An injection solution having a pH of 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

In one embodiment, the composition according to the invention is characterized in that the copolyamino acid carrying a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb: [Formula 1] During the ceremony, D independently represents either a -CH2- group (aspartic acid) or a -CH2-CH2- group (glutamic acid); X represents a cationic entity selected from the group comprising alkali cations, R b and R b ' may be the same or different and may be a hydrophobic radical -Hy or H, a C2-C10 straight-chain acyl group

Description

[Technical field]

[0001] The present 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, comprising at least one basal insulin, which is a copolyamino acid having an isoelectric point (pI) comprised between 5.8 and 8.5 and carrying a carboxylate charge and a hydrophobic radical, and having a pH comprised between 6.0 and 8.0. [Background technology]

[0003] Insulin therapy, or insulin injection diabetes therapy, has seen significant progress in recent years, particularly due to the development of new insulins that provide superior patient glycemic correction compared to human insulin and allow a better simulation of the physiological activity of the pancreas.

[0004] When type II diabetes is diagnosed in a patient, a stepwise treatment is started. The patient first takes an oral antidiabetic drug (OAD), such as metformin. When OAD alone is no longer sufficient to control blood glucose levels, treatment modification must be performed, and various combination treatments can be introduced based on patient specificity. For example, the patient can take OAD plus basal insulin-based treatment, such as insulin glargine or insulin detemir, and then, according to the progression of the disease, basal insulin and prandial insulin-based treatment.

[0005] Moreover, currently, injections of GLP-1 RA analogues are recommended to ensure the transition from OAD treatment to basal / prandial insulin therapy when OAD treatment is no longer able to control blood glucose levels.

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

[0007] Gut hormones are also known as satiety hormones. They include, in particular, 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 have peptide or protein structure). They also stimulate insulin secretion in response to glucose and fatty acids, which makes them potential candidates for treating diabetes by themselves.

[0008] Among the gastrointestinal hormones, GLP-1 RAs are the ones that have given the best results in drug development to date. They have enabled type II diabetes patients to lose weight while having excellent control over their blood sugar.

[0009] Therefore, GLP-1 RA analogues or derivatives have been developed specifically to enhance their stability.

[0010] Moreover, a diabetic patient currently has two types of insulin with complementary action readily available to cover his / her daily insulin requirements: prandial insulin (or so-called fast-acting insulin) and basal insulin (or so-called slow-acting insulin).

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

[0012] Basal insulins help maintain the patient's glucose homeostasis outside of mealtimes. They act essentially to inhibit endogenous glucose production (hepatic glucose). The daily dose of basal insulin is generally equal to 40-50% of the total daily insulin requirement. Depending on the basal insulin used, this dose is distributed in one or two injections at regular intervals during the day. The most commonly used basal insulins are Levemir® (insulin detemir manufactured by NOVO NORDISK) and Lantus® (insulin glargine manufactured by SANOFI).

[0013] To be thorough, it is worth noting that NPH (NPH insulin for intermediate acting insulin; Humulin NPH®, Insulatad®) is the oldest form of basal insulin. This formulation is the result of precipitation of human insulin (anionic at neutral pH) by a cationic protein, protamine. The formed microcrystals are dispersed in an aqueous suspension and are gradually dissolved after subcutaneous injection. This gradual dissolution provides a sustained release of insulin. However, this release does not provide 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 analogues, giving rise to so-called "premixed" products that offer both fast and intermediate action. NovoLog Mix® (NOVO NORDISK) and Humalog Mix® (ELI LILLY) are preparations that contain fast-acting insulin analogues, Novolog® and Humalog® (partially complexed with protamine). Thus, these preparations contain insulin analogue microcrystals that are said to be intermediate-acting and a portion of insulin that remains soluble, which is fast-acting. Although these preparations do indeed 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" shape. However, these products allow patients to inject themselves with intermediate-acting basal insulin together with fast-acting prandial insulin in a single injection. Nevertheless, many patients are eager to reduce the number of injections.

[0015] The basal insulins currently on the market can be classified according to the technical solution used to achieve a sustained action; currently, two approaches are used.

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

[0017] However, its pharmacokinetic profile does not allow for full day coverage, which means that it is generally used as a twice daily injection.

[0018] An additional insulin that is soluble at pH 7 is available under the trade name Tresiba®. dand insulin degludec, available commercially from Sigma Co. It also contains a fatty acid side chain attached to the insulin (hexadecandioyl-γ-L-Glu).

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

[0020] It was also assumed that the substitution of A21 would make insulin glargine stable at acidic pH, allowing it to be formulated in the form of an injection solution at acidic pH. Following subcutaneous injection, the change in insulin glargine from acidic pH (pH 4-4.5) to physiological pH (neutral pH) induces its precipitation subcutaneously. The slow redissolution of insulin glargine microparticles provides a slow sustained action.

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

[0022] Insulin glargine is now considered the most commonly used basal insulin.

[0023] However, the necessarily acidic pH (isoelectric point comprised between 5.8 and 8.5) of basal insulin preparations such as insulin glargine can be a genuine drawback, since this acidic pH of insulin glargine preparations sometimes causes pain on injection in patients and prevents formulation with other proteins, especially prandial insulins, since the latter are not stable at acidic pH. The inability to formulate prandial insulins at acidic pH derives from the fact that under these conditions, prandial insulins undergo a secondary deamidation reaction at position A21, which is not suitable to meet the stability requirements applicable to injectable medicinal products.

[0024] To date, in applications WO2013 / 021143A1, WO2013 / 104861A1, WO2014 / 124994A1 and WO2014 / 124993A1 it has been possible to solubilize these basal insulins, such as insulin glargine, with an isoelectric point comprised between 5.8 and 8.5, 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 WO 2013 / 104861 A1 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, comprising at least (a) a basal insulin (having an isoelectric point pI comprised between 5.8 and 8.5) and (b) a copolyamino acid having a carboxylate charge substituted by a hydrophobic radical.

[0026] These prior art compositions do not make it possible to satisfactorily meet the applicable specifications for pharmaceutical formulations.

[0027] It is therefore necessary to find a solution suitable for solubilizing basal insulin, comprised of an isoelectric point (pI) between 5.8 and 8.5, while preserving its basal profile after injection, and also for meeting standard physical stability requirements for insulin-based pharmaceuticals.

[0028] Surprisingly, the Applicant has discovered 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 furthermore make it possible to obtain a composition in the form of a solution, which is able to meet all requirements without the need to increase the amount of excipients used.

[0029] These performances, never before obtained, are even 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.

[0030] 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; these results are further obtained without compromising and even improving the tendency of insulin glargine to precipitate, as demonstrated in the experimental part.

[0031] This improvement in compatibility further makes it possible to limit the level of exposure to the excipients in the context of long-term treatment.

[0032] 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).

[0033] Moreover, forced oxidation tests, for example of the Fenton oxidation type, demonstrate that copolyamino acids carrying a carboxylate charge and a hydrophobic radical Hy exhibit good resistance to oxidation. Summary of the Invention

[0034] The present invention relates to a physically stable composition in the form of an aqueous injection 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 at least one hydrophobic radical according to formula X, said copolyamino acid being chosen among the copolyamino acids according to formula I.

[0035] The present invention therefore relates to a physically stable composition in the form of an aqueous injection solution, the pH of which is comprised between 6.0 and 8.0 and which comprises at least: a) Basal insulin with an isoelectric point (pI) of 5.8 to 8.5; b) prandial insulin, and c) A copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to formula X, said copolyamino acid being chosen among the copolyamino acids according to formula I.

[0036] The present invention therefore relates to a physically stable composition in the form of an aqueous injection solution, the pH of which is comprised between 6.0 and 8.0 and which comprises at least: a) Basal insulin with an isoelectric point (pI) of 5.8 to 8.5 b) gut hormones, and c) A copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to formula X, said copolyamino acid being chosen among the copolyamino acids according to formula I.

[0037] The present invention therefore relates to a physically stable composition in the form of an aqueous injection solution, the pH of which is comprised between 6.0 and 8.0 and which comprises at least: a) Basal insulin with an isoelectric point (pI) of 5.8 to 8.5 b) Meal insulin and gut hormones, and c) A copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to formula X, said copolyamino acid being chosen among the copolyamino acids according to formula I.

[0038] The present invention therefore relates to a physically stable composition in the form of an aqueous injection solution, the pH of which is comprised between 6.0 and 8.0 and which comprises 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, said copolyamino acid being chosen from among the copolyamino acids according to formula I: [Q(PLG) k ][Hy] j [Hy] j’ Formula I During the ceremony: -j≧1; 0≦j′≦n′1 and j+j′≧1 and k≧2 - said copolyamino acid according to formula I has at least one hydrophobic radical -Hy, a carboxylate charge and at least a divalent linear or branched radical consisting of an alkyl chain containing one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or having one or more heteroatoms consisting of nitrogen and oxygen radicals or a spacer Q[- * ] k and / or a radical having one or more heteroatoms consisting of nitrogen and oxygen atoms, and / or a carboxyl functional group, -the radical or spacer Q[- * ] k is linked to at least two glutamic or aspartic acid unit chains of PLG via amide functional groups, and - the amide functional group is, respectively, a radical or a spacer Q[— * ] k or the radical or spacer Q[-] obtained from the reaction between an amine functional group and an acid functional group of either the glutamic acid or aspartic acid unit, which is bonded to the at least two chains of glutamic acid or aspartic acid units. * ] k Combine the - said hydrophobic radical -Hy is attached to a terminal "amino acid" unit, with j>=1, or to a carboxyl function carried by one of the chains of the glutamic or aspartic acid units PLG, with j'=n'1, n'1 being the average number of monomer units carrying the hydrophobic radical -Hy.

[0039] In one embodiment, k is 2, 3, 4, 5 or 6.

[0040] In one embodiment, k=2.

[0041] In one embodiment, k=3.

[0042] In one embodiment, k=4.

[0043] In one embodiment, k=5.

[0044] In one embodiment, k=6.

[0045] In one embodiment, j is 1, 2, 3, 4, 5 or 6.

[0046] In one embodiment, j=1.

[0047] In one embodiment, j=2.

[0048] In one embodiment, j=3.

[0049] In one embodiment, j=4.

[0050] In one embodiment, j=5.

[0051] In one embodiment, j=6.

[0052] In one embodiment, g+h≧2 and b is equal to 0 (b=0).

[0053] In one embodiment, g or h is greater than or equal to 2 (g≧2) and b is equal to 0.

[0054] In one embodiment, g+h≧2, b is equal to zero (b=0), and e is equal to one (e=1).

[0055] 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).

[0056] In one embodiment, g+h≧2.

[0057] In one embodiment, g is greater than or equal to 2 (g≧2).

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

[0059] In one embodiment, g+h≧2 and a and l are equal to 0 (a=l=0).

[0060] In one embodiment, the hydrophobic radical Hy is selected in the group of hydrophobic radicals according to formula X, where h is 2 or more, and GpC is according to formula Ixe.

[0061] In one embodiment, the hydrophobic radical Hy is selected in the group of hydrophobic radicals 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.

[0062] In one embodiment, when r≧1 and g+l=1, GpR is a radical according to formula VII′ or VII″.

[0063] In one embodiment, when r≧1 and g+l=1, GpR is a radical according to formula VII′ or VII″ and e=0.

[0064] In one embodiment, when r≧1 and g+l=1, GpR is a radical according to formula VII′ or VII″ and e=1.

[0065] In one embodiment, j'=0, g+h≧1, a=l=0 and e=0.

[0066] In one embodiment, j'=0, g+h≧1, a=l=0 and e=1.

[0067] In one embodiment, j'=0, g+h≧1, a+l≧1 and e=1.

[0068] In one embodiment, j'=0, g+h≧1, a+l≧1 and e=0.

[0069] In one embodiment, j'=0, g=h=0, a=l=0 and e=0.

[0070] In one embodiment, j'=0, g=h=0, a=l=0 and e=1.

[0071] In one embodiment, j'=0, g=h=0, a+l≧1 and e=1.

[0072] In one embodiment, j'=0, g=h=0, a+l≧1 and e=0.

[0073] Said copolyamino acids having a carboxylate charge and a hydrophobic radical -Hy are soluble in aqueous solutions at a pH between 6.0 and 8.0, at a temperature of 25° C. and at a concentration of less than 100 mg / ml.

[0074] Said copolyamino acids having a carboxylate charge and a hydrophobic radical -Hy are soluble in aqueous solutions at a pH between 6.0 and 8.0, at a temperature of 25° C. and at a concentration of less than 60 mg / ml.

[0075] The term "alkyl radical" refers to straight or branched carbon chains that do not contain heteroatoms.

[0076] Said copolyamino acids are statistical copolyamino acids in a chain of glutamic and / or aspartic acid units.

[0077] In the formula: * indicates the binding sites of the different elements represented.

[0078] The term "physically stable composition" refers to a composition that meets the visual inspection criteria set forth in the European, American and International Pharmacopoeias, i.e., is transparent, contains no visible particles and is colorless.

[0079] The term "aqueous solution for injection" refers to a solution in which the solvent is water and which meets the requirements of the European and US Pharmacopoeias.

[0080] The composition according to the invention in the form of an aqueous solution for injection is a transparent solution. The term "transparent solution" refers to a composition that meets the criteria set out in the US and European Pharmacopoeias for injection solutions. In the US Pharmacopoeias, solutions are classified as part <1151> So, injection <1> It is defined by referring to USP35. <788> Refer to USP35. <788> In addition, USP38 <787> , <788> and <790> (Specified in USP38 (from August 1, 2014). In the European Pharmacopoeia, injection solutions must comply with the criteria provided in sections 2.9.19 and 2.9.20.

[0081] The term "copolyamino acid composed of glutamic or aspartic acid units" denotes an acyclic linear chain of glutamic or aspartic acid units linked together by peptide bonds, said chain having a C-terminal moiety corresponding to a carboxylic acid at one end and an N-terminal moiety corresponding to an amine at the other end of the chain.

[0082] The term "soluble" indicates suitability to allow the preparation of a clear, particle-free solution in distilled water at 25°C at a concentration of less than 100 mg / ml.

[0083] The term "soluble" indicates suitability to allow the preparation of a clear, particle-free solution at a concentration of less than 60 mg / ml in distilled water at 25°C.

[0084] The radicals -Hy, GpR, GpG, GpA, GpL, GpH and GpC are each independently the same or different from each other.

[0085] In one embodiment, the composition is characterized in that it has a pH of 6.0 to 8.0.

[0086] In one embodiment, the composition is characterized by having a pH of 6.6 to 7.8.

[0087] In one embodiment, the composition is characterized by having a pH of 7.0 to 7.8.

[0088] In one embodiment, the composition is characterized by having a pH of 6.8 to 7.4.

[0089] In one embodiment, the composition according to the invention is characterized in that Hy contains from 15 to 100 carbon atoms.

[0090] In one embodiment, the composition according to the invention is characterized in that Hy contains from 30 to 70 carbon atoms.

[0091] In one embodiment, the composition according to the invention is characterized in that Hy contains from 40 to 60 carbon atoms.

[0092] In one embodiment, the composition according to the invention is characterized in that Hy contains from 20 to 30 carbon atoms.

[0093] In one embodiment, Hy contains more than 15 carbon atoms.

[0094] In one embodiment, Hy contains more than 30 carbon atoms.

[0095] In one embodiment, the radical or spacer Q[— * ] k is represented by a radical according to formula II: Q[― * ] k =([Q'] q )[― * ] k Formula II In the formula, 1≦q≦5. - radicals Q' are identical or different and are selected from the group consisting of radicals of the following formulae III to VI': Q[- * ] k Form: A radical according to formula III [ka] In the formula, 1≦t≦8. A radical according to formula IV: [ka] During the ceremony: At least one of u1'' or u2'' is different from 0, If u1″≠0, then u1′≠0; if u2″≠0, then u2′≠0; u1' and u2' are the same or different, and 2≦u≦4, 0≦u1′≦4, 0≦u1″≦4, 0≦u2′≦4, 0≦u2″≦4, A radical according to formula V: [ka] During the ceremony: v, v' and v'' are identical or different and are integers ≧0; and v+v'+v''≦15, A radical according to formula VI: [ka] During the ceremony: w1' is different from 0, 0≦w2″≦1, w1≦6 and w1'≦6 and / or w2≦6 and w2'≦6 where Fd and Fd' are the same or different and represent a functional group -NH- or -CO-; Fy represents a trivalent nitrogen atom -N=; where Fx=Fa, Fb, Fc, Fd, Fa', Fb', Fc', Fc'' and Fd' in each of the above radicals are identical or different and represent the functional group -NH- or -CO-, Fy represents a trivalent nitrogen atom -N=, Two radicals Q' are linked together by a covalent bond between a carbonyl function, Fx=-CO-, and an amine function Fx=-NH- or Fy=-N=, thus forming an amide bond; if the functions Fx=Fa, Fb, Fc, Fd, Fa', Fb', Fc', Fc'' and Fd' are not used in the bond between two Q', this function is free and salified.

[0096] In one embodiment, the radical Q' is selected from among radicals according to formula VI, with formula VI' defined below, where w2=0: [ka] During the ceremony: w'1 is different from 0, 0≦w′′2≦1, w1≦6 and w'1≦6 and / or w'2≦6 where Fd and Fd' are the same or different and represent a functional group -NH- or -CO-; Fy represents a trivalent nitrogen atom -N=; Two radicals Q' are linked together by a covalent bond between a carbonyl function, Fx=-CO-, and an amine function, Fx=-NH- or Fy=-N=, thus forming an amide bond; where in each of the radicals represented above, Fx=Fa, Fb, Fc, Fd, Fa', Fb', Fc', Fc'' and Fd' are identical or different and represent the functional group -NH- or -CO-, Fy represents a trivalent nitrogen atom -N=, The two radicals Q' are linked together by a covalent bond between a carbonyl function, Fx=-CO-, and an amine function, Fx=-NH- or Fy=-N=, thus forming an amide bond.

[0097] In one embodiment, when Fa and Fa' are -NH-, t > 2.

[0098] In one embodiment, when F a and F a′ are —CO—, t≧1.

[0099] In one embodiment, when Fa and Fa' are -CO- and -NH-, t > 1.

[0100] In one embodiment, when Fb and Fb' are -NH-, u and u1' > 2 and / or u2' > 2.

[0101] In one embodiment, when Fc, Fc' and Fc'' are -NH-, at least two of v, v' and v'' are different from 0.

[0102] In one embodiment, when Fc, Fc' and Fc'' are two -NH- and one -CO-, at least one of the indices of the nitrogen-bearing -(CH2)- is different from 0.

[0103] In one embodiment, without the proviso that Fc, Fc' and Fc'' are one -NH- and two -CO-.

[0104] In one embodiment, when Fc, Fc' and Fc'' are -CO-, at least one of v, v' and v'' is different from 0.

[0105] In one embodiment, when Fd and Fd' are -NH-, w1 and w1' > 2 and / or w2 and w'2 > 2.

[0106] In one embodiment, when Fd and Fd' are -CO-, w1 and w1' >= 1 and / or w2 and w2' >= 1.

[0107] In one embodiment, when Fd and Fd' are -CO- and -NH-, w1 and w1' >= 1 and / or w2 and w2' >= 1.

[0108] At least two chains of glutamic acid or aspartic acid units PLG are connected by covalent bonds forming amide bonds with the functional groups -NH- or -CO- of PLG, respectively, via the functional groups Fx or Fy, respectively, Q[- * ] k is combined with

[0109] In one embodiment, 1≦q≦5.

[0110] In one embodiment, v+v'+v''≦15.

[0111] In one embodiment, at least one Q′ is a radical according to formula III: [ka] Here, the precursor is a diamine.

[0112] In one embodiment, the precursor of the radical according to formula III is a diamine selected in the group consisting of ethylenediamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5-diaminopentane, propylenediamine, pentylenediamine.

[0113] In one embodiment, t=2 and the precursor of the radical according to formula III is ethylenediamine.

[0114] In one embodiment, t=4 and the precursor of the radical according to formula III is butylenediamine.

[0115] In one embodiment, t=6 and the precursor of the radical according to formula III is hexylenediamine.

[0116] In one embodiment, t=3 and the precursor of the radical according to formula III is 1,3-diaminopropane.

[0117] In one embodiment, t=5 and the precursor of the radical according to formula III is 1,5-diaminopentane.

[0118] In one embodiment, the precursor of the radical according to formula III is an amino acid.

[0119] In one embodiment, the precursor of the radical according to formula III is an amino acid selected in the group consisting of aminobutanoic acid, aminohexanoic acid and β-alanine.

[0120] In one embodiment, t=2 and the precursor of the radical according to formula III is β-alanine.

[0121] In one embodiment, t=6 and the precursor of the radical according to formula III is aminohexanoic acid.

[0122] In one embodiment, t=4 and the precursor of the radical according to formula III is aminobutanoic acid.

[0123] In one embodiment, the precursor of the radical according to formula III is a diacid.

[0124] In one embodiment, the precursor of the radical according to formula III is a diacid selected in the group consisting of succinic acid, glutaric acid and adipic acid.

[0125] In one embodiment, t=2 and the precursor of the radical according to formula III is succinic acid.

[0126] In one embodiment, t=3 and the precursor of the radical according to formula III is glutaric acid.

[0127] In one embodiment, t=4 and the precursor of the radical according to formula III is adipic acid.

[0128] In one embodiment, at least one Q′ is a radical according to formula IV: [ka] Here, the precursor is a diamine.

[0129] In one embodiment, the precursor of the radical according to formula IV is a diamine selected in the group consisting of diethylene glycol diamine, triethylene glycol diamine, 1-amino-4,9-dioxa-12-dodecanamine and 1-amino-4,7,10-trioxa-13-tridecanamine.

[0130] In one embodiment, u=u′1=2, u″1=1, u″2=0 and the precursor of the radical according to formula IV is diethylene glycol diamine.

[0131] In one embodiment, u=u′1=u′2=2, u″1=u″2=1, and the precursor of the radical according to formula IV is triethylene glycol diamine.

[0132] In one embodiment, u=u'2=3, u'1=4, u''1=u''2=1, and the precursor of the radical according to formula IV is 4,9-dioxa-1,12-dodecanediamine.

[0133] In one embodiment, u=u'2=3, u'1=u''1=2, u''2=1 and the precursor of the radical according to formula IV is 4,7,10-trioxa-1,13-tridecanediamine.

[0134] In one embodiment, at least one Q′ is a radical according to formula V: [ka] wherein the precursor is selected from the group consisting of amino acids.

[0135] In one embodiment, the precursor of the radical according to formula V is an amino acid selected in the group consisting of lysine, ornithine, 1,3-diaminopropionic acid.

[0136] In one embodiment, v=4, v'=v''=0 and the precursor of the radical according to formula V is lysine.

[0137] In one embodiment, v=3, v'=v''=0 and the precursor of the radical according to formula V is ornithine.

[0138] In one embodiment, v=2, v'=v''=0 and the precursor of the radical according to formula V is 2,3-diaminopropionic acid.

[0139] In one embodiment, at least one Q′ is a radical according to formula V: [ka] Here, the precursor is selected in the group consisting of triacids.

[0140] In one embodiment, the precursor of the radical according to formula V is a triacid selected in the group consisting of tricarballylic acid.

[0141] In one embodiment, v=0, v'=v''=1 and the precursor of the radical according to formula V is tricarballylic acid.

[0142] In one embodiment, at least one of Q' is a radical according to formula V [ka] Here, the precursor is selected in the group consisting of triamines.

[0143] In one embodiment, the precursor of the radical according to formula V is a triamine selected in the group consisting of (2-(aminomethyl)propane-1,3-diamine).

[0144] In one embodiment, v=v'=v''=1 and the precursor of the radical according to formula V is (2-(aminomethyl)propane-1,3-diamine).

[0145] In one embodiment, at least one Q′ is a radical according to formula VI: [ka] Here, the precursor is a triamine.

[0146] In one embodiment, w''2=0 and the precursor of the radical according to formula VI is spermidine, norspermidine, and a triamine selected in the group consisting of diethylenetriamine and bis(hexamethylene)triamine.

[0147] In one embodiment, w''2=0 and the precursor of the radical according to formula VI is spermidine.

[0148] In one embodiment, w''2=0 and the precursor of the radical according to formula VI is norspermidine.

[0149] In one embodiment, w''2=0 and the precursor of the radical according to formula VI is diethylenetriamine.

[0150] In one embodiment, w''2=0 and the precursor of the radical according to formula VI is bis(hexamethylene)triamine.

[0151] In one embodiment, at least one of Q' is a radical according to formula VI [ka] Here, the precursor is tetramine.

[0152] In one embodiment, w''2=1 and the precursor of the radical according to formula VI is a tetramine.

[0153] In one embodiment, w''2=1 and the precursor of the radical according to formula VI is a tetramine selected in the group consisting of spermine and triethylenetetramine.

[0154] In one embodiment, w''2=1 and the precursor of the radical according to formula VI is spermine.

[0155] In one embodiment, w''2=1 and the precursor of the radical according to formula VI is triethylenetetramine.

[0156] In one embodiment, the radical or spacer Q[— * ] k The precursor of has four reactive functional groups selected from amine and carboxylic acid functional groups. Such a precursor may be 1,2,3,4-butanetetraoic acid.

[0157] In one embodiment, at least one of Q' is a radical according to formula VI': [ka] Here, the precursor is a triamine.

[0158] In one embodiment, w''2=0 and the precursor of the radical according to formula VI' is spermidine, norspermidine, and a triamine selected in the group consisting of diethylenetriamine and bis(hexamethylene)triamine.

[0159] In one embodiment, w''2=0 and the precursor of the radical according to formula VI' is spermidine.

[0160] In one embodiment, w''2=0 and the precursor of the radical according to formula VI' is norspermidine.

[0161] In one embodiment, w''2=0 and the precursor of the radical according to formula VI' is diethylenetriamine.

[0162] In one embodiment, w''2=0 and the precursor of the radical according to formula VI is bis(hexamethylene)triamine.

[0163] In one embodiment, at least one of Q' is a radical according to formula VI': [ka] Here, the precursor is tetramine.

[0164] In one embodiment, w''2=1 and the precursor of the radical according to formula VI' is a tetramine.

[0165] In one embodiment, w''2=1 and the precursor of the radical according to formula VI' is a tetramine selected in the group consisting of spermine and triethylenetetramine.

[0166] In one embodiment, w''2=1 and the precursor of the radical according to formula VI' is spermine.

[0167] In one embodiment, w''2=1 and the precursor of the radical according to formula VI' is triethylenetetramine.

[0168] In one embodiment, the radical or spacer Q[— * ] k The precursor of has four reactive functional groups selected from among amine and carboxylic acid functional groups.

[0169] In one embodiment, the radical or spacer Q[— * ] k The precursor of has four reactive functional groups, and the radical or spacer Q[― * ] k The precursor of is 1,2,3,4-butanetetraacid.

[0170] In one embodiment, all Fx are conjugated to PLG or other Fx or Fy.

[0171] In one embodiment, one or more Fx are free, ie, not bound to PLG, or to another Fx, or to Fy.

[0172] In one embodiment, one Fx is free, ie, not bound to PLG, or to another Fx, or to Fy.

[0173] In one embodiment, the -CO- type Fx(s) is free and is in the carboxylate form.

[0174] In one embodiment, the free —CO— type Fx is carried by a radical Q′ according to formula V.

[0175] In one embodiment, the -NH- type Fx(s) is free and is in the amine or ammonium form.

[0176] In one embodiment, the PLG is linked to Fx (where Fx=-NH-) or Fy through at least one carbonyl functional group of the PLG.

[0177] In one embodiment, the PLG is linked to Fx (where Fx=-NH-) or Fy through at least one carbonyl functional group that is not at the C-terminal position of the PLG.

[0178] In one embodiment, PLG is attached to Fx (where Fx=-NH-) or Fy through a carbonyl functionality at the C-terminal functionality of PLG.

[0179] In one embodiment, PLG is attached to Fx (where Fx=-NH-) through a carbonyl functionality at the C-terminal functionality of PLG.

[0180] In one embodiment, PLG is linked to Fx (where Fx=Fy) through a carbonyl functionality at the C-terminal functionality of PLG.

[0181] In one embodiment, PLG is linked to Fx (where Fx=-CO-) through a nitrogen atom in the N-terminal functional group of PLG.

[0182] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXa: [ka] During the ceremony, -D independently represents either a -CH2- group (aspartic acid) or a -CH2-CH2- group (glutamic acid); -X represents a cationic entity selected from the group comprising alkaline cations, -, -Ra and R'a are the same or different and are either the hydrophobic radical -Hy or a radical selected from the group consisting of H, C2-C10 linear acyl groups, C3-C10 branched acyl groups, benzyl, terminal "amino acid" units and pyroglutamic acid; At least one of -Ra and R'a is a hydrophobic radical -Hy; -Q is as defined above, --Hy is as defined below, -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.

[0183] In one embodiment, the composition according to the invention comprises a copolyamino acid having a carboxylate charge and at least one hydrophobic radical -Hy, selected from among the copolyamino acids according to formula XXXa, in which R a and R' a are identical and are characterized by the hydrophobic radical -Hy.

[0184] In one embodiment, the composition according to the invention comprises a copolyamino acid having a carboxylate charge and at least one hydrophobic radical -Hy, selected from among the copolyamino acids according to formula XXXa, in which R a and R' a is characterized by the hydrophobic radical -Hy.

[0185] In one embodiment, the composition according to the invention comprises a copolyamino acid having a carboxylate charge and at least one hydrophobic radical -Hy, selected from among the copolyamino acids according to formula XXXa, in which R a is the hydrophobic radical -Hy, and R' a is characterized in that it is not a hydrophobic radical -Hy.

[0186] In one embodiment, the composition according to the invention comprises a copolyamino acid having a carboxylate charge and at least one hydrophobic radical -Hy, selected from among the copolyamino acids according to formula XXXa, in which R' a is the hydrophobic radical -Hy, and R a is characterized in that it is not a hydrophobic radical -Hy.

[0187] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXa': [ka] During the ceremony: -D, X, Ra and R'a are as defined above, -Q and Hy are as defined above, -n1+m1 represents the number of glutamic or aspartic acid units in the PLG chain of the copolyamino acid bearing the radical -Hy, -n2+m2 represents the number of glutamic or aspartic acid units in the PLG chain of the copolyamino acid that does not have the radical -Hy, -n1+n2=n' and m1+m2=m', 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.

[0188] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXa', where Ra and R'a are identical and are the hydrophobic radical -Hy.

[0189] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid having a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXa', where Ra and R'a are different and are the hydrophobic radical -Hy.

[0190] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXa', where Ra is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.

[0191] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids having a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXa', where R'a is a hydrophobic radical -Hy and Ra is not a hydrophobic radical -Hy.

[0192] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXb: [ka] During the ceremony, -D and X are as defined above, -Rb and R'b are identical or different and are either the hydrophobic radical -Hy or a radical selected from the group consisting of -OH, an amine group, a terminal "amino acid" unit and pyroglutamic acid, At least one of -Rb and R'b is a hydrophobic radical -Hy; -Q and Hy are as defined above, -n+m is as defined above.

[0193] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb, where Rb and R'b are identical and are the hydrophobic radical -Hy.

[0194] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb, where Rb and R'b are different and are the hydrophobic radical -Hy.

[0195] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb, in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.

[0196] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids bearing a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXb, in which R'b is a hydrophobic radical -Hy and Rb is not a hydrophobic radical -Hy.

[0197] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXb': [ka] During the ceremony: -D and X are as defined above, -Q and Hy are as defined above, -Rb and Rb' are identical or different and are either a hydrophobic radical -Hy or a radical selected from the group consisting of -OH, an amine group, a terminal "amino acid" unit and pyroglutamic acid, At least one of -Rb and R'b is a hydrophobic radical -Hy; -n1+m1 represents the number of glutamic or aspartic acid units in the PLG chain of the copolyamino acid bearing the radical -Hy, -n2+m2 represents the number of glutamic or aspartic acid units in the PLG chain of the copolyamino acid that does not have the radical -Hy, -n1+n2=n' and m1+m2=m', -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.

[0198] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb', where Rb and R'b are identical and are the hydrophobic radical -Hy.

[0199] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb', where Rb and R'b are different and are the hydrophobic radical -Hy.

[0200] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb', where Rb is the hydrophobic radical -Hy and R'b is not the hydrophobic radical -Hy.

[0201] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid bearing a carboxylate charge and at least one hydrophobic radical -Hy is chosen from among the copolyamino acids according to formula XXXb', where R'b is a hydrophobic radical -Hy and Rb is not a hydrophobic radical -Hy.

[0202] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from among copolyamino acids according to formula XXXa, XXXb, XXXa' or XXXb', in which the D group is a -CH2-CH2- group (glutamic acid unit).

[0203] In one embodiment, the composition is characterized in that the copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from among copolyamino acids according to formula XXXa, XXXa', XXXb', in which the D group is a -CH2- group (aspartic acid unit).

[0204] When the copolyamino acids contain one or more aspartic acid unit(s), they may undergo structural rearrangement.

[0205] 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 further comprise monomer units according to the formula XXXX and / or XXXX': [ka]

[0206] The term "statistical graft copolyamino acid" denotes a copolyamino acid having a carboxylate charge and at least one hydrophobic radical, as represented by copolyamino acids according to formulas XXXa' and XXXb'.

[0207] The term "defined graft copolyamino acid" refers to a copolyamino acid having a carboxylate charge and at least one hydrophobic radical, represented by copolyamino acids according to formulas XXXa and XXXb.

[0208] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is 60 mg / mL or less.

[0209] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is 40 mg / mL or less.

[0210] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is less than or equal to 20 mg / mL.

[0211] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is 10 mg / mL or less.

[0212] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is less than or equal to 5 mg / ml.

[0213] In one embodiment, the concentration of the copolyamino acid having a carboxylate charge and a hydrophobic radical is less than or equal to 2.5 mg / ml.

[0214] In one embodiment, the composition according to the present invention is characterized in that n+m is 10-250.

[0215] In one embodiment, the composition according to the present invention is characterized in that n+m is 10-200.

[0216] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-150.

[0217] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-100.

[0218] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-80.

[0219] In one embodiment, the composition according to the present invention is characterized in that n+m is 15-65.

[0220] In one embodiment, the composition according to the present invention is characterized in that n+m is 20-60.

[0221] In one embodiment, the composition according to the present invention is characterized in that n+m is 20-50.

[0222] In one embodiment, the composition according to the present invention is characterized in that n+m is 20-40.

[0223] In one embodiment, the present invention relates to 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: Basal insulin consisting of an isoelectric point pI of 5.8 to 8.5; Copolyamino acids according to formula I as defined above having a carboxylate charge and a hydrophobic radical -Hy, said at least one hydrophobic radical Hy being chosen among radicals according to formula X: [ka] During the ceremony, GpR is selected from among radicals according to formula VII, VII' or VII": [ka] GpG and GpH are identical or different and are selected from among the 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 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 sites of different groups linked by the amide functional group; - 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, where l' = 1 if l = 0, and l' = 2 if l = 1; - r is an integer equal to 0, 1 or 2, and - s' is an integer equal to 0 or 1; - 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 a radical selected from the group consisting of unsubstituted ether or polyether radicals containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or linear or branched alkyl radicals, optionally containing an aromatic nucleus and containing 1 to 9 carbon atoms; -C x is a linear or branched monovalent alkyl radical, optionally containing a cyclic moiety, where x is the number of carbon atoms; <x<25であり: 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; if the hydrophobic radical -Hy has at least 5-GpC, then 6≦x≦11; -G is a linear or branched divalent alkyl radical of 1 to 8 carbon atoms, said alkyl radical having one or more free carboxylic acid functional group(s); -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 functional groups -CONH2 or unsubstituted ether or polyether radicals 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 of the amine function of the PLG with the acid function of the precursor of the hydrophobic radical -Hy'), and / or 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 cation salt selected from the group consisting of:

[0224] 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.

[0225] In one embodiment, when a'=2, x is comprised between 9 and 15 (9≦x≦15).

[0226] In one embodiment, when r=2, the GpR group attached to the PLG is selected from among the GpR according to Formula VII.

[0227] In one embodiment, when r=2, the GpR group attached to the PLG is selected from among the GpRs according to formula VII, and the second GpR is selected from among the GpRs according to formula VII″.

[0228] In one embodiment, when r=2, the GpR group attached to the PLG is selected from among the GpR according to formula VII″.

[0229] In one embodiment, when r=2, the GpR group attached to the PLG is selected from among the GpRs according to formula VII″, and the second GpR is selected from among the GpRs according to formula VII.

[0230] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where r=1, according to formula Xc defined below: [ka] In the formula, GpR, GpG, GpA, GpL, GpH, GpC, a, a', g, h, l and l' are as defined above.

[0231] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where r=1, according to formula Xc defined below: [ka] in which GpR is a radical according to formula VII, [ka] wherein GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l and l' are as defined above.

[0232] In one embodiment, the at least one hydrophobic radical -Hy is selected from among the radicals according to formula Xc defined below: [ka] in which GpR is a radical according to formula VII′, [ka] wherein GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l and l' are as defined above.

[0233] In one embodiment, the at least one hydrophobic radical -Hy is selected from among the radicals according to formula Xc defined below: [ka] in which GpR is a radical according to formula VII″, [ka] wherein GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l and l' are as defined above.

[0234] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where r=2, according to formula Xc′ defined below: [ka] in which GpR1 is a radical according to formula VII, [ka] wherein GpR, GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l and l' are as defined above.

[0235] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where r=2, according to formula Xc′ defined below: [ka] in which GpR1 is a radical according to formula VII″, [ka] wherein GpR, GpG, GpA, GpL, GpH, GpC, R, a, a', g, h, l and l' are as defined above.

[0236] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X (wherein r=0) according to formula Xq defined below: [ka] wherein GpG, GpA, GpL, GpH, GpC, g, a, a', l, h and l' are as defined above.

[0237] In one embodiment, the at least one hydrophobic radical -Hy is selected from among the radicals according to formula Xr defined below, where G=0: [ka] wherein GpR, GpA, GpL, GpH, GpC, r, a, a', l, h and l' are as defined above.

[0238] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where h=0 and g=0, represented by the following formula Xj: [ka] where GpR, GpA, GpC, r, a' and a are as defined above.

[0239] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where h=0 and g=0 and a′=1, represented by the following formula Xk: [ka] wherein GpR, GpA, GpC, r and a are as defined above.

[0240] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where h=0 and g=0 and a=1 and a′=2, represented by the following formula Xl: [ka] where GpR, GpA, GpC and r are as defined above.

[0241] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where a=1 and a′=1 and g=1=0, represented by the following formula Xn: [ka] where GpR, GpA, GpH, GpC, r and h are as defined above.

[0242] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where a=1 and a′=2 and g=1=0, represented by the following formula Xp: [ka] where GpR, GpA, GpH, GpC, r and h are as defined above.

[0243] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where a=1, g, h and l=0 and a′=3, represented by the following formula Xm: [ka] wherein GpA is a radical selected from among the radicals according to formula VIIId, and GpR, GpC, r are as defined above.

[0244] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where a, g, h and l=0, represented by the following formula Xm′: [ka] In the formula, GpR, GpC, and r are as defined above.

[0245] In one embodiment, said at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where r, g, a, l, h are equal to 0, according to formula Xo defined below: [ka] where GpC is as defined above.

[0246] In one embodiment, said at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where r, g, a, l, h are equal to 0, according to formula Xo defined below: [ka] where GpC is a radical according to formula IX (wherein e=0, b=0) and GpC is a radical according to formula IXc [ka]

[0247] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X (wherein a=0), according to formula Xs defined below: [ka] where GpR, GpG, GpL, GpH, GpC, r, g, l, h and l' are as defined above.

[0248] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where a=1 and a′=1, according to formula Xa as defined below: [ka] where GpA, GpR, GpG, GpL, GpH, GpC, r, g, h, l and l' are as defined above.

[0249] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where a=1 and a′=1, according to formula Xa as defined below: [ka] wherein GpA is a radical according to formula VIII, A' is selected from among radicals according to formula VIII' (wherein s'=0), and GpA is a radical according to formula VIIIb [ka] where GpR, GpG, GpL, GpH, GpC, r, g, h, l and l' are as defined above.

[0250] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where a=1 and a′=2, according to formula Xb as defined below: [ka] where GpA, GpR, GpG, GpL, GpH, GpC, r, g, h, l and l' are as defined above.

[0251] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where a=1 and a′=2, according to formula Xb as defined below: [ka] where GpA is a radical according to formula VIII, A' is selected from among radicals according to formula VIII' (where s'=1), and GpA is a radical according to formula VIIIa (where a'=2); [ka] where GpR, GpG, GpL, GpH, GpC, A1, r, g, h, l and l' are as defined above.

[0252] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where a=1 and a′=2, according to formula Xb as defined below: [ka] wherein GpA is a radical according to formula VIII, A is selected from among radicals according to formula VIII″ (where s′=1), and GpA is a radical according to formula VIIIc [ka] where GpR, GpG, GpL, GpH, GpC, A1, A2, r, g, h, l and l' are as defined above.

[0253] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where a=1 and a′=3, according to formula Xb defined below: [ka] wherein GpA is a radical according to formula VIII, A is selected from among radicals according to formula VIII''', where s'=1, and GpA is a radical according to formula VIIId. [ka] wherein GpR, GpG, GpL, GpH, GpC, A1, A2, A3, r, g, h, l and l' are as defined above.

[0254] In one embodiment, said at least one hydrophobic radical -Hy is selected from among radicals according to formula Xd defined below and according to formula X defined above, where l=0: [ka] wherein GpR, GpG, GpA, GpH, GpC, r, g, a, h and a' are as defined above.

[0255] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, where -l=0, according to formula Xd defined below: [ka] During the ceremony, -GpA is selected from among radicals according to formula VIII represented by formula VIIIa, where s'=1, or according to formula VIII represented by formula VIIIb, where s'=0: [ka] - b, c, d, e, g, h, r, and s' are as defined above; -GpR, GpH, GpG, GpC, A 1、 B, Cx, G, H, R are as defined above.

[0256] In one embodiment, said at least one hydrophobic radical -Hy is selected from among radicals according to formula Xd defined below, according to formula X defined above, where l=0: [ka] During the ceremony, GpA is selected from among radicals according to formula VIII (wherein s'=1), represented by formula VIIIc or formula VIIId: [ka] wherein GpR, GpG, GpH, GpC, A1, A2, A3, r, g, a, h and a' are as defined above.

[0257] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula Xe, where GpA is a radical according to formula VIIIb, a′=1 and l=0, represented by the following formula Xe: [ka] wherein GpR, GpG, GpA, GpH, GpC, r, g, h, and a are as defined above.

[0258] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where a'=2 and a=1 and l=0, represented by the following formula Xf: [ka] where GpR, GpG, GpA, GpH, GpC, r, g and h are as defined above.

[0259] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where h=0, l=0 and l′=1, represented by the following formula Xg: [ka] wherein GpR, GpG, GpA, GpC, r, g, a and a' are as defined above.

[0260] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where h=0 and a′=1, represented by the following formula Xh: [ka] wherein GpR, GpG, GpA, GpC, r, a and g are as defined above.

[0261] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where h=0, a′=2 and a=1, represented by the following formula Xi: [ka] wherein GpR, GpG, GpA, GpC, r and g are as defined above.

[0262] In one embodiment, said at least one hydrophobic radical -Hy is selected from among radicals according to formula Xt defined below, according to formula X defined above, where h=0: [ka] wherein GpR, GpG, GpA, GpL, GpC, r, g, a, l, l' and a' are as defined above.

[0263] In one embodiment, said at least one hydrophobic radical -Hy is selected from among radicals according to formula Xt′ defined below, according to formula X defined above, where h and g=0: [ka] where GpR, GpA, GpL, GpC and r are as defined above.

[0264] In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is chosen from among the hydrophobic radicals according to formula X, where l′=2 and a′=2, represented by the following formula Xu: [ka] where GpR, GpA, GpL and GpC are as defined above.

[0265] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formulas X, Xa to Xu: wherein at least one of g and / or h is 1 or greater; in which GpC is a radical according to formula IX (wherein e=0) and GpC is a radical according to formula IXa, [ka] wherein B, b and Cx are as defined above.

[0266] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, Xa to Xu, GpC is a radical according to formula IX (wherein e=0), GpC is a radical according to formula IXa, [ka] wherein B, b and Cx are as defined above.

[0267] In one embodiment, the at least one hydrophobic radical -Hy is selected from among the radicals according to formula X, Xa to Xu, GpC is a radical according to formula IX (wherein e=1, b=0), and GpC is a radical according to formula IXd, [ka] wherein c, d and Cx are as defined above.

[0268] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, GpC is a radical according to formula IX (wherein e=0, b=0), and GpC is a radical according to formula IXc, [ka] In the formula, Cx is as defined above.

[0269] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, Xa to Xu, GpC is a radical according to formula IX (wherein e=1), and GpC is a radical according to formula IXb, [ka] wherein c, d, B, b and Cx are as defined above.

[0270] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, -GpA is selected from among the radicals according to formula VIII (s'=1), represented by formula VIIIa, or according to formula VIII (s'=0), represented by formula VIIIb: [ka] wherein A1 is as defined above.

[0271] In one embodiment, the at least one hydrophobic radical -Hy is selected from among radicals according to formula X, -GpA is selected from among radicals according to formula VIII (s'=1), represented by formula VIIIc or formula VIIId: [ka] wherein A1, A2 and A3 are as defined above.

[0272] In one embodiment, GpA is a radical according to formula VIIIc, where 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 via -GpR. α1 is combined with

[0273] In one embodiment, GpA is a radical according to formula VIIIc, where 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

[0274] In one embodiment, GpA is a radical according to formula VIIId, where r=1. -GpC directly or indirectly binds to N α1 , N α2 and N β1PLG binds directly or indirectly to N β2 or -GpC directly or indirectly binds to N α1 , N α2 and N β2 PLG binds directly or indirectly to N β1 or -GpC directly or indirectly binds to N α1 , N β1 and N β2 PLG is bound to N directly or indirectly via -GpR-. 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

[0275] In one embodiment, GpA is a radical according to formula VIIId, where 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

[0276] In the formula: * shows the attachment sites of hydrophobic radicals to PLG or between the different groups GpR, GpG, GpA, GpL, GpH and GpC, resulting in the formation of an amide functional group.

[0277] The radical -Hy is attached to the PLG via an amide function.

[0278] In formulas VII, VII' and VII'', * From left to right, respectively, indicate the binding sites of GpR for: -PLG, and - GpR (if r=2) or GpG (if g≧1) or GpA (if g=0) or GpL (if l=1 and g=a=0) or GpH (if h≧1 and g=a=l=0) or GpC (if a'=1 and g=a=l=h=0).

[0279] In formulae VIIIa, VIIIb, VIIIc and VIIId: * From left to right, respectively, indicate the binding sites of GpA for: - GpG (if g≧1) or GpR (if r=1 or 2 and g=0) or PLG (if g=r=0) and - GpL (if l=1) or GpH (if h≧1 and l=0) or GpC (if l=h=0).

[0280] In formula IX: * indicates the binding site of GpC to: - GpH(h≧1), -GpL (for l=1 and h=0) -GpA (for a=1 and h=l=0) -GpG (for g≧1 and h=l=a=0) -GpR (when r=1 or 2 and h=l=a=g=0) -PLG (where h=l=a=g=r=0).

[0281] In one embodiment, a=0.

[0282] In one embodiment, h=1 and g=0.

[0283] In one embodiment, h=0 and g=1.

[0284] In one embodiment, r=0, g=1 and h=0.

[0285] In one embodiment, r=1, GpR is selected from among the radicals according to formula VII' or VII'', and h=0.

[0286] In one embodiment, r=1, g=0, GpR is a radical according to formula VII' and h=0.

[0287] In one embodiment, r=1, g=0, GpR is a radical according to formula VII' and h=1.

[0288] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is selected from among radicals according to formula VIIIa or VIIIb, and h=0.

[0289] In one embodiment, r=1, g=0, GpR is a radical according to formula VII', GpA is selected from among radicals according to formula VIIIa or VIIIb, and h=1.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] In one embodiment, r=0, g=0 and GpA is selected from among the radicals according to formulas VIIIa and VIIIb.

[0295] In one embodiment, r=0, g=0, GpA is selected from among radicals according to formulas VIIIa and VIIIb, and h=0.

[0296] In one embodiment, g+h≧2.

[0297] In one embodiment, g is greater than or equal to 2 (g≧2).

[0298] In one embodiment, h is greater than or equal to 2 (h≧2).

[0299] In one embodiment, g+h≧2 and a and l are equal to 0 (a=l=0).

[0300] In one embodiment, g+h≧2 and b is equal to 0 (b=0).

[0301] In one embodiment, g or h is greater than or equal to 2 (g≧2) and b is equal to 0.

[0302] In one embodiment, g+h≧2, b is equal to zero (b=0), and e is equal to one (e=1).

[0303] 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).

[0304] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent linear alkyl radical containing from 2 to 12 carbon atoms.

[0305] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent alkyl radical containing 2 to 6 carbon atoms.

[0306] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent linear alkyl radical containing 2 to 6 carbon atoms.

[0307] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent alkyl radical containing 2 to 4 carbon atoms.

[0308] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent linear alkyl radical containing 2 to 4 carbon atoms.

[0309] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent alkyl radical containing 2 carbon atoms.

[0310] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent linear alkyl radical containing 1 to 11 carbon atoms.

[0311] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent alkyl radical containing 1 to 6 carbon atoms.

[0312] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent alkyl radical containing 2 to 5 carbon atoms and having one or more amide functional groups (-CONH2).

[0313] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent linear alkyl radical containing 2 to 5 carbon atoms and having one or more amide functional groups (-CONH2).

[0314] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical in which R is selected from the group consisting of radicals represented by the following formula: [ka]

[0315] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a radical according to formula X1.

[0316] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a radical according to formula X2.

[0317] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical in which R is attached to the copolyamino acid via an amide functionality carried by a carbon at the δ or ε position (or at the 4 or 5 position) relative to the amide functionality (-CONH2).

[0318] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is an unsubstituted ether or polyether straight chain radical containing from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

[0319] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is an ether radical.

[0320] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical in which R is an ether radical containing from 4 to 6 carbon atoms.

[0321] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a divalent alkyl radical containing 6 carbon atoms.

[0322] In one embodiment, the composition comprises a hydrophobic radical according to formula X, wherein R is of the formula [ka] The radical is an ether radical represented by the formula:

[0323] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a polyether radical.

[0324] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a polyether linear radical containing 6 to 10 carbon atoms and 2 to 3 oxygen atoms.

[0325] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical in which R is a polyether radical selected in the group consisting of radicals represented by the following formulas: [ka]

[0326] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a radical according to formula X3.

[0327] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a radical according to formula X4.

[0328] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a radical according to formula X5.

[0329] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where R is a radical according to formula X6.

[0330] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical in which R is a polyether radical selected in the group consisting of radicals represented by formulas X5 and X6: [ka]

[0331] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical according to formula XI′, where G is an alkyl radical containing 6 carbon atoms as represented by formula Z: [ka]

[0332] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical according to formula XI, where G is an alkyl radical containing 4 carbon atoms and represented by formula Z′: [ka]

[0333] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical according to formula XI, where G is an alkyl radical containing 4 carbon atoms and represented by -(CH2)2-CH(COOH)-.

[0334] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical according to formula XI, where G is an alkyl radical containing 4 carbon atoms and represented by -CH((CH2)2COOH)-.

[0335] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical GpG and / or GpH is a radical according to formula XI, where G is an alkyl radical containing 3 carbon atoms and represented by -CH2-CH-(COOH).

[0336] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical GpG and / or GpH is a radical according to formula XI, where G is an alkyl radical containing 3 carbon atoms and represented by -CH(CH2)(COOH)-.

[0337] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical according to formula VIII, and A1, A2 or A3 is selected from the group consisting of radicals represented by the following formulas: [ka]

[0338] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of radicals according to formula IXe, IXf or IXg, represented below: [ka]

[0339] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected in the group consisting of radicals according to formula IXe, IXf or IXg, where b is equal to 0, and where the radical GpC according to formula IX corresponds to formulas IXh, IXi and IXj, respectively, represented below: [ka]

[0340] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical corresponding to formula IX or IXe (wherein b=0) and a radical corresponding to formula IVh.

[0341] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of straight chain alkyl radicals.

[0342] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of branched alkyl radicals.

[0343] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected in the group consisting of alkyl radicals containing 9 to 14 carbon atoms.

[0344] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of radicals represented by the following formulas: [ka]

[0345] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where Cx is selected in the group consisting of alkyl radicals containing 15 to 16 carbon atoms.

[0346] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of radicals represented by the following formulas: [ka]

[0347] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of radicals represented by the following formulas: [ka]

[0348] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected in the group consisting of alkyl radicals containing 17 to 25 carbon atoms.

[0349] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected in the group consisting of alkyl radicals containing 17 to 18 carbon atoms.

[0350] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of alkyl radicals represented by the following formula: [ka]

[0351] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical where Cx is selected in the group consisting of alkyl radicals containing 18 to 25 carbon atoms.

[0352] In one embodiment, the composition is characterized in that the hydrophobic radical according to formula X is a radical selected from the group consisting of alkyl radicals represented by the following formula: [ka]

[0353] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical according to formula X and the radical GpC according to formula IV is selected from the group consisting of radicals where Cx is selected from the group consisting of alkyl radicals containing 14 or 15 carbon atoms.

[0354] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical according to formula X and the radical GpC according to formula IV is selected from the group consisting of radicals selected from the group consisting of radicals represented by the following formulas: [ka]

[0355] In one embodiment, when l' or 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.

[0356] In one embodiment, when l' or a'=2, x is comprised between 9 and 15 (9≦x≦15).

[0357] In one embodiment, the composition 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 0.35.

[0358] In one embodiment, the composition 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.

[0359] In one embodiment the composition 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.

[0360] In one embodiment, the composition 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.

[0361] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to the formula X, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.007 and 0.15.

[0362] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to the formula X, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.01 and 0.1.

[0363] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to the formula X, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.02 and 0.08.

[0364] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to the formula X, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.007 and 0.3.

[0365] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to the formula X, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.01 and 0.3.

[0366] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to the formula X, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.015 and 0.2.

[0367] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 9 to 10 carbon 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.

[0368] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 11 to 12 carbon atoms, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.015 and 0.2.

[0369] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 11 to 12 carbon atoms, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.015 and 0.1.

[0370] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 11 to 12 carbon atoms, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.02 and 0.08.

[0371] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 13 to 15 carbon atoms, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.01 and 0.1.

[0372] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 13 to 15 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 0.06.

[0373] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 11 to 14 carbon atoms, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is between 0.1 and 0.2.

[0374] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 15 to 16 carbon 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.

[0375] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 17 to 18 carbon atoms, and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic acid units is comprised between 0.02 and 0.06.

[0376] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 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 0.06.

[0377] In one embodiment, the composition is characterized in that the hydrophobic radicals are according to formula X, the radical Cx comprises 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 between 0.01 and 0.05.

[0378] The hydrophobic radical to basal insulin ratio 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.

[0379] The lowest value of the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin] measured is the value at which the basal insulin is solubilized, since solubilization is the minimum effect that can be obtained; this solubilization is a prerequisite for all other technical effects that can only be observed if the basal insulin is solubilized at a pH of 6.0 to 8.0.

[0380] 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.

[0381] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦3.

[0382] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦2.

[0383] In one embodiment, the hydrophobic radical to basal insulin ratio [Hy] / [basal insulin]≦1.75.

[0384] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦1.5.

[0385] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦1.25.

[0386] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦1.00.

[0387] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦0.75.

[0388] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦0.5.

[0389] In one embodiment, the ratio of hydrophobic radicals to basal insulin [Hy] / [basal insulin]≦0.25.

[0390] The invention also relates to a method for preparing a stable injectable composition.

[0391] The invention also relates to said copolyamino acids I carrying a carboxylate charge and a hydrophobic radical according to formula X and to precursors of said hydrophobic radical.

[0392] The invention also relates to a copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to formula X, said copolyamino acid being chosen from among the copolyamino acids according to formula I: [Q(PLG) k ][Hy] j [Hy] j’ Formula I During the ceremony: -j≧1; 0≦j′≦n′1 and j+j′≧1 and k≧2 - said copolyamino acid according to formula I has at least one hydrophobic radical -Hy, a carboxylate charge and at least a divalent linear or branched radical consisting of an alkyl chain containing one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or having one or more heteroatoms consisting of nitrogen and oxygen radicals or a spacer Q[- * ] k and / or a radical having one or more heteroatoms consisting of nitrogen and oxygen atoms, and / or a carboxyl functional group, -the radical or spacer Q[- * ] k is linked to at least two glutamic or aspartic acid unit chains of PLG via amide functional groups, and - the amide functional group is, respectively, a radical or a spacer Q[— * ] kor the radical or spacer Q[-] obtained from the reaction between an amine functional group and an acid functional group of either the glutamic acid or aspartic acid unit, which is bonded to the at least two chains of glutamic acid or aspartic acid units. * ] k Combine the - said hydrophobic radical -Hy is attached to a terminal "amino acid" unit, with j>=1, or to a carboxyl function carried by one of the chains of the glutamic or aspartic acid units PLG, with j'=n'1, n'1 being the average number of monomer units carrying the hydrophobic radical -Hy.

[0393] The copolyamino acids having a carboxylate charge and a hydrophobic radical according to formula I are soluble in distilled water at a pH of 6.0 to 8.0, at a temperature of 25° C. and at a concentration of less than 100 mg / ml.

[0394] In one embodiment, the invention also relates to a precursor Hy′ of said hydrophobic radical according to formula X′ defined below: [ka] During the ceremony, GpR is selected from among radicals according to formula VII, VII' or VII'': [ka] GpG and GpH are identical or different and are selected from among radicals according to formula XI or XI': [ka] GpA is selected from radicals according to formula VIII [ka] wherein A' is selected from the radicals according to 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 sites of different groups linked by the amide functional group; 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, where l' = 1 if l = 0, and l' = 2 if l = 1; - l' is an integer equal to 1 or 2; - r is an integer equal to 0, 1 or 2, and - s' is an integer equal to 0 or 1; - 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 a radical selected from the group consisting of unsubstituted ether or polyether radicals containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or linear or branched alkyl radicals, optionally containing an aromatic nucleus and containing 1 to 9 carbon atoms; -C xis a radical selected from the group consisting of linear or branched monovalent alkyl radicals, optionally including cyclic moieties, where x represents the number of carbon atoms, 6≦x≦25: 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; if the hydrophobic radical -Hy has at least 5-GpC, then 6≦x≦11; G is a linear or branched divalent alkyl radical containing 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 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 functional groups -CONH2, or unsubstituted ether or polyether radicals 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 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 cation salt selected from the group consisting of:

[0395] In one embodiment, the copolyamino acid is selected from the group of copolyamino acids according to formula I, * ] k is a radical according to formula III.

[0396] In one embodiment, the copolyamino acid is sodium poly-L-glutamate modified at two of its ends according to the formula represented below, as described in Example B14. [ka]

[0397] In one embodiment, the copolyamino acid is sodium poly-L-glutamate modified at two of its ends according to the formula represented below, as described in Example B19. [ka]

[0398] In one embodiment, the copolyamino acid is sodium poly-L-glutamate modified at two of its ends according to the formula represented below, as described in Example B23. [ka]

[0399] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by polymerization.

[0400] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by ring-opening polymerization of a glutamic acid N-carboxyanhydride derivative or an aspartic acid N-carboxyanhydride derivative.

[0401] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are obtained from polyamino acids obtained by polymerization of glutamic acid N-carboxyanhydride derivatives or aspartic acid N-carboxyanhydride derivatives, as described in the journal article Adv. Polym. Sci. 2006, 202, 1-18 (Deming, TJ).

[0402] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative.

[0403] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative selected in the group consisting of poly-methylglutamic acid N-carboxyanhydride (GluOMe-NCA), poly-benzylglutamic acid N-carboxyanhydride (GluOBzl-NCA), poly-t-butylglutamic acid N-carboxyanhydride (GluOtBu-NCA).

[0404] In one embodiment, the glutamic acid N-carboxyanhydride derivative is poly-L-methylglutamic acid N-carboxyanhydride (L-GluOMe-NCA).

[0405] In one embodiment, the glutamic acid N-carboxyanhydride derivative is poly-L-benzylglutamic acid N-carboxyanhydride (L-GluOBzl-NCA).

[0406] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are obtained from polyamino acids obtained by polymerization of glutamic acid N-carboxyanhydride derivatives or aspartic acid N-carboxyanhydride derivatives using organometallic complexes as initiators, as described in the publication Nature 1997, 390, 386-389 (Deming, TJ).

[0407] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by polymerization of glutamic acid N-carboxyanhydride derivatives or aspartic acid N-carboxyanhydride derivatives using ammonia or primary amines as initiators, as described in patent FR 2,801,226 (Touraud, F. et al.) and the references cited by this patent. Likewise, the initiator may be a polyamine, in order to obtain a polyamino acid containing a plurality of PLGs. The said polyamines may be chosen among diamines, triamines and tetraamines. The amines of these polyamines may be primary amines.

[0408] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are obtained from polyamino acids obtained by polymerization of glutamic acid N-carboxyanhydride derivatives or aspartic acid N-carboxyanhydride derivatives 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.).

[0409] In one embodiment, the composition according to the invention is characterized in that the process for the synthesis of polyamino acids obtained by polymerization of glutamic acid N-carboxyanhydride derivatives or aspartic acid N-carboxyanhydride derivatives, which results in copolyamino acids, comprises a step of ester functional hydrolysis.

[0410] In one embodiment, this ester function hydrolysis step may consist of hydrolysis in an acidic medium or in a basic medium, or may be carried out by hydrogenation.

[0411] In one embodiment, the ester group hydrolysis step is hydrolysis in an acidic medium.

[0412] In one embodiment, this ester group hydrolysis step is carried out by hydrogenation.

[0413] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight.

[0414] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.

[0415] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.

[0416] In one embodiment, the composition according to the invention is characterized in that the copolyamino acids are obtained from polyamino acids obtained by enzymatic and chemical depolymerization of polyamino acids of higher molecular weight.

[0417] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by depolymerization of a higher molecular weight polyamino acid selected in the group consisting of sodium polyglutamate and sodium polyaspartate.

[0418] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by depolymerization of a higher molecular weight sodium polyglutamate.

[0419] In one embodiment, the composition according to the invention is characterized in that the copolyamino acid is obtained from a polyamino acid obtained by depolymerization of a higher molecular weight sodium polyaspartate.

[0420] 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, using amide bond formation methods well known to those skilled in the art.

[0421] 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 using the amide bond formation methods used for peptide synthesis.

[0422] 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 patent FR 2,840,614 (Chan, YP; et al.).

[0423] During the synthesis of the intermediate compound Hy, and during grafting, conventional protection and deprotection techniques are used: The free carboxylic acid functional group(s) of Hy may be in protected form with an acid protecting group prior to grafting onto the PLG, this protection being carried out, for example, by esterification using methanol, ethanol, benzyl alcohol or t-butanol. After grafting, the functional groups are deprotected, i.e. a deprotection reaction is carried out, so that the carboxyl functional group(s) is / are free or in the form of an alkaline cation salt selected in the group consisting of Na+ and K+. The amine functional group(s) may be in protected form by an amine protecting group prior to grafting on the PLG, for example by acid or base hydrolysis with heat via a phenylmethoxycarbonyl or 1,1-dimethylethoxycarbonyl group. After grafting, the functional group is deprotected, i.e. a deprotection reaction is carried out so that the amine functional group is liberated.

[0424] Hereafter, the units used are those for insulin, those recommended by the Pharmacopoeia, whose equivalent amounts expressed in mg / ml are given in the table below: [Table 1]

[0425] Basal insulin, which has an isoelectric point of 5.8 to 8.5, is insoluble at pH 7 and has a duration of action of 8 to 24 hours or more in standard diabetic models.

[0426] These basal insulins, with an isoelectric point between 5.8 and 8.5, are recombinant insulins whose primary structure has been essentially modified by the introduction of basic amino acids such as 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:

[0427] In one embodiment, the basal insulin with an isoelectric point comprised between 5.8 and 8.5 is insulin glargine, marketed by SANOFI under the trade names Lantus® (100 U / ml) or Toujeo® (300 U / ml).

[0428] In one embodiment, the basal insulin having an isoelectric point of 5.8 to 8.5 is biosimilar insulin glargine.

[0429] Biosimilar insulin glargine is currently being developed for the market by ELI LILLY under the trade names Abasaglar® or Basaglar®.

[0430] In one embodiment, the composition according to the present invention comprises 40-500 U / mL of basal insulin having an isoelectric point of 5.8-8.5.

[0431] 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.

[0432] In one embodiment, the composition according to the invention comprises 100 U / mL (or about 3.6 mg / mL) of basal insulin having an isoelectric point of 5.8 to 8.5.

[0433] 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.

[0434] In one embodiment, the composition according to the invention comprises 200 U / mL of basal insulin having an isoelectric point of 5.8 to 8.5.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] 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.

[0440] In one embodiment, the mass ratio between the basal insulin and the 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.

[0441] In one embodiment, the mass ratio is comprised between 0.2 and 6.

[0442] In one embodiment, the mass ratio is comprised between 0.2 and 5.

[0443] In one embodiment, the mass ratio is comprised between 0.2 and 4.

[0444] In one embodiment, the mass ratio is comprised between 0.2 and 3.

[0445] In one embodiment, the mass ratio is comprised between 0.2 and 2.

[0446] In one embodiment, the mass ratio is comprised between 0.2 and 1.

[0447] In one embodiment, the composition according to the invention further comprises prandial insulin, which is soluble at pH 7.

[0448] Meal insulin refers to the so-called fast acting or "regular" insulin.

[0449] So-called fast-acting prandial insulins are insulins required to meet the needs induced by the ingestion of protein and carbohydrates in a meal, and they must act in less than 30 minutes.

[0450] In one embodiment, the so-called "regular" prandial insulin is human insulin.

[0451] In one embodiment, the prandial insulin is recombinant human insulin as described in the European Pharmacopoeia and the United States Pharmacopoeia.

[0452] Human insulin is commercially available, for example, under the trade names Humulin® (ELI LILLY) and Novolin® (NOVO NORDISK).

[0453] The so-called ultrarapid (fast-acting) prandial insulins are recombinantly derived insulins whose primary structures have been altered to reduce their duration of action.

[0454] In one embodiment, the so-called ultrarapid (fast acting) insulin is selected in the group comprising insulin lispro (Humalog®), insulin glulisine (Apidra®) and insulin aspart (NovoLog®).

[0455] In one embodiment, the prandial insulin is insulin lispro.

[0456] In one embodiment, the prandial insulin is insulin glulisine.

[0457] In one embodiment, the prandial insulin is insulin aspart.

[0458] In one embodiment, the composition according to the present invention contains a total of 60 to 800 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0459] In one embodiment, the composition according to the present invention contains a total of 100 to 500 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0460] In one embodiment, the composition according to the present invention contains a total of 800 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0461] In one embodiment, the composition according to the present invention contains a total of 700 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0462] In one embodiment, the composition according to the present invention contains a total of 600 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0463] In one embodiment, the composition according to the present invention contains a total of 500 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0464] In one embodiment, the composition according to the present invention contains a total of 400 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0465] In one embodiment, the composition according to the present invention contains a total of 300 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0466] In one embodiment, the composition according to the present invention contains a total of 266 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0467] In one embodiment, the composition according to the present invention contains a total of 200 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0468] In one embodiment, the composition according to the present invention contains a total of 100 U / mL insulin using a combination of prandial insulin and a basal insulin having an isoelectric point of 5.8 to 8.5.

[0469] The ratio between basal insulin and prandial insulin with an isoelectric point of 5.8 to 8.5 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 may also be embodied.

[0470] In one embodiment, basal insulin and prandial insulin, each with an isoelectric point comprised between 5.8 and 8.5, are present in the following concentrations (expressed in U / ml): 75 / 25, 150 / 50, 200 / 66 or 300 / 100.

[0471] In one embodiment, basal insulin and prandial insulin, respectively, with an isoelectric point comprised between 5.8 and 8.5, are present in the following concentrations (expressed in U / ml): 75 / 25.

[0472] In one embodiment, basal insulin and prandial insulin, respectively, with an isoelectric point comprised between 5.8 and 8.5, are present in the following concentrations (expressed in U / ml): 150 / 50.

[0473] In one embodiment, the composition according to the invention further comprises a gastrointestinal hormone.

[0474] The term "gastrointestinal hormone" refers to hormones selected in the group consisting of 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, their analogs or derivatives and / or their pharma- ceutically acceptable salts.

[0475] In one embodiment, the gastrointestinal hormone is an analog 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), analogs or derivatives thereof or pharma- ceutically acceptable salts thereof.

[0476] In one embodiment, the gut hormone is pramlintide or Symlin® (ASTRA-ZENECA).

[0477] In one embodiment, the gastrointestinal hormone is exenatide or Byetta®, analogs or derivatives thereof, and pharma- ceutically acceptable salts thereof.

[0478] In one embodiment, the gastrointestinal hormone is liraglutide or Victoza®, analogues or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0479] In one embodiment, the gastrointestinal hormone is lixisenatide or Lyxumia®, analogs or derivatives thereof, and pharma- ceutically acceptable salts thereof.

[0480] In one embodiment, the gastrointestinal hormone is albiglutide or Tanzeum®, analogues or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0481] In one embodiment, the gastrointestinal hormone is dulaglutide or Trulicity®, analogs or derivatives thereof, and pharma- ceutically acceptable salts thereof.

[0482] In one embodiment, the gastrointestinal hormone is pramlintide or Symlin®, analogues or derivatives thereof and pharma- ceutically acceptable salts thereof.

[0483] The term "analog" when used in reference to a peptide or protein refers to a peptide or protein in which one or more of its constituent amino acid residues have been replaced by other amino acid residues and / or one or more of its constituent amino acid residues have been removed and / or one or more of its constituent amino acid residues have been added. The percentage of homology accepted for the current definition of an analog is 50%.

[0484] The term "derivative", when used in reference to a peptide or protein, refers to a peptide or protein or analog that has been chemically modified with a substituent not present in the reference peptide or protein or analog, i.e., a peptide or protein that has been modified by creating a covalent bond to introduce a substituent.

[0485] In one embodiment, the substituents are selected from the group consisting of aliphatic chains.

[0486] In one embodiment, the concentration of the gastrointestinal hormone is in the range of 0.01 to 100 mg / mL.

[0487] In one embodiment, the concentration of exenatide, its analogues or derivatives, and its pharma- ceutically acceptable salts is in the range of 0.04 to 0.5 mg / mL.

[0488] In one embodiment, the concentration of liraglutide, its analogues or derivatives and its pharma- ceutically acceptable salts is in the range of 1-10 mg / mL.

[0489] In one embodiment, the concentration of lixisenatide, its analogues or derivatives, and its pharma- ceutically acceptable salts is in the range of 0.01 to 1 mg / mL.

[0490] In one embodiment, the concentration of albiglutide, its analogues or derivatives and its pharma- ceutically acceptable salts is comprised between 5 and 100 mg / mL.

[0491] In one embodiment, the concentration of dulaglutide, its analogues or derivatives and its pharma- ceutically acceptable salts is comprised between 0.1 and 10 mg / mL.

[0492] In one embodiment, the concentration of pramlintide, its analogues or derivatives and its pharma- ceutically acceptable salts is comprised between 0.1 and 5 mg / mL.

[0493] In one embodiment, the composition according to the invention is obtained by mixing a commercially available solution of basal insulin with an isoelectric point comprised between 5.8 and 8.5 and a commercially available solution of GLP-1 RA, an analogue or derivative of GLP-1 RA in a volume ratio ranging from 10 / 90 to 90 / 10.

[0494] In one embodiment, the composition according to the invention comprises a daily dose of basal insulin and a daily dose of a gut hormone.

[0495] In one embodiment, the composition according to the present invention comprises 40 U / mL to 500 U / mL of basal insulin having an isoelectric point of 5.8 to 8.5, and 0.05 to 0.5 mg / mL of exanatide.

[0496] In one embodiment, the composition according to the present invention comprises 40 U / mL to 500 U / mL of basal insulin having an isoelectric point of 5.8 to 8.5, and 1 to 10 mg / mL of liraglutide.

[0497] In one embodiment, the composition according to the invention comprises 40 U / ml to 500 U / mL of basal insulin with an isoelectric point of 5.8 to 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0498] In one embodiment, the composition according to the invention comprises 40 U / mL to 500 U / mL of basal insulin having an isoelectric point of 5.8 to 8.5, and 5 to 100 mg / mL of albiglutide.

[0499] In one embodiment, the composition according to the present invention comprises 40 U / mL to 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.

[0500] In one embodiment, the composition according to the invention comprises 500 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.

[0501] 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 1 to 10 mg / mL of liraglutide.

[0502] In one embodiment, the composition according to the invention comprises 500 U / mL of basal insulin with an isoelectric point of 5.8 to 8.5 and 0.01 to 1 mg / mL of lixisenatide.

[0503] In one embodiment, the composition according to the invention comprises 500 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0504] 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.

[0505] 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.

[0506] 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, and 1 to 10 mg / mL of liraglutide.

[0507] In one embodiment, the composition according to the invention comprises 400 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0508] In one embodiment, the composition according to the invention comprises 400 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0509] 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 and 0.1 to 10 mg / mL of dulaglutide.

[0510] 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 0.04 to 0.5 mg / mL of exenatide.

[0511] 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 and 1 to 10 mg / mL of liraglutide.

[0512] In one embodiment, the composition according to the invention comprises 300 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0513] In one embodiment, the composition according to the invention comprises 300 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0514] 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 and 0.1 to 10 mg / mL of dulaglutide.

[0515] In one embodiment, the composition according to the invention comprises 225 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.

[0516] 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 and 1 to 10 mg / mL of liraglutide.

[0517] In one embodiment, the composition according to the invention comprises 225 U / mL of basal insulin with an isoelectric point of 5.8 to 8.5 and 0.01 to 1 mg / mL of lixisenatide.

[0518] In one embodiment, the composition according to the invention comprises 225 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0519] 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 and 0.1 to 10 mg / mL of dulaglutide.

[0520] In one embodiment, the composition according to the invention comprises 200 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 0.04 to 0.5 mg / mL of exenatide.

[0521] In one embodiment, the composition according to the invention comprises 200 U / mL of basal insulin having an isoelectric point of 5.8 to 8.5 and 1 to 10 mg / mL of liraglutide.

[0522] In one embodiment, the composition according to the invention comprises 200 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0523] In one embodiment, the composition according to the invention comprises 200 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0524] In one embodiment, the composition according to the invention comprises 200 U / mL of basal insulin having an isoelectric point of 5.8 to 8.5 and 0.1 to 10 mg / mL of dulaglutide.

[0525] 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.

[0526] 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.

[0527] 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.

[0528] In one embodiment, the composition according to the invention comprises 100 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0529] In one embodiment, the composition according to the invention comprises 100 U / mL of basal insulin having an isoelectric point of 5.8 to 8.5 and 0.1 to 10 mg / mL of dulaglutide.

[0530] 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 0.04 to 0.5 mg / mL of exenatide.

[0531] 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 and 1 to 10 mg / mL of liraglutide.

[0532] In one embodiment, the composition according to the invention comprises 40 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 0.01 to 1 mg / mL of lixisenatide.

[0533] In one embodiment, the composition according to the invention comprises 40 U / mL of basal insulin with an isoelectric point comprised between 5.8 and 8.5, and 5 to 100 mg / mL of albiglutide.

[0534] 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 and 0.1 to 10 mg / mL of dulaglutide.

[0535] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 0-5000 μM.

[0536] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 0-4000 μM.

[0537] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 0-3000 μM.

[0538] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 0-2000 μM.

[0539] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 0-1000 μM.

[0540] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 50-600 μM.

[0541] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 100-500 μM.

[0542] In one embodiment, the composition according to the present invention further comprises a zinc salt at a concentration of 200-500 μM.

[0543] In one embodiment, the composition according to the invention further comprises a buffer.

[0544] In one embodiment, the composition according to the present invention comprises a buffer at a concentration of 0 to 100 mM.

[0545] In one embodiment, the composition according to the present invention comprises a buffer at a concentration of 15 to 50 mM.

[0546] In one embodiment, the composition according to the invention comprises a buffer selected in the group consisting of phosphate buffer, Tris (trishydroxymethylaminomethane) and sodium citrate.

[0547] In one embodiment, the buffer is sodium phosphate.

[0548] The invention also relates to a composition further comprising an ionic species, said ionic species being suitable for improving the physicochemical stability of the composition.

[0549] The invention also relates to the use of ionic species selected in the group of anions, cations and / or zwitterions to improve the physicochemical stability of the composition.

[0550] In one embodiment, the ionic species comprises less than 10 carbon atoms.

[0551] The ionic species are selected in the group of anions, cations and / or zwitterions. The term zwitterion denotes a species having at least one positive charge and at least one negative charge on two non-adjacent atoms.

[0552] The ionic species may be used alone or in mixtures, preferably in mixtures.

[0553] In one embodiment, the anion is selected from among organic anions.

[0554] In one embodiment, the organic anion contains fewer than 10 carbon atoms.

[0555] In one embodiment, the organic anion is selected from the group consisting of acetate, citrate and succinate.

[0556] In one embodiment, the anion is selected from inorganic anions.

[0557] In one embodiment, the inorganic anion is selected in the group consisting of sulfate, phosphate and halide, particularly chloride.

[0558] In one embodiment, the cations are selected from among organic cations.

[0559] In one embodiment, the organic cation contains less than 10 carbon atoms.

[0560] In one embodiment, the organic cation is selected in the group consisting of ammonium, for example 2-amino-2-(hydroxymethyl)propane-1,3-diol, where the amine is in the ammonium form.

[0561] In one embodiment, the cations are selected from among inorganic cations.

[0562] In one embodiment, the inorganic cation is selected in the group consisting of zinc, particularly Zn2+, and the alkali metals, particularly Na+ and K+.

[0563] In one embodiment, the zwitterions are selected from among organic zwitterions.

[0564] In one embodiment, the organic zwitterions are selected from among amino acids.

[0565] In one embodiment, the amino acids are selected from among the aliphatic amino acids in the group consisting of glycine, alanine, valine, isoleucine and leucine.

[0566] In one embodiment, the amino acid is selected from among the cyclic amino acids in the group consisting of proline.

[0567] In one embodiment, the amino acid is selected from among the hydroxylated amino acids in the group consisting of cysteine, serine, threonine, and methionine.

[0568] In one embodiment, the amino acid is selected from among the aromatic amino acids in the group consisting of phenylalanine, tyrosine and tryptophan.

[0569] In one embodiment, the amino acid is selected from the group consisting of asparagine and glutamine, the carboxyl function of the side chain being amidated.

[0570] In one embodiment, the organic zwitterion is selected from the group consisting of amino acids having uncharged side chains.

[0571] In one embodiment, the organic zwitterion is selected in the group consisting of an amino diacid or an acidic amino acid.

[0572] In one embodiment, the amino diacid is selected in the group consisting of glutamic acid and aspartic acid (optionally in salt form).

[0573] In one embodiment, the organic zwitterion is selected from the group consisting of basic or so-called "cationic" amino acids.

[0574] In one embodiment, the so-called "cationic" amino acids are selected from among arginine, histidine and lysine, in particular arginine and lysine.

[0575] Most specifically, zwitterions contain the same number of negative charges as positive charges at the isoelectric point and / or at a pH of 6-8, thus resulting in an overall charge of zero.

[0576] Said ionic species are introduced into the composition in the form of a salt, which can be carried out in solid form prior to solubilization in the composition, or in the form of a solution, in particular a concentrated solution.

[0577] For example, inorganic cations are added in the form of salts selected from among sodium chloride, zinc chloride, sodium phosphate, sodium sulfate, and the like.

[0578] For example, the organic cation is added in the form of a salt selected from among sodium or potassium citrate, sodium acetate.

[0579] For example, the amino acids are added in the form of salts selected from among arginine hydrochloride, histidine hydrochloride, or in non-salted form, such as histidine, arginine, etc.

[0580] In one embodiment, the total molar concentration of the ionic species in the composition is 10 mM or greater.

[0581] In one embodiment, the total molar concentration of ionic species in the composition is 20 mM or greater.

[0582] In one embodiment, the total molar concentration of ionic species in the composition is 30 mM or greater.

[0583] In one embodiment, the total molar concentration of the ionic species in the composition is 50 mM or greater.

[0584] In one embodiment, the total molar concentration of ionic species in the composition is 75 mM or greater.

[0585] In one embodiment, the total molar concentration of the ionic species in the composition is 100 mM or greater.

[0586] In one embodiment, the total molar concentration of ionic species in the composition is 200 mM or greater.

[0587] In one embodiment, the total molar concentration of ionic species in the composition is 300 mM or greater.

[0588] In one embodiment, the total molar concentration of the ionic species in the composition is 500 mM or greater.

[0589] In one embodiment, the total molar concentration of ionic species in the composition is 600 mM or greater.

[0590] In one embodiment, the total molar concentration of ionic species in the composition is 700 mM or greater.

[0591] In one embodiment, the total molar concentration of ionic species in the composition is 800 mM or greater.

[0592] In one embodiment, the total molar concentration of ionic species in the composition is 900 mM or greater.

[0593] In one embodiment, the total molar concentration of ionic species in the composition is 1000 mM or less.

[0594] In one embodiment, the total molar concentration of ionic species in the composition is 1500 mM or less.

[0595] In one embodiment, the total molar concentration of ionic species in the composition is 1200 mM or less.

[0596] In one embodiment, the total molar concentration of ionic species in the composition is 1000 mM or less.

[0597] In one embodiment, the total molar concentration of ionic species in the composition is 900 mM or less.

[0598] In one embodiment, the total molarity of the ionic species in the composition is 800 mM or less.

[0599] In one embodiment, the total molar concentration of ionic species in the composition is 700 mM or less.

[0600] In one embodiment, the total molarity of the ionic species in the composition is 600 mM or less.

[0601] In one embodiment, the total molar concentration of ionic species in the composition is 500 mM or less.

[0602] In one embodiment, the total molar concentration of ionic species in the composition is 400 mM or less.

[0603] In one embodiment, the total molar concentration of ionic species in the composition is 300 mM or less.

[0604] In one embodiment, the total molar concentration of ionic species in the composition is 200 mM or less.

[0605] In one embodiment, the total molar concentration of ionic species in the composition is 100 mM or less.

[0606] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 1000 mM.

[0607] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 1000 mM.

[0608] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 1000 mM.

[0609] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 1000 mM.

[0610] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 1000 mM.

[0611] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 1000 mM.

[0612] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 1000 mM.

[0613] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 1000 mM.

[0614] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 1000 mM.

[0615] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 1000 mM.

[0616] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 1000 mM.

[0617] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 900 mM.

[0618] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 900 mM.

[0619] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 900 mM.

[0620] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 900 mM.

[0621] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 900 mM.

[0622] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 900 mM.

[0623] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 900 mM.

[0624] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 900 mM.

[0625] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 900 mM.

[0626] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 900 mM.

[0627] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 900 mM.

[0628] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 900 mM.

[0629] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 800 mM.

[0630] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 800 mM.

[0631] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 800 mM.

[0632] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 800 mM.

[0633] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 800 mM.

[0634] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 800 mM.

[0635] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 800 mM.

[0636] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 800 mM.

[0637] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 800 mM.

[0638] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 800 mM.

[0639] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 700 mM.

[0640] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 700 mM.

[0641] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 700 mM.

[0642] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 700 mM.

[0643] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 700 mM.

[0644] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 700 mM.

[0645] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 700 mM.

[0646] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 700 mM.

[0647] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 700 mM.

[0648] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 700 mM.

[0649] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 600 and 700 mM.

[0650] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 600 mM.

[0651] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 600 mM.

[0652] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 600 mM.

[0653] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 600 mM.

[0654] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 600 mM.

[0655] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 600 mM.

[0656] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 600 mM.

[0657] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 600 mM.

[0658] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 600 mM.

[0659] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 500 and 600 mM.

[0660] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 500 mM.

[0661] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 500 mM.

[0662] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 500 mM.

[0663] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 500 mM.

[0664] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 500 mM.

[0665] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 500 mM.

[0666] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 500 mM.

[0667] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 500 mM.

[0668] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 400 and 500 mM.

[0669] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 400 mM.

[0670] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 400 mM.

[0671] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 400 mM.

[0672] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 400 mM.

[0673] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 400 mM.

[0674] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 400 mM.

[0675] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 400 mM.

[0676] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 300 and 400 mM.

[0677] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 300 mM.

[0678] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 300 mM.

[0679] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 300 mM.

[0680] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 300 mM.

[0681] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 300 mM.

[0682] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 300 mM.

[0683] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 200 and 300 mM.

[0684] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 200 mM.

[0685] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 200 mM.

[0686] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 200 mM.

[0687] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 200 mM.

[0688] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 200 mM.

[0689] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 100 and 200 mM.

[0690] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 100 mM.

[0691] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 100 mM.

[0692] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 100 mM.

[0693] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 100 mM.

[0694] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 75 and 100 mM.

[0695] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 75 mM.

[0696] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 75 mM.

[0697] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 75 mM.

[0698] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 50 and 75 mM.

[0699] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 10 and 50 mM.

[0700] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 20 and 50 mM.

[0701] In one embodiment, the total molar concentration of the ionic species in the composition is comprised between 30 and 50 mM.

[0702] In one embodiment, the ionic species is present at a concentration in the range of 5 to 400 mM.

[0703] In one embodiment, the ionic species is present at a concentration in the range of 5 to 300 mM.

[0704] In one embodiment, the ionic species is present at a concentration in the range of 5 to 200 mM.

[0705] In one embodiment, the ionic species is present at a concentration in the range of 5 to 100 mM.

[0706] In one embodiment, the ionic species is present at a concentration in the range of 5 to 75 mM.

[0707] In one embodiment, the ionic species is present at a concentration in the range of 5 to 50 mM.

[0708] In one embodiment, the ionic species is present at a concentration in the range of 5 to 25 mM.

[0709] In one embodiment, the ionic species is present at a concentration in the range of 5 to 20 mM.

[0710] In one embodiment, the ionic species is present at a concentration in the range of 5 to 10 mM.

[0711] In one embodiment, the ionic species is present at a concentration in the range of 10 to 400 mM.

[0712] In one embodiment, the ionic species is present at a concentration in the range of 10 to 300 mM.

[0713] In one embodiment, the ionic species is present at a concentration in the range of 10 to 200 mM.

[0714] In one embodiment, the ionic species is present at a concentration in the range of 10 to 100 mM.

[0715] In one embodiment, the ionic species is present at a concentration in the range of 10 to 75 mM.

[0716] In one embodiment, the ionic species is present at a concentration in the range of 10 to 50 mM.

[0717] In one embodiment, the ionic species is present at a concentration in the range of 10 to 25 mM.

[0718] In one embodiment, the ionic species is present at a concentration in the range of 10 to 20 mM.

[0719] In one embodiment, the ionic species is present at a concentration in the range of 20 to 300 mM.

[0720] In one embodiment, the ionic species is present at a concentration in the range of 20 to 200 mM.

[0721] In one embodiment, the ionic species is present at a concentration in the range of 20 to 100 mM.

[0722] In one embodiment, the ionic species is present at a concentration in the range of 20 to 75 mM.

[0723] In one embodiment, the ionic species is present at a concentration in the range of 20 to 50 mM.

[0724] In one embodiment, the ionic species is present at a concentration in the range of 20-25 mM.

[0725] In one embodiment, the ionic species is present at a concentration in the range of 50 to 300 mM.

[0726] In one embodiment, the ionic species is present at a concentration in the range of 50-200 mM.

[0727] In one embodiment, the ionic species is present at a concentration in the range of 50-100 mM.

[0728] In one embodiment, the ionic species is present at a concentration in the range of 50-75 mM.

[0729] Inorganic cations, especially Zn 2+ In this case, 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.

[0730] In one embodiment, the composition comprises zinc.

[0731] In one embodiment, the composition comprises 0.2 to 2 mM zinc.

[0732] In one embodiment, the composition comprises NaCl.

[0733] In one embodiment, NaCl is present at a concentration in the range of 2-25 mM.

[0734] In one embodiment, NaCl is present at a concentration in the range of 2.5 to 20 mM.

[0735] In one embodiment, NaCl is present at a concentration in the range of 4-15 mM.

[0736] In one embodiment, NaCl is present at a concentration in the range of 5-10 mM.

[0737] In one embodiment, the buffer is Tris (trishydroxymethylaminomethane).

[0738] In one embodiment, the buffer is sodium citrate.

[0739] In one embodiment, the composition according to the invention further comprises a preservative.

[0740] In one embodiment, the preservative is selected in the group consisting of m-cresol and phenol (alone or in a mixture).

[0741] In one embodiment, the concentration of the preservative is comprised between 10 and 50 mM.

[0742] In one embodiment, the concentration of the preservative is comprised between 10 and 40 mM.

[0743] In one embodiment, the composition according to the present invention further comprises a surfactant.

[0744] In one embodiment, the surfactant is selected from the group consisting of propylene glycol and polysorbates.

[0745] The composition according to the invention may further comprise additives such as isotonicity agents.

[0746] In one embodiment, the tonicity agent is selected in the group consisting of glycerin, sodium chloride, mannitol and glycine.

[0747] The composition according to the invention may further comprise any excipient compatible with insulin used in the concentrations customary according to the pharmacopoeias.

[0748] The invention also relates to a pharmaceutical preparation according to the invention, characterized in that it is obtained by drying and / or freeze-drying.

[0749] For local and systemic delivery, contemplated modes of administration are by intravenous, subcutaneous, intradermal or intramuscular routes.

[0750] Dermal, oral, nasal, intravaginal, ocular, buccal and pulmonary routes of administration are also contemplated.

[0751] 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.

[0752] The invention also relates to a single dose formulation comprising basal and prandial insulin with an isoelectric point comprised between 5.8 and 8.5, at a pH between 6.0 and 8.0.

[0753] 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 a gastrointestinal hormone as defined above, at a pH between 6.0 and 8.0.

[0754] 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.

[0755] 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.

[0756] The invention also relates to a single dose formulation comprising basal and prandial insulin with an isoelectric point comprised between 5.8 and 8.5, and a pH between 6.6 and 7.8.

[0757] 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 a gastrointestinal hormone as defined above, with a pH between 6.6 and 7.8.

[0758] 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.

[0759] 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.

[0760] The invention also relates to a single dose formulation comprising basal and prandial insulin with an isoelectric point comprised between 5.8 and 8.5, and a pH between 6.6 and 7.6.

[0761] 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 a gastrointestinal hormone as defined above, with a pH between 6.6 and 7.6.

[0762] 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, at a pH between 6.6 and 7.6.

[0763] In one embodiment, the single dose formulation further comprises a copolyamino acid as defined above.

[0764] In one embodiment, the formulation is in the form of an injectable solution.

[0765] In one embodiment, the composition according to the invention is characterized in that it is administered once a day.

[0766] In one embodiment, the composition according to the invention is characterized in that it is administered at least twice a day.

[0767] In one embodiment, the composition according to the invention is characterized in that it is administered twice a day.

[0768] In one embodiment, the composition according to the invention is characterized in that it further comprises prandial insulin.

[0769] 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 once a day.

[0770] 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.

[0771] 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.

[0772] In one embodiment, the composition according to the present invention is characterized in that it further comprises a gastrointestinal hormone.

[0773] 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 once a day.

[0774] 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.

[0775] 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.

[0776] In one embodiment, the composition according to the invention is characterized in that the gastrointestinal hormone is GLP-1 RA.

[0777] In one embodiment, the composition according to the invention further comprising at least one GLP-1 RA is characterized in that it is administered once a day.

[0778] In one embodiment, the composition according to the invention further comprising at least one GLP-1 RA is characterized in that it is administered at least twice a day.

[0779] 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.

[0780] The solubilization of basal insulin with an isoelectric point of 5.8-8.5 by copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical according to the invention at a pH of 6.0-8.0 can be easily observed and controlled with the naked eye by a change in the appearance of the solution.

[0781] The solubilization of basal insulin with an isoelectric point of 5.8-8.5 by copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical according to the invention at a pH of 6.6-7.8 can be easily observed and controlled with the naked eye by a change in the appearance of the solution.

[0782] 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, retains its slow acting insulin action, whether alone or in combination with prandial insulin or gut hormones.

[0783] The Applicant has also confirmed that 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 retains its fast-acting insulin action.

[0784] The preparation of the composition according to the invention offers the advantage that it is suitable to be carried out 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 freeze-dried form. If necessary, the pH of the preparation is adjusted to a pH between 6 and 8.

[0785] The preparation of the composition according to the invention offers the advantage that it is suitable to be carried out 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 and a copolyamino acid having a carboxylate charge and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form, and, if necessary, the pH of the preparation is adjusted to a pH between 6 and 8.

[0786] The preparation of the composition according to the invention offers the advantage that it is suitable to be carried out 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 freeze-dried form. If necessary, the pH of the preparation is adjusted to a pH between 6 and 8.

[0787] The preparation of the composition according to the invention offers the advantage that it is suitable to be carried out by simply mixing an aqueous solution of basal insulin, a solution of prandial insulin, 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 freeze-dried form, with an isoelectric point comprised between 5.8 and 8.5. If necessary, the pH of the preparation is adjusted to a pH between 6 and 8.

[0788] In one embodiment, the mixture of basal insulin and copolyamino acid is concentrated by ultrafiltration before mixing with prandial insulin in aqueous solution or freeze-dried form.

[0789] 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 6-8.

[0790] The following examples illustrate the invention in a non-limiting manner. Working Example Part A - Synthesis of hydrophobic intermediate compound Hyd to obtain radical-Hy [ka] TIFF0007638508000108.tif173162TIFF0007638508000109.tif197162TIFF0007638508000110.tif226162TIFF0007638508000111.tif195162

[0791] Example A1: Molecule A1 To a solution of L-proline (300.40 g, 2.61 mol) in 2N aqueous sodium hydroxide (1.63 L) at 0° C., a solution of myristoyl chloride (322 g, 1.30 mol) in dichloromethane (DCM, 1.63 L) is slowly added over 1 hour. At the end of the addition, the reaction medium is allowed to return to 20° C. in 3 hours and then stirred for a further 2 hours. The mixture is cooled to 0° C. and then 37% aqueous HCl (215 mL) is added in 15 minutes. The reaction medium is stirred from 0° C. to 20° C. for 3 hours and then cooled to 3° C. 37% HCl (213 mL) is added in 15 minutes and the mixture is stirred from 0° C. to 20° C. for 1 hour. The organic phase is separated, washed with 10% aqueous HCl (3×430 mL), aqueous saturated NaCl solution (430 mL), dried over Na2SO4, filtered on cotton and then concentrated under reduced pressure. The residue is solubilized in heptane (1.31 L) at 50° C., then the solution is gradually allowed to return to ambient temperature. After initiating crystallization using a glass rod, the medium is once again heated to 40° C. for 30 minutes and then allowed to return to ambient temperature for 4 hours. The white solid of molecule A1 is obtained after filtration on a sintered filter, washed with heptane (2×350 mL) and dried under reduced pressure. Yield: 410g (97%) 1 H NMR (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).

[0792] Example A2: Molecule A2 Molecule 1: Products obtained by the reaction between decanoyl chloride and L-proline Using a method similar to that used for the preparation of molecule A1, applied to decanoyl chloride (75.0 g, 393.27 mmol) and L-proline (90.55 g, 786.53 mmol), a colorless oil of molecule 1 is obtained after washing the organic phase with 10% aqueous HCl (3×125 mL), an aqueous solution saturated with NaCl (125 mL), drying over Na2SO4, cotton filtration and then concentration under reduced pressure. Yield: 104.64g (99%) 1 H NMR(CDCl3, ppm):0.86(3H);1.10-1.51(12H);1.56-1.80(2H);1.83-2.4 6(6H);3.42-3.66(2H);4.37-4.41(0.1H);4.53-4.60(0.9H);10.12(1H). LC / MS(ESI):270.1;(calculation([M+H] + ):270.2).

[0793] Molecule A2 To a solution of molecule 1 (90.0 g, 334.09 mmol) in THF (600 mL) at 0 ° C, N-hydroxysuccinimide (NHS, 40.4 g, 350.80 mmol) and then a solution of dicyclohexylcarbodiimide (DCC, 72.38 g, 350.80 mmol) in THF (60 mL) are successively added. After 16 hours of stirring at ambient temperature, the reaction medium is filtered and introduced onto a solution of L-lysine hydrochloride (30.51 g, 167.05 mmol) and N,N-diisopropylethylamine (DIPEA, 97.16 g, 751.71 mmol) in water (66 mL) and the mixture is stirred for 48 hours at 20 ° C. After concentration under reduced pressure, water (360 mL) is added and the mixture obtained is treated by successive addition of ethyl acetate (AcOEt, 500 mL), followed by 5% aqueous Na2CO3 (1 L). The aqueous phase is then washed once more with AcOEt (200 mL), acidified by addition of 6N aqueous HCl and the product is extracted with dichloromethane (DCM, 3 x 250 mL). The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. The white solid obtained after crystallization in AcOEt is solubilized in DCM (400 mL) and the organic phase is washed with 1N aqueous HCl (200 mL), followed by an aqueous solution saturated with NaCl (200 mL), dried over Na2SO4, filtered and concentrated under vacuum. A white solid of molecule A2 is obtained after crystallization in AcOEt. Yield: 75.90g (70%) 1 H NMR (DMSO-d6, ppm):0.85(6H);1.10-2.04(42H);2.07-2.30(4H);2.92-3.08(2H);3.28-3.57(4H) );4.07-4.28(2H);4.32-4.40(1H);7.66-7.73(0.6H);7.96-8.09(1H);8.27(0.4H);12.51(1H). LC / MS(ESI):649.5(calculation([M+H] + ):649.5).

[0794] Example A3: Molecule A3 Molecule 2: Product obtained by reaction between lauroyl chloride and L-proline Using a method similar to that used for the preparation of molecule A1, applied to lauroyl chloride (27.42 g, 685.67 mmol) and L-proline (60.0 g, 247.27 mmol), molecule 2 is obtained as a white solid. Yield: 78.35g (96%) 1 H NMR (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).

[0795] Molecule A3 Using a method similar to that used for the preparation of molecule A2, applied to molecule 2 (42.49 g, 142.86 mmol) and L-lysine hydrochloride (13.7 g, 75.0 mmol), a white solid of molecule A3 is obtained after crystallization in acetone. Yield: 30.17g (60%) 1 H NMR (DMSO-d6, ppm):0.86(6H);1.07-2.05(50H);2.08-2.30(4H);2.93-3.09(2H);3.28-3.57 (4H);4.08-4.29(2H);4.33-4.41(1H);7.70(0.6H);7.97-8.07(1H);8.28(0.4H);12.52(1H). LC / MS(ESI):705.6;(calculation([M+H] + ):705.6).

[0796] Example A4: Molecule A4 Using a method similar to that used for the preparation of molecule A2, applied to molecule A1 (200.0 g, 614.44 mmol) and L-lysine hydrochloride (56.11 g, 307.22 mmol), a white solid of molecule A4 is obtained after crystallization in ethyl acetate. Yield: 176.0g (95%) 1H NMR (DMSO-d6, ppm):0.85(6H);1.08-1.51(48H);1.53-2.04(10H);2.08-2.30(4H);2.93-3 .09(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] + ):761.6).

[0797] Example A5: Molecule A5 Molecule 3: 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 ambient 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 reaction vessel suitable for solid substrate peptide synthesis. After 2 h of stirring at ambient temperature, HPLC grade methanol (0.8 mL / g resin, 3.2 mL) is added and the medium is stirred at ambient 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).

[0798] Molecule 4: Products obtained by reaction between molecule 3 and an 80:20 DMF / piperidine mixture Molecule 3, previously washed with DMF, is treated with a 80:20 DMF / piperidine mixture (60 mL). After 30 min of stirring at ambient temperature, the resin is filtered and washed successively with DMF (3×60 mL), isopropanol (1×60 mL) and DCM (3×60 mL).

[0799] Molecule 5:The product obtained by reaction between molecule 4 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 4. After 2 h of stirring at ambient temperature, the resin is filtered and washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and DCM (3 x 60 mL).

[0800] Molecule 6: Products obtained by reaction between molecule 5 and an 80:20 DMF / piperidine mixture A method similar to that used for molecule 4 is applied to molecule 5 to give molecule 6.

[0801] Molecule 7: Products obtained by reaction between molecule 6 and lauric acid Using a method similar to that used for molecule 5, molecule 6 and lauric acid (4.97 g, 24.80 mmol) in DMF (60 mL) are applied to give molecule 7.

[0802] Molecule 8: Products obtained by reaction between molecule 7 and an 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) mixture Molecule 7 is treated with an 80:20 dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) mixture (60 mL). After 20 min of stirring at ambient temperature, the resin is filtered and washed successively with dichloromethane (2 x 60 mL). The solvent is evaporated under reduced pressure. The residue is then subjected to two coevaporations with dichloromethane (60 mL) followed by diisopropyl ether (60 mL). A white solid of molecule 8 is obtained after recrystallization in acetonitrile. Yield: 2.63g (66% over 6 steps) 1 H NMR(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).

[0803] Molecule 9: The product obtained by reaction between molecule 8 and N-Boc ethylenediamine To a solution of molecule 8 (2.63 g, 3.29 mmol) in chloroform (20 mL) at ambient temperature, N-hydroxybenzotriazole (HOBt, 654 mg, 4.27 mmol) and N-Boc ethylenediamine (BocEDA, 580 mg, 3.62 mmol) are added successively. The mixture is cooled to 0 °C and then (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (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 ambient temperature. The organic phase is washed with an aqueous solution saturated with NH4Cl (2 × 10 mL), an aqueous solution saturated with NaHCO3 (2 × 10 mL) and an aqueous solution saturated with NaCl (2 × 10 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel chromatography (eluent: dichloromethane, methanol), molecule 9 is obtained as a white solid. Yield: 2.37g (76%) 1 H NMR(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).

[0804] Molecule A5 To a solution of molecule 9 (2.37 g, 2.51 mmol) in dichloromethane (50 mL) at ambient temperature, a solution of 4 M HCl in dioxane (6.3 mL) is added and the medium is then stirred for 2 h at ambient temperature. After concentration under reduced pressure, the residue is solubilized in dichloromethane (50 mL) and then washed with an aqueous solution of 1 N NaOH (2 × 12.5 mL) and an aqueous solution saturated with NaCl (25 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule A5 is obtained after recrystallization in acetonitrile. Yield: 1.57g (74%) 1 H NMR (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. 17-3.71(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).

[0805] Example A6: Molecule A6 Molecule 10: Products obtained by hydrogenating 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 in a hydrogen atmosphere (1 atm) at ambient temperature. After one night, the reaction medium is filtered on a sintered filter and the filtrate is then concentrated under reduced pressure. A colorless oil of molecule 10 is obtained. Yield: 19.50g (99%) 1 H NMR (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).

[0806] Molecule 11: Boc-1-amino-4,7,10-trioxa-13-tridecanamine (BocTOTA) and the product obtained by coupling of molecule 10 A method similar to that used for the preparation of molecule 9 is applied to molecule 10 (19.3 g, 62.15 mmol) and BocTOTA (23.9 g, 74.58 mmol) to give molecule 11, an orange oil. Yield: 37.05g (97%) 1 H NMR (CDCl3, ppm):0.43-1.71(49H);2.13-2.17(1H);3.17-3.24(2H);3.32-3. 39(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).

[0807] Molecule A6 A method similar to that used for the preparation of molecule A5 is applied to molecule 11 (34.9 g, 56.94 mmol) to give an orange oil of molecule A6. Yield: 28.5g (97%) 1H NMR (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).

[0808] Example A7: Molecule A7 Molecule 12: The product obtained by reaction between molecule 4 and Fmoc-Glu(OtBu)-OH To a suspension of Fmoc-Glu(OtBu)-OH (10.55 g, 24.80 mmol) and HATU (9.43 g, 24.80 mmol) in a 1:1 DMF / dichloromethane mixture (60 mL) is added DIPEA (8.64 mL, 49.60 mmol). After complete solubilization, the resulting solution is poured onto molecule 4. After 2 h of stirring at ambient 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).

[0809] Molecule 13: Products obtained by reaction between molecule 12 and a 50:50 DMF / morpholine mixture Molecule 12, previously washed with DMF, is treated with a 50:50 DMF / morpholine mixture (60 mL). After stirring for 1 h 15 min at ambient 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).

[0810] Molecule 14: The product obtained by the reaction between molecule A1 and molecule 13 Using a method similar to that used for molecule 12, molecule 13 and molecule A1 (8.07 g, 24.80 mmol) in DMF (60 mL) are applied to give molecule 14.

[0811] Molecule A7 Using a method similar to that used for the preparation of molecule 8, applied to molecule 14, a white solid of molecule A7 is obtained after purification by silica gel chromatography (eluents: DCM, methanol). Yield: 2.92g (52% over 6 steps) 1 H NMR (DMSO-d6, ppm):0.85(6H);1.07-2.32(88H);2.95-3.09(2H);3.28-3.60(4H);4.06-4.19(1.7H);4. 21-4.38(2.6H);4.40-4.46(0.7H);7.56-7.63(0.7H);7.78-8.09(2.6H);8.22-8.31(0.7H);12.64(1H). LC / MS(ESI):1131.8(calculation([M+H] + ):1131.8).

[0812] Example A8: Molecule A8 Molecule 15: Products obtained by the reaction between decanoic acid and L-leucine Using a method similar to that used for the preparation of molecule A2, applied to decanoic acid (8.77 g, 50.94 mmol) and L-leucine (7.00 g, 53.36 mmol), molecule 15 is obtained as a white solid. Yield: 9.17g (66%) 1 H NMR (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).

[0813] Molecule 16: The product obtained by reaction between molecule 15 and L-lysine methyl ester To a solution of molecule 15 (9.16 g, 32.11 mmol) in THF (160 mL), triethylamine (8.12 g, 80.27 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) are successively added and the medium is stirred for 30 minutes at ambient temperature. L-Lysine methyl ester dihydrochloride (3.93 g, 16.86 mmol) is added, the reaction medium is stirred for 3 hours and then concentrated under reduced pressure. The residue is diluted with AcOEt (200 mL), the organic phase is filtered, washed with 1N aqueous HCl, then with water, dried over Na2SO4, filtered and concentrated under reduced pressure. After trituration of the residue in acetonitrile, a white solid of molecule 16 is obtained. Yield: 7.33g (66%) 1 H NMR (DMSO-d6, ppm):0.80-0.91(18H);1.06-1.72(38H);2.03-2.16(4H);2.91-3.07(2H);3. 60(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).

[0814] Molecule 17: Products obtained by saponification of molecule 16 To a solution of molecule 16 (7.33 g, 10.55 mmol) in a THF / methanol / water mixture (105 mL) is added LiOH (505.13 mg, 21.09 mmol) at 0 °C, then the medium is stirred for 20 h at ambient temperature and concentrated under reduced pressure. The aqueous phase is acidified to pH 1 with a 1N HCl solution, the solid formed is filtered, washed with water and dried under reduced pressure to give a white solid of molecule 17. Yield: 7.09g (99%) 1H NMR (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).

[0815] Molecule 18: The product obtained by reaction between molecule 17 and N-Boc ethylenediamine Using a method similar to that used for the preparation of molecule 16, applied to molecule 17 (7.09 g, 10.41 mmol) and N-Boc ethylenediamine (1.83 g, 11.45 mmol), a white solid of molecule 18 is obtained after trituration in acetonitrile. Yield: 6.64g (77%) 1 H NMR (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).

[0816] Molecule A8 Using a method similar to that used for molecule A5, applied to molecule 18 (3.00 g, 3.64 mmol), without base washing, a beige solid of molecule A8 in hydrochloride form is obtained after coevaporating the residue four times in methanol. Yield: 2.66g (96%) 1H NMR (DMSO-d6, ppm):0.80-0.91(18H);1.15-1.76(40H);2.03-2.19(4H);1.78-2.89(2 H);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).

[0817] Example A9: Molecule A9 Molecule 19: 13-Methyltetradecanoic acid In a dry three-necked round-bottom flask, under argon, magnesium (5.50 g, 226.3 mmol) chips are introduced. The magnesium is covered with anhydrous THF (25 mL) and a few drops of 1-bromo-2-methylpropane are added at ambient temperature to start the reaction. After observing the exotherm and slight turbidity of the medium, the remaining 1-bromo-2-methylpropane (28.42 g, 207 mmol) diluted in THF (60 mL) is added dropwise over 1 h, while the temperature of the medium remains stable at 65-70 °C. The reaction medium is then heated at reflux for 2 h.

[0818] In a three-necked round-bottom flask, under argon, a solution of CuCl (280 mg, 2.83 mmol) dissolved in N-methylpyrrolidone (NMP) previously distilled at 0 °C is added dropwise to a solution of 11-bromoundecanoic acid (25 g, 94.27 mmol) dissolved in THF (60 mL). A slightly warm solution of organomagnesium diluted in THF (50 mL) is then added dropwise to this solution, maintaining the temperature of the medium below 25 °C. The mixture is then stirred at ambient temperature for 16 hours. The medium is cooled to 0 °C and the reaction is quenched by gradually adding 1N aqueous HCl (300 mL) until a pH of 1 is reached, and the medium is extracted with hexane (100 mL) and ethyl acetate (2 × 75 mL). The organic phase is washed with 1N aqueous HCl (100 mL), water (100 mL), then dried over Na2SO4, the solution is filtered and concentrated under vacuum to obtain a brown solid. After purification by flash chromatography (cyclohexane, ethyl acetate) a white solid is obtained. Yield: 18.1g (79%) 1 H NMR (CDCl3, ppm): 0.87 (6H); 1.11-1.18 (2H); 1.20-1.38 (16H); 1.51 (1H); 1.63 (2H); 2.35 (2H).

[0819] Molecule 20: Products obtained by reacting molecule 19 and L-leucine To a solution of molecule 19 (18.05 g, 74.46 mmol) in THF (745 mL) at ambient temperature, DCC (14.63 g, 70.92 mmol) and NHS (8.16 g, 70.92 mmol) are successively added. After 40 h of stirring at ambient temperature, the medium is cooled to 0 °C for 20 min and filtered on a sintered filter. L-leucine (9.77 g, 74.46 mmol), DIPEA (86 mL) and water (150 mL) are added to the filtrate. After 20 h of stirring at ambient temperature, the medium is diluted with a saturated aqueous solution of NaHCO3 (200 mL). The aqueous phase is washed with ethyl acetate (2 × 200 mL) and acidified to pH 1 with a 2N HCl solution. The precipitate is filtered, thoroughly rinsed with water and dried under vacuum at 50 °C. The solid is triturated in pentane and sonicated three times, then filtered to produce a white solid. Yield: 18.8g (75%) 1 H NMR (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).

[0820] Molecule 21: 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) are added successively at ambient temperature DIPEA (20.3 mL) and TBTU. After 20 min of stirring, Boc-tri(ethylene glycol)diamine (14 g, 56.36 mmol) is added. After 5 h of stirring at ambient temperature, the mixture is concentrated under vacuum. The residue is dissolved in ethyl acetate (500 mL) and washed with a saturated aqueous solution of NaHCO3 (3 x 200 mL), an aqueous solution of 1N HCl (3 x 200 mL) and an aqueous solution saturated with 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 yield a colorless oil. Yield: 23.5g (85%) 1 H NMR(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( 12H);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).

[0821] Molecule A9 A method similar to that used for the preparation of molecule A5 is applied to molecule 21 (23.46 g, 40.04 mmol) without base washing, and the residue obtained after concentration under vacuum is triturated in an acetonitrile / acetone mixture. The supernatant is removed and the pasty residue is dried under vacuum. The residue is triturated in acetone (150 mL) and the white solid of molecule A9 in hydrochloride form is filtered, rinsed with acetone and then dried under vacuum. Yield: 13.0g (64%) 1 H NMR (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).

[0822] Example A10: Molecule A10 Molecule 22: Products obtained by the reaction between octanoyl chloride and L-proline Using a method similar to that used for the preparation of molecule A1, applied to octanoyl chloride (150.0 g, 0.922 mol) and L-proline (212.3 g, 1.844 mol), the organic phase is washed with 10% aqueous HCl (3×300 mL), an aqueous solution saturated with NaCl (300 mL) and, after drying over Na2SO4, filtration on cotton and concentration under reduced pressure, a colorless oil of molecule 22 is obtained, the residue being then purified by flash chromatography (eluents: DCM, MeOH). Yield: 134g (60%) 1 H NMR(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).

[0823] Molecule 23: Products obtained by coupling molecule 22 and L-leucine NHS (66.1 g, 0.574 mol) and DCC (118.5 g, 0.574 mol) are added successively to a solution of molecule 22 (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 in 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 ambient temperature, the reaction medium is concentrated under reduced pressure to produce an oily residue which is diluted in water (1.3 L). The aqueous phase is washed twice with AcOEt (2 x 0.5 L), cooled to a temperature below 10°C, acidified to pH 1 by adding 6N HCl solution (120 mL), then extracted three times with DCM (3 x 0.6 L). The organic phases are combined, washed with saturated NaCl solution (0.6 L), dried over Na2SO4, then concentrated under reduced pressure. The resulting foam is dissolved by refluxing with acetone (240 mL) for 2 h. After standing overnight at 10°C, pentane (240 mL) is added dropwise. After stirring for 1 h, the precipitate is recovered by filtration under vacuum, washed with a 1:1 mixture of pentane and acetone (150 mL), then dried under vacuum. Yield: 83.9g (52%) 1 H NMR (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).

[0824] Molecule 24: Coupling of molecule 23 with L-lysine methyl ester (LysOMe) To molecule 23 (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). DMF (600 mL), previously cooled to 5 °C, is then added. After dissolution, triethylamine (43.9 mL, 0.315 mol) is added dropwise while maintaining a temperature below 5 °C for 2 hours after the addition. After leaving overnight at ambient temperature, the reaction medium is poured onto a mixture of water / ice (2 kg) and DCM (0.5 L). After 15 minutes of stirring, the phases are separated. The aqueous phase is extracted twice with DCM (2 × 0.4 L). The organic phases are combined, washed with a 1N HCl solution (0.5 L), then with a saturated NaCl solution (0.5 L), dried over Na2SO4, concentrated under reduced pressure, and the residue is purified by flash chromatography (eluents: DCM, MeOH). Yield: 56.7g (67%) 1 H NMR (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).

[0825] Molecule A10 A solution of molecule 24 (4.0 g, 3.05 mmol) in ethylenediamine (30 mL) is heated at 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 concentrated under reduced pressure. The residue is solubilized at reflux in acetonitrile for 30 minutes, then the solution is cooled to ambient temperature overnight with stirring. The white precipitate is then recovered by filtration under vacuum, washed with cold acetonitrile (2×20 mL) and then dried under vacuum. Yield: 3.0g (74%) 1 H NMR (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).

[0826] Example A11: Molecule A11 Molecule 25: Products obtained by reaction between molecule 13 and lauric acid Using a method similar to that used for molecule 5, molecule 25 is obtained by applying molecule 13 (28 mmol) and lauric acid (28.04 g, 140 mmol) to DMF (330 mL).

[0827] Molecule A11 Using a method similar to that used for molecule 8, applied to molecule 25, a white solid of molecule A11 is obtained after recrystallization in acetonitrile. Yield: 13.9g (56% over 6 steps) 1 H NMR (DMSO-d6, ppm):0.85(6H);1.05-1.61(60H);1.62-1.75(2H);1.78-1.91(2H);2.04-2.27(8H);2.96-3.06 (2H);4.08-4.13(1H);4.17-4.22(1H);4.27-4.34(1H);7.82(1H);7.86(1H);7.90(1H);8.03(1H);12.54(1H). LC / MS(ESI+):881.7(calculation([M+H] + ):881.7).

[0828] Example A12: Molecule A12 Molecule 26: The product obtained by reaction between molecule 13 and Fmoc-Glu(OtBu)-OH Using a method similar to that used for molecule 5, applied to molecule 13 (9.92 mmol) and Fmoc-Glu(OtBu)-OH (21.10 g, 49.60 mmol) in N-methyl-2-pyrrolidone (NMP, 120 mL), molecule 26 is obtained.

[0829] Molecule 27:Products obtained by reaction between molecule 26 and an 80:20 NMP / piperidine mixture A method similar to that used for molecule 4 is applied to molecule 26, using NMP instead of DMF, to give molecule 27.

[0830] Molecule 28: The product obtained by reaction between molecule 27 and Fmoc-Glu(OtBu)-OH A method similar to that used for molecule 26 is applied to molecule 27 and Fmoc-Glu(OtBu)-OH (21.10 g, 49.60 mmol) to give molecule 28.

[0831] Molecule 29: Products obtained by reaction between molecule 28 and an 80:20 NMP / piperidine mixture A similar methodology to that used for molecule 27 is applied to molecule 28 to give molecule 29.

[0832] Molecule 30: The product obtained by the reaction between molecule 29 and molecule A1 A method similar to that used for molecule 26 is applied to molecule 29 (4.96 mmol) and molecule A1 (8.07 g, 24.80 mmol) to give molecule 30.

[0833] Molecule A12 Using a method similar to that used for molecule 8, applied to molecule 30, a white solid of molecule A12 is obtained after purification by flash chromatography (DCM, MeOH). Yield: 4.6g (50% over 10 steps) 1 H NMR (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).

[0834] Example A14: Molecule A14 Molecule 33: Products obtained by the reaction between N-α-Boc-L-lysine and palmitoyl chloride Using a method similar to that used for the preparation of molecule A1, applied to N-α-Boc-L-lysine (53.76 g, 218.28 mmol) and palmitoyl chloride (50.00 g, 181.90 mmol), a white solid of molecule 33 is obtained after two recrystallizations in acetonitrile and purification by flash chromatography (eluents: dichloromethane, methanol). Yield: 49.10g (70%) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.09-1.66(32H);1.37(9H);2.01(2H);2.93-3.06(2H );3.78-3.85(1H);6.61-6.68(0.2H);6.96-6.98(0.8H);7.66-7.75(1H);12.38(1H). LC / MS(ESI):385.1(calculation([M-Boc+H] + ):385.3).

[0835] Molecule 34: Products obtained by reaction between molecule 33 and methyl iodide To a solution of molecule 33 (23.40 g, 48.28 mmol) in DMF (200 mL) at ambient temperature, K2CO3 (10.01 g, 72.41 mmol) is added followed by methyl iodide (5.96 mL, 98.55 mmol). The medium is stirred for 48 h. Water (350 mL) is added and the suspension is stirred for 15 min. The mixture is then filtered on a sintered filter and the solid obtained is rinsed with water (2 x 250 mL) and dried under vacuum. The solid is then solubilized in DCM (300 mL). The solution is washed with water (200 mL), then with an aqueous solution saturated with NaCl (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule 34 is obtained after recrystallization in acetonitrile. Yield: 19.22g (80%) 1H NMR (CDCl3, ppm): 0.87 (3H); 1.06-2.23 (34H); 1.43 (9H); 3.09-3.33 (2H); 3.72 (3H); 3.94-4.35 (1H); 4.69-5.23 (1H); 5.33-5.75 (1H). LC / MS(ESI):543.3(calculation([M-H+HCOOH] - ):543.4).

[0836] Molecule 35: Products obtained by hydrolysis of molecule 34 with hydrochloric acid Using a method similar to that used for the preparation of molecule A5, applied to a solution of molecule 34 in a 1:1 DCM / methanol mixture (385 mL), a white solid of molecule 35 is obtained after concentration under reduced pressure and co-evaporation with DCM followed by methanol. Yield: 16.73g (99%) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.08-1.50(30H);1.67-1.84(2H);2.03(2H); 2.94-3.13(2H);3.74(3H);3.92-4.01(1H);7.77-7.87(1H);8.25-8.73(3H). LC / MS(ESI):399.2(calculation([M+H] + ):399.4).

[0837] Molecule A14 To a suspension of molecule 35 (14.70 g, 33.79 mmol) in a mixture of methyl-THF (338 mL) and DMF (30 mL) are successively added DIPEA (17.70 mL, 101.40 mmol), followed by a solution of succinic anhydride (5.07 g, 50.68 mmol) in THF (60 mL). The medium is stirred for 4 h at ambient temperature. Methyl-THF (100 mL) is added and the organic phase is washed with 5% aqueous HCl (300 mL). The aqueous phase is extracted with methyl-DCM (2×150 mL). The organic phases are combined, washed with water (2×150 mL), then with an aqueous solution saturated with NaCl (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: DCM, methanol) and then solubilized in methyl-THF. The purified product is then suspended in water. The suspension is stirred by ultrasonication for 20 minutes, followed by magnetic stirring for 30 minutes. A white solid of molecule A14 is obtained after filtration and drying under reduced pressure. Yield: 12.99g (77%) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.08-1.71(32H);2.02(2H);2.29-2.45(4H); 2.94-3.04(2H);3.61(3H);4.14-4.22(1H);7.70(1H);8.20(1H);12.04(1H). LC / MS(ESI):499.3(calculation([M+H] + ):499.4).

[0838] Example A15: Molecule A15 Molecule 36: Products obtained by coupling L-proline and palmitoyl chloride Using a method similar to that used for the preparation of molecule A1, applied to L-proline (38.05 g, 906.00 mmol) and palmitoyl chloride (14.01 g, 350.16 mmol), molecule 36 is obtained as a white solid. Yield: 47.39g (96%) 1H NMR(CDCl3, ppm):0.88(3H);1.19-1.45(24H);1.58-1.74(2H);1.88-2.14(3H); 2.15-2.54(3H);3.47(1H);3.58(1H);4.41(0.1H);4.61(0.9H)6.60-8.60(1H). LC / MS(ESI):354.5(calculation([M+H] + ):354.3).

[0839] Molecule 37: The product obtained by reaction between molecule 36 and N-Boc ethylenediamine Using a method similar to that used for molecule 9, applied to molecule 36 (75.1 g, 212.4 mmol), a white solid of molecule 37 is obtained after trituration in diisopropyl ether (3×400 mL) and drying in vacuum at 40° C. Yield: 90.4g (86%). 1 H NMR(CDCl3, ppm):0.88(3H);1.20-1.37(24H);1.44(9H);1.54-1.70(2H);1.79-1.92(1H);1.92-2.04(1H);2.03-2.17(1H);2.17 -2.44(3H);3.14-3.36(4H);3.43(1H);3.56(1H);4.29(0.1H);4.51(0.9H);4.82(0.1H);5.02(0.9H);6.84(0.1H);7.22(0.9H).

[0840] Molecule 38: Products obtained by hydrolysis of molecule 37 with hydrochloric acid A method similar to that used for the preparation of molecule A5 is applied to molecule 37 (38.17 g, 76.99 mmol) to give molecule 38 as a white solid. 1H NMR(CDCl3, ppm):0.88(3H);1.07-1.40(24H);1.49-1.63(2H);1.77-2.18(4H);2.18-2.45(2H );3.14-3.32(2H);3.42-3.63(2H);3.63-3.84(2H);4.37(0.1H);4.48(0.9H);6.81-8.81(4H). LC / MS(ESI):396.5;(calculation([M+H] + ):396.4).

[0841] Molecule A15 A method similar to that used for the preparation of molecule A14 is applied to molecule 38 (10.00 g, 253.00 mmol) to give a white solid of molecule A15. Yield: 10.00g (80%) 1 H NMR (DMSO, ppm):0.85(3H);1.07-1.51(26H);1.69-2.02(4H);2.08-2.53(6H);3.01-3.18(4H);3.39-3.58(2H );4.13-4.18(0.7H);4.23-4.27(0.3H);7.70-7.78(1.4H);7.81-7.86(0.3H);8.00-8.04(0.3H);12.08(1H). LC / MS(ESI):496.3(calculation([M+H] + ):496.4).

[0842] Example A16: Molecule A16 Molecule 39: The product obtained by reaction between molecule 36 and Boc-1-amino-4,7,10-trioxa-13-tridecanamine A method similar to that used for the preparation of molecule 9 is applied to molecule 36 (17.00 g, 48.08 mmol) and Boc-1-amino-4,7,10-trioxa-13-tridecanamine (18.49 g, 57.70 mmol) to give molecule 39, a pale yellow oil. Yield: 31.11g (98%) 1H NMR (DMSO-d6, ppm):0.85(3H);1.17-1.31(24H);1.37(9H);1.41-1.51(2H);1.54-1.67(4H);1.69-2.02(4H);2.08-2.29(2H) ;2.91-3.00(2H);3.01-3.17(2H);3.31-3.58(14H);4.20(0.65H);4.26(0.35H);6.29-6.82(1H);7.68(0.65H);8.02(0.35H). LC / MS(ESI):656.4(calculation([M+H] + ):656.5).

[0843] Molecule 40: Products obtained by hydrolysis of molecule 39 with hydrochloric acid A method similar to that used for the preparation of molecule A5 is applied to molecule 39 (31.11 g, 47.43 mmol) to give a yellow wax of molecule 40. Yield: 27g (97%) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.18-1.31(24H);1.40-1.51(2H);1.55-1.67(2H);1.70-2.04(6H);2.09-2 .30(2H);2.78-2.89(2H);2.99-3.18(2H);3.33-3.58(14H);4.19(0.65H);4.27(0.35H);7.55-8.14(4H). LC / MS(ESI):556.3(calculation([M+H] + ):556.5).

[0844] Molecule A16 Molecule 40 (26.40 g, 44.50 mmol) in hydrochloride form is solubilized in a mixture of DCM (350 mL) and aqueous NaHCO3 (350 mL). The organic phase is separated and the aqueous phase is extracted with DCM (2 x 150 mL). The organic phases are combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a colorless oil. Using a method similar to that used for the preparation of molecule A14, a yellow resin of molecule A16 is obtained after purification by flash chromatography (eluent: DCM, methanol). Yield: 19.93g (68%) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.18-1.30(24H);1.40-1.51(2H);1.55-1.67(4H);1.70-2.02(4H);2.07-2.45(6H) ;2.99-3.18(4H);3.33-3.57(14H);4.19(0.65H);4.26(0.35H);7.68(0.65H);7.78(1H);8.02(0.35H);12.03(1H). LC / MS(ESI):656.3(calculation([M+H] + ):656.5).

[0845] Example A17: Molecule A17 Molecule 41: Products obtained by solid phase peptide synthesis (SPPS) Molecule 41 is obtained by conventional solid phase peptide synthesis (SPPS) methods on 2-chlorotrityl resin.

[0846] DIPEA (60.96 mL, 350 mmol) is added to a solution of 4,7,10-trioxa-1,13-tridecanediamine (TOTA, 76.73 mL, 350 mmol) in DCM (350 mL). This solution is then poured onto 2-chlorotrityl resin (47.30 g, 0.74 mmol / g), previously washed with DCM, in a reaction vessel suitable for SPPS. After stirring for 1.5 h at ambient temperature, methanol (26 mL) is added and the medium is stirred for 15 min. The resin is filtered and washed successively with DCM (3 x 350 mL), DMF (2 x 350 mL), DCM (2 x 350 mL), isopropanol (1 x 350 mL) and DCM (3 x 350 mL). The γ-methyl ester of N-Fmoc-L-glutamic acid (1,5 eq) is coupled followed by molecule 36 (1.5 eq) using the coupling agents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.5 eq) and DIPEA (3 eq) in a 1:1 DCM / DMF mixture. A 1:1 DMF / morpholine mixture is used for the cleavage step of the Fmoc protecting group. The resin is washed with DCM, DMF and methanol after each coupling and deprotection step. Cleavage of the product from the resin is carried out using a 1:1 TFA / DCM mixture. The solvent is then evaporated under vacuum; the residue is solubilized in DCM (500 mL) and the organic phase is washed with 5% aqueous Na2CO3 solution (500 mL). After drying over Na2SO4, the organic phase is filtered and concentrated under vacuum to give a yellow oil of molecule 41 after drying under reduced pressure. Yield: 15.95g (65%) 1H NMR (DMSO-d6, ppm):0.85(3H);1.16-1.31(24H);1.38-1.68(6H);1.68-2.37(12H);2.58(2H);3.01-3.17(2H);3.31-3.55( 14H);3.58(3H);4.09-4.18(0.7H);4.18-4.29(1H);4.36-4.43(0.3H);7.62(0.7H);7.86(0.7H);7.98(0.3H);8.23(0.3H). LC / MS (ESI): 699.4 (calculated ([M+H]+): 699.5).

[0847] Molecule A17 A method similar to that used for the preparation of molecule A14 is applied to molecule 41 (14.05 g, 20.10 mmol) to give a yellow resin of molecule A17 after purification by flash chromatography (eluents: DCM, methanol). Yield: 7.70g (48%) 1H NMR (DMSO-d6, ppm):0.85(3H);1.17-1.31(24H);1.38-1.54(2H);1.54-1.6 8(4H);1.68-2.21(7H);2.21-2.36(5H);2.36-2.44(2H);3.01-3.16(4H);3 .34-3.55(14H);3.57(3H);4.10-4.18(0.7H);4.18-4.30(1H);4.40(0.3H) ;7.60(0.7H);7.78(1H);7.85(0.7H);7.95(0.3H);8.22(0.3H);12.06(1H). LC / MS (ESI): 799.5 (calculated ([M+H]+): 799.5).

[0848] Example A18: Molecule A18 Molecule 42: The product obtained by reaction between molecule A1 and Boc-1-amino-4,7,10-trioxa-13-tridecanamine A method similar to that used for the preparation of molecule 18 is applied to molecule A1 (44.80 g, 137.64 mmol) and Boc-1-amino-4,7,10-trioxa-13-tridecanamine (52.92 g, 165.16 mmol) to give molecule 42, an orange oil. Yield: 85.63g (99%) 1H NMR(CDCl3, ppm):0.87(3H);1.08-1.56(20H);1.43(9H);1.58-1.67(2H);1.70-2.00(6H);2.04-2.41( 4H);3.16-3.77(18H);4.26-4.29(0.2H);4.50-4.54(0.8H);4.68-5.10(1H);6.74(0.2H);7.19(0.8H). LC / MS(ESI):628.4;(calculation([M+H] + ):628.5).

[0849] Molecule 43: Products obtained by hydrolysis of molecule 42 with hydrochloric acid Using a method similar to that used for the preparation of molecule A5, applied to molecule 42 (43.40 g, 69.12 mmol), a white solid of molecule 43 in hydrochloride form is obtained after trituration in diethyl ether, solubilization of the residue in water and lyophilization. Yield: 38.70g (98%) 1H NMR (DMSO, ppm):0.85(3H);1.07-1.38(20H);1.41-1.52(2H);1.55-1.66(2H);1.70-2.02(6H);2.08-2.30(2H);2.78-2.8 7(2H);3.00-3.16(2H);3.29-3.66(14H);4.16-4.22(0.65H);4.25-4.30(0.35H);7.74(0.65H);7.86(3H);8.10(0.35H). LC / MS(ESI):528.4;(calculation([M+H] + ):528.4).

[0850] Molecule A18 A method similar to that used for the preparation of molecule A14 is applied to molecule 43 (13.09 g, 24.8 mmol) to give a yellow resin of molecule A18 after purification by flash chromatography (eluents: DCM, methanol). Yield: 8.53g (55%) 1H NMR (DMSO-d6, ppm):0.86(3H);1.10-1.39(20H);1.42-1.51(2H);1.57-1.67(4H);1.71-2.03(4H);2.09-2.32(4H);2.42(2H); 3.01-3.17(4H);3.36-3.57(14H);4.18-4.21(0.65H);4.24-4.28(0.35H);7.69(0.65H);7.80(1H);8.03(0.35H);12.04(1H). LC / MS(ESI):628.5(calculation([M+H] + ):628.5).

[0851] Example A19: Molecule A19 Molecule 44: Products obtained by SPPS A SPPS method similar to that used for the preparation of molecule 41 was applied to TOTA, N-Fmoc-L-leucine, N-Fmoc-L-proline and myristic acid to give molecule 44, an orange oil. Yield: 19.87g (69%) 1 H NMR (CDCl3, ppm): 0.72-1.06(9H); 1.09-1.42(20H); 1.42-2.40(17H); 2.80(2H); 3.22-3.81(16H); 4.25-4.61(2H); 6.56-7.23(2H). LC / MS(ESI):641.5;(calculation([M+H] + ):641.5).

[0852] Molecule A19 After applying a method similar to that used for the preparation of molecule A14 to molecule 44 (13.09 g, 204.42 mmol), 4.81 g of product obtained by purification by flash chromatography (eluent: DCM, methanol) is solubilized in a mixture of DCM (50 mL) and THF (5.5 mL) and then washed with an aqueous solution saturated with NaCl (50 mL), an aqueous solution of 0.1 N HCl (50 mL) and an aqueous solution saturated with NaCl (50 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A yellow oil of molecule A19 is obtained. Yield: 4.20g 1 H NMR (DMSO-d6, ppm):0.72-1.02(9H);1.08-1.34(20H);1.34-2.23(14H);2.23-2.35(3H); 2.42(2H);3.01-3.17(4H);3.17-3.66(14H);4.15-4.44(2H);7.53-8.23(3H);12.06(1H). LC / MS(ESI):741.5;(calculation([M+H] + ):741.5).

[0853] Example A21: Molecule A21 Molecule 46: Products obtained by SPPS A SPPS method similar to that used for the preparation of molecule 41 was applied to TOTA, N-Fmoc-L-phenylalanine and molecule A1 to give molecule 46, an orange oil, which was used without purification. Yield: 15.07g (72%) 1 H NMR(CDCl3, ppm):0.87(3H);1.08-1.42(20H);1.42-1.62(2H);1.62-1.99(7H);1.99 -2.26(3H);2.72(2H);2.86(2H);2.94-3.72(18H);4.20-4.72(2H);6.63-7.37(7H). LC / MS(ESI):675.65;(calculation([M+H] + ):675.5).

[0854] Molecule A21 A method similar to that used for the preparation of molecule A19 is applied to molecule 46 (13.79 g, 20.43 mmol) to give a white solid of molecule A21. Yield: 7.56g (48%) 1 H NMR (DMSO-d6, ppm):0.86(3H);1.02-1.42(21H);1.42-2.20(10H);2.23-2.38(3H);2.42(2H);2 .78-3.18(6H);3.23-3.59(14H);4.12-4.58(2H);7.10-7.30(5H);7.53-8.33(3H);12.08(1H). LC / MS(ESI):775.5;(calculation([M+H] + ):775.5).

[0855] Example A22: Molecule A22 A method similar to that used for the preparation of molecule A14 is applied to molecule A6 (22.15 g, 43.19 mmol) to give a yellow oil of molecule A22. Yield: 25.19g (95%) 1 H NMR (DMSO-d6, ppm):0.42-1.51(33H);1.51-2.05(8H);2.29(2H);2.41(2H );3.07(4H);3.38(4H);3.43-3.54(8H);7.72(1H);7.79(1H);12.03(1H). LC / MS(ESI):613.5(calculation([M+H] + ):613.5).

[0856] Example A23: Molecule A23 Molecule 47: Products obtained by hydrogenating phytol To a solution of phytol (30.00 g, 101.20 mmol) in THF (450 mL) under argon, platinum dioxide (PtO2, 1.15 g, 6.61 mmol) is added. The medium is placed under 1 bar of dihydrogen and then stirred for 4 hours at ambient temperature. After filtration under Celite by rinsing with THF, a black oil of molecule 47 is obtained after concentration under reduced pressure. Yield: 29.00g (96%) 1 H NMR (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). Molecule 48: Products obtained by oxidation of molecule 47

[0857] To a solution of molecule 47 (29.0 g, 97.13 mmol) in a dichloroethane / water mixture (485 mL / 388 mL), tetrabutylammonium bromide (16.90 g, 52.45 mmol), acetic acid (150 mL, 2.62 mol) and then KMnO4 (46.05 g, 291.40 mmol) are successively added in portions, while maintaining the temperature at 16-19 °C. The reaction medium is then stirred at reflux for 4.5 h, cooled to 10 °C and then acidified with 6 N HCl solution (20 mL) until pH 1. Na2SO3 (53.90 g) is added progressively, while maintaining the temperature at 10 °C, and the medium is stirred until complete discolouration. Water (200 mL) is added, the phases are separated and the aqueous phase is extracted with DCM (2 × 400 mL). The organic phases are combined, washed with 10% aqueous HCl (20 mL), water (2×200 mL), saturated aqueous NaCl (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A yellow oil of molecule 48 is obtained after purification by flash chromatography (eluent: cyclohexane, AcOEt). Yield: 28.70g (94%) 1H NMR (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).

[0858] Molecule 49: Products obtained by coupling molecule 48 with L-proline methyl Using a method similar to that used for the preparation of molecule 9, molecule 48 (18.00 g, 57.59 mmol) and L-proline methyl hydrochloride (14.31 g, 86.39 mmol) are applied in DCM (380 mL) to give a yellow oil of molecule 49, which is obtained after washing the organic phase with an aqueous solution saturated with NaHCO3 (2 x 150 mL), 10% aqueous HCL (2 x 150 mL), an aqueous solution saturated with NaCl (2 x 150 mL), followed by drying over Na2SO4, filtration and concentration under reduced pressure. Yield: 23.20g (95%) 1 H NMR (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).

[0859] Molecule 50: Products obtained by saponification of molecule 49 A method similar to that used for the preparation of molecule 17 was applied to molecule 49 (21.05 g, 49.68 mmol) to give molecule 50, a yellow oil. Yield: 20.40g (99%) 1H NMR (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).

[0860] Molecule 51: Products obtained by coupling molecule 50 with Boc-1-amino-4,7,10-trioxa-13-tridecanamine A method similar to that used for the preparation of molecule 9 is applied to molecule 50 (8.95 g, 21.85 mmol) and TOTA (8.40 g, 26.21 mmol) to give molecule 51, a colorless oil, after purification by flash chromatography (eluents: DCM, AcOEt, methanol). Yield: 10.08g (65%) 1 H NMR (DMSO-d6, ppm):0.78-0.89(15H);0.97-1.43(29H);1.43-1.55(1H);1.55-1.66(4H);1.71-2.30(7H); 2.95(2H);3.00-3.19(2H);3.34-3.58(14H);4.17-4.29(1H);6.30-6.79(1H);7.67(0.65H);8.00(0.35H). LC / MS(ESI):712.6(calculation([M+H] + ):712.6).

[0861] Molecule 52: Products obtained by hydrolysis of molecule 42 with hydrochloric acid A method similar to that used for the preparation of molecule A5 is applied to molecule 51 (10.08 g, 14.16 mmol) and the residue obtained after concentration under reduced pressure is solubilized in DCM (200 mL). The organic phase is washed with 2N aqueous NaOH (2×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. A colorless oil of molecule 52 in neutral amine form is obtained. Yield: 8.23g (95%) 1 H NMR (DMSO-d6, ppm):0.78-0.89(15H);0.97-1.43(20H);1.43-1.69(6H);1.69-2.30(8H); 2.56 (2H); 2.99-3.19 (2H); 3.31-3.58 (14H); 4.15-4.29 (1H); 7.70 (0.65H); 8.04 (0.35H). LC / MS (ESI): 612.5 (calculated ([M+H]+): 612.5).

[0862] Molecule A23 A method similar to that used for the preparation of molecule A14 is applied to molecule 52 (15.40 g, 25.17 mmol) to give a yellow oil of molecule A23. Yield: 15.19g (85%) 1 H NMR (DMSO-d6, ppm):0.76-0.91(15H);0.98-2.26(32H);2.29(2H);2.41(2H);2.98-3.18 (4H);3.32-3.63(14H);4.15-4.29(1H);7.68(0.7H);7.78(1H);8.01(0.3H);12.02(1H). LC / MS(ESI):712.5(calculation([M+H] + ):712.5).

[0863] Example A26: Molecule A26 molecule 55 : Products obtained by SPPS Molecule 55 is obtained by conventional solid phase peptide synthesis (SPPS) methods on 2-chlorotrityl chloride (CTC) resin (47.56 g, 0.74 mmol / g).

[0864] The grafting of the first amino acid Fmoc-Glu(OtBu)-OH (2.5 eq.) is carried out in the presence of DIPEA (5.0 eq.) in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0865] The protected amino acid Fmoc-Glu(OtBu)-OH (1.5 equivalents (x2)) is coupled with molecule A1 (1.5 equivalents) in the presence of HATU (1.0 equivalent relative to acid) and DIPEA (2.0 equivalent relative to acid) in DMF (10 V).

[0866] The protecting group Fmoc is removed using a 80:20 DMF / piperidine solution (10V).

[0867] The product is cleaved from the resin using a 80:20 DCM / HFIP solution (10V).

[0868] After concentration under reduced pressure, two co-evaporations are carried out on the residue with dichloromethane followed by diisopropyl ether. The product is purified by silica gel chromatography (dichloromethane, methanol). A colorless gum of molecule 55 is obtained. Yield: 21.4g (69% over 8 steps) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.16-1.30(20H);1.34-1.41(27H);1.41-1.53(2H);1.67-2.33(18H);3.26-3. 60(2H);4.09-4.44(4H);7.73(0.65H);7.85(0.65H);7.93-8.04(1H);8.17(0.35H);8.27(0.35H);12.64(1H). LC / MS(ESI+):881.7(calculation([M+H] + ):881.6).

[0869] molecule 56 : Product obtained by reaction between molecule 55 and 2-phthalimidoethylamine Using a method similar to that used for the preparation of molecule 9, molecule 55 (21.38 g, 24.26 mmol) and 2-phthalimidoethylamine hydrochloride (HCl·PhthalEDA, 6.60 g, 29.12 mmol) in DCM in the presence of DIPEA (5.07 mL, 29.12 mmol) are applied to obtain a beige foam of molecule 56 without purification. Yield: 25.56g (100%) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.17-1.30(20H);1.34-1.41(27H);1.41-1. 52(2H); 1.56-2.32(18H); 3.18-3.69(6H); 4.01-4.43(4H); 7.64-8.30(8H). LC / MS(ESI):1053.8;(calculation([M+H] + ):1053.6).

[0870] Molecule A26 Molecule 56 (25.56 g, 24.26 mmol) is solubilized in a solution of 40% methylamine in MeOH (242.5 mL, 2.38 mol) at 4 °C, then the mixture is stirred at ambient temperature for 5 hours. Silica is added to the reaction medium and then the mixture is concentrated under reduced pressure. The residue is purified by silica gel chromatography (solid precipitation, dichloromethane, methanol, NH3), yielding molecule A26 in the form of a pale yellow gum. This product is solubilized in DCM (250 mL) and then the solution is washed with 10% aqueous HCl. The aqueous phase is extracted with DCM (100 mL). The organic phases are combined, dried over Na2SO4, filtered and then concentrated under reduced pressure, yielding the hydrochloride salt of molecule A26 in the form of a white solid. Yield: 13.5g (58%) 1 H NMR (DMSO-d6, ppm):0.85(3H);1.18-1.30(20H);1.34-1.42(27H);1.42-1.53(2H);1.66-2. 02(9H);2.02-2.39(9H);2.79-2.91(2H);3.25-3.64(4H);4.08-4.46(4H);7.68-8.37(7H). LC / MS(ESI):923.8;(calculation([M+H] + ):923.6).

[0871] Example A27: Molecule A27 Molecule A27 is obtained by conventional solid phase peptide synthesis (SPPS) methods on 2-chlorotrityl chloride (CTC) resin (24.00 g, 1.37 mmol / g).

[0872] The grafting of the first amino acid Fmoc-6-aminohexanoic acid (1.5 eq.) is carried out in the presence of DIPEA (2.5 eq.) in DCM (10 V). Unreacted sites are capped with methanol (0.8 mL / g resin) at the end of the reaction.

[0873] The protected amino acid Fmoc-Glu-OMe (1.5 eq.) is coupled with palmitic acid (1.5 eq.) in the presence of HATU (1.0 eq. relative to acid) and DIPEA (1.5 eq. relative to acid) in DMF (10 V).

[0874] The protecting group Fmoc is removed using a 80:20 DMF / piperidine solution (10V).

[0875] The product is cleaved from the resin using a 80:20 DCM / HFIP solution (10V).

[0876] After concentration under reduced pressure, two co-evaporations are carried out on the residue with dichloromethane and then with toluene. The product is purified by recrystallization in ethyl acetate. A white solid of molecule A27 is obtained. Yield: 11.54g (68% over 6 steps) 1 H NMR(CDCl3, ppm):0.88(3H);1.19-1.35(24H);1.35-1.44(2H);1.50-1.70(6H);1.91-2.0 1(1H);2.14-2.40(7H);3.14-3.34(2H);3.75(3H);4.51-4.59(1H);6.53(1H);6.70(1H). LC / MS(ESI+):513.4(calculation([M+H] + ):513.4).

[0877] Part B - Hydrophobic copolyamino acid synthesis [ka] TIFF0007638508000113.tif210162TIFF0007638508000114.tif216162TIFF00076385080 00115.tif236162TIFF0007638508000116.tif240162TIFF0007638508000117.tif245162 TIFF0007638508000118.tif203162TIFF0007638508000119.tif244162TIFF00076385080 00120.tif196162TIFF0007638508000121.tif238162TIFF0007638508000122.tif156162

[0878] Example B1: Copolyamino acid B1 - sodium poly-L-glutamate modified at its ends with molecules A1 and having a number-average molar mass (Mn) of 3600 g / mol Copolyamino acid B1-1 : Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine, the ends of which are modified with molecule A1. In an oven-dried flask, γ-benzyl-L-glutamic acid N-carboxyanhydride (34.74 g, 132 mmol) is solubilized in anhydrous DMF (78 mL). The mixture is then stirred until complete dissolution and cooled to 0° C., then ethylenediamine (0.205 g, 3.41 mmol) is rapidly introduced and the medium is stirred at 0° C.

[0879] In parallel, molecule A1 (2.26 g, 6.94 mmol) is solubilized in DMF (44 mL), then NHS (0.82 g, 7.12 mmol) and DCC (1.47 g, 7.12 mmol) are added successively. After stirring overnight at ambient temperature, the heterogeneous mixture is filtered on a sintered filter. The filtrate is then added to the polymer solution maintained at 0° C. After 24 h, the solution is left at ambient temperature. After stirring for 6 h, the reaction medium is poured onto diisopropyl ether (IPE, 1.8 L). The precipitate is filtered on a sintered filter, washed with IPE (3×30 mL) and dried at 30° C. under reduced pressure.

[0880] Copolyamino acid B1 Copolyamino acid B1-1 is diluted in trifluoroacetic acid (TFA, 132 mL) and the solution is then cooled to 4° C. Then, a solution of 33% HBr in acetic acid (92.5 mL, 0.528 mol) is added dropwise. The mixture is stirred at ambient 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 (2×66 mL) and then with water (2×66 mL). The resulting solid is then solubilized in water (690 mL) by adjusting the pH to 7 by adding 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by adding water (310 mL), the solution is filtered on a 0.45 μm filter, and then purified by ultrafiltration against 0.9% NaCl solution followed by water until the conductivity measurement of the permeate is less than 50 μS / cm. The resulting solution is filtered on a 0.2 μm filter and stored at 2-8° C. Dry extract: 24.3mg / g DP( 1 Estimated by H NMR): 40 1 By H NMR: i=0.050 The calculated average molar mass of copolyamino acid B1 is 6719 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3600 g / mol.

[0881] Example B2: Copolyamino acid B2 - sodium poly-L-glutamate modified at its ends with stearic acid and having a number-average molar mass (Mn) of 3400 g / mol Copolyamino acid B2-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by hexamethylenediamine In a previously oven-dried flask, γ-benzyl-L-glutamic acid N-carboxyanhydride (30.0 g, 114 mmol) is solubilized in anhydrous DMF (67 mL). The mixture is then stirred until complete dissolution, cooled to 0° C., and then hexamethylenediamine (0.442 g, 3.8 mmol) is rapidly introduced. After stirring for 23 hours at 0° C., a 4 M solution of HCl in dioxane (4.7 mL, 18.8 mmol) is added, and then the reaction medium is poured in 5 minutes onto a mixture of methanol (94 mL) and IPE (375 mL). The precipitate is filtered on a sintered filter, washed with IPE (2×70 mL) and dried under reduced pressure at 30° C.

[0882] Copolyamino acid B2-2 : Poly-L-benzyl glutamic acid whose ends are modified with stearic acid To a solution of stearic acid (0.851 g, 2.99 mmol) in DMF (20 mL) at 0 ° C, HATU (1.484 g, 3.89 mmol) and DIPEA (1.166 g, 9.02 mmol) are successively added. The solution is then introduced onto a solution of copolyamino acid B2-1 (10.0 g) and triethylamine (TEA, 0.309 g, 3.04 mmol) in DMF (110 mL) at 0 ° C, and the medium is stirred for 18 hours from 0 ° C to ambient temperature. Dichloromethane (390 mL) is added and the organic phase is washed with an aqueous 0.1 N HCl solution (3 × 190 mL), an aqueous solution saturated with NaHCO3 (2 × 190 mL), an aqueous solution saturated with NaCl (2 × 190 mL) and then with water (190 mL). The medium is then poured onto IPE (1.4 L). The precipitate is filtered on a sintered filter, washed with IPE (2×100 mL) and dried at 30° C. under reduced pressure.

[0883] Copolyamino acid B2 A method similar to that used for the preparation of copolyamino acid B1 is applied to copolyamino acid B2-2 (8.80 g, 36.5 mmol) to obtain sodium poly-L-glutamate modified at its ends with stearic acid. Dry extract: 17.9mg / g DP( 1 Estimated by H NMR): 30 1 H NMR: i=0.0657 The calculated average molar mass of copolyamino acid B2 is 5174 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3400 g / mol.

[0884] Example B3: Copolyamino acid B3 - sodium poly-L-glutamate modified at its ends with molecules A2 and having a number-average molar mass (Mn) of 3000 g / mol Copolyamino acid B3-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (0.765 g, 12.73 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (80.0 g, 304 mmol) to give copolyamino acid B3-1.

[0885] Copolyamino acid B3-2 : Poly-L-benzylglutamic acid whose ends are modified with A2 A method similar to that used for the preparation of copolyamino acid B2-2 is applied to copolyamino acid B3-1 (30.0 g, 5.56 mmol) and molecule A2 (7.94 g, 12.24 mmol) to obtain poly-L-benzyl glutamic acid modified at its ends with molecule A2.

[0886] Copolyamino acid B3 To a solution of copolyamino acid B3-2 (36.6 g, 133.5 mmol) in N,N-dimethylacetamide (DMAc, 146 mL) is added 5% palladium / alumina (7.3 g) and the solution is then placed at 60° C. and 10 bar of hydrogen. After standing overnight, the reaction medium is filtered on a sintered filter and then on a 0.2 μm PTFE filter. The filtrate is then placed under stirring, after which water (1.4 L) previously acidified to pH 2 with 1 N HCl solution (14 mL) is added dropwise. After overnight, the precipitate is filtered on a sintered filter, washed with water (4×110 mL) and dried at 30° C. under reduced pressure.

[0887] The solid obtained is then solubilized in water (1.09 L) by adjusting the pH to 7 by adding 1N aqueous sodium hydroxide solution (121 mL). After solubilization, the solution is basified to pH 12 by adding 1N sodium hydroxide (26 mL). After 2 hours, the solution is neutralized by adding 1N HCl solution (28 mL). The theoretical concentration is adjusted to 12 g / L theoretical by adding water (650 mL) and ethanol (1040 mL), and the solution is then filtered at a rate of 12 mL / min on a R53SLP carbon filter (3M) and then on a 0.2 μm PES filter. The solution is then purified by ultrafiltration against a 0.9% NaCl solution followed by water until the conductivity measurement of the permeate is less than 50 μS / cm. The resulting solution is filtered on a 0.2 μm filter and stored at 2-8° C. Dry extract: 21.6mg / g DP( 1 1H NMR):24 1 H NMR: i=0.0808 The calculated average molar mass of copolyamino acid B3 is 4948 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3000 g / mol.

[0888] Example B4: Copolyamino acid B4 - sodium poly-L-glutamate modified at its ends with molecules A3 and having a number-average molar mass (Mn) of 2500 g / mol Copolyamino acid B4-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (1.644 g, 27.35 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (100.0 g, 380 mmol) to give copolyamino acid B4-1.

[0889] Copolyamino acid B4-2 : Poly-L-benzylglutamic acid whose ends are modified with molecule A3 A method similar to that used for the preparation of copolyamino acid B2-2 is applied to copolyamino acid B4-1 (10.0 g, 3.12 mmol) and molecule A3 (4.412 g, 6.26 mmol) to obtain poly-L-benzyl glutamic acid modified at its ends with molecule A3.

[0890] Copolyamino acid B4 A method similar to that used for the preparation of copolyamino acid B3 is applied to copolyamino acid B4-2 (12.0 g, 37.3 mmol) to obtain sodium poly-L-glutamate modified at its ends with molecule A3. Dry extract: 21.7mg / g DP( 1 1H NMR):14 1 H NMR: i=0.134 The calculated average molar mass of copolyamino acid B4 is 3464 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2500 g / mol.

[0891] Example B5: Copolyamino acid B5 - sodium poly-L-glutamate modified at its ends with molecules A3 and having a number-average molar mass (Mn) of 2800 g / mol Copolyamino acid B5-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (0.95 g, 15.83 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (100.0 g, 380 mmol) to give copolyamino acid B5-1.

[0892] Copolyamino acid B5-2 : Poly-L-benzylglutamic acid whose ends are modified with molecule A3 A method similar to that used for the preparation of copolyamino acid B2-2 is applied to copolyamino acid B5-1 (20.0 g, 3.71 mmol) and molecule A3 (5.233 g, 7.42 mmol) to obtain poly-L-benzyl glutamic acid modified at its ends with molecule A3.

[0893] Copolyamino acid B5 A method similar to that used for the preparation of copolyamino acid B1 is applied to copolyamino acid B5-2 (15.6 g, 55.93 mmol) to obtain sodium poly-L-glutamate modified at its ends with molecule A3. Dry extract: 27.4mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.077 The calculated average molar mass of copolyamino acid B5 is 4956 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2800 g / mol.

[0894] Example B6: Copolyamino acid B6: sodium poly-L-glutamate modified at its ends with molecules A4 and having a number-average molar mass (Mn) of 2900 gmol Copolyamino acid B6-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (0.951 g, 15.83 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (100.0 g, 380 mmol) to give copolyamino acid B6-1.

[0895] Copolyamino acid B6-2 : Poly-L-benzylglutamic acid whose ends are modified with molecule A4 A method similar to that used for the preparation of copolyamino acid B2-2 is applied to copolyamino acid B6-1 (20.0 g, 3.71 mmol) and molecule A4 (6.649 g, 8.74 mmol) to obtain poly-L-benzyl glutamic acid modified at its ends with molecule A4.

[0896] Copolyamino acid B6 A method similar to that used for the preparation of copolyamino acid B1 is applied to copolyamino acid B6-2 (19.7 g, 69.47 mmol) to obtain sodium poly-L-glutamate modified at its ends with molecule A4. Dry extract: 28.7mg / g DP( 1 1H NMR):24 1 H NMR: i=0.0812 The calculated average molar mass of copolyamino acid B6 is 5135 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2900 g / mol.

[0897] Example B9: Copolyamino acid B9 - sodium poly-L-glutamate modified at its ends by molecule A7 (side chains deprotected) and having a number-average molar mass (Mn) of 3200 g / mol Copolyamino acid B9-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine Using a method similar to that used for the preparation of copolyamino acid B2-1, applied to ethylenediamine (0.96 g, 15.94 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (100.0 g, 380 mmol), copolyamino acid B9-1 is obtained.

[0898] Copolyamino acid B9-2 : Poly-L-benzylglutamic acid whose ends are modified with molecule A7 A method similar to that used for the preparation of copolyamino acid B2-2 is applied to copolyamino acid B9-1 (25.0 g, 4.64 mmol) and molecule A7 (10.49 g, 9.27 mmol) to obtain poly-L-benzyl glutamic acid modified at its ends with molecule A7.

[0899] Copolyamino acid B9-3 : Poly-L-benzylglutamic acid modified at its ends with molecule A7 (with deprotected side chains) Copolyamino acid B9-2 (18.6 g) is solubilized in TFA (100 mL). After 2 hours under stirring, the reaction medium is concentrated under reduced pressure.

[0900] Copolyamino acid B9 A method similar to that used for the preparation of copolyamino acid B3 is applied to copolyamino acid B9-3 (18.0 g, 59.0 mmol) to obtain sodium poly-L-glutamate modified at its ends with molecule A7. Dry extract: 21.8mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.0833 The calculated average molar mass of copolyamino acid B9 is 5776 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3200 g / mol.

[0901] Example B13: Copolyamino acid B13 - sodium poly-L-glutamate modified at its ends with molecules A11 (ester deprotected) and having a number-average molar mass (Mn) of 3200 g / mol Copolyamino acid B13-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (4.76 g, 15.94 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (500.0 g, 1900 mmol) to give copolyamino acid B13-1.

[0902] Copolyamino acid B13-2 : Poly-L-benzylglutamic acid whose ends are modified with molecule A11 To a solution of copolyamino acid B13-1 (12.0 g) in DMF (40 mL) at 0 ° C, a solution of molecule A11 (5.88 g, 6.67 mmol) in DMF (20 mL), N-2-hydroxypyridine oxide (HOPO, 0.82 g, 7.34 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) (1.66 g, 8.68 mmol) and then DIPEA (0.97 mL, 5.56 mmol) are added successively. The reaction medium is stirred for 16 h at 0 ° C and for 2 h at 20 ° C. Dichloromethane (150 mL) is added and the organic phase is washed with 0.1 N aqueous HCl solution (6 × 75 mL), dried over Na2SO4 and then filtered. The organic phase is then poured onto IPE (600 mL) and then left for 18 h. The white precipitate is collected by filtration, washed with IPE (2×150 mL), and then dried under reduced pressure at 30° C.

[0903] Copolyamino acid B13-3: Poly-L-benzylglutamic acid modified at its ends with molecule A11 (ester deprotected) Copolyamino acid B13-2 is solubilized in TFA (60 mL), the solution is stirred for 2 h at ambient temperature, then poured dropwise with stirring onto diisopropyl ether (600 mL). After 18 h, the white precipitate is collected by filtration, triturated with IPE and dried under reduced pressure.

[0904] Copolyamino acid B13 A method similar to that used for the preparation of copolyamino acid B3 is applied to copolyamino acid B13-3 (14.5 g) to obtain sodium poly-L-glutamate modified at its ends with molecule A11 (ester deprotected). Dry extract: 18.0mg / g DP( 1 1H NMR):24 1 H NMR: i=0.079 The calculated average molar mass of copolyamino acid B13 is 5194 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3200g / mol

[0905] Example B14: Copolyamino acid B14 - sodium poly-L-glutamate modified at its ends with molecule A12 (ester deprotected) and having a number-average molar mass (Mn) of 3700 g / mol Copolyamino acid B14-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (4.76 g, 15.94 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (500.0 g, 1900 mmol) to give copolyamino acid B14-1.

[0906] Copolyamino acid B14-2: Poly-L-benzylglutamic acid whose ends are modified with molecule A12 A method similar to that used for the preparation of copolyamino acid B2-2 is applied to molecule A12 (2.67 g, 1.43 mmol) and copolyamino acid B14-1 (3.5 g) to obtain poly-L-benzylglutamic acid modified at its two ends by molecule A2.

[0907] Copolyamino acid B14-3 : Poly-L-benzylglutamic acid modified at its ends with molecule A12 (ester deprotected) A method similar to that used for the preparation of copolyamino acid B13-3 is applied to copolyamino acid B14-2 to obtain poly-L-benzylglutamic acid modified at its two ends with molecule A12 (ester deprotected).

[0908] Copolyamino acid B14 Using a method similar to that used for the preparation of copolyamino acid B3, in a hydrogen atmosphere (1 atm, 48 h, 65° C.), it is applied to copolyamino acid B14-3 (1.97 g) to obtain sodium poly-L-glutamate modified at its two ends with molecule A12 (ester deprotected). Dry extract: 13.2mg / g DP( 1 1H NMR):24 1 H NMR: i=0.072 The calculated average molar mass of copolyamino acid B14 is 6537 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3700g / mol

[0909] Example B15: Copolyamino acid B15 - butyl tetracarboxylic acid substituted with molecule A13 (ester deprotected) and having a number average molar mass (Mn) of 2700 g / mol Molecule A13 [ka] i=0.182, DP(n)=5.5 Molecule 31: Products obtained by polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by N-Boc-ethylenediamine A solution of BocEDA (12.00 g, 74.9 mmol) in DMF (12 mL) is prepared. In a reaction vessel, γ-benzyl-L-glutamic acid N-carboxyanhydride (78.87 g, 300.0 mmol) is solubilized in DMF (165 mL) at 25° C. The mixture is then stirred until complete dissolution, cooled to −10° C., and then the BocEDA solution is rapidly introduced. The reaction medium is stirred for 4 hours at 0° C., then a solution of HCl in 1,4-dioxane (3.33 M, 19.8 mL, 65.34 mmol) is added. The reaction medium is stirred at ambient temperature, then the solution is poured onto a solution of MeOH / IPE (245 mL / 990 mL) cooled by an ice bath. After 62 h of stirring at ambient temperature, the white precipitate is filtered on a sintered filter, washed with IPE (2×160 mL) and dried at 30° C. under reduced pressure. 1 H NMR (DMSO-d6, ppm):1.35(9H);1.70-2.10(10H);2.26-2.65(10H);2.85-3.18(4H);3.85(1H);4 .14-4.42(4H);4.87-5.24(10H);6.34-6.86(1H);7.11-7.56(25H);7.90-8.44(7H);8.69(1H). DP( 1 Estimated by H NMR): 5.0

[0910] The calculated average molar mass of molecule 31 in the hydrochloride salt form is 1292.9 g / mol.

[0911] Molecule 32: Product obtained by coupling molecule 31 with molecule A1 Molecule 31 (10.0 g, 7.73 mmol) is solubilized in a mixture of DCM (90 mL) and DIPEA (1.585 g, 9.32 mmol) at 0 °C. HOPO (1.242 g, 11.18 mmol), Molecule A1 (3.335 g, 10.25 mmol) and EDC (2.141 g, 11.17 mmol) are added successively to this solution. After stirring overnight, the reaction medium is washed twice with a 0.1 N HCl solution (2 × 100 mL), twice with a 5% aqueous Na2CO3 solution (2 × 100 mL) and then with a saturated NaCl solution (100 mL). The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is solubilized in DCM (30 mL) and the solution is poured onto isopropyl alcohol (600 mL) with stirring at 0 °C. The precipitate that forms is collected by vacuum filtration and then dried under vacuum at 30°C. Yield: 7.58g (62%) 1 H NMR (CDCl3, ppm): 0.87 (3H); 1.06-2.76 (58.6H); 3.06-4.45 (12.4H); 4.88-5.25 (10.8H); 5.72-8.40 (34.4H). DP( 1 Estimated by H NMR): 5.4

[0912] The calculated average molar mass of molecule 32 in the hydrochloride salt form is 1651.6 g / mol.

[0913] Molecule A13 After solubilization of molecule 32 (5.93 g, 3.59 mmol) in DCM (40 mL), the solution is cooled to 0° C. and TFA (40 mL) is added. The reaction medium is stirred at 0° C. for 3 h and then concentrated to dryness under reduced pressure at ambient temperature. The residue is dissolved in DCM (120 mL) and washed with an aqueous carbonate buffer solution at pH 10.4 (3×240 mL) and then with an aqueous 0.1 N HCl solution (2×240 mL). The organic solution is dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid of molecule A13 in hydrochloride form is obtained. Yield: 5.17g (91%) 1H NMR (TFA-d, ppm):0.87(3H);1.06-1.46(20H);1.46-1.68(2H);1.68-2.81(28H);3.13-4.59(12.5H);4.83-5.25(11H);7.02-9.13(37H) DP( 1 Estimated by H NMR): 5.5

[0914] The calculated average molar mass of molecule A13 in the hydrochloride salt form is 1609.8 g / mol.

[0915] Copolyamino acid B15-1 : Molecule A13 (3.47 g, 2.16 mmol) is solubilized in DCM (17 mL) and then, at 0° C., butyl tetracarbonate (BTCA, 115 mg, 0.49 mmol), HOPO (275 mg, 2.48 mmol), DIPEA (377 μL, 2.16 mmol) followed by EDC (473 mg, 2.47 mmol) are added in succession. After stirring overnight at 0° C., the reaction medium is poured onto MeOH (220 mL) with stirring at 0° C. After overnight, the white precipitate is collected by vacuum filtration, triturated with cold MeOH and then dried under vacuum at 30° C.

[0916] Copolyamino acid B15 A solution of copolyamino acid B15-1 (2.33 g, 0.362 mmol) in DMAc (33 mL) is placed in a hydrogen atmosphere (1 atm) in the presence of 5% palladium / alumina (465 mg) and then the solution is heated to 60° C. After standing overnight, the solution is cooled and filtered on Celite® and the filtrate is then poured onto a 15% NaCl solution (500 mL) at pH 2. After standing overnight, the precipitate is filtered on a sintered filter and then washed twice with a 15% NaCl solution (2×8 mL). The solid obtained is then solubilized in water (70 mL) by adjusting the pH to 7 by adding a 1N aqueous solution of sodium hydroxide. After solubilization, the solution is filtered on a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution followed by water until the conductivity measurement of the permeate is less than 50 μS / cm. The resulting solution is filtered on a 0.2 μm filter and stored at 2-8° C. Dry extract: 25.8mg / g 1 H NMR(D2O, ppm):0.90(10.2H);1.18-1.46(68H);1.53-1.9(6.8H);1.86-3.04(101.2H);3,17-3.80(20.4H);4.19-4.68(22.1H) DP( 1 Estimated by H NMR): 5.5 1 By H NMR: i=3.4 The calculated average molar mass of copolyamino acid B15 is 4261.3 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2700 g / mol.

[0917] Example B16: Copolyamino acid B16 - sodium poly-L-glutamate modified at its ends with molecule A14 (ester deprotected) and having a number-average molar mass (Mn) of 3200 g / mol Copolyamino acid B16-1Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by 1-amino-4,7,10-trioxa-13-tridecanamine (TOTA). A method similar to that used for the preparation of copolyamino acid B2-1 is applied to TOTA (13.96 g, 63.37 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (400.0 g, 1519 mmol) to give copolyamino acid B16-1.

[0918] Copolyamino acid B16 To a solution of molecule A14 (6.74 g, 13.5 mmol) in DMAc (38 mL) are added successively HOPO (1.65 g, 14.8 mmol), and EDC (3.36 g, 17.6 mmol).

[0919] To a solution of copolyamino acid B16-1 (30.0 g) in DMAc (113 mL) at ambient temperature is added successively DIPEA (1.90 mL, 13.5 mmol) followed by the solution of previously prepared molecule A14.

[0920] After stirring for 24 hours at ambient temperature, DMAc (82 mL) is added and the solution is placed under 10 bar of hydrogen at 60° C. in the presence of 5% palladium on alumina (7.0 g). After 17 hours of reaction, the reaction medium is filtered on a sintered filter and then on a 0.2 μm PTFE filter.

[0921] The filtrate is placed under stirring and then a 300 g / L sodium carbonate solution (46 mL) is added, followed by acetone (275 mL), dropwise in succession. After 3 hours, the precipitate is filtered on a sintered filter, washed with acetone (3×70 mL) and dried under reduced pressure.

[0922] The solid obtained is solubilized in water (1.3 L) and then diluted with ethanol (0.7 L) before basifying the solution by adding 10N sodium hydroxide (13 mL) until a pH of 13 is obtained. After 3 hours of stirring at ambient temperature, the solution is neutralized by adding 1N HCl solution (190 mL) and then the solution is filtered on a R53SLP carbon filter (3M) and then on a 0.2 μm PES filter. The solution is then purified by ultrafiltration against a 0.9% NaCl solution followed by water until the conductivity measurement of the permeate is less than 50 μS / cm. The resulting solution is filtered on a 0.2 μm filter and stored at 2-8° C. Dry extract: 21.4mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.078 The calculated average molar mass of copolyamino acid B16 is 4761 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3200 g / mol.

[0923] Example B17: Copolyamino acid B17 - sodium poly-L-glutamate modified at its two ends with molecule A15 and having a number-average molar mass (Mn) of 3200 g / mol Copolyamino acid B17-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (4.77 g, 79.37 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (500.0 g, 1899 mmol) to give copolyamino acid B17-1.

[0924] Copolyamino acid B17 A method similar to that used for the preparation of copolyamino acid B16 is applied to copolyamino acid B17-1 (15.0 g) and molecule A15 (3.45 g) together with a saponification step at pH 12 for 50 minutes to obtain copolyamino acid B17. Dry extract: 20.3mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.048 The calculated average molar mass of copolyamino acid B17 is 4237 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3200g / mol

[0925] Example B18: Copolyamino acid B18 - sodium poly-L-glutamate modified at its two ends with molecule A16 and having a number-average molar mass (Mn) of 3150 g / mol Copolyamino acid B18-1 Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by ethylenediamine A method similar to that used for the preparation of copolyamino acid B2-1 is applied to ethylenediamine (4.74 g, 78.89 mmol) and γ-benzyl-L-glutamic acid N-carboxyanhydride (498.4 g, 1893 mmol) to give copolyamino acid B18-1.

[0926] Copolyamino acid B18 A method similar to that used for the preparation of copolyamino acid B17 is applied to copolyamino acid B18-1 (14.0 g) and molecule A16 (4.26 g) to give copolyamino acid B18. Dry extract: 9.7mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.075 The calculated average molar mass of copolyamino acid B18 is 4839 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3150g / mol

[0927] Example B19: Copolyamino acid B19 - sodium poly-L-glutamate modified at its ends with molecule A17 (ester deprotected) and having a number-average molar mass (Mn) of 3400 g / mol A method similar to that used for the preparation of copolyamino acid B16 is applied to copolyamino acid B18-1 (20.39 g) and molecule A17 (7.553 g) to give copolyamino acid B19. Dry extract: 18.6mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.066 The calculated average molar mass of copolyamino acid B19 is 4936 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3400g / mol

[0928] Example B20: Copolyamino acid B20 - sodium poly-L-glutamate modified at its two ends with molecule A18 and having a number-average molar mass (Mn) of 3200 g / mol A method similar to that used for the preparation of copolyamino acid B17 is applied to copolyamino acid B17-1 (12.45 g) and molecule A18 (3.56 g) to give copolyamino acid B20. Dry extract: 16.8mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.075 The calculated average molar mass of copolyamino acid B20 is 4784 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3200g / mol

[0929] Example B21: Copolyamino acid B21 - sodium poly-L-glutamate modified at its two ends with molecule A19 and having a number-average molar mass (Mn) of 3600 g / mol A method similar to that used for the preparation of copolyamino acid B17 is applied to copolyamino acid B17-1 (12.16 g) and molecule A19 (4.16 g) to give copolyamino acid B21. Dry extract: 26.4mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.077 The calculated average molar mass of copolyamino acid B21 is 5023 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3600g / mol

[0930] Example B23: Copolyamino acid B23 - sodium poly-L-glutamate modified at its two ends with molecule A21 and having a number-average molar mass (Mn) of 3350 g / mol A method similar to that used for the preparation of copolyamino acid B17 is applied to copolyamino acid B17-1 (18.68 g) and molecule A21 (7.03 g) to give copolyamino acid B23. Dry extract: 23.2mg / g DP( 1 1H NMR):24 1 H NMR: i=0.080 The calculated average molar mass of copolyamino acid B23 is 5140 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3350g / mol

[0931] Example B24: Copolyamino acid B24 - sodium poly-L-glutamate modified at its ends with molecules A1 and having a number-average molar mass (Mn) of 2300 g / mol Copolyamino acid B24-1: Poly-L-benzylglutamic acid obtained from the polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by molecule 4, the ends of which are modified by molecule A1. To a suspension of molecule 4 (9.92 mmol) in anhydrous DMF (80 mL) cooled to 0 °C, a solution of γ-benzyl-L-glutamic acid N-carboxyanhydride (26.11 g, 99.2 mmol) in anhydrous DMF (20 mL) at 0 °C is rapidly added. After stirring at 0 °C for 24 h, a freshly prepared solution of molecule A1 (16.1 g, 49.6 mmol), HATU (18.9 g, 49.6 mmol) and DIPEA (8.64 mL, 49.6 mmol) in DMF (80 mL) is added to the medium and the mixture is stirred from 0 °C to 25 °C for 3.5 h. The resin is filtered and washed successively with DMF (3 × 100 mL), isopropanol (1 × 100 mL) and DCM (3 × 100 mL). The resin obtained is then treated with an 80:20 DCM / HFIP mixture (120 mL). After 30 min of stirring at ambient temperature, the resin is filtered and washed successively with DCM (3×100 mL). The solvent is evaporated under reduced pressure to yield copolyamino acid B24-1.

[0932] Copolyamino acid B24 A method similar to that used for the hydrogenation step of copolyamino acid B16 is applied to copolyamino acid B24-1 (27.4 g) together with a saponification step at pH 12 for 50 minutes without a carbofiltration step to obtain copolyamino acid B24. Dry extract: 14.1mg / g DP( 1 1H NMR):14 1 H NMR: i=0.143 The calculated average molar mass of copolyamino acid B24 is 2899 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2300 g / mol.

[0933] Example B25: Copolyamino acid B25 - sodium poly-L-glutamate modified at its ends with molecules A22 and having a number-average molar mass (Mn) of 3050 g / mol Using a method similar to that used for the preparation of copolyamino acid B17, applied to copolyamino acid B18-1 (30.0 g) and molecule A22 (8.56 g), copolyamino acid B25 is obtained, using a four times larger amount of 300 g / l sodium carbonate solution to precipitate the polymer after the hydrogenolysis step. Dry extract: 23.7mg / g DP( 1 1H NMR):24 1 H NMR: i=0.074 The calculated average molar mass of copolyamino acid B25 is 4743 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3050g / mol

[0934] Example B26: Copolyamino acid B26 - sodium poly-L-glutamate modified at its two ends with molecule A23 and having a number-average molar mass (Mn) of 3400 g / mol A method similar to that used for the preparation of copolyamino acid B25 is applied to copolyamino acid B17-1 (25.78 g) and molecule A23 (8.27 g) to give copolyamino acid B21. Dry extract: 11.8mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.073 The calculated average molar mass of copolyamino acid B21 is 4902 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3400g / mol

[0935] Example B27: Copolyamino acid B27 - butyl tetracarboxylic acid substituted with molecule A24 (ester deprotected) and having a number average molar mass (Mn) of 2500 g / mol Molecule A24 [ka] i=0.21, DP(n)=4.75 molecule 53 : the product obtained by polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by N-Boc-ethylenediamine and then capped with molecule 2 A solution of BocEDA (12.00 g, 74.9 mmol) in DMF (12 mL) is prepared. In a reaction vessel, γ-benzyl-L-glutamic acid N-carboxyanhydride (78.87 g, 300.0 mmol) is solubilized in DMF (165 mL) at 25 ° C. The mixture is then stirred until complete dissolution, cooled to −10 ° C, and then the BocEDA solution is rapidly introduced. The reaction medium is stirred at 0 ° C for 3 hours, then DMF (100 mL), molecule 2 (26.73 g, 89.88 mmol), HOPO (9.99 g, 89.88 mmol) and EDC (17.23 g, 89.88 mmol) are successively introduced. The reaction mixture is stirred at 0 ° C for 1 hour, from 0 ° C to 20 ° C for 2 hours, then at 20 ° C for 16 hours. It is then poured onto a 1:12-propanol / H2O solution (10 V) while stirring. After 3 h, the white precipitate is filtered on a sintered filter, washed with a 1:12-propanol / H2O mixture (2 x 360 mL) and dried under reduced pressure at 30 °C. Yield: 70g (71%) 1 H NMR (TFA-d, ppm):0.99(3H);1.34-1.59(16H);1.68-2.85(36H);3.52-3.62(2H );3.79-3.99(4H);4.70-4.92(5.75H);5.20-5.38(9.5H);7.36-7.52(23.75H). DP( 1 Estimated by H NMR): 4.75 The calculated average molar mass of molecule 53 is 1481.0 g / mol.

[0936] Molecule A24 A method similar to that used for the preparation of molecule A13 is applied to molecule 53 (34.00 g, 22.96 mmol) to give a white solid of molecule A24 in hydrochloride form. Yield: 29.40g (90%) 1 H NMR (TFA-d, ppm):1.00(3H);1.35-1.61(16H);1.79-1.93(2H);2.05-2.90(25H);3.53- 3.65(2H); 3.79-4.02(4H); 4.74-4.94(5.75H); 5.20-5.43(9.5H); 7.32-7.58(23.75H). DP( 1 Estimated by H NMR): 4.75 The calculated average molar mass of molecule A13 in the hydrochloride salt form is 1417.2 g / mol.

[0937] Copolyamino acid B27-1 : Using a method similar to that used for the preparation of copolyamino acid B15-1, applied to a DMF solution containing molecule A24 (11.9 g, 8.40 mmol) and BTCA (0.41 g, 1.75 mmol), a white solid is obtained after drying under reduced pressure at 30° C.

[0938] Copolyamino acid B27 Using a method similar to that used for the preparation of copolyamino acid B15, copolyamino acid B27-1 (9.31 g, 1.64 mmol) is subjected to a saponification step under hydrogen pressure (6 bar) at pH 12 for 1 h, followed by an ultrafiltration step, to obtain copolyamino acid B27. Dry extract: 19.9mg / g DP( 1 Estimated by H NMR): 4.75 1 By H NMR: i=3.7 The calculated average molar mass of copolyamino acid B27 is 4085.8 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2500 g / mol.

[0939] Example B28: Copolyamino acid B28 - tricarballylic acid substituted with molecule A25 (ester deprotected) and having a number average molar mass (Mn) of 2200 g / mol Molecule A25 [ka] i=0.19, DP(n)=5.15 molecule 54 : the product obtained by polymerization of γ-benzyl-L-glutamic acid N-carboxyanhydride initiated by N-Boc-ethylenediamine and then capped with molecule A1 Using a method similar to that used for the preparation of molecule 53, applied to BocEDA (6.00 g, 37.45 mmol), γ-benzyl-L-glutamic acid N-carboxyanhydride (39.44 g, 150.00 mmol) and molecule A1 (14.63 g, 44.94 mmol), a white solid of molecule 54 is obtained. Yield: 23.71g (40%) 1 H NMR (CDCl3, ppm): 0.87 (3H); 1.12-2.76 (57.6H); 3.06-4.50 (12.15H); 4.90-5.25 (10.3H); 5.91-8.49 (32.9H). DP( 1 Estimated by H NMR): 5.15 The calculated average molar mass of molecule 54 is 1596.8 g / mol.

[0940] Molecule A25 A method similar to that used for the preparation of molecule A13 is applied to molecule 54 (23.29 g, 14.59 mmol) to give a translucent solid of molecule A25 in hydrochloride form. Yield: 19.08g (85%) 1 H NMR (CDCl3, ppm): 0.87 (3H); 1.17-1.32 (20H); 1.48-1.63 (2H); 1.69-2.78 (29.6H); 3.15-4.40 (12.15H); 4.89-5.18 (10.3H); 7.06-9.13 (31.9H). DP( 1 Estimated by H NMR): 5.15 The calculated average molar mass of molecule A25 in the hydrochloride salt form is 1533.1 g / mol.

[0941] Copolyamino acid B28-1 : Using a method similar to that used for the preparation of copolyamino acid B15-1, a white solid is obtained after drying under reduced pressure at 30° C. by applying to a DMF solution containing molecule A25 (3.93 g, 2.56 mmol) and tricarballylic acid (TCA, 125.2 mg, 0.71 mmol).

[0942] Copolyamino acid B28 A method similar to that used for the preparation of copolyamino acid B15 is applied to copolyamino acid B28-1 (2.98 g, 0.65 mmol) with a saponification step at pH 12 for 1 h followed by an ultrafiltration step to obtain copolyamino acid B28. Dry extract: 25.8mg / g DP( 1 Estimated by H NMR): 5.15 1 By H NMR: i=3.0 The calculated average molar mass of copolyamino acid B28 is 3559.2 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2200 g / mol.

[0943] Example B29: Copolyamino acid B29 - 4,7,10-trioxa-1,13-tridecanediamine (TOTA) substituted with molecule A12 (ester deprotected) and having a number average molar mass (Mn) of 2000 g / mol Copolyamino acid B29-1 : To a solution of molecule A12 (3.70 g, 1.98 mmol) in chloroform (31 mL) at ambient temperature, HOBt (304 mg, 1.98 mmol) and 4,7,10-trioxa-1,13-tridecanediamine (TOTA, 208 mg, 0.94 mmol) are added successively. The mixture is cooled to 0 °C and then EDC (380 mg, 1.98 mmol) is added. The reaction medium is stirred for 15 min at 0 °C and then for 18 h at ambient temperature. The organic phase is washed with 0.1 N aqueous HCl solution (2 × 28 mL), the organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The solid obtained is solubilized in CHCl3 (40 mL) and the solution is added dropwise, with stirring, to IPE (400 mL). The suspension is placed in an ice bath without stirring for 17 h. The suspension is centrifuged at 3200 rpm for 10 minutes at 25° C. The colorless supernatant is removed and the resulting solid is concentrated under reduced pressure. Yield: 4.59g (quant.) 1 H NMR (CDCl3, ppm):0.88(12H);1.12-1.58(192H);1.58-2.17(48H);2.17-2. 62(44H);3.08(2H);3.13-3.38(6H);3.48(4H);3.53-3.66(12H);3.74-3.8 3(4H);3.92(2H);4.00-4.12(4H);4.12-4.33(10H);4.37(2H);6.72-6.84( 4H);7.06(2H);7.31(2H);7.52(2H);7.82(2H);7.94(2H);8.57-8.69(4H).

[0944] Copolyamino acid B29 Molecule B29-1 (3.67 g, 0.93 mmol) is solubilized in TFA (11.5 mL) and the solution is stirred at ambient temperature for 6 h. The solution is poured dropwise onto IPE (18 mL) at 5° C. and then water (18 mL) is added. The suspension is placed in an ice bath with stirring for 15 h. The suspension is filtered and triturated with IPE (10 mL) and water (2×10 mL). The residue is dried under reduced pressure and then solubilized in 1N NaOH solution (56 mL) with regular addition of 1N NaOH to maintain the pH at 7. The solution is diluted with water to 20 g / L theory and then purified by ultrafiltration against 0.9% NaCl solution followed by water until the conductivity measurement of the permeate is less than 50 μS / cm. The resulting solution is filtered on a 0.2 μm filter and stored at 2-8° C. Dry extract: 8.0mg / g The calculated average molar mass of copolyamino acid B29 is 3520 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2000 g / mol.

[0945] Example B30: Copolyamino acid B30 - tricarballylic acid substituted with molecule A26 (ester deprotected) and having a number-average molar mass (Mn) of 2100 g / mol Copolyamino acid B30-1 : Using a method similar to that used for the preparation of copolyamino acid B15-1, applied to a DMF solution containing molecule A26 (10.87 g, 11.33 mmol) and tricarballylic acid (TCA, 0.605 g, 3.43 mmol), a white solid is obtained after two successive precipitations of the product in a DMF solution in a 50:50 HO / MeCN mixture (10 V), filtration, trituration with a 50:50 HO / MeCN mixture, followed by drying at 30° C. under reduced pressure.

[0946] Copolyamino acid B30 Copolyamino acid B30-1 (8.53 g, 2.95 mmol) is solubilized in TFA (30 mL), the solution is stirred for 3 hours at ambient temperature, then poured dropwise onto water (300 mL) with stirring. After 1 hour, the white precipitate is collected by filtration, triturated with water and dried under reduced pressure. The solid obtained is then solubilized in water (350 mL) by adding an aqueous solution of 1N sodium hydroxide to adjust the pH to 7. The solution is filtered on a 0.2 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution followed by water until the conductivity measurement of the permeate is less than 50 μS / cm. The solution obtained is filtered on a 0.2 μm filter and stored at 2-8° C. Dry extract: 28.8mg / g The molar mass of copolyamino acid B30 is 2585 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=2100 g / mol.

[0947] Example B31: Copolyamino acid B31 - sodium poly-L-glutamate modified at its ends with molecule A27 (ester deprotected) and having a number-average molar mass (Mn) of 3800 g / mol A method similar to that used for the preparation of copolyamino acid B16 is applied to copolyamino acid B18-1 (28.6 g) and molecule A27 (6.799 g) to give copolyamino acid B31. Dry extract: 20.5mg / g DP( 1 1H NMR):24 1 By H NMR: i=0.075 The calculated average molar mass of copolyamino acid B31 is 4591 g / mol. HPLC-Organic SEC (PEG calibrator): Mn=3800g / mol

[0948] Part CE - Copolyamino acid counterexamples [ka] TIFF0007638508000127.tif128162 The copolyamino acids CE1 and CE2 are synthesized according to the method described in application WO2017211916.

[0949] Part C: Composition Example C1: Fast-acting insulin analog solution (Humalog®) at 100 U / mL This solution is a commercially available insulin lispro solution sold under the brand name Humalog® by ELI LILLY. This product is a fast-acting insulin analog. The excipients in Humalog® are m-cresol (3.15 mg / mL), glycerol (16 mg / mL), disodium phosphate (1.88 mg / mL), zinc oxide (to obtain 0.0197 mg zinc ion / mL), sodium hydroxide and hydrochloric acid (to adjust the pH (pH 7-7.8)) and water.

[0950] Example C2: Fast-acting insulin lispro analog solution at 100-600 U / mL This solution is an insulin solution prepared from insulin lispro powder produced by Gan & Lee. This product is a fast-acting insulin analog. 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 IU / mL insulin. The excipient concentrations are varied with the concentration of lispro to obtain the desired concentration in the final formulation.

[0951] Example C3: Delayed-acting insulin analog solution (Lantus®) at 100 U / mL This solution is a commercially available insulin glargine solution sold under the trade name Lantus® by SANOFI. This product is a delayed-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.

[0952] Example C4: Insulin glargine solution at 100-400 U / mL This solution is an insulin glargine solution prepared from insulin glargine powder produced by Gan & Lee. This product is a delayed-acting insulin analogue. The excipients used are zinc chloride, m-cresol, glycerol. * , sodium hydroxide and hydrochloric acid (to adjust pH (pH 4)) and water. Zinc concentration is 460 μM per 100 IU / mL insulin. The concentrations of other excipients vary with the concentration of glargine to obtain the desired concentration in the final formulation.

[0953] Part CA - Compositions containing insulin glargine Preparation method CA1: Preparation of a dilute copolyamino acid / 50 U / mL insulin glargine solution at pH 7.1 by a method using insulin glargine in liquid form (solution) and copolyamino acid in liquid form (solution) A concentrated solution of m-cresol and glycerin was added to the stock solution of copolyamino acid at pH 7.1 to obtain a concentration of C ストックコポリアミノ酸 / 賦形剤 (mg / mL) copolyamino acid solution is obtained. The amount of excipients added is adjusted to obtain a concentration of 35 mM m-cresol and 184 mM glycerin in the copolyamino acid / 50 U / mL insulin glargine composition at pH 7.1.

[0954] In a sterile container, prepare a volume V of insulin glargine solution 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 希薄コポリアミノ酸 (mg / mL) / concentration C to obtain 50 U / mL insulin glargine ストックコポリアミノ酸 / 賦形剤 Volume of the copolyamino acid solution V (mg / mL) ストックコポリアミノ酸 / 賦形剤 Add 100 ml of 100 ml of 100% NaOH to the flask. Turbidity appears. The pH is adjusted to pH 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.

[0955] Preparation method CA2: Preparation of concentrated copolyamino acid / insulin glargine composition at pH 7.1 using copolyamino acid by dilute composition concentration method The pH 7.1 copolyamino acid / 50 U / mL insulin glargine composition described in Example CA1 is concentrated by ultrafiltration on a 3 kDa membrane made of regenerated cellulose (Amicon® Ultra-15 sold by Millipore). After this ultrafiltration step, the retentate is clear and the insulin glargine concentration in the composition is determined by reversed phase chromatography (RP-HPLC). The insulin glargine concentration in the composition is then adjusted to the desired value by dilution in a solution of m-cresol / glycerin excipient to obtain a final concentration of 35 mM m-cresol, 52 μM Tween 20 and an osmolality of 300 mOsmol / kg. The pH is measured and adjusted to pH 7.1 by adding NaOH and concentrated HCl. This visually clear solution at pH 7.1 has an insulin glargine concentration C インスリングラルギン (U / mL) and copolyamino acid concentration C コポリアミノ酸 (mg / mL) = C 希薄コポリアミノ酸 (mg / mL) x C インスリングラルギン (U / mL) / 50(U / mL).

[0956] Preparation method CA3: Preparation of a concentrated copolyamino acid / insulin glargine solution at pH 7.1 by a method using insulin glargine in liquid form (solution) and copolyamino acid in liquid form (solution) To the stock solution of copolyamino acids at pH 7.1, 220-400 IU / mL of the glargine solution containing the excipients described in Example C4 is added. The concentration of the excipients in the glargine solution is adjusted to obtain a concentration of 35 mM m-cresol, 184 mM glycerin in the copolyamino acids / insulin glargine composition at pH 7.1. Turbidity appears. The pH is adjusted to pH 7.1 by adding concentrated NaOH, and the solution is left under static conditions at 40° C. for 2 hours until complete solubilization. This visually clear solution is placed at 4° C. after adding a volume of concentrated polysorbate 20 solution to obtain a final concentration of 52 μM.

[0957] Copolyamino acid / insulin glargine compositions were prepared by preparation method CA2 or CA3, for example with insulin glargine concentrations of 200 U / mL to 300 U / mL.

[0958] Example CA4: Preparation of a copolyamino acid / 200 U / ml insulin glargine composition at pH 7.1 The copolyamino acid / 200 U / mL insulin glargine composition was added at an insulin glargine concentration of C インスリングラルギン = 200 U / mL and copolyamino acid concentration C コポリアミノ酸 (mg / mL) were prepared by the methods described in CA2 and CA3.

[0959] These compositions are shown in Table 1. [Table 2] Table 1: Insulin glargine (200 U / mL) composition in the presence of copolyamino acids

[0960] The copolyamino acids allow solubilization of insulin glargine at neutral pH, leading to a clear solution.

[0961] Example CA5: Minimum copolyamino acid concentration to solubilize 50 IU / mL insulin glargine at pH 7.1 To the stock solution of copolyamino acid at pH 7.2±0.3, concentrated solutions of zinc chloride, sodium chloride, m-cresol and glycerin are added. 0.5 mL of insulin glargine solution at a concentration of 100 U / mL prepared according to example C3 or C4 is added to a volume of 0.5 mL of the solution of copolyamino acid and excipients to obtain a copolyamino acid / 50 U / ml insulin glargine composition with the desired composition. The copolyamino acid concentration varies from preparation to preparation: solutions with copolyamino acid concentrations varying less than 1 mg / ml are thus prepared.

[0962] After the addition of the glargine solution, turbidity appears. The pH is adjusted to pH 7.1 by adding concentrated NaOH and the solution is placed in a 40°C oven overnight. After standing 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 suitable for solubilizing insulin glargine is defined as the lowest concentration at which the copolyamino acid / insulin glargine mixture at pH 7.1±0.1 is visually clear, has no visible particles, and has a scattering intensity of less than 1500 kcps / s.

[0963] Preparation method CA5a: Preparation of a copolyamino acid / insulin glargine solution at pH 7.2 by a method using insulin glargine in liquid form (solution) and copolyamino acid in liquid form (solution) Sodium chloride solution and ZnCl2 solution are added to the stock solution of copolyamino acid at pH 7-7.5 to obtain the target concentration in the copolyamino acid / insulin glargine composition. 100-220 U / mL glargine solution described in Example C4 is added. The concentration of excipients in the glargine solution is adjusted to obtain a concentration of 35 mM m-cresol and 230 mM glycerin in the copolyamino acid / insulin glargine composition. Turbidity appears. The pH is adjusted to pH 7.5 by adding concentrated NaOH, and the solution is placed in a 40°C oven for 2 hours until complete solubilization. The resulting solution is visually clear.

[0964] Example CA6: Determination of the lowest concentration of copolyamino acid B20 that solubilizes 50 IU / ml insulin glargine in the presence of glycerin (184 mM), m-cresol (35 mM) and different NaCl and zinc chloride concentrations at pH 7.1 The lowest concentration of copolyamino acid B20 that solubilizes insulin glargine is determined for different zinc chloride and sodium chloride contents by preparation method CA5. The results are listed in Table 1a.

[0965] Example CA6a: Determination of the minimum concentration of different copolyamino acids to solubilize 50 IU / ml insulin glargine in the presence of glycerin (184 mM) and m-cresol (35 mM) at pH 7.1 Using a method similar to that described in Example CA6, the minimum concentrations determined for different copolyamino acids according to the invention are shown in Table 1a. [Table 3] Table 1a: Minimum concentrations of different copolyamino acids to solubilize insulin glargine

[0966] Copolyamino acids B14, B26 and B9 are suitable for solubilizing 50 U / mL glargine at copolyamino acid concentrations of 1 mg / mL or less.

[0967] Example CA6b: Determination of the percentage improvement of the lowest concentration of different copolyamino acids to solubilize 50 IU / ml insulin glargine in the presence of glycerin (184 mM), m-cresol (35 mM) and different NaCl and zinc chloride concentrations at pH 7.1 Using a method similar to that described in Example CA6, the percentage reduction in the minimum concentration determined for different copolyamino acids according to the invention provided by the addition of NaCl and zinc chloride is shown in Table 1b. [Table 4] Table 1b: Reduction in the minimum concentration of different copolyamino acids to solubilize insulin glargine in the presence of NaCl and zinc chloride.

[0968] The addition of salt and / or zinc chloride helps to enhance the effectiveness of the copolyamino acids according to the invention relative to salt-free copolyamino acid / glargine compositions: Addition of 10 mM NaCl can reduce the minimum concentration of copolyamino acids by at least 14%, and supplemental addition of zinc chloride can reduce it by at least 37%, relative to a reference composition without NaCl.

[0969] Part CB - Compositions Comprising Insulin Glargine and Insulin Lispro Preparation method CB1: Preparation of a dilute copolyamino acid / 43 (U / mL) insulin glargine / 13.5 (U / mL) insulin lispro composition To obtain the copolyamino acid / 43 (U / mL) insulin glargine / 13.5 (U / mL) insulin lispro composition, the volume V コポリアミノ酸 / 希薄インスリングラルギン of a dilute copolyamino acid / 50 U / mL insulin glargine composition at pH 7.1, volume V インスリンリスプロ Add 100 U / mL Lispro solution and water.

[0970] Preparation method CB2: Preparation of a concentrated copolyamino acid / insulin glargine / insulin lispro composition at pH 7.1 The copolyamino acid / 43 (U / mL) insulin glargine / 13.5 (U / ml) insulin lispro composition described in Example CB1 is concentrated by ultrafiltration on a 3 kDa membrane made of regenerated cellulose (Amicon® Ultra-15 sold by MILLIPORE). After this ultrafiltration step, the retentate is clear and the insulin glargine concentration in the composition is determined by reversed phase chromatography (RP-HPLC). The insulin glargine and insulin lispro concentrations in the composition are then adjusted to the desired values ​​by dilution in a solution of m-cresol / glycerin excipient to obtain a final concentration of m-cresol of 35 mM and an osmolality of 300 mOsm / kg. During this dilution step, a volume of concentrated polysorbate 20 solution is also added to obtain a final concentration of 52 μM. The pH is measured and adjusted to pH 7.1 by adding NaOH and concentrated HCl if necessary. This visually clear solution with a pH of 7.1 has an insulin glargine concentration of 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 希薄コポリアミノ酸 (mg / mL) x C インスリングラルギン (U / mL) / 50(U / mL).

[0971] Preparation method CB3: Preparation of a concentrated copolyamino acid / insulin glargine / insulin lispro composition at pH 7.1 Volume V of pH 7.1 as described in Example CA3 コポリアミノ酸 / 濃インスリングラルギン of concentrated copolyamino acid / insulin glargine composition, インスリンリスプロ A volume of lispro solution is also added to obtain a final concentration of 52 μM. The resulting solution, pH 7.1, has an insulin glargine concentration of 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 希薄コポリアミノ酸 (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.

[0972] Preparation method CB4: Preparation of a pH 7.2 Copolyamino Acid / 75 U / mL Insulin Glargine / 25 U / mL Insulin Lispro Composition A volume of concentrated copolyamino acid / insulin glargine composition as described in Example CA5a is added to a volume of insulin lispro solution as described in Example C2. The pH is adjusted to 7.2 by adding concentrated hydrochloric acid solution. The resulting visually clear solution has a concentration of 75 U / mL insulin glargine and 25 U / mL insulin lispro. The concentration of m-cresol is 35 mM and the concentration of glycerin is 230 mM.

[0973] Preparation method CB5: Preparation of a pH 7.2 Copolyamino Acid / 150 U / mL Insulin Glargine / 50 U / mL Insulin Lispro Composition A volume of concentrated copolyamino acid / insulin glargine composition as described in Example CA5a is added to a volume of lispro solution as described in Example C2. The pH is adjusted to 7.2 by adding concentrated hydrochloric acid solution. The resulting visually clear solution has a concentration of 150 U / mL insulin glargine and 50 U / mL insulin lispro. The concentration of m-cresol is 35 mM and the concentration of glycerin is 230 mM.

[0974] Examples CB2 and CB3: Preparation of a copolyamino acid / 200 U / mL insulin glargine / 66 U / mL insulin lispro composition at pH 7.1 The copolyamino acid / 200 U / mL insulin glargine / 66 U / ml insulin lispro composition was administered at an insulin glargine concentration of 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(mg / mL) is prepared by the methods described in Examples CB2 and CB3.

[0975] These compositions are shown in Table 2. [Table 5] Table 2: Insulin glargine (200 U / mL) and insulin lispro (66 U / ml) compositions in the presence of copolyamino acids

[0976] Example CB4: Preparation of a copolyamino acid / insulin glargine / insulin lispro composition at pH 7.2 A copolyamino acid / 75 U / ml insulin glargine / 25 U / ml insulin lispro composition is prepared by the method described in Example CB4. [Table 6] Table 2a: Insulin glargine (75 U / mL) and insulin lispro (25 U / ml) compositions in the presence of copolyamino acids

[0977] Example CB5: Preparation of a Copolyamino Acid B23 / Insulin Glargine / Insulin Lispro Composition at pH 7.2 A copolyamino acid / 150 U / ml insulin glargine / 50 U / ml insulin lispro composition is prepared by the method described in Example CB5. [Table 7] Table 2b: Insulin glargine (150 U / mL) and insulin lispro (50 U / ml) compositions in the presence of copolyamino acid B23

[0978] Copolyamino acid B23 allows the solubilization of insulin glargine in the presence of insulin lispro at neutral pH, leading to a clear solution.

[0979] Part CD - Results Demonstration of the physical stability of the composition Example CD1 : Accelerated stability at 25℃ under dynamic conditions 3 x 3 mL vials filled with 1 mL of copolyaminoacid / insulin glargine or copolyaminoacid / insulin glargine / prandial insulin composition are placed vertically on an orbital stirrer. The stirrer is placed in an oven at 25°C, with the vials being stirred at 250 rpm. The vials are 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 vials are placed under illumination of at least 2000 Lux and observed against a white background and a black background. The days of stability correspond to the period from that time when at least two vials show visible particles or are turbid.

[0980] Accelerated stability results using copolyamino acid B5 are shown in Table 3. [Table 8] Table 3: Stability results of the copolyamino acid B5 / insulin glargine (200 U / mL) / insulin lispro (66 U / mL) composition under dynamic conditions at 25°C.

[0981] Example CD2: Accelerated stability at 30℃ under static conditions At least 5 x 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 twice a 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 vials are placed under illumination of at least 2000 Lux and observed against a white background and a black background. The weeks of stability correspond to the period from which the majority of the cartridges show visible particles or are turbid.

[0982] The accelerated stability results under static conditions are shown in Table 4. [Table 9] Table 4: Stability results of copolyamino acid / insulin glargine insulin lispro compositions under static conditions at 30°C.

[0983] Copolyamino acids B23, B14, B26 allow the solubilization of insulin glargine at neutral pH in the presence of insulin lispro, leading to compositions with good physical stability. The addition of salts and zinc to compositions containing copolyamino acid B23 allows the maintenance of good physical stability while using reduced copolyamino acid B23 concentrations.

[0984] Example CD3: Precipitation of insulin glargine after mixing a copolyamino acid / 75 U / mL insulin glargine / 25 U / mL insulin lispro composition in simulated physiological media This test demonstrates the precipitation of insulin glargine after injection in a simulated physiological medium containing albumin at physiological pH and ionic strength. These conditions help to mimic the behavior of the composition after subcutaneous injection. To 100 μL of copolyamino acid / 75 U / ml insulin glargine / 25 U / ml insulin lispro, 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 content are 140 mM and 10 mM, respectively. Precipitation of the glargine in this medium at ambient temperature (20-25° C.) is followed by absorbance measurement at 450 nm of the mixture for 30 minutes. The absorbance measurement is carried out using a UV-visible multiwell plate reader.

[0985] The absorbance increases until a plateau is reached. The precipitation time of glargine is defined as the time required for the measured absorbance to be 80% or greater of the plateau value. [Table 10] Table 5: Precipitation time of insulin glargine after mixing of copolyamino acid / insulin glargine / insulin lispro compositions in a medium simulating a subcutaneous medium.

[0986] The copolyamino acid / insulin glargine / insulin lispro composition according to the invention results in rapid precipitation of glargine after mixing with a medium simulating a subcutaneous medium.

[0987] Part D Pharmacokinetics D1: Pharmacokinetic measurement protocol for insulin glargine and insulin lispro formulations A study in dogs was conducted to evaluate the pharmacokinetics of insulin following administration of a copolyamino acid B23 / insulin glargine (150 U / mL) / insulin lispro (50 U / mL) composition.

[0988] 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.

[0989] Ten animals, placed under fasting conditions for approximately 17.5 hours, are injected by subcutaneous route with a dose of 0.68 U / kg insulin. Blood samples are taken for 16 hours after administration to characterize the pharmacokinetics of insulin. Glargine, glargine-M1 and lispro levels are determined by specific bioanalytical methods.

[0990] The pharmacokinetic parameters determined were as follows: - AUC, which corresponds to the area under the curve of the concentration of insulin glargine (and its metabolite M1) as a function of time, 0-1 h, 0-2 h, 10-16 h and 13-16 h, respectively, after administration 0-1h , AUC 0-2h , AUC 10-16h , AUC 13-16h ; - AUC, which corresponds to the area under the curve of insulin lispro concentration as a function of 0-0.5 hours, 0-1 hour, and 8-16 hours after administration, respectively 0-30min , AUC 0-1h , AUC 8-16h ; - AUC, which corresponds to the area under the curve from time 0 to the last measurement performed on the subject last .

[0991] Table 6 below reports the different pharmacokinetic parameters of insulin glargine and insulin lispro. [Table 11] Table 6: Mean pharmacokinetic parameters (mean ratios) of composition CB5-1 containing copolyamino acid B23 / 150 U / mL insulin glargine / 50 U / mL insulin lispro

[0992] The results obtained showed that, on the one hand, the glargine component of the formulation is rapidly absorbed (AUC 0-1h and AUC 0-2h ), but retains its basic characteristics and has a significant coverage in the final part of the observation period (AUC 10-16h and AUC 13-16h ) is proved.

[0993] In addition, the lispro component is rapidly absorbed (AUC 0-30min and AUC 0-1h ), retaining its meal properties. In fact, lispro is no longer 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 of 5.8 to 8.5; A copolyamino acid composed of glutamic or aspartic acid units, selected from among the copolyamino acids according to formula I defined below: [(#)) ｋ [|] ｊ [|] ｊ’ Formula I During the ceremony: j≧1; 0≦j′≦n′1; k≧2 Said copolyamino acid according to formula I comprises at least one hydrophobic radical -Hy, a carboxylate charge and at least two chains of glutamic or aspartic acid units PLG linked together by Q, Q is selected from among radicals according to formula II: Q[― ＊ ] ｋ =([Q’] ｑ )[― ＊ ] ｋ Formula II During the ceremony: 1≦q≦5, The precursors Q′ are the same or different and are selected from the group consisting of radicals according to formula III: ＊ ]k, The radical Q′ according to formula III: 【Chemistry 1】 (In the formula: 1≦t≦8 Fx=Fa, Fa', which may be the same or different, and represent the functional group -NH- or -CO-. Two precursors Q' are linked by an amide bond; Q is linked to at least two glutamic or aspartic acid unit chains PLG by amide functional groups; said amide functional group resulting from a reaction between an amine functional group and an acid functional group carried by either a precursor Q′ of Q or a glutamic or aspartic acid unit, respectively, linking Q which is linked to said at least two chains of glutamic or aspartic acid units, said hydrophobic radical -Hy is attached to a terminal "amino acid" unit, j>1, or to a carboxyl function of one of the chains of glutamic or aspartic acid units PLG, j'=n'1, n'1 being the average number of monomer units carrying the hydrophobic radical -Hy; The hydrophobic radical -Hy is selected from among the radicals according to formula Xb defined below: 【Chemistry 2】 During the ceremony, GpR is selected from among the radicals according to formula VII, VII' or VII'': 【Chemistry 3】 GpG and GpH are the same or different and are selected from among radicals according to formula XI or XI′: 【Chemistry 4】 GpA is selected from among radicals according to formula VIIIa: 【Chemistry 5】 GpL is selected from among radicals according to formula XII: 【Chemistry 6】 GpC is a radical according to formula IX: 【Chemistry 7】 ＊ indicates the attachment site of the different groups linked by the amide functionality; b is an integer equal to 0 or 1; c is an integer equal to 0 or 1; d is an integer equal to 0, 1, or 2, provided that when c is equal to 0, then d is equal to 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, if l=0 then l′=1, if l=1 then l′=2; r is an integer equal to 0, 1, or 2; A is a linear or branched alkyl radical containing 1 to 8 carbon atoms and optionally substituted with a radical derived from a saturated, unsaturated or aromatic ring; A 1 is a linear or branched alkyl radical containing 1 to 8 carbon atoms and optionally substituted with a saturated, unsaturated or aromatic ring-derived radical; B is a radical selected from the group consisting of unsubstituted ether or polyether radicals containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or linear or branched alkyl radicals, 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 represents the number of carbon atoms, 6<x<25: when the hydrophobic radical -Hy has one GpC, 9≦x≦25; if the hydrophobic radical -Hy has two GpCs, 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 at least 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 group(s); R is a linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms, one or more functional groups -CONH ２ or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, having the formula: 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; When the copolyamino acid has multiple hydrophobic radicals, they may be the same or different. The degree of polymerization DP of glutamic or aspartic acid units for the PLG chain is comprised between 5 and 250; The free carboxylic acid functional group is Na ＋ and K. ＋ The compound is in the form of an alkali cation salt selected from the group consisting of:

2. 2. The composition according to claim 1, characterized in that said copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXb: 【Chemistry 8】 During the ceremony, D is independently -CH ２ - group (aspartic acid) or -CH ２ -CH ２ - group (glutamic acid), X represents a cationic entity selected from the group comprising alkaline cations, R ｂ and R ｂ ' are the same or different and are either the hydrophobic radical -Hy or a radical selected from the group consisting of H, C2-C10 linear acyl group, C3-C10 branched acyl group, benzyl, terminal "amino acid" unit and pyroglutamic acid; Q and Hy are as defined above; n+m represents the degree of polymerization DP of said copolyamino acid, ie the average number of monomer units per copolyamino acid chain, with 5≦n+m≦250.

3. 3. The composition according to claim 1 or 2, characterized in that the copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to formula XXXa: 【Chemistry 9】 During the ceremony, D is independently -CH ２ - group (aspartic acid) or -CH ２ -CH ２ - group (glutamic acid), X represents a cationic entity selected from the group comprising alkaline cations, R ａ and R' ａ are the same or different and are either the hydrophobic radical -Hy or a radical selected from the group consisting of H, C2-C10 linear acyl group, C3-C10 branched acyl group, benzyl, terminal "amino acid" unit and pyroglutamic acid; At least one of Ra and R'a is a hydrophobic radical -Hy; Q and -Hy are as defined above; n+m represents the degree of polymerization DP of said copolyamino acid, ie the average number of monomer units per copolyamino acid chain, with 5≦n+m≦250.

4. Composition according to any one of claims 1 to 3, characterized in that the copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to the following formula XXXb': 【Chemistry 10】 During the ceremony: D and X are as defined above; Q and Hy are as defined above; Rb and Rb' are identical or different and are either the hydrophobic radical -Hy or a radical selected from the group consisting of -OH, an amine group, a terminal "amino acid" unit and pyroglutamic acid; At least one of Rb and R'b is a hydrophobic radical -Hy; n1+m1 represents the number of glutamic or aspartic acid units of the PLG chain of the copolyamino acid bearing the radical -Hy, n2+m2 represents the number of glutamic or aspartic acid units of the PLG chain of the copolyamino acid that does not have a radical -Hy, n1+n2=n' and m1+m2=m', n'+m' represents the degree of polymerization DP of said copolyamino acid, ie the average number of monomer units per copolyamino acid chain, with 5≦n'+m'≦250.

5. Composition according to any one of claims 1 to 4, characterized in that the copolyamino acids carrying a carboxylate charge and at least one hydrophobic radical -Hy are chosen from among the copolyamino acids according to the following formula XXXa': 【Chemistry 11】 During the ceremony: D, X, Ra and R'a are as defined above; Q and Hy are as defined above; n １ +m １ represents the number of glutamic or aspartic acid units of the PLG chain of the copolyamino acid bearing the radical -Hy, n ２ +m ２ represents the number of glutamic or aspartic acid units of the PLG chain of the copolyamino acid that does not have a radical -Hy, n １ +n ２ = n' and m １ +m ２ = m'.

6. The copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from among copolyamino acids according to formula XXXa, XXXa', XXXb or XXXb', wherein the D group is -CH ２ 6. The composition according to claim 1, wherein the copolyamino acids are selected from among the copolyamino acids in which the aspartic acid unit is -.

7. The copolyamino acid having a carboxylate charge and a hydrophobic radical is selected from among copolyamino acids according to formula XXXa, XXXa', XXXb or XXXb', wherein the D group is -CH ２ -CH ２ 6. The composition according to claim 1, wherein the copolyamino acids are selected from the group consisting of (glutamic acid units) copolyamino acids having a - group.

8. Composition according to any one of claims 1 to 7, characterized in that the basal insulin is insulin glargine, with an isoelectric point comprised between 5.8 and 8.

5.

9. Composition according to any one of claims 1 to 8, characterized in that it contains between 40 and 500 U / mL of basal insulin with an isoelectric point between 5.8 and 8.

5.

10. A composition according to any one of claims 1 to 9, characterized in that the concentration of the copolyamino acid carrying a carboxylate charge and a hydrophobic radical is less than or equal to 60 mg / mL.

11. A composition according to any one of claims 1 to 10, characterized in that the concentration of the copolyamino acid carrying a carboxylate charge and a hydrophobic radical is less than or equal to 40 mg / mL.

12. A composition according to any one of claims 1 to 11, characterized in that the concentration of the copolyamino acid carrying a carboxylate charge and a hydrophobic radical is less than or equal to 20 mg / mL.

13. A 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 less than or equal to 10 mg / mL.

14. A copolyamino acid contained in the composition according to any one of claims 1 to 13, A copolyamino acid selected from among the copolyamino acids according to formula I, composed of glutamic or aspartic acid units and carrying a carboxylate charge: [(#)) ｋ [|] ｊ [|] ｊ’ Formula I During the ceremony: j≧1; 0≦j′≦n′1 and j+j′≧1 and k≧2 Said copolyamino acid according to formula I comprises at least one hydrophobic radical -Hy, a carboxylate charge and at least two chains of glutamic or aspartic acid units PLG linked together by Q, Q is selected from among radicals according to formula II: Q[― ＊ ] ｋ =([Q’] ｑ )[― ＊ ] ｋ Formula II During the ceremony: 1≦q≦5, The precursors Q′ are the same or different and are selected from the group consisting of radicals according to formula III: ＊ ]k, The radical Q′ according to formula III: 【Chemistry 12】 During the ceremony: 1≦t≦8 Fx=Fa, Fa', which may be the same or different, represents the functional group -NH- or -CO-; Two precursors Q' are linked by an amide bond; Q is linked to at least two glutamic or aspartic acid unit chains PLG by amide functional groups; said amide functional group resulting from a reaction between an amine functional group and an acid functional group carried by either said precursor Q′ of Q or a glutamic or aspartic acid unit, respectively, linking Q which is linked to said at least two chains of glutamic or aspartic acid units, said hydrophobic radical -Hy is attached to a terminal "amino acid" unit, j>1, or to a carboxyl function of one of the chains of glutamic or aspartic acid units PLG, j'=n'1, n'1 being the average number of monomer units carrying the hydrophobic radical -Hy; The hydrophobic radical -Hy is selected from among the radicals according to formula Xb defined below: 【Chemistry 13】 During the ceremony, GpR is selected from among the radicals according to formula VII, VII' or VII'': 【Chemistry 14】 GpG and GpH are the same or different and are selected from among radicals according to formula XI or XI′: 【Chemistry 15】 GpA is selected from among radicals according to formula VIIIa: 【Chemistry 16】 GpL is selected from the radicals according to formula XII 【Chemistry 17】 GpC is a radical according to formula IX: 【Chemistry 18】 ＊ indicates the attachment site of the different groups linked by the amide functionality; b is an integer equal to 0 or 1; c is an integer equal to 0 or 1; d is an integer equal to 0, 1, or 2, with the proviso that if c is equal to 0, then d is equal to 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, if l=0 then l′=1, if l=1 then l′=2; r is an integer equal to 0, 1 or 2; A is a linear or branched alkyl radical containing 1 to 8 carbon atoms and optionally substituted with a radical derived from a saturated, unsaturated or aromatic ring; A 1 is a linear or branched alkyl radical containing 1 to 8 carbon atoms and optionally substituted with a saturated, unsaturated or aromatic ring-derived radical; B is a radical selected from the group consisting of unsubstituted ether or polyether radicals containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, or linear or branched alkyl radicals, 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 represents the number of carbon atoms, 6<x<25: when the hydrophobic radical -Hy has one GpC, 9≦x≦25; if the hydrophobic radical -Hy has two GpCs, 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 at least 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 group(s); R is a linear or branched, divalent alkyl radical containing 1 to 12 carbon atoms, one or more functional groups -CONH ２ or an unsubstituted ether or polyether radical containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms, having the formula: 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; When the copolyamino acid has multiple hydrophobic radicals, they may be the same or different. The degree of polymerization DP of glutamic or aspartic acid units for the PLG chain is comprised between 5 and 250; The free carboxylic acid functional group is Na ＋ and K. ＋ The compound is in the form of an alkali cation salt selected from the group consisting of:

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