WO2019086559A1 - Composition comprising a glp-2 receptor agonist and a co-polyamino acid carrying carboxylate charges and hydrophobic radicals - Google Patents

Composition comprising a glp-2 receptor agonist and a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Download PDF

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Publication number
WO2019086559A1
WO2019086559A1 PCT/EP2018/079912 EP2018079912W WO2019086559A1 WO 2019086559 A1 WO2019086559 A1 WO 2019086559A1 EP 2018079912 W EP2018079912 W EP 2018079912W WO 2019086559 A1 WO2019086559 A1 WO 2019086559A1
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radical
formula
hydrophobic
polyamino acid
glp
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PCT/EP2018/079912
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French (fr)
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Rémi SOULA
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Adocia
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Priority claimed from FR1760307A external-priority patent/FR3072875B1/en
Priority claimed from FR1852661A external-priority patent/FR3079414B1/en
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Publication of WO2019086559A1 publication Critical patent/WO2019086559A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • 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 a composition
  • a composition comprising a human GLP-2 receptor agonist, also called GLP-2 RA, and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals.
  • GLP-2 RA may in particular be a human GLP-2 analogue.
  • this peptide is degraded very rapidly by cleavage at the level of alanine in the second N-terminal position by the DPP-IV: its half-life is thus particularly short, of the order of 7 minutes in one patient. healthy subject (Tavares et al (2000) Am J Physiol Endocrinol, Metab 278, E134-E139).
  • GLP-2 analogues having an increased half-life.
  • these are analogs in which alanine at the 2-position is substituted with another amino acid residue to enhance the resistance against DPP-IV degradation.
  • alanine is replaced by glycine, or h [Gly2] GLP-2.
  • This analogue is called teduglutide, and has a significantly increased plasma half-life, about 2 hours vs 7 minutes for natural GLP-2.
  • WO01 / 49314 discloses that teduglutide does not lead to stable aqueous solutions that can be prepared with a commercially acceptable process and seeks ways to solve this problem.
  • WO01 / 49314 does not disclose excipients for stabilizing GLP-2 analogues since conventional Tween 80® type additives, such as glutamate, citrate, serine, proline, glycine, that arginine does not improve the stability, or even have a negative effect on it.
  • Tween 80® type additives such as glutamate, citrate, serine, proline, glycine, that arginine does not improve the stability, or even have a negative effect on it.
  • histidine makes it possible to produce a lyophilisate easily solubilizable in an aqueous solution, the resulting solution having a sufficient stability to proceed to the administration within a few hours.
  • WO 99/43361 discloses GLP-2 analogues substituted with an alkyl chain. This alkylation by tetradecanoyl or carboxynonadecanoyl type chains makes it possible in particular to significantly lengthen the half-life of these analogs.
  • WO2006 / 117565 discloses novel GLP-2 analogues having better chemical stability and biological activity similar to or better than natural GLP-2.
  • glepaglutide is currently engaged in phase II clinical studies.
  • composition comprising a GLP-2 receptor agonist and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals has a higher physical stability than the solutions proposed in US Pat. prior art.
  • the invention relates to the preparation of a composition comprising an analogue of GLP-2 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals having improved physical stability properties compared with those described in the prior art. .
  • This invention is remarkable because it is well known to those skilled in the art that the physical stability properties are very difficult to predict.
  • the invention further relates to a method for preparing physically stable injectable compositions.
  • compositions in the form of an aqueous solution for injection according to the invention are clear solutions.
  • the invention also relates to stable pharmaceutical formulations comprising such compositions.
  • inflammatory diseases of the digestive system such as Crohn's disease or ulcerative colitis, diseases associated with the destruction of the epithelial mucosa such as ulcers (ulcers associated with infections, peptic ulcers, medicated ulcers, Zollinger-Ellison syndrome), for autoimmune diseases of the digestive system, including the intestine, and / or
  • these pharmaceutical formulations are indicated for the treatment of massive small bowel resection, or "massive small intestine resection", inflammatory bowel disease, or “inflammatory bowel disease” , mucositis associated with chemotherapy, or “chemotherapy induced mucositis”, and / or ischemic injury, or "ischemia injury”.
  • these pharmaceutical formulations are indicated for the treatment of short bowel syndrome, or "short bowel syndrome”, abbreviated as "SBS”.
  • the invention thus relates to physically stable compositions in the form of an injectable aqueous solution, whose pH is between 6.0 and 8.0, comprising at least:
  • - GpR is a radical of formulas II or IV:
  • GpA is a radical of formulas III or III ';
  • GpC is a radical of formula IV:
  • p is an integer equal to 1 or 2 and
  • GpA is a radical of formula ⁇ and
  • - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2;
  • d is an integer equal to 0, 1 or 2;
  • r is an integer equal to 0 or 1
  • the hydrophobic radical of formula I is bonded to the co-polyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amino function at the N-terminal position of the precursor of the co-polyamino acid and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1, then the hydrophobic radical of formula I is bound to the polyamino acid:
  • Via a covalent bond between a nitrogen atom of the hydrophobic group and a carbonyl co-polyamino acid, thus forming an outlet amide from the reaction of an amine functional group of the precursor of the hydrophobic group and an acidic functional group carried by the precursor of the co-polyamino acid or
  • R is a radical chosen from the group consisting of:
  • GpR is a radical of formula II of 2 to 12 carbon atoms or if GpR is a radical of formula ⁇ of 1 to 11 carbon atoms;
  • an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;
  • A is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical comprising from 1 to 8 carbon atoms and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring;
  • B is a linear or branched alkyl radical, optionally comprising an aromatic nucleus 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 is between 11 and 25 (11 ⁇ x ⁇ 25): o if p is equal to 2, x is between 9 and 15 (9 ⁇ x ⁇ 15),
  • the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ i ⁇ 0.5;
  • the degree of DP polymerization in glutamic or aspartic units is between 5 and 250;
  • the free acid functions are in the form of an alkaline cation salt selected from the group consisting of Na + and K + .
  • the invention also relates to a composition in which the GLP-2 analogue is h [Gly2] GLP-2.
  • the invention also relates to a composition in which the GLP-2 analogue is a GLP-2 receptor agonist.
  • the invention also relates to a composition comprising at least one GLP-2 analogue,
  • the radicals Hy, GpR, GpA, GpC, and D are each independently identical or different from one monomeric unit to another.
  • soluble a compound capable of allowing to prepare a clear solution and free of particles at a concentration of less than 100 mg / ml in distilled water at 25 ° C.
  • nuclear solution means compositions that meet the criteria described in the US and European pharmacopoeia for injectable solutions.
  • the solutions are defined in the ⁇ 1151> part referring to the 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).
  • injectable solutions must meet the criteria given in sections 2.9.19 and 2.9.20.
  • solution means a liquid composition devoid of visible particles, using the procedure according to EP 8.0 pharmacopoeia, point 2.9.20, and US ⁇ 790>.
  • compositions which after a certain storage period at a certain temperature satisfy the criteria of the visual inspection described in the European, American and international pharmacopoeia, that is to say compositions that are clear and do not contain visible particles.
  • compositions which, after storage for a certain time and at a certain temperature, have a minimum recovery of the active ingredients and are in accordance with the specifications applicable to pharmaceutical products.
  • a conventional method for measuring the stability of proteins or peptides is to measure the formation of fibrils using Thioflavine T, also called ThT.
  • ThT Thioflavine T
  • This method makes it possible to measure, under temperature and agitation conditions that allow an acceleration of the phenomenon, the latency time before the formation of fibrils by measuring the increase in fluorescence.
  • the compositions according to the invention have a lag time before the formation of fibrils significantly greater than that of the compositions described in the prior art.
  • compositions according to the invention have a higher physical stability than those described in the prior art
  • aqueous injectable solution water-based solutions that meet the requirements of the EP and US pharmacopoeia, and which are sufficiently fluid to be injected.
  • co-polyamino acid consisting of glutamic or aspartic units of non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a C terminal part, corresponding to the carboxylic acid of one end, and an N-terminal portion, corresponding to the amine of the other end of the sequence.
  • alkyl radical is understood to mean a linear or branched carbon chain which does not comprise a heteroatom.
  • the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical of formula I may also be called “ co-polyamino acid "in the present description.
  • the invention also relates to said co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula I and the precursors of said hydrophobic radicals.
  • co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula I are soluble in distilled water at a pH of between 6 and 8, at a temperature of 25 ° C. and at a concentration of less than 100 mg / ml. ml.
  • GpR, GpA, GpC, r and a have the definitions given above.
  • V * indicates the site of attachment of the hydrophobic radicals to the co-polyamino acid.
  • the radicals Hy are attached to the co-polyamino acid via amide functions.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a linear divalent alkyl radical comprising from 2 to 12 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 atoms of carbon.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II wherein R is a divalent alkyl radical having 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising 2 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula ⁇ .
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula ⁇ in which R is a linear divalent alkyl radical comprising from 1 to 11 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula IV in which R is a divalent alkyl radical comprising from 1 to 6 atoms of carbon.
  • the composition is characterized in that the radical R is bonded to the co-polyamino acid via an amide function carried by the carbon in the delta or epsilon position (or in position 4 or 5) with respect to the amide function (-
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or II ', in which R is a linear ether or polyether radical. unsubstituted compound comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or ⁇ , in which R is an unsubstituted ether radical.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or IV, in which R is an unsubstituted ether radical comprising 4 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula R is an unsubstituted ether radical represented by
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or II ', in which R is an unsubstituted polyether radical.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or II ', in which R is an unsubstituted linear polyether radical. comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.
  • the composition is characterized in that the hydrophobic radical of formula I or V in which GpR is a radical of formula II or II ', in which R is a polyether radical chosen from the group consisting of the radicals
  • composition is characterized in that the hydrophobic radical of formula I or V in which GpR is a radical of formula II in which R is an unsubstituted polyether radical chosen from the group consisting of radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc hereinafter represented:
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical is of formula IVa.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, respectively corresponding to formulas IVd, IVe and IVf below: 0 0 Formula îVd
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of linear alkyl radicals.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of branched alkyl radicals.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 11 and 14 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of the radicals represented by the formulas below: In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 17 and 25 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of the alkyl radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms. carbon.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms .
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms. carbon.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is an alkyl radical comprising from 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms. carbon.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising 2 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ⁇ . In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ⁇ in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms. carbon.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ⁇ in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms .
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
  • the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or in which R is an unsubstituted ether radical.
  • the composition is characterized in that the unsubstituted ether radical R is a radical comprising from 4 to 6 carbon atoms.
  • the composition is characterized in that the unsubstituted ether radical is "vv
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted polyether radical.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted polyether linear radical comprising from 6 to 10 carbon atoms. to 10 carbon atoms and 2 to 3 oxygen atoms.
  • the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted polyether linear radical comprising from 6 to 10 carbon atoms. to 10 carbon atoms and 2 to 3 oxygen atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or in which R is a linear polyether radical chosen from the group consisting of the radicals represented by the formulas below: [000120]
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the radical GpA of formula III is chosen from the group consisting of the radicals of formulas IIIa and IIIb below
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula III is a radical of formula IIIb represented below
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of the radicals of formulas IVa, IVb and IVc ci - after represented
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical is of formula IVa.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, respectively corresponding to the formulas IVd, IVe, and IVf shown below;
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of linear alkyl radicals comprising between 9 and 15 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by branched alkyl radicals comprising between 9 and 15 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by the alkyl radicals comprising 9 or 10 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising between 11 and 15 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicau in which Cx is chosen from the group consisting of by alkyl radicals comprising between 11 and 13 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising 14 or 15 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by the radicals represented by the foemules below:
  • composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the following co-polyamino acids of formula VII:
  • D represents, independently, either a -CH 2 - (aspartic unit) or a -CH 2 -CH 2 - (glutamic unit) group,
  • Formula IV or a radical selected from the group consisting of H, a C 2 -C 10 linear acyl group, a C 3 -C 10 branched acyl group, a benzyl, a terminal "amino acid” unit and a pyroglutamate,
  • radical -NR'R ", R 'and R” identical or different being selected from the group consisting of H, linear or branched or cyclic C2 to C10 alkyls, benzyl and said R' and R "alkyls which may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may contain heteroatoms selected from the group consisting of O, N and S,
  • X represents an H or a cationic entity selected from the group comprising metal cations; [000143] n + m represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n + m ⁇ 250.
  • "random polyamino acid” a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula VIIa.
  • R 1 is a radical selected from the group consisting of H, linear C 2 -C 10 acyl group, branched C 3 -C 10 acyl group, benzyl, terminal amino acid unit and pyroglutamate,
  • - R'2 is a radical -NR'R ", R 'and R" identical or different being selected from the group consisting of H, linear or branched or cyclic C2 to C10 alkyls, benzyl and R' and R alkyls which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may comprise heteroatoms selected from the group consisting of O, N and S.
  • defined co-polyamino acid is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula VIIIb.
  • Formula VIIIb in which m, X, D, R1 and R2 have the definitions given above and at least R1 or R2 is a hydrophobic radical of formula I, V or VI.
  • the composition is characterized in that R 1 is a radical chosen from the group consisting of a C 2 to C 10 linear acyl group, a C 3 to C 10 branched acyl group and a benzyl unit. terminal amino acid and a pyroglutamate.
  • the composition is characterized in that R 1 is a radical selected from the group consisting of a C 10 to C 10 linear acyl group or a C 3 to C 10 branched acyl group.
  • 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 XXXa below: Formula XXXa
  • Ra and R'a which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of an H, a linear acyl group of C2 to C10, a branched acyl group of C3 to C10, a benzyl, a terminal "amino acid” unit and a pyroglutamate,
  • Ra and R'a being a hydrophobic radical -Hy
  • Q- linear or branched divalent consists of an alkyl chain
  • heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or
  • radical or spacer -Q- being bonded to two glutamic or aspartic unit chains PLG by an amide function and said amide bonds linking said radical or spacer -Q- to the two chains of glutamic or aspartic units result of the reaction between an amino function and an acid function respectively carried by the precursor Q 'of the radical or spacer -Q- or by a glutamic or aspartic unit,
  • 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 co-polyamino acids of formula XXXa in which Ra and R'a, identical are a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one radical hydrophobic -Hy is chosen from co-polyamino acids of formula XXXa in which Ra and R'a, different are hydrophobic radicals -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 co-polyamino acids of formula XXXa in which Ra is a hydrophobic radical -Hy and R ' a is not 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 co-polyamino acids of formula XXXa in which R'a is a hydrophobic radical -Hy, and R a is not 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 XXXa 'below :
  • ni + mi represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid bearing a radical -Hy,
  • ⁇ 2 + ⁇ 2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid having no -Hy radical
  • n '+ m' represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n '+ m' ⁇ 250.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one radical hydrophobic -Hy is chosen from co-polyamino acids of formula XXXa 'in which Ra and R'a, 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 XXXa 'in which Ra and R'a, different are hydrophobic radicals -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 co-polyamino acids of formula XXXa 'in which Ra is a hydrophobic radical -Hy and R'a is not 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 XXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.
  • composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb below:
  • Rb and R'b which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of -OH, an amino group, a terminal "amino acid” unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy,
  • n + m has the same definition as given above.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one radical hydrophobic -Hy is chosen from co-polyamino acids of formula XXXb in which Rb and R'b, 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 co-polyamino acids of formula XXXb in which Rb and R'b, different are hydrophobic radicals -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb is a hydrophobic radical -Hy and R'b is not 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 co-polyamino acids of formula XXXb in which R'b is a hydrophobic radical -Hy, and Rb is not 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:
  • nl + ml, n2 + m2 and n '+ m' have the definitions given previously.
  • the composition according to the invention is characterized in that n + m is between 10 and 250. In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 200.
  • composition according to the invention is characterized in that n + m is between 15 and 150.
  • composition according to the invention is characterized in that n + m is between 15 and 100.
  • composition according to the invention is characterized in that n + m is between 15 and 80.
  • 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.
  • composition according to the invention is characterized in that n + m is between 20 and 50.
  • composition according to the invention is characterized in that n + m is between 20 and 40.
  • 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 co-polyamino acids of formula XXXb 'in which Rb and R'b, 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 XXXb 'in which Rb and R'b are different hydrophobic radicals -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 co-polyamino acids of formula XXXb 'in which Rb is a hydrophobic radical -Hy and R'b is not 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 XXXb 'in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
  • the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, VIIa, VIIIb, XXXa, XXXa, XXXb or XXXb 'in which the group D is a group -CH2- (aspartic unit).
  • the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, VIIa, VIIIb, XXXa, XXXa, XXXb or XXXb 'in which the group D is a group -CH2-CH2- (glutamic unit).
  • the co-polyamino acid is a random co-polyamino acid or block.
  • the co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
  • co-polyamino acid comprises one or more aspartic unit (s), that (s) can (s) undergo structural rearrangements.
  • composition according to the invention is characterized in that the co-polyamino acids may further comprise monomeric units of formula VIII and / or VIN ':
  • the radical or spacer -Q- is represented by a radical of formula QUI:
  • the radical or spacer -Q- is represented by a radical of formula by a radical of formula QIV:
  • At least one of the u "i or u" is different from 0.
  • F x F a , Fb, F a 'and F-, identical or different, representing -NH- or -CO- functions.
  • the at least two PLG chains of glutamic or aspartic units are bound to Q by a function F x or F y by a covalent bond to form an amide bond with a -NH- or -CO- function of PLG.
  • the precursor of the radical of formula MI is a diamine selected from the group consisting of ethylenediamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5-diaminopentane.
  • t 2 and the precursor of the radical of formula QUI is ethylenediamine.
  • t 4 and the precursor of the radical of formula QUI is butylenediamine.
  • t 6 and the precursor of the radical of formula QUI is hexylenediamine.
  • t 3 and the precursor of the radical of formula QUI is 1,3-diaminopropane.
  • t 5 and the precursor of the radical of formula QUI is 1,5-diaminopentane.
  • the precursor of the radical of formula QUI is an amino acid.
  • the precursor of the radical of the formula III is an amido acid selected from the group consisting of aminobutanoic acid, aminohexanoic acid and beta-alanine.
  • t 2 and and the precursor of the radical of formula QUI is beta-alanine.
  • t 6 and and the precursor of the radical of formula QUI is the naphthalic amino acid.
  • t 4 and the precursor of the radical of formula QUI is nobutanoic amide acid
  • the precursor of the radical of formu the QUI is a diacid.
  • the precursor of the radical of the formula II is a diacid chosen from the group consisting of succinic acid, glutaric acid and adipic acid.
  • t 2 and and the precursor of the radical of formula QUI is succinic acid.
  • t 3 and the precursor of the radical of formula MI is glutaric acid.
  • t 4 and the precursor of the radical of formula QUI is the adi picic acid.
  • Q is a radical of formula QIV, c H 2 HH CH 2 kbM c Formula QIV whose precursor is a diamine.
  • the precursor of the radical of the formula IVIV is a diamine selected from the group consisting of diethylene glycol diamine, triethylene glycol, diamine, 4,9-dioxal, 12-dodecanediamine, and 1-amino-4,7,10-trioxa-13-tridecanamine.
  • the precursor of the radical of formula QIV is diethylene glycol diamine
  • the precursor of the radical of formula QIV is triethyleneglycol diamine.
  • the PLGs are linked to Fx with Fx by the carbonyl function at the C-terminal position of the PLG.
  • the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by ring opening polymerization of a glutamic acid N-carboxyanhydride derivative. or an aspartic acid N-carboxyanhydride derivative.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative thereof. aspartic acid N-carboxyanhydride as described in Adv. Polym. Salt. 2006, 202, 1-18 (Deming, T.J.).
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative chosen from the group consisting of by N-carboxyanhydride methyl glutamate (GluOMe-NCA), benzyl N-carboxyanhydride glutamate (GluOBzl-NCA) and t-butyl N-carboxyanhydride glutamate (GluOtBu-NCA).
  • GluOMe-NCA N-carboxyanhydride methyl glutamate
  • GluOBzl-NCA benzyl N-carboxyanhydride glutamate
  • GluOtBu-NCA t-butyl N-carboxyanhydride glutamate
  • the glutamic acid ⁇ -carboxyanhydride derivative is methyl N-carboxyanhydride L-glutamate (L-GluO e-NCA).
  • the glutamic acid N-carboxyanhydride derivative is benzyl N-carboxyanhydride L-glutamate (L-GluOBzl-NCA).
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid ⁇ -carboxyanhydride derivative or a derivative thereof. of aspartic acid N-carboxyanhydride using as initiator an organometallic complex of a transition metal as described in Nature 1997, 390, 386-389 (Deming, T.J.).
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a N-derivative.
  • the initiator may be a polyamine to obtain polyamino acid comprising several PLG.
  • Said polyamines can be chosen from diamines, triamines and tetramines. The amines of these polyamines may be primary amines.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or an aspartic acid N-carboxyanhydride derivative using hexamethyldisilazane as initiator as described in J. Am. Chem. Soc. 2007, 129, 14114-14115 (Lu H. et al.) Or a silylated amine as described in J. Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H., et al.).
  • the composition according to the invention is characterized in that the process for the synthesis of the polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or of an N-carboxyanhydride derivative aspartic acid from which the co-polyamino acid is derived comprises a step of hydrolysis of ester functions.
  • this step of hydrolysis of ester functions may consist of hydrolysis in an acid medium or hydrolysis in a basic medium or may be carried out by hydrogenation.
  • this step of hydrolysis of ester groups is a 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 co-polyamino acid is derived 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 co-polyamino acid is derived 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 co-polyamino acid is derived 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 co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight selected from the group consisting of polyglutamate. of sodium and sodium polyaspartate.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived 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 co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid using amide bond forming processes well known to those skilled in the art.
  • the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid using the amide bond formation processes used for peptide synthesis.
  • the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on an acidic poly-L-glutamic or poly-L-aspartic acid as described above. in FR 2,840,614 (Chan, YP et al.).
  • the concentration of co-polyamino acid bearing 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 30 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 bearing carboxylate charges and hydrophobic radicals is at most 10 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 5 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 2.5 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 1 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 0.5 mg / ml.
  • the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
  • the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3. In one embodiment, the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.08.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio i to the number of radicals hydrophobic and the number of glutamic or aspartic units is between 0.007 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0, 2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 17 and 18 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.05.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0, 2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.25.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.15 and 0.20.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.25.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspheric units are between 0.15 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0, 15 and 0.25
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.15 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.25.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.15 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0, 15 and 0.25
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.15 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.05 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. glutamic or aspartic units is between 0.1 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.1 and 0.25.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. glutamic or aspartic units is between 0, 1 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.15 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. glutamic or aspartic units is between 0, 15 and 0.25
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.15 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.04 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio I between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio I between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.05.
  • the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
  • the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
  • the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.03 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.015 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.08. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • analogue when used with reference to a peptide or a protein, a peptide or a protein, in which one or more constituent amino acid residues have been substituted by other residues of amino acid and / or wherein one or more constituent amino acid residues have been deleted and / or wherein one or more constituent amino acid residues have been added.
  • the percentage of homology allowed for the present definition of an analogue is 50%. In particular, the percentage of homology is at least 60%, especially at least 70%; at least 80%, even more particularly at least 90%, or even at least 95%.
  • derivative when used by reference to a peptide or a protein, a peptide or a protein or a chemically modified analogue with a substituent that is not present in the peptide or protein or the reference analogue, i.e., a peptide or protein that has been modified by creation of covalent bonds, to introduce substituents.
  • GLP-2 receptor agonists, or GLP-2 RAs which are potentially useful, activate GLP-2 receptors by binding first to the GLP-2 receptor, and then stimulate an intracellular second messenger system. to the receiver.
  • the GLP-2 peptide is an analogue of human GLP-2 which incorporates one or more substitutions, additions, deletions, or modifications and which retains a GLP-2 type biological activity.
  • GLP-2 RAs can be identified by screening peptides against genetically engineered cells to produce GLP-2 receptors.
  • the GLP-2 receptor has been cloned, see Munroe et al. al., Proc. Natl. Acad. Sci. USA, 96 (4): 1569 (1999).
  • Functional cells incorporating the GLP-2 receptor, and their use for screenerizing GLP-2 RAs have also been described in WO 98/25955.
  • GLP-2 RAs with agonist activity have been modified to confer resistance to degradation by endogenous enzymes, such as DPP-IV.
  • These GLP-2 RAs may include a replacement of the Alanine residue at the 2-position.
  • the Ala2 residue is replaced by Glycine or Serine or other residues described for example in US Pat. No. 5,789,379.
  • the GLP-2 analog is a GLP-2 receptor agonist.
  • the analogue of GLP-2 is an analogue lacking an acyl chain, i.e. no chain derived from acid ras comprising an alkyl chain of more than 10 carbons.
  • the analogue of GLP-2 is an analogue selected from the compounds described in application WO 97/39031.
  • the GLP-2 receptor agonist is teduglutide, also called h [Gly2] GLP-2 or (Gly2) GLP-2.
  • the GLP-2 RA is teduglutide.
  • GLP-2 analog is teduglutide, also called h [Gly2] GLP-2 or (Gly2) GLP-2 of sequence: His-Gly-Asp-Gly-Ser-Phe-Ser-Asp- Glu- and-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp ( HGDGSFSDEM N TILDNLAAR DFINWLIQTK ITD).
  • the GLP-2 analogue is an analogue selected from the analogs described in WO2011 / 050174 or in the article Wisniewski K. et al., J. Med. Chem. , 2016, 59.3129-3139.
  • the analogue of GLP-2 is an analogue whose pharmacokinetic is improved with the following substitutions G2, NLel0, DPhel1, Leu16 and an amide radical -CON H2, whose end C-terminal is amidated.
  • the analogue of GLP-2 is a His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-D-Phe-Thr-Ile-sequence analogue.
  • the GLP-2 analogue is an analogue selected from the analogs described in WO2006 / 117565.
  • the GLP-2 analog is an improved stability analogue having substitutions at positions 8, 16, 24 and 28 in combination with substitutions at position 2 and optionally at positions 3.5. , 7, 10 and 11 and further deletions at positions 31 and 33.
  • the GLP-2 analogue is a His-Gly-Glu-Gly-Ser-Phe-Ser-Ser-Glu-Leu-Ser-Thr-Ile-Leu-sequence analog.
  • Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys-Lys- Lys whose C-terminal end is amidated (X Nle (Norleucine)
  • F * DP e (DP-phenylalanine)).
  • the analogue of GLP-2 is a His-Gly-Glu-Gly-Thr-Phe-Ser-Ser-Glu-Leu-Ala-Thr-Ile-Leu-sequence analogue.
  • GLP-2, GLP-2RA and the like have the following sequences
  • Glp-2 homo sapiens
  • the GLP-2 receptor agonist can be obtained in various ways by peptide synthesis by recombination.
  • the daily dose is from 0.01 to 0.1 mg / kg.
  • the daily dose is from 0.02 to 0.075.
  • the daily dose is from 0.025 to 0.05 mg / kg.
  • the agonist concentration of the GLP-2 receptor or GLP-2 analog ranges from 0.5 to 20 mg / ml.
  • the agonist concentration of the GLP-2 receptor or GLP-2 analog ranges from 1 to 18 mg / ml.
  • the agonist concentration of the GLP-2 receptor or of the GLP-2 analog ranges from 2 to 15 mg / ml.
  • the agonist concentration of the GLP-2 receptor or of the GLP-2 analog ranges from 4 to 12 mg / ml.
  • the agonist concentration of the GLP-2 receptor or of the GLP-2 analog ranges from 5 to 10 mg / ml.
  • the agonist concentration of the GLP-2 receptor or of the GLP-2 analog is 10 mg / ml.
  • the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on teduglutide is between 0.2 and 15.
  • the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.25 and 15.
  • the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 0.25 and 10.
  • the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.3 and 5.
  • the molar ratio of co-polyamino acid carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.1 and 10.
  • the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 0.15 and 8. In one embodiment, the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.2 and 5.
  • the molar ratio of co-polyamino acid carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 0.2 and 3.
  • the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 2 and 7.
  • the composition further comprises a nicotinic compound or a derivative thereof.
  • the composition comprises nicotinamide.
  • the concentration of nicotinamide ranges from 10 to 160 mM.
  • the concentration of nicotinamide ranges from 20 to 150 mM.
  • the concentration of nicotinamide ranges from 40 to 120 mM.
  • the concentration of nicotinamide ranges from 60 to 100 mM.
  • the composition further comprises a polyanionic compound.
  • the polyanionic compound is selected from the group consisting of polycarboxylic acids and their Na + , K + , Ca 2+ or Mg 2+ salts.
  • the polycarboxylic acid is selected from the group consisting of citric acid, tartaric acid, and their salts of Na + , K + , Ca 2+ or Mg 2+ .
  • the polyanionic compound is selected from the group consisting of polyphosphoric acids and their Na + , K + , Ca 2+ or Mg 2+ salts.
  • the polyphosphoric acid is triphosphate and its Na + , K + , Ca 2+ or Mg + salts.
  • the polyanionic compound is citric acid and its Na + , K + , Ca 2+ or Mg + salts.
  • the polyanionic compound is tartaric acid and its Na + , K + , Ca + or Mg 2+ salts. [000373] In one embodiment, the polyanionic compound is triposporic acid and its Na + , K + , Ca 2+ or Mg 2+ salts.
  • the concentration of polyanionic compound is between 1 and 20 m.
  • the concentration of polyanionic compound is between 2 and 15 mM.
  • the concentration of polyanionic compound is between 3 and 12 mM.
  • the polyanionic compound concentration is 10 mM.
  • the concentration of polyanionic compound is 5 mM. In one embodiment, the concentration of polyanionic compound is 10 mM for GLP-2 RA concentrations of between 0.5 mg / ml and 3 mg / ml.
  • the concentration of polyanionic compound is 10 mM for GLP-2 concentrations of between 0.5 mg / ml and 2 mg / ml.
  • the concentration of polyanionic compound is 10 mM for GLP-2 concentrations of between 1 mg / ml and 2 mg / ml.
  • the concentration of polyanionic compound is 5 mM for GLP-2 concentrations of between 0.5 mg / ml and 3 mg / ml.
  • the concentration of polyanionic compound is 5 mM for GLP-2 concentrations of between 0.5 mg / ml and 2 mg / ml.
  • the concentration of polyanionic compound is 5 mM for GLP-2 concentrations of between 1 mg / ml and 2 mg / ml.
  • compositions according to the invention further comprise a gastrointestinal hormone.
  • gastrointestinal hormones the hormones selected from the group consisting of GLP-1 RA for agonists of the human Glucagon receptor-Like Peptide-1 (Glucagon like peptide-1 receptor agonist) Glucagon like) and the GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of human proglucagon), peptide YY, cholecystokinin, ghrelin, motilin and enterostatin, their analogues or derivatives and / or their pharmaceutically acceptable salts. It is particularly advantageous to combine in aqueous solution a GLP-2 RA and GLP-1, a GLP-1 analogue, or an agonist at the GLP-1 receptor. This combination would in particular make it possible to potentiate the effects of each hormone and to be able to potentially reduce the doses of each of them.
  • the gastrointestinal hormones are analogues or derivatives of GLP-1 RA (glucagon like peptide-1 receptor agonist) selected from the group consisting of exenatide or Byetta® (ASTRA- ZENECA), liraglutide or Victoza® (NOVO NORDISK), lixisenatide or Lyxumia® (SANOFI), albiglutide or Tanzeum® (GSK) and dulaglutide or Trulicity® (ELI LILLY & CO), semaglutide, and their analogs or derivatives and their pharmaceutically acceptable salts.
  • GLP-1 RA glycoliraglutide or Victoza®
  • STEMOFI lixisenatide or Lyxumia®
  • GSK albiglutide or Tanzeum®
  • ELI LILLY & CO dulaglutide
  • semaglutide and their analogs or derivatives and their pharmaceutically acceptable salts.
  • compositions according to the invention further comprise a pancreatic hormone.
  • Pantencreatic hormones means the hormones selected from the group consisting of amylin, glucagon, pancreatic polypeptide and their analogues or derivatives.
  • the pancreatic hormone is pramlintide or Symlin® (ASTRA-ZE ECA).
  • the gastrointestinal hormone is exenatide or Byetta® its analogues or derivatives and their pharmaceutically acceptable salts.
  • the gastrointestinal hormone is liraglutide or Victoza® its analogues or derivatives and their pharmaceutically acceptable salts.
  • the gastrointestinal hormone is lixisenatide or Lyxumia® its analogues or derivatives and their pharmaceutically acceptable salts.
  • the gastrointestinal hormone is albiglutide or Tanzeum® its analogues or derivatives and their pharmaceutically acceptable salts.
  • the gastrointestinal hormone is dulaglutide or Trulicity® its analogues or derivatives and their pharmaceutically acceptable salts.
  • the compositions according to the invention are produced by mixing solutions of GLP-2 RA, and solutions of GLP-1, GLP-1 analog or GLP-1 RA in ratios. volume in the range of 10/90 to 90/10.
  • compositions according to the invention further comprise one or more compounds slowing intestinal motility.
  • the substituent is selected from the group consisting of fatty chains.
  • the concentration of gastrointestinal hormone is in a range of 0.01 to 10 mg / mL.
  • the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in a range of 0.04 to 0.5 mg / mL.
  • the concentration of liraglutide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 1 to 10 mg / mL.
  • the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1 mg / mL.
  • the compositions according to the invention are produced by mixing GLP-2 RA solutions obtained by reconstitution of lyophilisate and GLP-1 RA (Glucagon-like peptide-1 receptor agonist) solutions. analog or derivative of GLP-1 RA, said GLP-1 RA solutions being commercial or reconstituted from lyophilisate.
  • 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) or sodium citrate.
  • the buffer is sodium phosphate.
  • the buffer is Tris (trishydroxymethylaminomethane).
  • the buffer is sodium citrate. In one embodiment, the compositions comprise histidine.
  • compositions comprise histidine at a concentration ranging from 5 to 10 mg / ml.
  • the composition further comprises a zinc salt, in particular zinc chloride.
  • compositions according to the invention further comprise preservatives.
  • the preservatives are selected from the group consisting of m-cresol and phenol alone or as a mixture.
  • compositions according to the invention further comprise antioxidants.
  • the antioxidants are chosen from methionine.
  • the concentration of the preservatives is between 10 and 50 mM.
  • the concentration of the preservatives is between 10 and 40 mM.
  • compositions according to the invention further comprise a surfactant.
  • the surfactant is selected from the group consisting of propylene glycol or polysorbate.
  • compositions according to the invention may further comprise additives such as tonicity agents.
  • the tonicity agents are selected from the group consisting of sodium chloride, mannitol, sucrose, sorbitol and glycerol.
  • the composition comprises mannitol.
  • the composition comprises mannitol at a concentration ranging from 20 to 50 mg / ml.
  • the composition comprises mannitol at a concentration ranging from 25 to 35 mg / ml.
  • the composition comprises mannitol at a concentration of 30 mg / ml.
  • compositions according to the invention may also comprise all excipients compatible with the pharmacopoeia and compatible with human glucagon and GLP-1 RA used at the use concentrations.
  • the composition is characterized in that the pH is between 6.6 and 7.8.
  • the composition is characterized in that the pH is between 7.0 and 7.8.
  • the composition is characterized in that the pH is between 7.3 and 7.4.
  • the composition is characterized in that the pH is between 6.8 and 7.4.
  • the composition is characterized in that the pH is between 6.9 and 7.9.
  • the invention also relates to single-dose formulations with a pH of between 6.6 and 7.8 comprising GLP-2 RA and a gastrointestinal hormone or a pancreatic hormone, as defined above.
  • the single-dose formulations further comprise a substituted co-polyamino acid as defined above.
  • the formulations are in the form of an injectable solution.
  • GLP-1 RA, analogue or derivative of GLP-1 RA is selected from the group consisting of exenatide (Byetta®), liraglutide (Victoza®), lixisenatide (Lyxumia®), albylgluttide (Tanzeum®), dulaglutide (Trulicity®), semaglutide, or one of their derivatives.
  • the gastrointestinal hormone is exenatide.
  • the gastrointestinal hormone is liraglutide.
  • the gastrointestinal hormone is lixisenatide.
  • the gastrointestinal hormone is albiglutide.
  • the gastrointestinal hormone is dulaglutide.
  • the preparation of a composition according to the invention has the advantage of being possible by simple mixing of a solution of GLP-2 RA, a solution of GLP-1 RA, an analogue or a derivative of GLP-1 RA, and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH 7. In one embodiment, the mixture of GLP-2 RA and substituted co-polyamino acid is concentrated by ultrafiltration before mixing with GLP-1 RA, an analogue or a derivative of GLP-1 RA in aqueous solution. or in freeze-dried form.
  • composition of the mixture is adjusted to excipients.
  • compositions are characterized in that said compositions solubilize GLP-2, GLP-2 analog or GLP-2 receptor agonist at pH 7.0 and physical stability. measured by ThT higher than that of a reference composition comprising a GLP-2, a GLP-2 analogue or a GLP-2 receptor agonist, optionally in combination with a gastrointestinal hormone, in particular a GLP-1 , a GLP-1 analog or a GLP-1 receptor agonist, or in combination with a pancreatic hormone such as amylin or glucagon or their analogs or derivatives, or an active substance reducing intestinal motility, such as octreotide or loperamide.
  • a reference composition comprising a GLP-2, a GLP-2 analogue or a GLP-2 receptor agonist, optionally in combination with a gastrointestinal hormone, in particular a GLP-1 , a GLP-1 analog or a GLP-1 receptor agonist, or in combination with a pancreatic hormone such as amylin or glucagon
  • 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 intravenous, subcutaneous, intradermal or intramuscular.
  • the mode of administration is the subcutaneous route.
  • transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
  • hydrophobic radicals are represented in the following table by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.
  • Molecule 1-01 product obtained by the reaction between myristoyl chloride and L-proline
  • Molecule 1-02 product obtained by the reaction between the molecule 1-01 and N-Boc-ethylenediamine
  • reaction mixture is then washed with a saturated aqueous solution of NaHCO 3 (2 ⁇ 1.5 L), an aqueous solution of 1N HCl (2 ⁇ 1.5 L), a saturated aqueous solution of NaCl (1.5 L). then dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid is obtained after recrystallization from acetonitrile.
  • N-hydroxysuccinimide MHS, 132.2 g, 1.15 mol
  • ⁇ , ⁇ '-dicyclohexylcarbodiimide DCC, 237, 1 g, 1, 15 mol
  • the reaction medium is stirred for 43 hours between 0 ° C. and room temperature, filtered on sintered, then added over 50 min to a solution of L-lysine (84 g, 574.5 mmol) and N, N-diisopropylethylamine (DIPEA). , 707, 1 g, 5.47 mol) in water (220 mL).
  • the medium is concentrated under reduced pressure, the residue is diluted with water (3 L) and the aqueous phase is washed with ethyl acetate (AcOEt, 2 x 1.3 L) then acidified to pH 1 by addition of an aqueous solution of HCl 6 N.
  • the aqueous phase is extracted with DCM, the organic phase is then washed with a saturated aqueous solution of NaCl (2 x 1.3 L), dried over a2SO4, filtered on cotton and concentrated under reduced pressure.
  • a white solid of the molecule 2 is obtained after recrystallization in acetone.
  • Molecule 3-01 product obtained by coupling between molecule 2 and IM-Boc-ethylenediamine
  • NMR 1 (DMSO-d6, ppm): 0.85 (6H); 1.20-1.55 (55H); 1.50-2.25 (14H); 2.95-3.10 (6H); 3.31-3.55 (4H); 4, 10-4.40 (3H); 6.74 (1H); 7.60-8.25 (3H).
  • Molecule 4-01 product obtained by the reaction between lauric acid and L-proline.
  • Molecule 5-01 product obtained by coupling between molecule 4 and N-Bocethylenediamine
  • Co-polyamino acid Al sodium poly-L-glutamate modified with molecule 1 and having a number-average molar mass (Mn) of 4771 g / mol
  • Co-polyamino acid Al-1 poly-L-glutamic acid of number-average molar mass (Mn) 5360 g / mol resulting from the polymerization of y-benzyl-L-glutamate N-carboxyanhydride initiated by hexylamine
  • ⁇ -benzyl-L-glutamate IM-carboxyanhydride (200.8 g, 763 mmol) is solubilized in anhydrous DMF (480 mL). The mixture is then stirred under argon until complete dissolution, cooled to 0 ° C., and then hexylamine (2.5 mL, 19.1 mmol) is introduced rapidly. The mixture is stirred between 0 ° C and room temperature for 18 h. The reaction medium is then heated at 70 ° C. for 2 h, cooled to room temperature and then poured dropwise into diisopropyl ether (6.7 L) with stirring.
  • the white precipitate is recovered by filtration, washed with diisopropyl ether (3 x 450 mL) and then dried under vacuum at 30 ° C to give a poly (gamma-benzyl-L-glutamic acid) (PBLG).
  • PBLG poly (gamma-benzyl-L-glutamic acid)
  • the solid obtained is then solubilized in water (3.2 L) by adjusting the pH to 7 by adding an aqueous solution of 10 N sodium hydroxide and an aqueous solution of 1N sodium hydroxide. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by addition of water (1.7 L). The solution is filtered through a 0.45 ⁇ m filter and then purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 ⁇ S / cm. The co-polyamino acid solution is then concentrated to a final volume of 2.5 L.
  • aqueous solution is then acidified by addition of 12 N HCl solution (55 ml) until a pH of 2 is reached. After stirring for 16 hours, the precipitate obtained is filtered and washed with water ( 2 x 730 mL) then dried under vacuum at 30 ° C to give a poly-L-glutamic acid of number average molecular weight (Mn) 5360 g / mol relative to a standard of polyoxyethylene glycol (PEG).
  • Mn number average molecular weight
  • the co-polyamino acid Al-1 (12.0 g) is solubilized in DMF (500 mL) by heating for 10 min at 40 ° C, and then are added successively and at room temperature N-methylmorpholine (NMM 9.1 g, 90.3 mmol) and 2-hydroxypyridine N-oxide (HOPO, 3.0 g, 27.1 mmol).
  • NMM 9.1 g, 90.3 mmol N-methylmorpholine
  • HOPO 2-hydroxypyridine N-oxide
  • the reaction medium is then cooled to 0 ° C. and then EDC.
  • HCl, 5.2 g, 27.1 mmol is added and the medium is stirred for 1 hour at 0 ° C. and then raised to room temperature.
  • a solution of molecule 1 (5.5 g, 13.5 mmol) and triethylamine (TEA, 1.9 mL, 13.5 mmol) in DMF (72 mL) is added, and the solution is stirred for 2 hours. h.
  • the reaction medium is filtered through a 0.2 mm woven filter and dripped onto 4.6 L of water containing 15% NaCl and HCl (pH 2) with stirring.
  • pH is readjusted to 2 with 37% HCl solution, and the suspension is allowed to stand overnight.
  • the precipitate is collected by filtration and then rinsed with water (3 x 250 mL).
  • the white solid obtained is solubilized in water (850 mL) by slow addition of a 1N aqueous NaOH solution until pH 12 with stirring, and the solution is then stirred for 45 min.
  • the pH is adjusted to 7 with an aqueous solution of HCl, water (150 mL) and ethanol (580 mL) are added and the solution is filtered on activated carbon disc R53SLP (3M).
  • the solution obtained is filtered through a 0.2 ⁇ m PES membrane and then purified by ultrafiltration against a 0.9% NaCl solution and then with water, until the conductimetry of the permeate is less than 50 MS / cm.
  • the solution is filtered through a 0.2 ⁇ m filter and stored at 2-8 ° C.
  • Co-polyamino acid A2 sodium poly-L-glutamate modified with molecule 3 and having a number-average molar mass (Mn) of 6471 g / mol
  • Co-polyamino acid A3 sodium poly-L-glutamate modified at one of its ends by molecule 3 and having a number-average molecular weight (Mn) of 3264 g / mol
  • ⁇ -benzyl-L-glutamate N-carboxyanhydride 144.2 g, 548 mmol is solubilized in anhydrous DMF (525 mL).
  • the mixture is stirred under argon until complete solubilization, cooled to -10 ° C, and then a solution of molecule 3 (20.0 g, 24.9 mmol) in DCM (100 mL) is introduced rapidly.
  • the mixture is stirred for 13 h at 0 ° C, 6 h at 20 ° C and then heated at 65 ° C for 2 h.
  • the whole of the DCM and 60% of the DMF are distilled under reduced pressure at 70 ° C., then the reaction medium is cooled to 55 ° C. and methanol (1.1 L) is added over a period of 50 minutes.
  • the suspension obtained is stirred for 18 h at 0 ° C. and then filtered on sinter.
  • the resulting white PBLG solid is rinsed with diisopropyl ether (IPE, 2 x 275 mL) and dried at 30 ° C under reduced pressure.
  • the PBLG (25.0 g) is diluted in TFA (150 mL), and a solution of hydrobromic acid (HBr) at 33% in acetic acid (70 mL, 400 mmol) is then added. dropwise at 0 ° C.
  • the solution is then stirred for 2 hours at room temperature and then cooled to 10 ° C.
  • IPE 125 mL
  • water 125 mL
  • the suspension obtained is stirred for 30 min, sintered and rinsed with water.
  • IPE (2 x 100 mL) followed by water (2 x 100 mL).
  • the solid obtained is suspended in an aqueous solution of 0.1 N NaOH (310 mL), and then solubilized by adjusting the pH to 7 by addition of a 1N aqueous sodium hydroxide solution.
  • the pH is raised to 12 by adding a 1N aqueous solution of sodium hydroxide and the mixture is stirred for 30 min before being neutralized to pH 7 by addition of an acid solution acetic at 27%.
  • Acetone (30% by weight) is added to the solution and the product is filtered through an activated carbon disc R535LP (3M) with a flow rate of 5.4 g / min.
  • the acetone is then distilled at 40 ° C. and under reduced pressure, and the product is then purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 ⁇ S. / cm.
  • the co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7.
  • the aqueous solution is filtered through 0.2 ⁇ m and stored at 2-8 ° C.
  • co-polyamino acid A4 - sodium poly-L-glutamate modified at one of its ends by the molecule 5 and having a number-average molar mass (Mn) of 3317 g / mol
  • ⁇ -benzyl-L-glutamate N-carboxyanhydride (30 g, 11.4 mmol) is solubilized in anhydrous DMF (57 ml).
  • the mixture is cooled to 4 ° C, then the solution of molecule 5 in DMF is introduced rapidly.
  • the mixture is stirred at 4 ° C. and ambient temperature for 17 hours. then heated at 65 ° C for 2 hours.
  • the reaction mixture is then cooled to ambient temperature and then poured dropwise into diisopropyl ether (860 ml) with stirring.
  • the white precipitate is recovered by filtration, washed twice with diisopropyl ether (2 x 60 mL) and then dried under vacuum at 30 ° C to obtain a white solid.
  • the solid (26.3 g) is diluted in TFA (105 mL), and a solution of hydrobromic acid (HBr) at 33% in acetic acid (74 mL, 424 mmol) is then added to the drop. drop and at 0 ° C.
  • the solution is stirred for 2 hours at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (1.3 L). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight.
  • the white precipitate is recovered by filtration, washed successively with ⁇ (2 ⁇ 100 mL) and then with water (2 ⁇ 100 mL).
  • the solid obtained is solubilized in water (660 ml) by adjusting the pH to 7 by addition of a 1N aqueous sodium hydroxide solution.
  • Water (200 ml) is added, the mixture is filtered through a filter. , 45 pm and then purified by ultrafiltration against 0.9% NaCl solution and then with water until the conductimetry 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.
  • the aqueous solution is filtered through 0.2 ⁇ and stored at 2-8 ° C.
  • Co-polyamino acid A5-1 poly-L-glutamic acid of number-average molar mass (Mn) 2512 g / mol modified at one of its ends by molecule 3 and capped at the other end by pidolic acid.
  • ⁇ -benzyl-L-glutamate N-carboxyanhydride (122.58 g, 466 mmol) is placed under vacuum for 30 min and then anhydrous DMF (220 mL) is introduced. . The mixture is stirred under argon until complete solubilization, cooled to -10 ° C, then a solution of molecule 3 (17.08 g, 21.3 mmol) in chloroform (40 mL) is introduced rapidly. The mixture is stirred between 0 ° C and room temperature for 2 days and then heated at 65 ° C for 4 h. The reaction mixture is then cooled to 25 ° C.
  • pidolic acid 13.66 g, 105.8 mmol
  • HOBt 2.35 g, 15.3 mmol
  • EDC 20.4 g
  • the solution is concentrated in vacuo to remove chloroform and 50% DMF.
  • the reaction mixture is then heated to 55 ° C. and 1150 ml of methanol are introduced over 1 hour.
  • the reaction mixture is then cooled to 0 ° C. After 18 h, the white precipitate is recovered by filtration, washed three times with 270 mL of diisopropyl ether and then dried under vacuum at 30 ° C to obtain a white solid.
  • the solid is diluted in TFA (390 mL), and a solution of 33% hydrobromic acid (HBr) in acetic acid (271 mL, 1547 mmol) is then added dropwise at 0 ° C.
  • the solution is stirred for 2 hours at room temperature and is then poured dropwise on a mixture of 1: 1 (v / v) diisopropyl ether / water and with stirring (970 ml). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight.
  • the white precipitate is recovered by filtration, washed successively with diisopropyl ether (380 mL) and then twice with water (380 mL).
  • the solid obtained is solubilized in water (3.6 L) by adjusting the pH to 7 by adding a 10N aqueous solution of sodium hydroxide and then a 1N aqueous sodium hydroxide solution.
  • the mixture is filtered through a 0 filter. 45 ⁇ and then purified by ultrafiltration against 0.9% NaCl solution, 0.1 N NaOH solution, 0.9% NaCl solution, phosphate buffer solution (150 m), NaCl solution, , 9% and then water until the conductimetry of the permeate is less than 50 pS / cm.
  • the co-polyamino acid solution is then concentrated to about 30 g / liter, filtered through 0.2 ⁇ and then acidified to pH 2 with stirring by adding a solution of 37% HCl.
  • the precipitate is then recovered by filtration, washed twice with water and then dried under vacuum at 30 ° C to obtain a white solid.
  • Co-polyamino acid ⁇ 6 sodium poly-L-glutamate modified at its ends by molecule 2 and having a number-average molar mass (Mn) of 2877 g / mol
  • Co-polyaminoacid A6-1 poly-L-benzylglutamate resulting from the polymerization of ⁇ -benzyl-L-glutamate / ⁇ -carboxyanhydride initiated by ethylenediamine.
  • the medium is then poured on ⁇ (2.8 L), the precipitate is filtered on sintered, washed with ⁇ (2 ⁇ 50 mL) and dried at 30 ° C. under reduced pressure.
  • the solid is then diluted in TFA (69 mL) and the solution is cooled to 4 ° C.
  • a solution of 33% HBr in acetic acid (48 mL, 0.274 mol) is then added dropwise.
  • the mixture is stirred at ambient temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and stirring water (0.8 L). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight.
  • the white precipitate is collected by filtration, washed with ⁇ (2 x 80 mL) and then with water (2 x 80 mL).
  • the solid obtained is then solubilized in water (500 mL) by adjusting the pH to 7 by adding a 1N aqueous sodium hydroxide solution.
  • the theoretical concentration is adjusted to 20 g / L theoretical by addition of water (174 mL), the solution is filtered through a 0.45 ⁇ m filter and then purified by ultrafiltration against a 0.9 NaCl solution. %, then water until the conductimetry of the permeate is less than 50 pS / cm.
  • the resulting solution is filtered through a 0.2 ⁇ m filter and stored at 2-8 ° C.
  • Co-polyamino acid A7 sodium poly-L-glutamate modified at its ends by molecule 4 and having a number-average molar mass (Mn) of 2827 g / mol
  • Example B1 Preparation of an SI solution of 10 mg / ml teduglutide containing mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
  • a solution of teduglutide concentrated at 10 mg / ml is prepared by dissolving a freeze-dried product sold by Shire containing 5 mg of teduglutide, 3.88 mg of L-histidine, 15 mg of mannitol, 0.644 mg of sodium phosphate. monobasic and 3,434 mg of sodium phosphate dibasic heptahydrate. This lyophilizate is taken up with 500 ⁇ l of sterile water. The pH of the solution obtained is 7.4.
  • Example B2 Preparation of an aqueous solution S2 of mannitol (165 mM), L-histidine (50 mM) and phosphate (35 mM) at pH 7.4
  • a solution of excipients is prepared from concentrated aqueous solutions of L-histidine, mannitol, phosphate buffer pH 7.4 and water so as to obtain a final concentration of 50 mM of L-histidine. 165 mM mannitol and 35 mM phosphate pH 7.4.
  • Example B3 Preparation of solutions S3 to S6 comprising varying concentrations of 0.5 to 3 mg / ml of teduglutide and containing mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at a pH of 7.4
  • a solution S2 of excipients is added to the concentrated solution of teduglutide SI so as to obtain the solutions S3 to S6 having a final concentration of teduglutide as presented in Table 3, and a final mannitol concentration of 165 mM, a final L-histidine concentration of 50 mM and a final phosphate concentration of 35 mM, and with a pH of 7.4.
  • Example B4 Preparation of 1 mg / ml solutions of teduglutide containing co-polyamino acid Al, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
  • Solutions B4-1 and B4-2 are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid Al.
  • Example B5 Preparation of solutions of teduglutide at 1 mg / ml containing co-polyamino acid A 2, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7.4
  • Solutions B5-1 and B5-2 are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated IF solution, and a concentrated solution of co-polyamino acid A2.
  • Example B6 Preparation of 1 mg / ml solutions of teduglutide containing A3 co-polyamino acid, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
  • Solutions B6-1 to B6-5 are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid A3.
  • Table 6 Compositions and visual appearance of solutions B6-1 to B6-5.
  • Example B7 Preparation of solutions of teduglutide at 10 mg / ml containing A3 co-polyamino acid, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
  • Solution B7-6 (described in Table 7) is obtained by dissolving a freeze-dried product marketed by Shire containing 5 mg of teduglutide, 3.88 mg of L-histidine, 15 mg of mannitol and 0.644 mg of phosphate. of sodium monobasic and 3,434 mg of sodium phosphate dibasic heptahydrate. This lyophilizate is taken up with 500 ⁇ l of a sterile aqueous solution of co-polyamino acid A3 at 36.2 mg / ml. The final pH is 7.4.
  • Example B8 preparation of a solution of teduglutide at 1 mg / ml containing co-polyamino acid A4, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7, 4
  • composition B8-1 (described in Table 8) is obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer at pH 7.4) with a concentrated SI solution. teduglutide, and a concentrated solution of co-polyamino acid A4.
  • Table 8 Composition and visual appearance of solution B8-1.
  • Example B9 Preparation of solutions of teduglutide at 1 mg / ml containing co-polyamino acid A5, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
  • Solutions B9-1 and B9-2 are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid A5.
  • Table 9 compositions and visual appearance of solutions B9-1 and B9-2.
  • Example B10 Preparation of solutions of teduglutide at 1 mg / ml containing co-polyamino acid A6, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
  • the solutions B10-1 to B10-4 are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid D1.
  • Table 10a compositions and visual appearance of solutions B10-1 and B10-4.
  • Example B11 Preparation of solutions of teduglutide at 3 mg / ml containing co-polyamino acid A6, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7.4
  • Solutions B1-5 and B1 1-6 are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4). , a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid A6.
  • Table 1 Compositions and visual appearance of teduglutide solutions at 3 mg / ml D1-
  • Example B12 preparation of a solution of teduglutide at 1 mg / ml containing co-polyamino acid A7, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7, 4
  • the solution A7-1 (described in Table 12a) is obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer at pH 7.4), with a concentrated SI solution. teduglutide, and a concentrated solution of co-polyamino acid A7.
  • Table 12a compositions and visual appearance of the teduglutide solution B12-1.
  • Example B13 Preparation of a 10 mg / ml solution of exenatide S7 containing mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7.4
  • a concentrated exenatide solution is prepared by dissolving 10 mg of powder marketed by Bachem in 1 ml of the solution of excipients S2. The pH of the solution obtained is 7.4.
  • Example B14 Preparation of 0.5 mg / ml solution of exenatide S8 containing mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
  • a solution S2 of excipients is added to the concentrated solution S7 of exenatide so as to obtain a solution S8 with a final concentration of exenatide of 0.5 mg / ml, and a final concentration of mannitol of 165 mM, a final concentration of L-histidine of 50 mM and a final phosphate concentration of 35 mM, and with a pH of 7.4.
  • Example B15 Preparation of solutions of teduglutide at 1 mg / ml containing varying concentrations of exenatide ranging from 8 to 50 ⁇ g / ml, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer ( 35 mM) at pH 7.4
  • the solutions S9 to S10 are obtained by mixing the appropriate volumes of a solution of excipients S2, a concentrated solution SI teduglutide, and a solution S8 of exenatide for a final mannitol concentration of 165 mM, 50 mM L-histidine and 35 mM phosphate, and a final pH of 7.4.
  • Table 13 compositions and visual appearance of solutions Bl-1 to B-5.
  • Example B16 Preparation of solutions of teduglutide at 1 mg / ml containing varying concentrations of exenatide ranging from 8 to 50 ⁇ g / ml, co-polyamino acid A3, mannitol (165 mM), L-histidine (50 mM) ) and phosphate buffer (35 mM) at pH 7.4
  • the solutions B1-7 to B1-8 are obtained by mixing the appropriate volumes of a solution of excipients S2, a concentrated solution SI teduglutide, a solution S8 of exenatide and a concentrated solution of co-polyamino acid A3, for a final mannitol concentration of 165 mM,
  • Table 14 compositions and visual appearance of solutions B16-7 and B16-8.
  • compositions obtained above are physically stable injectable compositions.
  • C Physico-Chemistry
  • amyloid fibrils defined as ordered macromolecular structures. These may eventually lead to gel formation within the sample.
  • Thioflavin T is a small probe molecule with a characteristic fluorescence signature when it binds to amyloid-type fibrils (Naiki et al (1989) Anal BioChem 177, 244-249, LeVine (1999) ethods, Enzymol. 309, 274-284).
  • This method makes it possible to follow the formation of fibrils within undiluted solutions.
  • This monitoring is performed under accelerated stability conditions: with stirring and at 37 ° C.
  • a volume of 150 ⁇ L of the composition was introduced into a well of a 96-well plate. Each composition was analyzed with at least two tests (duplicate) within the same plate. The plate was sealed with transparent film to prevent evaporation of the composition.
  • This plate was then placed in the enclosure of a plate reader (EnVision 2104 Multilabel, Perkin Elmer). The temperature is set at 37 ° C, and side shaking of 960 rpm with 1 mm amplitude is imposed.
  • a reading of the fluorescence intensity in each well is made with an excitation wavelength of 442 nm, and an emission wavelength of 482 nm over time.
  • the fibrillation process is manifested by a sharp increase in fluorescence after a delay called latency.
  • this delay was determined graphically as the intersection between the baseline of the fluorescence signal and the slope of the fluorescence curve as a function of time determined during the sharp initial increase in fluorescence.
  • the reported latency value is the average of latency measurements made on two wells.
  • FIG. 1 An example of a graphical determination is shown in FIG. 1.
  • LT lag time
  • Example C1 Latency of solutions of teduglutide at different concentrations
  • the latency time of a teduglutide solution over a concentration range of 0.5 to 3 mg / ml is between 1.15 and 1.55 h.
  • the lag time of the peptide alone is therefore substantially identical over a concentration range close to that of the commercial product (10 mg / ml).
  • Example C2 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of polyamino acid Al
  • Table 11 ThT lag times for solutions B4-1 and B4-2 compared to S4.
  • the latency time of an S4 solution of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; solutions B4-1 and B4-2, allow latency times respectively at least 7 and 13 h.
  • Example C3 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A2
  • Table 12 ThT latency for B5-1 and B5-2 solutions, compared with S4 solution.
  • the latency time of a solution S4 of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; the solutions B5-1 and B5-2 make it possible to obtain latency times respectively at least greater than 3 and 21 h.
  • Example C4 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A3
  • Table 13 Latency by ThT (solutions B6-1 to B6-5, compared with solution S4).
  • the latency time of a solution S4 of teduglutide, free of co-polyamino acid, is less than 1.5 h; the solutions B6-1 to B6-5, containing molar ratios A3 / teduglutide of 0.5 to 3, make it possible to obtain latencies at least greater than 5 hours, a molar ratio of 3 allowing to obtain a time Latency greater than 69 hours.
  • Example C5 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A4
  • the latency time of a solution S4 of teduglutide devoid of co-polyamino acid is less than 1.5 h; Solution B8-1 provides a latency of more than 11 hours.
  • Example C6 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A5
  • Table 15 ThT Latency of Solutions B9-1 and B9-2, Comparison with S4 Solution.
  • the latency time of a solution S4 of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; solutions B9-1 and B9-2 provide latency times of at least 8 hours.
  • Table 16a ThT Latency of Solutions B10-1 to B10-4, Comparison with S4 Solution
  • the latency of a S4 solution of teduglutide, free of co-polyamino acid, is less than 1, 5 h; the solutions B10-1 to B10-4 according to the invention, containing molar ratios A6 / teduglutide of 0.25 to 2, make it possible to obtain latency times of at least 13 h, a molar ratio of 2 allowing obtain latency times greater than 62 hours.
  • Example C8 Stability of teduglutide at 3 mg / ml at pH 7.4 in the presence of co-polymamino acid A6
  • Table 17a ThT latency time of the solutions Bl l-5 and Bl l-6, comparison with the solution S6.
  • the latency time of a solution S6 of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; the solutions B10-5 and B1 1-6 according to the invention, containing Dl / teduglutide molar ratios of 0.25 to 0.5, make it possible to obtain latency times respectively at least greater than 13 and 16 h.
  • Example C9 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polymamino acid A7
  • Table 18a ThT lag time of the D2-1 solution, comparison with the S4 solution.
  • the latency time of a solution S4 of teduglutide, free of co polyamino acid, is less than 1.5 h; solution B12-1, containing an A7 / teduglutide molain ratio of 1, makes it possible to obtain a latency time greater than 12 hours.
  • Example CIO Physical stability of teduglutide (1 mg / mL) at 30 ° C. in the presence or absence of co-polyamino acid A3
  • Table 16 Physical stability at 30 ° C (static) of an S4 solution of teduglutide without co-polyamino acid, and solutions B6-3 and B6-5
  • An S4 solution of teduglutide, devoid of co-polyamino acid, is less than 7 days compliant with the physical stability criteria by visual observation.
  • the B6-5 solution, containing an A3 / teduglutide molar ratio of 3, makes it possible to prolong the physical stability at 30 ° C. for at least 63 days.
  • Example Cil Physical stability of teduglutide (10 mg / ml) at 30 ° C. in the presence or absence of co-polyamino acid A3
  • Table 17 Physical stability at 30 ° C (static) of a solution SI of teduglutide without co-polyamino acid, and solution B7-6
  • Example C12 Physical stability of teduglutide at 30 ° C. in the presence or absence of co-polyamino acid A6
  • Table 18b comparison of the physical stability at 30 ° C. (static) of a solution 54 of co-polyamino acid-free teduglutide and a B10-3 solution
  • An S4 solution of teduglutide, devoid of co-polyamino acid, is less than 7 days compliant with the physical stability criteria by visual observation.
  • Example C13 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polaminoacid A3 and hexenatide
  • Table 20 ThT latency for B16-7 and B16-8 solutions compared to S4 and S9 and S10 solutions.
  • the latency time of a solution S4 of teduglutide, devoid of co-polyamino acid, is less than 3.5 h.
  • the latency times of solutions S9 and S10 of teduglutide + exenatide, lacking co-polyamino acid A3, are also less than 3.5 h.
  • the solutions Bl-7 and Bl-8, containing the two teduglutide and exenatide peptides and a molar ratio A3 / teduglutide of 3 make it possible to obtain a latency time greater than 63 h.
  • the chemical stability of the formulations was evaluated by RP-HPLC on an Agilent 1200 Series HPLC system according to the method described in Table 18. The analysis is carried out with a C18 type reverse phase chromatography column following a gradient. conventional in acidic conditions with the addition of 0.05% trifluoroacetic acid and 0.05% formic acid in aqueous phase A and organic phase B. The signal area of native teduglutide and its degradation products are then manually determined using ChemStation software to calculate total teduglutide coverage (native peptide and degradation products) and native teduglutide coverage. Attribution setting
  • Table 19 Total and native teduglutide and teduglutide degradation product content at 7 and 49 days for solutions stored at 30 ° C.

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Abstract

The invention relates to a stable composition physically in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least: a) a GLP-2 analog, and b) a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic radicals Hy.

Description

COMPOSITION COMPRENANT UN AGONISTE DU RECEPTEUR OU GLP-2 ET UN CO-POLYAMINOACIDE PORTEUR DE CHARGES CARBOXYLATES ET DE RADICAUX HYDROPHOBES  COMPOSITION COMPRISING A RECEPTOR OR GLP-2 AGONIST AND A CO-POLYAMINOACIDE CARBOXYLATE AND HYDROPHOBIC RADICAL CARRIERS
[0001] L'invention concerne une composition comprenant un agoniste du récepteur du GLP-2 humain, encore appelé GLP-2 RA, et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes. Un GLP-2 RA peut en particulier être un analogue de GLP-2 humain. The invention relates to a composition comprising a human GLP-2 receptor agonist, also called GLP-2 RA, and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals. A GLP-2 RA may in particular be a human GLP-2 analogue.
[0002] Le GLP-2 est un peptide composé de 33 amino-acides formé à partir du proglucagon, comme d'autres peptides tels que le GLP-1 ou encore le glucagon. Il est notamment co-secrété avec le GLP- 1 en réponse à l'ingestion des nutriments lors de la prise alimentaire. En 1996, le rôle inducteur du GLP-2 sur la croissance de l'épithélium intestinal a pu être mis en évidence (Drucker et al . (1996) Proc. Natl. Acad. Sci. USA 93, 7911 -7916). La démonstration des effets bénéfiques du GLP-2 sur l'intestin grêle a suscité un réel intérêt à appliquer ces propriétés au traitement de différentes maladies ou altérations de l'intestin. GLP-2 is a peptide composed of 33 amino acids formed from proglucagon, as other peptides such as GLP-1 or glucagon. It is in particular co-secreted with GLP-1 in response to ingestion of nutrients during food intake. In 1996, the inducing role of GLP-2 on the growth of the intestinal epithelium could be demonstrated (Drucker et al (1996) Proc Natl Acad Sci USA 93, 7911-7916). The demonstration of the beneficial effects of GLP-2 on the small intestine has generated a real interest in applying these properties to the treatment of various diseases or alterations of the intestine.
[0003] Cependant, ce peptide est dégradé très rapidement par le clivage au niveau de l'alanine en deuxième position N-terminale par la DPP-IV : sa demi-vie est ainsi particulièrement courte, de l'ordre de 7 minutes chez un sujet sain (Tavares et al (2000) Am. J. Physiol . Endocrinol. Metab. 278, E134-E139).  However, this peptide is degraded very rapidly by cleavage at the level of alanine in the second N-terminal position by the DPP-IV: its half-life is thus particularly short, of the order of 7 minutes in one patient. healthy subject (Tavares et al (2000) Am J Physiol Endocrinol, Metab 278, E134-E139).
[0004] Afin de pallier ce problème, la demande WO97/39031 décrit des analogues du GLP-2 ayant une demi-vie augmentée. Selon un mode de réalisation, il s'agit d'analogues dans lesquels l'alanine en position 2 est substituée par un autre résidu d'acide aminé afin d'améliorer la résistance contre la dégradation par la DPP-IV. Parmi les analogues décrits figure celui dans lequel l'alanine est remplacée par la glycine, ou h[Gly2]GLP-2. Cet analogue a pour nom le téduglutide, et présente une demi-vie plasmatique nettement augmentée, environ 2 heures vs 7 minutes pour le GLP-2 naturel .  In order to overcome this problem, the application WO97 / 39031 describes GLP-2 analogues having an increased half-life. In one embodiment, these are analogs in which alanine at the 2-position is substituted with another amino acid residue to enhance the resistance against DPP-IV degradation. Among the analogs described is that in which alanine is replaced by glycine, or h [Gly2] GLP-2. This analogue is called teduglutide, and has a significantly increased plasma half-life, about 2 hours vs 7 minutes for natural GLP-2.
[0005] Cependant, la demande WOOl/49314 décrit que le téduglutide ne conduit pas à des solutions aqueuses stables qui peuvent être préparées avec un procédé commercialement acceptable et recherche des moyens permettant de résoudre ce problème. La demande WOOl/49314 ne décrit pas d'excipients permettant de stabiliser les analogues de GLP-2 puisque des additifs classiques de type Tween 80®, de sels, comme le glutamate, le citrate, la sérine, la proline, la glycine, ainsi que l'arginine ne permettent pas d'améliorer la stabilité, voire même ont un effet négatif sur celle-ci. En revanche, il est décrit que l'ajout d'histidine permet de produire un lyophilisât facilement solubilisable dans une solution aqueuse, la solution obtenue présentant une stabilité suffisante pour procéder à l'administration dans un délai de quelques heures. [0005] However, WO01 / 49314 discloses that teduglutide does not lead to stable aqueous solutions that can be prepared with a commercially acceptable process and seeks ways to solve this problem. WO01 / 49314 does not disclose excipients for stabilizing GLP-2 analogues since conventional Tween 80® type additives, such as glutamate, citrate, serine, proline, glycine, that arginine does not improve the stability, or even have a negative effect on it. In contrast, it is described that the addition of histidine makes it possible to produce a lyophilisate easily solubilizable in an aqueous solution, the resulting solution having a sufficient stability to proceed to the administration within a few hours.
[0006] Cette demande couvre d'ailleurs la formulation commerciale de téduglutide (dénommée Revestive® en Europe et Gattex® aux Etats-Unis), qui est aujourd'hui le seul produit commercial d'un GLP-2 RA. Ce médicament est approuvé pour le traitement du syndrome de l'intestin court, en anglais « short bowel syndrome », abrégé en « SBS » . This application also covers the commercial formulation of teduglutide (called Revestive® in Europe and Gattex® in the United States), which is today the only commercial product of a GLP-2 RA. This drug is approved for the treatment of short bowel syndrome, abbreviated as "SBS".
[0007] Les notices de ces produits précisent que l'utilisation de la solution préparée à partir du lyophilisât doit avoir lieu dans les 3 heures suivant la reconstitution. La forme galénique choisie pour ce produit, c'est-à-dire un lyophilisât, est la conséquence de la très médiocre stabilité physique du peptide en solution aqueuse.  The records of these products specify that the use of the solution prepared from the lyophilisate must take place within 3 hours of reconstitution. The dosage form chosen for this product, that is to say a lyophilizate, is the consequence of the very poor physical stability of the peptide in aqueous solution.
[0008] Par ailleurs, d'autres analogues sont décrits afin de proposer aux patients une alternative au traitement existant.  Moreover, other analogs are described to provide patients with an alternative to existing treatment.
[0009] Par exemple, WO 99/43361 décrit des analogues du GLP-2 substitués par une chaîne alkyle. Cette alkylation par des chaînes type tétradécanoyl ou carboxynonadécanoyl permet notamment d'allonger significativement la demi-vie de ces analogues.  For example, WO 99/43361 discloses GLP-2 analogues substituted with an alkyl chain. This alkylation by tetradecanoyl or carboxynonadecanoyl type chains makes it possible in particular to significantly lengthen the half-life of these analogs.
[00010] La demande WO2006/117565 décrit de nouveaux analogues du GLP-2 présentant une meilleure stabilité chimique et une activité biologique similaire, voire meilleure que le GLP-2 naturel . Parmi ces analogues, le glepaglutide est actuellement engagé dans des études cliniques de phase II.  WO2006 / 117565 discloses novel GLP-2 analogues having better chemical stability and biological activity similar to or better than natural GLP-2. Among these analogues, glepaglutide is currently engaged in phase II clinical studies.
[00011] Cependant, à la connaissance de la demanderesse aucun moyen permettant d'obtenir une solution aqueuse d'agoniste au récepteur du GLP-2 ou d'analogues du GLP-2 ayant une stabilité physique véritablement améliorée, notamment par rapport à la demande WO01/49314 n'est décrite dans la littérature. Or, considérant la fréquence quotidienne d'injection de ce produit et la complexité du mode de reconstitution du lyophilisât du produit existant, il serait très avantageux pour les patients d'avoir accès à une composition sous forme de solution aqueuse prête à l'emploi, voire à un dispositif d'injection sous cutané comprenant une telle solution aqueuse. However, to the knowledge of the applicant no means for obtaining an aqueous agonist solution to the GLP-2 receptor or GLP-2 analogues having a truly improved physical stability, particularly with respect to the application WO01 / 49314 is not described in the literature. However, considering the daily frequency of injection of this product and the complexity of the method of reconstituting the freeze-dried product, it would be very advantageous for patients to have access to a composition in the form of aqueous solution ready for use, even to a subcutaneous injection device comprising such an aqueous solution.
[00012] Il serait en outre extrêmement avantageux de disposer de solutions aqueuses de GLP-2 RA stables physiquement, en particulier de GLP-2 ou d'analogues de GLP-2, déjà mis sur le marché, comme le téduglutide, afin de disposer d 'une solution aqueuse prête à l'emploi, ou tout au moins présentant une stabilité physique améliorée, comprenant un GLP-2 RA avec des coûts de développement bien inférieurs à ceux d'un nouvel actif pharmaceutique. Cela peut également permettre d'utiliser un principe actif ayant des données d'efficacité et de toxicité bien établies, diminuant les risques associés au développement d'un nouveau principe actif. [00013] La demanderesse a ainsi trouvé, de manière surprenante, qu'une composition comprenant un agoniste du récepteur du GLP-2 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes présente une stabilité physique supérieure aux solutions proposées dans l'art antérieur. It would also be extremely advantageous to have physically stable aqueous solutions of GLP-2 RA, in particular GLP-2 or GLP-2 analogues, already placed on the market, such as teduglutide, in order to dispose of an aqueous solution ready for use, or at least having improved physical stability, comprising a GLP-2 RA with development costs well below those of a new pharmaceutical active. It can also make it possible to use an active ingredient with well-established efficacy and toxicity data, reducing the risks associated with the development of a new active ingredient. The Applicant has thus found, surprisingly, that a composition comprising a GLP-2 receptor agonist and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals has a higher physical stability than the solutions proposed in US Pat. prior art.
[00014] L'invention concerne la préparation d'une composition comprenant un analogue du GLP-2 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes présentant des propriétés de stabilité physique améliorées par rapport à celles décrites dans l'art antérieur. Cette invention est remarquable car il est bien connu de l'homme de l'art que les propriétés de stabilité physique sont très difficiles à prédire. The invention relates to the preparation of a composition comprising an analogue of GLP-2 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals having improved physical stability properties compared with those described in the prior art. . This invention is remarkable because it is well known to those skilled in the art that the physical stability properties are very difficult to predict.
[00015] L'invention concerne en outre en une méthode de préparation de compositions injectables stables physiquement.  The invention further relates to a method for preparing physically stable injectable compositions.
[00016] Les compositions sous forme d'une solution aqueuse injectable selon l'invention sont des solutions limpides. The compositions in the form of an aqueous solution for injection according to the invention are clear solutions.
[00017] L'invention concerne également des formulations pharmaceutiques stables comprenant de telles compositions. The invention also relates to stable pharmaceutical formulations comprising such compositions.
[00018] Ces formulations pharmaceutiques peuvent être indiquées : [00018] These pharmaceutical formulations may be indicated:
- pour traiter des pathologies du tractus digestif, notamment, de l'œsophage, de l'estomac, du duodénum, de l'intestin grêle, du colon, du rectum.  - To treat pathologies of the digestive tract, including the esophagus, stomach, duodenum, small intestine, colon, rectum.
- pour traiter des inflammations du tractus digestif, notamment de l'estomac ou de l'intestin, des maladies inflammatoires chroniques de l'appareil digestif telles que la maladie de Crohn ou la rectocolite hémorragique, les maladies associées à la destruction de la muqueuse épithéliale tels que les ulcères (ulcères liés à des infections, ulcères peptiques, ulcères médicamenteux, syndrome de Zollinger- Ellison), pour des maladies auto-immune de l'appareil digestif, notamment de l'intestin, et/ou  - to treat inflammations of the digestive tract, in particular of the stomach or intestine, inflammatory diseases of the digestive system such as Crohn's disease or ulcerative colitis, diseases associated with the destruction of the epithelial mucosa such as ulcers (ulcers associated with infections, peptic ulcers, medicated ulcers, Zollinger-Ellison syndrome), for autoimmune diseases of the digestive system, including the intestine, and / or
- pour traiter des ischémies intestinales.  to treat intestinal ischemia.
[00019] Selon un mode de réalisation particulier, ces formulations pharmaceutiques sont indiquées pour le traitement de la résection massive de l'intestin grêle, ou « massive small intestine resection », la maladie inflammatoire de l'intestin, ou « inflammatory bowel disease », la mucosité associée au chimiothérapies, ou « chemotherapy induced mucositis », et/ou une atteinte ischémique, ou « ischémie injury ». [00020] Selon un mode de réalisation particulier, ces formulations pharmaceutiques sont indiquées pour le traitement du syndrome de l'intestin court, ou « short bowel syndrome », abrégé en « SBS ». According to a particular embodiment, these pharmaceutical formulations are indicated for the treatment of massive small bowel resection, or "massive small intestine resection", inflammatory bowel disease, or "inflammatory bowel disease" , mucositis associated with chemotherapy, or "chemotherapy induced mucositis", and / or ischemic injury, or "ischemia injury". According to a particular embodiment, these pharmaceutical formulations are indicated for the treatment of short bowel syndrome, or "short bowel syndrome", abbreviated as "SBS".
[00021] L'invention concerne ainsi 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 : The invention thus relates to physically stable compositions in the form of an injectable aqueous solution, whose pH is between 6.0 and 8.0, comprising at least:
a) un agoniste du récepteur du GLP-2 ou un analogue du GLP-2, ou h[Gly2]GLP-2 , et  a) a GLP-2 receptor agonist or a GLP-2 analogue, or h [Gly2] GLP-2, and
b) 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 I suivante :
Figure imgf000005_0001
Formule I b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid being constituted by glutamic or aspartic units and said hydrophobic radicals Hy being of formula I below:
Figure imgf000005_0001
Formula I
dans laquelle  in which
- GpR est un radical de formules II ou IV : - GpR is a radical of formulas II or IV:
O O
H H H H H H
*— N-R-N— * Formule II ou * -R— N— * Formule II';  * - N-R-N- * Formula II or * -R- N- * Formula II ';
- GpA est un radical de formules III ou III' ; GpA is a radical of formulas III or III ';
O HN— * O HN- *
JLA' o JL A 'o
H H
HN Formule III ou A — * Formule III'; HN Formula III or A - * Formula III ';
GpC est un radical de formule IV : GpC is a radical of formula IV:
Figure imgf000005_0002
Figure imgf000005_0002
- les -* indiquent les sites de rattachement des différents groupes ;  - the - * indicate the sites of attachment of the different groups;
- a est un entier égal à 0 ou à 1 ; - b est un entier égal à 0 ou à 1 ; - a is an integer equal to 0 or 1; b is an integer equal to 0 or 1;
p est un entier égal à 1 ou à 2 et  p is an integer equal to 1 or 2 and
o si p est égal à 1 alors a est égal à 0 ou à 1 et GpA est un radical de formule ΙΙΓ et,  o if p is equal to 1 then a is equal to 0 or 1 and GpA is a radical of formula ΙΙΓ and,
o si p est égal à 2 alors a est égal à 1, et GpA est un radical de formule III; o if p is equal to 2 then a is equal to 1, and GpA is a radical of formula III;
- 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 1, and if c is equal to 0 then d is equal to 1 or 2;
- d est un entier égal à 0, à 1 ou à 2; d is an integer equal to 0, 1 or 2;
- r est un entier égal à 0 ou à 1, et  r is an integer equal to 0 or 1, and
o si r est égal à 0 alors le radical hydrophobe de formule I est lié au co- polyaminoacide via une liaison covalente entre un carbonyl du radical hydrophobe et un atome d'azote en position N terminale du co- polyaminoacide, formant ainsi une fonction amide issue de la réaction d'une fonction aminé en position N terminale du précurseur du co-polyaminoacide et une fonction acide portée par le précurseur du radical hydrophobe , et o si r est égal à 1 alors le radical hydrophobe de formule I est lié au co- polyaminoacide :  if r is equal to 0, then the hydrophobic radical of formula I is bonded to the co-polyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amino function at the N-terminal position of the precursor of the co-polyamino acid and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1, then the hydrophobic radical of formula I is bound to the polyamino acid:
» via une liaison covalente entre un atome d 'azote du radical hydrophobe et un carbonyl du co-polyaminoacide, formant ainsi une fonction amide issue de la réaction d'une fonction aminé du précurseur du radical hydrophobe et une fonction acide portée par le précurseur du co-polyaminoacide ou »Via a covalent bond between a nitrogen atom of the hydrophobic group and a carbonyl co-polyamino acid, thus forming an outlet amide from the reaction of an amine functional group of the precursor of the hydrophobic group and an acidic functional group carried by the precursor of the co-polyamino acid or
■ via une liaison covalente entre un carbonyl du radical hydrophobe et un atome d'azote en position N terminal du co-polyaminoacide, formant ainsi une fonction amide issue de la réaction d'une fonction acide du précurseur du radical hydrophobe et une fonction aminé en position N terminale portée par le précurseur du co- polyaminoacide;  Via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thereby forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and an amine function in N-terminal position carried by the precursor of the co-polyamino acid;
- R est un radical choisi dans le groupe constitué par :  R is a radical chosen from the group consisting of:
o un radical alkyle divalent, linéaire ou ramifié, comprenant si GpR est un radical de formule II de 2 à 12 atomes de carbone ou si GpR est un radical de formule Ι de 1 à 11 atomes de carbone ;  a divalent alkyl radical, linear or branched, comprising if GpR is a radical of formula II of 2 to 12 carbon atoms or if GpR is a radical of formula Ι of 1 to 11 carbon atoms;
o un radical éther ou polyéther non substitué comprenant de 4 à 14 atomes de carbone et de 1 à 5 atomes d'oxygène ;  an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;
- A est un radical choisi dans le groupe constitué par un radical éther ou polyéther non substitué comprenant de 4 à 14 atomes de carbone et de 1 à 5 atomes d'oxygène ou un radical alkyle linéaire ou ramifié comprenant de 1 à 8 atomes de carbone et éventuellement substitué par un radical issu d'un cycle saturé, insaturé ou aromatique; - B est un radical alkyle linéaire ou ramifié, éventuellement comprenant un noyau aromatique, comprenant de 1 à 9 atomes de carbone; - A is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical comprising from 1 to 8 carbon atoms and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring; B is a linear or branched alkyl radical, optionally comprising an aromatic nucleus 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 :  Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:
o si p est égal à 1, x est compris entre 11 et 25 ( 11 < x < 25) : o si p est égal à 2, x est compris entre 9 et 15 (9 < x < 15),  o if p is equal to 1, x is between 11 and 25 (11 <x <25): o if p is equal to 2, x is between 9 and 15 (9 <x <15),
le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques étant compris entre entre 0 < i < 0,5 ;  the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <i <0.5;
lorsque plusieurs radicaux hydrophobes -Hy sont portés par un co- polyaminoacide alors ils sont identiques ou différents,  when several hydrophobic radicals -Hy are borne by a co-polyamino acid then they are identical or different,
le degré de polymérisation DP en unités glutamiques ou aspartiques est compris entre 5 et 250 ; et  the degree of DP polymerization in glutamic or aspartic units is between 5 and 250; and
les fonctions acides libres sont sous forme de sel de cation alkalin choisi dans le groupe constitué par Na+ et K+. the free acid functions are in the form of an alkaline cation salt selected from the group consisting of Na + and K + .
[00022] L'invention concerne également une composition dans laquelle l'analogue du GLP-2 est h[Gly2]GLP-2. The invention also relates to a composition in which the GLP-2 analogue is h [Gly2] GLP-2.
[00023] L'invention concerne également une composition dans laquelle l'analogue du GLP-2 est un agoniste du récepteur du GLP-2.  The invention also relates to a composition in which the GLP-2 analogue is a GLP-2 receptor agonist.
L'invention concerne également une composition comprenant au moins un un analogue du GLP-2, The invention also relates to a composition comprising at least one GLP-2 analogue,
[00024] Dans les formules les -* indiquent les sites de rattachements des différents éléments représentés. [00025] Dans la formule I -* indique le site de rattachement des radicaux hydrophobes au co-polyaminoacide. Les radicaux Hy sont rattachés au co- polyaminoacide via des fonctions amides.  In the formulas - * indicate the sites of attachment of the various elements shown. In the formula I - * indicates the site of attachment of the hydrophobic radicals to the co-polyamino acid. The radicals Hy are attached to the co-polyamino acid via amide functions.
[00026] [00026]
[00027] Dans les formules II et IV, les -* indiquent, de gauche à droite respectivement, les sites de rattachement de GpR :  In the formulas II and IV, the - * indicate, from left to right respectively, the sites of attachment of GpR:
au co-polyaminoacide et  with co-polyamino acid and
- à GpA si a = 1 ou à G PC si a = 0.  - to GpA if a = 1 or G PC if a = 0.
[00028] Dans les formules III et ΙΙΓ, les -* indiquent, de gauche à droite respectivement, les sites de rattachement de GpA :  In the formulas III and ΙΙΓ, the - * indicate, from left to right respectively, the sites of attachment of GpA:
- à GpR si r = 1 ou au co-polyaminoacide si r = 0 et  to GpR if r = 1 or to the co-polyamino acid if r = 0 and
- à GpC.  - at GpC.
[00029] Dans la formule IV, le * indique le site de rattachement de GpC : - à GpA si a = 1, GpR si r = 1 et a = 0 ou au co-polyaminoacide si r = 0 et a = 0. In formula IV, the * indicates the site of attachment of GpC: to GpA if a = 1, GpR if r = 1 and a = 0 or to the co-polyamino acid if r = 0 and a = 0.
[00030] Tous les rattachements entre les différents groupes GpR, GpA et GpC sont des fonctions amides. All connections between the different groups GpR, GpA and GpC are amide functions.
[00031] Les radicaux Hy, GpR, GpA, GpC, et D sont chacun indépendamment identiques ou différents d'une unité monomérique à l'autre.  The radicals Hy, GpR, GpA, GpC, and D are each independently identical or different from one monomeric unit to another.
[00032] On entend par « soluble », un composé susceptible de permettre de préparer une solution limpide et dépourvue de particules à une concentration inférieure à 100 mg/ml dans de l'eau distillée à 25°C. The term "soluble", a compound capable of allowing to prepare a clear solution and free of particles at a concentration of less than 100 mg / ml in distilled water at 25 ° C.
[00033] On entend par « solution limpide », des compositions qui satisfont aux critères décrits dans les pharmacopées américaines et européenne concernant les solutions injectables. Dans la pharmacopée US, les solutions 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. The term "clear solution" means compositions that meet the criteria described in the US and European pharmacopoeia for injectable solutions. In the US Pharmacopoeia, the solutions are defined in the <1151> part referring to the 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, injectable solutions must meet the criteria given in sections 2.9.19 and 2.9.20.
[00034] On entend par « solution » une composition liquide dépourvue de particules visibles, en utilisant la procédure conforme aux pharmacopées EP 8.0, au point 2.9.20, et US <790> . The term "solution" means a liquid composition devoid of visible particles, using the procedure according to EP 8.0 pharmacopoeia, point 2.9.20, and US <790>.
[00035] On entend par « composition stable physiquement » des compositions qui après une certaine durée de stockage à une certaine température satisfont aux critères de l'inspection visuelle décrite dans la pharmacopée européenne, américaine et internationale, c'est-à-dire des compositions qui sont limpides et qui ne contiennent pas de particules visibles.  By "physically stable composition" is meant compositions which after a certain storage period at a certain temperature satisfy the criteria of the visual inspection described in the European, American and international pharmacopoeia, that is to say compositions that are clear and do not contain visible particles.
[00036] On entend par « composition stable chimiquement » des compositions qui, après stockage un certain temps et à une certaine température, présentent une recouvrance minimum des principes actifs et sont conformes aux cahiers des charges applicables aux produits pharmaceutiques.  The term "chemically stable composition" means compositions which, after storage for a certain time and at a certain temperature, have a minimum recovery of the active ingredients and are in accordance with the specifications applicable to pharmaceutical products.
[00037] Une méthode classique pour mesurer les stabilités des protéines ou peptides consiste à mesurer la formation de fibrilles à l'aide de Thioflavlne T, encore appelée ThT. Cette méthode permet de mesurer dans des conditions de température et d'agitation qui permettent une accélération du phénomène, le temps de latence avant la formation de fibrilles par mesure de l'augmentation de la fluorescence. Les compositions selon l'invention ont un temps de latence avant la formation de fibrilles nettement supérieur à celui des compositions décrites dans l'art antérieur. Avantageusement, les compositions selon l'invention présentent une stabilité physique supérieure à celles décrites dans l'art antérieur A conventional method for measuring the stability of proteins or peptides is to measure the formation of fibrils using Thioflavine T, also called ThT. This method makes it possible to measure, under temperature and agitation conditions that allow an acceleration of the phenomenon, the latency time before the formation of fibrils by measuring the increase in fluorescence. The compositions according to the invention have a lag time before the formation of fibrils significantly greater than that of the compositions described in the prior art. Advantageously, compositions according to the invention have a higher physical stability than those described in the prior art
[00038] On entend par « solution aqueuse injectable » des solutions à base d'eau qui répondent aux conditions des pharmacopées EP et US, et qui sont suffisamment fluides pour être injectées.  The term "aqueous injectable solution" water-based solutions that meet the requirements of the EP and US pharmacopoeia, and which are sufficiently fluid to be injected.
[00039] 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 l'enchaînement.  The term "co-polyamino acid consisting of glutamic or aspartic units" of non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a C terminal part, corresponding to the carboxylic acid of one end, and an N-terminal portion, corresponding to the amine of the other end of the sequence.
[00040] On entend par « radical alkyl » une chaîne carbonée, linéaire ou ramifiée, qui ne comprend pas d'hétéroatome.Le co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe de formule I peut également être appelé « co- polyaminoacide » dans la présente description.  The term "alkyl radical" is understood to mean a linear or branched carbon chain which does not comprise a heteroatom. The co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical of formula I may also be called " co-polyamino acid "in the present description.
[00041] L'invention concerne également lesdits co-polyaminoacides porteurs de charges carboxylates et de radicaux hydrophobes de formule I et les précurseurs desdits radicaux hydrophobes.  The invention also relates to said co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula I and the precursors of said hydrophobic radicals.
[00042] Les co-polyaminoacides porteurs de charges carboxylates et de radicaux hydrophobes de formule I sont solubles dans l'eau distillée à un pH compris entre 6 et 8, à une température de 25°C et à une concentration inférieure à 100 mg/ml.  The co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula I are soluble in distilled water at a pH of between 6 and 8, at a temperature of 25 ° C. and at a concentration of less than 100 mg / ml. ml.
Dans un mode de réalisation, la composition est caractérisée en ce que lesdits radicaux hydrophobes sont choisis parmi les radicaux hydrophobes de formule I dans laquelle si p est égal à 1 et si x est inférieur ou égal à 14 ( x < 14) alors r = 0 ou r = 1. In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which if p is equal to 1 and if x is less than or equal to 14 (x <14) then r = 0 or r = 1.
[00043] Dans un mode de réalisation, la composition est caractérisée en ce que lesdits radicaux hydrophobes sont choisis parmi les radicaux hydrophobes de formule I dans laquelle si p est égal à 1 et si x est compris entre 15 et 16 ( 15≤ x < 16), alors r = 1. In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which if p is equal to 1 and if x is between 15 and 16 (15 x x < 16), then r = 1.
[00044] Dans un mode de réalisation, la composition est caractérisée en ce que lesdits radicaux hydrophobes sont choisis parmi les radicaux hydrophobes de formule I dans laquelle si p est égal à 1 et si x est supérieur à 17 ( 17 ≤ x ) alors r = 1 et R est un radical éther ou polyéther. In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which if p is equal to 1 and if x is greater than 17 (17 ≤ x) then r = 1 and R is an ether or polyether radical.
[00045] Dans un mode de réalisation, la composition est caractérisée en ce que lesdits radicaux hydrophobes sont choisis parmi les radicaux hydrophobes de formule I dans laquelle si p est égal à 1 alors x est compris entre 17 et 25 ( 17≤ x≤ 25). [00046] Dans un mode de réalisation, la composition est caractérisée en ce que lesdits radicaux hydrophobes sont choisis parmi les radicaux hydrophobes de formule I dans laquelle p = 1, représentée par la formule V suivante :
Figure imgf000010_0001
In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which, if p is equal to 1, then x is between 17 and 25 (17 x x 25 25 ). In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which p = 1, represented by the following formula V:
Figure imgf000010_0001
GpR, GpA, GpC, r et a ont les définitions données précédemment. GpR, GpA, GpC, r and a have the definitions given above.
[00047] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule V dans laquelle : r est égal à 1 (r= l) et a est égal à 0 (a = 0). In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which: r is equal to 1 (r = 1) and a is equal to 0 (a = 0).
[00048] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule V dans laquelle r est égal à 1 (r= l) et a est égal à 1 (a = l).  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which r is equal to 1 (r = 1) and a is equal to 1 (a = 1).
[00049] Dans la formule V * indique le site de rattachement des radicaux hydrophobes au co-polyaminoacide. Les radicaux Hy sont rattachés au co- polyaminoacide via des fonctions amides. In the formula V * indicates the site of attachment of the hydrophobic radicals to the co-polyamino acid. The radicals Hy are attached to the co-polyamino acid via amide functions.
[00050] [00051] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II .  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II.
[00052] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle linéaire divalent comprenant de 2 à 12 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a linear divalent alkyl radical comprising from 2 to 12 carbon atoms.
[00053] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle divalent comprenant de 2 à 6 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 atoms of carbon.
[00054] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle linéaire divalent comprenant de 2 à 6 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.
[00055] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle divalent comprenant de 2 à 4 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II wherein R is a divalent alkyl radical having 2 to 4 carbon atoms.
[00056] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle linéaire divalent comprenant de 2 à 4 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.
[00057] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle divalent comprenant 2 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising 2 carbon atoms.
[00058] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule Ι . In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula Ι.
[00059] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule Ι dans laquelle R est un radical alkyle linéaire divalent comprenant de 1 à 11 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula Ι in which R is a linear divalent alkyl radical comprising from 1 to 11 carbon atoms.
[00060] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule IV dans laquelle R est un radical alkyle divalent comprenant de 1 à 6 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula IV in which R is a divalent alkyl radical comprising from 1 to 6 atoms of carbon.
[00061] Dans un mode de réalisation, la composition est caractérisée en ce que le radical R est lié au co-polyaminoacide via une fonction amide portée par le carbone en position delta ou epsilon (ou en position 4 ou 5) par rapport à la fonction amide ( -In one embodiment, the composition is characterized in that the radical R is bonded to the co-polyamino acid via an amide function carried by the carbon in the delta or epsilon position (or in position 4 or 5) with respect to the amide function (-
CONHz). CONH).
[00062] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II ou II', 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.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or II ', in which R is a linear ether or polyether radical. unsubstituted compound comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
[00063] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II ou ΙΓ, dans laquelle R est un radical éther non substitué. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or ΙΓ, in which R is an unsubstituted ether radical.
[00064] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II ou IV, dans laquelle R est un radical éther non substitué comprenant de 4 à 6 atomes de carbone. [00065] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule R est un radical éther non substitué représenté par la
Figure imgf000012_0001
In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or IV, in which R is an unsubstituted ether radical comprising 4 to 6 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula R is an unsubstituted ether radical represented by
Figure imgf000012_0001
[00066] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II ou II', dans laquelle R est un radical polyéther non substituté. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or II ', in which R is an unsubstituted polyether radical.
[00067] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle GpR est un radical de formule II ou II', dans laquelle R est un radical linéaire polyéther non substitué comprenant de 6 à 10 atomes de carbone et de 2 à 3 atomes d'oxygène. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which GpR is a radical of formula II or II ', in which R is an unsubstituted linear polyether radical. comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.
[00068] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe de formule I ou V dans laquelle GpR est un radical de formule II ou II', dans laquelle R est un radical polyéther choisi dans le groupe constitué par les radicaux In one embodiment, the composition is characterized in that the hydrophobic radical of formula I or V in which GpR is a radical of formula II or II ', in which R is a polyether radical chosen from the group consisting of the radicals
représentés par les represented by
Figure imgf000012_0002
Figure imgf000012_0002
[00069] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe de formule I ou V dans laquelle GpR est un radical de formule II dans laquelle R est un radical polyéther non substituté choisi dans le groupe constitué par les radicaux représentés par les formules ci-dessous :
Figure imgf000012_0003
In one embodiment, the composition is characterized in that the hydrophobic radical of formula I or V in which GpR is a radical of formula II in which R is an unsubstituted polyether radical chosen from the group consisting of radicals represented by the formulas below:
Figure imgf000012_0003
[00070] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 0 (a=0) et r est égal à 0 (r=0).  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 0 (a = 0) and r is equal to 0 (r = 0). .
[00071] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égael 1 (a = l) dans laquelle GpA est de formule III ou ΙΙΓ dans laquelle A A est un radical alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone. [00072] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a = 1) dans laquelle GpA est un radical de formule ΙΙΓ dans laquelle A est choisi dans le In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) in which GpA is of formula III or ΙΙΓ in which AA is a linear or branched alkyl radical comprising from 1 to 6 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) in which GpA is a radical of formula ΙΙΓ in which A is chosen in the
Figure imgf000013_0001
Figure imgf000013_0001
[00073] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule III dans laquelle A est choisi dans le groupe constitué des radicaux représentés par la formule ci -dessous : In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula III in which A is selected from the group consisting of the radicals represented by the formula below:
Figure imgf000013_0002
Figure imgf000013_0002
[00074] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule III' dans laquelle A 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. [00075] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule ΙΙ dans laquelle A est un radical linéaire éther non substitué. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula III ' wherein A is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula ΙΙ in which A is an unsubstituted linear ether radical.
[00076] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule ΙΙΓ dans laquelle A est un radical éther comprenant de 4 à 6 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula ΙΙΓ in which A is an ether radical comprising from 4 to 6 carbon atoms.
[00077] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule ΙΙ dans laquelle Aest un radical éther non substitué représenté par la formule *.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula ΙΙ in which A is an unsubstituted ether radical represented by the formula *.
[00078] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a = l) et le radical GpA est un radical de formule Π dans laquelle A est un radical polyether non substituté.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula Π in which A is an unsubstituted polyether radical.
[00079] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule ΙΙΓ dans laquelle A est un radical linéaire polyéther non substitué comprenant de 6 à 10 atomes de carbone et de 2 à 3 atomes d'oxygène.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula ΙΙΓ in which A is an unsubstituted linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.
[00080] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule ΙΙ dans laquelle A est un radical polyéther choisi dans le groupe  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula ΙΙ in which A is a polyether radical chosen from the group
Figure imgf000014_0001
Figure imgf000014_0001
[00081] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 1 (a= l) et le radical GpA est un radical de formule ΙΙΓ dans laquelle A est un radical polyéther non substituté choisi dans le groupe constitué par les radicaux représentés par les formules ci-dessous :
Figure imgf000015_0001
In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 1 (a = 1) and the radical GpA is a radical of formula ΙΙΓ in wherein A is an unsubstituted polyether radical selected from the group consisting of the radicals represented by the formulas below:
Figure imgf000015_0001
[00082] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle a est égal à 0 (a=0) et r est égal à 0 (r=0).  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which a is equal to 0 (a = 0) and r is equal to 0 (r = 0). .
[00083] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux de formules IVa, IVb ou IVc ci-après représentées : In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc hereinafter represented:
Figure imgf000015_0002
Figure imgf000015_0002
[00084] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC est de formule IVa. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical is of formula IVa.
[00085] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux de formules IVa, IVb ou IVc dans lesquels b est égal à 0, répondant respectivement aux formules IVd, IVe, et IVf ci- après représentées : 0 0 Formule îVd In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, respectively corresponding to formulas IVd, IVe and IVf below: 0 0 Formula îVd
0 0 Formule IVe 0 0 Formula IVe
0 Γ) o Formule IVf 0 Γ) o Formula IVf
[00086] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC répond à la formule IV ou IVa dans lesquelles b = 0, et répond à la formule IVd. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical corresponds to formula IV or IVa in which b = 0, and corresponds to the formula IVd.
[00087] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV 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  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV in which b = 1 is chosen from the group consisting of radicals in which B is an amino acid residue selected from the group consisting of radicals
Figure imgf000016_0001
Figure imgf000016_0001
[00088] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV ou IVa dans lesquelles b = 1, est choisi dans le groupe constitué des radicaux dans lesquels B est un résidu d'acide aminé choisi dans le rou e constitué par les In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV or IVa in which b = 1 is chosen from the group consisting of radicals wherein B is an amino acid residue selected from the group consisting of
Figure imgf000017_0001
Figure imgf000017_0001
Figure imgf000017_0003
Figure imgf000017_0003
[00089] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéaires. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of linear alkyl radicals.
[00090] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of branched alkyl radicals.
[00091] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant entre 11 et 14 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 11 and 14 carbon atoms.
[00092] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi
Figure imgf000017_0002
Figure imgf000017_0004
In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen
Figure imgf000017_0002
Figure imgf000017_0004
[00093] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant entre 15 et 16 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.
[00094] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux représentés par les formules ci-dessous : [00095] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi
Figure imgf000018_0001
In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of the radicals represented by the formulas below: In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen
Figure imgf000018_0001
[00096] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant entre 17 et 25 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 17 and 25 carbon atoms.
[00097] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant entre 17 et 18 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.
[00098] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hyd rophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles représentés par les formules ci - dessous: In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below:
Figure imgf000018_0002
Figure imgf000018_0002
[00099] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant entre 18 et 25 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.
[000100] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule I ou V dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles représentés par les formules ci - dessous: In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I or V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of the alkyl radicals represented by the formulas below:
x= 19 [000101] Dans un mode de réalisation, la composition est caractérisée en ce que lesdits radicaux hydrop obes sont choisis parmi les radicaux hydrophobes de formule I dans laquelle a = 1 et p = 2, I suivante :
Figure imgf000019_0001
Formule VI dans laquelle GpR, GpA, GpC et r ont les définitions données précédemment. x = 19 In one embodiment, the composition is characterized in that said hydropoic radicals are chosen from hydrophobic radicals of formula I in which a = 1 and p = 2, I:
Figure imgf000019_0001
Formula VI in which GpR, GpA, GpC and r have the definitions given above.
[000102] Dans la formule VI * indique le site de rattachement des radicaux hydrophobes au co-polyaminoacide. Les radicaux Hy sont rattachés au co- polyaminoacide via des fonctions amides.  In the formula VI * indicates the site of attachment of the hydrophobic radicals to the co-polyamino acid. The radicals Hy are attached to the co-polyamino acid via amide functions.
[000103] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II.
[000104] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II dans lequel R est un radical alkyle linéaire divalent comprenant de 2 à 12 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms. carbon.
[000105] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle divalent comprenant de 2 à 6 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms .
[000106] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle linéaire divalent comprenant de 2 à 6 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms. carbon.
[000107] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle comprenant de 2 à 4 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is an alkyl radical comprising from 2 to 4 carbon atoms.
[000108] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle linéaire divalent comprenant de 2 à 4 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms. carbon.
[000109] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II dans laquelle R est un radical alkyle linéaire divalent comprenant 2 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising 2 carbon atoms.
[000110] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule ΙΓ. [000111] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule ΙΓ dans laquelle R est un radical alkyle linéaire divalent comprenant de 1 à 11 atomes de carbone. [000110] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ΙΓ. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ΙΓ in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms. carbon.
[000112] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule Ι dans laquelle R est un radical alkyle divalent comprenant de 1 à 6 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula Ι in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms .
[000113] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II ou IV, 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.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
[000114] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II ou Ι dans laquelle R est un radical éther non substitué. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or in which R is an unsubstituted ether radical.
[000115] Dans un mode de réalisation, la composition est caractérisée en ce que le radical éther non substitué R est un radical comprenant de 4 à 6 atomes de carbone.  In one embodiment, the composition is characterized in that the unsubstituted ether radical R is a radical comprising from 4 to 6 carbon atoms.
[000116] Dans un mode de réalisation, la composition est caractérisée en ce que le radical éther non substitué est " v v [000116] In one embodiment, the composition is characterized in that the unsubstituted ether radical is "vv
[000117] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II ou IV, dans laquelle R est un radical polyéther non substitué. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted polyether radical.
[000118] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II ou IV, dans laquelle R est un radical linéaire polyéther non substitué comprenant de 6 à 10 atomes de carbone et de 2 à 3 atomes d'oxygène. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is an unsubstituted polyether linear radical comprising from 6 to 10 carbon atoms. to 10 carbon atoms and 2 to 3 oxygen atoms.
[000119] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle GpR est un radical de formule II ou Ι dans laquelle R est un radical linéaire polyéther choisi dans le groupe constitué par les radicaux représentés par les formules ci-dessous : [000120] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle a est égal 1 (a=l) dans laquelle GpA est de formule III dans laquelle A est un radical alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or in which R is a linear polyether radical chosen from the group consisting of the radicals represented by the formulas below: [000120] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which a is equal to 1 (a = 1) in which GpA is of formula III in which A is an alkyl radical. linear or branched comprising from 1 to 6 carbon atoms.
[000121] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpA de formule III est choisi dans le groupe constitué des radicaux de formules Illa et Illb ci -après représentée In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the radical GpA of formula III is chosen from the group consisting of the radicals of formulas IIIa and IIIb below
Figure imgf000021_0002
Figure imgf000021_0002
[000122] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpA de formule III est un radical de formule Illb ci-après représentée In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula III is a radical of formula IIIb represented below
Figure imgf000021_0003
Figure imgf000021_0003
[000123] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux de formules IVa, IVb et IVc ci -après représentées In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of the radicals of formulas IVa, IVb and IVc ci - after represented
Figure imgf000021_0001
* 0 Formule IVb
Figure imgf000021_0001
* 0 Formula IVb
Formule IVc Formula IVc
[000124] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC est de formule IVa. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical is of formula IVa.
[000125] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux de formules IVa, IVb ou IVc dans lesquels b est égal à 0, répondant respectivement aux formules IVd, IVe, et IVf ci -après représentées ;  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, respectively corresponding to the formulas IVd, IVe, and IVf shown below;
Figure imgf000022_0001
Figure imgf000022_0001
[000126] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC répond à la formule IV ou IVa dans lesquelles b = 0, et répond à la formule IVd. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical corresponds to formula IV or IVa in which b = 0, and corresponds to formula IVd.
[000127] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles linéaires comprenant entre 9 et 15 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from group consisting of linear alkyl radicals comprising between 9 and 15 carbon atoms.
[000128] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles ramifiés comprenant entre 9 et 15 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by branched alkyl radicals comprising between 9 and 15 carbon atoms.
[000129] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant 9 ou 10 atomes de carbone.  In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by the alkyl radicals comprising 9 or 10 carbon atoms.
[000130] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant entre 11 et 15 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising between 11 and 15 carbon atoms.
[000131] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicau dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant entre 11 et 13 atomes de carbone. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicau in which Cx is chosen from the group consisting of by alkyl radicals comprising between 11 and 13 carbon atoms.
[000132] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from
Figure imgf000023_0001
[000133] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux alkyles comprenant 14 ou 15 atomes de carbone.
Figure imgf000023_0001
In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising 14 or 15 carbon atoms.
[000134] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe est un radical de formule VI dans laquelle le radical GpC de formule IV est choisi dans le groupe constitué des radicaux dans lesquels Cx est choisi dans le groupe constitué par les radicaux représentés par les fo rmules ci-d essous : [000135] Dans un mode de réalisation, le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 0, p = 1, GpR répond à la formule II dans laquelle R est -CH2-CH2-, GpC répond à la formule IVd dans laquelle x = 13 et Cx est :In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by the radicals represented by the foemules below: In one embodiment, the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is -CH 2 -CH2-, GpC corresponds to the formula IVd in which x = 13 and Cx is:
Figure imgf000024_0001
Figure imgf000024_0001
[000136] Dans un mode de réalisation, le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 1, p = 2, GpR répond à la formule II dans laquelle R est -CH2-CH2-, GpA répond à la formule Illb, GpC répond à la formule IVd dans laquelle x = 13 et Cx est :In one embodiment, the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH 2 -CH2-, GpA corresponds to formula IIIb, GpC corresponds to formula IVd in which x = 13 and Cx is:
Figure imgf000024_0002
Figure imgf000024_0002
[000137] Dans un mode de réalisation, le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 1, p = 2, GpR répond à la formule II dans laquelle R est -CH2-CH2-, GpA répond à la formule Illb, GpC répond à la formule IVd dans laquelle x = 11 et Cx est :In one embodiment, the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH 2 -CH2-, GpA corresponds to formula IIIb, GpC corresponds to formula IVd in which x = 11 and Cx is:
H3 H 3
[000138] Dans un mode de réalisation, le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 0, a = 1, p = 2, GpA répond à la formule Illb, GpC répond à la formule IVd dans laquelle x = 13 et Cx est : In one embodiment, the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 0, a = 1, p = 2, GpA corresponds to formula IIIb, GpC corresponds to the formula IVd in which x = 13 and Cx is:
,CH3 , CH 3
[000139] Dans un mode de réalisation, le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 0, a = 1, p = 2, GpA répond à la formule Mb, GpC répond à la formule IVd dans laquelle x = 11 et Cx est : In one embodiment, the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 0, a = 1, p = 2, GpA corresponds to formula Mb, GpC corresponds to the formula IVd in which x = 11 and Cx is:
XH3 XH 3
[000140] Dans un mode de réalisation, le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 1, p = 2, GpR répond à la formule II dans laquelle R est -CH2-CH2-, GpA répond à la formule Illb, GpC répond à la
Figure imgf000024_0003
In one embodiment, the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH 2 -CH2-, GpA meets the formula Illb, GpC responds to the
Figure imgf000024_0003
[000141] 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 copolyaminoacides dont les monomères sont constitués de monomères et/ou d'oligomères liés entre eux directement ou par l'intermédiaire de bras de liaison. In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen. among the copolyamino acids whose monomers consist of monomers and / or oligomers bonded to one another directly or via linker arms.
[000142] 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 formule VII suivante : In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the following co-polyamino acids of formula VII:
Figure imgf000025_0001
formule VII dans laquelle,
Figure imgf000025_0001
formula VII in which,
• D représente, indépendamment, soit un groupe -CH2- (unité aspartique) soit un groupe -CH2-CH2- (unité glutamique),  D represents, independently, either a -CH 2 - (aspartic unit) or a -CH 2 -CH 2 - (glutamic unit) group,
• Hy est un radical hydrophobe choisi parmi les radicaux hydrophobes de formules I, V ou VI, dans lesquelles r = 1 et GpR est un radical de Formule II,  Hy is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI, in which r = 1 and GpR is a radical of Formula II,
• Ri est un radical hydrophobe choisi parmi les radicaux hydrophobes de formules I, V ou VI dans lesquelles r=0 ou r= l et GpR est un radical de Ri is a hydrophobic radical chosen from hydrophobic radicals of formula I, V or VI in which r = 0 or r = 1 and GpR is a radical of
Formule IV, ou un radical choisi dans le groupe constitué par un H, un groupe acyle linéaire en C2 à C10, un groupe acyle ramifié en C3 à C10, un benzyle, une unité « acide aminé » terminale et un pyroglutamate,Formula IV, or a radical selected from the group consisting of H, a C 2 -C 10 linear acyl group, a C 3 -C 10 branched acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate,
• R2 est un radical hydrophobe choisi parmi les radicaux hydrophobes de formules I, V ou VI dans lesquelles r = 1 et GpR est un radical de FormuleR2 is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI in which r = 1 and GpR is a radical of Formula
II, ou un radical -NR'R", R' et R" identiques ou différents étant choisis dans le groupe constitué par H, les alkyles linéaires ou ramifiés ou cycliques en C2 à C10, le benzyle et lesdits R' et R" alkyles pouvant former ensemble un ou des cycles carbonés saturés, insaturés et/ou aromatiques et/ou pouvant comporter des hétéroatomes, choisis dans le groupe constitué par O, N et S, II, or a radical -NR'R ", R 'and R" identical or different being selected from the group consisting of H, linear or branched or cyclic C2 to C10 alkyls, benzyl and said R' and R "alkyls which may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may contain heteroatoms selected from the group consisting of O, N and S,
• X représente un H ou une entité cationique choisie dans le groupe comprenant les cations métalliques ; [000143] 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. On appelle « co-polyaminoacide statistique » un co-polyaminoacide porteur de charges carboxylates et d 'au moins un radical hydrophobe, un co- polyaminoacide de formule Vlla . X represents an H or a cationic entity selected from the group comprising metal cations; [000143] n + m represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 <n + m <250. "random polyamino acid" a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula VIIa.
[000144] 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 VII, dans laquelle Ri = R'i et 2 = R'2, de formule Vlla suivante : In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, in which Ri = R'i and 2 = R '2, of the following formula VIIa:
Figure imgf000026_0001
Formule Vlla
Figure imgf000026_0001
Formula Vlla
dans laquelle, in which,
- m, n, X, D et Hy ont les définitions données précédemment,  m, n, X, D and Hy have the definitions given above,
- R'i est un radical choisi dans le groupe constitué par un H, un groupe acyle linéaire en C2 à C10, un groupe acyle ramifié en C3 à C10, un benzyle, une unité « acide aminé » terminale et un pyroglutamate,  R 1 is a radical selected from the group consisting of H, linear C 2 -C 10 acyl group, branched C 3 -C 10 acyl group, benzyl, terminal amino acid unit and pyroglutamate,
- R'2 est un radical -NR'R", R' et R" identiques ou différents étant choisis dans le groupe constitué par H, les alkyles linéaires ou ramifiés ou cycliques en C2 à C10, le benzyle et lesdits R' et R" alkyles pouvant former ensemble un ou des cycles carbonés saturés, insaturés et/ou aromatiques et/ou pouvant comporter des hétéroatomes, choisis dans le groupe constitué par O, N et S.  - R'2 is a radical -NR'R ", R 'and R" identical or different being selected from the group consisting of H, linear or branched or cyclic C2 to C10 alkyls, benzyl and R' and R alkyls which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may comprise heteroatoms selected from the group consisting of O, N and S.
[000145] On appelle « co-polyaminoacide défini » un co-polyaminoacide porteur de charges carboxylates et d'au moins un radical hydrophobe, un co-polyaminoacide de formule Vllb.  The term "defined co-polyamino acid" is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula VIIIb.
[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 formule VII dans laquelle n = 0 de formule Vllb suivante : In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n = 0 of formula Vllb below:
Figure imgf000027_0001
Formule Vllb dans laquelle m, X, D, Ri et R2 ont les définitions données précédemment et au moins Ri ou R2 est un radical hydrophobe de formule I, V ou VI. [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 formule VII dans laquelle n = 0 de formule Vllb et Ri ou R2 est un radical hydrophobe de formule I, V ou VI.
Figure imgf000027_0001
Formula VIIIb in which m, X, D, R1 and R2 have the definitions given above and at least R1 or R2 is a hydrophobic radical of formula I, V or VI. In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n = 0 of formula Vllb and R1 or R2 is a hydrophobic radical of formula I, V or VI.
[000148] 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 formule Vllb dans laquelle Ri est un radical hydrophobe de formule I, V ou VI dans lesquelles r = 0 ou r = 1 et GpR est de Formule II'.  In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VIIb in which R1 is a hydrophobic radical of formula I, V or VI wherein r = 0 or r = 1 and GpR is of Formula II '.
[000149] 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 Vllb dans laquelle R2 est un radical hydrophobe de formule I, V ou VI dans lesquelles r = 1 et GpR est de Formule II.  In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VIIb in which R2 is a hydrophobic radical of formula I, V or VI in which r = 1 and GpR is of Formula II.
[000150] Dans un mode de réalisation, la composition est caractérisée en ce que Ri est un radical choisi dans le groupe constitué par un groupe acyle linéaire en C2 à C10, un groupe acyle ramifié en C3 à C10, un benzyle, une unité « acide aminé » terminale et un pyroglutamate. In one embodiment, the composition is characterized in that R 1 is a radical chosen from the group consisting of a C 2 to C 10 linear acyl group, a C 3 to C 10 branched acyl group and a benzyl unit. terminal amino acid and a pyroglutamate.
[000151] Dans un mode de réalisation, la composition est caractérisée en ce que Ri est un radical choisi dans le groupe constitué par un groupe acyle linéaire en Cz à C10 ou un groupe acyle ramifié en C3 à C10.  In one embodiment, the composition is characterized in that R 1 is a radical selected from the group consisting of a C 10 to C 10 linear acyl group or a C 3 to C 10 branched acyl group.
[000152] 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 XXXa suivante :
Figure imgf000028_0001
Formule XXXa 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 XXXa below:
Figure imgf000028_0001
Formula XXXa
dans laquelle, in which,
• D et X ont les définitions données précédemment,  • D and X have the definitions given above,
• Ra et R'a, identiques ou différents, sont soit un radical hydrophobe -Hy, soit un radical choisi dans le groupe constitué par un H, un groupe acyle linéaire en C2 à C10, un groupe acyle ramifié en C3 à C10, un benzyle, une unité « acide aminé » terminale et un pyroglutamate,  Ra and R'a, which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of an H, a linear acyl group of C2 to C10, a branched acyl group of C3 to C10, a benzyl, a terminal "amino acid" unit and a pyroglutamate,
au moins un de Ra et R'a étant un radical hydrophobe -Hy,  at least one of Ra and R'a being a hydrophobic radical -Hy,
Q- linéaire ou ramifié divalent est constitué d'une chaîne alkyle Q- linear or branched divalent consists of an alkyl chain
o comprenant un ou plusieurs hétéroatomes choisis dans le groupe constitué des atomes d'azote et d'oxygène et/ou  o comprising one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or
o portant un ou plusieurs hétéroatomes constitué des atomes d'azote et d'oxygène et/ou  o carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and / or
o des radicaux portant un ou plusieurs hétéroatomes constitué des atomes d'azote et d'oxygène et/ou  radicals bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or
o des fonctions carboxyles, ledit radical ou spacer -Q- étant lié aux deux chaînes d'unités glutamiques ou aspartiques PLG par une fonction amide et lesdites liaisons amides liant ledit radical ou spacer -Q- aux deux chaînes d'unités glutamiques ou aspartiques résultent de la réaction entre une fonction aminé et une fonction acide respectivement portées soit par le précurseur Q' du radical ou spacer -Q- soit par une unité glutamique ou aspartique, o carboxyl functions, said radical or spacer -Q- being bonded to two glutamic or aspartic unit chains PLG by an amide function and said amide bonds linking said radical or spacer -Q- to the two chains of glutamic or aspartic units result of the reaction between an amino function and an acid function respectively carried by the precursor Q 'of the radical or spacer -Q- or by a glutamic or aspartic unit,
• Hy a la définition donnée ci-dessus. • Hy has the definition given above.
• n + m a la définition donnée ci-dessus.  • n + m has the definition given above.
[000153] 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 XXXa dans laquelle Ra et R'a, 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 co-polyamino acids of formula XXXa in which Ra and R'a, identical are a hydrophobic radical -Hy.
[000154] 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 XXXa dans laquelle Ra et R'a, différents sont des radicaux hydrophobe -Hy. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one radical hydrophobic -Hy is chosen from co-polyamino acids of formula XXXa in which Ra and R'a, different are hydrophobic radicals -Hy.
[000155] 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 XXXa dans laquelle Ra est un radical hydrophobe -Hy et R'a n'est pas 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 co-polyamino acids of formula XXXa in which Ra is a hydrophobic radical -Hy and R ' a is not a hydrophobic radical -Hy.
[000156] 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 XXXa dans laquelle R'a est un radical hydrophobe -Hy, et Ra n'est pas 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 co-polyamino acids of formula XXXa in which R'a is a hydrophobic radical -Hy, and R a is not a hydrophobic radical -Hy.
[000157] 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 XXXa' suivante : 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 XXXa 'below :
Figure imgf000029_0001
Formule XXXa'
Figure imgf000029_0001
Formula XXXa '
Dans laquelle : In which :
D, X, Ra et R'a ont les définitions données précédemment, -Q- et Hy ont les définitions données ci-dessus, D, X, Ra and R'a have the definitions given above, -Q- and Hy have the definitions given above,
ni+mi représente le nombre d'unités glutamiques ou unités aspartiques des chaînes PLG du co-polyaminoacide portant un radical -Hy,  ni + mi represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid bearing a radical -Hy,
Π2+ιτΐ2 représente le nombre d'unités glutamiques ou unités aspartiques des chaînes PLG du co-polyaminoacide ne portant pas de radical -Hy,
Figure imgf000029_0002
Π2 + ιτΐ2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid having no -Hy radical,
Figure imgf000029_0002
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 DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 <n '+ m' <250.
[000158] 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 XXXa' dans laquelle Ra et R'a, identiques sont un radical hydrophobe -Hy. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one radical hydrophobic -Hy is chosen from co-polyamino acids of formula XXXa 'in which Ra and R'a, identical are a hydrophobic radical -Hy.
[000159] 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 XXXa' dans laquelle Ra et R'a, 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 XXXa 'in which Ra and R'a, different are hydrophobic radicals -Hy.
[000160] 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 XXXa' dans laquelle Ra est un radical hydrophobe -Hy et R'a n'est pas 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 co-polyamino acids of formula XXXa 'in which Ra is a hydrophobic radical -Hy and R'a is not a hydrophobic radical - Hy.
[000161] 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 XXXa' dans laquelle R'a est un radical hydrophobe -Hy, et Ra n'est pas 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 XXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.
[000162] 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 XXXb suivante : In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb below:
Figure imgf000030_0001
Formule XXXb dans laquelle,
Figure imgf000030_0001
Formula XXXb 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 soit un radical hydrophobe -Hy, soit un radical choisi dans le groupe constitué par un -OH, un groupe aminé, une unité « acide aminé » terminale et un pyroglutamate, au moins un de Rb et R'b est un radical hydrophobe -Hy, Rb and R'b, which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of -OH, an amino group, a terminal "amino acid" unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy,
• -Q-et Hy ont les définitions données ci-dessus. • -Q- and Hy have the definitions given above.
• n + m a la même définition que donnée précédemment.  • n + m has the same definition as given above.
[000163] 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 XXXb 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 bearing carboxylate charges and at least one radical hydrophobic -Hy is chosen from co-polyamino acids of formula XXXb in which Rb and R'b, identical are a hydrophobic radical -Hy.
[000164] 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 XXXb 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 co-polyamino acids of formula XXXb in which Rb and R'b, different are hydrophobic radicals -Hy.
[000165] 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 XXXb dans laquelle Rb est un radical hydrophobe -Hy et R'b n'est pas un radical hydrophobe -Hy. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.
[000166] 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 XXXb dans laquelle R'b est un radical hydrophobe -Hy, et Rb n'est pas 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 co-polyamino acids of formula XXXb in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
[000167] 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 hydrophob uivante : 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:
Figure imgf000031_0001
Figure imgf000031_0001
Formule XXXb' dans laquelle ;  Formula XXXb 'in which;
• D, X, Rb et Rb' ont les définitions données précédemment,  D, X, Rb and Rb 'have the definitions given above,
• -Q- et -Hy ont les définitions données ci-dessus,  • -Q- and -Hy have the definitions given above,
• nl+ml, n2+m2 et n'+m' ont les définitions données précédemment..  • nl + ml, n2 + m2 and n '+ m' have the definitions given previously.
[000168] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 10 et 250. [000169] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 10 et 200. In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 250. In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 200.
[000170] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 150.  In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 150.
[000171] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 100. In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 100.
[000172] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 80.  In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 80.
[000173] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 15 et 65.  In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 65.
[000174] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 20 et 60.  [000174] In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 60.
[000175] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 20 et 50.  In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 50.
[000176] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que n + m est compris entre 20 et 40. In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 40.
[000177] 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 XXXb' 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 co-polyamino acids of formula XXXb 'in which Rb and R'b, identical are a hydrophobic radical -Hy.
[000178] 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 XXXb' 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 XXXb 'in which Rb and R'b are different hydrophobic radicals -Hy.
[000179] 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 XXXb' dans laquelle Rb est un radical hydrophobe -Hy et R'b n'est pas 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 co-polyamino acids of formula XXXb 'in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.
[000180] 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 XXXb' dans laquelle R'b est un radical hydrophobe -Hy, et Rb n'est pas un radical hydrophobe -Hy. [000181] 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 VII, Vlla, Vllb, XXXa, XXXa', XXXb ou XXXb' dans lesquels le groupe D est un groupe -CH2- (unité aspartique). [000182] 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 VII, Vlla, Vllb, XXXa, XXXa', XXXb ou XXXb' dans lesquels le groupe D est un groupe -CH2-CH2- (unité glutamique). 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 XXXb 'in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy. In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, VIIa, VIIIb, XXXa, XXXa, XXXb or XXXb 'in which the group D is a group -CH2- (aspartic unit). In one embodiment, the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, VIIa, VIIIb, XXXa, XXXa, XXXb or XXXb 'in which the group D is a group -CH2-CH2- (glutamic unit).
[000183] Le co-polyaminoacide est un co-polyaminoacide statistique ou bloc. [000183] The co-polyamino acid is a random co-polyamino acid or block.
[000184] Le co-polyaminoacide est un co-polyaminoacide statistique dans l'enchaînement des unités glutamiques et/ou aspartiques. [000184] The co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
[000185] Lorsque le co-polyaminoacide comprend une ou plusieurs d'unité(s) aspartique(s), celle(s)-ci peu(ven)t subir des réarrangements structuraux. [000185] When the co-polyamino acid comprises one or more aspartic unit (s), that (s) can (s) undergo structural rearrangements.
[000186] Dans un mode de réalisation la composition selon l'invention est caractérisée en ce que les co-polyaminoacides peuvent en outre comprendre des unités monomériques de formule VIII et/ou VIN' : [000186] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acids may further comprise monomeric units of formula VIII and / or VIN ':
Figure imgf000033_0001
Figure imgf000033_0001
Formule VIII Formule VIII'  Formula VIII Formula VIII '
[000187] Dans un mode de réalisation, le radical ou spacer -Q-est représenté par un radical de formule QUI : In one embodiment, the radical or spacer -Q- is represented by a radical of formula QUI:
*— Fa— (CH2^- Fa— * * - F a - (CH 2 ^ - F a - *
Formule QUI  Formula WHO
dans laquelle 1 < t < 8  in which 1 <t <8
[000188] Dans un mode de réalisation, le radical ou spacer -Q-est représenté par un radical de formule par un radical de formule QIV :
Figure imgf000033_0002
In one embodiment, the radical or spacer -Q- is represented by a radical of formula by a radical of formula QIV:
Figure imgf000033_0002
dans laquelle :  in which :
Au moins un des u"i ou u" est différent de 0.  At least one of the u "i or u" is different from 0.
Si u"i≠ 0 alors u'i ≠ 0 et si u"2≠ 0 alors u'2≠ 0, u'i et u'z sont identiques ou différents et, If u "i ≠ 0 then u'i ≠ 0 and if u" 2 ≠ 0 then u'2 ≠ 0, u'i and u'z are identical or different and,
2 < u < 4, 2 <u <4,
Figure imgf000034_0001
Figure imgf000034_0001
0 < u"i < 4,  0 <u "i <4,
0 < u'2≤ 4, 0 <u ' 2 ≤ 4,
0 < u"2 < 4 ; 0 <u " 2 <4;
[000189] Dans chacun des radicaux ci-dessus représentés, Fx = Fa, Fb, Fa' et F.-, identiques ou différentes représentant des fonctions -NH- ou -CO- . In each of the above radicals, F x = F a , Fb, F a 'and F-, identical or different, representing -NH- or -CO- functions.
[000190] Dans un mode de réalisation, si Fa et Fa' sont -NH-, alors t≥2. [000190] In one embodiment, if Fa and Fa 'are -NH-, then t≥2.
[000191] Dans un mode de réalisation, si Fa et Fa* sont -CO-, alors t≥l . [000191] In one embodiment, if F a and F a * are -CO-, then t≥l.
[000192] Dans un mode de réalisation, si Fa et Fa- sont -CO- et -NH- , alors t≥l . [000192] In one embodiment, if F a and F a - are -CO- and -NH-, then t≥l.
[000193] Dans un mode de réalisation, si Fb et Fb' sont -NH-, alors u et u'i>2 et/ou u'2> 2. [000193] In one embodiment, if Fb and Fb 'are -NH-, then u and u'i> 2 and / or u' 2 > 2.
[000194] Les au moins deux chaînes d'unités glutamiques ou aspartiques PLG étant liées à Q par une fonction Fx ou Fy par une liaison covalente pour former une liaison amide avec une fonction -NH- ou -CO- du PLG. The at least two PLG chains of glutamic or aspartic units are bound to Q by a function F x or F y by a covalent bond to form an amide bond with a -NH- or -CO- function of PLG.
[000195] Dans un mode l de formule QUI,
Figure imgf000034_0002
[000195] In a mode l of formula QUI,
Figure imgf000034_0002
Formule QUI  Formula WHO
dont le précurseur est une diamine. whose precursor is a diamine.
[000196] Dans un mode de réalisation, le précurseur du radical de formule QUI est une diamine choisie dans le groupe constitué par l'éthylènediamine, la butylènediamine, l'hexylènediamine, le 1,3-diaminopropane et le 1,5-diaminopentane.  In one embodiment, the precursor of the radical of formula MI is a diamine selected from the group consisting of ethylenediamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5-diaminopentane.
[000197] Dans un mode de réalisation, t = 2 et le précurseur du radical de formule QUI est l'éthylènediamine. In one embodiment, t = 2 and the precursor of the radical of formula QUI is ethylenediamine.
[000198] Dans un mode de réalisation, t = 4 et le précurseur du radical de formule QUI est la butylènediamine.  In one embodiment, t = 4 and the precursor of the radical of formula QUI is butylenediamine.
[000199] Dans un mode de réalisation, t = 6 et le précurseur du radical de formule QUI est l'hexylènediamine.  [000199] In one embodiment, t = 6 and the precursor of the radical of formula QUI is hexylenediamine.
[000200] Dans un mode de réalisation, t = 3 et le précurseur du radical de formule QUI est le 1,3-diaminopropane.  In one embodiment, t = 3 and the precursor of the radical of formula QUI is 1,3-diaminopropane.
[000201] Dans un mode de réalisation, t = 5 et le précurseur du radical de formule QUI est le 1,5-diaminopentane.  In one embodiment, t = 5 and the precursor of the radical of formula QUI is 1,5-diaminopentane.
[000202] Dans un mode de réalisation, le précurseur du radical de formule QUI est un aminoacide. [000203] Dans un mode de réalisation, le précurseur du radical de formu le QUI est un am inoacide choisi dans le groupe constitué par l 'acide aminobutanoïque, l'acide am inohexanoïque et la béta-alanine. In one embodiment, the precursor of the radical of formula QUI is an amino acid. [000203] In one embodiment, the precursor of the radical of the formula III is an amido acid selected from the group consisting of aminobutanoic acid, aminohexanoic acid and beta-alanine.
[000204] Dans u n mode de réalisation, t = 2 et et le précurseu r du radical de formule QUI est la béta-alani ne.  In an embodiment, t = 2 and and the precursor of the radical of formula QUI is beta-alanine.
[000205] Dans u n mode de réalisation, t = 6 et et le précurseur du radical de formule QUI est l'acide ami nohexanoïque.  In an embodiment, t = 6 and and the precursor of the radical of formula QUI is the naphthalic amino acid.
[000206] Dans un mode de réalisation, t = 4 et le précu rseur du radical de formule QUI est l'acide ami nobutanoïque  [000206] In one embodiment, t = 4 and the precursor of the radical of formula QUI is nobutanoic amide acid
[000207] Dans un mode de réal isation, le précurseu r du radical de formu le QUI est un diacide . [000207] In a mode of real isation, the precursor of the radical of formu the QUI is a diacid.
[000208] Dans un mode de réalisation, le précurseu r du radical de formu le QUI est un diacide choisi dans le grou pe constitué par l'acide succinique, l'acide glutarique et l 'acide adipique.  [000208] In one embodiment, the precursor of the radical of the formula II is a diacid chosen from the group consisting of succinic acid, glutaric acid and adipic acid.
[000209] Dans un mode de réalisation, t = 2 et et le précurseur du radical de formule QUI est l'acide succinique. In one embodiment, t = 2 and and the precursor of the radical of formula QUI is succinic acid.
[000210] Dans un mode de réalisation, t = 3 et le précu rseur du radical de formule QUI est l'acide glutarique.  [000210] In one embodiment, t = 3 and the precursor of the radical of formula MI is glutaric acid.
[000211] Dans un mode de réalisation, t = 4 et le précurseur du radical de formule QUI est l 'acide adi pique.  [000211] In one embodiment, t = 4 and the precursor of the radical of formula QUI is the adi picic acid.
[000212] Dans un mode de réal isation, Q est un radical de formule QIV, cH 2HHCH2kbMc Formule QIV dont le précurseur est une diamine. In a mode of real isation, Q is a radical of formula QIV, c H 2 HH CH 2 kbM c Formula QIV whose precursor is a diamine.
[000213] Dans u n mode de réalisation, le précurseur du radical de formu le QIV est une diamine choisie dans le groupe constitué par le diéthylèneglycol diamine, le triéthylèneg lycol diamine, le 4,9-dioxa- l , 12-dodécanediami ne et le l-amino-4,7, 10- trioxa- 13-tridecanamine.  In one embodiment, the precursor of the radical of the formula IVIV is a diamine selected from the group consisting of diethylene glycol diamine, triethylene glycol, diamine, 4,9-dioxal, 12-dodecanediamine, and 1-amino-4,7,10-trioxa-13-tridecanamine.
[000214] Dans un mode de réalisation , u = u 'i = 2,
Figure imgf000035_0001
l, u"i = 0 et le précurseur du radical de formule QIV est le diéthylèneglycol diami ne. [000214] In one embodiment, u = u 'i = 2,
Figure imgf000035_0001
and the precursor of the radical of formula QIV is diethylene glycol diamine.
[000215] Dans un mode de réalisation, u = u'i = u'z = 2, u"i= u"z = 1 et le précurseur du radical de formule QIV est le triéthylèneglycol diamine.  [000215] In one embodiment, u = u'i = u'z = 2, u "i = u" z = 1 and the precursor of the radical of formula QIV is triethyleneglycol diamine.
[000216] Dans un mode de réalisation, u = u'2 = 3, u'i = 4, u"i = u"2 = 1 et le précurseur du radical de formule QIV est le 4,9-dioxa- l , 12-dodécanediamine. [000217] Dans un mode de réalisation, u = u'2 = 3, u'i = u"i= 2, u"2 = 1 et le précurseur du radical de formule QIV est le 4,7,10-trioxa-l, 13-tridecanediamine. [000216] In one embodiment, u = u'2 = 3, u'i = 4, u "i = u" 2 = 1 and the precursor of the radical of formula QIV is 4,9-dioxal, 12-dodecane. [000217] In one embodiment, u = u'2 = 3, u'i = u "i = 2, u" 2 = 1 and the precursor of the radical of formula QIV is 4,7,10-trioxa. 1,3-tridecanediamine.
[000218] Dans un mode de réalisation, les PLG sont liés à Fx avec F* = -NH- par au moins une fonction carbonyle du PLG. In one embodiment, the PLGs are linked to Fx with F * = -NH- by at least one carbonyl function of the PLG.
[000219] Dans un mode de réalisation, les PLG sont liés à Fx avec Fx = -NH- par au moins une fonction carbonyle qui n'est pas en position C terminale du PLG. In one embodiment, the PLGs are bound to F x with Fx = -NH- by at least one carbonyl function which is not in the C-terminal position of the PLG.
[000220] Dans un mode de réalisation, les PLG sont liés à Fx avec Fx = -NH- par la fonction carbonyle en position C terminale du PLG. In one embodiment, the PLGs are linked to F x with F x = -NH- by the carbonyl function at the C-terminal position of the PLG.
[000221] Dans un mode de réalisation, les PLG sont liés à Fx avec Fx = -NH- par la fonction carbonyle en position C terminale du PLG. In one embodiment, the PLGs are linked to F x with F x = -NH- by the carbonyl function at the C-terminal position of the PLG.
[000222] Dans un mode de réalisation, les PLG sont liés à Fx avec Fx par la fonction carbonyle en position C terminale du PLG.  In one embodiment, the PLGs are linked to Fx with Fx by the carbonyl function at the C-terminal position of the PLG.
[000223] Dans un mode de réalisation, les PLG sont liés à Fx, avec Fx = -CO- par l'atome d'azote en position N terminale du PLG. In one embodiment, the PLGs are linked to F x , with F x = -CO- by the nitrogen atom in the N-terminal position of the PLG.
[000224] Dans un mode de réalisation, le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est un co-polyaminoacide de formule VII ou Vllb, dans laquelle DP = 39, i = 0,15 et le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 0, p = 1, GpR répond à la formule II dans laquelle R est CH2-CH2, GpC répond à la formule IVd dans laquelle x = In one embodiment, the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP = 39, i = 0.15 and the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is CH2-CH2, GpC corresponds to formula IVd in which x =
[000225] Dans un mode de réalisation, le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est un co-polyaminoacide de formule VII ouIn one embodiment, the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or
Vllb, dans laquelle DP = 60, i = 0,045 et le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 1, p = 2, GpR répond à la formule II dans laquelle R est CH2-CH2, GpA répond à la formule Illb, GpC répond à la formule IVd dans laquelle x = 13 et Cx est Vllb, in which DP = 60, i = 0.045 and the hydrophobic radical of formula I is selected from the radicals of formula I wherein, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is CH2-CH2, GpA has the formula IIIb, GpC has the formula IVd in which x = 13 and Cx is
,CH3 , CH 3
[000226] Dans un mode de réalisation, le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est un co-polyaminoacide de formule VII ou Vllb, dans laquelle DP = 24, i = 0,042 et le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 1, p = 2, GpR répond à la formule II dans laquelle R est CH2-CH2, GpA répond à la formule Illb, GpC répond à la et Cx est
Figure imgf000037_0001
In one embodiment, the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP = 24, i = 0.042 and the hydrophobic radical of formula I is chosen among the radicals of formula I in which, r = 1, a = 1, p = 2, GpR is of formula II wherein R is CH2-CH2, GpA is IIIb, GpC is and Cx is
Figure imgf000037_0001
[000227] Dans un mode de réalisation, le co-polyami noacide porteur de charges carboxylates et de radicaux hydrophobes est un co-polyaminoacide de formule VII ou Vllb, dans laquelle DP = 22, i = 0,045 et le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 1, p = 2, GpR répond à la formule II dans laquelle R est CH2-CH2, GpA répond à la formule Illb, GpC répond à la formule IVd dans laquelle x = 11 et Cx est
Figure imgf000037_0002
In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP = 22, i = 0.045 and the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is CH2-CH2, GpA corresponds to formula IIIb, GpC corresponds to formula IVd in which x = 11 and Cx is
Figure imgf000037_0002
[000228] Dans un mode de réalisation , le co-polyami noacide porteur de charges carboxylates et de radicaux hydrophobes est un co-polyam inoacide de formule VII ou Vllb, dans laquelle DP = 22, i = 0,089 et le radical hydrophobe de formule I est choisi parmi les radicaux de formule I dans laquelle, r = 1, a = 1, p = 2, GpR répond à la form ule II dans laquelle R est CH2-CH2, GpA répond à la formule Illb, GpC répond à la In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is an inoacidic co-polyam of formula VII or VIIb, in which DP = 22, i = 0.089 and the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is CH 2 -CH 2, GpA corresponds to formula IIIb, GpC corresponds to
Cx est
Figure imgf000037_0003
Cx is
Figure imgf000037_0003
[000229] Dans un mode de réalisation, le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est un co-polyaminoacide de formu le XXXa, dans laquelle DP = 24, i = 0,081 et le radical hydrophobe de formule I est choisi parmi les radicaux de formu le I dans laquelle, r = 0, a = 1 , p = 2, GpA répond à la formule  In one embodiment, the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula XXXa, in which DP = 24, i = 0.081 and the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 0, a = 1, p = 2, GpA corresponds to the formula
13 et Cx est
Figure imgf000037_0004
13 and Cx is
Figure imgf000037_0004
[000230] Dans un mode de réalisation , le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est un co-polyaminoacide de formule VU ou Vllb, dans laquelle DP = 24, i = 0,077 et le radica l hydrophobe de formule I est choisi parmi les radicaux de form ule I dans laquelle, r = 0, a = 1, p = 2, GpA répond à la elle x = 11 et Cx est
Figure imgf000037_0005
In one embodiment, the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP = 24, i = 0.077 and the hydrophobic radical of formula I is chosen from radicals of formula I in which, r = 0, a = 1, p = 2, GpA corresponds to la x = 11 and Cx is
Figure imgf000037_0005
[000231] Dans un mode de réalisation, la composition selon l 'i nvention est caractérisée en ce que le co-polyaminoacide est issu d 'un polyam inoacide obtenu par polymérisation. [000232] Dans un mode de réalisation, la composition selon l'i nvention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par polymérisation par ouverture de cycle d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique. [000231] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization. [000232] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by ring opening polymerization of a glutamic acid N-carboxyanhydride derivative. or an aspartic acid N-carboxyanhydride derivative.
[000233] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N- carboxyanhydride d'acide aspartique comme décrit dans l'article de revue Adv. Polym . Sel. 2006, 202, 1-18 (Deming, T.J. ). In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative thereof. aspartic acid N-carboxyanhydride as described in Adv. Polym. Salt. 2006, 202, 1-18 (Deming, T.J.).
[000234] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique. [000234] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative.
[000235] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique choisi dans le groupe constitué par le N-carboxyanhydride glutamate de méthyle (GluOMe-NCA), le N- carboxyanhydride glutamate de benzyle (GluOBzl-NCA) et le N-carboxyanhydride glutamate de t-butyle (GluOtBu-NCA) .  [000235] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative chosen from the group consisting of by N-carboxyanhydride methyl glutamate (GluOMe-NCA), benzyl N-carboxyanhydride glutamate (GluOBzl-NCA) and t-butyl N-carboxyanhydride glutamate (GluOtBu-NCA).
[000236] Dans un mode de réalisation, le dérivé de Ν-carboxyanhydride d'acide glutamique est le N-carboxyanhydride L-glutamate de méthyle (L-GluO e-NCA).  In one embodiment, the glutamic acid Ν-carboxyanhydride derivative is methyl N-carboxyanhydride L-glutamate (L-GluO e-NCA).
[000237] Dans un mode de réalisation, le dérivé de N-carboxyanhydride d'acide glutamique est le N-carboxyanhydride L-glutamate de benzyle (L-GluOBzl-NCA).  [000237] In one embodiment, the glutamic acid N-carboxyanhydride derivative is benzyl N-carboxyanhydride L-glutamate (L-GluOBzl-NCA).
[000238] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par polymérisation d'un dérivé de Ν-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, T. J .). Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu 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 aminé primaire comme décrit dans le brevet FR 2,801,226 (Touraud, F. ; et al.) et les références citées par ce brevet. De la même manière, l'initiateur peut être une polyamine afin d'obtenir polyaminoacide comprenant plusieurs PLG. Lesdites polyamines peuvent être choisies parmi les diamines, les triamines et les tétramines. Les aminés de ces polyamines peuvent être des aminés primaires. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid Ν-carboxyanhydride derivative or a derivative thereof. of aspartic acid N-carboxyanhydride using as initiator an organometallic complex of a transition metal as described in Nature 1997, 390, 386-389 (Deming, T.J.). In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a N-derivative. aspartic acid carboxyanhydride using as initiator ammonia or a primary amine as described in FR 2,801,226 (Touraud, F. et al.) and references cited therein. In the same way, the initiator may be a polyamine to obtain polyamino acid comprising several PLG. Said polyamines can be chosen from diamines, triamines and tetramines. The amines of these polyamines may be primary amines.
[000239] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu 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, 14114-14115 (Lu H . ; et al.) ou une aminé silylée comme décrit dans la publication J. Am. Chem . Soc. 2008, 130, 12562-12563 (Lu H. ; et al.) . In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or an aspartic acid N-carboxyanhydride derivative using hexamethyldisilazane as initiator as described in J. Am. Chem. Soc. 2007, 129, 14114-14115 (Lu H. et al.) Or a silylated amine as described in J. Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H., et al.).
[000240] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le procède de synthèse du polyaminoacide obtenu par polymérisation d'un dérivé de N-carboxyanhydride d'acide glutamique ou d'un dérivé de N-carboxyanhydride d'acide aspartique dont est issu le co-polyaminoacide comprend une étape d'hydrolyse de fonctions ester.  In one embodiment, the composition according to the invention is characterized in that the process for the synthesis of the polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or of an N-carboxyanhydride derivative aspartic acid from which the co-polyamino acid is derived comprises a step of hydrolysis of ester functions.
[000241] 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.  In one embodiment, this step of hydrolysis of ester functions may consist of hydrolysis in an acid medium or hydrolysis in a basic medium or may be carried out by hydrogenation.
[000242] Dans un mode de réalisation, cette étape d'hydrolyse de groupements ester est une hydrolyse en milieu acide.  In one embodiment, this step of hydrolysis of ester groups is a hydrolysis in an acidic medium.
[000243] Dans un mode de réalisation, cette étape d'hydrolyse de groupements ester est effectuée par hydrogénation.  In one embodiment, this step of hydrolysis of ester groups is carried out by hydrogenation.
[000244] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par dépolymérisation d'un polyaminoacide de plus haut poids moléculaire.  In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight.
[000245] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par dépolymérisation enzymatique d'un polyaminoacide de plus haut poids moléculaire.  In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.
[000246] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par dépolymérisation chimique d'un polyaminoacide de plus haut poids moléculaire. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.
[000247] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par dépolymérisation enzymatique et chimique d'un polyaminoacide de plus haut poids moléculaire. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight.
[000248] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu 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 .  In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight selected from the group consisting of polyglutamate. of sodium and sodium polyaspartate.
[000249] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par dépolymérisation d'un polyglutamate de sodium de plus haut poids moléculaire. [000250] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est issu d'un polyaminoacide obtenu par dépolymérisation d'un polyaspartate de sodium de plus haut poids moléculaire. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyaspartate of higher molecular weight.
[000251 ] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est obtenu par greffage d 'un groupe hydrophobe sur un poly-L-glutamique acide ou poly-L-aspartique acide en utilisant les procédés de formation de liaison amide bien connus de l'homme de l'art. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid using amide bond forming processes well known to those skilled in the art.
[000252] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est obtenu par greffage d'un groupe hydrophobe sur un poly-L-glutamique acide ou poly-L-aspartique acide en utilisant les procédés de formation de liaison amide utilisés pour la synthèse peptidique.  In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid using the amide bond formation processes used for peptide synthesis.
[000253] Dans un mode de réalisation, la composition selon l'invention est caractérisée en ce que le co-polyaminoacide est obtenu par greffage d'un groupe hydrophobe sur un poly-L-glutamique acide ou poly-L-aspartique acide comme décrit dans le brevet FR 2,840,614 (Chan, Y. P. ; et al .).  In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on an acidic poly-L-glutamic or poly-L-aspartic acid as described above. in FR 2,840,614 (Chan, YP et al.).
[000254] 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.  In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 40 mg / ml.
[000255] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 30 mg/mL. In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 30 mg / ml.
[000256] 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. In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 20 mg / ml.
[000257] 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. In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 10 mg / ml.
[000258] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 5 mg/mL. In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 5 mg / ml.
[000259] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 2,5 mg/mL.  In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 2.5 mg / ml.
[000260] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 1 mg/mL. In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 1 mg / ml.
[000261] Dans un mode de réalisation, la concentration en co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est au plus de 0,5 mg/mL. In one embodiment, the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 0.5 mg / ml.
[000262] Dans un mode de réalisation, la composition est caractérisée en ce que le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,007 et 0,3. In one embodiment, the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
[000263] Dans un mode de réalisation, la composition est caractérisée en ce que le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,3. [000264] Dans un mode de réalisation, la composition est caractérisée en ce que le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,2. In one embodiment, the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3. In one embodiment, the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.
[000265] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,007 et 0, 15.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 15.
[000266] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0, 1.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
[000267] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,08.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
[000268] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 9 et 10 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,03 et 0,15. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.15.
[000269] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,015 et 0,1. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0.1.
[000270] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,08. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.08.
[000271] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,1. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.1.
[000272] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,06. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
[000273] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,007 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio i to the number of radicals hydrophobic and the number of glutamic or aspartic units is between 0.007 and 0.3.
[000274] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,3.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
[000275] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,015 et 0,2.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0, 2.
[000276] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 11 et 14 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,1 et 0,2.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
[000277] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 15 et 16 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,04 et 0,15. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.15.
[000278] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 17 et 18 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,06. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical C x comprises between 17 and 18 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.06.
[000279] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 19 et 25 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,06. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
[000280] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule I dans laquelle le radical Cx comprend entre 19 et 25 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,05. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.05.
[000281] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,007 et 0,3.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 3.
[000282] Dans un mode de réalisation , la composition est caractérisée en ce que le radical hydrophobe répond à la formule V et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,3. [000283] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,015 et 0,2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0, 2.
[000284] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 14 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
[000285] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 9 et 10 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,05 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.3.
[000286] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 9 et 10 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,25. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.25.
[000287] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 9 et 10 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,20. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.15 and 0.20.
[000288] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,05 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.3.
[000289] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.3.
[000290] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,25.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.25.
[000291 ] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,2. [000292] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspa rtiques est compris entre 0, 15 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspheric units are between 0.15 and 0.3.
[000293] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,25 In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0, 15 and 0.25
[000294] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.15 and 0.2.
[000295] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,05 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.3.
[000296] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,1 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.3.
[000297] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,25.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.25.
[000298] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
[000299] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.15 and 0.3.
[000300] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,25 In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0, 15 and 0.25
[000301] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.15 and 0.2.
[000302] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend 11 ou 13 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,05 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.05 and 0.3.
[000303] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend 11 ou 13 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. glutamic or aspartic units is between 0.1 and 0.3.
[000304] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend 11 ou 13 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,25. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.1 and 0.25.
[000305] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend 11 ou 13 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 1 et 0,2.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. glutamic or aspartic units is between 0, 1 and 0.2.
[000306] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend 11 ou 13 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.15 and 0.3.
[000307] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend 11 ou 13 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,25 In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. glutamic or aspartic units is between 0, 15 and 0.25
[000308] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend 11 ou 13 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0, 15 et 0,2. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises 11 or 13 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of carbon atoms. Glutamic or aspartic units are between 0.15 and 0.2.
[000309] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 15 et 16 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,04 et 0, 15. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.04 and 0.15.
[000310] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 17 et 18 atomes de carbone et le ratio I entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,06. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio I between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.06.
[000311] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 19 et 25 atomes de carbone et le ratio I entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,06. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio I between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
[000312] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule V dans laquelle le radical Cx comprend entre 19 et 25 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,05. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.05.
[000313] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,007 et 0, 15. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 15.
[000314] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0, 1.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
[000315] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,08. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
[000316] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI dans laquelle le radical Cx comprend entre 9 et 10 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,03 et 0,15.  In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.03 and 0.15.
[000317] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,015 et 0, 1. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.015 and 0.1.
[000318] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI dans laquelle le radical Cx comprend entre 11 et 12 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,02 et 0,08. [000319] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0, 1. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.08. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.1.
[000320] Dans un mode de réalisation, la composition est caractérisée en ce que le radical hydrophobe répond à la formule VI dans laquelle le radical Cx comprend entre 13 et 15 atomes de carbone et le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques est compris entre 0,01 et 0,06. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
[000321] On entend par « analogue », lorsqu'il est utilisé par référence à un peptide ou une protéine, un peptide ou une protéine, dans lequel un ou plusieurs résidus d'acides aminés constitutifs ont été substitués par d'autres résidus d'acides aminés et/ou dans lequel un ou plusieurs résidus d'acides aminés constitutifs ont été supprimés et/ou dans lequel un ou plusieurs résidus d'acides aminés constitutifs ont été ajoutés. Le pourcentage d'homologie admis pour la présente définition d'un analogue est de 50%. En pa rticulier le pourcentage d'homologie est d'au moins 60 %, notamment d'au moins 70 % ; voire d'au moins 80 %, encore plusparticulièrement d'au moins 90 %, voire d'au moins 95 %. By "analogue", when used with reference to a peptide or a protein, a peptide or a protein, in which one or more constituent amino acid residues have been substituted by other residues of amino acid and / or wherein one or more constituent amino acid residues have been deleted and / or wherein one or more constituent amino acid residues have been added. The percentage of homology allowed for the present definition of an analogue is 50%. In particular, the percentage of homology is at least 60%, especially at least 70%; at least 80%, even more particularly at least 90%, or even at least 95%.
[000322] On entend par « dérivé », lorsqu'il est utilisé par référence à un peptide ou une protéine, un peptide ou une protéine ou un analogue chimiquement modifié par un substituant qui n'est pas présent dans le peptide ou la protéine ou l'analogue de référence, c'est-à-dire un peptide ou une protéine qui a été modifié par création de liaisons covalentes, pour introduire des substituants. [000323] Les agonistes de récepteurs du GLP-2, ou GLP-2 RA, potentiellement utiles activent les récepteurs de GLP-2 en se liant d'abord au récepteur du GLP-2, puis stimulent un système de second messager intra-cellulaire au récepteur.  By "derivative" is meant, when used by reference to a peptide or a protein, a peptide or a protein or a chemically modified analogue with a substituent that is not present in the peptide or protein or the reference analogue, i.e., a peptide or protein that has been modified by creation of covalent bonds, to introduce substituents. GLP-2 receptor agonists, or GLP-2 RAs, which are potentially useful, activate GLP-2 receptors by binding first to the GLP-2 receptor, and then stimulate an intracellular second messenger system. to the receiver.
[000324] Dans un autre mode de réalisation, le peptide GLP-2 est un analogue du GLP- 2 humain qui incorpore une ou plusieurs substitutions, additions, délétions, ou modifications et qui conserve une activité biologique de type GLP-2. In another embodiment, the GLP-2 peptide is an analogue of human GLP-2 which incorporates one or more substitutions, additions, deletions, or modifications and which retains a GLP-2 type biological activity.
[000325] Les GLP-2 RA peuvent être identifiés par screening des peptides contre des cellules génétiquement designées pour produire des récepteurs du GLP-2. Le récepteur du GLP-2 a été cloné, cf Munroe et. al ., Proc. Natl . Acad. Sci. USA, 96 (4) : 1569 (1999) . Des cellules fonctionnelles incorporant le récepteur du GLP-2, et leur utilisation pour screener des GLP-2 RA ont été également décrites dans WO 98/25955.  GLP-2 RAs can be identified by screening peptides against genetically engineered cells to produce GLP-2 receptors. The GLP-2 receptor has been cloned, see Munroe et al. al., Proc. Natl. Acad. Sci. USA, 96 (4): 1569 (1999). Functional cells incorporating the GLP-2 receptor, and their use for screenerizing GLP-2 RAs have also been described in WO 98/25955.
[000326] Dans un mode de réalisation, les GLP-2 RA avec une activité agoniste ont été modifiés afin de leur conférer une résistance à la dégradation par des enzymes endogènes, comme la DPP-IV. Ces GLP-2 RA peuvent comprendre un remplacement du résidu alanine à la position 2. Tout particulièrement, le résidu Ala2 est remplacé par Glycine ou Sérine ou d'autres résidus décrits par exemple dans US 5, 789, 379. In one embodiment, GLP-2 RAs with agonist activity have been modified to confer resistance to degradation by endogenous enzymes, such as DPP-IV. These GLP-2 RAs may include a replacement of the Alanine residue at the 2-position. In particular, the Ala2 residue is replaced by Glycine or Serine or other residues described for example in US Pat. No. 5,789,379.
[000327] Dans un mode de réalisation, l'analogue du GLP-2 est un agoniste du récepteur du GLP-2. In one embodiment, the GLP-2 analog is a GLP-2 receptor agonist.
[000328] Dans un mode de réalisation, l'analogue du GLP-2, est un analogue ne comportant pas de chaîne acyle, i .e. pas de chaîne issue d'acide g ras comprenant une chaîne alkyle de plus de 10 carbones. In one embodiment, the analogue of GLP-2 is an analogue lacking an acyl chain, i.e. no chain derived from acid ras comprising an alkyl chain of more than 10 carbons.
[000329] Dans un mode de réalisation, l'analogue du GLP-2, est un analogue choisi parmi les composés décrits dans la demande WO97/39031.  In one embodiment, the analogue of GLP-2 is an analogue selected from the compounds described in application WO 97/39031.
[000330] Selon un mode de réalisation, l'agoniste du récepteur du GLP-2 est le téduglutide, encore appelé h[Gly2]GLP-2 ou (Gly2)GLP-2.  According to one embodiment, the GLP-2 receptor agonist is teduglutide, also called h [Gly2] GLP-2 or (Gly2) GLP-2.
[000331] Dans un mode de réalisation particulier, le GLP-2 RA est le téduglutide.  In a particular embodiment, the GLP-2 RA is teduglutide.
Selon un mode de réalisation, analogue de GLP-2 est le téduglutide, encore appelé h[Gly2]GLP-2 ou (Gly2)GLP-2 de séquence : His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu- et-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr- Lys-Ile-Thr-Asp (HGDGSFSDEM N TILDNLAAR DFINWLIQTK ITD). According to one embodiment, GLP-2 analog is teduglutide, also called h [Gly2] GLP-2 or (Gly2) GLP-2 of sequence: His-Gly-Asp-Gly-Ser-Phe-Ser-Asp- Glu- and-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp ( HGDGSFSDEM N TILDNLAAR DFINWLIQTK ITD).
[000332] Dans un mode de réalisation, l'analogue du GLP-2, est un analogue choisi parmi les analogues décrits dans la demande WO2011/050174 ou dans l'article Wisniewski K. et al ., J. Med. Chem. , 2016, 59,3129-3139. In one embodiment, the GLP-2 analogue is an analogue selected from the analogs described in WO2011 / 050174 or in the article Wisniewski K. et al., J. Med. Chem. , 2016, 59.3129-3139.
[000333] Dans un mode de réalisation, l'analogue du GLP-2, est un analogue dont la phamacocinétique est améliorée comportant les substitutions suivantes G2, NLelO, DPhel l, Leu l6 et un radical amide -CON H2, dont l'extrémité C-terminale est amidée.  In one embodiment, the analogue of GLP-2 is an analogue whose pharmacokinetic is improved with the following substitutions G2, NLel0, DPhel1, Leu16 and an amide radical -CON H2, whose end C-terminal is amidated.
[000334] Dans un mode de réalisation particulier, l'analogue du GLP-2 est un analogue de séquence His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle - D-Phe-Thr-Ile-Leu-Asp-Leu- Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp, dont l'extrémité C-terminale est amidée (HGDGSFSDEX F*TILDLLAAR DFINWLIQTK ITD-NH2) (X=Nle (Norleucine) F* = D-Phe(DPhénylalanine)) . [000335] . Dans un mode de réalisation, l'analogue du GLP-2, est un analogue choisi parmi les analogues décrits dans la demande WO2006/117565. In a particular embodiment, the analogue of GLP-2 is a His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-D-Phe-Thr-Ile-sequence analogue. Leu-Asp-Leu-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp, whose C-terminal end is amidated ( HGDGSFSDEX F * TILDLLAAR DFINWLIQTK ITD-NH2) (X = Nle (Norleucine) F * = D-Phe (DPhénylalanine)). [000335]. In one embodiment, the GLP-2 analogue is an analogue selected from the analogs described in WO2006 / 117565.
[000336] Dans un mode de réalisation, l'analogue du GLP-2, est un analogue de stabilité améliorée, comportant des substitutions en positions 8, 16 24 et 28 en combinaison avec des substitutions en position 2 et éventuellement en positions 3,5,7, 10 et 11 et en outre des délétions en position 31 et 33.  In one embodiment, the GLP-2 analog is an improved stability analogue having substitutions at positions 8, 16, 24 and 28 in combination with substitutions at position 2 and optionally at positions 3.5. , 7, 10 and 11 and further deletions at positions 31 and 33.
[000337] Dans un mode de réalisation particulier, l'analogue du GLP-2 est un analogue de séquence His-Gly-Glu-Gly-Ser-Phe-Ser-Ser-Glu-Leu-Ser-Thr-Ile-Leu-Asp-Ala-Leu- Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys- Lys dont l'extrémité C-terminale est amidée (HGEGSFSSEL S TILDALAAR DFIAWLIATK ITDKKKKKK-N H2) (X=Nle (Norleucine) F* = D-P e(DPhénylalanine)) . In a particular embodiment, the GLP-2 analogue is a His-Gly-Glu-Gly-Ser-Phe-Ser-Ser-Glu-Leu-Ser-Thr-Ile-Leu-sequence analog. Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys- Lys whose C-terminal end is amidated (X = Nle (Norleucine) F * = DP e (DP-phenylalanine)).
[000338] Dans un mode de réalisation particulier, l 'analogue du GLP-2 est un analogue de séquence His-Gly-Glu-Gly-Thr-Phe-Ser-Ser-Glu-Leu-Ala-Thr-Ile-Leu-Asp-Ala-Leu- Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys- Lys dont l'extrémité C-terminale est amidée ( HGEGTFSSEL A TILDALAAR DFIAWLIATK ITDKKKKKK-N H2) (X=Nle (Norleucine) F*= D-Phe(DPhénylalanine)) In a particular embodiment, the analogue of GLP-2 is a His-Gly-Glu-Gly-Thr-Phe-Ser-Ser-Glu-Leu-Ala-Thr-Ile-Leu-sequence analogue. Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys-Lys Which the C-terminal end is amidated (X = Nle (Norleucine) F * = D-Phe (DPhénylalanine))
[000339] Les GLP-2, GLP-2RA et analogues ont les séquences suivantes GLP-2, GLP-2RA and the like have the following sequences
Figure imgf000049_0001
Figure imgf000049_0001
Nie (Norleucine)  Nie (Norleucine)
- D-Phe (DP énylalanine)  - D-Phe (DP enylalanine)
Analogue WO2011/050174 SEQID n°55 : Analogous WO2011 / 050174 SEQID No. 55:
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle - D-Phe-Thr-Ile-Leu-Asp-Leu-Leu-Ala-Ala- Arg-Asp-P e-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-D-Phe-Thr-Ile-Leu-Asp-Leu-Leu-Ala-Ala-Arg-Asp-P-Ile-Asn Trp-Leu-Gln-Ile-Thr-Lys-Ile-Thr-Asp
C-term amidated C-term amidated
Analogue WO2006/117565 SEQID n°39 :  Analog WO2006 / 117565 SEQ ID No. 39:
His-Gly-Glu-Gly-Ser-P e-Ser-Ser-Glu-Leu-Ser-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-His-Gly-Glu-Gly-Ser-P-Ser-Ser-Glu-Leu-Ser-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-
Asp-Phe-Ile-Aia-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys- Lys-Lys-Lys Asp-Phe-Ile-Aia-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys-Lys
C-term amidated C-term amidated
Analogue WO2006/117565 SEQID n°41 ou Glepaglutide :  Analog WO2006 / 117565 SEQ ID No. 41 or Glepaglutide:
His-Gly-Glu-Gly-Thr-Phe-Ser-Ser-Glu-Leu-Ala-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-His-Gly-Glu-Gly-Thr-Phe-Ser-Ser-Glu-Leu-Ala-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-
Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys- Lys-Lys-Lys Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys-Lys
C-term amidated C-term amidated
Teduglutide :  Teduglutide:
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg- Asp-Phe-lle-Asn-Trp-Leu -Ile-GIn-Thr-Lys-Ile-Thr-Asp His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp- Leu -Ile-GIn-Thr-Lys-Ile-Thr-Asp
Glp-2 homo sapiens :  Glp-2 homo sapiens:
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn -Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg- Asp-Phe-Ile-Asn-Trp-Leu-Ile-GIn-Thr-Lys-Ile-Thr-Asp [000340] L'agoniste du récepteur du GLP-2 peut être obtenu de différentes manières, par synthèse peptidique par recombinaison. His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp- Leu-Gln-Ile-Thr-Lys-Ile-Thr-Asp The GLP-2 receptor agonist can be obtained in various ways by peptide synthesis by recombination.
[000341] Les agonistes du récepteur du GLP-2 et les analogues de GLP-2 peuvent être utilisées à des posologies variant selon les indications et/ou les patients. GLP-2 receptor agonists and GLP-2 analogs may be used at varying dosages depending upon indications and / or patients.
[000342] Selon un mode de réalisation, la dose journalière va de 0,01 à 0, 1 mg/kg.  According to one embodiment, the daily dose is from 0.01 to 0.1 mg / kg.
[000343] Selon un mode de réalisation, la dose journalière va de 0,02 à 0,075. [000343] According to one embodiment, the daily dose is from 0.02 to 0.075.
[000344] Selon un mode de réalisation, la dose journalière va de 0,025 à 0,05 mg/kg . [000344] According to one embodiment, the daily dose is from 0.025 to 0.05 mg / kg.
[000345] Selon un mode de réalisation, la concentration en agoniste du récepteur du GLP-2 ou en analogue de GLP-2 va de 0,5 à 20 mg/ml . According to one embodiment, the agonist concentration of the GLP-2 receptor or GLP-2 analog ranges from 0.5 to 20 mg / ml.
[000346] Selon un mode de réalisation, la concentration en agoniste du récepteur du GLP-2 ou en analogue de GLP-2 va de 1 à 18 mg/ml.  According to one embodiment, the agonist concentration of the GLP-2 receptor or GLP-2 analog ranges from 1 to 18 mg / ml.
[000347] Selon un mode de réalisation, la concentration en agoniste du récepteur du GLP-2 ou en analogue de GLP-2 va de 2 à 15 mg/ml.  According to one embodiment, the agonist concentration of the GLP-2 receptor or of the GLP-2 analog ranges from 2 to 15 mg / ml.
[000348] Selon un mode de réalisation, la concentration en agoniste du récepteur du GLP-2 ou en analogue de GLP-2 va de 4 à 12 mg/ml . According to one embodiment, the agonist concentration of the GLP-2 receptor or of the GLP-2 analog ranges from 4 to 12 mg / ml.
[000349] Selon un mode de réalisation, la concentration en agoniste du récepteur du GLP-2 ou en analogue de GLP-2 va de 5 à 10 mg/ml.  According to one embodiment, the agonist concentration of the GLP-2 receptor or of the GLP-2 analog ranges from 5 to 10 mg / ml.
[000350] Selon un mode de réalisation, la concentration en agoniste du récepteur du GLP-2 ou en analogue de GLP-2 est de 10 mg/ml.  According to one embodiment, the agonist concentration of the GLP-2 receptor or of the GLP-2 analog is 10 mg / ml.
[000351] Dans un mode de réalisation, le ratio massique co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur téduglutide est compris entre 0,2 et 15.  In one embodiment, the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on teduglutide is between 0.2 and 15.
[000352] Dans un mode de réalisation, le ratio massique co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0,25 et 15.  In one embodiment, the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.25 and 15.
[000353] Dans un mode de réalisation, le ratio massique co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0,25 et 10.  In one embodiment, the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 0.25 and 10.
[000354] Dans un mode de réalisation, le ratio massique co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0,3 et 5. In one embodiment, the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.3 and 5.
[000355] Dans un mode de réalisation, le ratio molaire co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0, 1 et 10.  In one embodiment, the molar ratio of co-polyamino acid carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.1 and 10.
[000356] Dans un mode de réalisation, le ratio molaire co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0, 15 et 8. [000357] Dans un mode de réalisation, le ratio molaire co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0,2 et 5. In one embodiment, the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 0.15 and 8. In one embodiment, the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analog is between 0.2 and 5.
[000358] Dans un mode de réalisation, le ratio molaire co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0,2 et 3.  In one embodiment, the molar ratio of co-polyamino acid carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 0.2 and 3.
[000359] Dans un mode de réalisation, le ratio molaire co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 2 et 7.  In one embodiment, the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on GLP-2 receptor agonist or GLP-2 analog is between 2 and 7.
[000360] Dans un mode de réalisation, la composition comprend en outre un composé nicotinique ou un de ses dérivés. In one embodiment, the composition further comprises a nicotinic compound or a derivative thereof.
[000361 ] Dans un mode de réalisation, la composition comprend de la nicotinamide.  In one embodiment, the composition comprises nicotinamide.
[000362] Dans un mode de réalisation, la concentration de nicotinamide va de 10 à 160 mM. In one embodiment, the concentration of nicotinamide ranges from 10 to 160 mM.
[000363] Dans un mode de réalisation, la concentration de nicotinamide va de 20 à 150 mM.  In one embodiment, the concentration of nicotinamide ranges from 20 to 150 mM.
[000364] Dans un mode de réalisation, la concentration de nicotinamide va de 40 à 120 mM.  In one embodiment, the concentration of nicotinamide ranges from 40 to 120 mM.
[000365] Dans un mode de réalisation, la concentration de nicotinamide va de 60 à 100 mM. In one embodiment, the concentration of nicotinamide ranges from 60 to 100 mM.
[000366] Dans un mode de réalisation, la compoosition comprend en outre un composé polyanionique. In one embodiment, the composition further comprises a polyanionic compound.
[000367] Dans un mode de réalisation, le composé polyanionique est choisie dans le groupe constitué des polyacides carboxyliques et leurs sels de Na+, K+, Ca2+ ou Mg2+. In one embodiment, the polyanionic compound is selected from the group consisting of polycarboxylic acids and their Na + , K + , Ca 2+ or Mg 2+ salts.
[000368] Dans un mode de réalisation, le polyacide carboxylique est choisi dans le groupe constitué par l'acide citrique, l'acide tartrique, et leurs sels de Na+, K+, Ca2+ ou Mg2+. In one embodiment, the polycarboxylic acid is selected from the group consisting of citric acid, tartaric acid, and their salts of Na + , K + , Ca 2+ or Mg 2+ .
[000369] Dans un mode de réalisation, le composé polyanionique est choisi dans le groupe constitué des polyacides phosphoriques et leurs sels de Na +, K+, Ca2+ ou Mg2+. In one embodiment, the polyanionic compound is selected from the group consisting of polyphosphoric acids and their Na + , K + , Ca 2+ or Mg 2+ salts.
[000370] Dans un mode de réalisation, le polyacide phosphorique est le triphosphate et ses sels de Na+, K+, Ca2+ ou Mg +. [000370] In one embodiment, the polyphosphoric acid is triphosphate and its Na + , K + , Ca 2+ or Mg + salts.
[000371] Dans un mode de réalisation, le composé polyanionique est l'acide citrique et ses sels de Na+, K+, Ca2+ ou Mg +. In one embodiment, the polyanionic compound is citric acid and its Na + , K + , Ca 2+ or Mg + salts.
[000372] Dans un mode de réalisation, le composé polyanionique est l'acide tartrique et ses sels de Na+, K+, Ca + ou Mg2+. [000373] Dans un mode de réalisation, le composé polyanionique est l'acide trip osp orique et ses sels de Na+, K+, Ca2+ ou Mg2+. In one embodiment, the polyanionic compound is tartaric acid and its Na + , K + , Ca + or Mg 2+ salts. [000373] In one embodiment, the polyanionic compound is triposporic acid and its Na + , K + , Ca 2+ or Mg 2+ salts.
[000374] Dans un mode de réalisation, la concentration en composé polyanionique est comprise entre 1 et 20 m . In one embodiment, the concentration of polyanionic compound is between 1 and 20 m.
[000375] Dans un mode de réalisation, la concentration en composé polyanionique est comprise entre 2 et 15 mM .  [000375] In one embodiment, the concentration of polyanionic compound is between 2 and 15 mM.
[000376] Dans un mode de réalisation, la concentration en composé polyanionique est comprise entre 3 et 12 mM .  In one embodiment, the concentration of polyanionic compound is between 3 and 12 mM.
[000377] Dans un mode de réalisation, la concentration en composé polyanionique est de 10 mM . [000377] In one embodiment, the polyanionic compound concentration is 10 mM.
[000378] Dans un mode de réalisation, la concentration en composé polyanionique est de 5 mM . [000379] Dans un mode de réalisation, la concentration en composé polyanionique est de 10 mM pour des concentrations en GLP-2 RA comprises entre 0,5 mg/ml et 3 m g/ml .  In one embodiment, the concentration of polyanionic compound is 5 mM. In one embodiment, the concentration of polyanionic compound is 10 mM for GLP-2 RA concentrations of between 0.5 mg / ml and 3 mg / ml.
[000380] Dans un mode de réalisation, la concentration en composé polyanionique est de 10 mM pour des concentrations en GLP-2 comprises entre 0,5 mg/ml et 2 mg/ml . In one embodiment, the concentration of polyanionic compound is 10 mM for GLP-2 concentrations of between 0.5 mg / ml and 2 mg / ml.
[000381] Dans un mode de réalisation, la concentration en composé polyanionique est de 10 mM pour des concentrations en GLP-2 comprises entre 1 mg/ml et 2 mg/ml . In one embodiment, the concentration of polyanionic compound is 10 mM for GLP-2 concentrations of between 1 mg / ml and 2 mg / ml.
[000382] Dans un mode de réalisation, la concentration en composé polyanionique est de 5 mM pour des concentrations en GLP-2 comprises entre 0,5 mg/ml et 3 mg/ml. In one embodiment, the concentration of polyanionic compound is 5 mM for GLP-2 concentrations of between 0.5 mg / ml and 3 mg / ml.
[000383] Dans un mode de réalisation, la concentration en composé polyanionique est de 5 mM pour des concentrations en GLP-2 comprises entre 0,5 mg/ml et 2 mg/ml. In one embodiment, the concentration of polyanionic compound is 5 mM for GLP-2 concentrations of between 0.5 mg / ml and 2 mg / ml.
[000384] Dans un mode de réalisation, la concentration en composé polyanionique est de 5 mM pour des concentrations en GLP-2 comprises entre 1 mg/ml et 2 mg/ml.  In one embodiment, the concentration of polyanionic compound is 5 mM for GLP-2 concentrations of between 1 mg / ml and 2 mg / ml.
[000385] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre une hormone gastrointestinale. In one embodiment, the compositions according to the invention further comprise a gastrointestinal hormone.
[000386] On entend par « hormones gastrointestinales », les hormones choisies dans le groupe constitué par les GLP-1 RA pour agonistes du récepteur du Glucagon humain- Like Peptide-1 (Glucagon like peptide-1 receptor agonist)Glucagon like) et le GIP (Glucose-dependent insulinotropic peptide), l'oxyntomoduline (un dérivé du proglucagon humain), le peptide YY, la cholecystokinine, la ghreline, a motiline et l'entérostatine, leurs analogues ou dérivés et/ou leurs sels pharmaceutlquement acceptables. [000387] Il est particulièrement intéressant de combiner en solution aqueuse un GLP-2 RA et le GLP- 1 , un analogue du GLP-1, ou un agoniste au récepteur du GLP-1. Cette combinaison permettrait notamment de potentialiser les effets de chaque hormone et de pouvoir potentiellement réduire les doses de chacune d'elles. The term "gastrointestinal hormones", the hormones selected from the group consisting of GLP-1 RA for agonists of the human Glucagon receptor-Like Peptide-1 (Glucagon like peptide-1 receptor agonist) Glucagon like) and the GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of human proglucagon), peptide YY, cholecystokinin, ghrelin, motilin and enterostatin, their analogues or derivatives and / or their pharmaceutically acceptable salts. It is particularly advantageous to combine in aqueous solution a GLP-2 RA and GLP-1, a GLP-1 analogue, or an agonist at the GLP-1 receptor. This combination would in particular make it possible to potentiate the effects of each hormone and to be able to potentially reduce the doses of each of them.
[000388] Ainsi, dans un mode de réalisation, les hormones gastro-intestinales sont des analogues ou dérivés de GLP-1 RA (Glucagon like peptide- 1 receptor agonist) choisis dans le groupe constitué par l'exenatide ou Byetta® (ASTRA-ZENECA), le liraglutide ou Victoza® (NOVO NORDISK), le lixisenatide ou Lyxumia® (SANOFI), l'albiglutide ou Tanzeum® (GSK) et le dulaglutide ou Trulicity® (ELI LILLY & CO), le semaglutide, ainsi que leurs analogues ou dérivés et leurs sels pharmaceutiquement acceptables. [000388] Thus, in one embodiment, the gastrointestinal hormones are analogues or derivatives of GLP-1 RA (glucagon like peptide-1 receptor agonist) selected from the group consisting of exenatide or Byetta® (ASTRA- ZENECA), liraglutide or Victoza® (NOVO NORDISK), lixisenatide or Lyxumia® (SANOFI), albiglutide or Tanzeum® (GSK) and dulaglutide or Trulicity® (ELI LILLY & CO), semaglutide, and their analogs or derivatives and their pharmaceutically acceptable salts.
[000389] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre une hormone pancréatique.  In one embodiment, the compositions according to the invention further comprise a pancreatic hormone.
[000390] On entend par « hormones pancréatiques », les hormones choisies dans le groupe constitué par l'amyline, le glucagon, le polypeptide pancréatique et leurs analogues ou dérivés.  [000390] "Pancreatic hormones" means the hormones selected from the group consisting of amylin, glucagon, pancreatic polypeptide and their analogues or derivatives.
[000391] Dans un mode de réalisation, l'hormone pancréatique est le pramlintide ou Symlin®(ASTRA-ZE ECA).  [000391] In one embodiment, the pancreatic hormone is pramlintide or Symlin® (ASTRA-ZE ECA).
[000392] Dans un mode de réalisation, l'hormone gastrointestinale est l'exenatide ou Byetta® ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables. In one embodiment, the gastrointestinal hormone is exenatide or Byetta® its analogues or derivatives and their pharmaceutically acceptable salts.
[000393] Dans un mode de réalisation, l'hormone gastrointestinale est le liraglutide ou Victoza® ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables.  In one embodiment, the gastrointestinal hormone is liraglutide or Victoza® its analogues or derivatives and their pharmaceutically acceptable salts.
[000394] Dans un mode de réalisation, l'hormone gastrointestinale est le lixisenatide ou Lyxumia® ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables. [000394] In one embodiment, the gastrointestinal hormone is lixisenatide or Lyxumia® its analogues or derivatives and their pharmaceutically acceptable salts.
[000395] Dans un mode de réalisation, l'hormone gastrointestinale est l'albiglutide ou Tanzeum® ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables. [000395] In one embodiment, the gastrointestinal hormone is albiglutide or Tanzeum® its analogues or derivatives and their pharmaceutically acceptable salts.
[000396] Dans un mode de réalisation, l'hormone gastrointestinale est le dulaglutide ou Trulicity® ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables. [000397] Dans un mode de réalisation, les compositions selon l'invention sont réalisées par mélange de solutions de GLP-2 RA, et de solutions de GLP-1, d'analogue de GLP-1 ou de GLP-1 RA en ratios volumiques compris dans un intervalle de 10/90 à 90/10. In one embodiment, the gastrointestinal hormone is dulaglutide or Trulicity® its analogues or derivatives and their pharmaceutically acceptable salts. In one embodiment, the compositions according to the invention are produced by mixing solutions of GLP-2 RA, and solutions of GLP-1, GLP-1 analog or GLP-1 RA in ratios. volume in the range of 10/90 to 90/10.
[000398] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre un ou plusieurs composés ralentissant la motilité intestinale. In one embodiment, the compositions according to the invention further comprise one or more compounds slowing intestinal motility.
[000399] Parmi ces composés on peut citer le Loperamide et l 'Octreotide. [000400] Dans un mode de réalisation, le substituant est choisi dans le groupe constitué des chaînes grasses. Among these compounds, mention may be made of Loperamide and Octreotide. In one embodiment, the substituent is selected from the group consisting of fatty chains.
[000401] Dans un mode de réalisation, la concentration en hormone gastrointestinale est comprise dans un intervalle de 0,01 à 10 mg/mL  In one embodiment, the concentration of gastrointestinal hormone is in a range of 0.01 to 10 mg / mL.
[000402] Dans un mode de réalisation, la concentration en exenatide, ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables est comprise dans un intervalle de 0,04 à 0,5 mg/mL. In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in a range of 0.04 to 0.5 mg / mL.
[000403] Dans un mode de réalisation, la concentration en liraglutide, ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables est comprise dans un intervalle de 1 à 10 mg/mL.  In one embodiment, the concentration of liraglutide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 1 to 10 mg / mL.
[000404] Dans un mode de réalisation, la concentration en lixisenatide, ses analogues ou dérivés et leurs sels pharmaceutiquement acceptables est comprise dans un intervalle de 0,01 à 1 mg/mL. [000405] Dans un mode de réalisation, les compositions selon l'invention sont réalisées par mélange de solutions GLP-2 RA obtenues par reconstitution de lyophilisât et de solutions de GLP-1 RA (Glucagon like peptide- 1 receptor agonist), d'analogue ou de dérivé de GLP-1 RA, lesdites solutions de GLP-1 RA étant commerciales ou reconstituées à partir de lyophilisât.  In one embodiment, the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1 mg / mL. In one embodiment, the compositions according to the invention are produced by mixing GLP-2 RA solutions obtained by reconstitution of lyophilisate and GLP-1 RA (Glucagon-like peptide-1 receptor agonist) solutions. analog or derivative of GLP-1 RA, said GLP-1 RA solutions being commercial or reconstituted from lyophilisate.
[000406] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des tampons. In one embodiment, the compositions according to the invention further comprise buffers.
[000407] Dans un mode de réalisation, les compositions selon l'invention comprennent des tampons à des concentrations comprises entre 0 et 100 mM .  In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM.
[000408] Dans un mode de réalisation, les compositions selon l'invention comprennent des tampons à des concentrations comprises entre 15 et 50 mM. In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 15 and 50 mM.
[000409] 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) ou le citrate de sodium .  In one embodiment, the compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer, Tris (trishydroxymethylaminomethane) or sodium citrate.
[000410] Dans un mode de réalisation, le tampon est le phosphate de sodium. [000410] In one embodiment, the buffer is sodium phosphate.
[000411] Dans un mode de réalisation, le tampon est le Tris (trishydroxyméthylaminométhane).  In one embodiment, the buffer is Tris (trishydroxymethylaminomethane).
[000412] Dans un mode de réalisation, le tampon est le citrate de sodium . [000413] Dans un mode de réalisation les compositions comprennent de l'histidine.  [000412] In one embodiment, the buffer is sodium citrate. In one embodiment, the compositions comprise histidine.
[000414] Dans un mode de réalisation les compositions comprennent de l'histidine à une concentration allant de 1 à 20 mg/ml . [000415] Dans un mode de réalisation les compositions comprennent de l'histidine à une concentration allant de 2 à 15 mg/ml . In one embodiment, the compositions comprise histidine at a concentration ranging from 1 to 20 mg / ml. In one embodiment, the compositions comprise histidine at a concentration ranging from 2 to 15 mg / ml.
[000416] Dans un mode de réalisation les compositions comprennent de l'histidine à une concentration allant de 5 à 10 mg/ml.  In one embodiment, the compositions comprise histidine at a concentration ranging from 5 to 10 mg / ml.
[000417] Dans un mode de réalisation, la composition comprend en outre un sel de zinc, en particulier du chlorure de zinc. In one embodiment, the composition further comprises a zinc salt, in particular zinc chloride.
[000418] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des conservateurs. In one embodiment, the compositions according to the invention further comprise preservatives.
[000419] Dans un mode de réalisation, les conservateurs sont choisis dans le groupe constitué par le m-crésol et le phénol seuls ou en mélange.  In one embodiment, the preservatives are selected from the group consisting of m-cresol and phenol alone or as a mixture.
[000420] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre des antioxydants.  In one embodiment, the compositions according to the invention further comprise antioxidants.
[000421] Dans un mode de réalisation, les antioxydants sont choisis parmi la méthionine. In one embodiment, the antioxidants are chosen from methionine.
[000422] Dans un mode de réalisation, la concentration des conservateurs est comprise entre 10 et 50 mM.  [000422] In one embodiment, the concentration of the preservatives is between 10 and 50 mM.
[000423] Dans un mode de réalisation, la concentration des conservateurs est comprise entre 10 et 40 mM.  [000423] In one embodiment, the concentration of the preservatives is between 10 and 40 mM.
[000424] Dans un mode de réalisation, les compositions selon l'invention comprennent en outre un tensioactif.  In one embodiment, the compositions according to the invention further comprise a surfactant.
[000425] Dans un mode de réalisation, le tensioactif est choisi dans le groupe constitué par le propylène glycol ou le polysorbate.  In one embodiment, the surfactant is selected from the group consisting of propylene glycol or polysorbate.
[000426] Les compositions selon l'invention peuvent en outre comprendre des additifs tels que des agents de tonicité. The compositions according to the invention may further comprise additives such as tonicity agents.
[000427] Dans un mode de réalisation, les agents de tonicité sont choisis dans le groupe constitué par le chlorure de sodium, le mannitol, du sucrose, du sorbitol et le glycérol.  In one embodiment, the tonicity agents are selected from the group consisting of sodium chloride, mannitol, sucrose, sorbitol and glycerol.
[000428] Dans un mode de réalisation, la composition comprend du mannitol . In one embodiment, the composition comprises mannitol.
[000429] Dans un mode de réalisation, la composition comprend du mannitol à une concentration allant de 20 à 50 mg/ml. In one embodiment, the composition comprises mannitol at a concentration ranging from 20 to 50 mg / ml.
[000430] Dans un mode de réalisation, la composition comprend du mannitol à une concentration allant de 25 à 35 mg/ml.  In one embodiment, the composition comprises mannitol at a concentration ranging from 25 to 35 mg / ml.
[000431] Dans un mode de réalisation, la composition comprend du mannitol à une concentration de 30 mg/ml.  In one embodiment, the composition comprises mannitol at a concentration of 30 mg / ml.
[000432] Les compositions selon l'invention peuvent comprendre en outre tous les excipients conformes aux pharmacopées et compatibles avec le glucagon humain et les GLP-1 RA utilisés aux concentrations d'usage. [000433] Dans un mode de réalisation, la composition est caractérisée en ce que le pH est compris entre 6,6 et 7,8. [000432] The compositions according to the invention may also comprise all excipients compatible with the pharmacopoeia and compatible with human glucagon and GLP-1 RA used at the use concentrations. In one embodiment, the composition is characterized in that the pH is between 6.6 and 7.8.
[000434] Dans un mode de réalisation, la composition est caractérisée en ce que le pH est compris entre 7,0 et 7,8.  [000434] In one embodiment, the composition is characterized in that the pH is between 7.0 and 7.8.
[000435] Dans un mode de réalisation, la composition est caractérisée en ce que le pH est compris entre 7,3 et 7,4.  [000435] In one embodiment, the composition is characterized in that the pH is between 7.3 and 7.4.
[000436] Dans un mode de réalisation, la composition est caractérisée en ce que le pH est compris entre 6,8 et 7,4. In one embodiment, the composition is characterized in that the pH is between 6.8 and 7.4.
[000437] Dans un mode de réalisation, la composition est caractérisée en ce que le pH est compris entre 6,9 et 7,9.  [000437] In one embodiment, the composition is characterized in that the pH is between 6.9 and 7.9.
[000438] L'invention concerne également des formulations unidoses à pH compris entre 6 et 8 comprenant du GLP-2 RA. The invention also relates to single-dose formulations with a pH of between 6 and 8 comprising GLP-2 RA.
[000439] L'invention concerne également des formulations unidoses à pH compris entre 6,6 et 7,8 comprenant du GLP-2 RA et une hormone gastrointestinale ou une hormone pancréatique, telle que définie précédemment.  The invention also relates to single-dose formulations with a pH of between 6.6 and 7.8 comprising GLP-2 RA and a gastrointestinal hormone or a pancreatic hormone, as defined above.
[000440] Dans un mode de réalisation les formulations unidoses comprennent en outre un co-polyaminoacide substitué tel que défini précédemment.  In one embodiment, the single-dose formulations further comprise a substituted co-polyamino acid as defined above.
[000441] Dans un mode de réalisation, les formulations sont sous forme d 'une solution injectable. Dans un mode de réalisation, le GLP-1 RA, analogue ou dérivé de GLP- 1 RA est choisi dans le groupe comprenant exenatide (Byetta®), liraglutide (Victoza®), lixisenatide (Lyxumia®), albîglutide (Tanzeum®), dulaglutide (Trulicity®), sémaglutide, ou l'un de leurs dérivés.  [000441] In one embodiment, the formulations are in the form of an injectable solution. In one embodiment, GLP-1 RA, analogue or derivative of GLP-1 RA is selected from the group consisting of exenatide (Byetta®), liraglutide (Victoza®), lixisenatide (Lyxumia®), albylgluttide (Tanzeum®), dulaglutide (Trulicity®), semaglutide, or one of their derivatives.
[000442] Dans un mode de réalisation, l'hormone gastrointestinale est l'exenatide.  [000442] In one embodiment, the gastrointestinal hormone is exenatide.
[000443] Dans un mode de réalisation, l'hormone gastrointestinale est le liraglutide. [000443] In one embodiment, the gastrointestinal hormone is liraglutide.
[000444] Dans un mode de réalisation, l'hormone gastrointestinale est le lixisenatide. [000444] In one embodiment, the gastrointestinal hormone is lixisenatide.
[000445] Dans un mode de réalisation, l'hormone gastrointestinale est l'albiglutide. [000445] In one embodiment, the gastrointestinal hormone is albiglutide.
[000446] Dans un mode de réalisation, l'hormone gastrointestinale est le dulaglutide. [000446] In one embodiment, the gastrointestinal hormone is dulaglutide.
[000447] La préparation d'une composition selon l'invention présente l'avantage de pouvoir être réalisée par simple mélange d'une solution de GLP-2 RA, d'une solution de GLP-1 RA, d'un analogue ou un dérivé de GLP-1 RA, et d'un co-polyaminoacide porteurs de charges carboxylates et d'au moins un radical hydrophobe selon l'invention, en solution aqueuse ou sous forme lyophilisée. Si nécessaire, le pH de la préparation est ajusté à pH 7. [000448] Dans un mode de réalisation le mélange de GLP-2 RA et de co-polyaminoacide substitué est concentré par ultrafiltration avant le mélange avec de GLP-1 RA, d'un analogue ou un dérivé de GLP-1 RA en solution aqueuse ou sous forme lyophilisée. [000447] The preparation of a composition according to the invention has the advantage of being possible by simple mixing of a solution of GLP-2 RA, a solution of GLP-1 RA, an analogue or a derivative of GLP-1 RA, and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH 7. In one embodiment, the mixture of GLP-2 RA and substituted co-polyamino acid is concentrated by ultrafiltration before mixing with GLP-1 RA, an analogue or a derivative of GLP-1 RA in aqueous solution. or in freeze-dried form.
[000449] Si nécessaire, la composition du mélange est ajustée en excipients. [000449] If necessary, the composition of the mixture is adjusted to excipients.
[000450] Dans un mode de réalisation, les compositions sont caractérisées en ce que lesdites compositions solubilisent le GLP-2, l'analogue de GLP-2 ou l'agoniste de récepteur du GLP-2 à pH 7,0 et une stabilité physique mesurée par ThT supérieure à celle d'une composition de référence comprenant un GLP-2, un analogue de GLP-2 ou un agoniste de récepteur du GLP-2, éventuellement en combinaison avec une hormone gastro-intestinale, en particulier un GLP- 1 , un analogue de GLP- 1 ou un agoniste de récepteur du GLP-1, ou en combinaison avec une hormone pancréatique telle que l'amyline ou le glucagon ou leurs analogues ou dérivés, ou une substance active réduisant la motilité intestinale, telle que l'octréotide ou le lopéramide.. In one embodiment, the compositions are characterized in that said compositions solubilize GLP-2, GLP-2 analog or GLP-2 receptor agonist at pH 7.0 and physical stability. measured by ThT higher than that of a reference composition comprising a GLP-2, a GLP-2 analogue or a GLP-2 receptor agonist, optionally in combination with a gastrointestinal hormone, in particular a GLP-1 , a GLP-1 analog or a GLP-1 receptor agonist, or in combination with a pancreatic hormone such as amylin or glucagon or their analogs or derivatives, or an active substance reducing intestinal motility, such as octreotide or loperamide.
[000451] L'invention concerne également une formulation pharmaceutique selon l'invention, caractérisée en ce qu'elle est obtenue par séchage et/ou lyophilisation. [000451] The invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
[000452] Dans le cas des libérations locale et systémique, les modes d'administration envisagés sont par voie intraveineuse, sous-cutanée, intradermique ou intramusculaire. In the case of local and systemic releases, the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.
[000453] Selon un mode de réalisation particulier le mode d'administration est la voie sous-cutanée. According to a particular embodiment, the mode of administration is the subcutaneous route.
[000454] Les voies d'administration transdermique, orale, nasale, vaginale, oculaire, buccale, pulmonaire sont également envisagées. [000454] The transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
Partie A. Part A.
Al ; Synthèse des m iécjJÎea- ydrjgphobes  Al; Synthesis of mildewings
[000455] Les radicaux hydrophobes sont représentés dans le tableau suivant par la molécule hydrophobe correspondante avant greffage sur le co-polyaminoacide.  The hydrophobic radicals are represented in the following table by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000058_0001
Figure imgf000059_0001
y rophobes avant greffage sur le co-polyaminoacide.  rophobes before grafting on the co-polyamino acid.
Molécule 1 Molecule 1
Molécule 1-01 : produit obtenu par la réaction entre le chlorure de myristoyle et la L- proline  Molecule 1-01: product obtained by the reaction between myristoyl chloride and L-proline
[000456] A 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). A la fin de l'ajout, le milieu réactionnel est remonté à 20°C en 3 h, puis agité 2 h supplémentaires. Le mélange est refroidi à 0 °C puis une solution aqueuse de HCI 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 HCI 10% (3 x 430 mL), une solution aqueuse saturée en NaCI (430 mL), séchée sur a2SC" , 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 fritte, lavage à l' eptane (2 x 350 mL) et séchage sous pression réduite. To a solution of L-proline (300.40 g, 2.61 mol) in 2N aqueous sodium hydroxide solution (1.63 L) at 0 ° C. is slowly added over 1 h of myristoyl chloride (322 ° C.). g, 1.30 mol) dissolved in dichloromethane (DCM, 1.63 L). At the end of the addition, the reaction medium is raised to 20 ° C in 3 h, then stirred for 2 more hours. The mixture is cooled to 0 ° C. and then an aqueous solution of 37% HCl (215 ml) is added over 15 minutes. The reaction medium is stirred for 1 h at 0 ° C. to 20 ° C. The organic phase is separated, washed with an aqueous 10% HCl solution (3 × 430 mL), saturated aqueous NaCl solution (430 mL), dried over a 2 SC, filtered on cotton and then concentrated under reduced pressure. solubilized 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 to ambient temperature for 4 h, a white solid is obtained after filtration on frit, washing with eptane (2 x 350 mL) and drying under reduced pressure.
Rendement : 410 g (97%)  Yield: 410 g (97%)
RMN *H (CDC , ppm) : 0,88 (3H) ; 1,28 (20H) ; 1,70 (2H) ; 1,90-2,10 (3H) ; 2,36 (2H) ; 2,51 ( 1H) ; 3,47 (1 H) ; 3,56 (1H) ; 4,61 (1H).  1 H NMR (CDC, ppm): 0.88 (3H); 1.28 (20H); 1.70 (2H); 1.90-2.10 (3H); 2.36 (2H); 2.51 (1H); 3.47 (1H); 3.56 (1H); 4.61 (1H).
LC/MS (ESI) : 326,4 ; 651,7 ; (calculé ([M + H]+) : 326,3 ; ([2M + H]+) : 651,6). LC / MS (ESI): 326.4; 651.7; (calculated ([M + H] + ): 326.3; ([2M + H] + ): 651.6).
Molécule 1-02 : produit obtenu par la réaction entre la molécule 1-01 et la N-Boc- éthylènediamine Molecule 1-02: product obtained by the reaction between the molecule 1-01 and N-Boc-ethylenediamine
[000457] A une solution de molécule 1-01 (190,0 g, 583,7 mmol) à 0°C dans le DCM (2,9 L) est ajouté du 1-hydroxybenzotriazole (HOBt, 8,94 g, 58,37 mmol), puis de la N- Boc-éthylènediamine ( 112,2 g, 700,5 mmol) en solution dans le DCM (150 mL) est introduite sur une période de 15 min. Du chlorhydrate de (3-diméthylaminopropyl)-N'- éthylcarbodiimide (EDC, 123, 1 g, 642,1 mmol) est ensuite ajouté par portions, puis le mélange est agité pendant 1 h à 0°C et 17 h entre 0°C et température ambiante. Le mélange réactionnel est ensuite lavé avec une solution aqueuse saturée en NaHC03 (2 x 1,5 L), une solution aqueuse de HCI 1 N (2 x 1,5 L), une solution aqueuse saturée en NaCI ( 1,5 L), puis séché sur Na2S04, filtré et concentré sous pression réduite. Un solide blanc est obtenu après recristallisation dans l'acétonitrile. To a solution of 1-01 molecule (190.0 g, 583.7 mmol) at 0 ° C in DCM (2.9 L) was added 1-hydroxybenzotriazole (HOBt, 8.94 g, 58 ° C). 37 mmol), then N-Boc-ethylenediamine (112.2 g, 700.5 mmol) dissolved in DCM (150 mL) is introduced over a period of 15 minutes. (3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC, 123.1 g, 642.1 mmol) is then added in portions, and the mixture is stirred for 1 hour at 0 ° C. and 17 hours at 0 ° C. C and room temperature. The reaction mixture is then washed with a saturated aqueous solution of NaHCO 3 (2 × 1.5 L), an aqueous solution of 1N HCl (2 × 1.5 L), a saturated aqueous solution of NaCl (1.5 L). then dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid is obtained after recrystallization from acetonitrile.
Rendement : 256,5 g (93 %) . Yield: 256.5 g (93%).
RMN lH (CDCb, ppm) : 0,88 (3H) ; 1, 16-1,38 (20H) ; 1,44 (9H) ; 1,56-1,71 (2H) ; 1,78-2,45 (6H) ; 3, 11 -3,72 (6H) ; 4,30 (0, 1H) ; 4,51 (0,9H) ; 4,87 (0,1 H) ; 5,04 (0,9Η) ; 6,87 (0, 1H) ; 7,23 (0,9H). 1 H NMR (CDCl3, ppm): 0.88 (3H); 1, 16-1.38 (20H); 1.44 (9H); 1.56-1.71 (2H); 1.78-2.45 (6H); 3, 11 -3.72 (6H); 4.30 (0, 1H); 4.51 (0.9H); 4.87 (0.1H); 5.04 (0.9); 6.87 (0, 1H); 7.23 (0.9H).
LC/MS (ESI) : 468,3 ; (calculé ([M+H]+) : 468,4) . LC / MS (ESI): 468.3; (calculated ([M + H] + ): 468.4).
Molécule 1 Molecule 1
[000458] A une solution de molécule 1-02 (256,5 g, 548,4 mmol) dans le DCM (2,75 L) est ajoutée goutte à goutte et à 0°C une solution d'acide chlorhydrique 4 M dans le dioxane (685 mL, 2,74 mol). Après 16 h d'agitation à 0°C, le milieu réactionnel est ramené à température ambiante en 1 h et la solution est concentrée sous pression réduite. Le résidu est trituré dans du pentane ( 1,6 L) filtré sur fritté et séché à 40°C sous pression réduite pour donner un solide blanc de molécule 1 sous forme de sel de chlorhydrate.  To a solution of molecule 1-02 (256.5 g, 548.4 mmol) in DCM (2.75 L) is added dropwise and at 0 ° C. a solution of 4 M hydrochloric acid in dioxane (685 mL, 2.74 mol). After stirring for 16 h at 0 ° C., the reaction medium is brought to ambient temperature over 1 h and the solution is concentrated under reduced pressure. The residue was triturated in pentane (1.6 L) filtered on sintered and dried at 40 ° C under reduced pressure to give a white solid of molecule 1 as the hydrochloride salt.
Rendement : 220,0 g (99 %)  Yield: 220.0 g (99%)
RMN H (MeOD-d4, ppm) : 0,90 (3H) ; 1,21-1,43 (20H) ; 1,54-1,66 (2H) ; 1,85-2,28 (4H) ; 2,39 (2H) ; 3,00-3,17 (2H) ; 3,30-3,40 (1H) ; 3,43-3,71 (3H) ; 4,29 (0,94H) ; 4,48 (0,06H) . 1 H NMR (MeOD-d4, ppm): 0.90 (3H); 1.21-1.43 (20H); 1.54-1.66 (2H); 1.85-2.28 (4H); 2.39 (2H); 3.00-3.17 (2H); 3.30-3.40 (1H); 3.43-3.71 (3H); 4.29 (0.94H); 4.48 (0.06H).
LC/MS (ESI) : 368,2 ; (calculé ([M+H]+) : 368,3). Molécule 2 LC / MS (ESI): 368.2; (calculated ([M + H] + ): 368.3). Molecule 2
[000459] A une solution de la molécule 1-01 (356, 1 g, 1, 1 mol) dans le tétrahydrofurane [000459] To a solution of the molecule 1-01 (356, 1 g, 1, 1 mol) in tetrahydrofuran
(THF, 1,7 L) à 0°C sont ajoutés successivement du N-hydroxysuccinimide (MHS, 132,2 g, 1, 15 mol) puis du Ν,Ν'-dicyclohexylcarbodiimide (DCC, 237, 1 g, 1, 15 mol). Le milieu réactionnel est agité pendant 43 h entre 0°C et température ambiante, filtré sur fritté, puis ajouté en 50 min sur une solution de L-lysine (84 g, 574,5 mmol) et de N,N- diisopropyléthylamine (DIPEA, 707, 1 g, 5,47 mol) dans l'eau (220 mL). Après 17 h d'agitation à température ambiante, le milieu est concentré sous pression rédu ite, le résidu est dilué dans de l'eau (3 L) et la phase aqueuse est lavée avec de l'acétate d'éthyle (AcOEt, 2 x 1,3 L) puis acidifée jusqu'à pH 1 par addition d'une solution aqueuse de HCI 6 N . La phase aqueuse est extraite au DCM, la phase organique est ensuite lavée par une solution aqueuse saturée en NaCI (2 x 1,3 L), séchée sur a2S04, filtrée sur coton et concentrée sous pression réduite. Un solide blanc de la molécule 2 est obtenu après recristallisation dans l'acétone. (THF, 1.7 L) at 0 ° C are successively added N-hydroxysuccinimide (MHS, 132.2 g, 1.15 mol) and then Ν, Ν'-dicyclohexylcarbodiimide (DCC, 237, 1 g, 1, 15 mol). The reaction medium is stirred for 43 hours between 0 ° C. and room temperature, filtered on sintered, then added over 50 min to a solution of L-lysine (84 g, 574.5 mmol) and N, N-diisopropylethylamine (DIPEA). , 707, 1 g, 5.47 mol) in water (220 mL). After stirring for 17 hours at ambient temperature, the medium is concentrated under reduced pressure, the residue is diluted with water (3 L) and the aqueous phase is washed with ethyl acetate (AcOEt, 2 x 1.3 L) then acidified to pH 1 by addition of an aqueous solution of HCl 6 N. The aqueous phase is extracted with DCM, the organic phase is then washed with a saturated aqueous solution of NaCl (2 x 1.3 L), dried over a2SO4, filtered on cotton and concentrated under reduced pressure. A white solid of the molecule 2 is obtained after recrystallization in acetone.
Rendement : 224,2 g (54 %) Yield: 224.2 g (54%)
RMN XH (DMSO-de, ppm) : 0,85 (6H) ; 1,26 (40H) ; 1 ,35- 1,50 (6H) ; 1,50-2, 10 (10H) ; 2, 10-2,25 (4H) ; 3,01 (2H) ; 3,31 -3,55 (4H) ; 4, 10-4,40 (3H) ; 7,68 (0,6H) ; 7,97 (1H) ; 8,27 (0,4H) ; 12,50 (1H). X NMR (DMSO-de, ppm): 0.85 (6H); 1.26 (40H); 1.35- 1.50 (6H); 1.50-2.10 (10H); 2, 10-2.25 (4H); 3.01 (2H); 3.31-3.55 (4H); 4, 10-4.40 (3H); 7.68 (0.6H); 7.97 (1H); 8.27 (0.4H); 12.50 (1H).
LC/MS (ESI) : 761,8 ; (calculé ([M + H]+) : 761,6). LC / MS (ESI): 761.8; (calculated ([M + H] + ): 761.6).
Molécule 3 Molecule 3
Molécule 3-01 : produit obtenu par couplage entre la molécule 2 et la IM-Boc- éthylènediamine  Molecule 3-01: product obtained by coupling between molecule 2 and IM-Boc-ethylenediamine
[000460] Par un procédé similaire à celui utilisé pour la préparation de la molécule 1- 02 appliqué à la molécule 2 (174,0 g, 228,6 mmol ) et à la Boc-éthylènediamine (44 g, 274,3 mmol), un solide blanc de la molécule 3-01 est obtenu après recristallisation dans l'acétonitrile. By a process similar to that used for the preparation of the molecule I-02 applied to molecule 2 (174.0 g, 228.6 mmol) and Boc-ethylenediamine (44 g, 274.3 mmol) a white solid of the molecule 3-01 is obtained after recrystallization in acetonitrile.
Rendement : 195,0 g (94 %)  Yield: 195.0 g (94%)
RMN l (DMSO-de, ppm) : 0,85 (6H) ; 1,20-1,55 (55H) ; 1,50-2,25 (14H) ; 2,95-3,10 (6H) ; 3,31-3,55 (4H) ; 4, 10-4,40 (3H) ; 6,74 (1H) ; 7,60-8,25 (3H) . NMR 1 (DMSO-d6, ppm): 0.85 (6H); 1.20-1.55 (55H); 1.50-2.25 (14H); 2.95-3.10 (6H); 3.31-3.55 (4H); 4, 10-4.40 (3H); 6.74 (1H); 7.60-8.25 (3H).
LC/MS (ESI) : 903,7 ; (calculé ([M+H]+) : 903,7). LC / MS (ESI): 903.7; (calculated ([M + H] + ): 903.7).
Molécule 3 Molecule 3
[000461] Après un procédé similaire à celui utilisé pour la préparation de la molécule 1 appliqué à la molécule 3-01 (192,3 g, 212,9 mmol), le résidu obtenu après évaporation du mélange réactionnel sous pression réduite est dilué dans le DCM ( 1,1 L), la phase organique est lavée par une solution aqueuse de soude 2 M (2 x 0,7 L), séchée sur a2S04, filtrée sur coton et concentrée sous pression réduite. Un solide blanc de la molécule 3 est obtenu après recristallisation dans l'acétonitrile. After a process similar to that used for the preparation of the molecule 1 applied to the molecule 3-01 (192.3 g, 212.9 mmol), the residue obtained after evaporation of the reaction mixture under reduced pressure is diluted in the DCM (1.1 L), the organic phase is washed with an aqueous 2M sodium hydroxide solution (2 × 0.7 L), dried over a2SO4, filtered through cotton and concentrated under reduced pressure. A white solid of the molecule 3 is obtained after recrystallization in acetonitrile.
Rendement : 152,1 g (89 %) Yield: 152.1 g (89%)
RMN JH (DMSO-de, ppm) : 0,85 (6H) ; 1, 10-1,65 (48H) ; 1,70-2,35 ( 12H) ; 2,85 (2H) ; 3,01 (2H) ; 3,25-3,65 (6H) ; 4, 10-4,50 (3H) ; 7,70-8,40 (6H). H NMR J (DMSO-de, ppm): 0.85 (6H); 1, 10-1.65 (48H); 1.70-2.35 (12H); 2.85 (2H); 3.01 (2H); 3.25-3.65 (6H); 4. 10-4.50 (3H); 7.70-8.40 (6H).
LC/MS (ESI) : 803,9 ; (calculé ([M+H]+) : 803,7). LC / MS (ESI): 803.9; (calculated ([M + H] + ): 803.7).
Macule 4 Macule 4
Molécule 4-01 : produit obtenu par la réaction entre l'acide laurique et la L-proline.  Molecule 4-01: product obtained by the reaction between lauric acid and L-proline.
[000462] Par un procédé similaire à celui utilisé pour la préparation de la molécule 1 - 01 appliqué au chlorure de lauroyle (60,0 g, 274,3 mmol ) et à la L-proline (63,15 g, 548,5 mmol), un solide blanc de la molécule 4 est obtenu. By a process similar to that used for the preparation of the 1 - 01 molecule applied to lauroyl chloride (60.0 g, 274.3 mmol) and L-proline (63.15 g, 548.5 g). mmol), a white solid of the molecule 4 is obtained.
Rendement : 78.3 g (96 %) Yield: 78.3 g (96%)
RMN *Η (CDC , ppm) : 0,87 (3H) ; 1,26 ( 16H) ; 1,70 (2H) ; 1,90-2, 10 (3H) ; 2,35 (2H) ; 2,49 ( 1H) ; 3,48 (1H) ; 3,56 ( 1H) ; 4,60 ( 1 H).  NMR * Η (CDC, ppm): 0.87 (3H); 1.26 (16H); 1.70 (2H); 1.90-2.10 (3H); 2.35 (2H); 2.49 (1H); 3.48 (1H); 3.56 (1H); 4.60 (1H).
LC/MS (ESI) : 298,2 ; (calculé ([M+H]+) : 298,2). LC / MS (ESI): 298.2; (calculated ([M + H] + ): 298.2).
Molécule 4 Molecule 4
[000463] Par un procédé similaire à celui utilisé pour la préparation de la molécule 2 appliqué à la molécule 4-01 (42,5 g, 142,9 mmol) et à la L-lysine (13,7 g, 75 mmol), un solide blanc de la molécule 4 est obtenu.  By a process similar to that used for the preparation of the molecule 2 applied to the molecule 4-01 (42.5 g, 142.9 mmol) and L-lysine (13.7 g, 75 mmol) a white solid of the molecule 4 is obtained.
Rendement : 30,2 g (60 %) Yield: 30.2 g (60%)
RMN !H (CDCb, ppm) : 0,88 (6H) ; 1,26 (32H) ; 1,35-1,65 (8H) ; 1,85-2,35 (15H) ; 2,87 (1H) ; 3,40-3,75 (5H) ; 4,50-4,75 (3H) ; 7,87 (1H). NMR ! H (CDCl3, ppm): 0.88 (6H); 1.26 (32H); 1.35-1.65 (8H); 1.85-2.35 (15H); 2.87 (1H); 3.40-3.75 (5H); 4.50-4.75 (3H); 7.87 (1H).
LC/MS (ESI) : 705,6 ; (calculé ([M+H]+) : 705,6) . LC / MS (ESI): 705.6; (calculated ([M + H] +): 705.6).
Molécule 5 Molecule 5
Molécule 5-01 : produit obtenu par couplage entre la molécule 4 et la N-Boc- éthylènediamine  Molecule 5-01: product obtained by coupling between molecule 4 and N-Bocethylenediamine
[000464] A une solution de la molécule 4 (36,7 g, 52,1 mmol) dans le THF (350 mL) sont ajoutés successivement de la Ν, Ν-diisopropyléthylamine (DIPEA, 16,8 g, 130, 1 mmol) et du 2-( lH-benzotriazol-l-yl)-l, l,3,3-tétraméthyluronium tétrafluoroborate (TBTU, 17,5 g, 54,7 mmol) . Après 30 min d'agitation à température ambiante, la N- Boc-éthylènediamine (9,2 g, 57,3 mmol) est ajoutée et le milieu est agité pendant 20 h . Le solvant est éliminé sous pression réduite, le résidu est dilué dans l'AcOEt (500 mL), puis la phase organique est lavée par une solution aqueuse de HCI 0,5 N (3 x 500 mL), une solution aqueuse saturée en NaHCCb (3 x 500 mL), une solution aqueuse saturée en NaCl (3 x 150 mL), séchée sur NazSCM, filtrée sur fritté et concentrée sous pression réduite. Une huile épaisse de la molécule 5-01 est obtenue après purification par chromatographie flash (éluant : AcOEt, MeOH). To a solution of molecule 4 (36.7 g, 52.1 mmol) in THF (350 mL) is added successively Ν, Ν-diisopropylethylamine (DIPEA, 16.8 g, 130, 1 mmol). ) and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 17.5 g, 54.7 mmol). After stirring for 30 minutes at room temperature, N-Boc-ethylenediamine (9.2 g, 57.3 mmol) is added and the medium is stirred for 20 h. The solvent is removed under reduced pressure, the residue is diluted in AcOEt (500 mL), and then the organic phase is washed with an aqueous solution of 0.5N HCl (3 × 500 mL), a saturated aqueous solution of NaHCCb (3 x 500 mL), saturated aqueous NaCl solution (3 x 150 mL), dried over NazSCM, sinter filtered and concentrated reduced pressure. A thick oil of the molecule 5-01 is obtained after purification by flash chromatography (eluent: AcOEt, MeOH).
Rendement : 41,8 g, 95 % Yield: 41.8 g, 95%
RM XH (DMSO-de, ppm) : 0,85 (6H) ; 1, 10-2,40 (63H) ; 2,90-3,60 ( 10H) ; 4,00-4,45 (3H) ; 6,25-6.80 (1H) ; 7,50-8,25 (3H) . RM X H (DMSO-d6, ppm): 0.85 (6H); 1, 10-2.40 (63H); 2.90-3.60 (10H); 4.00-4.45 (3H); 6.25-6.80 (1H); 7.50-8.25 (3H).
LC/MS (ESI) : 847,8 ; (calculé ([M+H]+) : 847,7). LC / MS (ESI): 847.8; (calculated ([M + H] + ): 847.7).
Molécule 5 Molecule 5
[000465] Après un procédé similaire à celui utilisé pour la préparation de la molécule 1 appliqué à la molécule 5-01 (30,9 g, 36,47 mmol ), le résidu obtenu après concentration sous vide est dissous dans le méthanol et évaporé sous vide, cette opération étant répétée 4 fois pour donner un solide blanc de molécule 5 sous forme de sel de chlorhydrate après séchage sous pression réduite.  After a process similar to that used for the preparation of the molecule 1 applied to the 5-01 molecule (30.9 g, 36.47 mmol), the residue obtained after concentration in vacuo is dissolved in methanol and evaporated. under vacuum, this operation being repeated 4 times to give a white solid of molecule 5 as hydrochloride salt after drying under reduced pressure.
Rendement : 27,65 g (97%)  Yield: 27.65 g (97%)
RMN XH (DMSO-de, ppm) : 0,85 (6H) ; 1,10-2,40 (54H) ; 2,75-3, 15 (4H) ; 3,25-3,60 X NMR (DMSO-de, ppm): 0.85 (6H); 1.10-2.40 (54H); 2.75-3, 15 (4H); 3.25 to 3.60
(6H) ; 4,05-4,50 (3H) ; 7,50-8,50 (6H). (6H); 4.05-4.50 (3H); 7.50-8.50 (6H).
LC/MS (ESI) : 747,6 ; (calculé ([M + H] +) : 747,6). LC / MS (ESI): 747.6; (calculated ([M + H] + ): 747.6).
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Tableau 2 : Co-polyaminoacides porteur de charges carboxylates et de radicaux hydrophobes  Table 2: Co-polyamino acids bearing carboxylate charges and hydrophobic radicals
Exemple Al  Example Al
Co-polyaminoacide Al : poly-L-glutamate de sodium modifié par la molécule 1 et ayant une masse molaire moyenne en nombre (Mn) de 4771 g/mol  Co-polyamino acid Al: sodium poly-L-glutamate modified with molecule 1 and having a number-average molar mass (Mn) of 4771 g / mol
[000466] Co-polyaminoacide Al - 1 : acide poly-L-glutamique de masse molaire moyenne en nombre (Mn) 5360 g/mol issu de la polymérisation du y-benzyl-L- glutamate N-carboxyanhydride initiée par l'hexylamine  [000466] Co-polyamino acid Al-1: poly-L-glutamic acid of number-average molar mass (Mn) 5360 g / mol resulting from the polymerization of y-benzyl-L-glutamate N-carboxyanhydride initiated by hexylamine
[000467] Dans un ballon préalablement séché à l'étuve, du γ-benzyl-L-glutamate IM- carboxyanhydride (200,8 g, 763 mmol) est solubilisé dans du DMF anhydre (480 mL). Le mélange est alors agité sous argon jusqu'à complète dissolution, refroidi à 0°C, puis de l'hexylamine (2,5 mL ; 19, 1 mmol) est introduite rapidement. Le mélange est agité entre 0°C et température ambiante pendant 18 h. Le milieu réactionnel est ensuite chauffé à 70°C pendant 2 h, refroidi à température ambiante puis coulé goutte à goutte dans du diisopropyléther (6,7 L) sous agitation. Le précipité blanc est récupéré par filtration, lavé avec du diisopropyléther (3 x 450 mL) puis séché sous vide à 30°C pour donner un acide poly(gamma-benzyl-L-glutamique) (PBLG). In an oven dried flask, γ-benzyl-L-glutamate IM-carboxyanhydride (200.8 g, 763 mmol) is solubilized in anhydrous DMF (480 mL). The mixture is then stirred under argon until complete dissolution, cooled to 0 ° C., and then hexylamine (2.5 mL, 19.1 mmol) is introduced rapidly. The mixture is stirred between 0 ° C and room temperature for 18 h. The reaction medium is then heated at 70 ° C. for 2 h, cooled to room temperature and then poured dropwise into diisopropyl ether (6.7 L) with stirring. The white precipitate is recovered by filtration, washed with diisopropyl ether (3 x 450 mL) and then dried under vacuum at 30 ° C to give a poly (gamma-benzyl-L-glutamic acid) (PBLG).
[000468] A une solution de PBLG ( 159,3 g) dans l'acide trifluoroacétique (TFA, 730 mL) à 4°C est ajoutée goutte à goutte une solution d'acide bromhydrique (HBr) à 33% dans l'acide acétique (510 mL, 2,9 mol). Le mélange est agité à température ambiante pendant 2 h, puis coulé goutte à goutte sur un mélange 1 : 1 (v/v) de diisopropyléther et d'eau sous agitation (8,7 L). Après 2 h d'agitation, le mélange hétérogène est laissé au repos pendant une nuit. Le précipité blanc est récupéré par filtration, lavé au diisopropyléther (2 x 725 mL) puis avec de l'eau (2 x 725 mL) .  To a solution of PBLG (159.3 g) in trifluoroacetic acid (TFA, 730 mL) at 4 ° C. is added dropwise a solution of hydrobromic acid (HBr) at 33% in the acid. acetic acid (510 mL, 2.9 mol). The mixture was stirred at room temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and stirring water (8.7 L). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight. The white precipitate is collected by filtration, washed with diisopropyl ether (2 x 725 mL) and then with water (2 x 725 mL).
[000469] Le solide obtenu est alors solubilisé dans de l'eau (3,2 L) en ajustant le pH à 7 par ajout d'une solution aqueuse de soude 10 N puis une solution aqueuse de soude 1 N. Après solubilisation, la concentration théorique est ajustée à 20 g/L théorique par addition d'eau ( 1,7 L). La solution est filtrée sur filtre 0,45 pm puis 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 jusqu 'à obtenir un volume final de 2,5 L. The solid obtained is then solubilized in water (3.2 L) by adjusting the pH to 7 by adding an aqueous solution of 10 N sodium hydroxide and an aqueous solution of 1N sodium hydroxide. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by addition of water (1.7 L). The solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 μS / cm. The co-polyamino acid solution is then concentrated to a final volume of 2.5 L.
[000470] La solution aqueuse est alors acidifiée par ajout de solution de HCI 12 N (55 mL) jusqu'à atteindre un pH de 2. Après 16 h d'agitation, le précipité obtenu est filtré, lavé avec de l'eau (2 x 730 mL) puis séché sous vide à 30°C pour donner un acide poly- L-glutamique de masse molaire moyenne en nombre (Mn) 5360 g/mol par rapport à un standard de polyoxyéthylène glycol (PEG).  The aqueous solution is then acidified by addition of 12 N HCl solution (55 ml) until a pH of 2 is reached. After stirring for 16 hours, the precipitate obtained is filtered and washed with water ( 2 x 730 mL) then dried under vacuum at 30 ° C to give a poly-L-glutamic acid of number average molecular weight (Mn) 5360 g / mol relative to a standard of polyoxyethylene glycol (PEG).
Co-polyaminoacide Al Co-polyamino acid Al
[000471] Le co-polyaminoacide Al- 1 ( 12,0 g) est solubilisé dans du DMF (500 mL) en chauffant pendant 10 min à 40°C, puis sont ajoutées successivement et à température ambiante de la N-méthylmorpholine (NMM, 9,1 g, 90,3 mmol) et de la N-oxyde de 2- hydroxypyridine (HOPO, 3,0 g, 27, 1 mmol). Le milieu réactionnel est alors refroidi à 0°C, puis de l'EDC. HCI, 5,2 g, 27, 1 mmol) est ajouté et le milieu est agité pendant 1 h à 0°C puis remonté à température ambiante. Une solution de la molécule 1 (5,5 g, 13,5 mmol) et de triéthylamine (TEA, 1,9 mL, 13,5 mmol) dans le DMF (72 mL) est ajoutée, et la solution est agitée pendant 2 h . Le milieu réactionnel est filtré sur filtre tissé 0,2 mm et coulé au goutte-à-goutte sur 4,6 L d 'eau contenant du NaCI à 15% massique et du HCI (pH 2) sous agitation . A la fin de l'ajout, le pH est réajusté à 2 avec une solution de HCI 37%, et la suspension est laissée reposer une nuit. Le précipité est collecté par filtration, puis rincé par de l'eau (3 x 250 mL) . Le solide blanc obtenu est solubilisé dans l'eau (850 mL) par ajout lent d'une solution aqueuse de NaOH 1 N jusqu'à pH 12 sous agitation, puis la solution est agitée 45 min. Le pH est ajusté à 7 avec une solution aqueuse de HCI, de l'eau ( 150 mL) et de l 'éthanol (580 mL) sont ajoutés et la solution est filtrée sur disque de charbon actif R53SLP (3M). La solution obtenue est filtrée sur membrane de PES 0,2 pm puis 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 MS/cm. La solution est filtrée sur filtre 0,2 pm et stockée à 2-8°C. The co-polyamino acid Al-1 (12.0 g) is solubilized in DMF (500 mL) by heating for 10 min at 40 ° C, and then are added successively and at room temperature N-methylmorpholine (NMM 9.1 g, 90.3 mmol) and 2-hydroxypyridine N-oxide (HOPO, 3.0 g, 27.1 mmol). The reaction medium is then cooled to 0 ° C. and then EDC. HCl, 5.2 g, 27.1 mmol) is added and the medium is stirred for 1 hour at 0 ° C. and then raised to room temperature. A solution of molecule 1 (5.5 g, 13.5 mmol) and triethylamine (TEA, 1.9 mL, 13.5 mmol) in DMF (72 mL) is added, and the solution is stirred for 2 hours. h. The reaction medium is filtered through a 0.2 mm woven filter and dripped onto 4.6 L of water containing 15% NaCl and HCl (pH 2) with stirring. At the end of the addition, the pH is readjusted to 2 with 37% HCl solution, and the suspension is allowed to stand overnight. The precipitate is collected by filtration and then rinsed with water (3 x 250 mL). The white solid obtained is solubilized in water (850 mL) by slow addition of a 1N aqueous NaOH solution until pH 12 with stirring, and the solution is then stirred for 45 min. The pH is adjusted to 7 with an aqueous solution of HCl, water (150 mL) and ethanol (580 mL) are added and the solution is filtered on activated carbon disc R53SLP (3M). The solution obtained is filtered through a 0.2 μm PES membrane and then purified by ultrafiltration against a 0.9% NaCl solution and then with water, until the conductimetry of the permeate is less than 50 MS / cm. The solution is filtered through a 0.2 μm filter and stored at 2-8 ° C.
Extrait sec : 17,7 mg/g Dry extract: 17.7 mg / g
DP (estimé d'après la R N Η) : 39  DP (estimated from R N Η): 39
D'après la RMN : I = 0,15 According to the NMR: I = 0.15
La masse molaire moyenne calculée du co-polyaminoacide Al est de 7870 g/mol. HPLC-SEC aqueuse (calibrant PEG) : Mn = 4771 g/mol.  The calculated average molar mass of co-polyamino acid Al is 7870 g / mol. Aqueous HPLC-SEC (PEG calibrant): Mn = 4771 g / mol.
Exemple A2 Example A2
Co-polyaminoacide A2 : poly-L-glutamate de sodium modifié par la molécule 3 et ayant une masse molaire moyenne en nombre (Mn) de 6471 g/mol  Co-polyamino acid A2: sodium poly-L-glutamate modified with molecule 3 and having a number-average molar mass (Mn) of 6471 g / mol
[000472] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide Al appliqué à la molécule 3 (2,46 g, 3,07 mmol) et à un acide poly-L- glutamique de Mn relative 6611g/mol (8,0 g) obtenu par un procédé similaire à celui utilisé pour la préparation du co-polyaminoacide Al-1, 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 A1 applied to molecule 3 (2.46 g, 3.07 mmol) and a poly-L-glutamic acid of relative Mn 6611 g / mol ( 8.0 g) obtained by a method similar to that used for the preparation of the co-polyamino acid Al-1, a sodium poly-L-glutamate modified with the molecule 3 is obtained.
Extrait sec : 25,3 mg/g  Dry extract: 25.3 mg / g
DP (estimé d'après la RMN JH) : 60 DP (estimated by NMR J H): 60
D'après la RMN JH : i = 0,045 According NMR J H i = 0.045
La masse molaire moyenne calculée du co-polyaminoacide A2 est de 11188 g/mol. HPLC-SEC organique (calibrant PEG) : Mn = 7552 g/mol. Exemple A3  The calculated average molar mass of co-polyamino acid A2 is 11188 g / mol. Organic HPLC-SEC (PEG Calibrator): Mn = 7552 g / mol. Example A3
Co-polyaminoacide A3 : poly-L-glutamate de sodium modifié à une de ses extrémités par la molécule 3 et ayant une masse molaire moyenne en nombre (Mn) de 3264 g/mol  Co-polyamino acid A3: sodium poly-L-glutamate modified at one of its ends by molecule 3 and having a number-average molecular weight (Mn) of 3264 g / mol
[000473] Dans un ballon préalablement séché à l'étuve, du γ-benzyl-L-glutamate N- carboxyanhydride (144,2 g, 548 mmol) est solubilisé dans du DMF anhydre (525 mL). Le mélange est agité sous argon jusqu'à solubilisation complète, refroidi à -10°C, puis une solution de molécule 3 (20,0 g, 24,9 mmol) dans le DCM (100 mL) est introduite rapidement. Le mélange est agité pendant 13 h à 0°C, 6 h à 20°C puis chauffé à 65°C pendant 2 h. La totalité du DCM et 60 % du DMF sont distillés sous pression réduite à 70°C, puis le milieu réaction nel et refroidi à 55°C et du méthanol (1,1 L) est ajouté sur une période de 50 min. La suspension obtenue est agitée pendant 18 h à 0°C puis filtrée sur fritté. Le solide blanc de PBLG obtenu est rincé avec du diisopropyléther (IPE, 2 x 275 mL) et séché à 30 °C sous pression réduite. [000474] Le PBLG (25,0 g) est dilué dans du TFA (150 mL), et une solution d'acide bromhydrique (HBr) à 33% dans de l'acide acétique (70 mL, 400 mmol ) est alors ajoutée au goutte à goutte et à 0°C. La solution est ensuite agitée pendant 2 h à température ambiante puis refroidie à 10°C. De l'IPE ( 125 mL) puis de l'eau (125 mL) sont introduits sur le mélange réactionnel en maintenant la température à 10°C, la suspension obtenue est agitée pendant 30 min, filtrée sur fritté et rincée avec de l'IPE (2 x 100 mL) puis de l'eau (2 x 100 mL) . Le solide obtenu est mis en suspension dans une solution aqueuse de NaOH 0.1 N (310 mL), puis solubilisé en ajustant le pH à 7 par ajout d'une solution aqueuse de soude 1 N . Une fois la solubllisation complète, le pH est monté à 12 par ajout d'une solution aqueuse de soude 1 N et le mélange est agité pendant 30 min avant d'être neutralisé jusqu'à pH 7 par ajout d'une solution d'acide acétique à 27%. De l'acétone (30% en masse) est ajouté à la solution et le produit est filtré sur disque de charbon actif R535LP (3M) avec un débit de 5,4 g / min . L'acétone est ensuite distillée à 40°C et sous pression réduite, puis le produit est purifié 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 à environ 30 g/L théorique et le pH est ajusté à 7. La solution aqueuse est filtrée sur 0,2 pm et conservée à 2-8°C. In a previously oven-dried flask, γ-benzyl-L-glutamate N-carboxyanhydride (144.2 g, 548 mmol) is solubilized in anhydrous DMF (525 mL). The mixture is stirred under argon until complete solubilization, cooled to -10 ° C, and then a solution of molecule 3 (20.0 g, 24.9 mmol) in DCM (100 mL) is introduced rapidly. The mixture is stirred for 13 h at 0 ° C, 6 h at 20 ° C and then heated at 65 ° C for 2 h. The whole of the DCM and 60% of the DMF are distilled under reduced pressure at 70 ° C., then the reaction medium is cooled to 55 ° C. and methanol (1.1 L) is added over a period of 50 minutes. The suspension obtained is stirred for 18 h at 0 ° C. and then filtered on sinter. The resulting white PBLG solid is rinsed with diisopropyl ether (IPE, 2 x 275 mL) and dried at 30 ° C under reduced pressure. The PBLG (25.0 g) is diluted in TFA (150 mL), and a solution of hydrobromic acid (HBr) at 33% in acetic acid (70 mL, 400 mmol) is then added. dropwise at 0 ° C. The solution is then stirred for 2 hours at room temperature and then cooled to 10 ° C. IPE (125 mL) and then water (125 mL) are added to the reaction mixture while maintaining the temperature at 10 ° C, the suspension obtained is stirred for 30 min, sintered and rinsed with water. IPE (2 x 100 mL) followed by water (2 x 100 mL). The solid obtained is suspended in an aqueous solution of 0.1 N NaOH (310 mL), and then solubilized by adjusting the pH to 7 by addition of a 1N aqueous sodium hydroxide solution. Once the solubllisation complete, the pH is raised to 12 by adding a 1N aqueous solution of sodium hydroxide and the mixture is stirred for 30 min before being neutralized to pH 7 by addition of an acid solution acetic at 27%. Acetone (30% by weight) is added to the solution and the product is filtered through an activated carbon disc R535LP (3M) with a flow rate of 5.4 g / min. The acetone is then distilled at 40 ° C. and under reduced pressure, and the product is then purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 μS. / cm. The co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 2-8 ° C.
Extrait sec : 25,5 mg/g Dry extract: 25.5 mg / g
DP (estimé d'après la RMN *Η) : 24 DP (estimated by NMR * Η): 24
D'après la RMN XH : i = 0,042 According to the X-ray H: i = 0.042
La masse molaire moyenne calculée du co-polyaminoacide A3 est de 4390 g/mol. HPLC-SEC aqueuse (calibrant PEG) : Mn = 3264 g/mol. Exemple A4  The calculated average molar mass of co-polyamino acid A3 is 4390 g / mol. Aqueous HPLC-SEC (PEG calibrant): Mn = 3264 g / mol. Example A4
co-polyaminoacide A4 - poly-L-glutamate de sodium modifié à une de ses extrémités par la molécule 5 et ayant une masse molaire moyenne en nombre (Mn) de 3317 g/mol co-polyamino acid A4 - sodium poly-L-glutamate modified at one of its ends by the molecule 5 and having a number-average molar mass (Mn) of 3317 g / mol
[000475] Dans un contenant adapté sont introduits successivement le sel de chlorhydrate de la molécule 5 (5,07 g, 5,18 mmol), du chloroforme ( 127 mL) et de la résine échangeuse d'ion Amberlite IRN 150 (50 g). Après 1 h d'agitation sur rouleaux, le milieu est filtré et la résine est rincée avec du chloroforme. Le mélange est évaporé puis co-évaporé avec du toluène. Le résidu (3,87 g, 5, 18 mmol) est solubilisé dans du DMF anhydre ( 10 mL) pour être utilisé directement dans la réaction de polymérisation.  In a suitable container are successively introduced the hydrochloride salt of the molecule 5 (5.07 g, 5.18 mmol), chloroform (127 mL) and the Amberlite IRN 150 ion exchange resin (50 g ). After stirring for 1 hour on rollers, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then coevaporated with toluene. The residue (3.87 g, 5.8 mmol) is solubilized in anhydrous DMF (10 mL) for direct use in the polymerization reaction.
[000476] Dans un ballon préalablement séché à l'étuve, du γ-benzyl-L-glutamate N- carboxyanhydride (30 g, 11,4 mmol) est solubilisé dans du DMF anhydre (57 mL). Le mélange est refroidi à 4°C, puis la solution de molécule 5 dans le DMF est introduite rapidement. Le mélange est agité entre 4°C et température ambiante pendant 17 h, puis chauffé à 65°C pendant 2 h. Le mélange réactionnel est alors refroidi à température ambiante puis versé goutte à goutte dans du diisopropyléther (860 mL) sous agitation. Le précipité blanc est récupéré par filtra tion, lavé deux fois avec du diisopropyléther (2 x 60 mL) puis séché sous vide à 30°C pour obtenir un solide blanc. Le solide (26,3 g) est dilué dans du TFA ( 105 mL), et une solution d'acide bromhydrique (HBr) à 33% dans de l'acide acétique (74 mL, 424 mmol) est alors ajoutée au goutte à goutte et à 0°C. La solution est agitée pendant 2 h à température ambiante puis est coulée goutte à goutte sur un mélange 1 : 1 (v/v) de diisopropyléther / eau et sous agitation (1,3 L). Après 2 h d'agitation, le mélange hétérogène est laissé au repos pendant une nuit. Le précipité blanc est récupéré par filtration, lavé successivement avec de ΙΡΕ (2 x 100 mL) puis avec de l 'eau (2 x 100 mL). Le solide obtenu est solubilisé dans de l'eau (660 mL) en ajustant le pH à 7 par ajout d'une solution aqueuse de soude 1 N. De l'eau (200 mL) est ajoutée, le mélange est filtré sur filtre 0,45 pm puis purifié 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 à environ 30 g/L théorique et le pH est ajusté à 7. La solution aqueuse est filtrée sur 0,2 μπΊ et conservée à 2-8°C. In a balloon previously dried in an oven, γ-benzyl-L-glutamate N-carboxyanhydride (30 g, 11.4 mmol) is solubilized in anhydrous DMF (57 ml). The mixture is cooled to 4 ° C, then the solution of molecule 5 in DMF is introduced rapidly. The mixture is stirred at 4 ° C. and ambient temperature for 17 hours. then heated at 65 ° C for 2 hours. The reaction mixture is then cooled to ambient temperature and then poured dropwise into diisopropyl ether (860 ml) with stirring. The white precipitate is recovered by filtration, washed twice with diisopropyl ether (2 x 60 mL) and then dried under vacuum at 30 ° C to obtain a white solid. The solid (26.3 g) is diluted in TFA (105 mL), and a solution of hydrobromic acid (HBr) at 33% in acetic acid (74 mL, 424 mmol) is then added to the drop. drop and at 0 ° C. The solution is stirred for 2 hours at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (1.3 L). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight. The white precipitate is recovered by filtration, washed successively with ΙΡΕ (2 × 100 mL) and then with water (2 × 100 mL). The solid obtained is solubilized in water (660 ml) by adjusting the pH to 7 by addition of a 1N aqueous sodium hydroxide solution. Water (200 ml) is added, the mixture is filtered through a filter. , 45 pm and then purified by ultrafiltration against 0.9% NaCl solution and then with water until the conductimetry 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. The aqueous solution is filtered through 0.2 μπΊ and stored at 2-8 ° C.
Extrait sec : 20,6 mg/g Dry extract: 20.6 mg / g
DP (estimé d'après la MIM *H) : 22 DP (estimated from MIM * H): 22
D'après la RMN 3 H : i = 0,045 From the 3 H NMR: i = 0.045
La masse molaire moyenne calculée du co-polyaminoacide A4 est de 4031 g/mol. HPLC-SEC aqueuse (calibrant PEG) : Mn = 3317 g/mol  The calculated average molar mass of co-polyamino acid A4 is 4031 g / mol. Aqueous HPLC-SEC (PEG calibrant): Mn = 3317 g / mol
Exemple A5 Example A5
co-polyaminoacide A5 - poly-L-glutamate de sodium modifié à l'une de ses extrémités par la molécule 3 et modifié par la molécule 3 et ayant une masse molaire moyenne en nombre (Mn) de 2904 g/mol co-polyamino acid A5 - sodium poly-L-glutamate modified at one of its ends by molecule 3 and modified by molecule 3 and having a number-average molar mass (Mn) of 2904 g / mol
Co-polyaminoacide A5-1 : acide poly-L-glutamique de masse molaire moyenne en nombre (Mn) 2512 g/mol modifié à une de ses extrémités par la molécule 3 et cappé à l'autre extrémité par l'acide pidolique.  Co-polyamino acid A5-1: poly-L-glutamic acid of number-average molar mass (Mn) 2512 g / mol modified at one of its ends by molecule 3 and capped at the other end by pidolic acid.
[000477] Dans un ballon préalablement séché à l'étuve, du γ-benzyl-L-glutamate N- carboxyanhydride ( 122,58 g, 466 mmol) est placé sous vide pendant 30 min puis du DMF anhydre (220 mL) est introduit. Le mélange est agité sous argon jusqu'à solubilisation complète, refroidi à -10°C, puis une solution de molécule 3 ( 17,08 g, 21,3 mmol ) dans le chloroforme (40 mL) est introduite rapidement. Le mélange est agité entre 0°C et température ambiante pendant 2 jours, puis chauffé à 65°C pendant 4 h. Le mélange réactionnel est alors refroidi à 25°C puis est ajouté de l'acide pidolique ( 13,66 g, 105,8 mmol ), du HOBt (2,35 g, 15,3 mmol) et de l'EDC (20,28 g, 105,8 mmol) . Après 24 h d'agitation à 25°C, la solution est concentrée sous vide pour éliminer le chloroforme et 50% du DMF. Le mélange réactionnel est alors chauffé à 55°C et 1150 mL de méthanol sont introduit en 1 h . Le mélange réactionnel est alors refroidi à 0°C. Après 18 h, le précipité blanc est récupéré par filtration, lavé trois fois avec 270 mL de diisopropyl éther puis séché sous vide à 30°C pour obtenir un solide blanc. Le solide est dilué dans du TFA (390 mL), et une solution d'acide bromhydrique (HBr) à 33% dans de l'acide acétique (271 mL, 1547 mmol) est alors ajoutée goutte à goutte et à 0°C. La solution est agitée pendant 2 h à température ambiante puis est coulée goutte à goutte sur un mélange 1 : 1 (v/v) de diisopropyléther / eau et sous agitation (970 mL). Après 2 h d'agitation, le mélange hétérogène est laissé au repos pendant une nuit. Le précipité blanc est récupéré par filtration, lavé successivement avec du diisopropyléther (380 mL) puis deux fois avec de l'eau (380 mL) . Le solide obtenu est solubilisé dans de l 'eau (3,6 L) en ajustant le pH à 7 par ajout d'une solution aqueuse de soude 10 N puis une solution aqueuse de soude 1 N. Le mélange est filtré sur filtre 0,45 μηι puis est purifié par ultrafiltration contre une solution de NaCI 0,9%, une solution de NaOH 0,1 N, une solution de NaCI 0,9%, une solution de tampon phosphate (150 m ), 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 à environ 30 g/L théorique, filtrée sur 0,2 μιτι puis acidifiée à pH 2 sous agitation par addition d'une solution de HCI à 37% . Le précipité est alors récupéré par filtration, lavé deux fois avec de l'eau puis séché sous vide à 30°C pour obtenir un solide blanc. In a balloon previously dried in the oven, γ-benzyl-L-glutamate N-carboxyanhydride (122.58 g, 466 mmol) is placed under vacuum for 30 min and then anhydrous DMF (220 mL) is introduced. . The mixture is stirred under argon until complete solubilization, cooled to -10 ° C, then a solution of molecule 3 (17.08 g, 21.3 mmol) in chloroform (40 mL) is introduced rapidly. The mixture is stirred between 0 ° C and room temperature for 2 days and then heated at 65 ° C for 4 h. The reaction mixture is then cooled to 25 ° C. and then pidolic acid (13.66 g, 105.8 mmol), HOBt (2.35 g, 15.3 mmol) and EDC (20.4 g) are added. , 28 g, 105.8 mmol). After stirring for 24 h at 25 ° C., the solution is concentrated in vacuo to remove chloroform and 50% DMF. The reaction mixture is then heated to 55 ° C. and 1150 ml of methanol are introduced over 1 hour. The reaction mixture is then cooled to 0 ° C. After 18 h, the white precipitate is recovered by filtration, washed three times with 270 mL of diisopropyl ether and then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (390 mL), and a solution of 33% hydrobromic acid (HBr) in acetic acid (271 mL, 1547 mmol) is then added dropwise at 0 ° C. The solution is stirred for 2 hours at room temperature and is then poured dropwise on a mixture of 1: 1 (v / v) diisopropyl ether / water and with stirring (970 ml). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight. The white precipitate is recovered by filtration, washed successively with diisopropyl ether (380 mL) and then twice with water (380 mL). The solid obtained is solubilized in water (3.6 L) by adjusting the pH to 7 by adding a 10N aqueous solution of sodium hydroxide and then a 1N aqueous sodium hydroxide solution. The mixture is filtered through a 0 filter. 45 μηι and then purified by ultrafiltration against 0.9% NaCl solution, 0.1 N NaOH solution, 0.9% NaCl solution, phosphate buffer solution (150 m), NaCl solution, , 9% and then water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to about 30 g / liter, filtered through 0.2 μιτι and then acidified to pH 2 with stirring by adding a solution of 37% HCl. The precipitate is then recovered by filtration, washed twice with water and then dried under vacuum at 30 ° C to obtain a white solid.
Co-polyaminoacide A5 Co-polyamino acid A5
[000478] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide Al appliqué à la molécule 3 ( 1,21 g, 1,50 mmol) et au co- polyaminoacide A5- 1 (5,5 g, 33,4 mmol), un poly-L-glutamate de sodium modifié à l'une de ses extrémités par la molécule 3 et modifié par la molécule 3 est obtenu.  By a process similar to that used for the preparation of the co-polyamino acid A1 applied to molecule 3 (1.21 g, 1.50 mmol) and co-polyamino acid A5-1 (5.5 g, 33, 4 mmol), a sodium poly-L-glutamate modified at one of its ends by molecule 3 and modified with molecule 3 is obtained.
Extrait sec : 19,0 mg/g Dry extract: 19.0 mg / g
DP (estimé d'après la RMN 1H) : 22 DP (estimated from 1H NMR): 22
D'après la RMN 1H : I = 0,089 According to 1H NMR: I = 0.089
La masse molaire moyenne calculée du co-polyaminoacide A5 est de 4826 g/mol. HPLC-SEC organique (calibrant PEG) : Mn = 2904 g/mol . Exemple A6 The calculated average molar mass of co-polyamino acid A5 is 4826 g / mol. Organic HPLC-SEC (PEG Calibrator): Mn = 2904 g / mol. Example A6
Co-polyaminoacid Λ6 : poly-L-glutamate de sodium modifié à ses extrémités par la molécule 2 et ayant une masse molaire moyenne en nombre (Mn) de 2877 g/mol  Co-polyamino acid Λ6: sodium poly-L-glutamate modified at its ends by molecule 2 and having a number-average molar mass (Mn) of 2877 g / mol
Co-polyaminoacid A6-1 : poly-L-benzylglutamate issu de la polymérisation du y-benzyl- L-glutamate /V-carboxyanhydride initiée par l'éthylènediamine. Co-polyaminoacid A6-1: poly-L-benzylglutamate resulting from the polymerization of γ-benzyl-L-glutamate / γ-carboxyanhydride initiated by ethylenediamine.
[000479] Dans un ballon préalablement séché à l'étuve, du γ-benzyl-L-glutamate /V-carboxyanhydride ( 100,0 g, 380 mmol) est solubilisé dans du DMF anhydre (230 mL). Le mélange est alors agité jusqu'à complète dissolution, refroidi à 0 °C, puis de l'éthylène diamine (1,06 mL, 15,8 mmol) est introduit rapidement. Après 18 h d'agitation à 0 °C, une solution de HCI 4 N dans le dioxane (20 mL, 79 mmol) est ajoutée puis le milieu réactionnel est coulé au goutte à goutte sur un mélange de méthanol (313 mL) et d'IPE ( 1,2 L). Le précipité est filtré sur fritté, lavé par de ΙΊΡΕ (2 x 220 mL) et séché à 30 °C sous pression réduite.  In an oven-dried flask, γ-benzyl-L-glutamate / γ-carboxyanhydride (100.0 g, 380 mmol) is solubilized in anhydrous DMF (230 mL). The mixture is then stirred until complete dissolution, cooled to 0 ° C, and then ethylenediamine (1.06 mL, 15.8 mmol) is introduced rapidly. After stirring for 18 h at 0 ° C., a solution of 4 N HCl in dioxane (20 mL, 79 mmol) is added and then the reaction mixture is poured dropwise over a mixture of methanol (313 mL) and d IPE (1.2 L). The precipitate is sintered, washed with ΙΊΡΕ (2 x 220 mL) and dried at 30 ° C under reduced pressure.
Co-polyaminoacid A6 Co-polyaminoacid A6
[000480] A une solution de la molécule 2 (5,65 g, 7,42 mmol) dans du DMF (68 mL) à 0 °C est ajouté du ( l-[Bis(diméthylamino)methylène]-lH-l,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate) (HATU, 3,68 g, 9,64 mmol ) et de la DIPEA (3,87 mL, 22,2 mmol). La solution est ensuite introduite sur une solution de co- polyaminoacide Dl-1 (20,0 g) et de triéthylamine (TEA, 1,04 mL, 7,42 mmol) dans du DMF (238 mL) à 0 °C, et le milieu est agité pendant 18 h entre 0 °C et température ambiante. Du dichlorométhane (780 mL) est ajouté, la phase organique est lavée par une solution aqueuse de HCI 0,1 N (2 x 380 mL), une solution aqueuse saturée en NaHCO (2 x 380 mL), u ne solution aqueuse saturée en NaCI (2 x 380 mL) puis de l'eau (380 mL). Le milieu est ensuite coulé sur de ΙΊΡΕ (2,8 L), le précipité est filtré sur fritté, lavé avec de ΙΊΡΕ (2 x 50 mL) et séché à 30 °C sous pression réduite. Le solide est ensuite dilué dans du TFA (69 mL), puis la solution est refroidie à 4 °C. Une solution de HBr à 33 % dans l'acide acétique (48 mL, 0,274 mol) est alors ajoutée goutte à goutte. Le mélange est agité à température ambiante pendant 2 h, puis coulé goutte à goutte sur un mélange 1 : 1 (v/v) de diisopropyléther et d'eau sous agitation (0,8 L). Après 2 h d'agitation, le mélange hétérogène est laissé au repos pendant une nuit. Le précipité blanc est récupéré par filtration, lavé avec de ΙΊΡΕ (2 x 80 mL) puis avec de l'eau (2 x 80 mL). Le solide obtenu est alors solubilisé dans de l'eau ( 500 mL) en ajustant le pH à 7 par ajout d'une solution aqueuse de soude 1 N . Après solubilisation, la concentration théorique est ajustée à 20 g/L théorique par addition d'eau ( 174 mL), la solution est filtrée sur filtre 0,45 pm puis 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 obtenue est filtrée sur filtre 0,2 pm et stockée à 2-8 °C. To a solution of molecule 2 (5.65 g, 7.42 mmol) in DMF (68 mL) at 0 ° C is added (1- [bis (dimethylamino) methylene] -1H-1, 2,3-triazolo [4,5-bjpyridinium 3-oxid hexafluorophosphate) (HATU, 3.68 g, 9.64 mmol) and DIPEA (3.87 mL, 22.2 mmol). The solution is then added to a solution of co-polyamino acid D1-1 (20.0 g) and triethylamine (TEA, 1.04 mL, 7.42 mmol) in DMF (238 mL) at 0 ° C, and the medium is stirred for 18 h at 0 ° C. and ambient temperature. Dichloromethane (780 mL) is added, the organic phase is washed with an aqueous solution of 0.1N HCl (2 x 380 mL), a saturated aqueous solution of NaHCO (2 x 380 mL), a saturated aqueous solution of NaCl (2 x 380 mL) then water (380 mL). The medium is then poured on ΙΊΡΕ (2.8 L), the precipitate is filtered on sintered, washed with ΙΊΡΕ (2 × 50 mL) and dried at 30 ° C. under reduced pressure. The solid is then diluted in TFA (69 mL) and the solution is cooled to 4 ° C. A solution of 33% HBr in acetic acid (48 mL, 0.274 mol) is then added dropwise. The mixture is stirred at ambient temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and stirring water (0.8 L). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight. The white precipitate is collected by filtration, washed with ΙΊΡΕ (2 x 80 mL) and then with water (2 x 80 mL). The solid obtained is then solubilized in water (500 mL) by adjusting the pH to 7 by adding a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by addition of water (174 mL), the solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9 NaCl solution. %, then water until the conductimetry of the permeate is less than 50 pS / cm. The resulting solution is filtered through a 0.2 μm filter and stored at 2-8 ° C.
Extrait sec : 28,7 m g/g Dry extract: 28.7 m g / g
DP (estimé d'après la RMN JH) : 24 DP (estimated by NMR J H): 24
D'après la RMN lH : \ = 0,081 According to the NMR H: \ = 0.081
La masse molaire moyenne calculée du co-polyaminoacide Dl est de 5135 g/mol . HPLC-SEC organique (calibrant PEG) : Mn = 2877 g/mol .  The calculated average molar mass of the co-polyamino acid D1 is 5135 g / mol. Organic HPLC-SEC (PEG Calibrator): Mn = 2877 g / mol.
Exemple A7 Example A7
Co-polyaminoacid A7 : poly-L-glutamate de sodium modifié à ses extrémités par la molécule 4 et ayant une masse molaire moyenne en nombre (Mn) de 2827 g/mol Co-polyamino acid A7: sodium poly-L-glutamate modified at its ends by molecule 4 and having a number-average molar mass (Mn) of 2827 g / mol
[000481] Par un procédé similaire à celui utilisé pour la préparation du co- polyaminoacide A6 appliqué au co-polyaminoacide A6-1 (20,0 g) et à la molécule 4 (5,23 g, 7,42 mmol), un poly-L-glutamate de sodium modifié à ses extrémités par la molécule 4 est obtenu .  By a method similar to that used for the preparation of the co-polyamino acid A6 applied to the co-polyamino acid A6-1 (20.0 g) and to the molecule 4 (5.23 g, 7.42 mmol), a sodium poly-L-glutamate modified at its ends by the molecule 4 is obtained.
Extrait sec : 27,4 mg/g Dry extract: 27.4 mg / g
DP (estimé d'après la RMN ]H) : 24 DP (estimated by NMR ] H): 24
D'après la RM N *Η : i = 0,077 From the RM N * Η: i = 0.077
La masse molaire moyenne calculée du co-polyaminoacide A7 est de 4956 g/mol . HPLC-SEC organique (calibrant PEG) : Mn = 2827 g/mol . The calculated average molar mass of the co-polyamino acid A7 is 4956 g / mol. Organic HPLC-SEC (PEG Calibrator): Mn = 2827 g / mol.
B. Compositions B. Compositions
Exemple Bl : préparation d'une solution SI de teduglutide à 10 mg/ml contenant du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4  Example B1: Preparation of an SI solution of 10 mg / ml teduglutide containing mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
[000482] Une solution de teduglutide concentrée à 10 mg/ml est préparée par dissolution d'un lyophilisât commercialisé par Shire contenant 5 mg de teduglutide, 3,88 mg de L-histidine, 15 mg de mannitol, 0,644 mg de phosphate de sodium monobasique et 3,434 mg de phosphate de sodium dibasique heptahydrate. Ce lyophilisât est repris avec 500 pL d'eau stérile. Le pH de la solution obtenue est de 7,4.  A solution of teduglutide concentrated at 10 mg / ml is prepared by dissolving a freeze-dried product sold by Shire containing 5 mg of teduglutide, 3.88 mg of L-histidine, 15 mg of mannitol, 0.644 mg of sodium phosphate. monobasic and 3,434 mg of sodium phosphate dibasic heptahydrate. This lyophilizate is taken up with 500 μl of sterile water. The pH of the solution obtained is 7.4.
Exemple B2 : préparation d'une solution aqueuse S2 de mannitol ( 165 mM), de L-histidine (50 mM ) et de phosphate (35 mM) à pH 7,4 Example B2: Preparation of an aqueous solution S2 of mannitol (165 mM), L-histidine (50 mM) and phosphate (35 mM) at pH 7.4
[000483] Une solution d'excipients est préparée à partir de solutions aqueuses concentrées de L-histidine, de mannitol, de tampon phosphate à pH 7,4 et d'eau de manière à obtenir une concentration finale de 50 mM de L-histidine, 165 mM de mannitol et 35 mM de phosphate à pH 7,4. Exemple B3 : préparation de solutions S3 à S6 comprenant des concentrations variables de 0,5 à 3 mg/ml de teduglutide et contenant du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM), à un pH de 7,4 [000484] Une solution S2 d'excipients est ajoutée à la solution SI concentrée de teduglutide de manière à obtenir les solutions S3 à S6 ayant une concentration finale en teduglutide telles que présentées dans le Tableau 3, et une concentration finale de mannitol de 165 mM, une concentration finale de L-histidine de 50 mM et une concentration finale en phosphate de 35 mM, et avec un pH de 7,4. A solution of excipients is prepared from concentrated aqueous solutions of L-histidine, mannitol, phosphate buffer pH 7.4 and water so as to obtain a final concentration of 50 mM of L-histidine. 165 mM mannitol and 35 mM phosphate pH 7.4. Example B3: Preparation of solutions S3 to S6 comprising varying concentrations of 0.5 to 3 mg / ml of teduglutide and containing mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at a pH of 7.4 [000484] A solution S2 of excipients is added to the concentrated solution of teduglutide SI so as to obtain the solutions S3 to S6 having a final concentration of teduglutide as presented in Table 3, and a final mannitol concentration of 165 mM, a final L-histidine concentration of 50 mM and a final phosphate concentration of 35 mM, and with a pH of 7.4.
Figure imgf000074_0001
Figure imgf000074_0001
Tableau 3 : concentrations en teduglutide des solutions S3 à S6  Table 3: Teduglutide Concentrations of Solutions S3 to S6
Exemple B4 : préparation de solutions de teduglutide à 1 mg/ml contenant du co-polyaminoacide Al, du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B4: Preparation of 1 mg / ml solutions of teduglutide containing co-polyamino acid Al, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
[000485] Les solutions B4-1 et B4-2 (décrites dans le Tableau 4) sont obtenues en mélangeant les volumes adéquats de solutions concentrées d'excipients (mannitol, L- histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée de teduglutide, et d'une solution concentrée de co-polyaminoacide Al .  Solutions B4-1 and B4-2 (described in Table 4) are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid Al.
Figure imgf000074_0002
Figure imgf000074_0002
Tableau 4 : compositions et aspect visuel des solutions B4-1 et B4-2  Table 4: compositions and visual appearance of solutions B4-1 and B4-2
Exemple B5 : préparation de solutions de teduglutide à 1 mg/ml contenant du co-polyaminoacide A 2, du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B5: Preparation of solutions of teduglutide at 1 mg / ml containing co-polyamino acid A 2, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7.4
[000486] Les solutions B5-1 et B5-2 (décrites dans le Tableau 5) sont obtenues en mélangeant les volumes adéquats de solutions concentrées d'excipients (mannitol, L- histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée, et d'une solution concentrée de co-polyaminoacide A2.
Figure imgf000075_0001
Solutions B5-1 and B5-2 (described in Table 5) are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated IF solution, and a concentrated solution of co-polyamino acid A2.
Figure imgf000075_0001
Exemple B6 : préparation de solutions de teduglutide à 1 mg/ml contenant du co-polyaminoacide A3, du mannitol ( 165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM ) à pH 7,4  Example B6: Preparation of 1 mg / ml solutions of teduglutide containing A3 co-polyamino acid, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
[000487] Les solutions B6-1 à B6-5 (décrites dans le Tableau 6) sont obtenues en mélangeant les volumes adéquats de solutions concentrées d 'excipients (mannitol, L- histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée de teduglutide, et d'une solution concentrée de co-polyaminoacide A3.  Solutions B6-1 to B6-5 (described in Table 6) are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid A3.
Figure imgf000075_0002
Figure imgf000075_0002
Tableau 6 : compositions et aspect visuel des so utions B6-1 à B6-5.  Table 6: Compositions and visual appearance of solutions B6-1 to B6-5.
Exemple B7 : préparation de solutions de teduglutide à 10 mg/ml contenant du co-polyaminoacide A3, du mannitol ( 165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B7: Preparation of solutions of teduglutide at 10 mg / ml containing A3 co-polyamino acid, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
[000488] La solution B7-6 (décrite dans le Tableau 7) est obtenue par dissolution d'un lyophilisât commercialisé par Shire contenant 5 mg de teduglutide, 3,88 mg de L- histidine, 15 mg de mannitol, 0,644 mg de phosphate de sodium monobasique et 3,434 mg de phosphate de sodium dibasique heptahydrate. Ce lyophilisât est repris avec 500 pL d'une solution aqueuse stérile de co-polyaminoacide A3 à 36,2 mg/ml . Le pH final est de 7,4.  Solution B7-6 (described in Table 7) is obtained by dissolving a freeze-dried product marketed by Shire containing 5 mg of teduglutide, 3.88 mg of L-histidine, 15 mg of mannitol and 0.644 mg of phosphate. of sodium monobasic and 3,434 mg of sodium phosphate dibasic heptahydrate. This lyophilizate is taken up with 500 μl of a sterile aqueous solution of co-polyamino acid A3 at 36.2 mg / ml. The final pH is 7.4.
Figure imgf000075_0003
Figure imgf000075_0003
Tableau 7 : composition et aspect visuel de la solution B7-6. Exemple B8 : préparation d'une solution de teduglutide à 1 mg/ml contenant du co-polyaminoacide A4, du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Table 7: composition and visual appearance of solution B7-6. Example B8: preparation of a solution of teduglutide at 1 mg / ml containing co-polyamino acid A4, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7, 4
[000489] La composition B8-1 (décrite dans le Tableau 8) est obtenue en mélangeant les volumes adéquats de solutions concentrées d'excipients (mannitol, L-histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée de teduglutide, et d'une solution concentrée de co-polyaminoacide A4.  The composition B8-1 (described in Table 8) is obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer at pH 7.4) with a concentrated SI solution. teduglutide, and a concentrated solution of co-polyamino acid A4.
Figure imgf000076_0001
Figure imgf000076_0001
Tableau 8 : composition et aspect visuel de la solution B8-1.  Table 8: Composition and visual appearance of solution B8-1.
Exemple B9 : préparation de solutions de teduglutide à 1 mg/ml contenant du co-polyaminoacide A5, du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B9: Preparation of solutions of teduglutide at 1 mg / ml containing co-polyamino acid A5, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
[000490] Les solutions B9-1 et B9-2 (décrites dans le Tableau 9) sont obtenues en mélangeant les volumes adéquats de solutions concentrées d'excipients (mannitol, L- histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée de teduglutide, et d'une solution concentrée de co-polyaminoacide A5.  Solutions B9-1 and B9-2 (described in Table 9) are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid A5.
Figure imgf000076_0002
Figure imgf000076_0002
Tableau 9 : compositions et aspect visuel des solutions B9-1 et B9-2.  Table 9: compositions and visual appearance of solutions B9-1 and B9-2.
Exemple B10 : préparation de solutions de teduglutide à 1 mg/ml contenant du co-polyaminoacide A6, du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B10: Preparation of solutions of teduglutide at 1 mg / ml containing co-polyamino acid A6, mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
[000491] Les solutions B10-1 à B10-4 (décrites dans le Tableau 10a) sont obtenues en mélangeant les volumes adéquats de solutions concentrées d'excipients (mannitol, L- histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée de teduglutide, et d'une solution concentrée de co-polyaminoacide Dl.
Figure imgf000077_0001
The solutions B10-1 to B10-4 (described in Table 10a) are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4), a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid D1.
Figure imgf000077_0001
Tableau 10a : compositions et aspect visuel des solutions B10-1 et B10-4.  Table 10a: compositions and visual appearance of solutions B10-1 and B10-4.
Exemple Bll : préparation de solutions de teduglutide à 3 mg/ml contenant du co-polyaminoacide A6, du mannitoi (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B11: Preparation of solutions of teduglutide at 3 mg / ml containing co-polyamino acid A6, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7.4
[000492] Les solutions Bl l-5 et Bl l-6 (décrites dans le Tableau l ia) sont obtenues en mélangeant les volumes adéquats de solutions concentrées d 'excipients (mannitoi, L- histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée de teduglutide, et d'une solution concentrée de co-polyaminoacide A6.  [000492] Solutions B1-5 and B1 1-6 (described in Table IIa) are obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer pH 7.4). , a concentrated SI solution of teduglutide, and a concentrated solution of co-polyamino acid A6.
Figure imgf000077_0002
Figure imgf000077_0002
Tableau l ia : compositions et aspect visuel des solutions de teduglutide à 3 mg/ml Dl- Table 1: Compositions and visual appearance of teduglutide solutions at 3 mg / ml D1-
5 et Dl-6. 5 and Dl-6.
Exemple B12 : préparation d'une solution de teduglutide à 1 mg/ml contenant du co-polyaminoacide A7, du mannitoi (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B12: preparation of a solution of teduglutide at 1 mg / ml containing co-polyamino acid A7, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7, 4
[000493] La solution A7-1 (décrites dans le Tableau 12a) est obtenue en mélangeant les volumes adéquats de solutions concentrées d'excipients (mannitoi, L-histidine, tampon phosphate à pH 7,4), d'une solution SI concentrée de teduglutide, et d'une solution concentrée de co-polyaminoacide A7.  The solution A7-1 (described in Table 12a) is obtained by mixing the appropriate volumes of concentrated solutions of excipients (mannitol, L-histidine, phosphate buffer at pH 7.4), with a concentrated SI solution. teduglutide, and a concentrated solution of co-polyamino acid A7.
Figure imgf000077_0003
Figure imgf000077_0003
Tableau 12a : compositions et aspect visuel de la solution de teduglutide B12-1. Exemple B13 : Préparation d'une solution S7 d'exenatide à 10 mg/ml contenant du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Table 12a: compositions and visual appearance of the teduglutide solution B12-1. Example B13: Preparation of a 10 mg / ml solution of exenatide S7 containing mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer (35 mM) at pH 7.4
[000494] Une solution d'exenatide concentrée est préparée par dissolution de 10 mg de poudre commercialisée par Bachem dans 1 ml de la solution d'excipients S2. Le pH de la solution obtenue est de 7,4.  [000494] A concentrated exenatide solution is prepared by dissolving 10 mg of powder marketed by Bachem in 1 ml of the solution of excipients S2. The pH of the solution obtained is 7.4.
Exemple B14 : Préparation d'une solution S8 d'exenatide à 0,5 mg/ml contenant du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B14: Preparation of 0.5 mg / ml solution of exenatide S8 containing mannitol (165 mM), L-histidine (50 mM) and phosphate buffer (35 mM) at pH 7.4
[000495] Une solution S2 d'excipients est ajoutée à la solution S7 concentrée d'exenatide de manière à obtenir une solution S8 avec une concentration finale en exenatide de 0,5 mg/ml, et une concentration finale de mannitol de 165 mM, une concentration finale de L-histidine de 50 mM et une concentration finale en phosphate de 35 mM, et avec un pH de 7,4.  A solution S2 of excipients is added to the concentrated solution S7 of exenatide so as to obtain a solution S8 with a final concentration of exenatide of 0.5 mg / ml, and a final concentration of mannitol of 165 mM, a final concentration of L-histidine of 50 mM and a final phosphate concentration of 35 mM, and with a pH of 7.4.
Exemple B15 : Préparation de solutions de teduglutide à 1 mg/ml contenant des concentrations variables d'exenatide allant de 8 à 50 pg/ml, du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Example B15: Preparation of solutions of teduglutide at 1 mg / ml containing varying concentrations of exenatide ranging from 8 to 50 μg / ml, mannitol (165 mM), L-histidine (50 mM) and a phosphate buffer ( 35 mM) at pH 7.4
[000496] Les solutions S9 à S10 (décrites dans le Tableau 13) sont obtenues en mélangeant les volumes adéquats d'une solution d'excipients S2, d'une solution SI concentrée de teduglutide, et d'une solution S8 d'exenatide pour une concentration finale en mannitol de 165 mM, en L-histidine de 50 m M et en phosphate de 35 mM, et pour un pH final de 7,4.  The solutions S9 to S10 (described in Table 13) are obtained by mixing the appropriate volumes of a solution of excipients S2, a concentrated solution SI teduglutide, and a solution S8 of exenatide for a final mannitol concentration of 165 mM, 50 mM L-histidine and 35 mM phosphate, and a final pH of 7.4.
Figure imgf000078_0001
Figure imgf000078_0001
Tableau 13 : compositions et aspect visuel des solutions Bl-1 à Bl-5. Exemple B16 : Préparation de solutions de teduglutide à 1 mg/ml contenant des concentrations variables d'exenatide allant de 8 à 50 pg/ml, du co- polyaminoacide A3, du mannitol (165 mM), de la L-histidine (50 mM) et un tampon phosphate (35 mM) à pH 7,4 Table 13: compositions and visual appearance of solutions Bl-1 to B-5. Example B16: Preparation of solutions of teduglutide at 1 mg / ml containing varying concentrations of exenatide ranging from 8 to 50 μg / ml, co-polyamino acid A3, mannitol (165 mM), L-histidine (50 mM) ) and phosphate buffer (35 mM) at pH 7.4
[000497] Les solutions Bl-7 à B l-8 (décrites dans le Tableau 14) sont obtenues en mélangeant les volumes adéquats d'une solution d'excipients S2, d'une solution SI concentrée de teduglutide, d'une solution S8 d'exenatide et d'une solution concentrée de co-polyaminoacide A3, pour une concentration finale en mannitol de 165 mM, en L-  [000497] The solutions B1-7 to B1-8 (described in Table 14) are obtained by mixing the appropriate volumes of a solution of excipients S2, a concentrated solution SI teduglutide, a solution S8 of exenatide and a concentrated solution of co-polyamino acid A3, for a final mannitol concentration of 165 mM,
Figure imgf000079_0001
Figure imgf000079_0001
Tableau 14 : compositions et aspect visuel des solutions B16-7 et B16-8. Table 14: compositions and visual appearance of solutions B16-7 and B16-8.
[000498] Les compositions obtenues précédemment (B4 à B16) sont des compositions injectables stables physiquement. C. Physico-Chimie [000498] The compositions obtained above (B4 to B16) are physically stable injectable compositions. C. Physico-Chemistry
Résultats des observations visuelles au mélange et des mesures de fibrillation Par ThT  Results of Visual Observations on Mixing and Fibrillation Measurements by ThT
Observations visuelles  Visual observations
[000499] 2 vials de 1,5 mL remplis avec 0,5 mL de solutions co- polyaminoacide/teduglutide sont placés verticalement à 30°C en conditions statiques. Les vials sont inspectés visuellement de manière quotidienne/hebdomadaire afin de détecter l 'apparition de particules visibles ou d'une turbidité. Cette inspection est réalisée selon les recommandations de la Pharmacopée Européenne (EP 2.9.20) : les vials sont soumis à un éclairage d'au moins 2000 Lux et sont observés face à un fond blanc et un fond noir. Le nombre de jours de stabilité correspond à la durée à partir de laquelle au moins un via! présente des particules visibles ou une turbidité. Mesures de fibrillation à ia ThT [000499] 2 vials of 1.5 ml filled with 0.5 ml of co-polyamino acid / teduglutide solutions are placed vertically at 30 ° C. under static conditions. The vials are inspected visually daily / weekly to detect the appearance of visible particles or turbidity. This inspection is carried out according to the recommendations of the European Pharmacopoeia (EP 2.9.20): the vials are subjected to a lighting of at least 2000 Lux and are observed facing a white background and a black background. The number of days of stability corresponds to the duration from which at least one via! has visible particles or turbidity. Fibrillation measures at ThT
Principe Principle
[000500] La mauvaise stabilité d'un peptide peut conduire à la formation de fibrilles amyloïdes, définies comme des structures macromoléculaires ordonnées. Celles-ci peuvent éventuellement conduire à la formation de gel au sein de l'échantillon .  [000500] The poor stability of a peptide can lead to the formation of amyloid fibrils, defined as ordered macromolecular structures. These may eventually lead to gel formation within the sample.
[000501] L'essai de suivi de la fluorescence de la thioflavine T (ThT) est utilisé pour analyser la stabilité physique des solutions. La Thioflavine est une petite molécule sonde ayant une signature de fluorescence caractéristique lorsqu'elle se lie à des fibrilles de type amyloïdes (Naiki et al. (1989) Anal . BioChem. 177, 244-249 ; LeVine (1999) ethods. Enzymol . 309, 274-284).  [000501] The fluorescence monitoring test of thioflavin T (ThT) is used to analyze the physical stability of the solutions. Thioflavin is a small probe molecule with a characteristic fluorescence signature when it binds to amyloid-type fibrils (Naiki et al (1989) Anal BioChem 177, 244-249, LeVine (1999) ethods, Enzymol. 309, 274-284).
[000502] Cette méthode permet de suivre la formation de fibrilles au sein de solutions non diluées. Ce suivi est réalisé dans des conditions de stabilité accélérées : sous agitation et à 37°C.  This method makes it possible to follow the formation of fibrils within undiluted solutions. This monitoring is performed under accelerated stability conditions: with stirring and at 37 ° C.
Conditions expérimentales Experimental conditions
[000503] Les échantillons ont été préparés juste avant le début de la mesure. La préparation de chaque composition est décrite dans l'exemple associé. La Thioflavine T a été ajoutée dans la composition à partir d'une solution mère concentrée de manière à induire une dilution négligeable de la composition. La concentration de Thioflavine T dans la composition est de 40 μΜ.  [000503] The samples were prepared just before the start of the measurement. The preparation of each composition is described in the associated example. Thioflavin T was added to the composition from a concentrated stock solution so as to induce a negligible dilution of the composition. The concentration of Thioflavine T in the composition is 40 μΜ.
[000504] Un volume de 150 pL de la composition a été introduit dans un puits d'une plaque 96 puits. Chaque composition a été analysée avec au moins deux essais (duplicat) au sein d'une même plaque. La plaque a été scellée par du film transparent afin d'éviter l'évaporation de la composition.  A volume of 150 μL of the composition was introduced into a well of a 96-well plate. Each composition was analyzed with at least two tests (duplicate) within the same plate. The plate was sealed with transparent film to prevent evaporation of the composition.
[000505] Cette plaque a ensuite été placée dans l'enceinte d'un lecteur de plaques (EnVision 2104 Multilabel, Perkin Elmer). La température est réglée à 37°C, et une agitation latérale de 960 rpm avec 1 mm d'amplitude est imposée. [000505] This plate was then placed in the enclosure of a plate reader (EnVision 2104 Multilabel, Perkin Elmer). The temperature is set at 37 ° C, and side shaking of 960 rpm with 1 mm amplitude is imposed.
[000506] Une lecture de l'intensité de fluorescence dans chaque puits est réalisée avec une longueur d'onde d'excitation de 442 nm, et une longueur d'onde d'émission de 482 nm au cours du temps. A reading of the fluorescence intensity in each well is made with an excitation wavelength of 442 nm, and an emission wavelength of 482 nm over time.
[000507] Le processus de fibrillation se manifeste par une forte augmentation de la fluorescence après un délai appelé temps de latence.  [000507] The fibrillation process is manifested by a sharp increase in fluorescence after a delay called latency.
[000508] Pour chaque puits, ce délai a été déterminé graphiquement comme l'intersection entre la ligne de base du signal de fluorescence et la pente de la courbe de fluorescence en fonction du temps déterminée pendant la forte augmentation initiale de fluorescence. La valeur de temps de latence reportée correspond à la moyenne des mesures de temps de latence faites sur deux puits.  For each well, this delay was determined graphically as the intersection between the baseline of the fluorescence signal and the slope of the fluorescence curve as a function of time determined during the sharp initial increase in fluorescence. The reported latency value is the average of latency measurements made on two wells.
[000509] Un exemple de détermination graphique est représenté à la figure 1. [000510] Sur cette figure est représentée de façon graphique la détermination du temps de latence (LT) par suivi de la fluorescence de la Thioflavine T, sur une courbe ayant en ordonnées la valeur de la fluorescence (en u.a. unités arbitraires) et en abscisses le temps en minutes. An example of a graphical determination is shown in FIG. 1. In this figure is graphically represented the determination of the lag time (LT) by monitoring the fluorescence of Thioflavin T, on a curve having on the ordinate the value of the fluorescence (in ua arbitrary units) and on the abscissa. the time in minutes.
Exemple Cl : temps de latence de solutions de teduglutide à différentes concentrations Example C1: Latency of solutions of teduglutide at different concentrations
Figure imgf000081_0001
Figure imgf000081_0001
Tableau 10 : Temps de latence par ThT des solutions S3 à S6.  Table 10: ThT Latency of Solutions S3 to S6.
[000511] Le temps de latence d'une solution de teduglutide sur une gamme de concentrations allant de 0,5 à 3 mg/ml est compris entre 1, 15 et 1,55 h. Le temps de latence du peptide seul est donc sensiblement identique sur une gamme de concentrations proches de celle du produit commercial ( 10 mg/ml). [000511] The latency time of a teduglutide solution over a concentration range of 0.5 to 3 mg / ml is between 1.15 and 1.55 h. The lag time of the peptide alone is therefore substantially identical over a concentration range close to that of the commercial product (10 mg / ml).
Exemple C2 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de polyaminoacide Al Example C2 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of polyamino acid Al
Figure imgf000081_0002
Figure imgf000081_0002
Tableau 11 : Temps de latence par ThT des solutions B4-1 et B4-2, en comparaison avec la référence S4 .  Table 11: ThT lag times for solutions B4-1 and B4-2 compared to S4.
[000512] Le temps de latence d'une solution S4 de teduglutide, dépourvue de co- polyaminoacide, est inférieur à 1,5 h; les solutions B4-1 et B4-2 , permettent d'obtenir des temps de latence respectivement au moins supérieurs à 7 et 13 h. The latency time of an S4 solution of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; solutions B4-1 and B4-2, allow latency times respectively at least 7 and 13 h.
Exemple C3 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de co- polyaminoacide A2 Example C3: Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A2
Figure imgf000081_0003
Figure imgf000081_0003
Tableau 12 : Temps de latence par ThT des solutions B5-1 et B5-2, en comparaison avec la solution S4. [000513] Le temps de latence d'une solution S4 de teduglutide, dépourvue de co- polyaminoacide, est inférieur à 1,5 h; les solutions B5-1 et B5-2 permettent d'obtenir des temps de latence respectivement au moins supérieurs à 3 et 21 h. Table 12: ThT latency for B5-1 and B5-2 solutions, compared with S4 solution. The latency time of a solution S4 of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; the solutions B5-1 and B5-2 make it possible to obtain latency times respectively at least greater than 3 and 21 h.
Exemple C4 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de co- polyaminoacide A3 Example C4 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A3
Figure imgf000082_0001
Figure imgf000082_0001
Tableau 13 : Temps de latence par ThT (des solutions B6-1 à B6-5, en comparaison avec la solution S4).  Table 13: Latency by ThT (solutions B6-1 to B6-5, compared with solution S4).
[000514] Le temps de latence d'une solution S4 de teduglutide, dépourvue de co- polyaminoacide, est inférieur à 1,5 h; les solutions B6-1 à B6-5, contenant des ratios molaires A3/teduglutide de 0,5 à 3, permettent d'obtenir des temps de latence au moins supérieurs à 5 h, un ratio molaire de 3 permettant d'obtenir un temps de latence supérieur à 69 h. The latency time of a solution S4 of teduglutide, free of co-polyamino acid, is less than 1.5 h; the solutions B6-1 to B6-5, containing molar ratios A3 / teduglutide of 0.5 to 3, make it possible to obtain latencies at least greater than 5 hours, a molar ratio of 3 allowing to obtain a time Latency greater than 69 hours.
Exemple C5 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de co- polyaminoacide A4
Figure imgf000082_0002
Example C5: Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A4
Figure imgf000082_0002
Tableau 14 : Temps de latence par ThT de la solution B8-1, en comparaison avec la solution S4.  Table 14: Latency per ThT of solution B8-1, compared with solution S4.
[000515] Le temps de latence d'une solution S4 de teduglutide dépourvue de co- polyaminoacide, est inférieur à 1,5 h; la solution B8-1 permet d'obtenir un temps de latence supérieur à 11 h. Exemple C6 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de co- polyaminoacide A5 [000515] The latency time of a solution S4 of teduglutide devoid of co-polyamino acid, is less than 1.5 h; Solution B8-1 provides a latency of more than 11 hours. Example C6: Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A5
Figure imgf000083_0001
Figure imgf000083_0001
Tableau 15 : Temps de latence par ThT des solutions B9-1 et B9-2, comparaison avec la solution S4.  Table 15: ThT Latency of Solutions B9-1 and B9-2, Comparison with S4 Solution.
[000516] Le temps de latence d 'une solution S4 de teduglutide, dépourvue de co- polyaminoacide, est inférieur à 1,5 h; les solutions B9-1 et B9-2 , permettent d'obtenir des temps de latence au moins supérieurs à 8 h. Exemple C7 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de co- polyaminoacide A6 à différentes concentrations  [000516] The latency time of a solution S4 of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; solutions B9-1 and B9-2 provide latency times of at least 8 hours. Example C7 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polyamino acid A6 at different concentrations
Figure imgf000083_0002
Figure imgf000083_0002
Tableau 16a : Temps de latence par ThT des solutions B10- 1 à B10-4, comparaison avec la solution S4, [000517] Le temps de latence d'une solution S4 de teduglutide , dépourvue de co- polyaminoacide, est inférieur à 1,5 h ; les solutions B10-1 à B10-4 selon l'invention, contenant des ratios molaires A6/teduglutide de 0,25 à 2, permettent d'obtenir des temps de latence au moins supérieurs à 13 h, un ratio molaire de 2 permettant d'obtenir des temps de latence supérieurs à 62 h.  Table 16a: ThT Latency of Solutions B10-1 to B10-4, Comparison with S4 Solution [000517] The latency of a S4 solution of teduglutide, free of co-polyamino acid, is less than 1, 5 h; the solutions B10-1 to B10-4 according to the invention, containing molar ratios A6 / teduglutide of 0.25 to 2, make it possible to obtain latency times of at least 13 h, a molar ratio of 2 allowing obtain latency times greater than 62 hours.
Exemple C8 : Stabilité du teduglutide à 3 mg/ml à pH 7,4 en présence de co- polymaminoacide A6 Example C8: Stability of teduglutide at 3 mg / ml at pH 7.4 in the presence of co-polymamino acid A6
Figure imgf000083_0003
Figure imgf000083_0003
Tableau 17a : Temps de latence par ThT des solutions Bl l-5 et Bl l-6, comparaison avec la solution S6. [000518] Le temps de latence d'une solution S6 de teduglutide, dépourvue de co- polyaminoacide, est inférieur à 1,5 h ; les solutions B10-5 et Bl l-6 selon l'invention, contenant des ratios molaires Dl/teduglutide de 0,25 à 0,5, permettent d'obtenir des temps de latence respectivement au moins supérieurs à 13 et 16 h. Ces résultats sont identiques à ceux obtenus dans l'exemple C7 pour les mêmes ratios à une concentration en teduglutide de 1 mg/ml . Table 17a: ThT latency time of the solutions Bl l-5 and Bl l-6, comparison with the solution S6. The latency time of a solution S6 of teduglutide, devoid of co-polyamino acid, is less than 1.5 h; the solutions B10-5 and B1 1-6 according to the invention, containing Dl / teduglutide molar ratios of 0.25 to 0.5, make it possible to obtain latency times respectively at least greater than 13 and 16 h. These results are identical to those obtained in Example C7 for the same ratios at a teduglutide concentration of 1 mg / ml.
Exemple C9 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de co- polymaminoacide A7 Example C9 Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polymamino acid A7
Figure imgf000084_0001
Figure imgf000084_0001
Tableau 18a : Temps de latence par ThT de la solution D2-1, comparaison avec la solution S4.  Table 18a: ThT lag time of the D2-1 solution, comparison with the S4 solution.
[000519] Le temps de latence d 'une solution S4 de teduglutide, dépourvue de co polyaminoacide, est inférieur à 1,5 h ; la solution B12-1, contenant un ratio molain A7/teduglutide de 1, permet d'obtenir un temps de latence supérieur à 12 h. [000519] The latency time of a solution S4 of teduglutide, free of co polyamino acid, is less than 1.5 h; solution B12-1, containing an A7 / teduglutide molain ratio of 1, makes it possible to obtain a latency time greater than 12 hours.
Exemple CIO : Stabilité physique du teduglutide (1 mg/mL) à 30°C en présence ou non de co-polyaminoacide A3 Example CIO: Physical stability of teduglutide (1 mg / mL) at 30 ° C. in the presence or absence of co-polyamino acid A3
Figure imgf000084_0002
Figure imgf000084_0002
Tableau 16 : stabilité physique à 30°C (statique) d'une solution S4 de teduglutide sans co-polyaminoacide, et de solutions B6-3 et B6-5  Table 16: Physical stability at 30 ° C (static) of an S4 solution of teduglutide without co-polyamino acid, and solutions B6-3 and B6-5
[000520] Une solution S4 de teduglutide, dépourvue de co-polyaminoacide, est conforme moins de 7 jours aux critères de stabilité physique par observation visuelle. La solution B6-5, contenant un ratio molaire A3/teduglutide de 3, permet de prolonger la stabilité physique à 30°C jusqu'à au moins 63 jours. Exemple Cil : Stabilité physique du teduglutide (10 mg/mL) à 30°C en présence ou non de co-polyaminoacide A3 [000520] An S4 solution of teduglutide, devoid of co-polyamino acid, is less than 7 days compliant with the physical stability criteria by visual observation. The B6-5 solution, containing an A3 / teduglutide molar ratio of 3, makes it possible to prolong the physical stability at 30 ° C. for at least 63 days. Example Cil: Physical stability of teduglutide (10 mg / ml) at 30 ° C. in the presence or absence of co-polyamino acid A3
Figure imgf000085_0001
Figure imgf000085_0001
Tableau 17 : stabilité physique à 30°C (statique) d'une solution SI de teduglutide sans co-polyaminoacide, et de la solution B7-6  Table 17: Physical stability at 30 ° C (static) of a solution SI of teduglutide without co-polyamino acid, and solution B7-6
[000521] Une solution SI de teduglutide, dépourvue de co-polyaminoacide, est conforme moins de 11 jours aux critères de stabilité physique par observation visuelle. La solution B7-6, permet de prolonger la stabilité physique à 30°C jusqu'à au moins 21 jours. [000521] An SI solution of teduglutide, devoid of co-polyamino acid, is less than 11 days compliant with the physical stability criteria by visual observation. Solution B7-6 prolongs the physical stability to 30 ° C until at least 21 days.
Exemple C12 : Stabilité physique du teduglutide à 30°C en présence ou non de co-polyaminoacide A6 Example C12: Physical stability of teduglutide at 30 ° C. in the presence or absence of co-polyamino acid A6
Figure imgf000085_0002
Figure imgf000085_0002
Tableau 18b : comparaison de la stabilité physique à 30°C (statique) d'une solution 54 de teduglutide sans co-polyaminoacide, et d'une solution B10-3 Table 18b: comparison of the physical stability at 30 ° C. (static) of a solution 54 of co-polyamino acid-free teduglutide and a B10-3 solution
[000522] Une solution S4 de teduglutide, dépourvue de co-polyaminoacide, est conforme moins de 7 jours aux critères de stabilité physique par observation visuelle. La solution B10-3, contenant un ratio molaire A6/teduglutide de 1, permet de prolonger la stabilité physique à 30°C jusqu'à 28 jours. [000522] An S4 solution of teduglutide, devoid of co-polyamino acid, is less than 7 days compliant with the physical stability criteria by visual observation. The solution B10-3, containing a molar ratio A6 / teduglutide of 1, prolongs the physical stability at 30 ° C up to 28 days.
Exemple C13 : Stabilité du teduglutide à 1 mg/ml à pH 7,4 en présence de co- pol maminoacide A3 et d'cxenatide Example C13: Stability of teduglutide at 1 mg / ml at pH 7.4 in the presence of co-polaminoacid A3 and hexenatide
Figure imgf000086_0001
Figure imgf000086_0001
Tableau 20 : Temps de latence par ThT des solutions B16-7 et B16-8 en comparaison avec la solution S4 et les solutions S9 et S10.  Table 20: ThT latency for B16-7 and B16-8 solutions compared to S4 and S9 and S10 solutions.
[000523] Le temps de latence d'une solution S4 de teduglutide, dépourvue de co- polyaminoacide, est inférieur à 3,5 h . De même, les temps de latence de solutions S9 et S10 de teduglutide+exenatide, dépourvues de co-polyaminoacide A3, sont également inférieurs à 3,5 h. En comparaison, les solutions Bl-7 et Bl-8, contenant les deux peptides teduglutide et exenatide et un ratio molaire A3/teduglutide de 3, permettent d'obtenir un temps de latence supérieur à 63 h. [000523] The latency time of a solution S4 of teduglutide, devoid of co-polyamino acid, is less than 3.5 h. Similarly, the latency times of solutions S9 and S10 of teduglutide + exenatide, lacking co-polyamino acid A3, are also less than 3.5 h. In comparison, the solutions Bl-7 and Bl-8, containing the two teduglutide and exenatide peptides and a molar ratio A3 / teduglutide of 3, make it possible to obtain a latency time greater than 63 h.
D. Analyse D. Analysis
[000524] La stabilité chimique des formulations a été évaluée par RP- HPLC sur un système HPLC Agilent 1200 Séries selon la méthode décrite dans le tableau 18. L'analyse est effectuée avec une colonne de chromatographie de phase inverse type C18 en suivant un gradient classique en conditions acides avec l'ajout de 0,05 % d'acide trifluoroacétique et 0,05 % d'acide formique dans la phase A aqueuse et la phase B organique. L'aire des signaux du téduglutide natif et de ses produits de dégradations sont ensuite déterminés manuellement via le logiciel ChemStation pour calculer le recouvrement en téduglutide total (peptide natif et produits de dégradation) et le recouvrement en téduglutide natif. Paramètre de la Attribution The chemical stability of the formulations was evaluated by RP-HPLC on an Agilent 1200 Series HPLC system according to the method described in Table 18. The analysis is carried out with a C18 type reverse phase chromatography column following a gradient. conventional in acidic conditions with the addition of 0.05% trifluoroacetic acid and 0.05% formic acid in aqueous phase A and organic phase B. The signal area of native teduglutide and its degradation products are then manually determined using ChemStation software to calculate total teduglutide coverage (native peptide and degradation products) and native teduglutide coverage. Attribution setting
méthode  method
Waters XBridge peptide BEH C18 150 x 4,6 mm, Waters XBridge peptide BEH C18 150 x 4.6 mm,
Colonne Column
qranulométrie de 3,5 D m  size of 3.5 D m
A: H20 + 0,05 % TFA and 0,05 % HA A: H 2 O + 0.05% TFA and 0.05% HA
Phases mobiles B: MeCN + 0,05 % TFA and 0,05 % HA  Moving Phases B: MeCN + 0.05% TFA and 0.05% HA
C : Ammonium acétate 10 mM pH 9 H20/MeCN 2 : 8C: Ammonium acetate 10 mM pH 9 H 2 O / MeCN 2: 8
Débit 1,0 mL/min Flow rate 1.0 mL / min
Volume d'injection 5 DL  Injection volume 5 DL
Température de four 30°C  Oven temperature 30 ° C
Température auto- Auto temperature
2-8°C 2-8 ° C
injecteur  injector
Tableau 18 : Description de la méthode analytique  Table 18: Description of the analytical method
[000525] Les résultats de stabilité des solutions stockées à 30°C (S4, B6-3, B6-5 et B10-3) sont présentés dans le tableau 19. Les conditions de l'étude sont décrites dans la partie « Observations visuelles » de la partie C. Des échantillons ont été prélevés à 7 et 49 jours, dans un flacon dédié, pour effectuer l'analyse RP-HPLC. Ce tableau contient pour chaque solution, le recouvrement total et natif en téduglutide ainsi que la teneur en produits de dégradation du téduglutide (obtenu par différence entre le recouvrement total et natif en téduglutide) . The stability results of the solutions stored at 30 ° C. (S4, B6-3, B6-5 and B10-3) are presented in Table 19. The conditions of the study are described in the "Visual Observations" section. Of Part C. Samples were taken at 7 and 49 days in a dedicated vial to perform RP-HPLC analysis. This table contains for each solution, the total and native recovery of teduglutide as well as the content of degradation products of teduglutide (obtained by difference between total recovery and native teduglutide).
Figure imgf000087_0001
Figure imgf000087_0001
NP : not performed  NP: not performed
Tableau 19 : Recouvrement total et natif en téduglutide et teneur en produits de dégradation du téduglutide à 7 et 49 jours pour des solutions conservées à 30°C.  Table 19: Total and native teduglutide and teduglutide degradation product content at 7 and 49 days for solutions stored at 30 ° C.
[000526] La comparaison des recouvrements en téduglutide des solutions placées en stabilité montre que la présence de co-polyaminoacide permet d'obtenir une stabilité chimique du téduglutide. En effet, après un stockage de 7 jours à 30°C des formulations, une perte de recouvrement de plus de 85 % est observée pour le téduglutide sans co- polyaminoacide (S4) contre une perte de maximum 5 % en présence de co- polyaminoacide. La solution B6-5 montre une stabilité globale particulièrement bonne sur 49 jours à 30°C. The comparison of the overlays with teduglutide solutions placed in stability shows that the presence of co-polyamino acid makes it possible to obtain a chemical stability of the teduglutide. Indeed, after a storage of 7 days at 30 ° C of the formulations, a recovery loss of more than 85% is observed for teduglutide without co- polyamino acid (S4) against a loss of up to 5% in the presence of co-polyamino acid. The B6-5 solution shows a particularly good overall stability over 49 days at 30 ° C.

Claims

REVENDICATIONS
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 : A physically stable composition in the form of an aqueous injectable solution, the pH of which is between 6.0 and 8.0, comprising at least:
a) un analogue du GLP-2, et  a) an analogue of GLP-2, and
b) un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes Hy, ledit co-polyaminoacide étant constitué d'unités giutamiques ou aspartiques et lesdits radicaux hydrophobes Hy étant de formule I suivante :
Figure imgf000089_0001
Formule I dans laquelle b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid being constituted by glutamic or aspartic units and said hydrophobic radicals Hy being of formula I below:
Figure imgf000089_0001
Formula I in which
- GpR est un radical de formules II ou Ι : - GpR is a radical of formulas II or Ι:
O O
H H H H H H
"-N-R-N-* ii ou N "-NRN- * ii or N
- GpA est un radical de formules III ou ΙΙ : GpA is a radical of formulas III or ΙΙ:
9 HN— * 9 HN- *
O O
HH
HN-* m -A-N-*„r; HN- * m -AN- * "r;
- GpC est un radical de formule IV : GpC is a radical of formula IV:
Figure imgf000089_0002
les -* indiquent les sites de rattachement des différents groupes;
Figure imgf000089_0002
the - * indicate the sites of attachment of the different groups;
a est un entier égal à 0 ou à 1 ;  a is an integer equal to 0 or 1;
b est un entier égal à 0 ou à 1;  b is an integer equal to 0 or 1;
p est un entier égal à 1 ou à 2 et o si p est égal à 1 alors a est égal à 0 ou à 1 et GpA est un radical de formule III' et, p is an integer equal to 1 or 2 and o if p is equal to 1 then a is equal to 0 or 1 and GpA is a radical of formula III 'and,
o si p est égal à 2 alors a est égal à 1, et GpA est un radical de formule III; o if p is equal to 2 then a is equal to 1, and GpA is a radical of formula III;
- 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; - d est un entier égal à 0, à 1 ou à 2; - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2; d is an integer equal to 0, 1 or 2;
- r est un entier égal à 0 ou à 1, et  r is an integer equal to 0 or 1, and
o si r est égal à 0 alors le radical hydrophobe de formule I est lié au co- polyaminoacide via une liaison covalente entre un carbonyl du radical hydrophobe et un atome d'azote en position N terminale du co- polyaminoacide, formant ainsi une fonction amide issue de la réaction d'une fonction aminé en position N terminale du précurseur du co-polyaminoacide et une fonction acide portée par le précurseur du radical hydrophobe , et o si r est égal à 1 alors le radical hydrophobe de formule I est lié au co- polyaminoacide :  if r is equal to 0, then the hydrophobic radical of formula I is bonded to the co-polyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amino function at the N-terminal position of the precursor of the co-polyamino acid and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1, then the hydrophobic radical of formula I is bound to the polyamino acid:
■ via une liaison covalente entre un atome d'azote du radical hydrophobe et un carbonyl du co-polyaminoacide, formant ainsi une fonction amide issue de la réaction d'une fonction aminé du précurseur du radical hydrophobe et une fonction acide portée par le précurseur du co-polyaminoacide ou  Via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amine function of the precursor of the hydrophobic radical and an acid function carried by the precursor of the co-polyamino acid or
« via une liaison covalente entre un carbonyl du radical hydrophobe et un atome d'azote en position N terminal du co-polyaminoacide, formant ainsi une fonction amide issue de la réaction d'une fonction acide du précurseur du radical hydrophobe et une fonction aminé en position N terminale portée par le précurseur du co- polyaminoacide;  Via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and an amine function in N-terminal position carried by the precursor of the co-polyamino acid;
- R est un radical choisi dans le groupe constitué par :  R is a radical chosen from the group consisting of:
o un radical alkyle divalent, linéaire ou ramifié, comprenant si GpR est un radical de formule II de 2 à 12 atomes de carbone ou si GpR est un radical de formule Ι de 1 à 11 atomes de carbone ; et  a divalent alkyl radical, linear or branched, comprising if GpR is a radical of formula II of 2 to 12 carbon atoms or if GpR is a radical of formula Ι of 1 to 11 carbon atoms; and
o un radical éther ou polyéther non substitué comprenant de 4 à 14 atomes de carbone et de 1 à 5 atomes d'oxygène ;  an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;
- A est un radical choisi dans le groupe constitué par un radical éther ou polyéther non substitué comprenant de 4 à 14 atomes de carbone et de 1 à 5 atomes d'oxygène ou un radical alkyle linéaire ou ramifié comprenant de 1 à 8 atomes de carbone et éventuellement substitué par un radical issu d'un cycle saturé, insaturé ou aromatique;  - A is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical comprising from 1 to 8 carbon atoms and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring;
- B est un radical alkyle linéaire ou ramifié, éventuellement comprenant un noyau aromatique, comprenant de 1 à 9 atomes de carbone; - Cx est un radical alkyl monovalent linéaire ou ramifié, dans lequel x indique le nombre d'atomes de carbone et : B is a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms; - C x is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:
o si p est égal à 1, x est compris entre 11 et 25 (11 < x < 25) : o si p est égal à 2, x est compris entre 9 et 15 (9 < x < 15),  o if p is equal to 1, x is between 11 and 25 (11 <x <25): o if p is equal to 2, x is between 9 and 15 (9 <x <15),
le ratio i entre le nombre de radicaux hydrophobes et le nombre d'unités glutamiques ou aspartiques étant compris entre entre 0 < i < 0,5  the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <i <0.5
lorsque plusieurs radicaux hydrophobes sont portés par un co-polyaminoacide alors ils sont identiques ou différents,  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 est compris entre 5 et 250 ;  the degree of DP polymerization in glutamic or aspartic units is between 5 and 250;
les fonctions acides libres étant sous forme de sel de cation alkaiin choisi dans le groupe constitué par Na+ et K+. the free acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
2. Composition selon la revendication 1, caractérisée en ce que le pH est com entre 6,6 et 7,8. 2. Composition according to claim 1, characterized in that the pH is com between 6.6 and 7.8.
3. Composition selon l'une des revendications précédentes, caractérisée en ce que le co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes est choisi parmi les co-polyaminoacides de formule VII suivante : 3. Composition according to one of the preceding claims, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII below:
Figure imgf000091_0001
formule VII dans laquelle,
Figure imgf000091_0001
formula VII in which,
D représente, indépendamment, soit un groupe -CH2- (unité aspartique) soit un groupe -CH2-CH2- (unité glutamique),  D is, independently, either -CH2- (aspartic unit) or -CH2-CH2- (glutamic unit),
Hy est un radical hydrophobe choisi parmi les radicaux hydrophobes de formule I, dans laquelle r = 1 et GpR est un radical de Formule II,  Hy is a hydrophobic radical selected from hydrophobic radicals of formula I, wherein r = 1 and GpR is a radical of Formula II,
Ri est un radical hydrophobe choisi parmi les radicaux hydrophobes de formule I, dans laquelle r=0 ou r= l et GpR est un radical de Formule ΙΓ, ou un radical choisi dans le grou e constitué par un H, un groupe acyle linéaire en C2 à C10, un groupe acyle ramifié en C3 à C10, un benzyle, une unité « acide aminé » terminale et un pyroglutamate,R 1 is a hydrophobic radical chosen from hydrophobic radicals of formula I, in which r = 0 or r = 1 and GpR is a radical of Formula ΙΓ, or a radical selected from the group consisting of H, a C 2 -C 10 linear acyl group, a C 3 -C 10 branched acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate,
• R2 est un radical hydrophobe choisi parmi les radicaux hydrophobes de formule I, dans laquelle r = 1 et GpR est un radical de Formule II, ou un radical -NR'R", R' et R" identiques ou différents étant choisis dans le groupe constitué par H, les alkyles linéaires ou ramifiés ou cycliques en C2 à C10, le benzyle et lesdits R' et R" alkyles pouvant former ensemble un ou des cycles carbonés saturés, insaturés et/ou aromatiques et/ ou pouvant comporter des hétéroatomes, choisis dans le groupe constitué par O, N et S, R2 is a hydrophobic radical chosen from hydrophobic radicals of formula I, in which r = 1 and GpR is a radical of formula II, or a radical -NR'R ", R 'and R" identical or different being chosen from group consisting of H, linear or branched or cyclic C2 to C10 alkyls, benzyl and said R 'and R "alkyls may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may contain heteroatoms, selected from the group consisting of O, N and S,
• X représente un H ou une entité cationique choisie dans le groupe comprenant les cations métalliques ;  X represents an H or a cationic entity selected from the group comprising metal cations;
• 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 DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 <n + m <250;
4. Composition selon l'une des revendications précédentes, caractérisée en ce que l'analogue du GLP-2 est le téduglutide, encore appelé h[Gly2]GLP-2 ou (Gly2)GLP-2 de séquence : His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu- Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-GIn-Thr-Lys-Ile-Thr-Asp (HGDGSFSDEM N TILDNLAAR DFINWLIQTK ITD). 4. Composition according to one of the preceding claims, characterized in that the analogue of GLP-2 is teduglutide, also called h [Gly2] GLP-2 or (Gly2) GLP-2 sequence: His-Gly-Asp -Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-GIn -Thr-Lys-Ile-Thr-Asp (HGDGSFSDEM N TILDNLAAR DFINWLIQTK ITD).
5. Composition selon l'une des revendications 1 à 3, caractérisée en ce que l'analogue du GLP-2 est un analogue de séquence His-Gly-Asp-Gly-Ser-Phe-Ser-Asp- Glu-Nle-D-Phe-Thr-Ile-Leu-Asp-Leu-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln- Thr-Lys-Ile-Thr-Asp, dont l'extrémité C-terminale est amidée (HGDGSFSDEX F*TILDLLAAR DFINWLIQTK ITD-N H2) (X=Nle (Norleucine) F* = D-Phe(DPhénylalanine)). 5. Composition according to one of claims 1 to 3, characterized in that the analogue of GLP-2 is a sequence analogue His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-D -Phe-Thr-Ile-Leu-Asp-Leu-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp, whose C-terminus is amidated (HGDGSFSDEX F * TILDLLAAR DFINWLIQTK ITD-N H2) (X = Nle (Norleucine) F * = D-Phe (DPhenylalanine)).
6. Composition selon l'une des revendications 1 à 3, caractérisée en ce que l'analogue du GLP-2 est un analogue de séquence His-Gly-Glu-Gly-Ser-Phe-Ser-Ser-6. Composition according to one of claims 1 to 3, characterized in that the analog of GLP-2 is a sequence analog His-Gly-Glu-Gly-Ser-Phe-Ser-Ser-
Glu-Leu-Ser-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala- Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys-Lys dont l'extrémité C-terminale est amidée (HGEGSFSSEL S TILDALAAR DFIAWLIATK ITDKKKKKK-NH2) (X= Nle (Norleucine) F* = D-Phe(DPhénylalanine)). Glu-Leu-Ser-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp- Lys-Lys-Lys-Lys-Lys-Lys whose C-terminal end is amidated (X = Nle (Norleucine) F * = D-Phe (DP-phenylalanine)).
7. Composition selon l'une des revendications 1 à 3, caractérisée en ce que l'analogue du GLP-2 est un analogue de séquence His-Gly-Glu-Gly-Thr-Phe-Ser-Ser- Glu-Leu-Ala-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr- Lys-Ile-Thr- Asp- Lys- Lys- Lys-Lys- Lys- Lys dont l'extrémité C-terminale est amidée (HGEGTFSSEL A TILDALAAR DFIAWLIATK ITDKKKKKK-NH2) (X=Nle (Norleucine) F*= D-Phe(DPhénylalanine)). 7. Composition according to one of claims 1 to 3, characterized in that the GLP-2 analogue is a His-Gly-Glu-Gly-Thr-Phe-Ser-Ser-sequence analogue. Glu-Leu-Ala-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp- Lys-Lys-Lys-Lys-Lys-Lys whose C-terminal end is amidated (X = Nle (Norleucine) F * = D-Phe (DPhénylalanine)).
8. Composition selon la revendication 4, caractérisée en ce que le ratio massique co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur téduglutide est compris entre 0,2 et 15. 8. Composition according to claim 4, characterized in that the weight ratio co-polyamino acid bearing carboxylate charges and hydrophobic radicals on teduglutide is between 0.2 and 15.
9. Composition selon l'une des revendications précédentes, caractérisée en ce que le ratio massique co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes sur agoniste du récepteur du GLP-2 ou analogue de GLP-2 est compris entre 0,25 et 15. 9. Composition according to one of the preceding claims, characterized in that the weight ratio co-polyamino acid bearing carboxylate charges and hydrophobic radicals on agonist of the GLP-2 receptor or GLP-2 analogue is between 0.25 and 15.
10. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle comprend en outre un composé nicotinique ou un de ses dérivés. 10. Composition according to one of the preceding claims, characterized in that it further comprises a nicotinic compound or a derivative thereof.
11. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle comprend en outre un composé polyanionique. 11. Composition according to one of the preceding claims, characterized in that it further comprises a polyanionic compound.
12. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle comprend en outre une hormone gastrointestinale, les compositions selon l'invention comprennent en outre une hormone pancréatique. 12. Composition according to one of the preceding claims, characterized in that it further comprises a gastrointestinal hormone, the compositions according to the invention further comprise a pancreatic hormone.
13. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle comprend en outre un ou plusieurs composés ralentissant la motilité intestinale. 13. Composition according to one of the preceding claims, characterized in that it further comprises one or more compounds slowing the intestinal motility.
PCT/EP2018/079912 2017-10-31 2018-10-31 Composition comprising a glp-2 receptor agonist and a co-polyamino acid carrying carboxylate charges and hydrophobic radicals WO2019086559A1 (en)

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FR1760307A FR3072875B1 (en) 2017-10-31 2017-10-31 COMPOSITION CONSISTING OF A GLP-2 RECEPTOR AGONIST AND A CO-POLYAMINOACID CARBOXYLATE CHARGES AND HYDROPHOBIC RADICALS
FR1852661A FR3079414B1 (en) 2018-03-27 2018-03-27 COMPOSITION COMPRISING A GLP-2 RECEPTOR AGONIST AND A CO-POLYAMINOACID CARRYING CARBOXYLATE LOADS AND HYDROPHOBIC RADICALS
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