimes causes injection pain in patients and above all prevents formulation with other proteins which are not stable at acidic pH.
  • compositions 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 p1 of which is between 5.8 and 8.5 and (b) a carboxylate-charged co-polyamino acid substituted by hydrophobic groups.
  • compositions further comprising liraglutide requires a large amount of co-polyamino acid carrying carboxylate charges substituted by hydrophobic radicals.
  • co-polyamino acids carrying carboxylate charges substituted by hydrophobic radicals make it possible to obtain this solubility and / or this stability with a quantity of co-polyamino acid carrying carboxylate charges substituted by hydrophobic radicals which is smaller and /or a improved stability with an equal concentration of carboxylate-charged co-polyamino acid substituted by hydrophobic groups.
  • the invention relates to a physically stable composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
  • GpG and GpH which are identical or different, are chosen from the radicals of formulas XI or XI ': * - NH - G - NH - *
  • - GpC is a radical of formula IX: Formula IX; - The * indicate the attachment sites of the various groups linked by amide functions;
  • b is an integer equal to 0 or 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;
  • - g is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6;
  • r is an integer equal to 0 or 1
  • - A is a linear or branched trivalent alkyl radical comprising from 1 to 6 carbon atoms;
  • - B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
  • - Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and x> 13.
  • - G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
  • - R is a radical chosen from the group consisting of a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms bearing one or more functions - CONH2 or an ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
  • the degree of polymerization DP in glutamic or aspartic units for the polyglutamate chains is between 5 and 250;
  • the free carboxylic acid functions being in the form of an alkaline cation salt chosen from the group consisting of Na + and K + .
  • g 0 and h> 2.
  • GpR corresponds to Formula VII.
  • the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of the following formula XXXa:
  • -D- represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit);
  • • -Z represents a cationic entity chosen from the group comprising alkali metal cations
  • -R a and -R a ' are a radical chosen from the group consisting of an H, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, a benzyl, a "unit" terminal amino acid and a pyroglutamate;
  • Q [- *] 3 is a trivalent spacer chosen from formulas XII, XII 'or XII", said spacer
  • Ai and A2 are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms
  • ⁇ N + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomer units per chain of co-polyamino acid and 5 ⁇ n + m ⁇ 250.
  • the precursor of the radical of formula XII is an amino acid selected from the group consisting of lysine, ornithine and 2,3-diaminopropionic acid.
  • the precursor of the radical of formula XII is a triamine selected from the group consisting of spermidine, norspermidine, diethylenetriamine and bis (hexamethylene) triamine.
  • the precursor of the radical of formula XII is spermidine.
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula
  • the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of the following formula XXXb:
  • - D represents, independently, either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),
  • - Z represents a cationic entity chosen from the group comprising alkali metal cations
  • - m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomer units per chain of co-polyamino acid and 5 ⁇ n + m ⁇ 250;
  • R 1 or R 2 which are identical or different, are a radical chosen from the group consisting of an H, a hydrophobic radical of formula X, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, a benzyl, a terminal “amino acid” unit and a pyroglutamate and at least R 1 or R 2 is a hydrophobic radical of formula X.
  • the co-polyamino acid carrying carboxylate charges (PLG) and hydrophobic radicals is chosen from the co-polyamino acids described in applications PCT / EP2018 / 083896, PCT / EP2018 / 083897 and PCT / 2018/083558 whose numbers publication are W02019110773, W02019110774 and W02019110625 respectively.
  • the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb in which R1 or R2 is a hydrophobic radical.
  • the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb in which RI is a hydrophobic radical of formula X but not R2.
  • the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb in which R2 is a hydrophobic radical of formula X but not R1.
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula
  • GpR is of Formula VII.
  • composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of the following formula XXXd: Formula XXXd in which,
  • D represents, independently, either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),
  • X represents a cationic entity chosen from the group comprising alkali metal cations
  • Rd and R'd are a hydrophobic radical -Hy of formula
  • K is a divalent spacer chosen from the following formulas III or IV,
  • spacer K being linked to at least two chains of glutamic or aspartic PLG units via amide functions;
  • n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomer units per chain of co-polyamino acid and 5 ⁇ n + m ⁇ 250.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which Rd and R'd, which are identical, are a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which Rd and R'd, different are a hydrophobic radical -Hy.
  • composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which K is of formula III and identical Rd and R'd are a hydrophobic radical of formula X.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which K is of formula III and Rd and R'd which are identical are a hydrophobic radical of formula Xa.
  • composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of the following formula XXXe:
  • Rb and R'b are a hydrophobic radical -Hy
  • o Fa and Fa ' identical or different represent a -CO- function and o Fb and Fb', identical or different, represent a -CO- function.
  • n + m have the same definition as given previously.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe in which Rb and R'b, which are identical, are a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe in which Rb and R'b, different are hydrophobic radicals -Hy.
  • the at least two chains of glutamic or aspartic units P LG being linked to K by a function Fa, Fa 'or Fb, Fb' by a covalent bond to form an amide bond with an -NH- or -CO function - of the PLG.
  • K is a radical of formula III
  • the precursor of the radical of formula III is a diamine chosen from the group consisting of ethylenediamine, butylenediamine, rhexylenediamine, 1,3-diaminopropane and 1,5-diaminopentane, propylene diamine, pentylene diamine.
  • the precursor of the radical of formula III is ethylene diamine.
  • the precursor of the radical of formula III is a diacid.
  • the precursor of the radical of formula III is a diacid chosen from the group consisting of succinic acid, glutaric acid and adipic acid.
  • K is a radical of formula IV, Formula IV, the precursor of which is a diamine.
  • the precursor of the radical of formula IV is a diamine chosen from the group consisting of diethylene glycoldiamine, triethylene glycol diamine, 1-amino-4,9-dioxa-12-dodecanamine and 1- amino-4,7,10-trioxa-13-tridecanamine.
  • the precursor of the radical of formula IV is triethyleneglycol diamine.
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula
  • the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula
  • the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXd or XXXe in which the group D is a -CH2 group -CH2- (glutamic unit).
  • the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXd or XXXe in which the group D is a -CH2 group - (aspartic unit).
  • the co-polyamino acid comprises one or more aspartic unit (s), that (s) -ci little (come) t undergo structural rearrangements.
  • the composition according to the invention is characterized in that when the co-polyamino acids comprises aspartate units, then the co-polyamino acids can also comprise monomeric units of formula XXXX and / or XXXX ' :
  • said hydrophobic radical — Hy is chosen from radicals of formula X as defined below of formula Xa
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa, in which g> 1 and / or h> 1 and GpG and / or GpH is a radical of Formula Xlb.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa, in which g> 1 and / or h> 1 and GpG and / or GpH is a radical of Formula Xla
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa, in which g> 1 and / or h> 1 and GpG and / or GpH is / are chosen from the radicals of formulas Xla, Xlb, XIc, Xld, Xl'e or Xl'f shown below.
  • the hydrophobic radical is a radical of formula X or Xa, in which g> 1 and / or h> 1 and GpG and / or GpH is / are chosen from the radicals of formulas Xla, Xlb, XIc, Xld, Xl'e or Xl'f shown below.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpL radical of formula XII is chosen from the group consisting of radicals of formulas Xlla and Xllb hereinafter represented:
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpL radical is a radical of Formula Xlla.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpL radical is a radical of Formula Xllb.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXa ', IXb' or IXe 'shown below:
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXa ', IXb' or IXe 'in which b is equal to 0, corresponding respectively to formulas IXd, IXe, and IXf shown below:
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is a radical of formula IXd.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising from 13 to 19 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising from 13 to 19 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising from 13 to 17 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising from 13 to 17 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising from 13 to 15 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising from 13 to 15 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in WO 2020/245470 PCT / EP2020 / 065884
  • GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising 13 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising 13 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising 15 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising 15 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising 17 carbon atoms.
  • the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising 17 carbon atoms.
  • the co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy is chosen from the copolyamino acids of formula XXXa in which Q is a radical of formula XII ",
  • Formula XII in which Ai and A2 are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms.
  • -Al- is a radical - [CH2] 3- and -A2- is a radical - [Cl-h] ⁇ -.
  • -Al- is a radical - [CH2] 2- and -A2- is a radical - [CH2] 2-.
  • -Al- is a radical - [O-te e- and -A2- is a radical - [CH2] 6-. In one embodiment -Al- is a radical - [CH2] 3- and -A2- is
  • GpC corresponds to Formula IXd.
  • GpC corresponds to Formula IXd.
  • composition according to the invention allows insulin glargine and liraglutide to have pharmacokinetic profiles similar respectively to:
  • the hydrophobic radical ratio per basal insulin is defined as being the ratio of their respective molar concentrations: [Hy] / [basal insulin] (mol / mol) 5 to obtain the expected performances, namely the solubilization of the basal insulin at pH between 6.0 and 8.0, the precipitation of basal insulin after injection into the subcutaneous medium and the stability of the compositions according to the invention.
  • the hydrophobic radical ratio per basal insulin [Hy] / [basal insulin] may be greater than the minimum value determined by the solubilization limit.
  • the hydrophobic radical ratio per basal insulin [Hy] / [basal insulin] is between 1 and 4.
  • the ratio of hydrophobic radical to basal insulin is the ratio of hydrophobic radical to basal insulin
  • the mass ratio (mass of co-polyamino acid) / (total mass of insulin glargine and liraglutide) is between 0.5 and 1.5.
  • the mass ratio (mass of co-polyamino acid) / (total mass of insulin glargine and liraglutide) is between 0.6 and 1.2. [000201] In one embodiment, the mass ratio (mass of co-polyamino acid) / (total mass of insulin glargine and of liraglutide) is between 0.7 and 1.1 [000202] In one embodiment, the composition is free from prandial insulin.
  • the composition is characterized in that the mealtime insulin is human insulin.
  • human insulin is understood to mean an insulin obtained by synthesis or recombination, the peptide sequence of which is the sequence of human insulin, including allelic variations and homologs.
  • the composition is characterized in that the mealtime insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
  • the composition is characterized in that the mealtime insulin is an insulin analogue.
  • insulin analog is meant a recombinant insulin whose primary sequence contains at least one modification relative to the primary sequence of human insulin.
  • the prandial insulin analogue is an insulin selected from the group consisting of insulin lispro (Humalog ®), insulin aspart (Novolog ®, Novorapid ®) and insulin glulisine (Apidra ® ).
  • the composition is characterized in that the prandial insulin is insulin lispro (Humalog ®).
  • the composition is characterized in that the prandial insulin is insulin aspart (Novolog ®, Novorapid ®).
  • the composition is characterized in that the prandial insulin is insulin glulisine (Apidra ®).
  • the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
  • the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
  • the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2. [000215] In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.1.
  • the composition according to the invention is characterized in that n + m is between 10 and 200.
  • the composition according to the invention is characterized in that n + m is between 15 and 150.
  • the composition according to the invention is characterized in that n + m is between 15 and 100.
  • the composition according to the invention is characterized in that n + m is between 15 and 80.
  • the composition according to the invention is characterized in that n + m is between 15 and 65.
  • the composition according to the invention is characterized in that n + m is between 20 and 60.
  • the composition according to the invention is characterized in that n + m is between 20 and 50.
  • the composition according to the invention is characterized in that n + m is between 20 and 40.
  • the invention also resides in a method for preparing stable injectable compositions.
  • the invention also concerns the precursors of said hydrophobic radicals of formula X.
  • the composition according to the invention is characterized in that the polyamino acid chains, called PLGs, constituting the co-polyamino acid are obtained by polymerization.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by ring-opening polymerization of a derivative of N-carboxyanhydride of glutamic acid or d a derivative of N -ca rboxya n hyd ri of aspartic acid.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N -ca rboxya n hyd ri de of aspartic acid as described in the review article Adv. Polym. Sci. 2006, 202, 1-18 (Deming, TJ).
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride chosen from the group consisting of Methyl N-carboxyanhydride poly-glutamate (GluOMe-NCA), Benzyl N-carboxyanhydride poly-glutamate (GluOBzl-NCA) and N-carboxyanhydride poly t-butyl glutamate (GluOtBu-NCA).
  • GluOMe-NCA Methyl N-carboxyanhydride poly-glutamate
  • GluOBzl-NCA Benzyl N-carboxyanhydride poly-glutamate
  • GluOtBu-NCA N-carboxyanhydride poly t-butyl glutamate
  • the derivative of N -carboxyanhydride of glutamic acid is methyl N-carboxyanhydride poly-L-glutamate (L-GluOMe-NCA).
  • the glutamic acid N-carboxyanhydride derivative is benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzl-NCA).
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride using as initiator an organometallic complex of a transition metal as described in Nature 1997, 390, 386-389 (Deming, TJ.).
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride using ammonia or a primary amine as initiator as described in patent FR 2,801,226 (Touraud, F.; et al.) And the references cited by this patent.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride using hexamethyldisilazane as initiator as described in the publication J. Am. Chem. Soc. 2007, 129,
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride, polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride chosen from the group consisting of Methyl N-carboxyanhydride poly-glutamate (GluOMe- N CA), poly-benzyl N-carboxyanhydride poly-glutamate (GluOBzl-NCA) and N-carboxyanhydride poly t-butyl glutamate (GluOtBu-NCA), polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3 .
  • GluOMe- N CA Methyl N-carboxyanhydride poly-glutamate
  • GluOBzl-NCA poly-benzyl N-carboxyanhydride poly-glutamate
  • GluOtBu-NCA N-carboxyanhydride poly t-butyl glutamate
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of methyl N-carboxyanhydride poly-L-glutamate (L-GluOMe-NCA) , polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3.
  • L-GluOMe-NCA methyl N-carboxyanhydride poly-L-glutamate
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzl- NCA) , polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride, polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride chosen from the group consisting of methyl N-carboxyanhydride poly-glutamate (GluOMe-NCA), poly-benzyl N-carboxyanhydride-glutamate (GluOBzl-NCA) and poly-t-butyl N-carboxyanhydride (GluOtBu-NCA), polymerization initiated by amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
  • GluOMe-NCA methyl N-carboxyanhydride poly-glutamate
  • GluOBzl-NCA poly-benzyl N-carboxyanhydride-glutamate
  • GluOtBu-NCA poly-tBu-NCA
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of methyl N-carboxyanhydride poly-L-glutamate (L-GluOMe-NCA) , polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
  • L-GluOMe-NCA methyl N-carboxyanhydride poly-L-glutamate
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of N-carboxyanhydride poly-L-benzyl glutamate (L-GluOBzl- NCA), polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
  • N-carboxyanhydride poly-L-benzyl glutamate L-GluOBzl- NCA
  • the composition according to the invention is characterized in that the process for the synthesis of the P LG chains constituting the co-polyamino acid including the polymerization of a derivative of N-carboxyanhydride of glutamic acid or d an aspartic acid N-carboxyanhydride derivative comprises a step of hydrolysis of ester functions.
  • this step of hydrolysis of ester functions may consist of hydrolysis in acidic medium or hydrolysis in basic medium or be carried out by hydrogenation.
  • this step of hydrolysis of ester groups is hydrolysis in an acidic medium.
  • this step of hydrolysis of ester groups is carried out by hydrogenation.
  • the composition according to the invention is characterized in that the P LG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight chosen from the group consisting of sodium polyglutamate and sodium polyaspartate.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained of a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight.
  • the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by depolymerization of a sodium polyaspartate of higher molecular weight.
  • the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid result from processes for forming an amide bond well known to those skilled in the art.
  • the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid result from processes for forming an amide bond used for peptide synthesis.
  • the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid result from processes for forming an amide bond described in patent FR 2,840,614 (Chan, YP; and al.).
  • the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] 3 and between the radical or spacer Q [- *] 3 and the hydrophobic radical -Hy are derived from processes for forming amide bonds well known to those skilled in the art.
  • the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] 3 and between the radical or spacer Q [- *] 3 and the hydrophobic radical -Hy are derived from amide bond formation processes used for peptide synthesis.
  • the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] 3 and between the radical or spacer Q [- *] 3 and the hydrophobic radical -Hy are derived from processes for forming an amide bond described in patent FR 2,840,614 (Chan, YP; et al.).
  • the one or more free carboxylic acid function (s) of -Hy can be in protected form before grafting onto the PLG via an acid protecting group, this protection is carried out for example by esterification using of methanol, ethanol, benzyl alcohol or t-Butanol.
  • the functions are deprotected, that is to say that a deprotection reaction is carried out so that the carboxylic function (s) is (are) free or in the form of an alkaline cation salt chosen from the group consisting of Na + and K +.
  • one or more amine function (s) can be in protected form before grafting onto the PLG via an amine protecting group, this protection is carried out for example by acidic or basic hydrolysis under heat via the group phenylmethoxycarbonyl or the 1,1-dimethylethoxycarbonyl group.
  • the functions are deprotected, that is to say that a deprotection reaction is carried out so that the amine function (s) is (are) free (s).
  • the units used are for the insulins those recommended by the pharmacopoeias whose correspondences in mg / ml are given in the table below:
  • Basal insulin is understood to mean the isoelectric point of which is between
  • basal insulins the isoelectric point of which is between 5.8 and 8.5
  • recombinant insulins the primary structure of which has been modified mainly by the introduction of basic amino acids such as arginine or lysine. They are described for example in the following patents, patent applications or publications WO 2003/053339, WO 2004/096854, US 5,656,722 and US 6,100,376, the content of which is incorporated by reference.
  • the basal insulin isoelectric point of which is between 5.8 and 8.5
  • insulin glargine is insulin glargine.
  • Insulin glargine is marketed under the brand Lantus ® (100 U / ml) or Toujeo ® (300 U / ml) by SAIMOFI.
  • the basal insulin is a biosimilar insulin glargine.
  • a biosimilar Insulin glargine is being commercialized under the brand Abasaglar ® or Basaglar ® by Eli Lilly.
  • compositions according to the invention comprise between 40 and 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 40 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 100 U / mL (ie approximately 3.6 mg / mL) of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 150 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 200 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 225 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 250 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 400 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
  • the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the co-polyamino acid, or co-polyamino acid / basal insulin is between 0.2 and 8.
  • the mass ratio is between 0.5 and 6.
  • the mass ratio is between 0.8 and 5. [000281] In one embodiment, the mass ratio is between 1 and 4.
  • the mass ratio is between 1 and 3.
  • the mass ratio is between 1 and 2.
  • the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 40 mg / mL .
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 20 mg / ml.
  • the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 10 mg / ml.
  • the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 5 mg / ml.
  • the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 2.5 mg / ml.
  • the concentration of liraglutide is within a range of 0.01 to 100 mg / mL.
  • the concentration of liraglutide is within a range of 0.01 to 40 mg / mL.
  • the concentration of liraglutide is within a range of 0.01 to 30 mg / mL.
  • the concentration of liraglutide is within a range of 1 to 100 mg / mL.
  • the concentration of liraglutide is within a range of 1 to 40 mg / mL.
  • the concentration of liraglutide is within a range of 1 to 30 mg / mL.
  • the concentration of liraglutide is in a range of 5 to 100 mg / mL.
  • the concentration of liraglutide is within a range of 5 to 40 mg / mL.
  • the concentration of liraglutide is within a range of 5 to 30 mg / mL.
  • the concentration of liraglutide is within a range of 5 to 20 mg / mL.
  • compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 75 mg / mL of liraglutide.
  • compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 75 mg / mL of liraglutide.
  • compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between
  • compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between
  • compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between
  • compositions according to the invention comprise 100 U / mL (or approximately 3.6 mg / mL) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, 2 to 10 mg / mL of liraglutide.
  • compositions according to the invention comprise 40 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.
  • compositions according to the invention comprise from 1 to 15 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
  • compositions according to the invention comprise from 2 to 10 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
  • compositions according to the invention comprise from 3 to 8 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
  • compositions according to the invention comprise from 2 to 5 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
  • compositions according to the invention comprise from 3 to 5 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
  • compositions according to the invention comprise from 3 to 4 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
  • compositions according to the invention comprise from 5 to 8 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin whose isoelectric point is between 5.8 and 8 , 5. [000312] In one embodiment, the compositions according to the invention comprise from 3.0 to 4.2 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5 , 8 and 8.5.
  • compositions according to the invention comprise from 3.2 to 4.0 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5 , 8 and 8.5.
  • compositions according to the invention comprise from 3.4 to 3.8 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5 , 8 and 8.5.
  • compositions according to the invention comprise 3.6 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
  • compositions according to the invention further comprise zinc salts at a concentration of between 0 and 5000 mM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 0 and 4000 mM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 0 and 3000 pM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 0 and 2000 pM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 0 and 1000 pM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 50 and 600 pM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 100 and 500 pM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 200 and 500 pM.
  • compositions according to the invention further comprise zinc salts at a concentration between 500 and 2000 pM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 800 and 1500 pM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 1000 and 1500 mM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 1100 and 1300 mM.
  • compositions according to the invention further comprise buffers.
  • compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM.
  • compositions according to the invention comprise buffers at concentrations of between 15 and 50 mM.
  • compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer, Tris (trishydroxymethylaminomethane) and sodium citrate.
  • the buffer is sodium phosphate.
  • the buffer is Tris
  • the buffer is sodium citrate.
  • compositions according to the invention further comprise preservatives.
  • the preservatives are chosen from the group consisting of m-cresol and phenol, alone or as a mixture.
  • the preservative is m-cresol.
  • the concentration of the preservatives is between 10 and 50 mM.
  • the concentration of preservatives is between 10 and 40 mM.
  • the concentration of the preservatives is between 20 and 40 mM.
  • the concentration of the preservatives is between 20 and 35 mM.
  • the concentration of the preservatives is between 25 and 30 mM.
  • compositions according to the invention further comprise a surfactant.
  • the surfactant is chosen from the group consisting of propylene glycol and polysorbate.
  • compositions according to the invention can further comprise additives such as tonicity agents.
  • the tonicity agents are chosen from the group consisting of glycerin, sodium chloride, mannitol and glycine.
  • the tonicity agents are chosen from the group consisting of glycerin, sodium chloride, mannitol and glycine.
  • the composition comprises glycerin.
  • the composition comprises glycerin in a concentration of between 100 and 450 mM.
  • the composition comprises glycerin in a concentration of between 150 and 300 mM.
  • the composition comprises glycerin in a concentration of between 200 and 250 mM;
  • the compositions according to the invention can also comprise all the excipients in accordance with the pharmacopoeias and compatible with the insulins used at the usual concentrations.
  • the invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
  • the modes of administration envisaged are by intravenous, subcutaneous, intradermal or intramuscular route.
  • transdermal, oral, nasal, vaginal, ocular, buccal, pulmonary administration routes are also envisaged.
  • the invention also relates to single-dose formulations with a pH of between 6.0 and 8.0 comprising a basal insulin, the isoelectric point of which is between 5.8 and 8.5 and liraglutide.
  • the invention also relates to single-dose formulations at a pH of between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and liraglutide.
  • the invention also relates to single-dose formulations at a pH of between
  • the single-dose formulations further comprise a co-polyamino acid as defined above.
  • the formulations are in the form of an injectable solution.
  • the basal insulin the isoelectric point of which is between 5.8 and 8.5, is insulin glargine.
  • the pH of the compositions according to the invention is between 6.0 and 8.0, from
  • Said co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals is soluble in aqueous solution at pH between 6.0 and 8.0, at a temperature of 25 ° C and at a concentration of less than 100 mg / ml .
  • Hydrophobic Hy is soluble in aqueous solution at pH between 6.0 and 8.0, at a temperature of 25 ° C and at a concentration below 60 mg / ml.
  • the * indicate the sites of attachment of the hydrophobic radicals to P LG or between the different groups GpR, GpG, GpH, GpA, GpL and GpC to form amide functions
  • compositions which meet the criteria of visual inspection described in the European, American and International Pharmacopoeia that is to say compositions which are clear and which do not contain visible particles, but also colorless.
  • injectable aqueous solution is understood to mean solutions in which the solvent
  • compositions in the form of an injectable aqueous solution according to the invention are clear solutions.
  • the term “clear solution” is understood to mean compositions which meet the criteria described in the American and European pharmacopoeias relating to injectable solutions. In the US pharmacopoeia, solutions
  • co-polyamino acid consisting of glutamic or aspartic units is understood to mean non-cyclic linear chains of glutamic acid or aspartic acid units linked together by peptide bonds, said chains having a C-terminal part, corresponding to the carboxylic acid of one end, and an N-terminal part, corresponding to the amine of the other end of
  • hydrophobic intermediate compounds Hyd and the intermediate compounds Hyd linked to the spacer Q-Hyd are represented in the table below by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.
  • Molecule 1 Product obtained by the reaction between myristoyl chloride and L-proline
  • the organic phase is separated, washed with an aqueous solution of 10% HCl (3 x 430 mL), a saturated aqueous solution of NaCl (430 mL), dried over Na2SO4, filtered through cotton wool and then concentrated under reduced pressure.
  • the residue is dissolved in heptane (1.31 L) at 50 ° C., then the solution is gradually brought back to room temperature.
  • the medium is again heated to 40 ° C. for 30 min and then brought back to room temperature for 4 h.
  • a white solid is obtained after filtration on a frit, washing with heptane (2 ⁇ 350 mL) and drying under reduced pressure.
  • Molecule 2 product obtained by the reaction between spermidine and benzyl phenyl carbonate
  • Benzyl phenyl carbonate (34.6 g, 151 mmol) is added to a solution of spermidine (10 g, 68.8 mmol) in DMF (70 mL) and the reaction medium is stirred for 16 h at temperature ambient, then introduced into 0.025 M phosphate buffer (2 L). The pH is adjusted to 3 with a 2 M sulfuric acid solution and washed with DCM. The pH of the aqueous phase is adjusted to 12 with a 9 M NaOH solution and the product is extracted with DCM. The organic phase is dried over NazSC, filtered through a frit and then concentrated under vacuum. Molecule 2 is obtained in the form of a white solid after drying under reduced pressure.
  • Molecule 3 product obtained by synthesis on a solid support
  • Molecule 3 is obtained by the conventional method of solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride (CTC) resin (11.1 g, 1.24 mmol / g).
  • SPPS solid phase peptide synthesis
  • CTC 2-chlorotrityl chloride
  • the grafting of the first amino acid Fmoc-Lys (Fmoc) -OH (20.3 g, 34.4 mmol, 2.5 equivalents) on the resin (11 g) is carried out in DCM (15 V), in the presence of N, IM-diisopropylethylamine (DIPEA, 5.0 equivalents). The unreacted sites are “capped” with methanol (0.8 mL / g resin) at the end of the reaction.
  • the couplings of the protected amino acids Fmoc-Glu (OtBu) -OH (5.0 equivalents) and of molecule 1 (5.0 equivalents) are carried out in DMF (15 V), in the presence of
  • Molecule 4 product obtained by the coupling between molecule 2 and molecule 3
  • Molecule Al product obtained by hydrogenolysis of molecule 4
  • Molecule 5 product obtained by synthesis on a solid support
  • Molecule 6 product obtained by coupling between molecule 5 and molecule 2.
  • Molecule A2 product obtained by hydrogenolysis of molecule 6
  • Molecule 7 Product obtained by the reaction between proline and palmitoyl chloride
  • Molecule 8 product obtained by synthesis on a solid support
  • molecule 8 is obtained in the form of a white solid.
  • Molecule 9 product obtained by coupling between molecule 8 and molecule 2
  • Molecule A3 product obtained by hydrogenolysis of molecule 9
  • Molecule 10 product obtained by synthesis on a solid support
  • Molecule 11 product obtained by coupling between molecule 10 and molecule 2
  • Molecule A4 product obtained by hydrogenolysis of molecule 11
  • the A5 molecule is obtained by the conventional method of peptide synthesis in solid phase (SPPS) on 2-chlorotrityl chloride (CTC) resin (16.0 g, 1.36 mmol / g).
  • the Fmoc protecting groups are removed using a solution of DMF / piperidine 80:20 (10 V), except in the case of deprotection of the Fmoc group of glutamic acid for which a solution of 1% DBU in DMF is used (10 V).
  • the product is cleaved from the resin using a solution of DCM / TFA 50:50 (15 V). After evaporation to dryness, the residue is dissolved in AcOEt (300 mL) and the organic phase is washed successively with 1 N NaOH (300 mL), 0.1 N NaOH (300 mL) and a saturated aqueous solution of NaCl (300 mL). ).
  • Molecule 12 product obtained by coupling between molecule 3 and N-CBz ethylenediamine hydrochloride.
  • Molecule A7 product obtained by hydrogenolysis of molecule 12
  • hydrophobic co-polyamino acids are shown in Table 2.
  • g-tert-butyl-L-glutamate / V-carboxyanhydride 16.9 g, 73.7 mmol
  • anhydrous DMF 48 mL
  • the mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then a solution of Al molecule (6.0 g, 3.7 mmol) in DMF is introduced rapidly.
  • the mixture is stirred between 4 ° C and room temperature for 18 h, then heated to 65 ° C for 2 h.
  • the reaction mixture is then cooled to room temperature and then poured dropwise into water (500 mL) with stirring.
  • the white precipitate is collected by filtration, washed twice with water and then dried under vacuum at 30 ° C. to obtain a white solid.
  • the solid is diluted in trifluoroacetic acid (100 mL), and the solution is stirred for 2 h at room temperature then poured dropwise into water (1000 mL). After 2 h of stirring, the white precipitate is recovered by filtration and dissolved in water (25 g / L) by adjusting the pH to 7.5 by adding a 1N aqueous sodium hydroxide solution. ethanol is added to obtain a 30% solution by mass of ethanol which is filtered through an R53SP carbon filter.
  • the mixture is filtered through a 0.45 ⁇ m filter, then is purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductivity of the permeate is less than 50 pS / cm.
  • the co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7.0.
  • the aqueous solution is filtered through 0.2 ⁇ m and stored at 4 ° C.
  • the calculated average molar mass of the co-polyamino acid B1 is 4435 g / mol.
  • the calculated average molar mass of the co-polyamino acid B3 is 4491 g / mol.
  • Co-polyamino acid B5 sodium poly-L-glutamate modified at one of its ends by molecule 5, the esters of which are deprotected
  • g-benzyl-L-glutamate N-carboxyanhydride 24.50 g, 93.05 mmol
  • anhydrous DMF 55 mL
  • the mixture is then stirred until complete dissolution, cooled to 0 ° C., then hexylamine (0.56 mL, 4.23 mmol) is introduced rapidly.
  • IPE diisopropyl ether
  • the solid obtained is solubilized in N, N-dimethylacetamide (DMAc, 210 mL) then 5% Pd / Al2O3 (2.1 g) is added under an argon atmosphere.
  • the mixture0 is placed under a hydrogen atmosphere (6 bar) and stirred at 60 ° C. for 24 h.
  • a solution of water at pH 2 containing 15% NaCl (6 V) is poured dropwise onto the solution. of DMAc, over a period of 45 min and with stirring. After 18 h under stirring, the white precipitate is recovered by filtration, washed with water and then dried under reduced pressure.
  • the solid obtained is dissolved in water (600 mL) by adjusting the pH to 7 by adding a 1N aqueous sodium hydroxide solution. The pH is then adjusted to pH 12 and the solution is kept stirred for 1 h. . After neutralization to pH 7, the solution is filtered through 0.2 ⁇ m, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, 0 then filtered through an activated carbon filter (3M R53SLP). The solution obtained is filtered through 0.45 ⁇ m and purified by ultrafiltration against a 0.9% IMaCl solution and then water until the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 ⁇ m and stored at 4 ° C.
  • the calculated average molar mass of the co-polyamino acid B5 is 5377 g / mol. 0
  • Co-polvaminoadde B6-1 poly-L-benzylglutamate resulting from the polymerization of ⁇ -benzyl-L-glutamate / V-carboxyanhydride initiated by ethylenediamine.
  • the product is recovered by filtration on a frit, triturated in acetone then dried under reduced pressure and dissolved in water at a theoretical concentration of 20 g / L.
  • the pH is then adjusted to 12 and the solution is kept under stirring for 45 min.
  • the solution is filtered through 0.2 ⁇ m, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, then filtered through an activated carbon filter (3M R53SLP).
  • the solution obtained is filtered through 0.2 ⁇ m and purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductivity of the permeate is less than 50 pS / cm.
  • the co-polyamino acid solution is then concentrated and the pH is adjusted to 7.
  • the aqueous solution is filtered through 0.2 ⁇ m and stored at 4 ° C. Dry extract: 14.6 mg / g
  • the calculated average molar mass of the co-polyamino acid B6 is 6814 g / mol.
  • the solution is neutralized to pH 7 with a solution of 'AcOH 27% then diluted with water and ethanol until a solution containing 30% by weight of ethanol and at a theoretical concentration of 25 mg / mL is obtained.
  • This solution is then filtered on activated carbon filters (R053SP) then on 0.2 ⁇ m filters before being purified by ultrafiltration against an aqueous solution of NaCl at 0.9% then against GH20 until a lower conductivity is obtained. at 50 pS / cm 2 .
  • the co-polyamino acid solution is then concentrated and the pH adjusted to 7.
  • the aqueous solution is filtered through 0.2 ⁇ m and stored at 4 ° C.
  • the calculated average molar mass of the co-polyamino acid B8 is 5776 g / mol.
  • the calculated average molar mass of the co-polyamino acid B9 is 7097 g / mol.
  • g-benzyl-L-glutamate / V-carboxyanhydride 146.3 g, 0.556 mol
  • anhydrous DMF 132 mL
  • the mixture is then stirred until complete dissolution, cooled to ⁇ 10 ° C., then a solution of the A7 molecule (38.04 g, 24.6 mmol) in DMF (100 mL) is introduced rapidly.
  • the reaction medium is poured over 37 min on GIRE (1.4 L).
  • the precipitate is filtered off on a frit, washed with I ⁇ RE (2 x 200 mL) then dried under reduced pressure before being dissolved in TFA (400 mL). After 2 h of stirring at room temperature, the product is precipitated in water (1.2 L), stirred for 18 h then filtered on frit, triturated with water then dried at 30 ° C under reduced pressure. .
  • the product is recovered by filtration on a frit, triturated with EtOH (2 x 250 mL) then dried under reduced pressure and dissolved in water at a theoretical concentration of 20 g / L.
  • the pH is then adjusted to 12 and the solution is kept under stirring for 90 min.
  • the solution is filtered through 0.2 ⁇ m, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, then filtered through an activated carbon filter (3M R53SLP).
  • the solution obtained is filtered through 0.2 ⁇ m and purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductivity of the permeate is less than 50 pS / cm.
  • the co-polyamino acid solution is then concentrated and the pH is adjusted to 7.
  • the aqueous solution is filtered through 0.2 ⁇ m and stored at 4 ° C.
  • Co-polvaminoacid B12-1 poly-L-benzylglutamate resulting from the polymerization of y-benzyl-L-glutamate / V-carboxy anhydride initiated by 4,7,10-trioxa-13-tridecadiaminenediamine.
  • y-benzyl-L-glutamate N-carboxyanhydride (0.0 g, 0.19 mol) is dissolved in anhydrous DMF (1.12 L). The mixture is then stirred until complete dissolution, cooled to 0 ° C., then 4,7,10-trioxa-13-tridecadiaminenediamine (TOTA) (1.74 g, 7.9 mmol) is introduced rapidly.
  • TOTA 4,7,10-trioxa-13-tridecadiaminenediamine
  • the calculated average molar mass of the co-polyamino acid B12 is 6089 g / mol.
  • Example C1 Insulin olaroine solution at 100-460 IU / ml
  • This solution is an insulin glargine solution prepared from an insulin glargine powder (basal insulin analogue).
  • the excipients used are zinc chloride or oxide, m-cresol, glycerol, sodium hydroxide, hydrochloric acid for pH adjustment (pH 3, 8-4.0) and water.
  • the zinc concentration is 210 mM per 100 IU / mL of insulin.
  • the concentrations of m-cresol and of glycerol are chosen to arrive at the desired target in the compositions described in example CAI.
  • Example C2 20-45 ma / mL liraalutide solution
  • This solution is a solution of liraglutide prepared from a powder of liraglutide (GLP-1 receptor agonist). If necessary, the pH is adjusted to pH 8.6 with hydrochloric acid or sodium hydroxide.
  • Example C3 fLantus® Slow Insulin Analogue Solution! at 100 U / mL
  • This solution is an insulin glargine commercial solution marketed by Sanofi under the name of Lantus ®.
  • This product is a slow insulin analogue.
  • the excipients in Lantus ® are zinc chloride (30 pg / mL), m-cresol (2.7 mg / mL), glycerol (20 mg / mL), polysorbate 20 (16 pM), hydroxide sodium and hydrochloric acid for pH adjustment (pH 4) and water.
  • This solution is a liraglutide solution marketed by the company NOVO NORDISK under the name Victoza ® .
  • the excipients in Victoza ® are disodium phosphate dihydrate, propylene glycol (1.42 mg / mL), phenol (5.5 mg / mL) and water at pH 8, 15.
  • Part CA - Compositions comprising insulin glargine and liraglutide
  • CAI preparation process Preparation of a co-Dolvamino acid / Insulin olaram / liraalutirie composition at oH 7.2
  • a stock solution of co-polyamino acid at pH 6.5-7.5 is added a solution of insulin glargine described in Example C1 with magnetic stirring at 300 rpm. A cloudiness appears.
  • the pH is adjusted to pH 8.6 by adding a 1M NaOH solution. The mixture is stirred for 30 minutes at room temperature of 20-25 ° C.
  • the pH is adjusted to 7.2 by adding a 0.1 M hydrochloric acid solution.
  • CAI example Compositions of co-polvaminoadde / lnsulin olaraine / liraolutide at oH
  • Example CB1 Demonstration of the physical stability of the compositions co-polvaminoadde / insulin alaroine / liraQlutide
  • compositions were filtered (0.22 ⁇ m) before being introduced into glass cartridges with a capacity of 3 ml produced by the company OMPI.
  • the cartridges are visually inspected at weekly intervals in order to detect the appearance of visible particles or turbidity. For this, the cartridges are subjected to lighting of at least 2000 Lux; they are considered compliant when they do not contain visible particles and when they appear clear in comparison with an opalescence standard (standard according to the European Pharmacopoeia).
  • Table 4a Physical stability of compositions CA1-10, CA1-12 to CA1-15 and CA1-17 stored at 4 ° C.
  • the compounds according to the invention make it possible to obtain compositions exhibiting excellent physical stability at 4 ° C., greater than at least 10 weeks.
  • the co-polyamino acid B6 makes it possible to obtain compositions which are particularly stable, at least 47 weeks, at 4 ° C.
  • compositions according to the invention exhibit good physical stability at 30 ° C.
  • the co-polyamino acid B6 makes it possible to obtain compositions which are stable for at least 12 weeks at 30 ° C.
  • Example CB2 Precipitation of insulin alaraine after mixing the compositions co-DolvaminoacIde / insulin olaraine with a solution of DH and physiological ionic strength containing albumin.
  • This test demonstrates the precipitation of insulin glargine during injection into a physiological medium simulated at physiological pH and ionic strength and containing albumin. These conditions make it possible to mimic the behavior of the composition during subcutaneous injection.
  • To 160 ⁇ l of co-polyamino acid / insulin glargine composition are added 40 ⁇ l of a solution of bovine albumin at 20 mg / ml in a phosphate buffer at pH 7.4.
  • the phosphate buffer (PBS or phosphate buffer saline) is concentrated so that the NaCl and phosphate contents are respectively 140 mM and 10 mM after mixing with the composition.
  • the precipitation of glargine in this medium is followed at ambient temperature (20-25 ° C.) by absorbance measurements at 500 nm of the mixtures for 30 minutes. The absorbance measurements are carried out using a UV-visible reader of multi-well plates.
  • the absorbance increases until it reaches a plateau.
  • the glargine precipitation time is defined as the time required for the measured absorbance to be greater than or equal to 80% of the plateau value.
  • the precipitation times obtained with the compositions described above are presented in Table 5.
  • Table 5 Precipitation time of insulin glargine after mixing the co-polyamino acid / insulin glargine / liraglutide compositions in a medium which simulates the subcutaneous medium.
  • co-polyamino acid / insulin glargine / Liraglutide compositions of the invention lead to rapid precipitation of glargine after mixing with a medium which simulates the subcutaneous medium. Particularly rapid precipitation is observed with compounds B5 and B6, but the fastest precipitation is observed with compound B6.
  • DI Protocol for measuring the pharmacokinetics of insulin glargine and insulin lispro formulations.
  • composition CA1-12 comprising the co-polyamino acid B6 / insulin glargine (200 U / mL) / liraglutide (7.2 mg / mL), the composition of insulin glargine C3 and liraglutide C4 solution.
  • Table 6 shows various pharmacokinetic parameters of insulin glargine, and of its metabolite M1, and of liraglutide.
  • Table 6 Pharmacokinetic parameters of insulin glargine, and of its metabolite5 Ml-, and of liraglutide after subcutaneous administration of composition CA1-12, C3 or C4 in dogs (means and (CV%)).
  • compositions according to the invention make it possible for insulin glargine to obtain a pharmacokinetic profile similar to that of a composition of insulin glargine U100 alone at pH 4.
  • the pharmacokinetic profile obtained is similar to that of a composition of liraglutide alone at 6.0 mg / ml and at pH 8.15.

Abstract

The invention relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, containing at least one basal insulin, the isoelectric point (pI) of which is between 5.8 and 8.5, liraglutide, and a copolyamino acid carrying carboxylate charges and hydrophobic radicals.

Description

SOLUTION INJECTABLE A PH 7 COMPRENANT AU MOINS UNE INSULINE BASALE DONT LE PI EST COMPRIS ENTRE 5,8 ET 8,5, DU LIRAGLUTIDE ET UN 5 CO-POLYAMINOACIDE PORTEUR DE CHARGES CARBOXYLATES ET DE SOLUTION FOR INJECTION AT PH 7 COMPRISING AT LEAST ONE BASAL INSULIN WHOSE PI IS BETWEEN 5.8 AND 8.5, LIRAGLUTIDE AND A 5 CO-POLYAMINOACIDE CARBOXYLATE CHARGING AND
RADICAUX HYDROPHOBES HYDROPHOBIC RADICALS
[0001] L'invention concerne les thérapies par injection d'insuline(s) pour traiter le 10 diabète. [0001] The invention relates to insulin injection therapy (s) for treating diabetes.
[0002] L'invention concerne des compositions stables physiquement sous forme d'une solution aqueuse injectable, dont le pH est compris entre 6,0 et 8,0, comprenant au moins une insuline basale dont le point isoélectrique (pi) est compris entre 5,8 et 8,5, du liraglutide et un co-polyaminoacide porteur de charges carboxylates et de 15 radicaux hydrophobes. The invention relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least one basal insulin whose isoelectric point (pi) is between 5.8 and 8.5, liraglutide and a co-polyamino acid carrying carboxylate charges and hydrophobic radicals.
[0003] L'insuline glargine est considérée aujourd'hui comme l'insuline basale la plus utilisée. [0003] Insulin glargine is considered today to be the most widely used basal insulin.
[0004] Cependant le pH nécessairement acide des formulations d'insulines basales, dont le point isoélectrique est compris entre 5,8 et 8,5, de type insuline 20 glargine, peut être un réel inconvénient, car ce pH acide de la formulation d'insuline glargine entraîne parfois chez les patients des douleurs à l'injection et surtout empêche toute formulation avec d'autres protéines qui ne sont pas stables à pH acide. However, the necessarily acidic pH of the basal insulin formulations, the isoelectric point of which is between 5.8 and 8.5, of the insulin glargine type, can be a real drawback, because this acidic pH of the formulation of insulin glargine sometimes causes injection pain in patients and above all prevents formulation with other proteins which are not stable at acidic pH.
[0005] Par ailleurs, aujourd'hui, pour assurer la transition des traitements par les OAD, lorsque ceux-ci ne sont plus en mesure de contrôler le niveau de glucose dans le 25 sang, vers un traitement insuline basale/insuline prandiale, l'injection d'analogues de GLP-1 ou de GLP-1 RA (agoniste du récepteur au GLP-1) est préconisée. [0005] Furthermore, today, to ensure the transition from treatments by ADOs, when the latter are no longer able to control the level of glucose in the blood, towards a basal insulin / mealtime insulin treatment, the Injection of GLP-1 or GLP-1 RA analogues (GLP-1 receptor agonist) is recommended.
[0006] Notamment les demandes WO 2013/104861 Al et W02017/211903 décrivent des compositions sous forme d'une solution aqueuse injectable, dont le pH est compris entre 6,0 et 8,0, comprenant au moins (a) une insuline basale dont le point 30 isoélectrique pi est compris entre 5,8 et 8,5 et (b) un co-polyaminoacide porteur de charges carboxylates substitué par des radicaux hydrophobes. [0006] In particular, applications WO 2013/104861 A1 and WO2017 / 211903 describe compositions 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 p1 of which is between 5.8 and 8.5 and (b) a carboxylate-charged co-polyamino acid substituted by hydrophobic groups.
[0007] Cependant la solubilisation et/ou la stabilisation de compositions comprenant en outre du liraglutide nécessite une quantité de co-polyaminoacide porteur de charges carboxylates substitué par des radicaux hydrophobes importante. [0007] However, the solubilization and / or stabilization of compositions further comprising liraglutide requires a large amount of co-polyamino acid carrying carboxylate charges substituted by hydrophobic radicals.
35 [0008] De façon inattendue certains co-polyaminoacides porteurs de charges carboxylates substitué par des radicaux hydrophobes permettent d'obtenir cette solubilité et/ou cette stabilité avec une quantité de co-polyaminoacide porteur de charges carboxylates substitué par des radicaux hydrophobes plus réduite et/ou une stabilité améliorée avec une concentration égale de co-polyaminoacide porteur de charges carboxylates substitué par des radicaux hydrophobes. Unexpectedly, certain co-polyamino acids carrying carboxylate charges substituted by hydrophobic radicals make it possible to obtain this solubility and / or this stability with a quantity of co-polyamino acid carrying carboxylate charges substituted by hydrophobic radicals which is smaller and /or a improved stability with an equal concentration of carboxylate-charged co-polyamino acid substituted by hydrophobic groups.
[0009] L'invention concerne une composition stable physiquement sous forme d'une solution aqueuse injectable, dont le pH est compris entre 6,0 et 8,0, comprenant au moins : [0009] The invention relates to a physically stable composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
a) une insuline basale dont le point isoélectrique (pi) est compris entre a) a basal insulin whose isoelectric point (pi) is between
5,8 et 8,5 et 5.8 and 8.5 and
b) du liraglutide, b) liraglutide,
c) un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes Hy, ledit co-polyaminoacide étant constitué d'unités glutamiques ou aspartiques (PLG) et lesdits radicaux hydrophobes -Hy étant de formule X suivante :
Figure imgf000003_0001
Formule X dans laquelle : c) a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, said co-polyamino acid consisting of glutamic or aspartic (PLG) units and said hydrophobic radicals -Hy being of the following formula X:
Figure imgf000003_0001
Formula X in which:
- GpR est choisi parmi les radicaux de formules VII, VU' ou VII" : Formule VU' ou
Figure imgf000003_0002
- GpR is chosen from the radicals of formulas VII, VU 'or VII ": Formula VU' or
Figure imgf000003_0002
LL.R_LJ Formule VII"; LL.R_LJ Formula VII ";
GpG et GpH identiques ou différents sont choisis parmi les radicaux de formules XI ou XI':
Figure imgf000003_0003
* - NH - G - NH - * GpG and GpH, which are identical or different, are chosen from the radicals of formulas XI or XI ':
Figure imgf000003_0003
* - NH - G - NH - *
Formule XI Formule CG Formula XI Formula CG
- -GpL est choisi parmi les radicaux de formule XII
Figure imgf000003_0004
Formule XII, - -GpL is chosen from the radicals of formula XII
Figure imgf000003_0004
Formula XII,
- GpC est un radical de formule IX :
Figure imgf000004_0001
Formule IX; - les * indiquent les sites de rattachement des différents groupes liés par des fonctions amides ; - GpC is a radical of formula IX:
Figure imgf000004_0001
Formula IX; - The * indicate the attachment sites of the various groups linked by amide functions;
b est un entier égal à 0 ou à 1 ; b is an integer equal to 0 or 1;
- c est un entier égal à 0 ou à 1, et si c est égal à 0 alors d est égal à 1 ou à 2; - 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 est un entier égal à 0, à 1 ou à 2 ; - d is an integer equal to 0, to 1 or to 2;
- g est un entier égal à 0, à 1, à 2, à 3 à 4 à 5 ou à 6; - g is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6;
- h est un entier égal à 0, à 1, à 2, à 3 à 4 à 5 ou à 6 et au moins un des g ou h > 2 si x< 16, et si g = 0 alors h > 1 ; - h is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6 and at least one of g or h> 2 if x <16, and if g = 0 then h> 1;
I est un entier égal à 1 et = 2 ; I is an integer equal to 1 and = 2;
r est un entier égal à 0 ou à 1, et r is an integer equal to 0 or 1, and
- A est un radical alkyle trivalent linéaire ou ramifié comprenant de 1 à 6 atomes de carbone ; - A is a linear or branched trivalent alkyl radical comprising from 1 to 6 carbon atoms;
- B est un radical alkyle linéaire ou ramifié, éventuellement comprenant un noyau aromatique, comprenant de 1 à 9 atomes de carbone ; - B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
- Cx est un radical alkyl monovalent linéaire ou ramifié, dans lequel x indique le nombre d'atomes de carbone et x > 13. - Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and x> 13.
- G est un radical alkyle ramifié de 1 à 8 atomes de carbone ledit radical alkyle portant une ou plusieurs fonction(s) acide carboxylique libre. - G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
- R est un radical choisi dans le groupe constitué par un radical alkyle divalent, linéaire ou ramifié comprenant de 1 à 12 atomes de carbone, un radical alkyle divalent, linéaire ou ramifié comprenant de 1 à 12 atomes de carbone portant une ou plusieurs fonctions -CONH2 ou un radical éther ou polyéther non substitué comprenant de 4 à 14 atomes de carbone et de 1 à 5 atomes d'oxygène : - R is a radical chosen from the group consisting of a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms bearing one or more functions - CONH2 or an ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
- Le ou les radicaux hydrophobes -Hy de formule X étant liés au co-polyaminoacide - The hydrophobic radical (s) -Hy of formula X being linked to the co-polyamino acid
• via une liaison covalente entre un carbonyle du radical hydrophobe -Hy et un atome d'azote porté par un spacer entre deux polyaminoacides, formant ainsi une fonction amide issue de la réaction d'une fonction amine portée par le précurseur du spacer et une fonction acide portée par le précurseur Hy' du radical hydrophobe -Hy, et • via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by a spacer between two polyamino acids, thus forming an amide function resulting from the reaction of an amine function carried by the precursor of the spacer and an acid function carried by the precursor Hy 'of the hydrophobic radical -Hy, and
• via une liaison covalente entre un atome d'azote du radical hydrophobe - • via a covalent bond between a nitrogen atom of the hydrophobic radical -
Hy et un carbonyle porté par un spacer entre deux polyaminoacides, formant ainsi une fonction amide issue de la réaction d'une fonction amine du précurseur Hy' du radical hydrophobe -Hy et une fonction acide portée par le précurseur du spacer, Hy and a carbonyl carried by a spacer between two polyamino acids, thus forming an amide function resulting from the reaction of an amine function of the precursor Hy 'of the hydrophobic radical -Hy and an acid function carried by the precursor of the spacer,
• via une liaison covalente entre un carbonyle du radical hydrophobe -Hy et un atome d'azote porté par au moins une fonction amine terminale du co- polyaminoacide, • via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by at least one terminal amine function of the co-polyamino acid,
• via une liaison covalente entre un atome d'azote porté par au moins une fonction amine du radical hydrophobe -Hy et un un carbonyl porté par au moins une fonction acide terminale par le co-polyaminoacide, • via a covalent bond between a nitrogen atom carried by at least one amine function of the hydrophobic radical -Hy and a carbonyl carried by at least one terminal acid function by the co-polyamino acid,
• via une liaison covalente entre un atome d'azote porté par au moins une fonction amine du radical hydrophobe -Hy et un carbonyl porté par au moins une fonction acide d'un glutamate par le co-polyaminoacide, lorsque plusieurs radicaux hydrophobes sont portés par un co-polyaminoacide alors ils sont identiques ou différents, • via a covalent bond between a nitrogen atom carried by at least one amine function of the hydrophobic radical -Hy and a carbonyl carried by at least one acid function of a glutamate by the co-polyamino acid, when several hydrophobic radicals are carried by a co-polyamino acid then they are identical or different,
le degré de polymérisation DP en unités glutamiques ou aspartiques pour les chaînes polyglutamates est compris entre 5 et 250 ; the degree of polymerization DP in glutamic or aspartic units for the polyglutamate chains is between 5 and 250;
les fonctions acides carboxyliques libres étant sous forme de sel de cation alcalin choisi dans le groupe constitué par Na+ et K+. the free carboxylic acid functions being in the form of an alkaline cation salt chosen from the group consisting of Na + and K + .
[00010] Dans l'intégralité du texte, le co-polyaminoacide constitué d'unités glutamiques ou aspartiques est désigné par (PLG) ou PLG. [00010] In the entire text, the co-polyamino acid consisting of glutamic or aspartic units is designated by (PLG) or PLG.
[00011] Dans un mode de réalisation, g + h> 2. [00011] In one embodiment, g + h> 2.
[00012] Dans un mode de réalisation, g ou h ³ 2. [00012] In one embodiment, g or h ³ 2.
[00013] Dans un mode de réalisation, g > 2 et h = 0. [00013] In one embodiment, g> 2 and h = 0.
[00014] Dans un mode de réalisation, g = 0 et h > 2. [00014] In one embodiment, g = 0 and h> 2.
[00015] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 2 ou 3 et G = 2. In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 2 or 3 and G = 2.
[00016] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 2 et I' = 2. [00016] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 2 and I '= 2.
[00017] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 3 et = 2. [00018] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3 et = 2. [00017] In a particular embodiment, said hydrophobic radicals —Hy are of formula X in which g = 0, I = 1, h = 3 and = 2. [00018] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3 and = 2.
[00019] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 et I' = 2. [00019] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 and I '= 2.
[00020] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3 et G = 2. [00020] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3 and G = 2.
[00021] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, G = 2 et GpH répond à la Formule XI. In a particular embodiment, said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3, G = 2 and GpH corresponds to Formula XI.
[00022] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, I' = 2 et GpH répond à la Formule XI. In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, I '= 2 and GpH corresponds to Formula XI.
[00023] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3 , I' = 2 et GpH répond à la Formule XI. In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, I '= 2 and GpH corresponds to Formula XI.
[00024] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, G = 2, GpH répond à la Formule XI et x = 13. [00024] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3, G = 2, GpH corresponds to Formula XI and x = 13.
[00025] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, = 2, GpH répond à la Formule XI et x = 13. [00025] In a particular embodiment, said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, = 2, GpH corresponds to Formula XI and x = 13.
[00026] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, G = 2, GpH répond à la Formule XI et x = 13. [00026] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, G = 2, GpH corresponds to Formula XI and x = 13 .
[00027] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, I' = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00027] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3, I '= 2, GpH corresponds to Formula XI, GpC has the formula IXd and x = 13.
[00028] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00028] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, G = 2, GpH corresponds to Formula XI, GpC corresponds to the formula IXd and x = 13.
[00029] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00029] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, = 2, GpH corresponds to Formula XI, GpC corresponds to formula IXd and x = 13.
[00030] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3 et I' = 2. [00031] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 et V = 2. [00030] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3 and I ′ = 2. [00031] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 and V = 2.
[00032] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1 , g = 0, I = 1, h = 3 et = 2. [00032] In a particular embodiment, said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 3 and = 2.
[00033] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, ! = 1, h = 2 ou 3, I' = 2 et GpH répond à la Formule XI. [00033] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0,! = 1, h = 2 or 3, I '= 2 and GpH corresponds to Formula XI.
[00034] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, = 2 et GpH répond à la Formule XI. In a particular embodiment, said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2, = 2 and GpH corresponds to Formula XI.
[00035] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3, G = 2 et GpH répond à la Formule XI. [00035] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 3, G = 2 and GpH corresponds to Formula XI.
[00036] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, I' = 2, GpH répond à la[00036] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3, I '= 2, GpH corresponds to the
Formule XI et x = 13. Formula XI and x = 13.
[00037] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, G = 2, GpH répond à la Formule XI et x = 13. [00037] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2, G = 2, GpH corresponds to Formula XI and x = 13 .
[00038] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3, = 2, GpH répond à la Formule XI et x = 13. [00039] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, I' = 2, GpH répond à la [00038] In a particular embodiment, said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 3, = 2, GpH corresponds to Formula XI and x = 13. In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3, I '= 2, GpH corresponds to the
Formule XI, GpC répond à la formule IXd et x = 13. Formula XI, GpC has the formula IXd and x = 13.
[00040] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00040] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2, G = 2, GpH corresponds to Formula XI, GpC corresponds to the formula IXd and x = 13.
[00041] Dans un mode de réalisation particulier lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00041] In a particular embodiment, said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 3, G = 2, GpH corresponds to Formula XI, GpC corresponds to the formula IXd and x = 13.
[00042] Dans un mode de réalisation, lorsque r = 1 alors GpR répond à la Formule VII. [00042] In one embodiment, when r = 1 then GpR corresponds to Formula VII.
[00043] Dans un mode de réalisation, l'invention concerne une composition selon l'invention, caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXa suivante : [00043] In one embodiment, the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of the following formula XXXa:
Figure imgf000008_0001
dans laquelle,
Figure imgf000008_0001
in which,
• -D- représente, indépendamment, soit un groupe -CH2- (unité aspartique) soit un groupe -CH2-CH2- (unité glutamique) ; • -D- represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit);
• -Z représente une entité cationique choisie dans le groupe comprenant les cations alcalins ; • -Z represents a cationic entity chosen from the group comprising alkali metal cations;
• -Ra et -Ra', identiques ou différents, sont un radical choisi dans le groupe constitué par un H, un groupe acyle linéaire en C2 à CIO, un groupe acyle ramifié en C3 à CIO, un benzyle, une unité « acide aminé » terminale et un pyroglutamate ; • -R a and -R a ', identical or different, are a radical chosen from the group consisting of an H, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, a benzyl, a "unit" terminal amino acid and a pyroglutamate;
• -Hy est un radical hydrophobe de formule X ; • -Hy is a hydrophobic radical of formula X;
« Q[— *]3 est un spacer trivalent choisi parmi les formules XII, XII' ou XII", ledit spacer"Q [- *] 3 is a trivalent spacer chosen from formulas XII, XII 'or XII", said spacer
Q[— *]3 étant lié aux au moins deux chaînes d'unités glutamiques ou aspartiques P LG par des fonctions amides et,- ledit radical ou spacer Q[— *]3 étant lié au moins un radical hydrophobe— Hy de formule X par une fonction amide ; Q [- *] 3 being linked to at least two chains of glutamic or aspartic units P LG by amide functions and, - said radical or spacer Q [- *] 3 being linked to at least one hydrophobic radical - Hy of formula X by an amide function;
Figure imgf000008_0002
Figure imgf000008_0002
dans lesquelles A a la signification donnée ci-dessus, et Ai et A2 sont des radicaux alkyles linéaires ou ramifiés comprenant de 1 à 6 atomes de carbone where A has the meaning given above, and Ai and A2 are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms
• j= 1 est le nombre de radicaux hydrophobes de formule X liés au spacer • j = 1 is the number of hydrophobic radicals of formula X linked to the spacer
Q ; Q;
· n + m représente le degré de polymérisation DP du co-polyaminoacide, c'est-à-dire le nombre moyen d'unités monomériques par chaîne de co- polyaminoacide et 5 < n + m < 250. · N + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomer units per chain of co-polyamino acid and 5 <n + m <250.
[00045] Dans un mode de réalisation, le précurseur du radical de formule XII est un acide aminé choisi dans le groupe constitué par la lysine, l'ornithine et l'acide 2,3- diaminopropionique. [00045] In one embodiment, the precursor of the radical of formula XII is an amino acid selected from the group consisting of lysine, ornithine and 2,3-diaminopropionic acid.
[00046] Dans un mode de réalisation, le précurseur du radical de formule XII" est une triamine choisie dans le groupe constitué par la spermidine, la norspermidine, la diéthylènetriamine et la bis(hexaméthylène)triamine. In one embodiment, the precursor of the radical of formula XII "is a triamine selected from the group consisting of spermidine, norspermidine, diethylenetriamine and bis (hexamethylene) triamine.
[00047] Dans un mode de réalisation, le précurseur du radical de formule XII" est la spermidine. In one embodiment, the precursor of the radical of formula XII "is spermidine.
[00048] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 2 ou 3 et I' = 2. [00048] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals —Hy are of formula X in which g = 0, I = 1, h = 2 or 3 and I '= 2.
[00049] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1 , h = 2 et G = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 2 and G = 2.
[00050] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 3 et G = 2. [00051] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3 et G = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 3 and G = 2. [00051] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3 and G = 2.
[00052] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 et I' = 2. [00053] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3 et = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 and I '= 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3 and = 2.
[00054] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, I' = 2 et GpH répond à la Formu le XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3, I '= 2 and GpH responds to Formula XI.
[00055] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, G = 2 et GpH répond à la Formule XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, G = 2, and GpH meets Formula XI.
[00056] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, G = 2 et GpH répond à la Formule XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, G = 2, and GpH meets Formula XI.
[00057] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formuleIn one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, I' = 2, GpH répond à la Formule XI et x = 13. X where r = 0, g = 0, I = 1, h = 2 or 3, I '= 2, GpH corresponds to Formula XI and x = 13.
[00058] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, I' = 2, GpH répond à la Formule XI et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, I '= 2, GpH meets Formula XI and x = 13.
[00059] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 0, g = 0, I = 1 , h = 3, G = 2, GpH répond à la Formule XI et x = 13. X where r = 0, g = 0, I = 1, h = 3, G = 2, GpH is Formula XI and x = 13.
[00060] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formuleIn one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00061] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, V = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. X where r = 0, g = 0, I = 1, h = 2 or 3, G = 2, GpH has Formula XI, GpC has formula IXd and x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, V = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[00062] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXa et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXa and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[00063] Dans un mode de réalisation, l'invention concerne une composition selon l'invention, caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est choisi parmi les co-polyaminoacides de formule XXXb suivante : In one embodiment, the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of the following formula XXXb:
Figure imgf000011_0001
dans laquelle,
Figure imgf000011_0001
in which,
- D représente, indépendamment, soit un groupe -CH2- (unité aspartique) soit un groupe -CH2-CH2- (unité glutamique), - D represents, independently, either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),
- Z représente une entité cationique choisie dans le groupe comprenant les cations alcalins ; - Z represents a cationic entity chosen from the group comprising alkali metal cations;
- m représente le degré de polymérisation DP du co-polyaminoacide, c'est-à-dire le nombre moyen d'unités monomériques par chaîne de co-polyaminoacide et 5 < n + m < 250 ; - m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomer units per chain of co-polyamino acid and 5 <n + m <250;
- Ri et R2 identiques ou différents, sont un radical choisi dans le groupe constitué par un H, un radical hydrophobe de formule X, un groupe acyle linéaire en C2 à CIO, un groupe acyle ramifié en C3 à CIO, un benzyle, une unité « acide aminé » terminale et un pyroglutamate et au moins Ri ou R2 est un radical hydrophobe de formule X. [00064] Le co-polyaminoacide porteur de charges carboxylates (PLG) et de radicaux hydrophobes est choisi parmi les co-polyaminoacides décrits dans les demandes PCT/EP2018/083896, PCT/EP2018/083897 et PCT/2018/083558 dont les numéros de publication sont respectivement W02019110773, W02019110774 et W02019110625. - Ri and R 2 , which are identical or different, are a radical chosen from the group consisting of an H, a hydrophobic radical of formula X, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, a benzyl, a terminal “amino acid” unit and a pyroglutamate and at least R 1 or R 2 is a hydrophobic radical of formula X. The co-polyamino acid carrying carboxylate charges (PLG) and hydrophobic radicals is chosen from the co-polyamino acids described in applications PCT / EP2018 / 083896, PCT / EP2018 / 083897 and PCT / 2018/083558 whose numbers publication are W02019110773, W02019110774 and W02019110625 respectively.
[00065] Dans un mode de réalisation, l'invention concerne une composition selon l'invention, caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXb dans laquelle RI ou R2 est un radical hydrophobe. In one embodiment, the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb in which R1 or R2 is a hydrophobic radical.
[00066] Dans un mode de réalisation, l'invention concerne une composition selon l'invention, caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXb dans laquelle RI est un radical hydrophobe de formule X mais pas R2. In one embodiment, the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb in which RI is a hydrophobic radical of formula X but not R2.
[00067] Dans un mode de réalisation, l'invention concerne une composition selon l'invention, caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXb dans laquelle R2 est un radical hydrophobe de formule X mais pas RI. In one embodiment, the invention relates to a composition according to the invention, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb in which R2 is a hydrophobic radical of formula X but not R1.
[00068] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 2 ou 3 et I' = 2. [00068] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which g = 0, I = 1, h = 2 or 3 and I '= 2.
[00069] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 2 et = 2. [00069] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which g = 0, I = 1, h = 2 and = 2.
[00070] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 3 et G = 2. [00071] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3 et = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 3 and G = 2. [00071] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3 and = 2.
[00072] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 et = 2. [00073] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3 et G = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 and = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 3 and G = 2.
[00074] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule[00074] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, I' = 2 et GpH répond à la Formule XI. X where r = 0, g = 0, I = 1, h = 2 or 3, I '= 2, and GpH is Formula XI.
[00075] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, G = 2 et GpH répond à la Formule XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, G = 2, and GpH meets Formula XI.
Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, I' = 2 et GpH répond à la Formule XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, I '= 2 and GpH corresponds to Formula XI.
[00076] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule [00076] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 0, g = 0, I = 1 , h = 2 ou 3, I' = 2, GpH répond à la Formule XI et x = 13. X where r = 0, g = 0, I = 1, h = 2 or 3, I '= 2, GpH corresponds to Formula XI and x = 13.
[00077] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, G = 2, GpH répond à la Formule XI et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, G = 2, GpH meets Formula XI and x = 13.
[00078] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule [00078] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula
X dans laquelle r = 0, g = 0, I = 1 , h = 3, G = 2, GpH répond à la Formule XI et x = 13. X where r = 0, g = 0, I = 1, h = 3, G = 2, GpH is Formula XI and x = 13.
[00079] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule[00079] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00080] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. X where r = 0, g = 0, I = 1, h = 2 or 3, G = 2, GpH has Formula XI, GpC has formula IXd and x = 13. [00080] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, = 2, GpH has Formula XI, GpC has Formula IXd and x = 13.
[00081] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[00082] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3 et I' = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3 and I '= 2.
[00083] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 et G = 2. [00083] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 and G = 2.
[00084] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3 et G = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 3 and G = 2.
[00085] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, = 2 et GpH répond à la Formule XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3, = 2 and GpH meets Formula XI.
[00086] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, = 2 et GpH répond à la Formule XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2, = 2 and GpH meets Formula XI.
[00087] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3, I' = 2 et GpH répond à la Formule XI. [00088] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, G = 2, GpH répond à la Formule XI et x = 13. [00087] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 3, I '= 2 and GpH meets Formula XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3, G = 2, GpH meets Formula XI and x = 13.
[00089] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, I' = 2, GpH répond à la Formule XI et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2, I '= 2, GpH corresponds to Formula XI and x = 13.
[00090] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3, I' = 2, GpH répond à la Formule XI et x = 13. [00090] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 3, I '= 2, GpH meets Formula XI and x = 13.
[00091] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00091] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3, G = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[00092] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, I' = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00092] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2, I '= 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[00093] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXb et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [00093] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXb and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 3, G = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[00094] Dans un mode de réalisation lorsque le co-polyaminoacide est de formule XXXb et que r = 1 alors GpR est de Formule VII. [00094] In one embodiment when the co-polyamino acid is of formula XXXb and that r = 1 then GpR is of Formula VII.
[00095] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXd suivante :
Figure imgf000016_0001
Formule XXXd dans laquelle, In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of the following formula XXXd:
Figure imgf000016_0001
Formula XXXd in which,
D représente, indépendamment, soit un groupe -CH2- (unité aspartique) soit un groupe -CH2-CH2- (unité glutamique), D represents, independently, either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),
X représente une entité cationique choisie dans le groupe comprenant les cations alcalins, X represents a cationic entity chosen from the group comprising alkali metal cations,
Rd et R'd, identiques ou différents, sont un radical hydrophobe -Hy de formule Rd and R'd, identical or different, are a hydrophobic radical -Hy of formula
X, X,
K est un spacer divalent choisi parmi les formules III ou IV suivantes,
Figure imgf000016_0002
K is a divalent spacer chosen from the following formulas III or IV,
Figure imgf000016_0002
Formule III Formula III
dans laquelle in which
• 1 £ t < 8, autrement dit t est un entier compris entre 1 et 8, • 1 £ t <8, in other words t is an integer between 1 and 8,
• Fa et Fa', identiques ou différentes représentent une fonction -NH-
Figure imgf000016_0003
Formule IV • Fa and Fa ', identical or different, represent an -NH- function
Figure imgf000016_0003
Formula IV
dans laquelle : in which :
• Fb et Fb', identiques ou différentes représentent une fonction -NH-• Fb and Fb ', identical or different, represent an -NH- function
• Au moins un des ui" ou U2" est différent de 0. • At least one of ui "or U2" is different from 0.
• Si Ui" ¹ 0 alors ui' ¹ 0 et si U2" ¹ 0 alors U2' ¹ 0, • If Ui "¹ 0 then ui '¹ 0 and if U2" ¹ 0 then U2' ¹ 0,
* ui' et U2' sont identiques ou différents et, * ui 'and U2' are the same or different and,
• 2 < u < 4, • 2 <u <4,
• 0 < Ui' < 4, • 0 <Ui '<4,
• 0 £ ui" < 4, • 0 £ ui "<4,
• 0 < U2' < 4 • 0 <U2 '<4
· 0 < U2" < 4 , 0 <U2 "<4,
ledit spacer K étant lié aux au moins deux chaînes d'unités glutamiques ou aspartiques PLG par des fonctions amides ; said spacer K being linked to at least two chains of glutamic or aspartic PLG units via amide functions;
n + m représente le degré de polymérisation DP du co-polyaminoacide, c'est-à- dire le nombre moyen d'unités monomériques par chaîne de co-polyaminoacide et 5 < n + m < 250. n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomer units per chain of co-polyamino acid and 5 <n + m <250.
[00096] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXd dans laquelle Rd et R'd, identiques sont un radical hydrophobe -Hy. [00096] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which Rd and R'd, which are identical, are a hydrophobic radical -Hy.
[00097] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXd dans laquelle Rd et R'd, différents sont un radical hydrophobe -Hy. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which Rd and R'd, different are a hydrophobic radical -Hy.
[00098] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule[00098] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula
XXXd dans laquelle K est de formule III. XXXd in which K is of formula III.
[00099] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXd dans laquelle K est de formule III et Rd et R'd identiques sont un radical hydrophobe de formule X. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which K is of formula III and identical Rd and R'd are a hydrophobic radical of formula X.
[000100] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXd dans laquelle K est de formule III et Rd et R'd identiques sont un radical hydrophobe de formule Xa. [000100] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd in which K is of formula III and Rd and R'd which are identical are a hydrophobic radical of formula Xa.
[000101] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 2 ou 3 et I' = 2. [000101] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 2 or 3 and I '= 2.
[000102] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 2 et G = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 2 and G = 2.
[000103] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 3 et G = 2. [000103] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 3 and G = 2.
[000104] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3 et = 2. [000104] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from co-polyamino acids of formula XXXd and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3 and = 2.
[000105] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 et I' = 2. [000105] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 and I '= 2.
[000106] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3 et G = 2. [000106] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from co-polyamino acids of formula XXXd and said hydrophobic radicals —Hy are of formula X in which r = 0, g = 0, I = 1, h = 3 and G = 2.
[000107] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, = 2 et GpH répond à la Formule XI. [000107] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3, = 2 and GpH is Formula XI.
[000108] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, I' = 2 et GpH répond à la Formule XI. Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, G = 2 et GpH répond à la Formule XI. [000108] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, I '= 2 and GpH has Formula XI. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, G = 2 and GpH corresponds to Formula XI.
[000109] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, G = 2, GpH répond à la Formule XI et x = 13. [000109] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3, G = 2, GpH meets Formula XI and x = 13.
[000110] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2, I' = 2, GpH répond à la Formule XI et x = 13. [000110] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, I '= 2, GpH meets Formula XI and x = 13.
[000111] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, G = 2, GpH répond à la Formule XI et x = 13. [000112] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hyd rophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 2 ou 3, I' = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [000111] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, G = 2, GpH corresponds to Formula XI and x = 13. [000112] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least a hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2 or 3, I '= 2 , GpH has Formula XI, GpC has formula IXd and x = 13.
[000113] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1 , h = 2, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 2, G = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[000114] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXd et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 0, g = 0, I = 1, h = 3, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXd and said hydrophobic radicals -Hy are of formula X in which r = 0, g = 0, I = 1, h = 3, G = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[000115] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXe suivante : [000115] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of the following formula XXXe:
Figure imgf000020_0001
Formule XXXe dans laquelle,
Figure imgf000020_0001
Formula XXXe in which,
D et X ont les définitions données précédemment, D and X have the definitions given above,
Rb et R'b, identiques ou différents, sont un radical hydrophobe -Hy, Rb and R'b, identical or different, are a hydrophobic radical -Hy,
K a la signification donnée ci-dessus, excepté que K has the meaning given above, except that
o Fa et Fa', identiques ou différentes représentent une fonction -CO- et o Fb et Fb', identiques ou différentes représentent une fonction -CO-. o Fa and Fa ', identical or different represent a -CO- function and o Fb and Fb', identical or different, represent a -CO- function.
n + m ont la même définition que donnée précédemment. n + m have the same definition as given previously.
[000116] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXe dans laquelle Rb et R'b, identiques sont un radical hydrophobe -Hy. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe in which Rb and R'b, which are identical, are a hydrophobic radical -Hy.
[000117] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXe dans laquelle Rb et R'b, différents sont des radicaux hydrophobe -Hy. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe in which Rb and R'b, different are hydrophobic radicals -Hy.
[000118] Les au moins deux chaînes d'unités glutamiques ou aspartiques P LG étant liées à K par une fonction Fa, Fa' ou Fb, Fb' par une liaison covalente pour former une liaison amide avec une fonction -NH- ou -CO- du PLG. [000118] The at least two chains of glutamic or aspartic units P LG being linked to K by a function Fa, Fa 'or Fb, Fb' by a covalent bond to form an amide bond with an -NH- or -CO function - of the PLG.
[000119] Dans un mode de réalisation, K est un radical de formule III,
Figure imgf000020_0002
[000119] In one embodiment, K is a radical of formula III,
Figure imgf000020_0002
Formule III Formula III
dont le précurseur est une diamine. the precursor of which is a diamine.
[000120] Dans un mode de réalisation, le précurseur du radical de formule III est une diamine choisie dans le groupe constitué par l'éthylène diamine, la butylènediamine, rhexylènediamine, le 1,3-diaminopropane et le 1,5-diaminopentane, la propylène diamine, la pentylène diamine. [000120] In one embodiment, the precursor of the radical of formula III is a diamine chosen from the group consisting of ethylenediamine, butylenediamine, rhexylenediamine, 1,3-diaminopropane and 1,5-diaminopentane, propylene diamine, pentylene diamine.
[000121] Dans un mode de réalisation, le précurseur du radical de formule III est l'éthylène diamine. [000121] In one embodiment, the precursor of the radical of formula III is ethylene diamine.
[000122] Dans un mode de réalisation, le précurseur du radical de formule III est un diacide. [000122] In one embodiment, the precursor of the radical of formula III is a diacid.
[000123] Dans un mode de réalisation, le précurseur du radical de formule III est un diacide choisi dans le groupe constitué par l'acide succinique, l'acide glutarique et l'acide adipique. [000123] In one embodiment, the precursor of the radical of formula III is a diacid chosen from the group consisting of succinic acid, glutaric acid and adipic acid.
[000124] Dans un mode de réalisation, K est un radical de formule IV,
Figure imgf000021_0001
Formule IV dont le précurseur est une diamine. [000124] In one embodiment, K is a radical of formula IV,
Figure imgf000021_0001
Formula IV, the precursor of which is a diamine.
[000125] Dans un mode de réalisation, le précurseur du radical de formule IV est une diamine choisie dans le groupe constitué par le diéthylèneglycoldiamine, le triéthylèneglycol diamine, le l-amino-4,9-dioxa- 12-dodecanamine et le 1-amino- 4,7, 10-trioxa-13-tridecanamine. [000125] In one embodiment, the precursor of the radical of formula IV is a diamine chosen from the group consisting of diethylene glycoldiamine, triethylene glycol diamine, 1-amino-4,9-dioxa-12-dodecanamine and 1- amino-4,7,10-trioxa-13-tridecanamine.
[000126] Dans un mode de réalisation, u = u'i = 2, u"i= l, u"2 = 0 et le précurseur du radical de formule IV est le diéthylèneglycol diamine. [000126] In one embodiment, u = u'i = 2, u "i = 1, u" 2 = 0 and the precursor of the radical of formula IV is diethylene glycol diamine.
[000127] Dans un mode de réalisation, u = u'i = u'2 = 2, u"i= u"2 = 1 et le précurseur du radical de formule IV est le triéthylèneglycol diamine. [000127] In one embodiment, u = u'i = u'2 = 2, u "i = u" 2 = 1 and the precursor of the radical of formula IV is triethyleneglycol diamine.
[000128] Dans un mode de réalisation, u = u'2 = 3, u'i = 4, u"i= u"2 = 1 et le précurseur du radical de formule IV est le 4,9-dioxa-l,12-dodécanediamine. [000128] In one embodiment, u = u'2 = 3, u'i = 4, u "i = u" 2 = 1 and the precursor of the radical of formula IV is 4,9-dioxa-1, 12-dodecanediamine.
[000129] Dans un mode de réalisation, u = u'2 = 3, u'i = u"i= 2, u"2 = 1 et le précurseur du radical de formule IV est le 4,7, 10-trioxa-l ,13-tridecanediamine. [000129] In one embodiment, u = u'2 = 3, u'i = u "i = 2, u" 2 = 1 and the precursor of the radical of formula IV is 4,7,10-trioxa- 1,3-tridecanediamine.
[000130] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1 , h = 2 ou 3 et I' = 2. [000130] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula X in which g = 0, I = 1, h = 2 or 3 and I '= 2.
[000131] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1 , h = 2 et = 2. [000132] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle g = 0, I = 1, h = 3 et = 2. [000131] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula X in which g = 0, I = 1, h = 2 and = 2. [000132] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula X in which g = 0, I = 1, h = 3 and = 2.
[000133] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1 , g = 0, I = 1, h = 2 ou 3 et G = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3 and G = 2.
[000134] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 et G = 2. [000134] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 and G = 2.
[000135] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3 et = 2. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 3 and = 2.
[000136] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, I' = 2 et GpH répond à la Formule XI. [000136] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3, I '= 2 and GpH corresponds to Formula XI.
[000137] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule[000137] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 1, g = 0, I = 1, h = 2, I' = 2 et GpH répond à la Formule XI. X where r = 1, g = 0, I = 1, h = 2, I '= 2 and GpH is Formula XI.
[000138] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 3, I' = 2 et GpH répond à la Formule XI. [000138] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 3, I '= 2 and GpH meets Formula XI.
[000139] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, G = 2, GpH répond à la Formule XI et x = 13. [000139] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula X in which r = 1, g = 0, I = 1, h = 2 or 3, G = 2, GpH meets Formula XI and x = 13.
[000140] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, G = 2, GpH répond à la Formule XI et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula X where r = 1, g = 0, I = 1, h = 2, G = 2, GpH has Formula XI and x = 13.
[000141] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule [000141] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula
X dans laquelle r = 1, g = 0, I = 1, h = 3, G = 2, GpH répond à la Formule XI et x = 13. X where r = 1, g = 0, I = 1, h = 3, G = 2, GpH has Formula XI and x = 13.
[000142] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule[000142] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula
X dans laquelle r = 1, g = 0, I = 1, h = 2 ou 3, = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. X where r = 1, g = 0, I = 1, h = 2 or 3, = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[000143] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1, g = 0, I = 1, h = 2, I' = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals -Hy are of formula X in which r = 1, g = 0, I = 1, h = 2, I '= 2, GpH corresponds to Formula XI, GpC corresponds to formula IXd and x = 13.
[000144] Dans un mode de réalisation le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co- polyaminoacides de formule XXXe et lesdits radicaux hydrophobes -Hy sont de formule X dans laquelle r = 1 g = 0, I = 1, h = 3, G = 2, GpH répond à la Formule XI, GpC répond à la formule IXd et x = 13. [000144] In one embodiment, the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of formula XXXe and said hydrophobic radicals —Hy are of formula X in which r = 1 g = 0, I = 1, h = 3, G = 2, GpH has Formula XI, GpC has formula IXd and x = 13.
[000145] Dans un mode de réalisation lorsque le co-polyaminoacide est de formule XXXe et que r = 1 alors GpR est de Formule VII. [000145] In one embodiment when the co-polyamino acid is of formula XXXe and that r = 1 then GpR is of Formula VII.
[000146] Dans un mode de réalisation, la composition est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est choisi parmi les co-polyaminoacides de formules XXXd ou XXXe dans lesquelles le groupe D est un groupe -CH2-CH2- (unité glutamique). [000146] In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXd or XXXe in which the group D is a -CH2 group -CH2- (glutamic unit).
[000147] Dans un mode de réalisation, la composition est caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est choisi parmi les co-polyaminoacides de formules XXXd ou XXXe dans lesquelles le groupe D est un groupe -CH2- (unité aspartique). [000148] Lorsque le co-polyaminoacide comprend une ou plusieurs d'unité(s) aspartique(s), celle(s)-ci peu(ven)t subir des réarrangements structuraux. [000149] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que lorsque le co-polyaminoacides comprend des unités aspartate, alors le co-polyaminoacides peut en outre comprendre des unités monomériques de formule XXXX et/ou XXXX' : [000147] In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXd or XXXe in which the group D is a -CH2 group - (aspartic unit). [000148] When the co-polyamino acid comprises one or more aspartic unit (s), that (s) -ci little (come) t undergo structural rearrangements. [000149] In one embodiment, the composition according to the invention is characterized in that when the co-polyamino acids comprises aspartate units, then the co-polyamino acids can also comprise monomeric units of formula XXXX and / or XXXX ' :
Figure imgf000024_0001
Figure imgf000024_0001
[000150] Dans un mode de réalisation ledit radical hydrophobe— Hy est choisi parmi les radicaux de formule X telle que définie ci-dessous de formule Xa
Figure imgf000024_0002
In one embodiment, said hydrophobic radical — Hy is chosen from radicals of formula X as defined below of formula Xa
Figure imgf000024_0002
Formule Xa Formula Xa
dans laquelle r = g = 0 et h > 2. where r = g = 0 and h> 2.
[000151] Dans un mode de réalisation ledit radical hydrophobe— Hy est choisi parmi les radicaux de formule Xa dans laquelle 1 = 1, h=2 et l'=2. In one embodiment, said hydrophobic radical — Hy is chosen from the radicals of formula Xa in which 1 = 1, h = 2 and l '= 2.
[000152] Dans un mode de réalisation ledit radical hydrophobe— Hy est choisi parmi les radicaux de formule Xa dans laquelle 1= 1, h=3 et l'=2. [000152] In one embodiment, said hydrophobic radical — Hy is chosen from radicals of formula Xa in which 1 = 1, h = 3 and l ′ = 2.
[000153] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule de formule X dans laquelle r= l et GpR est un radical de formule VII, VII' ou VU", dans laquelle R est un radical linéaire éther ou polyéther non substitué comprenant de 4 à 14 atomes de carbone et de 1 à 5 atomes d'oxygène. [000153] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X in which r = 1 and GpR is a radical of formula VII, VII 'or VU " , wherein R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
[000154] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa, dans laquelle g > 1 et/ou h > 1 et GpG et/ou GpH est un radical de Formule Xlb. [000154] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa, in which g> 1 and / or h> 1 and GpG and / or GpH is a radical of Formula Xlb.
[000155] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa, dans laquelle g > 1 et/ou h > 1 et GpG et/ou GpH est un radical de Formule Xla [000155] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa, in which g> 1 and / or h> 1 and GpG and / or GpH is a radical of Formula Xla
[000156] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe de formule X dans laquelle r= l et GpR est un radical de formule VII, VU' ou VU", dans laquelle R est un radical polyéther choisi dans le groupe constitué par les radicaux représentés par les formules ci-dessous : [000156] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical of formula X in which r = 1 and GpR is a radical of formula VII, VU 'or VU ", in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below:
Figure imgf000025_0001
Figure imgf000025_0001
[000157] Dans un mode de réalisation, la composition selon l'invention est 5 caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa, dans laquelle g > 1 et/ou h > 1 et GpG et/ou GpH est/sont choisis parmi les radicaux de formules Xla, Xlb, XIc, Xld, Xl'e ou Xl'f ci-dessous représentées. [000157] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa, in which g> 1 and / or h> 1 and GpG and / or GpH is / are chosen from the radicals of formulas Xla, Xlb, XIc, Xld, Xl'e or Xl'f shown below.
Figure imgf000025_0002
Figure imgf000025_0002
[000158] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpL de formule XII est choisi dans le groupe constitué des radicaux de formules Xlla et Xllb ci-après représentées : [000158] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpL radical of formula XII is chosen from the group consisting of radicals of formulas Xlla and Xllb hereinafter represented:
15
Figure imgf000026_0002
15
Figure imgf000026_0002
[000159] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpL est un radical de Formule Xlla. [000160] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpL est un radical de Formule Xllb. [000159] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpL radical is a radical of Formula Xlla. [000160] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpL radical is a radical of Formula Xllb.
[000161] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux de formules IXa', IXb' ou IXe' ci-après représentées : [000161] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXa ', IXb' or IXe 'shown below:
Figure imgf000026_0001
Figure imgf000026_0001
[000162] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux de formules IXa', IXb' ou IXe' dans lesquels b est égal à 0, répondant respectivement aux formules IXd, IXe, et IXf ci-après représentées : [000162] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXa ', IXb' or IXe 'in which b is equal to 0, corresponding respectively to formulas IXd, IXe, and IXf shown below:
Figure imgf000027_0001
Figure imgf000027_0001
[000163] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est un radical de formule IXd. [000164] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX dans laquelle b = 1 est choisi dans le groupe constitué des radicaux dans lesquels B est un résidu d'acide aminé choisi dans le groupe constitué par les radicaux représentés par les formules ci-dessous ; [000163] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is a radical of formula IXd. [000164] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX in which b = 1 is chosen from the group consisting radicals in which B is an amino acid residue selected from the group consisting of radicals represented by the formulas below;
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000027_0002
Figure imgf000028_0001
[000165] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéai res comprenant de 13 à 19 atomes de carbone. [000165] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising from 13 to 19 carbon atoms.
[000166] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés comprenant de 13 à 19 atomes de carbone. [000166] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising from 13 to 19 carbon atoms.
[000167] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéaires comprenant de 13 à 17 atomes de carbone. [000167] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising from 13 to 17 carbon atoms.
[000168] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés comprenant de 13 à 17 atomes de carbone. [000168] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising from 13 to 17 carbon atoms.
[000169] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéaires comprenant de 13 à 15 atomes de carbone. [000169] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising from 13 to 15 carbon atoms.
[000170] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés comprenant de 13 à 15 atomes de carbone. [000170] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising from 13 to 15 carbon atoms.
[000171] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans WO 2020/245470 PCT/EP2020/065884 [000171] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in WO 2020/245470 PCT / EP2020 / 065884
28 28
laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéaires comprenant 13 atomes de carbone. in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising 13 carbon atoms.
[000172] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés comprenant 13 atomes de carbone. [000172] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising 13 carbon atoms.
[000173] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéaires comprenant 15 atomes de carbone. [000173] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising 15 carbon atoms.
[000174] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le radical hydrophobe est un radical de X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés comprenant 15 atomes de carbone. [000174] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising 15 carbon atoms.
[000175] Dans un mode de réalisation, la composition selon l'invention est0 caractérisée en ce que le radical hydrophobe est un radical de formule X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéaires comprenant 17 atomes de carbone. [000175] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals comprising 17 carbon atoms.
[000176] Dans un mode de réalisation, la composition selon l'invention est 5 caractérisée en ce que le radical hydrophobe est un radical de X ou Xa dans laquelle le radical GpC de formule IX est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés comprenant 17 atomes de carbone. 0 [000177] Dans un mode de réalisation, le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes Hy, est choisi parmi les copolyaminoacides de formule XXXa dans laquelle Q est un radical de formule XII", [000176] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of X or Xa in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals comprising 17 carbon atoms. 0 [000177] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy, is chosen from the copolyamino acids of formula XXXa in which Q is a radical of formula XII ",
Formule XII”
Figure imgf000029_0001
dans laquelle Ai et A2 sont des radicaux alkyles linéaires ou ramifiés comprenant de 1 à 6 atomes de carbone. Formula XII ”
Figure imgf000029_0001
in which Ai and A2 are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms.
[000178] Dans un mode de réalisation -Al- est un radical -[CH2]3- et -A2- est un radical -[Cl-h]· -. [000178] In one embodiment -Al- is a radical - [CH2] 3- and -A2- is a radical - [Cl-h] · -.
[000179] Dans un mode de réalisation -Al- est un radical -[CH2]2- et -A2- est un radical -[CH2]2-. [000179] In one embodiment -Al- is a radical - [CH2] 2- and -A2- is a radical - [CH2] 2-.
[000180] Dans un mode de réalisation -Al- est un radical -[O-te e- et -A2- est un radical -[CH2]6-. Dans un mode de réalisation -Al- est un radical -[CH2]3- et -A2- est [000180] In one embodiment -Al- is a radical - [O-te e- and -A2- is a radical - [CH2] 6-. In one embodiment -Al- is a radical - [CH2] 3- and -A2- is
10 un radical -[CH2Î3-. A radical - [CH2Î3-.
[000181] [000181]
[000182] Dans un mode de réalisation, le radical hydrophobe -Hy est choisi parmi les radicaux de formule X dans laquelle r=g = 0 de formule Xa suivante : [000182] In one embodiment, the hydrophobic radical -Hy is chosen from the radicals of formula X in which r = g = 0 of the following formula Xa:
(GpL) {GpH^— GpC (GpL) {GpH ^ - GpC
15 l\ Formule Xa 15 l \ Formula Xa
dans laquelle GpL, GpH, GpC et I ont les valeurs données ci-dessus, l'=2, 2 < h <3 et Cx est un radical alkyl monovalent linéaire ou ramifié, dans lequel 13< x < 19. in which GpL, GpH, GpC and I have the values given above, l '= 2, 2 <h <3 and Cx is a linear or branched monovalent alkyl radical, in which 13 <x <19.
[000183] Dans un mode de réalisation GpC répond à la Formule IXd.[000183] In one embodiment GpC corresponds to Formula IXd.
0 0
[000184] Dans un mode de réalisation, le radical hydrophobe -Hy est choisi parmi les radicaux de formule X dans laquelle g=0 de formule Xb suivante [000184] In one embodiment, the hydrophobic radical -Hy is chosen from the radicals of formula X in which g = 0 of the following formula Xb
[000185]
Figure imgf000030_0001
[000185]
Figure imgf000030_0001
25 Formule Xb dans laquelle GpR, GpL, GpH, GpC et I ont les valeurs données ci-dessus, l'=2, 2 < h <3 et Cx est un radical alkyl monovalent linéaire ou ramifié, dans lequel 13 < x < 19. Formula Xb in which GpR, GpL, GpH, GpC and I have the values given above, l '= 2, 2 <h <3 and Cx is a linear or branched monovalent alkyl radical, in which 13 <x <19 .
» [000186] Dans un mode de réalisation GpC répond à la Formule IXd. [000186] In one embodiment GpC corresponds to Formula IXd.
[000187] La composition selon l’invention permet à l’insuline glargine et au liraglutide d’avoir des profils pharmacocinétiques similaires respectivement à : [000187] The composition according to the invention allows insulin glargine and liraglutide to have pharmacokinetic profiles similar respectively to:
- Lantus® 100 U (composition d’insuline glargine à 100 U/ml et à pH 4), et 30 - Lantus® 100 U (composition of insulin glargine at 100 U / ml and at pH 4), and 30
- Victoza (composition de liraglutide à 6,0 g/ml et à pH 8,15). - Victoza (composition of liraglutide at 6.0 g / ml and at pH 8.15).
[000188] On définit par le ratio radical hydrophobe par insuline basale comme étant le ratio de leurs concentrations molaires respectives : [Hy]/[insuline basale] (mol/mol) 5 pour obtenir les performances attendues, à savoir la solubilisation de l'insuline basale à pH compris entre 6,0 et 8,0, la précipitation de l'insuline basale après injection dans le milieu sous-cutané et la stabilité des compositions selon l'invention. [000188] The hydrophobic radical ratio per basal insulin is defined as being the ratio of their respective molar concentrations: [Hy] / [basal insulin] (mol / mol) 5 to obtain the expected performances, namely the solubilization of the basal insulin at pH between 6.0 and 8.0, the precipitation of basal insulin after injection into the subcutaneous medium and the stability of the compositions according to the invention.
[000189] La valeur minimale du ratio radical hydrophobe par insuline basale [000189] The minimum value of the hydrophobic radical ratio per basal insulin
[Hy]/[insuline basale], mesurée est la valeur à laquelle l'insuline basale est solubilisée, 10 car la solubilisation est l'effet minimum à obtenir ; cette solubilisation conditionne tous les autres effets techniques qui ne peuvent être observés que si l'insuline basale est solubilisée à pH compris entre 6,0 et 8,0. [Hy] / [basal insulin], measured is the value at which basal insulin is solubilized, since solubilization is the minimum effect to be obtained; this solubilization conditions all the other technical effects which can only be observed if the basal insulin is solubilized at pH between 6.0 and 8.0.
[000190] Dans les compositions selon l'invention, le ratio radical hyd rophobe par insuline basale [Hy]/[insuline basale] peut être supérieur à la valeur minimale 15 déterminée par la limite de solubilisation . [000190] In the compositions according to the invention, the hydrophobic radical ratio per basal insulin [Hy] / [basal insulin] may be greater than the minimum value determined by the solubilization limit.
[000191] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale [Hy]/[insuline basale] <4. [000191] In one embodiment, the ratio of hydrophobic radical per basal insulin [Hy] / [basal insulin] <4.
[000192] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale [Hy]/[insuline basale] < 3. [000192] In one embodiment, the ratio of hydrophobic radical per basal insulin [Hy] / [basal insulin] <3.
0 [000193] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale 0 [000193] In one embodiment, the ratio of hydrophobic radical per basal insulin
[Hy]/[insuline basale] <2. [Hy] / [basal insulin] <2.
[000194] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale [Hy]/[insuline basale] > 0,5. [000194] In one embodiment, the ratio of hydrophobic radical per basal insulin [Hy] / [basal insulin]> 0.5.
[000195] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale 5 [Hy]/[insuline basale] > 1,00. [000195] In one embodiment, the hydrophobic radical ratio per basal insulin 5 [Hy] / [basal insulin]> 1.00.
[000196] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale [Hy]/[insuline basale] > 1,25. [000196] In one embodiment, the hydrophobic radical ratio per basal insulin [Hy] / [basal insulin]> 1.25.
[000197] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale [Hy]/[insuline basale] est compris entre 1 et 4. [000197] In one embodiment, the hydrophobic radical ratio per basal insulin [Hy] / [basal insulin] is between 1 and 4.
30 [000198] Dans un mode de réalisation, le ratio radical hydrophobe par insuline basale [000198] In one embodiment, the ratio of hydrophobic radical to basal insulin
[Hy]/[insuline basale] est compris entre 1 et 2. [Hy] / [basal insulin] is between 1 and 2.
[000199] Dans un mode de réalisation, le ratio massique (masse de co- polyaminoacide) / (masse total d’insuline glargine et de liraglutide) est compris entre 35 0,5 et 1,5. [000199] In one embodiment, the mass ratio (mass of co-polyamino acid) / (total mass of insulin glargine and liraglutide) is between 0.5 and 1.5.
[000200] Dans un mode de réalisation, le ratio massique (masse de co- polyaminoacide) / (masse total d’insuline glargine et de liraglutide) est compris entre 0,6 et 1,2. [000201] Dans un mode de réalisation, le ratio massique (masse de co- polyaminoacide) / (masse total d’insuline glargine et de liraglutide) est compris entre 0,7 et 1,1 [000202] Dans un mode de réalisation, la composition est exempte d'insuline prandiale. [000200] In one embodiment, the mass ratio (mass of co-polyamino acid) / (total mass of insulin glargine and liraglutide) is between 0.6 and 1.2. [000201] In one embodiment, the mass ratio (mass of co-polyamino acid) / (total mass of insulin glargine and of liraglutide) is between 0.7 and 1.1 [000202] In one embodiment, the composition is free from prandial insulin.
[000203] Dans un mode de réalisation, la composition est caractérisée en ce que l'insuline prandiale est l'insuline humaine. [000203] In one embodiment, the composition is characterized in that the mealtime insulin is human insulin.
[000204] On entend par insuline humaine une insuline obtenue par synthèse ou recombinaison dont la séquence peptidique est la séquence de l'insuline humaine, incluant les variations alléliques et les homologues. [000204] The term “human insulin” is understood to mean an insulin obtained by synthesis or recombination, the peptide sequence of which is the sequence of human insulin, including allelic variations and homologs.
[000205] Dans un mode de réalisation, la composition est caractérisée en ce que l'insuline prandiale est une insuline humaine recombinante telle que décrite dans la Pharmacopée Européenne et la Pharmacopée américaine. [000205] In one embodiment, the composition is characterized in that the mealtime insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
[000206] Dans un mode de réalisation, la composition est caractérisée en ce que l'insuline prandiale est une insuline analogue. [000206] In one embodiment, the composition is characterized in that the mealtime insulin is an insulin analogue.
[000207] On entend par insuline analogue une insuline recombinante dont la séquence primaire contient au moins une modification par rapport à la séquence primaire de l'insuline humaine. [000207] By insulin analog is meant a recombinant insulin whose primary sequence contains at least one modification relative to the primary sequence of human insulin.
[000208] Dans un mode de réalisation l'insuline prandiale est une insuline analogue choisie dans le groupe constitué par l'insuline lispro (Humalog®), l'insuline aspart (Novolog®, Novorapid®) et l'insuline glulisine (Apidra®). [000208] In one embodiment, the prandial insulin analogue is an insulin selected from the group consisting of insulin lispro (Humalog ®), insulin aspart (Novolog ®, Novorapid ®) and insulin glulisine (Apidra ® ).
[000209] Dans un mode de réalisation, la composition est caractérisée en ce que l'insuline prandiale est l'insuline lispro (Humalog®). [000209] In one embodiment, the composition is characterized in that the prandial insulin is insulin lispro (Humalog ®).
[000210] Dans un mode de réalisation, la composition est caractérisée en ce que l'insuline prandiale est l'insuline aspart (Novolog®, Novorapid®). [000210] In one embodiment, the composition is characterized in that the prandial insulin is insulin aspart (Novolog ®, Novorapid ®).
[000211] Dans un mode de réalisation, la composition est caractérisée en ce que l'insuline prandiale est l'insuline glulisine (Apidra®). [000212] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le ratio M entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,007 et 0,3. [000211] In one embodiment, the composition is characterized in that the prandial insulin is insulin glulisine (Apidra ®). [000212] In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
[000213] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le ratio M entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,3. [000213] In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
[000214] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le ratio M entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,2. [000215] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le ratio M entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,03 et 0, 1. [000214] In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2. [000215] In one embodiment, the composition according to the invention is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.1.
[000216] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 10 et 200. [000216] In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 200.
[000217] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 150. [000217] In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 150.
[000218] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 100. [000218] In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 100.
[000219] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 80. [000219] In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 80.
[000220] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 65. [000220] In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 65.
[000221] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 20 et 60. [000221] In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 60.
[000222] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 20 et 50. [000222] In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 50.
[000223] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 20 et 40. [000223] In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 40.
[000224] L'invention réside en outre en une méthode de préparation de compositions injectables stables. [000224] The invention also resides in a method for preparing stable injectable compositions.
[000225] Dans un mode de réalisation, l'invention concerne aussi les précurseurs desdits radicaux hydrophobes de formule X. [000225] In one embodiment, the invention also concerns the precursors of said hydrophobic radicals of formula X.
[000226] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes de polyaminoacides, dites PLG, constituant le co- polyaminoacide sont obtenues par polymérisation . [000226] In one embodiment, the composition according to the invention is characterized in that the polyamino acid chains, called PLGs, constituting the co-polyamino acid are obtained by polymerization.
[000227] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation par ouverture de cycle d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N -ca rboxya n hyd ri de d'acide aspartique. [000227] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by ring-opening polymerization of a derivative of N-carboxyanhydride of glutamic acid or d a derivative of N -ca rboxya n hyd ri of aspartic acid.
[000228] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N -ca rboxya n hyd ri de d'acide aspartique comme décrit dans l'article de revue Adv. Polym. Sci . 2006, 202, 1-18 (Deming, T.J.). [000229] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique. [000228] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N -ca rboxya n hyd ri de of aspartic acid as described in the review article Adv. Polym. Sci. 2006, 202, 1-18 (Deming, TJ). [000229] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid.
[000230] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique choisi dans le groupe constitué par le N-carboxyanhydride poly-glutamate de méthyle (GluOMe- NCA), le N-carboxyanhydride poly-glutamate de benzyle (GluOBzl-NCA) et le N- carboxyanhydride poly glutamate de t-butyle (GluOtBu-NCA). [000230] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride chosen from the group consisting of Methyl N-carboxyanhydride poly-glutamate (GluOMe-NCA), Benzyl N-carboxyanhydride poly-glutamate (GluOBzl-NCA) and N-carboxyanhydride poly t-butyl glutamate (GluOtBu-NCA).
[000231] Dans un mode de réalisation, le dérivé de N -carboxyanhydride d'acide glutamique est le N-carboxyanhydride poly-L-glutamate de méthyle (L-GluOMe-NCA). [000231] In one embodiment, the derivative of N -carboxyanhydride of glutamic acid is methyl N-carboxyanhydride poly-L-glutamate (L-GluOMe-NCA).
[000232] Dans un mode de réalisation, le dérivé de N-carboxyanhydride d'acide glutamique est le N-carboxyanhydride poly-L-glutamate de benzyle (L-GluOBzl-NCA). [000232] In one embodiment, the glutamic acid N-carboxyanhydride derivative is benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzl-NCA).
[000233] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique en utilisant comme initiateur un complexe organométallique d'un métal de transition comme décrit dans la publication Nature 1997, 390, 386-389 (Deming, TJ.). [000233] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride using as initiator an organometallic complex of a transition metal as described in Nature 1997, 390, 386-389 (Deming, TJ.).
[000234] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique en utilisant comme initiateur l'ammoniaque ou une amine primaire comme décrit dans le brevet FR 2,801,226 (Touraud, F. ; et al.) et les références citées par ce brevet. [000234] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride using ammonia or a primary amine as initiator as described in patent FR 2,801,226 (Touraud, F.; et al.) And the references cited by this patent.
[000235] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique en utilisant comme initiateur l'hexaméthyldisilazane comme décrit dans la publication J. Am. Chem . Soc. 2007, 129, [000235] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride using hexamethyldisilazane as initiator as described in the publication J. Am. Chem. Soc. 2007, 129,
14114-14115 (Lu H . ; et al . ) ou une amine silylée comme décrit dans la publication J.14114-14115 (Lu H .; et al.) Or a silylated amine as described in the publication J.
Am . Chem . Soc. 2008, 130, 12562-12563 (Lu H . ; et al.) . Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H.; Et al.).
[000236] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique, polymérisation initiée par les fonctions amine portées par le radical ou spacer Q[— *]3. [000237] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique choisi dans le groupe constitué par le N-carboxyanhydride poly-glutamate de méthyle (GluOMe- N CA), le N-carboxyanhydride poly-glutamate de benzyle (GluOBzl-NCA) et le N- carboxyanhydride poly glutamate de t-butyle (GluOtBu-NCA), polymérisation initiée par les fonctions amine portées par le radical ou spacer Q[— *]3. [000236] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride, polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3. [000237] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride chosen from the group consisting of Methyl N-carboxyanhydride poly-glutamate (GluOMe- N CA), poly-benzyl N-carboxyanhydride poly-glutamate (GluOBzl-NCA) and N-carboxyanhydride poly t-butyl glutamate (GluOtBu-NCA), polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3 .
[000238] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation du N-carboxyanhydride poly-L-glutamate de méthyle (L-GluOMe- NCA), polymérisation initiée par les fonctions amine portées par le radical ou spacer Q[-*]3. [000238] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of methyl N-carboxyanhydride poly-L-glutamate (L-GluOMe-NCA) , polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3.
[000239] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation du N-carboxyanhydride poly-L-glutamate de benzyle (L-GluOBzl- NCA), polymérisation initiée par les fonctions amine portées par le radical ou spacer Q[-*]3. In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzl- NCA) , polymerization initiated by the amine functions carried by the radical or spacer Q [- *] 3.
[000240] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique, polymérisation initiée par les fonctions amine portées par le précurseur du radical Q[— *]3[Hy]j. [000240] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of Aspartic acid N-carboxyanhydride, polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
[000241] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique choisi dans le groupe constitué par le N-carboxyanhydride poly-glutamate de méthyle (GluOMe- NCA), le N-carboxyanhydride poly-glutamate de benzyle (GluOBzl-NCA) et le N- carboxyanhydride poly glutamate de t-butyle (GluOtBu-NCA), polymérisation initiée par les fonctions amine portées par le précurseur du radical Q[— *]3[Hy]j. [000241] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride chosen from the group consisting of methyl N-carboxyanhydride poly-glutamate (GluOMe-NCA), poly-benzyl N-carboxyanhydride-glutamate (GluOBzl-NCA) and poly-t-butyl N-carboxyanhydride (GluOtBu-NCA), polymerization initiated by amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
[000242] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation du N-carboxyanhydride poly-L-glutamate de méthyle (L-GluOMe- NCA), polymérisation initiée par les fonctions amine portées par le précurseur du radical Q[-*]3[Hy]j. [000242] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of methyl N-carboxyanhydride poly-L-glutamate (L-GluOMe-NCA) , polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
[000243] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont obtenues par polymérisation du N-carboxyanhydride poly-L-glutamate de benzyle (L-GluOBzl- NCA), polymérisation initiée par les fonctions amine portées par le précurseur du radical Q[— *]3[Hy]j. [000243] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of N-carboxyanhydride poly-L-benzyl glutamate (L-GluOBzl- NCA), polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] 3 [Hy] j.
[000244] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le procédé de synthèse des chaînes P LG constituant le co- polyaminoacide incluant la polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique comprend une étape d'hydrolyse de fonctions ester. [000244] In one embodiment, the composition according to the invention is characterized in that the process for the synthesis of the P LG chains constituting the co-polyamino acid including the polymerization of a derivative of N-carboxyanhydride of glutamic acid or d an aspartic acid N-carboxyanhydride derivative comprises a step of hydrolysis of ester functions.
[000245] Dans un mode de réalisation, cette étape d'hydrolyse de fonctions ester peut consister en une hydrolyse en milieu acide ou une hydrolyse en milieu basique ou être effectuée par hydrogénation. [000245] In one embodiment, this step of hydrolysis of ester functions may consist of hydrolysis in acidic medium or hydrolysis in basic medium or be carried out by hydrogenation.
[000246] Dans un mode de réalisation, cette étape d'hydrolyse de groupements ester est une hydrolyse en milieu acide. [000246] In one embodiment, this step of hydrolysis of ester groups is hydrolysis in an acidic medium.
[000247] Dans un mode de réalisation, cette étape d'hydrolyse de groupements ester est effectuée par hydrogénation. [000247] In one embodiment, this step of hydrolysis of ester groups is carried out by hydrogenation.
[000248] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes P LG constituant le co-polyaminoacide sont issues d'un polyaminoacide obtenu par dépolymérisation d'un polyaminoacide de plus haut poids moléculaire. [000248] In one embodiment, the composition according to the invention is characterized in that the P LG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight.
[000249] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont issues d'un polyaminoacide obtenu par dépolymérisation enzymatique d'un polyaminoacide de plus haut poids moléculaire. [000249] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.
[000250] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont issues d'un polyaminoacide obtenu par dépolymérisation chimique d'un polyaminoacide de plus haut poids moléculaire. [000250] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.
[000251] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont issues d'un polyaminoacide obtenu par dépolymérisation enzymatique et chimique d'un polyaminoacide de plus haut poids moléculaire. [000251] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight.
[000252] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont issues d'un polyaminoacide obtenu par dépolymérisation d'un polyaminoacide de plus haut poids moléculaire choisi dans le groupe constitué par le polyglutamate de sodium et le polyaspartate de sodium. [000252] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight chosen from the group consisting of sodium polyglutamate and sodium polyaspartate.
[000253] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont issues d'un polyaminoacide obtenu par dépolymérisation d'un polyglutamate de sodium de plus haut poids moléculaire. [000253] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained of a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight.
[000254] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les chaînes PLG constituant le co-polyaminoacide sont issues d'un polyaminoacide obtenu par dépolymérisation d'un polyaspartate de sodium de plus haut poids moléculaire. [000254] In one embodiment, the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained from a polyamino acid obtained by depolymerization of a sodium polyaspartate of higher molecular weight.
[000255] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les liaisons amides présentes dans le co-polyaminoacide sont issues de procédés de formation de liaison amide bien connus de l'homme de l'art. [000255] In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid result from processes for forming an amide bond well known to those skilled in the art.
[000256] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les liaisons amides présentes dans le co-polyaminoacide sont issues de procédés de formation de liaison amide utilisés pour la synthèse peptidique. [000256] In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid result from processes for forming an amide bond used for peptide synthesis.
[000257] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les liaisons amides présentes dans le co-polyaminoacide sont issues de procédés de formation de liaison amide décrits dans le brevet FR 2,840,614 (Chan, Y. P. ; et al.). [000257] In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid result from processes for forming an amide bond described in patent FR 2,840,614 (Chan, YP; and al.).
[000258] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les liaisons amides présentes dans le co-polyaminoacide entre les chaînes PLG et le radical ou spacer Q[— *]3 et entre le radical ou spacer Q[— *]3 et le radical hydrophobe -Hy sont issues de procédés de formation de liaison amide bien connus de l'homme de l'art. [000258] In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] 3 and between the radical or spacer Q [- *] 3 and the hydrophobic radical -Hy are derived from processes for forming amide bonds well known to those skilled in the art.
[000259] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les liaisons amides présentes dans le co-polyaminoacide entre les chaînes PLG et le radical ou spacer Q[— *]3 et entre le radical ou spacer Q[— *]3 et le radical hydrophobe -Hy sont issues de procédés de formation de liaison amide utilisés pour la synthèse peptidique. [000259] In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] 3 and between the radical or spacer Q [- *] 3 and the hydrophobic radical -Hy are derived from amide bond formation processes used for peptide synthesis.
[000260] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que les liaisons amides présentes dans le co-polyaminoacide entre les chaînes PLG et le radical ou spacer Q[— *]3 et entre le radical ou spacer Q[— *]3 et le radical hydrophobe -Hy sont issues de procédés de formation de liaison amide décrits dans le brevet FR 2,840,614 (Chan, Y. P. ; et al.). [000260] In one embodiment, the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the PLG chains and the radical or spacer Q [- *] 3 and between the radical or spacer Q [- *] 3 and the hydrophobic radical -Hy are derived from processes for forming an amide bond described in patent FR 2,840,614 (Chan, YP; et al.).
[000261] En cours de synthèse des composés intermédiaires -Hy et lors du greffage les techniques classsiques de protection et déprotection sont utilisées : [000261] During the synthesis of the intermediate compounds -Hy and during the grafting, the conventional techniques of protection and deprotection are used:
les une ou plusieurs fonction(s) acide carboxylique libre de -Hy peu(ven)t être sous forme protégée avant le greffage sur le PLG via un groupe protecteur d'acide, cette protection s'effectue par exemple par estérification à l'aide de méthanol, éthanol, alcool benzylique ou t-Butanol. Après le greffage, les fonctions sont déprotégées, c'est-à-dire qu'une réaction de déprotection est réalisée afin que la ou les fonction(s) carboxylique soi(en)t libre(s) ou sous forme de sel de cation alcalin choisi dans le groupe constitué par Na+ et K+. the one or more free carboxylic acid function (s) of -Hy can be in protected form before grafting onto the PLG via an acid protecting group, this protection is carried out for example by esterification using of methanol, ethanol, benzyl alcohol or t-Butanol. After grafting, the functions are deprotected, that is to say that a deprotection reaction is carried out so that the carboxylic function (s) is (are) free or in the form of an alkaline cation salt chosen from the group consisting of Na + and K +.
les unes ou plusieurs fonction(s) amine peu(ven)t être sous forme protégée avant le greffage sur le PLG via un groupe protecteur d'amine, cette protection s'effectue par exemple par une hydrolyse acide ou basique sous chaleur via le groupe phénylméthoxycarbonyle ou le groupe 1,1-diméthyléthoxycarbonyle. Après le greffage, les fonctions sont déprotégées, c'est-à-dire qu'une réaction de déprotection est réalisée afin que la ou les fonction(s) amine soi(en)t libre(s). [000262] Dans la suite, les unités utilisées sont pour les insulines celles recommandées par les pharmacopées dont les correspondances en mg/ml sont données dans le tableau ci-après : one or more amine function (s) can be in protected form before grafting onto the PLG via an amine protecting group, this protection is carried out for example by acidic or basic hydrolysis under heat via the group phenylmethoxycarbonyl or the 1,1-dimethylethoxycarbonyl group. After grafting, the functions are deprotected, that is to say that a deprotection reaction is carried out so that the amine function (s) is (are) free (s). [000262] In the following, the units used are for the insulins those recommended by the pharmacopoeias whose correspondences in mg / ml are given in the table below:
Figure imgf000038_0001
[000263] On entend par insuline basale dont le point isoélectrique est compris entre
Figure imgf000038_0001
[000263] Basal insulin is understood to mean the isoelectric point of which is between
5,8 et 8,5 une insuline insoluble à pH 7 et dont la durée d'action est comprise entre 8 et 24 heures ou supérieure dans les modèles standards de diabète. 5.8 and 8.5 an insulin insoluble at pH 7 and whose duration of action is between 8 and 24 hours or more in standard models of diabetes.
[000264] Ces insulines basales dont le point isoélectrique est compris entre 5,8 et 8,5 sont des insulines recombinantes dont la structure primaire a été modifiée principalement par introduction d'aminoacides basiques comme l'Arginine ou la Lysine. Elles sont décrites par exemple dans les brevets, demandes de brevets ou publications suivants WO 2003/053339, WO 2004/096854, US 5,656,722 et US 6,100,376 dont le contenu est incorporé par référence. [000264] These basal insulins, the isoelectric point of which is between 5.8 and 8.5, are recombinant insulins the primary structure of which has been modified mainly by the introduction of basic amino acids such as arginine or lysine. They are described for example in the following patents, patent applications or publications WO 2003/053339, WO 2004/096854, US 5,656,722 and US 6,100,376, the content of which is incorporated by reference.
[000265] Dans un mode de réalisation, l'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 est l'insuline glargine. L'insuline glargine est commercialisée sous la marque Lantus® (100 U/ml) ou Toujeo® (300 U/ml) par SAIMOFI. [000265] In one embodiment, the basal insulin, the isoelectric point of which is between 5.8 and 8.5, is insulin glargine. Insulin glargine is marketed under the brand Lantus ® (100 U / ml) or Toujeo ® (300 U / ml) by SAIMOFI.
[000266] Dans un mode de réalisation, l'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 est une insuline glargine biosimilaire. [000267] Une insuline glargine biosimilaire est en voie de commercialisation sous la marque Abasaglar® ou Basaglar® par ELI LILLY. [000266] In one embodiment, the basal insulin, the isoelectric point of which is between 5.8 and 8.5, is a biosimilar insulin glargine. [000267] A biosimilar Insulin glargine is being commercialized under the brand Abasaglar ® or Basaglar ® by Eli Lilly.
[000268] Dans un mode de réalisation, les compositions selon l'invention comprennent entre 40 et 500 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000268] In one embodiment, the compositions according to the invention comprise between 40 and 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000269] Dans un mode de réalisation, les compositions selon l'invention comprennent 40 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000269] In one embodiment, the compositions according to the invention comprise 40 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000270] Dans un mode de réalisation, les compositions selon l'invention comprennent 100 U/mL (soit environ 3,6 mg/mL) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000270] In one embodiment, the compositions according to the invention comprise 100 U / mL (ie approximately 3.6 mg / mL) of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000271] Dans un mode de réalisation, les compositions selon l'invention comprennent 150 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000271] In one embodiment, the compositions according to the invention comprise 150 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000272] Dans un mode de réalisation, les compositions selon l'invention comprennent 200 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000272] In one embodiment, the compositions according to the invention comprise 200 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000273] Dans un mode de réalisation, les compositions selon l'invention comprennent 225 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000273] In one embodiment, the compositions according to the invention comprise 225 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000274] Dans un mode de réalisation, les compositions selon l'invention comprennent 250 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000274] In one embodiment, the compositions according to the invention comprise 250 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000275] Dans un mode de réalisation, les compositions selon l'invention comprennent 300 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000275] In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000276] Dans un mode de réalisation, les compositions selon l'invention comprennent 400 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000276] In one embodiment, the compositions according to the invention comprise 400 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000277] Dans un mode de réalisation, les compositions selon l'invention comprennent 500 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000277] In one embodiment, the compositions according to the invention comprise 500 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
[000278] Dans un mode de réalisation, le ratio massique entre l'insuline basale, dont le point isoélectrique est compris entre 5,8 et 8,5, et le co-polyaminoacide, soit co- polyaminoacide/insuline basale, est compris entre 0,2 et 8. [000278] In one embodiment, the mass ratio between basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the co-polyamino acid, or co-polyamino acid / basal insulin, is between 0.2 and 8.
[000279] Dans un mode de réalisation, le ratio massique est compris entre 0,5 et 6. [000279] In one embodiment, the mass ratio is between 0.5 and 6.
[000280] Dans un mode de réalisation, le ratio massique est compris entre 0,8 et 5. [000281] Dans un mode de réalisation, le ratio massique est compris entre 1 et 4. [000280] In one embodiment, the mass ratio is between 0.8 and 5. [000281] In one embodiment, the mass ratio is between 1 and 4.
[000282] Dans un mode de réalisation, le ratio massique est compris entre 1 et 3. [000282] In one embodiment, the mass ratio is between 1 and 3.
[000283] Dans un mode de réalisation, le ratio massique est compris entre 1 et 2. [000284] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 40 mg/mL. [000283] In one embodiment, the mass ratio is between 1 and 2. [000284] In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 40 mg / mL .
[000285] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 20 mg/mL. [000285] In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 20 mg / ml.
[000286] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 10 mg/mL. [000286] In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 10 mg / ml.
[000287] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus 5 mg/ml . [000287] In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 5 mg / ml.
[000288] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus 2,5 mg/ml. [000288] In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 2.5 mg / ml.
[000289] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 0,01 à 100 mg/mL. [000289] In one embodiment, the concentration of liraglutide is within a range of 0.01 to 100 mg / mL.
[000290] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 0,01 à 40 mg/mL. [000290] In one embodiment, the concentration of liraglutide is within a range of 0.01 to 40 mg / mL.
[000291] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 0,01 à 30 mg/mL. [000291] In one embodiment, the concentration of liraglutide is within a range of 0.01 to 30 mg / mL.
[000292] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 1 à 100 mg/mL. [000292] In one embodiment, the concentration of liraglutide is within a range of 1 to 100 mg / mL.
[000293] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 1 à 40 mg/mL. [000293] In one embodiment, the concentration of liraglutide is within a range of 1 to 40 mg / mL.
[000294] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 1 à 30 mg/mL. [000294] In one embodiment, the concentration of liraglutide is within a range of 1 to 30 mg / mL.
[000295] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 5 à 100 mg/mL. [000295] In one embodiment, the concentration of liraglutide is in a range of 5 to 100 mg / mL.
[000296] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 5 à 40 mg/mL. [000296] In one embodiment, the concentration of liraglutide is within a range of 5 to 40 mg / mL.
[000297] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 5 à 30 mg/mL. [000297] In one embodiment, the concentration of liraglutide is within a range of 5 to 30 mg / mL.
[000298] Dans un mode de réalisation, la concentration en liraglutide est comprise dans un intervalle de 5 à 20 mg/mL. [000298] In one embodiment, the concentration of liraglutide is within a range of 5 to 20 mg / mL.
[000299] Dans un mode de réalisation, les compositions selon l'invention comprennent entre 40 U/mL et 500 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 et, de 1 à 75 mg/mL de liraglutide. [000300] Dans un mode de réalisation, les compositions selon l'invention comprennent 400 U/mL d'insuline basale dont le point isoélectrique est compris entre[000299] In one embodiment, the compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 75 mg / mL of liraglutide. [000300] In one embodiment, the compositions according to the invention comprise 400 U / ml of basal insulin, the isoelectric point of which is between
5,8 et 8,5 et, de 8 à 40 mg/mL de liraglutide. 5.8 and 8.5 and, 8 to 40 mg / mL of liraglutide.
[000301] Dans un mode de réalisation, les compositions selon l'invention comprennent 300 U/mL d'insuline basale dont le point isoélectrique est compris entre [000301] In one embodiment, the compositions according to the invention comprise 300 U / ml of basal insulin, the isoelectric point of which is between
5,8 et 8,5 et, de 6 à 30 mg/mL de liraglutide. 5.8 and 8.5, and from 6 to 30 mg / mL of liraglutide.
[000302] Dans un mode de réalisation, les compositions selon l'invention comprennent 200 U/mL d'insuline basale dont le point isoélectrique est compris entre [000302] In one embodiment, the compositions according to the invention comprise 200 U / ml of basal insulin, the isoelectric point of which is between
5,8 et 8,5 et, de 4 à 20 mg/mL de liraglutide. 5.8 and 8.5 and, from 4 to 20 mg / mL of liraglutide.
[000303] Dans un mode de réalisation, les compositions selon l'invention comprennent 100 U/mL (soit environ 3,6 mg/mL) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 et, de 2 à 10 mg/mL de liraglutide. [000303] In one embodiment, the compositions according to the invention comprise 100 U / mL (or approximately 3.6 mg / mL) of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, 2 to 10 mg / mL of liraglutide.
[000304] Dans un mode de réalisation, les compositions selon l'invention comprennent 40 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 et, de 1 à 10 mg/mL de liraglutide. [000304] In one embodiment, the compositions according to the invention comprise 40 U / ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and, from 1 to 10 mg / ml of liraglutide.
[000305] Dans un mode de réalisation, les compositions selon l'invention comprennent de 1 à 15 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000305] In one embodiment, the compositions according to the invention comprise from 1 to 15 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
[000306] Dans un mode de réalisation, les compositions selon l'invention comprennent de 2 à 10 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000306] In one embodiment, the compositions according to the invention comprise from 2 to 10 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
[000307] Dans un mode de réalisation, les compositions selon l'invention comprennent de 3 à 8 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000307] In one embodiment, the compositions according to the invention comprise from 3 to 8 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
[000308] Dans un mode de réalisation, les compositions selon l'invention comprennent de 2 à 5 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000308] In one embodiment, the compositions according to the invention comprise from 2 to 5 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
[000309] Dans un mode de réalisation, les compositions selon l'invention comprennent de 3 à 5 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000309] In one embodiment, the compositions according to the invention comprise from 3 to 5 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
[000310] Dans un mode de réalisation, les compositions selon l'invention comprennent de 3 à 4 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000310] In one embodiment, the compositions according to the invention comprise from 3 to 4 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
[000311] Dans un mode de réalisation, les compositions selon l'invention comprennent de 5 à 8 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000312] Dans un mode de réalisation, les compositions selon l'invention comprennent de 3,0 à 4,2 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. In one embodiment, the compositions according to the invention comprise from 5 to 8 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin whose isoelectric point is between 5.8 and 8 , 5. [000312] In one embodiment, the compositions according to the invention comprise from 3.0 to 4.2 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5 , 8 and 8.5.
[000313] Dans un mode de réalisation, les compositions selon l'invention comprennent de 3,2 à 4,0 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000313] In one embodiment, the compositions according to the invention comprise from 3.2 to 4.0 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5 , 8 and 8.5.
[000314] Dans un mode de réalisation, les compositions selon l'invention comprennent de 3,4 à 3,8 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000314] In one embodiment, the compositions according to the invention comprise from 3.4 to 3.8 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5 , 8 and 8.5.
[000315] Dans un mode de réalisation, les compositions selon l'invention comprennent de 3,6 mg de liraglutide pour 100 U (soit environ 3,6 mg) d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. [000315] In one embodiment, the compositions according to the invention comprise 3.6 mg of liraglutide per 100 U (ie approximately 3.6 mg) of basal insulin, the isoelectric point of which is between 5.8 and 8 , 5.
[000316] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 0 et 5000 mM. [000316] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 0 and 5000 mM.
[000317] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 0 et 4000 mM. [000317] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 0 and 4000 mM.
[000318] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 0 et 3000 pM. [000318] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 0 and 3000 pM.
[000319] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 0 et 2000 pM. [000319] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 0 and 2000 pM.
[000320] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 0 et 1000 pM . [000320] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 0 and 1000 pM.
[000321] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 50 et 600 pM. [000321] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 50 and 600 pM.
[000322] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 100 et 500 pM. [000322] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 100 and 500 pM.
[000323] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 200 et 500 pM . [000323] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 200 and 500 pM.
[000324] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 500 et 2000 pM. [000324] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration between 500 and 2000 pM.
[000325] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 800 et 1500 pM. [000326] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 1000 et 1500 mM. [000325] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 800 and 1500 pM. [000326] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 1000 and 1500 mM.
[000327] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des sels de zinc à une concentration comprise entre 1100 et 1300 mM. [000327] In one embodiment, the compositions according to the invention further comprise zinc salts at a concentration of between 1100 and 1300 mM.
[000328] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des tampons. [000328] In one embodiment, the compositions according to the invention further comprise buffers.
[000329] Dans un mode de réalisation, les compositions selon l'invention comprennent des tampons à des concentrations comprises entre 0 et 100 mM. [000329] In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM.
[000330] Dans un mode de réalisation, les compositions selon l'invention comprennent des tampons à des concentrations comprises entre 15 et 50 mM . [000330] In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 15 and 50 mM.
[000331] Dans un mode de réalisation, les compositions selon l'invention comprennent un tampon choisi dans le groupe constitué par un tampon phosphate, le Tris (trishydroxyméthylaminométhane) et le citrate de sodium. [000331] In one embodiment, the compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer, Tris (trishydroxymethylaminomethane) and sodium citrate.
[000332] Dans un mode de réalisation, le tampon est le phosphate de sodium. [000332] In one embodiment, the buffer is sodium phosphate.
[000333] Dans un mode de réalisation, le tampon est le Tris [000333] In one embodiment, the buffer is Tris
(trishydroxyméthylaminométhane). (trishydroxymethylaminomethane).
[000334] Dans un mode de réalisation, le tampon est le citrate de sodium. [000334] In one embodiment, the buffer is sodium citrate.
[000335] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des conservateurs. [000335] In one embodiment, the compositions according to the invention further comprise preservatives.
[000336] Dans un mode de réalisation, les conservateurs sont choisis dans le groupe constitué par le m-crésol et le phénol, seuls ou en mélange. [000336] In one embodiment, the preservatives are chosen from the group consisting of m-cresol and phenol, alone or as a mixture.
[000337] Dans un mode de réalisation, le conservateur est du m-crésol. [000337] In one embodiment, the preservative is m-cresol.
[000338] Dans un mode de réalisation, la concentration des conservateurs est comprise entre 10 et 50 mM . [000338] In one embodiment, the concentration of the preservatives is between 10 and 50 mM.
[000339] Dans un mode de réalisation, la concentration des conservateurs est comprise entre 10 et 40 mM. [000339] In one embodiment, the concentration of preservatives is between 10 and 40 mM.
[000340] Dans un mode de réalisation, la concentration des conservateurs est comprise entre 20 et 40 mM. [000340] In one embodiment, the concentration of the preservatives is between 20 and 40 mM.
[000341] Dans un mode de réalisation, la concentration des conservateurs est comprise entre 20 et 35 mM. [000341] In one embodiment, the concentration of the preservatives is between 20 and 35 mM.
[000342] Dans un mode de réalisation, la concentration des conservateurs est comprise entre 25 et 30 mM . [000342] In one embodiment, the concentration of the preservatives is between 25 and 30 mM.
[000343] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre un tensioactif. [000344] Dans un mode de réalisation, le tensioactif est choisi dans le groupe constitué par le propylène glycol et le polysorbate. [000343] In one embodiment, the compositions according to the invention further comprise a surfactant. [000344] In one embodiment, the surfactant is chosen from the group consisting of propylene glycol and polysorbate.
[000345] Les compositions selon l'invention peuvent en outre comprendre des additifs tels que des agents de tonicité. [000345] The compositions according to the invention can further comprise additives such as tonicity agents.
[000346] Dans un mode de réalisation, les agents de tonicité sont choisis dans le groupe constitué par la glycérine, le chlorure de sodium, le mannitol et la glycine. [000346] In one embodiment, the tonicity agents are chosen from the group consisting of glycerin, sodium chloride, mannitol and glycine.
[000347] Dans un mode de réalisation, les agents de tonicité sont choisis dans le groupe constitué par la glycérine, le chlorure de sodium, le mannitol et la glycine. [000347] In one embodiment, the tonicity agents are chosen from the group consisting of glycerin, sodium chloride, mannitol and glycine.
[000348] Dans un mode de réalisation, la composition comprend de la glycérine. [000348] In one embodiment, the composition comprises glycerin.
[000349] Dans un mode de réalisation, la composition comprend de la glycérine en une concentration comprise entre 100 et 450 mM . [000349] In one embodiment, the composition comprises glycerin in a concentration of between 100 and 450 mM.
[000350] Dans un mode de réalisation, la composition comprend de la glycérine en une concentration comprise entre 150 et 300 mM. [000350] In one embodiment, the composition comprises glycerin in a concentration of between 150 and 300 mM.
[000351] Dans un mode de réalisation, la composition comprend de la glycérine en une concentration comprise entre 200 et 250 mM ; Les compositions selon l'invention peuvent comprendre en outre tous les excipients conformes aux pharmacopées et compatibles avec les insulines utilisées aux concentrations d'usage. [000351] In one embodiment, the composition comprises glycerin in a concentration of between 200 and 250 mM; The compositions according to the invention can also comprise all the excipients in accordance with the pharmacopoeias and compatible with the insulins used at the usual concentrations.
[000352] L'invention concerne également une formulation pharmaceutique selon l'invention, caractérisée en ce qu'elle est obtenue par séchage et/ou lyophilisation . [000352] The invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
[000353] Dans le cas des libérations locale et systémique, les modes d'administration envisagés sont par voie intraveineuse, sous-cutanée, intradermique ou intramusculaire. [000353] In the case of local and systemic releases, the modes of administration envisaged are by intravenous, subcutaneous, intradermal or intramuscular route.
[000354] Les voies d'administration transdermique, orale, nasale, vaginale, oculaire, buccale, pulmonaire sont également envisagées. [000354] The transdermal, oral, nasal, vaginal, ocular, buccal, pulmonary administration routes are also envisaged.
[000355] L'invention concerne également des formulations unidoses à pH compris entre 6,0 et 8,0 comprenant une insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 et du liraglutide. [000355] The invention also relates to single-dose formulations with a pH of between 6.0 and 8.0 comprising a basal insulin, the isoelectric point of which is between 5.8 and 8.5 and liraglutide.
[000356] L'invention concerne également des formulations unidoses à pH compris entre 6,6 et 7,8 comprenant une insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 et du liraglutide. [000356] The invention also relates to single-dose formulations at a pH of between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and liraglutide.
[000357] L'invention concerne également formulations unidoses à pH compris entre [000357] The invention also relates to single-dose formulations at a pH of between
6.8 et 7,6 comprenant une insuline basale dont le point isoélectrique est compris entre6.8 and 7.6 comprising a basal insulin whose isoelectric point is between
5.8 et 8,5 et du liraglutide. 5.8 and 8.5 and liraglutide.
[000358] Dans un mode de réalisation, les formulations unidoses comprennent en outre un co-polyaminoacide tel que défini précédemment. [000358] In one embodiment, the single-dose formulations further comprise a co-polyamino acid as defined above.
[000359] Dans un mode de réalisation, les formulations sont sous forme d'une solution injectable. [000360] Dans un mode de réalisation, l'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 est l'insuline glargine. [000359] In one embodiment, the formulations are in the form of an injectable solution. [000360] In one embodiment, the basal insulin, the isoelectric point of which is between 5.8 and 8.5, is insulin glargine.
[000361] Le pH des compositions selon l'invention est compris entre 6,0 et 8,0, de[000361] The pH of the compositions according to the invention is between 6.0 and 8.0, from
5 préférence compris entre 6,6 et 7,8 ou encore plus préférentiellement entre 6,8 et 7,6. 5 preferably between 6.6 and 7.8 or even more preferably between 6.8 and 7.6.
[000362] Ledit co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes Hy est soluble en solution aqueuse à pH compris entre 6,0 et 8,0, à une température de 25 °C et à une concentration inférieure à 100 mg/ml. Said co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals is soluble in aqueous solution at pH between 6.0 and 8.0, at a temperature of 25 ° C and at a concentration of less than 100 mg / ml .
[000363] Ledit co-polyaminoacide porteur de charges carboxylates et de radicaux [000363] Said co-polyamino acid carrying carboxylate charges and radicals
10 hydrophobes Hy est soluble en solution aqueuse à pH compris entre 6,0 et 8,0, à une température de 25 °C et à une concentration inférieure à 60 mg/ml. Hydrophobic Hy is soluble in aqueous solution at pH between 6.0 and 8.0, at a temperature of 25 ° C and at a concentration below 60 mg / ml.
[000364] Dans les formules, les * indiquent les sites de rattachement des radicaux hydrophobes au P LG ou entre les différents groupes GpR, GpG, GpH, GpA, GpL et GpC pour former des fonctions amides [000364] In the formulas, the * indicate the sites of attachment of the hydrophobic radicals to P LG or between the different groups GpR, GpG, GpH, GpA, GpL and GpC to form amide functions
15 [000365] On entend par « composition stable physiquement » des compositions qui satisfont aux critères de l'inspection visuelle décrite dans la pharmacopée européenne, américaine et internationale, c'est-à-dire des compositions qui sont claires et qui ne contiennent pas de particules visibles, mais également incolores. [000365] The term "physically stable composition" is understood to mean compositions which meet the criteria of visual inspection described in the European, American and International Pharmacopoeia, that is to say compositions which are clear and which do not contain visible particles, but also colorless.
[000366] On entend par « solution aqueuse injectable » des solutions dont le solvant [000366] The term “injectable aqueous solution” is understood to mean solutions in which the solvent
» est l'eau et qui satisfont aux conditions des pharmacopées EP et US. Is water and which meet the conditions of the EP and US pharmacopoeias.
[000367] Les compositions sous forme d'une solution aqueuse injectable selon l'invention sont des solutions limpides. On entend pa r « solution limpide », des compositions qui satisfont aux critères décrits dans les pharmacopées américaine et européenne concernant les solutions injectables. Dans la pharmacopée US, les solutions [000367] The compositions in the form of an injectable aqueous solution according to the invention are clear solutions. The term “clear solution” is understood to mean compositions which meet the criteria described in the American and European pharmacopoeias relating to injectable solutions. In the US pharmacopoeia, solutions
25 sont définies dans la partie < 1151 > faisant référence à l'injection < 1 > (faisant référence à <788> selon USP 35 et précisé dans <788> selon USP 35 et dans <787>, <788> et <790> USP 38 (à partir du 1er août 2014), selon USP 38) . Dans la pharmacopée européenne, les solutions injectables doivent remplir les critères donnés dans les sections 2.9.19 et 2.9.20. 25 are defined in part <1151> referring to injection <1> (referring to <788> according to USP 35 and specified in <788> according to USP 35 and in <787>, <788> and <790> USP 38 (from 1 August 2014), according to USP 38). In the European Pharmacopoeia, solutions for injection must meet the criteria given in sections 2.9.19 and 2.9.20.
30 [000368] On entend par « co-polyaminoacide étant constitué d'unités glutamiques ou aspartiques » des enchaînements linéaires non cycliques d'unités acide glutamique ou acide aspartique liées entre elles par des liaisons peptidiques, lesdits enchaînements présentant une partie C-terminale, correspondant à l'acide carboxylique d'une extrémité, et une partie N-terminale, correspondant à l'amine de l'autre extrémité de [000368] The term “co-polyamino acid consisting of glutamic or aspartic units” is understood to mean non-cyclic linear chains of glutamic acid or aspartic acid units linked together by peptide bonds, said chains having a C-terminal part, corresponding to the carboxylic acid of one end, and an N-terminal part, corresponding to the amine of the other end of
35 l'enchaînement. 35 the sequence.
[000369] On entend par « soluble », susceptible de permettre de préparer une solution limpide et dépourvue de particules dans de l'eau distillée à 25 °C. Partie A - Synthèse des composés intermédiaires hydrophobes Hvd et des composés intermédiaires Hvd liés au soacer permettant d'obtenir les radicaux OGHnΊ The term "soluble" means, capable of making it possible to prepare a clear solution free of particles in distilled water at 25 ° C. Part A - Synthesis of the hydrophobic intermediate compounds Hvd and of the intermediate compounds Hvd linked to the soacer allowing to obtain the radicals OGHnΊ
[000370] Les composés intermédiaires hydrophobes Hyd et les composés intermédiaires Hyd liés au spacer Q-Hyd sont représentés dans le tableau ci-dessous par la molécule hydrophobe correspondante avant greffage sur le co-polyaminoacide. [000370] The hydrophobic intermediate compounds Hyd and the intermediate compounds Hyd linked to the spacer Q-Hyd are represented in the table below by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000048_0001
Tableau 1 Liste des composés intermédiaires Hyd et des composés intermédiaires Q- Hyd obtenus avant greffage. Exemple Al : molécule Al Table 1 List of intermediate compounds Hyd and of intermediate compounds Q — Hyd obtained before grafting. Example Al: Al molecule
Molécule 1 : Produit obtenu par la réaction entre le chlorure de myristoyle et la L-proline Molecule 1: Product obtained by the reaction between myristoyl chloride and L-proline
[000371] À une solution de L-proline (300,40 g, 2,61 mol) dans de la soude aqueuse 2 N (1,63 L) à 0 °C est ajouté lentement sur 1 h du chlorure de myristoyle (322 g, 1,30 mol) en solution dans du dichlorométhane (DCM, 1,63 L) . À la fin de l'ajout, la température du milieu réactionnel est remontée à 20 °C en 3 h, et l'agitation est poursuivie 2 h supplémentaires. Le mélange est refroidi à 0 °C puis une solution aqueuse de HCl à 37 % (215 mL) est ajoutée en 15 min. Le milieu réactionnel est agité pendant 1 h entre 0 °C et 20 °C. La phase organique est séparée, lavée avec une solution aqueuse de HCl 10 % (3 x 430 mL), une solution aqueuse saturée en NaCI (430 mL), séchée sur Na2SÛ4, filtrée sur coton puis concentrée sous pression réduite. Le résidu est solubilisé dans de l'heptane ( 1,31 L) à 50 °C, puis la solution est ramenée progressivement à température ambiante. Après amorçage de la cristallisation à l'aide d'une tige en verre, le milieu est à nouveau chauffé à 40 °C pendant 30 min puis ramené à température ambiante pendant 4 h . Un solide blanc est obtenu après filtration sur fritté, lavage à l'heptane (2 x 350 mL) et séchage sous pression réduite. [000371] To a solution of L-proline (300.40 g, 2.61 mol) in 2N aqueous sodium hydroxide (1.63 L) at 0 ° C is slowly added over 1 h of myristoyl chloride (322 g, 1.30 mol) dissolved in dichloromethane (DCM, 1.63 L). At the end of the addition, the temperature of the reaction medium rose to 20 ° C. over 3 h, and stirring was continued for a further 2 h. The mixture is cooled to 0 ° C. then an aqueous 37% HCl solution (215 mL) is added over 15 min. The reaction medium is stirred for 1 h between 0 ° C and 20 ° C. The organic phase is separated, washed with an aqueous solution of 10% HCl (3 x 430 mL), a saturated aqueous solution of NaCl (430 mL), dried over Na2SO4, filtered through cotton wool and then concentrated under reduced pressure. The residue is dissolved in heptane (1.31 L) at 50 ° C., then the solution is gradually brought back to room temperature. After initiation of crystallization using a glass rod, the medium is again heated to 40 ° C. for 30 min and then brought back to room temperature for 4 h. A white solid is obtained after filtration on a frit, washing with heptane (2 × 350 mL) and drying under reduced pressure.
Rendement : 410 g (97 %) Yield: 410 g (97%)
LC/MS (ESI) : 326,4 ; 651,7 ; (calculé ([M + H]+) : 326,3 ; ([2M + H]+) : 651,6). LC / MS (ESI): 326.4; 651.7; (calcd ([M + H] + ): 326.3; ([2M + H] + ): 651.6).
Molécule 2 : produit obtenu par la réaction entre la spermidine et le benzyl phényl carbonate Molecule 2: product obtained by the reaction between spermidine and benzyl phenyl carbonate
[000372] A une solution de spermidine ( 10 g, 68,8 mmol) dans le DMF (70 mL) est ajouté du benzyl phényl carbonate (34,6 g, 151 mmol) et le milieu réactionnel est agité pendant 16 h à température ambiante, puis introduit dans du tampon phosphate 0,025 M (2 L). Le pH est ajusté à 3 avec une solution d'acide sulfurique 2 M et lavée par du DCM. Le pH de la phase aqueuse est ajusté à 12 avec une solution de NaOH 9 M et le produit est extrait au DCM. La phase organique est séchée sur NazSC , filtré sur fritté puis concentrée sous vide. La molécule 2 est obtenue sous forme den solide blanc de après séchage sous pression réduite. Benzyl phenyl carbonate (34.6 g, 151 mmol) is added to a solution of spermidine (10 g, 68.8 mmol) in DMF (70 mL) and the reaction medium is stirred for 16 h at temperature ambient, then introduced into 0.025 M phosphate buffer (2 L). The pH is adjusted to 3 with a 2 M sulfuric acid solution and washed with DCM. The pH of the aqueous phase is adjusted to 12 with a 9 M NaOH solution and the product is extracted with DCM. The organic phase is dried over NazSC, filtered through a frit and then concentrated under vacuum. Molecule 2 is obtained in the form of a white solid after drying under reduced pressure.
Rendement : 18,5 g (65 %) Yield: 18.5 g (65%)
LC/MS (ESI) : 414,3 ; (calculé ([M+ H]+) : 414,2) . LC / MS (ESI): 414.3; (calculated ([M + H] + ): 414.2).
Molécule 3 : produit obtenu par synthèse sur support solide Molecule 3: product obtained by synthesis on a solid support
[000373] La molécule 3 est obtenue par la méthode conventionnelle de synthèse peptidique en phase solide (SPPS) sur résine 2-chlorotrityle chloride (CTC) (11,1 g, 1 ,24 mmol/g) . [000374] Le greffage du premier acide aminé Fmoc-Lys(Fmoc)-OH (20,3 g, 34,4 mmol, 2,5 équivalents) sur la résine (11 g) est effectué dans le DCM (15 V), en présence de N,IM-diisopropyléthylamine (DIPEA, 5,0 équivalents). Les sites n'ayant pas réagi sont « cappés » au méthanol (0,8 mL/g résine) en fin de réaction. Les couplages des acides aminés protégés Fmoc-Glu(OtBu)-OH (5,0 équivalents) et de la molécule 1 (5,0 équivalents) sont effectués dans le DMF (15 V), en présence de 1-[000373] Molecule 3 is obtained by the conventional method of solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride (CTC) resin (11.1 g, 1.24 mmol / g). [000374] The grafting of the first amino acid Fmoc-Lys (Fmoc) -OH (20.3 g, 34.4 mmol, 2.5 equivalents) on the resin (11 g) is carried out in DCM (15 V), in the presence of N, IM-diisopropylethylamine (DIPEA, 5.0 equivalents). The unreacted sites are “capped” with methanol (0.8 mL / g resin) at the end of the reaction. The couplings of the protected amino acids Fmoc-Glu (OtBu) -OH (5.0 equivalents) and of molecule 1 (5.0 equivalents) are carried out in DMF (15 V), in the presence of 1-
[bis(dimethylamino)methyèlene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1,0 équivalent par rapport à l'acide) et de N,N - diisopropyléthylamine (DIPEA, 2,0 équivalents par rapport à l'acide). Les groupements protecteurs Fmoc sont retirés à l'aide d'une solution de DMF/pipéridine 80 : 20 (15 V). Le produit est clivé de la résine à l'aide d'une solution de DCM/HFIP 80 : 20 (15 V) . [bis (dimethylamino) methyelene] -lH-l, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 1.0 equivalent with respect to the acid) and N, N - diisopropylethylamine (DIPEA, 2.0 equivalents based on acid). The Fmoc protecting groups are removed using an 80:20 (15 V) DMF / piperidine solution. The product is cleaved from the resin using an 80:20 (15 V) DCM / HFIP solution.
[000375] Après concentration sous pression réduite, deux co-évaporations sont effectuées sur le résidu avec du DCM puis le produit est purifié par chromatographie sur gel de silice (éluant : DCM, méthanol). La molécule 3 est obtenue sous forme de solide blanc. After concentration under reduced pressure, two co-evaporations are carried out on the residue with DCM then the product is purified by chromatography on silica gel (eluent: DCM, methanol). Molecule 3 is obtained in the form of a white solid.
Rendement : 13,4 g (65 %) Yield: 13.4 g (65%)
LC/ MS (ESI) : 1524,1 (calculé ([M + Na] + ) : 1524,0). LC / MS (ESI): 1524.1 (calcd ([M + Na] +): 1524.0).
Molécule 4 : produit obtenu par le couplage entre la molécule 2 et la molécule 3 Molecule 4: product obtained by the coupling between molecule 2 and molecule 3
[000376] A une solution de molécule 3 (12,0 g, 8,0 mmol) dans le chloroforme (150 mL) sont ajoutés successivement de la triéthylamine (1,05 g, 10,4 mmol), du 1 - hydroxybenzotriazole (HOBt, 1,41 g, 10,4 mmol) et du chlorhydrate de N-(3- diméthylaminopropyl)-N'-éthylcarbodiimide (EDC.HCI, 2,0 g, 10,4 mmol). Après 15 min, la molécule 2 (3,6 g, 8,7 mmol) est ajoutée et le milieu réactionnel est agité pendant 18 h à température ambiante. La phase organique est lavée successivement avec une solution aqueuse saturée en NH4CI ( 150 mL), une solution aqueuse saturée en NaHC03 (150 mL), une solution aqueuse saturée en NaCI (150 mL), séchée sur MgS04, filtrée et concentrée sous pression réduite. La molécule 4 est obtenue sous forme de solide blanc après purification par chromatographie sur gel de silice (éluant : DCM, méthanol). Rendement : 11,4 g (75 %) To a solution of molecule 3 (12.0 g, 8.0 mmol) in chloroform (150 mL) are successively added triethylamine (1.05 g, 10.4 mmol), 1 - hydroxybenzotriazole ( HOBt, 1.41 g, 10.4 mmol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC.HCl, 2.0 g, 10.4 mmol). After 15 min, molecule 2 (3.6 g, 8.7 mmol) is added and the reaction medium is stirred for 18 h at room temperature. The organic phase is washed successively with a saturated aqueous solution of NH4Cl (150 mL), a saturated aqueous solution of NaHCO3 (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4, filtered and concentrated under reduced pressure. . Molecule 4 is obtained in the form of a white solid after purification by chromatography on silica gel (eluent: DCM, methanol). Yield: 11.4 g (75%)
LC/ MS (ESI) : 1897,2 ; (calculé ([M + H] + ) : 1897,3). LC / MS (ESI): 1897.2; (calculated ([M + H] +): 1897.3).
Molécule Al : produit obtenu par hydrogénolyse de la molécule 4 Molecule Al: product obtained by hydrogenolysis of molecule 4
[000377] Une solution de molécule 4 (8,1 g, 4,3 mmol) dans du DMAc (81 mL) en présence de palladium sur alumine 5 % (0,81 g) est placée sous 10 bar d'hydrogène à température ambiante. Après une nuit, le milieu réactionnel est filtré sur fritté puis sur membrane 0,2 pm, et le filtrat est concentré sous pression réduite pour donner la molécule Al . Rendement : 6,6 g (95 %) [000377] A solution of molecule 4 (8.1 g, 4.3 mmol) in DMAc (81 mL) in the presence of 5% palladium on alumina (0.81 g) is placed under 10 bar of hydrogen at temperature. ambient. After one night, the reaction medium is filtered on a frit and then on a 0.2 μm membrane, and the filtrate is concentrated under reduced pressure to give the Al molecule. Yield: 6.6 g (95%)
LC/MS (ESI) : 1629,1 ; (calculé ([M+H]+) : 1629,2). LC / MS (ESI): 1629.1; (calculated ([M + H] + ): 1629.2).
Exemple A2 : molécule A2 Example A2: molecule A2
Molécule 5 : produit obtenu par synthèse sur support solide Molecule 5: product obtained by synthesis on a solid support
[Chem 18] [Chem 18]
Figure imgf000051_0001
Figure imgf000051_0001
[000378] Par un procédé similaire à celui utilisé pour la molécule 3, un solide blanc de la molécule 5 est obtenu. By a process similar to that used for molecule 3, a white solid of molecule 5 is obtained.
Rendement : 9,2 g (50 %) Yield: 9.2 g (50%)
LC/MS (ESI+) : 1894,2 (calculé ([M+ Na]+) : 1894,2). LC / MS (ESI +): 1894.2 (calcd ([M + Na] + ): 1894.2).
[000379] [000379]
Molécule 6 : produit obtenu par couplage entre la molécule 5 et la molécule 2. Molecule 6: product obtained by coupling between molecule 5 and molecule 2.
[000380] Par un procédé similaire à celui utilisé pour la molécule 4 appliqué à la molécule 5 (8 g, 4,3 mmol) et à la molécule 2 (2,0 g, 4,8 mmol), la molécule 6 est obtenue sous forme de solide blanc. [000380] By a method similar to that used for molecule 4 applied to molecule 5 (8 g, 4.3 mmol) and to molecule 2 (2.0 g, 4.8 mmol), molecule 6 is obtained as a white solid.
Rendement : 6,5 g (67 %) Yield: 6.5 g (67%)
LC/MS (ESI+) : 2267,3 (calculé ([M+H]+) : 2267,5). LC / MS (ESI +): 2267.3 (calcd ([M + H] + ): 2267.5).
Molécule A2 : produit obtenu par hydrogénolyse de la molécule 6 Molecule A2: product obtained by hydrogenolysis of molecule 6
[000381] Par un procédé similaire à celui utilisé pour la molécule Al appliqué à la molécule 6 (6,0 g, 2,6 mmol), la molécule A2 est obtenue sous forme de solide blanc. Rendement : 4,8 g (93 %) By a process similar to that used for the Al molecule applied to the 6 molecule (6.0 g, 2.6 mmol), the A2 molecule is obtained in the form of a white solid. Yield: 4.8 g (93%)
LC/MS (ESI) : 1999,4 ; (calculé ([M+H]+) : 1999,4). Exemple A3 : molécule A3 LC / MS (ESI): 1999.4; (calculated ([M + H] + ): 1999.4). Example A3: molecule A3
Molécule 7 : Produit obtenu par la réaction entre la proline et le chlorure de palmitoyleMolecule 7: Product obtained by the reaction between proline and palmitoyl chloride
[000382] À une solution de L-proline (25,13 g, 218,29 mmol) dans un mélange d'eau ( 121,5 mL) et de NaOH 10 N (27,3 mL, 272,86 mmol) à 0 °C est ajoutée goutte-à- goutte une solution de chlorure de palmitoyle (33 mL, 109, 14 mmol) dans du méthyl- THF ( 138 mL) sous agitation vigoureuse en maintenant la température du milieu réactionnel < 5 °C. Le milieu réactionnel est agité entre 4 °C et 20 °C pendant 1,5 h puis 3 h à température ambiante. Après refroidissement à 0 °C, le pH est ajusté à 1,5 avec de l'acide chlorhydrique concentré (18,2 mL). Le mélange est réchauffé à 20 °C et les phases sont séparées. La phase organique est lavée par une solution aqueuse à 5 % de KHSO4 (3 x 100 mL), de l'eau ( 100 mL) puis concentrée sous pression réduite. Le résidu est ensuite recristallisé dans l'heptane (200 mL). La molécule 3 est obtenue sous forme de solide. To a solution of L-proline (25.13 g, 218.29 mmol) in a mixture of water (121.5 mL) and 10 N NaOH (27.3 mL, 272.86 mmol) at 0 ° C. is added dropwise a solution of palmitoyl chloride (33 mL, 109, 14 mmol) in methyl-THF (138 mL) with vigorous stirring while maintaining the temperature of the reaction medium <5 ° C. The reaction medium is stirred between 4 ° C and 20 ° C for 1.5 h then 3 h at room temperature. After cooling to 0 ° C., the pH is adjusted to 1.5 with concentrated hydrochloric acid (18.2 mL). The mixture is warmed to 20 ° C and the phases are separated. The organic phase is washed with a 5% aqueous solution of KHSO4 (3 × 100 mL), water (100 mL) and then concentrated under reduced pressure. The residue is then recrystallized from heptane (200 mL). Molecule 3 is obtained in the form of a solid.
Rendement : 36,6 g (95 %) Yield: 36.6 g (95%)
LC/MS (ESI) : 354,4, 707,7 (calculé ([M + H]+) : 354,3 ; ([2M + H]+) : 707,6). LC / MS (ESI): 354.4, 707.7 (calcd ([M + H] + ): 354.3; ([2M + H] + ): 707.6).
Molécule 8 : produit obtenu par synthèse sur support solide Molecule 8: product obtained by synthesis on a solid support
[000383] Par un procédé similaire à celui utilisé pour la molécule 3 et en utilisant la molécule 7 à la place de la molécule 1 , la molécule 8 est obtenue sous forme de solide blanc. By a process similar to that used for molecule 3 and using molecule 7 instead of molecule 1, molecule 8 is obtained in the form of a white solid.
Rendement : 12,4 g (71 %) Yield: 12.4 g (71%)
LC/MS (ESI) : 1580, 1 ; (calculé ([M+Na]+) : 1580, 1). LC / MS (ESI): 1580, 1; (calculated ([M + Na] + ): 1580.1).
Molécule 9 : produit obtenu par couplage entre la molécule 8 et la molécule 2 Molecule 9: product obtained by coupling between molecule 8 and molecule 2
[000384] Par un procédé similaire à celui utilisé pour la molécule 4 appliqué à la molécule 8 (10,0 g, 6,4 mmol) et à la molécule 2 (2,9 g, 7,0 mmol), la molécule 9 est obtenue sous forme de solide blanc. [000384] By a process similar to that used for molecule 4 applied to molecule 8 (10.0 g, 6.4 mmol) and to molecule 2 (2.9 g, 7.0 mmol), molecule 9 is obtained in the form of a white solid.
Rendement : 9,7 g (78 %) Yield: 9.7 g (78%)
LC/MS (ESI+) : 1953,4 ; (calculé ([M+ H]+) : 1953,3). LC / MS (ESI +): 1953.4; (calculated ([M + H] + ): 1953.3).
Molécule A3 : produit obtenu par hydrogénolyse de la molécule 9 Molecule A3: product obtained by hydrogenolysis of molecule 9
[000385] Par un procédé similaire à celui utilisé pour la molécule Al appliqué à la molécule 9 (9,0 g, 4,6 mmol), la molécule A3 est obtenue sous forme de solide blanc. Rendement : 7,4 g (95 %) By a process similar to that used for the Al molecule applied to the 9 molecule (9.0 g, 4.6 mmol), the A3 molecule is obtained in the form of a white solid. Yield: 7.4 g (95%)
LC/MS (ESI+) : 1685,3 ; (calculé ([M + H]+) : 1685,2) . WO 2020/245470 PCT/EP2020/065884 LC / MS (ESI +): 1685.3; (calculated ([M + H] + ): 1685.2). WO 2020/245470 PCT / EP2020 / 065884
52 52
Exemple A4 : molécule A4 Example A4: A4 molecule
Molécule 10 : produit obtenu par synthèse sur support solide Molecule 10: product obtained by synthesis on a solid support
[000386] Par un procédé similaire à celui utilisé pour la molécule 8, la molécule 10 5 est obtenue sous forme de solide blanc. [000386] By a process similar to that used for molecule 8, molecule 10 is obtained in the form of a white solid.
Rendement : 8,7 g (69 %) Yield: 8.7 g (69%)
LC/ S (ESI+) : 1950,3 ; (calculé ([M+Na]+) : 1950,3). LC / S (ESI +): 1950.3; (calculated ([M + Na] + ): 1950.3).
Molécule 11 : produit obtenu par couplage entre la molécule 10 et la molécule 2Molecule 11: product obtained by coupling between molecule 10 and molecule 2
10 [000387] Par un procédé similaire à celui utilisé pour la molécule 4 appliqué à la molécule 10 (7 g, 3,6 mmol) et à la molécule 2 (1,6 g, 3,9 mmol), la molécule 11 est obtenue sous forme de solide blanc. [000387] By a method similar to that used for molecule 4 applied to molecule 10 (7 g, 3.6 mmol) and to molecule 2 (1.6 g, 3.9 mmol), molecule 11 is obtained in the form of a white solid.
Rendement : 6,2 g (74 %) Yield: 6.2 g (74%)
LC/ S (ESI+) : 2323,6 ; (calculé ([M+ H]+) : 2323,5). LC / S (ESI +): 2323.6; (calculated ([M + H] + ): 2323.5).
15 15
Molécule A4 : produit obtenu par hydrogénolyse de la molécule 11 Molecule A4: product obtained by hydrogenolysis of molecule 11
[000388] Par un procédé similaire à celui utilisé pour la molécule Al appliqué à la molécule 11 (5,4 g, 2,3 mmol), la molécule A4 est obtenue sous forme de solide blanc.. Rendement : 4,6 g (97 %) By a process similar to that used for the Al molecule applied to the molecule 11 (5.4 g, 2.3 mmol), the A4 molecule is obtained in the form of a white solid. Yield: 4.6 g ( 97%)
20 LC/MS (ESI+) : 2055,5 ; (calculé ([M+ H]+) : 2055,5). LC / MS (ESI +): 2055.5; (calculated ([M + H] + ): 2055.5).
Exemple A5 : molécule AS Example A5: AS molecule
[000389] La molécule A5 est obtenue par la méthode conventionnelle de synthèse peptidique en phase solide (SPPS) sur résine 2-chlorotrityle chloride (CTC) (16,0 g, 1,36 25 mmol/g) . [000389] The A5 molecule is obtained by the conventional method of peptide synthesis in solid phase (SPPS) on 2-chlorotrityl chloride (CTC) resin (16.0 g, 1.36 mmol / g).
[000390] Le greffage de l'éthylène diamine (20 équivalents) est effectué dans le DCM (10 V). Les sites n'ayant pas réagi sont cappés au méthanol (0,8 mL/g résine) en fin de réaction. [000390] The grafting of ethylene diamine (20 equivalents) is carried out in DCM (10 V). The unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.
[000391] Les couplages des acides aminés protégés Fmoc-Lys(Fmoc)-OH (3,0 30 équivalents), Fmoc-Glu(OBn)-OH (4,0 équivalents), Fmoc-Pro-OH (4,0 équivalents) et de l'acide palmitique (4,0 équivalents) sont effectués dans le DMF (10 V), en présence de HATU ( 1,0 équivalent par rapport à l'acide) et de DIPEA ( 1,5 équivalents par rapport à l'acide) . [000391] The protected amino acid couplings Fmoc-Lys (Fmoc) -OH (3.0 equivalents), Fmoc-Glu (OBn) -OH (4.0 equivalents), Fmoc-Pro-OH (4.0 equivalents) ) and palmitic acid (4.0 equivalents) are carried out in DMF (10 V), in the presence of HATU (1.0 equivalent relative to the acid) and of DIPEA (1.5 equivalents relative to acid).
[000392] Les groupements protecteurs Fmoc sont retirés à l'aide d'une solution de 35 DMF/pipéridine 80 : 20 ( 10 V), sauf dans le cas de la déprotection du groupement Fmoc de l'acide glutamique pour lequel une solution de 1% DBU dans le DMF est utilisée ( 10 V). [000393] Le produit est clivé de la résine à l'aide d'une solution de DCM/TFA 50 : 50 (15 V). Après évaporation à sec, le résidu est solubilisé dans AcOEt (300 mL) et la phase organique est lavée successivement avec NaOH 1 N (300 mL), NaOH 0, 1 N (300 mL) et une solution aqueuse saturée de NaCI (300 mL). La phase organique est séchée sur a2SÜ4, filtrée puis concentrée sous pression réduite. Le résidu est purifié par colonne de chromatographie sur gel de silice (dichlorométhane, méthanol, NH4OH) pour donner la molécule A5 sous la forme d'un solide blanc. [000392] The Fmoc protecting groups are removed using a solution of DMF / piperidine 80:20 (10 V), except in the case of deprotection of the Fmoc group of glutamic acid for which a solution of 1% DBU in DMF is used (10 V). [000393] The product is cleaved from the resin using a solution of DCM / TFA 50:50 (15 V). After evaporation to dryness, the residue is dissolved in AcOEt (300 mL) and the organic phase is washed successively with 1 N NaOH (300 mL), 0.1 N NaOH (300 mL) and a saturated aqueous solution of NaCl (300 mL). ). The organic phase is dried over a2SO4, filtered and then concentrated under reduced pressure. The residue is purified by chromatography column on silica gel (dichloromethane, methanol, NH4OH) to give the A5 molecule in the form of a white solid.
Rendement : 11,59 g (41 % global sur 9 étapes). Yield: 11.59 g (41% overall over 9 steps).
LC/MS (ESI+) : 1298,1 (calculé ([M+ H]+) : 1297,9). LC / MS (ESI +): 1298.1 (calcd ([M + H] + ): 1297.9).
Exemple A6 : molécule A6 Example A6: molecule A6
[000394] Par un procédé similaire à celui utilisé pour la molécule A5 appliqué à l'acide myristique (183,9 g, 0,81 mmol), la molécule A6 est obtenue sous forme de solide blanc. [000394] By a process similar to that used for the A5 molecule applied to myristic acid (183.9 g, 0.81 mmol), the A6 molecule is obtained in the form of a white solid.
Rendement : 91,4 g (37 %) Yield: 91.4 g (37%)
LC/ MS (ESI+) : 1241,9 ; (calculé ([M+H]+) : 1241,9). LC / MS (ESI +): 1241.9; (calculated ([M + H] + ): 1241.9).
Exemple A7 : molécule A7 Example A7: molecule A7
Molécule 12 : produit obtenu par couplage entre la molécule 3 et le chlorhydrate de N- CBz éthylènediamine. Molecule 12: product obtained by coupling between molecule 3 and N-CBz ethylenediamine hydrochloride.
Par un procédé similaire à celui utilisé pour la molécule 4 appliqué à la molécule 3 (50,0 g, 33,3 mmol) et au chlorhydrate de N-CBz éthylènediamine (9,22 g, 40,0 mmol), la molécule 12 est obtenue sous forme de solide blanc. By a process similar to that used for molecule 4 applied to molecule 3 (50.0 g, 33.3 mmol) and N-CBz ethylenediamine hydrochloride (9.22 g, 40.0 mmol), molecule 12 is obtained in the form of a white solid.
Rendement : 48,3 g (86 %) Yield: 48.3 g (86%)
LC/ MS (ESI+) : 1678,2 ; (calculé ([M + H]+) : 1678,1). LC / MS (ESI +): 1678.2; (calculated ([M + H] + ): 1678.1).
Molécule A7 : produit obtenu par hydrogénolyse de la molécule 12 Molecule A7: product obtained by hydrogenolysis of molecule 12
[000395] Par un procédé similaire à celui utilisé pour la molécule Al appliqué à la molécule 12 (48,2 g, 28,7 mmol) dans du MeOH (603 mL) et en présence de palladium sur charbon 5 % (4,8 g), la molécule A7 est obtenue sous forme de solide blanc. Rendement : 40,4 g (91 %) By a process similar to that used for the Al molecule applied to molecule 12 (48.2 g, 28.7 mmol) in MeOH (603 mL) and in the presence of 5% palladium on carbon (4.8 g), the A7 molecule is obtained in the form of a white solid. Yield: 40.4 g (91%)
LC/ MS (ESI+) : 1544,1 ; (calculé ([M + H]+) : 1544,1). Partie B - Synthèse des co-polvaminoacides hydrophobes LC / MS (ESI +): 1544.1; (calculated ([M + H] + ): 1544.1). Part B - Synthesis of hydrophobic co-polvamino acids
Les co-polyaminoacides hydrophobes sont représentés dans le Tableau 2.
Figure imgf000055_0001
The hydrophobic co-polyamino acids are shown in Table 2.
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0001
WO 2020/245470 PCT/EP2020/065884 WO 2020/245470 PCT / EP2020 / 065884
Figure imgf000061_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000062_0001
Figure imgf000063_0001
Tableau 2 : Liste des co-polyaminoacides synthétisés Exemple B1 :
Figure imgf000063_0001
Table 2: List of synthesized co-polyamino acids Example B1:
Co-polyaminoacide B1 - poly-L-glutamate de sodium modifié par la molécule Al dont les esters sont déprotégés Co-polyamino acid B1 - sodium poly-L-glutamate modified by the Al molecule, the esters of which are deprotected
[000396] Dans un ballon préalablement séché à l'étuve, du g-tert-butyl-L-glutamate /V-carboxyanhydride (16,9 g, 73,7 mmol) est placé sous vide pendant 2 h puis du DMF anhydre (48 mL) est introduit. Le mélange est agité sous argon jusqu'à solubilisation complète, refroidi à 4 °C, puis une solution de molécule Al (6,0 g, 3,7 mmol) dans le DMF est introduite rapidement. Le mélange est agité entre 4 °C et température ambiante pendant 18 h, puis chauffé à 65 °C pendant 2 h. Le mélange réactionnel est alors refroidi à température ambiante puis versé goutte à goutte dans de l'eau (500 mL) sous agitation. Le précipité blanc est récupéré par filtration, lavé deux fois avec de l'eau puis séché sous vide à 30 °C pour obtenir un solide blanc. Le solide est dilué dans de l'acide trifluoroacétique (100 mL), et la solution est agitée pendant 2 h à température ambiante puis coulée goutte à goutte dans de l'eau (1000 mL). Après 2 h d'agitation, le précipité blanc est récupéré par filtration et solubilisé dans de l'eau (25 g /L) en ajustant le pH à 7,5 par ajout d'une solution aqueuse de soude 1 N. De l'éthanol est ajouté pour obtenir une solution à 30 % massique en éthanol qui est filtrée sur filtre charbon R53SP. Le mélange est filtré sur filtre 0,45 pm, puis est purifié par ultrafiltration contre une solution de NaCl 0,9 %, puis de l'eau jusqu'à ce que la conductimétrie du perméat soit inférieure à 50 pS/cm. La solution de co-polyaminoacide est ensuite concentrée à environ 30 g/L théorique et le pH est ajusté à 7,0. La solution aqueuse est filtrée sur 0,2 pm et conservée à 4 °C. In a flask previously dried in an oven, g-tert-butyl-L-glutamate / V-carboxyanhydride (16.9 g, 73.7 mmol) is placed under vacuum for 2 h then anhydrous DMF ( 48 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then a solution of Al molecule (6.0 g, 3.7 mmol) in DMF is introduced rapidly. The mixture is stirred between 4 ° C and room temperature for 18 h, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to room temperature and then poured dropwise into water (500 mL) with stirring. The white precipitate is collected by filtration, washed twice with water and then dried under vacuum at 30 ° C. to obtain a white solid. The solid is diluted in trifluoroacetic acid (100 mL), and the solution is stirred for 2 h at room temperature then poured dropwise into water (1000 mL). After 2 h of stirring, the white precipitate is recovered by filtration and dissolved in water (25 g / L) by adjusting the pH to 7.5 by adding a 1N aqueous sodium hydroxide solution. ethanol is added to obtain a 30% solution by mass of ethanol which is filtered through an R53SP carbon filter. The mixture is filtered through a 0.45 μm filter, then is purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7.0. The aqueous solution is filtered through 0.2 µm and stored at 4 ° C.
Extrait sec : 23,4 mg/g Dry extract: 23.4 mg / g
DP (estimé par RMN 1H) = 20 donc i = 0,05 DP (estimated by 1 H NMR) = 20 so i = 0.05
La masse molaire moyenne calculée du co-polyaminoacide B1 est de 4435 g/mol. The calculated average molar mass of the co-polyamino acid B1 is 4435 g / mol.
Exemple B2 : Example B2:
Co-polyaminoacide B2 - poly-L-glutamate de sodium modifié par la molécule A2 dont les esters sont déprotégés Co-polyamino acid B2 - sodium poly-L-glutamate modified by the A2 molecule whose esters are deprotected
[000397] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide B1 appliqué à la molécule A2 (4,5 g, 2,3 mmol) et au y-tert-butyl-L- glutamate N-carboxyanhydride (10,3 g, 45,0 mmol), un poly-L-glutamate de sodium modifié par la molécule A2 est obtenu. Extrait sec : 24,3 mg/g By a process similar to that used for the preparation of the co-polyamino acid B1 applied to the molecule A2 (4.5 g, 2.3 mmol) and to the y-tert-butyl-L-glutamate N-carboxyanhydride (10 , 3 g, 45.0 mmol), a sodium poly-L-glutamate modified by the A2 molecule is obtained. Dry extract: 24.3 mg / g
DP (estimé par RMN 1H) = 20 donc i = 0,05 DP (estimated by 1 H NMR) = 20 so i = 0.05
La masse molaire moyenne calculée du co-polyaminoacide B2 est de 4737 g/mol. Exemple B3 : The calculated average molar mass of the co-polyamino acid B2 is 4737 g / mol. Example B3:
Co-polyaminoacide B3 - poly-L-glutamate de sodium modifié par la molécule A3 dont les esters sont déprotégés Co-polyamino acid B3 - sodium poly-L-glutamate modified by the A3 molecule whose esters are deprotected
[000398] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide B1 appliqué à la molécule A3 (7,1 g, 4,2 mmol) et au y-tert-butyl-L- glutamate N-carboxyanhydride (19,3 g, 84,3 mmol), un poly-L-glutamate de sodium modifié par la molécule A3 est obtenu. By a process similar to that used for the preparation of the co-polyamino acid B1 applied to the molecule A3 (7.1 g, 4.2 mmol) and to γ-tert-butyl-L-glutamate N-carboxyanhydride (19 , 3 g, 84.3 mmol), a sodium poly-L-glutamate modified with the A3 molecule is obtained.
Extrait sec : 26,1 mg/g Dry extract: 26.1 mg / g
DP (estimé par RMN XH) = 20 donc i = 0,05 DP (estimated by NMR X H) = 20 therefore i = 0.05
La masse molaire moyenne calculée du co-polyaminoacide B3 est de 4491 g/mol. The calculated average molar mass of the co-polyamino acid B3 is 4491 g / mol.
Exemple B4 : Example B4:
Co-polyaminoacide B4 - poly-L-glutamate de sodium modifié par la molécule A4 dont les esters sont déprotégés Co-polyamino acid B4 - sodium poly-L-glutamate modified by the A4 molecule whose esters are deprotected
[000399] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide B1 appliqué à la molécule A4 (4,1 g, 2,0 mmol) et au y-tert-butyl-L- glutamate N-carboxyanhydride (9,1 g, 39,9 mmol), un poly-L-glutamate de sodium modifié par la molécule A4 est obtenu. By a process similar to that used for the preparation of the co-polyamino acid B1 applied to the molecule A4 (4.1 g, 2.0 mmol) and to y-tert-butyl-L-glutamate N-carboxyanhydride (9 , 1 g, 39.9 mmol), a sodium poly-L-glutamate modified with the A4 molecule is obtained.
Extrait sec : 26,1 mg/g Dry extract: 26.1 mg / g
DP (estimé par RMN 1H) = 20 donc i = 0,05 DP (estimated by 1 H NMR) = 20 so i = 0.05
La masse molaire moyenne calculée du co-polyaminoacide B4 est de 4793 g/mol. Exemple B5 : The calculated average molar mass of the co-polyamino acid B4 is 4793 g / mol. Example B5:
Co-polyaminoacide B5 : poly-L-glutamate de sodium modifié à l'une de ses extrémités par la molécule 5 dont les esters sont déprotégés Co-polyamino acid B5: sodium poly-L-glutamate modified at one of its ends by molecule 5, the esters of which are deprotected
[000400] Dans un réacteur à double enveloppe, du g-benzyl-L-glutamate N- carboxyanhydride (24,50 g, 93,05 mmol) est solubilisé dans du DMF anhydre (55 mL). Le mélange est alors agité jusqu'à complète dissolution, refroidi à 0 °C, puis de l'hexylamine (0,56 mL, 4,23 mmol) est introduite rapidement. Le mélange est agité à 0 °C pendant 48 h puis sont successivement ajoutés une solution de molécule 5 (9,51 g, 5,08 mmol) dans le DMF (50 mL), du 2-hydroxypyridine-N-oxide (FIOPO, 564 mg, 5,08 mmol) et EDC.FICI (973 mg, 5,08 mmol). Le milieu réactionnel est agité à 0 °C pendant 1 h, entre 0 °C et 20 °C pendant 2 h, puis à 20 °C pendant 16 h. Cette solution est ensuite coulée dans un mélange H20/MeOH 1 : 1 (10 V) à température ambiante et sous agitation. Après 4 h sous agitation, le précipité blanc est récupéré par filtration, lavé WO 2020/245470 PCT/EP2020/065884 [000400] In a jacketed reactor, g-benzyl-L-glutamate N-carboxyanhydride (24.50 g, 93.05 mmol) is dissolved in anhydrous DMF (55 mL). The mixture is then stirred until complete dissolution, cooled to 0 ° C., then hexylamine (0.56 mL, 4.23 mmol) is introduced rapidly. The mixture is stirred at 0 ° C for 48 h then are successively added a solution of molecule 5 (9.51 g, 5.08 mmol) in DMF (50 mL), 2-hydroxypyridine-N-oxide (FIOPO, 564 mg, 5.08 mmol) and EDC.FICI (973 mg, 5.08 mmol). The reaction medium is stirred at 0 ° C for 1 h, between 0 ° C and 20 ° C for 2 h, then at 20 ° C for 16 h. This solution is then poured into a 1: 1 H2O / MeOH mixture (10 V) at room temperature and with stirring. After 4 h under stirring, the white precipitate is recovered by filtration, washed. WO 2020/245470 PCT / EP2020 / 065884
66 66
avec du diisopropyl éther (IPE, 2 x 100 mL), de l'eau (2 x 100 mL) et un mélange FhO/MeOH 1 : 1 (2 x 100 mL) puis séché sous pression réduite. with diisopropyl ether (IPE, 2 x 100 mL), water (2 x 100 mL) and a 1: 1 FhO / MeOH mixture (2 x 100 mL) then dried under reduced pressure.
[000401] Le solide obtenu est solubilisé dans du TFA (220 mL) et agité à température ambiante pendant 2 h 30. Cette solution est ensuite coulée dans de l'eau (10 V) à 5 température ambiante et sous agitation. Après 2 h 30 sous agitation, le précipité blanc est récupéré par filtration, lavé avec de l'eau (2 x 200 mL) puis séché sous pression réduite. [000401] The solid obtained is solubilized in TFA (220 mL) and stirred at room temperature for 2 h 30 min. This solution is then poured into water (10 V) at room temperature and with stirring. After 2 h 30 min with stirring, the white precipitate is recovered by filtration, washed with water (2 x 200 mL) and then dried under reduced pressure.
[000402] Le solide obtenu est solubilisé dans du N,N-diméthylacétamide (DMAc, 210 mL) puis du Pd/AI203 à 5 % (2,1 g) est ajouté sous atmosphère d'argon. Le mélange0 est placé sous atmosphère d'hydrogène (6 bar) et agité à 60 °C pendant 24 h. Après refroidissement à température ambiante et filtration du catalyseur sur fritté P4 puis sur membrane Omnipore 0,2 pm PTFE hydrophile, une solution d'eau à pH 2 contenant 15 % de NaCI (6 V) est coulée goutte-à-goutte sur la solution de DMAc, sur une période de 45 min et sous agitation. Après 18 h sous agitation, le précipité blanc est récupéré par5 filtration, lavé avec de l'eau puis séché sous pression réduite. Le solide obtenu est solubilisé dans de l'eau (600 mL) en ajustant le pH à 7 par ajout d'une solution aqueuse de soude 1 N. Le pH est ensuite ajusté à pH 12 et la solution est maintenue sous agitation pendant 1 h. Après neutralisation à pH 7, la solution est filtrée sur 0,2 pm, diluée avec de l'éthanol afin d'obtenir une solution contenant 30 % massique d'éthanol,0 puis filtrée sur filtre de charbon actif (3M R53SLP). La solution obtenue est filtrée sur 0,45 pm et purifiée par ultrafiltration contre une solution de IMaCI 0,9 % puis de l'eau jusqu'à ce que la conductimétrie du perméat soit inférieure à 50 pS/cm. La solution de co-polyaminoacide est ensuite concentrée et le pH est ajusté à 7. La solution aqueuse est filtrée sur 0,2 pm et conservée à 4 °C. The solid obtained is solubilized in N, N-dimethylacetamide (DMAc, 210 mL) then 5% Pd / Al2O3 (2.1 g) is added under an argon atmosphere. The mixture0 is placed under a hydrogen atmosphere (6 bar) and stirred at 60 ° C. for 24 h. After cooling to ambient temperature and filtration of the catalyst on a P4 frit and then on an Omnipore 0.2 μm hydrophilic PTFE membrane, a solution of water at pH 2 containing 15% NaCl (6 V) is poured dropwise onto the solution. of DMAc, over a period of 45 min and with stirring. After 18 h under stirring, the white precipitate is recovered by filtration, washed with water and then dried under reduced pressure. The solid obtained is dissolved in water (600 mL) by adjusting the pH to 7 by adding a 1N aqueous sodium hydroxide solution. The pH is then adjusted to pH 12 and the solution is kept stirred for 1 h. . After neutralization to pH 7, the solution is filtered through 0.2 μm, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, 0 then filtered through an activated carbon filter (3M R53SLP). The solution obtained is filtered through 0.45 μm and purified by ultrafiltration against a 0.9% IMaCl solution and then water until the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 µm and stored at 4 ° C.
5 5
Extrait sec : 23,5 mg/g Dry extract: 23.5 mg / g
DP (estimé par RMN 1H) = 24 donc i = 0,042 DP (estimated by 1 H NMR) = 24 therefore i = 0.042
La masse molaire moyenne calculée du co-polyaminoacide B5 est de 5377 g/mol. 0 The calculated average molar mass of the co-polyamino acid B5 is 5377 g / mol. 0
Exemple B6 : Example B6:
Co-polyaminoacide B6 - poly-L-glutamate de sodium modifié par la molécule 5 dont les esters sont déprotégés Co-polyamino acid B6 - sodium poly-L-glutamate modified by molecule 5 whose esters are deprotected
Co-polvaminoadde B6-1 : poly-L-benzylglutamate issu de la polymérisation du y- 5 benzyl-L-glutamate /V-carboxyanhydride initiée par l'éthylènediamine. Co-polvaminoadde B6-1: poly-L-benzylglutamate resulting from the polymerization of γ-benzyl-L-glutamate / V-carboxyanhydride initiated by ethylenediamine.
[000403] Dans un réacteur à double enveloppe, du y-benzyl-L-glutamate N-carboxyanhydride (500,0 g, 1,90 mol) est solubilisé dans du DMF anhydre (1,12 L). Le mélange est alors agité jusqu'à complète dissolution, refroidi à 0 °C, puis de l'éthylènediamine (4,76 g, 79,14 mmol) est introduit rapidement. Après 24 h d'agitation à 0 °C, une solution de HCl 4 M dans le dioxane (99 mL, 396 mmol) est ajoutée puis le milieu réactionnel est coulé en 35 min sur un mélange de méthanol ( 1,6 L) et d'IPE (6,3 L). Après 19 h sous agitation, le précipité est filtré sur fritté, lavé par de IΊRE (2 x 1,12 L) et séché à 30 °C sous pression réduite. [000403] In a jacketed reactor, y-benzyl-L-glutamate N-carboxyanhydride (500.0 g, 1.90 mol) is dissolved in anhydrous DMF (1.12 L). The mixture is then stirred until complete dissolution, cooled to 0 ° C., then ethylenediamine (4.76 g, 79.14 mmol) is introduced rapidly. After 24 h of stirring at 0 ° C, a 4 M HCl solution in dioxane (99 mL, 396 mmol) is added then the reaction medium is poured over 35 min into a mixture of methanol (1.6 L) and of PEI (6.3 L). After 19 h with stirring, the precipitate is filtered through a frit, washed with IΊRE (2 x 1.12 L) and dried at 30 ° C. under reduced pressure.
Co-polyaminoacide B6 Co-polyamino acid B6
[000404] À une solution de molécule 5 (76,4 g, 40,0 mmol) dans du DMAc ( 110 mL) est ajouté du HOPO (4,89 g, 44,1 mmol), le milieu réactionnel est refroidi à 4 °C puis de l'EDC.HCI (9,98 g, 52,1 mmol) est ajouté. [000404] To a solution of molecule 5 (76.4 g, 40.0 mmol) in DMAc (110 mL) is added HOPO (4.89 g, 44.1 mmol), the reaction medium is cooled to 4 ° C then EDC.HCl (9.98 g, 52.1 mmol) is added.
[000405] À une solution de co-polyaminoacide B6- 1 (89, 1 g, 16,0 mmol) dans du DMAc (334 mL) à 4 °C sont successivement ajoutés de la DIPEA (5,2 g, 40,0 mmol) puis la solution de la molécule 5 préalablement préparée comme décrit ci-dessus. Le mélange est agité pendant 15 min à 0 °C puis 18 h à 25 °C, dilué avec du DCM (1, 11 L) et la phase organique est lavée avec une solution de HCl 0, 1 N (3 X 560 mL), séchée sur Na2S04 et le produit est précipité dans de IΊRE (5,6 L). Après une nuit d'agitation, le solide est filtré sur fritté, lavé à GIRE (2 X 220 mL) puis solubilisé dans du TFA (723 mL). Après 2 h d'agitation à température ambiante, le produit est précipité dans de l'eau (7,2 L), agité pendant 18 h puis filtré sur fritté, trituré avec de l'eau puis séché sous pression réduite. [000405] To a solution of co-polyamino acid B6-1 (89.1 g, 16.0 mmol) in DMAc (334 mL) at 4 ° C are successively added DIPEA (5.2 g, 40.0 mmol) then the solution of molecule 5 previously prepared as described above. The mixture is stirred for 15 min at 0 ° C then 18 h at 25 ° C, diluted with DCM (1.11 L) and the organic phase is washed with a 0.1 N HCl solution (3 X 560 mL) , dried over Na2SO4 and the product is precipitated in IΊRE (5.6 L). After stirring overnight, the solid is filtered through a frit, washed with IWRM (2 × 220 mL) and then dissolved in TFA (723 mL). After 2 h of stirring at room temperature, the product is precipitated in water (7.2 L), stirred for 18 h then filtered on frit, triturated with water and then dried under reduced pressure.
[000406] Le solide obtenu est solubilisé dans du DMAc (670 mL) puis du Pd/AI203 5 % ( 13,4 g) est ajouté sous atmosphère d'argon . Le mélange est placé sous atmosphère d'hydrogène (6 bar) et agité à 60 °C pendant 24 h . Après refroidissement à température ambiante et filtration du catalyseur sur fritté P4 puis sur membrane Omnipore 0,2 pm PTFE hydrophile, une solution de Na2C03 à 300 g/L (204 mL) est ajoutée au goutte-à-goutte sur le milieu réactionnel, puis de l'acétone (726 mL) est ajoutée. Après 30 min, le produit est récupéré par filtration sur fritté, trituré dans l'acétone puis séché sous pression réduite et solubilisé dans de l'eau à une concentration théorique de 20 g/L. Le pH est ensuite ajusté à 12 et la solution est maintenue sous agitation pendant 45 min . Après neutralisation à pH 7, la solution est filtrée sur 0,2 pm, diluée avec de l'éthanol afin d'obtenir une solution contenant 30 % massique d'éthanol, puis filtrée sur filtre de charbon actif (3M R53SLP). La solution obtenue est filtrée sur 0,2 pm et purifiée par ultrafiltration contre une solution de NaCI 0,9 % puis de l'eau jusqu'à ce que la conductimétrie du perméat soit inférieure à 50 pS/cm. La solution de co-polyaminoacide est ensuite concentrée et le pH est ajusté à 7. La solution aqueuse est filtrée sur 0,2 pm et conservée à 4 °C. Extrait sec : 14,6 mg/g [000406] The solid obtained is dissolved in DMAc (670 mL) and then 5% Pd / Al2O3 (13.4 g) is added under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (6 bar) and stirred at 60 ° C. for 24 h. After cooling to room temperature and filtration of the catalyst on a P4 frit and then on an Omnipore 0.2 μm hydrophilic PTFE membrane, a 300 g / L Na2CO3 solution (204 mL) is added dropwise to the reaction medium, then acetone (726 mL) is added. After 30 min, the product is recovered by filtration on a frit, triturated in acetone then dried under reduced pressure and dissolved in water at a theoretical concentration of 20 g / L. The pH is then adjusted to 12 and the solution is kept under stirring for 45 min. After neutralization to pH 7, the solution is filtered through 0.2 μm, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, then filtered through an activated carbon filter (3M R53SLP). The solution obtained is filtered through 0.2 μm and purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 µm and stored at 4 ° C. Dry extract: 14.6 mg / g
DP (estimé par RMN *H) = 24 DP (estimated by NMR * H) = 24
D'après la RMN ^ : i = 0,079 According to the NMR ^: i = 0.079
La masse molaire moyenne calculée du co-polyaminoacide B6 est de 6814 g/mol. The calculated average molar mass of the co-polyamino acid B6 is 6814 g / mol.
Exemple B7 : Example B7:
Co-polyaminoacide B7 - poly-L-glutamate de sodium modifié par la molécule AS dont les esters sont déprotégés Co-polyamino acid B7 - sodium poly-L-glutamate modified by the AS molecule, the esters of which are deprotected
[000407] Dans un ballon préalablement séché à l'étuve, du y-benzyl-L-glutamate N-carboxyanhydride (29,8 g, 113,2 mmol) est solubilisé dans du DMF anhydre (45 mL). Le mélange est agité sous argon jusqu'à solubilisation complète, refroidi à -10 °C, puis une solution de molécule A5 (5,81 g, 5,15 mmol) dans le DMF (21 mL) est introduite rapidement. Le mélange est agité pendant 18 h entre 0 °C et température ambiante, puis chauffé à 65 °C pendant 2 h. Après retour à température ambiante, de l'éthanol (73 L), puis du Pd/C à 5% (3,1 g) sont ajoutés et le milieu est placé sous 10 bar d'hydrogène et à 60 °C pendant 24 h. Après refroidissement à température ambiante et filtration sur fritté puis sur membrane Omnipore 0,2 pm PTFE, le produit est précipité par ajout au goutte-à-goutte d'une solution de NaOH 10 N (12,4 mL) dans l'éthanol (50 mL). Après 2 h d'agitation, le précipité est récupéré par filtration sur fritté et séché sous pression réduite à 30 °C. Le produit est ensuite solubilisé dans de l'eau (760 mL) et le pH de la solution est ajustée à 12 avec une solution de NaOH 10 N. Après 45 minutes d'agitation, la solution est neutralisée à pH 7 avec une solution d'AcOH 27 % puis diluée par de l'eau et de l'éthanol jusqu'à obtenir une solution contenant 30 % massique d'éthanol et à une concentration théorique de 25 mg/mL. Cette solution est alors filtrée sur filtres de charbon actif (R053SP) puis sur filtres de 0,2 pm avant d'être purifiée par ultrafiltration contre une solution aqueuse de NaCI à 0,9 % puis contre de GH20 jusqu'à obtenir une conductimétrie inférieure à 50 pS/cm2. La solution de co-polyaminoacide est ensuite concentrée et le pH ajusté à 7. La solution aqueuse est filtrée sur 0,2 pm et conservée à 4 °C. [000407] In a flask previously dried in an oven, y-benzyl-L-glutamate N-carboxyanhydride (29.8 g, 113.2 mmol) is dissolved in anhydrous DMF (45 mL). The mixture is stirred under argon until complete solubilization, cooled to -10 ° C., then a solution of molecule A5 (5.81 g, 5.15 mmol) in DMF (21 mL) is introduced rapidly. The mixture is stirred for 18 h between 0 ° C and room temperature, then heated to 65 ° C for 2 h. After returning to ambient temperature, ethanol (73 L), then 5% Pd / C (3.1 g) are added and the medium is placed under 10 bar of hydrogen and at 60 ° C for 24 h . After cooling to room temperature and filtration on frit and then on an Omnipore 0.2 μm PTFE membrane, the product is precipitated by adding, dropwise, a solution of 10 N NaOH (12.4 mL) in ethanol ( 50 mL). After 2 h of stirring, the precipitate is recovered by filtration on a frit and dried under reduced pressure at 30 ° C. The product is then dissolved in water (760 mL) and the pH of the solution is adjusted to 12 with a 10 N NaOH solution. After 45 minutes of stirring, the solution is neutralized to pH 7 with a solution of 'AcOH 27% then diluted with water and ethanol until a solution containing 30% by weight of ethanol and at a theoretical concentration of 25 mg / mL is obtained. This solution is then filtered on activated carbon filters (R053SP) then on 0.2 μm filters before being purified by ultrafiltration against an aqueous solution of NaCl at 0.9% then against GH20 until a lower conductivity is obtained. at 50 pS / cm 2 . The co-polyamino acid solution is then concentrated and the pH adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.
Extrait sec : 22,5 mg/g Dry extract: 22.5 mg / g
DP (estimé par RM ^) = 24 donc i = 0,042 DP (estimated by RM ^) = 24 so i = 0.042
La masse molaire moyenne calculée du co-polyaminoacide B7 est de 4748 g/mol. Exemple B8 : The calculated average molar mass of the co-polyamino acid B7 is 4748 g / mol. Example B8:
Co-polyaminoacide B8 - poly-L-g I uta ate de sodium modifié par la molécule 3 dont les esters sont déprotégés Co-polyamino acid B8 - sodium poly-L-g I uta ate modified by molecule 3 whose esters are deprotected
[000408] Par un procédé similaire à celui utilisé pou r la préparation du co- polyaminoacide B6 appliqué à la molécule 3 ( 10,5 g, 9,28 mmol) et au co- polyaminoacide B6-1 (25,0 g, 4,64 mmol), un poly-L-glutamate de sodium modifié par la molécule 3 est obtenu. By a process similar to that used for the preparation of the co-polyamino acid B6 applied to molecule 3 (10.5 g, 9.28 mmol) and to the co-polyamino acid B6-1 (25.0 g, 4 , 64 mmol), a sodium poly-L-glutamate modified by molecule 3 is obtained.
Extrait sec : 21,8 mg/g Dry extract: 21.8 mg / g
DP (estimé par RMN CH) = 24 donc i = 0,083 DP (estimated by C H NMR) = 24 therefore i = 0.083
La masse molaire moyenne calculée du co-polyaminoacide B8 est de 5776 g/mol . The calculated average molar mass of the co-polyamino acid B8 is 5776 g / mol.
Exemple B9 : Example B9:
Co-polyaminoacide B9 - poly-L-glutamate de sodium modifié par la molécule 10 dont les esters sont déprotégés Co-polyamino acid B9 - sodium poly-L-glutamate modified by molecule 10 whose esters are deprotected
[000409] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide B6 appliqué à la molécule 10 (16,1 g, 8,35 mmol) et au co- polyaminoacide B6-1 (18,0 g, 3,34 mmol), un poly-L-glutamate de sodium modifié par la molécule 10 est obtenu. [000409] By a process similar to that used for the preparation of the co-polyamino acid B6 applied to the molecule 10 (16.1 g, 8.35 mmol) and to the co-polyamino acid B6-1 (18.0 g, 3, 34 mmol), a sodium poly-L-glutamate modified by molecule 10 is obtained.
Extrait sec : 9,1 mg/g Dry extract: 9.1 mg / g
DP (estimé par RMN ^) = 24 donc i = 0,083 DP (estimated by NMR ^) = 24 so i = 0.083
La masse molaire moyenne calculée du co-polyaminoacide B9 est de 7097 g/mol. The calculated average molar mass of the co-polyamino acid B9 is 7097 g / mol.
Exemple B10 : Example B10:
Co-polyaminoacide B10 - poly-L-glutamate de sodium modifié par la molécule A6 dont les esters sont déprotégés Co-polyamino acid B10 - sodium poly-L-glutamate modified by the A6 molecule, the esters of which are deprotected
[000410] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide B7 appliqué à la molécule A6 (85,8 g, 69,1 mmol) et au y-benzyl-L- glutamate /V-carboxyanhydride (400 g, 1,52 mmol), un poly-L-glutamate de sodium modifié par la molécule A6 dont les esters sont déprotégés est obtenu. Extrait sec : 28,4 mg/g [000410] By a process similar to that used for the preparation of the co-polyamino acid B7 applied to the molecule A6 (85.8 g, 69.1 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (400 g , 1.52 mmol), a sodium poly-L-glutamate modified with the A6 molecule, the esters of which are deprotected is obtained. Dry extract: 28.4 mg / g
DP (estimé par RMN !H) = 23 donc i = 0,043 DP (estimated by NMR ! H) = 23 so i = 0.043
La masse molaire moyenne calculée du co-polyaminoacide B10 est de 4541 g/mol. Exemple Bl l : The calculated average molar mass of the co-polyamino acid B10 is 4541 g / mol. Example B1 l:
Co-polyaminoacide Bl l - poly- L-g I uta m ate de sodium modifié par la molécule A7 dont les esters sont déprotégés Co-polyamino acid Bl l - poly- L-g I uta m ate of sodium modified by the molecule A7 whose esters are deprotected
[000411] Dans un réacteur à double enveloppe, du g-benzyl-L-glutamate /V-carboxyanhydride ( 146,3 g, 0,556 mol) est solubilisé dans du DMF anhydre ( 132 mL). Le mélange est alors agité jusqu'à complète dissolution, refroidi à - 10 °C, puis une solution de la molécule A7 (38,04 g, 24,6 mmol) dans le DMF (100 mL) est introduit rapidement. Après 6 h d'agitation à 0 °C, 13 h à 20 °C et 2 h à 60 °C, le milieu réactionnel est coulé en 37 min sur de GIRE ( 1,4 L). Après une nuit, le précipité est filtré sur fritté, lavé par de IΊRE (2 x 200 mL) puis séché sous pression réduite avant d'être solubilisé dans du TFA (400 mL). Après 2 h d'agitation à température ambiante, le produit est précipité dans de l'eau ( 1,2 L), agité pendant 18 h puis filtré sur fritté, trituré avec de l'eau puis séché à 30 °C sous pression réduite. In a jacketed reactor, g-benzyl-L-glutamate / V-carboxyanhydride (146.3 g, 0.556 mol) is dissolved in anhydrous DMF (132 mL). The mixture is then stirred until complete dissolution, cooled to −10 ° C., then a solution of the A7 molecule (38.04 g, 24.6 mmol) in DMF (100 mL) is introduced rapidly. After 6 h of stirring at 0 ° C, 13 h at 20 ° C and 2 h at 60 ° C, the reaction medium is poured over 37 min on GIRE (1.4 L). After one night, the precipitate is filtered off on a frit, washed with IΊRE (2 x 200 mL) then dried under reduced pressure before being dissolved in TFA (400 mL). After 2 h of stirring at room temperature, the product is precipitated in water (1.2 L), stirred for 18 h then filtered on frit, triturated with water then dried at 30 ° C under reduced pressure. .
[000412] Le solide obtenu est solubilisé dans un mélange de DMF (270 mL) et d'éthanol (325 mL) puis du Pd/C 5 % (21 g) est ajouté sous atmosphère d'argon . Le mélange est placé sous atmosphère d'hydrogène ( 10 bar) et agité à 60 °C pendant 24 h. Après refroidissement à température ambiante et filtration du catalyseur sur fritté P4 puis sur membrane Omnipore 0,2 pm PTFE hydrophile en utlisant du DMF (50 mL) et de l'EtOH (50 mL) pour rincer les filtres, une solution de Na2CÛ3 à 300 g/L ( 157 mL) est ajoutée au goutte-à-goutte sur le milieu réactionnel . Après 30 min, le produit est récupéré par Filtration sur fritté, trituré avec de l'EtOH (2 x 250 mL) puis séché sous pression réduite et solubilisé dans de l'eau à une concentration théorique de 20 g/L. Le pH est ensuite ajusté à 12 et la solution est maintenue sous agitation pendant 90 min. Après neutralisation à pH 7, la solution est filtrée sur 0,2 pm, diluée avec de l'éthanol afin d'obtenir une solution contenant 30 % massique d'éthanol, puis filtrée sur filtre de charbon actif (3M R53SLP). La solution obtenue est filtrée sur 0,2 pm et purifiée par ultrafiltration contre une solution de NaCI 0,9 % puis de l'eau jusqu'à ce que la conductimétrie du perméat soit inférieure à 50 pS/cm. La solution de co-polyaminoacide est ensuite concentrée et le pH est ajusté à 7. La solution aqueuse est filtrée sur 0,2 pm et conservée à 4 °C. [000412] The solid obtained is dissolved in a mixture of DMF (270 mL) and ethanol (325 mL) then 5% Pd / C (21 g) is added under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (10 bar) and stirred at 60 ° C. for 24 h. After cooling to room temperature and filtering the catalyst through a P4 frit and then through an Omnipore 0.2 μm hydrophilic PTFE membrane using DMF (50 mL) and EtOH (50 mL) to rinse the filters, a solution of Na 2 CO 3 at 300 g / L (157 mL) is added dropwise to the reaction medium. After 30 min, the product is recovered by filtration on a frit, triturated with EtOH (2 x 250 mL) then dried under reduced pressure and dissolved in water at a theoretical concentration of 20 g / L. The pH is then adjusted to 12 and the solution is kept under stirring for 90 min. After neutralization to pH 7, the solution is filtered through 0.2 μm, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, then filtered through an activated carbon filter (3M R53SLP). The solution obtained is filtered through 0.2 μm and purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 µm and stored at 4 ° C.
Extrait sec : 41 ,9 mg/g Dry extract: 41.9 mg / g
DP (estimé par RMN 1H) = 23 donc i = 0,043 DP (estimated by 1 H NMR) = 23 so i = 0.043
La masse molaire moyenne calculée du co-polyaminoacide Bl l est de 4843 g/mol. Exemple B12 : The calculated average molar mass of the co-polyamino acid B1 is 4843 g / mol. Example B12:
Co-polyaminoacide B12 - poly-L-glutamate de sodium modifié par la molécule 5 dont les esters sont déprotégés Co-polyamino acid B12 - sodium poly-L-glutamate modified by molecule 5 whose esters are deprotected
Co-polvaminoacide B12-1 : poly-L-benzylglutamate issu de la polymérisation du y- benzyl-L-glutamate /V-carboxy anhydride initiée par le 4,7,10-trioxa-13- tridecadiaminenediamine. Co-polvaminoacid B12-1: poly-L-benzylglutamate resulting from the polymerization of y-benzyl-L-glutamate / V-carboxy anhydride initiated by 4,7,10-trioxa-13-tridecadiaminenediamine.
[000413] Dans un réacteur à double enveloppe, du y-benzyl-L-glutamate N-carboxyanhydride (50,0 g, 0, 19 mol) est solubilisé dans du DMF anhydre ( 1,12 L). Le mélange est alors agité jusqu'à complète dissolution, refroidi à 0 °C, puis du 4,7,10- trioxa-13-tridecadiaminenediamine (TOTA) (1,74 g, 7,9 mmol) est introduit rapidement. Après 24 h d'agitation à 0 °C, une solution de HCl 4 M dans le dioxane (9 ,9 mL, 39,6 mmol) est ajoutée puis le milieu réactionnel est coulé en 35 min sur un mélange de méthanol ( 156 mL) et d'IPE (626 mL). Après 19 h sous agitation, le précipité est filtré sur fritté, lavé par de IΊRE (2 x 120 mL) et séché à 30 °C sous pression réduite. [000413] In a jacketed reactor, y-benzyl-L-glutamate N-carboxyanhydride (50.0 g, 0.19 mol) is dissolved in anhydrous DMF (1.12 L). The mixture is then stirred until complete dissolution, cooled to 0 ° C., then 4,7,10-trioxa-13-tridecadiaminenediamine (TOTA) (1.74 g, 7.9 mmol) is introduced rapidly. After 24 h of stirring at 0 ° C, a 4 M HCl solution in dioxane (9.9 mL, 39.6 mmol) is added then the reaction medium is run over 35 min on a mixture of methanol (156 mL ) and IPE (626 mL). After 19 h with stirring, the precipitate is filtered through a frit, washed with IΊRE (2 x 120 mL) and dried at 30 ° C. under reduced pressure.
Co-polyaminoacide B12 Co-polyamino acid B12
[000414] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide B6 appliqué à la molécule 5 ( 16,5 g, 9,10 mmol) et au co- polyaminoacide B12-1 (20,0 g, 3,46 mmol), un poly-L-glutamate de sodium modifié par la molécule 5 dont les esters sont déprotégés est obtenu. By a process similar to that used for the preparation of the co-polyamino acid B6 applied to molecule 5 (16.5 g, 9.10 mmol) and to the co-polyamino acid B12-1 (20.0 g, 3, 46 mmol), a sodium poly-L-glutamate modified with molecule 5 whose esters are deprotected is obtained.
Extrait sec : 14,1 mg/g Dry extract: 14.1 mg / g
DP (estimé par RM IM *H) = 25 donc i = 0,08 PD (estimated by RM IM * H) = 25 so i = 0.08
La masse molaire moyenne calculée du co-polyaminoacide B12 est de 6089 g/mol. The calculated average molar mass of the co-polyamino acid B12 is 6089 g / mol.
Partie BA - EXEMPLES COMPARATIFS Part BA - COMPARATIVE EXAMPLES
Figure imgf000073_0001
[000415] Les co-polyaminoacides B13 et B14 ont été synthétisés selon le protocole décrit dans la demande de brevet WO2018122278A1
Figure imgf000073_0001
[000415] The co-polyamino acids B13 and B14 were synthesized according to the protocol described in patent application WO2018122278A1
Partie C - Solutions d'insuline basale et d'agoniste de récepteur du GLP-1 Part C - Basal Insulin and GLP-1 Receptor Agonist Solutions
Exemple Cl : Solution d'insuline olaroine à 100-460 UI /ml Example C1: Insulin olaroine solution at 100-460 IU / ml
[000416] Cette solution est une solution d'insuline glargine préparée à partir d'une poudre d'insuline glargine (insuline analogue basale). Les excipients utilisés sont le chlorure ou l'oxyde de zinc, le m-crésol, le glycérol, l'hydroxyde de sodium, l'acide chlorhydrique pour l'ajustement du pH (pH 3, 8-4,0) et l'eau. La concentration de zinc est de 210 mM pour 100 IU/mL d'insuline. Les concentrations de m-crésol et de glycérol sont choisies pour arriver à la cible souhaitée dans les compositions décrites dans l'exemple CAI . Exemple C2 : Solution de liraalutide à 20-45 ma/mL This solution is an insulin glargine solution prepared from an insulin glargine powder (basal insulin analogue). The excipients used are zinc chloride or oxide, m-cresol, glycerol, sodium hydroxide, hydrochloric acid for pH adjustment (pH 3, 8-4.0) and water. The zinc concentration is 210 mM per 100 IU / mL of insulin. The concentrations of m-cresol and of glycerol are chosen to arrive at the desired target in the compositions described in example CAI. Example C2: 20-45 ma / mL liraalutide solution
[000417] Cette solution est une solution de liraglutide préparée à partir d'une poudre de liraglutide (agoniste de récepteur du GLP-1) . Si besoin le pH est ajusté à pH 8,6 avec de l'acide chlorhydrique ou de l'hyd roxyde sodium. Exemple C3 : Solution d'insuline analogue lente fLantus®! à 100 U/mL [000417] This solution is a solution of liraglutide prepared from a powder of liraglutide (GLP-1 receptor agonist). If necessary, the pH is adjusted to pH 8.6 with hydrochloric acid or sodium hydroxide. Example C3: fLantus® Slow Insulin Analogue Solution! at 100 U / mL
[000418] Cette solution est une solution commerciale d'insuline glargine commercialisée par la société SANOFI sous le nom de Lantus®. Ce produit est une insuline analogue lente. Les excipients dans Lantus® sont le chlorure de zinc (30 pg/mL), le m-crésol (2,7 mg/mL), le glycérol (20 mg/mL), le polysorbate 20 (16 pM), l'hydroxyde de sodium et l'acide chlorhydrique pour l'ajustement du pH (pH 4) et de l'eau. [000418] This solution is an insulin glargine commercial solution marketed by Sanofi under the name of Lantus ®. This product is a slow insulin analogue. The excipients in Lantus ® are zinc chloride (30 pg / mL), m-cresol (2.7 mg / mL), glycerol (20 mg / mL), polysorbate 20 (16 pM), hydroxide sodium and hydrochloric acid for pH adjustment (pH 4) and water.
Exemple C4 i Solution de GLP-1 RA liraglutide (Victoza®) à 6 ma/mL Example C4 i GLP-1 RA liraglutide (Victoza ® ) solution at 6 ml / mL
[000419] Cette solution est une solution de liraglutide commercialisée par la société NOVO NORDISK sous le nom de Victoza®. Les excipients dans Victoza® sont le phosphate disodique dihydrate, le propylène glycol (1,42 mg/mL), le phénol (5,5 mg/mL) et l'eau à pH 8, 15. This solution is a liraglutide solution marketed by the company NOVO NORDISK under the name Victoza ® . The excipients in Victoza ® are disodium phosphate dihydrate, propylene glycol (1.42 mg / mL), phenol (5.5 mg / mL) and water at pH 8, 15.
[000420] Partie CA - Compositions comprenant de l'insuline glargine et du liraglutide [000420] Part CA - Compositions comprising insulin glargine and liraglutide
Procédé de préparation CAI : Préparation d'une composition co-Dolvaminoacide/Insuline olarame/liraalutirie à oH 7.2 CAI preparation process: Preparation of a co-Dolvamino acid / Insulin olaram / liraalutirie composition at oH 7.2
[000421] A une solution mère de co-polyaminoacide à pH 6, 5-7, 5 est ajoutée une solution d'insuline glargine décrite dans l'exemple Cl sous agitation magnétique à 300 rpm. Un trouble apparaît. Le pH est ajusté à pH 8,6 par ajout d'une solution de NaOH 1 M. Le mélange est agité pendant 30 minutes à la température ambiante de 20-25 °C. A stock solution of co-polyamino acid at pH 6.5-7.5 is added a solution of insulin glargine described in Example C1 with magnetic stirring at 300 rpm. A cloudiness appears. The pH is adjusted to pH 8.6 by adding a 1M NaOH solution. The mixture is stirred for 30 minutes at room temperature of 20-25 ° C.
[000422] Un volume approprié d'une solution mère de chlorure de zinc est ajouté sous agitation magnétique à 300 rpm pour atteindre la concentration souhaitée dans la composition finale. Le mélange est agité pendant 30 minutes à 25°C. [000422] An appropriate volume of a stock solution of zinc chloride is added with magnetic stirring at 300 rpm to reach the desired concentration in the final composition. The mixture is stirred for 30 minutes at 25 ° C.
[000423] Un volume approprié d'une solution de liraglutide préparée selon l'exemple C2 est ajouté pour atteindre la concentration souhaitée dans la composition finale. [000423] An appropriate volume of a liraglutide solution prepared according to Example C2 is added to achieve the desired concentration in the final composition.
[000424] Le pH est ajusté à 7,2 par ajout d'une solution 0,1 M d'acide chlorhydrique. [000424] The pH is adjusted to 7.2 by adding a 0.1 M hydrochloric acid solution.
Exemple CAI : Compositions de co-polvaminoadde/lnsuline olaraine/liraolutide à oHCAI example: Compositions of co-polvaminoadde / lnsulin olaraine / liraolutide at oH
7.2 contenant différents co-polvaminoacldes 7.2 containing different co-polvaminoacids
[000425] Selon le procédé de préparation CAI, des compositions co- polyaminoacide/insuline glargine/liraglutide ont été préparées. Leur composition est détaillée dans le tableau 3. [000425] According to the CAI preparation process, co-polyamino acid / insulin glargine / liraglutide compositions were prepared. Their composition is detailed in Table 3.
Figure imgf000076_0001
Figure imgf000076_0001
Tableau 3 Aspect visuel des compositions de co-polyaminoacide/insuline glargine/ liraglutide à pH 7,2. [000426] Les co-polyaminoacides selon l'invention permettent de solubiliser la combinaison glargine/liraglutide contrairement aux composés B13 et B14 de l'art antérieur aux concentrations données et à pH 7,2. Partie CB - Stabilité des compositions comprenant de l'insuline glargine et du liraglutide Table 3 Visual appearance of the compositions of co-polyamino acid / insulin glargine / liraglutide at pH 7.2. [000426] The co-polyamino acids according to the invention make it possible to solubilize the glargine / liraglutide combination, unlike the compounds B13 and B14 of the prior art at the given concentrations and at pH 7.2. Part CB - Stability of compositions comprising insulin glargine and liraglutide
Exemple CB1 ; Mise en évidence de la stabilité physique des compositions co- polvaminoadde/insuline alaroine/liraQlutide Example CB1; Demonstration of the physical stability of the compositions co-polvaminoadde / insulin alaroine / liraQlutide
[000427] La stabilité des compositions co-polyaminoacide /insuline glargine/liraglutide à 4 °C et 30 °C a été étudiée. [000427] The stability of the co-polyamino acid / insulin glargine / liraglutide compositions at 4 ° C and 30 ° C was studied.
[000428] Les compositions ont été filtrées (0,22 pm) avant d'être introduites dans des cartouches en verre d'une contenance de 3 mL produites par la société OMPI. [000428] The compositions were filtered (0.22 μm) before being introduced into glass cartridges with a capacity of 3 ml produced by the company OMPI.
[000429] Pour chaque composition étudiée, au moins 4 cartouches ont été remplies avec 1 mL de chacune des compositions décrites ci-dessus, puis placées à 4 °C et 30 °C (au moins 2 cartouches par condition de température). [000429] For each composition studied, at least 4 cartridges were filled with 1 mL of each of the compositions described above, then placed at 4 ° C and 30 ° C (at least 2 cartridges per temperature condition).
[000430] Les cartouches sont inspectées visuellement à des échéances hebdomadaires afin de détecter l'apparition de particules visibles ou d'une turbidité. Pour cela, les cartouches sont soumises à un éclairage d'au moins 2000 Lux; elle sont considérées conformes quand elles ne contiennent pas de particules visibles et qu'elles apparaissent limpides en comparaison avec un standard d'opalescence (standard selon la pharmacopée européenne) . [000430] The cartridges are visually inspected at weekly intervals in order to detect the appearance of visible particles or turbidity. For this, the cartridges are subjected to lighting of at least 2000 Lux; they are considered compliant when they do not contain visible particles and when they appear clear in comparison with an opalescence standard (standard according to the European Pharmacopoeia).
[000431] Les résultats de stabilité sont respectivement présentés dans les tableaux 4a et 4b. [000431] The stability results are respectively presented in Tables 4a and 4b.
Figure imgf000077_0001
Figure imgf000077_0001
Tableau 4a Stabilité physique des compositions CA1- 10, CA1-12 à CA1-15 et CA1-17 stockées à 4 °C. Table 4a Physical stability of compositions CA1-10, CA1-12 to CA1-15 and CA1-17 stored at 4 ° C.
[000432] Les composés selon l'invention permettent d'obtenir des compositions présentant une excellente stabilité physique à 4 °C, supérieure à au moins 10 semaines. Le co-polyaminoacide B6 permet d'obtenir des compositions particulièrement stables, au moins 47 semaines, à 4°C. [000432] The compounds according to the invention make it possible to obtain compositions exhibiting excellent physical stability at 4 ° C., greater than at least 10 weeks. The co-polyamino acid B6 makes it possible to obtain compositions which are particularly stable, at least 47 weeks, at 4 ° C.
Figure imgf000078_0001
Figure imgf000078_0001
Tableau 4b Stabilité physique des compositions CA1-10 et CA1-12 à CA1-15 stockées à 30 °C Table 4b Physical stability of compositions CA1-10 and CA1-12 to CA1-15 stored at 30 ° C
[000433] Les compositions selon l'invention présentent une bonne stabilité physique à 30°C. Le co-polyaminoacide B6 permet d'obtenir des compositions stables au moins 12 semaines à 30°C. [000433] The compositions according to the invention exhibit good physical stability at 30 ° C. The co-polyamino acid B6 makes it possible to obtain compositions which are stable for at least 12 weeks at 30 ° C.
Exemple CB2 : Précipitation de l'insuline alaraine après mélange des compositions co- DolvaminoacIde/insuUne olaraine avec une solution à DH et force ionique Physiologique contenant de l'albumine. [000434] Ce test met en évidence la précipitation de l'insuline glargine lors de l'injection dans un milieu physiologique simulé à pH et force ionique physiologiques et contenant de l'albumine. Ces conditions permettent de mimer le comportement de la composition lors de l'injection sous-cutanée. A 160 pL de composition co- polyaminoacide/insuline glargine sont ajoutés 40 pL d'une solution d'albumine bovine à 20 mg/mL dans un tampon phosphate à pH 7.4. Le tampon phosphate (PBS ou phosphate buffer saline) est concentré de manière à ce que les teneurs en NaCI et en phosphate soient respectivement de 140 mM et 10 mM à l'issue du mélange avec la composition. La précipitation de glargine dans ce milieu est suivie à température ambiante (20-25 °C) par des mesures d'absorbance à 500 nm des mélanges pendant 30 minutes. Les mesures d'absorbance sont réalisées à l'aide d'un lecteur UV-visible de plaques multi-puits. Example CB2 Precipitation of insulin alaraine after mixing the compositions co-DolvaminoacIde / insulin olaraine with a solution of DH and physiological ionic strength containing albumin. This test demonstrates the precipitation of insulin glargine during injection into a physiological medium simulated at physiological pH and ionic strength and containing albumin. These conditions make it possible to mimic the behavior of the composition during subcutaneous injection. To 160 μl of co-polyamino acid / insulin glargine composition are added 40 μl of a solution of bovine albumin at 20 mg / ml in a phosphate buffer at pH 7.4. The phosphate buffer (PBS or phosphate buffer saline) is concentrated so that the NaCl and phosphate contents are respectively 140 mM and 10 mM after mixing with the composition. The precipitation of glargine in this medium is followed at ambient temperature (20-25 ° C.) by absorbance measurements at 500 nm of the mixtures for 30 minutes. The absorbance measurements are carried out using a UV-visible reader of multi-well plates.
[000435] L'absorbance augmente jusqu'à atteindre un plateau. On définit le temps de précipitation de glargine comme le temps nécessaire pour que l'absorbance mesurée soit supérieure ou égale à 80 % de la valeur du plateau. Les temps de précipitations obtenues avec les compositions précédemment décrites sont présentés dans le tableau 5.
Figure imgf000079_0001
[000435] The absorbance increases until it reaches a plateau. The glargine precipitation time is defined as the time required for the measured absorbance to be greater than or equal to 80% of the plateau value. The precipitation times obtained with the compositions described above are presented in Table 5.
Figure imgf000079_0001
Tableau 5 : Temps de précipitation de l'insuline glargine après mélange des compositions co-polyaminoacide/insuline glargine/liraglutide dans un milieu qui simule le milieu sous-cutanée. Table 5: Precipitation time of insulin glargine after mixing the co-polyamino acid / insulin glargine / liraglutide compositions in a medium which simulates the subcutaneous medium.
[000436] Les compositions co-polyaminoacide/insuline glargine/Liraglutide de l'invention mènent à une précipitation rapide de glargine après mélange avec un milieu qui simule le milieu sous-cutanée. Une précipitation particulièrement rapide est observée avec les composés B5 et B6, mais la précipitation la plus rapide est observée avec le composé B6. The co-polyamino acid / insulin glargine / Liraglutide compositions of the invention lead to rapid precipitation of glargine after mixing with a medium which simulates the subcutaneous medium. Particularly rapid precipitation is observed with compounds B5 and B6, but the fastest precipitation is observed with compound B6.
Partie D Pharmacocinétique Part D Pharmacokinetics
DI : Protocole de mesure de la pharmacocinétique de formulations d'insuline glargine et d'insuline lispro. DI: Protocol for measuring the pharmacokinetics of insulin glargine and insulin lispro formulations.
[000437] Des études chez le chien ont été conduites dans l'objectif d'évaluer la pharmacocinétique de l'insuline et du liraglutide après administration de la composition CA1- 12 comprenant le co-polyaminoacide B6/insuline glargine (200 U/mL)/liraglutide (7,2 mg/mL), de la composition d'insuline glargine C3 et de la solution de liraglutide C4. [000437] Studies in dogs were carried out with the objective of evaluating the pharmacokinetics of insulin and liraglutide after administration of the composition CA1-12 comprising the co-polyamino acid B6 / insulin glargine (200 U / mL) / liraglutide (7.2 mg / mL), the composition of insulin glargine C3 and liraglutide C4 solution.
[000438] Les profils pharmacocinétiques de l'insuline glargine (somme de la concentration circulante en insuline glargine et en son principal métabolite, l'insuline M l) et du liraglutide ont été obtenus pour ces compositions. [000438] The pharmacokinetic profiles of insulin glargine (sum of the circulating concentration of insulin glargine and of its main metabolite, insulin M1) and of liraglutide were obtained for these compositions.
[000439] Dix animaux qui ont été mis à jeûn depuis 17,5 heures environ ont été injectés par voie sous-cutanée à la dose de 0,5 U/ kg d'insuline et 18 pg/kg de liraglutide. Des prélèvements sanguins sont réalisés pendant les 18 heures suivant l'administration pour décrire la pharmacocinétique de l'insuline glargine et du liraglutide. Les niveaux d'insuline glargine, d'insuline M l et de liraglutide ont été déterminés par une méthode de bioanalyse spécifique. 79 [000439] Ten animals which had been fasted for approximately 17.5 hours were injected subcutaneously at a dose of 0.5 U / kg of insulin and 18 pg / kg of liraglutide. Blood samples are taken within 18 hours of administration to describe the pharmacokinetics of insulin glargine and liraglutide. The levels of insulin glargine, insulin M1 and liraglutide were determined by a specific bioanalytical method. 79
[000440] Les paramètres pharmacocinétiques suivants ont été déterminés pour l'insuline glargine (et son métabolite M l) : [000440] The following pharmacokinetic parameters were determined for insulin glargine (and its metabolite M1):
• AUC0-lh, AUC0-2h, AUC8-18H, AUCIast correspondant à la surface sous la courbe des concentrations en fonction du temps entre respectivement 0 et 1 h, 0 et 2 h, • AUC0-1h, AUC0-2h, AUC8-18H, AUCIast corresponding to the area under the curve of concentrations as a function of time between 0 and 1 h, 0 and 2 h, respectively,
5 8 et 18 h et 0 et et la dernière concentration mesurable post-administration . 5 8 and 6 p.m. and 0 and the last measurable concentration post-administration.
[000441] Les paramètres pharmacocinétiques suivants ont été déterminés pour le liraglutide : [000441] The following pharmacokinetic parameters were determined for liraglutide:
• AUCIast correspondant à la surface sous la courbe entre le temps 0 et la dernière concentration mesurable post-administration ; et • AUCIast corresponding to the area under the curve between time 0 and the last measurable concentration post-administration; and
0 • Cmax correspondant à la concentration plasmatique maximale observée. 0 • Cmax corresponding to the maximum plasma concentration observed.
[000442] Le tableau 6 suivant reporte différents paramètres pharmacocinétiques d'insuline glargine, et de son métabolite M l, et du liraglutide. [000442] Table 6 below shows various pharmacokinetic parameters of insulin glargine, and of its metabolite M1, and of liraglutide.
Figure imgf000080_0001
Figure imgf000080_0001
Tableau 6 : Paramètres pharmacocinétiques de l'insuline glargine, et de son métabolite5 M l-, et du liraglutide après administration sous-cutanée de la composition CA1-12, C3 ou C4 chez le chien (moyennes et (CV%)). Table 6: Pharmacokinetic parameters of insulin glargine, and of its metabolite5 Ml-, and of liraglutide after subcutaneous administration of composition CA1-12, C3 or C4 in dogs (means and (CV%)).
[000443] Les résultats obtenus montrent que la composante insuline glargine de la composition CA1-12 conserve son caractère basal avec des expositions similaires à0 celles de la composition d'insuline glargine C3 sur la parties initiale (AUC0-2h), terminale (AUC8-18h) ainsi que sur la totalité du temps d'observation (AUCIast). [000443] The results obtained show that the insulin glargine component of the composition CA1-12 retains its basal character with exposures similar to those of the composition of insulin glargine C3 on the initial (AUC0-2h), terminal (AUC8-) parts. 18h) as well as over the entire observation time (AUCIast).
[000444] Les AUCC0-lh et AUC0-2h pour l'insuline glargine de la composition CA1- 12 selon l'invention et de la composition d'insuline glargine C3 sont extrêmement proches. [000444] The AUCC0-1h and AUC0-2h for insulin glargine of the composition CA1-12 according to the invention and of the composition of insulin glargine C3 are extremely close.
5 [000445] Ces deux compositions ont donc des comportement similaires dans les temps précoces et sur la totalité du temps d'observation. [000446] Ces résultats montrent également que la composante liraglutide de la composition CA1-12 présente des caractéristiques pharmacocinétiques similaires à celle de la solution de liraglutide C4 (Cmax et AUCIast). [000447] Les compositions selon l'invention permettent pour l’insuline glargine d'obtenir un profil pharmacocinétique similaire à celui d’une composition d’insuline glargine U100 seule à pH 4. [000445] These two compositions therefore have similar behavior in the early stages and over the entire observation time. [000446] These results also show that the liraglutide component of the composition CA1-12 has pharmacokinetic characteristics similar to that of the solution of C4 liraglutide (Cmax and AUCIast). [000447] The compositions according to the invention make it possible for insulin glargine to obtain a pharmacokinetic profile similar to that of a composition of insulin glargine U100 alone at pH 4.
[000448] S'agissant du liraglutide le profil pharmacocinétique obtenu est similaire à celui d'une composition de liraglutide seul à 6,0 mg/ml et à pH 8,15. [000448] With regard to liraglutide, the pharmacokinetic profile obtained is similar to that of a composition of liraglutide alone at 6.0 mg / ml and at pH 8.15.

Claims

WO 2020/245470 PCT/EP2020/065884 81 REVENDICATIONS 5 WO 2020/245470 PCT / EP2020 / 065884 81 CLAIMS 5
1. Composition stable physiquement sous forme d'une solution aqueuse injectable, dont le pH est compris entre 6,0 et 8,0, comprenant au moins : 1. Physically stable composition in the form of an aqueous solution for injection, the pH of which is between 6.0 and 8.0, comprising at least:
a) une insuline basale dont le point isoélectrique (pi) est compris entre 5,8 et 8,5 et a) a basal insulin with an isoelectric point (pi) between 5.8 and 8.5 and
10 b) du liraglutide, 10 b) liraglutide,
c) un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes Hy, ledit co-polyaminoacide étant constitué d'unités glutamiques ou aspartiques et lesdits radicaux hydrophobes -Hy étant de formule X suivante : c) a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic radicals -Hy being of the following formula X:
15
Figure imgf000082_0001
15
Figure imgf000082_0001
Formule X dans laquelle : Formula X in which:
- GpR est choisi parmi les radicaux de formules VII, VU' ou VU" : - GpR is chosen from the radicals of formulas VII, VU 'or VU ":
O O
0 •
Figure imgf000082_0002
Formule VII ou
Figure imgf000082_0003
0 •
Figure imgf000082_0002
Formula VII or
Figure imgf000082_0003
Formule
Figure imgf000082_0004
Formule VU"; Formula
Figure imgf000082_0004
Formula VU ";
GpG et GpH identiques ou différents sont choisis parmi les radicaux de formules XI ou CG: GpG and GpH, which are identical or different, are chosen from the radicals of formulas XI or CG:
25 •
Figure imgf000082_0005
Formule XI 25 •
Figure imgf000082_0005
Formula XI
* - NH - G - NH - * * - NH - G - NH - *
Formule CG Formula CG
-GpL est choisi parmi les radicaux de formule XII
Figure imgf000082_0006
Formule XII, -GpL is chosen from the radicals of formula XII
Figure imgf000082_0006
Formula XII,
30 GpC est un radical de formule IX :
Figure imgf000083_0001
Formule IX; 30 GpC is a radical of formula IX:
Figure imgf000083_0001
Formula IX;
les * indiquent les sites de rattachement des différents groupes liés par des fonctions amides ; the * indicate the attachment sites of the various groups linked by amide functions;
b est un entier égal à 0 ou à 1 ; b is an integer equal to 0 or 1;
c est un entier égal à 0 ou à 1, et si c est égal à 0 alors d est égal à 1 ou à 2; 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 est un entier égal à 0, à 1 ou à 2 ; - d is an integer equal to 0, to 1 or to 2;
g est un entier égal à 0, à 1, à 2, à 3 à 4 à 5 ou à 6; g is an integer equal to 0, to 1, to 2, to 3 to 4 to 5 or to 6;
h est un entier égal à O, à 1, à 2, à 3 à 4 à 5 ou à 6 et au moins un des g ou h h is an integer equal to 0, 1, 2, 3 to 4 to 5 or to 6 and at least one of g or h
> 2 si x< 16, et si g = 0 alors h > 1 ; > 2 if x <16, and if g = 0 then h> 1;
I est un entier égal à 1 et G = 2 ; I is an integer equal to 1 and G = 2;
r est un entier égal à 0 ou à 1, et r is an integer equal to 0 or 1, and
A est un radical alkyle trivalent linéaire ou ramifié comprenant de 1 à 6 atomes de carbone ; A is a linear or branched trivalent alkyl radical comprising from 1 to 6 carbon atoms;
B est un radical alkyle linéaire ou ramifié, éventuellement comprenant un noyau aromatique, comprenant de 1 à 9 atomes de carbone ; B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
Cx est un radical alkyl monovalent linéaire ou ramifié, dans lequel x indique le nombre d'atomes de carbone et x > 13. C x is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and x> 13.
G est un radical alkyle ramifié de 1 à 8 atomes de carbone ledit radical alkyle portant une ou plusieurs fonction(s) acide carboxylique libre. G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
R est un radical choisi dans le groupe constitué par un radical alkyle divalent, linéaire ou ramifié comprenant de 1 à 12 atomes de carbone, un radical alkyle divalent, linéaire ou ramifié comprenant de 1 à 12 atomes de carbone portant une ou plusieurs fonctions -CONH2 ou un radical éther ou polyéther non substitué comprenant de 4 à 14 atomes de carbone et de 1 à 5 atomes d'oxygène : R is a radical chosen from the group consisting of a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms bearing one or more -CONH2 functions or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
Le ou les radicaux hydrophobes -Hy de formule X étant liés au co-polyaminoacide d) via une liaison covalente entre un carbonyle du radical hydrophobe -Hy et un atome d'azote porté par un spacer entre deux polyaminoacides, formant ainsi une fonction amide issue de la réaction d'une fonction amine portée par le précurseur du spacer et une fonction acide portée par le précurseur Hy' du radical hydrophobe -Hy, et e) via une liaison covalente entre un atome d'azote du radical hydrophobe - Hy et un carbonyle porté par un spacer entre deux polyaminoacides, formant ainsi une fonction amide issue de la réaction d'une fonction amine du précurseur Hy' du radical hydrophobe -Hy et une fonction acide portée par le précurseur du spacer, The hydrophobic radical (s) -Hy of formula X being linked to the co-polyamino acid d) via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by a spacer between two polyamino acids, thus forming an amide function resulting from of the reaction of an amine function carried by the precursor of the spacer and an acid function carried by the precursor Hy 'of the hydrophobic radical -Hy, and e) via a covalent bond between a nitrogen atom of the hydrophobic radical - Hy and a carbonyl carried by a spacer between two polyamino acids, thus forming an amide function resulting from the reaction of an amine function of the precursor Hy 'of the hydrophobic radical - Hy and an acid function carried by the precursor of the spacer,
f) via une liaison covalente entre un carbonyle du radical hydrophobe -Hy et un atome d'azote porté par au moins une fonction amine terminale du co- polyaminoacide, f) via a covalent bond between a carbonyl of the hydrophobic radical -Hy and a nitrogen atom carried by at least one terminal amine function of the co-polyamino acid,
g) via une liaison covalente entre un atome d'azote porté par au moins une fonction amine du radical hydrophobe -Hy et un un carbonyl porté par au moins une fonction acide terminale par le co-polyaminoacide, h) via une liaison covalente entre un atome d'azote porté par au moins une fonction amine du radical hydrophobe -Hy et un carbonyl porté par au moins une fonction acide d'un glutamate par le co-polyaminoacide, lorsque plusieurs radicaux hydrophobes sont portés par un co-polyaminoacide alors ils sont identiques ou différents, g) via a covalent bond between a nitrogen atom carried by at least one amine function of the hydrophobic radical -Hy and a carbonyl carried by at least one terminal acid function by the co-polyamino acid, h) via a covalent bond between a nitrogen atom carried by at least one amine function of the hydrophobic radical -Hy and a carbonyl carried by at least one acid function of a glutamate by the co-polyamino acid, when several hydrophobic radicals are carried by a co-polyamino acid then they are identical or different,
le degré de polymérisation DP en unités glutamiques ou aspartiques pour les chaînes polyglutamates est compris entre 5 et 250 ; the degree of polymerization DP in glutamic or aspartic units for the polyglutamate chains is between 5 and 250;
les fonctions acides carboxyliques libres étant sous forme de sel de cation alcalin choisi dans le groupe constitué par Na+ et K+. the free carboxylic acid functions being in the form of an alkaline cation salt chosen from the group consisting of Na + and K + .
2. Composition selon la revendication 1, caractérisée en ce que le co- polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe -Hy est choisi parmi les co-polyaminoacides de formule XXXa suivante : 2. Composition according to Claim 1, characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical —Hy is chosen from the co-polyamino acids of the following formula XXXa:
Figure imgf000084_0001
Figure imgf000084_0001
dans laquelle, in which,
-D- représente, indépendamment, soit un groupe -CH2- (unité aspartique) soit un groupe -CH2-CH2- (unité glutamique) ; -Z représente u ne entite cationique choisie dans le groupe comprenant les cations alcali ns ; -D- represents, independently, either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit); -Z represents a cationic entity chosen from the group comprising alkali cations;
- -Ra et -R'a, identiques ou différents, sont un radical choisi dans le groupe constitué par un H, un groupe acyle linéaire en C2 à CIO, un groupe acyle ramifié en C3 à CIO, un benzyle, une unité « acide aminé » terminale et un pyroglutamate ; - -R a and -R ' a , identical or different, are a radical chosen from the group consisting of an H, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, a benzyl, a "unit" terminal amino acid and a pyroglutamate;
-Hy est un radical hydrophobe de formule X ; -Hy is a hydrophobic radical of formula X;
Q[— *]Î est un spacer au moins trivalent chosi parmi les formules XII, XII' ou XII", ledit spacer Q[— *]B étant lié aux au moins deux chaînes d'unités glutamiques ou aspartiques P LG par des fonctions amides et,- ledit radical ou spacer Q[— *]3 étant lié au au moins un radical hydrophobe— Hy de formule X par une fonction amide ; Q [- *] Î is an at least trivalent spacer chosen from among formulas XII, XII 'or XII ", said spacer Q [- *] B being linked to at least two chains of glutamic or aspartic units P LG by functions amides and, - said radical or spacer Q [- *] 3 being linked to at least one hydrophobic — Hy radical of formula X via an amide function;
Figure imgf000085_0001
dans lesquelles A a la signification donnée ci-dessus, et
Figure imgf000085_0001
where A has the meaning given above, and
- Ai et A2 sont des radicaux alkyles linéaires ou ramifiés comprenant de 1 à 6 atomes de ca rbone , - A1 and A2 are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms,
j = 1 est le nombre de radicaux hydrophobes de formule X liés au spacer Q j = 1 is the number of hydrophobic radicals of formula X linked to the spacer Q
n + m représente le degré de polymérisation DP du co-polyaminoacide, c'est-à-dire le nombre moyen d'unités monomériques par chaîne de co-polyaminoacide et 5 < n + m < 250. n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomer units per chain of co-polyamino acid and 5 <n + m <250.
3. Composition selon la revendication 1 , ca ractérisée en ce que le co- polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est choisi parmi les co-polyaminoacides de de formule XXXb suivante :
Figure imgf000086_0001
dans laquelle, 3. Composition according to claim 1, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of the following formula XXXb:
Figure imgf000086_0001
in which,
5 D représente, indépendamment, soit un groupe -CH2- (unité aspartique) soit un groupe -CH2-CH2- (unité glutamique), 5 D represents, independently, either a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),
Z représente une entité cationique choisie dans le groupe comprenant les cations alcalins ; Z represents a cationic entity chosen from the group comprising alkali metal cations;
m représente le degré de polymérisation DP du co-polyaminoacide, c'est-à-dire m represents the degree of polymerization DP of the co-polyamino acid, that is to say
10 le nombre moyen d'unités monomériques par chaîne de co-polyaminoacide et 5 10 the average number of monomer units per co-polyamino acid chain and 5
< n + m < 250 ; <n + m <250;
Ri et R2 identiques ou différents, sont un radical choisi dans le groupe constitué par un H, un radical hydrophobe de formule X, un groupe acyle linéaire en C2 à CIO, un groupe acyle ramifié en C3 à CIO, un benzyle, une unité « acide aminé » terminale et un pyroglutamateR 1 and R 2 , which are identical or different, are a radical chosen from the group consisting of an H, a hydrophobic radical of formula X, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, a benzyl, a unit Terminal "amino acid" and a pyroglutamate
15 et au moins Ri ou R2 est un radical hydrophobe de formule X. And at least R 1 or R 2 is a hydrophobic radical of formula X.
4. Composition selon l'une quelconque des revendications 1 à 3, caractérisée en ce que l'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 est l'insuline glargine. 4. Composition according to any one of claims 1 to 3, characterized in that the basal insulin the isoelectric point of which is between 5.8 and 8.5 is insulin glargine.
20 20
5. Composition selon l'une quelconque des revendications 1 à 4, caractérisée en ce qu'elle comprend entre 40 et 500 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5. 5. Composition according to any one of claims 1 to 4, characterized in that it comprises between 40 and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5.
25 6. Composition selon l'une quelconque des revendications 1 à 5, caractérisée en ce que la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 60 mg/mL. 6. Composition according to any one of claims 1 to 5, characterized in that the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 60 mg / ml.
7. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce que la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 40 mg/mL. 7. Composition according to any one of the preceding claims, characterized in that the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 40 mg / ml.
8. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce que la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 20 mg/mL. 8. Composition according to any one of the preceding claims, characterized in that the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 20 mg / ml.
9. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce que la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 10 mg/mL. 9. Composition according to any one of the preceding claims, characterized in that the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 10 mg / ml.
10. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce que la concentration en liraglutide est comprise dans un intervalle de 0,01 à 100 mg/mL. 10. Composition according to any one of the preceding claims, characterized in that the concentration of liraglutide is within a range of 0.01 to 100 mg / mL.
11. Composition selon l'une quelconque des revendications 21 ou 24, caractérisée en ce qu'elle comprend entre 40 U/mL et 500 U/mL d'insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 et de 1 à 100 mg/mL de liraglutide. 11. Composition according to any one of claims 21 or 24, characterized in that it comprises between 40 U / mL and 500 U / mL of basal insulin, the isoelectric point of which is between 5.8 and 8.5 and from 1 to 100 mg / mL of liraglutide.
12. Formulation unidose à pH compris entre 7,0 et 7,8 comprenant une insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5 , du liraglutide et un copolyaminoacide porteur de charges carboxylates et de radicaux hydrophobes. 12. Unidose formulation at pH between 7.0 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, liraglutide and a copolyamino acid carrying carboxylate charges and hydrophobic radicals.
13. Formulation unidose à pH compris entre 7,0 et 7,8 comprenant une insuline basale dont le point isoélectrique est compris entre 5,8 et 8,5, du liraglutide et un copolyaminoacide porteur de charges carboxylates et de radicaux hydrophobes. 13. Unidose formulation at pH between 7.0 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, liraglutide and a copolyamino acid carrying carboxylate charges and hydrophobic radicals.
PCT/EP2020/065884 2019-06-07 2020-06-08 Injectable solution at ph 7 containing at least one basal insulin, the pi of which is between 5.8 and 8.5, liraglutide, and a copolyamino acid carrying carboxylate charges and hydrophobic radicals WO2020245470A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4091625A1 (en) 2021-05-22 2022-11-23 Adocia Compositions comprising short-acting hormones for treating or preventing obesity and pumps comprising said composition
WO2022248419A2 (en) 2021-05-22 2022-12-01 Adocia Compositions comprising short-acting hormones for treating or preventing obesity and pumps comprising said composition
EP4144362A1 (en) 2021-09-06 2023-03-08 Adocia Compositions comprising short-acting hormones for treating or preventing obesity and pumps comprising said composition

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656722A (en) 1988-11-08 1997-08-12 Hoechst Aktiengesellschaft A21 -, B30 - modified insulin derivatives having an altered action profile
FR2801226A1 (en) 1999-11-23 2001-05-25 Flamel Tech Sa Colloidal suspensions of block and diblock polyaminoacid copolymers useful as carriers for pharmaceutical, nutritional, phytosanitary, and cosmetically active materials, giving increased biodispersibility
WO2003053339A2 (en) 2001-12-20 2003-07-03 Eli Lilly And Company Insulin molecule having protracted time action
FR2840614A1 (en) 2002-06-07 2003-12-12 Flamel Tech Sa New polyamino acids having grafted alpha-tocopherol moieties, useful as biodegradable, biocompatible carriers for active agents, e.g. drugs, nutrients, cosmetic agents or plant protectants
WO2004096854A2 (en) 2003-04-29 2004-11-11 Eli Lilly And Company Insulin analogs having protracted time action
FR2985428A1 (en) * 2012-01-09 2013-07-12 Adocia Composition in injectable aqueous solution form with specific pH value, useful to treat diabetes, comprises basal insulin with specific isoelectric point and polyamino acid bearing carboxylate charges and substituted with hydrophobic group
WO2013104861A1 (en) 2012-01-09 2013-07-18 Adocia Injectable solution having a ph of 7 and including at least basal insulin, the pi of which is between 5.8 and 8.5, and a substituted co-poly(amino acid)
WO2017211903A1 (en) 2016-06-07 2017-12-14 Adocia Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid bearing carboxylate charges and hydrophobic radicals
WO2018083558A1 (en) 2016-11-07 2018-05-11 International Business Machines Corporation Storing and retrieving restricted datasets to and from a cloud network with non-restricted datasets
WO2018122278A1 (en) 2016-12-27 2018-07-05 Adocia Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analogue and a copolyamino acid
WO2019110773A1 (en) 2017-12-07 2019-06-13 Adocia Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid carrying carboxylate charges and hydrophobic radicals
WO2019110774A1 (en) 2017-12-07 2019-06-13 Adocia Injectable solution with a ph of 7 comprising at least one basal insulin with a pi of between 5.8 and 8.5 and a co-polyaminoacid bearing carboxylate charges and hydrophobic radicals
WO2019110625A1 (en) 2017-12-06 2019-06-13 Adocia Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid carrying carboxylate charges and hydrophobic radicals

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656722A (en) 1988-11-08 1997-08-12 Hoechst Aktiengesellschaft A21 -, B30 - modified insulin derivatives having an altered action profile
US6100376A (en) 1988-11-08 2000-08-08 Hoechst Aktiengesellschaft A21, B30, modified insulin derivatives having an altered action profile
FR2801226A1 (en) 1999-11-23 2001-05-25 Flamel Tech Sa Colloidal suspensions of block and diblock polyaminoacid copolymers useful as carriers for pharmaceutical, nutritional, phytosanitary, and cosmetically active materials, giving increased biodispersibility
WO2003053339A2 (en) 2001-12-20 2003-07-03 Eli Lilly And Company Insulin molecule having protracted time action
FR2840614A1 (en) 2002-06-07 2003-12-12 Flamel Tech Sa New polyamino acids having grafted alpha-tocopherol moieties, useful as biodegradable, biocompatible carriers for active agents, e.g. drugs, nutrients, cosmetic agents or plant protectants
WO2004096854A2 (en) 2003-04-29 2004-11-11 Eli Lilly And Company Insulin analogs having protracted time action
FR2985428A1 (en) * 2012-01-09 2013-07-12 Adocia Composition in injectable aqueous solution form with specific pH value, useful to treat diabetes, comprises basal insulin with specific isoelectric point and polyamino acid bearing carboxylate charges and substituted with hydrophobic group
WO2013104861A1 (en) 2012-01-09 2013-07-18 Adocia Injectable solution having a ph of 7 and including at least basal insulin, the pi of which is between 5.8 and 8.5, and a substituted co-poly(amino acid)
WO2017211903A1 (en) 2016-06-07 2017-12-14 Adocia Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid bearing carboxylate charges and hydrophobic radicals
WO2018083558A1 (en) 2016-11-07 2018-05-11 International Business Machines Corporation Storing and retrieving restricted datasets to and from a cloud network with non-restricted datasets
WO2018122278A1 (en) 2016-12-27 2018-07-05 Adocia Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analogue and a copolyamino acid
WO2019110625A1 (en) 2017-12-06 2019-06-13 Adocia Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid carrying carboxylate charges and hydrophobic radicals
WO2019110773A1 (en) 2017-12-07 2019-06-13 Adocia Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid carrying carboxylate charges and hydrophobic radicals
WO2019110774A1 (en) 2017-12-07 2019-06-13 Adocia Injectable solution with a ph of 7 comprising at least one basal insulin with a pi of between 5.8 and 8.5 and a co-polyaminoacid bearing carboxylate charges and hydrophobic radicals

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DEMING, T.J., ADV. POLYM. SCI., vol. 202, 2006, pages 1 - 18
DEMING, T.J., NATURE, vol. 390, 1997, pages 386 - 389
LU H., J. AM. CHEM. SOC., vol. 129, 2007, pages 14114 - 14115
LU H., J. AM. CHEM. SOC., vol. 130, 2008, pages 12562 - 12563

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4091625A1 (en) 2021-05-22 2022-11-23 Adocia Compositions comprising short-acting hormones for treating or preventing obesity and pumps comprising said composition
WO2022248419A2 (en) 2021-05-22 2022-12-01 Adocia Compositions comprising short-acting hormones for treating or preventing obesity and pumps comprising said composition
EP4144362A1 (en) 2021-09-06 2023-03-08 Adocia Compositions comprising short-acting hormones for treating or preventing obesity and pumps comprising said composition

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