An injection solution at pH 7 comprising at least one basal insulin having a pI of 5.8 to 8.5 and a copolyamino acid having a carboxylate charge and a hydrophobic radical

Abstract

The present invention relates to a physically stable composition in the form of an injectable aqueous solution having a pH of 6.0 to 8.0, comprising at least: a) basal insulins with an isoelectric point (pI) of 5.8 to 8.5, and b) A copolyamino acid having a carboxylate charge and at least one hydrophobic radical.

Description

[Technical field]

[0001] The invention relates to insulin injection therapy for treating diabetes.

[0002] The present invention relates to a physically stable composition in the form of an injectable aqueous solution, the pH of which is comprised between 6.0 and 8.0, comprising at least one basal insulin and a copolyamino acid having a carboxylate charge and a hydrophobic radical, the isoelectric point (pI) of which is comprised between 5.8 and 8.5. [Background technology]

[0003] Insulin therapy, or the treatment of diabetes by insulin injections, has seen significant progress in recent years, in particular due to the development of new insulins that, compared to human insulin, allow an improved simulation of the physiological activity of the pancreas, with a better glycemic correction in patients.

[0004] When type II diabetes is diagnosed in a patient, treatment is carried out gradually. At first, the patient takes oral antidiabetic drugs (OAD), such as metformin. When OAD alone is no longer sufficient to control blood glucose level, depending on the patient's specificity, treatment must be changed and different combination treatments can be carried out. For example, the patient can be treated with insulin glargine type basal insulin or insulin detemir in addition to OAD, and then with basal insulin and prandial insulin depending on the progression of the disease.

[0005] Moreover, today injections of GLP-1 RA analogues are recommended to transition from treatment with OADs to basal / prandial insulin therapy when the latter are no longer able to control glucose levels in the blood.

[0006] GLP-1 RA, Glucagon-Like Peptide-1 Receptor Agonist, is an insulinotropic peptide or incretin, belonging to a family of gut hormones (or gastrointestinal hormones) that stimulate the secretion of insulin when blood sugar is too high, for example after a meal.

[0007] Gut hormones (gastrointestinal hormones) are also called satiety hormones. Specifically, they include GLP-1 RA (glucagon-like peptide-1 receptor agonist) and GIP (glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon), peptide YY, amylin, cholecystokinin, pancreatic polypeptide (PP), ghrelin and enterostatin (which are peptide or protein structures). They also stimulate the secretion of insulin in response to glucose and fatty acids, and as such are potential candidates for the treatment of diabetes.

[0008] Among these, GLP-1 RAs are the ones that have given the best results in drug development to date: they could enable patients affected by type II diabetes to lose weight while maintaining better control of their blood sugar.

[0009] Therefore, GLP-1 RA analogues or derivatives have been developed, in particular to improve their stability.

[0010] On the other hand, to meet their daily insulin requirements, diabetic patients currently utilize roughly two types of insulin with complementary effects: prandial insulin (or so-called fast-acting insulin) and basal insulin (or so-called slow-acting insulin).

[0011] Meal insulin allows for the rapid management (metabolism and / or storage) of glucose provided during meals and snacks. Patients must inject themselves with prandial insulin before each food intake or approximately 2-3 injections per day. The most widely used prandial insulins are: recombinant human insulin, NovoLog® (NOVO NORDISK insulin aspart), Humalog® (ELI LILLY insulin aspart) and Apidra® (SANOFI insulin glulisine).

[0012] Basal insulins ensure the maintenance of blood glucose homeostasis in patients outside of periods of food intake. Essentially, they act to block the production of endogenous glucose (hepatic glucose). The daily dose of basal insulin generally corresponds to 40-50% of the total daily insulin requirement. Depending on the basal insulin used, this dose is distributed in one or two injections, distributed regularly over the course of the day. The most commonly used basal insulins are Levemir® (NOVO NORDISK insulin detemir) and Lantus® (SANOFI insulin glargine).

[0013] For completeness, it should be noted that NPH (insulin NPH for intermediate-acting insulin; Humiline NPH®, Insulatard®) is the oldest basal insulin. This preparation originates from the precipitation of human insulin (anionic at neutral pH) by the cationic protein, protamine. The microcrystals formed in this process are dispersed in an aqueous suspension and dissolve gradually after subcutaneous injection. This gradual dissolution ensures an extended insulin release. However, this release does not ensure a constant insulin concentration over time. The release profile is bell-shaped and lasts only 12-16 hours. Therefore, it is injected twice a day. This NPH basal insulin is much less effective than the modern basal insulins, Levemir® and Lantus®. NPH is an intermediate-acting basal insulin.

[0014] The principle of NPH evolved with the advent of fast-acting insulin analogs, including products called "premixes" that offer both fast and intermediate action. Novolog Mix® (NOVO NORDISK) and Humalog Mix® (ELI LILLY) are formulations that contain fast-acting insulin analogs, Novolog® and Humalog® (partially complexed with protamine). Thus, these formulations contain insulin analog microcrystals, whose action is said to be intermediate, and a portion of insulin that remains soluble, whose action is fast. Although these formulations offer the advantages of fast-acting insulin, they also have the disadvantages of NPH, namely a limited duration of action of 12-16 hours, and insulin released in a "bell" curve. However, these products allow patients to inject intermediate-acting basal insulin along with fast-acting prandial insulin. However, many patients are interested in reducing the number of injections.

[0015] The basal insulins currently on the market can be classified according to the technical solution that makes it possible to obtain a prolonged action; currently, two approaches are used.

[0016] First, that of insulin detemir is its in vivo binding to albumin. It is a pH 7 soluble analogue that contains a fatty acid side chain (tetradecanoyl) attached at position B29, which allows this insulin to bind to albumin in vivo. Its prolonged action is mainly due to this affinity for albumin after subcutaneous injection.

[0017] However, its pharmacokinetic profile cannot be made to last an entire day, so it is most frequently used as a twice-daily injection.

[0018] Another insulin that is soluble at pH 7 is insulin degludec, available as Tresiba®. dIt is commercially available under the name . It also contains a fatty acid side chain attached to insulin (hexadecandioyl-γ-L-Glu).

[0019] Secondly, that of insulin glargine is precipitation at physiological pH. Insulin glargine is an analogue of human insulin obtained by elongation of the C-terminal part of the B chain of human insulin by two arginine residues, substituting the asparagine residue A21 by a glycine residue (US Pat. No. 5,656,722). The addition of the two arginine residues was designed to adjust the pI (isoelectric point) of insulin glargine to physiological pH, making this analogue of human insulin insoluble in physiological media.

[0020] In addition, the substitution of A21 was designed to make insulin glargine stable at acidic pH, so that it can be formulated in the form of an injection solution at acidic pH. Upon subcutaneous injection, the transition of insulin glargine from acidic pH (pH 4-4.5) to physiological pH (neutral pH) causes its precipitation under the skin. The slow redissolution of the insulin glargine microparticles ensures a slow and prolonged action.

[0021] The blood glucose lowering effect of insulin glargine is quasi-constant over a 24-hour period, which allows most patients to require only a single injection per day.

[0022] Insulin glargine is considered the most widely used basal insulin today.

[0023] However, the necessarily acidic pH of basal insulin preparations, consisting of insulin glargine type, with an isoelectric point between 5.8 and 8.5, can be a real problem, since this acidic pH of insulin glargine preparations sometimes causes pain on injection in patients and prevents, among other things, the formulation with other proteins, and in particular with prandial insulin, since the latter are not stable at acidic pH. The inability to formulate prandial insulin at acidic pH is linked to the fact that prandial insulin undergoes a secondary deamidation reaction at position A21 in these conditions, which makes it impossible to meet the stability requirements applicable for injectable drugs.

[0024] So far, in applications WO2013 / 021143A1, WO2013 / 104861A1, WO2014 / 124994A1 and WO2014 / 124993A1 it has been demonstrated that these basal insulins of the insulin glargine type, with an isoelectric point comprised between 5.8 and 8.5, can be solubilized at neutral pH, while maintaining the solubility difference between the in vitro medium (container) and the in vivo medium (subcutaneous), independent of the pH.

[0025] Application WO2013 / 104861A1 describes, inter alia, a composition in the form of an injectable aqueous solution, the pH of which is comprised between 6.0 and 8.0 and which comprises at least: a) one basal insulin having an isoelectric point (pI) comprised between 5.8 and 8.5, and b) a copolyamino acid having a carboxylate charge and a hydrophobic radical.

[0026] These compositions of the prior art have the important disadvantage that they are not stable enough to meet the specifications applicable for pharmaceutical formulations.

[0027] In the examples of the experimental part of this patent application, it is demonstrated that in particular the compositions described in WO2013 / 104861A1 have unsatisfactory stability over time.

[0028] It is therefore necessary to find a solution that would make basal insulin, composed of an isoelectric point (pI) between 5.8 and 8.5, soluble while preserving its basal profile after injection, but also satisfying standard physical stability conditions for insulin-based pharmaceuticals.

[0029] Surprisingly, the Applicant has found that the copolyamino acids having a carboxylate charge and a hydrophobic radical according to the invention not only meet the requirements described in WO 2013 / 104861 A1, but also make it possible to obtain a composition in the form of a solution that is able to provide said composition with improved physical stability, without the need to increase the number of excipients used.

[0030] These performances, never before obtained, are also maintained when the basal insulin, comprised of an isoelectric point between 5.8 and 8.5, is associated in a composition with prandial insulin and / or gastrointestinal hormones.

[0031] Thus, surprisingly, the affinity of the copolyamino acids according to the invention for insulin glargine is increased, in that it makes it possible to obtain solubilization and stabilization of insulin glargine solutions at lower [Hy] / [basal insulin] ratios than in the prior art; in addition, these results are obtained without changing, and even improving, the tendency of insulin glargine to precipitate, as demonstrated in the experimental part.

[0032] This improvement in compatibility also makes it possible to limit the level of exposure to the excipients in the context of long-term treatment.

[0033] The copolyamino acids having a carboxylate charge and a hydrophobic radical Hy according to the invention show excellent resistance to hydrolysis, which can be confirmed in particular by hydrolysis tests under accelerated conditions, for example at basic pH (pH 12).

[0034] In addition, forced oxidation tests, for example of the Fenton oxidation type, show that copolyamino acids bearing carboxylate charges and hydrophobic radicals Hy exhibit good resistance to oxidation. Summary of the Invention

[0035] The invention thus relates to a physically stable composition in the form of an aqueous injection solution, the composition having a pH comprised between 6.0 and 8.0, comprising at least: a) basal insulin with an isoelectric point (pI) of 5.8 to 8.5, and b) a copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to formula X.

[0036] In one embodiment, the invention relates to a composition in the form of an injectable aqueous solution, the composition having a pH between 6.0 and 8.0 and comprising at least: a) basal insulin with an isoelectric point pI of 5.8 to 8.5, and 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 according to the following formula X: [ka] During the ceremony, GpR is selected from the radicals according to formula VII, VII' or VII': [ka] - GpG and GpH, which are identical or different, are selected from radicals according to formula XI or XI'; [ka] -GpA is selected from the radicals according to formula VIII [ka] wherein A' is selected from the radicals according to formula VIII', VIII" or VIII'" [ka] -GpL is selected from the radicals according to formula XII [ka] -GpC is a radical according to formula IX: [ka] - * indicates the attachment site of the different groups linked by the 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; - 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, optionally substituted by radicals derived from saturated, unsaturated or aromatic rings, containing 1 to 8 carbon atoms, -B is a linear or branched alkyl radical, optionally containing an aromatic nucleus, containing 1 to 9 carbon atoms, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -C x is a linear or branched monovalent 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; if the hydrophobic radical -Hy has 5-GpC, then 6≦x≦11; -G is a branched 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 linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms, a linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms 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(s) -Hy according to formula X are 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 function resulting from the reaction between the amine function of the PLG and the acid function 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 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 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 functional group is Na + and K. + The compound is in the form of an alkali metal salt selected from the group consisting of:

[0037] The invention also relates to a method for the preparation of a stable, injectable composition.

[0038] The pH of the composition according to the present invention is comprised between 6.0 and 8.0, preferably between 6.6 and 7.8, and even more preferably between 6.8 and 7.6.

[0039] Said copolyamino acids having a carboxylate charge and a hydrophobic Hy radical are soluble in aqueous solutions having a pH between 6.0 and 8.0, at a temperature of 25° C. and at a concentration of less than 100 mg / ml.

[0040] Said copolyamino acids having a carboxylate charge and a hydrophobic Hy radical are soluble in aqueous solutions having a pH between 6.0 and 8.0, at a temperature of 25° C. and at a concentration of less than 60 mg / ml.

[0041] Copolyamino acids are statistical copolyamino acids in a chain of glutamic and / or aspartic acid units.

[0042] By "alkyl radical" is meant a straight or branched carbon-containing chain that does not contain heteroatoms.

[0043] In the formula: * indicates the attachment sites of the various elements represented.

[0044] By "physically stable composition" is meant a composition that meets the visual inspection criteria set forth in the European, American and International Pharmacopoeias, i.e., a composition that is transparent and free of visible particles, but also colorless.

[0045] By "aqueous solution for injection" is meant a solution in which the solvent is water and which meets the European and US Pharmacopoeia requirements.

[0046] The composition according to the invention in the form of an aqueous solution for injection is a transparent solution. By "transparent 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 as <1151> So, injection <1> It is defined by referring to USP35. <788> According to USP35, <788> In addition, USP38 <787> , <788> and <790> (Specified in USP38 (starting August 1, 2014). In the European Pharmacopoeia, injection solutions must meet the criteria provided in sections 2.9.19 and 2.9.20.

[0047] By "the copolyamino acid is composed of glutamic or aspartic acid units" is meant acyclic linear chains of glutamic or aspartic acid units linked to one another by peptide bonds, said chains presenting a C-terminus corresponding to a carboxylic acid at one end and an N-terminus portion corresponding to an amine at the other end of the chain.

[0048] By "soluble" it is meant suitable to allow the preparation of a clear, particle-free solution at a concentration of less than 100 mg / ml in distilled water at 25°C.

[0049] The radicals Hy, GpR, GpG, GpH, GpA, GpL and GpC are each independently the same or different from one residue to another.

[0050] In one embodiment, the composition according to the invention is characterized in that Hy contains from 15 to 100 carbon atoms.

[0051] In one embodiment, the composition according to the invention is characterized in that Hy contains from 30 to 70 carbon atoms.

[0052] In one embodiment, the composition according to the invention is characterized in that Hy contains from 40 to 60 carbon atoms.

[0053] In one embodiment, the composition according to the invention is characterized in that Hy contains from 20 to 30 carbon atoms.

[0054] In one embodiment, the composition according to the invention is characterized in that Hy contains more than 30 carbon atoms.

[0055] In the formula: * indicates the attachment sites of hydrophobic radicals to PLG or between different GpR, GpG, GpH, GpA, GpL and GpC, resulting in the formation of amide functional groups.

[0056] The Hy radical is attached to the PLG via an amide functionality.

[0057] 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 a nitrogen atom of the PLG, thus forming an amide functionality resulting from the reaction of an amine functionality of the PLG precursor with an acid functionality of the precursor Hy′ of the hydrophobic radical.

[0058] In one embodiment, r=1 or 2 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), A covalent bond between the carbonyl of the hydrophobic radical and the nitrogen atom of PLG (thus 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 amine functional group of PLG).

[0059] In one embodiment, when GpA is a radical according to formula VIIIc and r=1: -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 α1 is combined with

[0060] 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

[0061] In one embodiment, when GpA is a radical according to formula VIIId and r=1, -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 N β2PLG 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 α1 is combined with

[0062] 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 to 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 binds to N α2 , N β1 and N β2 PLG is directly or indirectly bound to N α1 is combined with

[0063] In one embodiment, when r=2, the GpR group attached to the PLG is selected from GpR according to Formula VII.

[0064] In one embodiment, when r=2, the GpR group attached to the PLG is selected from a GpR according to formula VII and the second GpR is selected from a GpR according to formula VII″.

[0065] In one embodiment, when r=2, the GpR attached to the PLG is selected from the GpR according to formula VII″.

[0066] In one embodiment, when r=2, the GpR group attached to the PLG is selected from a GpR according to formula VII″ and the second GpR is selected from a GpR according to formula VII.

[0067] In one embodiment, a=0.

[0068] In one embodiment, h=1 and g=0.

[0069] In one embodiment, h=0 and g=1.

[0070] In one embodiment, r=0, g=1 and h=0.

[0071] In one embodiment, at least one of g, h, or l is different from 0.

[0072] In one embodiment, at least one of g and h is equal to 1.

[0073] In one embodiment, at least one of g and h is equal to 1.

[0074] In one embodiment, a=1 and l=1.

[0075] In one embodiment, when l=0, at least one of g or h is equal to 0.

[0076] In one embodiment, when l=1, at least one of g or h is equal to 0.

[0077] In one embodiment, g+h≧2.

[0078] In one embodiment, g is greater than or equal to 2 (g≧2).

[0079] In one embodiment, h is greater than or equal to 2 (h≧2).

[0080] In one embodiment, g+h≧2 and a and l are equal to 0 (a=l=0).

[0081] In one embodiment, g+h≧2 and b is equal to 0 (b=0).

[0082] In one embodiment, g or h is greater than or equal to 2 (g≧2) and b is equal to 0.

[0083] In one embodiment, g+h≧2, b is equal to zero (b=0), and e is equal to one (e=1).

[0084] 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).

[0085] In one embodiment, the at least one hydrophobic radical -Hy is selected from 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.

[0086] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where r=2, according to formula Xc′ defined below: [ka] wherein GpR 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.

[0087] 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.

[0088] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where r=2, according to formula Xc′ defined below: [ka] wherein GpR 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.

[0089] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where r=2, according to formula Xc′ defined below: [ka] wherein GpR 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.

[0090] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X (wherein l=0) according to formula Xb′ defined below: [ka] During the ceremony, GpR is selected from the radicals according to formula VII, VII' or VII': [ka] -GpG is selected from radicals according to formula XI, XII': [ka] -GpA is selected from the radicals according to formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe ... [ka] -GpC is a radical according to formula IX: [ka] - * indicates the attachment site of the different groups linked by the 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; -A1 is a linear or branched alkyl radical, optionally substituted by a saturated, unsaturated or aromatic ring-derived radical, containing 1 to 6 carbon atoms; -B is a linear or branched alkyl radical, optionally containing an aromatic nucleus, containing 1 to 9 carbon atoms, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -C x is a linear or branched monovalent 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 branched 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 linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms, a linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms 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 Hy radical(s) 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), 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 precursor of the hydrophobic radical -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 functional group is Na + and K. + The compound is in the form of an alkali metal salt selected from the group consisting of:

[0091] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X defined below, where l=0, -GpA is selected from the radicals in formula VIII, where s'=1 and A' is selected from the radicals according to formula VIII'' or VIII''', according to the formula Xb' defined below: [ka] During the ceremony, GpR is selected from the radicals according to formula VII, VII' or VII': [ka] -GpG is selected from the radicals according to formula XI or XI': [ka] -GpA is selected from the radicals according to formula VIIIc or VIIId: [ka] -GpC is a radical according to formula IX: [ka] - * indicates the attachment site of the different groups linked by the amide functionality; - a is an integer equal to 0 or 1, and if a=0 then a'=1, and if a=1 then a'=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 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 1; -A, A2, A3 are identical or different and are linear or branched alkyl radicals, optionally substituted by radicals derived from saturated, unsaturated or aromatic rings, containing 1 to 6 carbon atoms, -B is a linear or branched alkyl radical, optionally containing an aromatic nucleus, containing 1 to 9 carbon atoms, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -C x is a linear or branched monovalent 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; if the hydrophobic radical -Hy has 5-GpC, then 6≦x≦11; The hydrophobic Hy radical(s) 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 precursor of the hydrophobic radical -Hy' with the acid function of the PLG), -G is a branched 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 linear or branched, divalent alkyl radicals containing 1 to 12 carbon atoms, linear or branched, divalent alkyl radicals containing 1 to 12 carbon atoms having one or more -CONH2 functional groups, or unsubstituted ether or polyether radicals 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 functional group is Na + and K. + The compound is in the form of an alkali metal salt selected from the group consisting of:

[0092] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where a=1 and a′=1, according to formula Xa as defined below: [ka] where GpA is a radical according to formula VIII and A' is selected from radicals according to formula VIII', s'=0, and GpA is a radical according to formula VIIIb [ka] GpR, GpG, GpL, GpL, GpC, A1, r, g, h, l and l' have the definitions given above.

[0093] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X (wherein a=1), according to formula Xb defined below: [ka] where GpA is a radical according to formula VIII, A' is selected from 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.

[0094] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where a=1, as defined below: [ka] where GpA is a radical according to formula VIII, A is selected from radicals of 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.

[0095] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where a=1, as defined below: [ka] where GpA is a radical according to formula VIII, A is selected from 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.

[0096] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from hydrophobic radicals according to formula Xe, where 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.

[0097] In one embodiment, r=0 and GpA is selected from radicals according to formulas VIIIa and VIIIb.

[0098] In one embodiment, r=0 and GpA is selected from radicals according to formulas VIIIa and VIIIb.

[0099] In one embodiment, r=0, GpA is selected from radicals according to formulas VIIIa and VIIIb, and h=0.

[0100] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where r=1, according to formula Xc defined below: [ka] where GpR is a radical according to formula VII [ka] GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l, a' and l' have the definitions given above.

[0101] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X, where r=1, according to formula Xc defined below: [ka] where GpR is a radical according to formula VII′ [ka] GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l, a' and l' have the definitions given above.

[0102] In one embodiment, the at least one hydrophobic radical -Hy is selected from 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]

[0103] In one embodiment, r=1, GpR is selected from radicals according to formulae VII' and VII'', and h=0.

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

[0105] In one embodiment, r=1, g=0, GpR is a radical according to formula VII′ and h=1.

[0106] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is selected from a radical according to formula VIIIa or VIIIb, and h=0.

[0107] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is selected from a radical according to formula VIIIa or VIIIb, and h=1.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] In one embodiment, the at least one hydrophobic radical -Hy is selected from the radicals according to formula X defined below: [ka] where GpC is a radical according to formula IX, e=0 and GpC is a radical according to formula IXa. [ka]

[0113] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X defined below: [ka] where GpC is a radical according to formula IX, e=1, b=0, and GpC is a radical according to formula IXd. [ka]

[0114] In one embodiment, the at least one hydrophobic radical -Hy is selected from radicals according to formula X defined below: [ka] where GpC is a radical according to formula IX, e=1 and GpC is a radical according to formula IXb. [ka]

[0115] In one embodiment, said at least one hydrophobic radical -Hy is selected from 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, e=0, b=0, and GpC is a radical according to formula IXc. [ka]

[0116] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from 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.

[0117] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from 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.

[0118] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from 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.

[0119] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from 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.

[0120] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent linear alkyl radical containing 2 to 12 carbon atoms.

[0121] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent linear alkyl radical containing 2 to 6 carbon atoms.

[0122] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent linear alkyl radical containing 2 to 6 carbon atoms.

[0123] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent linear alkyl radical containing 2 to 4 carbon atoms.

[0124] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, straight-chain alkyl radical containing 2 to 4 carbon atoms.

[0125] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent alkyl radical containing 2 carbon atoms.

[0126] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent, straight chain alkyl radical containing 1 to 11 carbon atoms.

[0127] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi is a radical where R is a divalent, straight chain alkyl radical containing 1 to 6 carbon atoms.

[0128] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent alkyl radical containing 2 to 5 carbon atoms and having one or more amide functional groups (-CONH2).

[0129] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, 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).

[0130] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals in which R is a radical selected from the group consisting of radicals represented by the formula: [ka]

[0131] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals in which R is a radical according to formula X1.

[0132] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi is a radical wherein R is a radical according to formula X2.

[0133] In one embodiment, the composition is characterized in that the hydrophobic radicals according to the formulas X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals in which R is linked to the copolyamino acid via an amide function carried by a carbon at the δ or ε position (or at the 4 or 5 position) relative to the amide function (-CONH2).

[0134] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is an unsubstituted linear ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms.

[0135] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi is a radical where R is an ether radical.

[0136] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is an ether radical containing 4 to 6 carbon atoms.

[0137] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a divalent alkyl radical containing 6 carbon atoms.

[0138] In one embodiment, the composition is a hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi, wherein R is of the formula [ka] The radical is an ether radical represented by the formula:

[0139] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi is a radical where R is a polyether radical.

[0140] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals where R is a linear polyether or polyether radical containing 6 to 10 carbon atoms and 2 to 3 oxygen atoms.

[0141] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, 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]

[0142] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi is a radical wherein R is a radical according to formula X3.

[0143] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi is a radical wherein R is a radical according to formula X4.

[0144] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, 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:

[0145] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulas X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals in which R is a polyether radical according to formula X5.

[0146] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulas X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals in which R is a polyether radical according to formula X6. [ka]

[0147] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals according to formula XI', where G is an alkyl radical containing 6 carbon atoms as represented by formula Z: [ka]

[0148] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals according to formula XI, where G is an alkyl radical containing 4 carbon atoms as represented by formula Z: [ka]

[0149] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals according to formula XI, where G is an alkyl radical containing 4 carbon atoms, represented by -(CH2)2-CH(COOH)-.

[0150] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals according to formula XI, where G is an alkyl radical containing 4 carbon atoms, represented by -CH((CH2)2COOH)-.

[0151] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals according to formula XI, where G is an alkyl radical containing 3 carbon atoms represented by -CH2-CH-(COOH).

[0152] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi are radicals according to formula XI, where G is an alkyl radical containing 3 carbon atoms represented by -CH(CH2)COOH)-.

[0153] In one embodiment, the composition comprises a hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xe, Xf, Xg, Xh and Xi, each of which is selected from the group consisting of GpA source is a radical according to formula VIII, wherein A1, A2 or A3 is selected from the group consisting of radicals represented by the following formulae: [ka]

[0154] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulae X, Xa, Xb, Xb', Xc, Xd, 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]

[0155] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulas X, Xa, Xb, Xb', Xd, Xc, Xd, Xe, Xf, Xg, Xh and Xi are selected from the group consisting of radicals according to formula IXe, IXf or IXg, b is equal to 0 and correspond to the following formulas IXh, IXi and IXj, respectively: [ka]

[0156] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formulas X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals corresponding to formula IX or IXe (wherein b=0) and corresponding to formula IXh.

[0157] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical selected from the group consisting of linear alkyl radicals.

[0158] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical selected from the group consisting of branched alkyl radicals.

[0159] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals where Cx is selected from the group consisting of alkyl radicals containing 19 to 14 carbon atoms.

[0160] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals represented by the formula: [ka]

[0161] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, 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.

[0162] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals represented by the formula: [ka]

[0163] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of radicals represented by the formula: [ka]

[0164] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, 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.

[0165] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, 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.

[0166] In one embodiment, the composition is characterized in that the hydrophobic radicals according to the formulas X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of alkyl radicals represented by the formulas: [ka]

[0167] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, 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.

[0168] In one embodiment, the composition is characterized in that the hydrophobic radicals according to the formulas X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are radicals selected from the group consisting of alkyl radicals represented by the formulas: [ka]

[0169] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are selected from the group consisting of radicals selected from the group consisting of alkyl radicals containing 14 to 15 carbon atoms, and the radical GpC according to formula IX is selected from the group consisting of radicals selected from the group consisting of alkyl radicals containing 14 to 15 carbon atoms.

[0170] In one embodiment, the composition is characterized in that the hydrophobic radicals according to formula X, Xa, Xb, Xb', Xc, Xd, Xe, Xf, Xg, Xh and Xi are selected from the group consisting of radicals according to formula IX, GpC, Cx being selected from the group consisting of radicals represented by the following formulas: [ka]

[0171] In one embodiment, when a'=1, x is comprised between 11 and 25 (11≦x≦25). In particular, 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.

[0172] In one embodiment, when a'=2, x is comprised between 9 and 15 (9≦x≦15).

[0173] 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', Xa, Xb', Xc, Xe, Xg and Xh, a'=1 and l'=1, and GpC is a radical according to formula IXe.

[0174] 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', Xa, Xb', Xc, Xe, Xg and Xh, a'=1 and l'=1, and GpC is a radical according to formula IX and e=0.

[0175] 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', Xa, Xb', Xc, Xf, Xg and Xi, a'=2 or l'=2, and GpC is a radical according to formula IXe.

[0176] 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', Xa, Xb', Xc, Xf, Xg and Xi, a'=2 and l'=2, and GpC is a radical according to formula IX and e=0.

[0177] 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', Xa, Xb', Xc, Xe, Xg and Xh, a'=1 and l'=1, and GpC is a radical according to formula IXe.

[0178] 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', Xa, Xb, Xc, Xf, Xg and Xi, a'=2 and l'=2, and GpC is a radical according to formula IXe.

[0179] In one embodiment, the hydrophobic radical Hy is selected from the group of hydrophobic radicals according to formula X, h is 2 or more, and GpC is according to formula IXe.

[0180] In one embodiment, the hydrophobic radical Hy is selected from the group of hydrophobic moieties according to formula X, g is equal to or greater than 2, a, l and h are equal to 0, and GpC is according to formula IXe.

[0181] In one embodiment, the composition is characterized in that the hydrophobic radical is derived from a hydrophobic radical according to the formula X, Xc', Xa, Xb, Xb', Xc, Xe, Xg and Xh, where a'=1 and l'=1, and Cx is selected from the group consisting of linear alkyl radicals.

[0182] In one embodiment, the composition is characterized in that the hydrophobic radical is selected from hydrophobic radicals according to the formulas X, Xc', Xa, Xb, Xb', Xc, Xf, Xg and Xi, where a'=2 or l'=2 and Cx is selected from the group consisting of linear alkyl radicals.

[0183] In one embodiment, the hydrophobic radical -Hy is selected from the group of hydrophobic radicals according to formula X, GpR is a radical according to formula VII, GpH is a radical derived from XI, and GpC is according to formula IX, where e=1, b=0 and x=13.

[0184] 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]

[0185] 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]

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

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

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

[0189] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radicals correspond to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.007 and 0.15.

[0190] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radicals correspond to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.01 and 0.1.

[0191] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radicals correspond to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.02 and 0.08.

[0192] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 9 to 10 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.03 and 0.15.

[0193] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 11 to 12 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.015 and 0.1.

[0194] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 11 to 12 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.02 and 0.08.

[0195] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 13 to 15 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.01 and 0.1.

[0196] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 13 to 15 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.01 and 0.06.

[0197] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radicals correspond to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.007 and 0.3.

[0198] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radicals correspond to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.01 and 0.3.

[0199] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radicals correspond to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.015 and 0.2.

[0200] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 11 to 14 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.1 and 0.2.

[0201] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 15 to 16 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.04 and 0.15.

[0202] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 17 to 18 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.02 and 0.06.

[0203] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises 19 to 25 atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.01 and 0.06.

[0204] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical corresponds to formula X, the radical Cx comprises from 19 to 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.01 and 0.05.

[0205] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids carrying a carboxylate charge and a hydrophobic radical are chosen from copolyamino acids according to formula XXXa′: [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 hydrophobic radicals according to formula X, r=1, and GpR is a radical according to formula VII, -R1 is a hydrophobic radical selected from hydrophobic radicals according to formula X, where r=0 or r=1, GpR is a radical according to formula VII', or a radical selected from the group consisting of H, a C2-C10 linear acyl group, a C4-C10 branched acyl group, benzyl, a terminal "amino acid" unit, and pyroglutamic acid; -R2 is a hydrophobic radical selected from hydrophobic radicals according to formula X, r=1, GpR is a radical according to formula VII or is a radical -NR'R'', R' and R'' are identical or different and are selected from the group consisting of H, C2-C10 linear or branched or cyclic alkyl, benzyl, said alkyl R' and R'' together can form one or more saturated, unsaturated and / or aromatic carbonate 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 consisting of alkali cations; -n+m represents the degree of polymerization DP of the copolyamino acid, ie the average number of monomer units per copolyamino acid chain, where 5≦n+m≦250.

[0206] When the copolyamino acid contains one or more aspartic acid unit(s), the latter may undergo structural rearrangement.

[0207] In one embodiment, the composition according to the invention is characterized in that when the copolyamino acid comprises aspartic acid units, the copolyamino acid may also comprise monomer units according to formula XXXI and / or XXXI'. [ka]

[0208] We refer to copolyamino acids having a carboxylate charge and at least one hydrophobic radical, copolyamino acids according to formula XXXa, as "statistically grafted copolyamino acids".

[0209] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids carrying a carboxylate charge and a hydrophobic radical are chosen from copolyamino acids according to formula XXXa, 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, C4-C10 branched acyl groups, benzyl, terminal "amino acid" units and pyroglutamic acid; -R2 is 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 optionally together forming one or more carbonate, saturated, unsaturated and / or aromatic rings, and optionally containing heteroatoms selected from the group consisting of O, N and S.

[0210] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and a hydrophobic radical is chosen from copolyamino acids according to formula XXXa, and Hy is a radical according to formula X.

[0211] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXa, Hy is a radical according to formula X and r=1.

[0212] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXa, Hy is a radical according to formula X, r=1 and, for GpC, b=0.

[0213] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXa, Hy is a radical according to formula X and GpC is a radical according to formula IX.

[0214] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXa, Hy is a radical according to formula X, GpC is a radical according to formula IX and r=1.

[0215] We refer to copolyamino acids having a carboxylate charge and at least one hydrophobic radical, copolyamino acids according to formula XXXb, as "defined grafted copolyamino acids."

[0216] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids carrying a carboxylate charge and a hydrophobic radical are chosen from the copolyamino acids according to formula XXXb below, according to formula XXXa′, where n=0: [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.

[0217] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXb, according to formula XXXa' (wherein n=0), and R1 or R2 is a hydrophobic radical according to formula X.

[0218] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and a hydrophobic radical are chosen from copolyamino acids according to formula XXXb', according to formula XXXb, where R1=R'1: [ka] wherein m, X, D, R′1 and R2 have the definitions given above, and R2 is a hydrophobic radical according to formula X.

[0219] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and a hydrophobic radical are chosen from copolyamino acids according to formula XXXb″, according to formula XXXb, where R2=R′2: [ka] wherein m, X, D, R1 and R'2 have the definitions given above, and R1 is a hydrophobic radical according to formula X.

[0220] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXb or XXXb″, R1 is a radical according to formula X and GpR is according to formula VII′.

[0221] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXb or XXXb'', R1 is a radical according to formula X and GpR is according to formula VII''.

[0222] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXb or XXXb'', R1 is a hydrophobic radical according to formula X, GpR is according to formula VII' and GpC is according to formula IX.

[0223] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXb or XXXb'', R1 is a hydrophobic radical according to formula X, GpR is according to formula VII' and GpC is according to formula IX.

[0224] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXb or XXXb', R2 is a hydrophobic radical according to formula X, r=1 and GpR is according to formula VII.

[0225] In one embodiment, the composition is characterized in that the copolyamino acids having a carboxylate charge and a hydrophobic radical are chosen from copolyamino acids according to formula XXX below, according to formula XXXa′, where at least one of R1 or R2 is a hydrophobic radical as defined above: [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 hydrophobic radicals according to formula X, r=1, and GpR is a radical according to formula VII, -R1 is a hydrophobic radical selected from hydrophobic radicals according to formula X, where r=0 or r=1, GpR is a radical according to formula VII', or a radical selected from the group consisting of H, a C2-C10 linear acyl group, a C4-C10 branched acyl group, benzyl, a terminal "amino acid" unit, and pyroglutamic acid; -R2 is a hydrophobic radical selected from hydrophobic radicals according to formula X, r=1, GpR is a radical according to formula VII or is a -NR'R'' radical, R' and R'' are the same or different and are selected from the group consisting of H, C2-C10 linear or branched or cyclic alkyl, benzyl, said R' and R'' alkyl optionally together forming one or more carbonate, saturated, unsaturated and / or aromatic rings, optionally containing heteroatoms selected from the group consisting of O, N and S; - at least one of R1 or R2 is a hydrophobic radical as defined above, -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, ie the average number of monomer units per copolyamino acid chain, where 5≦n+m≦250.

[0226] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and a hydrophobic radical is chosen from copolyamino acids according to formula XXX, XXXa, XXXa', XXXb, XXXb' or XXXb'', in which the D groups are -CH2- groups (aspartic acid units).

[0227] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and a hydrophobic radical is chosen from copolyamino acids according to formula XXX, XXXa, XXXa', XXXb, XXXb' or XXXb'', in which the D groups are -CH2-CH2- groups (glutamic acid units).

[0228] In one embodiment, the composition according to the present invention is a compound in which R1 is C2 to C10 Straight chain acyl groups, C4-C 10 the radical being selected from the group consisting of branched acyl groups of the formula: benzyl, terminal "amino acid" units and polyglutamic acid.

[0229] In one embodiment, the composition according to the present invention is a compound in which R1 is C2 to C 10 Straight chain acyl groups, or C4-C 10 The branched acyl groups are preferably selected from the group consisting of:

[0230] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and a hydrophobic radical is chosen from copolyamino acids according to formula XXXa, XXXb, XXXb' or XXXb'', in which the D groups are -CH2- groups (aspartic acid units).

[0231] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXa, XXXb, XXXb' or XXXb'', the copolyamino acid being selected from copolyamino acids in which the D group is a -CH2-CH2- group (glutamic acid unit).

[0232] In one embodiment, the composition according to the present invention is characterized in that n+m is 10-200.

[0233] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-150.

[0234] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-100.

[0235] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-80.

[0236] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-65.

[0237] In one embodiment, the composition according to the present invention is characterized in that n+m is 20-60.

[0238] In one embodiment, the composition according to the present invention is characterized in that n+m is 20-50.

[0239] In one embodiment, the composition according to the present invention is characterized in that n+m is 20-40.

[0240] 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 from radicals according to formula X defined below: [ka] During the ceremony, GpR is selected from a radical according to formula VII, VII' or VII': [ka] - GpG and GpH, which are identical or different, are selected from radicals according to formula XI or XI'; [ka] -GpA is selected from the radicals according to formula VIII [ka] wherein A' is selected from the radicals according to formula VIII', VIII" or VIII'" [ka] -GpL is selected from the radicals according to formula XII [ka] -GpC is a radical according to formula IX: [ka] - * indicates the attachment site of the different groups linked by the 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 ether or polyether containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical, optionally containing an aromatic nucleus and containing 1 to 9 carbon atoms; -C xis a linear or branched monovalent 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, - 6≦x≦11 if the hydrophobic radical -Hy has at least 5-GpC, -G is a linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional group(s); -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 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(s) -Hy according to formula X are 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 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 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 in glutamic or aspartic acid units for the PLG chain is between 5 and 250; -Free carboxylic acid functional group is Na + and K. + The compound is in the form of an alkali metal salt selected from the group consisting of:

[0241] 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 from a radical according to formula VII, VII' or VII': [ka] - GpG and GpH, which are identical or different, are selected from radicals according to formula XI or XI'; [ka] -GpA is selected from the radicals according to formula VIII [ka] wherein A' is selected from the radicals according to formula VIII', VIII" or VIII'" [ka] -GpL is selected from the radicals according to formula XII [ka] -GpC is a radical according to formula IX: [ka] - * indicates the attachment site of the different groups linked by the 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 ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or a linear or branched alkyl radical, optionally containing an aromatic nucleus and containing 1 to 9 carbon atoms; -C x is a linear or branched monovalent 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, - 6≦x≦11 if the hydrophobic radical -Hy has at least 5-GpC, -G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional group(s); -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 having one or more -CONH2 functional groups(s), or 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 are 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 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 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 functional group is Na + and K. + The compound is in the form of an alkali metal salt selected from the group consisting of:

[0242] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is derived from a polyamino acid obtained by polymerization.

[0243] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is derived from a polyamino acid obtained by ring-opening polymerization of a derivative of glutamic acid N-carboxyanhydride or of a derivative of aspartic acid N-carboxyanhydride.

[0244] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by polymerization of derivatives of glutamic acid N-carboxyanhydride or of aspartic acid N-carboxyanhydride, as described in the article in the journal Adv. Polym. Sci. 2006, 202, 1-18 (Deming, TJ).

[0245] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride.

[0246] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of glutamic acid N-carboxyanhydride selected from the group consisting of polyglutamic acid methyl N-carboxyanhydride (GluOMe-NCA), polyglutamic acid benzyl N-carboxyanhydride (GluOBzl-NCA) and poly-t-butyl glutamate N-carboxyanhydride (GluOtBu-NCA).

[0247] In one embodiment, the glutamic acid N-carboxyanhydride derivative is poly-L-methylglutamate N-carboxyanhydride (L-GluOMe-NCA).

[0248] In one embodiment, the glutamic acid N-carboxyanhydride derivative is poly-L benzyl glutamate N-carboxyanhydride (L-GluOBzl-NCA).

[0249] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by polymerization of derivatives of glutamic acid N-carboxyanhydride or of aspartic acid N-carboxyanhydride by using organometallic compounds of transition metals as initiators, as described in the publication Nature 1997, 390, 386-389 (Deming, TJ).

[0250] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by polymerization of derivatives of glutamic acid N-carboxyanhydride or of aspartic acid N-carboxyanhydride by using ammonia or primary amines as initiators, as described in French patent FR 2,801,226 (Touraud, F., et al.) and the references cited therein.

[0251] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by polymerization of derivatives of glutamic acid N-carboxyanhydride or of aspartic acid N-carboxyanhydride, by using, as initiator, hexamethyldisilazane, as described in the publication J. Am. Chem. Soc. 2007, 129, 14114-14115 (Lu H. et al.), or silylated amines, as described in the publication J. Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H. et al.).

[0252] In one embodiment, the composition according to the invention is characterized in that the process for synthesizing polyamino acids obtained by polymerization of derivatives of glutamic acid N-carboxyanhydride or of aspartic acid N-carboxyanhydride, from which copolyamino acids are derived, comprises a step of ester function hydrolysis.

[0253] In one embodiment, the hydrolysis step of the ester group can consist of hydrolysis in an acidic medium or in a basic medium, or it can be carried out by hydrogenation.

[0254] In one embodiment, the ester group hydrolysis step is hydrolysis in an acidic medium.

[0255] In one embodiment, this ester group hydrolysis step is carried out by hydrogenation.

[0256] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by depolymerization of polyamino acids of higher molecular weight.

[0257] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by enzymatic depolymerization of polyamino acids of higher molecular weight.

[0258] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by chemical depolymerization of polyamino acids of higher molecular weight.

[0259] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by enzymatic and chemical depolymerization of polyamino acids of higher molecular weight.

[0260] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is derived from a polyamino acid obtained by depolymerization of a higher molecular weight polyamino acid selected from the group consisting of sodium polyglutamate and sodium polyaspartate.

[0261] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are derived from polyamino acids obtained by depolymerization of sodium polyglutamate of higher molecular weight.

[0262] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is derived from a polyamino acid obtained by depolymerization of a higher molecular weight sodium polyaspartate.

[0263] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained by grafting hydrophobic groups onto poly-L-glutamic acid or poly-L-aspartic acid by using amide bond formation processes well known to those skilled in the art.

[0264] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained by grafting hydrophobic groups onto poly-L-glutamic acid or poly-L-aspartic acid by using the amide bond formation process used for peptide synthesis.

[0265] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained by grafting hydrophobic groups onto poly-L-glutamic acid or poly-L-aspartic acid, as described in French patent FR 2,840,614 (Chan, YP; et al.).

[0266] Hereafter, the units used for insulin are those recommended by the Pharmacopoeia, whose mg / ml equivalents are provided in the table below: [Table 1]

[0267] By basal insulin with an isoelectric point of 5.8-8.5 is meant insulin that is insoluble at pH 7, the duration of action of which is comprised between 8 and 24 hours or more in standard diabetic models.

[0268] These basal insulins, with an isoelectric point between 5.8 and 8.5, are recombinant insulins whose primary structure has been modified by the introduction of basic amino acids, mainly arginine or lysine, as described, for example, in the following patents, patent applications or publications: WO2003 / 053339, WO2004 / 096854, US5,656,722 and US6,100,376, the contents of which are incorporated by reference.

[0269] In one embodiment, the basal insulin having an isoelectric point of 5.8 to 8.5 is insulin glargine, marketed by SANOFI under the brands Lantus® (100 U / ml) or Toujeo® (300 U / ml).

[0270] In one embodiment the basal insulin having an isoelectric point of 5.8 to 8.5 is biosimilar insulin glargine.

[0271] Biosimilar insulin glargine is marketed under the brands Abasaglar® or Basaglar® by ELI LILLY.

[0272] In one embodiment, the composition according to the invention comprises 40-500 U / ml of basal insulin having an isoelectric point of 5.8-8.5.

[0273] In one embodiment, the composition according to the invention comprises 40 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0274] In one embodiment, the composition according to the invention comprises 75 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0275] In one embodiment, the composition according to the invention comprises a total of 100 U / ml (or about 3.6 mg / mL) of basal insulin with an isoelectric point of 5.8 to 8.5.

[0276] In one embodiment, the composition according to the invention comprises 150 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0277] In one embodiment, the composition according to the invention comprises a total of 200 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5.

[0278] In one embodiment, the composition according to the invention comprises 225 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0279] In one embodiment, the composition according to the invention comprises 250 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0280] In one embodiment, the composition according to the invention comprises 300 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0281] In one embodiment, the composition according to the invention comprises 400 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0282] In one embodiment, the composition according to the invention comprises 500 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5.

[0283] In one embodiment, the mass ratio between basal insulin and copolyamino acid with an isoelectric point comprised between 5.8 and 8.5, or copolyamino acid / basal insulin is comprised between 0.2 and 8.

[0284] In one embodiment, the mass ratio is comprised between 0.2 and 6.

[0285] In one embodiment, the mass ratio is comprised between 0.2 and 5.

[0286] In one embodiment, the mass ratio is comprised between 0.2 and 4.

[0287] In one embodiment, the mass ratio is comprised between 0.2 and 3.

[0288] In one embodiment, the mass ratio is comprised between 0.2 and 2.

[0289] In one embodiment, the mass ratio is comprised between 0.2 and 1.

[0290] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is at most 60 mg / ml.

[0291] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is at most 40 mg / ml.

[0292] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is at most 20 mg / ml.

[0293] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is at most 10 mg / ml.

[0294] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is at most 5 mg / ml.

[0295] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is at most 2.5 mg / ml.

[0296] In one embodiment, the composition according to the invention also comprises prandial insulin. The prandial insulin is soluble at pH 7.

[0297] By prandial insulin is meant so-called fast acting or "regular" insulin.

[0298] So-called fast-acting prandial insulins are insulins which must respond to the needs caused by the intake of protein and sugar in a meal; they must act in less than 30 minutes.

[0299] In one embodiment, the so-called "regular" prandial insulin is human insulin.

[0300] In one embodiment, the prandial insulin is recombinant human insulin as described in the European Pharmacopoeia and the United States Pharmacopoeia.

[0301] Human insulin is commercially available, for example, under the brands Humulin® (ELI LILLY) and Novolin® (NOVO NORDISK).

[0302] The so-called fast-acting prandial insulins are recombinantly derived insulins whose primary structure has been modified to reduce their duration of action.

[0303] 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®).

[0304] In one embodiment, the prandial insulin is insulin lispro.

[0305] In one embodiment, the prandial insulin is insulin glulisine.

[0306] In one embodiment, the prandial insulin is insulin aspart.

[0307] In one embodiment, the composition according to the invention contains a total of 60-800 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8-8.5.

[0308] In one embodiment, the composition according to the present invention contains a total of 100-500 U / ml of insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8-8.5.

[0309] In one embodiment, the composition according to the invention contains a total of 800 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0310] In one embodiment, the composition according to the invention contains a total of 700 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0311] In one embodiment, the composition according to the invention contains a total of 600 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0312] In one embodiment, the composition according to the invention contains a total of 500 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0313] In one embodiment, the composition according to the invention contains a total of 400 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0314] In one embodiment, the composition according to the invention contains a total of 300 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0315] In one embodiment, the composition according to the invention contains a total of 266 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0316] In one embodiment, the composition according to the invention contains a total of 200 U / ml of insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0317] In one embodiment, the composition according to the invention contains a total of 100 U / ml insulin using a combination of prandial insulin and a basal insulin with an isoelectric point of 5.8 to 8.5.

[0318] The ratio between basal insulin with an isoelectric point of 5.8 to 8.5 and prandial insulin is, for example, in percentages, 25 / 75, 30 / 70, 40 / 60, 50 / 50, 60 / 40, 63 / 37, 70 / 30, 75 / 25, 80 / 20, 83 / 17, 90 / 10 for the above-described formulations containing 60 to 800 U / mL. However, any other ratio can also be achieved.

[0319] In one embodiment, the basal insulin having an isoelectric point of 5.8 to 8.5 and the prandial insulin are present in the following concentrations (expressed in U / ml): 75 / 25, 150 / 50, 200 / 66 or 300 / 100, respectively.

[0320] In one embodiment, basal insulin, having an isoelectric point between 5.8 and 8.5, and prandial insulin are present in the following concentrations (expressed in U / ml), respectively, 75 / 25.

[0321] In one embodiment, basal insulin, having an isoelectric point between 5.8 and 8.5, and prandial insulin are present in the following concentrations (expressed in U / ml), respectively, 150 / 50.

[0322] The ratio of hydrophobic radical to basal insulin is defined as the ratio of their respective molar concentrations: [Hy] / [basal insulin] (mol / mol) to obtain the expected performance, i.e. solubilization of basal insulin at a pH of 6.0-8.0, precipitation of basal insulin and stability of the composition according to the invention.

[0323] The lowest measured value of the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is the value at which the basal insulin is solubilized, since this is the lowest effect that can be obtained for solubilization; this solubilization is the condition for all other technical effects that are only observable when the basal insulin is solubilized at a pH between 6.0 and 8.0.

[0324] In the composition according to the invention, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin] may be greater than the minimum value determined by the solubilization limit.

[0325] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦3.

[0326] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦2.

[0327] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦1.75.

[0328] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦1.5.

[0329] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦1.25.

[0330] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦1.00.

[0331] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦0.75.

[0332] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦0.5.

[0333] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] is ≦0.25.

[0334] In one embodiment, the composition according to the invention also comprises a gut hormone.

[0335] By "gastrointestinal hormone" is meant a hormone selected from the group consisting of GLP-1 RA (glucagon-like peptide-1 receptor agonist) and GIP (glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon), YY peptide, amylin, cholecystokinin, pancreatic peptide (PP), ghrelin and enterostatin, their analogs or derivatives and / or pharma- ceutically acceptable salts thereof.

[0336] In one embodiment, the gastrointestinal hormone is an analogue or derivative of a GLP-1 RA selected from the group consisting of: exenatide or Byetta® (ASTRA-ZENECA), liraglutide or Victoza® (NOVO NORDISK), lixisenatide or Lyxumia® (SANOFI), albiglutide or Tanzeum® (GSK) or dulaglutide or Trulicity® (ELI LILLY & CO), analogues or derivatives thereof and / or pharma- ceutically acceptable salts thereof.

[0337] In one embodiment, the gut hormone is pramlintide or Symlin® (ASTRA-ZENECA).

[0338] In one embodiment, the gastrointestinal hormone is exenatide or Byetta®, analogs or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0339] In one embodiment, the gastrointestinal hormone is liraglutide or Victoza®, analogues or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0340] In one embodiment, the gastrointestinal hormone is lixisenatide or Lyxumia®, analogs or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0341] In one embodiment, the gastrointestinal hormone is albiglutide or Tanzeum®, analogues or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0342] In one embodiment, the gastrointestinal hormone is dulaglutide or Trulicity®, analogs or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0343] In one embodiment, the gastrointestinal hormone is pramlintide or Symlin®, analogues or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0344] By "analog" when used in reference to a peptide or protein is meant a peptide or protein in which one or more constituent amino acid residues have been replaced by other amino acid residues, and / or one or more constituent amino acid residues have been removed, and / or one or more constituent amino acid residues have been added. The percentage of homology allowed for this definition of an analog is 50%.

[0345] By "derivative", when used with respect to a peptide or protein, is meant a peptide or protein that has been chemically modified with a substituent not present in the reference peptide or protein or analog, or an analog, i.e., a peptide or protein that has been modified by creating a covalent bond to introduce a substituent.

[0346] In one embodiment, the substituents are selected from the group consisting of aliphatic chains.

[0347] In one embodiment, the concentration of the gastrointestinal hormone comprises 0.01 to 100 mg / mL.

[0348] In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharma- ceutically acceptable salts comprises 0.04-0.5 mg / mL.

[0349] In one embodiment, the concentration of liraglutide, its analogues or derivatives and their pharma- ceutically acceptable salts is comprised between 1 and 10 mg / mL.

[0350] In one embodiment, the concentration of lixisenatide, its analogues or derivatives and their pharma- ceutically acceptable salts is comprised between 0.01 and 1 mg / mL.

[0351] In one embodiment, the concentration of albiglutide, its analogues or derivatives and their pharma- ceutically acceptable salts is comprised between 5 and 100 mg / mL.

[0352] In one embodiment, the concentration of dulaglutide, its analogs or derivatives and their pharma- ceutically acceptable salts is comprised between 0.1 and 10 mg / mL.

[0353] In one embodiment, the concentration of pramlintide, its analogues or derivatives and their pharma- ceutically acceptable salts is comprised between 0.1 and 5 mg / mL.

[0354] In one embodiment, the composition according to the invention is prepared by mixing a commercially available solution of basal insulin having an isoelectric point of 5.8 to 8.5 and a commercially available solution of GLP-1 RA, an analogue or derivative of GLP-1 RA in a volume ratio of 10 / 90 to 90 / 10.

[0355] In one embodiment, the composition according to the invention comprises a daily dose of basal insulin and a daily dose of a gut hormone.

[0356] In one embodiment, the composition according to the invention comprises 40-500 U / ml of basal insulin with an isoelectric point of 5.8-8.5, and 0.05-0.5 mg / mL of exenatide.

[0357] In one embodiment, the composition according to the invention comprises 40-500 U / ml of basal insulin having an isoelectric point of 5.8-8.5, and 1-10 mg / mL of liraglutide.

[0358] In one embodiment, the composition according to the invention comprises a basal insulin composed of 40-500 U / ml with an isoelectric point of 5.8-8.5 and 0.01-1 mg / mL lixisenatide.

[0359] In one embodiment, the composition according to the invention comprises 40-500 U / ml of basal insulin with an isoelectric point of 5.8-8.5 and 5-100 mg / mL of albiglutide.

[0360] In one embodiment, the composition according to the invention comprises 40-500 U / ml of basal insulin having an isoelectric point of 5.8-8.5, and 0.1-10 mg / mL of dulaglutide.

[0361] In one embodiment, the composition according to the invention comprises a basal insulin composed of 500 U / ml with an isoelectric point between 5.8 and 8.5, and 0.04 to 0.5 mg / mL of exenatide.

[0362] In one embodiment, the composition according to the invention comprises basal insulin at 500 U / ml with an isoelectric point of 5.8 to 8.5 and 1 to 10 mg / mL liraglutide.

[0363] In one embodiment, the composition according to the invention comprises a basal insulin composed of 500 U / ml with an isoelectric point between 5.8 and 8.5, and 0.01 to 1 mg / mL lixisenatide.

[0364] In one embodiment, the composition according to the invention comprises 500 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0365] In one embodiment, the composition according to the invention comprises 500 U / ml of basal insulin having an isoelectric point of 5.8 to 8.5, and 0.1 to 10 mg / mL of dulaglutide.

[0366] In one embodiment, the composition according to the invention comprises 400 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5 and 0.04 to 0.5 mg / mL of exenatide.

[0367] In one embodiment, the composition according to the invention comprises 400 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5 and 1 to 10 mg / mL of liraglutide.

[0368] In one embodiment, the composition according to the invention comprises 400 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0369] In one embodiment, the composition according to the invention comprises 400 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0370] In one embodiment, the composition according to the invention comprises 400 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5, and 0.1 to 10 mg / mL of dulaglutide.

[0371] In one embodiment, the composition according to the invention comprises 300 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 0.04 to 0.5 mg / mL of exenatide.

[0372] In one embodiment, the composition according to the invention comprises 300 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5 and 1 to 10 mg / mL of liraglutide.

[0373] In one embodiment, the composition according to the invention comprises 300 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0374] In one embodiment, the composition according to the invention comprises 300 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0375] In one embodiment, the composition according to the invention comprises 300 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5, and 0.1 to 10 mg / mL of dulaglutide.

[0376] In one embodiment, the composition according to the invention comprises a basal insulin of 225 U / ml with an isoelectric point of 5.8 to 8.5 and 0.04 to 0.5 mg / mL of exenatide.

[0377] In one embodiment, the composition according to the invention comprises a basal insulin of 225 U / ml with an isoelectric point of 5.8 to 8.5 and 1 to 10 mg / mL liraglutide.

[0378] In one embodiment, the composition according to the invention comprises a basal insulin composed of 225 U / ml with an isoelectric point between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0379] In one embodiment, the composition according to the invention comprises a basal insulin of 225 U / ml with an isoelectric point between 5.8 and 8.5, and 5 to 100 mg / mL albiglutide.

[0380] In one embodiment, the composition according to the invention comprises a basal insulin composed of 225 U / ml with an isoelectric point of 5.8 to 8.5, and 0.1 to 10 mg / mL of dulaglutide.

[0381] In one embodiment, the composition according to the invention comprises 200 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5 and 0.04 to 0.5 mg / mL of exenatide.

[0382] In one embodiment, the composition according to the invention comprises 200 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5 and 1 to 10 mg / mL of liraglutide.

[0383] In one embodiment, the composition according to the invention comprises 200 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0384] In one embodiment, the composition according to the invention comprises 200 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0385] In one embodiment, the composition according to the invention comprises 200 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5, and 0.1 to 10 mg / mL of dulaglutide.

[0386] In one embodiment, the composition according to the invention comprises 100 U / ml (or about 3.6 mg / mL) of basal insulin with an isoelectric point of 5.8 to 8.5, and 0.04 to 0.5 mg / mL of exenatide.

[0387] In one embodiment, the composition according to the invention comprises 100 U / ml (or about 3.6 mg / mL) of basal insulin with an isoelectric point of 5.8 to 8.5, and 1 to 10 mg / mL of liraglutide.

[0388] In one embodiment, the composition according to the invention comprises 100 U / ml (or about 3.6 mg / mL) of basal insulin with an isoelectric point of 5.8 to 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0389] In one embodiment, the composition according to the invention comprises a basal insulin having an isoelectric point of 5.8 to 8.5 at 100 U / ml and 5 to 100 mg / mL albiglutide.

[0390] In one embodiment, the composition according to the invention comprises a basal insulin having an isoelectric point of 5.8 to 8.5 at 100 U / ml, and 0.1 to 10 mg / mL of dulaglutide.

[0391] In one embodiment, the composition according to the invention comprises a basal insulin composed of 40 U / ml with an isoelectric point between 5.8 and 8.5, and 0.04 to 0.5 mg / mL of exenatide.

[0392] In one embodiment, the composition according to the invention comprises 40 U / ml of basal insulin with an isoelectric point of 5.8 to 8.5 and 1 to 10 mg / mL of liraglutide.

[0393] In one embodiment, the composition according to the invention comprises a basal insulin composed of 40 U / ml with an isoelectric point between 5.8 and 8.5, and 0.01 to 1 mg / mL lixisenatide.

[0394] In one embodiment, the composition according to the invention comprises 40 U / ml of basal insulin with an isoelectric point between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0395] In one embodiment, the composition according to the invention comprises 40 U / ml basal insulin with an isoelectric point of 5.8 to 8.5 and 0.1 to 10 mg / mL dulaglutide.

[0396] The invention also relates to compositions further comprising an ionic species, said ionic species being capable of improving the stability of the composition.

[0397] 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.

[0398] In one embodiment, the ionic species comprises less than 10 carbon atoms.

[0399] 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.

[0400] The ionic species may be used alone or in mixtures, preferably in mixtures.

[0401] In one embodiment, the anion is selected from organic anions.

[0402] In one embodiment, the ionic organic anion contains less than 10 carbon atoms.

[0403] In one embodiment, the organic anion is selected from the group consisting of acetate, citrate and succinate.

[0404] In one embodiment, the anion is selected from anions of inorganic origin.

[0405] In one embodiment, the anion of the inorganic source is selected from the group consisting of sulfate, phosphate and halide, particularly chloride.

[0406] In one embodiment, the cation is selected from organic cations.

[0407] In one embodiment, the organic cation contains less than 10 carbon atoms.

[0408] In one embodiment, the organic cation is selected from the group consisting of ammonium, for example, 2-amino-2-(hydroxymethyl)propane-1,3, wherein the amine is in the ammonium form.

[0409] In one embodiment, the cations are selected from cations of inorganic origin.

[0410] In one embodiment, the cations of the inorganic source are selected from the group consisting of zinc, in particular Zn2+, and alkali metals, in particular Na+ and K+.

[0411] In one embodiment, the zwitterions are selected from zwitterions of organic origin.

[0412] In one embodiment, the zwitterions of organic origin are selected from amino acids.

[0413] In one embodiment, the amino acids are selected from aliphatic amino acids in the group consisting of glycine, alanine, valine, isoleucine and leucine.

[0414] In one embodiment, the amino acid is selected from cyclic amino acids in the group consisting of proline.

[0415] In one embodiment, the amino acid is selected from a hydroxylated or sulfur-containing amino acid in the group consisting of cysteine, serine, threonine, and methionine.

[0416] In one embodiment, the amino acid is selected from aromatic amino acids in the group consisting of phenylalanine, tyrosine and tryptophan.

[0417] 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.

[0418] In one embodiment, the zwitterion of organic origin is selected from the group consisting of amino acids with uncharged side chains.

[0419] In one embodiment, the zwitterion of organic origin is selected from the group consisting of amino diacids or acidic amino acids.

[0420] In one embodiment, the amino diacid is selected from the group consisting of glutamic acid and aspartic acid (optionally in the form of a salt).

[0421] In one embodiment, the zwitterion of organic origin is selected from the group consisting of basic or so-called "cationic" amino acids.

[0422] In one embodiment, the so-called "cationic" amino acids are selected from arginine, histidine and lysine, in particular arginine and lysine.

[0423] In particular, zwitterions contain the same number of negative charges as positive charges at the isoelectric point and / or at a pH comprised between 6.0 and 8.0, thus resulting in a zero overall charge.

[0424] Said ionic species are introduced into the composition in the form of salts. The introduction of these salts can be carried out in solid form before their dissolution in the composition, or in the form of solutions, in particular concentrated solutions.

[0425] For example, the cations of the inorganic source are added in the form of salts selected from sodium chloride, zinc chloride, sodium phosphate, sodium sulfate, and the like.

[0426] By way of example, the anion of the organic source is added in the form of a salt selected from sodium or potassium citrate, sodium acetate.

[0427] For example, the amino acids are added in the form of salts selected from arginine hydrochloride, histidine hydrochloride, or in unsalified form, for example histidine, arginine, and the like.

[0428] In one embodiment, the total molar concentration of the ionic species in the composition is 10 mM or greater.

[0429] In one embodiment, the total molar concentration of ionic species in the composition is 20 mM or greater.

[0430] In one embodiment, the total molar concentration of ionic species in the composition is 30 mM or greater.

[0431] In one embodiment, the total molar concentration of the ionic species in the composition is 50 mM or greater.

[0432] In one embodiment, the total molar concentration of ionic species in the composition is 75 mM or greater.

[0433] In one embodiment, the total molar concentration of the ionic species in the composition is 100 mM or greater.

[0434] In one embodiment, the total molar concentration of ionic species in the composition is 200 mM or greater.

[0435] In one embodiment, the total molar concentration of ionic species in the composition is 300 mM or greater.

[0436] In one embodiment, the total molar concentration of the ionic species in the composition is 500 mM or greater.

[0437] In one embodiment, the total molar concentration of ionic species in the composition is 600 mM or greater.

[0438] In one embodiment, the total molar concentration of ionic species in the composition is 700 mM or greater.

[0439] In one embodiment, the total molar concentration of ionic species in the composition is 800 mM or greater.

[0440] In one embodiment, the total molar concentration of ionic species in the composition is 900 mM or greater.

[0441] In one embodiment, the total molar concentration of ionic species in the composition is 1000 mM or less.

[0442] In one embodiment, the total molar concentration of ionic species in the composition is 1500 mM or less.

[0443] In one embodiment, the total molar concentration of ionic species in the composition is 1200 mM or less.

[0444] In one embodiment, the total molar concentration of ionic species in the composition is 1000 mM or less.

[0445] In one embodiment, the total molar concentration of ionic species in the composition is 900 mM or less.

[0446] In one embodiment, the total molarity of the ionic species in the composition is 800 mM or less.

[0447] In one embodiment, the total molar concentration of ionic species in the composition is 700 mM or less.

[0448] In one embodiment, the total molarity of the ionic species in the composition is 600 mM or less.

[0449] In one embodiment, the total molar concentration of ionic species in the composition is 500 mM or less.

[0450] In one embodiment, the total molar concentration of ionic species in the composition is 400 mM or less.

[0451] In one embodiment, the total molar concentration of ionic species in the composition is 300 mM or less.

[0452] In one embodiment, the total molar concentration of ionic species in the composition is 200 mM or less.

[0453] In one embodiment, the total molar concentration of ionic species in the composition is 100 mM or less.

[0454] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 1000 mM.

[0455] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 1000 mM.

[0456] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 1000 mM.

[0457] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 1000 mM.

[0458] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 1000 mM.

[0459] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 1000 mM.

[0460] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 1000 mM.

[0461] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 1000 mM.

[0462] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 1000 mM.

[0463] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 1000 mM.

[0464] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 1000 mM.

[0465] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 900 mM.

[0466] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 900 mM.

[0467] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 900 mM.

[0468] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 900 mM.

[0469] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 900 mM.

[0470] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 900 mM.

[0471] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 900 mM.

[0472] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 900 mM.

[0473] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 900 mM.

[0474] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 900 mM.

[0475] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 900 mM.

[0476] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 900 mM.

[0477] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 800 mM.

[0478] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 800 mM.

[0479] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 800 mM.

[0480] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 800 mM.

[0481] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 800 mM.

[0482] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 800 mM.

[0483] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 800 mM.

[0484] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 800 mM.

[0485] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 800 mM.

[0486] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 800 mM.

[0487] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 700 mM.

[0488] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 700 mM.

[0489] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 700 mM.

[0490] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 700 mM.

[0491] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 700 mM.

[0492] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 700 mM.

[0493] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 700 mM.

[0494] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 700 mM.

[0495] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 700 mM.

[0496] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 700 mM.

[0497] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 700 mM.

[0498] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 600 mM.

[0499] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 600 mM.

[0500] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 600 mM.

[0501] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 600 mM.

[0502] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 600 mM.

[0503] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 600 mM.

[0504] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 600 mM.

[0505] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 600 mM.

[0506] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 40 and 600 mM.

[0507] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 600 mM.

[0508] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 500 mM.

[0509] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 500 mM.

[0510] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 500 mM.

[0511] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 500 mM.

[0512] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 500 mM.

[0513] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 500 mM.

[0514] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 500 mM.

[0515] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 500 mM.

[0516] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 500 mM.

[0517] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 400 mM.

[0518] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 400 mM.

[0519] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 400 mM.

[0520] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 400 mM.

[0521] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 400 mM.

[0522] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 400 mM.

[0523] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 400 mM.

[0524] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 400 mM.

[0525] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 300 mM.

[0526] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 300 mM.

[0527] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 300 mM.

[0528] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 300 mM.

[0529] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 300 mM.

[0530] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 300 mM.

[0531] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 300 mM.

[0532] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 200 mM.

[0533] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 200 mM.

[0534] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 200 mM.

[0535] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 200 mM.

[0536] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 200 mM.

[0537] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 200 mM.

[0538] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 100 mM.

[0539] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 100 mM.

[0540] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 100 mM.

[0541] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 100 mM.

[0542] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 100 mM.

[0543] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 75 mM.

[0544] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 75 mM.

[0545] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 75 mM.

[0546] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 75 mM.

[0547] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 50 mM.

[0548] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 50 mM.

[0549] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 50 mM.

[0550] In one embodiment, the ionic species is present at a concentration of 5 to 400 mM.

[0551] In one embodiment, the ionic species is present at a concentration of 5 to 300 mM.

[0552] In one embodiment, the ionic species is present at a concentration of 5 to 200 mM.

[0553] In one embodiment, the ionic species is present at a concentration of 5 to 100 mM.

[0554] In one embodiment, the ionic species is present at a concentration of 5 to 75 mM.

[0555] In one embodiment, the ionic species is present at a concentration of 5 to 50 mM.

[0556] In one embodiment, the ionic species is present at a concentration of 5 to 25 mM.

[0557] In one embodiment, the ionic species is present at a concentration of 5 to 20 mM.

[0558] In one embodiment, the ionic species is present at a concentration of 5 to 10 mM.

[0559] In one embodiment, the ionic species is present at a concentration of 10 to 400 mM.

[0560] In one embodiment, the ionic species is present at a concentration of 10 to 300 mM.

[0561] In one embodiment, the ionic species is present at a concentration of 10 to 200 mM.

[0562] In one embodiment, the ionic species is present at a concentration of 10 to 100 mM.

[0563] In one embodiment, the ionic species is present at a concentration of 10 to 75 mM.

[0564] In one embodiment, the ionic species is present at a concentration of 10 to 50 mM.

[0565] In one embodiment, the ionic species is present at a concentration of 10 to 25 mM.

[0566] In one embodiment, the ionic species is present at a concentration of 10-20 mM.

[0567] In one embodiment, the ionic species is present at a concentration of 20 to 300 mM.

[0568] In one embodiment, the ionic species is present at a concentration of 20 to 200 mM.

[0569] In one embodiment, the ionic species is present at a concentration of 20 to 100 mM.

[0570] In one embodiment, the ionic species is present at a concentration of 20 to 75 mM.

[0571] In one embodiment, the ionic species is present at a concentration of 20-50 mM.

[0572] In one embodiment, the ionic species is present at a concentration of 20-25 mM.

[0573] In one embodiment, the ionic species is present at a concentration of 50 to 300 mM.

[0574] In one embodiment, the ionic species is present at a concentration of 50-200 mM.

[0575] In one embodiment, the ionic species is present at a concentration of 50-100 mM.

[0576] In one embodiment, the ionic species is present at a concentration of 50-75 mM.

[0577] Cations of inorganic origin, especially Zn 2+With regard to, its molar concentration in the composition may be 0.25 to 20 mM, in particular 0.25 to 10 mM or 0.25 to 5 mM.

[0578] In one embodiment, the composition comprises zinc.

[0579] In one embodiment, the composition comprises 0.2 to 2 mM zinc.

[0580] In one embodiment, the composition comprises NaCl.

[0581] In one embodiment, NaCl is present at a concentration of 2-25 mM.

[0582] In one embodiment, NaCl is present at a concentration of 2.5 to 20 mM.

[0583] In one embodiment, NaCl is present at a concentration of 4-15 mM.

[0584] In one embodiment, NaCl is present at a concentration of 5-10 mM.

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

[0586] In one embodiment, the composition according to the present invention comprises a buffer at a concentration of 0 to 100 mM.

[0587] In one embodiment, the composition according to the present invention comprises a buffer at a concentration of 15 to 50 mM.

[0588] In one embodiment, the composition according to the invention comprises a buffer selected from the group consisting of phosphate buffer, Tris (trishydroxymethyl) aminomethane and sodium citrate.

[0589] In one embodiment, the buffer is sodium phosphate.

[0590] In one embodiment, the buffer is Tris(trishydroxymethyl)aminomethane.

[0591] In one embodiment, the buffer is sodium citrate.

[0592] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-5000 μM.

[0593] In one embodiment, the composition according to the invention comprises a zinc salt at a concentration of 0 to 4000 μM.

[0594] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-3000 μM.

[0595] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-2000 μM.

[0596] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 0-1000 μM.

[0597] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 50-600 μM.

[0598] In one embodiment, the composition according to the invention also comprises a zinc salt at a concentration of 100-500 μM.

[0599] In one embodiment, the composition according to the invention comprises a zinc salt at a concentration of 200-500 μM.

[0600] In one embodiment, the composition according to the invention also comprises a preservative.

[0601] In one embodiment, the preservative is selected from the group consisting of m-cresol and phenol (alone or in a mixture).

[0602] In one embodiment, the concentration of the preservative is comprised between 10 and 50 mM.

[0603] In one embodiment, the concentration of the preservative is comprised between 10 and 40 mM.

[0604] In one embodiment, the composition according to the present invention further comprises a surfactant.

[0605] In one embodiment, the surfactant is selected from the group consisting of propylene glycol and polysorbates.

[0606] The composition according to the invention may further comprise additives such as isotonicity agents.

[0607] In one embodiment, the tonicity agent is selected from the group consisting of glycerin, sodium chloride, mannitol and glycine.

[0608] The composition according to the invention may further comprise all excipients compatible with insulin used in the concentrations customary according to the pharmacopoeias.

[0609] The invention also relates to pharmaceutical preparations according to the invention, characterized in that they are obtained by drying and / or lyophilization.

[0610] For local and systemic release, possible routes of administration are intravenous, subcutaneous, intradermal or intramuscular.

[0611] Dermal, oral, nasal, intravaginal, ocular, oral and pulmonary routes of administration are also contemplated.

[0612] In one embodiment, the composition according to the invention is characterized in that it is administered once a day.

[0613] In one embodiment, the composition according to the invention is characterized in that it is administered twice a day.

[0614] In one embodiment, the composition according to the invention is characterized in that it is administered twice a day.

[0615] In one embodiment, the composition according to the invention is characterized in that it also contains prandial insulin.

[0616] In one embodiment, the composition according to the invention further comprising at least one prandial insulin is characterized in that it is administered once a day.

[0617] In one embodiment, the composition according to the invention further comprising at least one prandial insulin is characterized in that it is administered at least twice a day.

[0618] In one embodiment, the composition according to the invention further comprising at least one prandial insulin is characterized in that it is administered twice daily.

[0619] In one embodiment, the composition according to the present invention is characterized in that it also comprises a gastrointestinal hormone.

[0620] In one embodiment, the composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered once a day.

[0621] In one embodiment, the composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered at least twice a day.

[0622] In one embodiment, the composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered twice daily.

[0623] In one embodiment, the composition according to the invention is characterized in that the gastrointestinal hormone is GLP-1 RA.

[0624] In one embodiment, the composition according to the invention further comprising a GLP-1 RA is characterized in that it is administered once a day.

[0625] In one embodiment, a composition according to the invention further comprising at least one GLP-1 RA is administered at least twice daily.

[0626] In one embodiment, the composition according to the invention further comprising at least one GLP-1 RA is characterized in that it is administered twice daily.

[0627] The invention also relates to a single dose formulation comprising a basal insulin having an isoelectric point comprised between 5.8 and 8.5, and a pH between 6.0 and 8.0.

[0628] The invention also relates to a single dose formulation comprising a basal insulin with an isoelectric point comprised between 5.8 and 8.5, and one prandial insulin, at a pH between 6.0 and 8.0.

[0629] The invention also relates to a single dose formulation, with a pH between 6.0 and 8.0, comprising a basal insulin having an isoelectric point comprised between 5.8 and 8.5, and a gastrointestinal hormone as defined above.

[0630] The invention also relates to a single dose formulation, with a pH between 6.0 and 8.0, comprising a basal insulin having an isoelectric point comprised between 5.8 and 8.5, a prandial insulin and a gastrointestinal hormone as defined above.

[0631] The invention also relates to a single dose formulation comprising a basal insulin having an isoelectric point comprised between 5.8 and 8.5, and a pH between 6.6 and 7.8.

[0632] The invention also relates to a single dose formulation comprising a basal insulin with an isoelectric point comprised between 5.8 and 8.5, and one prandial insulin, with a pH between 6.6 and 7.8.

[0633] The invention also relates to a single dose formulation, with a pH between 6.6 and 7.8, comprising a basal insulin having an isoelectric point comprised between 5.8 and 8.5, and a gastrointestinal hormone as defined above.

[0634] The invention also relates to a single dose formulation comprising basal insulin with an isoelectric point comprised between 5.8 and 8.5, prandial insulin and a gastrointestinal hormone as defined above, with a pH between 6.6 and 7.8.

[0635] The invention also relates to a single dose formulation comprising a basal insulin having an isoelectric point comprised between 5.8 and 8.5, and a pH between 6.6 and 7.6.

[0636] The invention also relates to a single dose formulation comprising basal insulin with an isoelectric point comprised between 5.8 and 8.5, and prandial insulin, at a pH between 6.6 and 7.6.

[0637] The invention also relates to a single dose formulation, with a pH between 6.6 and 7.6, comprising a basal insulin having an isoelectric point comprised between 5.8 and 8.5, and a gastrointestinal hormone as defined above.

[0638] The invention also relates to a single dose formulation comprising basal insulin with an isoelectric point comprised between 5.8 and 8.5, prandial insulin and a gastrointestinal hormone as defined above, with a pH between 6.6 and 7.6.

[0639] In one embodiment, the single dose formulation further comprises a copolyamino acid as defined above.

[0640] In one embodiment, the formulation is in the form of an injectable solution.

[0641] In one embodiment, the basal insulin having an isoelectric point of 5.8 to 8.5 is insulin glargine.

[0642] In one embodiment, the GLP-1 RA, analog or derivative of GLP-1 RA is selected from the group including exenatide (Byetta®), liraglutide (Victoza®), lixisenatide (Lyxumia®), albiglutide (Tanzeum®), dulaglutide (Trulicity®) or one of their derivatives.

[0643] In one embodiment, the gut hormone is exenatide.

[0644] In one embodiment, the gastrointestinal hormone is liraglutide.

[0645] In one embodiment, the gastrointestinal hormone is lixisenatide.

[0646] In one embodiment, the gut hormone is albiglutide.

[0647] In one embodiment, the gut hormone is dulaglutide.

[0648] The solubilization of basal insulin with an isoelectric point comprised between 5.8 and 8.5 by the copolyamino acids having a carboxylate charge and at least one hydrophobic radical according to the invention at a pH between 6.0 and 8.0 can be easily observed and monitored with the naked eye by a change in the appearance of the solution.

[0649] The solubilization of basal insulin with an isoelectric point comprised between 5.8 and 8.5 by the copolyamino acids having a carboxylate charge and at least one hydrophobic radical according to the invention at a pH between 6.6 and 7.8 can be easily observed and monitored with the naked eye by a change in the appearance of the solution.

[0650] Furthermore, and equally importantly, the Applicant has been able to determine that a basal insulin having an isoelectric point of 5.8 to 8.5, solubilized at a pH of 6.0 to 8.0 in the presence of a copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to the invention, whether alone or in combination with prandial insulin or gut hormones, preserves its slow acting insulin action.

[0651] The Applicant has also been able to confirm that a prandial insulin mixed at a pH of 6.0-8.0 in the presence of a copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to the present invention and a basal insulin having an isoelectric point of 5.8-8.5 preserves its fast-release insulin action.

[0652] It is convenient to prepare the composition according to the invention by simply mixing an aqueous solution of basal insulin with an isoelectric point comprised between 5.8 and 8.5 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. If necessary, the pH of the preparation is adjusted to a pH between 6.0 and 8.0.

[0653] It is convenient to prepare the composition according to the invention by simply mixing an aqueous solution of basal insulin, with an isoelectric point comprised between 5.8 and 8.5, and a solution of 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. If necessary, the pH of the preparation is adjusted to a pH between 6.0 and 8.0.

[0654] It is convenient to prepare the composition according to the invention by simply mixing an aqueous solution of basal insulin with an isoelectric point comprised between 5.8 and 8.5, a solution of GLP-1 RA, an analogue or derivative of GLP-1 RA 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. If necessary, the pH of the preparation is adjusted to a pH between 6.0 and 8.0.

[0655] It is convenient to prepare the composition according to the invention by simply mixing an aqueous solution of basal insulin, with an isoelectric point comprised between 5.8 and 8.5, a solution of prandial insulin, a solution of GLP-1 RA or an analogue or derivative of GLP-1 RA, 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. If necessary, the pH of the preparation is adjusted to a pH between 6.0 and 8.0.

[0656] In one embodiment, the mixture of basal insulin and copolyamino acid is concentrated by ultrafiltration before mixing with prandial insulin in aqueous solution or lyophilized form.

[0657] 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.

[0658] Part A - Synthesis of the intermediate hydrophobic compound Hy allowing to obtain the radical-Hy [ka] TIFF0007637965000093.tif217162TIFF0007637965000094.tif214161TIFF0007637965000095.tif212162TIFF0007637965000096.tif219160TIFF0007637965000097.tif150161Example A1: Molecule A1 molecule 1 : Product obtained by reaction between Fmoc-Lys(Fmoc)-OH and 2-Cl-trityl chloride resin 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 2-Cl-trityl chloride resin (100-200 mesh, 1% DVB, 1.24 mmol / g) (4.00 g, 4.96 mmol), previously washed with dichloromethane, in a reactor adapted 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 dichloromethane (3×60 mL), DMF (2×60 mL), dichloromethane (2×60 mL), isopropanol (1×60 mL) and dichloromethane (3×60 mL).

[0659] Molecule 2: Products obtained by reaction between molecule 1 and an 80:20 DMF / piperidine mixture Molecule 1, previously washed with DMF, is treated with a 80:20 DMF / piperidine mixture (60 mL). After stirring for 30 min at room temperature, the resin is filtered and washed successively with DMF (3×60 mL), isopropanol (1×60 mL) and dichloromethane (3×60 mL).

[0660] Molecule 3: The product obtained by reaction between molecule 2 and Fmoc-Glu(OtBu)-OH DIPEA (8.64 mL, 49.60 mmol) is added 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). After complete solubilization, the resulting solution is poured onto molecule 2. After stirring for 2 h 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).

[0661] Molecule 4: Products obtained by reaction between molecule 3 and a 50:50 DMF / morpholine mixture Molecule 3, previously washed with DMF, is treated with a 50:50 DMF / morpholine mixture (60 mL). After stirring for 1 h 15 min 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).

[0662] 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.

[0663] 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 treated with an 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) mixture (60 mL). After stirring for 20 min at room temperature, the resin is filtered and washed with dichloromethane (2 x 60 mL). The solvent is evaporated under reduced pressure. Two coevaporations are then carried out on the residue 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).

[0664] 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 added successively. The mixture is cooled to 0 ° C and then (3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC, 621 mg, 3.24 mmol) is added. The reaction 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) and 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 acetonitrile. Yield: 2.47g (78%) RMN 1 H(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).

[0665] 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, and the medium is then 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 the pH is then adjusted to 7 by adding an aqueous 1N NaOH solution. The solution is lyophilized and the lyophilizate is then dried by coevaporation in toluene. A white solid of molecule A1 is obtained. Yield: 1.64g (80%) RMN 1 H(D2O, 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).

[0666] Example A2: Molecule A2 Molecule 8: Products obtained by coupling between myristic acid and methyl L-glutamate To a solution of myristic acid (35.0 g, 153.26 mmol) in tetrahydrofuran (THF, 315 mL) at 0 ° C, 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 through a sinter, and then added to an aqueous solution (30 mL) containing methyl L-glutamate (24.95 g, 154.79 mmol) and N,N-diisopropylethylamine (DIPEA, 99.0 g, 766.28 mmol). The reaction mixture is stirred for 48 hours at 20 ° C and then concentrated under reduced pressure. Water (200 mL) is added and the resulting mixture is treated with successive additions 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 adding 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).

[0667] Molecule 9: Products 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). Molecule 10: Coupling product between molecule 9 and N-Boc ethylenediamine

[0668] 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 reaction 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) and saturated aqueous NaCl (500 mL). Methanol (40 ml) is added and 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).

[0669] Molecule A2 To a solution of molecule 10 (27.15 g, 41.33 mmol) in a mixture of DCM / methanol (410 mL) at 0° C., a 4N solution of HCl 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 the chloride salt 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(1H);8.14(1H). LC / MS(ESI+):557.3(calculation([M+H] + ):557.4).

[0670] Example A3: Molecule A3 Molecule 11: Products obtained by coupling between myristoyl chloride and L-proline To a solution of L-proline (300.40 g, 2.61 mol) in 2N aqueous sodium solution (1.63 L) at 0° C., myristoyl chloride (322 g, 1.30 mol) dissolved in dichloromethane (DCM, 1.63 L) is added gradually over 1 hour. At the end of this addition, the reaction medium is allowed to warm to 20° C. over 3 hours and then stirred for a further 2 hours. The mixture is cooled to 0° C. and then 37% aqueous HCl solution (215 mL) is added over 15 minutes. The reaction medium is stirred from 0° C. to 20° C. for 1 hour. The organic phase is separated, washed with 10% aqueous HCl solution (3×430 mL), saturated aqueous NaCl solution (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 allowed to warm to room temperature. After initiating the crystallization with a glass rod, the medium is again heated to 40° C. for 30 minutes and then allowed to return to room temperature for 4 hours. A white solid is obtained after sinter filtration, washed with heptane (2×350 mL) and dried 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;651.7(calculation([M+H] + ):326.3;([2M+H] + ):651.6).

[0671] 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 solubilization in refluxing acetone, cooling to room temperature and sinter filtration. The filtrate is evaporated and the residue is precipitated in acetone as above, this operation being 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 (2H);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).

[0672] Molecule 13: Coupling product 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 BocEDA (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).

[0673] 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).

[0674] Example A4: Molecule A4 Molecule 14: Coupling product 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).

[0675] Molecule 15: Products obtained by coupling between molecule 14 and methyl L-glutamate 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 1H(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(0.15);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).

[0676] Molecule 16: Coupling product 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 BocEDA (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).

[0677] 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 1H(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).

[0678] Example A5: Molecule A5 Molecule 17: Product obtained by 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 min 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 adding 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).

[0679] 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 is 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).

[0680] Molecule A5 A process similar to that used for the preparation of molecule A2 is applied to molecule 18 (30.0 g, 38.91 mmol) to obtain a white solid of molecule A5 in the form of its hydrochloride salt 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).

[0681] 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).

[0682] Molecule 22: The product obtained by coupling between molecule 21 and N-Boc-methyl 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 N-Boc-methyl 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).

[0683] 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 treated with the slow addition of an aqueous solution of LiOH (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 the addition of 10% aqueous HCl. The aqueous phase is extracted with DCM (2×300 mL), the organic phases are combined, washed with saturated aqueous NaCl solution (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).

[0684] 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 2N NaOH solution (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(0.4H). LC / MS(ESI):887.7(calculation([MH] + ):887.7).

[0685] Example A5a: Molecule A5a molecule 3a : Product obtained by reaction between Fmoc-Lys(Fmoc)-OH and 2-Cl-trityl chloride resin 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 2-Cl-trityl chloride resin (100-200 mesh, 1% DVB, 1.24 mmol / g) (4.00 g, 4.96 mmol) previously washed with DCM in a reactor used 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).

[0686] Molecule 4a: Products obtained by reaction between molecule 3a and a 80:20 DMF / piperidine mixture Molecule 3a, previously washed with DMF, is treated with a 80:20 DMF / piperidine mixture (60 mL). After stirring for 30 min at room temperature, the resin is filtered and washed successively with DMF (3×60 mL), isopropanol (1×60 mL) and DCM (3×60 mL).

[0687] 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 stirring for 2 h 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).

[0688] 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.

[0689] 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.

[0690] 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 treated with an 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) mixture (60 mL). After stirring for 20 min at room temperature, the resin is filtered and washed with dichloromethane (2 x 60 mL). The solvent is evaporated under low pressure. Two coevaporations are then carried out on the residue 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).

[0691] 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 added successively. The mixture is cooled to 0 ° C and then EDC (819 mg, 4.27 mmol) is added. The reaction 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);1.48-1.70(7H);1.78-1.87(1H);2.14-2.25(4H);3.16-3, 71(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).

[0692] 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).

[0693] 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) in the presence of 10% palladium on carbon (1.9 g) is placed under a hydrogen atmosphere (1 atm) at room temperature overnight. The reaction medium is filtered through a sinter 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).

[0694] Molecule 11a: Coupling product between Boc-1-amino-4,7,10-trioxa-13-tridecanamine (BocTOTA) 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).

[0695] Molecule A6a Molecule A5 a A process similar to that used for the preparation of was applied to molecule 11a (34.9 g, 56.94 mmol) to give the 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).

[0696] Example A8: Molecule A8 molecule 15a : The product 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).

[0697] molecule 16a : 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 min at room temperature. L-Lysine methyl ester dihydrochloride (3.93 g, 16.86 mmol) is added to the reaction medium, stirred for 3 h 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).

[0698] 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) at 0° C., LiOH (505.13 mg, 21.09 mmol) is added, then the medium is stirred for 20 h at room temperature and concentrated under reduced pressure. The aqueous phase is acidified with 1N HCl solution to a pH of 1, 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).

[0699] 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).

[0700] 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).

[0701] Example A9: Molecule A9 Molecule 19a: 13-Methyltetradecanoic acid Magnesium turnings (5.50 g, 226.3 mmol) are introduced into a dry three-neck 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 in THF (60 mL), is added dropwise during 1 hour, during which the medium temperature remains stable at 65-70 °C. The reaction medium is then heated to reflux for 2 hours.

[0702] 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 previously distilled N-methylpyrrolidone (NMP) at 0 °C in a three-neck flask under argon. A slightly warm solution of organomagnesium diluted in THF (50 mL) is then added dropwise to this solution, keeping the temperature of the solution 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 x 75 mL). The organic phase is washed with 1N aqueous HCl solution (100 mL), water (100 mL) and dried over Na2SO4, after which the solution is filtered and concentrated in 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).

[0703] 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 stirring for 40 h at room temperature, the medium is cooled to 0 °C for 20 min and filtered on a sinter. L-leucine (9.77 g, 74.46 mmol), DIPEA (86 mL) and water (150 mL) are added to the filtrate. After stirring for 20 h at room temperature, the medium is diluted in saturated aqueous NaHCO3 solution (200 mL). The aqueous phase is washed with ethyl acetate (2 × 200 mL) and acidified to pH 1 with 2N aqueous HCl solution. The precipitate is filtered, thoroughly rinsed with water and dried in vacuum at 50 °C. The solid is triturated in pentane and sonicated three times, 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).

[0704] 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 redissolved in 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).

[0705] Molecule A9 A process similar to that used in 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-Cl] + ):486.8).

[0706] 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% HCl solution (3×300 mL), aqueous NaCl solution (300 mL), drying over Na2SO4, filtering through cotton and 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).

[0707] 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 stirring for 21 h, 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 stirring for 23 h at room temperature, the reaction medium is concentrated under reduced pressure to obtain an oily mixture 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 adding 6N HCl solution (120 mL) to reach pH 1, then extracted three times with DCM (3×0.6 L). The organic phases are recombined, washed with saturated NaCl solution (0.6 L), dried over Na2SO4, then concentrated under reduced pressure. The resulting foam is redissolved in refluxing acetone (240 mL) for 2 h. After overnight at 10° C., pentane (240 mL) is added dropwise. After stirring for 1 h, the precipitate is collected by vacuum filtration, 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).

[0708] Molecule 24:The product obtained by coupling 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 maintaining the temperature below 5° C. for another 2 hours after the end of the addition. After overnight at room temperature, the reaction medium is poured into a mixture of water / ice (2 kg) and DCM (0.5 L). After stirring for 15 minutes, the phases are separated. The aqueous phase is extracted twice with DCM (2×0.4 L). The organic phases are recombined, 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).

[0709] Molecule A10 A solution of molecule 24 (4.0 g, 3.05 mmol) in ethylenediamine (30 mL) is heated to 50° C. overnight. 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 collected by vacuum filtration, washed with cold acetonitrile (2×20 mL) and then dried under vacuum. Yield: 3.0g (74%) RMN 1H(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).

[0710] Example A11: Molecule A11 Molecule A11 is obtained by conventional methods of solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride (CTC) resin (40.0 g, 1.16 mmol / g).

[0711] Grafting of the first amino acid Fmoc-Lys(Fmoc)-OH (1.5 eq.) 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.

[0712] 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.).

[0713] The Fmoc protecting 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+Na] + ):1894.2).

[0714] 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).

[0715] 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 mixture (1350 mL / 1080 mL) are successively added in small portions tetramethylammonium bromide (46.95 g, 145.63 mmol), acetic acid (416 mL, 7.28 mol) and then KMnO4 (127.85 g, 809.04 mmol), while maintaining the temperature at 11-13 ° C. The reaction medium is then stirred at reflux for 4 hours 30 minutes, cooled to 0 ° C and then acidified to pH 1 with a 37% HCl solution (50 mL). Na2SO3 (186.94 g) is gradually added, while maintaining the temperature at 0-10 ° C, and stirred until the medium is completely colorless. The medium is acidified with 37% HCl solution until pH 1, then water (500 mL) and DCM (500 mL) are added. The phases are separated and the aqueous phase is extracted with DCM (2×500 mL). The organic phases are combined, washed with 10% aqueous HCl solution (400 mL), water (2×400 mL), saturated aqueous NaCl solution (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 1 H(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).

[0716] Molecule 27: The product obtained by coupling between molecule 26 and 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 mL, 676.97 mmol), methyl L-prolinate hydrochloride (56.06 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 solution (2×1 L), 1N aqueous HCl solution (2×1000 mL) and saturated aqueous NaCl solution (2×1000 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil of molecule 27 which is used without further purification. Yield: 77.15g (97%) RMN 1 H(DMSO-d6, ppm):0.79-0.89(12H);0.981.43(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).

[0717] Molecule 28: Products obtained by saponification of molecule 27 To a solution of molecule 27 (77.15 g, 218.22 mmol) in a 1:1 THF / MeOH mixture (1454 mL) is added dropwise at 0° C. A solution of LiOH (7.84 g, 327.33 mmol) in water (727 mL) is added dropwise at 0° C. 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 recombined, washed with water (500 mL), saturated aqueous NaCl (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, which gives 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).

[0718] Molecule A12 Molecule A12 is obtained by conventional solid phase peptide synthesis (SPPS) methods on 2-chlorotrityl chloride (CTC) resin (34.5 g, 1.16 mmol / g).

[0719] Grafting of ethylenediamine (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.

[0720] 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).

[0721] The Fmoc protecting group is removed with a solution of 80:20 DMF / piperidine (10V) (after coupling with lysine) or with a solution of 50% morpholine in DMF (after coupling with glutamic acid).

[0722] The product is cleaved from the resin with 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 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% overall 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).

[0723] 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 solution of HCl in 1,4-dioxane (3.33 M, 11.8 mL, 39.29 mmol) is added. The reaction medium is stirred at room temperature, then poured onto a MeOH / IPE solution (125 mL / 495 mL) cooled by an ice bath. After stirring for 65 hours at room temperature, the precipitate is filtered off on a sinter, washed with IPE (2×90 mL) and dried under reduced pressure at 30° C. Yield: 21.71g (54%) DP(RMN 1 Estimated using H): 4.9 The calculated average molar mass of molecule 29 as 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).

[0724] Molecule 30: Products obtained by coupling between myristoyl chloride and molecule 29 After solubilization of molecule 29 (12.46 g, 9.80 mmol) as hydrochloride in DCM (115 mL), the solution is cooled to 0° C. Then, a solution of triethylamine (2.35 g, 23.24 mmol) and myristoyl chloride (3.16 g, 12.79 mmol) in DCM (16 mL) is added successively. The reaction medium is stirred for 4 h at 0° C. and then for 2 h at temperature, after which it is poured onto IPE (920 mL). After stirring for 14 h 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 using 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).

[0725] 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 mixture is stirred at 0° C. for 2 h and then concentrated under reduced pressure at room temperature. The residue is redissolved 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 using H): 5.2 The calculated average molar mass of molecule A13 in the form of the hydrochloride salt is 1446.9 g / mol. RMN 1 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).

[0726] 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);1.111.68(18H);1.41(9H);1.80-2.38(6H);3.06-3.35(4H);3.37-3.49( 1H);3.51-3,73(1H);4.26-4.31(0.1H);4.45-4.52(0.9H);4.91-5.19(1H);6.97(1H);7.23(0.9H). LC / MS(ESI+):440.4(calculation([M+H] + ):440.3).

[0727] Molecule A14 Using a process similar to that used for the preparation of molecule A2, after application to molecule 31 (8.85 g, 20.13 mmol) in DCM solution, 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 1 H(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).

[0728] Molecule A15 Molecule A15 is obtained by conventional solid phase peptide synthesis method (SPPS) on 2-chlorotrityl chloride (CTC) resin (16.0 g, 1.16 mmol / g).

[0729] Grafting of ethylenediamine (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.

[0730] The coupling of protected Fmoc-Lys(Fmoc)-OH amino acid (3.0 equivalents), Fmoc-Glu(OBn)-OH (4.0 equivalents) and molecule 11 (3.0 equivalents) is carried out in DMF (10 V) (Lys and molecule 11 coupling) or in a 1:1 DCM / DMF mixture (10 V) (Glu coupling) in the presence of HATU (1.0 equivalent relative to acid) and DIPEA (1.5 equivalent relative to acid).

[0731] The Fmoc protecting group is removed with a 80:20 DMF / piperidine solution (10V) (after coupling with lysine) or with 1% DBU in DMF (after coupling with glutamic acid).

[0732] The product is cleaved from the resin using a 50:50 DCM / TFA solution (10 V). After evaporation, 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 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) followed by recrystallization in acetonitrile. Yield: 16.20 g (70% overall 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).

[0733] Example A16: Molecule A16 Molecule 32: Products obtained by SPPS Molecule 32 is obtained by conventional solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride (CTC) resin (50.0 g, 1.14 mmol / g).

[0734] The grafting of the first Fmoc-Glu(OtBu)-OH amino acid (1.3 eq.) is carried out in the presence of DIPEA (2.6 eq.) in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0735] The coupling of the protected Fmoc-Glu(OtBu)-OH amino acid (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).

[0736] The Fmoc protecting group is removed using a 80:20 DMF / piperidine solution (10V).

[0737] 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 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).

[0738] 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 1 H(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).

[0739] 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 filtration of the catalyst over sintered P4 and then over an Omnipore 0.2 μm PTFE hydrophilic membrane, the filtrate is evaporated under reduced pressure to give molecule A16 in the form of a sticky oil. Yield: 31.06g (98%) RMN 1H(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).

[0740] Molecule A17 Molecule A17 is obtained by conventional solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride (CTC) resin (64.66 g, 1.16 mmol / g).

[0741] Grafting of ethylenediamine (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.

[0742] The coupling of the protected Fmoc-Glu(OMe)-OH amino acid (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 1:1 DCM / DMF mixture (10 V) for the coupling of glutamic acid or in DMF (10 V) for the coupling of molecule 28.

[0743] The Fmoc protecting group is removed using a 50:50 DMF / morpholine solution (10V).

[0744] 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 solution (3 x 250 mL), and the aqueous phase is then extracted with MeTHF (1 x 150 mL). The organic phases are recombined, 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 obtain the hydrochloride salt of molecule A17 in the form of a light brown solid. Yield: 12.48 g (30% overall 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).

[0745] 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 hydrogen and then stirred at room temperature for 8 days. After filtration on a pad of Celite / Silica / Celite, 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).

[0746] 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).

[0747] Molecule 36: Products obtained by coupling between molecule 35 and L-prolinate A process similar to that used for the preparation of molecule 27 is applied to molecule 35 (18.00 g, 57.59 mmol)) and methyl L-propionate hydrochloride (14.31 g, 86.39 mmol) to give molecule 36, a yellow oil. Yield: 23.20g (95%) RMN 1 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).

[0748] 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%) RMN1 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).

[0749] Molecule A18 Molecule A18 is obtained by conventional solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride (CTC) resin (26.72 g, 1.16 mmol / g).

[0750] 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), we obtain a yellow oil of molecule A18 in the form of its hydrochloride salt. Yield: 5.53 g (23% overall over 5 steps). RMN 1 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).

[0751] Example A19: Molecule A19 Molecule A19 is synthesized similarly to molecule A16, using molecule 14 instead of molecule 11 during the SPPS step. Total yield (3 steps): 32.6g (81%) RMN 1H(CDCl3, ppm):0.88(3H);1.201.35(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);3.19-3.29 (1H);3.38-3.48(1H);3.55-3.64(1H);3.74-3.82(1H);4.14-4.21(1H);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).

[0752] Example A20: Molecule A20 Molecule A20 is obtained by conventional solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride (CTC) resin (40.00 g, 1.16 mmol / g).

[0753] Grafting of ethylenediamine (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.

[0754] The coupling of protected Fmoc-Lys(Fmoc)-OH amino acid (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).

[0755] The Fmoc protecting group is removed using a 80:20 DMF / piperidine solution (10V).

[0756] 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% overall for 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).

[0757] Part B - Synthesis of hydrophobic copolyamino acids i) copolyamino acids according to the formulae XXXa, XXXb and XXXb', XXXb'' [ka] TIFF0007637965000099.tif195161TIFF0007637965000100.tif139162TIFF0007637965000101.tif2 30161TIFF0007637965000102.tif218162TIFF0007637965000103.tif226162TIFF0007637965000104 .tif174162TIFF0007637965000105.tif232162TIFF0007637965000106.tif200161TIFF0007637965000107.tif82162Copolyamino acid B1: poly-L-glutamate modified at one of its ends by molecule A1 and having a number-average molar mass (Mn) of 2800 g / mol γ-Benzyl-L-glutamic acid N-carboxyanhydride (8.95 g, 34 mmol) is solubilized in anhydrous DMF (34 mL) in a previously oven-dried receiving flask. 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 from 4° C. to room temperature for 68 hours and then heated to 65° C. for 2 hours. 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 dripped dropwise, with stirring, onto a mixture of 1:1 (v / v) diisopropyl ether / water (360 mL). After stirring for 2 h, the heterogeneous mixture is left 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) and 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 against water until the conductivity measurement of the permeate is less than 50 μS / cm. The copolyamino acid solution 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% acetone mass, 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(RMN1 H):26 RMN 1 By H: i = 0.038 The calculated average molar mass of copolyamino acid B1 is 4994 g / mol. Organic HPLC-SEC (calibration): Mn=2800g / mol

[0758] Copolyamino acid B2: poly-L-sodium glutamate modified with molecule A2 (the ester is saponified) and having a number-average molar mass (Mn) of 5200 g / mol Copolyamino acid B2-1 Poly-L-glutamic acid from hexylamine-initiated polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride 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 at 0° C. for 5 hours, from 0° C. to 20° C. for 7 hours, and then at 20° C. for 7 hours. The reaction medium is then heated to 65° C. for 2 hours, cooled to 55° C., and methanol (3300 mL) is introduced over 1 hour 30 minutes. The reaction mixture is then cooled to 0° C. and stirred for 18 hours. 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).

[0759] 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 a sintered P4, then through a 0.2 μm Omnipore hydrophilic PTFE membrane, an aqueous solution of pH 2 (2700 mL) is poured dropwise onto the DMAc solution with stirring over a period of 45 min. After stirring for 18 h, the white precipitate is collected by filtration, washed with water (4×225 mL) and then dried under reduced pressure at 30°C.

[0760] 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 of 2-hydroxypyridine (HOPO, 3.81 g, 34.3 mmol) and then EDC (6.58 g, 34.3 mmol) are added in succession. The reaction medium is stirred for 2 hours at 25°C, filtered through a 0.2 mm woven filter and dripped dropwise, with stirring, onto 2.6 L of water containing 15% by weight NaCl and HCl (pH 2). 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 by filtration and then rinsed with 2 x 100 mL of water. The resulting white solid is solubilized in 1.2 L of water by gradually adding, with stirring, a 1N aqueous NaOH solution 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, with stirring, to pH 13, and then the mixture is stirred for 2 hours. After neutralization to pH 7 by adding 37% HCl solution, the resulting clear solution is purified by ultrafiltration against 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: 22.6mg / g DP(RMN 1 Estimated using 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.

[0761] Copolyamino acid B3: poly-L-sodium glutamate modified with molecule A3 (the ester is 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 of 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 min at 0° C., the reaction medium is stirred for 2 h at 25° C., filtered through a 0.2 mm woven filter and dripped dropwise, with stirring, onto 950 L of water containing 15% by weight of NaCl and HCl (pH 2). At the end of this addition, the pH is readjusted to 2 with 1N HCl solution and the suspension is left overnight. The precipitate is collected by filtration and then rinsed with 3×100 mL of water. The white solid obtained is solubilized in 1 L of water by gradually adding, with stirring, a 1N aqueous NaOH solution up to pH 7. Once solubilization is complete, the pH is adjusted to pH 12 over 2 h and then to pH 13 over 1 h 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 (3M R53SLP). The resulting solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 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 is 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 Estimated using 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.

[0762] Copolyamino acid B4: poly-L-sodium glutamate modified with molecule A4 (the ester is 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 Estimated using 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.

[0763] Copolyamino acid B5: poly-L-sodium glutamate modified with molecule A5 (the ester is 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 Estimated using H): 40 RMN 1By 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.

[0764] Copolyamino acid B7: poly-L-sodium glutamate with a number-average molar mass (Mn) of 2500 g / mol, modified at one of its ends with molecule A7. 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 y-benzyl-L-glutamic acid N-carboxyanhydride (15.89 g, 60.4 mmol), poly-sodium 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

[0765] 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 a solution of molecule A11 (9.51 g, 5.08 mmol) in DMF (50 mL), HOPO (564 mg, 5.08 mmol) and EDC (973 mg, 5.08 mmol) are added in succession. 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 onto a 1:1 H2O / MeOH mixture (10 V), at room temperature, with stirring. After stirring for 4 h, the white precipitate is collected by filtration and washed with diisopropyl ether (2×100 mL), water (2×100 mL) and a 1:1 H2O / MeOH mixture (2×100 mL).

[0766] The resulting solid 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 2 h 30 min of stirring, the white precipitate is collected by filtration, washed with water (2×200 mL) and then dried under reduced pressure.

[0767] The solid obtained is solubilized in N,N-dimethylacetamide (DMAc, 210 mL) and then 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 sintered P4 and then through an Omnipore 0.2 μm PTFE hydrophilic membrane, an aqueous solution of pH 2 containing 15% NaCl (6V) is poured dropwise onto the DMAc solution with stirring over a period of 45 minutes. 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 (600 mL) by adjusting the pH to 7 by adding 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 (3M R53SLP). The resulting solution is filtered through a 0.45 μm filter and purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductivity measurement of the permeate is less than 50 μS / cm (3M R53SLP). 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 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.

[0768] 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-benzyl glutamate modified at one of its ends with molecule A12 γ-Benzyl-L-glutamic acid N-carboxyanhydride (50.00 g, 189.39 mmol) is solubilized in anhydrous DMF (65 mL) in a previously oven-dried receiving flask. The mixture is then stirred until complete dissolution, cooled to 0° C., and 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 into diisopropyl ether (1.8 L) with stirring. The white precipitate is collected by filtration, washed twice with diisopropyl ether and then dried in vacuum at 30° C. to obtain a white solid. Copolyamino acid B14

[0769] Copolyamino acid B14-1 is solubilized in (DMAc, 250 mL) and then Pd / Al2O3 (5.0 g) is added in an argon atmosphere. The mixture is placed in a hydrogen atmosphere (10 bar) and stirred at 60°C for 24 hours. After cooling to room temperature and filtration through a sintered catalyst filtration P4, then an Omnipore 0.2 μm PTFE hydrophilic membrane, an aqueous solution of pH 2 (6 V) is run dropwise over a period of 45 minutes, with stirring, 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) by adding a 1N aqueous soda solution, adjusting the pH to 7. 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 (3M R53SLP). The resulting solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductivity measurement of the permeate is less than 50 μS / cm (3M R53SLP). 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 1H) = 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.

[0770] 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 in a water mixture containing 30% by weight of ethanol at pH 13 for 5 h, to obtain poly-sodium L-glutamate modified with molecule A13 (ester deprotected). Dry extract: 15.7mg / g DP(RMN 1 Estimated using 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.

[0771] 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(RMN1 Estimated using 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.

[0772] 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 process 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 poured dropwise, with stirring, onto water (3 V). After stirring for 16 hours, 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 (carbon filtration and ultrafiltration). Poly-sodium L-glutamate modified with molecule A16 having a deprotected ester is obtained. Dry extract: 28.2mg / g DP(RMN 1 Estimated using 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.

[0773] 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 A process similar to that used for the preparation of copolyamino acid B3 is applied to the hydrochloride salt of molecule A17 (7.35 g, 13.09 mmol) and copolyamino acid B2-1 (11.45 g), together with a saponification step in a water mixture containing 30% by weight of ethanol at pH 13 for 3 hours, to obtain sodium poly-L-glutamate modified with molecule A17 (ester deprotected). Dry extract: 25.7mg / g DP(RMN 1 Estimated using 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.

[0774] 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 h at pH 13 in a water 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 Estimated using 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.

[0775] 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 A process similar to that used for the preparation of copolyamino acid B18 is applied to molecule A19 (32.64 g, 45.97 mmol) and copolyamino acid B2-1 (40.20 g) to obtain sodium poly-L-glutamate modified with molecule A19 (ester deprotected). Dry extract: 26.2mg / g DP(RMN 1 Estimated using 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.

[0776] 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 y-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, is applied to obtain 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.

[0777] ii) copolyamino acids according to the formulae XXXa, XXXb and XXXb', XXXb'' [ka] TIFF0007637965000109.tif187160 Copolyamino acid B7': poly-L-sodium glutamate modified at one of its ends with 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 γ-Benzyl-L-glutamic acid N-carboxyanhydride (10.1 g, 38.4 mmol) is solubilized in anhydrous DMF (19 mL) in a previously oven-dried receiving flask. 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 mL). The white precipitate is collected by filtration, washed twice with diisopropyl ether (5×50 mL), and then dried in vacuum at 30° C., yielding a white solid.

[0778] Copolyamino acid B7' Copolyamino acid B7'-1 (8.33 g, 33.0 mmol) is diluted in trifluoracetic 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 at room temperature for 2 hours and then poured dropwise, with stirring, onto a 1:1 (v / v) mixture of diisopropyl ether and water (0.8 L). After stirring for 2 hours, the heterogeneous mixture is left 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 conductivity measurement of the permeate is less than 50 μS / cm. The resulting solution is filtered through a 0.2 μm filter 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.

[0779] 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 γ-Benzyl-L-glutamic acid N-carboxyanhydride (19.0 g, 72.2 mmol) is solubilized in anhydrous DMF (19 mL) in a previously oven-dried receiving flask. The mixture is then stirred until completely dissolved, 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 L). The white precipitate is collected by filtration, washed twice with diisopropyl ether (5×50 mL), and then dried in vacuum at 30° C., yielding a white solid.

[0780] 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.

[0781] 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 4A (1.5 g) and Amberlite IRN 150 ion exchange resin (1.5 g) are successively introduced. After 1 hour of coil stirring, 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.

[0782] γ-Benzyl-L-glutamic acid N-carboxyanhydride (20.0 g, 76.0 mmol) is solubilized in anhydrous DMF (19 mL) in a previously oven-dried receiving flask. The mixture is then stirred until completely dissolved, cooled to 0° C., and 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 then cooled to room temperature and poured dropwise, with stirring, into diisopropyl ether (0.29 mL). The white precipitate is collected by filtration, washed twice with diisopropyl ether (5×50 mL), and then dried in vacuum at 30° C., yielding a white solid.

[0783] 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 g) 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.

[0784] 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 4A (1.5 g) and Amberlite IRN 150 ion exchange resin (1.5 g) are successively introduced. After 1 hour of coil stirring, 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.

[0785] A process similar to that used for the preparation of copolyamino acid B8-1 is applied to a solution of the previously prepared molecule A9 and to γ-benzyl-L-glutamic acid N-carboxyanhydride (25.5 g, 96.8 mmol) to obtain copolyamino acid B11-1.

[0786] 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 g) to obtain sodium poly-L-glutamate modified at one of its ends with molecule A9. Dry extract: 28.0mg / g DP(RMN 1 Estimated using 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.

[0787] 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 a solution of 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.

[0788] 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.

[0789] Part CE - Copolyamino acid counterexamples [ka] TIFF0007637965000111.tif153159 Copolyamino acids CE1 and CE2 are synthesized using the process described in patent application WO2017211916.

[0790] Part C - Composition Example C1: Fast-acting insulin analog solution (Humalog®) at 100 U / mL This solution is a commercial solution of insulin lispro sold under the name Humalog® by ELI LILLY. This product is a fast-acting insulin analog. The excipients in Humalog® are meta-cresol (3.15 mg / mL), glycerol (16 mg / mL), disodium phosphate (1.88 mg / mL), zinc oxide (to have 0.0197 mg zinc ion / mL), sodium hydroxide and hydrochloric acid (to adjust the pH (pH 7-7.8)) and water.

[0791] Example C2: Fast-acting insulin analog Lispro solution at 100-600 U / mL This is a solution of insulin prepared using insulin lispro powder produced by Gan & Lee. This product is a fast-acting insulin analogue. The excipients used are m-cresol, glycerol, zinc oxide, sodium hydroxide and hydrochloric acid (to adjust the pH (pH 7-7.8)) and water. The zinc concentration is 300 μM per 100 UI / mL of insulin. The concentrations of the other excipients vary as a function of the lispro concentration to obtain the desired concentration in the final formulation.

[0792] Example C3: Long-acting insulin analog solution (Lantus®) at 100 U / mL This solution is a commercial solution of insulin glargine sold by SANOFI under the name Lantus®. This product is a long-acting insulin analogue. The excipients in Lantus® are zinc chloride (30 μg / mL), m-cresol (2.7 mg / mL), glycerol (20 mg / mL), polysorbate 20 (16 μM), sodium hydroxide and hydrochloric acid (to adjust the pH (pH 4)) and water.

[0793] Example C4: Solution of insulin glargine at 100-400 U / mL This is a solution of insulin glargine prepared using insulin glargine powder produced by Gan & Lee. This product is a long-acting insulin analogue. The excipients used are zinc chloride, m-cresol, glycerol, sodium hydroxide and hydrochloric acid (to adjust the pH (pH 4)) and water. The zinc concentration is 460 μM per 100 UI / mL of insulin. The concentrations of the other excipients vary as a function of the glargine concentration to obtain the desired concentration in the final formulation.

[0794] Part CA - Compositions containing insulin glargine Preparation process of CA1: Preparation of a copolyamino / insulin glargine 50 U / mL dilution composition at pH 7.1 by a process using insulin glargine in liquid form (solution) and copolyamino acid in liquid form (solution) To the parent solution of copolyamino acid at pH 7.1, concentrated solutions of meta-cresol and glycerin were added to give a concentration of C 親コポリアミノ酸 / 賦形剤 A solution of (mg / mL) copolyamino acid is obtained. The amount of excipients added is adjusted to obtain a concentration of 35 mM meta-cresol and 184 mM glycerin in a copolyamino acid / insulin glargine 50 U / mL composition at pH 7.1.

[0795] In a sterile container, prepare a volume V of a solution of insulin glargine at a concentration of 100 U / mL as described in C3 or C4. インスリングラルギン , diluted copolyamino acid composition C at pH 7.1 希釈コポリアミノ酸 (mg / mL) / insulin glargine 50 U / mL, C 親コポリアミノ酸 / 賦形剤 Volume V of the solution of the copolyamino acid with a concentration (mg / mL) 親コポリアミノ酸 / 賦形剤 Add 100 ml of 100 ml of 100% NaOH to the flask. Turbidity appears. The pH is adjusted to 7.1 by adding concentrated NaOH and the solution is placed under static conditions at 40° C. for 2 hours until complete solubilization. The visually clear solution is placed at 4° C.

[0796] Preparation process CA2:Preparation of concentrated copolyamino acid / insulin glargine composition at pH 7.1 using copolyamino acid by a process of concentrating a dilute composition The composition of copolyamino / insulin glargine 50 U / mL at pH 7.1 described in Example CA1 is concentrated by ultrafiltration through a 3 kDa membrane of regenerated cellulose (Amicon® Ultra-15 sold by Millipore). At the end of this ultrafiltration step, the retentate is clear and the concentration of insulin glargine in the composition is determined by reversed phase chromatography (RP-HPLC). The concentration of insulin glargine in the composition is then adjusted to the desired value by dilution in a solution of excipients m-cresol / glycerin / Tween 20 to obtain a final m-cresol concentration of 35 mM, Tween 20 of 52 μM and an osmolality of 300 mOsm / kg. The pH is measured and adjusted to pH 7.1 by adding NaOH and concentrated HCl. This solution at pH 7.1 is visually clear and the concentration C of insulin glargine is determined. インスリングラルギン (U / mL) and C コポリアミノ酸 (mg / mL) = C 希釈コポリアミノ酸 (mg / mL) x C insuグラルギン (U / mL) / 50 (U / mL) of copolyamino acid.

[0797] Preparation process CA3: Preparation of a concentrated composition of copolyamino / insulin glargine at pH 7.1 by a process using insulin glargine in liquid form (solution) and copolyamino acid in liquid form (solution) A solution of 220-400 UI / mL of glargine containing the excipients described in Example C4 is added to the parent solution of copolyamino acids at pH 7.1. The concentration of excipients in the glargine solution is adjusted to obtain a meta-cresol concentration of 35 mM and glycerin of 184 mM in the copolyamino acids / insulin glargine composition at pH 7.1. Turbidity appears. The pH is adjusted to 7.1 by adding concentrated NaOH and the solution is placed under static conditions in a 40°C oven for 2 hours until it is completely solubilized. This visually clear solution is placed at 4°C after adding one volume of a concentrated solution of polysorbate 20 to obtain a final concentration of 52 μM.

[0798] Preparation process CA3a: Preparation of a copolyamino / insulin glargine composition at pH 7.1 by a process using insulin glargine in liquid form (solution) and copolyamino acid in liquid form (solution)

[0799] A solution of 100-220 U / mL of glargine is added to the parent solution of copolyamino acid at pH 7.0-7.5, containing the excipients described in Example C4. The concentration of the excipients in the glargine solution is adjusted to obtain a meta-cresol concentration of 35 mM and 230 mM glycerin in the copolyamino acid / insulin glargine composition. Turbidity appears. The pH is adjusted to 7.5 by adding concentrated NaOH, and the solution is left stationary in a 40°C oven for 2 hours until it is completely solubilized. The resulting solution is visually clear.

[0800] Preparation process CA3b: Preparation of a copolyamino / insulin glargine composition at pH 7.1 by a process using insulin glargine in liquid form (solution) and copolyamino acid in liquid form (solution) To the parent solution of copolyamino acid at pH 7.0-7.5, a solution of sodium chloride and a solution of 100-220 U / mL of glargine as described in Example C4 are added in this order. The concentration of excipients in the glargine solution is adjusted to obtain a concentration of m-cresol of 35 mM and glycerin of 230 mM in the copolyamino acid / insulin glargine composition at pH 7.1. Turbidity appears. The pH is adjusted to 7.5 by adding concentrated NaOH and the solution is left stationary in a 40°C oven for 2 hours until it is completely solubilized. The resulting solution is visually clear.

[0801] Copolyamino acid / insulin glargine compositions were prepared by preparation processes CA2, CA3 or CA3a and CA3b with insulin glargine concentrations of, for example, 100 U / mL to 300 U / mL.

[0802] Example CA4: Preparation of a copolyamino acid / insulin glargine 200 U / mL composition at pH 7.1 The copolyamino acid / insulin glargine 200 U / mL composition was インスリングラルギン = 200 U / mL insulin glargine concentration and C コポリアミノ酸 The solution is prepared by the process described in CA2 and CA3 to obtain a copolyamino acid concentration (mg / mL) of

[0803] These compositions are presented in Tables 1 and 1a. [Table 2] [Table 3]

[0804] The copolyamino acids make it possible to solubilize insulin glargine at neutral pH and obtain a clear solution.

[0805] Preparation process CA5: Protocol for determination of the minimum concentration to solubilize insulin glargine 50 U / mL at pH 7.1 Concentrated m-cresol and glycerin solutions are added to the copolyamino acid parent solution at pH 7-7.5. The amount of excipients added is adjusted to obtain a meta-cresol concentration of 35 mM and a glycerin concentration of 184 mM in the copolyamino acid / insulin glargine 50 U / mL composition.

[0806] In a 3 mL vial, 0.5 mL of insulin glargine solution at a concentration of 100 U / mL, as described in Example C3 or C4, is added to a volume of 0.5 mL of the copolyamino acid / m-cresol / glycerin solution, so as to obtain a copolyamino acid / m-cresol / glycerin 50 U / mL composition. A turbidity appears. The pH is adjusted to 7.1 by adding concentrated NaOH, and the solution is left under rest overnight in an oven at 40°C. This operation is carried out for various concentrations of copolyamino acid. After overnight at 40°C, the samples are visually inspected and subjected to static light scattering measurements using a Zetasizer (Malvern) at an angle of 173°. The minimum concentration of copolyamino acid that allows the solubilization of insulin glargine is defined as the lowest concentration at which the copolyamino acid / insulin glargine mixture at pH 7.1 is visually transparent and has a scattering intensity of 1000 kcps (thousands of photons per second) or less.

[0807] The minimum concentrations of the copolyamino acids are given in Table 1b below. [Table 4]

[0808] The copolyamino acids B22, B7 and B13 make it possible to solubilize insulin glargine at a mass concentration of less than or equal to 0.88 mg / mL and at a hydrophobicity / insulin glargine molar ratio of less than or equal to 0.64. [Table 5]

[0809] The copolyamino acids B2, B3, B9, B15, B18, B19 and B21 make it possible to solubilize insulin glargine at a mass concentration of less than or equal to 1.25 mg / mL and at a copolyamino acid / insulin glargine molar ratio of less than or equal to 0.42.

[0810] Preparation process CA6: Determination of the minimum concentration to solubilize 50 U / mL insulin glargine at pH 7.1 The preparation process follows preparation process CA5 with one difference: to the parent solution of copolyamino acid at pH 7-7.5, in addition to the solutions of m-cresol and glycerin, a concentrated solution of sodium chloride is added to achieve the target of the final composition. The results are shown in Table 1d below. [Table 6]

[0811] The addition of salt can reduce the concentration of copolyamino acid B22 to the solubilization threshold of glargine.

[0812] Part CB - Compositions Comprising Insulin Glargine and Insulin Lispro Preparation process CB1: Preparation of Dilute Copolyamino Acid / Insulin Glargine 43 (U / mL) / Insulin Lispro 13.5 (U / mL) Composition of pH 7.1 as described in Example CA1, volume V コポリアミノ酸 / 希釈インスリングラルギン Dilute copolyamino acid / insulin glargine 50 U / mL into one volume V インスリンリスプロ of insulin lispro 100 U / mL solution and water to obtain a copolyamino acid / insulin glargine 43 (U / mL) / insulin lispro 13.5 (U / mL) composition.

[0813] Preparation process CB2: Preparation of concentrated copolyamino acid insulin glargine / insulin lispro at pH 7.1 The concentrated copolyamino acid / insulin glargine 43 (U / mL) / insulin lispro 13.5 composition described in Example CB1 is concentrated by ultrafiltration using a 3 kDa membrane of regenerated cellulose (Amicon® Ultra-15 sold by Millipore). At the end of this ultrafiltration step, the retentate is clear and the concentration of insulin glargine in the composition is determined by reversed phase chromatography (RP-HPLC). The concentrations of insulin glargine and insulin lispro in the composition are then adjusted to the desired values ​​by dilution in a solution of excipients m-cresol / glycerin / Tween 20 to obtain a final m-cresol concentration of 35 mM, Tween of 52 μM and an osmolality of 300 mOsmol / kg. The pH is measured and adjusted to pH 7.1, if necessary, by adding concentrated NaOH and HCl. This visually clear pH 7.1 solution is then adjusted to the insulin glargine concentration C インスリングラルギン (U / mL) and insulin lispro concentration Cインスリンリスプロ =C インスリングラルギン × 0.33 and the copolyamino acid concentration C コポリアミノ酸 (mg / mL) = C 希釈コポリアミノ酸 (mg / mL) x C インスリングラルギン (U / mL) / 50(U / mL). CB3 preparation process: Preparation of concentrated copolyamino acid insulin glargate / insulin lispro at pH 7.1

[0814] Volume V at pH 7.1 as described in Example CA3 濃縮コポリアミノ酸 / インスリングラルギン of the copolyamino acid / insulin glargine concentrated composition, インスリンリスプロ Add one volume of lispro solution to obtain a final concentration of 52 μM. The resulting solution, visually clear, pH 7.1, is equivalent to the insulin glargine concentration C インスリングラルギン (U / mL), insulin lispro concentration C インスリンリスプロ =C インスリングラルギン × 0.33 and the copolyamino acid concentration C コポリアミノ酸 (mg / mL) = C 希釈コポリアミノ酸 (mg / mL) x C インスリングラルギン(U / mL) / 50(U / mL). The concentration of m-cresol is 35 mM and the concentration of glycerin is 230 mM.

[0815] CB4 preparation process: Preparation of diluted copolyamino acids / insulin glargine 75 U / mL / insulin lispro 25 (U / mL) at pH 7.2 A volume of concentrated copolyamino acid / insulin glargine composition with pH 7.2 as described in Example CA3a or CA3b is added with a volume of lispro solution as described in Example C2. The zinc concentration is adjusted to 0.5 mM by adding a concentrated solution of ZnCl2. The pH is adjusted to 7.2 by adding a concentrated solution of hydrochloric acid. The resulting solution is visually clear and has an insulin glargine concentration of 75 U / mL and an insulin lispro concentration of 25 U / mL. The concentration of m-cresol is 35 mM and the concentration of glycerin is 230 mM.

[0816] Preparation process CB5: Preparation of a Copolyamino Acid / Insulin Glargine 150 U / mL / Insulin Lispro 50 U / mL Composition at pH 7.2 A volume of concentrated copolyamino acid / insulin glargine composition as described in Example CA4 or CA5 is added to a volume of lispro solution as described in Example C2. The zinc concentration is adjusted to 1 mM by adding a concentrated solution of ZnCl2. The pH is adjusted to 7.2 by adding a concentrated solution of hydrochloric acid. The resulting solution is visually clear and has an insulin glargine concentration of 150 U / mL and an insulin lispro concentration of 50 U / mL. The concentration of m-cresol is 35 mM and the concentration of glycerin is 230 mM.

[0817] Examples CB2 and CB3: Preparation of a copolyamino acid / insulin glargine 200 U / mL / insulin lispro 66 U / mL composition at pH 7.1 A copolyamino acid / insulin glargine 200 U / mL / insulin lispro 66 U / mL composition was prepared by the process described in CB2 and CB3, and the insulin glargine concentration Cインスリングラルギン = 200U / mL, insulin lispro concentration C インスリンリスプロ = 66 U / mL and copolyamino acid concentration C コポリアミノ酸 Obtain (mg / mL).

[0818] These compositions are presented in Tables 2 and 2a. [Table 7] [Table 8]

[0819] Examples CB4 and CB5: Preparation of concentrated copolyamino acid / insulin glargate / insulin lispro composition at pH 7.2 Copolyaminoacids / insulin glargine 75 U / mL / insulin lispro 25 U / mL and copolyaminoacids / insulin glargine 150 U / mL / insulin lispro 50 U / mL compositions are prepared by the processes described in Examples CB4 and CB5. [Table 9]

[0820] The copolyamino acids make it possible to solubilize insulin glargine in the presence of insulin lispro at neutral pH, leading to a clear solution.

[0821] Part CD - Results A study of the compositions prepared above demonstrates the physical stability of the compositions according to the invention. Example CD1: Dynamic accelerated stability at 25°C A 3 mL vial filled with 1 mL of the copolyaminoacid / insulin glargine composition or the copolyaminoacid / insulin glargine / prandial insulin composition is placed vertically on an orbital shaker. The shaker is placed in an oven at 25° C. and the vial is shaken at 250 rpm. The vial is visually inspected daily / weekly to detect the appearance of visible particles or turbidity. This inspection is performed according to the European Pharmacopoeia recommendations (EP2.9.20): the vial is illuminated with at least 2000 Lux and observed in front of a white background and a black background. The days of stability correspond to the time when at least two vials show visible particles or become turbid.

[0822] The accelerated stability results using copolyamino acid B4 are shown in Table 3. [Table 10]

[0823] Copolyamino acid B4 makes it possible to solubilize insulin glargine at neutral pH in the presence of insulin lispro, leading to a composition with good physical stability.

[0824] Example CD2: Static and accelerated stability at 30°C At least five 3 mL cartridges filled with 1 mL of the copolyamino acid / insulin glargine / prandial insulin composition are placed in an oven at 30° C. under static conditions. The cartridges are visually inspected every other month to detect the appearance of visible particles or turbidity. This inspection is performed according to the recommendations of the European Pharmacopoeia (EP2.9.20): the cartridges are illuminated with at least 2000 Lux and observed in front of a white background and a black background. The weeks of stability correspond to the time when the majority of the cartridges show visible particles or become turbid compared to the reference standard.

[0825] Accelerated stability results under static conditions are presented in Table 4 below. [Table 11]

[0826] Example CD3: Precipitation of insulin glargine after mixing of a copolyamino acid / insulin glargine 75 U / mL / insulin lispro 25 U / mL composition with albumin This test highlights the precipitation of insulin glargine after injection in a simulated physiological medium containing albumin at physiological pH and ionic strength. These conditions make it possible to mimic the behavior of the composition during subcutaneous injection. To 100 μL of the copolyamino acid / insulin glargine 75 U / mL / insulin lispro 25 U / mL composition, 100 μL of a 20 mg / mL bovine albumin solution in phosphate buffer at pH 7.4 is added. After mixing with the composition, the phosphate buffer (PBS or phosphate buffered saline) is concentrated so that the NaCl and phosphate contents are 140 mM and 10 mM, respectively. The precipitation of glargine in this medium is monitored at room temperature (20-25° C.) by measuring the absorbance of the mixture at 450 nm for 30 minutes. The absorbance measurements are carried out using a multiwell plate UV-visible reader.

[0827] The absorbance increases until a plateau is reached. The glargine precipitation time is defined as the time required for the measured absorbance to be 80% or greater of the plateau value. The precipitation times obtained using the compositions described above are shown in Table 5. [Table 12]

[0828] The copolyamino acid / insulin glargine / insulin lispro composition of the invention leads to rapid precipitation of glargine after mixing with a medium simulating a subcutaneous medium.

[0829] Part D: Pharmacokinetics D1: Protocol for measuring the pharmacokinetics of insulin glargine and insulin lispro preparations A study was conducted in dogs to evaluate the pharmacokinetics of insulin following administration of a copolyamino acid B22 / insulin glargine composition (150 U / mL) / insulin lispro (50 U / mL).

[0830] Pharmacokinetic profiles of insulin glargine (the sum of the blood concentrations of insulin glargine and its main metabolite M1) and insulin lispro were obtained for this composition.

[0831] Ten animals, fasted for approximately 17.5 hours, were subcutaneously injected with a dose of 0.68 U / kg insulin. Blood samples were taken to follow the pharmacokinetics of insulin for 16 hours after administration. Glargine, glargine-M1 and lispro levels were determined using specific bioanalytical methods.

[0832] The following were the pharmacokinetic parameters determined: - AUC, which corresponds to the area under the curve of insulin glargine concentrations (and its metabolite, M1) as a function of time, 0-1 h, 0-2 h, and 10-16 h after administration, respectively 0-1h , AUC 0-2h , AUC 10-16h ; - AUC, which corresponds to the area under the curve for the concentration of insulin lispro as a function of time, 0-0.5 hours, 0-1 hour, and 8-16 hours after administration, respectively 0-30min , AUC 0-1h , AUC 8-16h ; - AUC corresponding to the area under the curve from time 0 to the last measurement obtained from the subject last .

[0833] Table 6 below provides various pharmacokinetic parameters for insulin glargine and insulin lispro. [Table 13]

[0834] The results obtained showed that, on the one hand, the glargine component of the formulation is rapidly absorbed (AUC 0-1h ~AUC 0-2h ) but preserves its basic properties and has significant coverage in the last part of the observation period (AUC 10-16h ) is shown.

[0835] On the other hand, the lispro component is rapidly absorbed (AUC 0-30min ~AUC 0-1h ), maintaining its meal characteristics. In fact, no lispro was observed after 8 hours (AUC 8-16h ).

Claims

1. A composition in the form of an aqueous injection solution having a pH of 6.0 to 8.0 and comprising at least: - basal insulin consisting of an isoelectric point pI between 5.8 and 8.5; - a copolyamino acid (PLG) 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 a copolyamino acid according to the formula Xf: 【Chemistry 1】 During the ceremony, GpR is selected from the radicals according to formula VII or VII′: 【Chemistry 2】 - GpG and GpH, which are identical or different, are selected from radicals according to formula XI or XI'; 【Chemistry 3】 -GpA is selected from the radical according to formula VIII: 【Chemistry 4】 wherein s′=1 and Formula VIII is represented by Formula VIIIa; 【Chemistry 5】 -GpC is a radical according to formula IX: 【Chemistry 6】 - ＊ indicates the attachment site of the different groups linked by the amide functionality; -b is an integer equal to 0; -c is equal to 0 and d is equal to 1; - 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; - 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; -A' and A １ are the same or different and are linear or branched alkyl radicals containing 1 to 8 carbon atoms, optionally substituted with radicals derived from saturated, unsaturated or aromatic rings; -B is a linear or branched alkyl radical, optionally containing an aromatic nucleus and containing 1 to 9 carbon atoms, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -C ｘ is a linear or branched monovalent 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 branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional groups; -R is a straight or branched, divalent alkyl radical containing 1 to 12 carbon atoms, one or more -CONH ２ a radical selected from the group consisting of linear or branched, divalent alkyl radicals containing 1 to 12 carbon atoms having a functional group, or unsubstituted ether or polyether radicals containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -Hy hydrophobic radical(s) according to formula Xf are 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 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'); 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 -Hy radical -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 acid 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 composed of glutamic or aspartic acid units of 5 to 250; - Free carboxylic acid functional group is Na ＋ and K. ＋ The compound is in the form of an alkali metal 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 from copolyamino acids according to the following formula XXXa': 【Chemistry 7】 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 from hydrophobic radicals according to formula Xf, r=1, and GpR is a radical according to formula VII, -R １ is a hydrophobic radical selected from hydrophobic radicals according to formula Xf, where r=0 or r=1, GpR is a radical according to formula VII′, or is a radical selected from the group consisting of H, a C2-C10 linear acyl group, a C4-C10 branched acyl group, benzyl, a terminal “amino acid” unit, and pyroglutamic acid; -R ２ is a hydrophobic glutamic acid selected from hydrophobic radicals according to formula Xf, where r=1, GpR is a radical according to formula VII, or is 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 or branched or cyclic alkyl, benzyl, said R' and R'' alkyls together can form one or more carbonate, saturated, unsaturated and / or aromatic ring(s), 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 alkali cations; −n+m represents the degree of polymerization DP of the copolyamino acid, ie 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 according to the following formula XXXa: １ = R' １ and R ２ = R' ２ 3. The composition according to claim 2, characterized in that the copolyamino acids are selected from the group consisting of copolyamino acids according to 【Chemistry 8】 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, a C2-C10 linear acyl group, a C4-C10 branched acyl group, benzyl, a terminal "amino acid" unit, and pyroglutamic acid; -R ２ is the radical -NR'R'', where R' and R'' are the same or different and are selected from the group consisting of H, C2-C10 straight or branched or cyclic alkyl, benzyl, said R' and R'' alkyl together can form one or more carbonate, saturated, unsaturated and / or aromatic ring(s) and can contain heteroatoms selected from the group consisting of O, N and S.

4. 3. The composition according to claim 2, characterized in that the copolyamino acids carrying carboxylate charges and hydrophobic radicals are chosen from the copolyamino acids according to formula XXXb, XXXa′, where n=0: 【Chemistry 9】 In the formula, m, X, D, R １ and R ２ has the definition given above, and at least R １ Or R ２ is a hydrophobic radical according to formula Xf.

5. The copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from the copolyamino acids of formula XXXa′, where n=0, according to formula XXXb, R １ Or R ２ The composition of claim 4, characterized in that: is a hydrophobic radical according to the formula Xf.

6. The copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from the copolyamino acids according to formula XXXb, R ２ 6. The composition according to claim 4, wherein: is a hydrophobic radical according to formula Xf, r=1, and GpR is according to formula VII.

7. R １ is C ２ ~C １０ A straight chain acyl group of C ４ ~C １０ 7. The composition according to claim 2, wherein the radical is selected from the group consisting of branched acyl groups of the formula: ##STR1## benzyl, a terminal "amino acid" unit and pyroglutamic acid.

8. R １ is C ２ ~C １０ or a straight chain acyl group of C ４ ~C １０ 8. The composition according to claim 2, wherein the branched acyl group is a radical selected from the group consisting of:

9. The copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXa′, XXXa or XXXb, wherein the D group is —CH ２ 9. The composition according to claim 2, wherein the copolyamino acids are selected from the group consisting of copolyamino acids having a - group (aspartic acid unit).

10. The copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from copolyamino acids according to formula XXXa′, XXXa or XXXb, wherein the D group is CH ２ -CH ２ 9. The composition according to claim 2, wherein the copolyamino acids are selected from the group consisting of copolyamino acids having a - group (glutamic acid unit).

11. Composition according to any one of claims 1 to 10, characterized in that the basal insulin is insulin glargine, with an isoelectric point comprised between 5.8 and 8.

5.

12. Composition according to any one of claims 1 to 11, characterized in that it contains between 40 and 500 U / mL of basal insulin with an isoelectric point between 5.8 and 8.

5.

13. Composition according to any one of claims 1 to 12, characterized in that the concentration of the copolyamino acid carrying a carboxylate charge and a hydrophobic radical is at most 60 mg / mL.

14. Composition according to any one of claims 1 to 12, characterized in that the concentration of the copolyamino acid carrying a carboxylate charge and a hydrophobic radical is at most 40 mg / mL.

15. Composition according to any one of claims 1 to 12, characterized in that the concentration of the copolyamino acid carrying a carboxylate charge and a hydrophobic radical is at most 20 mg / mL.

16. Composition according to any one of claims 1 to 12, characterized in that the concentration of the copolyamino acid carrying a carboxylate charge and a hydrophobic radical is at most 10 mg / mL.

17. A copolyamino acid (PLG) 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 a copolyamino acid according to the formula Xf: 【Chemistry 10】 During the ceremony, GpR is selected from the radicals according to formula VII or VII′: 【Chemistry 11】 - GpG and GpH, which are identical or different, are selected from radicals according to formula XI or XI'; 【Chemistry 12】 -GpA is selected from the radical according to formula VIII: 【Chemistry 13】 wherein s′=1 and Formula VIII is represented by Formula VIIIa; 【Chemistry 14】 -GpC is a radical according to formula IX: 【Chemistry 15】 - * indicates the site of attachment of different groups linked by an amide functionality; -b is an integer equal to 0; -c is equal to 0 and d is equal to 1; - 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; - 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; -A' and A 1 are identical or different and are linear or branched alkyl radicals, optionally substituted by radicals derived from saturated, unsaturated or aromatic rings, containing from 1 to 8 carbon atoms; -B is a linear or branched alkyl radical, optionally containing an aromatic nucleus and containing 1 to 9 carbon atoms, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -Cx is a linear or branched monovalent 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 branched 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 linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms, a linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms having one or more -CONH 2 functional groups, or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms; -Hy hydrophobic radical(s) according to formula Xf are 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 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'); 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 -Hy radical -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 acid 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 composed of glutamic or aspartic acid units of 5 to 250; the free carboxylic acid functions are in the form of an alkali metal salt selected from the group consisting of Na + and K + .

18. A copolyamino acid which is sodium poly-L-glutamate modified at one of its termini according to the formula: 【Chemistry 16】

Images