Compositions in form of injectable aqueous solution comprising amylin, amylin receptor agonist or amylin analog and copolyamino acid

Abstract

To provide a stable composition containing amylin, an amylin receptor agonist, or an amylin analog for the treatment of diabetes.SOLUTION: The invention relates to a composition in the form of an injectable aqueous solution having a pH between 6.0 and 8.0 and comprising at least: a) amylin, an amylin receptor agonist or an amylin analog; and b) a copolyamino acid bearing carboxylate charges and hydrophobic radicals Hy, the copolyamino acid being formed by glutamic acid or aspartic acid units and the hydrophobic radicals Hy being selected according to formula X defined below.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to amylin injection therapy, amylin agonist receptors or amylin analogues for the treatment of diabetes.

[0002] The present invention relates to a composition in the form of an injectable aqueous solution, comprising at least amylin, an amylin agonist receptor or an amylin analogue and a copolyamino acid having a carboxylate charge and a hydrophobic radical according to the invention, the composition comprising in addition insulin (excluding basal insulin, the isoelectric point pI of which is comprised between 5.8 and 8.5). The invention also relates to a pharmaceutical preparation comprising the composition according to the invention. Finally, the invention also relates to a composition of amylin, an amylin agonist receptor or an amylin analogue, as well as to the use of a copolyamino acid having a carboxylate charge and a hydrophobic radical according to the invention for stabilizing an amylin, amylin receptor agonist or amylin analogue composition further comprising insulin. [Background technology]

[0003] Type 1 diabetes is an autoimmune disease that leads to the destruction of pancreatic β-cells. These cells are known to produce insulin, whose main role is to control glucose use in peripheral tissues (Gerich 1993, Control of glycaemia). As a result, patients affected by type 1 diabetes suffer from chronic hyperglycemia and must self-administer exogenous insulin to control this hyperglycemia. Insulin therapy can significantly alter the life expectancy of these patients. However, glycemic control by exogenous insulin is not optimal, especially after ingesting a meal. This is associated with the fact that these patients produce glucagon after ingesting a meal, which leads to the release of a portion of the glucose stored in the liver, which is not the case in healthy humans. This glucagon-mediated production of glucose exacerbates the problem of glycemic control for these patients.

[0004] Amylin is another hormone produced by the beta cells of the pancreas and therefore deficient in type 1 diabetes patients, and has been shown to play an important role in the control of postprandial blood glucose. Amylin, also known as "islet amyloid polypeptide", or IAPP, is a 37 amino acid peptide that is stored and co-secreted with insulin (Schmitz 2004 Amylin Agonists). This peptide is described as blocking the production of glucagon by the alpha cells of the pancreas. Thus, insulin and amylin have complementary and synergistic roles, since insulin can reduce the concentration of glucose in the blood, whereas amylin can reduce endogenous glucose entering the blood by inhibiting the production (secretion) of endogenous glucagon.

[0005] This problem of postprandial glycemic control is very similar for type 2 diabetic patients who take insulin, insofar as their disease leads to a very significant loss of their β-cell mass and, consequently, their capacity to produce insulin and amylin.

[0006] Human amylin has properties that are not compatible with pharmaceutical requirements in terms of solubility and stability (Goldsbury CS, Cooper GJ, Goldie KN, Muller SA, Saafi EL, Gruijters WT, Misur MP, Engel A, Aebi U, Kistler J : Polymorphic fibrillar assembly of human amylin. J Struct Biol 119:17-27, 1997). Amylin is known to form amyloid fibrils, which lead to the formation of plaques, and they are not soluble in water. Even though it was the natural hormone, it was necessary to develop analogues to solve these solubility problems.

[0007] Thus, the physicochemical properties of amylin preclude its use: it is only stable for about 15 minutes at acidic pH and less than 1 minute at neutral pH.

[0008] Amylin has developed an amylin analog, pramlintide, to alleviate the lack of stability of human amylin. The product is marketed under the name Symlin and was approved by the FDA in 2005 for the treatment of type 1 and type 2 diabetes. It must be administered subcutaneously three times a day within one hour before meals to improve postprandial glycemic control. The peptide is formulated at an acidic pH and is described as fibrillating when the pH of the solution exceeds 5.5. Similar variants are described in patent US5.686.411.

[0009] This analogue is thus less than satisfactory in terms of stability when a neutral pH formulation is envisaged.

[0010] To date, there are no means by which human amylin can be stabilized to make it into a pharmaceutical product. However, it would be beneficial for patients to have access to the human form of this physiological hormone. It would also be beneficial to be able to formulate analogs or agonists of the pH-neutral amylin receptor.

[0011] In addition, there may be interest in being able to mix aqueous amylin solutions, amylin analogs, or amylin receptor agonists with prandial insulin, since these two products are administered before a meal, which would further mimic physiology, since these two hormones are secreted together by beta cells in response to a meal to improve postprandial glycemic control.

[0012] However, taking into account the fact that solutions of prandial insulin have a pH close to neutral for reasons of chemical stability, it is not possible to obtain aqueous solutions that meet pharmaceutical requirements in terms of solubility and stability.

[0013] For this reason, ROCHE's patent application US2016 / 001002 describes a pump containing two separate reservoirs to allow the simultaneous administration of these two hormones using a single medical device. However, this patent does not solve the problem of mixing these two hormones in a solution that would allow them to be administered using conventional pumps already on the market that contain only one reservoir.

[0014] XERIS patent application WO2013067022 provides a solution to the amylin stability problem and its compatibility with insulin by employing organic solvents instead of water. While the absence of water appears to solve the stability problem, the use of organic solvents poses problems in terms of long-term safety of use for diabetic patients, and also compatibility issues with common medical devices associated with tubing, connections and plasticizers used.

[0015] Patent application WO2007104786 of NOVO NORDISK describes a method that allows the stabilization of solutions of the amylin analogue pramlintide and insulin by the addition of phospholipids derived from glycerophosphoglycerol, in particular dimyristoylglycerophosphoglycerol (DMPG). However, this solution requires the use of significant amounts of DMPG, which may impose problems related to local tolerance. Moreover, DMPG leads to compositions that present relatively poor physical stability at 0-4°C, as described in application WO2018122278.

[0016] To Applicants' knowledge, there is no satisfactory means that allows for combining prandial insulin with human amylin, amylin agonist receptors or amylin analogues in an aqueous solution that can be administered by conventional devices.

[0017] The acidic formulation pH and rapid fibrillation pose obstacles to obtaining neutral pH pharmaceutical formulations based on amylin and pramlintide, but also to combining amylin or pramlintide with other pharmaceutical active ingredients, particularly peptides or proteins.

[0018] Applicants have surprisingly observed that copolyamino acids according to the invention stabilize compositions of amylin, amylin agonist receptors or amylin analogs at a pH between 6.0 and 8.0 Indeed, compositions comprising amylin, amylin agonist receptors or amylin analogs together with copolyamino acids according to the invention show increased stability over time, which is of great interest for pharmaceutical development.

[0019] The Applicant has also reported that the copolyamino acids according to the invention make it possible to obtain a composition comprising, in addition, prandial insulin and amylin, an amylin agonist receptor or an amylin analogue, said composition being transparent and having enhanced stability against fibrillation.

[0020] A typical method for measuring the stability of a protein or peptide consists in measuring the formation of fibrils using thioflavin, also called ThT. This method allows to measure the latency before the formation of fibrils by measuring the increase in fluorescence, and to do so under temperature and agitation conditions that allow the acceleration of the phenomenon. The composition according to the invention has a latency before the formation of fibrils that is clearly greater than that of amylin, amylin agonist receptors or amylin analogs at the pH of interest.

[0021] The compositions according to the present invention have physical stability, and possibly chemical stability, at a desired pH. Summary of the Invention

[0022] In one embodiment, the present invention relates to a composition in the form of an injectable aqueous solution consisting of 6.0 to 8.0 and containing at least: a) Amylin, amylin receptor agonists and amylin analogues; b) a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy, said copolyamino acid being composed of glutamic or aspartic acid units, said hydrophobic radical -Hy being chosen among the radicals according to formula X defined below: [ka] wherein GpR is selected among the radicals according to formula VII, VII' or VII": [ka] - GpG and GpH, which are identical or different, are selected among radicals according to formula XI or XI'; [ka] -GpA is selected among radicals according to formula VIII [ka] wherein A' is selected from among the radicals according to formula VIII', VIII'' or VIII''' [ka] -GpL is selected among radicals according to formula XII [ka] -GpC is a radical according to formula IX: [ka] - " * " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=0 then a'=1, and if a=1 then a'=1, 2 or 3; - a' is an integer equal to 1, 2 or 3; -b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g, h or l is different from 0; - l is an integer equal to 0 or 1, and if l=0 then l'=1, and if l=1 then l'=2; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - if e is different from 0, then at least one of g, h or l is different from 0; - if a=0 then l=0; - A, A1, A2 and A3 are identical or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with saturated, unsaturated or aromatic ring-derived radicals; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C x is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: if the hydrophobic radical -Hy has 1-GpC, then 9≦x≦25; if the hydrophobic radical -Hy has 2-GpC, then 9≦x≦15; if the hydrophobic radical -Hy has 3-GpC, then 7≦x≦13; if the hydrophobic radical -Hy has 4-GpC, then 7≦x≦11; - 6≦x≦11 if the hydrophobic radical -Hy has at least 5-GpC, -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups; -R is a radical selected from the group consisting of a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH2 functional groups, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; - the hydrophobic radical -Hy according to formula X is attached to PLG by: a covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of the PLG (thus forming an amide functional group resulting from the reaction of the amine functional group of the PLG with the acid functional group of the precursor of the hydrophobic radical -Hy, -Hy', and a covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of the PLG (thus forming an amide function resulting from the reaction of the amine function of the precursor of the hydrophobic radical -Hy -Hy' with the acid function of the PLG); - The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is 0 <M≦0.5であり; - if the copolyamino acid has several hydrophobic radicals, they may be the same or different, - the degree of polymerization DP of the glutamic or aspartic acid units for the PLG chain is comprised between 5 and 250; -Free carboxylic acid is Na + and K. + The compound is in the form of an alkali cation salt selected from the group consisting of:

[0023] In one embodiment, the composition is characterized in that the composition does not contain a basal insulin having an isoelectric point pI of 5.8 to 8.5.

[0024] In one embodiment, the composition is characterized in that the composition does not contain GLP-1, a GLP-1 analog, or a GLP-1 receptor agonist, currently referred to as GLP-1 RA.

[0025] In one embodiment, the composition is characterized in that it does not contain either basal insulin having an isoelectric point pI of 5.8 to 8.5, nor GLP-1, a GLP-1 analogue, or a GLP-1 receptor agonist, currently referred to as GLP-1 RA.

[0026] In one embodiment, the present invention relates to a composition in the form of an aqueous injection solution free of basal insulin, the isoelectric point of which is comprised between 5.8 and 8.5, the pH of which is comprised between 6.0 and 8.0, and which comprises at least: a) Amylin, amylin receptor agonists and amylin analogues; b) a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy, said copolyamino acid being composed of glutamic or aspartic acid units, said hydrophobic radical -Hy being chosen among the radicals according to formula X defined below: [ka] During the ceremony, -GpR is selected among the radicals according to formula VII, VII' or VII'': [ka] - GpG and GpH, which are identical or different, are selected among radicals according to formula XI or XI'; [ka] -GpA is selected among radicals according to formula VIII [ka] wherein A' is selected from among the radicals according to formula VIII', VIII'' or VIII''' [ka] -GpL is selected among radicals according to formula XII [ka] -GpC is a radical according to formula IX: [ka] - " * " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=1, then a'=1, 2 or 3; - a' is an integer equal to 1, 2 or 3; -b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g, h or l is different from 0; - l is an integer equal to 0 or 1, and if l=0 then l'=1, and if l=1 then l'=2; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - if e is different from 0, then at least one of g, h or l is different from 0; - if a=0 then l=0; - A, A1, A2 and A3 are identical or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with saturated, unsaturated or aromatic ring-derived radicals; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C xis a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: if the hydrophobic radical -Hy has 1-GpC, then 9≦x≦25; if the hydrophobic radical -Hy has 2-GpC, then 9≦x≦15; if the hydrophobic radical -Hy has 3-GpC, then 7≦x≦13; if the hydrophobic radical -Hy has 4-GpC, then 7≦x≦11; - 6≦x≦11 if the hydrophobic radical -Hy has at least 5-GpC, -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups. -R is a radical selected from the group consisting of a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH2 functional groups, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; - the hydrophobic radical -Hy according to formula X is attached to PLG by: a covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of the PLG (thus forming an amide functional group resulting from the reaction of the amine functional group of the PLG with the acid functional group of the precursor of the hydrophobic radical -Hy, -Hy', and a covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of the PLG (thus forming an amide function resulting from the reaction of the amine function of the precursor of the hydrophobic radical -Hy -Hy' with the acid function of the PLG); - The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is 0 <M≦0.5であり; - if the copolyamino acid has several hydrophobic radicals, they may be the same or different, - the degree of polymerization DP of the glutamic or aspartic acid units for the PLG chain is comprised between 5 and 250; -Free carboxylic acid is Na + and K. + The compound is in the form of an alkali cation salt selected from the group consisting of:

[0027] By "alkyl radical" is meant a straight or branched carbonate chain containing no heteroatoms.

[0028] Copolyamino acids are statistical copolyamino acids in a chain of glutamic and / or aspartic acid units.

[0029] Said copolyamino acid having a carboxylate charge and a hydrophobic radical Hy is soluble in aqueous solution at a pH between 6.0 and 8.0, at a temperature of 25° C. and at a concentration of less than 100 mg / ml.

[0030] The composition according to the invention in the form of an aqueous solution for injection is a clear solution. By "clear solution" is meant a composition that meets the criteria set out in the US and European Pharmacopoeias for injection solutions. In the US Pharmacopoeias, solutions are defined in Section <1151> So, injection <1> It is defined by referring to USP35. <788> Refer to USP35. <788> In addition, USP38 <787> , <788> and <790> (Specified in USP38 (from August 1, 2014). In the European Pharmacopoeia, injection solutions must comply with the criteria provided in sections 2.9.19 and 2.9.20.

[0031] By "soluble" it is meant suitable for the preparation of a clear, particle-free solution in distilled water at 25°C at a concentration of less than 100 mg / ml.

[0032] By basal insulin having an isoelectric point of 5.8 to 8.5 is meant insulin that is insoluble at pH 7 and has a duration of action of 8 to 24 hours, or more than 24 hours, in standard diabetic models.

[0033] In the formula * indicates the attachment sites of the various elements represented.

[0034] In one embodiment, Hy contains more than 30 carbon atoms.

[0035] In one embodiment, the composition according to the invention is characterized in that Hy contains from 15 to 100 carbon atoms.

[0036] In one embodiment, the composition according to the invention is characterized in that Hy contains from 30 to 70 carbon atoms.

[0037] In one embodiment, the composition according to the invention is characterized in that Hy contains from 40 to 60 carbon atoms.

[0038] In one embodiment, the composition according to the invention is characterized in that Hy contains from 20 to 30 carbon atoms.

[0039] In one embodiment, when a'=1, x is comprised between 11 and 25 (11≦x≦25). Specifically, when x is comprised between 15 and 16 (x=15 or 16), r=1 and R is an ether or polyether radical, and when x is greater than 17 (x≧17), r=1 and R is an ether or polyether radical.

[0040] In one embodiment, when a'=2, x is comprised between 9 and 15 (9≦x≦15).

[0041] In one embodiment, the composition is characterized by having a pH of 6.6 to 7.8.

[0042] In one embodiment, the composition is characterized by having a pH of 7.0 to 7.8.

[0043] In one embodiment, the composition is characterized by having a pH of 6.8 to 7.4.

[0044] In one embodiment, when r=2, the GpR group attached to the PLG is selected among the GpR according to Formula VII.

[0045] In one embodiment, when r=2, the GpR group attached to the PLG is selected among GpR according to formula VII and the second GpR is selected among GpR according to formula VII″.

[0046] In one embodiment, when r=2, the GpR group attached to the PLG is selected among the GpR according to formula VII″.

[0047] In one embodiment, when r=2, the GpR group attached to the PLG is selected among GpRs according to formula VII″ and the second GpR is selected among GpRs according to formula VII.

[0048] In one embodiment, at least one of g, h, or l is different from 0.

[0049] In one embodiment, at most one of g, h, or l is different from 0.

[0050] In one embodiment, at least one of g and h is equal to 1.

[0051] In one embodiment, a=1 and l=1.

[0052] In one embodiment, when l=0, at least one of g or h is equal to 0.

[0053] In one embodiment, when l=1, at least one of g and h is equal to 0.

[0054] In one embodiment, g=h=0, a=1, GpA is a radical according to formula VIII (s'=1), and A' is according to formula VIII' or VIII'' and l=1.

[0055] In one embodiment, at least one of g and h is equal to 1.

[0056] In one embodiment, a=0.

[0057] In one embodiment, g+h≧2.

[0058] In one embodiment, g is greater than or equal to 2 (g≧2).

[0059] In one embodiment, h is 2 or greater (g≧2).

[0060] In one embodiment, g+h≧2 and l is equal to 0 (a=l=0).

[0061] In one embodiment, g+h≧2 and b is equal to 0 (b=0).

[0062] In one embodiment, g or h is greater than or equal to 2 (g≧2) and b is equal to 0.

[0063] In one embodiment, g+h≧2, b is equal to zero (b=0), and e is equal to one (e=1).

[0064] In one embodiment, g or h is greater than or equal to 2 (g≧2), b is equal to 0 (b=0), and e is equal to 1 (e=1).

[0065] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X, where r=2, according to formula Xc′ defined below: [ka] wherein GpR1 is a radical according to formula VII, [ka] wherein GpR, GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l and l' have the definitions given above.

[0066] In one embodiment, the hydrophobic radical -Hy is selected among radicals according to formula X, where r=2, according to formula Xc′ defined below: [ka] in which GpR1 is a radical according to formula VII″, [ka] wherein GpR, GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l and l' have the definitions given above.

[0067] In one embodiment, the hydrophobic radical -Hy is selected from among radicals according to formula X (wherein l=0) according to formula Xd defined below: [ka] During the ceremony, -GpR is selected among the radicals according to formula VII, VII' or VII'': [ka] -GpG is selected among radicals according to formula XI or XI': [ka] -GpA is selected from the radicals according to formula VIIIa, where s'=1, or the radicals according to formula VIIIb, where s'=0: [ka] -GpC is a radical according to formula IX: [ka] - " * " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=0 then a'=1, and if a=1 then a'=1 or a'=2; - a' is an integer equal to 1 or 2; When a' is equal to 1, a is equal to 0 or 1 and GpA is a radical according to formula VIIIb when a' is equal to 2, a is equal to 1 and GpA is a radical according to formula VIIIa; -b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g or h is different from 0; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - if e is different from 0, then at least one of g, h or l is different from 0; - if a=0 then l=0; -A1 is a linear or branched alkyl radical containing 1 to 8 carbon atoms and optionally substituted with a radical derived from a saturated, unsaturated or aromatic ring; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C x is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: if the hydrophobic radical -Hy has 1-GpC, then 9≦x≦25; if the hydrophobic radical -Hy has 2-GpC, then 9≦x≦15; · When the hydrophobic radical -Hy has 3-GpC, 7 ≦ x ≦ 13, · When the hydrophobic radical -Hy has 4-GpC, 7 ≦ x ≦ 11, · When the hydrophobic radical -Hy has at least 5-GpC, 6 ≦ x ≦ 11, -G is an alkyl radical having 1 to 8 carbon atoms, and the alkyl radical has one or more free carboxylic acid functional groups, -R is a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH2 functional groups, or a radical selected from the group consisting of an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, - The hydrophobic radical(s) Hy according to formula X is / are bonded to PLG as follows: · A covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of PLG (thus forming an amide functional group obtained from the reaction of the amine functional group of PLG and the acid functional group of the -Hy precursor of the hydrophobic radical), and · A covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of PLG (thus forming an amide functional group obtained from the reaction of the amine functional group of the -Hy precursor of the hydrophobic radical and the acid functional group of PLG); - The ratio M between the number of hydrophobic radicals and the number of glutamic acid or aspartic acid units is constituted by 0 < M ≦ 0.5; - When the copolyamino acid has a plurality of hydrophobic radicals, they are the same or different, - The free carboxylic acid is in the form of an alkali metal cation salt selected from the group consisting of Na + and K + and is in the form of an alkali metal cation salt selected from the group consisting of.

[0068] In one embodiment, the hydrophobic -Hy is selected from among the radicals according to formula X as defined below, wherein l = 0, -GpA is selected among radicals according to formula VIII (wherein s'=1) and A' is selected among radicals according to formula VIII'' or VIII'''; [ka] During the ceremony, -GpR is selected among the radicals according to formula VII, VII' or VII'': [ka] -GpG is selected among radicals according to formula XI or XI': [ka] -GpA is selected among radicals according to formula VIIIc or VIIId: [ka] -GpC is a radical according to formula IX: [ka] - " * " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=0 then a'=1, or if a=1 then 2 or 3; - a' is an integer equal to 2 or 3; If a' is equal to 1, then a is equal to 0 when a' is equal to 2 or 3, a is equal to 1 and GpA is a radical according to formula VIIIc or VIIId; -b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g or h is different from 0; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 1; - if e is different from 0, then at least one of g, h or l is different from 0; - if a=0 then l=0; -A1, A2, A3 are identical or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with radicals derived from saturated, unsaturated or aromatic rings; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C x is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: if the hydrophobic radical -Hy has 1-GpC, then 9≦x≦25; if the hydrophobic radical -Hy has 2-GpC, then 9≦x≦15; if the hydrophobic radical -Hy has 3-GpC, then 7≦x≦13; if the hydrophobic radical -Hy has 4-GpC, then 7≦x≦11; - 6≦x≦11 if the hydrophobic radical -Hy has at least 5-GpC, - the hydrophobic radical(s) Hy according to formula X are attached to PLG by: a covalent bond between the carbonyl of the hydrophobic radical and the nitrogen atom of the PLG (thus forming an amide function resulting from the reaction of the amine function of the PLG with the acid function of the precursor of the hydrophobic radical -Hy'), and a covalent bond between the nitrogen atom of the hydrophobic radical and the carbonyl of the PLG (thus forming an amide function resulting from the reaction of the amine function of the -Hy precursor of the hydrophobic radical with the acid function of the PLG); -G is an alkyl radical of 1 to 8 carbon atoms, the alkyl radical having one or more free carboxylic acid functional groups; -R is a radical selected from the group consisting of a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH2 functional groups, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; - The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is 0 <M≦0.5であり; - if the copolyamino acid has several hydrophobic radicals, they may be the same or different, -Free carboxylic acid is Na + and K. + The compound is in the form of an alkali cation salt selected from the group consisting of:

[0069] In one embodiment, r=0 and the hydrophobic radical according to formula X is attached to the PLG by a covalent bond between the carbonyl of the hydrophobic radical and the nitrogen atom of the PLG (thus forming an amide functionality resulting from the reaction of the amine functionality of the PLG precursor with the acid functionality of the precursor Hy′ of the hydrophobic radical).

[0070] In one embodiment, r=1 and the hydrophobic radical according to formula X is attached to the PLG by: a covalent bond between the nitrogen atom of the hydrophobic radical and the carbonyl of the PLG (thus forming an amide function resulting from the reaction of the amine function of the precursor of the hydrophobic radical -Hy' with the acid function of the PLG), or A covalent bond between the carbonyl of the hydrophobic radical and the nitrogen atom of the PLG (thus forming an amide function resulting from the reaction of the acid function of the hydrophobic radical - the precursor of Hy - with the amine function of the PLG).

[0071] In one embodiment, when GpA is a radical according to formula VIIIc, where r=1 or 2: -GpC directly or indirectly binds to N α1 and N α2 PLG binds directly or indirectly to N β1 or -GpC directly or indirectly binds to N α1 and N β1 PLG binds directly or indirectly to N α2 or -GpC directly or indirectly binds to N α2 and N β1 PLG binds directly or indirectly to N via GpR. α1 is combined with

[0072] In one embodiment, when GpA is a radical according to formula VIIIc and r=0: -GpC directly or indirectly binds to N α1 and N α2 PLG is directly or indirectly bound to N β1 or -GpC directly or indirectly binds to N α1 and N β1 PLG is directly or indirectly bound to N α2 or -GpC directly or indirectly binds to N α2 and N β1 PLG is directly or indirectly bound to N α1 is combined with

[0073] In one embodiment, when GpA is a radical according to formula VIIId and r=1 or 2, -GpC directly or indirectly binds to N α1 , N α2 and N β1 PLG binds directly or indirectly to N β2 or -GpC directly or indirectly binds to N α1 , N α2 and Nβ2 PLG binds directly or indirectly to N β1 or -GpC directly or indirectly binds to N α1 , N β1 and N β2 PLG binds directly or indirectly to N α2 or -GpC directly or indirectly binds to N α2 , N β1 and N β2 PLG binds directly or indirectly to N via GpR. α1 is combined with

[0074] In one embodiment, when GpA is a radical according to formula VIIId and r=0, -GpC directly or indirectly binds to N α1 , N α2 and N β1 PLG is directly or indirectly bound to N β2 or -GpC directly or indirectly binds N α1 , N α2 and N β2 PLG is directly or indirectly bound to N β1 or -GpC directly or indirectly binds to N α1 , N β1 and N β2 PLG is directly or indirectly bound to N α2 or GpC directly or indirectly α2 , N β1 and N β2 PLG is directly or indirectly bound to N α1 is combined with

[0075] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X, where a=1 and a′=1, according to formula Xa defined below: [ka] where GpA is a radical according to formula VIII, A' is selected among radicals according to formula VIII' (s'=0), and GpA is a radical according to formula VIIIb [ka] GpR, GpG, GpL, GpH, GpC, A1, r, g, h, l and l' have the definitions given above.

[0076] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X (wherein a=1), according to formula Xb defined below: [ka] in which GpA is a radical according to formula VIII, A' is selected among radicals according to formula VIII' (s'=1), and GpA is a radical according to formula VIIIa, [ka] GpR, GpG, GpL, GpH, GpC, A1, a', r, g, h, l and l' have the definitions given above.

[0077] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X, where a=1, as defined below: [ka] in which GpA is a radical according to formula VIII, A is selected among radicals according to formula VIII″ (s′=1), and GpA is a radical according to formula VIIIc, [ka] GpR, GpG, GpL, GpH, GpC, A1, A2, r, g, h, a', l and l' have the definitions given above.

[0078] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X, where a=1, as defined below: [ka] where GpA is a radical according to formula VIII, A is selected among radicals according to formula VIII′″ (s′=1), and GpA is a radical according to formula VIIId, [ka] GpR, GpG, GpL, GpH, GpC, A1, A2, A3, a', r, g, h, l and l' have the definitions given above.

[0079] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X, where r=1, according to formula Xc defined below: [ka] wherein GpR is a radical according to formula VII, [ka] GpR, GpA, GpL, GpH, GpC, R, a, g, h, l, a' and l' have the definitions given above.

[0080] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X, where r=1, according to formula Xc defined below: [ka] wherein GpR is a radical according to formula VII′, [ka] GpR, GpA, GpL, GpH, GpC, R, a, g, h, l, a' and l' have the definitions given above.

[0081] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X, where r=1, according to formula Xc defined below: [ka] wherein GpR is a radical according to formula VII″, [ka] GpR, GpA, GpL, GpH, GpC, R, a, g, h, l, a' and l' have the definitions given above.

[0082] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X defined below: [ka] wherein GpC is a radical according to formula IX, where e=0 and GpC is a radical according to formula IXa′. [ka]

[0083] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X defined below: [ka] wherein GpC is a radical according to formula IX, where e=1, b=0, and GpC is a radical according to formula IXd′. [ka]

[0084] In one embodiment, the at least one hydrophobic radical -Hy is selected among radicals according to formula X defined below: [ka] wherein GpC is a radical according to formula IX, where e=1 and GpC is a radical according to formula IXd′. [ka]

[0085] In one embodiment, said at least one hydrophobic radical -Hy is selected among radicals according to formula X, where r, g, a, l, h are equal to 0, according to formula Xd′ defined below: [ka]

[0086] In one embodiment, said at least one hydrophobic radical -Hy is selected among radicals according to formula X, where r, g, a, l, h are equal to 0, according to formula Xd′ defined below: [ka] wherein GpC is a radical according to formula IX, where e=0, b=0, and GpC is a radical according to formula IXc′. [ka]

[0087] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen among hydrophobic radicals according to formula X, in which GpA is a radical according to formula VIIIb, a'=1 and l=0, [ka] GpR, GpG, GpA, GpH, GpC, r, g, h and a have the definitions given above.

[0088] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen among hydrophobic radicals according to formula X, where a'=2 and a=1 and l=0, represented by the following formula Xf: [ka] GpR, GpG, GpA, GpH, GpC, r, g and h have the definitions given above.

[0089] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen among hydrophobic radicals according to formula X, where h=0, l=0 and l′=1, as represented by the following formula Xg: [ka] GpR, GpG, GpA, GpC, r, g, a and a' have the definitions given above.

[0090] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen among hydrophobic radicals according to formula X, where h=0 and a′=1, represented by the following formula Xh: [ka] GpR, GpG, GpA, GpC, r, a and g have the definitions given above.

[0091] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen among hydrophobic radicals according to formula X, where h=0, a′=2 and a=1, as represented by the following formula Xi: [ka] GpR, GpG, GpA, GpC, r and g have the definitions given above.

[0092] In one embodiment, a=0.

[0093] In one embodiment, h=1 and g=0.

[0094] In one embodiment, h=0 and g=1.

[0095] In one embodiment, r=0, g=1 and h=0.

[0096] In one embodiment, r=1, GpR is selected among the radicals according to formula VII′ or VII″, and h=0.

[0097] In one embodiment, r=1, g=0, GpR is a radical according to formula VII' and h=0.

[0098] In one embodiment, r=1, g=0, GpR is a radical according to formula VII' and h=1.

[0099] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is selected among radicals according to formula VIIIa or VIIIb, and h=0.

[0100] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is selected among radicals according to formula VIIa' or VIIIb, and h=1.

[0101] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is a radical according to formula VIIIa, and h=0.

[0102] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is a radical according to formula VIIIa, and h=1.

[0103] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is a radical according to formula VIIIb, and h=0.

[0104] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is a radical according to formula VIIIb, and h=1.

[0105] In one embodiment, r=0 and GpA is selected among radicals according to formulae VIIIa and VIIIb.

[0106] In one embodiment, r=0, g=0 and GpA is selected among the radicals according to formulae VIIIa and VIIIb.

[0107] In one embodiment, r=0, GpA is selected among radicals according to formulas VIIIa and VIIIb, and h=0.

[0108] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, linear alkyl radical containing 2 to 12 carbon atoms.

[0109] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical where R is a divalent, linear alkyl radical containing 2 to 6 carbon atoms.

[0110] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical where R is a divalent, linear alkyl radical containing 2 to 6 carbon atoms.

[0111] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical where R is a divalent, linear alkyl radical containing 2 to 4 carbon atoms.

[0112] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical where R is a divalent, linear alkyl radical containing 2 to 4 carbon atoms.

[0113] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, straight-chain alkyl radical containing 2 carbon atoms.

[0114] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, linear alkyl radical containing 1 to 11 carbon atoms.

[0115] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical where R is a divalent, straight chain alkyl radical containing 1 to 6 carbon atoms.

[0116] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, linear alkyl radical containing 2 to 5 carbon atoms and having one or more amide functional groups (-CONH2).

[0117] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, linear alkyl radical containing 2 to 5 carbon atoms and having one or more amide functional groups (-CONH2).

[0118] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical selected from the group consisting of radicals represented by the following formulas: [ka]

[0119] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals in which R is a radical according to formula X1.

[0120] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical wherein R is a radical according to formula X2.

[0121] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical in which R is attached to the copolyamino acid via an amide functionality carried by a carbon at the δ or ε position (or at the 4 or 5 position) relative to the amide functionality (-CONH2).

[0122] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals in which R is an unsubstituted linear ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms.

[0123] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical where R is an ether radical.

[0124] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is an ether radical containing 4 to 6 carbon atoms.

[0125] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, linear alkyl radical containing 6 carbon atoms.

[0126] In one embodiment, the composition is a hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi, wherein R is of the formula [ka] The radical is an ether radical represented by the formula:

[0127] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a polyether radical.

[0128] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where R is a linear polyether radical containing 6 to 10 carbon atoms and 2 to 3 oxygen atoms.

[0129] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals in which R is a polyether radical selected from the group consisting of radicals represented by the following formulas: [ka]

[0130] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical wherein R is a radical according to formula X3.

[0131] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical wherein R is a radical according to formula X4.

[0132] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulas X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals in which R is a polyether radical selected from the group consisting of radicals represented by formulas X5 and X6:

[0133] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a polyether radical according to formula X5.

[0134] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a polyether radical according to formula X6. [ka]

[0135] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are GpG and / or GpH radicals according to formula XI', where G is an alkyl radical containing 6 carbon atoms and represented by formula Z: [ka]

[0136] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals comprised of formula XI, where G is an alkyl radical comprising 4 carbon atoms and represented by formula Z: [ka]

[0137] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi, GpG and / or GpH radicals are radicals comprised of formula XI, where G is an alkyl radical containing 4 carbon atoms and represented by -(CH2)2-CH(COOH)-.

[0138] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are GpG and / or GpH radicals are radicals comprised of formula XI, where G is an alkyl radical containing 4 carbon atoms and represented by -CH((CH2)2COOH)-.

[0139] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi, the GpG and / or GpH radicals are radicals comprised of formula XI, where G is an alkyl radical containing 3 carbon atoms and represented by the formula -CH2-CH-(COOH).

[0140] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals comprised of formula XI, where the G radical is an alkyl radical containing 3 carbon atoms and represented by -CH(CH2)COOH)-.

[0141] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi are selected from the group consisting of the GpA radicals according to formula VIII and A1, A2 or A3 are selected from the group consisting of radicals represented by the formula: [ka]

[0142] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulae X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals according to formulae IXe, IXf or IXg, where the radical GpC according to formula IX is represented by: [ka]

[0143] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulae X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals of formulae IXe, IXf or IXg (b equal to 0), which correspond to formulae IXh, IXi and IXj, respectively, represented below: [ka]

[0144] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulas X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi correspond to formula IX or Ixe (b=0) and the GpC radical is a radical corresponding to formula IXh.

[0145] In one embodiment, the composition is characterized in that the hydrophobic radicals according to the formulas X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals wherein Cx is selected from the group consisting of linear alkyl radicals.

[0146] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals wherein Cx is selected from the group consisting of branched alkyl radicals.

[0147] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals wherein Cx is selected from the group consisting of alkyl radicals containing 19 to 14 carbon atoms.

[0148] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals represented by the formula: [ka]

[0149] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals wherein Cx is selected from the group consisting of alkyl radicals containing 15 to 16 carbon atoms.

[0150] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals represented by the formula: [ka]

[0151] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals represented by the formula: [ka]

[0152] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals wherein Cx is selected from the group consisting of alkyl radicals containing 17 to 25 carbon atoms.

[0153] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals wherein Cx is selected from the group consisting of alkyl radicals containing 17 to 18 carbon atoms.

[0154] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of alkyl radicals represented by the formula: [ka]

[0155] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals wherein Cx is selected from the group consisting of alkyl radicals containing 18 to 25 carbon atoms.

[0156] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of alkyl radicals represented by the formula: [ka]

[0157] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are selected from the group consisting of GpC radicals according to formula IX, wherein Cx is selected from the group consisting of alkyl radicals containing 14 to 15 carbon atoms.

[0158] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xc', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi are selected from the group consisting of radicals represented by the following formulas: [ka]

[0159] In one embodiment, the copolyamino acid is selected from a copolyamino acid according to formula XXXb, the hydrophobic radical -Hy is selected from the group of hydrophobic radicals according to formulas X, Xc', XdXa, Xb, Xc, Xe, Xg and Xh, a'=1 and l'=1, and GpC is a radical according to formula IXe.

[0160] In one embodiment, the copolyamino acid is selected from a copolyamino acid according to formula XXXb, the hydrophobic radical -Hy is selected from the group of hydrophobic radicals according to formulas X, Xc', Xd, Xa, Xb, Xc, Xe, Xg and Xh, a'=1 and l'=1, and GpC is a radical according to formula IX and e=0.

[0161] In one embodiment, the copolyamino acid is selected from a copolyamino acid according to formula XXXb, the hydrophobic radical -Hy is selected from the group of hydrophobic radicals according to formulas X, Xc', Xd, Xa, Xb, Xc, Xf, Xg and Xi, a'=2 or l'=2, and GpC is a radical according to formula IXe.

[0162] In one embodiment, the copolyamino acid is selected from a copolyamino acid according to formula XXXb, the hydrophobic radical -Hy is selected from the group of hydrophobic radicals according to formulas X, Xc', Xd, Xa, Xb, Xc, Xf, Xg and Xi, a'=2 and l'=2, and GpC is a radical according to formula IX and e=0.

[0163] In one embodiment, the copolyamino acid is selected from a copolyamino acid according to formula XXXa, the hydrophobic radical -Hy is selected from the group of hydrophobic radicals according to formulas X, Xc', Xd, Xa, Xb, Xc, Xe, Xg and Xh, a'=1 and l'=1, and GpC is a radical according to formula IXe.

[0164] In one embodiment, the copolyamino acid is selected from a copolyamino acid according to formula XXXa, the hydrophobic radical -Hy is selected from the group of hydrophobic radicals according to formulas X, Xc', Xd, Xa, Xb, Xc, Xf, Xg and Xi, a'=2 or l'=2, and GpC is a radical according to formula IXe.

[0165] In one embodiment, the copolyamino acid is selected from the group of copolyamino acids according to formula X, GpR is a radical according to formula VII, GpH is a radical according to formula XI, and GpC is a radical according to formula IX, where e=1 and b=0.

[0166] In one embodiment, the copolyamino acid is selected from the group of copolyamino acids according to formula X, GpR is a radical according to formula VII, GpH is a radical according to formula XI, GpC is a radical according to formula IX, e=1 and b=0, and x=13.

[0167] In one embodiment, the copolyamino acid is sodium poly-L-glutamate modified at one of its termini according to the formula represented below, as described in Example B1. [ka]

[0168] In one embodiment, the copolyamino acid is sodium poly-L-glutamate modified at one of its termini according to the formula represented below, as described in Example B18. [ka]

[0169] In the formula: * indicates the attachment sites of hydrophobic radicals to PLG or between the different groups GpR, GpG, GpA, GpL and GpC, resulting in the formation of amide functionalities.

[0170] The Hy radical is attached to the PLG via an amide functional group.

[0171] The Hy, GpR, GpG, GpA, GpL and GpC radicals are each independently the same or different from one residue to another.

[0172] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from among the copolyamino acids according to the following formula XXX: [ka] During the ceremony, D independently represents either a -CH2- group (aspartic acid unit) or a -CH2-CH2- group (glutamic acid unit); Hy is a hydrophobic radical selected from among the hydrophobic radicals of formula X, R1 is a hydrophobic radical selected among hydrophobic radicals according to formula X, where r=0 or r=1, GpR is a radical according to formula VII' or VII'', or a radical selected from the group consisting of H, a linear acyl group of C2-C10, a branched acyl group of C3-C10, benzyl, a terminal "amino acid" unit and pyroglutamic acid, R2 is a hydrophobic radical selected among the hydrophobic radicals according to formula X or -NR'R'', where R' and R'' radicals are identical or different and are selected from the group consisting of H, C2-C10 linear, branched or cyclic alkyl, benzyl, said R' and R'' alkyl together can form one or more carbon saturated, unsaturated and / or aromatic rings and / or can contain heteroatoms selected from the group consisting of O, N and S, X represents a cationic entity selected from the group including H or a metal cation; ·n+m represents the degree of polymerization DP of the copolyamino acid, which is the average number of monomer units per copolyamino acid chain, with 5≦n+m≦250.

[0173] A copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to formula X may also be referred to in this description as a "copolyamino acid."

[0174] We refer to copolyamino acids having a carboxylate charge and at least one hydrophobic radical, copolyamino acids according to formula XXXa, as "statistical copolyamino acids".

[0175] In one embodiment, the composition is characterized in that the copolyamino acids having a carboxylate charge and a hydrophobic radical are chosen among the copolyamino acids according to formula XXXa, where R1=R'1 and R2=R'2: [ka] During the ceremony, - m, n, X, D and Hy have the definitions given above; -R'1 is a radical selected from the group consisting of H, C2-C10 linear acyl groups, C3-C10 branched acyl groups, benzyl, terminal "amino acid" units and pyroglutamic acid; -R'2 is a hydrophobic radical selected from the group consisting of H, C2-C10 linear, branched or cyclic alkyl, benzyl, wherein said R' and R'' alkyl together can form one or more carbon saturated, unsaturated and / or aromatic rings, and / or can contain heteroatoms selected from the group consisting of O, N and S.

[0176] We refer to copolyamino acids having a carboxylate charge and at least one hydrophobic radical, copolyamino acids according to formula XXXb, as "statistical copolyamino acids".

[0177] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is chosen among the copolyamino acids according to formula XXX (wherein n=0), according to formula XXXb: [ka] wherein m, X, D, R1 and R2 have the definitions given above, and at least R1 or R2 is a hydrophobic radical according to formula X.

[0178] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected among the copolyamino acids according to formula XXXb, according to formula XXX (wherein n=0), and R1 or R2 is a hydrophobic radical according to formula X.

[0179] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected among the copolyamino acids according to formula XXXb, R1 is a hydrophobic radical according to formula X, r=0, or r=1, and GpR is composed of formula VII'.

[0180] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected among the copolyamino acids according to formula XXXb, R1 is a hydrophobic radical according to formula X, r=0 or r=1, and GpR is composed of formula VII″.

[0181] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected among the copolyamino acids according to formula XXXb, wherein R2 is a hydrophobic radical according to formula X.

[0182] In one embodiment, the composition is a compound in which R1 is C2-C 10 Straight chain acyl groups, C3-C 10 a branched acyl group of the formula (I), benzyl, a terminal "amino acid" unit and pyroglutamic acid.

[0183] In one embodiment, the composition is a compound in which R1 is C2-C 10 Straight chain acyl groups, or C3-C 10The branched acyl group is characterized in that it is a radical selected from the group consisting of

[0184] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected among the copolyamino acids according to formula XXX, XXXa or XXXb, wherein the D group is a -CH2- group (aspartic acid unit).

[0185] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected among the copolyamino acids according to formula XXX, XXXa or XXXb, wherein the D group is a -CH2-CH2- group (glutamic acid unit).

[0186] In one embodiment, the composition is characterized in that the M ratio between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.007 and 0.3.

[0187] In one embodiment, the composition is characterized in that the M ratio between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.01 and 0.3.

[0188] In one embodiment, the composition is characterized in that the M ratio between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.02 and 0.2.

[0189] In one embodiment, the composition according to the present invention is characterized in that n+m is 10-250.

[0190] In one embodiment, the composition is characterized in that n+m is 10-200.

[0191] In one embodiment, the composition is characterized in that n+m is 15-150.

[0192] In one embodiment, the composition is characterized in that n+m is 15-100.

[0193] In one embodiment, the composition is characterized in that n+m is 15-80.

[0194] In one embodiment, the composition is characterized in that n+m is 15-65.

[0195] In one embodiment, the composition is characterized in that n+m is 20-60.

[0196] In one embodiment, the composition is characterized in that n+m is 20-50.

[0197] In one embodiment, the composition is characterized in that n+m is 20-40.

[0198] The invention also relates to a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy, said copolyamino acid being composed of glutamic or aspartic acid units, said hydrophobic radical -Hy being chosen among the radicals according to formula X defined below: [ka] During the ceremony, GpR is selected among radicals according to formula VII, VII' or VII'': [ka] - GpG and GpH, which are identical or different, are selected among radicals according to formula XI or XI'; [ka] -GpA is selected among radicals according to formula VIII [ka] wherein A' is selected from among the radicals according to formula VIII', VIII'' or VIII''' [ka] -GpL is selected among radicals according to formula XII [ka] -GpC is a radical according to formula IX: [ka] - " * " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=1, then a'=1, 2 or 3; - a' is an integer equal to 1, 2 or 3; -b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g, h or l is different from 0; - l is an integer equal to 0 or 1, and if l=0 then l'=1, and if l=1 then l'=2; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - if e is different from 0, then at least one of g, h or l is different from 0; - if a=0 then l=0; - A, A1, A2 and A3 are identical or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with saturated, unsaturated or aromatic ring-derived radicals; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C x is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: if the hydrophobic radical -Hy has 1-GpC, then 9≦x≦25; if the hydrophobic radical -Hy has 2-GpC, then 9≦x≦15; if the hydrophobic radical -Hy has 3-GpC, then 7≦x≦13; if the hydrophobic radical -Hy has 4-GpC, then 7≦x≦11; - 6≦x≦11 if the hydrophobic radical -Hy has at least 5-GpC, -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups; -R is a radical selected from the group consisting of a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH2 functional groups, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; - the hydrophobic radical -Hy according to formula X is attached to PLG by: a covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of the PLG (thus forming an amide functional group resulting from the reaction of the amine functional group of the PLG with the acid functional group of the precursor of the hydrophobic radical -Hy, -Hy', and a covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of the PLG (thus forming an amide function resulting from the reaction of the amine function of the precursor of the hydrophobic radical -Hy -Hy' with the acid function of the PLG); - The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is 0 <M≦0.5であり; - if the copolyamino acid has several hydrophobic radicals, they may be the same or different, - the degree of polymerization DP of the glutamic or aspartic acid units for the PLG chain is comprised between 5 and 250; -Free carboxylic acid is Na + and K. + The compound is in the form of an alkali cation salt selected from the group consisting of:

[0199] The invention also relates to a precursor Hy' of the hydrophobic radical -Hy according to formula X' defined below: [ka] During the ceremony, GpR is selected among radicals according to formula VII, VII' or VII'': [ka] - GpG and GpH, which are identical or different, are selected among radicals according to formula XI or XI'; [ka] -GpA is selected among radicals according to formula VIII [ka] wherein A' is selected from among the radicals according to formula VIII', VIII'' or VIII''' [ka] -GpL is selected among radicals according to formula XII [ka] -GpC is a radical according to formula IX: [ka] - " * " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=1, then a'=1, 2 or 3; - a' is an integer equal to 1, 2 or 3; -b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g, h or l is different from 0; - l is an integer equal to 0 or 1, and l' = 0, and if l = 1, then l' = 2; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - if e is different from 0, then at least one of g, h or l is different from 0; - if a=0 then l=0; - A, A1, A2 and A3 are identical or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with saturated, unsaturated or aromatic ring-derived radicals; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C x is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: if the hydrophobic radical -Hy has 1-GpC, then 9≦x≦25; if the hydrophobic radical -Hy has 2-GpC, then 9≦x≦15; if the hydrophobic radical -Hy has 3-GpC, then 7≦x≦13; if the hydrophobic radical -Hy has 4-GpC, then 7≦x≦11; - 6≦x≦11 if the hydrophobic radical -Hy has at least 5-GpC, -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups; -R is a radical selected from the group consisting of a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH2 functional groups, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; - the hydrophobic radical -Hy according to formula X is attached to PLG by: a covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of the PLG (thus forming an amide functional group resulting from the reaction of the amine functional group of the PLG with the acid functional group of the precursor of the hydrophobic radical -Hy, -Hy', and a covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of the PLG (thus forming an amide function resulting from the reaction of the amine function of the precursor of the hydrophobic radical -Hy -Hy' with the acid function of the PLG); - The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is 0 <M≦0.5であり; - if the copolyamino acid has several hydrophobic radicals, they may be the same or different, -Free carboxylic acid is Na + and K. + The compound is in the form of an alkali cation salt selected from the group consisting of:

[0200] Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from pancreatic β-cells in a ratio of approximately 100:1. Amylin plays a role in glycemic control by halting secretion of endogenous glucagon and by slowing gastric emptying, supporting satiety, and thus reducing postprandial glycemic excursions in blood glucose.

[0201] IAPP is derived using a coding sequence of 89 residues. The amyloid polypeptide Proislet (proIAPP, proamylin, proislet protein) is produced in pancreatic β-cells in the form of a 67 amino acid deRSO propeptide, 7404 daltons, which undergoes post-translational modifications including protease cleavage to generate amylin.

[0202] In the present application, the aforementioned amylin refers to the compounds described in patents US Pat. No. 5,124,314 and US Pat. No. 5,234,906.

[0203] By "analog", when used to denote a peptide or protein, is meant a peptide or protein in which one or more constituent amino acid residues of the primary sequence have been replaced by other amino acid residues and / or in which one or more constituent amino acid residues have been added. The percentage of homology allowed for this definition of analog is 50%. In the case of amylin, an analog may be derived from the primary amylin amino acid sequence, for example, by substituting one or more natural or non-natural or peptidomimetic acids.

[0204] By "derivative", when used in reference to a peptide or protein, is meant a peptide or protein or analog that has been chemically modified with a substituent not present in the aforementioned peptide or protein or analog, i.e., a peptide or protein that has been modified by creating a covalent bond to introduce a non-amino acid type substituent.

[0205] Amylin receptor agonists refer to compounds that mimic one or more properties of the action of amylin.

[0206] Amylin derivatives are described in the article Yan et al., PNAS, vol. 103, no. 7, p. 2046-2051, 2006.

[0207] In one embodiment, the substituents are selected from the group consisting of aliphatic chains.

[0208] Amylin analogues are described in patents US 5,686,411, US 6,114,304 or US 6,410,511.

[0209] In one embodiment, the composition is characterized in that the amylin, amylin receptor agonist or amylin analog is amylin.

[0210] In one embodiment, the amylin receptor agonist is amylin.

[0211] In one embodiment, the composition is characterized in that the amylin analog or amylin receptor agonist is pramlintide (Symlin®), marketed by ASTRAZENECA AB.

[0212] In one embodiment, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analog is 1 or greater.

[0213] In one embodiment, the copolyamino acid / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 1.5 and 75.

[0214] In one embodiment, the copolyamino acid / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 1.8-50.

[0215] In one embodiment, the molar ratio of the copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 2-35.

[0216] In one embodiment, the molar ratio of the copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 2.5 and 30.

[0217] In one embodiment, the molar ratio of the copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 3-30.

[0218] In one embodiment, the molar ratio of the copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 3.5 and 30.

[0219] In one embodiment, the molar ratio of the copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 4-30.

[0220] In one embodiment, the molar ratio of the copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 5-30.

[0221] In one embodiment, the copolyamino acid / amylin molar ratio, amylin receptor agonist or amylin analog is comprised between 7-30.

[0222] In one embodiment, the molar ratio of the copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 9-30.

[0223] In one embodiment, the copolyamino acid / amylin molar ratio is comprised between 3-75.

[0224] In one embodiment, the copolyamino acid / amylin molar ratio is comprised between 7-50.

[0225] In one embodiment, the copolyamino acid / amylin molar ratio is comprised between 10-30.

[0226] In one embodiment, the copolyamino acid / amylin molar ratio is comprised between 15-30.

[0227] In one embodiment, the copolyamino acid / pramlintide molar ratio is comprised between 1.5-75.

[0228] In one embodiment, the copolyamino acid / pramlintide molar ratio is comprised between 2-50.

[0229] In one embodiment, the copolyamino acid / pramlintide molar ratio is comprised between 3-30.

[0230] In one embodiment, the copolyamino acid / pramlintide molar ratio is comprised between 4-30.

[0231] In one embodiment, the copolyamino acid / pramlintide molar ratio is comprised between 5-30.

[0232] In one embodiment, the copolyamino acid / pramlintide molar ratio is comprised between 8-30.

[0233] In one embodiment, the copolyamino acid / pramlintide molar ratio is comprised between 10-30.

[0234] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 1.5-150.

[0235] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 1.8-100.

[0236] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 2-70.

[0237] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 2.5 and 60.

[0238] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 3-60.

[0239] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 3.5 and 60.

[0240] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 4-60.

[0241] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 5-60.

[0242] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 7-60.

[0243] In one embodiment, the hydrophobic radical Hy / amylin molar ratio of the amylin receptor agonist or amylin analog is comprised between 9-60.

[0244] In one embodiment, the hydrophobic radical Hy / amylin molar ratio is comprised between 5-60.

[0245] In one embodiment, the hydrophobic radical Hy / amylin molar ratio is comprised between 10 and 60.

[0246] In one embodiment, the hydrophobic radical Hy / amylin molar ratio is comprised between 15-60.

[0247] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 1.5 and 60.

[0248] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 2-60.

[0249] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 3-60.

[0250] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 4-60.

[0251] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 5-60.

[0252] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 8-60.

[0253] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 10-60.

[0254] In one embodiment, the copolyamino acid / amylin mass ratio, amylin receptor agonist or amylin analogue is comprised between 1.0 and 70.

[0255] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analog is comprised between 1.2 and 45.

[0256] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analogue is comprised between 1.3 and 30.

[0257] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analog is comprised between 1.7 and 27.

[0258] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analog is comprised between 2.0 and 27.

[0259] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analog is comprised between 2.3 and 27.

[0260] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analog is comprised between 2.7 and 27.

[0261] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analog is comprised between 3.3 and 27.

[0262] In one embodiment, the copolyamino acid / amylin mass ratio of the amylin receptor agonist or amylin analog is comprised between 4.7 and 27.

[0263] In one embodiment, the copolyamino acid / amylin mass ratio, amylin receptor agonist or amylin analogue is comprised between 6.0 and 27.

[0264] In one embodiment, the copolyamino acid / amylin mass ratio is comprised between 2.0 and 67.

[0265] In one embodiment, the copolyamino acid / amylin mass ratio is comprised between 4.7 and 27.

[0266] In one embodiment, the copolyamino acid / amylin mass ratio is comprised between 6.7 and 27.

[0267] In one embodiment, the copolyamino acid / amylin mass ratio is comprised between 10-27.

[0268] In one embodiment, the copolyamino acid / pramlintide mass ratio is comprised between 1.0 and 67.

[0269] In one embodiment, the copolyamino acid / pramlintide mass ratio is comprised between 1.3 and 45.

[0270] In one embodiment, the copolyamino acid / pramlintide mass ratio is comprised between 2.7 and 27.

[0271] In one embodiment, the copolyamino acid / pramlintide mass ratio is comprised between 3.3 and 27.

[0272] In one embodiment, the copolyamino acid / pramlintide mass ratio is comprised between 5.3 and 27.

[0273] In one embodiment, the copolyamino acid / pramlintide mass ratio is comprised between 6.7 and 27.

[0274] In one embodiment, the composition is characterized in that it also contains insulin.

[0275] In one embodiment, the composition is characterized in that the insulin is prandial insulin. Meal insulin is soluble at pH 7.

[0276] Meal insulin refers to the so-called fast acting or "regular" insulin.

[0277] So-called fast-acting prandial insulins are insulins which must meet the needs induced by the intake of protein and carbohydrates in a meal; they must act in less than 30 minutes.

[0278] In one embodiment, the so-called "regular" prandial insulin is human insulin.

[0279] In one embodiment, the prandial insulin is recombinant human insulin as described in the European Pharmacopoeia and the United States Pharmacopoeia.

[0280] Human insulin is commercially available, for example, under the trade names Humulin® (ELI LILLY) and Novolin® (NOVO NORDISK).

[0281] The so-called rapid-acting (fast-acting) prandial insulins are recombinantly derived insulins whose primary sequence has been altered to reduce their duration of action.

[0282] In one embodiment, the so-called fast-acting prandial insulin is selected from the group comprising insulin lispro (Humalog®), insulin glulisine (Apidra®) and insulin aspart (NovoLog®).

[0283] In one embodiment, the prandial insulin is insulin lispro.

[0284] In one embodiment, the prandial insulin is insulin glulisine.

[0285] In one embodiment, the prandial insulin is insulin aspart.

[0286] The insulins recommended by the Pharmacopoeias for insulin are presented in the table below together with their corresponding amounts expressed in mg: [Table 1]

[0287] For insulin glulisine, 100 U=3.49 mg of insulin glulisine (according to Appendix 1 - Summary of Product Characteristics for ADIPRA®).

[0288] Nevertheless, in the remainder of the text, U is used systematically and indifferently for all insulin amounts and concentrations. The respective corresponding values ​​expressed in mg are given above for values ​​expressed in U, UI or USP.

[0289] In one embodiment, the pharmaceutical preparation comprises an insulin concentration of 240 to 3000 μM (40 to 500 U / mL).

[0290] In one embodiment, the pharmaceutical preparation comprises an insulin concentration of 600 to 3000 μM (100 to 500 U / mL).

[0291] In one embodiment, the pharmaceutical preparation comprises an insulin concentration of 600 to 2400 μM (100 to 400 U / mL).

[0292] In one embodiment, the pharmaceutical preparation comprises an insulin concentration of 600 to 1800 μM (100 to 300 U / mL).

[0293] In one embodiment, the pharmaceutical preparation comprises an insulin concentration of 600 to 1200 μM (100 to 200 U / mL).

[0294] In one embodiment, the pharmaceutical preparation is characterized in that the concentration of insulin is 600 μM (100 U / mL).

[0295] In one embodiment, the pharmaceutical preparation is characterized in that the concentration of insulin is 1200 μM (200 U / mL).

[0296] In one embodiment, the pharmaceutical preparation is characterized in that the concentration of insulin is 1800 μM (300 U / mL).

[0297] In one embodiment, the pharmaceutical preparation is characterized in that the concentration of insulin is 2400 μM (400 U / mL).

[0298] In one embodiment, the pharmaceutical preparation is characterized in that the concentration of insulin is 3000 μM (500 U / mL).

[0299] In one embodiment, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analog is 1 or greater.

[0300] In one embodiment comprising prandial insulin, the copolyamino acid / amylin molar ratio, amylin receptor agonist or amylin analogue is comprised between 1.5 and 75.

[0301] In one embodiment comprising prandial insulin, the copolyamino acid / amylin molar ratio, amylin receptor agonist or amylin analogue is comprised between 1.8-50.

[0302] In one embodiment comprising prandial insulin, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analogue is comprised between 2-35.

[0303] In one embodiment comprising prandial insulin, the copolyamino acid / amylin molar ratio, amylin receptor agonist or amylin analogue is comprised between 2.5-30.

[0304] In one embodiment comprising prandial insulin, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analogue is comprised between 3-30.

[0305] In one embodiment comprising prandial insulin, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analogue is comprised between 3.5 and 30.

[0306] In one embodiment comprising prandial insulin, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analogue is comprised between 4-30.

[0307] In one embodiment comprising prandial insulin, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analogue is comprised between 5-30.

[0308] In one embodiment comprising prandial insulin, the copolyamino acid / amylin molar ratio, amylin receptor agonist or amylin analogue is comprised between 7-30.

[0309] In one embodiment comprising prandial insulin, the molar ratio of copolyamino acid / amylin, amylin receptor agonist or amylin analog is comprised between 9-30.

[0310] In one embodiment containing prandial insulin, the copolyamino acid / amylin molar ratio is comprised between 5-75.

[0311] In one embodiment containing prandial insulin, the copolyamino acid / amylin molar ratio is comprised between 10-50.

[0312] In one embodiment containing prandial insulin, the copolyamino acid / amylin molar ratio comprises 15-30.

[0313] In one embodiment, the copolyamino acid / pramlintide molar ratio is 1 or greater.

[0314] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide molar ratio is comprised between 1.5-75.

[0315] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide molar ratio is comprised between 2-50.

[0316] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide molar ratio is comprised between 3-30.

[0317] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide molar ratio is comprised between 4-30.

[0318] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide molar ratio is comprised between 5-30.

[0319] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide molar ratio is comprised between 8-30.

[0320] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide molar ratio is comprised between 10-30.

[0321] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 1.5-150.

[0322] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 1.8-100.

[0323] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 2-70.

[0324] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 2.5 and 60.

[0325] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 3-60.

[0326] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 3.5 and 60.

[0327] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 4-60.

[0328] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 5-60.

[0329] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 7-60.

[0330] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratio is comprised between 9-60.

[0331] In one embodiment containing prandial insulin, the hydrophobic radical Hy / amylin molar ratio is comprised between 5-60.

[0332] In one embodiment containing prandial insulin, the hydrophobic radical Hy / amylin molar ratio is comprised between 10-60.

[0333] In one embodiment containing prandial insulin, the hydrophobic radical Hy / amylin molar ratio is comprised between 15-60.

[0334] In one embodiment containing prandial insulin, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 1.5 and 60.

[0335] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 2-60.

[0336] In one embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 3-60.

[0337] In one embodiment containing prandial insulin, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 4-60.

[0338] In one embodiment containing prandial insulin, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 5-60.

[0339] In one embodiment containing prandial insulin, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 8-60.

[0340] In one embodiment containing prandial insulin, the hydrophobic radical Hy / pramlintide molar ratio is comprised between 10-60.

[0341] In one embodiment comprising prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 1.0-70.

[0342] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 1.2 and 45.

[0343] In one embodiment comprising prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 1.3 and 30.

[0344] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 1.7 and 27.

[0345] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 2.0 and 27.

[0346] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 2.3 and 27.

[0347] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 2.7 and 27.

[0348] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 3.3 and 27.

[0349] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 4.7 and 27.

[0350] In one embodiment containing prandial insulin, the copolyamino acid / amylin, amylin receptor agonist or amylin analogue mass ratio is comprised between 6.0 and 27.

[0351] In one embodiment containing prandial insulin, the copolyamino acid / amylin mass ratio is comprised between 3.3 and 67.

[0352] In one embodiment containing prandial insulin, the copolyamino acid / amylin mass ratio is comprised between 6.6 and 27.

[0353] In one embodiment containing prandial insulin, the copolyamino acid / amylin mass ratio is comprised between 10-27.

[0354] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 1.0 and 67.

[0355] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 1.2 and 45.

[0356] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 1.3 and 27.

[0357] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 1.7 and 27.

[0358] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 2.0 and 27.

[0359] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 2.3 and 27.

[0360] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 2.7 and 27.

[0361] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 3.3 and 27.

[0362] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 4.7 and 27.

[0363] In one embodiment containing prandial insulin, the copolyamino acid / pramlintide mass ratio is comprised between 6.0 and 27.

[0364] Furthermore, it is particularly advantageous to combine amylin, amylin receptor agonists or amylin analogs with GLP-1, GLP-1 analogs, GLP-1 receptor agonists (commonly called GLP-1 RAs), with or without prandial insulin, which makes it possible in particular to enhance the effect of insulin, which is recommended in the treatment of certain types of diabetes.

[0365] In one embodiment, the GLP-1, GLP-1 analogue or GLP-1 RA is referred to as "fast-acting". By "fast-acting" is meant a GLP-1, GLP-1 analogue or GLP-1 RA, such as, for example, exenatide and lixisenatide, that has an apparent elimination half-life in humans of less than 8 hours, in particular less than 5 hours, preferentially less than 4 hours, or even less than 3 hours after subcutaneous injection.

[0366] In one embodiment, the GLP-1, GLP-1 analog or GLP-1RA is selected from the group consisting of exenatide or Byetta® (ASTRA-ZENECA), lixisenatide or Lyxumia® (SANOFI), analogs or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0367] In one embodiment, the GLP-1, GLP-1 analog or GLP-1RA is exenatide or Byetta®, analogs or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0368] In one embodiment, the GLP-1, GLP-1 analogue or GLP-1RA is lixisenatide or Lyxumia®, analogues or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0369] In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharma- ceutically acceptable salts is comprised within the interval of 0.01 to 1.0 mg per 100 U of insulin.

[0370] In one embodiment, the concentration of exenatide, its analogs or derivatives, and their pharma- ceutically acceptable salts is 0.01-0.5 mg per 100 U of insulin.

[0371] In one embodiment, the concentration of exenatide, its analogs or derivatives, and their pharma- ceutically acceptable salts is 0.02-0.4 mg per 100 U of insulin.

[0372] In one embodiment, the concentration of exenatide, its analogs or derivatives, and their pharma- ceutically acceptable salts is 0.03-0.3 mg per 100 U of insulin.

[0373] In one embodiment, the concentration of exenatide, its analogs or derivatives, and their pharma- ceutically acceptable salts is 0.04-0.2 mg per 100 U of insulin.

[0374] In one embodiment, the concentration of exenatide, its analogs or derivatives, and their pharma- ceutically acceptable salts is 0.04-0.15 mg per 100 U of insulin.

[0375] In one embodiment, the concentration of lixisenatide, its analogues or derivatives and their pharma- ceutically acceptable salts is comprised within the interval of 0.01 to 1 mg per 100 U of insulin.

[0376] In one embodiment, the concentration of lixisenatide, its analogues or derivatives, and their pharma- ceutically acceptable salts is 0.01-0.5 mg per 100 U of insulin.

[0377] In one embodiment, the concentration of lixisenatide, its analogues or derivatives, and their pharma- ceutically acceptable salts is 0.02-0.4 mg per 100 U of insulin.

[0378] In one embodiment, the concentration of lixisenatide, its analogues or derivatives, and their pharma- ceutically acceptable salts is 0.03-0.3 mg per 100 U of insulin.

[0379] In one embodiment, the concentration of lixisenatide, its analogues or derivatives, and their pharma- ceutically acceptable salts is 0.04-0.2 mg per 100 U of insulin.

[0380] In one embodiment, the concentration of lixisenatide, its analogues or derivatives, and their pharma- ceutically acceptable salts is 0.04-0.15 mg per 100 U of insulin.

[0381] In one embodiment, the composition according to the invention is achieved by mixing a solution of amylin with a commercially available solution of GLP-1, a GLP-1 analogue or a GLP-1 RA receptor agonist in a volume ratio comprised in the interval 10 / 90 to 90 / 10 in the presence of a copolyamino acid.

[0382] In one embodiment, the composition according to the invention does not include prandial insulin.

[0383] In one embodiment, the compositions according to the invention do not contain GLP-1, GLP-1 analogues, or the GLP-1 receptor agonist currently referred to as GLP-1 RA.

[0384] The invention also relates to compositions that also include an ionic species, which can improve the stability of the composition.

[0385] The invention also relates to the use of ionic species selected from the group of anions, cations and / or zwitterions to improve the physicochemical stability of the composition.

[0386] In one embodiment, the ionic species comprises more than 10 carbon atoms.

[0387] The ionic species is selected from the group of anions, cations and / or zwitterions. By zwitterion is meant a species having at least one positive charge and at least one negative charge on two non-adjacent atoms.

[0388] The ionic species may be used alone or in mixtures, preferably in mixtures.

[0389] In one embodiment, the anion is selected among organic anions.

[0390] In one embodiment, the organic anion contains fewer than 10 carbon atoms.

[0391] In one embodiment, the organic anion is selected from the group consisting of acetate, citrate and succinate.

[0392] In one embodiment, the anion is selected from among the anions of an inorganic source.

[0393] In one embodiment, the anion of the inorganic source is selected from the group consisting of sulfate, phosphate and halide, particularly chloride.

[0394] In one embodiment, the cation is selected among organic cations.

[0395] In one embodiment, the organic cation contains less than 10 carbon atoms.

[0396] In one embodiment, the organic cation is selected from the group consisting of ammonium, for example, 2-amino-2-(hydroxymethyl)propane-1,3-diol, where the amine is in the ammonium form.

[0397] In one embodiment, the cations are selected among the cations of an inorganic source.

[0398] In one embodiment, the cation of the inorganic source is zinc, particularly Zn 2+ and alkali metals, especially Na + and K. + is selected from the group consisting of:

[0399] In one embodiment, the zwitterion is selected among zwitterions of organic origin.

[0400] In one embodiment, the zwitterions are selected among amino acids.

[0401] In one embodiment, the amino acids are selected among the aliphatic amino acids in the group consisting of glycine, alanine, valine, isoleucine and leucine.

[0402] In one embodiment, the amino acid is selected among cyclic amino acids in the group consisting of proline.

[0403] In one embodiment, the amino acid is selected among hydroxyl- or sulfur-containing amino acids in the group consisting of cysteine, serine, threonine, and methionine.

[0404] In one embodiment, the amino acid is selected among aromatic amino acids in the group consisting of phenylalanine, tyrosine and tryptophan.

[0405] In one embodiment, the amino acid is selected from the group consisting of asparagine and glutamine, the carboxyl function of the side chain of which is amidated.

[0406] In one embodiment, the zwitterion of organic origin is selected from the group consisting of amino acids with uncharged side chains.

[0407] In one embodiment, the zwitterion of organic origin is selected from the group consisting of diacids or acidic amino acids.

[0408] In one embodiment, the amino acid is selected from the group consisting of glutamic acid and aspartic acid (optionally in salt form).

[0409] In one embodiment, the zwitterions of organic origin are selected from the group consisting of basic amino acids or so-called cationic amino acids.

[0410] In one embodiment, the so-called "cationic" amino acids are selected among arginine, histidine and lysine, in particular arginine and lysine.

[0411] Very specifically, zwitterions contain as many negative charges as positive charges at the isoelectric point and / or at a pH between 6.0 and 8.0, thus resulting in an overall charge of zero.

[0412] Said ionic species are introduced into the composition in salt form, which can be carried out in solid form before dissolving them in the composition, or in the form of a solution, in particular a concentrated solution.

[0413] For example, the cations of the inorganic source are added in the form of salts selected from among sodium chloride, zinc chloride, sodium phosphate, sodium sulfate, and the like.

[0414] For example, the anion of the organic source is added in the form of a salt selected from among sodium citrate or sodium potassium or sodium acetate.

[0415] For example, the amino acid is added in the form of a salt selected from among arginine hydrochloride, histidine hydrochloride, or in a non-salt form, such as, for example, histidine or arginine.

[0416] In one embodiment, the total molar concentration of the ionic species in the composition is 10 mM or greater.

[0417] In one embodiment, the total molar concentration of ionic species in the composition is 20 mM or greater.

[0418] In one embodiment, the total molar concentration of ionic species in the composition is 30 mM or greater.

[0419] In one embodiment, the total molar concentration of the ionic species in the composition is 50 mM or greater.

[0420] In one embodiment, the total molar concentration of ionic species in the composition is 75 mM or greater.

[0421] In one embodiment, the total molar concentration of the ionic species in the composition is 100 mM or greater.

[0422] In one embodiment, the total molar concentration of ionic species in the composition is 200 mM or greater.

[0423] In one embodiment, the total molar concentration of ionic species in the composition is 300 mM or greater.

[0424] In one embodiment, the total molar concentration of the ionic species in the composition is 500 mM or greater.

[0425] In one embodiment, the total molar concentration of ionic species in the composition is 600 mM or greater.

[0426] In one embodiment, the total molar concentration of ionic species in the composition is 700 mM or greater.

[0427] In one embodiment, the total molar concentration of ionic species in the composition is 800 mM or greater.

[0428] In one embodiment, the total molar concentration of ionic species in the composition is 900 mM or greater.

[0429] In one embodiment, the total molar concentration of ionic species in the composition is 1000 mM or less.

[0430] In one embodiment, the total molar concentration of ionic species in the composition is 1500 mM or less.

[0431] In one embodiment, the total molar concentration of ionic species in the composition is 1200 mM or less.

[0432] In one embodiment, the total molar concentration of ionic species in the composition is 1000 mM or less.

[0433] In one embodiment, the total molar concentration of ionic species in the composition is 900 mM or less.

[0434] In one embodiment, the total molarity of the ionic species in the composition is 800 mM or less.

[0435] In one embodiment, the total molar concentration of ionic species in the composition is 700 mM or less.

[0436] In one embodiment, the total molarity of the ionic species in the composition is 600 mM or less.

[0437] In one embodiment, the total molar concentration of ionic species in the composition is 500 mM or less.

[0438] In one embodiment, the total molar concentration of ionic species in the composition is 400 mM or less.

[0439] In one embodiment, the total molar concentration of ionic species in the composition is 300 mM or less.

[0440] In one embodiment, the total molar concentration of ionic species in the composition is 200 mM or less.

[0441] In one embodiment, the total molar concentration of ionic species in the composition is 100 mM or less.

[0442] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 1000 mM.

[0443] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 1000 mM.

[0444] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 1000 mM.

[0445] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 1000 mM.

[0446] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 1000 mM.

[0447] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 1000 mM.

[0448] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 1000 mM.

[0449] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 1000 mM.

[0450] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 1000 mM.

[0451] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 1000 mM.

[0452] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 1000 mM.

[0453] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 900 mM.

[0454] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 900 mM.

[0455] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 900 mM.

[0456] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 900 mM.

[0457] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 900 mM.

[0458] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 900 mM.

[0459] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 900 mM.

[0460] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 900 mM.

[0461] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 900 mM.

[0462] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 900 mM.

[0463] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 900 mM.

[0464] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 800 mM.

[0465] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 800 mM.

[0466] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 800 mM.

[0467] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 800 mM.

[0468] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 800 mM.

[0469] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 800 mM.

[0470] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 800 mM.

[0471] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 800 mM.

[0472] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 800 mM.

[0473] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 800 mM.

[0474] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 800 mM.

[0475] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 700 mM.

[0476] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 700 mM.

[0477] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 700 mM.

[0478] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 700 mM.

[0479] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 700 mM.

[0480] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 700 mM.

[0481] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 700 mM.

[0482] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 700 mM.

[0483] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 700 mM.

[0484] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 700 mM.

[0485] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 700 mM.

[0486] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 600 mM.

[0487] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 600 mM.

[0488] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 600 mM.

[0489] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 600 mM.

[0490] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 600 mM.

[0491] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 600 mM.

[0492] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 600 mM.

[0493] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 600 mM.

[0494] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 600 mM.

[0495] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 600 mM.

[0496] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 500 mM.

[0497] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 500 mM.

[0498] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 500 mM.

[0499] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 500 mM.

[0500] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 500 mM.

[0501] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 500 mM.

[0502] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 500 mM.

[0503] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 500 mM.

[0504] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 500 mM.

[0505] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 400 mM.

[0506] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 400 mM.

[0507] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 400 mM.

[0508] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 400 mM.

[0509] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 400 mM.

[0510] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 400 mM.

[0511] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 400 mM.

[0512] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 400 mM.

[0513] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 300 mM.

[0514] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 300 mM.

[0515] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 300 mM.

[0516] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 300 mM.

[0517] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 300 mM.

[0518] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 300 mM.

[0519] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 300 mM.

[0520] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 200 mM.

[0521] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 200 mM.

[0522] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 200 mM.

[0523] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 200 mM.

[0524] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 200 mM.

[0525] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 200 mM.

[0526] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 100 mM.

[0527] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 100 mM.

[0528] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 100 mM.

[0529] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 100 mM.

[0530] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 100 mM.

[0531] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 75 mM.

[0532] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 75 mM.

[0533] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 75 mM.

[0534] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 75 mM.

[0535] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 50 mM.

[0536] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 50 mM.

[0537] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 50 mM.

[0538] In one embodiment, the ionic species is present at a concentration of 5 to 400 mM.

[0539] In one embodiment, the ionic species is present at a concentration of 5 to 300 mM.

[0540] In one embodiment, the ionic species is present at a concentration of 5 to 200 mM.

[0541] In one embodiment, the ionic species is present at a concentration of 5 to 100 mM.

[0542] In one embodiment, the ionic species is present at a concentration of 5 to 75 mM.

[0543] In one embodiment, the ionic species is present at a concentration of 5 to 50 mM.

[0544] In one embodiment, the ionic species is present at a concentration of 5 to 25 mM.

[0545] In one embodiment, the ionic species is present at a concentration of 5 to 20 mM.

[0546] In one embodiment, the ionic species is present at a concentration of 5 to 10 mM.

[0547] In one embodiment, the ionic species is present at a concentration of 10 to 400 mM.

[0548] In one embodiment, the ionic species is present at a concentration of 10 to 300 mM.

[0549] In one embodiment, the ionic species is present at a concentration of 10 to 200 mM.

[0550] In one embodiment, the ionic species is present at a concentration of 10 to 100 mM.

[0551] In one embodiment, the ionic species is present at a concentration of 10 to 75 mM.

[0552] In one embodiment, the ionic species is present at a concentration of 10 to 50 mM.

[0553] In one embodiment, the ionic species is present at a concentration of 10 to 25 mM.

[0554] In one embodiment, the ionic species is present at a concentration of 10 to 20 mM.

[0555] In one embodiment, the ionic species is present at a concentration of 20 to 300 mM.

[0556] In one embodiment, the ionic species is present at a concentration of 20 to 200 mM.

[0557] In one embodiment, the ionic species is present at a concentration of 20 to 100 mM.

[0558] In one embodiment, the ionic species is present at a concentration of 20 to 75 mM.

[0559] In one embodiment, the ionic species is present at a concentration of 20 to 50 mM.

[0560] In one embodiment, the ionic species is present at a concentration of 20-25 mM.

[0561] In one embodiment, the ionic species is present at a concentration of 50 to 300 mM.

[0562] In one embodiment, the ionic species is present at a concentration of 50 to 200 mM.

[0563] In one embodiment, the ionic species is present at a concentration of 50-100 mM.

[0564] In one embodiment, the ionic species is present at a concentration of 50-75 mM.

[0565] Cations of inorganic origin, especially Zn 2+ With regard to the molar concentration of the compound in the composition, it may be comprised between 0.25 and 20 mM, in particular between 0.25 and 10 mM or between 0.25 and 5 mM.

[0566] In one embodiment, the composition comprises zinc.

[0567] In one embodiment, the composition comprises 0.2 to 2 mM zinc.

[0568] In one embodiment, the composition comprises NaCl.

[0569] In one embodiment, the composition comprises 10-250 mM NaCl.

[0570] In one embodiment, the composition comprises 15-200 mM NaCl.

[0571] In one embodiment, the composition comprises 20-150 mM NaCl.

[0572] In one embodiment, the composition comprises 25-100 mM NaCl.

[0573] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-500 μM per 100 U of insulin.

[0574] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-400 μM per 100 U of insulin.

[0575] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-300 μM per 100 U of insulin.

[0576] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-200 μM per 100 U of insulin.

[0577] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-100 μM per 100 U of insulin.

[0578] In one embodiment, the composition according to the invention also comprises a buffer.

[0579] In one embodiment, the composition according to the present invention comprises a buffer at a concentration of 0 to 100 mM.

[0580] In one embodiment, the composition according to the present invention comprises a buffer at a concentration of 15 to 50 mM.

[0581] In one embodiment, the composition according to the invention comprises a buffer selected from the group consisting of phosphate buffer, Tris (trishydroxymethylaminomethane), and sodium citrate.

[0582] In one embodiment, the buffer is sodium phosphate.

[0583] In one embodiment, the buffer is Tris (trishydroxymethylaminomethane).

[0584] In one embodiment, the buffer is sodium citrate.

[0585] In one embodiment, the composition according to the invention also comprises a preservative.

[0586] In one embodiment, the preservative is selected from the group consisting of m-cresol and phenol, either alone or in mixture.

[0587] In one embodiment, the concentration of the preservative is comprised between 10 and 50 mM.

[0588] In one embodiment, the concentration of the preservative is comprised between 10 and 40 mM.

[0589] In one embodiment, the composition according to the invention also comprises a surfactant.

[0590] In one embodiment, the surfactant is selected from the group consisting of propylene glycol and polysorbates.

[0591] The compositions according to the invention may also include additives such as tonicity agents.

[0592] In one embodiment, the tonicity agent is selected from the group consisting of glycerin, sodium chloride, mannitol and glycine.

[0593] The composition according to the invention may also contain all the excipients compatible with insulin used in the concentrations customary according to the pharmacopoeias.

[0594] The invention also relates to pharmaceutical preparations according to the invention, characterized in that they are obtained by drying and / or lyophilization.

[0595] For local and systemic release, contemplated routes of administration are intravenous, subcutaneous, intradermal or intramuscular.

[0596] Transdermal, oral, nasal, intravaginal, ocular, buccal and pulmonary means of administration are also contemplated.

[0597] The invention also relates to an implantable or portable pump comprising the composition according to the invention.

[0598] The invention also relates to the use of a composition according to the invention that is intended to be placed in an implantable or portable pump.

[0599] The invention also relates to a formulation comprising amylin, an amylin agonist receptor or an amylin analogue and a copolyamino acid according to the invention, at a pH of 6.0 to 8.0.

[0600] The invention also relates to a single dose formulation, at a pH between 6.0 and 8.0, comprising amylin, an amylin agonist receptor or an amylin analogue, a copolyamino acid according to the invention and GLP-1, a GLP-1 analogue or a GLP-1 RA as defined above.

[0601] The invention also relates to a formulation comprising amylin, an amylin agonist receptor or an amylin analogue and a copolyamino acid according to the invention, at a pH of 6.6 to 7.8.

[0602] The invention also relates to a single dose formulation, at a pH between 6.6 and 7.8, comprising amylin, an amylin agonist receptor or an amylin analogue and a copolyamino acid according to the invention, and prandial insulin as defined above.

[0603] The invention also relates to a formulation comprising amylin, an amylin agonist receptor or an amylin analogue and a copolyamino acid according to the invention, at a pH of 6.6 to 7.6.

[0604] The invention also relates to a single dose formulation at a pH of 6.6 to 7.6 comprising amylin, an amylin agonist receptor or an amylin analogue and a copolyamino acid according to the invention, and prandial insulin as defined above.

[0605] In one embodiment, the single dose formulation also comprises a copolyamino acid as defined above.

[0606] In one embodiment, the formulation is in the form of an injectable solution.

[0607] The preparation of the composition according to the invention offers the advantage that it can be prepared by simply mixing an aqueous solution of amylin, an amylin agonist receptor or an amylin analogue and a copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form, and, if necessary, the pH of the preparation is adjusted to a pH of 6.0 to 8.0.

[0608] The preparation of the composition according to the invention offers the advantage that it can be prepared by simply mixing an aqueous solution of amylin, an amylin agonist receptor or an amylin analogue, prandial insulin and a copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form, and, if necessary, the pH of the preparation is adjusted to a pH of 6.0 to 8.0.

[0609] In one embodiment, the mixture of prandial insulin and copolyamino acid is concentrated by ultrafiltration.

[0610] If necessary, the composition of the mixture is adjusted with excipients such as glycerin, m-cresol, zinc chloride and polysorbate (Tween®) by adding concentrated solutions of these excipients to the mixture. If necessary, the pH of the preparation is adjusted to a pH of 6.0 to 8.0.

[0611] In one embodiment, the composition is characterized in that the composition has greater stability as measured by ThT than a reference composition comprising amylin, an amylin receptor agonist and an amylin analog, but not a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy.

[0612] In one embodiment, the composition is characterized in that said composition has greater stability as measured in ThT than a reference composition comprising an amylin receptor agonist and an amylin analog together with insulin but not a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy.

[0613] In one embodiment, the composition is characterized in that said composition has greater stability as measured by ThT than a reference composition comprising amylin, an amylin receptor agonist and an amylin analog in combination with GLP-1, a GLP-1 analog or a GLP-1 receptor agonist, but not a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy.

[0614] In one embodiment, the composition is characterized in that said composition has greater stability as measured by ThT than a reference composition comprising amylin, an amylin receptor agonist and an amylin analog together with GLP-1, a GLP-1 analog or a GLP-1 receptor agonist, but not a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy.

[0615] The invention also relates to the use of copolyamino acids having a carboxylate charge and a hydrophobic radical Hy to stabilize compositions containing amylin receptor agonists and amylin analogues.

[0616] The invention also relates to the use of copolyamino acids having a carboxylate charge and a hydrophobic radical Hy to stabilize compositions containing amylin receptor agonists and amylin analogues, and prandial insulin, and possibly GLP-1, GLP-1 analogues or GLP-1 receptor agonists.

[0617] The invention also relates to methods for stabilizing compositions amylin, and amylin receptor agonists and amylin analogues, or compositions comprising amylin receptor agonists and amylin analogues and prandial insulin, and possibly GLP-1, GLP-1 analogues or GLP-1 receptor agonists.

[0618] The following examples illustrate, but do not limit, the present application. [Brief description of the drawings]

[0619] [Figure 1] This figure graphically represents the determination of latency (LT) by Thioflavin T fluorescence monitoring, the curve having on the ordinate axis the values ​​of fluorescence (ua, arbitrary units) and on the abscissa the time in minutes.

[0620] Part A - Synthesis of intermediate hydrophobic Hyd to obtain radical -Hy [ka] TIFF2025032188000094.tif207132TIFF2025032188000095.tif193137TIFF2025032188000096.tif193137TIFF2025032188000097.tif193137TIFF2025032188000098.tif71137Example A1: Molecule A1 Molecule 1: Product obtained by reaction between Fmoc-Lys(Fmoc)-OH and resin 2-Cl-trityl chloride DIPEA (4.32 mL, 24.80 mmol) is added to a suspension of Fmoc-Lys(Fmoc)-OH (7.32 g, 12.40 mmol) in dichloromethane (60 mL) at room temperature. After complete solubilization (10 min), the resulting solution is poured onto the resin 2-Cl-trityl chloride (100-200 mesh, 1% DVB, 1.24 mmol / g) (4.00 g, 4.96 mmol) previously washed in dichloromethane. After stirring for 2 h at room temperature, HPLC grade methanol (0.8 mL / g resin, 3.2 mL) is added and the medium is stirred at room temperature for 15 min. The resin is filtered and washed successively with dichloromethane (3×60 mL), DMF (2×60 mL), dichloromethane (2×60 mL), isopropanol (1×60 mL) and dichloromethane (3×60 mL).

[0621] Molecule 2: Products obtained by reaction between molecule 1 and an 80:20 DMF / piperidine mixture Molecule 1, previously washed with DMF, is dissolved in a 80:20 DMF / piperidine mixture (60 mL). After 30 min of stirring at room temperature, the resin is filtered and washed successively with DMF (3×60 mL), isopropanol (1×60 mL) and dichloromethane (3×60 mL).

[0622] Molecule 3: The product obtained by reaction between molecule 2 and Fmoc-Glu(OtBu)-OH To a suspension of Fmoc-Glu(OtBu)-OH (10.55 g, 24.80 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 9.43 g, 24.80 mmol) in a 1:1 DMF / dichloromethane mixture (60 mL) is added DIPEA (8.64 mL, 49.60 mmol). After complete solubilization, the resulting solution is poured onto molecule 2. After 2 h of stirring at room temperature, the resin is filtered and washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and dichloromethane (3 x 60 mL).

[0623] Molecule 4: Products obtained by reaction between molecule 3 and a 50:50 DMF / morpholine mixture Molecule 3, previously washed with DMF, is dissolved in a 50:50 DMF / piperidine mixture (60 mL). After 1 h 15 min of stirring at room temperature, the resin is filtered and washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and dichloromethane (3 x 60 mL).

[0624] Molecule 5: The product obtained by the reaction between molecule 4 and molecule 11 Using a process similar to that used for molecule 3, molecule 4 and molecule 11 (8.07 g, 24.80 mmol) are applied to DMF (60 mL) to give molecule 5.

[0625] Molecule 6: Products obtained by reaction between molecule 5 and an 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) mixture Molecule 5 is dissolved in a mixture of 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (60 mL). After 20 min of stirring at room temperature, the resin is filtered and washed with dichloromethane (2 x 60 mL). The solvent is evaporated under reduced pressure. The residue is then coevaporated twice with dichloromethane (60 mL) and then with diisopropyl ether (60 mL). The product is purified by chromatography on silica gel (dichloromethane, methanol). A white solid of molecule 6 is obtained. Yield: 2.92g (52% over 6 steps) RMN 1 H (CD3OD, ppm): 0.90 (6H); 1.22-2.47 (88H); 3.13-3.25 (2H); 3.45-3.76 (4H); 4.24-4.55 (5H). LC / MS(ESI+):1131.9(calculation([M+H] + ):1131.8).

[0626] Molecule 7: The product obtained by reaction between molecule 6 and N-Boc ethylenediamine To a solution of molecule 6 (2.82 g, 2.49 mmol) in Me-THF (20 mL) at room temperature, N-hydroxybenzotriazole (HOBt, 496 mg, 3.24 mmol) and N-Boc ethylenediamine (BocEDA, 440 mg, 2.74 mmol) are successively added. The mixture is cooled to 0 ° C and then (3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC, 621 mg, 3.24 mmol) hydrochloride is added. The medium is stirred for 15 min at 0 ° C and then for 18 h at room temperature. The organic phase is diluted with dichloromethane (30 mL) and washed with saturated aqueous NH4Cl solution (2 × 20 mL), saturated aqueous NaHCO3 solution (2 × 20 mL), saturated aqueous NaCl solution (2 × 20 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 7 is obtained after recrystallization in acetontrile. Yield: 2.47g (78%) RMN 1H(CDCl3, ppm):0.87(6H);1.09-1.77(77H);1.84-2.49(20H);2.99-3.83(10H);4.16-4.25(1H);4.27-4.4 7(4H); 5.68(0.1H); 5.95-6.08(0.9H); 6.91-7.14(2H); 7.43-7.57(1H); 7.68-7.78(1H); 8.22-8.35(1H). LC / MS(ESI+):1273.9(calculation([M+H] + ):1273.9).

[0627] Molecule A1 To a solution of molecule 7 (2.47 g, 1.94 mmol) in dichloromethane (20 mL) at room temperature, a 4N solution of HCl in dioxane (7.27 mL) is added, then the medium is stirred for 16 hours at room temperature. After concentration under reduced pressure, coevaporation and washing with diisopropyl ether, a white solid of molecule A1 in the form of an HCl salt is obtained. This solid is solubilized in water (100 mL) and then the pH is adjusted to 7 by adding an aqueous 1N NaOH solution. The solution is lyophilized and the lyophilizate is dried by coevaporation in toluene. A white solid of molecule A1 is obtained. Yield: 1.64g (80%) RMN 1 H (CD2OD, ppm): 0.90 (6H); 1.15-2.59 (70H); 3.06-3.86 (10H); 4.19-4.43 (5H). LC / MS(ESI+):1061.8(calculation([M+H] + ):1061.8).

[0628] Example A2: Molecule A2 Molecule 8: Products obtained by coupling between myristic acid and methyl-L-glutamic acid To a solution of myrisitic acid (35.0 g, 153.26 mmol) in tetrahydrofuran (THF) (315 mL) at room temperature, N-hydroxysuccinimide (NHS, 17.81 g, 154.79 mmol) and N,N-dicyclohexylcarboxydiimide (DCC, 31.94 g, 154.79 mmol) are successively added. The medium is stirred for 48 hours, the temperature is allowed to rise to room temperature, filtered on a sintered filter and then added to an aqueous solution (30 mL) containing methyl-L-glutamic acid (24.95 g, 154.9 mmol) and N,N-diisopropylethylamine (DIPEA, 99.0 g, 766.28 mmol). The reaction medium is stirred for 48 hours at 20° C. and then concentrated under reduced pressure. Water (200 mL) is added and the resulting mixture is dissolved by successive addition of ethyl acetate (AcOEt, 100 mL) and then 5% aqueous Na2CO3 (50 mL). The aqueous phase is then washed again with AcOEt (100 mL), acidified by addition of 10% aqueous HCl and the product is extracted with dichloromethane (DCM, 3 x 150 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 8 is obtained. Yield: 47.11g (84%) RMN 1 H(CDCl3, ppm):0.87(3H);1.07-1.66(22H);2.02-2.11(1H);2.18-2.36(3H);2. 39-2.47(1H);2.50-2.58(1H);3.69(3H);4.54-4.59(1H);6.62(1H);8.26(1H). LC / MS(ESI+):372.2(calculation([M+H] + ):372.3).

[0629] Molecule 9: The product obtained by coupling between molecule 8 and methyl-L-glutamate Using a process similar to that used for the preparation of molecule 8, applied to molecule 8 (35.0 g, 94.21 mmol) and methyl-L-glutamate (15.33 g, 95.15 mmol), a white solid of molecule 9 is obtained after recrystallization in acetonitrile. Yield: 24.0g (49%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.06-1.51(22H);1.70-1.94(3H);1.96-2.15(3H);2.29-2.40( 4H);3.58(3H);3.58(3H);4.16-4.22(1H);4.25-4.32(1H);7.93(1H);8.16(1H);12.66(1H). LC / MS(ESI+):515.3(calculation([M+H] + ):515.3).

[0630] Molecule 10: The product obtained by reaction between molecule 9 and N-Boc ethylenediamine To a suspension of molecule 9 (24.0 g, 46.63 mmol) in DCM (285 mL) at 0° C., a solution of HOBt (714 mg, 46.66 mmol), BocEDA (8.97 g, 55.96 mmol) in DCM (25 mL) and then EDC (9.83 g, 51.30 mmol) are successively added. The medium is stirred for 1 h at 0° C. and then for 18 h at room temperature. The organic phase is washed with saturated aqueous NaHCO3 (2×300 mL), 1N aqueous HCl (2×300 mL), saturated aqueous NaCl (500 mL). Methanol (40 mL) is added, the organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 10 is obtained after recrystallization in acetonitrile. Yield: 27.15g (89%) RMN 1 H(CDCl3, ppm):0.87(3H);1.07-1.68(22H);1.42(9H);1.97-2.18(4H);2.22-2.31(2H);2.35-2.55(4H);3.19-3.2 9(2H);3.30-3.38(2H);3.66(3H);3.68(3H);4.34-4.41(1H);4.42-4.48(1H);5.54(1H);6.99-7.18(2H)7.56(1H). LC / MS(ESI+):657.4(calculation([M+H] + ):657.4).

[0631] Molecule A2 To a solution of molecule 10 (27.15 g, 41.33 mmol) in a DCM / methanol mixture (410 mL) at 0° C., a 4N HCl solution in dioxane (51.7 mL) is added, then the medium is stirred for 2 h at 0° C. and then for 16 h at room temperature. After concentration under reduced pressure and coevaporation in methanol (2×150 mL), a white solid of molecule A2 in the form of its hydrochloride is obtained after recrystallization in acetonitrile. Yield: 23.2g (95%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.05-1.52(22H);1.71-1.85(2H);1.87-2.03(2H);2.07-2.18(2H);2.24- 2.37(4H);2.84(2H);3.24-3.38(2H);3.58(3H);3.58(3H);4.17-4.24(2H);7.95-8.08(5H);8.14(1H). LC / MS(ESI+):557.3(calculation([M+H] + ):557.4).

[0632] Example A3: Molecule A3 Molecule 11: Products obtained by the reaction between myristoyl chloride and L-proline A solution of myristoyl chloride (322 g, 1.30 mol) in dichloromethane (DCM, 1.63 L) is added slowly over 1 h to a solution of L-proline (300.40 g, 2.61 mol) in 2N aqueous soda (1.63 L) at 0° C. After this addition, the reaction medium is allowed to warm to 20° C. over 3 h and then stirred for 2 h. The mixture is cooled to 0° C. and then 37% aqueous HCl (215 mL) is added over 15 min. The reaction medium is stirred from 0° C. to 20° C. for 1 h. The organic phase is separated, washed with 10% aqueous HCl (3×430 mL), saturated aqueous NaCl (430 mL), dried over Na2SO4, filtered through cotton and then concentrated under reduced pressure. The residue is solubilized in heptane (1.31 L) at 50° C. and then the solution is gradually cooled to room temperature. After initiating the crystallization using a glass rod, the medium is again heated at 40° C. for 30 min and then allowed to return to room temperature for 4 h. A white solid is obtained after filtration on a sintered filter, washing with heptane (2×350 mL) and drying under reduced pressure. Yield: 410g (97%) RMN 1 H(CDCl3, 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;326.4(calculation([M+H] + ):326.3;([2M+H] + ):651.6).

[0633] Molecule 12: Products obtained by coupling between molecule 11 and methyl-L-glutamate Using a process similar to that used for the preparation of molecule 8, applied to molecule 11 (30.0 g, 92.17 mmol) and methyl-L-glutamate (15.60 g, 96.78 mmol), a white solid of molecule 12 is obtained after recrystallization in refluxing acetone, cooling to room temperature and filtration on a sintered filter. As above, the filtrate is evaporated and the residue is precipitated in acetone, and this operation is repeated three times. Yield: 15.5g (36%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.07-1.37(20H);1.40-1.50(2H);1.71-2.27(8H);2.30-2.40(2H);3.28-3.54 (12H);3.58(1.3H);3.59(1.7H);4.14-4.28(1H);4.28-4.37(1H);8.06(0.55H);8.33(0.45H);12.64(1H). LC / MS(ESI+):469.2(calculation([M+H] + ):469.3).

[0634] Molecule 13: The product obtained by reaction between molecule 12 and N-Boc ethylenediamine Using a process similar to that used for the preparation of molecule 10, applied to molecule 12 (15.5 g, 33.05 mmol) and methyl-L-glutamate (5.83 g, 36.36 mmol), a white solid of molecule 13 is obtained after recrystallization in acetonitrile. Yield: 19.8g (83%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.07-1.55(22H);1.37(9H);1.69-2.19(7H);2.22-2.36(3H);2.91-3.17(4H);3.28-3.60(5 H);4.11-4.18(0.7H);4.20-4.28(1H);4.38-4.42(0.3H);6.74(1H);7.64(0.7H);7.87(0.7H);7.98(0.3H);8.22(0.3H). LC / MS(ESI+):611.4(calculation([M+H] + ):611.4).

[0635] Molecule A3 Using a process similar to that used for the preparation of molecule A2, applied to molecule 13 (16.8 g, 27.50 mmol), a white solid of molecule A3 in the form of its hydrochloride salt is obtained after recrystallization in acetonitrile. Yield: 13.5g (90%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.08-1.52(22H);1.70-2.37(10H);2.80-2.90(2H);3.22-3.62(4H);3.57( 3H);4.15-4.28(1.75H);4.41-4.44(0.25H);7.81-8.13(4.5H);8.24-8.29(0.25H)8.33-8.39(0.25H). LC / MS(ESI+):511.3(calculation([M+H] + ):511.4).

[0636] Example A4: Molecule A4 Molecule 14: Product obtained by reaction between lauroyl chloride and L-proline Using a process similar to that used for the preparation of molecule 11, applied to lauroyl chloride (27.42 g, 685.67 mmol) and L-proline (60.0 g, 247.27 mmol), molecule 14 is obtained as a white solid. Yield: 78.35g (96%) RMN 1 H(CDCl3, 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+):298.1(calculation([M+H] + ):298.2).

[0637] Molecule 15: Products obtained by coupling between molecule 14 and methyl-L-glutamic acid Using a process similar to that used for the preparation of molecule 8, applied to molecule 14 (34.64 g, 116.46 mmol) and methyl-L-glutamate (19.14 g, 118.79 mmol), a white solid of molecule 15 is obtained after recrystallization in acetonitrile. Yield: 37.28g (73%) RMN 1 H(CDCl3, ppm):0.85(3H);1.08-1.42(16H);1.54-1.06(2H);1.80-2.47(10H);3.42-3.80(2H);3.65(2.55H); 3.67(0.45H);4.37-4.40(0.15H);4.51-4.58(0.85H);4.58-4.67(1H);7.26(0.15H)7.65(0.85H);8.06(1H). LC / MS(ESI+):441.1(calculation([M+H] + ):441.3).

[0638] Molecule 16: The product obtained by reaction between molecule 15 and N-Boc ethylenediamine Using a process similar to that used for the preparation of molecule 10, applied to molecule 15 (37.30 g, 84.66 mmol) and methyl-L-glutamate (14.92 g, 93.13 mmol), a white solid of molecule 16 is obtained after recrystallization in acetonitrile. Yield: 43.10g (87%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.08-1.53(18H);1.37(9H);1.70-2.36(10H);2.91-3.60(9H);4.11-4.18(0.7H);4 .21-4.28(1H);4.38-4.42(0.3H);6.38(0.1H);6.74(0.9H);7.65(0.7H);7.87(0.7H);7.99(0.3H);8.22(0.3H). LC / MS(ESI+):583.4(calculation([M+H] + ):583.4).

[0639] Molecule A4 Using a process similar to that used for the preparation of molecule A2, applied to molecule 16 (43.10 g, 73.96 mmol), a white solid of molecule A4 in the form of its hydrochloride salt is obtained after recrystallization in acetonitrile. Yield: 31.90g (83%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.05-1.37(16H);1.39-1.52(2H);1.70-2.37(10H);2.29-2.91(2H);3 .20-3.62(7H);4.16-4.29(1.7H);4.42-4.46(0.3H);7.86-8.18(4.6H);8.32(0.3H);8.40(0.3H). LC / MS(ESI+):483.2(calculation([M+H] + ):483.3).

[0640] Example A5: Molecule A5 Molecule 17: Products obtained by the reaction between 1-amino-4,7,10-trioxa-13-tridecanamine and tert-butylphenyl carbonate To a solution of 1-amino-4,7,10-trioxa-13-tridecanamine (112.29 g, 509.71 mmol) in ethanol (510 mL) at 80° C., tert-butylphenyl carbonate (49.50 g, 254.86 mmol) is added dropwise. The reaction medium is stirred at 80° C. for 3 h 30 and then concentrated under reduced pressure. The residue is solubilized in water (250 mL), the pH is adjusted to 2.3 with a 37% HCl solution and the mixture is extracted with methyl tert-butyl ether (MTBE, 2×150 mL). The aqueous phase is basified to pH 12.6 by addition of a 2N NaOH solution and extracted with DCM (3×250 mL). The organic phase is washed with a 1N aqueous NaOH solution (1×100 mL), a saturated aqueous NaCl solution (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Molecule 17 is obtained as a yellow oil. Yield: 54.4g (67%) RMN 1 H(CDCl3, ppm): 1.40-1.58(11H); 1.73-1.81(4H); 2.80-2.84(2H); 3.20-3.70(14H); 5.11(1H). LC / MS(ESI+):321.2(calculation([M+H] + ):321.2).

[0641] Molecule 18: Products obtained by coupling between molecules 12 and 17 Using a process similar to that used for the preparation of molecule 10, applied to molecule 12 (20.46 g, 43.66 mmol) and molecule 17 (16.79 g, 52.39 mmol), the white wax of molecule 18 was obtained after purification by flash chromatography (eluents: DCM, methanol), solubilization of the residue in DCM (300 mL), washing of the organic phase with aqueous NaHCO3 (2 x 150 mL), aqueous 10% HCl (2 x 150 mL), aqueous saturated NaCl (2 x 150 mL), drying over Na2SO4 and concentration under reduced pressure. Yield: 30.15g (90%) RMN 1 H(DMSO-d6, ppm):0.85(3H);1.09-1.52(31H);1.55-1.67(4H);1.69-2.36(10H);2.91-2.98(2H);3.02-3.17(2H);3.28-3.61(17H); 4.12-4.17(0.7H);4.20-4.28(1H);4.39-4.42(0.3H);6.37(0.1H);6.71(0.9H);7.59(0.7H);7.85(0.7H);7.94(0.3H);8.21(0.3H). LC / MS(ESI+):771.4(calculation([M+H] + ):771.5).

[0642] Molecule A5 Using a process similar to that used for the preparation of molecule A2, applied to molecule 18 (30.0 g, 38.91 mmol), a white solid of molecule A5 in the form of its hydrochloride salt is obtained after solubilization of the residue in water (500 mL) and lyophilization. Yield: 25.2g (91%) RMN 1H(DMSO-d6, ppm):0.85(3H);1.06-1.37(20H);1.39-1.52(2H);1.58-1.66(2H);1.70-2.37(12H);2.78-2.85(2H);3.01-3.15(2H) ;3.31-3.62, (17H);4.11-4.17(0.7H);4.19-4.27(1H);4.41-4.44(0.3H);7.63-7.71(0.7H);7.90-8.24(4H);8.28-8.35(0.3H); LC / MS(ESI+):671.4(calculation([M+H] + ):671.5).

[0643] Example A7: Molecule A7 Molecule 21: Products obtained by coupling between molecule 11 and L-lysine Using a process similar to that used for the preparation of molecule 8, applied to molecule 11 (133.00 g, 408.61 mmol) and L-lysine (31.36 g, 214.52 mmol), a white solid of molecule 21 is obtained after two crystallizations in acetone. Yield: 106.50g (68%) RMN 1 H(DMSO-d6, 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(calculation([M+H] + ):762.1).

[0644] Molecule 22: The product obtained by coupling between molecule 21 and methyl N-Boc-L-lysinate Using a process similar to that used for the preparation of molecule 10, applied to a solution of molecule 21 (43.00 g, 56.50 mmol) in THF and methyl N-Boc-L-lysinate hydrochloride (20.12 g, 67.79 mmol), a clear solid of molecule 22 was obtained, which was used without further purification. Yield: 55.80g (98%) RMN 1 H(DMSO-d6, ppm):0.86(6H);1.08-2.03(64H);1.37(9H);2.07-2.30(4H);2.84-3.09(4H);3.29-3.57(4H);3.58-3.65(3 H);4.14-4.43(4H);6.40(0.1H);6.74(0.9H);7.69(0.6H);7.82(0.6H);7.95-8.06(1H);8.11-8.20(0.4H);8.26(0.4H). LC / MS(ESI):1003.8(calculation([M+H] + ):1003.8).

[0645] Molecule 23: Products obtained by saponification of molecule 23 A solution of molecule 22 (55.80 g, 55.61 mmol) in a 1:1 THF / water mixture (370 mL) at 0° C. is dissolved by slowly adding an aqueous solution of aLiOH (2.00 g, 83.41 mmol) (185 mL). After stirring for 16 h at 0° C., the medium is concentrated under reduced pressure and the residue is redissolved in water (500 mL). DCM (500 mL) is added, the heterogeneous mixture is cooled to 10° C. and acidified to pH 1 by adding 10% aqueous HCl. The aqueous phase is extracted with DCM (2×300 mL) and the organic phases are combined, washed with saturated aqueous NaCl (2×300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 23 is obtained after crystallization in acetone. Yield: 46.10g (84%) RMN 1H (pyridine-d6, ppm): 0.85 (6H); 1.05-2.03 (67H); 2.07-2.61 (10H); 3.12-3.93 (8H); 4.54-4.93 (2H); 4.98-5.16 (2H); 7.35-7.45 (1H); 8.34-8.63 (1H); 8.94-9.41 (2H). LC / MS(ESI):989.8(calculation([M+H] + ):989.8).

[0646] Molecule A7 To a solution of molecule 23 (12.00 g, 12.13 mmol) in dichloromethane (40 mL) at 0° C., a 4N HCl solution in dioxane (15.20 mL) is added, then the medium is stirred for 15 h at 0° C. and for 5 h at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is solubilized in a mixture of DCM (120 mL) and 2N NaOH (60 mL). After separation of the phases, the organic phase is washed with a solution of 2N NaOH (60 mL), dried over Na2SO4 and concentrated under reduced pressure. Yield: 10.90g (98%) RMN 1 H(DMSO-d6, ppm):0.86(6H);1.05-2.27(70H);2.45-2.52(2H);2.90-3.58(6H);3.67-3.76(1H);4.02-4.10(0.6H);4.11-4.17(0.4H);4.20- 4.26(0.6H);4.30-4.39(1h);4.42-4.46(0.4H);7.29-7.42(1H);7.71 -7.80(0.6H);7.97-8.05(0.6H);8.10-8.24(0.4H);8.33-8.45(0.3H); LC / MS(ESI):887.7(calculation([MH] - ):887.7).

[0647] Example A5a: Molecule A5a Molecule 3a: Product obtained by reaction between Fmoc-Lys(Fmoc)-OH and resin 2-Cl-trityl chloride DIPEA (4.32 mL, 24.80 mmol) is added to a suspension of Fmoc-Lys(Fmoc)-OH (7.32 g, 12.40 mmol) in DCM (60 mL) at room temperature. After complete solubilization (10 min), the resulting solution is poured onto resin 2-Cl-trityl chloride (100-200 mesh, 1% DVB, 1.24 mmol / g) (4.00 g, 4.96 mmol), previously washed with DCM, in a reactor suitable for peptide synthesis on solid media. After stirring for 2 h at room temperature, HPLC grade methanol (0.8 mL / g resin, 3.2 mL) is added and the medium is stirred at room temperature for 15 min. The resin is filtered and washed successively with DCM (3×60 mL), DMF (2×60 mL), DCM (2×60 mL), isopropanol (1×60 mL) and DCM (3×60 mL).

[0648] Molecule 4a: Products obtained by reaction between molecule 3a and a 80:20 DMF / piperidine mixture Molecule 3a, previously washed with DMF, is dissolved in a 80:20 DMF / piperidine mixture (60 mL). After 30 min of stirring at room temperature, the resin is filtered and washed successively with DMF (3×60 mL), isopropanol (1×60 mL) and DCM (3×60 mL).

[0649] Molecule 5a: The product obtained by reaction between molecule 4a and 8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid (Fmoc-O2Oc-OH) To a suspension of Fmoc-O2Oc-OH (9.56 g, 24.80 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 9.43 g, 24.80 mmol) in a 1:1 DMF / DCM mixture (60 mL) is added DIPEA (8.64 mL, 49.60 mmol). After complete solubilization, the resulting solution is poured onto molecule 4a. After 2 h of stirring at room temperature, the resin is filtered and washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and dichloromethane (3 x 60 mL).

[0650] Molecule 6a: Products obtained by reaction between molecule 5a and a 80:20 DMF / piperidine mixture A process similar to that used for molecule 4a can be applied to molecule 5a to give molecule 6a.

[0651] Molecule 7a: Products obtained by reaction between molecule 6a and lauric acid Using a process similar to that used for molecule 5a, molecule 6a and lauric acid (4.97 g, 24.80 mmol) in DMF (60 mL) give molecule 7a.

[0652] Molecule 8a: Products obtained by reaction between molecule 7a and an 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) mixture Molecule 7a is dissolved in a mixture of 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (60 mL). After 20 min of stirring at room temperature, the resin is filtered and washed with dichloromethane (2 x 60 mL). The solvent is evaporated under reduced pressure. The residue is then coevaporated twice with dichloromethane (60 mL) and then with diisopropyl ether (60 mL). A white solid of molecule 8a is obtained after recrystallization in acetonitrile. Yield: 2.63g (66% over 6 steps) RMN 1 H(CDCl3, ppm):0.87(6H);1.09-1.66(40H);1.77-1.98(2H);2.13-2.29(4H);3.24-3.75(18H);3. 95-4.07(4H);4.65-4.70(1H);6.23-6.37(1H);6.39-6.62(1H);6.74-6.91(1H);7.38-7.54(1H). LC / MS(ESI):801.6(calculation([M+H] + ):801.6).

[0653] Molecule 9a: The product obtained by reaction between molecule 8a and N-Boc ethylenediamine To a solution of molecule 8a (2.63 g, 3.29 mmol) in chloroform (20 mL) at room temperature, HOBt (654 mg, 4.27 mmol) and BocEDA (580 mg, 3.62 mmol) are successively added. The mixture is cooled to 0 ° C and then EDC (819 mg, 4.27 mmol) is added. The medium is stirred for 15 min at 0 ° C and then for 18 h at room temperature. The organic phase is washed with saturated aqueous NH4Cl (2 × 10 mL), saturated aqueous NaHCO3 (2 × 10 mL) and saturated aqueous NaCl (2 × 10 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 9a is obtained after purification by chromatography on silica gel (eluent: dichloromethane, methanol). Yield: 2.37g (76%) RMN 1 H(CDCl3, ppm):0.87(6H);1.08-1.47(34H);1.43(9H);1:48-170(7H);1.78-1.87(1H);2.14-2.25(4H);3.16-3.7 1(22H);3.92-4.04(4H);4.47-4.52(1H);5.33(1H);6.10(1H);6.65-7.01(1H);7.11-7.30(2H);7.47-7.63(1H).

[0654] Molecule A5a To a solution of molecule 9a (2.37 g, 2.51 mmol) in dichloromethane (50 mL) at room temperature, a 4N solution of HCl in dioxane (6.3 mL) is added, then the medium is stirred for 2 hours at room temperature. After concentration under reduced pressure, the residue is solubilized in dichloromethane (50 mL) and then washed with 1N aqueous NaOH solution (2×12.5 mL) and saturated aqueous NaCl solution (25 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule A5a is obtained after recrystallization in acetonitrile. Yield: 1.57g (74%) RMN 1H(CDCl3, ppm):0.87(6H);1.08-1.43(34H);1.48-1.71(7H);1:74-1.93(3H);2.14-2.25(4H);2.79-2.86(2H);3.1 7-3.71(20H);3.93-4.05(4H);4.47-4.54(1H);6.08-6.29(1H);6.84-7.01(1H);7.15-7.32(2H);7.50-7.64(1H). LC / MS(ESI):843.6(calculation([M+H] + ):843.7).

[0655] Example A6a: Molecule A6a Molecule 10a: Products obtained by hydrogenation of retinoic acid. A solution of retinoic acid (19.0 g, 63.24 mmol) in methanol (450 mL) is placed in a hydrogen atmosphere (1 atm) at room temperature in the presence of 10% palladium on carbon (1.9 g). After one night, the reaction medium is filtered on a sintered filter and the filtrate is then concentrated under reduced pressure. A colorless oil of molecule 10a is obtained. Yield: 19.50g (99%) RMN 1 H(CDCl3, ppm): 0.45-2.01(35H); 2.10-2.17(1H); 2.33-2.38(1H); 11.14(1H). LC / MS(ESI):309.3(calculation([MH] + ):309.3).

[0656] Molecule 11a: The product obtained by the reaction between Boc-1-amino-4,7,10-trioxa-13-tridecanamine and molecule 10a A process similar to that used for the preparation of molecule 9a was applied to molecule 10a (19.3 g, 62.15 mmol) and BocTOTA (23.9 g, 74.58 mmol) to give molecule 11a, an orange oil. Yield: 37.05g (97%) RMN 1H(CDCl3, ppm):0.43-1.71(49H);2.13-2.17(1H);3.17-3.24(2H);3.32-3.3 9(2H); 3.51-3.66(12H); 4.77(0.1H); 4.94(0.9H); 6.13(0.9H); 6.29(0.1H). LC / MS(ESI):613.5(calculation([M+H] + ):613.5).

[0657] Molecule A6a A process similar to that used for the preparation of molecule A5a was applied to molecule 11a (34.9 g, 56.94 mmol) to give an orange oil of molecule A6a. Yield: 28.5g (97%) RMN 1 H(CDCl3, ppm): 0.41-1.96(42H); 2.13(1H); 2.78(2H); 3.31-3.36(2H); 3.53(4H); 3.55-3.58(4H); 3.60-3.63(4H); 6.43(1H). LC / MS(ESI):513.5(calculation([M+H] + ):513.5).

[0658] Example A8: Molecule A8 Molecule 15a: Products obtained by the reaction between decanoic acid and L-leucine Using a process similar to that used for the preparation of molecule 8, applied to decanoic acid (8.77 g, 50.94 mmol) and L-leucine (7.00 g, 53.36 mmol), a white solid of molecule 15a is obtained. Yield: 9.17g (66%) RMN 1 H(DMSO-d6, ppm): 0.82-0.89(9H); 1.18-1.65(17H); 2.04-2.14(2H); 4.19-4.23(1H); 7.98(1H); 12.40(1H). LC / MS(ESI):286.2(calculation([M+H] + ):286.2).

[0659] Molecule 16a: The product obtained by reaction between molecule 15a and L-lysine methyl ester To a solution of molecule 15a (9.16 g, 32.11 mmol) in THF (160 mL), triethylamine (8.12 g, 80.27 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) are successively added and the medium is stirred for 30 minutes at room temperature. The dichlorhydride methyl ester of L-lysine (3,. g, 16.86 mmol) is added and the reaction medium is stirred for 3 hours and then concentrated under reduced pressure. The residue is diluted with AcOEt (200 mL), the organic phase is filtered, washed with 1N aqueous HCl solution, then with water, dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 16a is obtained after trituration of the residue in acetonitrile. Yield: 7.33g (66%) RMN 1 H(DMSO-d6, ppm):0.80-0.91(18H);1.06-1.72(38H);2.03-2.16(4H);2.91-3.07(2H);3.6 0(1.15H);3.61(1.85H);4.13-4.28(2H);4.33-4.44(1H);7.79-7.92(3H);8.13-8.26(1H). LC / MS(ESI)695.7(calculation([M+H] + ):695.6).

[0660] Molecule 17a: Products obtained by saponification of molecule 16a To a solution of molecule 16a (7.33 g, 10.55 mmol) in a mixture of THF / methanol / water (105 mL) is added LiOH (505.13 mg, 21.09 mmol) at 0° C., then the medium is stirred for 20 hours at room temperature and concentrated under reduced pressure. The aqueous phase is acidified to pH 1 with a 1N HCl solution, the solid formed is filtered, washed with water and dried under reduced pressure to give a white solid of molecule 17a. Yield: 7.09g (99%) RMN 1H(DMSO-d6, ppm):0.80-0.89(18H);1.18-1.73(40H);2.03-2.16(4H);2.91- 3.05(2H);4.03-4.13(1H);4.21-4.27(1H);4.31-4.40(1H);7.79-8.02(4H). LC / MS(ESI):681.7(calculation([M+H] + ):681.6).

[0661] Molecule 18a: The product obtained by reaction between molecule 17a and N-Boc ethylenediamine Using a process similar to that used for the preparation of molecule 16a, applied to molecule 17a (7.09 g, 10.41 mmol) and N-Boc ethylenediamine (1.83 g, 11.45 mmol), a white solid of molecule 18a is obtained after trituration in acetonitrile. Yield: 6.64g (77%) RMN 1 H(DMSO-d6, ppm): 0.80-0.91(18H); 1.15-1.73(49H); 2.03-2.18(4H); 2.92-3.13(6H); 4.05-4.30(3H); 6.71-6.83(1H); 7.69-8.23(5H). LC / MS(ESI):824.0(calculation([M+H] + ):823.7).

[0662] Molecule A8 Using a process similar to that used for the preparation of molecule A5a, applied to molecule 18a (3.00 g, 3.64 mmol), without basic washing, a beige solid of molecule A8 in the form of the hydrochloride is obtained after four coevaporations of the residue in methanol. Yield: 2.66g (96%) RMN 1H(DMSO-d6, ppm):0.80-0.91(18H);1.15-1.76(40H);2.03-2.19(4H);1.78-2.89(2H );2.91-3.07(2H);3.22-3.37(2H);4.08-4.14(1H);4.17-4.28(2H);7.81-8.36(8H). LC / MS(ESI):723.7(calculation([M+H] + ):723.6). Example A9: Molecule A9 Molecule 19a: 13-Methyltetradecanoic acid

[0663] Magnesium chips (5.50 g, 226.3 mmol) are introduced into an oven-dried three-necked round-bottom flask under argon. The magnesium is covered with anhydrous THF (25 mL) and a few drops of 1-bromo-2-methylpropane are added at room temperature to start the reaction. After observing an exotherm and a slight turbidity of the medium, the remainder of 1-bromo-2-methylpropane (28.42 g, 207 mmol), diluted with THF (60 mL), is added dropwise over a period of 1 h, during which the temperature of the medium remains stable at 65-70 °C. The reaction medium is then heated to reflux for 2 h.

[0664] In a three-necked round-bottom flask under argon, a solution of 11-bromoundecanoic acid (25 g, 94.27 mmol) dissolved in THF (60 mL) is added dropwise to a solution of CuCl (280 mg, 2.83 mmol) dissolved in N-methylpyrrolidone (NMP) previously distilled at 0 °C. A slightly hot solution of organomagnesium diluted in THF (50 mL) is then added dropwise to this solution, maintaining the temperature of the medium below 25 °C. The mixture is then stirred at room temperature for 16 hours. The medium is cooled to 0 °C and the reaction is quenched by gradually adding 1N aqueous HCl solution to pH 1 (300 mL), and the medium is extracted with hexane (100 mL) and ethyl acetate (2 × 75 mL). After washing the organic phase with 1N aqueous HCl solution (100 mL), water (100 mL) and drying over Na2SO4, the solution is filtered and concentrated under vacuum to obtain a brown solid. After purification by flash chromatography (cyclohexane, ethyl acetate) a white solid is obtained. Yield: 18.1g (79%) RMN 1 H(CDCl3, ppm): 0.87(6H); 1.11-1.18(2H); 1.20-1.38(16H); 1.51(1H); 1.63(2H); 2.35(2H).

[0665] Molecule 20: The product obtained by the reaction between molecule 19a and L-leucine To a solution of molecule 19a (18.05 g, 74.46 mmol) in THF (745 mL) at room temperature, DCC (14.63 g, 70.92 mmol) and NHS (8.16 g, 70.92 mmol) are successively added. After 40 h of stirring at room temperature, the medium is cooled to 0 °C for 20 min and filtered on a sintered filter. L-leucine (9.77 g, 74.46 mmol), DIPEA (86 mL) and water (150 mL) are added to the filtrate. After 20 h of stirring at room temperature, the medium is diluted with an aqueous solution saturated with NaHCO3 (200 mL). The aqueous phase is washed with ethyl acetate (2 × 200 mL) and acidified to pH 1 with 2N aqueous HCl. The precipitate is filtered, thoroughly rinsed with water and dried under vacuum at 50 °C. The solid is triturated three times in pentane and sonicated, then filtered to give a white solid. Yield: 18.8g (75%) RMN 1 H(CDCl3, ppm): 0.86(6H); 0.96(6H); 1.12-1.18(2H); 1.20-1.78(22H); 2.24(2H); 4.58-4.63(1H); 5.89(1H). LC / MS(ESI):356.2(calculation([M+H] + ):356.6).

[0666] Molecule 21a: The product obtained by the reaction between molecule 20 and Boc-tri(ethylene glycol)diamine To a solution of molecule 20 (16.7 g, 46.97 mmol) in THF (235 mL) at room temperature, DIPEA (20.3) and TBTU are added. After stirring for 20 min, Boc-tri(ethylene glycol)diamine (14 g, 56.36 mmol) is added. After stirring for 5 h at room temperature, the mixture is concentrated under vacuum. The residue is taken up with ethyl acetate (500 mL) and washed with saturated aqueous NaHCO3 (3 x 200 mL), 1N aqueous HCl (3 x 200 mL), and saturated aqueous NaCl (3 x 200 mL). After drying over Na2SO4, filtration and concentration under vacuum, the residue is purified by flash chromatography (cyclohexane, ethyl acetate, methanol) to give a colorless oil. Yield: 23.5g (85%) RMN 1 H(CDCl3, ppm):0.86(6H);0.93(6H);1.10-1.17(2H);1.19-1.08(31H);2.18(2H);3.23-3.65(1 2H);4.41-4.56(1H);5.12-5.47(1H);5.99-6.11(0.75H);6.48-6.65(1H);7.30-7.40(0.25H).

[0667] Molecule A9 A process similar to that used for the preparation of molecule A5a is applied to molecule 21a (23.46 g, 40.04 mmol), without basic washing, to triturate the residue obtained after concentration under vacuum in an acetonitrile / acetone mixture. The supernatant is removed and the pasty residue is dried under vacuum. The residue is then triturated in acetone (150 mL) and the white solid of molecule A9 in the form of hydrochloride is filtered, rinsed in acetone and then dried under vacuum. Yield: 13.0g (64%) RMN 1 H(DMSO-d6, ppm):0.79-0.90(12H);1.09-1.61(24H);2.03-2.17(2H);2.92-2.98(2H); 3.15-3.23(2H);3.40(2H);3.50-3.58(4H);3.61(2H);4.30-4.23(1H);7.88-8.14(5H). LC / MS(ESI):486.4(calculation([M-] + ):486.8).

[0668] Example A10: Molecule A10 Molecule 22a: Products obtained by the reaction between octanoyl chloride and L-proline Using a process similar to that used for the preparation of molecule 11, applied to octanoyl chloride (150.0 g, 0.922 mol) and L-proline (212.3 g, 1.844 mol), a colorless oil of molecule 22a is obtained after washing of the organic phase with 10% aqueous HCl (3×300 mL), saturated aqueous NaCl (300 mL), drying over Na2SO4, filtering through cotton, concentrating under reduced pressure, and then purifying the residue by flash chromatography (eluent: DCM, MeOH). Yield: 134g (60%) RMN 1 H(CDCl3, ppm): 0.87(3H); 1.10-1.52(8H); 1.57-1.74(2H); 1.79-2.52(6H); 3.37-3.67(2H); 4.37-4.42(0.07H); 4.53-5.63(0.93H); 9.83(1H). LC / MS(ESI):242.1(calculation([M+H] + ):242.2).

[0669] Molecule 23a: Coupling product between molecule 22a and L-lysine NHS (66.1 g, 0.574 mol) and DCC (118.5 g, 0.574 mol) are successively added to a solution of molecule 22a (132 g, 0.547 mol) in THF (924 mL) cooled to a temperature below 5° C. After 21 h of stirring, the precipitate is removed by settling and the filtrate is added over 30 min to a solution of L-lysine (41.98 g, 0.287 mol) in a mixture of deionized water (82 mL) and DIPEA (476 mL, 2.735 mol) at 15° C. After 23 h of stirring at room temperature, the reaction medium is concentrated under reduced pressure to give an oily residue which is diluted in water (1.3 L). The aqueous phase is washed twice with AcOEt (2×0.5 L), cooled to a temperature below 10° C., acidified by addition of 6N HCl solution (120 mL) to reach a pH of 1, then extracted three times with DCM (3×0.6 L). The organic phases are combined, washed with saturated NaCl solution (0.6 L), dried over Na2SO4, then concentrated under reduced pressure. The resulting foam is dissolved in acetone (240 mL) at reflux for 2 h. After overnight at 10° C., pentane (240 mL) is added dropwise. After stirring for 1 h, the precipitate is collected by filtration under vacuum, washed with a 1:1 mixture of pentane and acetone (150 mL), then dried under vacuum. Yield: 83.9g (52%) RMN 1 H(CDCl3, ppm): 0.87(6H); 1.06-1.78(25H); 1.80-2.41(13H); 2.80-3.72(6H); 4.30-4.39(0.15H); 4.46-4.70(2,.85H); 7.84(1H); 7.93(1H). LC / MS(ESI):593.5(calculation([M+H] + ):593.4).

[0670] Molecule 24: The product obtained by the reaction between molecule 23a and L-lysine methyl ester To the molecule 23a (76.26 g, 0.129 mol) are successively added HOPO (3.57 g, 32.1 mmol), LysOMe dihydrochloride (15.0 g, 64.3 mmol) and EDC (34.53 g, 0.18 mol), then DMF (600 mL) previously cooled to 5° C. is added. After dissolution, triethylamine (43.9 mL, 0.315 mol) is added dropwise while the temperature is maintained at 5° C. for 2 h after the end of the addition. After overnight at room temperature, the reaction medium is poured onto a water / ice mixture (2 kg) and DCM (0.5 L). After 15 min of stirring, the phases are separated. The aqueous phase is extracted with DCM (2×0.4 L). The organic phases are combined, washed with a 1N HCl solution (0.5 L), then with a saturated NaCl solution (0.5 L), dried over Na2SO4, concentrated under reduced pressure, and the residue is purified by flash chromatography (eluents: DCM, MeOH). Yield: 56.7g (67%) RMN 1 H(CDCl3, ppm): 0.87(12H); 1.10-2.40(82H); 2.86-3.72(17H); 4.16-4.60(7H); 6.83-8.01(6H).

[0671] Molecule A10 A solution of molecule 24 (4.0 g, 3.05 mmol) in ethylenediamine (30 mL) is heated overnight at 50° C. The reaction medium is then diluted with methyl-tetrahydrofuran and the organic phase is then washed four times with saturated NaCl solution (4×30 mL) and then twice with water (2×50 mL), after which it is dried over Na2SO4 and then concentrated under reduced pressure. The residue is solubilized in refluxing acetonitrile for 30 minutes and then the solution is cooled to room temperature with stirring overnight. The white precipitate is then recovered by filtration under vacuum, washed with cold acetonitrile (2×20 mL) and then dried under vacuum. Yield: 3.0g (74%) RMN 1 H(CDCl3, ppm): 0.87(12H); 1.09-2.37(84H); 2.74-4.56(25H); 6.85-8.00(7H). LC / MS(ESI):1338.0(calculation([M+H] + ):1338.0).

[0672] Example A11: Molecule A11 Molecule A11 is obtained by conventional methods of peptide synthesis in the solid phase (SPPS) on 2-chlorotrityl chloride (CTC) (40.0 g, 1.16 mmol / g) resin.

[0673] Grafting of the first Fmoc-Lys(Fmoc)-OH (1.5 eq.) amino acid is carried out in the presence of DIPEA (3.0 eq.) in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction. The coupling of the protected amino acids Fmoc-Glu(OtBu)-OH (2.5 eq.), Fmoc-Pro-OH (2.5 eq.) and myristic acid (2.5 eq.) is carried out in DMF (10 V) in the presence of HATU (2.5 eq.) and DIPEA (3.7 eq.). The protecting Fmoc group is removed using a 80:20 DMF / piperidine solution (10V). The product is cleaved from the resin using a 80:20 DCM / HFIP solution (10V). After concentration under reduced pressure, the residue is purified by chromatography on silica gel (dichloromethane, methanol). Yield: 56.5g (65%) RMN 1 H (CD3OD, ppm): 0.90 (6H); 1.22-2.53 (140H); 3.12-3.25 (2H); 3.43-3.80 (4H); 4.17-4.54 (9H). LC / MS(ESI+):1894.5(calculation([M+H] + ):1894.2).

[0674] Example A12: Molecule A12 Molecule 25: Products obtained by hydrogenation of farnesol To a solution of farnesol (60.00 g, 269.82 mmol) in THF (1200 mL) under argon, platinum oxide (PtO2, 613 mg, 2.70 mmol) is added, the medium is placed under 1 atm of dihydrogen, then stirred at room temperature for 6 h. After filtration through Celite and rinsing in THF, a black oil of molecule 25 is obtained after concentration under reduced pressure. This compound is used without further purification. Yield: 61.60g (100%) RMN 1 H(CDCl3, ppm): 0.85(3H); 0.87(6H); 0.90(3H) 1.01-1.43(15H); 1.47-1.66(3H); 3.62-3.76(2H).

[0675] Molecule 26: Products obtained by oxidation of molecule 25 To a solution of molecule 25 (61.60 g, 269.68 mmol) in a dichloroethane / water (1350 mL / 1080 mL) mixture, tetrabutylammonium bromide (46.95 g, 145.63 mmol), acetic acid (416 mL, 7.28 mol) and then KMnO4 (127.85 g, 809.04 mmol) are added in succession in small portions, while the temperature is maintained at 11-13 ° C. The reaction medium is then stirred at reflux for 4 hours and 30 minutes, cooled to 0 ° C and then acidified to pH 1 with a 37% HCl solution (50 mL). Na2SO3 (186.94 g) is added gradually, while the temperature is maintained at 0-10 ° C. and the medium is stirred until completely colorless. The medium is acidified to pH 1 with 37% HCl solution, then water (500 mL) and DCM (500 mL) are added. The phases are separated and the aqueous phase is extracted with DCM (2 x 500 mL). The organic phases are combined, washed with 10% aqueous HCl (400 mL), water (2 x 400 mL), saturated aqueous NaCl (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A yellow oil of molecule 26 is obtained after purification by flash chromatography (eluent: cyclohexane, AcOEt). Yield: 54.79g (84%) RMN 1H(CDCl3, ppm): 0.85(3H); 0.87(6H); 0.97(3H); 1.03-1.43(13H); 1.52(1H); 1.91-2.01(1H); 2.11-2.18(1H); 2.32-2.39(1H). LC / MS(ESI-):241.3(calculation([MH] - ):241.2).

[0676] Molecule 27: The product obtained by coupling between molecule 26 and methyl-L-prolinate To a solution of molecule 26 (54.70 g, 225.66 mmol) in DCM (1500 mL) at 0° C., HOBt (3.46 g, 22.57 mmol), DIPEA (117.92, 676.97 mmol), L-proline methyl hydrochloride (56.05 g, 338.49 mmol) and then EDC (64.89 g, 338.49 mmol) are added successively. The reaction mixture is stirred at 0° C. for 1 h and then at room temperature for 18 h. The medium is then diluted with DCM (1000 mL) and then washed with saturated aqueous NaHCO3 (2×1 L), 1N aqueous HCl (2×1000 mL) and aqueous NaCl (2×1000 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure to give molecule 27, a yellow oil, which is used without further purification. Yield: 77.15g (97%) RMN 1 H(DMSO-d6, ppm):0.79-0.89(12H);0.98-1.43(13H);1.51(1H);1.70-2.32(7H);3.33-3.42 (0.4H);3.46-3.57(1.6H);3.59(2.4H);3.67(0.6H);4.23-4.32(0,8H);4.53-4.62(0.2H). LC / MS(ESI+):354.2(calculation([M+H] + ):354.3).

[0677] Molecule 28: Products obtained by saponification of molecule 27 To a solution of molecule 27 (77.15 g, 218.22 mmol) in a mixture of THF / MeOH 1:1 (1454 mL) at 0° C., LiOH (7.84 g, 327.33 mmol) in water (727 mL) is added dropwise. The reaction mixture is stirred at 0° C. for 18 h and then at room temperature for 5 h. The organic solvents are evaporated under reduced pressure. Water (500 mL), 10% aqueous HCl (200 mL) and DCM (800 mL) are added and the phases are separated. The aqueous phase is extracted with DCM (2×1 L). The organic phases are combined, washed with water (500 mL), aqueous NaCl (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give molecule 28 as a yellow oil, which is used without further purification. Yield: 71.72g (97%) RMN 1 H(DMSO-d6, ppm):0.73-0.95(12H);0.95-1.42(13H);1.51(1H);1.65-2.3 2(7H); 3.24-3.64(2H); 4.13-4.28(0.8H); 4.37-4.50(0.2H); 12.44(1H). LC / MS(ESI+):340.2(calculation([M+H] + ):340.3).

[0678] Molecule A12 Molecule A12 is obtained by conventional methods of peptide synthesis in the solid phase (SPPS) on 2-chlorotrityl chloride (CTC) (34.5 g, 1.16 mmol / g) resin.

[0679] Grafting of diamine ethylene (10.0 equiv.) is carried out in the presence of DIPEA (10.0 equiv.) in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0680] The coupling of the protected amino acids Fmoc-Lys(Fmoc)-OH (1.5 eq.), Fmoc-Glu(OMe)-OH (3.0 eq.) and molecule 28 (3.0 eq.) is carried out in a 1:1 DCM / DMF mixture (10 V) in the presence of HATU (1.0 eq. relative to acid) and DIPEA (2.0 eq. relative to acid).

[0681] The protecting Fmoc group is removed using an 80:20 DMF / piperidine solution (10V) (after coupling with lysine) or a 50% solution of morpholine in DMF (after coupling with glutamic acid).

[0682] The product is cleaved from the resin using a 50:50 DCM / TFA solution (10 V). After evaporation, the residue is solubilized in MeTHF (450 mL) and the organic phase is washed with saturated aqueous NaHCO3 (3 x 450 mL) and saturated aqueous NaCl (200 mL). After drying over Na2SO4, the organic phase is filtered and concentrated under reduced pressure and the residue is purified by chromatography on silica gel (dichloromethane, methanol, NH4OH). Yield: 13.95 g (31% over 7 steps). RMN 1 H(DMSO-d6, ppm):0.73-0.91(24H);0.96-2.41(56H);2.72(2H);2.89-3.10(2H);3.15-3. 26(2H);3.26-3.51(4H);3.57(3H);3.58(3H);3.99-4.50(5H)6.07(2H);7.59-8.39(5H). LC / MS(ESI+):1118.2(calculation([M+H] + ):1117.8).

[0683] Example A13: Molecule A13 Molecule 29: Products obtained by polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by N-Boc-ethylenediamine In a reactor, γ-benzyl-L-glutamic acid N-carboxyanhydride (39.44 g, 149.82 mmol) is solubilized in DMF (81 mL) at 25° C. The mixture is then stirred until complete dissolution, cooled to −10° C., then a solution of BocEDA (6.00 g, 37.45 mmol) in DMF (7 mL) is rapidly introduced. The reaction medium is stirred for 3 hours at 0° C., then a 1.4 dioxane solution of HCl (3.33 M, 11.8 mL, 39.29 mmol) is added. The reaction medium is stirred at room temperature, then poured into a MeOH / IPE solution (125 mL / 495 mL) cooled by an ice bath. After 65 hours of stirring at room temperature, the precipitate is filtered on a sintered filter, washed with IPE (2×90 mL) and dried under reduced pressure at 30° C. Yield: 21.71g (54%) DP(RMN 1 Estimated by H): 4.9 The calculated average molar mass of molecule 29 in the form of the hydrochloride salt is 1270.9 g / mol. RMN 1 H(DMSO-d6, ppm):1.35(9H);1.72-2.09(9.8H);2.23-2.60(9.8H);2.86-3.19(4H);3.85(1H);4.14 -4.52(3.9H);4.86-5.23(9.8H);6.33-6.85(1H);7.09-7.55(24.5H);7.88-8.42(6.9H);8.67(1H).

[0684] Molecule 30: Products obtained by coupling between myristoyl chloride and molecule 29 After solubilization of molecule 29 (12.46 g, 9.80 mmol) in the form of hydrochloride in DCM (115 mL), the solution is cooled to 0° C. Then the following are added in succession: a solution of triethylamine (2.35 g, 23.24 mmol) and myristoyl chloride (3.16 g, 12.79 mmol) in DCM (16 mL). The reaction medium is stirred for 4 hours at 0° C. and then for 2 hours at room temperature, after which it is poured onto IPE (920 mL). After 14 hours of stirring at room temperature, the precipitate is filtered, washed with EtOH (2×145 ml, then 100 mL) and dried under reduced pressure at 30° C. Yield: 9.77g (69%) DP(RMN 1 Estimated by H): 5.1 The calculated average molar mass of molecule 30 is 1488.7 g / mol. RMN 1 H(CDCl3, ppm):0.87(3H);1.07-1.51(29H);1.51-1.64(2H);1.80-2.75(22.4H);2.98- 3.73 (4H); 3.84-4.50 (5.1H); 4.86-5.32 (10.2H); 5.71-6.47 (1H); 6.72-8.38 (31.6H).

[0685] Molecule A13 To a solution of molecule 30 (4.70 g, 3.16 mmol) in DCM (31 mL) at 0° C., TFA (31 mL) is added. The reaction medium is stirred at 0° C. for 2 h and then concentrated under reduced pressure at room temperature. The residue is taken back up in DCM (100 mL) and then concentrated to dryness under reduced pressure at room temperature. The residue is solubilized in DCM (100 mL) and washed with an aqueous carbonate buffer solution at pH=10.4 (326 mL, then 2×200 mL), then with an aqueous HCl solution (0.1 N, 2×200 mL). The organic solution is dried over Na2SO4, filtered and then concentrated to dryness under reduced pressure at 40° C. Yield: 3.96g (88%) DP(RMN 1 Estimated by H): 5.2 The calculated average molar mass of molecule A13 in the form of the hydrochloride salt is 1446.9 g / mol. RMN1 H(TFA-d, ppm):0.91(3H);1.17-1.47(20H);1.60-1.74(2H);1.99-2.78(22.8 H);3.41-4.05(4H);4.62-4.83(5.2H);5.05-5.35(10.4H);6.99-8.02(26H).

[0686] Example A14: Molecule A14 Molecule 31: Products obtained by reaction between molecule 14 and Boc-ethylenediamine Using a process similar to that used for the preparation of molecule 10, applied to molecule 14 (12.00 g, 40.35 mmol) and BocEDA (7.76 g, 48.42 mmol), a colorless oil of molecule 31 was obtained, which was used without further purification. Yield: 17.40g (94%) RMN 1 H(CDCl3, ppm):0.86(3H);1.11-1.68(18H);1.41(9H);1.80-2.38(6H);3.06-3.35(4H);3.37-3.49(1 H);3.51-3.73(1H);4.26-4.31(0.1H);4.45-4.52(0.9H);4.91-5.19(1H);6.97(0.1H);7.23(0.9H). LC / MS(ESI+):440.4(calculation([M+H] + ):440.3).

[0687] Molecule A14 Using a process similar to that used for the preparation of molecule A2, applied to a DCM solution containing molecule 31 (8.85 g, 20.13 mmol), a white solid of molecule A14 is obtained after basic washing, concentration under reduced pressure, and then recrystallization in acetonitrile. Yield: 6.53g (96%) RMN 1H(DMSO, ppm):0.85(3H);1.07-1.56(20H);1.68-2.03(4H);2.09-2.29(2H);2.50-2.58(2H);2.9 6-3.11(2H);3.21-3.59(2H);4.17-4.21(0.65H);4.25-4.29(0.35H);7.68(0.65H);8.00(0.35H) LC / MS(ESI):340.3(calculation([M+H] + ):340.3). .3).

[0688] Example A15: Molecule A15 Molecule A15 is obtained by conventional methods of peptide synthesis in the solid phase (SPPS) on 2-chlorotrityl chloride (CTC) (16.0 g, 1.16 mmol / g) resin.

[0689] Grafting of diamine ethylene (20.0 equiv.) is carried out in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0690] The coupling of the protected amino acids Fmoc-Lys(Fmoc)-OH (3.0 equivalents), Fmoc-Glu(OBn)-OH (4.0 equivalents) and molecule 11 (3.0 equivalents) is carried out in DCM (10V) (Lys and molecule 11 coupling) or in a 1:1 DCM / DMF mixture (10V) in the presence of HATU (1.0 equivalent relative to acid) and DIPEA mixture (1.5 equivalent relative to acid).

[0691] The protecting Fmoc group is removed using an 80:20 DMF / piperidine solution (10V) (after coupling with lysine) or 1% DBU in DMF (after coupling with glutamic acid).

[0692] The product is cleaved from the resin using a 50:50 DCM / TFA solution (10V). After concentration, the residue is solubilized in ethyl acetate (400 mL) and the organic phase is washed with an aqueous carbonate buffer solution (1 M) at pH 10 (2×400 mL) and then with a saturated aqueous NaCl solution (400 mL). After drying over Na2SO4, the organic phase is filtered and concentrated under reduced pressure and the residue is purified by chromatography on silica gel (dichloromethane, methanol, NH4OH) and then recrystallization in acetonitrile. Yield: 16.20 g (70% over 7 steps). RMN 1 H(DMSO-d6, ppm):0.85(6H);1.11-2.57(72H);2.50-5.57(2H);2.90-3.08(4H) ;3.36-3.61(4H);4.06-4.43(5H);5.08(4H);7.27-7.40(10H);7.51-8.31(5H). LC / MS(ESI+):1242.0(calculation([M+H] + ):1241.9).

[0693] Example A16: Molecule A16 Molecule 32: Products obtained by SPPS Molecule 32 is obtained by conventional methods of peptide synthesis in the solid phase (SPPS) on 2-chlorotrityl chloride (CTC) (50.0 g, 1.14 mmol / g) resin.

[0694] Grafting of the first Fmoc-Glu(OtBu)-OH (1.3 eq.) amino acid is carried out in DCM (10 V) in the presence of DIPEA (2.6 eq.) Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0695] The coupling of the protected amino acid Fmoc-Glu(OtBu)-OH (1.3 eq.) and molecule 11 (3.0 eq.) is carried out in DMF (10 V) in the presence of HATU (1.0 eq. relative to acid) and DIPEA (1.5 eq. relative to acid).

[0696] The protecting Fmoc group is removed using a 80:20 DMF / piperidine solution (10V).

[0697] The product is cleaved from the resin using a 80:20 DCM / HFIP solution (10V).

[0698] After concentration under reduced pressure, the residue is purified by trituration in diisopropyl ether. Yield: 35.78g (90%) RMN 1 H(CDCl3, ppm):0.88(3H);1.19-1.35(20H);1.43(9H);1.44(9H);1.55-1.67(2H);1.90-2.46(14H);3.46-3.54 (1H);3.63-3.71(1H);4.33-4.40(1H);4.43-4.52(2H)7.35(0.05H);7.40(0.05H);7.63(0.95H);7.94(0.95H). LC / MS(ESI+):696.4(calculation([M+H] + ):696.5).

[0699] Molecule 33: The product obtained by the reaction between molecule 32 and N-CBz ethylenediamine A process similar to that used for the preparation of molecule 7 is applied to molecule 32 (30.0 g, 43.11 mmol) and N-CBz ethylenediamine hydrochloride (CBzEDA·HCl, 11.93 g, 51.73 mmol) in the presence of DIPEA (15.0 mL, 86.22 mmol) to give a beige solid of molecule 33, which is used without further purification. Yield: 37.6g (100%) RMN 1H(CDCl3, ppm):0.88(3H);1.19-1.34(20H);1.42(9H);1.44(9H);1.52-2.54(16H);3.16-3.70(6H);4.08-4.15(1H) ;4.19-4.25(1H);4.43-4.53(1H);5.00(1H);5.08(1H);6.56(1H);7.00(1H);7.24-7.37(5H);7.59(1H);8.41(1H). LC / MS(ESI+):872.5(calculation([M+H] + ):872.6).

[0700] Molecule A16 To a solution of molecule 33 (37.6 g, 43.11 mmol) in methanol (376 mL) is added Pd / Al2O3 (3.76 g) under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (7 bar) and stirred at room temperature for 72 h. After P4 filtration of the catalyst on a P4 filter and then through an Omnipore 0.2 μm PTFE hydrophilic membrane, the filtrate is evaporated under reduced pressure to give molecule A16 in the form of a viscous oil. Yield: 31.06g (98%) RMN 1 H(CDCl3, ppm):0.88(3H);1.19-1.35(20H);1.43(9H);1.46(9H);1.56- 1.67(2H);1.92-2.12(6H);2.24-2.54(8H);2.71(2H);2.90(2H);3.22- 3.32(1H);3.42-3.51(1H);3.55-3.64(1H);3.73-3.81(1H);4.13-4.21 (1H);4.26-4.33(1H);4.39-4.48(1H);7.10(1H);7.71(1H);8.45(1H). LC / MS(ESI+):738.5(calculation([M+H] + ):738.5).

[0701] Molecule A17 Molecule A17 is obtained by conventional methods of peptide synthesis in the solid phase (SPPS) on 2-chlorotrityl chloride (CTC) (64.66 g, 1.16 mmol / g) resin.

[0702] Grafting of diamine ethylene (10.0 equiv.) is carried out in the presence of DIPEA (10.0 equiv.) in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0703] The coupling of the protected amino acid Fmoc-Glu(OtBu)-OH (1.5 eq.) and molecule 28 (1.5 eq.) is carried out in the presence of HATU (1.0 eq. relative to acid) and DIPEA (2.0 eq. relative to acid) in a DCM / DMF 1:1 (10 V) mixture for the coupling of glutamic acid or in DMF (10 V) for the coupling of molecule 28.

[0704] The protecting Fmoc group is removed using a 50:50 DMF / morpholine solution (10V).

[0705] The product is cleaved from the resin using a 50:50 DCM / TFA solution (10 V). After evaporation, the residue is solubilized in MeTHF (500 mL), the organic phase is washed with 5% aqueous Na2CO3 (3 x 250 mL), and the aqueous phase is then extracted with MeTHF (1 x 150 mL). The organic phases are combined, dried over Na2SO4 and filtered. A solution of HCl in MeOH (1.25 M) is added, and the medium is then concentrated under reduced pressure. The residue is purified on silica gel (dichloromethane, methanol) to give the hydrochloride salt of molecule A17 in the form of a light brown solid. Yield: 12.48 g (30% over 5 steps). RMN 1 H(DMSO-d6, ppm):0.76-0.90(12H);0.97-1.41(13H);1.45-1.55(1H);1.68-2.40( 11H);2.77-2.92(2H);3.20-3.64(4H);3.57(3H);4.15-4.49(2H);7.90-8.48(5H). LC / MS(ESI+):525.5(calculation([M+H] + ):525.4).

[0706] Example A18: Molecule A18 Molecule 34: Products obtained by hydrogenation of phytol To a solution of phytol (260.00 g, 878.78 mmol) in ethanol (1.25 L) under argon, 50% Raney nickel in water (30.75 g, 175.36 mmol) is added. The medium is placed under 1 bar of dihydrogen and then stirred at room temperature for 8 hours. After filtration on a Celite / Silica / Celite pad and rinsing in ethanol, a colorless oil of molecule 34 is obtained after concentration under reduced pressure. Yield: 261.40g (quant.) RMN 1 H(CDCl3, ppm): 0.84(6H); 0.86(6H); 0.89(3H) 1.00-1.46(22H); 1.46-1.68(3H); 3.61-3.73(2H).

[0707] Molecule 35: Products obtained by oxidation of molecule 34 A process similar to that used for the preparation of molecule 26 was applied to molecule 34 (29.00 g, 97.13 mmol) to give molecule 35, a yellow oil. Yield: 28.70g (94%) RMN 1 H(CDCl3, ppm): 0.84(6H); 0.86(6H); 0.97(3H); 1.00-1.41(20H); 1.52(1H); 1.96(1H); 2.14(1H); 2.35(1H); 11.31(1H). LC / MS(ESI):311.1(calculation([MH] + ):311.3).

[0708] Molecule 36: The product obtained by coupling between molecule 35 and methyl-L-prolinate A process similar to that used for the preparation of molecule 27 was applied to molecule 35 (18.00 g, 57.59 mmol) and methyl-L-prolinate (14.31 g, 86.39 mmol) to give molecule 36, a yellow oil. Yield: 23.20g (95%) RMN1 H(DMSO-d6, ppm):0.78-0.89(15H);0.97-1.43(20H);1.43-1.56(1H);1.70-1.96(4H) ;1.96-2.32(3H);3.33-3.56(2H);3.59(0.6H);3.67(2.4H);4.27(0.8H);4.57(0.2H). LC / MS(ESI):424.4(calculation([M+H] + ):424.4).

[0709] Molecule 37: Products obtained by saponification of molecule 36 A process similar to that used for the preparation of molecule 28 was applied to molecule 36 (21.05 g, 49.68 mmol) to give molecule 37, a yellow oil. Yield: 20.40g (99%) RMN 1 H(DMSO-d6, ppm):0.77-0.91(15H);0.97-1.43(20H);1.43-1.56(1H);1. 67-1.96(4H); 1.96-2.29(3H); 3.26-3.56(2H); 4.20(0.8H); 4.41(0.2H). LC / MS(ESI):410.3(calculation([M+H] + ):410.4).

[0710] Molecule A18 Molecule A18 is obtained by conventional methods of peptide synthesis in the solid phase (SPPS) on 2-chlorotrityl chloride (CTC) (26.72 g, 1.16 mmol / g) resin.

[0711] Using a process similar to that used for the preparation of molecule A17, applied to 4,7,10-trioxa-1,13-tridecanediamine (TOTA, 68.30 g, 310.0 mmol), Fmoc-Glu(OMe)-OH (23.77 mmol, 62.00 mmol) and molecule 37 (19.04 g, 46.50 mmol), a yellow oil of molecule A18 in hydrochloride form is obtained. Yield: 5.53 g (23% over 5 steps). RMN1 H(DMSO-d6, ppm):0.76-0.89(15H);0.97-2.38(36H);2.77-2.87(2H);3.00-3.17(3H);3.32-3 .54(13H);3.57(3H);4.09-4.18(0.75H);4.20-4.29(1H);4.39-4.47(0.25H);7.63-8.36(5H). LC / MS(ESI+):755.7(calculation([M+H] + ):755.6).

[0712] Example A19: Molecule A19 Molecule A19 is synthesized in the same manner as molecule A16 by substituting molecule 14 for molecule 11 during the SPPS step. Total yield (3 steps): 32.6g (81%) RMN 1 H(CDCl3, ppm):0.88(3H);1.20-1.35(16H);1.43(9H);1.46(9H);1.56-1.68(2H);1.93-2.11(6H);2.24-2.55(10H);2.85(2H);3.19-3.2 9(1H);3.38-3.48(1H);3.55-3.64(1H)3.74-3.82(1H);4.14-4.21(1 H);4.25-4.32(1H);4.41-4.50(1H);7.03(1H);7.69(1H);8.42(1H). LC / MS(ESI):710.4(calculation([M+H] + ):710.5).

[0713] Example A20: Molecule A20 Molecule A20 is obtained by conventional methods of peptide synthesis in the solid phase (SPPS) on 2-chlorotrityl chloride (CTC) (40.00 g, 1.16 mmol / g) resin.

[0714] Grafting of diamine ethylene (20.0 equiv.) is carried out in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0715] The coupling of the protected amino acids Fmoc-Lys(Fmoc)-OH (1.5 eq.), Fmoc-Glu(OtBu)-OH (2.5 eq.) and molecule 11 (2.5 eq.) is carried out in DMF (10 V) in the presence of HATU (1.0 eq. relative to acid) and DIPEA (1.5 eq. relative to acid).

[0716] The protecting Fmoc group is removed using a 80:20 DMF / piperidine solution (10V).

[0717] The product is cleaved from the resin using a 50:50 DCM / TFA solution (10 V). After evaporation, the residue is solubilized in water (600 mL), the pH of the solution is adjusted to 7 by adding a 5N NaOH solution, and the product is then lyophilized. The lyophilizate is purified by column chromatography on silica gel (dichloromethane, methanol, NH4OH) to obtain molecule A20 in the form of a white solid. Yield: 24.6 g (50% over 7 steps). RMN 1 H(MeOD-d4, ppm):0.90(6H);1.18-2.45(68H);2.45-2.60(2H);3.05-3.11(2H);3 .11-3.19(1H);3.23-3.33(1H);3.43-3.66(4H);3.82-3.94(2H);4.10-4.51(5H). LC / MS(ESI+):1061.9(calculation([M+H] + ):1061.8).

[0718] Part B - Synthesis of hydrophobic copolyamino acids i) copolyamino acids according to formulae XXX, XXXa, XXXb [ka] TIFF2025032188000100.tif184137TIFF2025032188000101.tif194137TIFF2025032188000102.tif20713 5TIFF2025032188000103.tif205137TIFF2025032188000104.tif207135TIFF2025032188000105.tif58137

[0719] Copolyamino acid B1: poly-L-sodium glutamate modified at one of its ends by molecule A1 and having a number-average molar mass (Mn) of 2800 g / mol In a previously oven-dried flask, γ-benzyl-L-glutamic acid N-carboxyanhydride (8.95 g, 34 mmol) is solubilized in anhydrous DMF (34 mL). The mixture is cooled to 4 °C and then a solution of molecule A1 (1.64 g, 1.55 mmol) in chloroform (6.6 mL) is rapidly introduced. The mixture is stirred at 4 °C to room temperature for 68 h and then heated to 65 °C for 2 h. Half of the solvent is distilled under reduced pressure, then the reaction medium is cooled to room temperature and poured dropwise into diisopropyl ether (300 mL) with stirring. The white precipitate is collected by filtration, washed with diisopropyl ether (5 × 50 mL) and then dried under reduced pressure at 30 °C to obtain a white solid. The solid (7.9 g) is diluted in TFA (30 mL) and then a solution of 33% hydrobromic acid (HBr) in acetic acid (21 mL, 120 mmol) is added dropwise at 0° C. The solution is stirred for 2 h at room temperature and then poured dropwise, with stirring, onto a 1:1 mixture (v / v) of diisopropyl ether / water (360 mL). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight. The white precipitate is collected by filtration and washed successively with IPE (2×30 mL) and then with water (2×30 mL). The resulting solid is solubilized in water (200 mL) while the pH is adjusted to 7 by adding 1N aqueous soda solution. Water (65 mL) is added. The mixture 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 conductivity measurement of the permeate is less than 50 μS / cm. The copolyamino acid is then concentrated to about theoretical 25 g / L, the pH is adjusted to 7, and the aqueous solution is filtered through 0.2 μm. The solution is diluted with water and acetone to obtain a 12 g / L solution containing 30% by weight of acetone, which is then filtered through an activated carbon filter (3M R53SLP). The acetone is distilled (40° C., 100 mbar), and the solution is purified by ultrafiltration against a 0.9% NaCl solution and then against water until the conductivity measurement of the permeate is less than 50 μS / cm. The copolyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4° C. Dry extract: 17.8mg / g DP(RMN 1H):26 RMN 1 By H: i = 0.038 The calculated average molar mass of copolyamino acid B1 is 4994 g / mol. Organic HPLC-SEC (PEG calibration): Mn = 2800 g / mol

[0720] Copolyamino acid B2: poly-L-sodium glutamate modified with molecule A2 (whose esters are saponified) and having a number-average molar mass (Mn) of 5200 g / mol Copolyamino acid B2-1: Poly-L-glutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by hexylamine In a jacketed reactor, γ-benzyl-L-glutamic acid N-carboxyanhydride (500 g, 1.90 mol) is solubilized in anhydrous DMF (1100 mL). The mixture is then stirred until complete dissolution, cooled to 0° C., and then hexylamine (6.27 mL, 47.5 mmol) is rapidly introduced. The mixture is stirred for 5 h at 0° C., 7 h at 0° C. to 20° C., and then 7 h at 20° C. The reaction medium is then heated to 65° C. for 2 h, cooled to 55° C., and methanol (3300 mL) is introduced over 1 h 30 min. The reaction mixture is then cooled to 0° C. and stirred for 18 h. The white precipitate is recovered by filtration, washed with diisopropyl ether (2×800 mL), and then dried under reduced pressure at 30° C. to obtain poly(γ-benzyl-L-glutamic acid) (PBLG).

[0721] To a solution of PBLG (180 g) in N,N-dimethylacetamide (DMAc, 450 mL) is added Pd / Al2O3 (36 g) under argon atmosphere. The mixture is placed under a hydrogen atmosphere (10 bar) and stirred at 60°C for 24 h. After cooling to room temperature and filtration of the catalyst on sintered P4, then through an Omnipore 0.2 μm PTFE hydrophilic membrane, an aqueous solution of pH 2 (2700 mL) is dripped dropwise onto the DMAc solution over a period of 45 min while stirring. After 18 h of stirring, the white precipitate is collected by filtration, washed with water (4 x 225 mL) and then dried under reduced pressure at 30°C.

[0722] Copolyamino acid B2 Copolyamino acid B2-1 (15.0 g) is solubilized in DMF (230 mL) at 40 ° C, then N-methylmorpholine (NMM, 11.57 g, 114.4 mmol) is added. At the same time, molecule A2 (10.17 g, 17.2 mmol) in the form of hydrochloride is suspended in DMF (250 mL), triethylamine (2.39 mL, 17.2 mmol) is added, then the mixture is heated slightly with stirring until complete dissolution. To the copolyamino acid solution cooled to 25 ° C, a solution of molecule A2, N-oxide 2-hydroxypyridine (HOPO, 3.81 g, 34.3 mmol) and then EDC (6.58 g, 34.3 mmol) are added successively. The reaction medium is stirred for 2 hours at 25°C, filtered through a 0.2 mm woven filter and dripped dropwise onto 2.6 L of water (pH 2) containing 15% NaCl solution and HCl, while stirring. At the end of the addition, the pH is readjusted to 2 with 1N HCl solution and the suspension is left to stand overnight. The precipitate is collected and then rinsed with 2 x 100 mL of water. The white solid obtained is solubilized in 1.2 L of water by gradually adding, while stirring, a 1N aqueous NaOH solution up to pH 7, and then the solution is filtered through a 0.45 μm filter. Ethanol (30% by weight) is added and then the solution is filtered through an activated charcoal filter (3M R53SLP). 10N NaOH solution is gradually added, while stirring, up to pH 13, and then the mixture is left under stirring for 2 hours. After neutralization to pH 7 by addition of 37% HCl solution, the resulting clear solution is purified by ultrafiltration against 0.9% NaCl solution and then water until the conductivity measurement of the permeate is less than 50 μS / cm. The copolyamino acid solution is then concentrated and the pH adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4° C. Dry extract: 22.6mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B2 is 9301 g / mol. Organic HPLC-SEC (PEG calibration): Mn=5200 g / mol.

[0723] Copolyamino acid B3: poly-L-sodium glutamate modified with molecule A3 (whose esters are saponified) and having a number-average molar mass (Mn) of 4900 g / mol Copolyamino acid B2-1 (12.0 g) is solubilized in DMF (92 mL) at 40 ° C, then N-methylmorpholine (NMM, 9.25 g, 91.5 mmol) is added. At the same time, a solution of molecule A3 (7.51 g, 13.7 mmol) in the form of hydrochloride and N,N-diisopropylethylamine (DIPEA, 2.39 mL, 13.7 mmol) in DMF (27 mL) is prepared. To the copolyamino acid solution cooled to 25 ° C, a solution of molecule A3, N-oxide 2-hydroxypyridine (HOPO, 3.05 g, 27.4 mmol) is added in succession. The mixture is cooled to 0 ° C, then EDC (5.26 g, 27.4 mmol) is added. After 5 minutes at 0° C., the reaction medium is stirred for 2 hours at 25° C., filtered through a 0.2 mm woven filter and dripped dropwise onto 950 mL of water (pH 2) containing 15% NaCl solution and HCl, while stirring. At the end of the addition, the pH is readjusted to 2 with 1N HCl solution and the suspension is left to stand overnight. The precipitate is collected and then rinsed with 3×100 mL of water. The solid obtained is solubilized in 1 L of water by gradually adding, while stirring, a 1N aqueous NaOH solution up to pH 7. Once completely solubilized, the pH is adjusted to pH 12 over 2 hours and then to pH 13 over 1 hour by adding a 10N NaOH solution. After neutralization to pH 7 by adding a 37% HCl solution, the solution is diluted with water and ethanol to obtain a 12 g / L solution containing 30% by weight of ethanol, which is then filtered through an activated charcoal filter (3MR53SLP). The solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution until the permeate has a conductivity measurement of less than 50 μS / cm. The copolyamino acid solution is then concentrated and the pH adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4° C. Dry extract: 20.6mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B3 is 8977 g / mol. Organic HPLC-SEC (PEG calibration): Mn=4900 g / mol.

[0724] Copolyamino acid B4: poly-L-sodium glutamate modified with molecule A4 (whose esters are saponified) and having a number-average molar mass (Mn) of 4700 g / mol Using a process similar to that used for the preparation of copolyamino acid B3, applied to the hydrochloride salt of molecule A4 (7.12 g, 13.7 mmol) and copolyamino acid B2-1 (12.0 g), sodium poly-L-glutamate modified with molecule A4 (the ester is saponified) is obtained. Dry extract: 19.4mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B4 is 8809 g / mol. Organic HPLC-SEC (PEG calibration): Mn=4700 g / mol.

[0725] Copolyamino acid B5: poly-L-sodium glutamate modified with molecule A5 (whose esters are saponified) and having a number-average molar mass (Mn) of 5400 g / mol Using a process similar to that used for the preparation of copolyamino acid B3, applied to the hydrochloride salt of molecule A5 (9.71 g, 13.7 mmol) and copolyamino acid B2-1 (12.0 g), sodium poly-L-glutamate modified with molecule A5 (the ester is saponified) is obtained. Dry extract: 20.8mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B5 is 9939 g / mol. Organic HPLC-SEC (PEG calibration): Mn=5400 g / mol.

[0726] Copolyamino acid B7: poly-L-sodium glutamate modified at one of its ends with molecule A7 and having a number-average molar mass (Mn) of 2500 g / mol Using a process similar to that used for the preparation of copolyamino acid B1, applied to molecule A7 (2.50 g, 2.74 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (15.89 g, 60.4 mmol), sodium poly-L-glutamate modified at one of its ends by molecule A7 is obtained. Dry extract: 20.3mg / g DP(RMN 1 H):26 RMN 1 By H: i = 0.038 The calculated average molar mass of copolyamino acid B7 is 3893 g / mol. Organic HPLC-SEC (PEG calibration): Mn=2500g / mol

[0727] Copolyamino acid B13: poly-L-sodium glutamate modified at one of its ends with molecule A11 (ester deprotected) and having a number-average molar mass (Mn) of 3000 g / mol. In a jacketed reactor, γ-benzyl-L-glutamic acid N-carboxyanhydride (24.50 g, 93.05 mmol) is solubilized in anhydrous DMF (55 mL). The mixture is then stirred until complete dissolution, cooled to 0 ° C, then hexylamine (0.56 mL, 4.23 mmol) is rapidly introduced. The mixture is stirred at 0 ° C for 48 h, then the following are added in succession: a solution of molecule A11 (9,.g, 5.08 mmol) in DMF (50 mL), HOPO (564 mg, 5.08 mmol) and EDC (973 mg, 5.08 mmol). The reaction medium is stirred for 1 h at 0 ° C, for 2 h at 0 ° C to 20 ° C, then for 16 h at 20 ° C. This solution is then poured into a 1:1 H2O / MeOH mixture (10 V) at room temperature and with stirring. After 4 h, the white precipitate is collected by filtration, washed with diisopropyl ether (2×100 mL), water (2×100 mL) and a 1:1 H2O / MeOH mixture (2×100 mL) and then dried under reduced pressure.

[0728] The solid obtained is solubilized in TFA (220 mL) and stirred at room temperature for 2 h 30 min. The solution is then poured into water (10 V) at room temperature with stirring. After stirring for 2 h 30 min, the white precipitate is collected by filtration, washed with water (2×200 mL) and then dried under reduced pressure.

[0729] The solid obtained is solubilized in N,N-dimethylacetamide (DMAc, 210 mL) and Pd / Al2O3 (2.1 g) is added under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (6 bar) and stirred at 60°C for 24 hours. After cooling to room temperature and filtration of the catalyst on a sintered P4, then through an Omnipore 0.2 μm PTFE hydrophilic membrane, an aqueous solution containing 15% NaCl at pH 2 (6 V) is added dropwise onto the DMAc solution, with stirring, over a period of 45 minutes. After stirring for 18 hours, the white precipitate is collected by filtration, washed with water and then dried under reduced pressure. The solid obtained is solubilized in water (600 mL), adjusting the pH to 7 by addition of a 1N aqueous soda solution. The pH is then adjusted to pH 12 and the solution is stirred for 1 hour. After neutralization to pH 7, the solution is filtered through 0.2 μm and diluted with ethanol to obtain a solution containing 30% by weight of ethanol, then filtered through an activated carbon filter (3MR53SLP). The solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution until the conductivity measurement of the permeate is less than 50 μS / cm. The copolyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4° C. Dry extract: 23.5mg / g DP(RMN 1 Estimated by H) = 24, so i = 0.042 The calculated average molar mass of copolyamino acid B13 is 5377 g / mol. Organic HPLC-SEC (PEG calibration): Mn=3000 g / mol.

[0730] Copolyamino acid B14: poly-L-sodium glutamate modified at one of its ends with molecule A12 (ester deprotected) and having a number-average molar mass (Mn) of 3300 g / mol Copolyamino acid B14-1: Poly-L-benzylglutamic acid modified at one of its ends with molecule A12 In a previously oven-dried flask, γ-benzyl-L-glutamic acid N-carboxyanhydride (50.00 g, 189.39 mmol) is solubilized in anhydrous DMF (65 mL). The mixture is then stirred until complete dissolution, cooled to 0° C., then a solution of molecule A12 (9.65 g, 8.63 mmol) in DMF (50 mL) is rapidly introduced. The mixture is stirred from 0° C. to room temperature for 2 hours and then heated to 65° C. for 2 hours. The reaction medium is cooled to room temperature and poured dropwise, with stirring, into diisopropyl ether (1.8 mL). The white precipitate is collected by filtration, washed twice with diisopropyl ether and then dried under vacuum at 30° C., yielding a white solid.

[0731] Copolyamino acid B14 Copolyamino acid B14-1 is solubilized in DMAc (250 mL) and then Pd / Al2O3 (5.0 g) is added under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (10 bar) and stirred at 60°C for 24 hours. After cooling to room temperature and filtration of the catalyst on a sintered P4, then filtration through an Omnipore 0.2 μm PTFE hydrophilic membrane, an aqueous solution of pH 2 (6 V) is added dropwise, with stirring, over a period of 45 minutes onto the DMAc solution. After 18 hours of stirring, the white precipitate is collected by filtration, washed with water and then dried under reduced pressure. The solid obtained is solubilized in water (1.25 L), adjusting the pH to 7 by addition of 1N aqueous soda solution. The pH is then adjusted to pH 13 and the solution is stirred for 3 hours. After neutralization to pH 7, the solution is filtered through 0.2 μm and diluted with ethanol to obtain a solution containing 30% by weight of ethanol, then filtered through an activated carbon filter (3MR53SLP). The solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution until the conductivity measurement of the permeate is less than 50 μS / cm. The copolyamino acid solution is then concentrated and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4° C. Dry extract: 25.7mg / g DP(RMN 1 Estimated by H) = 24, so i = 0.042 The calculated average molar mass of copolyamino acid B14 is 4720 g / mol. Organic HPLC-SEC (PEG calibration): Mn=3300g / mol.

[0732] Copolyamino acid B15: poly-L-sodium glutamate modified with molecule A13 (ester deprotected) and having a number-average molar mass (Mn) of 4400 g / mol A process similar to that used for the preparation of copolyamino acid B3 is applied to the hydrochloride salt of molecule A13 (3.39 g, 2.34 mmol) and copolyamino acid B2-1 (2.04 g), together with a saponification step at pH 13 for 5 h in a mixture containing 30% by weight of ethanol, to obtain sodium poly-L-glutamate modified with molecule A13 (ester deprotected). Dry extract: 15.7mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B15 is 12207 g / mol. Organic HPLC-SEC (PEG calibration): Mn=4400 g / mol.

[0733] Copolyamino acid B17: poly-L-sodium glutamate modified at one of its ends with molecule A15 (ester deprotected) and having a number-average molar mass (Mn) of 1000 g / mol. A process similar to that used for the preparation of copolyamino acid B14 is applied to molecule A15 (10.85 g, 8.74 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (23.00 g, 87.37 mmol), together with a saponification step at pH 12 for 2 h, to obtain sodium poly-L-glutamate modified at one of its ends by molecule A15 (the ester is deprotected). Dry extract: 23.9mg / g DP(RMN 1 H):10 RMN 1 By H: i = 0.1 The calculated average molar mass of copolyamino acid B17 is 2576 g / mol. Aqueous HPLC-SEC (PEG calibration): Mn=1000 g / mol.

[0734] Copolyamino acid B18: poly-L-sodium glutamate modified with molecule A16 (ester deprotected) and having a number-average molar mass (Mn) of 5000 g / mol Using a coupling similar to that used for the preparation of copolyamino acid B3, applied to molecule A16 (31.06 g, 42.08 mmol) and copolyamino acid B2-1 (36.80 g), a beige solid is obtained after an acid precipitation step. This solid is diluted in TFA (100 g / L) and the mixture is stirred at room temperature for 3 hours. The solution is then dripped dropwise onto water (3 V) under stirring. After 16 hours of stirring, the precipitate is collected by filtration and then washed with water. The solid obtained is solubilized in water, adjusting the pH to 7 by adding a 10N aqueous soda solution. Once solubilization is complete, the pH is adjusted to pH 12 by adding a 1N NaOH solution for 1 hour. After neutralization to pH 7 by adding a 1N HCl solution, the product is purified by a process similar to that used for the preparation of copolyamino acid B3 (charcoal filtration and ultrafiltration). Poly-sodium L-glutamate modified with molecule A16 (ester deprotected) is obtained. Dry extract: 28.2mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B18 is 9884 g / mol. Organic HPLC-SEC (PEG calibration): Mn=5000 g / mol.

[0735] Copolyamino acid B19: poly-L-sodium glutamate modified with molecule A17 (ester deprotected) and having a number-average molar mass (Mn) of 4900 g / mol Using a process similar to that used for the preparation of copolyamino acid B3, the hydrochloride salt of molecule A17 (7.35 g, 13.09 mmol) and copolyamino acid B2-1 (11.45 g) are applied with a saponification step for 3 hours at pH 13 in a mixture containing 30% by weight of ethanol to obtain sodium poly-L-glutamate modified with molecule A17 (ester deprotected). Dry extract: 25.7mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B19 is 9062 g / mol. Organic HPLC-SEC (PEG calibration): Mn=4900 g / mol.

[0736] Copolyamino acid B20: poly-L-sodium glutamate modified with molecule A18 (ester deprotected) and having a number-average molar mass (Mn) of 5800 g / mol A process similar to that used for the preparation of copolyamino acid B3 is applied to the hydrochloride salt of molecule A18 (5.43 g, 6.86 mmol) and copolyamino acid B2-1 (6.00 g), together with a saponification step for 3 hours at pH 13 in a mixture containing 30% by weight of ethanol, to obtain sodium poly-L-glutamate modified with molecule A18 (ester deprotected). Dry extract: 22.0mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B20 is 10444 g / mol. Organic HPLC-SEC (PEG calibration): Mn=5800 g / mol.

[0737] Copolyamino acid B21: poly-L-sodium glutamate modified with molecule A19 (ester deprotected) and having a number-average molar mass (Mn) of 5000 g / mol Using a process similar to that used for the preparation of copolyamino acid B18, applied to molecule A19 (32.64 g, 45.97 mmol) and copolyamino acid B2-1 (40.20 g), sodium poly-L-glutamate modified with molecule A19 (the ester is saponified) is obtained. Dry extract: 26.2mg / g DP(RMN 1 H): 40 RMN 1 By H: i = 0.15 The calculated average molar mass of copolyamino acid B21 is 9716 g / mol. Organic HPLC-SEC (PEG calibration): Mn=5000 g / mol.

[0738] Copolyamino acid B22: poly-L-sodium glutamate modified at one of its ends with molecule A20 and having a number-average molar mass (Mn) of 1900 g / mol Using a process similar to that used for the preparation of copolyamino acid B14, molecule A20 (13.28 g, 12.51 mmol) in CHCl3 (53 mL) and γ-benzyl-L-glutamic acid N-carboxyanhydride (72.46 g, 275.2 mmol) in DMF (270 mL) at pH 12, together with a saponification step of 1 h 30 min, gives sodium poly-L-glutamate modified at one of its ends by molecule A20. Dry extract: 27.3mg / g DP(RMN 1 H):20 RMN 1 By H: i = 0.05 The calculated average molar mass of copolyamino acid B22 is 4087 g / mol. Aqueous HPLC-SEC (PEG calibration): Mn=1900 g / mol.

[0739] ii) Copolyamino acids according to formulae XXX and XXXb [ka] TIFF2025032188000107.tif207132TIFF2025032188000108.tif7137Copolyamino acid B7': poly-L-glutamate modified at one of its ends by molecule A5a and having a number-average molar mass (Mn) of 2600 g / mol Copolyamino acid B7'-1: Poly-L-benzylglutamic acid modified at one of its ends with molecule A5a In a previously oven-dried flask, γ-benzyl-L-glutamic acid N-carboxyanhydride (10.1 g, 38.4 mmol) is solubilized in anhydrous DMF (19 mL). The mixture is then stirred until complete dissolution, cooled to 0° C., and then a solution of molecule A5a (1.47 g, 1.74 mmol) in chloroform (3.7 mL) is rapidly introduced. The mixture is stirred from 0° C. to room temperature for 2 hours and then heated to 65° C. for 2 hours. The reaction medium is cooled to room temperature and poured dropwise, with stirring, into diisopropyl ether (0.29 L). The white precipitate is recovered by filtration, washed twice with diisopropyl ether (5×50 mL), and then dried under vacuum at 30° C., yielding a white solid.

[0740] Copolyamino acid B7' Copolyamino acid B7'-1 (8.33 g, 33.0 mmol) is diluted in trifluoroacetic acid (TFA, 132 mL) and the solution is then cooled to 4°C. A 33% solution of HBr in acetic acid (92.5 mL, 0.528 mol) is then added dropwise. The mixture is stirred for 2 hours at room temperature and then poured dropwise (0.8 L) onto a 1:1 mixture (v / v) of diisopropyl ether and water, with stirring. After stirring for 2 hours, the heterogeneous mixture is allowed to stand overnight. The white precipitate is collected by filtration and washed with IPE (2 x 66 mL) and then with water (2 x 66 mL). The resulting solid is then solubilized in water (690 mL) while adjusting the pH to 7 by adding 1N aqueous soda solution. After solubilization, the theoretical concentration is adjusted to 20 g / L by adding water (310 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 permeate has a conductivity measurement of less than 50 μS / cm. The resulting solution is filtered through 0.2 μm and stored at 2-8° C. Dry extract: 17.3mg / g DP(RMN 1 H):24 RMN 1 By H: i = 0.042 The calculated average molar mass of copolyamino acid B7' is 4430 g / mol. Organic HPLC-SEC (PEG calibration): Mn=2600g / mol.

[0741] Example B8: Copolyamino acid B8 - sodium poly-L-glutamate modified at one of its ends with molecule A6a and having a number-average molar mass (Mn) of 2400 g / mol Copolyamino acid B8-1: Poly-L-benzylglutamic acid modified at one of its ends with molecule A6 In a previously oven-dried flask, γ-benzyl-L-glutamic acid N-carboxyanhydride (19.0 g, 72.2 mmol) is solubilized in anhydrous DMF (19 mL). The mixture is then stirred until complete dissolution, cooled to 0° C., and then a solution of molecule A6a (1.68 g, 3.28 mmol) in chloroform (3.7 mL) is rapidly introduced. The mixture is stirred from 0° C. to room temperature for 2 hours and then heated to 65° C. for 2 hours. The reaction medium is cooled to room temperature and poured dropwise, with stirring, into diisopropyl ether (0.29 mL). The white precipitate is recovered by filtration, washed twice with diisopropyl ether (5×50 mL), and then dried under vacuum at 30° C., yielding a white solid.

[0742] Copolyamino acid B8 A process similar to that used for the preparation of copolyamino acid B7' is applied to copolyamino acid B8-1 (14.6 g, 61.5 mmol) to obtain sodium poly-L-glutamate modified at one of its ends with molecule A6a. Dry extract: 21.3mg / g DP(RMN 1 H):23 RMN 1 By H: i = 0.043 The calculated average molar mass of copolyamino acid B8 is 3948 g / mol. Organic HPLC-SEC (PEG calibration): Mn=2400 g / mol.

[0743] Copolyamino acid B10: poly-L-sodium glutamate modified at one of its ends with molecule A8 and having a number-average molar mass (Mn) of 3100 g / mol Copolyamino acid B10-1: Poly-L-benzylglutamic acid modified at one of its ends with molecule A8 In a suitable vessel, the hydrochloride salt of molecule A8 (2.308 g, 3.04 mmol), chloroform (120 mL), molecular sieves 4 Å (1.5 g) and ion exchange resin Amberlite IRN 150 (1.5 g) are successively introduced. After stirring on a roller for 1 hour, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then coevaporated with toluene. The residue is solubilized in anhydrous DMF (40 mL) and used directly in the polymerization reaction.

[0744] In a previously oven-dried flask, γ-benzyl-L-glutamic acid N-carboxyanhydride (20.0 g, 76.0 mmol) is solubilized in anhydrous DMF (19 mL). The mixture is then stirred until complete dissolution, cooled to 0° C., then a solution of chloroform containing the previously prepared molecule A8 (3.7 mL) is rapidly introduced. The mixture is stirred from 0° C. to room temperature for 2 hours and then heated to 65° C. for 2 hours. The reaction medium is cooled to room temperature and poured dropwise, with stirring, into diisopropyl ether (0.29 mL). The white precipitate is recovered by filtration, washed twice with diisopropyl ether (5×50 mL), then dried under vacuum at 30° C., yielding a white solid.

[0745] Copolyamino acid B10 A process similar to that used for the preparation of copolyamino acid B7' is applied to copolyamino acid B10-1 (15.2 g, 60.8 mmol) to obtain sodium poly-L-glutamate modified at one of its ends with molecule A8. Dry extract: 34.1mg / g DP(RMN 1 H):31 RMN 1 By H: i = 0.032 The calculated average molar mass of copolyamino acid B10 is 5367 g / mol. Organic HPLC-SEC (PEG calibration): Mn=3100g / mol.

[0746] Example B11: Copolyamino acid B11 - sodium poly-L-glutamate modified at one of its ends with molecule A9 and having a number-average molar mass (Mn) of 3000 g / mol Copolyamino acid B11-1: Poly-L-benzylglutamic acid modified at one of its ends with molecule A9 In a suitable vessel, the hydrochloride salt of molecule A9 (2.023 g, 3.87 mmol), chloroform (120 mL), molecular sieves 4 Å (1.5 g) and ion exchange resin Amberlite IRN 150 (1.5 g) are successively introduced. After stirring on a roller for 1 hour, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then coevaporated with toluene. The residue is solubilized in anhydrous DMF (40 mL) and used directly in the polymerization reaction.

[0747] Using a process similar to that used for the preparation of copolyamino acid B8-1, it is applied to a solution of the previously prepared molecule A9 and γ-benzyl-L-glutamic acid N-carboxyanhydride (25.5 g, 96.8 mmol) to obtain copolyamino acid B11-1.

[0748] Copolyamino acid B11 A process similar to that used for the preparation of copolyamino acid B7' is applied to copolyamino acid B11-1 (18.4 g, 77.3 mmol) to obtain sodium poly-L-glutamate modified at one of its ends with molecule A9. Dry extract: 28.0mg / g DP(RMN 1 H):29 RMN 1 By H: i = 0.034 The calculated average molar mass of copolyamino acid B11 is 4828 g / mol. Organic HPLC-SEC (PEG calibration): Mn=3000 g / mol.

[0749] Copolyamino acid B12: poly-L-sodium glutamate modified at one of its ends with molecule A10 and having a number-average molar mass (Mn) of 2700 g / mol Copolyamino acid B12-1: Poly-L-benzylglutamic acid modified at one of its ends with molecule A10 A process similar to that used for the preparation of copolyamino acid B10-1 is applied to molecule A10 (3.0 g, 2.24 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (12.99 g, 49.3 mmol) to obtain copolyamino acid B12-1.

[0750] Copolyamino acid B12 A process similar to that used for the preparation of copolyamino acid B7' is applied to copolyamino acid B12-1 (13.2 g, 48.0 mmol) to obtain sodium poly-L-glutamate modified at one of its ends with molecule A10. Dry extract: 13.2mg / g DP(RMN 1 H):24 RMN 1 By H: i = 0.042 The calculated average molar mass of copolyamino acid B12 is 4924 g / mol. Organic HPLC-SEC (PEG calibration): Mn=2700g / mol.

[0751] Part C: Composition Example C1: Preparation of 0.6 mg / mL pramlintide solution with m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 A concentrated 5 mg / mL pramlintide solution is prepared by dissolving pramlintide in powder form purchased from Ambiopharm. This solution is added to a concentrated solution of excipients (m-cresol, glycerin) to obtain the desired final composition. The pH is adjusted to 6.6 by adding NaOH / HCl.

[0752] Example C1-1: Preparation of 0.9 mg / mL pramlintide solution with m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 A 0.9 mg / mL pramlintide solution is obtained with m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 by the same protocol as described in Example C1. The solution is clear.

[0753] Example C2: Preparation of 0.6 mg / mL pramlintide solution containing copolyamino acid B3, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 A concentrated solution of copolyamino acid B3 and excipients (m-cresol, glycerin) is prepared by adding a concentrated solution of the excipients to a concentrated solution of copolyamino acid B3.

[0754] A 5 mg / mL concentrated solution of pramlintide and excipients at pH 4 is added to this concentrated solution of copolyamino acid B3 to obtain final compositions C2-1 to C2-5 (Table 1). The pH is adjusted to 6.6 by adding NaOH / HCl. [Table 2] Table 1: Composition and appearance of pramlintide solutions at different concentrations of copolyamino acid B3, pH 6.6

[0755] Example C3: Preparation of 0.6 mg / mL pramlintide solution with different copolyamino acids according to the invention, m-cresol (29 mM) and glycerin (174 mM) at pH 6.6 Using a protocol similar to that described in Example C2, 0.6 mg / mL pramlintide solutions containing different copolyamino acids according to the invention, m-cresol (29 mM) and glycerin (174 mM) at pH 7.4 are obtained (Tables 2 and 2a). [Table 3] Table 2: Composition and appearance of 0.6 mg / mL pramlintide solutions at pH 6.6 in the presence of different copolyamino acids. [Table 4] Table 2a: Composition and appearance of 0.6 mg / mL pramlintide solutions at pH 6.6 in the presence of different copolyamino acids.

[0756] Example C8: Preparation of 0.6 mg / mL pramlintide solution with different copolyamino acids according to the invention, m-cresol (29 mM) and glycerin (174 mM), NaCl and optionally zinc chloride at pH 6.6 A concentrated solution of the copolyamino acid according to the invention and the excipients is prepared by adding a concentrated solution of the excipients (m-cresol, glycerin, NaCl, zinc chloride) to a concentrated solution of the copolyamino acid according to the invention.

[0757] A 5 mg / mL concentrated solution of pramlintide and excipients at pH 4 is added to this concentrated solution of the copolyamino acid according to the invention to obtain the final compositions C8-5 to C8-15 (Tables 2b and 2c). The pH is adjusted to 6.6 by adding NaOH / HCl. [Table 5] Table 2b: Composition and appearance of 0.6 mg / mL pramlintide solutions at pH 6.6 in the presence of different copolyamino acids according to the invention, sodium chloride and optionally zinc chloride. [Table 6] Table 2c: Composition and appearance of 0.6 mg / mL pramlintide solution at pH 6.6 in the presence of different copolyamino acids according to the invention, sodium chloride, and optionally zinc chloride.

[0758] Example C4: Preparation of a 0.6 mg / mL pramlintide solution and 100 IU / mL human insulin with m-cresol (29 mM) and glycerin (174 mM) and zinc chloride (229 μM) at pH 6.6 The 5mg / mL pramlintide concentrated solution described in C1 is added to the concentrated solution of excipients (m-cresol, glycerin, zinc chloride). A 500IU / mL human insulin solution is prepared by dissolving human insulin in powder form purchased from Amphastar. This solution is added to the concentrated solution of pramlintide and excipients to obtain the target final composition. The pH is adjusted to 6.6 by adding NaOH / HCl.

[0759] Example C5: Preparation of 0.6 mg / mL pramlintide solution and 100 IU / mL human insulin with copolyamino acid B3, m-cresol (29 mM) and glycerin (174 mM) and zinc chloride (229 μM) at pH 6.6 A concentrated solution of copolyamino acid B3 and excipients is prepared by adding a concentrated solution of the excipients (m-cresol, glycerin, zinc chloride) to a concentrated solution of copolyamino acid B3.

[0760] A 5 mg / mL pramlintide concentrated solution at pH 4, followed by a 500 IU / mL human insulin solution, is added to the concentrated solution of copolyamino acid B3 and excipients to obtain the final target composition (Table 3). The pH is adjusted to 6.6 by adding NaOH / HCl. Prepare solutions C4 and C5-1 to C5-5 according to the protocol above. [Table 7] Table 3: Composition and appearance of 0.6 mg / mL pramlintide solutions and human insulin at pH 6.6 with different concentrations of copolyamino acid B3.

[0761] Example C6: Preparation of 0.6 mg / mL pramlintide solution and 100 IU / mL human insulin with different copolyamino acids according to the invention, m-cresol (29 mM) and glycerin (174 mM) and zinc chloride (229 μM) at pH 6.6 Using a process similar to that of Example C5, a 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin is obtained, containing a copolyamino acid according to the invention, m-cresol (29 mM) and glycerin (174 mM) and zinc chloride (229 μM) at pH 6.6.

[0762] Solutions C6-1 and C6-11 (Tables 4 and d4a) are prepared according to the protocol above. [Table 8] Table 4: Composition and appearance of 0.6 mg / mL pramlintide solution and 100 IU / mL human insulin in the presence of different copolyamino acids at pH 6.6. [Table 9] Table 4a: Composition and appearance of 0.6 mg / mL pramlintide solution and 100 IU / mL human insulin in the presence of different copolyamino acids at pH 6.6.

[0763] Example C10: Preparation of 0.6 mg / mL pramlintide solutions and 100 IU / mL human insulin with copolyamino acid B8, m-cresol (29 mM) and glycerin (174 mM), and various concentrations of sodium chloride and zinc chloride A concentrated solution of copolyamino acid B8 and excipients is prepared by adding a concentrated solution of the excipients (m-cresol, glycerin, sodium chloride, zinc chloride) to a concentrated solution of copolyamino acid B8.

[0764] A concentrated solution of 5mg / mL pramlintide at pH 4, then a solution of 500IU / mL human insulin is added to this concentrated solution of copolyamino acid B8 and excipients to obtain the final target composition. The pH is adjusted to 6.6 by adding NaOH / HCl.

[0765] Solutions C10-6 and C10-7 are prepared according to the protocol above. [Table 10] Table 4b: Composition and appearance of 0.6 mg / mL pramlintide solutions and 100 IU / mL human insulin in the presence of different copolyamino acids and different concentrations of sodium chloride and zinc chloride at pH 6.6. * Composition containing 0.23 mM ZnCl2 from a solution of human insulin

[0766] Results of visual observation of the mixture and ThT fibrillation measurement principle Insufficient stability of peptides can lead to the formation of amyloid fibrils, defined as ordered macromolecular structures, which can result in the formation of gels in the sample.

[0767] The physical stability of the solutions is analyzed using a fluorescence tracing test of Thioflavin T (ThT), a small probe molecule that has a characteristic fluorescent signature when bound to amyloid fibrils (Naiki et al. (1989) Anal. BioChem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284).

[0768] This method makes it possible to monitor the formation of fibrils for low concentrations of ThT in undiluted solution, under accelerated, stable conditions, at 37° C. with stirring.

[0769] Experimental conditions Samples are prepared immediately before the start of measurement. The preparation of each composition is described in the relevant examples. Thioflavin T is added to the composition from concentrated parent solution to induce negligible dilution of the composition. The concentration of Thioflavin T in the composition is 2 μM.

[0770] A volume of 150 μL of the compositions was introduced into one of the wells of a 96-well tray. Each composition was analyzed (in triplicate) using three tests in the same tray. The tray was sealed with a transparent film to prevent evaporation of the compositions.

[0771] The tray was then placed in the housing of a tray reader (EnVision 2104 Multilabel, Perkin Elmer). The temperature was set to 37° C. and transverse stirring was started at 960 rpm with an amplitude of 1 mm.

[0772] Fluorescence intensity readings in each well were taken over time using an excitation wavelength of 442 nm and an emission wavelength of 482 nm.

[0773] The fibrotic process is manifested by a strong increase in fluorescence after a period called the latency period.

[0774] For each well, this period was determined graphically as the intersection between the fluorescence signal baseline and the slope of the fluorescence curve as a function of time determined during the initial strong increase in fluorescence. The recorded latency value corresponds to the average of the latency measurements obtained for the triplicate wells.

[0775] An example of a graph decision is shown in FIG.

[0776] This figure graphically represents the determination of the latency (LT) by monitoring the fluorescence of Thioflavin T on a curve with the fluorescence values ​​(ua, arbitrary units) on the ordinate axis and the time in minutes on the abscissa.

[0777] Example CA1:Stability of 0.6 mg / mL pramlintide solution at pH 6.6 in the presence of different concentrations of copolyamino acid B3 [Table 11] Table 5: Measurement of latency by ThT for solutions C1, C2-1 and C2-5 Pramlintide solution (C1), pH 6.6, without copolyamino acid, has a short latency; the solution containing copolyamino acid B3 has a higher latency.

[0778] Example CA2: Stability of 0.6 mg / mL pramlintide solution at pH 6.6 in the presence of different copolyamino acids [Table 12] Table 6: Composition and ThT latency measurements of C3-1 and C3-33 A pramlintide solution (C1), at pH 6.6, without copolyamino acids, has a short latency. The copolyamino acids according to the invention make it possible to obtain latencies of more than 3 hours under the conditions tested.

[0779] Example CA2a: Stability of 0.6 mg / mL pramlintide solutions at pH 6.6 in the presence of different copolyamino acids, m-cresol (29 mM) and glycerin (174 mM), and different contents of NaCl and zinc chloride [Table 13] Table 6a: Measurement of latency by ThT for compositions C3-7, C3-5, C3-18 and C8-5 to C8-10 A pramlintide solution (C1), at pH 6.6, without copolyamino acids, has a short latency; in the presence of sodium chloride or sodium chloride and zinc chloride, the latency of a solution containing a copolyamino acid according to the invention is higher.

[0780] Example CA2b: Stability of 0.6 mg / mL pramlintide solutions at pH 6.6 in the presence of different copolyamino acids, m-cresol (29 mM) and glycerin (174 mM), and different contents of NaCl and zinc chloride [Table 14] Table 6b: Measurement of latency by ThT for compositions C3-19, C3-27 and C8-11 to C8-16 A pramlintide solution (C1), at pH 6.6, without copolyamino acids, has a short latency; in the presence of sodium chloride or sodium chloride and zinc chloride, the latency of a solution containing a copolyamino acid according to the invention is higher.

[0781] Example CA3: Composition and appearance of 0.6 mg / mL pramlintide solution and 100 IU / mL human insulin in the presence of different concentrations of copolyamino acid B3 at pH 6.6 [Table 15] Table 7: Composition and ThT latency measurements of C5-1 and C5-5 " * " means that the solution is cloudy. A 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin (C4) without copolyamino acid at pH 6.6 is cloudy. A clear 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin in the presence of copolyamino acid B3 at pH 6.6 has a latency of more than 0.5 hours at a B3 / pramlintide molar ratio of 1, and can exceed 4 hours for B3 / pramlintide molar ratios of more than 2.

[0782] Example CA4: Stability of 0.6 mg / mL pramlintide solution and 100 IU / mL human insulin in the presence of different copolyamino acids at pH 6.6 [Table 16] Table 8: Measurement of latency by ThT for compositions C6-1 to C6-4 and C6-5 [Table 17] Table 8a: Composition and ThT latency measurements of C6-5 and C6-4 At pH 6.6, solutions of pramlintide and human insulin (C4) are turbid. The copolyamino acids according to the invention make it possible to obtain latencies of more than 1 hour under the conditions tested.

[0783] Example CA7: Preparation of 0.6 mg / mL pramlintide solutions and 100 IU / mL human insulin with copolyamino acid B8, m-cresol (29 mM) and glycerin (174 mM), and various contents of sodium chloride and zinc chloride. [Table 18] Table 14b: Measurement of latency by ThT for compositions C6-4 and C10-6 to C10-7 * Composition containing 0.23 mM ZnCl2 from human insulin solution At pH 6.6, solutions of pramlintide and human insulin (C4) are turbid. The addition of zinc chloride with B8 allows a significant increase in the latency compared to that obtained with solution C6-4' without zinc salt.

[0784] CB: Stability study of the composition according to the invention Visual Inspection Procedure: 3 mL vials or cartridges filled with 1 mL of formulation are visually inspected to detect the appearance of visible particles or turbidity. The inspection is performed according to the European Pharmacopoeia recommendations (EP2.9.20): vials are subjected to illumination of at least 2000 Lux and observed in front of a white and black background. The weeks or months of stability correspond to the duration when the solution contains visible particles or becomes turbid.

[0785] These results are in accordance with the United States Pharmacopoeia (USP <790> ).

[0786] Example CB1: Physical stability of solutions of pramlintide at 0.9 mg / mL and 0.6 mg / mL at pH 6.6 in the presence of copolyamino acids, m-cresol (29 mM) and glycerin (174 mM) at 30° C. in vials and cartridges Solutions C1, C1-1, C8-14 and C3-21 are filtered (0.22 μm). 1 mL of solution is introduced into a 3 mL glass cartridge and into a 3 mL glass vial by an automatic injection stylus. The cartridge and the vial are placed in a stationary 30° C. oven and then observed every 2 weeks. [Table 19] Table 15: Physical stability results of 0.6 mg / mL pramlintide compositions in the presence of copolyamino acids B1 and B13 at 30° C. in cartridges.

[0787] The 0.9 mg / mL and 0.6 mg / mL pramlintide solutions at pH 6.6 have a physical stability in vials of less than 7 weeks at 30° C. The physical stability of the 0.9 mg / mL pramlintide solution at pH 6.6 in cartridges is less than 2 weeks.

[0788] A 0.6 mg / mL pramlintide solution in the presence of copolyamino acid B1 at pH 6.6 has a physical stability in the cartridge at 30° C. for more than 12 weeks.

[0789] A 0.6 mg / mL solution of pramlintide in the presence of copolyamino acid B13 at pH 6.6 has a physical stability of more than 9 weeks at 30° C. in cartridges and vials.

[0790] Example CB2: Physical stability in vials and cartridges of 0.6 mg / mL pramlintide solution and insulin 100 IU / mL at pH 6.6 in the presence of copolyamino acids B1, B20, m-cresol (29 mM) and glycerin (174 mM) and zinc (229 μM) at pH 6.6 at 30° C. Solutions C6-6 and C6-7 are filtered (0.22 μm). 1 mL of solution is introduced into a 3 mL glass cartridge and into a 3 mL glass vial by an automatic injection stylus. The cartridge and vial are placed in a stationary 30° C. oven and then observed every 2 weeks. [Table 20] * The solution is cloudy since preparation. Table 16: Physical stability results of 6.6, 0.6 mg / mL pramlintide compositions and insulin 100 IU / mL in the presence of copolyamino acids at 30° C. in vials and cartridges.

[0791] A solution of 0.6 mg / mL pramlintide and 100 IU / mL human insulin at pH 6.6 is cloudy.

[0792] A 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin in the presence of copolyamino acid B1 at pH 6.6 has a physical stability of more than 12 weeks in vials and more than 12 weeks in cartridges at 30°C.

[0793] A 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin in the presence of copolyamino acid B20 at pH 6.6 has a physical stability of more than 9 weeks at 30° C. in the cartridge.

[0794] Example CB3: Physical stability of 0.6 mg / mL pramlintide solution in cartridge at pH 6.6 in the presence of copolyamino acids, m-cresol (29 mM) and glycerin (174 mM) at 37° C. Solution C3-21 is filtered (0.22 μm). 1 mL of the solution is introduced into a 3 mL autoinjection pen glass cartridge. The cartridge is placed in a 37° C. oven under static conditions and then observed every 2 weeks. [Table 21] Table 17: Physical stability results of 0.6 mg / mL pramlintide composition in cartridge at 37° C. in the presence of copolyamino acids.

[0795] A 0.6 mg / mL pramlintide solution in the presence of copolyamino acid B1 at pH 6.6 has a physical stability at 37° C. in the cartridge for more than 9 weeks.

[0796] Example CB4: Physical stability of 0.6 mg / mL pramlintide solution and 100 IU / mL insulin in cartridges at 37° C. in the presence of copolyamino acids, m-cresol (29 mM) and glycerin (174 mM) and zinc (229 μM) at pH 6.6 Solutions C6-6 and C6-7 are filtered (0.22 μm). 1 mL of solution is introduced into a 3 mL autoinjection pen glass cartridge. The cartridge is placed in a 37° C. oven under static conditions and then observed every 2 weeks. [Table 22] * The solution is cloudy since preparation. Table 18: Physical stability results of 0.6 mg / mL pramlintide composition in cartridge at 37° C. in the presence of copolyamino acids.

[0797] A 0.6 mg / mL solution of pramlintide and 100 IU / mL human insulin at pH 6.6 is turbid. A 0.6 mg / mL solution of pramlintide in the presence of copolyamino acids at pH 6.6 has a physical stability at 37° C. in the cartridge for more than 3 weeks.

Claims

1. A composition in the form of an injectable aqueous solution having a pH of 6.0 to 8.0 and comprising at least: a) amylin, an amylin receptor agonist or an amylin analog; b) a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy, said copolyamino acid being composed of glutamic or aspartic acid units, said hydrophobic radical Hy being chosen among the radicals according to formula X defined below: 【Chemistry 1】 During the ceremony, The GpR is selected among radicals according to formula VII, VII' or VII'': 【Chemistry 2】 - identical or different GpG and GpH are selected among radicals according to formula XI or XI'; 【Chemistry 3】 -GpA is selected among radicals according to formula VIII 【Chemistry 4】 wherein A' is selected from among the radicals according to formula VIII', VIII" or VIII'" 【Chemistry 5】 -GpL is selected among radicals according to formula XII 【Chemistry 6】 -GpC is a radical according to formula IX: 【Chemistry 7】 - " ＊ " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=0 then a'=1, and if a=1 then a'=1, 2 or 3; a' is an integer equal to 1, 2 or 3; - b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g, h or l is different from 0; - l is an integer equal to 0 or 1, and if l = 0 then l' = 1, and if l = 1 then l' = 2; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - when e is different from 0, at least one of g, h or l is different from 0; - if a=0 then l=0; -A, A １ , A ２ and A ３ are the same or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with radicals derived from saturated, unsaturated or aromatic rings; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C ｘ is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: when the hydrophobic radical -Hy has 1-GpC, 9≦x≦25; when the hydrophobic radical -Hy has 2-GpC, 9≦x≦15; when the hydrophobic radical -Hy has 3-GpC, 7≦x≦13; when the hydrophobic radical -Hy has 4-GpC, 7≦x≦11; when the hydrophobic radical -Hy has at least 5-GpC, 6≦x≦11; -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups; -R is a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH ２ is a radical selected from the group consisting of a divalent, linear or branched alkyl radical having a functional group, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -Hy, a hydrophobic radical(s) according to formula X, is attached to PLG by: a covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of the PLG (thereby forming an amide function resulting from the reaction of the amine function of the PLG with the acid function of the precursor of the hydrophobic radical -Hy'); and a covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of the PLG (thereby forming an amide functional group resulting from the reaction of the amine functional group of the precursor of the hydrophobic radical -Hy -Hy' with the acid functional group of the PLG), the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is 0<M≦0.5; if the copolyamino acid has several hydrophobic radicals, they may be identical or different, the degree of polymerization DP of the PLG chain is comprised between 5 and 250 in glutamic or aspartic acid units; - Free carboxylic acid is Na ＋ and K. ＋ The compound is in the form of an alkali cation salt selected from the group consisting of:

2. 2. The composition according to claim 1, characterized in that the copolyamino acids having a carboxylate charge and a hydrophobic radical are chosen among the copolyamino acids according to the following formula XXX: 【Chemistry 8】 During the ceremony, D is independently -CH ２ - group (aspartic acid unit) or -CH ２ -CH ２ - group (glutamic acid unit), Hy is a hydrophobic radical selected among the hydrophobic radicals according to formula X, ・R １ is a hydrophobic radical selected among hydrophobic radicals according to formula X, where r=0 or r=1, GpR is a radical according to formula VII′ or VII″ or a radical selected from the group consisting of H, a C2-C10 linear acyl group, a C3-C10 branched acyl group, benzyl, a terminal “amino acid” unit, and pyroglutamic acid; ・R ２ is a hydrophobic radical selected among the hydrophobic radicals according to formula X or a -NR'R'' radical, where R' and R'' are the same or different and are selected from the group consisting of H, C2-C10 linear, branched or cyclic alkyl, benzyl, said R' and R'' alkyl together can form one or more saturated, unsaturated and / or aromatic rings and / or can contain heteroatoms selected from the group consisting of O, N and S; X represents a cationic entity selected from the group comprising H or a metal cation; n+m represents the degree of polymerization DP of said copolyamino acid, which is the average number of monomer units per copolyamino acid chain, with 5≦n+m≦250.

3. The copolyamino acid having a carboxylate charge and a hydrophobic radical is a compound of formula XXX (wherein R １ = R' １ and R ２ = R' ２ 4. The composition according to claim 1, characterized in that it is selected from among the copolyamino acids according to 【Chemistry 9】 During the ceremony, - m, n, X, D and Hy are as defined in claim 2, -R' １ is a radical selected from the group consisting of H, a C2-C10 linear acyl group, a C3-C10 branched acyl group, benzyl, a terminal "amino acid" unit, and pyroglutamic acid; -R' ２ is a -NR'R'' radical, where R' and R'' are the same or different and are selected in the group consisting of H, C2-C10 straight chain, branched or cyclic alkyl, benzyl, said R' and R'' alkyl together can form one or more saturated, unsaturated and / or aromatic rings, and / or can contain heteroatoms selected from the group consisting of O, N and S.

4. 3. The composition according to claim 1, characterized in that the copolyamino acids having a carboxylate charge and a hydrophobic radical are chosen among the copolyamino acids according to formula XXXb, where n=0: 【Chemistry 10】 In the formula, m, X, D, R １ and R ２ is as defined in claim 2, and at least R １ Or R ２ is a hydrophobic radical according to formula X.

5. 2. A composition according to any one of the preceding claims, characterized in that the copolyamino acid / amylin, amylin receptor agonist or amylin analogue molar ratio is ≧1.

6. A composition according to any one of the preceding claims, characterized in that the amylin, amylin receptor agonist or amylin analogue is amylin.

7. A composition according to any one of the preceding claims, characterized in that the amylin, amylin receptor agonist or amylin analogue is pramlintide.

8. 10. A composition according to any one of the preceding claims, characterized in that it also contains prandial insulin.

9. 4. A composition according to any one of the preceding claims, characterized in that the copolyamino acid / insulin ratio is greater than or equal to 1.

10. The composition according to any one of claims 1 to 9, characterized in that the composition has a greater stability, as measured by ThT, than a reference composition comprising amylin, an amylin receptor agonist and an amylin analogue, but not a copolyamino acid having a carboxylate charge and a hydrophobic radical Hy.

11. A copolyamino acid having a carboxylate charge and a hydrophobic radical Hy, said copolyamino acid being composed of glutamic or aspartic acid units, said hydrophobic radical Hy being chosen among the radicals according to formula X defined below: 【Chemistry 11】 During the ceremony, The GpR is selected among radicals according to formula VII, VII' or VII'': 【Chemistry 12】 - identical or different GpG and GpH are selected among radicals according to formula XI or XI'; 【Chemistry 13】 -GpA is selected among radicals according to formula VIII 【Chemistry 14】 wherein A' is selected from among the radicals according to formula VIII', VIII" or VIII'" 【Chemistry 15】 -GpL is selected among radicals according to formula XII 【Chemistry 16】 -GpC is a radical according to formula IX: 【Chemistry 17】 - " ＊ " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=0 then a'=1, and if a=1 then a'=1, 2 or 3; a' is an integer equal to 1, 2 or 3; - b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g, h or l is different from 0; - l is an integer equal to 0 or 1, and if l = 0 then l' = 1, and if l = 1 then l' = 2; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - when e is different from 0, at least one of g, h or l is different from 0; - if a=0 then l=0; -A, A １ , A ２ and A ３ are the same or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with radicals derived from saturated, unsaturated or aromatic rings; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C ｘ is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: when the hydrophobic radical -Hy has 1-GpC, 9≦x≦25; when the hydrophobic radical -Hy has 2-GpC, 9≦x≦15; when the hydrophobic radical -Hy has 3-GpC, 7≦x≦13; when the hydrophobic radical -Hy has 4-GpC, 7≦x≦11; when the hydrophobic radical -Hy has at least 5-GpC, 6≦x≦11; -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups; -R is a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH ２ is a radical selected from the group consisting of a divalent, linear or branched alkyl radical having a functional group, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; A hydrophobic radical -Hy according to formula X is attached to the PLG by: a covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of the PLG (thereby forming an amide function resulting from the reaction of the amine function of the PLG with the acid function of the precursor of the hydrophobic radical -Hy'); and a covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of the PLG (thereby forming an amide functional group resulting from the reaction of the amine functional group of the precursor of the hydrophobic radical -Hy -Hy' with the acid functional group of the PLG), the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is 0<M≦0.5; if the copolyamino acid has several hydrophobic radicals, they may be identical or different, the degree of polymerization DP of the PLG chain is comprised between 5 and 250 in glutamic or aspartic acid units; - Free carboxylic acid is Na ＋ and K. ＋ The compound is in the form of an alkali cation salt selected from the group consisting of:

12. A precursor Hy' of said hydrophobic radical -Hy according to formula X' defined below: 【Chemistry 18】 During the ceremony, The GpR is selected among radicals according to formula VII, VII' or VII'': 【Chemistry 19】 - identical or different GpG and GpH are selected among radicals according to formula XI or XI'; 【Chemistry 20】 -GpA is selected among radicals according to formula VIII 【Chemistry 21】 wherein A' is selected from among the radicals according to formula VIII', VIII" or VIII'" 【Chemical 22】 -GpL is selected among radicals according to formula XII 【Chemistry 23】 -GpC is a radical according to formula IX: 【Chemistry 24】 - " ＊ " indicates the site of attachment of different groups linked by an amide functionality; - a is an integer equal to 0 or 1, and if a=0 then a'=1, and if a=1 then a'=1, 2 or 3; a' is an integer equal to 1, 2 or 3; - b is an integer equal to 0 or 1; - 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; - e is an integer equal to 0 or 1; - g is an integer equal to 0, 1, 2, 3, 4, 5 or 6; - h is an integer equal to 0, 1, 2, 3, 4, 5 or 6, and at least one of g, h or l is different from 0; - l is an integer equal to 0 or 1, and if l = 0 then l' = 1, and if l = 1 then l' = 2; - r is an integer equal to 0, 1 or 2, -s' is an integer equal to 0 or 1; - when e is different from 0, at least one of g, h or l is different from 0; - if a=0 then l=0; -A, A １ , A ２ and A ３ are the same or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms and optionally substituted with radicals derived from saturated, unsaturated or aromatic rings; -B is an unsubstituted radical ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical containing 1 to 9 carbon atoms, optionally containing an aromatic ring; -C ｘ is a monovalent linear or branched alkyl radical, optionally containing cyclic moieties, where x indicates the number of carbon atoms: when the hydrophobic radical -Hy has 1-GpC, 9≦x≦25; when the hydrophobic radical -Hy has 2-GpC, 9≦x≦15; when the hydrophobic radical -Hy has 3-GpC, 7≦x≦13; when the hydrophobic radical -Hy has 4-GpC, 7≦x≦11; when the hydrophobic radical -Hy has at least 5-GpC, 6≦x≦11; -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups; -R is a divalent, linear or branched alkyl radical containing 1 to 12 carbon atoms and having one or more -CONH ２ is a radical selected from the group consisting of a divalent, linear or branched alkyl radical having a functional group, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -Hy, a hydrophobic radical(s) according to formula X, is attached to the PLG by: a covalent bond between the carbonyl of the hydrophobic radical -Hy and the nitrogen atom of the PLG (thereby forming an amide function resulting from the reaction of the amine function of the PLG with the acid function of the precursor of the hydrophobic radical -Hy'); and a covalent bond between the nitrogen atom of the hydrophobic radical -Hy and the carbonyl of the PLG (thereby forming an amide functional group resulting from the reaction of the amine functional group of the precursor of the hydrophobic radical -Hy -Hy' with the acid functional group of the PLG), the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is 0<M≦0.5; if the copolyamino acid has several hydrophobic radicals, they may be identical or different, - Free carboxylic acid is Na ＋ and K. ＋ The compound is in the form of an alkali cation salt selected from the group consisting of:

13. The use of ionic species selected from the group of anions, cations and / or zwitterions to improve the physicochemical stability of said composition.

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