FR3083087A1 - COMPOSITIONS IN THE FORM OF AN AQUEOUS INJECTION SOLUTION COMPRISING HUMAN GLUCAGON AND A CO-POLYAMINOACID - Google Patents

Abstract

The invention thus relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least: a) human glucagon and b) a co-polyamino acid carrying Carboxylate and hydrophobic radical charges Hy, In one embodiment, the compositions according to the invention also comprise a gastrointestinal hormone.

Description

COMPOSITIONS IN THE FORM OF AN AQUEOUS SOLUTION

INJECTABLE COMPRISING HUMAN GLUCAGON AND A COPOLYAMINOACID [0001] Human glucagon is a hyperglycemic hormone with a short action which makes it possible to increase blood sugar, thus correcting a hypoglycemic level which may result from an excess of insulin. It allows the release of glucose by stimulation of hepatic glycogenolysis, and has antagonistic properties of insulin (hypoglycemic). Human glucagon is normally secreted by alpha 10 cells from the islets of Langerhans in the pancreas when hypoglycemia is detected.

Human glucagon is used for therapeutic purposes, such as the emergency treatment of severe hypoglycaemia, also called "rescue", but also in a diagnostic context when carrying out medical examinations, for example to inhibit the gastrointestinal motility. Other applications are also envisaged for human glucagon, in particular its use in a bi-hormonal blood sugar regulation system also called artificial pancreas and in congenital hyperinsulinism which is a rare disease characterized by very high levels of 'insulin.

The clinical use of human glucagon has been limited because of some of its unfavorable properties for developing a stable pharmaceutical product for therapeutic purposes. In fact, human glucagon has very low solubility at physiological pH, high physical instability, because of its propensity to form fibrils over a wide range of pH. It is for this reason that the only commercial products based on human glucagon (Glucagen®, NOVO NORDISK and Glucagon 25 for injection, ELI LILLY) are lyophilized forms to be reconstituted extemporaneously.

The work of Onoue et al. (Pharm. Res. 2004, 21 (7), 1274-83) have shown the potentially dangerous nature of these fibrils: human glucagon fi shine being cytotoxic in mammalian cells in culture.

In addition to its physical instability, human glucagon undergoes various types of chemical degradation. In aqueous solution, it degrades quickly to form several degradation products. At least 16 degradation products of human glucagon have been identified by Kirsh et al. (International Journal of Pharmaceutics, 2000, 203, 115-125). The chemical degradation of this human glucagon is therefore rapid and complex.

The poor chemical and physical stability of human glucagon in solution has led pharmaceutical companies such as NOVO NORDISK, ELI LILLY and more recently FRESENIUS KABI to market this human glucagon in the form of a lyophilisate to be reconstituted at acid pH (pH < 3) just before injection. Human glucagon in the form of lyophilisate is more stable, and the preparation of the formulation at acid pH just before use makes it possible to obtain a clear solution. However, once the product has been reconstituted, it must be used quickly because it undergoes extremely rapid chemical and physical degradation in the acid reconstitution buffer, with the appearance of human glucagon fibrils within 24 hours of reconstitution, and / or gelling of the composition. This presentation of the product is, however, unsatisfactory since it requires very rapid use of the formulation. This instability not only makes it impossible to use a pump, but it also has the disadvantage of leading to significant product losses in diagnostic use. Indeed, a composition of this type is no longer usable a few hours after preparation that causes wastage.

Finally, even in the application of emergency treatment for severe hypoglycemic reactions, which may occur during insulin therapy in diabetic patients, the formulation to be reconstituted is also not ideal, since it involves long preparation and complicated, for example the GlucaGen® leaflet describes a 5-step process for injecting the recommended dose. Moreover, a study by the company LOCEMIA shows that very few people (around 10% of the participants) having to carry out the reconstitution in an emergency were able to deliver the adequate dose. Finally, the acid pH of human glucagon solutions can cause pain when injected into the patient.

[0008] There is therefore a need for a ready-to-use human glucagon solution. Today, the most advanced solutions from a clinical point of view to allow the delivery of human glucagon bypass the problem of stability of human glucagon in aqueous solution in different ways.

LOCEMIA has developed a spray of lyophilized human glucagon, currently being tested in a phase 3 clinical study, which is intended to be administered by the intranasal route. This spray is suitable for use called "rescue", that is to say in the case of severe hypoglycemia, because it is ready for use and therefore easy to use, unlike the solutions to be reconstituted. However, this product is not suitable for pump use or for use requiring precise control of the quantity of human glucagon delivered.

For its part, XERIS has developed a liquid formulation of human glucagon based on a polar aprotic solvent, such as DMSO, currently tested in clinical studies. However, if the injection of solution of organic solvents for use of the “rescue” type is possible, it is largely preferable to have an aqueous solution of human glucagon for chronic use. Compositions comprising an association with other peptides are envisaged, in particular amylin or a GLP-1 RA (Glucagon like peptide-1 receptor agonist).

Finally, faced with the difficulties in formulating human glucagon, analogs of human glucagon are being developed by large pharmaceutical companies, such as NOVO NORDISK, SANOFI OR ELI LILLY, in order to obtain formulations having stability compatible with pharmaceutical use. However, these peptides whose primary sequence has been modified compared to the peptide of human origin may present a safety risk to patients.

There is therefore a major interest in a solution making it possible to improve the solubilization and the stability, both chemical and physical, of human glucagon in aqueous solution at a pH close to physiological pH, that is to say say between 6.0 and 8.0. This could make it possible to obtain a pharmaceutical product more easily usable by the patient in the event of an emergency, but also to open the field to new therapeutic applications of human glucagon, such as for example its use in an artificial bihormonal pancreas.

The prior art offers solutions to try to solve this problem.

Some documents suggest placing oneself at basic pH. for example

US2015291680 teaches the solubilization of human glucagon at 1 mg / ml by placing it at a pH between 8.8 and 9.4 and using ferulic acid or tetrahydrocurcumin. However, in addition to being placed at basic pH, this solution has the drawback of leading to a fairly limited stability of human glucagon over time. The article by Jackson et al (Curr. Diab. Rep., 2012, 12, 705-710) proposes to formulate human glucagon at basic pH (around 10) in order to limit the formation of fibrils. However, this solution does not prevent rapid chemical degradation of human glucagon.

Application W02014096440 (NOVOZYME), on the contrary, envisages placing itself at a slightly acidic pH (around 5.5) in the presence of albumin and polysorbate, in order to improve stability by reducing the speed of fibrillation. However, this solution has a limited improvement in stability. Most of the solutions described in the prior art making it possible to obtain a clear solution of human glucagon and to prevent the aggregation, gelling or precipitation of human glucagon involve the use of known surfactants, detergents or solubilizing agents .

For example, Matilainen et al (J. Pharm. Sci, 2008, 97, 2720-2729 and Eur. J. Pharm. Sci., 2009, 36, 412-420) described the use of cyclodextrin to to limit the rate of formation of human glucagon fibrils. However, the improvement made seems insufficient to envisage use as a pump.

Among the solutions proposed are hydrophilic surfactants:

- GB1202607 (NOVO NORDISK) describes the use of anionic or cationic detergents.

- US6384016 (NOVO NORDISK) and US2011097386 (BIODEL) use lysophospholipids (or lysolecithins).

- WO2015095389 (AEGIS) describes nonionic surfactants, such as dodecyl maltoside, for improving the bioavailability of therapeutic agents, in the case of delivery by application to the mucous membranes or the epidermis, and in particular in the case of ocular delivery , nasal, oral or nasolacrimal. This document describes that the presence of alkyl glycosides leads to an improvement in the absorption of human glucagon at the ocular level,

- Application WO2012059764 (ARECOR) describes cationic surfactants, and more specifically aromatic ammonium chlorides.

The surfactants indicated in the above documents may be too toxic or irritating for chronic use by the subcutaneous route. For example, lysophospholipids (or lysolecithins) are known to lyse red blood cells because of their hemolytic properties. During a subcutaneous injection, this can cause local tissue damage and pain at the injection site. In the case of a continuous injection by a pump, this can lead to pain and / or irritation at the needle insertion site. International application WO2011138802 (Sun Pharma) describes a ready-to-use solution of human glucagon in aqueous micellar solution at a pH between 5 and 7.5 in the presence of a pegylated lipid (pegylated distearoyl-phosphotidylethanolamine). However, Garay et al. (Expert Opin Drug Deliv (2012) 9, 1319-1323) teach that Poly Ethylene Glycol is both immunogenic and antigenic. This can be detrimental to patients with anti-PEG antibodies. Moreover, Ganson et al. (J. Allergy Clin. Immunol. (2015) doi: 10.1016 / j.jaci.2015.10.034) describe that a clinical study using pegnivacogin coupled to 40 kDa methoxypolyethylene glycol (mPEG) led to responses from the first dose of pegnivacogin in 3 of 640 patients. Among these three patients two met the criteria for anaphylaxis and one presented an isolated dermal reaction, each event was considered serious, and one was even considered to be endangering the patient's life. These adverse events caused the discontinuation of the clinical trial and raise the problem of the adverse effects of pegylated compounds.

Document W02013101749 (LATITUDE) describes nano-emulsions of human glucagon. However, it claims fairly modest performances in terms of chemical stability, that is to say that the composition comprises at least 75% of the initial concentration after 3-7 days at 37 ° C.

In addition, it should be noted that, to date, to the knowledge of the applicant, no pharmaceutical formulation comprising human glucagon in the form of an aqueous solution has been tested in a clinical study.

There therefore remains a need for an aqueous liquid formulation at a pH close to the physiological pH of between 6.0 and 8.0 making it possible to dissolve and obtain good stability of human glucagon, both in terms of physical stability and chemical stability. More particularly there is a need for such a formulation which can be used in a bihormonal pump (insulin / human glucagon).

This need is all the more clear since Tan et al. (Diabetes, 2013, 62, 1131138) shows that combining human glucagon with a GLP-1 RA is an attractive proposition for the treatment of obesity and diabetes. However, being able to formulate human glucagon in a stable manner in an aqueous solution at a pH close to the physiological pH of between 6.0 and 8.0 makes it possible to be in more favorable conditions in order to be able to improve the stability of GLP-1 RA sensitive to acidic or basic conditions.

The co-polyamino acids carrying carboxylate charges and hydrophobic Hy radicals according to the invention have excellent resistance to hydrolysis. This can in particular be viewed under accelerated conditions, for example by hydrolysis tests at basic pH (pH 12).

In addition, forced oxidation tests, for example of the fenton oxidation type, show that the co-polyamino acids carrying carboxylate charges and hydrophobic Hy radicals have good resistance to oxidation.

The invention thus relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:

a) human glucagon and

b) a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic Hy radicals being of formula I below:

* - ^ GpR j - ^ - GpA j — Gpcj ^ra P Formula I in which

GpR is a radical of formulas II, ΙΓ or II:

Η

RN- ' _n ' or

- GpA is a radical of formulas III or ΙΙΓ:

O HN— * • JL / o 'IlH

HN ™ * mouni ';

GpC is a radical of formula IV:

- the * indicate the sites of attachment of the different groups;

- a is an integer equal to 0 or to 1;

- b is an integer equal to 0 or to 1;

p is an integer equal to 1 or to 2 and o if p is equal to 1 then a is equal to 0 or to 1 and GpA is a radical of formula ΙΙΓ and, o if p is equal to 2 then a is equal to 1, and GpA is a radical of formulaIII;

- c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or to 2;

- d is an integer equal to 0, 1 or 2;

- r is an integer equal to 0, 1 or 2, and o if r is equal to 0 then the hydrophobic radical of formula I is linked to the copolyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N terminal position of the copolyamino acid, thus forming an amide function resulting from the reaction of an amine function in the N terminal position of the co-polyamino acid precursor and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1 or 2 then the hydrophobic radical of formula I is linked to the copolyamino acid:

via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amine function of the precursor of the hydrophobic radical and an acid function carried by the precursor of the co -polyamino acid or • via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and a amine function in the N terminal position carried by the precursor of the copolyamino acid;

- R is a radical chosen from the group consisting of a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions - CONH2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more unsaturated rings or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;

- more precisely, R is a radical chosen from the group consisting of:

o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 12 carbon atoms, if GpR is a radical of formula ΙΓ of 1 to 11 carbon atoms or if GpR is a radical of formula Π from 1 to 10 carbon atoms;

o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 11 carbon atoms, if GpR is a radical of formula ΙΓ of 1 to 11 carbon atoms or if GpR is a radical of formula Π from 1 to 10 carbon atoms, said alkyl radical carrying one or more -CONH2 functions, and o an ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;

- A is a linear or branched alkyl radical comprising from 1 to 8 carbon atoms and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring;

- B is a radical chosen from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;

- Cx is a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and:

o if p is equal to 1, x is between 11 and 25 (11 <x <25):

o if p is equal to 2, x is between 9 and 15 (9 <x <15), the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <i < 0.5;

when several hydrophobic radicals are carried by a co-polyamino acid then they are identical or different, the degree of polymerization DP in glutamic or aspartic units is between 5 and 250;

the free acid functions being in the form of an alkaline cation salt chosen from the group consisting of Na ⁺ and K ⁺ .

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 15 and 100 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 30 and 70 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 40 and 60 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms [00030] In one embodiment, Hy comprises more than 15 carbon atoms.

In one embodiment, Hy comprises more than 30 carbon atoms.

In one embodiment, when r = 2 then the group GpR linked to the PLG is chosen from the GpRs of formula II.

In one embodiment, when r = 2 then the GpR group linked to PLG 30 is chosen from the GpRs of formula II and the second GpR is chosen from the GpRs of formula II.

In one embodiment, one embodiment, when r = 2 then the GpR group linked to the PLG is chosen from the GpRs of formula Π.

In one embodiment, one embodiment, when r = 2 then the GpR group linked to the PLG is chosen from the GpRs of formula II and the second GpR is chosen from the GpRs of formula II.

In one embodiment, GpR is a radical of formula II:

HH * - _N - _R - _N - * _ÏL [ ₀₀₀₃₆ ] In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula I in which r = 2 of formula Xc ', as defined below below:

* —GpR —- GpR - (GpA) --- (GpC) ^ap Formula Xc 'in which GpRi is a radical of formula II.

H H N —- R —N Formula II in which GpR, GpA, GpC, R, a, and p have the definitions given above.

In one embodiment, said at least one hydrophobic radical —Hy is chosen from the radicals of formula X in which r = 2 of formula Xc ', as defined below:

* GpR — GpR - (GpA) - (GpC) ^{a P} Formula Xc 'in which GpRi is a radical of formula Π.

OO _Formu | _{e ir} , in which GpR, GpA, GpC, R, a, and p have the definitions given above.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent alkyl radical comprising 2 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent alkyl radical comprising from 1 to 10 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions ( -CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent linear alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:

XX x * Formula XI * Ά XA * Formula X2

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a radical of formula XI.

it is in one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a radical of formula X2.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R of GpR if r = 1 or of GpRl if r = 2 is linked to the co-polyamino acid via a function amide carried by the carbon in delta or epsilon position (or in position 4 or 5) with respect to the amide function (CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is an ether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is an ether radical comprising from 4 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a divalent alkyl radical comprising 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is an ether radical represented by the formula [00058] In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a polyether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms .

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a poiether radical chosen from the group consisting of the radicals represented by the formulas below:

* Formula X3 o Λ Formula X4 * Z \ / 0 Formula X5

Formula Χ6 [00061] In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a radical of formula X3.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a radical of formula X4.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas X5 and X6 below :

* / 0. Formula X5 : ^ X> ^ X. O Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a polyether radical of formula X5.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula I is a radical in which R is a polyether radical of formula X6.

In one embodiment, the composition is characterized in that the pH is between 6.6 and 7.8.

In one embodiment, the composition is characterized in that the pH is between 7.0 and 7.8.

In one embodiment, the composition is characterized in that the pH is between 6.8 and 7.4.

In one embodiment, the composition is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which if p is equal to 1 and if x is less than or equal to 14 (x <14) then r = 0 or r = 1.

In one embodiment, the composition is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which if p is equal to 1 and if x is between 15 and 16 (15 <x < 16), then r = 1.

In one embodiment, the composition is characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which if p is equal to 1 and if x is greater than 17 (17 <x) then r = 1 and R is an ether or polyether radical.

In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which if p is equal to 1 then x is between 17 and 25 (17 <x <25 ).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 0 (a = 0) and r is equal to 0 (r = 0).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is chosen from the group consisting radicals represented by the formulas below y ___________________

★ * Formula Yl ch ₃ ; ch ₃ Formula Y2 Formula Y3 * * ch ₃ | ^^ CH ₃ Formula Y4 h ₃ ct < ch ₃ Formula Y5 Formula Y6 * * * * • ". H ₃ cr H.C ^ CHG Formula Y7 Formula Y8 Formula Y9

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Yl .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula III 'is a radical of formula Y2.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y3 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y4 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y5 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y6 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y7 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y8 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which a is equal to 1 (a = 1) and the GpA radical of formula III 'is a radical of formula Y9.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc ci- after represented:

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical is of formula IVa.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, corresponding respectively to formulas IVd, IVe, and IVf below 10 represented:

O o /-vs, -NOT Formula IVd 0 O vy _: ........- r * / -N Formula IVe 0 O Formula IVf ^ N ^ Cx

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical corresponds to formula IV or IVa in which b = 0, and corresponds to formula IVd.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula

IV in which b = 1 is chosen from the group consisting of radicals in which B is an amino acid residue chosen from the group consisting of the radicals represented

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula

IV or IVa in which b = 1, is chosen from the group consisting of radicals in which B is an amino acid residue chosen from the group consisting of radicals

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula

IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula

IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of branched alkyl radicals.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 11 and 14 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula

IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of radicals represented by the formulas below:

' ' ' ' · ' 'OH. x = ll x = 13

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 15 and 16 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula

IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of radicals represented by the formulas below;

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by the radicals represented by the formulas below:

ch ₃ x = 16 * 1 ^ _C h ₃

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 17 and 25 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 17 and 18 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by the alkyl radicals represented by the formulas below;

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 18 and 25 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula I in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by the alkyl radicals represented by the formulas below:

x = 19 ". H ;. x = 21

In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which p = 1, represented by the following formula V:

* - ^ GpR j— ^ GpA ^ - GpC ^ra formula V

GpR, GpA, GpC, r and a have the definitions given above.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which: r is equal to 1 (r = 1) and a is equal to 0 (a = 0).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which r is equal to 1 (r = 1) and a is equal to 1 (a = l).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical comprising 2 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical comprising from 1 to 10 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions ( -CONHz).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent linear alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:

] o ^ nh ₂ Formula XI * * (o ^ nh ₂ Formula X2

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a radical of formula XI.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a radical of formula X2.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is linked to the copolyamino acid via an amide function carried by the carbon in delta or epsilon position (or in position 4 or 5) with respect to the amide function (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a linear ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is an ether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is an ether radical comprising from 4 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a divalent alkyl radical comprising 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is an ether radical represented by the formula * [000125] In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a polyether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms .

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below:

* Formula X3 * Formula X4 0 Formula X5 * Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a radical of formula X3.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a radical of formula X4.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas X5 and X6 below :

* s • k Formula X5 * O Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a polyether radical of formula X5.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V is a radical in which R is a polyether radical of formula X6.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 12 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 atoms of carbon.

[000137] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 4 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 20 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising 2 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ΙΓ.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ΙΓ in which R is a divalent linear alkyl radical comprising from 1 to 11 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ΙΓ in which R is a divalent alkyl radical comprising from 1 to 6 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula Π in which R is a divalent alkyl radical comprising from 1 to 10 carbon atoms .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or II, in which R is a divalent alkyl radical, comprising of 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

[000145] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of • formula II, ΙΓ or Π, in which R is a divalent linear alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or Π in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:

★ Formula XI 0 ^ ' ^x nh ₂ ★ * Formula X2

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is a radical of formula XI.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is a radical of formula X2.

In one embodiment, the composition is characterized in that the radical R of GpRi is linked to the co-polyamino acid via an amide function carried by the carbon in delta or epsilon position (or in position 4 or 5) relative to the amide function (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or II, in which R is a linear ether or non-polyether radical substituted comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is an ether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is an ether radical comprising from 4 to 6 carbon atoms.

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising 6 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or Π in zX XX in which R is an ether radical represented by the formula [000155] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is a polyether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is a linear polyether radical comprising of 6 with 10 carbon atoms and 2 to 3 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II, ΙΓ or II, in which R is a polyether radical chosen from the group consisting of radicals represented by the formulas below:

Yr ο. Formula X3 * X * X *. Formula X4 * zv O. Z \ / ° xz JS. * Formula X5 * X XX X „x Q Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II, ΙΓ or 30 II, in which R is a radical of formula X3.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is a radical of formula X4.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II, ΙΓ or II, in which R is a radical of formula X5.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II, ΙΓ or Π, in which R is a radical of formula X6.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas X5 and X6 below:

* z ° \ . * .......... Formula X5 & O * Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II in which R is a polyether radical of formula X5.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II in which R is a polyether radical of formula X6.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 0 (a = 0) and r is equal to 0 (r = 0).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula III 'is chosen from the group consisting of the radicals represented by the formulas below:

* * Formula Yl ch ₃ M Formula Y2 Formula Y3 * * ★ * ch _{3 :} p ^X 'CH ₃ Formula Y4 H <C ^Z ch ₃ Formula Y5 Formula Y6 * * ★ * h ₃ ct h ₃ c ^ ^K ch ₃ Formula Y7 Formula Y8 Formula Y9

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula III 'is a radical of formula yl.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y2 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y3 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y4 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula III 'is a radical of formula Y5.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y6 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula III 'is a radical of formula Y7.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y8 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which a is equal to 1 (a = 1) and the GpA radical of formula ΙΙΓ is a radical of formula Y9 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc ci- after represented:

T-D o Formula IVa ⁰ Formula IVb Formula IVc

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical is of formula IVa.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, corresponding respectively to formulas IVd, IVe, and IVf below represented:

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical corresponds to formula IV or IVa in which b = 0, and corresponds to formula IVd .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV in which b = 1 is chosen from the group consisting of radicals in which B is an amino acid residue chosen from the group consisting of the radicals represented by the formulas below ·

* * * * ★ Formula Y1 ch ₃ ch ₃ Formula Y2 Formula Y3 * * * * T ch ₃ Formula Y4 5 H / T Formula Y5 CH ₃ : Formula Y6 • k ★ * * h * h ₃ ct Formula Y7 Formula Y8 Formula Y9

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV or IVa in which b = 1, is chosen from the group consisting of radicals in which B is an amino acid residue selected from the group consisting of radicals

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which C _x is chosen from the group consisting of linear alkyl radicals.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by branched alkyl radicals.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which C _x is chosen from the group consisting of alkyl radicals comprising between 11 and 14 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which C _x is chosen from the group consisting of the radicals represented by the formulas below:

'' '' 'CH- x = ll '· - ch ₃ x = 13

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which C _x is chosen from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by the radicals represented by the formulas below:

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by the radicals represented by the formulas below · çh ₃ x = 16 [000189] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula

IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 25 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which C _x is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals represented by the formulas below:

x = 17 [000192] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 25 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below rx = 19 x = 21 In one embodiment, the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which a = 1 and p = 2, represented by the following formula VI:

- ^ GpR —GpA — GpC ^ ^{r 2} Formula VI in which

GpR, GpA, GpC, r and a have the definitions given above.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent alkyl radical comprising 2 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.

[000202] In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent alkyl radical comprising from 1 to 10 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions ( -CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R of GpR if r = 1 or GpRl if r = 2 is a divalent linear alkyl radical, comprising of 2 with 5 carbon atoms and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a radical of formula XI.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a radical of formula X2.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R of GpR if r = 1 or of GpRl if r = 2 is linked to the co-polyamino acid via a function amide carried by the carbon in delta or epsilon position (or in position 4 or 5) with respect to the amide function (CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a linear ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is an ether radical.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is an ether radical comprising from 4 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a divalent alkyl radical comprising 6 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is an ether radical represented by the formula * *.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a polyether radical. In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms .

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below>

Q '' AA ^- * Formula X3 * Ά ΧθΑΧ ^ ΑΧ ^ Formula X4 * X - / θχ / Α Z \ / ⁰ A ^Z ' * Formula X5 * O * Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a radical of formula X3.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a radical of formula X4.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas X5 and X6 below :

* \ ζ / \ Α ^Ο Α ^Ζχ θ ^ ^{/ ΟχχζΖΧ /} * Formula X5 / A AA O. AA XA AA AA AA AA Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a polyether radical of formula X5.

In one embodiment, the composition is characterized in that the hydrophobic radical of formula VI is a radical in which R is a polyether radical of formula X6.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula IL [000224] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is an alkyl radical comprising from 2 to 4 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising 2 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ΙΓ.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ΙΓ in which R is a divalent linear alkyl radical comprising from 1 to 11 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ΙΓ in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula Π.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 1 to 10 atoms of carbon.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II, in which R is a divalent alkyl radical, comprising of 2 to 5 carbon atoms, and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or Π, in which R is a divalent linear alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II in which R is a radical chosen from the group consisting of the radicals represented by the formulas below;

i O ^ NHj Formula XI * * o ^ \ h ₂ Formula X2

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the amine function of the GpR radical engaged in the formation of the amide function which binds said GpR radical to the co-polyamino acid is carried by a carbon in the delta or epsilon position (or in the 4 or 5 position) relative to the amide function (-CONH2).

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II, in which R is a linear ether or non-polyether radical substituted comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula Π, ΙΓ or Π in which R is an ether radical.

In one embodiment, the composition is characterized ether radical R is a radical comprising from 4 to 6 carbon atoms.

In one embodiment, the composition is characterized in that the ether radical is * [000243] In one embodiment, the composition is characterized hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or Π, in which R is a polyether radical.

In one embodiment, the composition is characterized in that the in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II, in which R is a linear radical polyether comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or Π in which R is a linear polyether radical chosen from the group consisting of the radicals represented by the formulas below;

* Formula X3 Formula X4 * * (X -χθχ Formula X5 * o * Formula X6

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II in which R is a linear polyether radical of formula X3.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or Π in which R is a linear polyether radical of formula X4.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or Π in which R is a linear polyether radical of formula X5.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II, ΙΓ or II in which R is a linear polyether radical of formula X6 .

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula 10 III is chosen from the group consisting of radicals of formulas Ilia, Illb and IIIc ci -after represented: ________________

O : || * HN Ilia formula 0 * HN S Illb Formula JL / X * n 1 H _z NH ★ Formula IIIc

[000251] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula 15 III is a radical of formula Illb below represented:

In one embodiment, the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula III is a radical of formula IIIc.

[000253] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula

IV is chosen from the group consisting of the radicals of formulas IVa, IVb and IVc below represented: _____________________________________________

Formula IVa ⁰ Formula IVb Formula IVc

[000254] In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical is of formula IVa.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in 15 which b is equal to 0, corresponding respectively to formulas IVd, IVe, and IVf below represented; · __________________________________

O O vs, IC Ί Formula IVd O 0 * f J— N; Formula IVe

O o Formula IVf ^ N ^ Cx

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical corresponds to formula IV or IVa in which b = 0, and corresponds to formula IVd.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by linear alkyl radicals comprising between 9 and 15 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by branched alkyl radicals comprising between 9 and 15 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising 9 or 10 carbon atoms.

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 11 and 15 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by alkyl radicals comprising between 11 and 13 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting by the radicals represented by the formulas below:

x = 9 x = 11 V ^ _C H ₃ x = 13

In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which C _x is chosen from the group consisting of alkyl radicals comprising 14 or 15 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula

IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of radicals represented by the formula below:

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII below:

O

^Hy formula VII in which, • D independently represents either a -CHz- group (aspartic unit) or a -CH2-CH2- group (glutamic unit), • Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, • Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, or a radical chosen from the group consisting of a

H, a linear C ₂ to C ₁₀ acyl group, a branched C3 to C ₁₀ acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate, • R ₂ is a hydrophobic radical chosen from the hydrophobic radicals of formulas I , V or VI, or a radical -NR'R, R 'and R''identical or different being chosen from the group consisting of H, linear or branched or cyclic C ₂ to C ₁₀ alkyl, benzyl and said R' and R alkyls which can together form one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, N and S, • X represents an H or a cationic entity chosen from the group comprising metal cations;

• n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of copolyamino acid and 5 <n + m <250.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII below

formula VII in which, • D represents, independently, either a group -CH ₂ - (aspartic unit) or a group -CH ₂ -CH ₂ - (glutamic unit), • Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, • Ri is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI, or a radical chosen from the group consisting of an H, a linear C ₂ to C ₁₀ acyl group, an acyl group branched at C3 to Cio, a benzyl, a terminal "amino acid" unit and a pyroglutamate, • Rz is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI in which r = 1 or 2 and GpR is a radical of Formula II, or a radical -NR'R, R 'and R identical or different being chosen from the group consisting of H, linear or branched or cyclic C2 to C10 alkyl, benzyl and said R' and R alkyl which may together form one or more saturated, unsaturated and / or aromatic carbon rings atics and / or possibly comprising heteroatoms, chosen from the group consisting of O, N and S, • at least one of Ri or R2 is a hydrophobic radical as defined above, • X represents an H or a chosen cationic entity in the group comprising metal cations;

• n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of copolyamino acid and 5 <n + m <250.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of Ri or R2 is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of the Ri or R2 is a hydrophobic radical of formula VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of the Ri or R2 is a hydrophobic radical of formula VI, and Hy is a radical of formula VI, in which r = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of Ri or R2 is a hydrophobic radical of formula VI, and Hy is a radical of formula VI, in which r = 1.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of Ri or Rz is a hydrophobic radical of formula VI, and Hy is a radical of formula VI, in which r = 2.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, in which at least one of the Ri or R2 is a hydrophobic radical of formula VI, in which r = 1, and for GpC, b = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, in which at least one of the Ri or R2 is a hydrophobic radical of formula VI, in which r = 2, and for GpC, b = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri is a hydrophobic radical of formula VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri is a hydrophobic radical of formula VI and R2 is a radical -NR'R, R 'and R being as defined above.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri is a hydrophobic radical of formula VI and R.2 is a radical -NR'R, R 'and R being as defined above, and Hy is a radical of formula VI, in which r = l.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, In one embodiment, the composition according to the invention is characterized in that the copolyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri is a hydrophobic radical of formula VI and Rz is a radical -NR'R , R 'and R being as defined above, and Hy is a radical of formula VI, in which r = 1, and for GpC, b = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri is a hydrophobic radical of formula VI and Rz is a radical -NR'R, R 'and R being as defined above, and Hy is a radical of formula VI, in which r = 2.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, In one embodiment, the composition according to the invention is characterized in that the copolyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri is a hydrophobic radical of formula VI and Rz is a radical -NR'R , R 'and R being as defined above, and Hy is a radical of formula VI, in which r = 2, and for GpC, b = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Rz is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Rz is a hydrophobic radical of formula VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Rz is a hydrophobic radical of formula VI and Ri is a radical -NR'R, R 'and R being as defined above.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Rz is a hydrophobic radical of formula VI and Ri is a radical -NR'R, R 'and R being as defined above, and Hy is a radical of formula VI, in which r = l.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Rz is a hydrophobic radical of formula VI and Ri is a radical -NR'R, R 'and R being as defined above, and Hy is a radical of formula VI, in which r = l, and for GpC, b = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and Rz is a radical hydrophobic of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and Rz is a radical hydrophobic of formula VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and Rz is a radical hydrophobic of formula VI, and Hy is a radical of formula VI, in which r = l.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and Rz is a radical hydrophobic of formula VI, and Hy is a radical of formula VI, in which r = 1, and for GpC, b = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Rz is a hydrophobic radical of formula I, V or VI in which r = 1 and GpR is of Formula IL [000290] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Rz is a hydrophobic radical of formula VI in which r = 1 and GpR is of Formula II.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which R2 is a hydrophobic radical of formula VI in which r = 1, GpR is of Formula II and GpC is of formula IV in which b = 0, c = 0 and d = l.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which R2 is a hydrophobic radical of formula VI in which r = 1, GpR is of Formula II and GpC is of formula IV in which b = 0, c = 0, d = l and x = 13.

In one embodiment, the composition according to the invention is characterized in that when the co-polyamino acids comprises aspartate units, then the co-polyamino acids may also comprise monomeric units of formula VIII and / or VIII ' :

Formula VIII

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII below:

formula VII in which, • D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, • Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, or a radical chosen from the group consisting of an H, a linear acyl group in C2 to Cio, a branched acyl group in C3 to Cio, a benzyl, a terminal “amino acid” unit and a pyroglutamate, • R2 is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI, or a radical -NR'R, R 'and R identical or different being chosen from the group consisting of H, linear or branched or cyclic C 1 to C 10 alkyl, benzyl and said R ′ and R alkyl which may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may comprise heteroatoms, chosen from gr oupe consisting of O, N and S;

• at least one of Ri or Rz is a hydrophobic radical as defined above, • X represents a cationic entity chosen from the group comprising alkaline cations;

• n> 1 and n + m represents the degree of polymerization DP of the copolyamino acid, that is to say the average number of monomeric units per chain of co-polyamino acid and 5 <n + m <250;

The co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula I can also be called "co-polyamino acid" in the present description.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1 and at least one of Ri or R2 is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1 and Ri is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1 and R ₂ is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1, Ri is a hydrophobic radical of formula I, V or VI in which r = 0.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula formula VII in which n> 1, R ₂ is a hydrophobic radical of formula I, V or VI in which r = 1 or 2 and GpR is of Formula II.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1, R ₂ is a hydrophobic radical of formula VI in which r = 1 or 2 and GpR is of Formula II.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1, R ₂ is a hydrophobic radical of formula VI in which r = 1 or 2, GpR is of Formula II and GpC is of formula IV.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1, R ₂ is a hydrophobic radical of formula VI in which r = 1 or 2, GpR is of Formula II and GpC is of formula IV in which b = 0, c = 0 and d = l.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n> 1, R ₂ is a hydrophobic radical of formula VI in which r = 1 or 2, GpR is of Formula II and GpA is of formula IV in which b = 0, c = 0, d = l and x = 13.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula VI in which r = 0.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula VI in which r = 0, and GpC is of formula IV.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula VI in which r = 0, and GpC is of formula IV with b = 0, c = 0 and d = 1.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula VI in which r = 0, and GpC is of formula IV with b = 0, c = 0, d = l and x = 13.

Called "defined co-polyamino acid" a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula Vllb.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n = 0 of formula Vllb below:

R.

Formula Vllb in which m, X, D, Ri and Rz have the definitions given above and at least

Ri or Rz is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which n = 0 of formula Vllb and Ri or R2 is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which at least one of the Ri or R2 is a hydrophobic radical of formula VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula VI and R2 is a radical -NR'R, R 'and R being as defined above.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which Ri is a hydrophobic radical of formula VI and R2 is a radical -NR'R, R 'and R being as defined above.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri is a hydrophobic radical of formula VI in which r = 1 or 2, and for GpC, b = 0 and R2 is a radical -NR'R, R 'and R being as defined above.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which R2 is a hydrophobic radical of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which R2 is a hydrophobic radical of formula VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which R2 is a hydrophobic radical of formula VI and Ri is a radical chosen from the group consisting of an H, a linear C2 to Cio acyl group, a branched C3 to Cio acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which R2 is a hydrophobic radical of formula VI in which r = 0 and Ri is a radical chosen from the group consisting of an H, a linear C2 to Cio acyl group, a branched C3 to Cio acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vllb in which R2 and Hy are radicals hydrophobes of formula VI in which r = 0, and for GpC, b = 0 and Ri is a radical chosen from the group consisting of an H, a linear C2 to Cio acyl group, a branched C3 to Cio acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and R2 are radicals hydrophobes of formula I, V or VI.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and R2 are radicals hydrophobes of formula VL [000323] In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and R2 are hydrophobic radicals of formula VI, in which r = 1 or 2 and GpR of formula II for R2 and r = 0 for Ri.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which Ri and

R2 are hydrophobic radicals of formula VI, GpA = 0 and b = 0, and in which r = 1 or 2 and GpR of formula II for R2 and r = 0 for Ri.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula Vlib in which Ri is a hydrophobic radical of formula I, V or VI in which r = 0 or r = 1 or r = 2 and GpR is of Formula ΙΓ or Π.

iO [000326] In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas Vlib in which R2 is a hydrophobic group of formula I, V or VI in which r = 1 or II and GpR is of Formula II. In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which R2 is a hydrophobic radical, in particular with n> 1, or Vlib in which R1 is a radical chosen from the group consisting of a linear C2 to C10 acyl group, a branched C3 to Cw acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which R2 is a hydrophobic radical, in particular with n> 1, or Vlib in which R 1 is a radical chosen from the group consisting of a linear C2 to C10 acyl group or a branched C3 to Cio acyl group.

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of Ri or

Rz is a hydrophobic radical, in particular with n> 1, or Vlib in which the group D is a group -CH2- (aspartic unit).

In one embodiment, the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of at least one of the Ri or R? is a hydrophobic radical, in particular with n> 1, or Vlib in which the group D is a group -CH2-CH2- (glutamic unit).

In one embodiment, the composition is characterized in that the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.

In one embodiment, the composition is characterized in that the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.

In one embodiment, the composition is characterized in that the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.3.

In one embodiment, the composition is characterized in that the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 3.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.05 and 0.2 .

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 15.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.1.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the Cx radical comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.05 and 0.3.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the Cx radical comprises between 9 5 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.15.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the C _x radical comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the iO number of glutamic or aspartic units is between 0.05 and 0.2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the C _x radical comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the Cx radical comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0.1.

[000345] In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical C _x comprises between and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the C _x radical comprises between 25 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.15.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the C _x radical comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the The number of glutamic or aspartic units is between 0.01 and 0.1.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the C _x radical comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.06.

In one embodiment, the composition is characterized in that the hydrophobic radicai corresponds to formula V and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 3.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.05 and 0.3.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.1 and 0.3.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0, 2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 11 and 14 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.1 and 0.3.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 11 and 14 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.1 and 0.2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.06 and 0.2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.15.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 17 and 18 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 17 and 18 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.15.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 17 and 18 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.06.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.1.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.06.

In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the Cx radical comprises between 19 and 25 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.05.

In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 250.

In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 200.

In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 100.

In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 50.

In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 150.

In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 100.

In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 80.

In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 65.

In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 60.

In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 50.

In one embodiment, the composition according to the invention is characterized in that n + m is between 20 and 40.

The invention also relates to said co-polyamino acids carrying carboxylate charges and hydrophobic radicals of formula I and the precursors of said hydrophobic radicals.

The co-polyamino acids carrying carboxylate charges and hydrophobic radicals of formula I are soluble in distilled water at a pH between 6 and 8, at a temperature of 25 ° C and at a concentration of less than 100 mg / ml.

In one embodiment, the invention also relates to the precursors of said hydrophobic radicals of formula Γ, V 'and VI':

h ^ g _p rUgpa) - (gpc) rap

H- (GPR) - (GpA) -Gpc _{formu, eV.}

r a ~ ^ GpR j — GpA — Gpcj formula VI '

GpR, GpA, GpC, r, a, p have the definitions given above.

The invention further relates to a method for preparing stable injectable compositions.

[000380] The term "soluble" is intended to make it possible to prepare a clear solution devoid of particles at a concentration of less than 100 mg / ml in distilled water at 25 ° C.

The term “solution” means a liquid composition devoid of visible particles, using the procedure in accordance with pharmacopoeias EP 8.0, in point 2.9.20, and US <790>.

The term “physically stable composition” is understood to mean compositions which, after a certain period of storage at a certain temperature, satisfy the criteria of visual inspection described in the European, American and international pharmacopoeia, that is to say, compositions which are clear and which contain no visible particles, but which are also colorless.

The term “chemically stable composition” is intended to mean compositions which, after storage for a certain time and at a certain temperature, have a minimum recovery of the active ingredients and comply with the specifications applicable to pharmaceutical products.

[000384] A conventional method for measuring the stability of proteins or peptides consists in measuring the formation of fibrils using Thioflavin T, also called ThT. This method makes it possible to measure, under temperature and agitation conditions which allow the phenomenon to accelerate, the latency time before the formation of fibrils by measuring the increase in fluorescence. The compositions according to the invention have a latency time before the formation of fibrils markedly greater than that of glucagon at the pH of interest.

The term "injectable aqueous solution" means water-based solutions which meet the conditions of the EP and US pharmacopoeias, and which are sufficiently liquid to be injected.

The term “co-polyamino acid consisting of glutamic or aspartic units” is understood to mean non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a terminal C portion, corresponding to the carboxylic acid at one end, and an N-terminal part, corresponding to the amine at the other end of the chain.

The term "alkyl radical" means a carbon chain, linear or branched, which does not include a heteroatom.

[000388] The co-polyamino acid is a statistical or block co-polyamino acid.

[000389] The co-polyamino acid is a statistical co-polyamino acid in the chain of glutamic and / or aspartic units.

In the formulas the * indicate the sites of attachment of the different elements represented.

In formulas I, V and VI, the * indicate the sites of attachment of hydrophobic radicals to the co-polyamino acid. The Hy radicals are attached to the copolyamino acid via amide functions.

In formulas II and ΙΓ, the * indicate, from left to right respectively, the attachment sites of GpR:

to the co-polyamino acid and to GpR if r = 2 or to GpA if a = 1 or to GPC if a = 0.

In formulas III and HT, the * indicate, from left to right respectively, the GpA attachment sites:

- to GpR if r = 1 or 2 or to the co-polyamino acid if r = 0 and to GpC.

In formula IV, the * indicates the GpC attachment site:

to GpA if a = 1, GpR if r = 1 or 2 and a = 0 or to the co-polyamino acid if r = 0 and a = 0.

All the connections between the different GpR, GpA and GpC groups are amide functions.

The radicals Hy, GpR, GpA, GpC, and D are each independently identical or different from one monomer unit to another.

When the co-polyamino acid comprises one or more aspartic unit (s), it (s) can (undergo) t undergo structural rearrangements.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acids can also comprise monomeric units of formula VIII and / or VIII ':

Formula VIII '[000399] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1,

GpR corresponds to formula II in which R is -CH2-CH2-, GpC corresponds to formula IVd in which x = 15 and C _x is [000400] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is -CH2-CH2-, GpC corresponds to formula IVd

ÇH ₃ in which x = 16 and Cx is ^ ^H 3.

In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p - 1, GpR corresponds to formula II in which R is *, _G p _C corresponds to formula IVd in which x = 15 and Cx is [000402] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is * .O.

, GpC corresponds to formula IVd in which x = 15 and Cx is Ύ [000403] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1,

hydrophobic radical of [000404] In one embodiment, the at least one formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is o corresponds to formula IVd in which x = [000405] In one embodiment, the at least one radical formula I is chosen from the radicals of formula I in which, r = which ^v , GpC and Cx is

GpR corresponds to formula II in * Y. X hydrophobic of

1, a = 0, p = 1,

R is which, GpC responds to formula IVd in

Cx is ch ₃ [000406] In one embodiment, the at least one radical formula I is chosen from the radicals of formula I in which, r = GpR corresponds to formula II in which R is -CH2-CH2-, GpC meets the hydrophobic formula IVa of

1, a = 0, p = 1,

and Cx is [000407] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, iO

GpR corresponds to formula II in which R is -CH2-CH2-, GpC corresponds to formula IVa

In one embodiment, the formula I is chosen from the radicals of formula GpR corresponds to formula II *, 0. / O. x \ ^ * which and Cx is less a hydrophobic radical of in which, r = 1, a = 0, p = 1, in which R is

GpC responds to formula IVf in ch ₃

Cx is [000409] In one embodiment, the at least one radical formula I is chosen from the radicals of formula I in which, r = GpR corresponds to formula II in which R is -CH2-CH2-, GpC corresponds to the formula IVd in which x = 13 and / ^CH 3 hydrophobic of

1, a = 0, p = 1,

Cx is hydrophobic

1, a = 1, p = 2, [000410] In one embodiment, the at least one radical formula I is chosen from the radicals of formula I in which, r = GpR corresponds to formula II in which R is - CH2-CH2-, GpA corresponds to the formula IIIb, GpC corresponds to the formula IVd in which x = 9 and Cx is / K x \ / K / CH ₃ [000411] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r - 1, a = 1, p = 2,

GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to formula IIIb, and Cx is

GpC corresponds to formula IVd in which x

In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2,

GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to formula IIIb,

GpC corresponds to formula IVd in which x = 13 and C _x is [000413] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is o, GpA corresponds to formula Illb, GpC corresponds to formula IVd in which x = 13 and Cx is ^ CH ₃ [000414] In one embodiment , the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to the formula Illb, GpC corresponds to the formula IVd in which x = 15 and C _x is [000415] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to formula Ilia, GpC corresponds to formula IVd in which x = 13 and C _x is [000416] In one embodiment, the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p ~ 2, GpR responds to the formula II in which R is - (CH2) e-, GpA corresponds to the formula Illb, GpC corresponds to the formula IVd in which x = 15 and C _x is [000417] The values of degree of polymerization DP and of ratio i are estimated by ¹ H NMR in D2O by comparing the integration of the signals from the hydrophobic groups with that of the signals from the main chain of the copolyamino acid.

In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or

Vllb, in which DP = 25 +/- 5, 0.033 <i <0.05 and the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is -CH2-CH2-, GpC corresponds to formula IVd in which x = 15 and Cx is [000419] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP - 30 +/- 5, 0.028 <i <0.04 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is o * _; gp £ corresponds to formula IVd in which x = 17 and C _x is [000420] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP = 45 +/- 10, 0.018 <i <0.028 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR responds to the formula II in which R is *, GpC corresponds to the formula IVd in which x = 17 and C _x is [000421] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or

Vllb, in which DP - 60 +/- 10, 0.014 <i <0.02 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a - 0, p = 1, GpR corresponds to formula II in which R is GpC _r £ p _Onc | £ | _has formula ivd in which x = 17 and C _x is XXxXXXX ^ XXX ^ XXXX ^ CHa ^

In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP = 25 +/- 5, 0.033 <i <0.05 and the hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is X ^ o, GpC corresponds to formula IVd in which x - 19 and

Cx is [000422] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP = 25 +/- 5, 0.025 <i <0, 07 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 0, p = 1, GpR corresponds to formula II in which R is o ζ GpC corresponds to the formula IVd in which x = 19 and C _x is [000423] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP = 27 + / - 5, 0.031 <i <0.045 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to the formula Illb, GpC corresponds to the formula IVd in which x = 11 and Cx is

In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP = 22 +/- 5, 0.037 <i <0.055 and the at at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to the formula Illb, GpC corresponds to formula IVd in which x = 13 and Cx is

In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or

Vllb, in which DP = 22 +/- 5, 0.037 <i <0.055 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r - 1, a = 1, p = 2, GpR corresponds to formula II in which R is

O _; GpA corresponds to the formula Illb, GpC and C _x is corresponds to the formula IVd in which x = 13

CH [000426] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VH or Vlib, in which DP - 60 +/- 10, 0.014 <i <0.02 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA has the formula Hlb, GpC has the formula IVd in which x = 13 and C _x is

In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vlib, in which DP = 40 +/- 5, 0.022 <i <0.029 and the at at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to the formula Hlb, GpC corresponds to formula IVd in which x = 13 and C _x is

[000428] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vlib, in which DP = 25 +/- 5, 0.02 <i <0, 06 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r - 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA responds to the IHb, GpC responds to the formula IVd in which x = 13 and xx x ^ x xx x ~ x / ^CH 3 formula

C _x is [000429] In one embodiment, the co-polyamino acid carrying carboxylates and hydrophobic radicals is a co-polyamino acid of formula VII or Vlib, in which DP = 17 +/- 4, 0.04 <i < 0.1 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2 -, GpA responds to Hlb, GpC responds to formula IVd in which x = 13 and x- ^ x ^ xx ^ x XX X ^ X ^ ^CH 3 charges formula

C _x is charges [000430] In one embodiment, the co-polyamino acid carrying carboxylates and hydrophobic radicals is a co-polyamino acid of formula VII or Vlib, in which DP = 9 +/- 2, 0.09 <i <0.2 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2- CH2-, GpA corresponds to the formula nib, GpC corresponds to the formula IVd in which x = 13 and Cx is

ZK / X XX XX XX XX / ^ch 3 [000431] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP = 20 +/- 5, 0.04 <i <0.08 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p =

2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to formula

Illb, GpC corresponds to the formula IVd in which x = 13 and Cx is

XX XX XX XX XX XX z ^ffl 3 [000432] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or

Vllb, in which DP = 23 +/- 5, 0.035 <i <0.08 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p =

2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to formula

Illb, GpC corresponds to formula IVd in which x and Cx is [000433] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP = 20 +/- 5, 0.04 <i <0.08 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR responds to formula II in which R is -CH2-CH2-, GpA corresponds to IIIc, GpC corresponds to formula IVd in which x = 13 and

XX XX XX XX XX XX ^ ^ch 3 formula

Cx is charged [000434] In one embodiment, the co-polyamino acid carrying carboxylates and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP = 20 +/- 5, 0.04 <i < 0.08 and Hy, as well as Ri and / or R2 is a hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to the formula IIIb, GpC corresponds to the formula IVd in which x = 13 and Cx is

XX XX XX XX XX ZX / ^ch 3 [000435] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or VIIb, in which DP - 20 +/- 5 , 0.04 <i <0.08 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 0, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to the formula

Ilib, GpC corresponds to formula IVd in which x = 13 and Cx is / K ^ ^CH 3 [000436] In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP = 20 +/- 5, 0.08 <i <0.20 and Ri is a hydrophobic radical of formula I chosen from the radicals of formula I in which, r = 0, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to formula IIIb, GpC corresponds to formula IVd in which x = 13 and Cx is / ' ^CH3 _and r _{2 a rac} ji _ca | hydrophobic of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is -CH2-CH2-, GpA corresponds to formula Ilib, GpC corresponds to the formula IVd in which x = 13 and Cx is

In one embodiment, the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or Vllb, in which DP = 25 +/- 5, 0.035 <i <0.08 and the at least one hydrophobic radical of formula I is chosen from the radicals of formula I in which, r = 1, a = 1, p = 2, GpR corresponds to formula II in which R is - (CH2) e-, GpA meets the formula Ilib and Cx is

GpC corresponds to the formula IVd in which x = 14

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid comes from a polyamino acid obtained by polymerization.

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid as described in the review article Adv. Polym. Sci. 2006, 202, 1-18 (Deming, T.J.).

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid chosen from the group consisting with methyl N-carboxyanhydride glutamate (GluOMe-NCA), benzyl Ncarboxyanhydride glutamate (GluOBzl-NCA) and N-carboxyanhydride t-butyl glutamate (GluOtBu-NCA).

In one embodiment, the N-carboxyanhydride derivative of glutamic acid is N-carboxyanhydride L-methyl glutamate (L-GluOMe-NCA).

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using as an initiator an organometallic complex of a transition metal as described in the publication Nature 1997, 390, 386-389 (Deming, TJ).

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using ammonia or a primary amine as initiator as described in patent FR 2,801,226 (Touraud, F.; et al.) and the references cited by this patent.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a N-carboxyanhydride derivative of glutamic acid or a derivative of N-carboxyanhydride of aspartic acid using as initiator hexamethyldisilazane as described in the publication J. Am. Chem. Soc. 2007, 129, 14114-14115 (Lu H.; et al.) Or a silylated amine as described in the publication J. Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H.; et al.).

In one embodiment, the composition according to the invention is characterized in that the process for the synthesis of the polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid from which the co-polyamino acid is derived comprises a step of hydrolysis of ester functions.

In one embodiment, this step of hydrolysis of ester functions may consist of a hydrolysis in an acid medium or a hydrolysis in a basic medium or be carried out by hydrogenation.

In one embodiment, this step of hydrolysis of ester groups is a hydrolysis in an acid medium.

In one embodiment, this step of hydrolysis of ester groups is carried out by hydrogenation.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid comes from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight.

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight.

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

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on an acid poly-L-glutamic acid or poly-L-aspartic acid using methods of amide bond formation well known to those of skill in the art.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on an acid poly-L-glutamic acid or poly-L-aspartic acid using the methods of amide bond formation used for peptide synthesis.

In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on a poly-L-glutamic acid or poly-L-aspartic acid as described in patent FR 2,840,614 (Chan, YP; et al.).

In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 40 mg / ml. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 30 mg / ml. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 20 mg / ml. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 10 mg / ml. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 5 mg / ml.

In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 2.5 mg / ml. In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 1 mg / ml.

In one embodiment, the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 0.5 mg / ml.

In one embodiment, the co-polyamino acid mass ratio carrying carboxylate charges and hydrophobic radicals on glucagon is between 1.5 and 25.

In one embodiment, the co-polyamino acid mass ratio carrying carboxylate charges and hydrophobic radicals on glucagon is between 2 and 20.

In one embodiment, the co-polyamino acid mass ratio carrying carboxylate charges and hydrophobic radicals on glucagon is between 2.5 and 15.

In one embodiment, the co-polyamino acid mass ratio carrying carboxylate charges and hydrophobic radicals on glucagon is between 2 and 10.

In one embodiment, the co-polyamino acid mass ratio carrying carboxylate charges and hydrophobic radicals on glucagon is between 2 and 7.

Human glucagon is used in dosages which vary according to the applications.

In emergency treatment of hypoglycaemia the recommended dosage is 1 mg intramuscularly or intravenously (0.5 mg if the body mass is less than 25 kg). This administration is carried out with a solution of human glucagon at the concentration of 1 mg / ml.

In pumps, the daily dose envisaged is approximately 0.5 mg, the solutions can thus comprise from 0.25 mg / ml to 5 mg / ml of human glucagon.

According to one embodiment, the solutions can comprise from 0.5 mg / ml to 3 mg / ml of human glucagon.

In the treatment of obesity the daily dose envisaged is approximately 0.5 mg, the solutions can thus comprise from 0.25 mg / ml to 5 mg / ml of human glucagon.

In one embodiment, between 0.25 and 5 mg / ml.

In one embodiment, between 0.5 and 4 mg / ml.

In one embodiment, between 0.75 and 3 mg / ml.

In one embodiment, between 0.75 and 2.5 mg / ml.

In one embodiment, between 0.75 and 2 mg / mL.

In one embodiment, the the the the the concentration the concentration concentration concentration concentration concentration concentration in en in en in glucagon glucagon glucagon glucagon glucagon glucagon human human human human human human human human is is is is is between 1 and 2 mg / mL.

In one embodiment, the ratio molar [radical hydrophobic] / [human glucagon] is less than 20. [000487] In one embodiment, hydrophobic] / [human glucagon] is less than 15. the ratio molar [radical [000488] In one embodiment, hydrophobic] / [human glucagon] is less than 10. the ratio molar [radical [000489] In one embodiment, hydrophobic] / [human glucagon] is less than 5. the ratio molar [radical In one embodiment, hydrophobic] / [human glucagon] is less than 2.5. the ratio molar [radical In one embodiment, hydrophobic] / [human glucagon] is less than 1.5. the ratio molar [radical

In one embodiment, the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 20.

In one embodiment, the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 15.

In one embodiment, the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 10.

In one embodiment, the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 5.

In one embodiment, the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 2.5.

In one embodiment, the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 1.5.

[000498] Human glucagon is a highly conserved polypeptide comprising a single chain of 29 amino acid residues having the following sequence HHis-Ser-GIn-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Phe-GInAsp-Val-Gln-Trp-Leu-Met-Asn-Thr-OH.

[000499] It can be obtained in various ways, by peptide synthesis by recombination.

Human glucagon is available from many sources. For example, it may be human glucagon produced by Bachem via peptide synthesis, in particular under the reference 407473.

In one embodiment, the composition further comprises a nicotinic compound or one of its derivatives.

[000502] In one embodiment, the composition comprises nicotinamide.

In one embodiment, the concentration of nicotinamide ranges from 10 to

160 mM.

In one embodiment, the concentration of nicotinamide ranges from 20 to 150 mM.

In one embodiment, the concentration of nicotinamide ranges from 40 to 120 mM.

In one embodiment, the concentration of nicotinamide ranges from 60 to

100 mM.

In one embodiment, the composition further comprises a polyanionic compound.

In one embodiment, the polyanionic compound is chosen from the group consisting of polycarboxylic acids and their Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, the carboxylic polyaclde is chosen from the group consisting of citric acid, tartaric acid, and their Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, the polyanionic compound is chosen from the group consisting of phosphoric polyacids and their Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, the phosphoric polyaclde is triphosphate and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, the polyanionic compound is citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, the polyanionic compound is tartaric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, the polyanionic compound is triphosphoric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, is between 1 and 20 mM.

In one embodiment, is between 2 and 15 mM.

In one embodiment, is between 3 and 12 mM.

Is 10

In mM.

I is 5 mM.

In la la une one mode of concentration mode concentration concentration in in embodiment, embodiment, the concentration concentration in polyanionic compound polyanionic compound polyanionic compound polyanionic compound polyanionic compound [000520] is 10

In one embodiment, the concentration of polyanionic compound mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml.

Is 10

In one embodiment, the concentration of polyanionic compound mM for glucagon concentrations of between 0.5 mg / ml and 2 mg / ml.

In one embodiment, the concentration of polyanionic compound is 10 mM for concentrations of glucagon of between 1 mg / ml and 2 mg / ml.

In one embodiment, the concentration of polyanionic compound is 5 mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml.

In one embodiment, the concentration of polyanionic compound is 5 mM for glucagon concentrations of between 0.5 mg / ml and 2 mg / ml.

In one embodiment, the concentration of polyanionic compound is 5 mM for concentrations of glucagon of between 1 mg / ml and 2 mg / ml.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is between 1 and 20 mM.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is between 2 and 15 mM.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is between 3 and 12 mM.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 10 mM.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 5 mM.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 10 mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 10 mM for glucagon concentrations of between 0.5 mg / ml and 2 mg / ml.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 10 mM for glucagon concentrations of between 1 mg / ml and 2 mg / ml.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 5 mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 5 mM for glucagon concentrations of between 0.5 mg / ml and 2 mg / ml.

In one embodiment, the concentration of citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts is 5 mM for glucagon concentrations of between 1 mg / ml and 2 mg / ml.

In one embodiment, the pharmaceutical composition also comprises at least one absorption promoter chosen from absorption promoters, diffusion promoters or vasodilators, alone or as a mixture.

Absorption promoters include, without limitation, surfactants, for example, bile salts, salts of fatty acids or phospholipids; nicotinic agents, such as nicotinamides, nicotinic acids, niacin, niacinamide, vitamin B3 and their salts; pancreatic trypsin inhibitors; magnesium salts; polyunsaturated fatty acids; ie didecanoyl phosphatidylcholine; aminopolycarboxylates; tolmetin; sodium caprate; salicylic acid; oleic acid; linoleic acid; eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA); benzylic acid; nitric oxide donors, for example, 3- (2-Hydroxy-1- (1-methylethyl) -2-nitrosohydrazino) -lpropanamine, N-ethyl-2- (1-ethyl-hydroxy-2- l-nitrosohydrazino) -ethanamine, or S-nitroso-N-acetylpenicillamine; bile acids, glycine in its form conjugated with a bile acid; sodium ascorbate, potassium ascorbate; sodium salicylate, potassium salicylate, acetylsalicylic acid, salicylosalicylic acid, aluminum acetylsalicylate, choline salicylate, salicylamide, lysine acetylsalicylate; exalamide; diflunisal; ethenzamide; EDTA; alone or as a mixture.

In one embodiment, the pharmaceutical composition also comprises at least one diffusion promoter. Examples of diffusion promoters include, but are not limited to, glycosaminoglycanases, for example hyaluronidase.

In one embodiment, the pharmaceutical composition also comprises at least one vasodilator.

In one embodiment, the pharmaceutical composition further comprises at least one vasodilator causing hyperpolarization by blocking the calcium ion channels.

In one embodiment, the vasodilator causing hyperpolarization by blocking the calcium ion channels is adenosine, a hyperpolarizing agent derived from the endothelium, a phosphodiesterase type 5 inhibitor (PDE5), a potassium channel opening agent or any combination of these agents.

In one embodiment, the pharmaceutical composition further comprises at least one vasodilator agent mediated by cAMP.

In one embodiment, the pharmaceutical composition also comprises at least one vasodilator agent mediated by cGMP.

In one embodiment, the pharmaceutical composition also comprises at least one vasodilating agent chosen from the group comprising vasodilating agents which act by causing hyperpolarization by blocking calcium ion channels, vasodilator agents mediated by cAMP, and cGMP mediated vasodilators.

The at least one vasodilator is chosen from the group comprising, nitrogen monoxide donors, for example, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, amyl nitrate, erythrityl, tetranitrate, and nitroprusside); prostacyclin and its analogs, for example sodium epoprostenol, iloprost, epoprostenol, treprostinil or selexipag; histamine, 2methylhistamine, 4-methylhistamine; 2- (2-pyridyl) ethylamine, 2- (2thiazolyl) ethylamine; papaverine, papaverine hydrochloride; minoxidil; dipyridamole; hydralazine; adenosine, adenosine triphosphate; uridine trisphosphate; GPLC; L-carnitine; arginine; prostaglandin D2; potassium salts; and in some cases, the al and a2 receptor antagonists, for example, prazosin, phenoxybenzamine, phentolamine, dibenamine, moxisylyte hydrochloride and tolazoline), betazole, dimaprit; β2 receptor agonists, for example, isoproterenol, dobutamine, albuterol, terbutaline, aminophylline, theophylline, caffeine; alprostadil, ambrisentan; cabergoline; diazoxide; dihydralazine mesilate; diltiazem hydrochloride; enoximone; flunarizine hydrochloride; Ginkgo biloba extract; levosimendan; molsidomine; naftidrofuryl acid oxalate; nicorandil; pentoxifylline; phenoxybenzamine chloride; base piribedil; piribedil mesilate; regadenoson monohydrate; riociguat; sildenafil citrate, tadalafil, vardenafil hydrochloride trihydrate; trimetazidine hydrochloride; trinitrine; verapamil hydrochloride; endothelin receptor antagonists, for example avanafil and bosentran monohydrate; and calcium channel blockers, for example, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, lacidipine, lercanidipine , manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, prandipine; alone or as a mixture.

In one embodiment, the composition comprises in combination a polyanionic compound and an absorption promoter.

In one embodiment, the composition comprises in combination citric acid and / or its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts and an absorption promoter.

In one embodiment, the polyanionic compound is citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts.

In one embodiment, the compositions according to the invention also comprise a gastrointestinal hormone.

The term "gastrointestinal hormones" means the hormones chosen from the group consisting of GLP-1 RA for agonists of the human Glucagon receptor-Like Peptide-1 (Glucagon like peptide-1 receptor agonist) Glucagon like) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of human proglucagon), peptide YY, amamyin, cholecystokinin, pancreatic polypeptide (PP), ghreline and enterostatin, their analogs or derivatives and / or their pharmaceutically acceptable salts.

In one embodiment, the gastrointestinal hormones are analogs or derivatives of GLP-1 RA (Glucagon like peptide-1 receptor agonist) chosen from the group consisting of exenatlde or Byetta® (ASTRA-ZENECA) , liraglutide or Victoza® (NOVO NORDISK), lixisenatide or Lyxumia® (SANOFI), albiglutide or Tanzeum® (GSK) or dulaglutide or Truiicity® (ELI LILLY & CO), their analogs or derivatives and their pharmaceutically salts acceptable.

[000553] In one embodiment, the gastrointestinal hormone is ie pramlintide or Symlin® (ASTRA-ZENECA).

In one embodiment, the gastrointestinal hormone is exenatlde or Byetta® its analogs or derivatives and their pharmaceutically acceptable salts.

In one embodiment, the gastrointestinal hormone is liraglutide or Victoza® its analogs or derivatives and their pharmaceutically acceptable salts.

In one embodiment, the gastrointestinal hormone is lixisenatide or Lyxumia® its analogs or derivatives and their pharmaceutically acceptable salts.

In one embodiment, the gastrointestinal hormone is albiglutide or Tanzeum® its analogs or derivatives and their pharmaceutically acceptable salts.

In one embodiment, the gastrointestinal hormone is dulaglutide or Trulicity® its analogs or derivatives and their pharmaceutically acceptable salts.

[000559] In one embodiment, the gastrointestinal hormone is pramlintide or Symlin®, its analogs or derivatives and their pharmaceutically acceptable salts.

The term “analog” is understood to mean, when used with reference to a peptide or a protein, a peptide or a protein, in which one or more constituent amino acid residues have been substituted with other residues d amino acids and / or in which one or more constituent amino acid residues have been deleted and / or in which one or more constitutive amino acid residues have been added. The percentage of homology accepted for the present definition of an analogue is 50%.

The term "derivative" means, when used with reference to a peptide or a protein, a peptide or a protein or an analog chemically modified by a substituent which is not present in the peptide or the protein or the reference analogue, that is to say a peptide or a protein which has been modified by creation of covalent bonds, to introduce substituents.

In one embodiment, the substituent is chosen from the group consisting of fatty chains.

In one embodiment, the concentration of gastrointestinal hormone is in the range of 0.01 to 10 mg / mL.

In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in the range of 0.04 to 0.5 mg / ml.

In one embodiment, the concentration of liraglutide, its analogs or derivatives and their pharmaceutically acceptable salts is in the range from 1 to 10 mg / ml.

In one embodiment, the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in the range of 0.01 to 1 mg / ml.

In one embodiment, the concentration of pramlintide, its analogs or derivatives and their pharmaceutically acceptable salts is between 0.1 to 5 mg / ml.

In one embodiment, the compositions according to the invention are produced by mixing solutions of human glucagon obtained by reconstitution of lyophilisate and solutions of GLP-1 RA (Glucagon like peptide-1 receptor agonist) GLP1 RA, d analog or derivative of GLP-1 RA said solutions of GLP-1 RA being commercial or reconstituted from lyophilisate.

In one embodiment, the compositions according to the invention further comprise buffers.

In one embodiment, the compositions according to the invention comprise buffers at concentrations between 0 and 100 mM.

In one embodiment, the compositions according to the invention comprise buffers at concentrations between 15 and 50 mM.

In one embodiment, the compositions according to the invention comprise a buffer chosen from the group consisting of a phosphate buffer or Tris (trishydroxymethylaminomethane) ..

In one embodiment, the buffer is sodium phosphate.

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

The invention also relates to compositions which further comprise ionic species, said ionic species making it possible to improve the stability of the compositions.

In one embodiment, the ionic species comprise less than 10 carbon atoms.

Said ionic species are chosen from the group of anions, cations and / or zwitterions. By zwitterion is meant a species carrying at least one positive charge and at least one negative charge on two nonadjacent atoms.

Said ionic species are used alone or in admixture and preferably in admixture.

In one embodiment, the anions are chosen from organic anions.

In one embodiment, the organic anions comprise less than 10 carbon atoms.

In one embodiment, the organic anions are chosen from the group consisting of acetate, citrate and succinate [000582] In one embodiment, the anions are chosen from anions of mineral origin.

In one embodiment, the anions of mineral origin are chosen from the group consisting of sulfates, phosphates and halides, in particular chlorides.

In one embodiment, the cations are chosen from organic cations.

In one embodiment, the organic cations comprise less than 10 carbon atoms.

In one embodiment, the organic cations are chosen from the group consisting of ammoniums, for example 2-Amino-2- (hydroxymethyl) propane-1,3-diol where the amine is in the form of ammonium.

In one embodiment, the cations are chosen from cations of mineral origin.

In one embodiment, the cations of mineral origin are chosen from the group consisting of zinc, in particular Zn2 + and alkali metals, in particular Na + and K +.

In one embodiment, the zwitterions are chosen from zwitterions of organic origin.

In one embodiment, the zwitterions of organic origin are chosen from amino acids.

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

In one embodiment, the amino acids are chosen from cyclic amino acids in the group consisting of proline.

In one embodiment, the amino acids are chosen from hydroxylated or sulfur-containing amino acids from the group consisting of cysteine, serine, threonine, and methionine.

In one embodiment, the amino acids are chosen from aromatic amino acids from the group consisting of phenylalanine, tyrosine and tryptophan.

In one embodiment, the amino acids are chosen from amino acids whose carboxyl function of the side chain is amidified in the group consisting of asparagine and glutamine.

In one embodiment, the zwitterions of organic origin are chosen from the group consisting of amino acids having an uncharged side chain.

In one embodiment, the zwitterions of organic origin are chosen from the group consisting of aminodiacids or acidic amino acids.

In one embodiment, the aminodiacides are chosen from the group consisting of glutamic acid and aspartic acid, optionally in the form of salts.

In one embodiment, the zwitterions of organic origin are chosen from the group consisting of basic or so-called "cationic" amino acids.

In one embodiment, the so-called “cationic” amino acids are chosen from arginine, histidine and lysine, in particular arginine and lysine.

In particular, the zwitterions include as many negative charges as positive charges and therefore an overall charge zero at point 5 isoelectric and / or at a pH between 6 and 8.

Said ionic species are introduced into the compositions in the form of salts. The introduction of these can be done in solid form before dissolving in the compositions, or in the form of solution, in particular of concentrated solution.

For example, cations of mineral origin are provided in the form of salts chosen from sodium chloride, zinc chloride, sodium phosphate, sodium sulfate, etc.

For example, the anions of organic origin are provided in the form of the salts chosen from sodium or potassium citrate, sodium acetate.

For example, the amino acids are added in the form of salts chosen from arginine hydrochloride, histidine hydrochloride or in non-salified form such as, for example, histidine, arginine.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 10 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 20 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 30 mM.

[000609] In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 50 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 75 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 100 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 200 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 300 mM.

[000614] In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 500 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 600 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 700 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 800 mM.

In one embodiment, the total molar concentration of ionic species in the composition is greater than or equal to 900 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.

[000620] In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 1500 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 1200 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 900 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 800 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 700 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 600 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 500 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 400 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 300 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 200 mM.

In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 100 mM.

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

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

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

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

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

In one embodiment, the total molar concentration of ionic species in the composition is between 100 and 1000 mM, In one embodiment, the total molar concentration of ionic species in the composition is between 200 and 1000 mM.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In a concentration [000731] In a concentration one embodiment, said ionic species ranging from 5 to 400 mM.

one embodiment, ranging from 5 to 300 mM.

said ionic species are present in [000732] In a concentration [000733] In a concentration [000734] In a concentration [000735] In one embodiment, ranging from 5 to 200 mM.

one embodiment, ranging from 5 to 100 mM.

one embodiment, ranging from 5 to 75 mM.

an embodiment, a concentration ranging from said ionic species said ionic species said ionic species said ionic species are are are present present present in in in [000736] In a concentration a mode ranging from [000737] In a concentration a mode said ionic species said ionic species at 50 mM. of realization, at 25 mM. of realization, going from 5 to 20 mM. one embodiment, said ionic species [000738] In a concentration ranging from 5 to 10 mM.

In a mode a concentration ranging from [000740] In a concentration a mode ranging from are are present are present in in [000741] In a concentration an embodiment, said ionic species 10 to 400 mM.

of production, said ionic species 10 to 300 mM.

of production, said ionic species 10 to 200 mM.

are are present present in en in [000742] In going from one embodiment, said ionic species are present in a concentration ranging from 10 to 100 mM.

In one embodiment, said ionic species are present in a concentration ranging from 10 to 75 mM.

In one embodiment, said ionic species are present in a concentration ranging from 10 to 50 mM.

In one embodiment, said ionic species are present in a concentration ranging from 10 to 25 mM.

In one embodiment, said ionic species are present in a concentration ranging from 10 to 20 mM.

In one embodiment, said ionic species are present in a concentration ranging from 20 to 300 mM.

In one embodiment, said ionic species are present in a concentration ranging from 20 to 200 mM.

In one concentration an embodiment, ranging from 20 to 100 mM. one embodiment, [000750] In a concentration ranging from 20 to 75 mM.

In one embodiment, a concentration ranging from 20 to 50 mM.

one embodiment, ranging from 20 to 25 mM.

an embodiment, [000752] In a concentration said ionic species said ionic species said ionic species said ionic species [000753] In a concentration ranging from 50 to 300 mM.

one embodiment, said ionic species ranging from 50 to 200 mM.

said ionic species are are are are present present present present in in in in [000754] In a concentration are present in [000755] In a concentration [000756] In a concentration are are present in in one embodiment, said ionic species ranging from 50 to 100 mM.

one embodiment, said ionic species ranging from 50 to 75 mM.

With regard to cations of mineral origin and in particular of Zn ²⁺ , molar concentration within the composition can be between 0.25 and mM, in particular between 0.25 and 10 mM or between 0, 25 and 5 mM.

In one embodiment, the composition also comprises a zinc salt, in particular zinc chloride.

In one embodiment, the zinc salt concentration is between 50 and 5000 μΜ.

In one embodiment, the zinc salt concentration is between 100 and 2000 μΜ.

In one embodiment, the zinc salt concentration is between 200 and 1500 μΜ.

In one embodiment, the zinc salt concentration is between 200 and 1000 μΜ.

In one embodiment, the zinc concentration is such that the [zinc] / [glucagon] molar ratio is between 0.1 and 2.5.

In one embodiment, the zinc concentration is such that the [zinc] / [glucagon] molar ratio is between 0.2 and 2.

In one embodiment, the zinc concentration is such that the [zinc] / [glucagon] molar ratio is between 0.5 and 1.5.

[000766] In one embodiment, the zinc concentration is such that the [zinc] / [glucagon] molar ratio is 1.

In one embodiment, the compositions according to the invention further comprise preservatives.

In one embodiment, the preservatives are chosen from the group consisting of m-cresol and phenol, alone or as a mixture.

In one embodiment, the compositions according to the invention also comprise antioxidants.

[000770] In one embodiment, the antioxidants are chosen from methionine.

In one embodiment, the concentration of preservatives is between 10 and 50 mM.

In one embodiment, the concentration of preservatives is between 10 and 40 mM.

In one embodiment, the compositions according to the invention further comprise a surfactant.

In one embodiment, the surfactant is chosen from the group consisting of propylene glycol or polysorbate.

The compositions according to the invention can also comprise additives such as tonicity agents.

In one embodiment, the tonicity agents are chosen from the group consisting of sodium chloride, mannitol, sucrose, sobitol and glycerol, [000777] The compositions according to the invention can also comprise all excipients in accordance with pharmacopoeias and compatible with human glucagon and gastrointestinal hormones, in particular GLP-1 RA, used at the usual concentrations.

The invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.

In the case of local and systemic releases, the modes of administration envisaged are by the intravenous, subcutaneous, intradermal or intramuscular route. [000780] The transdermal, oral, nasal, vaginal, ocular, oral, pulmonary administration routes are also envisaged.

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising human glucagon.

The invention also relates to single-dose formulations at pH between 6.6 and 7.8 comprising human glucagon and a gastrointestinal hormone, as defined above.

In one embodiment, the single-dose formulations further comprise a substituted co-polyamino acid as defined above.

In one embodiment, the formulations are in the form of an injectable solution. In one embodiment, GLP-1 RA, analog or derivative of GLP-1 RA is chosen from the group comprising exenatide (Byetta®), liraglutide (Victoza®), lixisenatide (Lyxumia®), albiglutide (Tanzeum®), dulaglutide (Trulicity®) or one of their derivatives.

[000785] In one embodiment, the gastrointestinal hormone is exenatide.

[000786] In one embodiment, the gastrointestinal hormone is liraglutide.

[000787] In one embodiment, the gastrointestinal hormone is lixisenatide. [000788] In one embodiment, the gastrointestinal hormone is albiglutide. [000789] In one embodiment, the gastrointestinal hormone is dulaglutide.

Furthermore and just as importantly, the Applicant has been able to verify that human glucagon in the presence of a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention retains its action as it either alone or in combination with a gastrointestinal hormone.

The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of a solution of human glucagon, of a solution of GLP-1 RA, of an analogue or a derivative of GLP-1 RA, and of a copolyamino acid carrying carboxylate charges and of at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form. If necessary, the pH of the preparation is adjusted to pH 7.

In one embodiment, the mixture of human glucagon and substituted copolyamino acid is concentrated by ultrafiltration before mixing with GLP1 RA, an analog or a derivative of GLP-1 RA in aqueous solution or in lyophilized form.

If necessary, the composition of the mixture is adjusted to excipients such as glycerol, m-cresol, and polysorbate (Tween®) by adding concentrated solutions of these excipients within the mixture. If necessary, the pH of the preparation is adjusted to 7.

Description of Figure 1:

In this figure is shown graphically the determination of the latency time (LT) by monitoring the fluorescence of Thioflavin T, on a curve having the ordinate the value of ia fluorescence (in ua arbitrary units) and on the abscissa time in minutes.

The following examples illustrate the present application.

AA: Synthesis of the hydrophobic intermediate compounds Hy making it possible to obtain the r ^^ jux ^ JjxdanLsj.esa.ue1jes, p 1 [000796] The hydrophobic intermediate compounds are represented in the following table by the corresponding hydrophobic molecule before grafting onto the polyamino acid co10 .

No. AA14- 1 ^ HYDROPHOBIC INTERMEDIATE COMPOUNDS * ' ^{ri 1} UN «',. ,, ..., h,, '<<i 1 AA15 >! - ^H '1 -. , h _N '- - r - j. AA16 I ^! ! o], i - ^^ 31 hl h ^Ntl f b AA17 ⁿ rh Nil · Ί N lt_N tll · Π i

Table ΙΑ: list and structures of the hydrophobic intermediate compounds synthesized according to the invention.

Example AAI: AAI molecule

Molecule Al: product obtained by the reaction between palmitoyie chloride and Lproline.

To a solution of L-proline (10.6 g, 92.1 mmol) in 1N aqueous sodium hydroxide solution (230 mL; 230 mmol) is added dropwise a solution of palmitoyie chloride ( 23.0 g, 83.7 mmol) in acetone (167 mL). After stirring for 14 h at room temperature, the heterogeneous mixture is cooled to 0 ° C., then filtered through a frit to give a white solid which is washed with water (2 x 100 mL) then diisopropyl ether (100 mL) . The solid is dried under reduced pressure. The solid is then dissolved at reflux in 200 ml of water and then 8 ml of a 37% hydrochloric acid solution are added to obtain a pH = 1. The opalescent reaction medium is then cooled to 0 ° C. The precipitate obtained is filtered on a frit and then washed with water (5 x 50 mL) until filtrates of physiological pH between 6.0 and 8.0 are obtained, then they are dried in an oven at 50 ° C. empty overnight. The product is purified by recrystallization from diisopropyl ether. A white solid is obtained.

Yield: 22.7 g (77%).

NMR (CDCh, 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).

Molecule A2: product obtained by reaction between the molecule Al and Bocethylenediamine.

To a solution of molecule Al (75.1 g, 212.4 mmol) in 1500 ml of chloroform are added successively and at room temperature N, Ndiisopropylethylamine (DIPEA) (68.8 g, 532.3 mmol ), 1-hydroxybenzotriazole (HOBt) (37.1 g, 274.6 mmol) then / V- (3-dimethylaminopropyl) - / V'-ethylcarbodiimide (EDC) (53.1 g, 277.0 mmol) . After 15 minutes of stirring at room temperature, a solution of Boc-ethylenediamine (Boc-ethylenediamine) (37.6 g, 234.7 mmol) in 35 ml of chloroform is added. After 18 h of stirring at room temperature, a 0.1 N HCl solution (2.1 L), then a saturated NaCl solution (1 L) are added. The phases are separated and then the organic phase is washed successively with a 0.1 N HCl / saturated NaCl solution (2.1 L / l L), a saturated NaCl solution (2 L), a saturated NaHCCh solution (2 L), then a saturated NaCi solution (2 L). The organic phase is dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained is purified by trituration in diisopropyl ether (3 x 400 mL), to give a solid after drying under vacuum at 40 ° C.

Yield: 90.4 g (86%).

NMR (CDCh, 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 (0.1 H); 4.51 (0.9 H); 4.82 (O, 1H); 5.02 (0.9H);

6.84 (O, 1H); 7.22 (0.9H).

Molecule AA1 To a solution of molecule A2 (20.1 g, 40.5 mmol) in 330 mL of dichloromethane is added dropwise and at 0 ° C a solution of 4 M hydrochloric acid in dioxane (100 mL, 400 mmol). After 3 h 30 min of stirring at room temperature, the solution is concentrated under reduced pressure. The residue is purified by flash chromatography (methanol, dichloromethane) to give a white solid of 10 AAI molecule in the form of the hydrochloride salt.

Yield: 16.3 g (93%).

NMR (CDCh, 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; (calculated ([M + H] +): 396.4).

Example AA2: AA2 molecule

Molecule A3 i 15-methylhexadecan-l-ol.

In a three-necked flask under argon is introduced magnesium (9.46 g, 389 mmol) 20 in shavings. The magnesium is covered with anhydrous THF (40 mL) and a few drops of l-bromo-3-methylbutane are added at room temperature to initiate the reaction. After observing an exotherm and a slight clouding of the medium, the rest of the 1-bromo-3-methylbutane (53.87 g, 357 mmol) is added dropwise over 90 min while the temperature of the medium remains stable between 50 and 60 ° C. The reaction medium 25 is then heated at 70 ° C for 2 h.

In a three-necked flask under argon, to a CuCl solution (482 mg, 4.86 mmol) dissolved in the NMP (62 mL) at 0 ° C. is added dropwise a solution of 12bromo-l-dodecanol ( 43 g, 162.1 mmol) in THF (60 mL). To this solution is then added dropwise the solution of the hot organomagnesium freshly prepared so as to maintain the temperature of the medium below 20 ° C. The mixture is then stirred at room temperature for 16 h. The medium is cooled to 0 ° C and the reaction is stopped by adding an aqueous solution of HCl IN to pH 1 and the medium is extracted with ethyl acetate. After washing the organic phase with a saturated NaCl solution and drying over Na2SO4, the solution is filtered and concentrated in vacuo to give an oil. After purification by DCVC on silica gel (cyclohexane, ethyl acetate), an oil which crystallizes at room temperature is obtained.

Yield: 32.8 g (74%)

1 H NMR (CDCh, ppm): 0.87 (6H); 1.14 (2H); 1.20-1.35 (22H); 1.50-1.55 (3H); 3.64 (2H).

A4 molecule: 15-methylhexadecanoic acid.

To a solution of molecule A3 (20.65 g, 80.5 mmol) and tetrabutylammonium bromide (14.02 g, 42.5 mmol) in a mixture of acetic acid / dichlorethane / water (124/400 / 320 mL) at room temperature is added in small portions of potassium permanganate (38.2 g, 241.5 mmol). After stirring at reflux for 5 h and returning to ambient temperature, the medium is acidified to pH 1 by progressive addition of 5N HCl. NaiSOa (44.6 g, 354.3 mmol) is then added gradually until the medium becomes discolored. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over NazSCh, filtered and concentrated in vacuo. After purification by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid), a white solid is obtained.

Yield: 19.1 g (quantitative)

NMR (CDCh, ppm): 0.87 (6H); 1.14 (2H); 1.22-1.38 (20H); 1.51 (1H); 1.63 (2H); 2.35 (2H).

Molecule A5: product obtained by reaction between the molecule A4 and L-proline. To a solution of molecule A4 (10 g, 37 mmol) in THF (360 mL) at 0 ° C are successively added dicyclohexyie carbodiimide (DCC) (8.01 g, 38.8 mmol) and / V-hydroxysuccinimide (NHS) (4.47 g, 38.8 mmol). After 17 h of stirring at room temperature, the medium is cooled to 0 ° C for 20 min, filtered through a frit. L-proline (4 g, 37.7 mmol), triethylamine (34 mL) and water (30 mL) are added to the filtrate. After 20 h of stirring at room temperature, the medium is treated with an aqueous solution of HCl IN to pH 1. The aqueous phase is extracted with dichloromethane (2 x 125 mL). The combined organic phases are washed with an aqueous solution of IN HCl (2 x 100 mL), water (100 mL), then an aqueous solution saturated with NaCl (100 mL). After drying over Na2SO4, the organic phase is filtered, concentrated under vacuum and the residue is purified by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid)

Yield: 9.2 g (72%)

NMR (CDCh, ppm): 0.86 (6H); 1.14 (2H); 1.22-1.38 (20H); 1.50 (1H); 1.67 (2H); 1.95-2.10 (3H); 2.34 (2H); 2.49 (1H); 3.47 (1H); 3.56 (1H); 4.61 (1H). LC / MS (ESI): 368.3; (calculated ([M + H] ⁺ ): 368.6).

A6 molecule: product obtained by reaction between the A5 molecule and Bocethylenediamine.

To a solution of molecule A5 (9.22 g, 25.08 mmol) in a THF / DMF mixture (200/50 mL) are added triethylamine (TEA) (5.23 mL) and 2- (1Henzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate (TBTU) at room temperature. After 10 min of stirring, Boc-ethylenediamine (4.42 g, 27.6 mmol) is added. After stirring at room temperature for 17 h, the mixture is diluted with water (300 mL) at 0 ° C and stirred cold for 20 min. The precipitate formed is filtered on a frit and the filtrate is extracted with ethyl acetate. The combined organic phases are washed with saturated NaHCOa solution, dried over NazSCU, filtered, concentrated in vacuo and the residue is purified by flash chromatography (ethyl acetate, methanol).

Yield: 6.9 g (54%)

NMR (CDCh, ppm): 0.86 (6H); 1.15 (2H); 1.22-1.38 (20H); 1.43 (9H); 1.50 (1H); 1.64 (4H); 1.85 (1H); 1.95 (1H); 2.10 (1H); 2.31 (2H); 3.20-3.35 (3H); 3.45 (1H); 3.56 (1H); 4.51 (1H); 5.05 (1H); 7.24 (1H).

LC / MS (ESI): 510.6; (calculated ([M + H] ⁺ ): 510.8).

AA2 molecule [000805] To a solution of the molecule A6 (5.3 g, 10.40 mmol) in dichloromethane (50 mL) at 0 ° C is added a solution of 4N HCl in dioxane (13 mL). After 5 hours of stirring at 0 ° C., the medium is concentrated under vacuum, taken up in water and lyophilized to give a white solid of molecule AA2 in the form of the hydrochloride salt.

Yield: 4.6 g (99%)

NMR ^X H (D ₂ O, ppm): 0.91 (6H); 1.22 (2H); 1.22-1.50 (20H); 1.63 (3H); 1.98 (1H); 2.10 (2H); 2.26 (1H); 2.39 (1H); 2.43 (1H); 3.22 (2H); 3.45-3.60 (3H); 3.78 (1H); 4.42 (1H).

LC / MS (ESI): 410.4; (calculated ([M + H] ⁺ ): 410.7).

Example AA3: AA3 molecule

Molecule A7: product obtained by the reaction between the molecule Al and Boctri (ethylene glycol) of lamin.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4.0 g, 11.3 mmol) and to Boc-tri (ethylene glycol) diamine (3.1 g, 12 , 4 mmol), a colorless oil is obtained after purification by flash chromatography (methanol, toluene).

Yield: 5.5 g (84%).

Ψ NMR (CDCh, ppm): 0.88 (3H); 1.09-1.39 (24H); 1.44 (9H); 1.64 (2H); 1.79-2.01 (2H); 2.06-2.43 (4H); 3.23-3.68 (14H); 4.33 (0.2H); 4.56 (0.8H); 5.25 (1H); 6.49 (0.2H); 7.13-7.50 (0.8H).

AA3 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A7 molecule (5.5 g, 9.4 mmol), a white solid of molecule AA3 in the form of the hydrochloride salt is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 4.3 g (92%).

Ψ NMR (DMSO-d6, ppm): 0.85 (3H); 1.08-1.40 (24H); 1.40-1.52 (2H); 1.71-2.02 (4H); 2.02-2.31 (2H); 2.90-2.98 (2H); 3.15-3.47 (5H); 3.50-3.66 (7H); 4.24 (0.6H); 4.32 (0.4H); 7.83 (0.6H); 7.95 (3H); 8.17 (0.4H).

LC / MS (ESI): 484.6; (calculated ([M + H] ⁺ ): 484.4).

Example AA4: AA4 molecule

Molecule A8: product obtained by the reaction between the molecule Al and Boc-1-amino-

4,7,10-trioxa-13-tridecane amine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4.5 g, 12.7 mmol) and to Boc-l-amino-4,7,10-trioxa -13tridecane amine (4.5 g, 14.0 mmol), a yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 7.7 g (92%).

1 H NMR (CDCl3, ppm): 0.88 (3H); 1.22-1.37 (24H); 1.44 (9H); 1.59-1.67 (2H); 1.67-2.00 (6H); 2.06-2.45 (4H); 3.18-3.76 (18H); 4.28 (0.2H); 4.52 (0.8H); 4,695.04 (1H); 6.77 (0.2H); 7.20 (0.8H).

AA4 molecule [000809] By a process similar to that used for the preparation of the AAI molecule applied to the A8 molecule (7.7 g, 11.8 mmol), a yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane). Coevaporation with diisopropyl ether allows the molecule AA4 to be obtained in the form of the hydrochloride salt in the form of a white solid which is dried under vacuum at 50 ° C.

Yield: 5.4 g (76%).

Ψ NMR (CDCI ₃ , ppm): 0.88 (3H); 1.08-1.40 (24H); 1.49-1.65 (2H); 1.76-2.39 (10H); 3.07-3.28 (3H); 3.34-3.80 (15H); 4.34 (0.05H); 4.64 (0.95H); 7.35 (0.05H); 7.66-8.58 (3.95H).

LC / MS (ESI): 556.7; (calculated ([M + H] ⁺ ): 556.5).

100

Example AA5: AA5 molecule [000810] A9 molecule: product obtained by reaction between the molecule Al and the methyl ester of A / -Boc-L-lysine.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule Al (4 g, 11.3 mmol) and to the methyl ester of / V-Boc-Llysine (3.2 g , 12.4 mmol), a colorless oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 4.9 g (73%).

¹ H NMR (CDCh, ppm): 0.88 (3H); 0.99-1.54 (37H); 1.54-1.75 (3H); 1.75-2.04 (3H); 2.04-2.41 (4H); 2.94-3.19 (2H); 3.19-3.81 (5H); 4.28-4.64 (2H); 4.94 (1H); 6.45 (0.1H); 7.36 (0.9H).

LC / MS (ESI): 596.7; (calculated ([M + H] ⁺ ): 596.5).

A10 molecule: product obtained by treatment of the A9 molecule with ammonia. To a suspension of molecule A9 (4.9 g, 8.2 mmol) in 10 ml of methanol are added 320 ml of a solution of 7 N ammonia in methanol. After 19 h of stirring at room temperature in a closed atmosphere, an additional 100 ml of ammonia solution are added. After 24 h of stirring at room temperature in a closed atmosphere, the reaction medium is concentrated under reduced pressure. The residue is purified by trituration in diisopropyl ether at reflux (100 ml), to give a white solid which is dried under vacuum at 50 ° C.

Yield: 4.1 g (85%).

NMR (CDCh, ppm): 0.88 (3H); 1.06-1.57 (37H); 1.57-1.79 (3H); 1.88-2.41 (7H); 3.09 (2H); 3.49 (1H); 3.62 (1H); 4.34 (1H); 4.51 (1H); 4.69-4.81 (1H); 5.43 (0.95H); 5.57 (0.05H); 6.25 (0.05H); 6.52 (0.95H); 6.83 (0.05H); 7.11 (0.95H).

AA5 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A10 molecule (388 mg, 0.67 mmol), a white solid of AA5 molecule in the form of the hydrochloride salt is obtained after purification. by trituration in diisopropyl ether.

Yield: 292 mg (85%).

1 H NMR (DMSO-d6, ppm): 0.85 (3H); 1.06-2.34 (38H); 2.61-2.81 (2H); 3.29-3.68 (2H); 4.05-4.17 (1.7H); 4.42 (0.3H); 7.00 (1H); 7.16 (0.7H); 7.43 (0.3H); 7,738.04 (3.7H); 8.16 (0.3H).

LC / MS (ESI): 481.6; (calculated ([M + H] ⁺ ): 481.4).

101

Example AA6: AA6 molecule

Garlic molecule: product obtained by the reaction between stearoyl chloride and Lproline.

By a process similar to that used for the preparation of the molecule Al applied to L-proline (5.0 g, 43.4 mmol) and to stearoyl chloride (12.0 g, 39.6 mmol) , a white solid is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 5.37 g (36%)

NMR (CDCI3, ppm): 0.88 (3H); 1.26-1.37 (28H); 1.64-1.70 (2H); 1.88-2.10 (3H);

2.36 (2H); 2.54-2.58 (1H); 3.46 (1H); 3.56 (1H); 4.62 (1H).

LC / MS (ESI): 382.6; (calculated ([M + H] ⁺ ): 382.3).

Moléoj] Î_jM2_j. product obtained by reaction between the Garlic molecule and Boctri (ethylene glycol) diamine.

By a process similar to that used for the preparation of the A6 molecule applied to the Ail molecule (33.81 g, 88.6 mmol) and to Boctri (ethylene glycol) diamine (26.4 g, 106.3 mmol) in THF using DIPEA instead of TEA, a white solid is obtained after purification by flash chromatography (ethyl acetate, methanol).

Yield: 43.3 g (80%)

Ψ NMR (CDCI3, ppm): 0.87 (3H); 1.24 (30H); 1.43 (9H); 1.61 (2H); 1.82 (1H); 1.96 (1H); 2.25-2.45 (2H); 3.25-3.65 (14H); 4.30 (0.15H); 4.53 (0.85H); 5.25 (1H); 6.43 (0.15H); 7.25 (0.85H).

LC / MS (ESI): 612.6; (calculated ([M + H] ⁺ ): 612.9).

AA6 molecule By a process similar to that used for the preparation of the AA2 molecule applied to the A12 molecule (43 g, 70.3 mmol), the residue obtained after concentration under vacuum is triturated in acetonitrile. The suspension is filtered and the solid washed with acetonitrile and then acetone. After drying under vacuum, a white solid of molecule AA6 in the form of the hydrochloride salt is obtained.

Yield: 31.2 g (81%)

NMR (DMSO-de, ppm): 0.85 (3H); 1.23 (28H); 1.45 (2H); 1.70-2.05 (4H); 2.13 (1H); 2.24 (1H); 2.95 (2H); 3.10-3.25 (2H); 3.30-3.65 (10H); 4.20-4.45 (1H); 7.85-8.25 (4H).

LC / MS (ESI): 512.4; (calculated ([M + H] ⁺ ): 512.8).

102

Example AA7: AA7 molecule

Al3 molecule: product obtained by reaction between arachidic acid and L-proline.

By a process similar to that used for the preparation of the molecule A5 applied to arachidic acid (15.51 g, 49.63 mmol) and to L-proline (6 g, 52.11 mmol) in using DIPEA instead of TEA, a white solid is obtained after purification by a chromatographic column on silica gel (cyclohexane, ethyl acetate, acetic acid).

Yield: 12.9 g (63%)

NMR (CDCh, ppm): 0.88 (3H); 1.28 (34H); 1.66 (2H); 1.95-2.15 (2H); 2.34 (2H); 2.45 (1H); 3.47 (1H); 3.56 (1H); 4.60 (1H).

LC / MS (ESI): 410.4; (calculated ([M + H] ⁺ ): 410.6).

A14 molecule: product obtained by the reaction between the A13 molecule and Boc-1-amino-

4,7,10-trioxa-13-tridecane.

By a process similar to that used for the preparation of the molecule A12 applied to the molecule A13 (10.96 g, 26.75 mmol) and to Boc-l-amino-4,7,10trioxa-13- tridecane (10.29 g, 32.11 mmol), a solid is obtained after purification by a chromatographic column on silica gel (cyclohexane, ethyl acetate, methanol). Yield: 14.2 g (75%)

Ψ NMR (CDCh, ppm): 0.88 (3H); 1.24 (32H); 1.43 (9H); 1.57-2.00 (8H); 2.10-2.45 (4H); 3.20-3.75 (18H); 4.30 (0.20H); 4.55 (0.80H); 5.03 (1H); 6.75 (0.20H); 7.20 (0.80H).

LC / MS (ESI): 712.8; (calculated ([M + H] ⁺ ): 713.1).

AA7 molecule After a process similar to that used for the preparation of the AA2 molecule applied to the A14 molecule (14.25 g, 20.01 mmol), the residue obtained after concentration under vacuum of the reaction medium is dissolved in the methanol and evaporated under reduced pressure, the operation being repeated 4 times to give a white solid of molecule AA7 in the form of the hydrochloride salt.

Yield: 12.7 g (98%)

H NMR ^J (DMSO-de, ppm): 0.85 (3H); 1.23 (32H); 1.45 (2H); 1.64 (2H); 1.70-2.05 (6H); 2.10-2.30 (2H); 2.82 (2H); 3.08 (2H); 3.30-3.60 (14H); 4.15-4.30 (1H); 7.73-8.13 (4H).

LC / MS (ESI): 612.7; (calculated ([M + H] ⁺ ): 612.9).

103

Example AA8: AA8 molecule

Al5 molecule: product obtained by the reaction between L-leucine and palmitoyl chloride.

By a process similar to that used for the preparation of the molecule Al applied to L-leucine (15.0 g, 114.4 mmol) and to palmitoyl chloride (34.5 g, 125 mmol), a white solid is obtained by trituration in diisopropyl ether. Yield: 13.0 g (31%)

NMR (CDCh, ppm): 0.88 (3H); 0.96 (6H); 1.16-1.35 (24H); 1.55-1.77 (5H); 2.23 (2H); 4.55-4.60 (1H); 5.88 (1H).

A16 molecule: product obtained by the reaction between the A15 molecule and the methyl ester of L-proline [000821] By a process similar to that used for the preparation of the A2 molecule applied to the A15 molecule (6.00 g, 16.2 mmol) and with the methyl ester of Lproline (3.23 g, 19.5 mmol), a slightly yellow oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 5.8 g (74%)

NMR ^X H (CDCl₃, ppm): 0.83 to 1.00 (9H); 1.18-1.32 (24H); 1.40-1.73 (5H); 1.84-2.33 (6H); 3.47-3.89 (2H); 3.70 (1.14H); 3.71 (1.21H); 3.74 (0.53H); 3.76 (0.12H); 4.40-4.56 (1H); 4.63-4.67 (0.04H); 4.84 (0.38); 4.90 (0.40); 5.06 (0.18); 5.99 (0.18H); 6.08-6.21 (0.82).

LC / MS (ESI): 481.6; (calculated ([M + H] ⁺ ): 481.4).

A17 molecule: product obtained by the saponification of the methyl ester of the A16 molecule.

To a solution of molecule A16 (5.8 g, 12.06 mmol) in 30 mL of methanol is added 1N sodium hydroxide (13.5 mL, 13.5 mmol). After 20 h of stirring at room temperature, the solution is diluted with water and then acidified with 20 ml of 1N hydrochloric acid at 0 ° C. The precipitate is filtered and then rinsed with water (50 ml) before being dissolved in 50 ml of dichloromethane. The organic phase is dried over NazSO4, filtered and then concentrated under reduced pressure to give a colorless oil. Yield: 4.5 g (80%)

¹ H NMR (CDCh, ppm): 0.85-0.99 (9H); 1.14-1.41 (24H); 1.43-1.72 (5H); 1.87-2.47 (7H); 3.48-3.55 (0.6H); 3.56-3.62 (0.4H); 3.83-3.90 (0.4H); 3.90-3.96 (0.6H); 4.52-4.56 (0.6H); 4.56-4.59 (0.4H); 4.80-4.86 (0.4H); 4.86-4.91 (0.6H); 6.05 (0.4H); 6.11 (0.6H).

LC / MS (ESI): 467.6; (calculated ([M + H] ⁺ ): 467.4).

104

Al8 molecule: product obtained by the reaction between Boc-ethylenediamine and the molecule A17.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule A17 (4.5 g, 9.64 mmol) and to Boc-ethylenediamine (1.70 g, 10.61 mmol) , a colorless oil is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 2.0 g (34%)

NMR ^X H (CDCl₃, ppm): 0.83 to 0.99 (9H); 1.19-1.32 (24H); 1.44 (9H); 1.48-2.37 (14H); 3.09-3.99 (4H); 4.28-5.01 (2H); 5.64-6.04 (1H); 6.87-7.06 (1H).

LC / MS (ESI): 609.7; (calculated ([M + H] ⁺ ): 609.5).

AA8 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A18 molecule (2 g, 3.28 mmol), a solid of molecule AA8 in the form of the hydrochloride salt is obtained after purification by flash chromatography (methanol, dichloromethane).

Yield: 1.5 g (90%)

NMR (CDCh, ppm): 0.83-1.00 (9H); 1.18-1.32 (24H); 1.37-1.77 (5H); 1.93-2.41 (6H); 3.07-3.97 (6H); 4.44-4.77 (2H); 7.66-8.21 (2H).

LC / MS (ESI): 509.6; (calculated ([M + H] ⁺ ): 509.4).

Example AA9: AA9 molecule

Molecule A19: product obtained by the reaction between Iauric acid and L-phenylalanine. By a process similar to that used for the preparation of the molecule A5 applied to Iauric acid (8.10 g, 40.45 mmol) and to L-phenylalanine (7 g, 42.38 mmol), a white solid is obtained.

Yield: 12.7 g (98%)

NMR M (DMSO-de, ppm): 0.86 (3H); 1.10-1.30 (16H); 1.36 (2H); 2.02 (2H); 2.82 (1H); 3.05 (1H); 4.42 (1H); 7.15-7.30 (5H); 8.05 (1H); 12.61 (1H).

LC / MS (ESI): 348.2; (calculated ([M + H] ⁺ ): 348.5).

A20 molecule: product obtained by the reaction between the A19 molecule and the hydrochloride salt of the methyl ester of L-proline.

By a process similar to that used for the preparation of the molecule A6 applied to the molecule A19 (9.98 g, 28.72 mmol) and to the hydrochloride salt of the methyl ester of L-proline (5, 23 g, 31.59 mmol), a colorless oil is obtained after purification by a chromatographic column on silica gel (cyclohexane, ethyl acetate).

105

Yield: 5.75 g (44%)

1 H NMR (CDCh, ppm): 0.88 (3H); 1.10-1.30 (16H); 1.50-1.75 (3H); 1.80-2.02 (3H);

2.17 (2H); 2.65 (0.5H); 2.95 (1H); 3.05-3.20 (1.5H); 3.50-3.65 (1H); 3.75 (3H);

4.29 (0.5H); 4.46 (0.5H); 4.70 (O, 1H); 4.95 (0.9H); 6.20-6.30 (1H); 7.15-7.30 5 (5H).

LC / MS (ESI): 459.2; (calculated ([M + H] ⁺ ): 459.6).

A21 molecule: product obtained by saponification of the A20 molecule.

To a solution of molecule A20 (5.75 g, 12.54 mmol) in a mixture 10 THF / methanol / water (40/40/40 mL) at 0 ° C is added lithium hydroxide ( LiOH) (600.49 mg, 25.07 mmol) then the mixture is stirred at room temperature for

h. After evaporation of the organic solvents under vacuum, the aqueous phase is diluted in water, acidified with a 1N aqueous HCl solution to pH 1. The product is then extracted with ethyl acetate. The combined organic phases are washed with a saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil.

Yield: 5.7 g (quantitative)

1 H NMR (CDCh, ppm): 0.88 (3H); 1.10-1.30 (16H); 1.50-1.80 (3H); 1.67-2.02 (2H);

2.20 (2H); 2.25 (0.4H); 2.60 (0.6H); 2.85-3.10 (2.6H); 3.55-3.65 (1.4H); 4.35 (0.6H); 4.55 (0.4H); 4.94 (1H); 6.28 (0.4H); 6.38 (0.6H); 7.20-7.30 (5H).

LC / MS (ESI): 445.2; (calculated ([M + H] ⁺ ): 445.6).

Molecule A22: product obtained by reaction between Boc-ethylenediamine and the molecule A21.

By a process similar to that used for the preparation of the molecule

A6 applied to the molecule A21 (5.67 g, 12.75 mmol) and to Boc-ethylenediamine (2.25 g, 14.03 mmol), a colorless oil is obtained after purification by chromatographic column on silica gel ( dichloromethane, methanol).

Yield: 5.7 g (76%)

N ^N NMR (CDCh, ppm): 0.88 (3H); 1.25 (16H); 1.43 (9H); 1.58 (2.6H); 1.75-1.95 (1.4H); 2.15-2.30 (3H); 2.64 (0.5H); 2.95-3.10 (2.5H); 3.20-3.40 (4H); 3.45 (0.5H); 3.55 (0.2H); 3.66 (1H); 4.44 (1H); 4.50 (0.2H); 4.60 (0.6H); 4.99 (0.7H); 5.54 (0.5H); 5.95 (0.2H); 6.17 (1H); 6.60 (0.5H); 7.07 (0.5H); 7.20-7.40 (5H). LC / MS (ESI): 587.4; (calculated ([M + H] ⁺ ): 587.8).

AA9 molecule After a process similar to that used for the preparation of the AA2 molecule applied to the A22 molecule (5.66 g, 9.65 mmol), the residue obtained after

The concentration of the reaction medium under vacuum is dissolved in methanol and evaporated under reduced pressure, the operation being repeated 4 times to give a white foam of molecule AA9 in the form of the hydrochloride salt.

Yield: 4.9 g (97%)

1 H NMR (DMSO-de, 120 ° C, ppm): 0.89 (3H); 1.26 (16H); 1.43 (2H); 1.68 (0.6H); 1.75-2.00 (3H); 2.05-2.25 (2.4H); 2.82-3.05 (5H); 3.38 (2H); 3.50-3.70 (1.4H); 4.25 (0.6H); 4.63 (0.4H); 4.77 (0.6H); 7.25-7.50 (5H); 7.55-8.20 (4H).

LC / MS (ESI): 487.4; (calculated ([M + H] ⁺ ): 487.7).

Example AA10: AA10 molecule

Molecule .. A23: product obtained by the reaction between nipecotic acid and arachidic acid.

By a process similar to that used for the preparation of the molecule A5 applied to arachidic acid (2.30 g, 7.37 mmol) and to nipecotic acid (1.00 g, 7.74 mmol ), a white solid is obtained after filtration of the acidified aqueous phase to pH 1 and washing of the solid with water and then with dichloromethane.

Yield: 1.65 g (53%)

1H NMR (CDCl3, ppm): 0.88 (3H); 1.07-1.88 (37H); 2.10 (1H); 2.28-2.45 (2H); 2.52 (1H); 2.91-3.17 (1.5H); 3.42 (0.5H); 3.72 (0.5H); 3.84 (0.5H); 4.08 (0.5H); 4.56 (0.5H).

LC / MS (ESI): 424.4; 848.0; (calculated ([M + H] ⁺ ): 424.4; ([2M + H] ⁺ ): 847.8).

A24 molecule: product obtained by the reaction between the A23 molecule and Boc-l-amino-

4,7,10-trioxa-13-tridecane amine.

To a suspension of molecule A23 (1.65 g, 3.89 mmol) in 20 mL of THF are successively added at room temperature DIPEA (1.01 g, 7.79 mmol) and TBTU ( 1.31 g, 4.09 mmol). After 30 minutes of stirring, Boc-1amino-4,7,10-trioxa-13-tridecane amine (1.37 g, 4.28 mmol) is added and the reaction medium is stirred at room temperature for 18 h . After evaporation of the solvent under reduced pressure, the residue is diluted with ethyl acetate (100 mL), the organic phase is washed successively with a saturated aqueous solution of NaHCOa, a 1N aqueous HCl solution, an aqueous solution saturated with NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. A white solid is obtained after purification by flash chromatography (cyclohexane, ethyl acetate, methanol).

Yield: 1.97 g (70%)

Ψ NMR (CDCI3, ppm): 0.88 (3H); 1.15-2.70 (54H); 3.10-3.46 (6H); 3.46-3.71 (12.6H); 3.92 (0.4H); 4.17 (0.6H); 4.49 (0.4H); 4.80-5.16 (1H); 6.35-6.76 (1H).

107

LC / MS (ESI): 726.8; (calculated ([M + H] ⁺ ): 726.6).

AA10 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A24 molecule (1.97 g, 2.71 mmol), a white solid of AA10 molecule is obtained after evaporation of the solvent, trituration in acetone, filtration and washing with acetone then drying under reduced pressure at 50 ° C.

Yield: 1.66 g (92%)

1 H NMR (DMSO-de, ppm): 0.86 (3H); 1.09-1.90 (42H); 2.05-2.68 (5H); 2.45-2.68 (1H); 2.78-3.19 (6H); 3.36-3.44 (2H); 3.44-3.60 (10H); 3.69-3.87 (1H); 4.20 (0.4H); 4.35 (0.6H).

LC / MS (ESI): 626.7; (calculated ([M + H] ⁺ ): 626.5).

Example AA12: AA12 molecule

Molecule A26: product obtained by the reaction between myristoyl chloride and Lproline (1646-22-CNI) [000834] To a solution of L-proline (300.40 g, 2.61 mol) in aqueous sodium hydroxide 2 N (1.63 L) at 0 ° C. is slowly added over 1 h of myristoyl chloride (322 g, 1.30 mol) dissolved in dichloromethane (1.63 L). At the end of the addition, the reaction medium is raised to 20 ° C in 2 h, then stirred for an additional 2 h. The mixture is cooled to 0 ° C. and then a 37% HCl solution (215 ml) is added over 15 minutes. The reaction medium is stirred for 10 min at 0 ° C and then 1 h between 0 ° C and 20 ° C. The organic phase is separated, washed with a 10% HCl solution (3 x 430 mL), an aqueous saturated NaCl solution (430 mL), dried over NazSCh, filtered through cotton and then concentrated under reduced pressure. The residue is dissolved in heptane (315 mL), then pentane (1.6 L) is added with mechanical stirring. A white solid is obtained after filtration on a frit and drying under reduced pressure.

Yield: 410.6 g (97%)

NMR ^X H (CDCl₃, ppm): 0.88 (3H); 1.28 (20H); 1.70 (2H); 1.90-2.10 (3H); 2.36 (2H); 2.51 (1H); 3.47 (1H); 3.56 (1H); 4.61 (1H).

LC / MS (ESI): 326.4; 651.7; (calculated ([M + H] ⁺ ): 326.3; ([2M + H] ⁺ ): 651.6).

Molecule A27: product obtained by the reaction between the molecule A26 and Bocethylenediamine [000835] To a solution of molecule A26 (3.00 g, 9.21 mmol) at room temperature in methyl-THF (50 mL) are added successively HOBt (1.83 g, 11.98 mmol) then Boc-ethylenediamine (1.62 g, 10.14 mmol) and the medium is

108 cooled to 0 ° C. EDC (2.29 g, 11.98 mmol) is added and then the mixture is stirred for 17 h between 0 ° C and room temperature. The reaction mixture is then washed with a saturated aqueous solution of NHÆI (50 mL), a saturated aqueous solution of NaHCCh (50 mL) then a saturated aqueous solution of NaCi (50 mL), dried over NazSO4, filtered and concentrated under reduced pressure . A white solid is obtained after recrystallization from methanol.

Yield: 2.34 g (49%).

¹ H NMR (CDCI3, ppm): 0.88 (3H); 1.16-1.38 (20H); 1.44 (9H); 1.56-1.71 (2H); 1.78-2.45 (6H); 3.11-3.72 (6H); 4.30 (0.1H); 4.51 (0.9H); 4.87 (0.1H); 5.04 (0.9H); 6.87 (0.1H); 7.23 (0.9H).

LC / MS (ESI): 468.0; (calculated ([M + H] ⁺ ): 468.4).

AA12 molecule By a process similar to that used for the preparation of the AAI molecule applied to the A27 molecule (2.34 g, 5.00 mmol), a white solid of AA12 molecule is obtained after evaporation of the solvent and triturations in diisopropyl ether. Yield: 1.5 g (74%)

Ψ NMR (MeOD-d4, ppm): 0.90 (3H); 1.21-1.43 (20H); 1.54-1.66 (2H); 1.85-2.28 (4H); 2.39 (2H); 3.00-3.17 (2H); 3.30-3.40 (1H); 3.43-3.71 (3H); 4.29 (0.94H);

4.48 (0.06H).

LC / MS (ESI): 368.2; (calculated ([M + H] ⁺ ): 368.3).

Example AA14: AA14 molecule

AA14-1 resin: Product obtained by the reaction between 4,7,10-trioxa-l, 13tridecanediamine and 2-CI-trityl chloride resin.

To a solution of 4.7.10-trioxa-1.13-tridecanediamine (10.87 mL, 49.60 mmol) in dichloromethane (50 mL) at room temperature is added DIPEA (8.64 mL, 49.60 mmol). This solution is poured onto 2-CI-trityl chloride resin previously washed with dichloromethane (100-200 mesh, 1% DVB, 1.24 mmol / g) (4.00 g, 4.96 mmol) in a suitable reactor to peptide synthesis on solid support. After 2 h of stirring at room temperature, methanol grade HPLC (0.8 mL / g resin, 3.2 mL) is added and the medium is stirred at room temperature for 15 minutes. The resin is filtered, washed successively with dichloromethane (3 x 50 mL), DMF (2 x 50 mL), dichloromethane (2 x 50 mL), isopropanol (1 x 50 mL) and dichloromethane (3 x 50 mL).

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Resin ..... AA14-2: Product obtained by reaction between resin AA14-1 and Fmoc-glycine.

A suspension of Fmoc-glycine (4.42 g, 14.88 mmol) and of 1 [bis (dimethylamino) methylene] -lH-1,2,3-triazolo [4,5-b] pyridinium 3 -oxide hexafluorophosphate (HATU, 5.66 g, 14.88 mmol) in a 5 DMF / dichloromethane 1: 1 mixture (60 mL) is added DIPEA (5.18 mL, 29.76 mmol).

After complete solubilization, the solution obtained is poured onto the AA14-1 resin. After 2 h of stirring at room temperature, the resin is filtered, washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and dichloromethane (3 x 60 mL).

Resin. AA 14-3: Product obtained by reaction between the AA14-2 resin and a 80:20 DMF / piperidine mixture. The AA14-2 resin is treated with a 80:20 DMF / piperidine mixture (50 mL). After 30 minutes of stirring at room temperature, the resin is filtered, washed successively with DMF (3 x 50 mL), isopropanol (1 x 50 mL) and dichloromethane (3 x 50 mL).

AA14-4 resin: Product obtained by reaction between AA14-3 resin and Fmoc-proline.

By a process similar to that used for the AA14-2 resin applied to the AA14-3 resin and to Fmoc-proline (5.02 g, 14.88 mmol) in DMF (50 mL), the resin AA14-4 is obtained.

Resin. AA 14-5: Product obtained by reaction between the AA14-4 resin and an 80:20 DMF / piperidine mixture.

By a process similar to that used for the AA14-3 resin applied to the AA14-4 resin and an 80:20 DMF / piperidine mixture (50 mL), the AA14-5 resin is obtained.

AA14-6 resin: Product obtained by reaction between AA14-5 resin and palmitic acid.

By a process similar to that used for the preparation of the AA14-4 resin applied to the AA14-5 resin and to palmitic acid (3.82 g, 14.88 mmol), the AA14-6 resin is obtained.

AA14 molecule [000843] The AA14-6 resin is treated with a TFA / dichloromethane 1: 1 mixture (50 mL). After 30 minutes of stirring at room temperature, the resin is filtered and washed with dichloromethane (3 x 50 mL). The solvents are evaporated in vacuo. Two coevaporations are then carried out on the residue with dichloromethane (50 mL) then diisopropyl ether (50 mL). The residue is dissolved in dichloromethane

110 (50 mL) and the organic phase is washed with a 1N aqueous NaOH solution (1 x 50 mL) then a saturated NaCl solution (2 x 50 mL). After drying on NazSCU, the organic phase is filtered, concentrated under vacuum and the residue is purified by chromatography on silica gel (dichloromethane, methanol, NH4OH)

Yield: 1.65 g (54% overall over 7 steps)

NMR (CDCh, ppm): 0.88 (3H); 1.18-2.39 (38H); 2.79 (2H); 3.23-3.44 (2H); 3.47-3.69 (14H); 3.76 (0.92H); 3.82 (0.08H); 3.98 (0.08H); 4.03 (0.92H); 4.34 (0.08H); 4.39 (0.92H); 7.00-7.40 (2H).

LC / MS (ESI): 613.7; (calculated ([M + H] ⁺ ): 613.5).

Example AA14-1: AA14-1 molecule

Molecule A27-1: Product obtained by hydrogenation of phytol.

To a solution of phytol (30.00 g, 101.20 mmol) in THF (450 mL) under argon is added platinum oxide (PtOz, 1.15 g, 6.61 mmol) and the medium is placed under 1 bar of dihydrogen then stirred for 4 h at room temperature. After filtration on celite by rinsing with THF, a black oil of molecule A27-1 is obtained after concentration under reduced pressure.

Yield: 29.00 g (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 A28: Product obtained by oxidation of the molecule A27-1 [000845] To a solution of molecule A27-1 (29.0 g, 97.13 mmol) in a dichloroethane / water mixture (485 mL / 388 mL) are added successively tetrabutylammonium bromide (16.90 g, 52.45 mmol), acetic acetide (150 mL, 2.62 mol) then KMnO4 (46.05 g, 291.40 mmol) in small portions while maintaining the temperature between 16 and 19 ° C. The reaction medium is then stirred for 4 h 30 at reflux, cooled to 10 ° C. and then acidified to pH 1 with a solution of 6N HCl (20 mL). NazSCh (53.90 g) is gradually added while maintaining the temperature at 10 ° C. and the medium is stirred until complete discoloration. Water (200 mL) is added, the phases are separated and the aqueous phase is extracted with DCM (2 x 400 mL). The combined organic phases are washed with an aqueous 10% HCl solution (20 mmL), water (2 x 200 mL), a saturated aqueous NaCl solution (200 mL), dried over NazSCU, filtered and concentrated under reduced pressure. A yellow molecule oil

111

A28 is obtained after purification by flash chromatography (eluent: cyclohexane, AcOEt).

Yield: 28.70 g (94%)

NMR ^X H (CDCl₃, ppm): 0.84 (6H); 0.86 (6H); 0.97 (3H); 1.00-1.41 (20H); 1.52 (1H); 1.96 (1H); 2.14 (1H); 2.35 (1H); 11.31 (1H).

LC / MS (ESI): 311.1 (calculated ([M-H]): 311.3).

A29 molecule: Product obtained by coupling between the A28 molecule and methyl L-prolinate.

By a process similar to that used for the preparation of the molecule A2 applied to the molecule A28 (18.00 g, 57.59 mmol) and to methyl L-prolinate hydrochloride (14.31 g, 86, 39 mmol), a yellow oil of molecule A29 is obtained after washing the organic phase with a saturated aqueous solution of NaHCCh (2 x 150 mL), a 10% aqueous HCl solution (2 x 150 mL), an aqueous solution saturated with NaCI (2 x 150 mL), then drying on NazSCM, filtration and concentration under reduced pressure.

Yield: 23.20 g (95%)

1 H NMR (DMSO-de, ppm): 0.78-0.89 (15H); 0.97-1.43 (20H); 1.43-1.56 (1H); 1.701.96 (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 (calculated ([M + H] ⁺ ): 424.4).

Molêc.ylg_A30 ". 1 Product obtained by the saponification of the molecule A29.

By a process similar to that used for the preparation of the molecule A21 applied to the molecule A29 (21.05 g, 49.68 mmol), a yellow oil of molecule A30 is obtained.

Yield: 20.40 g (99%)

NMR (DMSO-de, ppm): 0.77-0.91 (15H); 0.97-1.43 (20H); 1.43-1.56 (1H); 1,671.96 (4H); 1.96-2.29 (3H); 3.26-3.56 (2H); 4.20 (0.8H); 4.41 (0.2H).

LC / MS (ESI): 410.3 (calculated ([M + H] ⁺ ): 410.4).

A31 molecule: Product obtained by coupling between the A30 molecule and Boc-1-amino4,7,10-trioxa-13-tridecane amine.

By a process similar to that used for the preparation of the molecule A27 applied to the molecule A30 (8.95 g, 21.85 mmol) and to Boc-l-amino-4,7,10-trioxa13-tridecane amine (8.40 g, 26.21 mmol), a colorless oil of molecule A31 is obtained after purification by flash chromatography (eluent: DCM, AcOEt, methanol).

Yield: 10.08 g (65%)

112

H NMR ^J (DMSO-de, ppm): 0.78 to 0.89 (15H); 0.97-1.43 (29H); 1.43-1.55 (1H); 1,551.66 (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 (calculated ([M + H] +): 712.6).

AA14-1 molecule After a process similar to that used for the preparation of the AAI molecule applied to the A31 molecule (10.08 g, 14.16 mmol), the residue obtained after concentration under reduced pressure is dissolved in the DCM (200 mL), the organic phase is washed with an aqueous 2N NaOH solution (2 x 100 mL), dried over NazSO4, filtered and concentrated under reduced pressure. A colorless oil of molecule AA14-1 in the form of neutral amine is obtained.

Yield: 8.23 g (95%)

1 H NMR (DMSO-de, ppm): 0.78-0.89 (15H); 0.97-1.43 (20H); 1.43-1.69 (6H); 1.692.30 (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).

Example AA15: AA15 molecule The AA15 molecule is obtained by the conventional method of peptide synthesis in solid phase (SPPS) on 2-chlorotrityl resin.

To a solution of 4,7,10-trioxa-1,13-tridecanediamine (TOTA, 10.87 mL, 49.60 mmol) in DCM (50 mL) is added DIPEA (8.64 mL, 49, 60 mmol). This solution is then poured onto 2-chlorotrityl resin (4.00 g, 1.24 mmol / g) previously washed with DCM in a reactor suitable for SPPS. After 2 h of stirring at room temperature, methanol (0.8 ml / g, 3.2 ml) is added and the medium is stirred for 15 min. The resin is filtered, washed successively with DCM (3 x 50 mL), DMF (2 x 50 mL), DCM (2 x 50 mL), isopropanol (1 x 50 mL) and DCM (3 x 50 mL). The protected amino acids / V-Fmoc-L-glycine and N-Fmoc-L-proline then palmitic acid (3 equivalents) are successively coupled using 1 [bis (dimethylamino) methylene] -lH-1,2, 3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 3 equivalents) as coupling agent in the presence of DIPEA (6 equivalents) in a DCM / DMF 1: 1 mixture. A 20% piperidine solution in DMF is used for the steps of cleavage of the protective group Fmoc. The resin is washed with DCM, DMF and isopropanol after each coupling and deprotection step. The cleavage of the resin product is carried out using a TFA / DCM 1: 1 mixture. The solvents are evaporated under reduced pressure, the residue is dissolved

113 in DCM (50 mL) and the organic phase is washed with a 1N aqueous NaOH solution (1 x 50 mL) then a saturated NaCl solution (2 x 50 mL). After drying over NazSO4, the organic phase is filtered, concentrated under reduced pressure and the residue is purified by chromatography on silica gel (dichloromethane, methanol, NH4OH).

Yield: 1.65 g (54% overall over 7 steps).

Ψ NMR (CDCI3, ppm): 0.88 (3H); 1.18-2.39 (38H); 2.79 (2H); 3.23-3.44 (2H); 3.47-3.69 (14H); 3.76 (0.92H); 3.82 (0.08H); 3.98 (0.08H); 4.03 (0.92H); 4.34 (0.08H); 4.39 (0.92H); 7.00-7.40 (2H).

LC / MS (ESI): 613.7; (calculated ([M + H] ⁺ ): 613.5).

Example AA16: AA16 molecule By a SPPS process similar to that used for the preparation of the AA15 molecule and by using / V-Fmoc-L-phenylalanine (3 equivalents) instead of N-Fmoc- L-glycine, the molecule AA16 is obtained in the form of a yellow oil.

Yield: 14.07 g (69%)

1 H NMR (CDCl3, ppm): 0.88 (3H); 1.19-1.34 (24H); 1.41-1.61 (2H); 1.68-2.28 (12H); 2.84 (2H); 3.14 (2H); 3.23-3.67 (16H); 4.19-4.25 (0.1H); 4.38-4.45 (0.9H); 4.59-4.69 (1H); 6.86 (1H); 7.03 (1H); 7.12-7.30 (5H).

LC / MS (ESI): 703.5; (calculated ([M + H] ⁺ ): 703.5).

Example AA17: AA17 molecule By a SPPS process similar to that used for the preparation of the AA15 molecule and using EDA (30.48 mL, 0.456 mol) instead of TOTA, the AA17 molecule is obtained in the form of 'a solid white.

Yield: 9.19 g (89%)

^X H NMR (MeOD-d4, ppm): 0.90 (3H); 1.22-1.43 (24H); 1.55-1.67 (2H); 1.91-2.04 (2H); 2.04-2.15 (1H); 2.17-2.29 (1H); 2.39 (2H); 2.69-2.82 (2H); 3.25-3.36 (2H); 3.58-3.70 (2H); 3.70-3.97 (2H); 4.25-4.34 (0.9H); 4.44-4.50 (0.1H).

LC / MS (ESI): 453.3; (calculated ([M + H] ⁺ ): 453.4).

114 / X B · Co ο I v a m ι η o a ci des de definite of formula VU or Vllb

No.

CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER

AND HYDROPHOBIC RADICALS

AB14

AB15 i = 0.04, DP (m) = 25

Ri = H or pyroglutamate

We have

AB16 i = 0.033, DP (m) = 30

AB17 i = 0.021, DP (m) = 48 Ri = H or pyroglutamate

If i = 0.038, DP (m) = 26 Ri = H or pyroglutamate

115

No.

AB18

CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER

AND HYDROPHOBIC RADICALS______________

i = 0.045, DP (m) = 22 Ri = H or pyroglutamate

AB19

AB20

ΑΒ2Γ

We have

R

i = 0.015, DP (m) = 65 Ri = H or pyroglutamate

... î

i = 0.017, DP (m) = 60 R1-CH3-CO-, H or pyroglutamate

i = 0.04, DP (m) = 25

Ri = H or pyroglutamate

116

AB23 0., 0Na Ύ χ Ο ΥΜιι rT Xlx / XY 'χ- X χχ · \ Ρ κ ⁰ Ü L> 0 --— 2 i = 0.045, DP (m) = 22 Ri = Η or pyroglutamate AB33 ON4 ^η '<. L '^ s'''' Z \ X X '· -X -'X ZX Γν' χ χ ^ '' o 'X / X''' ν '' ^ χ XX Y '' \. ^h l [j Π ^H T) OO N ___ / V i = 0.045, DP (m) = 22 Ri = H or pyroglutamate AB34 • ON.l 1 i ^h [| LH \ ο ο Λ— ¹ i = 0.043, DP (m) = 23 Ri = H or pyroglutamate AB35 1 - a .... · - i = 0.045, DP (m) = 22 Ri = H or pyroglutamate

117

Table le: list of co-polyamino acids synthesized according to the invention.

Part AB: synthesis of co-polyamino acids

Example AB14: Co-polyamino acid AB14 - sodium poly-L-glutamate modified at one of its ends by the molecule AAI and having a number-average molar mass (Mn) of 3400 g / mol [000853] A suitable container is introduced successively the hydrochloride salt of the AAI molecule (2.03 g, 4.70 mmol), chloroform (5 mL), 4Â molecular sieve (1.3 g), as well as the ion exchange resin Amberlite IRN 150 (1.3 g). After 1 h of stirring on rollers, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then co-evaporated with toluene. The residue is dissolved in anhydrous DMF (30 mL) to be used directly in the polymerization reaction.

In a flask previously dried in an oven, y-benzyl-L-glutamate Ncarboxyanhydride (25.59 g, 97.2 mmol) is placed under vacuum for 30 min and then anhydrous DMF (140 mL) is introduced . The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of AAI molecule prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to ambient temperature then poured dropwise into

118 of diisopropyl ether (1.7 L) with stirring. The white precipitate is recovered by filtration, washed twice with diisopropyl ether (140 ml) then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (160 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (62 mL, 354 mmol) is then added dropwise and at 0 ° C . The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (1.9 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with a 1: 1 (v / v) mixture of diisopropyl ether and water (280 mL) then 10 with water (140 mL). The solid obtained is dissolved in water (530 ml) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 theoretical g / L by adding water to obtain a final volume of 800 mL. The mixture is filtered on a 0.45 μm filter and is then purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to approximately 30 g / L theoretical and the pH is adjusted to 7.0. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 24.1 mg / g

DP (estimated by NMR = 25 therefore i = 0.04

The calculated average molar mass of the AB14 co-polyamino acid is 3378 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3400 g / mol.

Example AB15: Co-polyamino acid AB15 - sodium poly-L-glutamate 25 modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) 4100 g / mol [000855] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA6 (2.16 g, 3.94 mmol) and to 25.58 g (97.2 mmol) of γ-benzyl-L-glutamate / V- carboxyanhydride, a sodium poly30 L-glutamate modified at one of its ends by the molecule AA6 is obtained.

Dry extract: 45.5 mg / g

DP (estimated by ¹ H NMR) = 30 therefore i = 0.033

The calculated average molar mass of the AB15 co-polyamino acid is 5005 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 4100 g / mol.

119

Example AB16: Co-polyamino acid AB16 - sodium poly-L-glutamate modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) of 6500 g / mol [000856] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA6 (2.39 g, 4.36 mmol) and to 50.0 g (189.9 mmol) of γ-benzyl-L-glutamate / V- carboxyanhydride, a sodium polyL-glutamate modified at one of its ends by the molecule AA6 is obtained. Dry extract: 28.5 mg / g

DP (estimated by NMR = 48 therefore i = 0.021

The calculated average molar mass of the AB16 co-polyamino acid is 7725 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 6500 g / mol.

Example AB17: Co-polyamino acid AB17 - sodium poly-L-glutamate modified at one of its ends by the molecule AA7 and having a number-average molar mass (Mn) of 3500 g / mol [000857] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA7 (2.80 g, 4.32 mmol) and to 25.0 g (94.9 mmol) of γ-benzyl-L-glutamate / V- carboxyanhydride, a sodium polyL-glutamate modified at one of its ends by the molecule AA7 is obtained. Dry extract: 25.2 mg / g

DP (estimated by NMR Ψ) = 26 therefore i = 0.038

The calculated average molar mass of AB17 co-polyamino acid is 4500 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3500 g / mol.

Example AB18: Co-polyamino acid AB18 - sodium poly-L-glutamate modified at one of its ends by the molecule AA7 and having a number-average molar mass (Mn) of 3700 g / mol [000858] A poly-L-glutamate sodium modified at one of its ends by the molecule AA7 is obtained by polymerization of γ-methyl / V-carboxyanhydride of glutamic acid (25.0 g, 133.6 mmol) using the hydrochloride salt of the molecule AA7 (2 , 80 g, 4.32 mmol) as initiator and by deprotecting the methyl esters by using a 37% hydrochloric acid solution according to the process described in patent application FR-A-2 801 226.

Dry extract: 44.3 mg / g

DP (estimated by NMR = 22 therefore i = 0.045

The calculated average molar mass of the AB18 co-polyamino acid is 3896 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3700 g / mol.

120

Example AB19: Co-polyamino acid AB19 - sodium poly-L-glutamate modified at one of its ends by the molecule AA6 and having a number average molar mass (Mn) of 10,500 g / mol [000859] By a process similar to that used for the preparation of co5 polyamino acid AB14 applied to the hydrochloride salt of the molecule AA6 (1.64 g, 2.99 mmol) and to y-benzyl-L-giutamate / V-carboxyanhydride (49.3 g, 187 mmol) , a sodium polyL-glutamate modified at one of its ends by the molecule AA6 is obtained. Dry extract: 23.4 mg / g

DP (estimated by NMR = 65 therefore i = 0.015

The calculated average molar mass of the AB19 co-polyamino acid is 10293 g / mol.

Aqueous HPLC-SEC (PEG calibrator): Mn = 10,500 g / mol.

Example AB20: Co-polyamino acid AB2O - sodium poly-L-glutamate capped at one of its ends by an acetyl group and modified at one of its ends by the molecule AA6 and having a number-average molar mass (Mn) of 10,400 g / mol [000860] In a suitable container are successively introduced the hydrochloride salt of the molecule AA6 (0.545 g, 1.00 mmol), chloroform (10 ml), molecular sieve 4 Â (3 g), as well as Amberlite IR.N 150 20 ion exchange resin (3 g). After 1 h of stirring on rollers, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then co-evaporated with toluene. The residue is dissolved in anhydrous DMF (10 mL) to be used directly in the polymerization reaction.

In a flask previously dried in an oven, γ-benzyl-L-glutamate N25 carboxyanhydride (17.0 g, 64.6 mmol) is placed under vacuum for 30 min then anhydrous DMF (30 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of molecule AA6 prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then precipitated in diisopropyl ether (0.6 L).

The precipitate is recovered by filtration, washed twice with diisopropyl ether (40 ml) then dried to give a white solid which is dissolved in 80 ml of THF. To this solution are successively added DIPEA (1.7 mL, 9.8 mmol) and then acetic anhydride (0.9 mL, 9.5 mmol). After stirring overnight at room temperature, the solution is poured slowly into diisopropyl ether (480 mL) over a period of 30 min and with stirring. After 1 h of stirring, the precipitate is filtered, washed twice with diisopropyl ether (80 mL) then dried under vacuum at 30 ° C to give a poly (gamma-benzyl-L-glutamic acid) capped at one of its ends by a group

121 acetyl and modified at the other of its ends by the molecule AA6 in the form of a white solid.

The solid is diluted in TFA (65 ml), and a solution of hydrobromic acid (HBr) at 33% in acetic acid (45 ml, 257.0 mmol) is then added dropwise and at 4 ° C. The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (780 mL). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with a 1: 1 (v / v) mixture of diisopropyl ether and water (70 mL) then with water (70 mL). The solid obtained is dissolved in water (300 ml) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by adding water to obtain a final volume of 440 mL. The mixture is filtered on a 0.45 μm filter and is then purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to around 30 g / L theoretical and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C. Dry extract: 21.5 mg / g

DP (estimated by NMR = 60 therefore i = 0.017

The calculated average molar mass of AB20 co-polyamino acid is 9619 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 10400 g / mol.

Example AB21 ':

Co-polyamino acid AB21 '- sodium poly-L-glutamate modified at one of its ends by the molecule AA10 and having a number-average molar mass (Mn) of 3478 g / mol [000863] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the hydrochloride salt of the molecule AA10 (0.916 g, 1.38 mmol) and to γ-benzyl-L-glutamate / V-carboxyanhydride (7.19 g, 27.3 mmol) -Sodium glutamate modified at one of its ends by the molecule AA10 is obtained.

Dry extract: 14.8 mg / g

DP (estimated by NMR Ψ) = 25 therefore i = 0.04

The calculated average molar mass of the AB21 'co-polyamino acid is 4364 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3478 g / mol.

122

Example AB23:

Co-polyamino acid AB23 - sodium poly-L-glutamate modified at one of its ends by the molecule AA14 and having a number-average molar mass (Mn) of 3600 g / mol [000864] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the molecule AA14 in the form of free amine (0.820 g, 1.34 mmol) and to γ-benzyl-L-glutamate W-carboxyanhydride (7.75 g, 29.4 mmol) -Sodium glutamate modified at one of its ends by the molecule AA14 is obtained.

Dry extract: 16.8 mg / g

DP (estimated by NMR = 22 therefore i = 0.045

The calculated average molar mass of the AB23 co-polyamino acid is 3897 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3600 g / mol.

Example AB33: Co-polyamino acid AB33 - sodium poly-L-glutamate modified at one of its ends by the molecule AA15 and having a number-average molar mass (Mn) of 1800 g / mol [000865] By a process similar to that used for the preparation of copolyamino acid AB14 applied to the molecule AA15 (0.82 g, 1.34 mmol) and to 7.75 g (29.4 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a solution of sodium poly-Lglutamate modified at one of its ends by the molecule AA15 is obtained. Dry extract: 16.8 mg / g

DP (estimated by NMR ^J H) = 22 therefore i = 0.045

The calculated average molar mass of the co-polyamino acid AB33 is 3897 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 1800 g / mol.

Example AB34: Co-polyamino acid AB34 - sodium poly-L-glutamate modified at one of its ends by the molecule AA4 and having a number-average molar mass (Mn) of 2600 g / mol [000866] In a flask previously dried at the oven, γ-benzyl-L-glutamate Ncarboxyanhydride (70.9 g, 269.3 mmol) is dissolved in anhydrous DMF (125 mL). The mixture is cooled to 4 ° C., then a solution of AA4 molecule in the form of neutral amine (6.80 g, 12.23 mmol) in DMF (35 mL) is rapidly introduced. The mixture is stirred between 4 ° C and room temperature for 18 h, then heated to 65 ° C for 2 h. The reaction medium is then cooled to room temperature and poured dropwise into diisopropyl ether (2.4 L) with stirring. The white precipitate is recovered by filtration, washed with diisopropyl ether (2 x 125 mL) and then dried under reduced pressure at 30 ° C to give a white solid. The solid is dissolved in

123 / V, / V-dimethylacetamide (DMAc, 150 mL) then Pd / AbCh (6 g) is added under an argon atmosphere. The mixture is placed under a hydrogen atmosphere (10 bar) and stirred at 60 ° C for 24 h. After cooling to room temperature and filtration of the catalyst on a sintered P4 then on a 0.2 μm hydrophilic PTFE Omnipore membrane, a solution of water at pH 2 (900 mL) is poured dropwise onto the DMAc solution, on a 45 min period and with stirring. After 18 h with stirring, the white precipitate is recovered by filtration, washed with water and then dried under reduced pressure at 30 ° C. The solid obtained is dissolved in water (1.25 L) by adjusting the pH to 7 by adding a 1N aqueous sodium hydroxide solution. The pH is then adjusted to pH 12 and the solution is stirred for 1 hr. After neutralization at pH 7, the solution is filtered over 0.2 μm, diluted with ethanol in order to obtain a solution containing 30% by mass of ethanol, then filtered on an activated carbon filter (3M R.53SLP). The solution obtained is filtered over 0.45 μm and purified by ultrafiltration against a 0.9% NaCl solution and then with water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to around 30 g / L theoretical and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C. Dry extract: 38.1 mg / g

DP (estimated by NMR ^) = 23 therefore i = 0.043

The calculated average molar mass of the AB34 co-polyamino acid is 3991 g / mol. Organic HPLC-SEC (PEG calibrator): Mn = 2600 g / mol.

Example AB35: Co-polyamino acid AB35 - sodium poly-L-glutamate modified at one of its ends by the molecule AA14-1 and having a number-average molar mass (Mn) of 2600 g / mol [000867] By a similar process to that used for the preparation of copolyamino acid AB34 applied to the molecule AA14-1 (0.4 g, 0.65 mmol) in solution in chloroform (6.5 mL) and 3.79 g (14.4 mmol) of y-benzyl-L-glutamate Ncarboxyanhydride in solution in DMF (6.5 mL), and omitting the filtration step on activated carbon, a solution of sodium poly-L-glutamate modified at one of its ends by the AA14-1 molecule is obtained. Dry extract: 21.0 mg / g

DP (estimated by 1 H NMR) = 22 so i = 0.045

The calculated average molar mass of AB35 co-polyamino acid is 3896 g / mol. Organic HPLC-SEC (PEG calibrator): Mn = 2600 g / mol.

124

Example AB36: Co-polyamino acid AB36 - sodium poly-L-glutamate modified at one of its ends by the molecule AA16 and having a number-average molar mass (Mn) of 2800 g / mol [000868] By a process similar to that used for the preparation of copolyamino acid AB34 applied to the molecule AA16 (3.28 g, 4.67 mmol) and to 27.02 g (102.6 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a solution of sodium poly-Lglutamate modified at one of its ends by the molecule AA16 is obtained. Dry extract: 23.9 mg / g

DP (estimated by NMR Ψ) = 22 therefore i = 0.045

The calculated average molar mass of the AB36 co-polyamino acid is 3987 g / mol. Organic HPLC-SEC (PEG calibrator): Mn - 2800 g / mol.

Example AB37: Co-polyamino acid AB37 - sodium poly-L-glutamate modified at one of its ends by the molecule AA17 and having a number-average molar mass (Mn) of 2800 g / mol [000869] By a process similar to that used for the preparation of copolyamino acid AB34 applied to the molecule AA17 (4.50 g, 9.73 mmol) and to 56.33 g (214.0 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a solution of sodium poly-Lglutamate modified at one of its ends by the molecule AA17 is obtained. Dry extract: 26.8 mg / g

DP (estimated by NMR = 24 therefore i = 0.042

The calculated average molar mass of the AB37 co-polyamino acid is 4049 g / mol. Organic HPLC-SEC (PEG calibrator): Mn = 2800 g / mol.

Part B:

BB: synthesis of the hydrophobic intermediate compounds Hy making it possible to obtain the -Hy radicals in which p - 2 [000870] The hydrophobic intermediate compounds are represented in the following table by the corresponding hydrophobic molecule before grafting on the copolyamino acid.

125

126

Table Id: List of hydrophobic intermediate compounds synthesized according to the invention.

127

Part BA: Synthesis of hydrophobic intermediate compounds in which p = 2

BAI example: BAI molecule

Molecule B1: product obtained by the reaction between decanoic acid and L-proline.

Dicyclohexyl carbodiimide (DCC) (16.29 g, 78.96) are successively added to a solution of decanoic acid (14.28 g, 82.91 mmol) in THF (520 ml) at 0 ° C mmol) and / V-hydroxysuccinimide (NHS) (9.09 g, 78.96 mmol). After 60 h of stirring at room temperature, the medium is cooled to 0 ° C for 20 min, filtered through sintered glass. L-proline (10 g, 86.86 mmol), diisopropylethylamine (DIPEA) (68.8 mL) and water (60 mL) are added to the filtrate. After 24 h of stirring at room temperature, the medium is diluted with water (300 ml). The aqueous phase is washed with ethyl acetate (2 x 250 mL), acidified to pH ~ 1 with a 1N aqueous HCl solution and then extracted with dichloromethane (3 x 150 mL). The combined organic phases are dried over NazSCTt, filtered, concentrated in vacuo and the residue is purified by chromatography on silica gel (cyclohexane, ethyl acetate).

Yield: 14.6 g (69%)

Ψ NMR (CDCh, ppm): 0.87 (3H); 1.26 (12H); 1.65 (2H); 2.02 (3H); 2.34 (2H); 2.41 (1H); 3.48 (1H); 3.56 (1H); 4.58 (1H).

LC / MS (ESI): 270.2; (calculated ([M + H] ⁺ ): 270.4).

Molecule 62: product obtained by the reaction between the molecule B1 and L-lysine.

By a process similar to that used for the preparation of the B1 molecule applied to the B1 molecule (14.57 g, 54.07 mmol) and to L-lysine (4.15 g, 28.39 25 mmol ), a yellow oil is obtained.

Yield: 16.4 g (93%)

NMR (CDCh, ppm): 0.88 (6H); 1.26 (24H); 1.35-1.65 (8H); 1.85-2.35 (12H);

2.53 (0.2H); 2.90 (0.8H); 3.45-3.75 (5H); 4.50-4.70 (3H); 7.82 (1H). LC / MS (ESI): 649.6; (calculated ([M + H] ⁺ ): 649.9).

Molecule B3: product obtained by reaction between the molecule B2 and Bocethylenediamine.

To a solution of molecule B2 (16.4 g, 25.27 mmol) in THF (170 mL) are added DIPEA (8.80 mL) and 2- (1H-benzotriazol-1-yl ) -1.3,335 tetramethyluronium tetrafluoroborate (TBTU, 8.52 g, 26.54 mmol) at room temperature. After 30 min of stirring, Boc-ethylenediamine (4.45 g, 27.8 mmol) is added. After stirring at room temperature for 2 h, the solvent is evaporated off under reduced pressure and the residue is diluted with ethyl acetate (400 ml). The sentence

128 organic is washed with water (250 ml), a saturated aqueous solution of NaHCCh (250 ml), an aqueous solution of 1 N HCl (250 ml), an aqueous saturated solution of NaCi (250 ml) and is dried on NaaSCh. After filtration and concentration under vacuum, the residue obtained is purified by chromatography on silica gel (ethyl acetate, methanol) to give a colorless oil.

Yield: 12.8 g (64%)

1 H NMR (CDCh, ppm): 0.87 (6H); 1.25-1.60 (42H); 1.80-2.05 (4H); 2.15-2.45 (9H); 3.10-3.75 (10H); 4.30 (1H); 4.50 (2H); 5.50 (0.6H); 5.89 (0.2H); 6.15 (0.2H); 7.03 (1H); 7.47 (1H).

LC / MS (ESI): 791.8; (calculated ([M + H] ⁺ ): 792.1).

BAI molecule To a solution of the molecule B3 (12.78 g, 16.15 mmol) in dichloromethane (110 mL) at 5 ° C is added a solution of 4N HCl in dioxane (20.2 mL ). After 20 h of stirring at 5 ° C, the medium is concentrated in vacuo. The residue obtained is dissolved in methanol and evaporated in vacuo, this operation being repeated 4 times to give a white solid of BAI molecule in the form of the hydrochloride salt. Yield: 11.4 g (97%)

Ψ NMR (DMSO-de, ppm): 0.85 (6H); 1.25-1.50 (33H); 1.57 (1H); 1.70-2.40 (12H); 2.82 (2H); 3.00 (2H); 3.25-3.70 (6H); 4.05-4.50 (3H); 7.75-8.45 (6H).

LC / MS (ESI): 691.6; (calculated ([M + H] ⁺ ): 692.0).

Example BA2: BA2 molecule

B4 molecule; Product obtained by the reaction between lauric acid and L-proline.

By a process similar to that used for the preparation of the molecule B1 applied to lauric acid (31.83 g, 157.9 mmol) and to L-proline (20 g, 173.7 mmol), a yellow oil is obtained.

Yield: 34.3 g (73%)

1 H NMR (CDCh, 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 (EST): 298.2; (calculated ([M + H] ⁺ ): 298.4).

Molecule B5: Product obtained by the reaction between the molecule B4 and L-lysine.

By a process similar to that used for the preparation of the B1 molecule applied to the B4 molecule (33.72 g, 113.36 mmol) and to L-lysine (8.70 g, 59.51 mmol) , a white solid is obtained.

Yield: 26.2 g (66%)

129

NMR! Η (CDCh, ppm): 0.88 (6H); 1.26 (32H); 1.35-1.65 (8H); 1.85-2.35 (15H); 2.87 (1H); 3.40-3.75 (5H); 4.50-4.75 (3H); 7.87 (1H).

LC / MS (ESI): 705.6; (calculated ([M + H] ⁺ ): 706.0).

Molecule B6: Product obtained by reaction between Boc-ethylenediamine and the molecule B5.

By a process similar to that used for the preparation of the B3 molecule applied to the B5 molecule (25.74 g, 36.51 mmol) and to Boc-ethylenediamine (6.43 g, 40.16 mmol) , a colorless oil is obtained.

Yield: 30.9 g (quantitative)

NMR ^X H (CDCl₃, ppm): 0.88 (6H); 1.35-1.65 (50H); 1.85-2.35 (13H); 3.05-3.75 (10H); 4.25-4.65 (3H); 5.50 (0.4H); 5.88 (0.2H); 6.16 (0.2H); 7.08 (1H); 7.26 (1H); 7.49 (0.2H)

LC / MS (ESI): 847.8; (calculated ([M + H] ⁺ ): 848.2).

BA2 molecule [000878] After a process similar to that used for the preparation of the BAI molecule applied to the B6 molecule (30.9 g, 36.47 mmol), the residue obtained after concentration in vacuo is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of BA2 molecule in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 27.65 g (97%)

NMR * Η (DMSO-de, ppm): 0.85 (6H); 1.10-2.40 (54H); 2.75-3.15 (4H); 3.25-3.60 (6H); 4.05-4.50 (3H); 7.50-8.50 (6H).

LC / MS (ESI): 747.6; (calculated ([M + H] ⁺ ): 748.1).

Example BA3: BA3 molecule

Molecule B7: Product obtained by the reaction between myristic acid and L-proline. By a process similar to that used for the preparation of the molecule B1 applied to myristic acid (18.93 g, 82.91 mmol) and to L-proline (10 g, 86.86 mmol), a yellowish oil is obtained.

Yield: 20 g (78%)

NMR (CDCh, 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): 326.2; (calculated ([M + H] ⁺ ): 326.6).

130

Molecule ...... B8 2 Product obtained by the reaction between the molecule B7 and L-lysine [000880] By a process similar to that used for the preparation of the molecule B1 applied to the molecule B7 (20.02 g , 61.5 mmol) and with L-lysine (4.72 g, 32.29 mmol), a white solid is obtained.

Yield: 12.3 g (53%)

NMR (DMSO-de, ppm): 0.85 (6H); 1.26 (40H); 1.35-1.50 (6H); 1.50-2.10 (10H); 2.10-2.25 (4H); 3.01 (2H); 3.31-3.55 (4H); 4.10-4.40 (3H); 7.68 (0.6H); 7.97 (1H); 8.27 (0.4H); 12.50 (1H).

LC / MS (ESI): 761.8; (calculated ([M + H] ⁺ ): 762.1).

Molecule B9: Product obtained by the reaction between Boc-ethylenediamine and the molecule B8.

By a process similar to that used for the preparation of the B3 molecule applied to the B8 molecule (12 g, 15.77 mmol) and to Boc-ethylenediamine (3.03 g, 18.92 mmol), a colorless oil is obtained after purification by a chromatographic column on silica gel (ethyl acetate, methanol).

Yield: 12.5 g (88%)

NMR (DMSO-de, ppm): 0.85 (6H); 1.20-1.55 (55H); 1.50-2.25 (14H); 2.95-3.10 (6H); 3.31-3.55 (4H); 4.10-4.40 (3H); 6.74 (1H); 7.60-8.25 (3H).

LC / MS (ESI): 904.1; (calculated ([M + H] ⁺ ): 904.3).

BA3 molecule [000882] After a process similar to that used for the preparation of the BAI molecule applied to the B9 molecule (12.5 g, 13.84 mmol), the residue obtained after concentration in vacuo is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of BA3 molecule in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 9.2 g (79%)

^Χ N NMR (DMSO-de, ppm): 0.85 (6H); 1.10-1.65 (48H); 1.70-2.35 (12H); 2.85 (2H);

3.01 (2H); 3.25-3.65 (6H); 4.10-4.50 (3H); 7.70-8.40 (6H).

LC / MS (ESI): 803.9; (calculated ([M + H] +): 804.2).

Example BA4: BA4 molecule

BIP molecule: Product obtained by the reaction between the B8 molecule and Boc-1-amino4,7,10-trioxa-13-tridecane.

By a process similar to that used for the preparation of the B3 molecule applied to the B8 molecule (29.80 g, 39.15 mmol) and to Boc-l-amino-4,7,10-trioxa13-tridecane (15.05 g, 46.96 mmol), a thick colorless oil is obtained.

131

Yield: 25.3 g (61%)

1 H NMR (DMSO-de, ppm): 0.85 (6H); 1.25-2.35 (75H); 2.85-3.20 (6H); 3.25-3.65 (16H); 4.10-4.45 (3H); 6.38 (O, 1H); 6.72 (0.9H); 7.50-8.25 (3H).

LC / MS (ESI): 1064.2; (calculated ([M + H] +): 1064.5).

BA4 molecule [000884] After a process similar to that used for the preparation of the BAI molecule applied to the B10 molecule (25.3 g, 23.8 mmol), the residue obtained after concentration in vacuo is dissolved in methanol and evaporated under vacuum, this operation being repeated 4 times to give a white solid of BA4 molecule in the form of the hydrochloride salt after drying under reduced pressure.

Yield: 20.02 g (84%)

Ή NMR (DMSO-de, ppm): 0.85 (6H); 1.15-2.35 (66H); 2.80-3.20 (6H); 3.30-3.65 (16H); 4.10-4.45 (3H); 7.55-8.60 (6H).

LC / MS (ESI): 964.9; (calculated ([M + HJ +): 964.6).

Example BA5: BA5 molecule

Bli molecule Product obtained by reaction between palmitoyl chloride and L-proline [000885] By a process similar to that used for the preparation of the molecule A26 applied to palmitoyl chloride (15.39 g, 55.99 mmol) and with L-proline (12.89 g, 111.98 mmol), a white solid of molecule Bli is obtained.

Yield: 19.10 g (96%)

NMR (CDCh, 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): 354.4; 707.8; (calculated ([M + H] ⁺ ): 354.3; ([2M + H] ⁺ ): 707.6).

MalesdeBia ..... r Product obtained by reaction between the molecule Bli and L-Lysine [000886] By a process similar to that used for the preparation of the molecule B1 applied to the molecule Bli (19.10 g, 54, 02 mmol) and with L-lysine (4.15 g, 28.36 mmol), an oily residue is obtained after concentration of the reaction medium under reduced pressure. This residue is diluted in water (150 mL), washed with ethyl acetate (2 x 75 mL) then the aqueous phase is acidified to pH 1 by slow addition of 6N HCl. The product is extracted 3 times with dichloromethane, the organic phase is dried over NazSCU then filtered and concentrated under reduced pressure to give 11.2 g of yellow oily residue. In parallel, the preceding ethyl acetate organic phase is washed with an aqueous 2N HCl solution (2 × 75 mL), an aqueous saturated NaCl solution (75 mL), dried over NazSCh, filtered and concentrated to give 10 , 2 g of residue

132 oily yellow. A white solid is obtained after recrystallization of each of these residues in acetone.

Yield: 11.83 g (54%)

NMR (CDCh, ppm): 0.87 (6H); 1.06-2.44 (70H); 2.78-2.96 (1H); 3.35-3.75 (5H); 4.28-4.43 (O, 1H); 4.43-4.52 (0.2H); 4.52-4.61 (1.8H); 4.61-4.75 (0.9H); 7,748.02 (2H).

LC / MS (ESI): 818.0; (calculated ([M + H] ⁺ ): 818.7).

Molecule B13: Product obtained by coupling between the molecule B12 and Bocethylenediamine [000887] By a process similar to that used for the preparation of the molecule A27 applied to the molecule B12 (18.00 g, 22.02 mmol) in solution in THF and Boc-ethylenediamine (4.23 g, 26.43 mmol), a white solid is obtained after recrystallization twice from acetonitrile

Yield: 17.5 g (83%)

1 H NMR (DMSO-d6, ppm): 0.85 (6H); 1.15-2.29 (79H); 2.92-3.12 (6H); 3.30-3.59 (4H); 4.06-4.13 (0.65H); 4.16-4.29 (2H); 4.38-4.42 (0.35H); 6.71-6.76 (1H); 7,607.69 (1.3H); 7.76-7.81 (0.65H); 7.93-7.97 (0.35H); 8.00-8.04 (0.35H); 8.10-8.17 (0.35H).

LC / MS (ESI): 960.4; (calculated ([M + H] +): 960.8).

BA5 molecule [000888] By a process similar to that used for the preparation of the BAI molecule applied to the B13 molecule (24.4 g, 25.43 mmol), the residue obtained after concentration under vacuum is dissolved in dichloromethane (150 mL), the organic phase is washed twice with a 2 M aqueous sodium hydroxide solution (90 mL). Acetonitrile (120 mL) is added and the dichloromethane is removed by concentration under reduced pressure. The medium is then left to stand for 72 h and a white solid is obtained after filtration and rinsing with acetonitrile then drying under reduced pressure. This operation is repeated 4 times.

Yield: 14.28 g (65%)

1 H NMR (DMSO-d6, ppm): 0.85 (6H); 1.06-2.32 (70H); 2.53-2.63 (2H); 2.89-3.61 (10H); 4.04-4.43 (3H); 7.55-7.62 (0.65H); 7.65-7.72 (0.65H); 7.80 (0.65H); 7.91 (0.35H); 8.03 (0.35H); 8.14-8.23 (0.35H).

LC / MS (ESI): 860.0; (calculated ([M + H] ⁺ ): 860.8).

133

Example BA6: BA6 molecule

Molecule B14: product obtained by coupling between the molecule A26 and 2,3diaminopropionic acid [000889] By a process similar to that used for the preparation of the molecule B1 applied to the molecule A26 (80.00 g, 245.78 mmol ) and with 2,3-diaminopropionic acid dihydrochloride (22.84 g, 129.04 mmol), a white solid is obtained after recrystallization from acetonitrile.

Yield: 69 g (78%)

NMR (DMSO-d6, ppm): 0.86 (6H); 1.08-1.38 (40H); 1.40-1.55 (4H); 1.68-2.30 (12H); 3.16-3.66 (6H); 4.20-4.39 (3H); 7.67-8.31 (2H); 12.70 (1H).

LC / MS (ESI): 719.4; 741.5; (calculated ([M + H] ⁺ ): 719.6; ([M + Na] ⁺ ): 741.6).

Molecule B15: product obtained by coupling between the molecule B14 and Bocethylenediamine [000890] By a process similar to that used for the preparation of the molecule A27 applied to the molecule B14 (32.00 g, 44.50 mmol) in solution in dichloromethane and with Boc-ethylenediamine (8.56 g, 53.40 mmol), a colorless oil is obtained after purification by chromatography on silica gel (ethyl acetate, methanol).

Yield: 24.5 g (64%)

NMR (DMSO-d6, ppm): 0.85 (6H); 1.16-2.42 (65H); 2.89-3.14 (4H); 3.17-3.66 (6H); 4.11-4.43 (3H); 6.77 (1H); 7.38-8.23 (3H).

LC / MS (ESI): 861.7; (calculated ([M + H] ⁺ ): 861.7).

BA6 molecule [000891] By a process similar to that used for the preparation of the BA5 molecule applied to the B15 molecule (24.50 g, 28.45 mmol), a white solid is obtained after recrystallization from acetonitrile.

Yield: 19.7 g (91%)

NMR (DMSO-d6, ppm): 0.85 (6H); 1.10-2.40 (58H); 2.51-2.62 (2H); 2.90-3.16 (2H); 3.16-3.67 (6H); 4.04-4.47 (3H); 7.33-8.27 (3H).

LC / MS (ESI): 761.5; (calculated ([M + H] ⁺ ): 761.6).

Example BA7: BA7 molecule

B16 molecule; product obtained by the reaction between A / - (tert-butoxycarbonyl) -1.6diaminohexane and the molecule B8 [000892] By a process similar to that used for the preparation of the molecule A27 applied to the molecule B8 (10 g, 13 , 14 mmol) and au / V- (tert-butoxycarbonyl) -1.3144 diaminohexane (3.41 g, 15.77 mmol) in dichloromethane, a white solid is obtained after recrystallization from acetonitrile.

Yield: 10.7 g (85%)

NMR (CDCh, ppm): 0.88 (6H); 1.17-2.40 (79H); 3.00-3.71 (10H); 4.26-4.58 (3H); 4.67 (1H); 6.74 (1H); 7.34-7.49 (2H).

LC / MS (ESI): 959.9; (calculated ([MtH] ⁺ ): 959.8).

BA7 molecule [000893] After a process similar to that used for the preparation of the BAI molecule applied to the B16 molecule (10.5 g, 10.94 mmol), an aqueous solution of NaOH 2 N is added dropwise to the medium reaction cooled to 0 ° C. The aqueous phase is extracted with dichloromethane then the organic phase is washed 3 times with a 5% aqueous NaCl solution. After drying over NazSO4, the organic phase is filtered, concentrated in vacuo and the residue is recrystallized from acetonitrile.

Yield: 5.4 g (58%)

1 H NMR (CDCh, ppm): 0.88 (6H); 1.19-2.40 (72H); 2.67 (2H); 3.03-3.70 (8H); 4.26-4.57 (3H); 6.71 (1H); 7.39-7.49 (2H).

LC / MS (ESI): 859.8; (calculated ([M + H] ⁺ ): 859.7).

fiBj_Synthèse des_coj _B Ojh £ aminoacids

Defined co-polyamino acids of formulas VII or Vllb

No. CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER AND HYDROPHOBIC RADICALS BB14 ONa r γΆ i rj .n. / TI »TI * · r ^m II v © ^Ν γΟ ⁰ i xr i i = 0.034, DP (m) = 29 Ri = H or pyroglutamate

135

No.

BB15

CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER AND

HYDROPHOBIC RADICALS_________________________

BB16 i = 0.042, DP (m) = 24 Ri = H or pyroglutamate

i = 0.043, DP (m) = 23 Ri = H or pyroglutamate

136

i = 0.015, DP (m) = 65 Ri = H or pyroglutamate

i = 0.025, DP (m) = 40 Ri = H or pyroqlutamate

137

No.

CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER AND

HYDROPHOBIC RADICALS

BB19 or η

Μ

ChHe 'W

ΒΒ20 i = 0.04, DP (m) = 25 Ri = H or pyroglutamate

We have

Ri - Η or pyroglutamate

138

No.

BB21

CO-POLYAMINOACIDS CARBOXYLATE CHARGE CARRIER AND

HYDROPHOBIC RADICALS

i = 0.11, DP (m) = 9

BB22

Ri = Hou pyroglutamate

i = 0.048, DP (m) = 21

Ri = H or pyroglutamate

139

N ° CO-POLYAMINOACIDS CARRIER OF CARBOXYLATES AND

HYDROPHOBIC RADICALS

i = 0.048, DP (m) = 21

Ri = H or pyroglutamate

BB24 ~

NOT

M3H27

O i = 0.040, DP (m) = 25

Ri = H or pyroglutamate

140

N ° CO-POLYAMINOACIDS CARRIER OF CARBOXYLATES AND ____ OF HYDROPHOBIC RADICALS

BB25

i = 0.043, DP (m) = 23

Ri = H or pyroglutamate

^C 13 ^H 27 i = 0.048, DP (m) = 21 Ri = H or pyroglutamate

141

142

BB42

143

144

BB43 »L ® Γ \ H 1 H / / J. _χ Ν XX XX. X ^ X. / 'X ^' Xf X ^ ^X N ^X 'X' ^ '' N h 1 h 1 \ 'II' ^m A ®- Z * ° jL ^ C _f3 H _y; ro ^z HN \ Z ^ 'N ⁰ , ÿZX _n H „0 i = 0,09, DP (m) = 22 \ ^^ N ^^ Z ^Cl3H 2 ⁷ X-. ⁰ 0 ^ ^V 'NH \ 9y Zx * ^ 13 ^ 27: || ^NH Ί3 Ri = ⁰ ) BB44 fled i fi \ R t, 1. 1 1 X _x ΖΊΚ j · Γ'Νΐί ^ Ϊ1Γ 'if' ^N J 'A «.i .O î k i = 0,04, DP (m) = 25 Ri = H or pyroglutamate

Table le: list of co-polyamino acids synthesized according to the invention

145

Part BB: synthesis of co-polyaminoacids

Example BB14: co-polyamino acid BB14 - sodium poly-L-glutamate modified at one of its ends by the molecule BA2 and having a number-average molar mass (Mn) of 4020 g / mol [000894] A suitable container is introduced successively the hydrochloride salt of the molecule BA2 (2.12 g, 2.70 mmol), chloroform (40 mL), 4 A molecular sieve (1.5 g), as well as the ion exchange resin Amberlite IRN 150 (1.5 g). After 1 hour of stirring on rollers, the medium is filtered and the resin is rinsed with chloroform. The mixture is evaporated and then co-evaporated with toluene. The residue is dissolved in anhydrous DMF (20 mL) to be used directly in the polymerization reaction.

In a balloon previously dried in an oven, y-benzyl-L-glutamate Ncarboxyanhydride (18 g, 68.42 mmol) is placed under vacuum for 30 min and then anhydrous DMF 15 (100 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then the solution of BA2 molecule prepared as described above is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 2 days, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to ambient temperature then poured dropwise into diisopropyl ether (1.2 L) with stirring. The white precipitate is recovered by filtration, washed twice with diisopropyl ether (100 ml) then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (105 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (38 mL, 220 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 2 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (600 ml). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with a 1: 1 mixture (v / v) of diisopropyl ether and water (200 ml) then with water (100 ml). The solid obtained is dissolved in water (450 mL) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. The mixture is filtered on a 0.45 filter. pm then is purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 22.3 mg / g

DP (estimated by NMR ^) = 29 so i = 0.034

The calculated average molar mass of the co-polyamino acid BB14 is 5089 g / mol.

146

Aqueous HPLC-SEC (PEG calibrator): Mn = 4020 g / mol.

Example BB15: co-polyamino acid BB15 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 3610 g / mol [000896] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA3 (3.62 g, 4.32 mmol) and to 25.0 g (94.97 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride , a sodium polyL-glutamate modified at one of its ends by the molecule BA3 is obtained. Dry extract: 26.5 mg / g

DP (estimated by NMR = 24 therefore i = 0.042

The calculated average molar mass of the co-polyamino acid BB15 is 4390 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3610 g / mol.

Example BB16: co-polyamino acid BB16 - sodium poly-L-glutamate modified at one of its ends by the molecule BA4 and having a number-average molar mass (Mn) of 3300 g / mol [000897] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA4 (5.70 g, 5.70 mmol) and to 29.99 g (113.9 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride , a sodium poly-L-glutamate modified at one of its ends by the molecule BA4 is obtained.

Dry extract: 32.3 mg / g

DP (estimated by NMR ^) = 23 therefore i - 0.043

The calculated average molar mass of the co-polyamino acid BB16 is 4399 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / mol.

Example BB17: co-polyamino acid BB17 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass of 10700 g / mol [000898] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA3 (2.51 g, 3 mmol) and to 52.7 g (200 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a sodium poly-Lglutamate modified at one of its ends by the BA3 molecule is obtained. Dry extract: 24.5 mg / g

DP (estimated by NMR * Η) = 65 therefore i = 0.015

The calculated average molar mass of the co-polyamino acid BB17 is 10585 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 10700 g / mol.

147

Example BB18: co-polyamino acid BB18 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass of 6600 g / mol [000899] By a process similar to that used for the preparation of copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA3 (2.51 g, 3 mmol) and to 31.6 g (120 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a sodium poly-Lglutamate modified at one of its ends by the BA3 molecule is obtained. Dry extract: 27.3 mg / g

DP (estimated by 1 H NMR) = 40 so i = 0.025

The calculated average molar mass of the co-polyamino acid BB18 is 6889 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 6600 g / mol.

Example BB19: co-polyamino acid BB19 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 3400 g / mol [000900] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the hydrochloride salt of the molecule BA3 (36.26 g, 43.2 mmol) and of y-benzyl-L-glutamate / V-carboxyanhydride (250.0 g, 949.7 mmol) , a sodium poly-L-glutamate modified at one of its ends by the molecule BA3 is obtained.

Dry extract: 22.4 mg / g

DP (estimated by ¹ H NMR) = 25 therefore i = 0.04

The calculated average molar mass of the co-polyamino acid BB19 is 4540 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3400 g / mol.

Example BB20:

co-polyamino acid BB20 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 2500 g / mol [000901] By a process similar to that used for the preparation of copolyamino acid BB14 applied to the BA3 molecule in the form of free amine (1.017 g, 12.7 mmol) and γ-benzyl-L-glutamate / V-carboxyanhydride (5.0 g, 19.0 mmol), a sodium poly-L-glutamate modified at one of its ends by the molecule BA3 is obtained.

Dry extract: 11.2 mg / g

DP (estimated by ¹ H NMR) = 17 therefore i = 0.059

The calculated average molar mass of the co-polyamino acid BB20 is 3332 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2500 g / mol.

148

Example BB21:

co-polyamino acid BB21 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 1100 g / mol [000902] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the BA3 molecule in the form of free amine (3.814 g, 4.75 mmol) and of γ-benzyl-L-glutamate / V-carboxyanhydride (10.0 g, 38.0 mmol), a sodium poly-L-glutamate modified at one of its ends by the molecule BA3 is obtained.

Dry extract: 16.1 mg / g

DP (estimated by NMR = 9 therefore i = 0.11

The calculated average molar mass of the co-polyamino acid BB21 is 2123 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 1100 g / mol.

Example BB22:

co-polyamino acid BB22 - sodium poly-D-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 2900 g / mol [000903] By a process similar to that used for the preparation of copolyamino acid BB14 applied to the BA3 molecule in the form of free amine (2.77 g, 3.45 mmol) and γ-benzyl-D-glutamate / V-carboxyanhydride (20.0 g, 76.0 mmol) , a sodium polyD-glutamate modified at one of its ends by the molecule BA3 is obtained. Dry extract: 15.2 mg / g

DP (estimated by NMR = 21 therefore i = 0.048

The calculated average molar mass of the co-polyamino acid BB22 is 3936 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2900 g / mol.

Example BB23:

co-polyamino acid BB23 - random copolymer of sodium D- or L-glutamate unit modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 2800 g / mol [000904] In a flask previously dried in an oven, γ-benzyl-L-glutamate Ncarboxyanhydride (20.0 g, 76.00 mmol) and γ-benzyl-D-glutamate Ncarboxyanhydride (20.0 g, 76.00 mmol) are placed under vacuum for 30 min then anhydrous DMF (75 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then a solution of BA3 molecule in the form

149 of free amine (5.55 g, 6.91 mmol) in chloroform (14.5 mL) is introduced quickly. The mixture is stirred between 4 ° C and room temperature for 18 h, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to room temperature then poured dropwise into diisopropyl ether (1.2 L) with stirring. The white precipitate is recovered by filtration, washed three times with diisopropyl ether (80 ml) then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (152 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (106 mL, 220 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 3 h at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (1.84 L). The aqueous phase is separated in a dropping funnel and the pH is adjusted to 7.2 by adding an aqueous 10N NaOH solution. After adding water (250 mL), the mixture is filtered on a 0.45 filter. pm then is purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to approximately 25 g / L, filtered through 0.2 μm and stored at 4 ° C.

[000905]

Dry extract: 28.2 mg / g

DP (estimated by NMR ^) = 21 so i = 0.048

The calculated average molar mass of the co-polyamino acid BB23 is 3936 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2800 g / mol.

Example BB24: co-polyamino acid BB24 - block copolymer of poly-Dglutamate and sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 2800 g / mol [ 000906] In a balloon previously dried in an oven, γ-benzyl-D-glutamate Ncarboxyanhydride (13.5 g, 51.3 mmol) is placed under vacuum for 30 min and then anhydrous DMF (52 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 0 ° C., then a solution of BA3 molecule in the form of free amine (3.43 g, 4.27 mmol) in chloroform (8.6 mL) is introduced quickly. The mixture is stirred at 0 ° C for 24 h, then a solution of y-tert-butyl-L-glutamate / V-carboxyanhydride (13.5 g, 58.9 mmol) in DMF (15 mL) is added. The mixture is then stirred between 0 ° C and room temperature for 21 h, then heated to 65 ° C for 2 h. The reaction mixture is then cooled to ambient temperature then poured dropwise into diisopropyl ether (0.8 L) with stirring. The white precipitate is recovered by filtration, washed three times with diisopropyl ether (52 mL) and then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (96 mL),

150 and a 33% solution of hydrobromic acid (HBr) in acetic acid (68 mL, 388 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 2 h at room temperature then is poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (1.2 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with a 1: 1 mixture (v / v) of diisopropyl ether and water (100 ml) then with water (100 ml). The solid obtained is dissolved in water (900 mL) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. The mixture is filtered on a 0.45 μm filter. then is purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to around 20 g / L theoretical and the pH is adjusted to 7. The aqueous solution is filtered through 0.2 μm and stored at 4 ° C.

Dry extract: 23.9 mg / g

DP (estimated by ¹ H NMR) = 25 therefore i = 0.04

The calculated average molar mass of the co-polyamino acid BB24 is 4541 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2800 g / mol.

Example BB25: co-polyamino acid BB25 - sodium poly-L-glutamate modified at one of its ends by the molecule BA5 and having a number-average molar mass (Mn) of 2800 g / mol [000907] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the molecule BA5 in the form of free amine (1.70 g, 1.98 mmol) and of y-benzyl-L-glutamate / V-carboxyanhydride (11.46 g, 43, 5 mmol), a sodium polyL-glutamate modified at one of its ends by the molecule BA5 is obtained. Dry extract: 19.8 mg / g

DP (estimated by NMR = 23 therefore i = 0.043

The calculated average molar mass of the co-polyamino acid BB25 is 4295 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2800 g / mol.

Example BB26:

co-polyamino acid BB26 - sodium poly-L-glutamate modified at one of its ends by the molecule BA6 and having a number-average molar mass (Mn) of 2900 g / mol [000908] By a process similar to that used for the preparation of copolyamino acid BB14 applied to the BA6 molecule in the form of free amine (3.05 g, 4.01

151 mmol) and γ-benzyl-L-glutamate / V-carboxyanhydride (22.78 g, 86.5 mmol), a sodium polyL-glutamate modified at one of its ends by the molecule BA6 is obtained. Dry extract: 16.9 mg / g

DP (estimated by NMR ’• H) = 21 so i = 0.048

The calculated average molar mass of the co-polyamino acid BB26 is 3894 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2900 g / mol.

Example BB27:

co-polyamino acid BB27 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and modified by the molecule BA3 and having a number-average molar mass (Mn) of 2300 g / mol [000909] Co -polyamino acid BB27-1: poly-L-glutamic acid of number average molar mass (Mn) 3600g / mol modified at one of its ends by the molecule BA3 and capped at the other end by pidolic acid.

In a balloon previously dried in an oven, γ-benzyl-L-glutamate Ncarboxyanhydride (122.58 g, 466 mmol) is placed under vacuum for 30 min and then anhydrous DMF (220 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to -10 ° C, then a solution of BA3 molecule in the form of free amine (17.08 g, 21.3 mmol) in chloroform (40 mL) is introduced quickly. The mixture is stirred between 0 ° C and room temperature for 2 days, then heated to 65 ° C for 4 h. The reaction mixture is then cooled to 25 ° C. and then added pidolic acid (13.66 g, 105.8 mmol), HOBt (2.35 g, 15.3 mmol) and EDC (20 , 28 g, 105.8 mmol). After 24 h of stirring at 25 ° C, the solution is concentrated under vacuum to remove the chloroform and 50% of the DMF. The reaction mixture is then heated to 55 ° C. and 1150 ml of methanol are introduced over 1 hour. The reaction mixture is then cooled to 0 ° C. After 18 h, the white precipitate is recovered by filtration, washed three times with 270 ml of diisopropyl ether and then dried under vacuum at 30 ° C to obtain a white solid. The solid is diluted in TFA (390 mL), and a 33% solution of hydrobromic acid (HBr) in acetic acid (271 mL, 1547 mmol) is then added dropwise and at 0 ° C. The solution is stirred for 2 h at room temperature then is poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (970 mL). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed successively with diisopropyl ether (380 mL) then twice with water (380 mL). The solid obtained is dissolved in water (3.6 L) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. The mixture is filtered on filter 0, 45 μm then is purified by ultrafiltration against a 0.9% NaCl solution, a 0.1 N NaOH solution, a NaCl solution

152

0.9%, a phosphate buffer solution (150 mM), a 0.9% NaCl solution and then water until the conductivity of the permeate is less than 50 pS / cm. The co-polyamino acid solution is then concentrated to around 30 g / L theoretical, filtered through 0.2 μm and then acidified to pH 2 with stirring by addition of a 37% HCl solution. The precipitate is then recovered by filtration, washed twice with water and then dried under vacuum at 30 ° C to obtain a white solid.

Co-polyamino acid BB27 By a process similar to that used for the preparation of copolyamino acid BB2 applied to the molecule BA3 in the form of free amine (1.206 g, 1.50 mmol) and to the co-polyamino acid BB27-1 (5 , 5 g, 33.4 mmol), a sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and modified by the molecule BA3 is obtained.

Dry extract: 19.0 mg / g

DP (estimated from NMR: 22

According to the NMR ^: 1 = 0.089

The calculated average molar mass of the co-polyaminoadde BB27 is 4826 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2300 g / mol.

Example BB42:

co-polyamino acid BB42 - sodium poly-L-glutamate modified at one of its ends by the molecule BS and having a number-average molar mass (Mn) of 3200 g / mol [000912] To a solution of molecule B8 (2.366 g , 3.11 mmol) in DMF (19.5 mL) are introduced DCC (0.659 g, 3.19 mmol) and NHS (0.365 g, 3.17 mmol). After 16 h of stirring at room temperature, the solution is filtered to be used directly in the following reaction.

In a balloon previously dried in an oven, γ-benzyl-L-glutamate Ncarboxyanhydride (18.0 g, 68.4 mmol) is placed under vacuum for 30 min and then anhydrous DMF (40 mL) is introduced . The mixture is then stirred under argon until complete dissolution, cooled to 0 ° C, then hexylamine (0.411 mL, 3.11 mmol) is introduced quickly. After 30 h of stirring at 0 ° C., the solution of molecule B8 prepared previously is added. The solution is stirred between 0 ° C and room temperature for 72 h then poured dropwise into diisopropyl ether (0.9 L) with stirring. The precipitate is recovered by filtration, washed with diisopropyl ether (5 times 100 ml) then dried under vacuum at 30 ° C to give a white solid. The solid is diluted in TFA (69 mL), then the solution is cooled to 4 ° C. A 33% solution of HBr in acetic acid (48 mL, 0.274 mol) is then added dropwise. The

The mixture is stirred at room temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (0.8 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed with a 1: 1 (v / v) mixture of diisopropyl ether and water (70 ml) then with water (70 ml). The solid obtained is then dissolved in water (0.42 L) by adjusting the pH to 7 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 g / L theoretical by addition of water to obtain a final volume of 0.63 L. The solution is filtered on a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution, then l until the conductivity of the permeate is less than 50 pS / cm. The solution obtained is filtered through a 0.2 μm filter and stored at 28 ° C.

Dry extract: 22.2 mg / g

DP (estimated from NMR: 22

According to the NMR ^: 1 = 0.045

The calculated average molar mass of the co-polyamino acid BB42 is 4160 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3200 g / mol.

Example BB25 ': co-polyamino acid BB25' - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and at the other end by the molecule B8 and having a number-average molar mass (Mn) of 2000 g / mol [000914] DCC (0.257 g, 1.24 mmol) and NHS (0.143 g, 1) are introduced into a solution of molecule B8 (0.946 g, 1.24 mmol) in DMF (8 mL) 24 mmol). After 16 h of stirring at room temperature, the solution is filtered to be used directly in the following reaction.

In a balloon previously dried in an oven, γ-benzyl-L-glutamate / V-carboxyanhydride (6.0 g, 22.8 mmol) is placed under vacuum for 30 min and then anhydrous DMF (14 mL ) is introduced. The mixture is then stirred under argon until complete dissolution, cooled to 0 ° C., then a solution of BA3 molecule in the form of free amine (0.832 g, 1.04 mmol) in chloroform (2.0 ml) is introduced quickly. After 18 h of stirring at 0 ° C., the solution of molecule B8 prepared previously is added. The solution is stirred between 0 ° C and room temperature for 22 h then poured dropwise into diisopropyl ether (0.34 L) with stirring. The precipitate is recovered by filtration, washed with diisopropyl ether (7 times 15 mL) then dried under vacuum at 30 ° C to give a white solid. The solid is diluted in TFA (23 mL), then the solution is cooled to 4 ° C. A 33% HBr solution in acetic acid (15 mL, 85.7 mmol) is then added dropwise. The mixture

154 is stirred at room temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether and water with stirring (0.28 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed twice with a 1: 1 (v / v) mixture of diisopropyl ether and water (24 mL) then twice with water (24 mL). The solid obtained is then dissolved in water (0.16 L) by adjusting the pH to 12 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After 30 min the pH is adjusted to 7 by slow addition of a 1N aqueous HCl solution. The solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductivity of the permeate is less than 50 pS / cm. The solution obtained is filtered through a 0.2 μm filter and stored at 2-8 ° C.

Dry extract: 18.9 mg / g

PD (estimated from N NMR): 22

According to ¹ H NMR: ii = 0.09

The calculated average molar mass of the co-polyamino acid BB25 'is 4871 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2000 g / mol.

Example BB43:

co-polyamino acid BB43 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and at the other end by the molecule B8 and having a number-average molar mass (Mn) of 2000 g / mol [000916 ] DCC (0.257 g, 1.24 mmol) and NHS (0.143 g, 1.24 mmol) are introduced into a solution of molecule B8 (0.946 g, 1.24 mmol) in DMF (8 ml). After 16 h of stirring at room temperature, the solution is filtered to be used directly in the following reaction.

In a balloon previously dried in an oven, γ-benzyl-L-glutamate Ncarboxyanhydride (6.0 g, 22.8 mmol) is placed under vacuum for 30 min and then anhydrous DMF (14 mL) is introduced . The mixture is then stirred under argon until complete dissolution, cooled to 0 ° C., then a solution of BA3 molecule in the form of free amine (0.832 g, 1.04 mmol) in chloroform (2.0 ml) is introduced quickly. After 18 h of stirring at 0 ° C., the solution of molecule B8 prepared previously is added. The solution is stirred between 0 ° C and room temperature for 22 h then poured dropwise into diisopropyl ether (0.34 L) with stirring. The precipitate is recovered by filtration, washed with diisopropyl ether (7 times 15 mL) then dried under vacuum at 30 ° C to give a white solid. The solid is diluted in TFA (23 mL), then the solution is cooled to 4 ° C. A 33% HBr solution in acetic acid (15 mL, 85.7 mmol) is then added dropwise. The mixture is stirred at room temperature for 2 h, then poured dropwise onto a 1: 1 (v / v) mixture of

155 diisopropyl ether and water with stirring (0.28 L). After 2 h of stirring, the heterogeneous mixture is left to stand overnight. The white precipitate is recovered by filtration, washed twice with a 1: 1 (v / v) mixture of diisopropyl ether and water (24 mL) then twice with water (24 mL). The solid obtained is then dissolved in water (0.16 L) by adjusting the pH to 12 by adding a 10N aqueous sodium hydroxide solution and then a 1N aqueous sodium hydroxide solution. After 30 minutes the pH is adjusted to 7 by slow addition of a 1N aqueous HCl solution. The solution is filtered through a 0.45 μm filter and then purified by ultrafiltration against a 0.9% NaCl solution, then water until the conductivity of the permeate is less than 50 pS / cm. The solution obtained is filtered through a 0.2 μm filter and stored at 2-8 ° C.

Dry extract: 18.9 mg / g

DP (estimated from NMR ^): 22

According to the NMR ^X H: ii = 0.09

The calculated average molar mass of the co-polyamino acid BB43 is 4871 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 2000 g / mol.

Example BB44: co-polyamino acid BB44 - sodium poly-L-glutamate modified at one of its ends by the molecule BA7 and having a number-average molar mass (Mn) of 3300 g / mol [000918] By a process similar to that used for the preparation of the copolyamino acid BB14 applied to the BA7 molecule in the form of free amine (4.45 g, 5.18 mmol) and to 30.0 g (113.96 mmol) of γ-benzyl-L-glutamate / V-carboxyanhydride, a sodium poly-L-glutamate modified at one of its ends by the molecule BA7 is obtained.

Dry extract: 29.0 mg / g

DP (estimated by NMR - 25 therefore i = 0.04

The calculated average molar mass of the co-polyamino acid BB44 is 4597 g / mol. Aqueous HPLC-SEC (PEG calibrator): Mn = 3300 g / mol.

Part C: Compositions The glucagon used is human glucagon resulting from a process of peptide synthesis. It comes from the company Bachem (reference 4074733).

The nicotinamide used, tested according to the recommendations of the European pharmacopoeia, comes from Sigma-Aldrich (reference 72347).

The Treprostinil used comes from Ferrer Internacional (reference 1100269).

156

Exfi.maleXl .... Solution of, G.toiLODAZ ... DigZm.Ldan..s ^^ containing ..2 ,.

mg / ml of L-methionine 94.7 mg of powdered glucagon DS is introduced into a 50 ml Falcon tube followed by 45 ml of a 0.003 N hydrochloric acid solution containing 2 mg / ml of L methionine. The glucagon powder is mixed by repeated inversions of the tube until the glucagon is completely dissolved. The 2 mg / mL glucagon solution is then filtered through a membrane (0.22 μm).

ExemMeX ^ ..... da0 „s ...... i: a, cLdej; blprJiY.drLQ.Ufi [000921] 23.4 mg of powdered glucagon DS is added to a 20 ml Falcon tube followed by 11.3 mL of 0.003 N hydrochloric acid solution. The glucagon powder is mixed by repeated inversions of the tube until the glucagon is completely dissolved. The 2 mg / mL glucagon solution is then filtered through a membrane (0.22 μm).

Example C3: Solution of Glucagon at 4 mg / ml in hydrochloric acid containing 2 [000922] Glucagon (160 mg) in powder is introduced into a Falcon tube of 45 ml then 40 ml of the aqueous hydrochloric acid solution to 0.006 N containing 2 mg / mL of L-methionine is added. The glucagon powder is mixed by repeated inversions of the tube until the glucagon is completely dissolved. The glucagon solution at 4 mg / ml is then filtered through a membrane (0.22 μm).

Example C4: Glucagon solution at 4 mg / ml in hydrochloric acid [000923] Glucagon (160 mg) in powder is introduced into a Falcon tube of 45 ml. A 0.003 N aqueous hydrochloric acid solution (40 ml) is added. The glucagon powder is mixed by repeated inversions of the tube until the glucagon is completely dissolved. The glucagon solution at 4 mg / ml is then filtered through a membrane (0.22 μm).

Example C5: Tris buffer solution at 500 mM pH 8.3 [000924] In a 50 ml flask, 3.0 g of Trizma® base (Sigma-Aldrich 04577) are weighed. Water is added without completing the dipstick. Once the powder has dissolved, the pH of the solution is adjusted to pH 7.2 ± 0.1 by addition of 1N NaOH / HCl then the solution is filtered through a membrane (0.22 μm). The volume of water is adjusted to obtain the concentrated Tris solution.

157

ExempJeCRO ....... Preparation ..... de.so.ludons de..ço _: .pp! Yaminpagde ..... 6815..3.7,6..111.3 / .011 eLde.ql.uca .gpn.

A solution of concentrated glycerol (to obtain 300 mOsmole / kg in the final formulation), in phosphate buffer (4 mM) and in m-cresol (54 mM), is added a solution of co-polyamino acid BB15 to 15.22 mg / mL. At this point additives, such as citrate, nicotinamide, Treprostinil and magnesium, can be added. The composition is briefly stirred until dissolution of the co-polyamino acid, then the solution is filtered through a membrane (0.22 μm).

6.5 ml of a freshly prepared glucagon solution, according to the protocol described in Example C2, are mixed with 6.5 ml of the co-polyamino acid solution BB15, as prepared above, so as to obtain the final compositions CR0-1 to CR0-11 (Table 1). The pH of the solution is adjusted to pH 7.2 ± 0.1 by addition of 1 N NaOH / HCl and then filtered through a membrane (0.22 μm).

A visual inspection is carried out to determine whether or not a clear solution is obtained. Visual inspection of the samples is carried out to detect visible particles, or turbidity. This inspection is carried out according to the recommendations of the European Pharmacopoeia (EP 2.9.20): the samples are subjected to lighting of at least 2000 Lux and are observed in front of a white background and a black background. When particles are visible in half of the samples, the composition is estimated to be not clear.

Example .CS0.; ...... Preparation of co-polyamino acid solutions BB.1.5 .. at .6.3 mq / .ml and glucagon at 2 mg / ml [000926] To solutions concentrated in glycerol ( to obtain 300 mOsmole / kg in the final formulation), in phosphate buffer (4 mM) and in m-cresol (54 mM), a solution of co-polyamino acid BB15 at 12.6 mg / ml is added. At this point additives, such as citrate, nicotinamide, Treprostinil and magnesium, can be added. The composition is briefly stirred until dissolution of the co-polyamino acid, then the solution is filtered through a membrane (0.22 μm).

6.5 ml of a freshly prepared glucagon solution, according to the protocol described in Example C2, are mixed with 6.5 ml of the co-polyamino acid solution, as prepared above, so as to obtain the final compositions CS0-1 to CS0-4 (Table 1). The pH of the solution is adjusted to pH 7.2 ± 0.1 by adding NaOH / HCl IN and then filtered through a membrane (0.22 μm).

A visual inspection is carried out to determine whether or not a clear solution is obtained. By comparison, the glucagon solution at neutral pH is not soluble above 0.2 mg / mL.

158

Composition BB15 copolyamino acid concentration (mg / ml) Ratio Noacid Copolyami / Glucag on Glycerol (mM) Additive Visual aspect of the solution CR0-1 7.6 3 260 limpid CRO-2 7.6 3 220 10 mM citrate limpid CRO-3 7.6 3 249 20 mM nicotinamide limpid CR0-4 7.6 3 228 40 mM nicotinamide limpid CRO-5 7.6 3 188 80 mM nicotinamide limpid CRO-6 7.6 3 263 2 mM Mg limpid CRO-7 7.6 3 255 5 mM Mg limpid CRO-8 7.6 3 242 10 mM Mg limpid CRO-9 7.6 3 268 13 ng / mL Treprostinil limpid CR0-10 7.6 3 268 128 ng / mL Treprostinil limpid CR0-11 7.6 3 268 1000 ng / mL treprostinil limpid CS0-1 6.3 2.5 257 : limpid CSO-2 6.3 2.5 248 5 mM citrate limpid CSO-3 6.3 2.5 163.7 5 mM citrate + 80 mM nicotinamide limpid CS0-4 6.3 2.5 188 80 mM nicotinamide limpid

Table 2: Compositions and visual appearance of the glucagon solutions at 2 mg / mL at pH

7.2 at different concentrations of co-polyamino acid BB15 containing m-cresol (27 mM), 1 mg / ml of L-methionine and phosphate buffer (2 mM).

ELIMINATEXVOJXREEaratÎonJlin ^ oluü ^^ ao.iÿ.a.minQ.a £ ideBBlOJlfLerentes concgnLraÜQ ^ and glycerin at pH 7.2.

In a bottle containing concentrated solutions of excipients (phosphate, glycerol) and potentially additives (m-cresol, citrate), a solution of co-polyamino acid BB15 is added. The composition is briefly stirred until dissolution of the co-polyamino acid, then the solution is filtered through a membrane (0.22 μm). The equivolumic mixture of this solution with the freshly prepared glucagon solution, as described in Example Cl, leads to the final compositions CV0-1 to CVO-13 containing 1 mg / ml of glucagon. The pH of the solution is adjusted to pH

7.2 ± 0.1 by addition of 1N NaOH / HCl then filtered through a membrane (0.22pm). The details of the compositions are summarized in the table below.

159 [000929] A visual inspection is carried out to determine whether or not a clear solution is obtained. By comparison, the glucagon solution at neutral pH is not soluble above 0.2 mg / mL.

Compositio n Concentration in copolyamino BB15 (Mg / ml) Ratio Copolya minoa eide / Gluca gon glycero 1 (mM) additives Visual aspect of the solution CV0-1 3.8 3 255 10 mM citrate limpid CVO-2 3.8 3 235 15 mM citrate limpid CVO-3 3.8 3 215 20 mM citrate limpid CVO-4 4.5 3 255 10 mM citrate limpid CVO-5 4.5 3 235 15 mM citrate limpid CVO-6 4.5 3 215 20 mM citrate limpid CVO-7 3.8 3 235 10 mM citrate + 20 mM nicotinamide limpid CVO-8 3.8 3 215 10 mM citrate + 40 mM nicotinamide limpid CVO-9 3.8 3 175 10 mM citrate + 80 mM nicotinamide limpid CV0-10 3.8 3 85 10 mM citrate + 170 mM nicotinamide limpid CVO-11 3.8 3 255 40 mM nicotinamide limpid CVO-12 3.8 3 215 80 mM nicotinamide limpid CVO-13 3.8 3 125 170 mM nicotinamide limpid

Table 3: Compositions and visual appearance of glucagon solutions at 1 mg / mL at pH

7.2 at different concentrations of co-polyamino acid BB15 containing 1 mg / mL of Lmethionine and phosphate buffer (2 mM).

Examples ........ THAT .......; ................. Preparation ....... of ... solutions, glucagon at 1 mg / mL containing ..... different

.......... .. mM). ............ ............... of the ..... .... glycerin ................ and ............... different CQn £ ent.tip..ns .... .de ... ch .. | .o.ru.re ...... de ........ sodium ........ and ..... chloride de ... ..zinc at .pH 7.2.

In a bottle are successively added a concentrated solution of glycerol (in order to obtain 300 mOsmole / kg in the final formulation), a concentrated solution of Tris buffer (example C5), additives (NaCl, zinc chloride) and copolyamino acid in solution or in the form of a lyophilisate. The composition is stirred until dissolution of the co-polyamino acid. The pH of the solution is adjusted to pH 7.2 ± 0.1 by addition of 1 N NaOH / HCl then the solution is filtered through a membrane (0.22 μm).

The equivolumic mixture of this solution is added to the freshly prepared glucagon solution, as described in Example Cl, and leads to the final compositions CAI to CA6 and CA7 to CA32 containing 1 mg / ml of glucagon. PH

160 of the solution is adjusted to pH 7.2 ± 0.1 by addition of 1N NaOH / HCl then filtered through a membrane (0.22pm). The details of the compositions are summarized in Tables 1 and 2.

A visual inspection is carried out to determine whether or not a clear solution is obtained (By comparison, the glucagon solution at neutral pH is not soluble above 0.2 mg / ml). Visual inspection of the samples is carried out to detect visible particles, or turbidity. This inspection is carried out according to the recommendations of the European Pharmacopoeia (EP 2.9.20): the samples are subjected to lighting of at least 2000 Lux and are observed in front of a white background and a black background. When particles are visible in half of the samples, the composition is estimated to be not clear.

Solution Copolyamino acid Copolyamino acid concentration (mg / mL) Copolyaminoa cide / glucagon ratio NaCl (MM) Zn (MM) Glycer ol (mM) Aspe and visue 1 of the solution CAI B3 10.7 9.0 0 0 289 clear CA2 10.7 9.0 25 0 239 limpid e CA3 10.7 9.0 50 0 189 limpid e CA4 10.7 9.0 0 1.29 285 limpid e CA5 10.7 9.0 25 1.29 235 clear CA6 10.7 9.0 50 1.29 185 clear

Table 4: Compositions and visual appearance of the glucagon solutions at 1 mg / ml containing Tris buffer (2 mM), 1 mg / ml of L-methionine in the presence of different concentrations of co-polyamino acid, sodium chloride and zinc chloride at pH 7.2.

161

Composition Copolyam inoacid e Concentration of acid copolyamino. (Mg / mL) Inoacid / glucagon Copolyam ratio NaCI (mM) ZnCI ₂ (mM) Glycerin (mM) Visual aspect of the solution CA7 5.9 5 0 0 274 limpid CA8 5.9 5 50 0 174 limpid CA9 5.9 5 100 0 74 limpid CA10 5.9 5 200 0 0 limpid CA11 5.9 5 300 0 0 limpid CA12 AB14 5.9 5 0 2.87 266 limpid CA13 5.9 5 50 2.87 166 limpid CA 14 5.9 5 100 2.87 66 limpid CA15 5.9 5 200 2.87 0 limpid CA16 5.9 5 00 2.87 0 limpid CA17 5.6 : 5 0 0 282 limpid CA18 5.6 5 25 0 232 limpid CA19 5.6 5 50 0 182 limpid CA20 5.6 5 100 0 82 limpid CA21 5.6 • 5 200 0 0 limpid CA22 5.6 5 300 0 0 limpid CA23 AB33 5.6 5 0 2.87 274 limpid CA24 5.6 5 25 2.87 224 limpid CA25 5.6 5 50 2.87 174 limpid CA26 5.6 5 100 2.87 74 limpid CA27 5.6 5 200 2.87 0 limpid CA28 5.6 5 300 2.87 0 limpid CA29 5.4 5 0 2.87 283 limpid CA 30 AB37 5.4 5 50 2.87 183 limpid CA31 5.4 5 100 2.87 83 limpid CA32 5.4 5 200 2.87 0 limpid

Table 5: Compositions and visual appearance of glucagon solutions at 1 mg / mL at pH

7.2 containing Tris buffer (2 mM), 1 mg / mL of L-methionine and varying concentrations of co-polyamino acid, sodium and zinc chloride.

Monitoring of the physical stability of the compositions The compositions previously prepared were transferred into cartridges (WIPO easy-to-fill of 3 ml - Ref P40B4100.3250) at a rate of 1 ml per cartridge and placed under static conditions at 37 ° C and 4 ° C.

Visual inspection of samples placed under static conditions is carried out at 0, 1, 2, 3, 4, 5, 6 weeks at 37 ° C and once a month for conditions at 4 ° C, to detect the appearance visible particles, fibrils or turbidity. This inspection is carried out according to the recommendations of the European Pharmacopoeia (EP

162

2.9.20): the samples are subjected to an illumination of at least 2000 Lux and are observed against a white background and a black background to comply with the recommendations of the European Pharmacopoeia. When particles are visible in half of the samples, the composition is estimated to be unstable. Stable therefore means that on day 5 of the inspection at least half of the samples were free of particles, fibrils or turbidity.

The study of the physical stability of the compositions previously prepared and described in the table below was carried out on volumes of 1 ml of composition in cartridges of 3 ml capacity (WIPO - ref:

P40B4100.3250). By comparison, the glucagon solution at acid pH at 2 mg / mL is only stable for 2 days at 37 ° C,

Examples Glucagon concentration (mg / mL) Concentration of copolyami noacids BB15 (mg / mL) additives Stability 37 ° C (weeks) Stability 4 ° C (month) CRO-2 2 7.6 10 mM citrate > 3 > 8 CR0-3 2 7.6 20 mM Nicotinamide > 6 > 10 CR0-4 2 7.6 40 mM nicotinamide > 6 > 10 CR0-5 2 7.6 80 mM Nicotinamide > 6 > 10 CRO-6 2 7.6 2 mM Mg > 6 > 10 CRO-8 2 7.6 13 ng / mL treprostinil > 6 > 10 CRO-9 2 7.6 128 ng / mL treprostinil > 6 > 10 CR0-10 2 7.6 1000 ng / mL treprostinil :> 6 d > 10 Table 6: Results of sta physical pility of compositions CRO-2 at CR0-10 at 37 ° C

and 4 ° C.

The compositions according to the invention, containing nicotinamide and

Treprostinil exhibit physical stability at 37 ° C in static cartridge conditions greater than three weeks at 37 ° C and eight months at 4 ° C. The addition of copolyamino acid therefore makes it possible to dissolve and stabilize the glucagon at neutral pH.

163

Examples Glucagon concentration (mg / mL) Co-polyamino acid concentration BB15 (mg / mL) additives Stability 37 ° C (Weeks) CV0-1 1 3.8 10 mM citrate > 3 CVO-2 1 3.8 15 mM citrate > 3 CVO-3 1 3.8 20 mM citrate > 3 CV0-4 1 4.5 10 mM citrate > 3 CVO-5 1 4.5 15 mM citrate > 3 CVO-6 1 4.5 20 mM citrate > 3 CVO-7 1 3.8 10 mM citrate + 20mM nicotinamide > 3 CVO-8 1 3.8 lOmM citrate + 40 mM Nicotinamide > 3 CVO-9 1 3.8 lOmM citrate + 80 mM Nicotinamide > 3 CV0-10 1 3.8 10 mM citrate + 170 mM Nicotinamide 3 CV0-11 1 3.8 40 mM nicotinamide 3

Table 7: Results of physical stability of CVO-1 to CVO-11 compositions at 37 ° C.

The compositions according to the invention, containing citrate, nicotinamide or a combination of the two have a physical stability at 37 ° C. under static conditions in a cartridge for at least two weeks at 37 ° C. The addition of copolyamino acid makes it possible to dissolve and stabilize the glucagon at neutral pH.

Example DA1: Physical stability in a cartridge at 37 ° C. of glucagon solutions at 1 mg / ml in the presence of co-polyamino acid B3, Tris buffer (2 mM), sodium chloride and zinc chloride at pH 7, 2.

The study of the physical stabilities of the compositions of the CAI and CA6 examples described in the table below was carried out on volumes of 1 ml of composition in cartridges of 3 ml capacity (WIPO - ref: P40B4100.3250 ). By comparison, the glucagon solution at acid pH at 1 mg / ml is only stable for 2 days at ° C.

164 [000938] The results of the visual inspections are reported in the following table.

Solution copolyamino Co-polyamino acid concentration (mg / mL) NaCl (MM) Zn (MM) Stability time at 37 ° C (week) CAI AB14 10.7 0 0 <2 CA6 10.7 50 1.29 > 4

Table 8: Results of the physical stability of glucagon solutions at 1 mg / mL at pH 7.2 containing Tris buffer (2 mM), 1 mg / mL of L-methionine and variable concentrations of co-polyamino acid, sodium chloride and zinc chloride.

The addition of BioChaperone makes it possible to dissolve and stabilize the glucagon at neutral pH while the glucagon in solution at acid pH is only stable for a few days at 37 ° C. (2 days). The combination of salt and zinc chloride makes it possible to improve the latency times of the compositions of the AB14 / glucagon co-polyamino acid.

Results of the visual observations with the mixture and of fibrillation measurements by ThT [000940] The compositions previously prepared were aliquoted in a 96-well plate in triplicate (3 * 150 μL) and placed under static conditions at 37 ° C. and at 4 ° C.

Principle [000941] The poor stability of a peptide can lead to the formation of amyloid fibrils, defined as ordered macromolecular structures. These can possibly result in the formation of gel within the sample.

The thioflavin T (ThT) fluorescence follow-up assay is used to analyze the physical stability of the solutions. Thioflavin is a small probe molecule with a characteristic fluorescence signature when it binds to amyloid-like fibrils (Naiki et al. (1989) Anal. BioChem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284).

This method makes it possible to follow the formation of fibrils for low concentrations of ThT in undiluted solutions. This monitoring is carried out under accelerated stability conditions: with stirring and at 37 ° C.

Experimental conditions [000943] The samples were prepared just before the start of the measurement. The preparation of each composition is described in the associated example. Thioflavin T was added to the composition from a concentrated stock solution so as to

165 induce a negligible dilution of the composition. The concentration of Thioflavin T in the composition is 40 μΜ.

A volume of 150 μL of the composition was introduced into a well of a 96-well plate and then 2.7 μL of concentrated solution of ThT was introduced. Each composition was analyzed in three trials (triplicate) within the same plate. The plate was sealed with transparent film to avoid evaporation of the composition. This plate was then placed in the enclosure of a plate reader (Xenius XC, SAFAS). The temperature is adjusted to 37 ° C., and lateral agitation of 960 rpm with 1 mm of amplitude is imposed.

[000946] A reading of the fluorescence intensity in each well is carried out with an excitation wavelength of 442 nm, and an emission wavelength of 482 nm over time.

The fibrillation process is manifested by a sharp increase in fluorescence after a delay called lag time.

The latency time is determined graphically, taking the time when the tangent to the linear growth phase intersects the abscissa axis.

The reported latency time value corresponds to the average of the latency time measurements made on three wells.

An example of graphical determination is shown in FIG. 1.

The latency results obtained are presented in the table below.

By comparison, the glucagon solution at acid pH at 2 mg / ml shows a fibrillation time of approximately 0.6 h.

compositions Glucagon concentration (mg / mL) BB15 copolyamino acid concentration (mg / mL) Ratio additives Fibrillation latency CSO-2 2 6.3 2.5 5 mM citrate > 3 p.m. CSO-3 2 6.3 2.5 5 mM citrate + 80 mM nicotinamide > 3 p.m. CS0-4 2 6.3 2.5 80 mM Nicotinamide > 3 p.m.

Table 9: Measurement of the latency time of solutions CS0-2 to CS0-4, [000953] The composition CSO-4 containing nicotinamide makes it possible to obtain latency times greater than 15 hours from a molar ratio BB15 / glucagon of 2.5 against a few minutes for the glucagon solution alone at acidic pH.

166

Example DB1: Stability of solutions at 1 mg / ml of glucagon containing copolyamino acid, Tris buffer (2 mM), glycerin and variable concentrations of sodium chloride and zinc chloride at pH 7.2.

The latency results obtained are presented in Table 5 below. By comparison, under these conditions, glucagon alone is insoluble in solution at physiological pH and the glucagon solution at acid pH at 1 mg / ml shows a fibrillation time of approximately 0.5 h.

Solution Copolyamino acid Ratio Copolyamino acid / glu cagon NaCi (mM) Zn (mM) Fibrillation time (H) CA7 5 0 0 <2 CA13 AB14 5 50 2.87 > 4 CA14 5 100 2.87 > 7 CAI 6 5 300 2.87 > 18 CA30 5 50 2.87 > 3 CA31 AB37 5 100 2.87 > 4 CA32 5 200 2.87 > 6

Table 10: Measurement of the latency time of solutions CA7, CA13, CA14, CA16 and

CA29 to CA31.

The addition of salt or zinc alone or as a mixture in the copolyamino acid / glucagon compositions makes it possible to obtain longer latency times.

Claims (20)

1. Composition in the form of an aqueous solution for injection, the pH of which is between 6.0 and 8.0, comprising at least: a) human glucagon; b) a co-polyamino acid carrying carboxylate charges and hydrophobic Hy radicals, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic Hy radicals being of formula I below:

P Formula I in which - GpR is a radical of formulas II, II 'or II: O HH II HOO • -NRN- · „“ -URN- · _or ._IL _r _U_ · „„ - GpA is a radical of formulas III or ΙΙΓ: O HN— * • -La ' HN— * III or * Il ^H U — A — N— * III '; - GpC is a radical of formula IV: O IV; the * indicate the sites of attachment of the different groups; a is an integer equal to 0 or 1; b is an integer equal to 0 or 1; p is an integer equal to 1 or 2 and 168 o if p is equal to 1 then a is equal to 0 or to 1 and GpA is a radical of formula ΙΙΓ and, o if p is equal to 2 then a is equal to 1, and GpA is a radical of formula III; c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2; d is an integer equal to 0, 1 or 2; r is an integer equal to 0, 1 or 2, and o if r is 0 then the hydrophobic radical of formula I is linked to the copolyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in N terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amine function in the N terminal position of the co-polyamino acid precursor and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1 or 2 then the hydrophobic radical of formula I is linked to the copolyamino acid: + via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amine function of the precursor of the hydrophobic radical and an acid function carried by the precursor of the co-polyamino acid or + via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an acid function of the precursor of the hydrophobic radical and an amine function in the N-terminal position carried by the precursor of the co-polyamino acid; R is a radical chosen from the group consisting of a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions -CONH2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more unsaturated rings or a unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms; more precisely, R is a radical chosen from the group consisting of: o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 12 carbon atoms, if GpR is a radical of formula II 'of 1 to 11 carbon atoms or if GpR is a radical of formula II from 1 to 10 carbon atoms; 169 o a divalent, linear or branched alkyl radical, comprising if GpR is a radical of formula II of 2 to 11 carbon atoms, if GpR is a radical of formula II 'of 1 to 11 carbon atoms or if GpR is a radical of formula II of 1 to 10 carbon atoms, said alkyl radical carrying one or more functions -CONH2, and - A is a linear or branched alkyl radical comprising from 1 to 8 carbon atoms and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring; - B is a radical chosen from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms; - Cx is a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and: o if p is equal to 1, x is between 11 and 25 (11 <x <25): o if p is equal to 2, x is between 9 and 15 (9 <x <15), the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 <i <0.5; when several hydrophobic radicals are carried by a co-polyamino acid then they are identical or different, the degree of polymerization DP in glutamic or aspartic units is between 5 and 250; the free acid functions being in the form of an alkaline cation salt chosen from the group consisting of Na ⁺ and K ⁺ . 2. Composition according to claim 1, characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which p = 1, represented by the following formula V: * - ^ - GpR ^ GpA ^ - GpC formula V GpR, GpA, GpC, r and atels as defined in claim 1. 170 3. Composition according to claim 1, characterized in that said hydrophobic radicals are chosen from hydrophobic radicals of formula I in which a = 1 and p = 2, represented by the following formula VI: Formula VI in which GpR, GpA, GpC and r as defined in claim 1. 4. Composition according to any one of the preceding claims, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII below:

Hy formula VII in which, • D represents, independently, either a group -CH2- (aspartic unit) or a group -CH2-CH2- (glutamic unit), • Hy is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, • Ri is a hydrophobic radical chosen from the hydrophobic radicals of formulas I, V or VI, or a radical chosen from the group consisting of an H, a linear acyl group in C2 to Cio, a branched acyl group in C3 to Cio, a benzyl, a terminal "amino acid" unit and a pyroglutamate, • R2 is a hydrophobic radical chosen from hydrophobic radicals of formulas I, V or VI, or a radical -NR'R, R 'and R identical or different being chosen from the group consisting of H, linear or branched or cyclic C2 to C10 alkyl, benzyl and said R 'and R alkyls which can form 171 together one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms, chosen from the group consisting of O, N and S, • X represents an H or a cationic entity chosen from the group comprising cations metallic; • n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of copolyamino acid and 5 <n + m <250. 5. Composition according to Claim 4, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the copolyamino acids of formula VII in which n = 0 of the following formula Vlib: Ri

N H

R ₂ O Formula VIb in which m, X, D, Ri and R2 as defined in claim 4 and at least Ri or R2 is a hydrophobic radical of formula I, V or VI. 6. Composition according to claim 5, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the copolyamino acids of formula Vlib in which R2 is a hydrophobic radical of formula I, V or VI in which r = 1 or 2 and GpR is Formula II '. 7. Composition according to any one of claims 4 to 6, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas VII, Vlib in which group D is a group -CH2- (aspartic unit). 8. Composition according to any one of claims 4 to 7, characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is 172 chosen from the co-polyamino acids of formulas VII, V11b in which the group D is a group -CH2-CH2- (glutamic unit). 9. Composition according to any one of the preceding claims, characterized in that the concentration of co-polyamino acid carrying carboxylate charges and hydrophobic radicals is at most 40 mg / ml. 10. Composition according to any one of the preceding claims, characterized in that the concentration of human glucagon is between 0.25 and 5 mg / ml. 11. Composition according to any one of the preceding claims, characterized in that the molar ratio [hydrophobic radical] / [human glucagon] is less than 15. 12. Composition according to any one of the preceding claims, characterized in that it also comprises a polyanionic compound. 13. Composition according to claim 12, characterized in that the polyanionic compound is chosen from the group consisting of polycarboxylic acids and their Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts. 14. Composition according to claim 13, characterized in that the polycarboxylic acid is chosen from the group consisting of citric acid, tartaric acid, and their Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts. 15. Composition according to claim 14, characterized in that the polycarboxylic acid is citric acid and its Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ salts. 16. Composition according to any one of the preceding claims, characterized in that it further comprises an absorption promoter chosen from the group consisting of chosen from absorption promoters, diffusion promoters or vasodilators, alone or mixed. 17. Composition according to any one of the preceding claims, characterized in that it also comprises a zinc salt. 173 18. Composition according to any one of the preceding claims, characterized in that it also comprises a gastrointestinal hormone. 19. Composition according to Claim 18, characterized in that the gastrointestinal hormone is chosen from the group consisting of exenatide, liraglutide, lixisenatide, albiglutide and dulaglutide, their analogs or derivatives and their pharmaceutically acceptable salts. 20. Composition according to any one of claims 18 and 19, characterized in that the concentration of gastrointestinal hormone is in the range of 0.01 to 10 mg / ml. 1/1